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Sponsor Protocol N°: CSET
EudraCT N°:
PHASE I / II STUDY OF SEQUENTIAL HIGH-DOSE CHEMOTHERAPY WITH STEM CELL SUPPORT IN
CHILDREN YOUNGER THAN 5 YEARS OF AGE WITH HIGH-RISK MEDULLOBLASTOMA
Abbreviated Protocol Title: HR MB - 5
Version n° 1.0 – 12/06/2012
COORDINATING INVESTIGATOR
Coordinating Investigator: Dr Christelle DUFOUR Address: 114 rue Edouard Vaillant – 94805 Villejuif Phone: 01 42 11 42 47 Fax: 01 42 11 52 75 Email: [email protected]
SPONSOR
Institut Gustave Roussy
114, rue Edouard Vaillant
94 805 Villejuif
France
Signature of the Clinical Research Department Directeur:
Date :
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STUDY CONTACTS
Name and Address Telephone Number/Fax Number
Sponsor Institut Gustave Roussy 114 rue Edouard Vaillant F-94805 Villejuif Cedex
Coordinating Investigator
Dr Christelle DUFOUR Département de pédiatrie Institut Gustave Roussy
Tel: 01 42 11 42 47 fax: 01 42 11 52 75 [email protected]
Co-coordinating investigator
Dr Nicolas ANDRE Hôpital pour enfants la Timone Hématologie &Oncologie Pédiatrique Avenue Jean Moulin 13385 Marseille cedex
Tel : 04 91 38 68 21 Fax : 04 91 38 68 32 [email protected]
Inclusion management/ Statistician/Data manager
Statistician : Dr Marie-Cécile LE DELEY Institut Gustave Roussy Data manager: Katty MALEKZADEH
Tel: 01 42 11 54 44 [email protected] Tel : 01 42 11 41 96 Fax : 01 42 11 52 58 [email protected]
Monitoring Thibaud MOTREFF Institut Gustave Roussy
Tel : 01 42 11 66 43 Fax : 01 42 11 62 90 [email protected]
Pharmacovigilance Dr Salim LAGHOUATI UFPV - DRCT Institut Gustave Roussy
Tel: 01 42 11 61 00 fax: 01 42 11 61 50 [email protected]
Pharmacy Dr Sylvie DEMIRDJAN Institut Gustave Roussy
Tel: 01 42 11 48 07 fax: 01 42 11 60 70 [email protected]
Anatomical pathology
Pr. Marie-Bernadette DELISLE Laboratoire d'Anatomie Pathologique C.H.U Rangueil (Bât. L3) 1 Avenue Jean Poulhès 31400 TOULOUSE
Tel : 05 61 32 27 05 Fax. 05 61 32 20 84 [email protected]
Radiotherapy
Dr. Christian CARRIE Département Radiothérapie Centre Léon Bérard, 28 rue Laennec 69373 LYON Cedex 08
Tel : 04 78 78 26 52 Fax: 04 78 78 51 40 [email protected]
Radiotherapy
Dr Laetitia PADOVANI Hopital de la Timone 264 rue St Pierre 13005 Marseille
Radiology Pr. Anne GEOFFRAY Imagerie médicale – Fondation Lenval. 57 avenue de la Californie 06200 NICE
Tel : 04 92 03 03 11 Tel : 04 92 03 03 12 Fax: 04 92 03 04 35 [email protected]
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Surgery
Pr Matthieu VINCHON Hôpital Roger Salengro Rue du Pr. Emile Laine 59037 LILLE Cedex
Tel : 03 20 44 64 64 Fax : 03 20 44 55 11 [email protected]
Rehabilitation
Docteur Mathilde CHEVIGNARD Hôpitaux de Saint Maurice 14, rue du val d'Osne 94415 Saint Maurice cedex
Tél : 01 43 96 63 40 [email protected]
Pharmacokinetics – pharmacogenetic Busulfan
Dr Angelo PACI Service de pharmacologie et d’analyse du médicament Institut Gustave Roussy
Tel : 01 42 11 47 30 Fax : 01 42 11 52 77 [email protected]
Pharmacokinetics – pharmacogenetic Cyclophosphamide
Dr Gareth VEAL Northern Institute for Cancer Research Paul O’Gorman Building North Terrace Newcastle upon Tyne NE2 4AD United Kingdom
Tel : +44 (0)191 246 4332 Fax: +44 (0)191 222 3452 [email protected]
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SYNOPSIS – PROTOCOL N° (CSET)
A) IDENTIFICATION OF CLINICAL TRIAL EudraCT NUMBER: VERSION AND DATE : 1.0 12/06/2012 STUDY TITLE: PHASE I / II STUDY OF SEQUENTIAL HIGH-DOSE CHEMOTHE RAPY WITH STEM CELL SUPPORT IN CHILDREN YOUNGER THAN 5 YEARS OF AGE WITH HIGH-RISK MEDULLOBLASTOMA ABBREVIATED TITLE : HR MB-5
COORDINATING INVESTIGATOR : Dr Christelle DUFOUR
Total France
NUMBER OF CENTRES: 28 28
NUMBER OF PATIENTS : 50 50
B) IDENTIFICATION OF SPONSOR Institut Gustave Roussy 114 rue Edouard Vaillant – 94 805 VILLEJUIF FRANCE Tel.: 01 42 11 48 84 Fax: 01 42 1162 90
C) GENERAL INFORMATION ON STUDY INDICATION: High-risk medulloblastoma
METHODOLOGY: Multicentre, non-randomised, Phase I/II Trial, using a Bayesian design
PRIMARY OBJECTIVES : Phase II: To assess the efficacy in terms of Event Free Survival (EFS) of the strategy intended to treat children younger than 5 years of age suffering from high-risk medulloblastoma with sequential high-dose chemotherapy without radiotherapy. Phase I: To determine the Maximum Tolerated Dose (MTD) of cyclophosphamide in combination with a fixed dose of busilvex in children with high-risk medulloblastoma who are in complete response after the intensification phase. SECONDARY OBJECTIVES :
• To assess feasibility and efficacy of a strategy without radiotherapy by estimating the rate of patients alive free of disease without having received radiation therapy
• To assess efficacy of this strategy in terms of Overall Survival (OS) • To assess the proportion of radiological tumour response (complete and partial response)
of VP16-Carboplatin courses • To assess the proportion of patients achieving complete response after 2 courses of
VP16-carboplatine followed by 2 courses of thiotepa • To characterize the pharmacokinetics of cyclophosphamide – busilvex combination
(Phase I) • To assess efficacy, feasibility and tolerance of salvage treatment • To evaluate the acute toxicity of this therapeutic strategy, overall and by treatment phase
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(induction / intensification / consolidation) • To evaluate the prognostic value of some immunohistochemical markers on the risk of
relapse or progression • To evaluate neurocognitive development of patients within 10 years after the end of
treatment INCLUSION CRITERIA:
• Histological diagnosis of medulloblastoma with no INI-1 loss • High risk medulloblastoma defined by at least one of the following conditions:
• Newly diagnosed classical metastatic medulloblastoma • Newly diagnosed anaplastic/large cell medulloblastoma • Newly diagnosed medulloblastoma with amplification of c-myc or N-myc
• Age at study entry less than 5 years of age • Weight > 8 kgs • Ability to comply with requirements for submission of materials for central review • Nutritional and general status compatible with this therapy, Lansky play score ≥ 30% • Estimated life expectancy ≥3 months • No organ toxicity other than alopecia and neurological symptoms due to disease (grade
>2 according to NCI-CTC v4 grading system) • No prior irradiation or chemotherapy (except VP16 – CBP) • Written informed consent from parents or legal guardian
INCLUSION CRITERIA FOR THE PHASE I PART OF THE STUDY: • Complete response after intensification phase confirmed by central review • Adequate hepatic and renal function
NON-INCLUSION CRITERIA :
• Desmoplastic medulloblastoma • Atypical Teratoid rhabdoid tumour • Uncontrolled active or symptomatic intracranial hypertension before chemotherapy
treatment • Patient incapable of undergoing medical follow-up
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D) DESCRIPTION OF STUDY TREATMENTS
TREATMENT DURATION : 6 to 12 months depending on the response
E) STATISTICAL CONSIDERATIONS PRIMARY ENDPOINT:
• For the whole study: Event-free survival • For the Phase I part of the study: Dose-Limiting Toxicity
SECONDARY ENDPOINTS: • Radiotherapy-free survival without event • Overall survival • Response (complete and partial response) to conventional chemotherapy assessed after
the first two courses • Complete response to induction and intensification phases assessed after the two
courses of thiotepa • Toxicity according to NCI-CTC v4 grading system, in particular after the course of
cyclophosphamide in combination with busilvex to estimate the maximum tolerated dose of cyclophosphamide in this setting (phase I part).
• Pharmacokinetics of cyclophosphamide and Busilvex • Response to salvage treatment • Cognitive assessments
TRIAL DESIGN The trial includes i) the evaluation of the efficacy of a treatment strategy, designed as a phase II trial, and ii) a dose-finding part. The Phase II trial is an open label, non-randomized, multicentre trial without control group. A Bayesian approach will be used to analyse the EFS, assuming a cure model. We will use three prior distributions of the EFS; (1) an enthusiastic prior distribution, (2) a pessimistic prior distribution, and (3) a non-informative prior distribution. As the patient outcomes in the trial will be recorded, the subsequent distribution of the outcome probability under experimental treatment will be computed by applying Bayes’ theorem, which yields an estimated EFS probability with a
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95% credibility interval (measure of Bayesian precision). Interim analyses are planned to monitor the efficacy data (early stopping rules for futility or inefficacy). The final analysis of efficacy will be made on an intention to treat basis, including all recruited patients, 3 years after recruitment of the last patient. Due to the uncertainty on the dose of cyclophosphamide that can be given in combination with busilvex for the last chemotherapy course in patients in complete response after intensification chemotherapy treatment, a dose-finding subtrial will be performed to address this issue (Phase I part). The dose escalation of cyclophosphamide will be performed using the Continual Reassessment Method in a Bayesian framework. SAMPLE SIZE Phase II part: In theory, Bayesian approach does not need to define a sample size in advance in order to obtain reliable results. However considering classical frequentist approach, 50 patients would be required if we had used a one-sample logrank test, with the following assumptions: statistical power of 0.85 for a 3-year improvement of 20% compared to historical data; type I error rate (one-sided) of 0.05. This sample size is reasonable considering possible accrual. We thus decided to recruit about 50 patients in the trial. Phase I part: All the patients in complete response after intensification chemotherapy treatment, eligible for the consolidation course of cyclophosphamide-busilvex course, will be included in the phase I part of the trial. They will be treated at the best current estimate of the MTD. Approximately 50% of the patients entering the trial are expected to be recruited in the phase I. ACCRUAL PERIOD: 5 YEARS
TREATMENT PERIOD: 6 TO 12 MONTHS
FOLLOW-UP PERIOD FOR THE MAIN ENDPOINT: 3 years OVERALL DURATION OF STUDY : 9 YEARS
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TABLE OF CONTENTS 1. INTRODUCTION AND RATIONAL OF THE STUDY ............. ................................................13 1.1 Information on the disease.........................................................................................................13
1.1.1 Medulloblastoma.................................................................................................................................... 13
1.1.2 Biology of medulloblastoma................................................................................................................... 13
1.1.3 Stratification of medulloblastoma........................................................................................................... 15 1.2 Information on treatments in medulloblastoma...........................................................................15
1.2.1 Induction chemotherapy ............................................................................................................................ 17
1.2.2 Intensification chemotherapy..................................................................................................................... 18
1.2.3 Consolidation chemotherapy..................................................................................................................... 19
1.2.4 Salvage treatment ..................................................................................................................................... 20
2. STUDY OBJECTIVES................................... .........................................................................24 Primary objective .............................................................................................................................24 Secondary objectives ......................................................................................................................25
3. STUDY DESIGN ....................................................................................................................25 Study centres ..................................................................................................................................25 Study period ....................................................................................................................................26
4. SELECTION OF PATIENTS .............................. ....................................................................26 4.1 Inclusion criteria for the study ....................................................................................................26 4.2 Non-inclusion criteria .................................................................................................................27 4.3 Inclusion criteria for the Phase I part of the study ......................................................................27
5. PATIENT REGISTRATION ............................... .....................................................................27
6. TREATMENTS.......................................................................................................................28 6.1 Surgery......................................................................................................................................29
6.1.1 Initial surgery for patients treated at diagnosis...................................................................................... 29
6.1.2 Secondary surgery .................................................................................................................................... 30 6.2 Induction phase .........................................................................................................................30
6.2.1 Drug administration ................................................................................................................................... 30
6.2.2 Patient monitoring...................................................................................................................................... 31
6.2.3 Concomitant therapies .............................................................................................................................. 31 6.3 Intensification phase..................................................................................................................31
6.3.1 Drug administration ................................................................................................................................... 31
6.3.2. Dose adaptation ....................................................................................................................................... 32
6.3.3 Patient monitoring...................................................................................................................................... 32
6.3.4 Concomitant therapies .............................................................................................................................. 32 6.4 Consolidation phase: Phase I ....................................................................................................32
6.4.1 Drug administration ................................................................................................................................... 33
6.4.3 Patient monitoring...................................................................................................................................... 34
6.4.4 Concomitant therapies .............................................................................................................................. 34 6.5 Salvage treatment .....................................................................................................................35
6.5.1 Salvage treatment’s first step: TEMIRI...................................................................................................... 36
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6.5.2 Chemo-radiotherapy.................................................................................................................................. 36
6.5.3 Maintenance treatment.............................................................................................................................. 40 6.6 Treatment Discontinuation .........................................................................................................40
7. BASELINE AND FOLLOW-UP ASSESSMENTS................. ..................................................41 7.1 Baseline assessments ...............................................................................................................41 7.2 Follow-up assessments during treatment and at the end of treatment .......................................43 7.3 Follow-up assessments after treatment .....................................................................................45
8. PK / PD / PG STUDIES..........................................................................................................45
8.1 BUSULFAN .................................................................................................................................................. 46
9. EVALUATION CRITERIA ................................ ......................................................................48 9.1 Primary endpoint .......................................................................................................................48 9.2 Secondary endpoints .................................................................................................................49
10. STATISTICAL CONSIDERATIONS ......................... ..............................................................50 10.1 Study design............................................................................................................................50 10.2 Sample size .............................................................................................................................51 10.3 Statistical analysis ...................................................................................................................52
10.3.1 Analysis of the main endpoint ................................................................................................................. 52
10.3.2 Others analyses....................................................................................................................................... 53
10.3.3 Phase I analyses ..................................................................................................................................... 54 10.4 Analysed population ................................................................................................................55 10.5 Monitoring of toxicity and stopping rules ..................................................................................55
10.5.1 Toxic death .............................................................................................................................................. 55
10.5.2 Severe toxicity ......................................................................................................................................... 56
11. ADVERSE EVENT COLLECTION & REPORTING............... .................................................57 11.1 Definition .................................................................................................................................57 11.2 Recording and assessing adverse events................................................................................59 11.3 Intensity criteria .......................................................................................................................61 11.4 Reporting of serious adverse events........................................................................................61 11.5 Follow-up.................................................................................................................................63 11.6 Information given to investigators, ethics committee and regulatory authority ..........................63
12. INDEPENDENT DATA MONITORING COMMITTEE.............. ...............................................64
13. STUDY DISCONTINUATION .................................................................................................64
14. ETHICAL AND REGULATORY ASPECTS..................... .......................................................65 14.1 Rules and regulations ..............................................................................................................65 14.2 Committee for the Protection of Persons (CPP) – Competent Authority...................................65 14.3 Information and Consent of Participants ..................................................................................66 14.4 Principal Investigator Responsibilities ......................................................................................66
15. DATA COLLECTION .................................... .........................................................................67
16. QUALITY ASSURANCE - MONITORING ..................... .........................................................67 16.1 Monitoring................................................................................................................................67 16.2 Central review..........................................................................................................................68
16.2.1 Central radiological review ...................................................................................................................... 68
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16.2.2 Central histology review .......................................................................................................................... 68
17. DATA OWNERSHIP / PUBLICATION POLICY ................ .....................................................68
REFERENCES................................................................................................................................70
APPENDIX A: LANSKY SCALE........................... ..........................................................................76
APPENDIX B: PERIPHERAL STEM CELL COLLECTION........ .....................................................77
APPENDIX C: IMAGING PROCEDURES..................... ..................................................................78
APPENDIX D: BUSILVEX (IV BUSULFAN) SAMPLING SHEET ...................... ..........................81
APPENDIX E : CYCLOPHOSPHAMIDE PHARMACOKINETICS SAMP LING SHEET ..................83
APPENDIX F: CLASSIFICATION CTC-AE (VERSION 4.0).... ........................................................85
APPENDIX G: TOXICITY AFTER HIGH DOSE CHEMOTHERAPY ( BEARMAN GRADING) ........86
APPENDIX H: STATISTICAL MODEL, SPECIFIC RULES AND O PERATING CHARACTERISTICS OF PHASE I DESIGN.................. .................................................................87
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List of abbreviations ALAT: Alanine Amino Transferase
ANSM: French competent authority (Agence nationale de sécurité du medicament et des produits de santé)
ASAT: Aspartate Amino Transferase
ASCT: Autologous Stem Cell Transplantation
AT/RT: Atypical Teratoid/Rhabdoid Tumour
CCE: Carboplatin – Cyclophosphamide - Etoposide
CNS : Central Nervous System
CPP: French ethic committee (Comité de Protection des Personnes)
CR: Complete Response
CRA: Clinical Research Assistant
CRF: Case Report Form
CSF: Cerebrospinal Fluid
CSI: Craniospinal Irradiation
CT: Computed Tomography
CTV: Clinical Target Volume
DLT: Dose Limiting Toxicity
DRR’s: Digitally Reconstructed Radiographs
EFS: Event Free Survival
G-CSF: Granulocyte Colony-Stimulating Factor
GTV: Gross Tumour Volume
HDCT: High-Dose ChemoTherapy
HDM: High-Dose Melphalan
IGR: Institut Gustave Roussy
ITT: Intent-to-Treat
MB: Medulloblastoma
MRI: Magnetic Resonance Image
MTD: Maximum Tolerated Dose
NCI-CTCAE V4: NCI Common Terminology Criteria for Adverse Events version 4.0
OS: Overall Survival
PBSC: Peripheral Blood Stem Cells
PD: Progressive Disease
PF: Posterior Fossa
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PFS: Progression-Free Survival
PNET: Primitive NeuroEctodermal Tumours
PR: Partial Response
PTV: Planning Target Volume
SAE: Serious Adverse Event
SD: Stable Disease
TMA: Tissue Micro-Array
VOD: Hepatic Veno occlusive Disease
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1. INTRODUCTION AND RATIONAL OF THE STUDY
1.1 Information on the disease
1.1.1 Medulloblastoma
Medulloblastoma (MB) is one of the most common malignant brain tumours during
childhood accounting for a 5-year overall survival at 70% to 80% for standard-risk
patients, and a 5-year survival of 55% to 76% for high-risk patients [1].
