general information - icon6 · general information this document describes the icon6 trial and...

ICON6

ICON6 Protocol V8.0 29th July 2013 of 122

GENERAL INFORMATION This document describes the ICON6 trial and provides information about procedures for entering patients into it. The protocol should not be used as an aide-memoire or guide for the treatment of other patients; every care was taken in its drafting, but corrections or amendments may be necessary. These will be circulated to the registered investigators in the trial, but centres entering patients for the first time are advised to contact the ICON6 Trial Manager in the Cancer Group, MRC Clinical Trials Unit, London to confirm they have the most up to date version. Clinical problems relating to this trial should be referred to the relevant Chief Investigator directly, or via the MRC CTU. Main Contacts:

Lead Chief Investigator Prof Jonathan Ledermann Consultant Medical Oncologist University College London Cancer Research UK and UCL Cancer Trials Centre 90 Tottenham Court Road London W1T 4TJ United Kingdom

MRC CTU Project Lead Prof Richard Kaplan MRC Clinical Trials Unit Aviation House 125 Kingsway London WC2B 6NH United Kingdom

Tel: Fax: Email:

+44 (207) 679 9898 +44 (207) 679 9899 [email protected]

Tel: Fax: Email:

+44 (0) 207 670 4849 +44 (0) 207 670 4818 [email protected]

ICON6 Trial Manager Elizabeth Clark MRC Clinical Trials Unit Aviation House 125 Kingsway London WC2B 6NH United Kingdom

ICON6 Statistician Andrew Embleton MRC Clinical Trials Unit Aviation House 125 Kingsway London WC2B 6NH United Kingdom

Tel: Fax: Email:

+44 (0) 207 670 4861 +44 (0) 207 670 4818 [email protected] [email protected]

Tel: Fax: Email:


ICON6 Data Manager Stephen Townsend MRC Clinical Trials Unit Aviation House 125 Kingsway London WC2B 6NH United Kingdom

ICON6 Trial Physician Fharat Raja University College London Cancer Research UK and UCL Cancer Trials Centre 90 Tottenham Court Road London W1T 4TJ United Kingdom

Tel: Fax: Email:


Tel: Fax: Email:

+44 (207) 679 9898 +44 (207) 679 9899 [email protected]

ICON6


RANDOMISATIONS AND EMERGENCY UNBLINDING

Via: http://www.clinphone.com/IWR provider or via IVRS (see below for

international access numbers).

Activation of individual access code, for approved staff in clinical centres or GCIG

group, required prior to first randomization

See User Manual for Clinical Trial Technology Services for further instructions.

Emergency unblinding of individual patients

by treating physician or responsible pharmacist via

http://www.clinphone.com/IWR.

SAE REPORTING

By fax within one working day to ICON6 Trial Manager +44 (0) 207 670 4818

An up to date list of numbers can be found at www.clinphone.com/support/phones

Country (Group) IVR System Primary (Free)

IVR System Secondary (Free)

ClinPhone Support Help (Free)

ClinPhone Support Fax (Free)

Alternative Number* (Not Free)

UK (MRC/NCRI) 0800 3892089

0800 371806 0800 3890918 0800 389 3669 0115 9340325*

Canada (NCIC) 1866672 0371

1877 428 1323 1 866 483 2983 1 800 654 0265

011 44 115 8534202*

Australia (ANZGOG)

1 800 504 336

1800 454186 1 800 504 340 1 800 555 614 00 11 44 115 9340203*

New Zealand (ANZGOG)

0800 174 047

0800 441770 0800 174048 0800 101 745 00 44 115 9340206*

Spain (GEICO) 900 810362 900 997158 900 997160 900 938 955 00 44 115 8534272*

Ireland (ICORG) 1800 946804

1800 409065 1 800 535 487 1 800 509 148 00 44 115 9340244*

For further information on the randomisation systems and procedures please refer to the ClinPhone User Manual for Clinical Trial Technology Services.

ICON6


CONTENTS

1 Compliance ....................................................................................................... 10

2 Trial Schema ..................................................................................................... 11

3 Summary .......................................................................................................... 12 3.1 Type of Design .................................................................................................... 12 3.2 Patients to be Included......................................................................................... 12 3.3 Treatment of Patients in the Trial .......................................................................... 12 3.4 Duration of Treatment .......................................................................................... 13 3.5 Outcome Measures .............................................................................................. 13 3.6 Evaluation of Outcome Measures........................................................................... 14 3.7 Sample Size ......................................................................................................... 14

4 Background and Rationale ............................................................................... 15 4.1 Introduction ........................................................................................................ 15 4.2 Standard Therapy for Relapsed Platinum-Sensitive Ovarian Cancer........................... 15 4.3 Rationale for Targeted therapy in Cancer ............................................................... 15 4.4 Rationale for Targeted Therapy in Ovarian Cancer .................................................. 16 4.5 Oral Growth Factor Inhibitors ................................................................................ 17 4.6 Cediranib (AZD2171) ............................................................................................ 17

5 Aims and Objectives ......................................................................................... 19 5.1 Stage One - Safety ............................................................................................... 19 5.2 Stage Two - Activity ............................................................................................. 19 5.3 Potential Ancillary Study ....................................................................................... 19

6 Selection of Sites/Clinicians ............................................................................ 20 6.1 Selection of Sites/Clinicians ................................................................................... 20 6.2 Group Approval.................................................................................................... 21 6.3 Site Approval ....................................................................................................... 21

7 Selection of Patients ........................................................................................ 22 7.1 Patient inclusion criteria........................................................................................ 22 7.2 Patient exclusion criteria ....................................................................................... 23 7.3 Concomitant medications ...................................................................................... 24 7.4 Number of patients .............................................................................................. 24 7.5 Screening procedures and pre-randomisation investigations ................................... 25 7.6 Tumour Assessment ............................................................................................. 26

8 Randomisation ................................................................................................. 27

9 Treatment of Patients ...................................................................................... 29 9.1 General Principles ................................................................................................ 29 9.2 Treatment Arms................................................................................................... 30 9.3 Specific Drug Information ..................................................................................... 31 9.4 Trial Treatment Recording .................................................................................... 36 9.5 Concomitant Therapy ........................................................................................... 36 9.6 Treatment for Progression .................................................................................... 36 9.7 Co-enrolment Guidelines....................................................................................... 36 9.8 Follow up ............................................................................................................ 36

10 Drug Safety Information .................................................................................. 37 10.1 General Information on Cediranib ..................................................................... 37 10.2 Unblinding ...................................................................................................... 43 10.3 General information on Paclitaxel, Carboplatin and Cisplatin ................................ 44

11 Assessments and Procedures .......................................................................... 51 11.1 Clinical Follow up (safety and efficacy) .............................................................. 51 11.2 Specific Procedures for Assessing Efficacy .......................................................... 51

ICON6


11.3 Procedures for Assessing Safety ........................................................................ 52 11.4 Translational Research (biomarkers and pharmacogenomics) .............................. 56 11.5 Quality of Life Assessment ................................................................................ 56 11.6 Trial Closure .................................................................................................... 56

12 Withdrawal of Patients and Loss to Follow Up ............................................... 57 12.1 Withdrawal from trial intervention ..................................................................... 57 12.2 Withdrawal of Consent ..................................................................................... 58 12.3 Patient Transfers ............................................................................................. 58 12.4 Loss to Follow-Up ............................................................................................ 58

13 Statistical Considerations ................................................................................ 59 13.1 Method of Randomisation ................................................................................. 59 13.2 Outcome Measures .......................................................................................... 59 13.3 Sample Size .................................................................................................... 59 13.4 Interim Monitoring and Analyses ....................................................................... 60 13.5 Brief Analysis Plan ........................................................................................... 61

14 Trial Monitoring ................................................................................................ 62 14.1 Risk Assessment .............................................................................................. 62 14.2 Monitoring at the MRC CTU .............................................................................. 62 14.3 Clinical Site Monitoring ..................................................................................... 62 14.4 Data Quality Assurance .................................................................................... 62 14.5 Confidentiality of Trial Documents and Patient Records ....................................... 63

15 Safety Reporting .............................................................................................. 64 15.1 Definitions of Adverse Events/Reactions ............................................................ 64 15.2 ICON6 Specific Exceptions to Seriousness Criteria ............................................... 65 15.3 ICON6 Notable Events ...................................................................................... 65 15.4 Clinical trial site/Investigator Responsibilities ...................................................... 65 15.5 Investigator Assessment................................................................................... 65 15.6 Notification ..................................................................................................... 67 15.7 MRC CTU Responsibilities ................................................................................. 67

16 Ethical Considerations and Approval ............................................................... 70 16.1 Ethical considerations ....................................................................................... 70 16.2 Ethical approval ............................................................................................... 70

17 Regulatory Approval ........................................................................................ 73

18 Sponsorship and Indemnity ............................................................................. 74

19 Ancillary Studies............................................................................................... 75 19.1 Translational Research (pharmacogenomics and predictive biomarkers) ............... 75 19.2 Quality Of Life ................................................................................................. 75

20 Finance ............................................................................................................. 76

21 Trial Committees .............................................................................................. 77

22 Publication........................................................................................................ 79

23 Protocol Amendments ...................................................................................... 80

24 References ........................................................................................................ 82

25 Appendices ....................................................................................................... 85 APPENDIX 1: ECOG Performance Status ....................................................................... 86 APPENDIX 2: NYHA Classification of Cardiac Disease ..................................................... 87 APPENDIX 3: Evaluation of Residual Disease, Evaluation of and Definitions of Progression 88 APPENDIX 4: ICON6 Trial Drug Supply Management and Accountability .......................... 90 APPENDIX 5: Nomogram for the Determination of the Body Surface Area ....................... 92

ICON6


APPENDIX 6: Estimation and measurement of Glomerular Filtration Rate and Recommendations for Calculation of Carboplatin Dose ............................................ 93

APPENDIX 7: Translational Research (biomarkers and pharmacogenomics) ..................... 95 APPENDIX 8: Quality of Life Information Sheet for Clinicians .......................................... 98 APPENDIX 9: Former planned statistical analysis and sample size calculations – for

information only. ................................................................................................ 100 APPENDIX 10: Patient Information Sheets: General Information for GCIG groups and Sites .................................................................................................................. 108 APPENDIX 11: GP Letter ............................................................................................ 108 APPENDIX 12: International Trial Management Group* ................................................ 116 APPENDIX 13: Carboplatin and Gemcitabine Combination ............................................. 117

LIST OF TABLES

TABLE 1: OUTCOME MEASURES OF ICON6 STAGES ................................................ 13 TABLE 2: TARGET AUC DEPENDING ON GFR CALCULATION METHOD ...................... 34 TABLE 3: DOSE LEVELS OF TRIAL DRUG ................................................................ 38 TABLE 4: TRIAL DRUG (CEDIRANIB/PLACEBO): SUGGESTED DOSE MODIFICATIONS

FOR OTHER TOXICITIES (EXCEPT FOR HYPERTENSION). ..................................... 43 TABLE 5: GUIDELINES FOR PACLITAXEL, CARBOPLATIN AND CISPLATIN DOSE

MODIFICATION FOR DELAYED HEMATOLOGICAL RECOVERY ............................... 46 TABLE 6: GUIDELINES FOR PACLITAXEL CARBOPLATIN AND CISPLATIN DOSE

MODIFICATION FOR DOSE LIMITING TOXICITY (DLT) ......................................... 47 TABLE 7: DOSE LEVELS FOR PACLITAXEL ± CARBOPLATIN AND CISPLATIN ............ 48 TABLE 8: DEFINITIONS OF PROGRESSION ............................................................ 52 TABLE 9: TRIAL ASSESSMENTS SCHEDULE ............................................................. 54 TABLE 10: OUTCOME MEASURES OF ICON6 STAGES ............................................. 59 TABLE 11: DEFINITIONS OF ADVERSE EVENTS/REACTIONS ................................... 64 TABLE 12: DEFINITIONS OF CAUSALITY ............................................................... 66 TABLE 13: SAE NOTIFICATION PROCEDURE ......................................................... 67 LIST OF FIGURES

FIGURE 1: ICON6 TRIAL SCHEMA ......................................................................... 11 FIGURE 2: ADVERSE EVENT ASSESSMENT AND NOTIFICATION FLOW CHART ......... 69 FIGURE 3: DIAGRAM OF RELATIONSHIPS BETWEEN TRIAL COMMITTEES ............... 78 FIGURE 4: SAMPLE SIZE - DETAILS OF SAMPLE SIZE CALCULATIONS ................... 104

ICON6


ABBREVIATIONS Ab Antibody

ACEIs Angiotensin Converting Enzyme Inhibitors

ADL Activities of Daily Living

AE Adverse Event AGO-OVAR Arbeitsgemeinschaft Gynaekologische Onkologie-Studiengruppe Ovarialkarzinom ALP Alkaline Phosphatase ALT Alanine Aminotransferase / Serum Glutamic Pyruvic Transaminase / SGPT APTT Activated ProThrombin Time ANC Absolute Neutrophil Count ANZGOG Australian and New Zealand Gynaecological Oncology Group ARB Angiotensin II Receptor Blockers ASCO American Society of Clinical Oncology AST Aspartate Aminotransferase / Serum Glutamic Oxaloacetic Transaminase / SGOT AR Adverse Reaction AUC Area Under the Curve BP Blood Pressure BR Bilirubin BSA Body Surface Area BUN Blood Urea Nitrogen Ca Calcium CBC Complete Blood Count CF Consent Form CHF Congestive Heart Failure CI Chief Investigator CK Creatinine Kinase CNS Central Nervous System Cr Serum Creatinine CR Complete Response CRF Case Report Form CrCl Creatinine Clearance CT Scan Computed Tomographic Scan CTA Clinical Trials Authorisation CTC Common Toxicity Criteria CTCAE Common Toxicity Criteria: Adverse Events CTU Clinical Trials Unit CVA Cerebrovascular Accident CVAD Central Venous Access Device DCF Data Clarification Form DHP CCB Dihydropyrimadole calcium channel blocker DCE-MRI Dynamic Contrast Enhanced- Magnetic Resonance Imaging DLT Dose Limiting Toxicity DMC Data Monitoring Committee ECG Electrocardiogram ECOG Eastern Cooperative Oncology Group EF Ejection Fraction EGF(-R) Epidermal Growth factor (-Receptor) EORTC European Organisation for Research and Treatment of Cancer EPO Erythropoietin ERC Endpoint Review Committee EUDRACT European Union Drug Regulatory Agency Clinical Trial FBC Full blood count FIGO International Federation of Gynaecology and Obstetrics GCIG Gynaecologic Cancer InterGroup GCP Good Clinical Practice G-CSF Granulocyte-Colony Stimulating Factor GEICO Grupo Espanol de Investigacion en Cancer de Ovario GFR Glomerular Filtration Rate GINECO Group d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens

ICON6


GOG Gynecologic Oncology Group HE Health Economics HT Hypertension 5HT3 Serotonin IB Investigator’s Brochure IC Informed Consent ICF Informed Consent Form ICH International Conference of Harmonisation ICON International Collaborative Ovarian Neoplasm IDMC Independent Data Monitoring Committee INR International Normalised Ratio IP Intra-Peritoneal IRMER Ionising Radiation Medical Exposure Regulations ISF Investigator Site File ISRCTN International Standard Randomised Controlled Trial Number ITT Intention To Treat IV Intravenous IVRS Interactive Voice Response System K Potassium LD Longest Diameter (RECIST) LDH Lactate Dehydrogenase LFT Liver Function Test LMW Low Molecular Weight Mg Magnesium mBC Metastatic Breast Cancer mCRC Metastatic Colorectal cancer MANGO Mario Negri Gynaecological Oncology Group MHRA Medicines and Healthcare Regulatory Authority MI Myocardial Infarction MRC Medical Research Council MRI Magnetic Resonance Imaging MRU Medical Resource Use N Normal Na Sodium NCIC CTG National Cancer Institute of Canada Clinical Trials Group NCI National Cancer Institute NCRI National Cancer Research Institute NHS National Health Service NICE National Institute of Clinical Excellence NRP Neuropilin NSCLC NGSO

Non Small Cell Lung Cancer Nordic Society of Gynecologic Oncology

NYHA New York Heart Association PFS Progression Free Survival PI Principal Investigator PIS Patient Information Sheet PLT PO

Platelets Orally

PR Partial Response PP Per Protocol PS Performance Score QL / QoL Quality of Life ORR Overall Response Rate OS Overall Survival RCC Renal Cell Carcinoma REC Research Ethics Committee RECIST Response Evaluation Criteria in Solid Tumours SAE Serious Adverse Event SAH Sub Arachnoid Haemorrhage SAR Serious Adverse Reaction SBP Systolic Blood Pressure

ICON6


SCr Serum Creatinine SF Shortening Fraction SNP Single nucleotide polymorphism SOP Standard Operating Procedure SPC SSA

Summary of Product Characteristics Site Specific Assessment

SUSAR Suspected Unexpected Serious Adverse Reaction TIA Transient Ischaemic Attack TMG Trial Management Group TR Translational Research TRM Translational Research Manual TSC Trial Steering Committee TSH Thyroid Stimulating Hormone UAR U&E ULN VEGF(-R) WBC Wt

Unexpected Adverse Reaction Urea and Electrolytes Upper Limit of Normal Vascular Endothelial Growth Factor (-Receptor) White Blood Count Weight

ICON6


1 COMPLIANCE The trial will be conducted in compliance with the protocol, the Data Protection Act (DPA number: Z5886415), National Health Service (NHS) research governance and other regulatory requirements, as appropriate. MRC CTU shall be responsible for the operational management of ICON6 at the participating Clinical Sites in UK and shall do so in compliance with the principles of Good Clinical Practice (GCP) as laid down by Commission Directive 2005/28/EC and by Statutory Instrument 2004/1031 [Amendments; 2006 No. 1928]. International sites shall be responsible for the operational management of ICON6 at their participating Clinical Sites and shall do so in compliance with the principles of Good Clinical Practice (GCP) as laid down by the ICH topic E6 (Note for Guidance on GCP), or Commission Directive 2005/28/EC (where applicable) and in accordance with applicable local laws or regulations.

ICON6


2 TRIAL SCHEMA Figure 1: ICON6 Trial Schema

* The recommended chemotherapy in ICON6 is carboplatin plus paclitaxel, however treatment with other platinum-based chemotherapy regimens may be permitted, as detailed in section 10.3. § Trial Drug (placebo or cediranib) continues for 18 months, or may continue beyond 18 months until disease progression if after discussion with the study Sponsor the clinician feels there is continuing clinical benefit and the patient wishes to continue (whilst supply lasts).

First Stage: Primary outcome measure: Safety Second Stage: Primary outcome measure: Progression-Free Survival (PFS) Secondary outcome measures: Overall Survival (OS) and Toxicity Ancilliary Studies: Translational Research (TR)

Eligible consenting patient relapsing > 6 months after

completion of first line platinum- based chemotherapy

RANDOMISE 2 : 3 : 3

Arm A (Reference Arm) Arm B Arm C

6 cycles of platinum-based chemotherapy* plus

Cediranib during chemotherapy


Placebo during chemotherapy

Placebo from randomisation §

Placebo §

Cediranib §

Follow up visits: Every 3 months until protocol defined disease

progression, then 6 monthly for up to 5 years after randomisation, then annually


Cediranib during chemotherapy

ICON6


3 SUMMARY

3.1 Type of Design

ICON6 is a randomised three-arm, multi-stage, double-blind, placebo-controlled multi-centre Gynaecologic Cancer InterGroup (GCIG) phase III trial. ICON6 is designed to evaluate the safety and efficacy of platinum-based chemotherapy in combination with cediranib in women with platinum-sensitive relapsed ovarian cancera. Cediranib is an oral targeted small molecule inhibitor of a key signalling molecule Vascular Endothelial Growth Factor (VEGF) which is an oral inhibitor of tyrosine kinase (TK) activity and acts through blockade of the TK receptor. Cediranib (AZD2171) will be administered during platinum-based chemotherapy only (concurrent cediranib), or given during chemotherapy and continued as single agent maintenance therapy (concurrent and maintenance cediranib).

3.2 Patients to be Included

Patients with relapsed epithelial ovarian, fallopian tube or primary serous peritoneal carcinoma who require platinum-based chemotherapy for first relapse 6 or more months after the last dose of first-line platinum-based therapy.

3.3 Treatment of Patients in the Trial

All patients, regardless of the arm they are randomised to, will be planned to receive 6 cycles of platinum-based chemotherapy. The results of the ICON4/AGO-OVAR-2.2[1, 2] trial demonstrated the benefit of adding paclitaxel to carboplatin in the second line treatment of ovarian cancer, with significant improvements in both progression free and overall survival. The recommendation therefore in ICON6 is that patients are treated with carboplatin AUC 6b over 30-60 minutes, in combination with paclitaxel 175 mg/m2 over three hours, three weekly for six cycles. Other platinum based regimens are allowed, for patients who are not fit enough to receive combination treatment or for whom other combinations are preferred due to pre-existing toxicity or patient and clinician choice including carboplatin alone, cisplatin replacing carboplatin in combination with paclitaxel or as a single agent. In addition, selected centres authorised by the Chief Investigator and TMG, may use the combination of gemcitabine and carboplatin (or cisplatin). This regimen has demonstrated efficacy in terms of improving progression free survival48 and may be of particular benefit for women with residual neurotoxicity from first line paclitaxel-platinum therapy. Patients will be stratified by type of planned chemotherapy at randomisation.

Trial Drug will be administered for up to 18 months from randomisation or until progression, whichever is sooner. Patients who have not progressed at 18 months from randomisation can continue Trial Drug until progression, if in the opinion of the clinician there is continuing clinical benefit (whilst supply lasts). However, investigators must

a Unless otherwise specified in the text, where mentioned ovarian cancer refers to epithelial ovarian cancer, primary serous peritoneal cancer or fallopian tube cancer b Carboplatin AUC6 in combination with paclitaxel 175mg/m2 is the recommended drug combination and dosage in ICON6. However single agent carboplatin or alternative dosages may be used at the discretion of the treating physician

ICON6


discuss the continuation of treatment for each patient with the Chief Investigator or Trial Physician first.

Patients in Arm A (the reference arm) will therefore receive a platinum-based chemotherapy regimen, as described above, plus a daily oral placebo tablet for the duration of the chemotherapy and up to 18 months from randomisation or until progression.

Patients in Arm B (concurrent cediranib arm) will also receive a platinum-based chemotherapy regimen, as described above, plus daily oral cediranib during chemotherapy only, and then an oral daily placebo tablet up to 18 months from randomisation or until progression.

Patients in Arm C (concurrent and maintenance cediranib arm) will also receive a platinum-based chemotherapy regimen, as described above, plus oral cediranib daily during chemotherapy and then continued up to 18 months from randomisation or until progression.

Non-protocol anti-cancer treatment is not allowed prior to documented protocol defined disease progression.

3.4 Duration of Treatment

The duration of chemotherapy is expected to be 6 cycles given every 21 days plus placebo or cediranib each day (18 weeks in total). Maintenance treatment (cediranib or placebo) will then continue daily up to 18 months from randomisation or may continue until disease progression, if in the opinion of the clinician, there is continuing clinical benefit and the patient wishes to continue (whilst supply lasts). Investigators must discuss the continuation of treatment for each patient with the Chief Investigator or Trial Physician first.

3.5 Outcome Measures

The main outcome measure in the first stage was safety of the research treatments. In the second stage, the main outcome measure is Progression Free Survival (PFS) with Overall Survival, Toxicity and Quality of Life (QoL) being secondary outcome measures. The outcome measures for each stage are summarised in Table 1.

Table 1: Outcome measures of ICON6 stages

First Stage Primary outcome measure Safety

Second Stage Primary outcome measure

Secondary outcome measures

Progression-Free Survival (PFS)

Overall Survival (OS) Toxicity Quality of Life (QoL)

The following ancillary study may also be associated with ICON6:

Translational (Biomarker) Research (TR)

ICON6


Further details of these are given in section 19.

3.6 Evaluation of Outcome Measures

Patients will be assessed by radiographic tumour assessments using CT or MRI which will be performed at baseline, after 6 cycles of chemotherapy and then at clinical progression or 12 and 18 months after randomisation (if not previously progressed). Patients will be clinically assessed and CA125 measured at the start of every chemotherapy cycle, then every six weeks until Trial Drug is discontinued and three monthly thereafter, until protocol defined disease progression.

After evidence of protocol defined disease progression patients will be followed for survival every six months during the first five years of their follow up in the trial, and yearly thereafter.

Quality of life will be assessed using the EORTC OV28 (which includes the EORTC QLQC30) and EQ-5D questionnaires.

Adverse events and medical resource use will be documented during the trial treatment and follow up period (see section 11 for further details).

3.7 Sample Size

The ICON6 trial was planned to randomise a target of 470 patients and this has now been achieved. Due to the suspension of plans for commercial development of cediranib, patients should not be consented after 31st December 2011.

The first stage was conducted in selected centres only to confirm the safety of using cediranib. For the final analysis (second stage), the analysis of the efficacy of cediranib will be performed with PFS as the primary outcome measure. The statistical methodology that underpins this trial design is now well developed.[3]

The first stage was analysed when approximately 33 patients in total had been randomised to the two cediranib arms together and completed 3 cycles of chemotherapy. The second stage will be analysed when approximately 176 events have been observed in arms A and C.

ICON6


4 BACKGROUND AND RATIONALE

4.1 Introduction

Ovarian carcinoma is the fourth most common cancer in women in developed countries and accounted for an estimated 114,000 deaths world-wide in 2000[4]. Improvements in progression free survival (PFS) and overall survival (OS) have occurred in the past few years with the use of radical cytoreductive surgery in the treatment of the initial disease, followed by the adoption of platinum-based chemotherapy, and also paclitaxel. Despite this, the large majority of patients diagnosed with ovarian cancer continue to relapse and die from their disease. For those relapsing more than six months after completing platinum-based chemotherapy, the median survival is approximately 2.5 years[1]. There is therefore a real need to develop new effective therapeutic options for ovarian cancer, to both improve PFS and OS, and also to maintain a good quality of life.

4.2 Standard Therapy for Relapsed Platinum-Sensitive Ovarian Cancer

A randomised trial of over 800 women who relapsed more than 6 months after completion of previous treatment, ICON4/OVAR2.2, showed for the first time that overall survival could be improved by the addition of paclitaxel to platinum-based chemotherapy. This established carboplatin plus paclitaxel as the standard of care for the treatment of women with recurrent ovarian cancer [1].

4.3 Rationale for Targeted therapy in Cancer

Angiogenesis, or the development of new blood vessels, is essential for the process of solid tumour growth and metastasis[5, 6]. As tumours increase in size pro-angiogenic factors are released from the tumour cells, activated macrophages and other tumour associated cells in response to localised tissue hypoxia and other factors[7]. This stimulates the development and maintenance of new tumour vasculature.

Tumour angiogenesis is controlled by a number of different pathways, and of all the growth factors involved Vascular Endothelial Growth Factor (also known as VEGF-A or VEGF) has been identified as the key mediator. VEGF-A is the proteotypic member of a closely related group of cytokines[8].

VEGF is produced by normal and neoplastic cells through the influence of hypoxia[9]. Its actions are mediated via its interaction with two tyrosine kinase cell surface receptors, VEGFR-1(Flt-1) and VEGFR-2(KDR/Flk-1), which are found in the vasculature of tumours expressing VEGF-A[10]. Binding of VEGF initiates a cascade of signalling events, initially causing autophosphorylation of tyrosine kinase, followed by activation of a number of downstream proteins. This leads to endothelial cell mitogenesis, proliferation and survival, as well as increased vascular permeability. Recently neuropilin (NRP), a non-kinase receptor, has been discovered to potentiate VEGF’s binding to VEGFR-2[11]. It is expressed on vascular endothelium, neurons and some tumour cells.