MB and other central nervous system (CNS) embryonic tumours are usually classified
according to their location within the CNS, and their histological features. The WHO
classification [2] identifies 5 histological variants: (a) the classical variant MB, in which
the cells occasionally display features of neuroblastic differentiation; (b) desmoplastic
MB, in which tumour cells commonly show neurocytic differentiation, and are
surrounded by a collagen-rich extracellular matrix; (c) large-cell / anaplastic MB,
associated with poor prognosis and short survival; and finally (d) the melanotic and (e)
medullomyoblastoma variants, which are less common [1].
1.1.2 Biology of medulloblastoma
Medulloblastoma (MB) is a heterogeneous disease at the molecular level and no
diagnostic cytogenetic or molecular abnormality has been identified. Nonetheless, a
series of major non-random molecular genetic abnormalities have been identified in
the human disease, which (i) have furthered our understanding of the molecular
mechanisms underlying its pathogenesis and (ii) offer significant potential for improved
treatment stratification and/or the identification of novel therapeutic targets. In
particular, a number of consistent chromosomal abnormalities have been identified, as
well as critical oncogenes and tumour suppressor genes, and an involvement for
specific molecular pathways.
Genomic abnormalities
Numerous studies have been performed on medulloblastoma though they often
involved only limited retrospective series. The two most frequently recurring
abnormalities are the loss of the short arm of chromosome 17 and the amplification of
the MYC (C, N and L-myc oncogenes).
The loss of the short arm of chromosome 17 is the most frequently described genetic
abnormality in MB, and may occur in up to 40 - 50% of the tumours investigated [3].
Although a limited number of studies have reported a significantly worse prognosis in
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the case of tumours with loss of 17p [4, 5], this has not been confirmed by all
investigators [6, 7]. However, these studies only enrolled a small number of patients or
used different techniques with heterogeneous levels of sensitivity to detect losses of
the 17p allele, therefore definitive conclusions are difficult to interpret.
A literature search suggests that approximately 6% of MB present an amplification of
the MYC oncogenes. Several studies have reported that these oncogenes are
predictors of a poor prognosis [8-10].
Sonic Hedgehog (SHH) Signalling
Aberrant SHH pathway activation by genetic mutation occurs in at least 15% of MB,
based on estimated from genetic data, and arises through mutations affecting multiple
alternative pathway components. In addition to PTCH1 mutations (〜 10% of cases),
SMO activating mutations have been reported in 〜 5% of cases. SUFU mutations
have also been described, although their incidence and involvement are likely to be
lower than initially reported (0-10% of cases) [11, 12]. Aberrant SHH pathway
activation appears to be associated with the development of the nodular/desmoplastic
MB histological sub-type. Similarly, PTCH mutations, deletion of chromosome 9q
elements, and SHH-associated gene expression profiles occur preferentially and in a
significant proportion (30-40%) of sporadic nodular / desmoplastic MB [12, 13].
However, the relationship between SHH defects and nodular/desmoplastic MB is not
absolute and up of 50% of SHH subgroup MBs are not nodular/desmoplastic [14].
Abnormalities of the Wnt/APC/betacatenin pathway
Cases of MB have been observed in patients with a personal or familial anamnesis of
familial polyposis of the colon, involving a hereditary mutation of the APC gene [15].
The incidence of abnormalities of this gene in sporadic forms of MB is under
investigation [16]. Wnt MBs can occur at all ages, but are uncommon in infants [14].
Investigation of this signal transduction pathway should be a priority as it was recently
shown that nuclear accumulation of β-catenin in MB tumour specimens was associated
with a favourable outcome [17]. There are metastatic cases with abnormalities of the
betacatenin route with an apparently better prognosis.
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Molecular subgroups of medulloblastoma: the current consensus.
On the basis of the published literature and some unpublished data presented at a
recent consensus conference, four molecular subgroups were identified in childhood
MB [14] : Wnt, SHH, group 3 and group 4. The Wnt and SHH were named for the
signalling pathways thought to play prominent roles in the pathogenesis of that
subgroup. Group 3 tumours are mostly « classic » MB and are found in infants and
children. Group 3 tumours have high incidence of large/anaplastic MB and, are very
frequently metastatic. The molecular Group 4 tumours are not currently clear. While
SHH subgroup tumours have high levels of amplification of MYCN, and Wnt subgroup
and Group 3 have high levels MYC expression, whereas Group 4 tumours have
relatively low expression of both MYC and MYCN, apart from the few cases that have
MYCN amplification.
1.1.3 Stratification of medulloblastoma
Based on the clinical, histopathologic and molecular criteria, patients affected by MB
may be categorized as high-risk, standard-risk and low-risk patients. The clinical
criteria followed are: extent of tumour resection and Chang metastasis staging groups
[18]. Low-risk patients are those with β-catenin-nucleopositive tumours without
metastatic disease and undergoing complete or near complete tumour resection
(largest diameter <1.5 cm2 of residual tumour on postoperative magnetic resonance
image (MRI)). High-risk medulloblastomas are defined as metastatic disease,
uncompleted resected disease, large-cell / anaplastic phenotype or MYC amplification.
Patients not fulfilling these criteria are considered standard-risk.
The 5-year survival rate of high risk MB is less than 55% [19, 20]. So far, the clinical
staging has helped to design treatment and predict prognosis.
1.2 Information on treatments in medulloblastoma
Treatment of very young children (< 3 years of age) with MB and sPNET is particularly
challenging because of the aggressive nature of these tumours and the potential long-
term sequelae related to treatment [21]. Disease-free survival for those brain tumours
in children younger than 4 years old is associated with a survival rate of less than 20%
[22]. Furthermore, late effects of therapy, in particular radiation therapy, on cognitive
function have been substantial among children treated for brain tumours at a young
age [23, 24]. Previous trials found potential for delaying and, in some cases, avoiding
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radiation therapy in treatment of young children with malignant brain tumours. The
possibility to cure MB without craniospinal radiotherapy was suggested in a pilot study
published in 1997 [25] and secondly in two large US prospective trials [26, 27] where
selected patients were cured by chemotherapy without any craniospinal radiotherapy.
In the BBSFOP protocol, the 5-year progression-free survival (PFS) and overall
survival (OS) in children who had no post-operative radiological residual disease and
no metastases was 29% and 73% respectively, and most of these children did not
receive any craniospinal radiation [28]. These findings are consistent with those of
others studies [29, 30] also including patients less than 3 years old cured without any
radiotherapy. The OS rates in localised disease could reach those observed in older
children despite omission or reduction radiotherapy and allowed us to treat them
upfront with chemotherapy alone. Metastatic disease in this age group is also a
challenging situation with a low rate of survival. In BBSFOP protocol, the 5-year PFS
and OS was 13% and 13%, respectively, in children with metastatic disease [28].
Strategies delaying the schedule of radiation therapy, usually using high dose
chemotherapies, are widely used to optimize the cure rate of these young children with
disseminated MB.
A small number of studies have evaluated the use of high-dose chemotherapy (HDCT)
with autologous stem cell transplantation (ASCT) and delayed radiation to improve
survival and minimize treatment-related sequelae. Perez et al. describe the outcome of
a small homogeneous group of children that were treated with HDCT followed by
ASCT: 7 children received HDCT with ASCT and 5/7 are alive without sequelae.
Disease-free survival was 71.4% with a median follow-up of only 21 months [31].
Mason et al. [32] evaluated HDCT with ASCT in children less than 6 years of age with
newly diagnosed malignant brain tumours (“Head start I protocol”), of whom 27 were
children with MB or sPNET. Patients received 5 cycles of induction chemotherapy
followed by consolidation chemotherapy. The 2-year OS rate was around 60%, while
event-free survival (EFS) rate from diagnosis and consolidation was reported to be 40
and 50%, respectively. The 3-year PFS was 49% [33].
In our previous study, 19 patients younger than 5 years with high-risk MB were
planned to receive two courses of carboplatin and etoposide, followed by two courses
of high-dose melphalan (HDM) and one course of high-dose busulfan-thiotepa
combination. The last three courses were followed by rescue by ASCT. Irradiation
limited to the posterior fossa was then performed. Six of the nineteen children treated
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according to this protocol are presently alive in first remission with a median follow-up
of 9 years. However, the visceral toxicity of the third course was severe and
inacceptable with 3 toxic deaths related to multiorgan failure and 11/18 (61%) cases of
hepatic veno-occlusive disease [34]. The high visceral toxicity observed led to modify
the treatment schedule. To reduce the alkylating agents’ toxicity, we introduced
between each high-dose melphalan course, a course of cisplatin and we omitted
Busulfan. Then, the treatment schedule (PNET HR) included, in absence of disease
progression after two courses of carboplatin and etoposide, five sequential
conventional and HDC followed by ASCT, i.e. melphalan, cisplatin twice each and
thiotepa. In case of persisting residual tumour, surgical excision was performed if
possible. Treatment was then completed by age-adapted craniospinal irradiation, and
not restricted to posterior fossa as in the previous protocol. The preliminary results
were encouraging. At last-update, 39 patients were evaluable. Among the 24 children
who completed procedure, 14 were in complete remission at the end of chemotherapy
and 12 were still alive without disease with a median follow-up of 30 months. The 3-
year EFS and OS were 48% and 52%, respectively [35]. This study suggests that pre-
HDCT tumour status is important for outcome: the 3-year OS was 59% in patients who
achieved partial or complete response after the induction chemotherapy. Similarly, the
3-year EFS of patients who were in complete response at the end of intensive
chemotherapy was 90%. These findings are consistent with others studies [33, 36].
These results demonstrated that children with disseminated medulloblastoma could be
also treated with HDCT avoiding radiotherapy if complete response is achieved before
radiation therapy. For patients who do not achieve a partial response initially, VP16-
Carboplatin, HDCT with ASCT may not be adequate and additional, possibly targeted,
therapies should be considered. In this study, sequential high-dose chemotherapy will
be used to treat children with high-risk medulloblastoma without radiotherapy in case
of CR.
1.2.1 Induction chemotherapy
Carboplatin alone has been proven to be effective in this tumour type [37]. Etoposide is
often used in combination with other anticancer drugs, and more particularly in
tumours of neuroectodermal origin. A phase II study evaluated the antitumor activity of
the Carboplatin - Etoposide combination in 26 children with high-risk medulloblastoma.
The response rate after two courses was 72 +/- 10% with an acceptable safety [38]. In
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our previous study, PNET HR regimen, the response rate of Etoposide-Carboplatin
was 54% [35].
1.2.2 Intensification chemotherapy
Alkylating agents appear to be the most appropriate class of drugs for use in a high-
dose setting since they are the most active drugs against CNS tumours along with
platinum derivatives. A step linear-log relationship characterizes them. Thiotepa and its
major metabolite, TEPA, reach the CSF at concentrations approximately equivalent to
their plasma concentrations [39]. They display in vitro activity against MB with a steep
dose-response curve [40].
Fagioli et al. reported a 3-year PFS of 31% in a cohort of 12 patients treated with
HDCT consisting of thiotepa and etoposide [41]. Chi et al. reported 3-years PFS of
49% for 21 patients with newly HR MB treated with HDCT (carboplatin, thiotepa,
etoposide) [33]. More recently, Thorarinsdottir et al. [42] evaluated HDCT with ASCT in
children less than 4 years with malignant central nervous system tumours, 9 of whom
were children with MB or sPNET. Patients received 3 cycles of induction
chemotherapy with vincristine, etoposide, cisplatin and cyclophosphamide, 3 weeks
apart, followed by 3 cycles of HDCT of thiotepa – carboplatin combination with ASCT.
The 2-year EFS was 52.2%.
Sung et al. [36] described 25 children with newly diagnosed HR or relapsed
MB/sPNET. After induction chemotherapy, children received tandem double HDCT
with cyclophosphamide and melphalan for the first HDCT and carboplatin, etoposide
and thiotepa for the second. The 3-year EFS in patients initially intended to receive
double HDCT and single HDCT was 66% and 40%, respectively. For patients in CR or
PR at first HDCT, 3-year EFS was 88.9% in tandem double HDCT group, and 44.4% in
single group, respectively (p = 0.037). These findings suggest that increased dose
intensity without significant toxicity in second HDCT may have contributed to the
improved survival in tandem double HDCT group.
An investigative pilot study was carried out at the Gustave Roussy Institute between
September 1996 and October 2005, in order to treat children aged over 5 years with
high-risk medulloblastoma or supratentorial PNET. The protocol included 2 courses of
conventional chemotherapy combining etoposide (500mg/m²) and carboplatin
(800mg/m²) followed by double dose-intensive chemotherapy (melphalan 100 mg/m²
or thiotepa 600 mg/m²) with stem cell rescue. If a tumour residue persisted at the end
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of this chemotherapy, the tumour was resected whenever possible. Craniospinal
irradiation was scheduled 45 days after the second intensification: 55 Gy to the primary
site, 30 Gy supratentorially and 36 Gy to the cord axis. A total of 26 children were
enrolled in this trial, including 19 metastatic medulloblastomas and 7 supratentorial
PNET. The median age at diagnosis was 8 years (5 – 14.4 years). Seventeen of these
21 children received melphalan and 9, thiotepa. The 3-year EFS after Melphalan
regimen and Thiotepa were 36.5% and 66.7%, respectively (p =0.01) [34].