The identification of novel compounds that interfere with angiogenesis provides important new avenues for the treatment of cancer. This approach is of particular interest since new cytotoxic agents have additive toxic effects and, to date, triple combinations have not proved superior to one or two drug regimens[12]. Thus, the addition of appropriately targeted therapeutics is a key strategy to improve ovarian cancer outcomes.

ICON6


Inhibition of angiogenic pathways using an antibody to VEGF (bevacizumab), in combination with chemotherapy, has led to significant improvements in PFS and OS of patients with metastatic colon cancer[13, 14], metastatic breast cancer[15], and non-squamous non small cell lung cancer[16].

4.4 Rationale for Targeted Therapy in Ovarian Cancer

Increased levels of VEGF have been found in most human solid malignancies[17], including ovarian cancer[18]. Increased serum levels of VEGF correlate with poor survival, in a number of different cancers[9]. In epithelial ovarian cancer angiogenesis has a central role in disease progression. Epithelial ovarian cancer lines frequently express VEGF. Decreased VEGF expression has been correlated with reduced vascularisation, reduced angiogenesis, reduced ascitic fluid volumes and prolonged survival[19].

In murine models of epithelial ovarian cancer, blocking VEGF slows tumour progression and inhibits ascites formation[20]. Mice inoculated with ovarian carcinoma cells which have been transfected to overexpress VEGF have a dramatically reduced time to the formation of ascites. Administration of a soluble high affinity decoy receptor which blocks the effects of VEGF, prevents further ascites accumulation and results in resolution of the fluid already present. Cessation of the decoy receptor causes rapid reaccumulation of the ascites, and disease progression[21].

A study using a murine model of ascites formation, associated with an ovarian carcinoma cell line, demonstrated that intraperitoneal inoculation with a monoclonal antibody to VEGF also resulted in significant inhibition of ascites formation, and significantly prolonged the lifespan of the mice[20]. In another murine study with intraperitoneal and subcutaneous tumours, administration of an antibody to VEGF inhibited subcutaneous tumour growth and ascites formation in the intraperitoneal model, with a variable inhibitory effect on subcutaneous tumour growth. When administration of the antibody to VEGF was ceased, the ascites rapidly reaccumulated and the mice became cachectic and died[22].

In humans a direct relationship has been demonstrated between the expression of biomarkers for angiogenesis such as VEGF and VEGF-R, in tumour samples and serum, and the clinical behaviour of epithelial ovarian carcinomas[19, 23-26]. VEGF overexpression has been correlated with the development of ascites, due to its effects on vascular permeability, as well as malignant progression and a worse overall prognosis[27]. VEGF receptors were initially thought only to be expressed on endothelial cells. However studies have now demonstrated that some ovarian cancer cells express VEGF-R1(flt-1) and VEGF-R2(KDR), hence there may also be a direct anti-tumour effect of anti-VEGF therapy[28].

Based on these data it has been hypothesized that pharmacological inhibitors of angiogenesis may have the capacity to inhibit ascites formation, arrest tumour progression and even cause tumour regression in patients with epithelial ovarian carcinoma. It is hoped that combining chemotherapeutic agents with anti-angiogenic therapies may have a synergistic effect due to improved delivery of the chemotherapeutic drug to the tumour. This is thought to be due to an initial reduction in vascular permeability and therefore a reduction in tumour interstitial pressure, and an initial overall increase in efficacy of the vascular system.

Two positive phase II trials of single agent bevacizumab (a monoclonal antibody to VEGF) were presented at ASCO 2005[29, 30] demonstrating sufficient efficacy to warrant further investigation in the phase III trials, ICON7[2] and GOG-218[31]. These phase III trials have now been completed and have both shown significant prolongation in PFS. In addition, for

ICON6


the first time a phase III trial in recurrent platinum sensitive ovarian cancer, the OCEANS study, also demonstrated a significant improvement in PFS[32].

There have also been two phase II studies[33, 34] of cediranib monotherapy in recurrent ovarian cancer that have demonstrated promising activity thus providing a good basis for investigating cediranib in combination with chemotherapy in ovarian cancer.

4.5 Oral Growth Factor Inhibitors

Several orally active small molecules have been developed to target the VEGF receptor family and have demonstrated a reduction in tumour blood flow, disease stabilisation and response in some tumours[35].

Most studies have been performed in patients with advanced cancer and the principal objectives have been to demonstrate safety and a biological effect, for example a reduction in tumour blood flow. It is unclear whether such agents should be given with chemotherapy, after chemotherapy or both. Clinical trials with VEGF inhibitors, VEGFR inhibitors or EGFR (Epidermal Growth Factor Receptor) inhibitors have shown responses in both settings. Clinical trials in both situations are needed. Given the number of agents becoming available trials need to be designed to provide a rapid assessment of activity of these agents at an early stage, with the option of continuing the trial of a promising agent to include larger numbers of patients.

4.6 Cediranib (AZD2171)

Cediranib has been developed as an oral, once daily, potent inhibitor of vascular endothelial growth factor-A (VEGF) signalling. The trade name is RECENTIN™. It acts by inhibiting the tyrosine kinase activity of VEGF receptors. It has high potency against VEGFR-2, considered the predominant signalling receptor for endothelial proliferation, differentiation and vascular permeability and has additional activity against VEGFR-1 and 3. Cediranib is expected to inhibit VEGF-driven angiogenesis and, constrain tumour growth[36, 37]. Since angiogenesis is necessary for the growth and metastasis of most tumours and VEGF is believed to have a pivotal role in this process, cediranib treatment may have broad-spectrum clinical utility.

Cediranib has been investigated as monotherapy, and in combination with gefitinib, in phase I trials. Up to October 2011 over 5000 patients with a range of solid tumours and metastatic liver disease have been treated with cediranib. Dynamic Contrast Enhanced MRI (DCE-MRI) has shown that at tolerable doses there is a significant reduction in tumour blood flow[38, 39]. The feasibility, activity and pharmacokinetics of cediranib have been explored in combination with carboplatin and paclitaxel by Seymour and colleagues at the National Cancer Institute of Canada Clinical Trials Unit[40-42]. Cediranib dose-dependently inhibits tumour growth in ovarian and other tumour xenografts. The in-vivo activity is consistent with inhibition of VEGF signalling and an indirect anti-tumour effect rather than a direct anti-proliferative effect on tumour cells[39]. For full details of ongoing trials please refer to the current Investigators Brochure (Table 10 and Appendix A).

The incorporation of these agents into the therapy of ovarian cancer could improve progression free and overall survival. There is strong scientific rationale for embarking on clinical trials to evaluate these new agents. The treatment of platinum-sensitive ovarian cancer presents an ideal setting in which to evaluate molecular targeted agents. A high response-rate to chemotherapy is expected and the tumour burden at the start of chemotherapy is often small. Events (progression and death) occur at higher rates in patients with relapsed ovarian cancer compared to patients treated in the first-line setting,

ICON6


allowing a more rapid comparison of these agents. A careful evaluation of toxicity is needed, particularly during the early phase of this trial.

Since ICON6 started the dose of cediranib in combination with some chemotherapies has been revised. Based on the advice of the HORIZON colorectal cancer programme IDMC, the dose selected by AstraZeneca for continuation in the Phase III studies was 20 mg, since this dose achieved all of the pre-defined efficacy criteria for continuation (for more details see current cediranib Investigators Brochure). After 24 patients were enrolled in ICON6 it became clear that the 30mg dose was resulting in a high proportion of patients requiring dose modifications. This along with information from these other trials led the TMG and IDMC to recommend a dose reduction to 20mg.

Following the negative results of the HORIZON, REGAL and the BR 29 studies (in patients with CRC, GBM and NSCLC respectively) not meeting its pre-defined end-point, AstraZeneca announced its decision to cease the development and manufacture of cediranib. It was therefore necessary to re-design the ICON6 trial in light of these developments. The details of the new statistical plan are outlined in section 13.

ICON6


5 AIMS AND OBJECTIVES ICON6 is a randomised (2:3:3), three arm, double-blind, placebo-controlled multi-centre Gynaecologic Cancer InterGroup (GCIG) trial. It is a phase III multi-arm multi-stage trial of cediranib given in combination with platinum-based chemotherapy, and continued as maintenance therapy, in patients with relapsed platinum-sensitive ovarian cancer (defined as relapsed disease six or more months after completion of first line treatment).

5.1 Stage One - Safety

Primary Aim: To determine the safety of adding cediranib (20mg) once daily to standard

platinum-based chemotherapy, carboplatin and paclitaxel preferred for stage 1 (Arm A vs Arms B plus C).

5.2 Stage Two - Activity

Primary Aim: To determine the efficacy of cediranib when given concurrently with chemotherapy

and continued as maintenance treatment in terms of PFS (Arm A vs Arm C). Secondary Aims: To determine the efficacy of cediranib when given concurrently with chemotherapy

in terms of PFS (Arm A vs Arm B). To compare the efficacy of cediranib when given concurrently versus concurrent

plus maintenance cediranib in terms of PFS (Arm B vs Arm C). To compare toxicity and quality of life across the 3 treatment arms.

5.3 Potential Ancillary Study

To investigate associated Translational Research (TR) endpoints including tissue and circulating markers of angiogenesis and circulating markers of early disease progression. There will also be an assessment of prognostic markers for ovarian cancer in the tissue.

ICON6


6 SELECTION OF SITES/CLINICIANS

In order to participate in the ICON6 trial, investigators and sites must be affiliated with a participating GCIG group and must fulfil a set of basic criteria which have been agreed by participating groups. Each site must complete a site accreditation form which verifies that the site is willing, and able, to comply with the requirements of the trial. This will be signed by the Principal Investigator for that site on behalf of all staff who will be working on the ICON6 trial.

6.1 Selection of Sites/Clinicians

Sites will be accredited on the following criteria:

The site will regularly undertake the treatment of ovarian cancer. The investigator will have appropriate experience of conducting trials according to

good clinical practice (GCP). The site will have an adequate number of qualified clinical staff and adequate

facilities for the foreseen duration of the trial to conduct the trial properly and safely.

The site will have appropriate pathologists who specialise in the reporting of gynae-oncology specimens.

The site will have oncologists trained in the delivery of chemotherapy who specialise in the treatment of ovarian cancer, and who are integrated into the gynae-oncology multi-disciplinary team and are experienced in the care of patients receiving platinum based chemotherapy.

The site will have adequate cover from other senior colleagues at time of PI absences’ to maintain best practice whilst managing trial patients. Delegation of responsibilities to junior staff should only be done after assurance of familiarity with trial protocol, GCP and clinical management guidelines.

The site will have physicians qualified to manage expected toxic effects of experimental medicines (including hypertension and diarrhoea).

Chemotherapy prescribing will conform to best local practice, including computerised prescribing, where available.

All staff assisting with the trial will be adequately informed about the protocol, the investigational product and their trial related duties.

The trial will be conducted in accordance with the current protocol and changes will only be made when necessary to protect the safety, rights and welfare of patients.

Standard local practice guidelines will be in place at the site to deal with acute medical or surgical complications of treatment.

The site will run a 24 hour specialised oncology on call service to which patients experiencing treatment-related toxicities will be referred.

The trial will be conducted in accordance with the ICON 6 protocol, to the principles of ICH GCP standards and applicable regulatory requirements.

The site agrees to participate in the monitoring and audit plans for ICON6 giving access, to representatives of their GCIG group and the MRC CTU, to all relevant trial documents including site files, patient records, reports and data. In addition sites may also be required to allow access to trial documents to representatives of AstraZeneca (as part of the agreed MRC audit plan) and to regulatory authorities should the trial be audited as part of a regulatory submission.

The site will maintain a trial master file which will contain essential documents for the conduct of the trial.

ICON6


All trial data will be submitted in a timely manner, and as described in the protocol. If participation fails to meet required standards in terms of data returns and protocol compliance or recommended trial conduct then a site’s continued participation will be addressed by the Trial Management Group.

All Serious Adverse Events (SAE) will be reported within one working day to the MRC CTU, except for those that the protocol identifies as not requiring immediate reporting.

Initial SAE reports will be promptly followed by detailed written reports as appropriate.

No trial data will be disclosed without the approval of the Trial Steering Committee (TSC).

All trial related documents will be retained for 15 years after the trial is closed.

6.2 Group Approval

Prior to group approval a contract must be signed between MRC and the participating GCIG group (or their legal entity). In addition, each participating group is required to send the following documents to the MRC CTU before they can activate their sites and start to randomise patients into the trial:

Confirmation of Regulatory Approval Confirmation of National or local Ethics approval of Protocol, Patient

Information Sheet and Informed Consent Form Copy of the National Patient Information Sheet Certificate of Trial Insurance or equivalent if applicable to National groups Copy of any group specific appendices.

6.3 Site Approval

Before a site can be approved to start randomising patients the following documents should be forwarded to the national GCIG participating group coordinating the trial:

Site Accreditation Form CVs for Principal and Co-Investigators Financial Disclosure Form for Principal and Co-Investigators Local Ethics Approval of Protocol, Patient Information Sheet and Informed

Consent Form Delegation of Responsibility Log

When these documents have been received by the national GCIG participating group, the GCIG group will activate the site and inform the site that initiation has been completed. The GCIG group will complete a site approval form and fax this to the MRC CTU.

Each person working on the ICON6 trial must complete a section of the Delegation of Responsibility log, indicating their responsibilities and giving contact details (phone, fax and email address). Sites must notify their GCIG group of any subsequent changes to trial personnel and/or their responsibilities. The GCIG participating group will update the MRC CTU. An up-to-date copy of the log must be stored in the Investigator Site file at the site, at the GCIG participating group.

Sites will not receive their first supply of cediranib until site initiation has been completed.

ICON6


7 SELECTION OF PATIENTS

Patients will be considered eligible for enrolment into this trial if they fulfil all of the inclusion criteria and none of the exclusion criteria, as defined below:

7.1 Patient inclusion criteria

1. Females aged 18 years with previous histologically proven diagnosis of

Epithelial ovarian carcinoma Fallopian tube carcinoma Primary serous peritoneal carcinoma

requiring treatment with further platinum-based chemotherapy > 6 months after their last cycle of first-line chemotherapy and 6 weeks after maintenance that is not chemotherapy based.

2. Signed informed consent and ability to comply with the protocol

3. Ability to commence treatment within approximately 2 weeks of randomisationc

4. CT or MRI proven relapsed disease (measurable or non-measureable)d

5. ECOG performance status 0-1e

6. Life expectancy more than 12 weeks

7. If there is a past history of a solid tumour (other than ovarian cancer), this must have been treated curatively more than five years ago with no evidence of recurrence, with the exception of patients who have synchronous endometrial cancer (Stage I G1,G2) with their ovarian cancer

8. If prior anthracycline or chest radiotherapy, Left Ventricular Ejection Fraction (LVEF) > institutional lower limit of normal

9. Adequate bone marrow function

Absolute Neutrophil Count (ANC) 1.5 x 109/l Platelets (Plt) 100 x 109/l Haemoglobin (Hb) 9g/dl (can be post transfusion)

10. Adequate liver function (within 14 days before randomisation)

Serum bilirubin (BR) ≤ 1.5 x ULN

Serum transaminases ≤ 2.5 x ULNf

11. Adequate renal function

Serum creatinine ≤ 1.5 ULN and calculated creatinine clearance >50 ml/min c See trial schedule for more details p53 d The initial baseline scan should be done within 4 weeks prior to randomisation. However, a six week window would be considered after discussion with the CI e See Appendix 1 f If the abnormal liver function tests are clearly attributable to liver metastases then serum transaminases (ALT and/or AST) values < 5x ULN are permitted

ICON6


Urine dipstick for proteinuria <2+. If urine dipstick is 2+ on two occasions more than one week apart then a 24 hour urine must demonstrate 1 g of protein in 24 hours or protein/creatinine ratio < 1.5.

7.2 Patient exclusion criteria

1. Non-epithelial ovarian cancer, including malignant mixed Mullerian tumours and mucinous carcinoma of the peritoneum

2. Poorly controlled hypertension (persistently elevated > 150/100mmHg, either systolic or diastolic or both, despite anti-hypertensive medication)

3. History of inflammatory bowel disease (Crohn’s Disease or Ulcerative Colitis) 4. Malignancies other than ovarian cancer within 5 years prior to randomisation,

except for synchronous endometrial cancer (Stage I G1, G2) with ovarian cancer, adequately treated carcinoma in situ of the cervix and/or basal cell skin cancer. Patients who have a past history of a solid tumour, treated curatively, more than five years prior to randomisation, with no evidence of recurrence, are still eligible to enter ICON6

5. Previous radiotherapy within approximately 21 days prior to anticipated start of treatment

6. Treatment with any other investigational agent within 6 weeks prior to entering this trial. Patients are still eligible for entry into ICON6 if they have received previous treatment for ovarian cancer with either bevacizumab, erlotinib, or a Cox-2 inhibitor as long as more than 6 weeks have elapsed since the last treatment

7. Arterial thrombotic event (including transient ischaemic attack [TIA], cerebrovascular accident [CVA] and peripheral arterial embolus) within the previous 12 months.

8. GI impairment that could affect ability to take, or adsorption of, oral medicines including sub acute or complete bowel obstruction

9. Known hypersensitivity to cediranib or other VEGF inhibitors 10. Major surgery within 2 weeks before anticipated start of treatment 11. Significant haemorrhage of > 30ml in a single episode within 3 months or any

haemoptysis 12. Evidence of severe or uncontrolled cardiac disease

Myocardial infarct [MI] or unstable angina within 12 months New York Health Association (NYHAg) ≥ grade 2 congestive heart failure (CHF)

Cardiac ventricular arrhythmias requiring medication. History of 2nd or 3rd degree atrioventricular conduction defects.

13. Prolonged QTc (corrected) interval of > 470msec on ECG, or a family history of long QT syndrome.

14. Persisting ≥ Grade 2 CTC toxicity (except alopecia and neuropathy) from previous anti-cancer treatment. If peripheral sensory or motor neuropathy ≥ grade 2 then paclitaxel can be omitted from the chemotherapy at the discretion of the treating physician

15. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory in the case of suspected brain metastases. Spinal MRI is mandatory in the case of suspected spinal cord compression. Patients with unstable, untreated brain or meningeal metastases are not eligible.

16. Inability to attend or comply with treatment or follow-up scheduling 17. Evidence of any other disease, metabolic dysfunction, physical examination finding

or laboratory finding giving reasonable suspicion of a disease or condition that

g See Appendix 2 NYHA Classification of Cardiac Disease

ICON6


contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications

18. Fertile women of childbearing potential not willing to use adequate contraception for the duration of trial treatment and at least 6 months after

19. Any other severe uncontrolled medical condition or disease

7.3 Concomitant medications

Cediranib is highly protein bound and is potentially metabolised by hepatic P450 enzyme systems. It is therefore recommended that concomitant use of potent inhibitors of CYP3A4 and 2C8 are stopped 2 weeks prior to Trial Drug being commenced. However, the decision to stop such drugs lies with the treating physician/investigator. If a decision is taken to continue the medication, patients should be monitored carefully to ensure there is not an excess of toxicity.

Patients who require oral anticoagulants (coumadin, warfarin) are eligible as long as the INR is stable and increased monitoring occurs during trial treatment. Patients may receive low molecular weight heparin while receiving Trial Drug, and physicians may prefer to anti-coagulate their patients with this, rather than warfarin, while they are receiving trial treatment.

There are insufficient data on other concomitant medications that may significantly affect hepatic P450 drug metabolising activity by way of enzyme induction and inhibition to specifically contraindicate or permit their use. It therefore may be best to avoid the use of very potent inhibitors of CYP3A4 and 2C8 such as amiodarone, clarithromycin, erythromycin, simvastatin, atorvastatin, lovastatin, montelukast sodium, verapamil, ketoconazole, miconazole, indinovir (and other antivirals) and diltiazem within 2 weeks of the first dose of cediranib and throughout the trial period.

Patients may switch to using zafirlukast instead of montelukast sodium, following the label recommendations, as it is not listed as a strong inhibitor of CYP3A4.

The statins, rosuvastatin, fluvastatin and pravastatin are not CYP3A4 inhibitors and therefore can be used without risk of interaction with cediranib. Women on any other statins at the time of screening and randomisation should have a two week washout period before starting Trial Drug and changed to one of the statins listed above if further treatment with a statin is required.

Patients should be advised to avoid grapefruit juice and St John’s Wort which are also hepatic cytochrome P450 inhibitors. Although the dihydropyridine calcium-channel blockers nifedipine and amlodipine are both metabolised via CYP 3A4 these drugs have been used with cediranib in other trials and can be used in the management of cediranib induced hypertension. Caution should be exercised for patients using any medication that may markedly affect renal function, particularly in patients receiving cisplatin in place of carboplatin. Such medications may be used with care if deemed essential for treatment or may be continued if already in use prior to entry in the trial with no effect on renal function.

7.4 Number of patients

Assuming randomisation continues as projected, the target of 470 patients will be consented by 31st December 2011. Due to the discontinuation of cediranib, it is preferable that patients should not be consented after 31st December 2011.

ICON6


7.5 Screening procedures and pre-randomisation investigations

Investigations, such as CT or MRI scans and CA125 measurements, which have been performed as part of routine clinical practice can be used as part of the screening process, however no other non-routine investigations or tests required for screening may be performed prior to signature of the informed consent form.

The following baseline information should be obtained within 28 days prior to randomisation:

Demographic data and medical history including previous and current diseases and medications (including confirmation of first-line platinum-based chemotherapy)

Baseline toxicity to document pre-existing toxicity from first-line chemotherapy (assessed using CTCAE v4.0)

Confirmation of radiological disease recurrence and disease by CT or MRI (can be measurable or non-measurable by RECIST)

Physical examination including the assessment of height, weight, pulse rate and blood pressure

ECOG performance status Blood tests

o FBC (CBC) o U&E: serum creatinine (SCr), urea (BUN), K+, Na+, Ca2+, Mg2+ o LFT: Bilirubin, ALP, AST/ALT, albumin o Coagulation: INR or aPTT o CA 125 o TSH, T4

Radiological investigations o CT or MRI scan to assess disease (usually abdomen and pelvis)d o CXR or Thoracic CT

Other tests o Urinalysis o Pregnancy testh o ECG to exclude prolonged QTc o Left Ventricular Ejection Fraction (patients who have received previous

anthracyclines or chest radiotherapy) o Correlative bloods for translational research (if applicable)

Check all inclusion and exclusion criteria

h Women of childbearing potential only. It is recognised that this will not apply to the majority of patients in ICON 6 as they will have undergone prior surgical debulking

Where laboratory investigations have not been performed within the 7 day period prior to starting treatment then they must be repeated on day 1 of cycle 1 to ensure that the patient is fit to receive platinum-based chemotherapy and cediranib. This applies to blood haematology, biochemistry, CA125 and urinalysis; except for TSH and T4 where the investigations can be performed within 28 days prior to starting treatment.

The above is summarised, along with the other assessments required throughout the trial, in Table 9 (Section 11).

ICON6


7.6 Tumour Assessment

All patients should have cross sectional imaging (preferably by CT scan although MRI is allowed) of the pelvis and abdomen. All subsequent follow up scans should be the same modality (CT or MRI) and performed using the same technique. Patients will be classified as having measurable or non-measurable disease (as per RECIST) and target and non-target lesions identified if relevant (see Appendix 3). The initial baseline scan should ideally be done within four weeks prior to randomisation, however, a six week window would be considered after discussion with the CI.

A chest X-ray must be performed to check for thoracic metastasis in all patients, and a chest CT or MRI performed if there is any clinical or radiological suspicion of parenchymal lung metastases or mediastinal metastases. Further evaluation of all other known lesions must be performed.

CA125 must be measured in the 7 day period prior to the first cycle of trial treatment.

ICON6


8 RANDOMISATION

Patients will be randomly assigned in a 2:3:3 ratio to

Platinum-based chemotherapy plus placebo during chemotherapy and for 18 months post randomisation or until progression (Arm A – reference arm)

Platinum-based chemotherapy plus cediranib during chemotherapy and then placebo up to 18 months post randomisation or until progression (Arm B – concurrent arm)

Platinum-based chemotherapy plus cediranib during chemotherapy and then continuing up to 18 months post randomisation or until progression (Arm C – concurrent and maintenance arm)

Trial Drug (placebo or cediranib) will continue for up to 18 months from randomisation or until progression, whichever is sooner. Patients who have not progressed at 18 months from randomisation can continue Trial Drug until progression, if in the opinion of the clinician there is continuing clinical benefit (whilst supply lasts). However, investigators must discuss the continuation of treatment for each patient with the Chief Investigator or Trial Physician first.

Patients can only be enrolled once on this trial. The patient randomisation numbers will be allocated sequentially in the order in which the patients are enrolled. Co-enrolment in any other clinical trial is not allowed (see 9.7 for details).

The following data will be required in order to enrol a patient:

Confirmation (yes or no) that the patient satisfies all the eligibility criteria Patient’s date of birth Patient’s initials Date and evidence of recurrence (confirm that this is greater than 6 months

since the completion of first-line treatment) Details of first line treatment of ovarian cancer Planned chemotherapy regimen (platinum alone, platinum plus paclitaxel or

platinum plus gemcitabine) Confirmation (yes/no) of whether the patient has previously received any VEGF

inhibitors

The date of commencing treatment should be as soon as possible after the patient is randomised, and should be within two weeks wherever possible. In extenuating circumstances a longer time period from randomisation to commencement of treatment can be discussed with the Chief Investigator or Trial Physician. This date should not be affected by the treatment arm the patient is allocated to.

Patients will be randomised using ClinPhone IVRS/IWRS system, via computer key-board data entry for web-based interface, or touch-tone phone key pad. (For access to the randomisation system see page 3).

Each member of the trial site team who is authorised to randomise patients will be provided with a unique system username and password, which will allow them to access the central randomisation system 24 hours per day, 7 days per week via a trial specific Internet site.

The randomisation database is linked to the Trial Drug supply management database.

ICON6


Site staff will be trained in how to access and use the randomisation system. After receiving training site staff will be provided with a randomisation system and drug supply management user-guide and a free-phone help-desk number.

ICON6


9 TREATMENT OF PATIENTS

9.1 General Principles

ICON6 is a trial of the addition of cediranib to standard platinum-based second-line chemotherapy for ovarian cancer. The platinum-based chemotherapy agents are not investigational products and are not provided as part of the patients’ Trial Drug. In order to maintain consistency in dose and administration between participating GCIG groups and individual sites, drug information on the platinum-based chemotherapy allowed is provided at the end of section 9.3 and Appendix 13.

Patients will be randomised in a 2:3:3 ratio between: Arm A; Arm B; Arm C (Section 8).

The preferred standard chemotherapy treatment in ICON6 is carboplatin and paclitaxel. However, it is recognised that some patients are unable, for reasons of previous toxicity, or unwilling to receive carboplatin and paclitaxel. These patients will still be eligible for entry into ICON6, and can receive single agent carboplatin as their second line chemotherapy. Planned chemotherapy must be specified before randomisation.

Some sites will be allowed to use gemcitabine and carboplatin in combination, but the site must be approved by the TMG to do this.

In certain situations (see 9.3.4) cisplatin can be given in place of carboplatin. Other regimens are not allowed because there may be limited information on safety and tolerability in combination with cediranib.

Patients should begin their allocated treatment as soon as possible ideally within 2 weeks of randomisation. Patients may receive full supportive care including transfusion of blood, products and growth factors according to local practice.

Treatment with oral Trial Drug, in all three arms should be continued as detailed in the schedule in table 9 until

Radiological, clinical or symptomatic disease progression Unacceptable adverse events Patient decision to stop treatment Patients are to receive a planned maximum of 6 cycles of chemotherapy, but may

stop earlier for toxicity or disease progression. Modifications of chemotherapy because of toxicity may lead to patients requiring treatment with cisplatin instead of carboplatin. In these situations treatment with Trial Drug can continue. Treatment with Trial Drug should be discontinued if other chemotherapy agents (topotecan or pegylated liposomal doxorubicin) are substituted for the original drug regimen. If patients have to stop chemotherapy for toxicity before 4 cycles of platinum chemotherapy then the Trial Drug should also be stopped. If they stop for toxicity after 4 cycles of platinum chemotherapy the Trial Drug can be continued.

These patients will continue to follow all other protocol defined procedures, including attending the clinic for a scheduled visit 21 weeks from day 1, cycle 1 (regardless of any chemotherapy delays) to switch their Trial Drug.

There is no CA125 progression endpoint in ICON6 and patients do not have to stop Trial Drug if their CA125 rises. It is recognised that monitoring CA125 is an important tool in

ICON6


clinical management. Data from ICON6 will be useful to explore the relationship between elevations in CA125 and clinical progression in the relapse setting as well as the impact of treatment with VEGF inhibitors such as cediranib on CA125.

During the first 3 cycles of chemotherapy, standard clinical practice should be followed, with a rising CA125 investigated by imaging (CT scan or MRI). If progressive disease is confirmed by imaging then Trial Drug should be stopped and chemotherapy altered according to normal clinical practice. If imaging does not confirm progressive disease then chemotherapy may be stopped according to standard local practice. However, if chemotherapy is stopped on the basis of non-response to chemotherapy, judged either by imaging or CA125, prior to administration of the 4th cycle of chemotherapy that includes platinum then Trial Drug must also be stopped.

Following completion of the 4th cycle of chemotherapy, a rising CA125 should be investigated according to standard local practice, although if progression is not confirmed by imaging, treatment with Trial Drug can be continued. There is no rationale for commencing second line chemotherapy on the basis of CA125 alone, treatment should only commence once clinical or radiological progression is confirmed.

Details for each treatment arm are given in section 8.2. It is the responsibility of the treating physician to ensure that these treatment schedules are followed. The chemotherapy guidelines in this protocol are in line with the manufacturers’ recommendations in the UK Summaries of Product Characteristics (SmPCs) at the time of writing. The SmPCs are updated from time to time and may also vary from country to country. Up-to-date UK SmPCs are posted on the Medicine Guides Website http://www.medicines.org.uk. Details of administration of the experimental Trial Drug are given in the protocol and Investigator’s Brochure (IB).

9.2 Treatment Arms

Further details regarding the dosing and reconstitution of individual drugs are given in section 9.3. Details regarding dose modifications, delays and omissions are given in section 10.

In all arms patients will receive:

6 cycles of intravenous chemotherapy given on day one every three weeks. Regardless of specific chemotherapy, patients are also required to take daily oral Trial Drug (cediranib or placebo) from day one for the duration of chemotherapy cycles. Chemotherapy drugs must be administered in the following order

If receiving carboplatin and paclitaxel

o Hypersensitivity prophylaxis o Anti-emetics o Intravenous paclitaxel infusion o Intravenous carboplatin infusion

If receiving single agent carboplatin

o Anti-emetics o Intravenous carboplatin

If receiving Carboplatin and Gemcitabine

o Anti-emetics o Gemcitabine o Carboplatin ( D1 only)

ICON6


Doses of chemotherapy, hypersensitivity prophylaxis and anti-emetics are for guidance only. In view of the performance status of the patient, or co-morbid conditions, doses may be adjusted according to the standard practice of the treating physician.

After chemotherapy is completed continue daily Trial Drug for up to 18 months from randomisation or until progression whichever is sooner. Patients who have not progressed at 18 months from randomisation can continue Trial Drug until progression, if in the opinion of the clinician there is continuing clinical benefit (whilst supply lasts). However, Investigators must discuss the continuation of treatment for each patient with the Chief Investigator or Trial Physician first.

9.3 Specific Drug Information

9.3.1 Trial Drug: Cediranib and Placebo

Cediranib is an investigational medicinal product. It is not licensed for the treatment of ovarian cancer or any other cancer.

Supplies

ICON6 is a double blind trial hence neither the patient nor the investigator will be aware of whether the patient’s Trial Drug is cediranib or placebo tablets.

Trial Drug will be provided by AstraZeneca for use by patients in ICON6 and will be special investigational medicinal product clinical trial stock.

Trial Drug will be supplied as beige, round, film-coated tablets. Active drug and placebo will be identical in appearance, as will be the bottles in which they are provided.

Unblinding without discussion with the Chief Investigator can only be performed in a medical emergency where knowledge of treatment assignment is critical to the immediate medical management of the patient (see section 10.2).

Cediranib will be supplied as 15 mg and 20 mg tablets, with matching placebo. Packaging, labelling and preparation of the Trial Drug will be performed in a

way that will ensure blinding throughout the trial. Trial Drug will be packaged into white high-density polyethylene bottles, with

child resistant, tamper evident closures. Labelling of the Trial Drug will be performed in accordance with Good Manufacturing Practice and in accordance with local labelling requirements, stating that the Trial Drug is for clinical trial use only and should be kept out of the reach of children.

Accountability and Unused Drugs

All investigational sites will maintain drug accountability documentation to include information on Trial Drug dispensing, destruction and drug supply inventory as specified in Appendix 4.

Preparation, Administration and Dose Guidelines

• Trial Drug (cediranib/placebo) will be taken from day 1 of cycle 1 of chemotherapy and continued for up to 18 months or until progression, whichever is sooner. Patients who have not progressed at 18 months from randomisation can continue Trial Drug until progression, if in the opinion of the clinician there is continuing clinical benefit (whilst supply lasts).

ICON6


Patients in Arm A will receive placebo tablets orally once daily. Patients in Arm B will receive active drug (cediranib tablets) orally once daily

and switch to placebo tablets orally once daily at a protocol scheduled visit 21 weeks from day 1 of cycle 1, even if they have stopped chemotherapy between cycles 4 and 6, and even if cycles have been delayed for toxicity.

Patients in Arm C will receive active drug (cediranib tablet) orally once daily. The starting dose of cediranib is 20 mg orally once daily. The tablet should be taken as a single mid-morning dose with approximately

240mls of water with the patient in the upright position. The tablet should be swallowed whole and not chewed, crushed or divided. The tablet should be taken at the same time each morning at least 1 hour

before OR 2 hours after a meal. If patients vomit after taking a tablet another tablet should not be taken until

the next scheduled dose. For elective surgery during the trial it is recommended that Trial Drug is

stopped for 2 consecutive weeks prior to the surgical procedure. Trial Drug can be restarted when the surgical wound has healed.

Trial Drug should be stopped as soon as possible if emergency surgery is being considered. Precautions should be taken to minimize the potential risk of bleeding and thrombosis in all patients. It is not necessary to routinely unblind patients who require emergency surgery. Trial Drug can be restarted when the surgical wound has healed.

If paracentesis or drainage of pleural effusions is required while patients are on Trial Drug then this should be performed under ultrasound guidance. If possible the Trial Drug should be stopped for 1-2 days and restarted after the procedure has been completed.

As a precautionary measure, it is recommended that an interval of 2 days is left between the insertion of any central venous access devices (CVADs) and treatment with the Trial Drug. The Trial Drug may be restarted after 2 days.

ICON6


9.3.2 Paclitaxeli

Pre-medication If paclitaxel is being given then prior to commencing chemotherapy give paclitaxel

hypersensitivity prophylaxis, including H1/H2 antagonists and corticosteroids, as per local standards, for example

30 minutes prior to paclitaxel

o dexamethasone 20 mg IV o chlorphenamine 10 mg IV (push diluted with 5-10ml Normal Saline) o Ranitidine 50 mg IV/Cimetidine 300 mg IV (in 20ml Normal Saline over

2 minutes)

Immediately pre-chemotherapy give anti-emetics as per local standards; this may include oral or intravenous 5HT3 antagonists

Anaphylaxis precautions should be available during infusion for the emergency

treatment of hypersensitivity reactions Paclitaxel

Use normally available stock in keeping with the standard local practice. There are no special drug accountability arrangements for paclitaxel. Reconstitute and administer via a non-PVC giving set and connectors incorporating

a filter ≤ 0.22μm. Reconstitute paclitaxel 175 mg/m2 (cap at BSA 2.0m2) in 500ml of N Saline or 5%

dextrose according to local standard practice.j Give paclitaxel intravenously over three hours via a rate-controlling device.

Monitor closely for allergic reactions and cardiac arrhythmias as per local

guidelines. If it becomes necessary to discontinue paclitaxel because of toxic effects then patients can continue treatment with single agent carboplatin (or cisplatin – see below) and Trial Drug can be continued. Docetaxel, or any other chemotherapeutic agent, may NOT be substituted for paclitaxel in any situation

i Paclitaxel should be given prior to carboplatin. The occurrence of a hypersensitivity reaction to paclitaxel is not considered a dose limiting toxicity. Patients may be retreated at full dose after administration of medication to prevent hypersensitivity reactions. If a hypersensitivity reaction does occur then it should be managed according to local protocols, or as suggested in section 10.3.2.2.5 j Body Surface Area (BSA) is worked out using a computer algorithm or according to the nomograms as specified in Appendix 5. The BSA should only be recalculated if real body weight changes by more than 10%

ICON6


9.3.3 Carboplatin

Use normally available stock in keeping with the standard local practice.

There are no special drug accountability arrangements for carboplatin. Reconstitute carboplatin AUC6 (calculated dose) or AUC5 (GFR measured), in

250ml of 5% dextrose according to local standard practice. Give carboplatin intravenously over 30-60 minutes (depending on standard local

practice).

Allergic reactions to carboplatin are not a dose limiting toxicity and should be managed according to standard local practice. Patients may be re-challenged with increased prophylactic medications and/or slowing of infusion rates at the discretion of the treating physician. If it becomes necessary to discontinue carboplatin due to hypersensitivity then patients will continue treatment with paclitaxel and Trial Drug. Cisplatin may be substituted for carboplatin in this instance at the discretion of the treating physician (see section 9.3.4).

Carboplatin Dose

The carboplatin dose should be calculated according to the Calvert formula[43] as follows

Carboplatin dose = Target AUC X (GFR + 25)

For the purpose of this protocol the GFR is considered equivalent to the creatinine clearance.

The exact dose of carboplatin therefore depends on the GFR and the method of calculating the GFR will also affect the carboplatin dose. The GFR can be calculated using a variety of different formulae (see appendix 6) and should be calculated as per local practice.

If the estimated serum creatinine clearance is <50 ml/minute, then a formal measurement of the GFR is required, using either a 24 hour urine collection or an isotopic clearance. If the isotopic clearance is measured then the value uncorrected for body surface area (BSA) should be used in dose calculations.

The target AUC for carboplatin depends on the method of GFR assessment. Where the carboplatin dose is based on a GFR measured by isotopic clearance, or a 24 hour creatinine clearance (urine collection), the target AUC is one unit lower than that based on the estimated GFR. This is summarised in Table 2.

Table 2: Target AUC Depending on GFR Calculation Method

Estimated GFR Measured GFR Cockcroft-Gault/Jellife/Wright Isotopic/24hr Urine AUC6 AUC5

ICON6


The GFR should be recalculated for

Renal toxicity (CTC Grade 2, serum creatinine >1.5 x ULN), Serum creatinine changes of ≥ 10% compared to baseline, or last creatinine value

used to calculate carboplatin dose (whichever is most recent), Each dose modification of carboplatin, Cycle 2, if there has been significant doubt about the true GFR at cycle 1

(according to clinical judgement).

Dose capping of carboplatin may be carried out according to standard local practice.

GFR Limitations

Isotopic GFR is inaccurate in patients with significant effusions, ascites or oedema as the isotope distributes into third space fluid collections.

Patients who have had complicated or prolonged post operative recovery and who have been maintained on prolonged IV fluids with poor nutrition will have a falsely low serum creatinine.

Formulae, such as the Cockcroft-Gault formula, are inaccurate at the extremes of age and weight. The calculated GFR may be falsely high in obese young women and falsely low in thin elderly women.

It is assumed that clinicians entering patients into this protocol will be aware of these issues and the clinical judgement of an experienced clinician should be applied to the calculation of the carboplatin dose.

9.3.4 Cisplatin

Please note that cisplatin should only be substituted for carboplatin in patients with carboplatin hypersensitivity.

The recommended dose of cisplatin is 75 mg/m2 three weekly, and a minimum of 50mg/m2 three weekly should be used.

Use normally available stock in keeping with the standard local practice. There are no special drug accountability arrangements for cisplatin. Reconstitute cisplatin with water for injections such that the reconstituted solution

contains 1 mg/ml of cisplatin. A suggested regimen for cisplatin administration is:

o Prehydration: 1000ml 0.9 % saline with 20 mmols potassium chloride over 1 hour, followed by 100 ml 10% mannitol over 15 minutes

o Cisplatin in 1000ml 0.9 % saline with 20 mmol potassium chloride over 1 hour

o Posthydration: 1000ml 0.9 % saline with 20 mmol potassium chloride and 10 mmol magnesium sulphate over 1 to 2 hours.

Platinum infusion should follow paclitaxel, and anti-emetics should be given according to local practice. Cisplatin should only be given if urine output is adequate. It is highly emetogenic and 5HT3 antagonists with or without aprepitant should be considered.

If it becomes necessary to discontinue cisplatin then patients will continue treatment with paclitaxel and Trial Drug.

Chemotherapy dose modifications should be in accordance with the guidance given in section 10.

ICON6


9.4 Trial Treatment Recording

Reasons for any dose delays, dose reductions, dose omissions or stopping chemotherapy treatment and/or Trial Drug should be documented in the appropriate part of the CRF. Patient reported data on missed doses and reasons for missed doses will be used to assess compliance.

9.5 Concomitant Therapy

All non-cancer treatments that the responsible physician feels are appropriate are allowed.

Any diagnostic, therapeutic or surgical procedure performed during the trial period should be recorded including the date of occurrence, description of the procedure(s) and any clinical findings.

Patients should receive full supportive care during and after the administration of chemotherapy, plus Trial Drug (cediranib or placebo). This includes transfusion of blood and blood products and/or the use of erythropoietin and/or G-CSF (as clinically indicated) and antibiotics for infective complications. Anti-emetics should be given according to local practice. The treatment details should be recorded in the CRF. Anaphylaxis precautions should be observed during administration of carboplatin and paclitaxel as per local practice.

Treatment with concomitant, systemic anti-tumour agents (apart from those specified in the protocol) or other concurrent investigational agents of any type are not allowed in this trial before protocol defined evidence of disease progression. The patient may only be entered into another therapeutic clinical trial after documented protocol defined disease progression or withdrawal from this trial, see section 10.2 and section 12.

See section 7.3 for important information on concomitant treatment with oral anticoagulants, drugs which may inhibit or induce the hepatic P450 enzyme system and drugs which may cause renal impairment.

9.6 Treatment for Progression

All anticancer treatments including chemotherapy, radiotherapy and surgery for progression will be recorded on trial CRFs during follow up. Any other additional treatment that the responsible physician feels is appropriate, and not prohibited by the trial treatment, is permitted.

9.7 Co-enrolment Guidelines

Co-enrolment in any type of clinical trial is not allowed prior to protocol defined disease progression, including any chemotherapy trial or any other trial of an investigational product for the treatment of ovarian cancer.

9.8 Follow up

Once randomised, patients remain evaluable for the intention to treat analysis regardless of their subsequent course of treatment. Specific follow up arrangements are described in Section 11.

ICON6


10 DRUG SAFETY INFORMATION

10.1 General Information on Cediranib

Cediranib has been investigated as monotherapy and in combination with gefitinib, carboplatin and paclitaxel and other chemotherapy regimens in a number of early phase trials in different indications. Full details are provided in the investigators Brochure (IB). To date over 5000 patients have been treated with cediranib. ICON6 is the first trial of cediranib specifically for the treatment of ovarian cancer.

Doses of up to 60mg have been explored in dose-finding studies. Maximum Tolerated Doses (MTD) have ranged between 20mg (in a trial which included elderly patients with advanced prostate cancer) and 45mg. Based on a review of safety data from all studies but particularly focusing on studies of cediranib in combination with chemotherapy, and based on the information accrued early in stage 1 of the ICON6 trial a dose of 20mg has been chosen as the dose of cediranib in combination with carboplatin and paclitaxel in ICON6. This is in line with the choice of a 20 mg dose for Phase III trials of cediranib given with chemotherapy (the glioblastoma multiforme REGAL study and the colorectal cancer HORIZON programme). In addition, the NCIC CTG has conducted a second international multi-centre randomised study (BR29) of AZD2171 in combination with carboplatin/paclitaxel in first-line NSCLC, at 20mg.

10.1.1 Potential Adverse Effects of Cediranib

Expected Adverse Events:

Information on expected adverse events with cediranib comes from current pre-clinical data, a general knowledge of anti-VEGF therapy and clinical experience from early studies of cediranib (as summarised in the current Investigators Brochure). These studies included a range of patients with different types of tumours.

Hypertension (up to approximately 70%, severe in 15% of patients) Nausea and vomiting (affecting up to 50% and 31% of patients respectively) Diarrhoea (mild to moderate diarrhoea estimated in 71% of patients severe in 7%) Proteinuria (observed in 12.5% patients at doses of 30 mg and above) Gastrointestinal perforation, sometimes complicated by the formation of a fistula

(< 3%) Muscle weakness (estimated to affect 8% of patients) Left ventricular dysfunction, in some cases leading to cardiac failure, has been

observed in patients (<1%) with risk factors for left ventricular dysfunction (including previous or concomitant anthracycline treatment).

Bleeding and haemorrhage (12% mild to moderate bleeding e.g. nosebleed, coughing up blood, blood in vomit or stools, fatal in <1% of patients)

Fatigue (estimated to occur in up to 68% of patients) Dehydration (observed in < 5% of patients with chemotherapy or cediranib

related diarrhoea and vomiting and exacerbated by reduced oral intake in patients received chemotherapy)

Hoarseness (dysphonia) (estimated to affect 52% of patients) Dry mouth (estimated to affect 9% of patients) Oral mucosal inflammation (estimated to affect 25% of patients)

ICON6


Elevated thyroid stimulating hormone (TSH) levels (which may be associated with clinical hypothyroidism) (AE of hypothyroidism <6%, elevated TSH estimated to affect up to 50% of patients)

Hand and foot syndrome (estimated to affect up to 17% of patients) Thrombocytopenia (CTC G1/2 in the majority of cases, seen with monotherapy

and combination treatment) (estimated to affect up to 80% of patients) Reversible Posterior Leukoencephalopathy Syndrome (estimated to affect <0.5%

of patients) Increases in transaminases (sometimes associated with increases in total bilirubin)

(estimated to affect <20% of patients) Weight loss (estimated to affect up to 40% of patients) Headache (estimated to affect up to 45% of patients) Anorexia (estimated to affect up to 65% of patients) Febrile neutropenia has been observed in patients with non-small cell lung cancer (NSCLC) who received cediranib in combination with carboplatin and paclitaxel. Other adverse events reported in early studies of cediranib that may or may not have a causal association with cediranib can be found in the Investigator’s Brochure (IB).

10.1.2 Dose Modifications and Delays for Trial Drug (cediranib and

placebo)

Guidelines in this section outline the recommended dose adjustments for Trial Drug in patients with specific adverse events, which may or may not be causally related to cediranib or chemotherapy but nonetheless for which a dose modification is recommended. The general principles are:

If a patient experiences several adverse events and there are conflicting recommendations then the dose adjustment that reduces the dose to the lowest level should be used.

If adverse events are considered to be potentially related to both the chemotherapy and Trial Drug then doses should be adjusted for both chemotherapy and Trial Drug. Details are provided in section 10.3 regarding dose adjustments and delays for chemotherapy.

Once a dose reduction of Trial Drug has been made it should not be escalated. The patient should remain on the reduced dose.

If an adverse event develops which is only attributable to chemotherapy and not to Trial Drug, then Trial Drug may be continued at the same dose.

If an adverse event develops which is only attributable to Trial Drug, and not to chemotherapy then chemotherapy can be given as scheduled. If Trial Drug doses are omitted due to toxicity then these doses should be missed and not administered later.

If Trial Drug is omitted for more than 3 weeks the continuation on the trial should be discussed with the Lead Chief Investigator, or the Trial Physician.

Table 3: Dose levels of Trial Drug

Drug Protocol Starting Dose Protocol Dose Level -1

Trial Drug 20 mg od 15 mg od

Trial Drug is available in 20 mg and 15 mg formulations to allow for dose adjustments.

ICON6


10.1.3 Adverse events requiring discontinuation of Trial Drug

Any patient who develops any of the following should not receive further treatment with Trial Drug:

Any gastrointestinal perforation or wound dehiscence Arterial thromboembolic events (including transient ischaemic attack [TIA],

cerebrovascular accident [CVA] and myocardial infarction [MI]) Grade 4 haemorrhagic event (requiring a blood transfusion or requiring a major

non-elective intervention) Grade 4 hypertension (hypertensive crisis) Nephrotic syndrome or Grade 4 proteinuria RPLS (confirmed by imaging)

If a patient develops a second episode of an event at CTCAE grade 3 then the investigator should not re-start Trial Drug without first discussing the risk versus the benefit with the Lead Chief Investigator, or the Trial Physician.

10.1.4 Guidance on specific Adverse Events.

For current information on the nature and frequency of all adverse events reported in cediranib trials please refer to the latest version of the IB.

AEs that are discussed in detail below are ones which are serious or relevant to the patient population being studied in this trial, as well as ones which could impact on overall medical or surgical management within the trial.

10.1.4.1 Hypertension

Hypertension is the major cardiovascular adverse event associated with cediranib therapy. This is thought to involve inhibition of the signal transduction pathway of VEGF, a vascular growth factor with potent vasodilatory properties. VEGF normally causes dilatation of blood vessels therefore VEGF inhibition by cediranib results in vasoconstriction.

Pre-clinical studies suggested that cediranib-induced hypertension was likely to be successfully managed by calcium channel antagonists. Clinical studies have reported success in managing hypertension with calcium channel antagonists and/or dose reductions.

Detailed information on the management of hypertension and suggested antihypertensive drugs can be found in the ICON6 trial specific clinical guidance document. The hypertension management guidelines for this trial are consistent with the approach being taken in other cediranib protocols. The guideline will provide comprehensive information about hypertension and its management.

ICON6 Recommendations

Monitoring of blood pressure is essential while patients are receiving Trial Drug. Blood pressure should be measured after at least 5 minutes of rest and with the patient in the sitting position.

There is no information on the effect of cediranib in patients with uncontrolled hypertension at the time of initiating cediranib. Patients with uncontrolled hypertension despite medical therapy will therefore not be eligible for entry into ICON6.

ICON6


Experience to date has demonstrated that cediranib may cause hypertension for a number of weeks after treatment and also over a relatively short timeframe. Patients need to be aware of any symptoms which may be associated with hypertension and that they must seek medical advice should they be concerned that any of these symptoms are developing. It is suggested that patients in ICON6 (stage 1) will have daily home blood pressure monitoring for the first 2 cycles of chemotherapy. A patient diary will be provided to allow the patient to record results of blood pressure monitoring. The patient should be instructed to measure their blood pressure each morning in the sitting position when the patient is at rest.

For Stage 2, patients will have their blood pressure monitored at baseline and then weekly for the first 3 cycles, by patient self-monitoring, clinic or GP as preferred by patient/clinician. If normotensive, continue monitoring on day 1 of each cycle. If hypertensive, blood pressure should be monitored daily until <grade 2.

Patients will be instructed that if their self-checked blood pressure exceeds 140/90mmHg then they should have their blood pressure checked by a nurse, GP or physician.

Please refer to the grading and management of hypertension table in the ICON6 specific clinical guidance document. Temporary interruption of Trial Drug should occur in patients with uncontrolled hypertension until adequate blood pressure control is achieved. If hypertension cannot be controlled with medical therapy, or a patient develops Grade 4 hypertension (hypertensive crisis), then Trial Drug should be permanently discontinued.

10.1.4.2 Diarrhoea

Diarrhoea has been reported in over approximately 70% of patients receiving cediranib, but usually at CTCAE grade 1 or 2. Only 7% of patient reported grade 3 or 4 diarrhoea.


Patients should be warned that diarrhoea may occur and that if it does then it should be proactively managed in the usual ways including treatment with loperamide followed by codeine if necessary, with doses according to local practice. It is recommended that patients be given a prescription for loperamide (or similar drug) so that they can obtain symptomatic treatment rapidly. Please refer to the diarrhoea management guidelines in the ICON6 specific clinical guidance document. Patients may be rested from Trial Drug until symptoms have improved. Note: patients must re-start Trial Drug within 3 weeks of a rest.

10.1.4.3 Proteinuria

Proteinuria is an expected adverse event with cediranib.


Monitoring of proteinuria by dipstick urinalysis is required prior to starting and during cediranib therapy. All patients should have urinalysis (urine dipstick, protein/creatinine ratio or 24 hour protein determination, as appropriate) performed at each clinical assessment. If the urine dipstick demonstrates 2+ or 3+ proteinuria then the proteinuria management guidelines in the ICON6 specific clinical guidance document should be followed. If nephrotic syndrome or Grade 4 proteinuria occurs then cediranib should be permanently discontinued.

ICON6


10.1.4.4 Muscular Weakness

Muscle weakness is an expected adverse event with cediranib.


Patients should be specifically asked about any symptoms of general, proximal or distal symmetrical or unilateral muscle weakness and if they report these symptoms, monitored closely with measurement of creatine kinase.

10.1.4.5 Thyroid function abnormalities and symptomatic hypothyroidism

Accumulating experience with cediranib indicates that hypothyroidism can occur with elevated TSH levels. Elevated TSH levels are expected adverse events with cediranib.


T4 and TSH should be monitored throughout the trial (see Table 9) and symptomatic hypothyroidism treated according to standard local practice.

10.1.4.6 Posterior reversible encephalopathy syndrome (PRES), including reversible posterior leukoencephalopathy syndrome (RPLS)

This is a very rare syndrome affecting vascular endothelial cells in the brain that may lead to capillary leak and oedema. It has been associated with a number of conditions including hypertension, fluid retention, renal failure and the use of cytotoxic or immunosuppressive drugs. The syndrome can present in a variety of non-specific ways, including headache, seizures, lethargy, confusion, blindness and other visual and neurological disturbances. Hypertension may be present and is a precipitating factor, but is not necessary for the diagnosis of RPLS. Magnetic Resonance Imaging (MRI) is the most sensitive imaging modality to detect RPLS and is recommended in suspected cases to confirm the diagnosis. RPLS is reversible upon control of hypertension and removal of any other possible precipitating factors. If RPLS is suspected it is recommended that cediranib should be immediately discontinued in addition to other measures to control blood pressure or alleviate symptoms. If RPLS is confirmed by imaging (CT or MRI), Trial Drug should be permanently discontinued.