In view of these results, we prefer to use high-dose thiotepa chemotherapy.
1.2.3 Consolidation chemotherapy
Cyclophosphamide
Cyclophosphamide has proven activity against many childhood solid tumours and
malignant tumours. High-dose cyclophosphamide has been demonstrated to be
effective in newly diagnosed MB [43]. Gajjar et al. recently showed a new approach:
patients with high-risk MB underwent craniospinal radiotherapy (36 Gy to 39.6 Gy)
with a three-dimensional conformal boost to the tumour bed( total 55.8 Gy) followed by
4 courses of high-dose cyclophosphamide with stem-cell rescue support to overcome
haematological toxic effect after radiotherapy [44]. They reported 5-year EFS of 83%
for the average risk patients and 70% for the HR patients. These results seem to be
excellent looking at the EFS compared with most published trials.
Busulfan
Busulfan crosses the blood-brain barrier with a CSF to plasma ratio of 1.39 when
administered at a dose of 600 mg/m2; and its tumour activity against MB xenografts has
been demonstrated in athymic nude mice [45]. The busulfan-thiotepa combination
efficiently induced a 75% response rate and cured patients with a local relapse without
additional craniospinal irradiation [46]. Ridola et al. [47] reported the outcome of 39
young children with local MB recurrence or progression after conventional
chemotherapy treated by HDCT with busulfan-thiotepa combination followed by local
irradiation. The 5-year EFS was 68.8%. Acute toxicity was manageable, and
characterised mainly by a significant percentage of hepatic veno-occlusive (VOD)
disease in 33% patients. None of the children died of liver toxicity. The liver toxicity is
reportedly caused mainly by busulfan but can be modified by the accompanying drug
[48].
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Chemotherapy combining busulfan and cyclophosphamide was identified as a major
VOD risk factor. Pharmacological studies have demonstrated a correlation between
busulfan exposure and the incidence of VOD following the busulfan-cyclophosphamide
combination [49]. Sageghi et al. [50] studied the effect of administration order of
busulfan and cyclophosphamide as a conditioning regimen for hematopoietic stem cell
transplantation in a mouse model. They showed that inverting the order of busulfan-
cyclophosphamide to cyclophosphamide-busulfan not only decreased conditioning-
related toxicity significantly, but also allowed the same level of donor hematopoietic
stem cell engraftment. A clinical trial using cyclophosphamide-busulfan as a
myeloablative conditioning regimen for HSCT was performed and the results were
compared with those of a historical control of patients with a conventional busulfan-
cyclophosphamide conditioning regimen. Significantly less hepatic toxicity was
observed in patients treated with cyclophosphamide-busulfan, and neutrophil recovery
did not differ from that in patients treated with busulfan-cyclophosphamide [51].
Cacchione et al. demonstrated that etoposide-carcoplatin combination administered
before HDCT can be a significant risk factor for the subsequent development of VOD
[52].
According to these data, we considered it is justified to use the cyclophosphamide -
busilvex combination. Due to potential toxicity of this combination after chemotherapy
containing alkylating agent, we plan a phase I study in order to determine the
Maximum Tolerated Dose (MTD) of cyclophosphamide in combination with a fixed
dose of busilvex. It is likely that the rate and the severity of VOD could be decreased
by refinement of the use of intravenous busulfan form (Busilvex) [53] and the
prophylactic use of defibrotide [54].
1.2.4 Salvage treatment
Temozolomide (TEMODAL®)
Temozolomide (TEMODAL®) has an excellent bioavailability after oral administration
with satisfactory CNS concentrations. Several paediatric trials have led to the
conclusion that temozolomide was an active drug in refractory or relapsing
medulloblastoma. First, two phase I trials [55, 56] showed efficacy in
medulloblastoma/PNET and allowed determination of the maximum tolerated dose of
Temozolomide in children (1000mg/m²/cycle). An Italian Phase II multicentre study
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showed that this molecule was effective in medulloblastoma relapses [57]. In this
study, Temozolomide was administered for 5 consecutive days, every 28 days with
dosages adjusted according to prior treatment. Treatment was continued until tumour
progression or for a maximum of 36 cycles. A total of 34 patients with metastatic MB
(32) or PNET (2) were enrolled in this study. The observed responses were 6 CR, 7 PR
and 3 minor effects, resulting in an overall 47% response rate with an acceptable
toxicity. The 6-month PFS was 67% for responding patients. Elsewhere, Nicholson and
al. reported a phase II study of temozolomide (150mg/m²/day for 5 days every 4 weeks
in children and adolescents with recurrent central nervous system tumours: 3 PR and 1
CR were observed in the medulloblastoma/primitive neuroectodermal tumour (PNET)
cohort [58]. Wang et al. reported their experience with 8 children, including four with
medulloblastoma (MB), three with atypical teratoid/rhabdoid tumour (AT/RT) and one
with supratentorial primitive neuroectodermal tumour, whose tumours recurred after
surgery and radiotherapy [59]. They all received daily oral temozolomide (150
mg/m2/day) once for five consecutive days in a 28-day cycle. The median PFS of the
eight patients was 15.7 months (range from 0 to 59 months). Complete response was
achieved in one patient with MB associated with a long lasting PFS of 26 months.
These data support the use of temozolomide for the salvage treatment of children with
refractory medulloblastoma.
Irinotecan (Hycantin®)
Irinotecan (Hycantin®) is an inhibitor of topoisomerase I and has demonstrated safety
and efficacy as a single agent in paediatric solid and CNS tumours with various
schedules. Importantly, the studies provided indications that protracted administration
such as daily x 5 for 2 weeks every 3-4 weeks/cycle could be administered safely and
were feasible.
According to Turner et al., 2 of 3 patients with medulloblastoma/primitive
neuroectodermal tumour had stable disease for 9 and 13 months. Toxicity was mainly
myelosuppression, with 12 out of 22 patients (50%) suffering from grade II-IV
neutropenia [60].
From these data and from preliminary data concerning efficacy in phase I studies,
irinotecan as a single agent can be considered as an active agent in recurrent
medulloblastoma.
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Temozolomide (Temodal®)-Irinotecan (Hycantin®) co mbination
The combination of temozolomide with irinotecan has been well evaluated in children.
Wagner and colleagues investigated the combination of protracted irinotecan and
temozolomide in a phase I study of paediatric patients with refractory solid tumours
using a 28-day cycle [61]. Twelve heavily pre-treated patients received 56 cycles of
oral temozolomide at 100 mg/m2/d for 5 consecutive days combined with intravenous
irinotecan given daily for 5 consecutive days for two consecutive weeks at either 10
mg/m2/d or 15 mg/m2/day. Two patients experienced DLT (Dose Limiting Toxicity) at the
15 mg/m2/d dose level (grade 4 diarrhoea and bacteraemia with grade 2 neutropenia),
while no DLT was experienced at the 10 mg/m2/d dose level. No pharmacokinetic
interaction was observed. One CR, 2 PR, and one minor response were observed in
patients with Ewing sarcoma and neuroblastoma. The MTD with this schedule for oral
temozolomide and intravenous irinotecan were 100 mg/m2/d and 10 mg/m2/day,
respectively [61]. Elsewhere, based on their previous phase I study, Wagner et al.
reported on the combination of temozolomide and irinotecan in 16 patients with
advanced Ewing sarcoma [62]. The patients received oral temozolomide 100 mg/m2/d
on 5 consecutive days plus intravenous irinotecan 10–20 mg/m2/d on 5 consecutive
days for 2 consecutive weeks with cycles repeated every 3 to 4 weeks. Sixteen
patients received a total of 95 cycles with a median of 5 cycles per patient. One CR, 3
PR and 3 minor responses were obtained. The median duration of response was 30
weeks. The 21-day cycles were tolerable and no more toxic that the 28-day cycles.
Myelosuppression was minimal, even in previously heavily treated patients. Grade 3-4
diarrhoea occurred in 11% of the cycles and was related to the higher (20 mg/m2/day)
irinotecan dose [62].
Recently, Wagner et al. reported a phase I study of oral irinotecan combined with
temozolomide in children with recurrent/resistant high-risk neuroblastoma [63]. Patients
received oral temozolomide on days 1 through 5 combined with oral irinotecan on days
1 through 5 and 8 through 12 in 3-week courses. Significantly, daily oral cefixime was
used to reduce irinotecan-associated diarrhoea. The dosages recommended for further
study in this patient population are temozolomide 75 mg/m2/d plus irinotecan 60
mg/m2/d when administered with cefixime. First-course grade 3 diarrhoea was dose-
limiting in one out of six patients treated at the irinotecan MTD of 60 mg/m2/d. Other
toxicities were mild and reversible [63].
Thus, paediatric data are consistent with a good tolerance of the combination as well
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as a promising activity in relapsing paediatric tumours.
Most importantly, the ITCC recently conducted a phase II study investigating the role of
the temozolomide-irinotecan combination in refractory or relapsing medulloblastoma.
Temozolomide is given at a dose of 100 mg/m2/day on days 1-5 (the dose was
increased to 125 mg/m2/day in cycle 2 if the patient did not experience ≥ grade 3
toxicity of any kind) and Irinotecan 10 mg/m2/day on days 1-5 and days 8-12 every
three weeks. Grill et al. have reported intermediate analysis on 40 patients (Grill,
ASCO, 2009). 19 patients were available for response assessment through a central
review and 7 patients had confirmed PR, 4 patients had SD and 8 patients had PD.
The irinotecan-temozolomide combination has promising activity in heavily pre-treated
patients with relapsed/refractory medulloblastoma and at the same time it is well
tolerated in patients with recurrent or refractory childhood medulloblastoma,
haematological toxicity was the main toxicity primarily in patients with prior cranio-
spinal irradiation.
Etoposide
Etoposide (Celltop®) is an inhibitor of topoisomerase II. Daily low dose etoposide
treatment is a known effective palliative approach for patients with refractory
medulloblastoma in whom chronic oral etoposide could induce response and stable
disease lasting over 6 months in more than 60% of the patients [64, 65]. Recently,
continuous low dose daily etoposide (25 mg/m² D1-D21) has been shown to be quite
effective in refractory medulloblastoma when used along with ablative carboplatin and
thiotepa with stem cell rescue. Indeed, none of the survivors required additional
salvage irradiation [66].
A phase I/II pilot study used oral etoposide given concurrently with radiotherapy
followed by dose-intensive adjuvant chemotherapy in children with HR MB [67]. During
craniospinal radiation, patient received daily oral etoposide 21 out of 28 days. 47
patients were included in this study. The dose level was reduced to 35 mg/m2/day due
to the toxicity, and 34 patients were treated in this way. The most common adverse
event was gastrointestinal toxicity. The proportion of objective response (CR+PR)
postchemoradiotherapy was 88% [67].
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According to these data, we propose to use oral etoposide concurrently with
craniospinal irradiation followed by 6 cycles of temozolomide for patients who do not
achieve response to chemotherapy.
Radiotherapy
The neurocognitive sequelae associated with radiotherapy in younger patients have
prevented oncologists from using irradiation in children younger than 3 years of age
until recently. However, for some of children with recurrent CNS Brain tumours without
upfront radiotherapy (majority of medulloblastoma) encouraging results of long-term
survival were reported after salvage regimen including irradiation either before or
immediately after HDCT [68-70]. In the St Jude’s study, 7 children younger than 3
years of age had a significantly better PFS (57%) than 20 children older than 3 years
of age. Of these 7 younger children, the 4 long-term survivors underwent irradiation as
part of salvage therapy with HDCT. Conventional craniospinal irradiation (CSI) is
responsible for the deleterious effect on the developing brain of very young children.
Nevertheless the efficacy of radiotherapy with reduced - dose and reduced - volume
led to propose an adapted-risk radiotherapy for refractory or recurrence high-risk MB of
younger children taking into account the age, the initial disease status and the nature
of recurrence. Goldwein et al. reported in 10 children younger than 5 years of age with
non-metastatic MB an actuarial survival rate at 6 years of 70% with sustained
Intellectual quotient scores in the normal range using a treatment with chemotherapy
and 18 Gy CSI [71]. Dufour et al. reported a pilot study using 5 sequential courses of
HDCT followed by age-adapted CSI with doses from 18 to 35 Gy and the OS rate of 34
patients younger than 5 years was 50% at 30 months [35].
2. STUDY OBJECTIVES
Primary objective
Phase II part: To assess efficacy in terms of Event Free Survival (EFS) of the strategy
intended to treat children younger than 5 years of age with high-risk medulloblastoma
with sequential high-dose chemotherapy without radiotherapy.
Phase I part: To determine the Maximum Tolerated Dose (MTD) of cyclophosphamide
in combination with a fixed dose of busilvex in children with high-risk medulloblastoma
who are in complete response after the intensification phase
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Secondary objectives
- To assess feasibility and efficacy of a strategy without radiotherapy by estimating the rate of patients alive free of disease without having received radiation therapy.
- To assess efficacy of this strategy in terms of Overall Survival (OS).
- To evaluate the effectiveness of the different treatment phases:
o Evaluation of the initial conventional chemotherapy based on the proportion of patients in complete or partial radiological response after the second induction VP16-Carboplatin course.
o Evaluation of induction and intensification chemotherapy based on the proportion of patients achieving a complete response after the second course of thiotepa
- To characterize the pharmacokinetics of cyclophosphamide – busilvex combination (Phase I)
- To assess the efficacy, feasibility and tolerance of salvage treatment
- To evaluate the acute toxicity of this therapeutic strategy, overall and per treatment phase (induction / intensification / consolidation/salvage treatment).
- To evaluate the prognostic value of some immunohistochemical markers on the risk of relapse or progression
- To evaluate neurocognitive development of patients within 10 years after the end of treatment.
3. STUDY DESIGN
The study is a multicentre, non-randomised, phase I/II trial using a Bayesian design.
The evaluation of the efficacy of the whole treatment strategy is designed as an open
label, non-randomised, multicentre trial without control group Phase II trial, with a
Bayesian analysis. No interim analysis is planned.
A Phase I dose-finding study is planned to identify the Maximum Tolerated Dose
(MTD) of cyclophosphamide in combination with a fixed dose of busilvex in children
who are in complete response after the intensification phase, using a Bayesian
Continual Reassessment Method (CRM).
Study centres
Patients will be accepted for registration into the trial from any SFCE centre
authorized. Due to toxicity, patients will undergo the intensification and consolidation
phases in only 7 centres:
- CHU de la Timone (Marseille)
- CHU Toulouse, Hopital d’enfants (Toulouse)
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- CHR Brabois (Nancy)
- IHOP (Lyon)
- Centre Oscar Lambret (Lille)
- Institut Curie (Paris)
- Institut Gustave Roussy (Villejuif)
Study period
The planned duration of the enrolment is 5 years. The planned duration of the study
(i.e. equal to the enrolment period with the treatment period plus the follow-up for the
main efficacy analysis) is 9 years.
4. SELECTION OF PATIENTS
4.1 Inclusion criteria for the study
1) Histological diagnostic of medulloblastoma with no INI-1 loss
2) High-risk medulloblastoma defined by at least one of the following conditions:
- Newly diagnosed metastatic classical medulloblastoma defined by the presence of metastasis and/or positive cerebrospinal fluid cytology
- Newly diagnosed medulloblastoma with amplification of MYC oncogenes whatever the risk criteria (localized or metastatic, complete or incomplete resection)
- Newly anaplastic and/or large cell medulloblastoma irrespective of the other risk criteria (localised or metastatic, complete or incomplete resection).