10.1.4.7 Asymptomatic VTE

In the case of asymptomatic VTE the patient should initially stop Trial Drug (for up to 21 days) and when deemed clinically stable by the treating physician and adequately anti-coagulated (preferably low molecular weight heparin rather than warfarin) can resume treatment with study drug. The time off study drug should not be greater than 3 weeks without discussion with CI

10.1.4.8 Fatigue k

Fatigue experienced by patients taking cediranib may be rapid in onset. During appointments patients fatigue levels should be discussed.

ICON6


Patients should be advised to take short treatment breaks of the blinded study tablets (initially 2-3 days-or longer-up to a maximum of 21 days), in order to help relieve this symptom. k Please refer to the most current version of the Clinical Management Guidelines for further advice Care should be taken to ensure that the patients’ nutritional status is optimised. Patients should be encouraged to manage fatigue by alternating periods of rest with frequent light exercise, which may improve the symptoms in some cases. Patients should restart treatment when symptoms have improved.

10.1.4.9 Dehydration Dehydration has been observed as a consequence of cediranib-related or chemotherapy-related diarrhoea, vomiting, anorexia, or reduced oral intake. Aggressive supportive care with anti-emetics is strongly recommended, especially for patients with grade 2 or 3 nausea and vomiting. Patients should be supplied with adequate anti-emetics after their chemotherapy infusion.

10.1.4.10 Liver Function Increases in transaminases, which are sometimes associated with increases in total bilirubin, have been seen in cediranib clinical studies. All patients, in whom abnormalities in AST, ALT, ALP, and total bilirubin are documented, either during a study or at the time of withdrawal, must have further tests performed until the values have returned to baseline levels, even if they have discontinued treatment, unless these values are not considered likely to improve because of underlying disease. The timing of follow-up tests is at the investigator’s discretion, but for patients with significant abnormalities (ALT/AST >3x ULN or total bilirubin >1.5x ULN) monitoring should occur at least every 48 hours until stabilisation. Possible alternative causes for the abnormalities should also be investigated and appropriate investigations performed.

10.1.4.11 Thrombocytopaenia Thrombocytopenia of CTC grade 1 or 2 in the majority of cases, has been seen with monotherapy and combination cediranib treatment. For more details of dose reduction of cediranib see section 10.3.2.1

10.1.4.12 Other Other expected adverse events with cediranib include nausea, vomiting, dysphonia (hoarseness) and oral mucositis which may be additive to those expected with carboplatin paclitaxel.

Patients should be asked about symptoms and examined for attributable signs of potential side effects at each clinical visit. In general dose modifications should be performed as indicated in table 4. These can be discussed with the CI or Trial Physician

All adverse events should be graded using the CTCAE version 4.0 and recorded on the CRF (see CRF booklet for selected categories or http://ctep.cancer.gov/reporting/ctc.html for a full list).

ICON6


Table 4: Trial Drug (cediranib/placebo): suggested dose modifications for other toxicities (except for hypertension).

10.2 Unblinding

Randomisation codes are held within the IVRS/IWRS randomisation system. All patients will be unblinded at the end of the trial when data are mature or earlier, at the recommendation of the IDMC. Following this patients still on Trial Drug can continue on open label cediranib until week 81. If patients have not progressed by week 81 and in the opinion of the treating clinician are deriving continued benefit, they may continue after discussion with the ICON6 trial team whilst cediranib supplies are still available.

Unblinding patient’s Trial Drug is discouraged during the trial as blinding is critical to its integrity. In the event of a medical emergency (emergency operation required or in the event of overdose) the blind for that subject may be broken by the treating physician or responsible pharmacist. Where unblinding is being considered, during working hours the case MUST first be discussed with the Chief Investigator or Trial Physician. Out of hours, in an emergency situation this is not necessary but before breaking the blind of an individual subject's blinded treatment, the Investigator should have determined that the information is necessary, i.e. that it will alter the subject's immediate management. In many cases, particularly when the emergency is clearly not investigational product related, the problem may be properly managed by assuming that the subject is receiving active product without the need for unblinding. For any treatment code unblinding, the reason for the decision to unblind and parties involved must be documented in the patient’s medical record and documented on the SAE form. Treatment identification information should be kept confidential and should be disseminated only to those individuals that must be informed for medical management of the patient.

The Trial Statistician at the MRC CTU will be notified of all emergency unblindings via the IVRS/IWRS system.

l Patients requiring a delay of > 2 weeks stop Trial Drug m Patients requiring > 1 dose reduction stop Trial Drug

Grade of Event Management / Next Dose Grade 1 Symptomatic care

No change in Trial Drug dose Grade 2 Treat symptomatically

If adverse event does not resolve within 48 hours to grade 1 then hold Trial Drug until recovery to grade 1 and resume Trial Drug at the same dose If adverse reaction recurs consider dose reduction at the discretion of the investigator

Grade 3 Treat symptomatically If adverse event does not resolve to grade 2 or below within 48 hours with maximal supportive care then Hold Trial Drugl until grade 1 or up to 21 days Resume Trial Drug at one dose level lowerm If Grade 3 event persists or recurs discuss with Lead Chief Investigator before recommencing Trial Drug

Grade 4 Discontinue Trial Drug permanently

ICON6


All principal investigators and site pharmacists will have web access status that allows them to break the blind for an individual patient in an emergency situation as described above.

Unblinding for any purpose other than a medical emergency is not allowed unless it would lead to the patient missing an opportunity to take part in another study because a critical requirement for eligibility is unblinding (i.e. the patient would be eligible if on the placebo arm and ineligible if on active treatment). In these situations individual cases should be discussed with the Lead CI before any decision is taken. Wherever possible, unblinding should be avoided to protect the integrity of the ICON6 trial. In cases where unblinding is approved, only local site staff should be aware of the result. The MRC CTU and CI should remain blinded.

Patients may only enter other clinical trials after formal documentation of disease progression or withdrawal from ICON6 for toxicity. Discontinuation to enter other trials without a good clinical reason should be discouraged.

Please see Page 3 for web and telephone access for randomisation and unblinding.

10.3 General information on Paclitaxel, Carboplatin and Cisplatin

For information on Carboplatin and Gemcitabine see Appendix 13 ICON6 is a trial of the addition of cediranib to standard platinum-based second-line chemotherapy for ovarian cancer. Drug information on paclitaxel, carboplatin and cisplatin is given in this section. These drugs are not investigational products in the trial. Their toxicities alone and in combination are well established, however, there may be previously unrecognised toxicities that occur in combination with cediranib. Haematological toxicities may be exacerbated. In addition, in order to maintain consistency in dose and administration between participating GCIG groups and individual sites, a standard approach to dose modifications and delays is being applied and the guidance below should be followed for patients who develop adverse events.

10.3.1 Expected Adverse Events with Paclitaxel, Carboplatin and

Cisplatin

A list of expected toxicities (based on the current UK SPCs) associated with carboplatin, cisplatin and paclitaxel which will assist the treating physician in the classification of expectedness of serious adverse reactions is given in the investigator site file. The SPCs, or equivalent national pharmaceutical source list, should be referred to for specific guidance.

10.3.2 Dose Modifications and Delays of Paclitaxel and Carboplatin (or

Cisplatin)

10.3.2.1 Haematological Toxicity

In order to maintain the dose-intensity and cumulative dose-delivery of carboplatin (or cisplatin) ± paclitaxel chemotherapy, reasonable efforts should be made to minimise dose reduction and treatment delays. Patients whose treatment is delayed because of adverse events should be evaluated at weekly intervals (or less) until adequate recovery has occurred. There are no dose escalations planned (including dose re-escalation after a

ICON6


dose reduction). Patients who do not tolerate two separate carboplatin (or cisplatin) and/or paclitaxel dose reductions should discontinue treatment with chemotherapy, but may continue treatment with Trial Drug if they have received a minimum of 4 cycles of platinum chemotherapy as described in the protocol (section 9.1). Any uncertainties about continuation should be discussed with the Lead Chief Investigator or the Trial Physician. The Trial Drug dose or schedule will not be affected by toxicities related to only chemotherapy.

If a patient experiences several toxicities and there are conflicting recommendations, please follow the most conservative dose adjustment recommended to minimise doses given.

Chemotherapy treatment should be delayed if either of the following occurs in the pre-chemotherapy full blood count:

ANC is less than 1.5 x 109/l PLT count is less than 100 x 109/l

FBC should be repeated at least weekly until haematological recovery has occurred (ANC ≥ 1.5 x 109/l and PLT ≥ 100 x 109/l).

If haematological recovery occurs within 7 days no dose modification is mandated and dosing is left to the discretion of the individual investigator. If haematological recovery occurs beyond 7 days, it is suggested that doses of carboplatin (or cisplatin) and paclitaxel are modified according to the day 22 blood count (or subsequent FBC if lower) according to the criteria in Table 5. If G-CSF is used it should be given according to standard local practice.

Dose limiting toxicities are defined, and dose modifications mandated, in Table 6.

Patients who fail to recover adequate counts after a delay of 2 weeks or more, or who have consecutive dose limiting toxicities, are not likely to be able to tolerate standard doses of chemotherapy with carboplatin (or cisplatin) ± paclitaxel. If it is considered in the patient’s best interest to remain within the trial and to continue to receive treatment according to the trial protocol, then significant modifications of chemotherapy dose or schedule may be required. Such extreme modifications are likely to be rare and should therefore be discussed on a case by case basis with the Lead Chief Investigators or the Trial Physician. In this situation patients may continue to receive Trial Drug (if they have received a minimum of 4 cycles of platinum chemotherapy).

Any deviation from the proposed dose modification schedule should be discussed with the Lead Chief Investigators or the Trial Physician.

ICON6


Table 5: Guidelines for Paclitaxel, Carboplatin and Cisplatin Dose Modification for Delayed Hematological Recovery n

Delayed ANC recovery (> 7 days)

Delayed PLT Recovery (> 7 days) ANC ≥ 1.5 x 109/l do ANC < 1.5 x 109/l

PLT ≥ 100 x 109/l

Paclitaxel: No modification Carboplatin: No modification Cisplatin: No modification

Paclitaxel: Either: Use G-CSF p and continue current dose Or Reduce by 1 dose level Carboplatin: Consider dose reduction by one dose level Or Use G-CSF Cisplatin: Consider dose reduction by one dose level Or Use of G-CSF

PLT < 100 x 109/l

Paclitaxel: No modification Carboplatin: Reduce by 1 dose level Cisplatin: Reduce dose by 1 dose level

Paclitaxel: Either: Use G-CSF and continue current dose Or Reduce by 1 dose level Carboplatin: Reduce by 1 dose level Cisplatin: Reduce dose by 1 dose level

n If blood counts are recovered by day 7 then no dose modification is mandated o Use day 22 ANC / PLT count if counts are not recovered by day 29 p G-CSF dose and duration of therapy should be according to local practice

ICON6


Table 6: Guidelines for Paclitaxel Carboplatin and Cisplatin Dose Modification for Dose Limiting Toxicity (DLT)

Dose Limiting Toxicity-Absolute Neutrophil Count q

Dose Limiting Toxicity-Platelets r

No Yes

No Paclitaxel: No modification Carboplatin: No modification Cisplatin: No modification

Paclitaxel: Either: Use G-CSF and continue current dose Or Reduce by 1 dose level Carboplatin: Consider dose reduction by one dose level Or Use of G-CSF Cisplatin: Consider dose reduction by one dose level Or Use of G-CSF

Yes

Paclitaxel: No modification Carboplatin: Reduce by 1 AUC Cisplatin: Reduce by 1 dose level

Paclitaxel: Either: Use G-CSF and continue current dose Or Reduce by 1 dose level Carboplatin: Consider dose reduction by one dose level Or Use of G-CSF Cisplatin: Consider dose reduction by one dose level Or Use of G-CSF

q This is defined by the occurrence of

febrile neutropenia (defined as fever with or without clinically or microbiologically documented infection with ANC less than 1 x 109/l and fever ≥ 38.5oC [CTCAEv4]) or

prolonged grade 4 neutropenia persisting ≥ 7 days There are no planned dose modifications for uncomplicated grade 4 neutropenia lasting less than 7 days.

r This is defined by the occurrence of grade 4 thrombocytopenia (defined as PLT < 25 x 109/l) or bleeding associated with grade 3 thrombocytopenia (PLT 25 – 50 x 109/l)

There are no modifications planned for uncomplicated grade 3 thrombocytopenia.

ICON6


Table 7: Dose Levels for Paclitaxel ± Carboplatin and Cisplatin s

Drug Protocol Starting Dose

Protocol Dose Level -1


Paclitaxel 175 mg/m2 135 mg/m2 110 mg/m2

Carboplatin AUC6 AUC5 AUC4.5

Carboplatin t AUC5 AUC4 AUC3.5

Cisplatin 75 mg/m2 60 mg/m2 50 mg/m2

Dose levels should be adjusted independently for each drug If there are still problems after 2 dose reductions then patients should be

discussed on an individual basis with the Lead Chief Investigator or Trial Physician

Patients may receive erythropoietin (EPO), iron supplements and/or blood transfusions as clinically indicated for the management of their anaemia.

10.3.2.2 Non Haematological Toxicity (apart from hypertension) 10.3.2.2.1 Renal toxicity-carboplatin ± paclitaxel

The combination of carboplatin ± paclitaxel, with or without cediranib, using the schedule previously described, is not directly expected to cause renal toxicity. There are therefore no specific dose modifications for renal toxicity.

The administered dose of carboplatin must however be recalculated, based on a measured GFR, for

Renal toxicity (CTC grade 2, serum creatinine >1.5 x ULN) Changes in serum creatinine of ≥ 10%, compared to their baseline serum

creatinine value or value most recently used to calculate carboplatin dose Each dose modification of carboplatin Cycle 2, if there has been significant doubt about the true GFR at cycle 1

10.3.2.2.2 Renal toxicity- cisplatin

Cisplatin produces cumulative nephrotoxicity. Renal function and serum electrolyte (magnesium, sodium, potassium and calcium) should be evaluated prior to initiating cisplatin treatment and prior to each subsequent course of therapy (For administration see section 9.3.4).

Dosage should be reduced for patients with renal impairment in line with standard local practice.

s The doses recommended for the ICON6 trial are carboplatin AUC6 (if calculated GFR used) paclitaxel 175mg/m2, however these doses may be modified at the discretion of the treating physician, as per local practice. This may therefore necessitate adjustment of dose reductions in line with this t Carboplatin dose levels if a measured GFR is used (isotopic or 24 hour urine collection)

ICON6


Special care has to be taken when cisplatin-treated patients are given concomitant therapies with other potentially nephrotoxic drugs.

10.3.2.2.3 Neuropathy

Grade 2 sensory or motor neuropathy requires paclitaxel treatment to be interrupted until neuropathy has resolved to a maximum of grade 1. On recovery paclitaxel should be reduced by 1 dose level. If this requires a delay of more than three weeks then the paclitaxel should be omitted from subsequent cycles and treatment continued with single agent carboplatin at the same AUC used in combination with paclitaxel.

Grade ≥ 3 sensory, or motor neuropathy requires paclitaxel to be omitted from subsequent cycles, and treatment continued with single agent carboplatin at the same dose as previously used.

10.3.2.2.4 Mucositis

For mucositis ≥ grade 3 then chemotherapy should be delayed until the mucositis has resolved to ≤ grade 1. Paclitaxel can be reduced by one dose level in subsequent cycles at the discretion of the treating physician. If the mucositis persists at ≥ grade 3 for more than three weeks, or recurs, then discuss chemotherapy dose modifications with the Lead Chief Investigators or the Trial Physician. Mucositis should be treated symptomatically as per standard local practice.

10.3.2.2.5 Hypersensitivity

Paclitaxel

A hypersensitivity reaction to paclitaxel is not a dose limiting toxicity.

If a hypersensitivity reaction occurs then patients may be retreated with paclitaxel. This will depend on the severity of the reaction and the specific reaction. Retreatment should be managed according to standard local practice.

In the case of recurrent hypersensitivity reactions, despite adequate premedication, the substitution of docetaxel (Taxotere) for paclitaxel is not permitted as there are limited data on the safety of this treatment with cediranib. Treatment should continue with carboplatin alone.

Carboplatin

A hypersensitivity reaction to carboplatin should be managed according to standard local practice. Patients may be retreated according to standard local practice, including escalations of hypersensitivity prophylaxis, in-patient monitoring and increases in the duration of the infusion. Cisplatin can be substituted for carboplatin. The dose and schedule of administration should be according to local practice and the usual monitoring when substituting carboplatin for cisplatin.

10.3.2.2.6 Liver toxicity

Hepatotoxicity is not expected with either chemotherapy drug. Its presence is more likely to be due to cediranib and dose adjustments should be made as outlined in 9.1.2.

ICON6


10.3.2.2.7 Other

There are no dose modifications planned for alopecia, nausea, diarrhoea or constipation. These side effects should be treated with supportive medical measures. Non-steroidal anti-inflammatory agents can be used prophylactically, or symptomatically, as per local practice.

Any CTCAE Grade 4 non-haematological adverse event (except nausea, asymptomatic thrombotic event, vomiting or alopecia) will require the patient to be taken off Trial Drug. For any Grade 3 non-haematological toxicity (except nausea or vomiting, and hypertension [see section 10.3.3.2]) the drugs should be withheld until symptoms resolve to ≤ Grade 1. If the Grade 3 event persists for ≥ 3 weeks, or recurs, then discussion with the Lead Chief Investigator, or the Trial Physician, is required.

Any patients who develop malignant effusions while on therapy may have them drained according to local practice, assuming coagulation parameters and platelet counts are appropriate.

ICON6


11 ASSESSMENTS AND PROCEDURES

All assessments and trial procedures must be performed in compliance with the most up to date version of the protocol, the principles of ICH GCP, any relevant research governance and other regulatory requirements as appropriate.

Summary information on timing of interventions and assessments for safety and efficacy are given in Table 9.

11.1 Clinical Follow up (safety and efficacy)

Patients will be seen prior to each cycle of chemotherapy, preferably on day 1 of the cycle. If this is not possible then patients can be seen up to three days prior to receiving chemotherapy. Blood tests that are required prior to cycle 1 may be taken up to 7 days prior to day 1 cycle 1 and up to 3 days prior to subsequent cycles. Following the completion of chemotherapy, blood tests may be taken at each follow up visit as long as abnormal blood test results are followed up with individual patients.

All patients who completed cycle 4 of chemotherapy and have not stopped Trial Drug due to toxicity or progressive disease (and including patients whose chemotherapy was delayed due to toxicity) will attend at week 21 (21 weeks from day 1 of cycle 1, regardless of chemotherapy delays) to return unused Trial Drug and to obtain a new supply of Trial Drug. At this point patients on Arm B will switch to placebo (but neither patient nor clinician will know which arm the patient is randomised to). Patients must then attend every 6 weeks while on Trial Drug whilst the trial remains blinded. Once the trial is unblinded, patient’s treatment with cediranib will be switched to an open label supply. For ICON6 follow up, patients may then attend every 12 weeks whilst receiving cediranib treatment. Patients must attend for a safety follow up visit 6 weeks after finishing Trial Drug/cediranib. This visit should be performed either 6 weeks after stopping Trial Drug (week 81 if stopping Trial Drug at 18 months) or prior to commencing other therapies (whichever is first). Patients who stop Trial Drug for any reason (including completion of 75 weeks of Trial Drug) will be seen every 12 weeks for the first 3 years from randomisation and then every 26 weeks (6 months) for years 4 and 5, and annually thereafter. After disease progression is documented, patients will be followed up 6 monthly for the first 5 years after randomisation and annually thereafter.

11.2 Specific Procedures for Assessing Efficacy

Progression definitions based RECIST and clinical criteria are given in Appendix 3.

11.2.1 CA125

CA125 values will not be used to determine progression. Serum CA125 will be assessed at baseline (within a 7 day period prior to first cycle of trial treatment). CA125 should be assessed by the same laboratory throughout the trial period and centres are required to submit the normal ranges for CA125 for the laboratories they use. Serum CA125 will be measured on day 1 of each cycle during the chemotherapy period and then every 6 weeks

ICON6


while on blinded treatment, 3 monthly thereafter until the end of the 3rd year, 6 monthly for the 4th and 5th year and yearly thereafter, or until protocol defined disease progression. CA125 measurement is not required following protocol defined disease progression.

11.2.2 Tumour Imaging

Tumour assessments for progression requires CT or MRI of the pelvis and abdomen. MRI scans can be used for patients who are allergic to radiographic contrast media but the same assessment technique must be used throughout the trial. Ultrasound scanning is not an acceptable substitute for CT or MRI scanning.

For all other patients, CT or MRI scans of the pelvis and abdomen should be performed at baseline and after 6 cycles of chemotherapy, and at 12 and 18 months from day 1 of cycle 1 for all patients who have not progressed by these time points. Once patients have progressed further scans are no longer required. CT or MRI scans can be performed as clinically indicated outside of the protocol schedule and should be performed to confirm clinical progression.

Table 8: Definitions of Progression

AT least ONE of: Pt with measurable

disease

Pt with non-measurable disease

ONLY At least a 20% increase in sum of LD of target lesions, compared to smallest sum LD not to baseline

X

New lesion(s) (including re-appearance of disease after CR)

X X

Unequivocal progression of existing non-target lesions (except for pleural effusion without cytological confirmation of neoplastic origin)

X X

Global deterioration in health status attributable to the disease requiring a change of therapy without objective evidence of progression

X X

Death due to disease without prior evidence of progression

X X

11.3 Procedures for Assessing Safety

Safety assessments will be performed as specified in Table 9.

Details on reporting of Serious Adverse Events are given in Section 15.

Physical examinations will be performed including an assessment of weight and vital signs (pulse rate and blood pressure). Blood tests including standard haematology (Hb, WBC, ANC, PLT), standard coagulation tests (PT or INR: if neither of these are available then APTT) and, when indicated, standard biochemistry (Na+, K+, Mg++, Ca++, Urea (BUN), creatinine, albumin, ALP, ALT (SGPT) or AST (SGOT) and bilirubin) will be performed to

ICON6


evaluate changes of these laboratory parameters. While on Trial Drug urinalysis for proteinuria (dipstick or 24 hour urine collection) will be performed at every visit.

ICON6


Table 9: Trial Assessments Schedule

Screening /Baseline Treatment Period Follow Up Visits

Day -28 to -1 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Week 21 21 Week 2722-7524

Week 81

22

6 weekly Follow-up if continuing on blinded TD beyond Week 81

All further follow up 26

Informed consent X

Demographics, medical history, height X

Physical examination including weight X X X X X X X X X X X X

ECG1 X

Vital signs (including BP)2 X X X X X X X X X X X X

Performance Status X X X X X X X X X X X X

Pregnancy test 3 X 3

Coagulation4 X X 19 X X X X X X X X X

LVEF5 X X X X

Haematology6 X X 19 X X X X X X X X X X

Biochemistry7 X X 19 X X X X X X X X X X

TSH, T48 X X X X X X X

Urinalysis X X 20 X X X X X X X X X

Platinum-based chemotherapy X X X X X X

Trial Drug9 X X X X X X X X X X X27

Tumour assessments10 X10 X10 X10 X10 X10

CA 125 X X 19 X X X X X X X X X X

Chest X-ray11 X

Concomitant medication X X X X X X X X X 25 X 25 X 25

Adverse Events X18 X X X X X X X X X23 X23 X

QoL Forms12 X X X X X X X X X X X X

Bio marker sampling13, 14 X X X X

Tumour Block14,15 X

Blood for DNA 13,16 X

Medical Resource Use 17 X X X X X X X X X X X

ICON6


1. Required at baseline, then as clinically indicated. 2. Daily home BP monitoring during first 2 cycles of chemotherapy for patients in stage 1. Home BP monitoring for other patients with hypertension G2 and above. Stage 2 patients

will have their blood pressure monitored at baseline and then weekly for the first 3 cycles, by patient self monitoring, clinic or GP as preferred by patient/clinician. If normotensive continue monitoring on day 1 of each cycle. If hypertensive blood pressure should be monitored daily until <grade 2.

3. Pregnancy test only required for fertile women of childbearing potential. 4. Coagulation (either PT, INR or aPTT) required at baseline. INR must be measured repeatedly in patients on warfarin/coumadin. 5. Left Ventricular Ejection Fraction required at baseline only in all patients who have previously received anthracyclines or chest radiotherapy. For these patients LVEF must be

repeated after cycle 3, cycle 6 and every 3 months while on Trial Drug. 6. FBC (plus differential) required during chemotherapy, within 7 days of D1 of cycle 1 and then within 3 days prior to administration of the other chemotherapy cycles. 7. Biochemistry (total bilirubin, creatinine, potassium, ALT or AST, alkaline phosphatase, calcium, phosphate, total protein, albumin). Required, during chemotherapy, within 7 days of

D1 of cycle 1 and then within 3 days prior to administration of the other chemotherapy cycles. 8. TSH/T4 required at baseline, cycle 3 and cycle 6, every 12 weeks while on Trial Drug and at each Safety Follow Up visit. 9. Trial Drug oral daily until progression, or 18 months from randomisation. If discontinuing at 18 months, the last 3 week supply will be given at week 75 10. Baseline scan (CT or MRI) to confirm recurrence, then same modality of scan within 3-6 weeks after d1, cycle 6, 12 months, 18 months and to confirm progression. The baseline

radiological imaging is required within 4 weeks of randomisation however, a six week window would be considered after discussion with the CI. If the most recent scan was done more than 6 weeks prior to randomisation then it must be repeated.

11. If baseline CXR suggests possible metastases, chest CT must be performed and measurable disease recorded according to RECIST. 12. Quality of Life forms required at baseline (prior to randomisation), on D1 of each cycle of chemotherapy, at each follow up visit while on Trial Drug, then every 3 months until 3

years from randomisation. Patients who progress within 18 months after randomisation should complete QoL forms on day 1 of the first cycle of third line chemotherapy, and at 12 and 24 months from randomisation.

13. Blood for biomarker sampling: depends on the level of participation. Blood sample at progression required for patients participating at Level 3 and above. Further information is given in Appendix 7.

14. No bloods or tumour specimens collected but patient consent for retrospective collection/later blood sampling obtained. 15. Tumour specimens from primary surgery for tissue microarrays. 16. Blood for DNA pharmacogenomics. 17. Not in stage 1. 18. Adverse events collected from consent. 19. Repeat assessments not required if already performed during previous 7 days for screening purposes. 20. Repeat assessment not required if already performed during previous 7 days for screening purposes. 21. All patients still on Trial Drug attend for change. 22. Safety follow up visit to be performed at this time, although if continuing on Trial Drug beyond week 81, this visit should be performed either 6 weeks after stopping Trial Drug or

prior to commencing other therapies (whichever is first). 23. All Adverse Events ongoing at the time of the safety follow-up visit that are judged to be related to Trial Drug should be followed until they have returned to baseline status,

stabilised, or the assessment of causal relationship has been changed. New serious adverse events judged to be related to trial treatment should be reported indefinitely. 24. 6 weekly follow up following completion of chemotherapy while on blinded Trial Drug. 25. Anticancer drugs only. 26. Prior to progression, patients should be seen 6 weekly whilst continuing on blinded Trial Drug (and 12 weekly if continuing Trial Drug on open label supply) until end of year 3,

every 6 months during years 4 and 5 and yearly thereafter (if no longer taking Trial Drug). After disease progression is documented, patients should be followed up 6 monthly during the first 5 years after randomisation and yearly thereafter.

27. Once unblinded, patients on Active Trial Drug may continue on open-label cediranib (whist supply lasts).

ICON6


11.4 Translational Research (biomarkers and pharmacogenomics)

Please refer to appendix 7 for more detailed information on the planned translational research. Although consent for sample collection will be requested for all patients in the trial, the actual collection of blood and tumour specimens will not commence until further notice is given from the MRC CTU.

Samples for translational research will only be collected from patients in participating centres who have consented separately to the translational research program.

Formalin-fixed paraffin-embedded surgical/biopsy specimens of the primary tumour and a single blood sample for DNA analysis are required at baseline for levels 1 and 2. At centres participating at level 3 or above, additional blood samples will be taken for proteomics and analysis of circulating angiogenic biomarkers. These samples are required prior to commencement of cycle 1, before cycles 2 and 6 and at documentation of disease progression (see Table 8). If LDH levels are routinely measured according to local practice, they will be recorded in the CRF for TR purposes.

Further details on the planned timing of samples can be found in Appendix 7. Detailed information on the processing, labelling, handling, storage and shipment of these specimens will be provided in the ICON6 translational research manual when specimen collection starts.

11.5 Quality of Life Assessment

Completion of QoL forms (OV-28 and EQ-5D) should occur before medical assessments are performed, or chemotherapy is administered. The first form that is required is at screening, after consent to participate has been given and prior to randomisation, as a baseline measurement. The QoL form should be completed at the onset of every chemotherapy cycle, then every 6 weeks while on blinded Trial Drug and then every 3 months (21, 24, 27, 30, 33 and 36 months after randomisation) until progression. Patients who progress within 18 months after randomisation should complete a QoL form on day 1 of the first cycle of third line chemotherapy and at 12 and 24 months from randomisation.

QoL forms should be completed without conferring with friends or relatives and patients should be encouraged to answer all questions, even if they feel irrelevant. The form should be checked to ensure that the dates of completion and patient identifiers are correct. The questionnaire should not be taken away to be completed at home. Patients should complete the QoL form on their own, whilst waiting to be seen in the clinic, prior to clinical assessment and any treatment, in a quiet area if possible. The patient should be offered an envelope in which the questionnaire can be sealed if the patient wishes to keep the information on the form confidential.

The clinician or nurse in charge of the patient should collect the envelope before the patient leaves and should be available to answer questions regarding the form if the patient wishes.

11.6 Trial Closure

Follow up as per protocol schedule should continue for all patients as there are still a large number of death events to be observed, and a fuller picture of the effect of cediranib should emerge with time. Sites will be informed when sufficient death events for a further overall survival analysis have been observed. Further observational follow-up of all patients enrolled in the trial may continue indefinitely. This will initially be via hospitals and clinics, but in the longer term may exploit national registers.

ICON6


12 WITHDRAWAL OF PATIENTS AND LOSS TO FOLLOW UP

In consenting to the trial, patients are consenting to trial treatment, trial follow-up and data collection. If a patient wishes to withdraw from trial treatment, centres should nevertheless explain the importance of remaining on trial follow-up, or failing this of allowing routine follow-up data to be used for trial purposes.

12.1 Withdrawal from trial intervention

A patient may withdraw, or be withdrawn, from trial treatment for the following reasons:

Progression whilst on therapy Unacceptable toxicity Intercurrent illness which prevents further treatment Withdrawal of consent for treatment by the patient Any alterations in the patient’s condition which justifies the discontinuation of

treatment in the investigator’s opinion

The patient should however remain in the trial for the purposes of follow-up (to assess disease progression) and data analysis.

12.1.1 Following Withdrawal from Trial Intervention

Rebound Ascites and pleural effusions. There have been reports of a “rebound” phenomenon with rapid accumulation of ascites and pleural effusions following the termination of VEGF inhibitors. This is thought to be a physiological response to vasodilatation and subsequent vascular pressure changes following removal of VEGF inhibition and is not malignant disease progression. It is likely to occur within a few weeks of stopping treatment with a VEGF inhibitor. In ICON 6 rebound serous effusions might be confused with disease progression in patients who stop cediranib treatment. This is of particular concern in patients in Arm B where there is a switch from concurrent cediranib and chemotherapy to placebo maintenance (though investigators will be unaware of which patients this applies to) and in patients who complete the full course of trial treatment. If pleural effusions or ascites develop in the absence of clinical disease progression (i.e. no evidence of new disease and stable existing lesions) then the serous effusions should be investigated further. In the first instance, repeat imaging is advised in a further 4 weeks, either CXRs or CT scan in addition to clinical assessment. At this stage, if the serous effusions are the only anomaly and persist in the absence of other signs of clinical progression, this can be considered ‘rebound phenomena’. If there is doubt over the cause of ascites/pleural effusions, then aspiration should be performed to ascertain cytological diagnosis. (It should be noted that there is a higher risk of haemorrhage with cediranib therefore aspiration should be performed under radiological guidance where possible.)

ICON6


12.2 Withdrawal of Consent

Patients may withdraw their consent to participate in the trial.

If the patient explicitly states their wish not to contribute further data to the trial, the relevant GCIG participating group and MRC CTU should be informed in writing and the withdrawal of consent should be documented by the investigator in the patient’s case report form. However, data up to the time of consent withdrawal will be included in the data reported for the trial.

12.3 Patient Transfers

For patients moving from a particular area, every effort should be made for them to be followed-up at another participating trial centre and for this trial centre to take over responsibility for the patient, or for follow-up to continue via other health care professionals e.g. General Practitioner. Details of other participating GCIG groups and clinical centres can be obtained from the MRC CTU.

A copy of the patient CRFs will need to be provided to the new site. The patient will have to sign a new consent form at the new site, and until this occurs, the patient remains the responsibility of the original centre.

The consent of patients will be sought for their names to be flagged for survival information through national registries. If the investigator moves then appropriate arrangements should be made to arrange for trial follow-up to continue at the centre.

12.4 Loss to Follow-Up

Every effort should be made to follow-up patients who have been randomised. Patients should, if possible, remain under the care of an oncologist or gynaecologist for the duration of the trial. If the care of a patient is returned to the General Practitioner, it is still the responsibility of the investigator to ensure that the follow-up data required by the protocol is collected and reported.

ICON6


13 STATISTICAL CONSIDERATIONS

13.1 Method of Randomisation

Patients will be randomly assigned in a 2:3:3 ratio to Arm A, Arm B or Arm C using stratified block randomisation stratifying for the following factors: GCIG group, planned chemotherapy regimen (carboplatin/cisplatin vs carboplatin/cisplatin+paclitaxel vs carboplatin/cisplatin+gemcitabine), first line chemotherapy (paclitaxel vs no paclitaxel), duration of relapse free interval (6-12 months vs >12 months), and any VEGF inhibitors previously received (yes vs no).

13.2 Outcome Measures

The outcome measure in the first stage is safety of the research treatments. The primary outcome measure for the second stage of the trial is Progression Free Survival (PFS). The outcome measures for each stage are summarised in Table 10:

Table 10: Outcome measures of ICON6 stages

First Stage Primary outcome measure Safety

Second Stage Primary outcome measure



Overall Survival (OS) Toxicity Quality of Life (QoL)

There may also be an ancillary study associated with ICON6, in

Translational (Biomarker) Research (TR): patients consented to retrospective sample collection if funding for the research can be obtained

13.3 Sample Size

The first stage plan was to randomise 33 patients and this stage was completed in December 2009. The second stage plan was modified as of October 2011 in light of the discontinuation of commercial development of cediranib. The revised sample size of 470 patients will include 440 patients randomised since the protocol was amended to a 20mg dose of cediranib and these will be the patients included in the formal analyses. Following 1 year of follow up, the trial is designed to detect a hazard ratio of 0.65 in PFS between Arm A (reference arm) and Arm C, with a 5% significance level, at least 80% power requiring a total of 176 events on Arms A and C. This plan was further revised in October 2012, as the required number of 176 progressions was imminent. It was recognised that there would remain a substantial proportion of patients who were continuing to receive maintenance therapy as they had not yet experienced disease progression. As a previous trial had been criticised for analysing whilst a substantial number of patients remained on trial drug, the plan was updated, independently of any accumulating outcome data in ICON6, and the analysis was delayed until approximately 5% of patients, or fewer, remained on cediranib. A number of events over and above the targeted sample size is expected and will only serve to increase the power of the primary comparison.

ICON6


As there are still large a number of death events to be observed, a further secondary endpoint analysis is planned as a fuller picture of the effect of cediranib should emerge with time. First Stage The first stage was conducted in selected centres only and confirmed the safety of using cediranib. The analysis was conducted when approximately 33 patients in total on the two cediranib Arms (B+C) completed 3 cycles of chemotherapy.

The primary outcome measure in stage 1 was safety. Although all toxicities were considered, particular consideration was given to CTCAE grade 3 and 4 toxicities that appear to be associated with cediranib including severe, uncontrolled hypertension, grade 3 fatigue and diarrhoea, or events that required dose reduction or discontinuation of Trial Drug. There was no evidence that the grade 3 and 4 adverse event rates exceeded 15% of patients (this would have been if more than 10 of the 33 patients on Trial Drug experienced these events) for any of these events and so the trial continued to stage 2.

Second Stage

For the final analysis, an analysis of the efficacy of cediranib will be performed with PFS as the primary outcome measure.

The structure of planned comparisons is

Arm A vs Arm C (reference arm vs concurrent and maintenance arm)

Exploratory analyses will include:

Arm A vs Arm B (reference arm vs concurrent arm) Arm B vs Arm C (if first two comparisons are positive: concurrent arm vs

concurrent and maintenance arm)

The justification for a comparison of the A vs C arms was due to benefit from bevacizumab being seen predominantly in trial arms that included the angiogenesis inhibitor as maintenance therapy[44]. This is the basis for prioritising the A vs C comparison as the largest effect size is anticipated. A comparison of arms A vs B will still be analysed but in an exploratory manner. A gain in power is achieved by the targeting of a reduced HR and not adjusting the alpha level.

13.4 Interim Monitoring and Analyses

An Independent Data Monitoring Committee (IDMC) will review data, unblinded by treatment group, on patients in the trial. The IDMC will meet approximately every 6 months during the accrual period. The first interim analysis will be performed when approximately 33 patients on the two cediranib Arms (B+C) have completed 3 cycles of chemotherapy if it occurs before the first scheduled 6 monthly IDMC meeting.

At each meeting, the IDMC will be asked to give advice on whether the accumulated data from the trial, together with results from other relevant trials, justifies continuing recruitment of further patients or further follow-up. A recommendation to discontinue recruitment, in all patients or in selected subgroups will be made only if the result is likely to convince a broad range of clinicians including participants in the trial and the general clinical community. If a recommendation is made to continue, the IDMC will advise on the frequency of future

ICON6


reviews of the data on the basis of accrual and event rates. The IDMC will make recommendations to the Trial Steering Committee as to the continuation of the trial.

13.5 Brief Analysis Plan

Analyses will be performed on an intention-to-treat basis. Progression-free survival (PFS) is calculated from the date of randomisation to date of first progression or death from any cause, whichever occurs first. If neither event is observed at the time of analysis, patients are censored at the date of last follow-up. Overall survival (OS) is calculated from the date of randomisation to date of death from any cause. Patients who are still alive at the time of analysis are censored at the date last known to be alive. The standard non-stratified log-rank test will be applied in the primary analysis for PFS and OS. Cox model analyses adjusting for patient baseline characteristics will also be performed for PFS and OS. Subgroup analysis by patient baseline characteristics on PFS and OS will be performed in an exploratory manner. Toxicity will be measured using the NCI Common Toxicity Criteria Adverse Events (CTCAE) (version 4) and the Mann-Whitney test will be used in the comparison.

A detailed analysis plan will be available on request. At the end of the trial, AstraZeneca will receive a copy of trial data.

ICON6


14 TRIAL MONITORING

14.1 Risk Assessment

The MRC CTU has performed a risk assessment to assess the impact of trial participation on the rights and safety of patients, the reliability of trial results and the impact of trial results on the research institution leading the trial. This has guided the development of procedures in the trial with respect to informed consent, confidentiality, trial monitoring and audit.

14.2 Monitoring at the MRC CTU

The MRC CTU will conduct day-to-day central monitoring of the trial. MRC CTU staff will:

Perform visual checks that CRFs are completed with no missing items or obvious inconsistencies

Check that CRFs are completed by authorised persons Perform data entry and check random 10% for errors Program database plausibility checks for validity and consistency of data Identify missing or inconsistent data and follow up with groups/sites for resolution by

performing data compliance checks approximately every 2-3 months Identify and address random or systematic errors which arise and review recruitment

rates Review copies of centrally requested source documents (e.g. pathology, patient

diaries, CT/MRI scan reports, Drug accountability records) to verify data consistency, completion and validity with CRF data when necessary.

14.3 Clinical Site Monitoring

Clinical site monitoring will be performed according to the ICON6 Monitoring Plan.

GCIG groups will be advised to visit all sites at least once during the trial (however this will be discussed on an individual country basis); priority will be given to high recruiters or those with data compliance issues.

Monitors will verify adherence to the protocol and the completeness, consistency and accuracy of the data being entered on Case Report Forms (CRFs). Any data recorded directly on the CRFs (i.e. no prior written or electronic record of data), may be considered to be source data.

Monitors will require access to all patient medical records including, but not limited to, laboratory test results and surgery, pathology and radiology reports and supporting documents. Monitors will also require access to pharmacy records relating to Trial Drug (including receipt, dispensation and inventory documentation). The principal investigator (or deputy) should work with the monitor to ensure that any problems detected are resolved.

14.4 Data Quality Assurance

The data collected will be entered into the trial database from the original CRF received from the site. The site will retain a copy of the CRF.

ICON6


All data recorded in each patient’s CRF will be entered onto the ICON6 clinical trial database at the MRC CTU.

A comprehensive validation check program will identify illogical and/or inconsistent data, data chases will be performed every 2-3 months approximately. Trained data management personnel will review validation check reports, correcting any data entry errors. If investigator input is required to clarify or correct any missing, ambiguous or inconsistent data, the data manager will generate a Data Query Form (DQF). The data manager will send this form to the relevant GCIG group, who will forward it to the investigator for completion. When the completed DQF is returned to the data manager, the data on the clinical database will be corrected accordingly.

Data compliance tables will be run from the database approximately every 2-3 months which will detail by site; number of patients randomised, number and percentage of missing forms. See Data Management Plan and Compliance Policy for further information.

14.5 Confidentiality of Trial Documents and Patient Records

The investigator must assure that patient's anonymity will be maintained and that their identities are protected from unauthorised parties. Patients will not be identified on CRFs by their names, but by an identification code. The investigator should keep a patient enrolment log showing codes, names and addresses.

ICON6


15 SAFETY REPORTING

ICH GCP requires that both investigators and sponsors follow specific procedures when reporting adverse events/reactions in clinical trials. These procedures are described in this section of the protocol. ICON6 is a double-blind, placebo controlled trial. All SAE and AE assessments of causality and expectedness will be made by the investigator whilst blind to patient’s actual treatment.

15.1 Definitions of Adverse Events/Reactions

The definitions from ICH GCP apply in this trial protocol. These definitions are given in Table 11.

Table 11: Definitions of Adverse Events/Reactions

Term Definition Adverse Event (AE) Any untoward medical occurrence in a patient or clinical trial

subject to whom a medicinal product has been administered including occurrences which are not necessarily caused by or related to that product.

Adverse Reaction (AR)

Any untoward and unintended response to an investigational medicinal product related to any dose administered.

Unexpected Adverse Reaction (UAR)

An adverse reaction, the nature and severity of which is not consistent with the medicinal product in question set out in the summary of product characteristics (or Investigator brochure) for that product.

Serious Adverse Events (SAE) or

Serious Adverse Reactions (SAR) or

Suspected Unexpected Serious Adverse Reaction (SUSAR)

Respectively any adverse event, adverse reaction or unexpected adverse reaction that:

results in death is life-threatening u requires hospitalisation or prolongation of existing

hospitalisation v results in persistent or significant disability or incapacity consists of a congenital anomaly or birth defect other important medical condition

Medical judgement should be exercised in deciding whether an AE/AR is serious in other situations. Important AE/ARs that are not immediately life-threatening or do not result in death or hospitalisation but may jeopardise the subject or may require intervention to prevent one of the other outcomes listed in the definition above, should also be considered serious.

u The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe

v Hospitalisation is defined as an inpatient admission, regardless of length of stay, even if the hospitalisation is a precautionary measure for continued observation. Hospitalisations for a pre-existing condition (including elective procedures that have not worsened) do not constitute an SAE

ICON6


15.2 ICON6 Specific Exceptions to Seriousness Criteria

The following events, in the context of this trial, should not be considered as SAEs. No SAE form is required and they are exempt from expedited reporting. They must be recorded on the appropriate CRF as detailed in the CRF completion guidelines.

Disease progression or death as a result of disease progression Elective hospitalisation and surgery for treatment of ovarian cancer, primary serous

peritoneal cancer, fallopian tube cancer or its complications Elective hospitalisation to simplify treatment or procedures Elective hospitalisation for pre-existing conditions that have not been exacerbated by

trial treatment

15.3 ICON6 Notable Events

The following events are regarded as notable events in ICON6 and should be notified to the MRC CTU within one working day using the Serious/Notable Adverse Event Reporting Form: It should be specified whether an event is regarded as a SAE or a notable event:

New cases of Grade 3 hypertension if 2 or more drugs have been used and blood pressure is not responding within 48 hours, which occur up to 4 weeks after stopping Trial Drug for any reason.

All grade 4 hypertension, that occurs up to 4 weeks after stopping Trial Drug for any re

All grades of gastro-intestinal perforation which occur up to 4 weeks after stopping Trial Drug for any reason.

15.4 Clinical trial site/Investigator Responsibilities

SAEs/SARs should be notified to the MRC CTU as described in 14.6. All non-serious AEs/ARs, whether expected or not should be recorded in the toxicity

(symptoms) section of the appropriate CRF. The severity (i.e. intensity) of all AEs/ARs (serious and non-serious) in this trial

should be graded using Common Terminology Criteria for Adverse Events (CTCAE) v4.0 (see CRF booklet for selected categories or http://ctep.cancer.gov/reporting/index.html for a full list)

A flowchart (Figure 2) is given at the end of this section to help explain the notification procedures. Any questions concerning this process should be directed to the MRC CTU and/or GCIG Group in the first instance.

15.5 Investigator Assessment

15.5.1 Seriousness Assessment

When an AE/AR occurs the investigator responsible for the care of the patient must first assess whether the event is serious using the definitions given in Table 11. If the event is serious and not exempt from expedited notification, then an SAE form must be completed and faxed to MRC CTU and/or the relevant GCIG group (see Table 13).

ICON6


15.5.2 Causality and Expectedness Assessment

The Investigator must assess the causality (relatedness) of all serious adverse events in relation to all trial therapy (chemotherapy and Trial Drug) using the definitions in Table 12. Expectedness (i.e. whether the event is included in the list of expected toxicities) should be assessed in relation to all trial therapy (chemotherapy and Trial Drug) when the causality is assessed as either possibly, probably or definitely related.

While the safety of patients in the ICON6 trial should always take priority, maintenance of blinding is crucial to the integrity of the trial. Investigators should only break the blind allocation when information about the patient’s treatment is necessary for the appropriate medical management of the patient, not for reporting purposes. Investigators should therefore evaluate the causality and expectedness of all serious events / reactions as though the patient was on active Trial Drug (cediranib).

Please see section 10.2 for unblinding procedures.

There are 5 causality categories: unrelated, unlikely, possible, probable and definitely related. If the causality assessment is unrelated or unlikely to be related then for reporting purposes the event will not be regarded as an adverse reaction to trial therapy. If the causality is assessed as either possibly, probably or definitely related, then for reporting purposes the event is classified as a potential SAR.

If the event is a possible SAR the Investigator must also assess the expectedness of the event. Please see the Investigator File for a list of expected toxicities associated with each of the drugs used in ICON6. These are based on information in the SPCs for carboplatin and paclitaxel and the IB for cediranib. If a possible SAR is assessed as being unexpected it becomes a possible SUSAR.

Table 12: Definitions of Causality

Relationship Description Event Type Unrelated There is no evidence of any causal relationship SAE Unlikely There is little evidence to suggest there is a causal

relationship (e.g. the event did not occur within a reasonable time after administration of the Trial Drug). There is another reasonable explanation for the event (e.g. the patient’s clinical condition, other concomitant treatment)

SAE

Possible There is some evidence to suggest a causal relationship (e.g. because the event occurs within a reasonable time after administration of the Trial Drug). However, the influence of other factors may have contributed to the event (e.g. the patient’s clinical condition, other concomitant treatments)

SAR

Probable There is evidence to suggest a causal relationship and the influence of other factors is unlikely

SAR

Definitely There is clear evidence to suggest a causal relationship and other possible contributing factors can be ruled out

SAR

ICON6


15.6 Notification

Investigators must notify the MRC CTU (and relevant GCIG group if required) of an event that requires expedited notification within one working day of becoming aware of the event. This includes all serious and notable adverse events occurring from the time of consent up until 4 weeks after stopping Trial Drug for any reason. Even when protocol treatment has stopped, new serious reactions (possible SARs and SUSARs) thought to be related to second-line chemotherapy and ICON6 Trial Drug must be notified indefinitely.

Notification Procedure:

1. The SAE form must be completed by the Investigator (consultant named on the signature list and delegation of responsibilities log who is responsible for the patient’s care), with due care being paid to the grading, causality and expectedness of the event as outlined above. In the absence of the responsible investigator the form should be completed, signed and faxed by a member of the site trial team. The responsible investigator should subsequently check the SAE form, make changes as appropriate, sign and then re-fax to MRC CTU or GCIG group (see Table 13) as soon as possible. The initial report shall be followed by detailed, written reports as appropriate.

2. Initial SAE reports must be faxed to the contacts shown in Table 13 within one working day of the investigator’s knowledge of the event.

3. Follow-up: Patients must be followed-up until clinical recovery is complete and laboratory results have returned to normal or baseline, or until the event has stabilised. Follow-up should continue after completion of protocol treatment if necessary. Follow-up information should be noted on a further SAE form by ticking the box marked ‘follow-up’ and faxing to the MRC CTU and/or GCIG group as information becomes available. Extra, annotated information and/or copies of test results may be provided separately. The patient must be identified by trial number, date of birth and initials only. The patient’s name should not be used on any correspondence.

Table 13: SAE Notification Procedure

Country (Group) Clinical Sites Procedure

Australia/New Zealand (ANZGOG) Notify MRC CTU by FAX: +44 (0) 20 7670 4818

Canada (NCIC-CTC) Clinical Sites: By fax to NCIC-CTG office on +613 533 2941

NCIC office: Notify MRC CTU by FAX on +44 (0) 20 7670 4818

Spain (GEICO) Notify MRC CTU by FAX: +44 (0) 20 7670 4818

UK (MRC/NCRI/SGCTG) Notify MRC CTU by FAX: +44 (0) 20 7670 4818

15.7 MRC CTU Responsibilities

Medically qualified staff at the MRC CTU and/or the Chief Investigator (or a medically qualified delegate) will review all SAE reports received. The causality assessment given by the local Investigator at the hospital cannot be overruled and in the case of disagreement, both opinions will be provided in any subsequent reports.

MRC CTU staff not involved in the day to day running of the trial will be responsible for unblinding possible SUSARs and notable events for expedited reporting.

ICON6


The MRC CTU is undertaking the duties of trial sponsor with respect to reporting of SUSARs, notable events and other SARs directly to the UK regulatory authority and MHRA and UK research ethics committees as appropriate.

All GCIG groups and AstraZeneca will be provided with the reports that they need to make the necessary regulatory and ethics committee submissions for their country (unless agreed that the MRC CTU will make these submissions).

The MRC CTU will also keep the Chief Investigators in each GCIG group informed of any safety issues that arise during the course of the trial, and through the GCIG groups will ensure that all other investigators are informed.

ICON6


No

No

Unlikely Not related

Yes

Yes

No

Expected

Figure 2: Adverse Event assessment and notification flow chart

Adverse Event/Adverse Reaction

Was the event listed as a notable event? or Was the event serious?

Resulted in death Life-threatening Required inpatient hospitalisation or prolongation of existing

hospitalisation Persistent or significant disability/incapacity Congenital anomaly/birth defect other important medical condition

Was the SAE specified in the protocol as being exempt from expedited reporting?

Causal relationship to protocol medication?

Was the SAE one of the recognised undesirable effects of the trial medication?

SUSAR Record on an SAE form. Notify MRC CTU and/or GCIG Group within one working day of becoming aware of the event

SAR Record on an SAE form. Notify MRC CTU and/or GCIG Group within one working day of becoming aware of the event

Unexpected

Exempt SAE Record on the appropriate CRF

AE/AR Record on the appropriate CRF

SAE Record on an SAE form. Notify MRC CTU and/or GCIG Group within one working day of becoming aware of the event

Definitely, Probably, Possibly

CRF: Case Report From SAE: Serious Adverse Event AE: Adverse Event SAR: Serious Adverse Reaction AR: Adverse Reaction SUSAR: Suspected Unexpected Serious Adverse Reaction

ICON6


16 ETHICAL CONSIDERATIONS AND APPROVAL

16.1 Ethical considerations

This is a randomised trial. Neither the patient nor the physician will be able to choose the patient’s trial treatment which will be allocated randomly using a computer-based algorithm. This is to ensure that the groups of patients allocated to the different treatment arms are as similar as possible. Patients in all arms of the trial will receive standard treatment with platinum-based chemotherapy and have access to all other supportive care. The only difference in the reference and experimental arms is whether patients also receive the experimental drug cediranib and for what duration.

After unblinding, patients who have not progressed at 18 months from randomisation can continue cediranib until progression, if in the opinion of the clinician there is continuing clinical benefit (whilst supply lasts). As AstraZeneca have discontinued the development of cediranib it will not be possible to supply cediranib indefinitely.

Patients who have not progressed at 18 months from randomisation can continue Trial Drug until progression, if in the opinion of the clinician there is continuing clinical benefit (whilst supply lasts)

Patients in this trial will be subject to more intensive monitoring and follow-up than in routine clinical practice. This is to ensure that the safety of patients in the trial can be closely monitored and has been balanced against the potential benefit of cediranib.

The trial is placebo-controlled to ensure that all patients in all arms are managed and all outcome measures assessed in an unbiased manner, that is, without knowledge of allocated treatment arm. In the event of a medical emergency in an individual subject, in which knowledge of the investigational product is critical to the subject's management, the blind for that subject may be broken by the treating physician. There is no reason to believe that any patient treated on the trial will receive substandard therapy.

Participating GCIG groups have been allocated per-case funding for national coordination and for re-imbursement of excess costs of participating in the trial to clinical sites. Per-case funding can be used to meet patients’ excess travel costs associated with participation in the trial depending on local practice.

The trial will abide by the principles of the Declaration of Helsinki (2008).

The MRC CTU is registered under the UK Data Protection Act to hold data as required for trial purposes. Trial databases will be held by MRC CTU and the external provider of the web based randomisation and drug supply management system (CLINPHONE/PERCEPTIVES) who will be acting on behalf of the MRC CTU and who also have the necessary approvals to hold data. Patients will be allocated a unique trial number that will link all of the clinical information held about them on the trial databases. It will also be used in all correspondence with participating clinical trial sites. At no point in presentations or publications of trial data will individual patients be identified.

16.2 Ethical approval

The protocol has the appropriate national ethics committee approval for the countries in which it will be conducted.

ICON6


Prior to allowing randomisation of any patient each clinical centre must obtain local research ethics approval including approval of the local patient information sheet. The centre must provide a copy of local approvals (research and development, ethics approval and copy of the local PIS and CF on local headed paper)

Each patient’s consent to participate in the trial should be obtained after a full explanation has been given of the treatment options, including the conventional and generally accepted methods of treatment.