3) Age on enrolment in study entry less than 5 years
4) Weight > 8 kgs
5) Ability to comply with requirements for submission of materials for central review
6) Nutritional and general status compatible with this therapy, Lansky play score > 30% (appendix A)
7) Estimated life expectancy > 3 month
8) No organ toxicity other than alopecia and neurological symptoms due to disease (Grade > 2 according to NCI-CTC grading system, version 4.0)
9) No prior irradiation or chemotherapy (except VP16 – CBP)
10) Written informed consent from parents or legal guardian.
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4.2 Non-inclusion criteria
1) Desmoplastic medulloblastoma
2) AT/RT
3) Uncontrolled active or symptomatic intracranial hypertension before chemotherapy treatment
4) Patients incapable of undergoing medical follow-up for geographical, social or mental reasons
5) Relapse of medulloblastoma
4.3 Inclusion criteria for the Phase I part of the study
1) Complete response after the intensification phase confirmed by central review
2) Adequate hepatic function:
- Serum bilirubin < 2.5 x ULN for age
- ASAT and ALAT < 2.5 x ULN
3) Adequate renal function:
- Creatinine < 1.5 x ULN for age; If serum creatinine is > 1.5 ULN of age,
then creatinine clearance (or radioisotope GFR) must be >
70 ml/min/1.73 m2
5. PATIENT REGISTRATION
Study entry: The registration will be performed after initial biopsy and/or surgery for
patients before start of study treatment. After signing the consent form and verifying
the eligibility criteria, eligible patients will be enrolled in the trial by faxing the
completed enrolment form (F1a) to the trial data manager at the Department of
Biostatistics and Epidemiology at the Gustave Roussy Institute. Patients may be
registered from 9 am to 5 pm, Monday to Friday, except on bank holidays. If there are
any problems, the data manager responsible for the trial or the data manager on call
may be contacted by telephone at: 01 42 11 49 00 (beeper).
After checking the study eligibility criteria, the data manager will send by fax to the
investigator the confirmation of patient enrolment with the patient study number. This
number must be used in all subsequent correspondence.
Treatment must begin within 30 days of registration in the trial.
Entry in the Phase I part: The patients in complete response confirmed by radiological
central review after the intensification course will be included in the dose-finding part of
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the trial. The dose of cyclophosphamide to be allocated will be determined on the basis
of all the information currently available. The completed F1b form is to be sent to the
trial data manager.
6. TREATMENTS
The treatment plan consists of the following phases:
Before registration in the study:
- Surgical biopsy and/or resection
After registration, the initial planned treatment includes three phases:
- Induction
- Intensification
- Consolidation
For the patients requiring salvage treatment, the planned treatment includes also three phases:
- Second line induction
- Chemo-radiotherapy
- Maintenance
The different phases are followed by assessment of the tumour response, resectability
and remission status.
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6.1 Surgery
6.1.1 Initial surgery for patients treated at diagn osis
The purpose of the initial surgical treatment is to treat intracranial hypertension when
this exists (using the method that the surgeon considers appropriate to the child's
clinical condition and status) and to conduct a more or less complete resection of the
tumour. The first goal of this resection is to allow histological diagnosis but also to
decompress the brainstem where necessary. At this stage of treatment, tumour
resection must not involve any excessive functional or vital risk to the child, or cause
complications that may delay or compromise the start of chemotherapy since the
priority is systemic treatment in a metastatic or high-risk disease. If a secondary lesion
is more easily accessible than the primary tumour, open sky or endoscopic biopsy of
this secondary lesion is a sufficient diagnostic criterion provided that all the
histopathologic and molecular studies may be carried out on these specimens. Early
postoperative MRI (before 72h) evaluates the existence and size of a local residue or,
where impossible, CT-scan immediately after surgery (< 48h) before and after contrast
agent injection, compared to the preoperative brain MRI imaging.
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6.1.2 Secondary surgery
If a residue remains at the level of the primary tumour, complementary surgical
excision should be proposed whenever possible according to the radiological data and
the patient’s status. This intervention must be performed either after the induction or
after intensification phase, as soon as a normal platelet count is restored (platelets >
75,000 Giga/L with spontaneous rising platelet count).
6.2 Induction phase
Induction consisting of 2 courses of Etoposide-Carboplatin should start as rapidly as
possible after histological diagnosis. The second course should start on day 21 of the
previous course or thereafter when peripheral counts recover with an absolute
granulocyte ≥ 800/mm3 and platelet count ≥ 100 000/ mm3 during hematologic
reparation phase and within day 28. The second course should start at least 48 hours
after discontinuation of G-CSF.
Leukapheresis: Peripheral stem cells should be collected by leukapheresis during
neutropenia resolution after the second course of chemotherapy. At least 9 x106 CD34
cells/kg should be collected. The procedures for collecting peripheral blood stem cells
are described in appendix B.
6.2.1 Drug administration
Day 1 Day 2 Day 3 Day 4 Day 5
carboplatin 160 mg/m2 • • • • •
etoposide 100 mg/m2 • • • • •
Carboplatin 160 mg/m 2 Day 1 to day 5
as an intravenous infusion over 1 hour
Dilution in 5 % glucose saline or sodium
chloride 9 mg/ml (0.9%)
Etoposide 100 mg/m 2 Day 1 to day 5
as an intravenous infusion over 1 hour
Dilution in physiological saline or 5 % glucose
saline while not exceeding a concentration of
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0.4 mg/ml etoposide in the infusion bottle.
6.2.2 Patient monitoring
A complete differential blood count will be carried out twice weekly from D7 of each
course and more often, if necessary, until haematological recovery.
6.2.3 Concomitant therapies
Antiemetic treatment with Setron should be systematically prescribed before the start
of chemotherapy and must be continued for 5 days.
To collect peripheral stem cells, treatment by G-CSF growth factor will be instituted on
day 9, at a dosage of 5 micrograms/kg/day, by the subcutaneous route. It should be
continued until collection of peripheral blood stem cells. If hospitalisation for febrile
neutropenia or other problem, GCSF can be administered intravenously
In the case of febrile neutropenia, patients must be hospitalised in the investigator’s
unit or in a nearby the patient’s home strictly controlled by the investigator.
6.3 Intensification phase
If partial or complete response confirmed by central radiological review is achieved
after conventional chemotherapy, the high-dose chemotherapy will be administered.
The time between courses shall be as short as possible when peripheral counts
recover with an absolute granulocyte ≥ 800/mm3, platelet count ≥ 75 000/ mm3 and
acquired platelet transfusion independence.
If the disease is stable or if progression occurs after the induction chemotherapy, the
patient should proceed to salvage treatment (cf. paragraph 6.5).
6.3.1 Drug administration
Day - 3 Day - 2 Day – 1 Day 0 thiotepa 200mg/m2 • • •
autologous stem cell rescue
(≥3 x 106 CD34/kg) •
Thiotepa 200 mg/m² Day-3 to day-1
As an intravenously infusion over 1 hour
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dilution in 200 ml/m² of 5% glucose saline or sodium
chloride 9 mg/ml (0.9%)
Autologous stem cells will be infused intravenously 24 hours after the last
infusion of thiotepa on D0, not more than 60 to 90 minutes after thawing.
Hydration: start at the beginning of chemotherapy at a rate of 3 L/m2/day and
continue until the transfusion of autologous peripheral blood stem cell.
6.3.2. Dose adaptation
No dose adjustment is planned during the intensification phase.
6.3.3 Patient monitoring
Monitoring during the intensive chemotherapy phase is performed according to the
usual institutional practices.
6.3.4 Concomitant therapies
Antiemetics chosen according to the normal procedures at each centre should be
administered 30 minutes before infusion of Thiotepa and repeated systematically.
G-CSF growth factors will be instituted on D5 after ASCT, at a dosage of 5
microgram/kg/day by the IV route and continued until the neutrophil count is greater
than 500 /mm3 on 2 samples collected at 24h intervals.
Care during the intensive chemotherapy phase is provided according to usual
institutional practices (bacteriological samples, antibiotic therapy, anti-CMV prevention
in CMV-positive patients, parenteral nutrition etc.).
Before the first course of high-dose chemotherapy, cryopreservation of gonads may be
proposed.
6.4 Consolidation phase: Phase I
The radiological response should be confirmed by the central review. If complete
response is achieved after the last course of high-dose thiotepa, one course of
cyclophosphamide-busilvex will be performed at day 28 of the previous course when
peripheral counts recover with an absolute granulocyte ≥ 800/mm3, platelet count ≥ 75
000/ mm3 and acquired platelet transfusion independence.
If complete response is not observed or if progression occurs after the intensification
phase, patient should proceed to salvage treatment.
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6.4.1 Drug administration
D - 10 D - 9 D - 8 D - 7 D -6 D - 5 D - 4 D - 3 D - 2 D - 1 D 0
cyclophosphamide • • • •
Mesna • • • • •
Busilvex • • • •
clonazepam • • • • • •
autologous stem cell rescue
(≥3 x 106 CD34/kg) •
The dose of busilvex is fixed. The initial dose of cyclophosphamide will be equal to 20
mg/kg/ day. Four dose levels are planned.
Cyclophosphamide
Level 1 20 mg/kg/day
Level 2 30 mg/kg/day
Level 3 40 mg/kg/day
Level 4 50 mg/kg/day
Busilvex
0.8 mg/kg/dose - 3.2 mg/kg/day
0.96 mg/kg/dose- 3.84 mg/kg/day
0.88 mg/kg/dose- 3.52 mg/kg/day
0.76 mg/kg/dose- 3.04 mg/kg/day
< 9 kgs
9 à < 16 kgs
16 à 23 kgs
> 23 à 34 kgs
> 34 kgs 0.64 mg/kg/dose
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Cyclophosphamide will be administered as a 1-hour intravenously infusion on Day -
10 to day – 7. Cyclophosphamide should be diluted in 5% glucose saline or sodium
chloride 9 mg/ml (0.9%)
Hydration: start at a rate of 750 ml/m2 per 6 hours and continue until stem cell rescue.
Mesna (120% of dose of cyclophosphamide) will be started with the first infusion of
cyclophosphamide and will be continued until 24 hours after the last infusion of
cyclophosphamide
Busilvex is administered as a two-hour infusion every 6 hours over 4 consecutive
days (Day – 5 to day – 2) for a total of 16 doses, via central venous catheter.
Busilvex must be diluted prior infusion. A final concentration of approximately
05.mg/ml busulfan should be achieved.
Autologous stem cells will be infused intravenously on D0, not more than 60 to 90
minutes after thawing.
A careful record of fluid input and output should be kept during the administration of
course. If diuresis falls below 350 ml/m2 per 6 hours, furosemide should be given at 0.5
mg/kg to 1 mg/kg.
6.4.3 Patient monitoring
This course will be administered in a laminar flow single room. Monitoring during the
intensive chemotherapy phase is provided according to usual institutional practices.
6.4.4 Concomitant therapies
Antiemetics chosen according to the normal procedures at each centre should be
administered before infusion of cyclophosphamide and repeated systematically.
Prophylactic therapy consisting of Clonazepam (0.1 mg/kg/day total dose) will be
administered one day prior to IV Busilvex administration and continued until 24 hours
after the last dose of IV Busilvex.
G-CSF growth factors will be instituted on D5 after ASCT, at a dosage of 5
microgram/kg/day by the IV route and continued until the neutrophil count is greater
than 500 /mm3 on 2 samples collected at 24h intervals.
Care during the intensive chemotherapy phase is provided according to usual
institutional practices (bacteriological samples, antibiotic therapy, anti-CMV prevention
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in CMV-positive patients, parenteral nutrition). Prophylactic antifungal treatment with
ketaconazole, itraconazole or fluconazole should be avoided, because of the increased
risk of veno-occlusive disease in particular in association with busulfan. For proven
fungal infection, amphotericin would be used.
Defibrotide should be administered as prophylactic treatment for veno-occlusive
disease [72]. The treatment should be started on day 1 of the Cyclophosphamide-
Busilvex combination upon at day 30 after ASCT or upon discharge from inpatient
care. The dose is 25 mg/kg/day. Defibrotide is administered in 5% D-Glucose
(Dextrose) water to a maximum concentration of 20 mg per 1 ml given IV in 4 divided
doses (every 6 hours), each infused over 2 hours. The duration of infusion can be
reduced to a minimum of 30 minutes if venous access is limited.
6.5 Salvage treatment
The interval between the last course of chemotherapy and the beginning of the
salvage treatment shall be as short as possible when peripheral counts recover with an
absolute granulocyte ≥ 800/mm3, platelet count ≥ 100 000/ mm3 and acquired platelet
transfusion independence.
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If progressive disease is observed during salvage treatment, patient should proceed to
phase I or II studies for recurrent and/or refractory MB.
6.5.1 Salvage treatment’s first step: TEMIRI
The induction phase will consist of 2 cycles of 21 days:
- Temozolomide 100 mg/m2/d on Days 1-5
- Irinotecan 10 mg/m2/d on Days 1-5 and Days 8-12
Temozolomide will be given orally, on an empty stomach, on Days 1-5 of repeated 3-
week cycles. Initially, irinotecan will be given intravenously over 1 hour on Days 1-5
and Days 8- 12. During Week 1 of each cycle, irinotecan will be given one hour after
the administration of temozolomide.
Haematological monitoring is required and a full blood count should be performed at
least once weekly. Hematopoietic growth factors must not be used.
6.5.2 Chemo-radiotherapy
Oral etoposide
Etoposide will be administered during the radiation treatment and should start on day
21 of the last cycle of temozolomide
The dosage is 35 mg/m2/day 21 days of 28 days. A single daily dose will be given. For
younger patients, pharmaceutical form of etoposide could be inappropriate and a
magistral prescription could be prepared in the pharmacy.
Haematological monitoring is required and a full blood count should be performed at
least once weekly. Hematopoietic growth factors must not be used.
In case of severe haematological toxicity, etoposide can be stopped, but radiation
therapy should be continued.
Radiation therapy
Radiation therapy should start on day 21 of the last course of temozolomide. In the
younger children < 3 years of age, radiation therapy should be performed under
general anaesthesia. Radiotherapy will consist of conventionally fractionated regimen
in a once daily schedule of 1.8 Gy per fraction and will deliver a total dose depending
on the age of children at the time of radiotherapy and at the maximal tolerable dose of
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each anatomical site (supratentorial area, posterior fossa, spinal cord above or under
the terminal cone on spinal MRI (cf. table 1).
Whenever possible, target volume definition should be based on magnetic resonance
imaging (MRI). Image fusion (=coregistration) of the MRI scans and the planning CT
scan should be used for target volume definitions and especially posterior fossa. The
accuracy of image co-registration should remain within <0.5 cm. Post-chemotherapy or
post-operative imaging after resection is mandatory. CT-based 3-D treatment planning
using beam’-eye-view is mandatory.
CSI: craniospinal irradiation; PF: posterior fossa; M0: without metastasis; M1M2M3
with metastases; spinal cone (above or under)
The Gross Tumour Volume is defined by:
- The tumour bed in case of complete or subtotal removal includes all tissues in
contact with the tumour (it can shift and the GTV (Gross tumour volume) should take
the new position of the abnormalities on MRI scan),
Total Dose (Gy)
CSI PF Tumour Bed
Residue Metastatic site
M0 M1M2M3 Above cone
Under cone and
supratentorial
Age < 3 years
18 18 35 50 54 30 54
Age > 3 years
24 24 35 54 59.4 45 54
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- The region of enhancement on postoperative CT/MRI (residue and metastatic
site).
The Clinical Target Volume is defined by a 5 mm volumetric expansion of the GTV.
The Posterior Fossa is delimited by the occipital foramen, the tentorium, the anterior
limit of brainstem and occipital bone.
The Planning Target Volume will take into account uncertainties of planning, setup and
repositioning. This margin should be based upon known departmental values but
usually be in order of 3 to 5 mm by volumetric expansion.
The tentorium and meninges should be considered as anatomical borders and limited
the PTV expansion.
Craniospinal volumes:
The Whole Brain must be included in cranial fields. Attention should be taken at the
ethmoidal level and at the craniospinal junction. The cervical spinal volume should be
included into lateral encephalic beams. The thyroid gland should be protected as much
as possible by a junction between the cord and encephala as down as possible. The
distance between the laryngeal shielding block and the second anterior vertebral body
must be at 5 mm. The inferior limit of CTV encompassing the dorsal and lumbar spinal
cord will be determined by MRI scan. It must encompass the entire medullar canal
including arachnoidal spaces and vertebral and sacral foramen (named as « bêche
sacree »).
Organs-at-risk:
All different organs-at-risk must be delineated: eyes, pituitary gland, optic chiasm, optic
nerves, lens, brainstem, inner ears, temporal, frontal lobes, hippocampic areas,
cervical cord, thyroid gland, kidneys.
Planning procedure:
The use of a Planning CT is mandatory with a maximum CT slice thickness of 3 mm in
order to obtain good quality of Digitally Reconstructed Radiographs (DRR’s) for cranial
volume and 10 mm for spinal volumes. Virtual simulation and planning with beams-
eye-views of each beam are mandatory. Planning should conform to ICRU50/62
criteria for target volume coverage, dose normalisation, homogeneity and dose
prescription and recording. Dose homogeneity requirements in the PTV shall be -5%,
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+7% and the PTV should be encompassed by 95% isodose. The 90% isodose is
acceptable in close proximity to organ-at-risk. Dose-Volume- Histograms of target
volumes and organs-at-risk must be registered.
The patient will be treated in supine position for techniques such as tomotherapy and
IMRT arc therapy.
With linear accelerator and 3D conformal technique, the treatment must be delivered
with a linear accelerator with minimal photon beam energy of 4-6 MeV for cranial
beam, greater than 8 MeV for PF and tumour bed, photon beam energy of 4-6 MeV or
electron beam greater than 18 MV for spinal volume. All vertebral bodies should be
irradiated homogeneously (at least the isodose 80%). The different junctions between
cranial and spinal irradiations must be calculated and must be mobile when necessary.
All fields will be treated for each fraction. At least weekly, carries out treatment position
verification is carried out by portal imaging. Conformal radiotherapy or intensity-
modulated radiotherapy must be used to deliver boost dose to tumour bed, residue
and metastatic nodular lesion. Cobalt unit is not permitted.
Organs-at-risk must be spared in order not receive doses higher than the following:
pituitary gland 50 Gy, eyes, 45 Gy, optic chiasm 50 Gy, optic nerves 45 Gy, inner ears
45 Gy, lens 10 Gy.
Dose reporting and Quality control:
The isodose distributions will be calculated and printed for documentation in three
planes (transverse, coronal, and sagittal planes) through the isocentre. Isodose
distributions with marked PTV and CTV and isodose lines with maximal, volume 98%,
mean, median, minimal dose, volume 2%, 100%, 95%, 90%, 80%, 60%, 50%, 40%,
20% of the prescription dose should be reported for a reviewer to evaluate the
adequacy of target coverage. The following volumes should be calculated and
documented in cm3: GTV, CTV, PTV, Total volume of the brain without PTV, Volume
98% and 2% as well as HDV of target volumes and organs-at-risk. Weekly portal
imaging will be undertaken for set-up verification.
Radiotherapy control quality should be performed prior to the start of radiotherapy. The
national radiotherapy quality control panel is Dr Carrie (Centre Léon Bérard, Lyon), Dr
Padovani (CHU la Timone, Marseille) and Dr Bernier-Chastagner (CHU Nancy).
Planning documentation (treatment plan, conventional imaging or computer generated
dose distributions) should be submitted via Aquishare plateform.
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6.5.3 Maintenance treatment
We also propose here to use temozolomide as a single agent for the maintenance
phase of the salvage treatment.
Maintenance treatment will be instituted as soon as the haematological criteria are
obtained, between 1 month and three months after the end of craniospinal irradiation.
Institution of this treatment after this period is ineffective. The haematological criteria
required to institute this course of maintenance treatment are:
- Leucocyte > 1500 G/L
- Absolute granulocyte > 800 G/L
- Platelets > 100 000 G/L
In cases of grade IV neutropenia or platelets bellow 50.000 G/L, the temozolomide
dosage may be reduced by 25%. Dose reduction can be performed no more than
twice.
Temozolomide will be given orally, on an empty stomach, at 150 mg/m2/d on Days 1-5,
every 28 days. A total of 6 cycles are scheduled. Antiemetics will be administered 30
minutes before each dose of temozolomide according to procedures, which depend on
practices at each centre. Haematological monitoring is required and a full blood count
should be performed once weekly. Hematopoietic growth factors must not be used.
6.6 Treatment Discontinuation
Treatment should be discontinued if this is considered to be in the best interest of the
patient. Treatment could be discontinued for the following reasons:
• Investigator’s decision: if this decision is made because of toxicity, a serious
adverse event, or a clinically significant laboratory value, appropriate measures
will be taken and the IGR will be notified immediately
• The parents or legal representative’s refusal, withdrawal of patient consent.
• The patient requires treatment with another therapeutic agent that has been
demonstrated to be effective for treatment of the study indication. In this case,
discontinuation from study treatment occurs immediately upon introduction of
the new agent.
• The investigator or sponsor, for significant safety or efficacy reason, stops the
study or stops the patient's participation in the study.
• Evidence of progressive disease exists.
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• Life threatening toxicity.
• Treatment delay of more than 3 weeks for any reason except in cases of
obvious patient benefit in continuing the treatment.
Study discontinuation, must be reported to the IGR as soon as possible and
immediately in case of discontinuation related to a serious adverse event. The primary
reason and date of removal for all patients will be documented in the case report form.
The final evaluation required by the protocol will be performed at the time of study
discontinuation. Further follow-up should be reported. The investigator will attempt to
complete all discharge procedures at the time a patient is withdrawn from the
treatment.
7. BASELINE AND FOLLOW-UP ASSESSMENTS
7.1 Baseline assessments
Patients eligible for the trial and for whom the parents have signed their consent for
participation, must undergo a baseline examination not more than 15 days before the
start of induction chemotherapy.
▪ Clinical examination
• History of present illness, main medical and surgical history with collection of
previous treatments.
• Physical examination, including neurological examination
• Height, body weight, surface area and temperature
• Lansky-Play scale
Particular care shall be given to report tumour-related neurological signs for
subsequent determination of a possible clinical response.
▪ Imaging (cf. procedures appendix C)
• Preoperative cerebral magnetic resonance imaging (MRI) before and after
contrast injection.
• Spinal MRI with injection of contrast product which should be performed
whenever possible preoperatively, but it may also be performed post-
operatively.
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• Post-operative cerebral MRI (or otherwise a CT-scan cf. above) before and
after contrast product injection and no later than 72 hours after and preferably
within 48h of the surgical procedure.
Central review of preoperative MRI imaging will be mandatory (cf. paragraph 16.2).
▪ Laboratory tests
• Full blood count, platelets
• Blood and 24-hour urine electrolytes: sodium, potassium, blood glucose,
calcium, phosphorus, magnesium, serum and urinary creatinine.
• ALAT, ASAT, alkaline phosphatases, gamma-GT, bilirubin
• Irregular agglutinin test, blood grouping with extensive phenotyping
• Viral serological tests (HBV, HCV, CMV, HSV, HIV 1+2)
▪ Cytological and histological examination
• Histological confirmation of diagnosis for patients treated at diagnosis (cf.
paragraph 16.2)
• Study of CSF cytospin collected by lumbar puncture between 7 and 15 days
after the surgical procedure, until CSF study become negative
▪ Translational research
An immunohistochemical study will be performed to refine the diagnosis and define the
value of probable markers of prognostic importance.
Five antibodies will be used: INI 1 (BAF47), MIB 1, beta-catenin, FSTL5 [73], p53 [74].
The first antibody (INI 1) will be used to define the diagnosis ruling out the rhabdoid
teratoid tumour diagnosis. The prognostic value of the latter markers remains to be
ascertained. The expression of these markers, which may be of prognostic value, will
be investigated in parallel by two laboratories. This double analysis will be integrated
within the scope of a quality procedure to evaluate the most suitable
immunohistochemistry method for the study of these markers and to compare these
techniques on very heterogeneous material (various types of fixative due to the varied
origins of the blocks). A tissue micro-array (TMA) will be carried out on this series of
tumours with the agreement of the local concerned pathologists. These TMA will allow
us to perform complementary studies.
We assume that neurofilament and synaptophysin are immunohistochemical markers,
which have been routinely applied by the pathologist who gave the initial diagnosis.
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In order to carry out this study, a tissue block embedded in paraffin, representative of
the tumour, will be sent to Professor M.B. DELISLE who will carry out histological
review and the immunohistochemical study +/- TMA. Stained and unstained slides will
be sent from Toulouse to Professor D. FIGARELLA-BRANGER for a second reading
and a comparative immunohistochemical study. Blocks will be returned to the local
pathologist after preparing unstained slides and +/- TMA.
The following antibodies will be used for the immunohistochemistry study:
- INI 1 (clone BAF 47), Toulouse : BD Transduction Laboratories, 1/50 dilution,
- Beta-catenin (clone β-catenin-1), Toulouse : Dako, 1/400 dilution
- p53 (clone DO7), Toulouse : Dako, 1/100 dilution
- KI67 (clone MIB-1), Toulouse : Dako, 1/150 dilution
- FSTL5 (Mouse polyclonal antibody), Abnova, the dilution will be soon determined.
Frozen tumour specimens will be preserved for future biological studies.
▪ Neuropsychological evaluation
Neuropsychological tests will performed as soon as possible after surgery or study
entry, using Brunet-Lezine or Weschler scales, adapted to the age. This evaluation
should be performed before radiation therapy for patients treated with salvage
treatment.
7.2 Follow-up assessments during treatment and at t he end of treatment
Assessments during treatment and salvage treatment are summarised in table 1 and
2, respectively.
Follow-up assessments for the disease:
- MRI of all measurable sites will be performed after the second course of
conventional chemotherapy, after the second course of high-dose thiotepa
and after the course of cyclophosphamide-busilvex combination. Central
review MRI imaging after the conventional chemotherapy and after the
intensification phase will be mandatory in real time (cf. Paragraph 16.2).
- A study of the CSF cytology will be conducted after the second course of
conventional chemotherapy and after the last course of chemotherapy
(cyclophosphamide-Busilvex).
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Follow-up assessments for the treatment:
- An echocardiography will be performed before leukapheresis.
- The safety of conventional chemotherapy (VP16-Carboplatin) courses will be
evaluated according to NCI-CTCAE V4 criteria (appendix D).
- The safety of high-dose chemotherapy courses will be assessed with the
Bearman grading system (appendix E).
- All examinations to detect treatment-related toxicity will be repeated
periodically until reversion of toxicity or until it is considered irreversible.
Table 1: Assessment during planned treatment
Registration Before VP-CBP
Before VP-CBP
Before Thiotepa1
Before Thiotepa2
Before Cyclophosphamide + Busilvex
After Cyclophosphamide + Busilvex
FBC/platelet X X X X X X X
Biochemistry(Blood and Urine)
X X X X X X X
Brain MRI X X X X
Spinal MRI X X X X
CSF cytology X X X X
Toxicity (NCI-CTC) X X
Toxicity (Bearman)
X X
Neuropsychological evaluation
X (as soon as possible after surgery or study entry) X
Table 2: Follow-up during salvage treatment
Before TEMERI1
Before TEMERI2
Before RT-CC
Before TMZ1
Before TMZ2 - 3
Before TMZ4
Before TMZ5-6
After TMZ
FBC/platelet X X X X X X X X
Biochemistry X X X X X X X X
Brain MRI X X X X X
Spinal MRI X X X X X
CSF cytology X X X
Toxicity (NCI-CTC) X X X X X X X X
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7.3 Follow-up assessments after treatment
• Tumour
After treatment, a craniospinal MRI shall be performed every 3 months during the first
2 years following the end of the treatment, every 6 months during the following 2 years
and then every year for 5 years.
• Sequelae
- Neuropsychological evaluation: The neuropsychological evaluation will be conducted
prospectively and for a minimum duration of 5 years. It will be carried out at the end of
treatment and then at 1 year, 2 years, 3 years, 5 years, 7 years and 10 years after the
end of treatment. Tests appropriate to the child’s age will be performed to investigate
their cognitive functions (Brunet-Lezine or Weschler scales). The purpose is to screen
for any cognitive deficiencies, prescribe rehabilitation therapy when required and help
the children integrate in school. Neuropsychological evaluations of children treated
according to this protocol will be analysed in order to study the outcome of the cognitive
deficiencies and to determine their cause.
- Follow-up of sequelae: This follow-up will involve the collection of prospective data,
and will be carried out at the same times as the neuropsychological evaluation:
reading, writing, motor activity, laterality, epilepsy, cranial nerve involvement, sensory
deficiency, integration at school, specialised support.
- Endocrine follow-up: Monitoring will be mainly clinical and concern growth in weight
and height and pubertal development as well as fertility during late follow-up.
- General assessment after treatment to evaluate the sequelae of the entire treatment.
8. PK / PD / PG STUDIES
The clinical trial includes a multi-institution pharmacological study exploring
pharmacokinetics, pharmaco-dynamics and pharmacogenetics of two anticancer
drugs, cyclophosphamide and busulfan, using limited blood sampling strategies and
NONMEM programmes.
This PK/PD/PG study will be conducted according to Good Laboratory Practice:
- To study the PK/PD relationships between exposure to busulfan and
cyclophosphamide and severe toxicities other than VOD.
- To identify the AUCs of busulfan and cyclophosphamide that could be
prospectively targeted to reduce the risk of severe toxicity in high-dose combined
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chemotherapy regimens including I.V. Busulfan (Busilvex) and
cyclophosphamide.
8.1 BUSULFAN
• Blood sampling/ assays (appendix D)
For all blood samples (2 ml), plasma will be separated at 0°C and stored at –20°C until
sample shipment. Samples should be sent to the reference laboratory as soon as
possible following collection, to avoid issues concerning sample stability.
Busulfan plasma levels will be assayed after doses 1 and 9, with three blood samples
withdrawn following these two doses (before administration and at 2.5 and 6 hours
after the START of infusion). In addition, plasma levels will be measured after dose 13,
with a single sample being taken 6 hours after the START of infusion.
Busulfan will be assayed by gas-chromatography with mass spectrometry in the
laboratory of Dr Angelo Paci (IGR, France).
Briefly, 0.2 ml (heparin) plasma is required for the analysis. Internal standard (1,5-bis
(methansulfonoxy) pentane) or Deuterium busulfan) is added along with 1 ml sodium
iodide (8M) and 0.4 ml n-heptane. A micro magnet is added to the screw cap tube. The
reaction is carried out at 70oC for 45 min under continuous magnet stirring. Then, the
organic phase (n-heptane) is taken to analysis in the GC system.
8.2 Cyclophosphamide
• Blood sampling (appendix E)
All patients must have a central venous catheter (single or multi-lumen catheter or
port-a-cath) in place in order for samples to be taken for pharmacokinetic analysis. No
samples will be taken by venipuncture. For patients with a double lumen line, samples
for pharmacokinetic analysis should be taken from a different lumen to that used for
infusion. For patients with a single lumen line, the line should be flushed with 10ml
normal saline prior to the withdrawal of blood samples. Wherever possible,
pharmacokinetic samples should be taken when clinical blood samples are obtained.
• Cyclophosphamide pharmacokinetics
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Blood samples (2ml) will be taken and transferred to heparinised tubes after
administration of a single dose of cyclophosphamide on Day -9 at the following times:
prior to treatment, end of infusion, 1, 2, 4, 6 and 23 hours after the end of infusion (i.e.
immediately prior to infusion of cyclophosphamide on Day -8). Samples will be
immediately centrifuged for 5 min at 2,000 rpm and 4ºC, plasma transferred to clean
labelled tubes and frozen at -20ºC prior to transport to the Northern Institute for Cancer
Research, Newcastle, UK, for analysis (see below). Methods for measurement of
cyclophosphamide and its metabolites in plasma using LC/MS (liquid
chromatography/mass spectrometry) are established in the Northern Institute for
Cancer Research [75].