ICON6


The right of the patient to refuse to participate in the trial without giving reasons must be respected. After the patient has entered the trial, the clinician must remain free to give alternative treatment to that specified in the protocol, at any stage, if he/she feels it to be in the best interest of the patient. However, the reason for doing so should be recorded and the patient will remain within the trial for the purpose of follow-up and data analysis according to the treatment option to which they have been allocated. Similarly, the patient must remain free to withdraw at any time from the protocol treatment and trial follow-up without giving reasons and without prejudicing his/her further treatment.

A statement of the MRC policy on ethical considerations in clinical trials of cancer therapy, including the question of informed consent, is available from the MRC Head Office web site (http://www.mrc.ac.uk).

ICON6


17 REGULATORY APPROVAL This trial has been registered in the UK with the MHRA and has been granted a Clinical Trial Authorisation (CTA). The CTA reference is 2007-001346-41. The trial will also be registered with other relevant regulatory authorities in EU countries, Canada and Australasia. Investigators may not enrol patients to this trial without:

The necessary notification or approval of the protocol and any amendments by the competent authorities of their country (in accordance with local regulations).

The approval of the protocol and any amendments by their Ethics

Committee/Institution Review Board (in accordance with local regulations).

ICON6


18 SPONSORSHIP AND INDEMNITY

ICON6 is a GCIG trial. The trial will be performed in accordance with the national laws and regulations of the countries in which it is being performed and applicable European laws and regulations. The MRC/NCRI is acting as the lead GCIG group and MRC, as an employer of the staff co-ordinating the trial at the MRC CTU, on behalf of the lead group, is the overall Sponsor of the trial worldwide. Where national laws require it, a legal representative of the participating GCIG group will be appointed who will fulfil the functions of sponsor in that country.

MRC is not allowed to purchase advance insurance to cover indemnity because they are backed by the resources of the UK treasury which covers patients entered from UK sites.

Within the UK, MRC will give sympathetic consideration to claims for non-negligent harm suffered by a person as a result of a trial or other work supported by the MRC. This does not extend to non-negligent harm arising from conventional treatment where this is one arm of a trial. Where studies are carried out in a UK hospital, the hospital continues to have a duty of care to a patient being treated within the hospital, whether or not the patient is participating in an MRC supported trial. MRC does not accept liability for any breach in the hospital's duty of care, or any negligence on the part of employees of hospitals.

MRC, as overall sponsor is responsible for ensuring that for each GCIG group there are appropriate arrangements for indemnity and/or clinical trial insurance as required by national regulatory authorities. Insurance certificates should be held for all GCIG groups where insurance is required under national laws. MRC will ensure that this is in place before a group is allowed to begin randomising patients.

ICON6


19 ANCILLARY STUDIES

19.1 Translational Research (pharmacogenomics and predictive biomarkers)

The ancillary translational research studies aim to assess whether biomarkers can be identified to predict which patients will benefit most from cediranib and also to identify markers of early disease progression so that in the future early changes in management can be instituted. A tissue microarray will be created from formalin-fixed paraffin-embedded sections of primary tumour specimens from each patient enrolled in the translational research studies. This will be used to assess expression of standard prognostic markers and putative biomarkers of angiogenesis. Patient consents for collection and analysis of samples of tumour from primary surgery will be collected for all patients randomised from stage 1 onwards but tissue collection will not commence until the final stage.

In the final stage, in selected centres where the necessary ethical approvals have been obtained and where there are appropriate facilities for handling and storage of specimens, blood and tumour DNA will be collected at baseline and used for single nucleotide polymorphism (SNP) analyses to try to identify the genes that control response to therapy and its side-effects, and potentially also susceptibility to the disease.

In a proportion of centres with appropriate storage/processing facilities (Level 3 and above, see Appendix 7), plasma/serum samples will be collected at baseline, during treatment and at disease progression, or 5 years from the start of treatment (whichever occurs first), for proteomic analyses and to assess levels of circulating angiogenic biomarkers.

Detailed information on sample timing, processing, labelling, handling, storage and shipment of these specimens is given in Appendix 7 and in the Translational Research Manual which will be provided when specimen collection starts.

19.2 Quality Of Life

The impact of each treatment arm on QoL will be explored. The EORTC QLQ OV-28 instrument (which incorporates the EORTC QLQ C-30) will be used as validated questionnaires are available in local languages of patients enrolled in the trial. The main focus of the quality of life study will be on the symptoms related to epithelial ovarian or primary serous peritoneal carcinoma and their treatments, and questions on overall health and overall quality of life.

An explanation sheet for clinicians about the use of the QoL forms is given in Appendix 8, and an explanation sheet for patients accompanies the ICON6 patient information sheet.

ICON6


20 FINANCE

ICON6 is a Gynaecologic Cancer Intergroup trial. The MRC/NCRI Group is the lead group. The trial will be coordinated at and by the MRC Clinical Trial Unit in London. The trial has public funding from the UK Clinical Trials Awards and Advisory Committee, and will also be supported by Medical Research Council core funding. AstraZeneca will provide clinical trial supplies of cediranib and placebo and some research funding to offset the costs of the research.

ICON6


21 TRIAL COMMITTEES

ICON6 is undertaken in accordance with the principles of ICH GCP. Figure 3 shows the relationships between the various trial committees.

The Lead Chief Investigator (CI) and the MRC CTU are responsible for the day to day running of the trial as detailed in trial SOPs. The MRC CTU will in addition prepare reports for the TMG, TSC and IDMC, including interim analysis, and will make safety and progress reports to the Main Research Ethics Committee (MREC) and Medicines and Healthcare products Regulatory Agency (MHRA) and to GCIG groups for their regulatory and ethics requirements as needed.

GCIG ICON6 International Trial Management Group (TMG) will meet by teleconference as required and will aim to meet in person at least once per year. The TMG will advise the Lead CI and MRC CTU in the promotion and running of the trial. TMG members will on a regular basis review serious adverse events which have occurred in the trial. If there are specific safety concerns these may be raised with the TSC and IDMC. TMG members will include active trial investigators who represent their GCIG group and members with specific interests (e.g. pharmacist; nurse, user representatives).

GCIG ICON6 TMG subgroups. TR, HE and QOL subgroups will meet as needed and report to the ICON6 TMG

Independent Trial Steering Committee (TSC). The MRC Gynaecology Trial Steering Committee is independent of investigators and the MRC CTU. It will provide overall supervision of the trial. It will meet at least annually, and will receive reports from the MRC CTU, CI and IDMC.

Independent Data Monitoring Committee (IDMC) is independent of investigators and the MRC CTU. The group will meet every 6 months while patients are receiving trial treatment. The IDMC will review reports from the MRC CTU and give advice on continuing recruitment. No formal stopping rules for efficacy are planned. The IDMC will make recommendations to the TSC as to the continuation of the trial. A copy of the IDMC charter is available from the MRC CTU on request. Details of data that will be provided to the IDMC at their meetings and monitoring are provided in the IDMC charter.

ICON6


Figure 3: Diagram of relationships between trial committees

TrialsUnit

TrialsUnit

DMC: Data Monitoring Committee

TSC: Trial Steering

Committee

TMG: Trial Management

Group

Participating centres

DMC feedback to TSC & TSC response to DMC

via Trials Unit

DMC feedback to TSC & TSC response to DMC

via Trials Unit

Report from Trials Unit

Question & Feedback

Trial expert panels

Sponsor/Funder

Report from Trials Unit

Question & Feedback

*The Trial Management Core Team will be made up of the Chief investigators and the MRC CTU ICON6 Clinical Operations Team.

ICON6


22 PUBLICATION

The results from all GCIG groups will be analysed together.

Individual clinicians or Groups must not publish data concerning their patients that are directly relevant to questions posed by the trial until the report on the trial is published. The Trial Management Group will form the basis of the Writing Committee and advise on the nature of publications. All requests for data will be approved by the TSC.

All publications shall include a list of participants. For the main ICON6 publication and for other publications where there are no named authors, the paper will be published in the name of the ICON6 GCIG collaborative groups and members of the writing committee will be identified. If, on other publications, there are named authors these should include the trial’s Chief Investigator(s), Clinical Trial Manager(s), Lead Scientist (s) and Statistician(s) involved in the trial.

The members of the TSC and IDMC should be listed with their affiliations in the Acknowledgements/Appendix of the main publication.

ICON6


23 PROTOCOL AMENDMENTS Please check with the relevant GCIG group that you are using the most recent version of the ICON6 clinical protocol. Protocol version 1.0 (30th April 2007) was submitted to EudraCT as part of the Clinical Trial Authorisation Application. Minor, non-substantial changes were made to make version 2.0 (12th June 2007): submitted as part of the National Research Ethics Service application. Protocol Version 2.1 (13th July 2007) and Protocol version 2.2 (20th August 2007) were submitted as non-substantial amendments. Changes were minor consisting of altering language to make sections more accurate and concise. This also included updated information regarding concomitant medications; addition of stratification factor. A substantial amendment to the CT Application (7th Nov 2007) was made to revise the medical physics risk assessment in proportion to an increase in dose constraint for the trial. The original assessment adopted a dose constraint based on the national survey of a standard diagnostic CT procedure. Further information from centres proposed to be included in the trial indicated that the CT protocol is more complex and therefore may result in a higher dose. Therefore the amendment constituted an increase in the dose constraint for the trial. Protocol versions 3.0 (05/11/2008) and 4.0 (17/11/2008) were submitted for Ethical and Regulatory approval but were subsequently withdrawn due to errors in tracked changes. These versions were not circulated to Investigators. Protocol version 5.0 (03/12/2008) was submitted to Ethics and MHRA as a substantial amendment as a result of a TMG decision that it is in the best interests of the patients to reduce the initial dose of Trial Drug to 20mg to bring the trial in line with the other trials in the cediranib development program. The investigator brochure was also updated with the following information - "The following results of laboratory tests have been observed in some patients taking cediranib: a decrease in platelets (which are blood cells involved in clotting) and an increase in liver enzymes (that are used to manage your liver function)." Protocol version 6.0 (25/02/2010) was submitted to ethics and MHRA as a substantial amendment as a result of an update to the Investigator Brochure and updates to management of asymptomatic thrombotic embolisms, unblinding post progression, updates to scheduling in the trial, an appendix allowing the use of gemcitabine and platinum chemotherapy and the inclusion of patients remaining on Trial Drug beyond 18 months (week 81) until progression. A substantial amendment to the CT application (23/12/2010) was made to clarify the radiological procedures in the ICON6 trial. The Chest x-ray/CT scan as specified in the approved protocol version 6.0 (Feb 2010) were not mentioned specifically in the original application and the application was amended to clarify these procedures. Protocol Version 7.0 (2011) was submitted as a substantial amendment to the Ethics Committee and the MHRA as a result of AstraZeneca’s decision to cease further development of cediranib. A new sample size was calculated and time-lines agreed with AstraZeneca to ensure that drug supply is maintained for all patients entered into the trial. Protocol Version 8.0 (2013) was submitted as a substantial amendment to the Ethics Committee and the MHRA to allow patients continuing on Trial Drug beyond 18 months to move on to open label cediranib from AstraZeneca, and to be resupplied every 3 months

ICON6


instead of every 6 weeks. An explanation has been given regarding the limited supply of cediranib.

ICON6


24 REFERENCES 1. Parmar, M.K., et al., Paclitaxel plus platinum-based chemotherapy versus

conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet, 2003. 361(9375): p. 2099-106.

2. Perren, T., et al., A phase III randomised Gynaecologic Cancer InterGroup trial of concurrent bevacizumab and chemotherapy followed by maintenance bevacizumab, versus chemotherapy alone in women with newly diagnosed epithelial ovarian (EOC), primary peritoneal (PPC) or fallopian tube cancer (FTC). . Annals of Oncology, 2010. 21((Supplement 8)).

3. Royston, P., M.K.B. Parmar, and W. Qian, Novel designs for multi-arm clinical trials with survival outcomes with an application in ovarian cancer. Statistics in Medicine, 2003. 22(14): p. 2239-2256.

4. Parkin, D.M., F.I. Bray, and S.S. Devesa, Cancer burden in the year 2000. The global picture. Eur J Cancer, 2001. 37 Suppl 8: p. S4-66.

5. Folkman, J., Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg, 1972. 175(3): p. 409-16.

6. Folkman, J., What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst, 1990. 82(1): p. 4-6.

7. Shweiki, D., et al., Vascular Endothelial Growth Factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature, 1992. 359(6398): p. 843-45.

8. Hicklin, D.J. and L.M. Ellis, Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol, 2005. 23(5): p. 1011-27.

9. Hasan, J. and G.C. Jayson, VEGF antagonists. Expert Opin Biol Ther, 2001. 1(4): p. 703-18.

10. Larrivee, B. and A. Karsan, Signaling pathways induced by vascular endothelial growth factor (review). Int J Mol Med, 2000. 5(5): p. 447-56.

11. Dvorak, H.F., Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol, 2002. 20(21): p. 4368-80.

12. Bookman, M. and E. al., GOG0182-ICON5: 5-arm phase III randomized trial of paclitaxel (P) and carboplatin (C) vs combinations with gemcitabine (G), PEG-lipososomal doxorubicin (D), or topotecan (T) in patients (pts) with advanced-stage epithelial ovarian (EOC) or primary peritoneal (PPC) carcinoma. J Clin Oncol, 2006. 24: p. 5002.

13. Hurwitz, H., et al., Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med, 2004. 350(23): p. 2335-42.

14. Giantonio, B., et al., High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200 J Clin Oncol, 2005. 23(2).

15. Miller, K.D., et al., Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol, 2005. 23(4): p. 792-9.

16. Sandler, A., R. Gray, and J. Brahmer, Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC #704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial - E4599 (Plenary Session I) Abstract 4. J Clin Oncol, 2005. 23: p. LBA4.

17. Yoneda, J., et al., Expression of angiogenesis-related genes and progression of human ovarian carcinomas in nude mice. J Natl Cancer Inst, 1998. 90(6): p. 447-54.

18. Brustmann, H. and S. Naude, Vascular endothelial growth factor expression in serous ovarian carcinoma: relationship with high mitotic activity and high FIGO stage. Gynecol Oncol, 2002. 84(1): p. 47-52.

19. Huang, S., et al., Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of

ICON6


vascular endothelial growth factor and interleukin 8. Cancer Res, 2000. 60(19): p. 5334-9.

20. Yukita, A., et al., Suppression of ascites formation and re-accumulation associated with human ovarian cancer by an anti-VPF monoclonal antibody in vivo. Anticancer Res, 2000. 20(1A): p. 155-60.

21. Byrne, A.T., et al., Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res, 2003. 9(15): p. 5721-8.

22. Mesiano, S., N. Ferrara, and R.B. Jaffe, Role of vascular endothelial growth factor in ovarian cancer: inhibition of ascites formation by immunoneutralization. Am J Pathol, 1998. 153(4): p. 1249-56.

23. Paley, P.J., et al., Vascular endothelial growth factor expression in early stage ovarian carcinoma. Cancer, 1997. 80(1): p. 98-106.

24. Alvarez, A.A., et al., The prognostic significance of angiogenesis in epithelial ovarian carcinoma. Clin Cancer Res, 1999. 5(3): p. 587-91.

25. Cooper, B.C., et al., Preoperative serum vascular endothelial growth factor levels: significance in ovarian cancer. Clin Cancer Res, 2002. 8(10): p. 3193-7.

26. Yamamoto, S., et al., Expression of vascular endothelial growth factor (VEGF) in epithelial ovarian neoplasms: correlation with clinicopathology and patient survival, and analysis of serum VEGF levels. Br J Cancer, 1997. 76(9): p. 1221-7.

27. Boocock, C.A., et al., Expression of vascular endothelial growth factor and its receptors flt and KDR in ovarian carcinoma. J Natl Cancer Inst, 1995. 87(7): p. 506-16.

28. Wildiers, H., et al., Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br J Cancer, 2003. 88(12): p. 1979-86.

29. Burger, R., et al., Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC): a Gynecologic Oncology Group (GOG) study. J Clin Oncol, 2005. 23: p. 5009.

30. Garcia, A., et al., Interim report of phase II clinical trial of Bevacizumab (Bev) and low dose metronomic oral cyclophosphamide (mCTX) in recurrent ovarian (OC) and primary peritoneal carcinoma (PPC): A California Cancer Consortium Trial. J Clin Oncol, 2005. 23: p. 5000.

31. Burger, R.A., et al., Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): A Gynecologic Oncology Group study. . J Clin Oncol, 2010. 28 (18s).

32. Aghajanian, C., et al., OCEANS: A randomized, double-blinded, placebo-controlled phase III trial of chemotherapy with or without bevacizumab (BEV) in patients with platinum-sensitive recurrent epithelial ovarian (EOC), primary peritoneal (PPC), or fallopian tube cancer (FTC). . J Clin Oncol, 2011. 29.

33. Hirte, H.W., et al., A phase II study of cediranib (AZD2171) in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: Final results of a PMH, Chicago and California consortia trial. . J Clin Oncol 2008. 20.

34. Matulonis, U.A., et al., Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. . J Clin Oncol, 2009. 27(33): p. 5601-5606.

35. Eskens, F.A., Angiogenesis inhibitors in clinical development; where are we now and where are we going? Br J Cancer, 2004. 90(1): p. 1-7.

36. Wedge, S., et al. The VEGF Receptor Tyrosine Kinase Inhibitor AZD2171 inhibits VEGF Signalling, Angiogenesis and Tumour Growth In Vivi. in Proc Am Assoc Can Res. 2004.

37. Hennequin, L., et al. Structure-activity relationship, physicochemical and pharmacokinetic properties of AZD2171: A highly potent inhibitor of VEGF receptor tyrosine kinases. in Proc Am Assoc Cancer Res. 2004.

ICON6


38. Medinger, M., K. Mross, and U. Zirrgiebel. Phase I dose escalation study of the highly potent VEGF receptor tyrosine kinase inhibitor, AZD2171, in patients with advanced cancer with liver metastases. in Proc Am Soc Clin Oncol. 2004.

39. AstraZeneca, AZD2171 Investigator's Brochure. 2005. 40. Chen, E., et al., Effects of AZD2171 on pharmacokinetics of carboplatin and paclitaxel

in patients with advanced non-small cell lung cancer: a study of the National Cancer Institute of Canada Clinical Trials Group. Eur J Can (Supplements) 2006. 4(12): p. 32.

41. Gauthier, I., et al. Hypertension: Experience in IND.171, a phase I dose-seeking trial combining AZD2171 with standard chemotherapy in patients with advanced incurable non-small cell lung cancer. . in 8th International Symposium on Anti-Agiogenic Agents. 2006.

42. Laurie, S., et al., Final results of a phase I study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor receptors, in combination with carboplatin + paclitaxel in patients with advanced non-small cell lung cancer: a study of the National Cancer Institute of Canada Clinical Trials Group. . Proc.Am.Soc.Clin.Oncol. , 2006. 24(18S Part 1): p. 134.

43. Calvert, A.H., et al., Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol, 1989. 7(11): p. 1748-56.

44. Burger, R.A. Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): A Gynecologic Oncology Group study. in ASCO Annual Meeting. 2010.

45. Oken, M.M., et al., Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol, 1982. 5(6): p. 649-55.

46. Oxford Texbook of Internal Medicine, ed. O.U. Press. Vol. 2. 1997. 2228. 47. Therasse, P., et al., New guidelines to evaluate the response to treatment in solid

tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst, 2000. 92(3): p. 205-16.

48. Du Bois, D. and E. Du Bois, A formula to estimate the approximate surface area if height and weight be known. Arch Int Med, 1916: p. 683-71.

49. Wright, J.G., et al., Estimation of glomerular filtration rate in cancer patients. Br J Cancer, 2001. 84(4): p. 452-9.

50. Jelliffe, R.W., Letter: Creatinine clearance: bedside estimate. Ann Intern Med, 1973. 79(4): p. 604-5.

51. Cockroft, D. and M. Gault, Prediction of creatinine clearance from serum creatinine. Nepheron, 1976. 16: p. 31-41.

52. Kind, P., The EuroQoL instrument: an index of health related quality of life. 2 ed. Quality of Life and Pharmacoeconomics in Clinical Trials, ed. Lippincott-Raven. 1996.

ICON6


25 APPENDICES

Appendix 1 ECOG Performance Status

Appendix 2 NYHA Classification of Cardiac Disease

Appendix 3 Evaluation of Residual Disease, Evaluation of and Definitions of Progression

Appendix 4 ICON6 Trial Drug Supply Management and Accountability

Appendix 5 Nomogram for the determination of the Body Surface Area

Appendix 6 Estimation and Measurement of GFR and Recommendations for Calculation of Carboplatin dose

Appendix 7 Translational research

Appendix 8 Quality of Life Information Sheet for Clinicians

Appendix 9 Details of former Sample Size Calculations - for information only

Appendix 10 Guidance on Patient Information Sheets: General Information for GCIG Groups and Sites

Appendix 11 GP letters

Appendix 12 International Trial Management Group

Appendix 13 Carboplatin and Gemcitabine Combination

ICON6


APPENDIX 1: ECOG Performance Status [45]

Description Scale Normal activity 0 Symptomatic but ambulatory self-care 1 Ambulatory more than 50% of the time 2 Ambulatory 50% or less of time, nursing care needed 3 Bedridden, may need hospitalisation 4

ICON6


APPENDIX 2: NYHA Classification of Cardiac Disease[46]

Class I Patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnoea or angina pectoris.

Class II Patients with cardiac disease resulting in slight limitations of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea or anginal pain.

Class III Patients with cardiac disease resulting in marked limitations of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnoea or anginal pain.

Class IV Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or the angina syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.

ICON6


APPENDIX 3: Evaluation of Residual Disease, Evaluation of and Definitions of Progression[47]

Assessment of Baseline Disease

An assessment of baseline disease within 4 weeks prior to commencement of trial treatment is required (a six week window would be considered after discussion with the CI). A patient is not required to have measurable disease as per RECIST for entry, but must have disease visible on radiological imaging and not just an elevated CA 125 alone.

Method of assessment

A CT or MRI scan of the pelvis and abdomen is the preferred method of evaluation. The same method of assessment should be used at baseline and for all scans during follow-up.

Definition of measurable disease lesions

Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter (LD) to be recorded). Each lesion must be 20mm when measured by conventional techniques, including palpation, plain X-ray, CT, and MRI, or 10mm when measured by spiral CT.

Definition of Non-measurable lesions

These are all other lesions, including small lesions (longest diameter <20 mm with conventional techniques or <10 mm with spiral CT scan), i.e. bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, inflammatory breast disease, lymphangitis, cystic lesions, and also abdominal masses that are not confirmed and followed by imaging techniques.

Baseline documentation of “Target” and “Non-Target” lesions

All measurable lesions, up to a maximum of five in total, representative of all involved organs should be identified as target lesions and recorded and measured at baseline.

Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically).

All other lesions (or sites of disease) should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, but the presence or absence of each should be noted throughout follow-up.

ICON6


Definition of progression For patients with measurable disease at randomisation

Progression is defined as ANY of the following:

At least a 20% increase in the sum of LD target lesions taking as reference the smallest sum LD recorded since trial entry

In the case where the ONLY target lesion is a solitary pelvic mass measured by physical exam which is not radiographically measurable, a 50% increase in the LD is required taking as reference the smallest LD recorded since trial entry

The appearance of one or more new lesions Death due to disease without prior objective documentation of progression Global deterioration in health status attributable to the disease requiring a

change in therapy without objective evidence of progression Unequivocal progression of existing non-target lesions, other than pleural

effusions without cytological proof of neoplastic origin, in the opinion of the treating physician (in this circumstance an explanation must be provided)

For patients with non-measurable disease at randomisation

Progression, for patients with non-measurable disease at randomisation, is defined as increasing clinical, radiological or histological evidence of disease since trial entry. All patients, including those with measurable disease whose progression is classified as ‘global deterioration without objective evidence of progression and those with non-measurable disease at randomisation, are expected to have a CT or MRI scan at the time of progression to formally document radiological disease status.

ICON6


APPENDIX 4: ICON6 Trial Drug Supply Management and Accountability ICON6 Trial Drug (cediranib and placebo) supply will be managed by a computer-based supply management system operated by a commercial organisation, CLINPHONE/PERCEPTIVES who have been contracted on behalf of the MRC. The system which can be accessed via the web or by a (free) country-specific telephone number will be linked to the randomisation database and accessed by authorised trial personnel with appropriate access codes. The supply management system will track ICON6 Trial Drug supply at each site and will automatically order drug/placebo for the patients randomised from that site. A system user guide, similar to that used in other ICON trials will be provided and site staff will be trained in how to access and use the drug supply management system. A free-phone help-desk number (the same number as for the randomisation system helpdesk) will also be provided. Once the ICON6 trial has been unblinded patients continuing on cediranib will move on to open label supply. The open label supply will be ordered on a per patient basis using a drug order form and the computer based supply management system will be discontinued. Open label supply will be ordered directly from AstraZeneca’s distribution company (Fisher Clinical Services) on a 3 monthly basis until supplies are exhausted.

ICON6 Trial Drug Accountability

All dispensed drug bottles will be returned to the pharmacy for storage until a drug accountability check is performed.

When the drug accountability check has been performed by the responsible pharmacist, stored previously dispensed drug bottles and unused drug can be destroyed locally. The amount of drug destroyed must be documented on a drug destruction log. Each participating investigational site will maintain supply inventory forms for Trial Drug. Each time Trial Drug is supplied to the site or dispensed to patients, the number of bottles will be recorded and a running total of the remaining number of bottles updated. This information will be required to be entered into the web based drug accountability system while using blinded Trial Drug supply.

ICON6 Trial Drug Dispensing Log

An ICON6 Trial Drug dispensing log will be maintained for each patient randomised. Each time Trial Drug is dispensed the following information will be recorded in the dispensing log:

Dispensing date Bottle number and Trial number Initials of person dispensing

ICON6


Any comments, if appropriate

ICON6


APPENDIX 5: Nomogram for the Determination of the Body Surface Area[48]

ICON6


APPENDIX 6: Estimation and measurement of Glomerular Filtration Rate and Recommendations for Calculation of Carboplatin Dose

Estimation and Measurement of Glomerular Filtration Rate (GFR)

For the purposes of this protocol, the GFR can be considered equivalent to the creatinine clearance (CrCl). The following methods are suggested, however it is advised that the centre calculates the GFR according to local guidelines:

Estimation of GFR using the Wright formula[49]

There are a number of different Wright formulae, depending on whether or not the creatinine kinase is available and used in the calculation, and also depending on how the serum creatinine is measured. The formula immediately below does not require a creatinine kinase measurement. This formula is also only valid if the laboratory measuring the serum creatinine uses the Jaffe method to do this. Centres will need to check with their local pathology laboratory how the serum creatinine is measured.

GFR = {[6580 – (38.8 x age)] x BSA x 0.832} SCr

If the creatinine is measured using enzymic methods then following Wright formula should be used:

GFR = {[6230-(32.8 x age)] x BSA x 0.77} SCr

Where: CrCl = Creatinine Clearance (ml/min) GFR = Glomerular Filtration Rate (ml/min) BSA = DuBois Body Surface Area (m2) SCr = Serum Creatinine (μmol/l) Wt = Weight (kg) Age = Age in years (20 to 80)

To convert serum creatinine in mg/dml to µmol/l use the following formula: Cr (μmol/l) = Cr (mg/dl) x 88.4

Estimation of GFR using the Jelliffe formula[50]

GFR = 0.9 x [98-{0.8(age-20)}] x [BSA/1.73] SCr x 0.0113

Estimation of GFR using the Cockcroft-Gault formula[51]

GFR = 1.05 x (140-age) x Wt

SCr

ICON6


Measurement of GFR

A measured GFR is recommended if the serum creatinine is less than or equal to 0.6 mg/dl or 53 µmol/l, or the estimated GFR is < 50ml/min. The lower of the two values of creatinine clearance should be used to calculate dose. The GFR can be measured by

24 hour urine collection or

Isotopic GFR (using the value uncorrected for body surface area, BSA)

ICON6


APPENDIX 7: Translational Research (biomarkers and pharmacogenomics)

The planned translational research programme associated with ICON6 will address two main questions.