• Pharmacogenetic studies
An additional 5ml blood sample for DNA extraction will be taken pre-treatment and
transferred to an EDTA tube to be genotyped for the known functional polymorphisms
in CYP2B6, CYP2C9 and other metabolic enzymes in addition to the determination of
genetic variation in MDR. This whole blood sample will be stored at -20ºC prior to
transport to Newcastle for analysis (see below). The techniques for genotyping
individuals for these polymorphisms have been established in the Northern Institute for
Cancer Research [76].
• Transport of samples for analysis
Clearly labelled samples should be sent to Newcastle in a single package by overnight
courier (Monday – Wednesday), packed on dry ice in an insulated container, following
completion of all pharmacokinetic and pharmacogenetic sampling. The Northern
Institute for Cancer Research should be notified on the day that the samples are sent
(Gareth Veal/Julie Errington, Tel. +44 (0)191 246 4332 or +44 (0)191 246 4357).
Address for shipment of samples:
Gareth Veal /Julie Errington Contact numbers
Northern Institute for Cancer Research Gareth Veal: 0191 246 4332
Paul O’Gorman Building Julie Errington: 0191 246 4357
North Terrace Fax: 0191 222 3452
Newcastle upon Tyne Email: [email protected]
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NE2 4AD [email protected]
• Pharmacokinetics and statistical analysis
The data obtained will be used to determine pharmacokinetic parameters such as area
under the plasma concentration-time curve (AUC), clearance and half-life (t½) for
cyclophosphamide in children with high-risk medulloblastoma following a single
intravenous dose. Pharmacokinetic modelling will then be carried out using these data
in conjunction with patient characteristics and clinical parameters in order to
investigate the key factors involved in determining individual exposure to parent drug
and metabolites within the defined patient population.
9. EVALUATION CRITERIA
9.1 Primary endpoint
The primary endpoint of the whole study is the Event-Free Survival (EFS). EFS is
defined by the time between registration and the first of the following events: disease
progression, relapse, secondary malignancy, death irrespective of the cause. Data will
be censored at the date of last follow-up visit for patients alive without disease
progression, relapse and secondary malignancy. As the trial aims at evaluating the
efficacy of the whole treatment strategy, patients who receive salvage treatment
because of an insufficient response to treatment (stable disease after the first two
induction courses, or partial response or stable disease after the two consolidation
courses) will not be considered as an event as long as there is no evidence of disease
progression. Patients who experience a disease progression at any stage of the
treatment will be counted as events in the EFS estimate.
The primary endpoint of the Phase I part of the trial is the Dose-Limiting Toxicity
defined as
- any grade 3 toxicity according to the Bearman grading system, in particular grade 3
veno-occlusive disease,
- or grade 2 or 3 pulmonary toxicity according to the Bearman grading system,
occurring in the 30 days following the autologous stem cell transplantation (DLT
observation period).
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9.2 Secondary endpoints
1. Radiotherapy-free survival without event is defined as the time between the
registration in the study and the first event (i.e., progression, relapse, secondary
malignancy, death whatever the cause) or the beginning of radiotherapy. Data
will be censored at the date of last follow-up for patients alive without event and
without radiotherapy.
2. Overall survival defined by the time between enrolment in the study and the
death whatever the cause. Data will be censored at the date of last follow-up for
patients alive.
3. The response to induction and intensification chemotherapy will be evaluated in
patients with measurable disease on enrolment in the study. Patients with non
measurable disease will be considered as having progressive disease in case of
appearance of new lesion, at the primitive site or in metastatic sites. Otherwise,
they will be considered as stable or complete remission in case of no residual
disease. In patients with measurable disease, responses will be evaluated
according to the WHO criteria.
Complete response (CR): complete disappearance of all the measurable
disease by appropriate imaging of residual tumour or absence of residual
tumour in cerebrospinal fluid.
Partial response (PR): The reduction in size of all the tumours by at least 50%
as determined by the sum of the products of the two maximum perpendicular
diameters of each lesion, as compared to initial assessment.
Progressive disease (PD): increase in size of one or several lesions by more
than 25% or appearance of new lesions, as compared to the best response
assessment.
Stable disease (SD): All other cases.
4. Establishment of Pharmacokinetics of cyclophosphamide and busilvex when the
two drugs are combined.
5. The response to salvage treatment will be evaluated according to the WHO
criteria.
6. Toxicity will be assessed using the National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE v 4.0). Any grade IV
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toxicity (except haematological) will be considered as severe toxicity. Toxic
death defined by a death not due to the disease, occurring during treatment or
after the end of the treatment, except if it can be proved that it is not related to
treatment.
7. Cognitive assessment at the end of treatment and then at 1 year, 2 years, 3
years, 5 years, 7 years and 10 years after the end of treatment. Cognitive
deficiencies will be assessed through neuropsychological tests appropriate to
the child’s age.
10. STATISTICAL CONSIDERATIONS
10.1 Study design
Phase II part
The survival of children less than 5 years of age with metastatic medulloblastoma
treated with standard treatment (surgery followed by conventional craniospinal
irradiation and chemotherapy) remains poor. Due to the low incidence of the disease, it
was not feasible to design a randomised study to assess the efficacy of this strategy
compared to conventional therapy including radiotherapy. Consequently a Phase II,
open label, non-randomised, multicentre trial will be achieved without control group,
using the 3-year EFS as efficacy endpoint.
In the previous study PNET HR, the observed 3-year EFS for patients with high-risk
medulloblastoma treated with sequential HDCT and age-adapted craniospinal
irradiation was 49%. However, there is some uncertainty regarding the null and
alternative hypotheses that should be considered to define a Simon’s or Fleming’s
design. This uncertainty led us to propose a Bayesian approach since such designs
may be more informative in terms of treatment effect estimate, allowing for several a
priori distribution of the considered outcome, compared to the classical test-driven
analyses using a single null hypothesis. Based on historical data, a cure model will be
used to model the EFS data.
Interim analyses will be performed, as soon as approximately half of the total expected
number of events will be observed (early stopping rules for futility or inefficacy).
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Phase I part
This is a single arm phase I using the continual reassessment method (CRM) design to
determine the dose of cyclophosphamide to be recommended (Maximum Tolerated
Dose, MTD) when given in combination with busilvex. A CRM design with an empiric
dose-toxicity model in a Bayesian framework will be adopted for dose-finding in this
trial [77]. The CRM design has been shown to have better operating characteristics
than traditional “3+3” design in simulations [78]. Additionally we will use a slightly
modified CRM design (Doussau 2012) to increase the flexibility by allowing continuous
accrual with no trial suspensions, which are classically needed when the toxicity
assessment of the patient(s) previously recruited is not completed: an eligible patient
can be included in the trial at any time, without waiting for the evaluation of prior
patients. The model will be re-estimated considering all the complete toxicity
observations currently available. The patient will be treated at the best current estimate
of the MTD. Patients may eventually be treated at a dose below the dose
recommended by the model for safety reasons (see rules in Appendix I). This is
particularly appealing in the context of this trial where all the patients eligible for the
chemotherapy course of cyclophosphamide-busilvex should participate in the dose-
finding trial. See appendix for the operating characteristics of this design.
Decision for dose-escalation recommended by the model will be confirmed by the
study committee, after discussion of all toxicity data currently available.
The initial dose level of cyclophosphamide is 80 mg/kg. Four dose levels are planned.
Dose level 1 2 3 4
Cyclophosphamide dose (mg/kg) 80 120 160 200
10.2 Sample size Phase II part: In theory the Bayesian approach does not need to define a sample size
in advance in order to give reliable results. However, considering classical frequentist
approach, 50 patients would be required to provide a 85% power of a one-sample
logrank test [79] if the true 3-year EFS improvement was 20% compared to historical
data, using a one-sided test with a type-I error of 0.05 (27.2 events required). This
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sample size is reasonable considering the possible accrual. We thus decided to recruit
about 50 patients in the trial.
Due to the low incidence of the disease and the selection of high-risk patients only
(around 10 patients per year included in the previous study), the accrual duration is
expected to be 5 years.
Phase I part: All the patients in complete response after intensification chemotherapy
treatment, eligible for the consolidation course of cyclophosphamide-busilvex course,
will be included in the phase I part of the trial. They will be treated at the best current
estimated MTD. The dose-finding part of the trial will be run until the end of the trial.
Approximately 50% of the patients entering the trial are expected to be recruited in the
phase I part (last chemotherapy course), leading to an estimated accrual of 25 patients
in the dose-finding part of the trial.
10.3 Statistical analysis
10.3.1 Analysis of the main endpoint
In the previous study PNET-HR including 38 patients with a medulloblastoma with a
median follow-up of 6.2 years, most of the events occurred in the first two years (1-
year and 2-year EFS at 62% and 52%, respectively), with few events after that (3-year
and 6-year EFS at 49% and 42%, respectively). The observed EFS distribution could
be modelled using a cure model, written as: S0(t) = π+ (1-π).{exp(-λ.t)}, with π = 0.435
and λ = 1.12, leading to a predicted EFS of 61.9%, 49.5%, 45.5% and 43.6% at 1, 2, 3
and 6 years respectively.
We plan to model the observed EFS data on the whole follow-up period using a cure
model assuming proportional hazards, written as follows:
S1(t) = S0(t)R, where R represents the treatment effect of the evaluated strategy
compared to the historical treatment. An a priori distribution of the parameter R will be
combined with its likelihood function given the observed data, to compute a posterior
distribution of the parameter. The posterior distribution of the 3-year EFS will then be
derived from the posterior distribution of the parameter R. We will use three prior
distributions of the parameter R; (1) one enthusiastic prior distribution, with an
expected R of 0.538, corresponding to an expected 3-year EFS of 65.5% (20%
increase of the 3-year EFS compared to historical data), (2) one pessimistic prior
distribution with an expected R of 1.162, corresponding to an expected EFS of 40%,
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and (3) a non-informative prior distribution. As the patient outcomes in the trial will be
recorded, the subsequent distribution of the outcome probability under experimental
treatment will be computed by applying Bayes’ theorem, which yields an estimated 3-
year EFS probability with a 95% credibility interval (measure of Bayesian precision).
This approach allows us to estimate the probability that the 3-year EFS is above or
below certain thresholds: probability that 3-year EFS is below 20%, is below 40%, or is
above 60%...
The final efficacy analysis will be performed 3 years after the recruitment of the last
patient. Two interim analyses will be performed, when approximately 50% and 75% of
the total expected number of events will be observed (14 and 21 events). Early
termination of the trial will be discussed if the estimated probability that 3-year EFS >
60% is lower than 5% (early stopping rules for futility or inefficacy).
10.3.2 Others analyses
In addition to the Bayesian approach, the EFS curve will be estimated on the entire
follow-up period (8 years of follow-up expected for the first patient recruited in the
study) using the Kaplan Meier method, with 95% confidence intervals estimated using
the Rothman method. A one-sample log-rank test [79] will also be used to compare the
observed EFS to a fixed null outcome defined as S0(t) = π+ (1-π).{exp(-λ.t)}, with π =
0.435 and λ =1.12. We will compare the number of events observed in our sample to
that predicted using the theoretical cure model defined above. Testing will be done at
the 5% level of statistical significance (1-sided). The sample of 50 patients will provide
85% power to detect a true 3-year EFS of 65.4% (derived from S1(t) = S0(t)R with
R=0.538, leading to a 20% improvement of the 3-year EFS) and 90% power to detect
a true 3-year EFS of 68% (22.5% increase, R=0.506). Power would be 60% to detect a
true 3-year EFS of 60% (14.6% increase, R=0.647).
The curves of radiotherapy-free survival without event as well as the overall survival
curves will be estimated by the Kaplan Meier method, with confidence intervals
estimated using the Rothman method.
The response rate of the initial conventional chemotherapy will be estimated
considering complete or partial response after the 2 first conventional courses as
success. Patients who stop protocol treatment due to clinical progression, without
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imaging confirming the progression, and patients who die before radiological
assessment will be considered as failures of conventional chemotherapy. Response
rate will be given with a 95% confidence interval (binomial distribution).
Repeated measurements of neurocognitive tests will be analysed to study the kinetic
of neurocognitive function using a linear mixed model.
In addition to the description of efficacy outcome and toxicity, a decision theory
approach will be developed to evaluate the benefice/risk ratio.
10.3.3 Phase I analyses
The recommended dose of cyclophosphamide as consolidation chemotherapy in the
strategy treatment for further consideration is defined as the dose level associated with
an estimated probability of dose-limiting toxicity (DLT) closest to the target of 0.30.
Dose-limiting toxicity is defined as any grade 3 toxicity according to the Bearman
grading system, in particular grade 3 veno-occlusive disease, or grade 2 or 3
pulmonary toxicity according to the Bearman grading system (See Appendix G),
occurring within 30 days following the autologous stem cell transplantation (DLT
observation period). An additional clause is that the MTD is a dose with no observed
grade 3 pulmonary toxicity (Bearman).
The estimated probability of dose-limiting toxicity will be based on a one-parameter
empirical power model in a Bayesian framework. The initial toxicity probabilities
guesses are 7%, 17%, 30%, and 44% of DLTs at dose levels 1 to 4, respectively. See
appendix I for further description of the model.
The dose-toxicity relationship is estimated for each new inclusion on the basis of
complete information for previous included patients. If complete information is not
available for all included patients, the estimate is based on all complete information,
ignoring incomplete information. If the model estimate recommends escalating to a
new dose level, we require that complete information about at least two patients at the
current dose level is known in order to escalate.
No dose skipping is allowed. That is, if a dose level i has not yet been explored, no
patient inclusion is allowed at a level >i. If the model estimate recommends escalating
to a level >i, inclusion is done at dose level i.
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The toxicity target is 30% for veno-occlusive disease grade III and 0% for pulmonary
grade III toxicity according to the Bearman grading. In order to meet this constraint, the
observation of a pulmonary toxicity at dose level i leads to the closure of the dose level
i and all higher dose levels. See appendix I for the specific rules.
10.4 Analysed population
For the phase II evaluation, all efficacy analyses will be performed on the Intent-to-
Treat (ITT) population: all subjects will be taken into account including those who were
erroneously enrolled and those who did not comply with the protocol.
For the toxicity analyses, including the Phase I part of study, the treated population will
be considered (as per protocol).
The relationship between the dose of cyclophosphamide and the outcome may be
studied according to the number of patients allocated at the different dose-levels. This
exploratory analysis will be performed on the subgroup of patients in complete
remission after the intensification phase participating in the phase I part of the study.
For the phase I part, dose-toxicity relationship will be estimated in patients who receive
cyclophosphamide combined with busilvex.
10.5 Monitoring of toxicity and stopping rules
Severe toxicity including toxic deaths will be monitored continuously. The coordinating
data centre must be immediately informed about any events corresponding to the
definitions given below.
10.5.1 Toxic death
Toxic death is defined by a death other than death due to the disease occurring during
treatment or after the end of the treatment, except if it can be proved that it is not
related to treatment. The acceptable limit toxic death rate is based on the literature
data: observed toxic death rates range from 0% [80] to 5.4% [44]. The acceptable limit
toxic death percentage is therefore fixed at 5%. The nominal alpha risk is set at 15%
(i.e. risk of wrongly concluding that there are too many toxic deaths, i.e. of stopping the
trial for an unacceptable toxic death rate when this rate is in fact lower than 5%) and to
have an alpha function following a gamma law with gamma equal to 4 (leading to a
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concave alpha function, i.e. high at the start, in order to be able to conclude early
about a “toxic death”) (ref “Early Stopping Rules in Clinical Trials Based on Sequential
Monitoring of Serious Adverse Events.” Med Decis Making. 2008 Dec 10.).