1) whether we can identify biomarkers that identify the patients who will most benefit from cediranib so that toxicity and costs can be minimized.

2) whether we can identify markers of early clinical progression during protocol defined treatment, so that ineffective therapy can be stopped and alternatives prescribed.

The translational research programme will be conducted at 4 levels (see Table entitled ‘Levels of participation in Translational Research’) as it is recognized that a variety of clinical centres with access to different levels of research support will enter patients into the ICON6 trial. All centres are encouraged to participate if local ethics and logistical support allows. The majority of centres are expected to participate at levels 2 and 3 and the broad requirements for these are documented below. Although consent for sample collection will be requested at the time of randomisation for all patients in the trial, the actual collection of blood and tumour specimens will not commence until further notice is given from the MRC CTU. Further detailed information on all levels of participation will be given in the ICON6 Translational Research Manual (TRM) which will be provided when specimen collection starts.

Level 1 Participation

(Tumour specimens)

All clinical centres are expected to participate in the translational research programme at this level. It is appropriate for centres with no additional facilities/support for sample collection/preparation. Formalin-fixed paraffin-embedded tumour tissue taken at the time of initial surgery (tumour blocks) will be collected.


(Tumour specimens and DNA blood sample)

All clinical centres are expected to participate in the translational research programme at this level. It is appropriate for centres with no additional facilities/support for sample collection/preparation. Tumour specimens and a single peripheral blood sample for DNA will be collected.


(Tumour specimens, DNA blood sample and limited blood biomarkers)

This level is appropriate for clinical centres with access to a centrifuge and -80oC freezer facilities. In addition to level 2 sampling, four blood samples (Pre-cycle 1, pre-cycle 2, pre-cycle 6 and at protocol defined disease progression, or at 5 years from the start of treatment if the disease has not recurred- see Tables 9 and 10) are required for immunoassay and proteomic analysis.

ICON6



(Tumour specimens, DNA blood sample and extended blood biomarkers)

This level is appropriate for clinical centres with access to a centrifuge and -80oC freezer facilities. It will consist of, in addition to level 3 sampling, another six blood samples (another pre cycle one to assess intra-patient variability, one after infusion of all drugs post cycle one, one after infusion of all drugs post cycle six, and a follow up from the end of treatment at 3, 6 and 9 months). These blood samples will also be required for immunoassay and proteomic analysis.

Levels of Participation in Translational Research Participation level Additional Research

Facilities required Samples to be collected

Level 1 Nil Tumour specimens

Level 2 Nil Tumour specimens and single peripheral blood for DNA analysis

Level 3 Centrifuge and -80oC freezer

As Level 2 and blood sampling for proteomics/ immunoassays

Level 4 Centrifuge and -80oC freezer

As Level 2 and extended blood sampling for proteomics/ immunoassays

Patient consent for Translational Research

In order to collect the samples for translational research, patients will be required to sign a specific consent form. Although most patients are expected to consent to participation in the translational research programme, the wishes of patients who do not want to be involved in the additional translational sample collection will be respected and they will be allowed to enter the clinical trial protocol only.

Sample collection, storage and processing

The distribution of all translational research samples to academic centres will be coordinated by the Translational Subgroup of the Trial Management Group. Detailed instructions for the processing, labelling, handling, storage and shipment of these specimens will be provided in the ICON6 Translational Research Manual at the time of study initiation. A brief overview of specimen requirements is given here.

Tumour specimens (all levels)

Formalin-fixed paraffin-embedded surgical/biopsy specimens of the primary tumour will be collected. It is preferable that an original block is sent but if this is not possible then 10 unstained slides may be sent instead. Tumour blocks will be used to create a tissue microarray for assessment of expression of standard prognostic markers for ovarian cancer and a panel of angiogenesis biomarkers. Tumour blocks will not normally be returned to the

ICON6


referring centre, but in exceptional circumstances (for example clinical decision making) every effort will be made to do so.

Peripheral blood for DNA analysis (pharmacogenomics and single nucleotide polymorphisms) (level 2 and above)

A single 10 ml blood sample will be collected into an EDTA collection tube. Samples will be stored at -20°C or -80°C and shipped to a central storage facility at set time intervals. DNA aliquots will be prepared from these samples.

Plasma/ serum sampling for proteomic analysis and immunoassays for circulating angiogenic biomarkers (levels 3 and 4)

In level 3 plasma and serum samples will be taken prior to administration of cycle 1, before cycle 2, before cycle 6 and at protocol defined disease progression or at 5 years from the start of treatment if there has been no disease progression by this point (see Table 10). At each of the time points 30mls of blood are required (25mls plasma and 5mls serum). An extra 10mls will also be required when the first sample is taken to allow for the sample required for DNA extraction. For plasma samples 25mls of blood collected directly into EDTA monovettes (to be supplied) is required. This is then centrifuged (2000g for 10 mins at 20oC) within 30 minutes of venupuncture. Plasma will then be aspirated, pooled into a single tube and subsequently aliquoted into 3 storage tubes and stored at -80oC. Samples will be shipped to a central storage facility at set time intervals. In order to prepare serum from peripheral blood, a single 5 ml blood sample will be collected into silica-activated tubes (to be supplied), allowed to stand at room temperature for 1 hour. This will then be centrifuged (2000g for 10 mins at 20oC). Serum will be aspirated and placed directly into a storage tube and stored at -80°C. Samples will be shipped to a central storage facility at set time intervals. The storage centre, at least initially in Leeds, will then distribute the samples to the appropriate academic centre.

Translational Research Contact:

Any questions related to the ICON6 translational research programme detailed in this appendix and the translational research manual should be directed to;

Professor Gordon Jayson Cancer Research UK Department of Medical Oncology, Christie Hospital Wilmslow Road Manchester M20 4BX UK Tel: +44 (0) 161 446 3606 Fax: +44 (0) 161 446 8565 E: [email protected]

ICON6


APPENDIX 8: Quality of Life Information Sheet for Clinicians Background

A detailed QoL analysis is being performed with the aim to broaden the assessment of the use of cediranib, to include its potential impact on functioning and well-being. QoL analysis will enable the exploration of hypotheses about the functional and symptomatic consequences of the addition of cediranib to first line chemotherapy for ovarian cancer using validated patient self-reporting measures.

An analysis plan for the main QoL analyses will be developed including testing specific hypotheses about QoL related to the expected physical, psychological and social consequences of ovarian cancer and its treatment. Hypotheses that will be explored include impact on ascites resolution, wound healing, and prolongation of treatment in the research arm.

Within ICON6 and ICON7 (another GCIG trial assessing the use of bevacizumab, a monoclonal antibody to VEGF, in the first line treatment of ovarian cancer) a set of questions of specific relevance to the assessment of QoL when anti-angiogenic drugs are administered will be developed. During the study contributing centres with a specialist interest and infrastructure for more specialised QoL measurement will collaborate in the collection of data assessing any additional problems or symptoms specific to the administration of anti-angiogenic agents. A QoL subgroup will develop new items based upon the principles in the EORTC guidelines.

QoL Questionnaires Information

The EORTC QLQ OV-28 scale (which includes the EORTC QLQ C-30) and the EQ-5D questionnaires have been selected to measure QoL in the ICON6 trial.

With respect to the EORTC QLQ OV-28 scale, the measures of abdominal symptoms, physical and social functioning scales it includes have better face validity to examine hypotheses relevant to ICON6 than other instruments, notably the FACT-O. The questionnaire will assess patients’ QoL within the last seven days of each time point.

The OV-28 instrument has 58 items. It is clear and easy to understand, acceptable to patients and usually completed in less than 15 minutes without assistance. The questionnaire has currently been translated into 14 languages: English, Croatian, Danish, Dutch, French, German, Italian, Portuguese, Spanish, Swedish, Taiwan-Chinese, Finnish, Norwegian and Polish.

ICON6 will provide a vehicle for the collection of data which will contribute to a cost-effectiveness analysis of cediranib. Patient-specific data will be collected in the trial on Medical Resource Use (MRU) during follow up. These will include days of in-patient hospitalisation, day-case and out-patient visits and anti-cancer therapies. In addition, patients’ health-related quality of life (HRQL) will be assessed at baseline and throughout follow-up using the EQ-5D instrument[52] as part of the QoL forms that all patients will complete. This will facilitate the expression of HRQL in terms of ‘utilities’ which are used to estimate patients’ quality-adjusted survival duration.

Each QoL form should be completed before medical assessment, chemotherapy is given or blood tests are performed. The first form that is required is as a baseline at screening. Thereafter a QoL form should be completed at the onset of every chemotherapy cycle and

ICON6


once patients are in the maintenance phase every 6 weeks at hospital visits whilst the patient is on blinded Trial Drug. After completion of the maintenance phase: QoL should be recorded every 3 months during years 2 and 3 (or 6 weekly if on Trial Drug). A QoL form should also be completed on day 1 of the first cycle of chemotherapy at next relapse.

Any questions related to the ICON6 QoL research programme detailed in this appendix should be directed to;

Dr Dan Stark Cancer Research UK Department of Medical Oncology, St James’s University Hospital Beckett St Leeds LS9 7TF UK Tel: +44 (0) 113 2065417 Fax: +44 (0) 113 2460136 E: [email protected]

ICON6


APPENDIX 9: Former planned statistical analysis and sample size calculations – for information only. This appendix contains the original planned analysis for ICON6 (protocol version 6.0) and details are provided for reference only. The current statistical plan for ICON6 is detailed in section 13. Outcome Measures The outcome measure in the first stage is safety of the research treatments. In the second stage the trial could be stopped early if there is not a minimal, pre-specified level of activity of cediranib detected based on Progression Free Survival (PFS). Assuming efficacy is demonstrated, accrual will continue into the third stage to investigate whether the addition of cediranib to standard chemotherapy confers a benefit on PFS and/or overall survival (OS). The outcome measures for each stage are summarised in Table 10: Table 10: Outcome measures of ICON6 stages First Stage Primary outcome measure Safety Second Stage Primary outcome measure



Overall Survival (OS) and Toxicity

Third Stage Primary outcome measure


Overall Survival (OS)

Progression Free Survival (PFS)

Toxicity

Quality of Life (QoL)

There will also be ancillary studies associated with ICON6, in

Translational (Biomarker) Research (TR)

Health Economics (HE)

Sample Size

ICON6 has a three-stage design and could be stopped at either of the first two stages. If it continues to the final stage of full accrual, a total of 2000 patients will be randomised. Following a further 2 years of follow up, the trial is designed to detect a hazard ratio of over 0.75 in OS between Arm A (reference arm) and each of the research arms (arm B or arm C), with a 2.5% significance level, at least 90% power, and a hazard ratio of 0.75 between the 2 research arms (Arm B vs Arm C in patients receiving at least 4 cycles of platinum chemotherapy), with a 5% significance level and 90% power. Please refer to appendix 9 for further information.

Stage One The first stage will be conducted in selected centres only and will aim to confirm the safety of using cediranib. The analysis will be conducted when approximately 33 patients in total on the two cediranib Arms (B+C) have completed 3 cycles of chemotherapy.

The primary outcome measure in stage 1 is safety. Although all toxicities will be considered, particular consideration will be given to CTCAE grade 3 and 4 toxicities that appear to be associated with cediranib including severe, uncontrolled hypertension, grade 3 fatigue and diarrhoea, or events that require dose reduction or discontinuation of Trial Drug. As a guideline, if there was good evidence that the grade 3 and 4 adverse event rates exceeded

ICON6


15% of patients for any of these events (or other grade 3 or 4 toxicities that are identified) then the nature of the research arms of the trial will be reconsidered. This would occur if more than 10 of the 33 patients on Trial Drug experiences these events (in which case the lower end of the 95% confidence interval would exceed 15%).

Stage Two

The second stage includes an analysis of efficacy and the trial could be stopped early if a minimal level of activity of cediranib, based on PFS and OS, is not detected. The analysis for OS will be performed when at least 50 deaths have occurred and the analysis for PFS when at least 90 progressions or deaths have occurred in Arm A (reference). It is anticipated that these events will have occurred after 150 patients have been randomised in Arm A and 450 patients in total have been randomised to Arms B and C. Stage 2 analyses will be performed when the target number of events for both PFS and OS have been reached. It is anticipated that the stage two analysis will be performed approximately 2 years later (estimated from 400 patient recruitments/year but with an adjustment for a lower accrual rate at the beginning of the trial).

The analysis will include Arm A vs Arms (B+C) to evaluate the effect of any cediranib (concurrent or concurrent and maintenance) vs no cediranib. If the estimated hazard ratio is close to 1 for PFS and OS, additional analyses will be performed to explore the effect of Arm A vs Arm B and Arm A vs Arm C to ensure that the observation of no worthwhile effect appears to be similar in the two cediranib arms. The trial could be stopped early if a minimal level of activity of cediranib, based on PFS and OS, is not detected. This second comparison will be based on patients recruited during the first 18 months only. This is so that the analysis is not dominated by early events (within the first 6 months of treatment). These early events cannot contribute to an assessment of the effect of maintenance cediranib.

Stage Three

For the final analysis (third stage), an analysis of the efficacy of cediranib will be performed with OS as the primary outcome measure.

The structure of planned comparisons is

Arm A vs Arm B (reference arm vs concurrent arm) Arm A vs Arm C (reference arm vs concurrent and maintenance arm) Arm B vs Arm C (if first two comparisons are positive: concurrent arm vs

concurrent and maintenance arm)

ICON6


The third comparison will only be performed if benefits of cediranib are observed in both of the first two comparisons. Otherwise it is not possible to make a reliable statement of the clinical benefit of the three strategies (placebo, concurrent cediranib, and concurrent and maintenance cediranib). The third comparison will only be performed in patients who completed at least 4 cycles of protocol treatment.

A significance level of 2.5% for the first two comparisons has been chosen because a common reference arm is being used. A significance level of 5% for the third comparison is chosen because a closed test is being performed – that is it will only be performed if the first two tests are statistically significant. Power is set as 90% for the third comparison (and is over 90% for the first two comparisons). The proportion of patients with no progressive disease is estimated as 60%-70% (based on ICON4 and the AGO OVAR2.5 trials). With these assumptions a sample size of approximately 2000 patients (accrued in 5 years with a further 2 years follow-up) is required to detect the following improvements in overall survival

A hazard ratio of 0.75 for Arm A vs Arm B (improvement in 2-year OS from 50% to 59%)

A hazard ratio of 0.62-0.67 for Arm A vs Arm C (improvement in 2-year OS from 50% to 63-65%) depending on the percentage of patients receiving maintenance cediranib treatment in Arm C

A hazard ratio of 0.75 for Arm B vs Arm C (improvement in 2-year OS from 59% to 67%)

Interim Monitoring and Analyses

An Independent Data Monitoring Committee (IDMC) will review data, unblinded by treatment group, on patients in the trial. The IDMC will meet approximately every 6 months during the accrual period. The first interim analysis will be performed when approximately 33 patients on the two cediranib Arms (B+C) have completed 3 cycles of chemotherapy if it occurs before the first scheduled 6 monthly IDMC meeting.

At each meeting, the IDMC will be asked to give advice on whether the accumulated data from the trial, together with results from other relevant trials, justifies continuing recruitment of further patients or further follow-up. A recommendation to discontinue recruitment, in all patients or in selected subgroups will be made only if the result is likely to convince a broad range of clinicians including participants in the trial and the general clinical community. If a recommendation is made to continue, the IDMC will advise on the frequency of future reviews of the data on the basis of accrual and event rates. The IDMC will make recommendations to the Trial Steering Committee as to the continuation of the trial. Brief Analysis Plan Analyses will be performed on an intention-to-treat basis. Progression-free survival (PFS) is calculated from the date of randomisation to date of first progression or death from any cause, whichever occurs first. If neither event is observed at the time of analysis, patients are censored at the date of last follow-up. Overall survival (OS) is calculated from the date of randomisation to date of death from any cause. Patients who are still alive at the time of analysis are censored at the date last known to be alive. The standard non-stratified log-rank test will be applied in the primary analysis for PFS and OS. Cox model analyses adjusting for patient baseline characteristics will also be performed for PFS and OS. Subgroup analysis by patient baseline characteristics on PFS and OS will be performed in an exploratory manner. Toxicity will be measured using the NCI Common Toxicity Criteria Adverse Events (CTCAE) (version 4) and the Mann-Whitney test will be used in the comparison.

ICON6


Baseline parameters in the reference arm: Baseline parameters for PFS and OS have been obtained by combining results from the ICON4/OVAR 2.2 and the AGO gemcitabine-carboplatin OVAR 2.5 trials. From ICON4/OVAR2.2, 1-year PFS is approximately 50% and 2-year OS approximately 55%. From the AGO trial, median PFS is 8.6 months and median OS is 18 months. This gives, on average, 1-year PFS of 45% and 2-year OS of 50% for the reference arm of ICON6. Accrual rate: 450-550 patients per year

Proportion of patients who contribute to maintenance phase: Patients with no progressive disease (PD) at the end of chemotherapy will continue with the maintenance treatment (placebo or cediranib) based on the randomisation at trial entry. The proportion of patients who will continue cediranib i.e. those who have not had PD during chemotherapy is estimated as 60%-70% (based on the 6-month PFS from ICON4 and the AGO gemcitabine-carboplatin OVAR2.5 trials). Structure of planned comparisons Stage one

Not applicable Stage two

Arm A vs Arms (B + C) Arm A vs Arm B, Arm A vs Arm C

The analysis will include Arm A vs Arms (B+C) to evaluate the effect of any cediranib (concurrent or maintenance) vs no cediranib. If the estimated hazard ratio is close to 1 for PFS and OS additional analyses will be performed to explore the effect of Arm A vs Arm B and Arm A vs Arm C to ensure that the observation of no worthwhile effect appears to be similar in the two cediranib arms. The trial could be stopped if no evidence of activity of any cediranib (concurrent or maintenance).

Stage three

First comparison: Arm A vs Arm B Second comparison: Arm A vs Arm C Third comparison: Arm B vs Arm C (only performed if the first two comparisons are ‘positive’)

The third comparison will be performed only if benefits of cediranib are observed in both of the first two comparisons. Otherwise it is not possible to make reliable statement of the clinical benefit of the three strategies (placebo, concurrent cediranib, and concurrent and maintenance cediranib). The third comparison will only be performed in patients who complete at least 4 cycles of platinum chemotherapy, so as not to dilute treatment effect. The comparison of Arm A vs Arms (B + C) will not be performed as a primary analysis. Such a comparison, if positive for OS or PFS, is not helpful, as it would not be clear whether the benefit is coming from concurrent or maintenance cediranib.

ICON6


Figure 4: Sample size - details of sample size calculations

2:3:3 randomisation

Arm A

(reference)

Arm B (Concurrent cediranib)

Arm C (Concurrent

+ maintenance cediranib)

HR (H1) 2-year OS HR (H1) 1-year PFS

50%

45%

0.75 0.70

59%

57%

0.75

0.70

67%

67%

2-year OS Arm B = 59% Arm C = (1-r) * 59% + r * 67% = 0.3*0.59 + 0.7*0.67 = 65% for r=70% 0.4*0.59 + 0.6*0.67 = 64% 60% 0.5*0.59 + 0.5*0.67 = 63% 50% r: proportion of patients completing protocol treatment in Arm C

minimum of 2-year follow-up after completion of accrual 2.5% significance level for the first two comparisons (as a common reference arm

is used) and 5% significance level for the third comparison (as a closed test is being performed), 90% power

proportion of patients completing protocol treatment in Arm C (r) being 70%, 60% or 50%

First comparison (reference vs concurrent cediranib) Arm A vs Arm B

Patient allocation 2 3 2-year OS 50% 59% HR 1 0.75 Total number of events required 608 Number of patients required (Arm A + Arm B)

3-year accrual 4-year accrual 966 907

ICON6


Second comparison (reference vs concurrent and maintenance cediranib)

Arm A vs Arm C Patient allocation 2 3

2-year OS 50% 65% (r=70%), 64% (r=60%), 63% (r=50%) HR 1 0.62 0.64 0.67 Total number of events required 216 249 310 Number of patients required (Arm A + Arm C)

r 3-year accrual 4-year accrual 70% 366 343 60% 417 391 50% 512 480

Third comparison (concurrent vs concurrent and maintenance cediranib) This comparison will be performed only if both the first and second comparisons are positive in favour of cediranib.

Arm B vs Arm C Patient allocation 1 1 2-year OS 59% 67% HR 1 0.75 Total number of events required = 510 Number of patients required (Arm B + Arm C)

R 3-year accrual 4-year accrual 100% 940 870 70% 1343 1243 60% 1567 1450 50% 1880 1740

The third comparison will only be performed in patients who completed at least 4 cycles of platinum chemotherapy. Total sample size (with a 4-year accrual period) (Arm A + Arm B + Arm C)

R Total no. of pts No. of pts in Arm A 70% 1243*(4/3) = 1657 414 60% 1450*(4/3) = 1934 483 50% 1740*(4/3) = 2320 580

Total sample size: Assuming 60% of patients complete protocol treatment in Arm C, it will require a total of 2000 patients to be randomised, with a minimum of 2 years follow up, after completion of accrual.

NB: Assuming that 70% of patients complete protocol treatment in Arm C, 2000 patients

will give 80% power, at the 5% significance level, to detect a hazard ratio of 0.80 in the comparison of Arm B versus Arm C.

ICON6


Schedule for the first two stages of analysis

Stage one: The first stage analysis will be performed when approximately 33 patients in total on the two cediranib arms (B and C) have completed 3 cycles of chemotherapy. Stage two: The analysis will include Arm A vs Arms (B + C) to evaluate the effect of any cediranib (concurrent or maintenance) vs no cediranib. If the estimated hazard ratio is close to 1 for PFS and OS additional analyses will be performed to explore the effect of Arm A vs Arm B and Arm A vs Arm C to ensure that the observation of no worthwhile effect appears to be similar in the two cediranib arms. The trial could be stopped if there is no evidence of activity of any cediranib (concurrent or concurrent and maintenance).

Arm A vs Arms (B+C) Stage 2 based on PFS

1-year PFS in Arm A = 45% 1-year PFS in Arm B = 57%, HR = 0.70 1-year PFS in Arm C = 0.50*0.57+0.50*0.67 = 62%, HR = 0.60, for r = 50%. 1-year PFS in Arms (B+C) = 0.50*0.57+0.50*0.62 = 60%, HR = 0.64, for r = 50%

1- Critical value No. of events

in Arm A No. of patients

in Arm A Duration (years)

0.25 99.8% 0.922 45% to 48%

91 150 1.99

0.30 99.9% 0.939 45% to 47%

94 150 2.06

Arm A vs Arms (B+C) Stage 2 based on OS

2-year OS in Arm A = 50% 2-year OS in Arm B = 59%, HR = 0.75 2-year OS in Arm C = 63%, HR = 0.67, r = 50% 2-year OS in Arms (B+C) = 0.50*0.59 + 0.50*0.63 = 61%, HR = 0.71, r = 50%




0.35 95% 0.939 50% to 52%

50 150 1.95

0.40 96.5% 0.960 50% to 51.4%

52 150 2.0

ICON6


Arm A vs Arm B Stage 2 based on PFS

1-year PFS in Arm A = 45% 1-year PFS in Arm B = 57%, HR=0.70




0.25 97% 0.913 45% to 48%

91 150 2.0

0.35 98% 0.947 45% to 47%

85 150 2.0

Arm A vs Arm B Stage 2 based on OS

2-year OS in Arm A = 50% 2-year OS in Arm B = 59%, HR=0.75




0.40 90% 0.956 50% to 52%

52 150 2.0

0.45 92% 0.978 50% to 51%

52 150 2.0

Arm A vs Arm C Stage 2 based on PFS

1-year PFS in Arm A = 45% 1-year PFS in Arm C =0.50*0.57+0.50*0.67=62%, HR=0.60, for r=50%.




0.25 99% 0.913 45% to 48%

91 150 2.0

0.30 99.9%

0.932 45% to 47.5%

92 150 2.0

Arm A vs Arm C Stage 2 based on OS

2-year OS in Arm A = 50% 2-year OS in Arm C = 63%, HR = 0.67, r = 50%




0.32 95% 0.92 50% to 53%

52 150 2.0

0.40 97% 0.956 50% to 52%

54 150 2.07

ICON6


APPENDIX 10: Patient Information Sheets: General Information for GCIG groups and Sites

The guidance that follows encompasses the ICH Good Clinical Practice guidelines.

Potential recruits to ICON6 must be given sufficient information to allow them to decide whether or not they want to take part.

Generic versions of the ICON6 Patient Information Sheet (PIS), Informed Consent Form (ICF) and a Supplementary ICF for Biological Samples have been developed and will be supplied to each GCIG group.

Wording that will require tailoring for each GCIG group is given in square brackets [like this]. It should be written in simple, non-technical terms using short words, sentences and paragraphs, which should be easily understood by a lay person with the average reading ability of a 12-year old.

Each participating GCIG group must produce a local version of the PIS and IC (Informed Consent) documents. The MRC must be given the opportunity to review and comment any country-specific changes before the clinical trial application is submitted in that country.

In countries where English is not the local language, the participating GCIG group will produce a local language translation of the country-specific English language version. This local language version must be provided to the MRC, accompanied by a signed statement by a representative of the GCIG group confirming that the local language version is correct and that it provides patients with the same information as that included in the country-specific English language version.

All PIS submitted to a national or main research ethics committee should be headed simply ‘Hospital/Institution headed paper’.

Local PIS should be printed on headed paper of the hospital/institution where the research is being carried out, with local contact names and telephone numbers, before being submitted to the local research ethics committee. Unheaded paper is not acceptable.

APPENDIX 11: GP Letter

(To be presented on local headed paper)

[To be presented on local headed paper]

Centre Name: ………………………………....

Centre Number: …………….. ……………….

Trial Number: ………………………………..

Local date and version: _ _/_ _/_ _ _ _, V _ _._ _

Affix patient sticker here

ICON6


A randomised trial of concurrent cediranib (with platinum-based chemotherapy) and maintenance cediranib in women with platinum-sensitive relapsed ovarian cancer.

EudraCT: 2007-001346-41

Dear Dr _______________________

Your patient, _______________________ (date of birth ___/___/_____), has been diagnosed with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (delete as applicable).

Following discussion of treatment options and review of the Patient Information Sheets she has consented to enter the ICON6 trial.

All patients will receive standard chemotherapy which is six cycles of platinum-based chemotherapy. Each cycle of chemotherapy is given on day one of a twenty one day cycle. Alongside this patients will receive a ‘Trial Drug’ tablet which they will take once per day. Trial Drug will be either cediranib or placebo. Cediranib is an oral inhibitor of the vascular endothelial growth factor receptor (VEGFR) involved in the control of angiogenesis and tumour growth. One group of patients will have a placebo for the entire duration of the trial (i.e. during chemotherapy and up to 18 months post randomisation). Another group will receive cediranib during their chemotherapy, and will then take placebo up to 18 months post randomisation and the third group of patients will receive cediranib for the entire duration of the study (i.e. during chemotherapy and then up to 18 months post randomisation). Some patients may continue taking Trial Drug for longer than 18 months, if after discussion with their oncologist, it is believed to be of benefit.

The expected side effects from chemotherapy are listed in the patient information sheet (current version attached). Cediranib has been shown in previous studies to cause; Hypertension (up to approximately 70%, severe in 15% of patients) Nausea and vomiting (affecting up to 50% and 31% of patients respectively) Diarrhoea (mild to moderate diarrhoea estimated in 71% of patients severe in 7%) Proteinuria (observed in 12.5% patients at doses of 30 mg and above) Gastrointestinal perforation, sometimes complicated by the formation of a fistula (<

3%) Muscle weakness (estimated to affect 8% of patients) Left ventricular dysfunction, in some cases leading to cardiac failure, has been



Fatigue (estimated to occur in up to 68% of patients) Dehydration (observed in < 5% of patients with chemotherapy or cediranib related

diarrhoea and vomiting and exacerbated by reduced oral intake in patients received chemotherapy)

Hoarseness (dysphonia) (estimated to affect 52% of patients) Dry mouth (estimated to affect 9% of patients) Oral mucosal inflammation (estimated to affect 25% of patients) Elevated thyroid stimulating hormone (TSH) levels (which may be associated with

clinical hypothyroidism) (AE of hypothyroidism <6%, elevated TSH estimated to affect up to 50% of patients)

Hand and foot syndrome (estimated to affect up to 17% of patients)

ICON6


Thrombocytopenia (CTC G1/2 in the majority of cases, seen with monotherapy and combination treatment) (estimated to affect up to 80% of patients)

Reversible Posterior Leukoencephalopathy Syndrome (estimated to affect <0.5% of patients)

Increases in transaminases (sometimes associated with increases in total bilirubin) (estimated to affect <20% of patients)

Weight loss (estimated to affect up to 40% of patients) Headache (estimated to affect up to 45% of patients) Anorexia (estimated to affect up to 65% of patients)

Febrile neutropenia has been observed in patients with non-small cell lung cancer (NSCLC) who received cediranib in combination with carboplatin and paclitaxel.

Patients will have their blood pressure monitored at baseline and then weekly for the first 3 cycles, by patient self monitoring, clinic or GP as preferred by patient/clinician. If normotensive continue monitoring on day 1 of each cycle. If hypertensive, blood pressure should be monitored daily until <grade 2.

Patients will be instructed that if their self-checked blood pressure exceeds 140/90mmHg then they should have their blood pressure checked by a nurse, GP or physician.

If your patient develops hypertension then this will be actively treated according to an algorithm which has been developed alongside development of the drug. A simplified version is reproduced below with the steps that we would like you to follow if you are asked to check a patient’s blood pressure reading.

ICON6


GRADE 1 diastolic > 20mm/Hg above baseline Note blood pressure level in patient’s diary and reassure.

GRADE 2

Persistent mild HT

(140-149/90-99)

Note blood pressure level in patient’s diary. Ask patient to make a hospital clinic appointment if no routine visit within one week.

Persistent moderate HT

(150-179/100-109)

Note blood pressure level in patient’s diary.

Start/add long acting dihydropyridine calcium-channel blocker e.g. nifedipine, amlodipine.

GRADE 3

Severe HT

(SBP>180mmHg and/or

DBP >110)

If asymptomatic, ask patient to stop Trial Drug.

Refer to clinic for immediate antihypertensive therapy with 2 drug combination including at least a DHP CCB

If symptomatic: ask patient to stop Trial Drug. Refer to clinic for hospitalisation for close monitoring/intensive treatment.

GRADE 4

Hypertensive crisis Urgent medical management and permanently discontinue Trial

Drug

Cediranib is highly protein bound and is potentially metabolised by hepatic P450 enzyme systems. There is therefore the potential for interaction with warfarin.

There is insufficient data on other concomitant medications that may significantly affect hepatic P450 drug metabolising activity by way of enzyme induction and inhibition to specifically contraindicate or permit their use. It therefore may be best to avoid the use of very potent inhibitors of CYP3A4 and 2C8 such as amiodarone, clarithromycin, erythromycin, simvastatin, atorvastatin, lovastatin, montelukast sodium, verapamil, ketoconazole, miconazole, indinovir (and other antivirals) and diltiazem within 2 weeks of the first dose of cediranib and throughout the trial period.

Patients may switch to using zafirlukast instead of montelukast sodium, following the label recommendations, as it is not listed as a strong inhibitor of CYP3A4. The statins, rosuvastatin, fluvastatin and pravastatin are not CYP3A4 inhibitors and therefore can be used without risk of interaction with cediranib. If further treatment with a statin is required women on any other statin at the time of screening and randomisation should have a two week washout period before starting Trial Drug and changed to one of the statins listed above. Although the dihydropyridine calcium-channel blockers nifedipine and amlodipine are both metabolised via CYP 3A4 these drugs have been used with cediranib in other trials and can be used in the management of cediranib induced hypertension. Patients have also been advised to avoid grapefruit juice and St John’s wort which are hepatic cytochrome P450 inhibitors.

We recommend that essential medication that may markedly affect renal function (including ibuprofen) should be used with care particularly in patients receiving cisplatin as part of their chemotherapy regimen.

ICON6


Please find enclosed a copy of the Patient Information Sheet for this trial, as well as a trial summary. You will be kept up to date with your patient’s progress but if you have any concerns or questions regarding this study please contact the responsible doctor:

Dr _____________________________ at __________________________ (Hospital)

Tel: ____________________________

If the patient contacts you and is unwell, or you are worried, please contact the above doctor, or if out of hours then contact

____________________________________________________________________

Kind regards,

Name: ________________________________________________

Position: ______________________________________________

ICON6 Trial Summary for GPs Trial Design and Rationale ICON6 is a randomised three arm, double blind, placebo controlled, multistage, multicentre phase III trial. It has been designed to evaluate the safety and efficacy of adding cediranib during, and after, chemotherapy for patients with ovarian carcinoma relapsing six or more months after completion of first line platinum based chemotherapy. Solid tumours must develop and maintain a new vasculature in order to grow and survive (a process known as angiogenesis). One of the main factors promoting this, produced by tumour and normal cells, is Vascular Endothelial Growth Factor (VEGF). There is pre-clinical and clinical data demonstrating the importance of VEGF in the growth and development of ovarian cancer. Cediranib is an orally active potent inhibitor of the tyrosine kinase activity of the VEGF receptor. Cediranib is expected, at chronic oral dosing, to inhibit VEGF-driven angiogenesis and hoped therefore to constrain tumour growth. Patients to be included Patients with relapsed epithelial ovarian, fallopian tube or primary serous peritoneal carcinoma who require platinum based chemotherapy for first relapse six or more months after completion of first line platinum-based therapy will be eligible. The trial aims to accrue 470 patients worldwide. The trial is planned in two stages with formal review by the Independent Data Monitoring Committee at the end of each stage. Progression from the first stage to the second stage occurs only if certain endpoints are met. Trial Design The first stage was to evaluate treatment toxicity. The trials Independent Data Monitoring Committee met in December 2009 and concluded that cediranib could be given without a pre-specified level of excess toxicity thus allowing accrual to continue into the second stage. The second stage, which is now recruiting patients, will evaluate whether the addition of cediranib to standard chemotherapy confers a benefit on progression-free survival. Treatment of Patients in the Trial

ICON6


The standard treatment of patients with ovarian cancer relapsing six or more months after completion of their initial chemotherapy is platinum-based chemotherapy. Chemotherapy is usually given for up to 6 cycles every 3 weeks. Patients in all three arms of the trial will receive standard chemotherapy. The preferred standard chemotherapy treatment in ICON6 is carboplatin and paclitaxel (as this was established as the standard of care for these patients from the results of the ICON4/OVAR2.2 trial) however carboplatin alone may be used, at the discretion of the treating physician for reasons of previous toxicity, or unwillingness on the part of the patient. Some sites will be allowed to use gemcitabine and carboplatin in combination, but the site must be approved by the Trial Management Group to do this.

In certain situations cisplatin can be given in place of carboplatin. Other regimens are not allowed because there may be limited information on safety and tolerability in combination with cediranib.

All patients treated on ICON6 will take an oral tablet of Trial Drug once daily, in addition to their chemotherapy. After randomisation Trial Drug treatment will continue daily up to 18 months from randomisation or may continue until disease progression, if in the opinion of the clinician, there is continuing clinical benefit and the patient wishes to continue (whilst supply lasts). Patients in arm A will receive placebo both during chemotherapy and as maintenance afterwards. Patients in arm B will receive cediranib tablets (20mg starting dose) to take while on chemotherapy but will switch to placebo after completion of chemotherapy. Patients in arm C will receive cediranib (20mg starting dose) while on chemotherapy, and as maintenance afterwards. The trial is double blinded so neither the patients, doctors or researchers will know what the patient is taking. Patients are randomised to the three arms in a ratio of 2:3:3. . Non protocol anti-cancer treatment is not allowed prior to documented protocol defined disease progression. Patients may also choose to discontinue treatment at any time. Outcome Measures There are a number of outcome measures for each stage of the trial. For stage one assessing safety the primary outcome measure is safety. For stage two assessing efficacy, the primary outcome measure is progression free survival and the secondary outcome measures are overall survival, toxicity, quality of life, as well as translational research outcomes. If you have any worries, or concerns, regarding this patient or their treatment please contact their oncology team, or the emergency out-of-hours oncology service.

ICON6


GP Letter – ICON6 unblinded (To be presented on local headed paper)

[To be presented on local headed paper]

Centre Name: ………………………………....

Centre Number: …………….. ……………….

Trial Number: ………………………………..

Local date and version: _ _/_ _/_ _ _ _, V _ _._ _

A randomised trial of concurrent cediranib (with platinum-based chemotherapy) and maintenance cediranib in women with platinum-sensitive relapsed ovarian cancer.

EudraCT: 2007-001346-41

Dear Dr _______________________

Your patient, _______________________ (date of birth ___/___/_____), has been unblinded and is on the active drug cediranib. Your patient may continue cediranib until progression, if in the opinion of the treating clinician there is continuing clinical benefit (whilst supply lasts) and your patient agrees to continue treatment. Cediranib has been shown in previous studies to cause; Hypertension (up to approximately 70%, severe in 15% of patients) Nausea and vomiting (affecting up to 50% and 31% of patients respectively) Diarrhoea (mild to moderate diarrhoea estimated in 71% of patients severe in 7%) Proteinuria (observed in 12.5% patients at doses of 30 mg and above) Gastrointestinal perforation, sometimes complicated by the formation of a fistula (<

3%) Muscle weakness (estimated to affect 8% of patients) Left ventricular dysfunction, in some cases leading to cardiac failure, has been



Fatigue (estimated to occur in up to 68% of patients) Dehydration (observed in < 5% of patients with chemotherapy or cediranib related

diarrhoea and vomiting and exacerbated by reduced oral intake in patients received chemotherapy)

Hoarseness (dysphonia) (estimated to affect 52% of patients) Dry mouth (estimated to affect 9% of patients) Oral mucosal inflammation (estimated to affect 25% of patients) Elevated thyroid stimulating hormone (TSH) levels (which may be associated with

clinical hypothyroidism) (AE of hypothyroidism <6%, elevated TSH estimated to affect up to 50% of patients)

Affix patient sticker here

ICON6


Hand and foot syndrome (estimated to affect up to 17% of patients) Thrombocytopenia (CTC G1/2 in the majority of cases, seen with monotherapy and

combination treatment) (estimated to affect up to 80% of patients) Reversible Posterior Leukoencephalopathy Syndrome (estimated to affect <0.5% of

patients) Increases in transaminases (sometimes associated with increases in total bilirubin)

(estimated to affect <20% of patients) Weight loss (estimated to affect up to 40% of patients) Headache (estimated to affect up to 45% of patients) Anorexia (estimated to affect up to 65% of patients)

Cediranib is highly protein bound and is potentially metabolised by hepatic P450 enzyme systems. There is therefore the potential for interaction with warfarin.

There is insufficient data on other concomitant medications that may significantly affect hepatic P450 drug metabolising activity by way of enzyme induction and inhibition to specifically contraindicate or permit their use. It therefore may be best to avoid the use of very potent inhibitors of CYP3A4 and 2C8 such as amiodarone, clarithromycin, erythromycin, simvastatin, atorvastatin, lovastatin, montelukast sodium, verapamil, ketoconazole, miconazole, indinovir (and other antivirals) and diltiazem within 2 weeks of the first dose of cediranib and throughout the trial period.

Patients may switch to using zafirlukast instead of montelukast sodium, following the label recommendations, as it is not listed as a strong inhibitor of CYP3A4. The statins, rosuvastatin, fluvastatin and pravastatin are not CYP3A4 inhibitors and therefore can be used without risk of interaction with cediranib. If further treatment with a statin is required women on any other statin at the time of screening and randomisation should have a two week washout period before starting Trial Drug and changed to one of the statins listed above. Although the dihydropyridine calcium-channel blockers nifedipine and amlodipine are both metabolised via CYP 3A4 these drugs have been used with cediranib in other trials and can be used in the management of cediranib induced hypertension. Patients have also been advised to avoid grapefruit juice and St John’s wort which are hepatic cytochrome P450 inhibitors.

Please find enclosed a trial summary. You will be kept up to date with your patient’s progress but if you have any concerns or questions regarding this study please contact the responsible doctor:

Dr _____________________________ at __________________________ (Hospital)

Tel: ____________________________

If the patient contacts you and is unwell, or you are worried, please contact the above doctor, or if out of hours then contact

____________________________________________________________________

Kind regards,

ICON6


APPENDIX 12: International Trial Management Group*

MRC/NCRI (UK) Professor Jonathan Ledermann (Lead CI)

Professor Richard Kaplan (MRC CTU Senior Scientist) Dr. Fharat Raja (Trial Physician) Laura Farrelly (Clinical Project Manager) Elizabeth Clark (Trial Manager) Stephen Townsend (Data Manager) Andrew Embleton (Statistician) Adrian Cook (Statistician)

NCIC (Canada) Dr. Hal Hirte (Canadian CI, NCIC-CTG) Dr. Ralph Meyer (Director, NCIC-CTG) Cathy Davidson (NCIC-CTG)

ANZGOG (Australia and New Zealand) Dr. Michelle Vaughan (Aus/NZ CI, ANZGOG) Dr. Julie Martyn (Program Manager, Uni. Of Sydney) Kerri Carlton (Trials Co-ordinator, Uni. Of Sydney)

GEICO (Spain) Dr. Antonio González Martín (Spain CI, GEICO) Federico Nepote (Secretariat, GEICO)

Translational Research Professor Gordon Jayson Quality of Life Dr. Dan Stark Patient representative Dianna Fry, Sue Mannix and Eva Burnett AstraZeneca representatives Dr. Marcelo Marotti (Medical Science Director,

cediranib) Hilary Bagguley (Study Leader)

* The Trial Management Group will be made up of MRC/NCRI and NCIC only in stage 1 of the trial. The remaining groups may be involved in the trial from stage 2 onwards.

ICON6


APPENDIX 13: Carboplatin and Gemcitabine Combination

The preferred standard chemotherapy treatment in ICON6 is carboplatin and paclitaxel. However, it is recognised that some patients are unable or unwilling to receive this combination for reasons of previous toxicity. The results of the Intergroup Trial of the AGO-OVAR, NCIC CTG and EORTC GCG48 demonstrated a benefit of PFS with gemcitabine plus carboplatin compared to carboplatin alone in the second line treatment of ovarian cancer though no significant benefit was seen in overall survival. The trial was not powered to detect a difference in overall survival. This regimen may be of particular benefit in women with residual neurotoxicity from first line paclitaxel-platinum therapy, or in those in whom hair loss would not be acceptable. Information on treatment with carboplatin, paclitaxel and cisplatin is given in the main body of the protocol (section 9.2, 9.3). This appendix describes the ICON6 recommendations with respect to the use of a carboplatin and gemcitabine combination. Planned chemotherapy must be specified before randomisation. The recommendation in ICON6 is that patients are treated with carboplatin AUC 4 over 30 minutes in combination with gemcitabine 1000mg/m2 over 30-60 minutes. Gemcitabine will be given on day 1 in combination with carboplatin and on day 8 alone. Specific Drug Information: Gemcitabine Pre-medication: Day 1:

Granisetron 1 mg iv and dexamethasone 8 mg iv before chemotherapy Metoclopramide 20mg po tds for 5 days and dexamethasone 4mg po bd for 3 days

after This may be varied according to local practice

Day 8: Metoclopramide 20mg iv before chemotherapy No routine post chemotherapy anti-emetics

Gemcitabine

Use normally available stock in keeping with the standard local practice There are no special drug accountability arrangements for gemcitabine Reconstitute gemcitabine 1000mg/m2 in 500mls of N saline (Cap at 2.0 m2). Give gemcitabine as continuous infusion over 30 minutes on day 1 and day 8. Gemcitabine will be given before carboplatin on day 1.

Carboplatin given with gemcitabine

Use normally available stock in keeping with the standard local practice. There are no special drug accountability arrangements for carboplatin. Reconstitute carboplatin AUC4 (GFR calculated), in 250ml of 5% dextrose

according to local standard practice. Give carboplatin intravenously over 30-60 minutes (depending on standard local

practice).

ICON6


Allergic reactions to carboplatin are not a dose limiting toxicity and should be managed according to standard local practice. Patients may be re-challenged with increased prophylactic medications and/or slowing of infusion rates at the discretion of the treating physician. If it becomes necessary to discontinue carboplatin due to hypersensitivity then cisplatin could be substituted (see section 9.3.4).

Carboplatin Dose

The carboplatin dose should be calculated according to the Calvert formula[43] as follows

Carboplatin dose = Target AUC X (GFR + 25)

For the purpose of this protocol the GFR is considered equivalent to the creatinine clearance.

The exact dose of carboplatin therefore depends on the GFR and the method of calculating the GFR will also affect the carboplatin dose. The GFR can be calculated using a variety of different formulae (see appendix 6) and should be calculated as per local practice.

The dose of carboplatin is capped at 640mg for the carboplatin/gemcitabine regimen only. In addition, the dose of carboplatin is based on calculated formulae (appendix 6) rather than measured isotopic GFR.

If the estimated serum creatinine clearance is <50 ml/minute, then a formal measurement of the GFR is required, using either a 24 hour urine collection or an isotopic clearance as patients with creatinine clearance of <50 ml/minute are excluded from the trial. If the isotopic clearance is measured then the value uncorrected for body surface area (BSA) should be used in dose calculations.

The GFR should be recalculated for

Renal toxicity (CTC Grade 2, serum creatinine >1.5 x ULN), Serum creatinine changes of ≥ 10% compared to baseline, or last creatinine value

used to calculate carboplatin dose (whichever is most recent), Each dose modification of carboplatin, Cycle 2, if there has been significant doubt about the true GFR at cycle 1

(according to clinical judgement).

Dose capping of gemcitabine may be carried out according to standard local practice. Carboplatin dose should be capped at 640mg when given in combination with gemcitabine. Cisplatin Dose Cisplatin should only be substituted in patients with carboplatin hypersensitivity.

The recommended dose of cisplatin is 75mg/m2 three weekly, and a minimum of 50mg/m2 three weekly should be used.

Use normally available stock in keeping with standard local practice. Reconstitute cisplatin with water for injections such that the reconstituted solution

contains 1mg/ml of cisplatin A suggested regimen for cisplatin administration is:

ICON6


o Prehydration: 1000ml 0.9% saline with 20mmols potassium chloride over 1 hour, followed by 100ml 10% mannitol over 15 minutes

o Cisplatin in 1000ml 0.9% saline with 20mmol potassium chloride over 1 hour

o Posthydration: 1000ml 0.9% saline with 20mmol potassium chloride and 10mmol magnesium sulphate over 1 hour

Platinum infusion should follow gemcitabine and anti-emetics should be given according to local practice. Cisplatin should only be given if urine output is adequate. It is highly emetogenic and 5HT3 antagonists with or without aprepitant should be considered.

If it becomes necessary to discontinue cisplatin then patients should stop gemcitabine too as there is no good evidence for single agent gemcitabine in this setting. If patients stop chemotherapy for toxicity before 4 cycles of platinum chemotherapy then the Trial Drug should also be stopped, if they stop for toxicity after 4 cycles of platinum chemotherapy the Trial Drug can be continued (see section 9.1).

Cisplatin dose modifications should be in accordance with the guidance given in the tables below.

General Information on Gemcitabine, Carboplatin and Cisplatin. These drugs are not investigational products in the trial. Their toxicities alone and in combination are well established, however, there may be previously unrecognised toxicities that occur in combination with cediranib. In order to maintain consistency in dose and administration between participating GCIG groups and individual sites, a standard approach to dose modifications and delays is being applied and the guidance below should be followed for patients who develop adverse events. Expected Adverse Events with Gemcitabine, Carboplatin and Cisplatin

A list of expected toxicities (based on the current UK SPCs) associated with carboplatin, cisplatin and gemcitabine which will assist the treating physician in the classification of expectedness of serious adverse reactions is given in the investigator site file. The SPCs, or equivalent national pharmaceutical source list, should be referred to for specific guidance.

Dose Modifications and Delays of Gemcitabine given with Carboplatin (or Cisplatin).

Haematological Toxicity

In order to maintain the dose-intensity and cumulative dose-delivery of carboplatin (or cisplatin) ± gemcitabine chemotherapy, reasonable efforts should be made to minimise dose reduction and treatment delays. Patients whose treatment is delayed because of adverse events should be evaluated at weekly intervals (or less) until adequate recovery has occurred. There are no dose escalations planned (including dose re-escalation after a dose reduction). Patients who do not tolerate two separate carboplatin (or cisplatin) and/or gemcitabine dose reductions should discontinue treatment with chemotherapy, but may continue treatment with Trial Drug if they have received a minimum of 4 cycles of platinum chemotherapy as described in the protocol (section 9.1). Any uncertainties about continuation should be discussed with the Lead Chief Investigator or the Trial Physician. The Trial Drug dose will not be affected by toxicities related to only chemotherapy.

If a patient experiences several toxicities and there are conflicting recommendations, please follow the most conservative dose adjustment recommended to minimise doses given.

ICON6


On Day 1 of any cycle, full doses of both chemotherapy drugs will be given if pre-chemotherapy full blood count on day 1 of the cycle:

ANC is ≥ 1.5 x 109/l PLT count ≥100 x 109/l

Dose limiting toxicities are defined, and dose modifications mandated, in Table below.

Patients who fail to recover adequate counts after a delay of 2 weeks or more, or who have consecutive dose limiting toxicities, are not likely to be able to tolerate standard doses of chemotherapy with carboplatin (or cisplatin) + gemcitabine. If it is considered in the patient’s best interest to remain within the trial and to continue to receive treatment according to the trial protocol, then significant modifications of chemotherapy dose or schedule may be required. Such extreme modifications are likely to be rare and should therefore be discussed on a case by case basis with the Chief Investigators or the Trial Physician. In this situation patients may continue to receive Trial Drug (if they have received a minimum of 4 cycles of platinum chemotherapy).

Any deviation from the proposed dose modification schedule should be discussed with the Lead Chief Investigators or the Trial Physician.

Table: Dose levels for Gemcitabine + Carboplatin and Cisplatin

Drug Protocol Starting Dose



Gemcitabine 1000 mg/m2 on days 1 and 8

800 mg/m2 on days 1 and 8

800 mg/m2 on day 1 Omit day 8

Carboplatin AUC4 AUC4 AUC4

Cisplatin 75 mg/m2 60 mg/m2 50 mg/m2

ICON6


Dose reductions will follow the following scheme.

Haematological toxicity Gemcitabine Day 1

Carboplatin Day 1

Cisplatin Day 1

Gemcitabine Day 8

Day 1 Full blood count Neutrophil <1.5 OR Plt <100 (Protocol Starting Dose)

Delay until recovery then full dose



Delay in Day 1 of >1 week or ≤2 weeks OR Neutropenic fever OR Grade IV thrombocytopenia (Protocol Dose Level -1)

800 mg/m2 AUC 4 60mg/m2 800 mg/m2

Further occurrence despite first dose reduction (Protocol Dose level -2)

800 mg/m2 AUC 4 50mg/m2 Omit drug

Day 8 Gemcitabine – Dose modifications for Day 8 gemcitabine will be based on a full blood count taken within 24 hours of treatment for each cycle. If day 8 gemcitabine is omitted for one cycle it can still be given on subsequent cycles depending on the full blood count.

Day 8 blood count Gemcitabine dose

Neutrophils 1.5 AND platelets 100 100% dose Neutrophils 1.0 to 1.4 AND/OR platelets 75-99

50% dose

Neutrophils 1.0 AND/OR platelets 75 Omit dose

Dose levels should be adjusted independently for each drug If there are still problems after 2 dose reductions then patients should be discussed on an individual basis with the Lead Chief Investigator or Trial Physician

Patients should be treated for anaemia according to local practice.

Non Haematological Toxicity (apart from hypertension)

In general, in cases of severe non-haematological toxicity i.e. grade 3 or 4 (except nausea and vomiting), chemotherapy should be delayed or a dose reduction should be implemented. Once dose has been reduced there should be no dose re-escalation.

Renal toxicity

There are no specific dose reductions for gemcitabine in the case of renal toxicity. The administered dose of carboplatin must however be recalculated based on a measured GFR, for

Renal toxicity (CTC grade 2, serum creatinine >1.5 x ULN) Changes in serum creatinine of ≥ 10%, compared to their baseline serum

creatinine value or value most recently used to calculate carboplatin dose Each dose modification of carboplatin Cycle 2, if there has been significant doubt about the true GFR at cycle 1

ICON6


Renal toxicity – cisplatin

Cisplatin produces cumulative nephrotoxicity. Renal function and serum electrolyte (magnesium, sodium, potassium and calcium) should be evaluated prior to initiating cisplatin treatment and prior to each subsequent course of therapy.

Dosage should be reduced for patients with renal impairment in line with standard local practice.

Special care has to be taken when cisplatin-treated patients are given concomitant therapies with other potentially nephrotoxic drugs.

For other non haematological toxicities see section 10.3.2.2.

Gemcitabine related toxicities:

Hepatic toxicity

Administration of gemcitabine in patients with concurrent liver metastases or a pre-existing medical history of hepatitis, may lead to exacerbation of underlying hepatic insufficiency.

Patients with hepato-toxicity secondary to gemcitabine of CTCAE grade 2 or greater will have chemotherapy delayed until resolution of toxicity to grade 0 or 1.

Pulmonary Toxicity

Pulmonary effects have been reported in association with gemcitabine therapy (e.g. rarely pulmonary oedema, interstitial pneumonitis or ARDS). If CTCAE grade 2 or greater toxicity occurs gemcitabine should be stopped.

Hypersensitvity

Hypersensitivity reactions with gemcitabine are not an expected toxicity.

Carboplatin: A hypersensitivity reaction to carboplatin should be managed according to standard local practice. Patients may be retreated according to standard local practice, including escalations of hypersensitivity prophylaxis, in-patient monitoring and increases in the duration of the infusion. Cisplatin can be substituted for carboplatin. The dose and schedule of administration should be according to local practice and the usual monitoring when substituting carboplatin for cisplatin.

Other

There are no dose modifications planned for alopecia, nausea, diarrhoea or constipation. These side effects should be treated with supportive medical measures. Non-steroidal agents can be used prophylactically or symptomatically as per local practice.