The stopping rules used to monitor toxic death rate are based on the estimation of the
toxic death rate with its appropriate confidence interval, estimated after occurrence of
each new toxic death (from the second toxic death).
The following scenario illustrates the method:
If the 2nd toxic death occurs:
� Among the first 9 patients, the observed toxic rate death is significantly higher
than the limit of acceptable toxic death rate (for example, 2/9=22%, 84.74%CI,
5.2 to 51%) and the Trial Safety Board could decide to stop the trial,
� After the 9th patient, the observed toxic death rate is not significantly higher
than the limit (for example, 2/10=20%, 83.6%CI, 4.9 to 47%); the trial will go on.
Similar rule applies for further deaths.
E.g., if the 2nd toxic death occurs at the 10th patient and the 3rd death occurs:
� Among the first 19 patients, the observed toxic rate death is significantly higher
than the limit of acceptable toxic death rate and the Trial Safety Board could
decide to stop the trial,
� After the 19th patients, the observed toxic death rate is not significantly higher
than the limit; the trial will go on.
10.5.2 Severe toxicity
Any grade IV toxicity (except haematological toxicity) will be monitored. The acceptable
severe toxicity rate limit is set at 20%. The method used to monitor severe toxicity is
similar used to monitor toxic deaths (ref “Early Stopping Rules in Clinical Trials Based
on Sequential Monitoring of Serious Adverse Events.” Med Decis Making. 2008 Dec
10.), with a nominal alpha risk equal to 15% and an alpha function following a gamma
law with gamma equal to 4.
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The stopping rules used to monitor severe toxicity rate are based on the estimation of
the toxic death rate with its appropriate confidence interval, estimated after occurrence
of each new severe toxic event (from the second toxic event).
11. ADVERSE EVENT COLLECTION & REPORTING
11.1 Definition Adverse event (AE) An adverse event (AE) is any untoward medical occurrence in a patient or clinical trial
subject administered a medicinal product and which does not necessarily have a causal
relationship with this treatment. An AE can therefore be any unfavourable and unintended
sign (including an abnormal laboratory finding) symptom, or disease temporally associated
with the use of a medicinal product whether or not considered related to the medicinal
product.
Serious Adverse event (SAE) A serious adverse event (SAE) is any untoward medical occurrence that at any dose:
• Results in death;
• Is life-threatening
• Requires inpatient hospitalization or prolongation of existing hospitalization
• Results in persistent or significant disability/incapacity;
• Results in congenital anomaly/birth defect.
• Or is otherwise considered medically significant by the Investigator*
• Results in the development of a secondary malignant neoplasm
*Medical judgement should be exercised in deciding whether an AE is serious in other
situations. AEs 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 SAE definition above, should be considered
serious.
If a patient dies as a result of a SAE any post-mortem findings including histopathology
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should be provided.
An SAE judged either by the investigator and/or the sponsor as potentially related to a
study drug qualifies as Serious Adverse Drug Reaction (SADR).
SAEs that are related to the study drug and unexpected (ie, not previously described in
the reference document are termed as Suspected Unexpected Serious Adverse
Reactions (SUSARs).
Events not to be considered as SAEs Due to the seriousness of the disease in this study, certain conditions defined as SAEs will be excluded from expedited reporting on a SAE report form:
• AE (symptoms, signs) unequivocally related to tumour relapse or progression
that meet criteria for seriousness, must not be reported as a SAE (in case of
doubt, please report)
• A visit to the emergency room or other hospital department for less than 24
hours that does not result in admission (unless considered an “important
medical event” or a life-threatening event)
• Outpatient or same-day or ambulatory procedures
• Observation or short-stay units
• Hospitalization due to diagnostic procedures or standard supportive care (e.g.
implant of central venous catheter)
• A pre-planned hospitalization for a condition which existed at the start of study
drug and which did not worsen during the course of study drug treatment
• Social admission (e.g., subject has no place to sleep; hospice facilities)
• Administrative admission (e.g., for yearly physical examinations)
• Protocol-specified admission during a clinical trial (e.g., for a procedure required
by the study protocol or for clinical research)
• Optional admission not associated with a precipitating clinical AE (e.g., for
elective cosmetic surgery)
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11.2 Recording and assessing adverse events
Any AE which occurs or comes to the attention of the investigator at any time during
the study, since consent is given, regardless of time elapsed since last study drug
administration, whether or not considered related to study drugs must be recorded in
the CRF.
If in any one subject the same AE occurs on several occasions, then the AE in
question must be documented and assessed anew each time.
For SAEs, a SAE report form (initial or follow up) must be completed in addition.
The following aspects must be recorded for each event in the CRF.
• A description of the AE in medical terms, not as reported by the subject;
• The date of onset (start date)
• The date of recovery (stop date)
• The grade as assessed by the investigator according to NCI-CTCAE scale,
version 4.0.
• Action taken on study drugs (e.g. none, medication discontinued, dose reduction, medication delayed, reduction of infusion rate…).
• Other action (none, corrective treatment given, surgery..).
• The outcome according to the following definitions: - Recovered with sequelae (if so specify nature of the sequelae). - Recovered without sequelae. - Ongoing - Change in toxicity grade/severity - Died.
• Seriousness: yes or no
• In addition, if the investigator determines a serious adverse event is associated with study procedures, the investigator must record this causal relationship in the source documents and CRF, as appropriate, and report such an assessment in accordance with the serious adverse event reporting requirements, if applicable.
• The causal relationship with study drugs as assessed by the investigator
The site investigator is responsible for assessing the relationship between the AE and
study drugs. Sites investigators must determine whether there is a reasonable
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possibility that the study agent(s) caused or contributed to an AE/SAE. The
relationship assessment, based on clinical judgment, often relies the following:
• A temporal relationship between the event and the administration of the study
drug(s).
• A plausible biological mechanism for the agent to cause the AE/SAE
• Previous reports of similar AEs/SAEs associated with the study drug(s), or other
drug in the same class
• Recurrence of the AE/SAE after re-challenge or resolution after de-challenge
(drug withdrawal), if applicable
• Another possible aetiology for the AE/SAE (concomitant drug, concurrent
disease/condition, underlying cancer disease…)
The terms used to assess the relationship of an event to study drug(s) are:
• Related: there is a reasonable possibility that the AE/SAE may be related to the
study drug(s)/protocol
• Not related: there is not a reasonable possibility that the AE/SAE is related to
the study drug(s)/protocol
If there is insufficient or incomplete evidence to make a clinical judgement of the
casual relationship, the site investigator is allowed to qualify the event as ‘not
assessable’.
If new information becomes available, the relationship assessment of any AE/SAE
should be reviewed again and updated, as required.
The causality assessment given by the investigator will not be downgraded by the
Pharmacovigilance Unit. If the Pharmacovigilance Unit disagrees with the
investigator’s causality assessment, both, the opinion of the investigator and the
Pharmacovigilance Unit will be provided in the case report.
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11.3 Intensity criteria
Intensity criteria must not be confused with criteria for seriousness, which serve as
guidelines for definition of reporting obligations.
Intensity of events will be estimated according to the NCI-CTCAE classification,
version 4.0 (toxicity score grade 1 to 5). Intensity of adverse events not listed in this
classification will be evaluated according to the following terms:
- Mild (grade 1): does not affect the patient's usual daily activity
- Moderate (grade 2): perturbs the patient's usual daily activity
- Severe (grade 3): prevents the patient carrying out his usual daily activities
- Very severe (grade 4): necessitates intensive care or is life-threatening
- Death (grade 5)
11.4 Reporting of serious adverse events
All Serious Adverse Events (SAE), related or not to study drugs, occurring at any time
during the study (since consent is given) and through 30 days after the last
administration of study drugs, independent of the circumstances or suspected cause,
must be reported, within 24 hours of knowledge by fax .
The investigator must fill in the SAE Form and assess the relationship to study drugs,
then send it signed and dated , within 24 hours of learning of its occurrence, even if it
does not appear to be treatment-related, to the: Pharmacovigilance Unit at IGR : +33
(0) 1 42 11 61 50.
Phone +33 (0) 1 42 11 61 00 (from 9 a.m to 6 p.m from Monday to Friday except
bank holidays). Emai: [email protected]
Serious Adverse drug Reactions (SADR) must be repor ted regardless of time elapsed since last study drug dose (no time limit).
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Information collected in the SAE form is crucial to assess the case and for this reason
diligence in collecting as much verifiable and reliable information are of capital
importance. BOTH QUALITY and TIMELINES are key factors.
The investigator must provide any relevant information for the required 8 days follow
up report for any SAE which is fatal or life-threatening.
As far as possible, for each event, the following should be noted:
1) As clear a description as possible in medical terminology
2) Whether the event is expected or not
3) Its duration (start and end dates)
4) Action taken and the necessity for corrective treatment or not, action taken on study
drug(s) (delayed, dose reduction….)
5) Its intensity (grade 1-5), according to the NCI-CTCAE version 4.0
6) Its relationship to study drug(s), the underlying cancer disease, a concurrent
disease/condition, a concomitant drug/treatment, …..
7) Documentation of all co-medication and/or therapies
8) Documentation of all relevant medical history and/or co-existing diseases
9) The outcome (where applicable). For non fatal events, developments should be
followed up until either recovery or recovery of a previous state of health or until the
stabilization of possible after-effects.
The investigator must also attach the following to the serious adverse event report
form, wherever possible:
• A copy of the summary of hospitalization or prolongation of hospitalization
• A copy of the post-mortem report (if applicable)
• A copy of all relevant laboratory examinations and the dates on which these
examinations were carried out, including relevant negative results, as well as
normal laboratory ranges.
• All other document that he judges useful and relevant.
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All these documents will remain anonymous.
The Pharmacovigilance Unit of IGR will assess the adverse event in terms of
seriousness, expectedness, severity (NCI-CTCAE v4.0) and relationship to the study
drug. All SAEs will be coded using MedDRA.
“Expectedness” will be assessed with regard to the valid SPC of XXXXXX
In case of Suspected Unexpected Serious Adverse Reaction (or SUSAR), a CIOMS-1
form will be sent by the sponsor to the French competent authority and ethic
Committee. The SUSARs will also be transmitted by the sponsor to the EMA
pharmacovigilance database (EUDRAVIGILANCE)
11.5 Follow-up
The investigator is responsible for the appropriate medical follow-up of patients until
resolution or stabilization of the adverse event or until the patient's death. This may
mean that follow-up should continue once the patien t has left the trial.
Follow up information about a previously reported serious adverse event must be
reported by the investigator to the Pharmacovigilance Unit within 24 hours of receiving
it (on the serious adverse event report form, by ticking the box marked Follow-up
N°…). The investigator also transmits the final rep ort at the time of resolution or
stabilization of the SAE.
11.6 Information given to investigators, ethics com mittee and regulatory authority
The Pharmacovigilance Unit sends all study investigators and the IDMC a copy of any
unexpected serious adverse reaction (SUSAR) and/or toxic death.
The Pharmacovigilance Unit also informs investigators, the IDMC, the ethics
committee and the competent authority of any information at its disposition that might
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be relevant to patient safety and that might lead to an (unfavourable) reappraisal of the
benefit/risk ratio of the research, originating from other studies carried out on the same
products or according to the same methodology or from publication, spontaneous
notification or another authorized authority.
The sponsor will submit the Development Safety Update report (DSUR) within 60
days of the data lock point (date of the first authorisation of the concerned clinical)
to the French competent authority and Ethic Committee, according to national
legislation.
12. INDEPENDENT DATA MONITORING COMMITTEE
An Independent Data Monitoring Committee (IDMC) composed of x experts
(including one statistician) will monitor the progress of the study on ethical and
scientific grounds. The Committee will meet approximately every x months (by
meeting or conference call).
The role of the IDMC will be:
a) To review accrual rate
b) To monitor toxicity
c) To examine first stage analyses
d) Other
The IDMC may be asked to review a major modification to the study prior to its
implementation as a study amendment.
13. STUDY DISCONTINUATION
The study could be interrupted or terminated by the sponsor in agreement with the
coordinator and with the competent authority for the following reasons:
- Frequency and/or unexpected severity of the toxicity,
- Recruitment of patients too low,
- Poor quality of the data collected,
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- Request of the Data Monitoring Committee
14. ETHICAL AND REGULATORY ASPECTS
14.1 Rules and regulations
The clinical trial is conducted in compliance with:
- The Huriet Law (n° 88-1138) of December 20, 1988 concerning the Protection of
Persons Undergoing Biomedical Research,
- The Public Healthcare Law (n° 2004-806) of August 9, 2004, a partial adaptation of
the European Directive (2001/20/EC) on the conduct of clinical trials,
- The Data Processing and Civil Liberties Law (n° 7 8-17) of January 6, 1978 modified
by Law n° 2004-801 of August 6, 2004 relative to th e protection of physical persons
with respect to the processing of personal information.
- Law n° 2002-303 of March 4, 2002 relative to pati ents’ rights and to the quality of the
healthcare system,
- Appendix 13 of the E. U. Guide to Good Manufacturing Practices (revised and
adopted in July 2003 by the European Commission),
- Article R5121-16 of the “Code de la Santé Publique” (Public Health Regulations)
concerning the labelling of trial products.
14.2 Committee for the Protection of Persons (CPP) – Competent Authority
This protocol was submitted to the XXXX Committee for the Protection of Persons
which gave its approval during the session on XX/XX/XXXX. This protocol has also
been approved by the ANSM [French Health Products Safety Agency] on
XX/XX/XXXX.
The Institut Gustave Roussy has taken out a legal liability insurance policy (N°124895).
The Institut Gustave Roussy will declare the date of the start and of the end of the trial
to the ANSM.
A final report on the trial will be written at the latest, 6 months after the end of the trial
(defined as the time of the main analysis) and sent to the competent authority and to
the CPP.
The Institut Gustave Roussy will keep records of essential trial documentation in the
Sponsor file for a minimum duration of 15 years after the end of the trial.
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14.3 Information and Consent of Participants
Written informed consent is required prior enrolment in the study. This consent is
obtained once the investigator has informed the parents / legal guardian of the patient
during a consultation and after the person had been given sufficient time to think it
over.
Having read the information notice, the parents / legal guardian patient must date and
sign the consent form if they accept the participation of their child. The investigator
must also sign this consent form. The original consent form must be kept in the study
file by the investigator and the study participant should receive a copy.
14.4 Principal Investigator Responsibilities
The principal investigator of each establishment concerned promises to conduct the
clinical trial in compliance with the protocol that has been approved by the CPP and
the competent authority.
The principal investigator should not modify any aspect of the protocol without prior
written permission from the Sponsor or without the approval of the proposed
modifications by the CPP and the competent authority.
The Principal Investigator is responsible for:
- Providing the Sponsor with his/her CV as well as that of co-investigators,
- Identifying members of his/her team participating in the trial and defining their
responsibilities,
- Recruiting patients after receiving the Sponsor’s approval,
Each investigator is responsible for:
- Personally obtaining the informed consent form which has been dated and signed by
the participant in the research prior to any specific trial selection procedure,
- Regularly completing the case report form (CRF) for each patient included in the trial
and ensuring that the Clinical Research Assistant (CRA) mandated by the Sponsor has
direct access to source documents in order to validate information on the CRF,
- Dating, correcting and signing the corrections on the CRF for each patient included in
the trial,
- Accepting regular visits from a CRA and possibly visits from auditors mandated by the Sponsor or inspectors from the regulatory authorities.
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All documentation concerning the trial (protocol, consent form, case report form,
investigator file, etc…), as well as the original documents (laboratory results, imaging
studies, medical consultation reports, clinical examination reports, etc.) is considered
confidential and should be kept in a safe place. The Principal Investigator should keep
data as well as a list of patient-identifying data for at least 15 years after the end of the
study.
15. DATA COLLECTION
Data are collected using a CRF. Data will be sent to the Data Manager after they have
been made anonymous by the CRA at the centres participating in the study. The data
for each phase must be sent within one month of the completion of each phase
(conventional chemotherapy, intensification, consolidation, salvage treatment, end of
treatment).
16. QUALITY ASSURANCE - MONITORING
In order to guarantee the authenticity and the credibility of the data in compliance with
good clinical practices, the Sponsor has implemented a quality assurance system that
includes:
- Trial management in accordance with the procedures at the Institut Gustave
Roussy,
- Quality control of data at the investigating site by the Sponsor’s CRA,
- Possible auditing of investigating centres,
- a central review of certain protocol criteria
16.1 Monitoring
Quality control on the site will be ensured by the Sponsor’s CRA.
The CRA must check that the investigator’s file exists and that it is updated.
The CRA must verify the consent forms, that subjects fulfil eligibility criteria, the validity
of evaluation criteria and treatment toxicity with the help of source documents
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The CRA will check drug accountability and ensure that the drug accountability forms
are validated and signed by the in-house pharmacist before any request for
destruction.
16.2 Central review
16.2.1 Central radiological review
The cerebral and spinal MRI films recorded at the start of treatment, those conducted
after conventional chemotherapy, those conducted after the intensification phase, and
at the end of the treatment will be subject to central review and must be sent to Dr
Anne Geoffay (Medical imaging, Lenval Foundation, 57 avenue de la Californie, 06200
NICE) for subsequent second reading. The imaging after conventional chemotherapy
and the intensification phase must be sent in the real time to confirm the response.
In the event of tumour progression either during or after the end of treatment, the
imaging must be sent with the previous examinations in real time to confirm the failure
of treatment and validate the decision to withdraw the patient from the trial. The result
of this centralised review will be used as a study endpoint.
16.2.2 Central histology review
The initial biopsy from each patient enrolled in the study must undergo centralised
reading by Professor Marie-Bernadette Delisle (Laboratory of pathological anatomy
and cytology - Rangueil Hospital - 1, avenue du Professeur Jean Poulhès - TSA 50032
- 31059 Toulouse cedex 9). The protocol requires that the slides are sent for a second
reading.
17. DATA OWNERSHIP / PUBLICATION POLICY
The investigator promises, on his/her behalf as well as that of all the persons involved
in the conduct of the trial, to guarantee the confidentiality of all the information provided
by Institut Gustave Roussy until the publication of the results of the trial.
All publications, abstracts or presentations including the results of the trial require prior
approval by the Sponsor (Institut Gustave Roussy).
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All oral presentations, manuscripts must include a section mentioning the Sponsor, the
investigators / institutions that participated in the trial, the cooperative groups, learned
societies which contributed to the conduct of the trial and the bodies which funded the
research.
The Study Investigator-Coordinator will write an article reporting on the results as soon
as possible after the final analysis and will be the first author of the publication.
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48. Bouligand, J., et al., In children and adolescents, the pharmacodynamics of high-dose busulfan is dependent on the second alkylating agent used in the combined regimen (melphalan or thiotepa). Bone Marrow Transplant, 2003. 32(10): p. 979-86.
49. McCune, J.S., et al., Cyclophosphamide following targeted oral busulfan as conditioning for hematopoietic cell transplantation: pharmacokinetics, liver toxicity, and mortality. Biol Blood Marrow Transplant, 2007. 13(7): p. 853-62.
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52. Cacchione, A., et al., Risk factors for hepatic veno-occlusive disease: a retrospective unicentric study in 116 children autografted after a high-dose BU-thiotepa regimen. Bone Marrow Transplant, 2008. 42(7): p. 449-54.
53. Lee, J.H., et al., Decreased incidence of hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults conditioned with busulfan + cyclophosphamide for allogeneic bone marrow transplantation. Ann Hematol, 2005. 84(5): p. 321-30.
54. Richardson, P.G., et al., Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. Blood, 2002. 100(13): p. 4337-43.
55. Estlin, E.J., et al., Phase I study of temozolomide in paediatric patients with advanced cancer. United Kingdom Children's Cancer Study Group. Br J Cancer, 1998. 78(5): p. 652-61.
56. Nicholson, H.S., et al., Phase I study of temozolomide in children and adolescents with recurrent solid tumors: a report from the Children's Cancer Group. J Clin Oncol, 1998. 16(9): p. 3037-43.
57. Riccardi, R., et al. Antitumor activity of temozolomide in medulloblastoma - PNET. in 12th International Symposium on Pediatric Neuro-Oncology. 2006. Nara, Japon.
58. Nicholson, H.S., et al., Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumors: a report from the Children's Oncology Group. Cancer, 2007. 110(7): p. 1542-50.
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59. Wang, C.H., et al., Efficacy of temozolomide for recurrent embryonal brain tumors in children. Childs Nerv Syst, 2009. 25(5): p. 535-41.
60. Turner, C.D., et al., Phase II study of irinotecan (CPT-11) in children with high-risk malignant brain tumors: the Duke experience. Neuro Oncol, 2002. 4(2): p. 102-8.
61. Wagner, L.M., et al., Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors. Clin Cancer Res, 2004. 10(3): p. 840-8.
62. Wagner, L.M., et al., Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer, 2007. 48(2): p. 132-9.
63. Wagner, L.M., et al., Phase I trial of oral irinotecan and temozolomide for children with relapsed high-risk neuroblastoma: a new approach to neuroblastoma therapy consortium study. J Clin Oncol, 2009. 27(8): p. 1290-6.
64. Ashley, D.M., et al., Response of recurrent medulloblastoma to low-dose oral etoposide. J Clin Oncol, 1996. 14(6): p. 1922-7.
65. Chamberlain, M.C. and P.A. Kormanik, Chronic oral VP-16 for recurrent medulloblastoma. Pediatr Neurol, 1997. 17(3): p. 230-4.
66. Grodman, H., L. Wolfe, and C. Kretschmar, Outcome of patients with recurrent medulloblastoma or central nervous system germinoma treated with low dose continuous intravenous etoposide along with dose-intensive chemotherapy followed by autologous hematopoietic stem cell rescue. Pediatr Blood Cancer, 2009. 53(1): p. 33-6.
67. Moghrabi, A., et al., A phase I/II feasibility study of oral etoposide given concurrently with radiotherapy followed with dose-intensive adjuvant chemotherapy for children with newly diagnosed high-risk medulloblastoma COG P9631. Neuro Oncol, 2008. 10(3): p. 476.
68. Bowers, D.C., et al., Impact of site of tumor recurrence upon survival for children with recurrent or progressive medulloblastoma. J Neurosurg, 2007. 107(1 Suppl): p. 5-10.
69. Dunkel, I.J., et al., High-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue for patients with recurrent medulloblastoma. Children's Cancer Group. J Clin Oncol, 1998. 16(1): p. 222-8.
70. Dupuis-Girod, S., et al., Will high dose chemotherapy followed by autologous bone marrow transplantation supplant cranio-spinal irradiation in young children treated for medulloblastoma? J Neurooncol, 1996. 27(1): p. 87-98.
71. Goldwein, J.W., et al., Updated results of a pilot study of low dose craniospinal irradiation plus chemotherapy for children under five with cerebellar primitive neuroectodermal tumors (medulloblastoma). Int J Radiat Oncol Biol Phys, 1996. 34(4): p. 899-904.
72. Corbacioglu, S., et al., Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet, 2012. 379(9823): p. 1301-9.
73. Remke, M., et al., FSTL5 is a marker of poor prognosis in non-WNT/non-SHH medulloblastoma. J Clin Oncol, 2011. 29(29): p. 3852-61.
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74. Gessi, M., et al., p53 expression predicts dismal outcome for medulloblastoma patients with metastatic disease. J Neurooncol, 2012. 106(1): p. 135-41.
75. Chinnaswamy, G., et al., Pharmacokinetics of cyclophosphamide and its metabolites in paediatric patients receiving high-dose myeloablative therapy. Eur J Cancer, 2011. 47(10): p. 1556-63.
76. Bray, B.C., S.T. Lanza, and L.M. Collins, Modeling Relations Among Discrete Developmental Processes: A General Approach to Associative Latent Transition Analysis. Struct Equ Modeling, 2010. 17(4): p. 541-569.
77. O'Quigley, J., M. Pepe, and L. Fisher, Continual reassessment method: a practical design for phase 1 clinical trials in cancer. Biometrics, 1990. 46(1): p. 33-48.
78. Ahn, C., An evaluation of phase I cancer clinical trial designs. Stat Med, 1998. 17(14): p. 1537-49.
79. Finkelstein, D.M., A. Muzikansky, and D.A. Schoenfeld, Comparing survival of a sample to that of a standard population. J Natl Cancer Inst, 2003. 95(19): p. 1434-9.
80. Massimino, M., et al., Supratentorial primitive neuroectodermal tumors (S-PNET) in children: A prospective experience with adjuvant intensive chemotherapy and hyperfractionated accelerated radiotherapy. Int J Radiat Oncol Biol Phys, 2006. 64(4): p. 1031-7.
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APPENDIX A: LANSKY SCALE (Lansky et al., Cancer, 1987)
This questionnaire is designed to be filled in with the help of the parents according to the child’s daily life and is useful during the course of the disease.
100% Fully active, normal.
90% Minor restrictions in physically strenuous activity.
80% Active, but tires more quickly.
70% Both greater restriction of, and less time spent in, active play
60% Up and around but minimal active play, keeps busy with quieter activities.
50% Gets dressed, but lies around much of the day; no active play; able to participate in quiet play and activities.
40% Mostly in bed; participates in quiet activities.
30 % In bed; needs assistance even for quiet play.
20 % Often sleeping; play entirely limited to very passive activities.
10 % No play. Does not get out of bed.
0% Unresponsive.
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APPENDIX B: PERIPHERAL STEM CELL COLLECTION
1/ COLLECTION OF PERIPHERAL BLOOD STEM CELLS (PBSC)
Approach
Collection of PBSC requires 2 venous access lines. A central venous line will be used if possible with a second peripheral access. If there is no solid peripheral venous line, a central indwelling catheter will be inserted and then removed after the end of leukapheresis. The diameter of the catheter must be adjusted according to patient body weight. The catheter will be chosen according to the practices in each centre, though it is important for at least one of the 2 catheters to be adapted to the high pressures generated by the pump used to collect whole blood.
Collection
Whole blood is collected from the venous access line and anticoagulated with citrate solution (ACDA). After separation of whole blood, the mononuclear cells layer is removed and the rest of the blood cells are returned to the patient. In parallel with mononuclear cells, plasma, red blood cells and platelets are collected leading to a reduction in haemoglobin concentration from 1 to 2 g/100ml and an approximately 30% reduction in platelet mass after each leukapheresis. Each leukapheresis will involve the processing of at least one and a half times the patient’s blood mass.
Possible complications
These will be prevented by a medical examination before each leukapheresis as well as follow-up by the leukapheresis operator and a doctor during collection.
In the event of hypovolemic malaise due to the extracorporeal volume (200 to 300 ml), the collection flow rate will be reduced or even stopped. If the malaise persists despite discontinuation of collection it may be necessary to infuse a macromolecular solution.
Citrated solutions may cause hypocalcaemia reactions. If paraesthesia or gastrointestinal disorders (nausea) occur, the citrate infusion rate should be reduced or a calcium salt used. In children weighing less than 20 kg, the intravenous administration of 1 g of calcium morning and evening is recommended throughout the duration of leukapheresis.
Heparin is not systematically administered though it may be necessary if there is a venous obstruction problem . A minimum haemoglobin concentration of 12g/100ml is required for satisfactory leukapheresis.
Blood products must be irradiated and the white blood cells removed.
Thrombocytopenia secondary to leukapheresis is transient and only requires platelet transfusion in the event of bleeding or disease.
2/ DEEP-FREEZING OF STEM CELLS
The PBSC must be frozen within 8 hours of collection.
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APPENDIX C: IMAGING PROCEDURES
Imaging is essential to evaluate the initial tumour, any postoperative tumour residue
and its outcome after chemotherapy.
It must be possible to compare the different examinations and conduct a second
reading by other doctors during this trial.
The tumour and any post-operative residue should be measured in all 3 planes for the
calculation of tumour volume (a x b x c/2). 3D-volume calculations may be performed
additionally. These volume calculations are the basis for follow-up evaluation and
every effort should be made to ensure the highest possible accuracy
Cranial MRI:
The standard imaging plane for the brain should be the axial plane (aligned to the AC-
PC axis). Slice thickness should not exceed 4mm and must be adapted to the
individual problem. As the signal of a tumour depends on the field strength of the MRI
scanner the field strength must not be changed during the study.
For 1-1.5 Tesla MR scanners Sequences:
Pre-contrast Axial T1, T2 and PD or FLAIR
Coronal FLAIR
Post contrast Axial, coronal and sagittal T1
Axial DWI with ADC
Optional: 3D gradient echo T1 post contrast (particularly for computer guided surgical
planning); functional imaging (e.g. perfusion, MRS, DTI and any other individual local
imaging protocols).
For 3 Tesla MRI scanners:
The T1 imaging should be undertaken using a 3D-gradient echo T1 volume sequence
pre- and post-contrast in addition to a T1 SE or gradient echo sequence (e.g. in the
axial plane).
Spinal MRI:
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Avoid 3T MRI for spinal imaging, as the image quality is often inferior to that of 1.5T
MR-scanners and more unpredictable. The entire dural sac must be fully visualised.
As only meningeal disease is of interest only sagittal post-contrast T1-weighted
sequences are necessary. Slice thickness must not e xceed 3 mm . The
physiological veins of the cord can be mistaken for dissemination nodules and
therefore axial slices without gaps (slice thickness can be chosen individually) are
essential for all suspicious areas . As fat suppression often leads to artefacts and is
not necessary for the delineation of meningeal disease it should not be used routinely.
Optional:
T2 TSE sequences (particularly when the primary tumour does not enhance or
minimally enhances) or fat suppression techniques.
Early postoperative imaging:
As non-specific intracranial enhancement is often seen after 3 days following surgery
the postoperative MRI must be obtained within this time. Optimal evaluation is made
within the first 48 hours following surgery, and therefore should be undertaken within
this period. However, even within this time false positive nodular enhancement can be
seen with haemostatic materials and after electrocoagulation and therefore the pre-
and post-contrast T1-weighted images need to be carefully evaluated in combination
with the signal intensities on the T2-weighted and FLAIR series. Comparability with the
preoperative MRI is essential for the detection of residual tumour. The size of a
possible residuum has to be measured in all three planes. If the residuum is best
visible on T2-weighted images a second plane incorporating a T2-weighted sequence
must be employed.
A residuum is considered to be any area of pathological signal and/or enhancement
comparable with the appearance of the pre-operative tumour.
For the evaluation of residual tumour seen on imaging the surgical report is often
valuable and should be available.
Sequences for cranial and spinal imaging see prescriptions for cranial and spinal MRI:
Spatial resolution for postoperative MR should definitely be increased, including
sequences with 1 to 2 mm slice thickness and 512 matrix. T2 sequences are
recommending.
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Please note if spinal MRI is performed post-operatively:
Non-specific subdural and intradural enhancement and possible intradural blood
products may be identified on early post-operative imaging of the spine and must not
be mistaken for meningeal dissemination. Where there is on-going doubt or if intense
subdural enhancement is seen, the spinal MRI should be repeated after 2 weeks to
clarify the situation.
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APPENDIX D: Busilvex (iv Busulfan) Sampling Sheet
DAY OF STUDY
DATE INITIALS HR-MB-5 STUDY No.
WEIGHT S.A GFR
BUSULFAN DOSE (mg):
INFUSION TIME START: FINISH:
(busulfan)
Samples to be taken for busulfan analysis.
Label all tubes with the patient initials, date of study and time of sample or sample number.
Sample number
Day of busulfan treatment
Time from START
busulfan
Time due
Time taken
1 Day 1 Pre-treatment
2 Day 1 2.5 h post-dose 1
3 Day 1 6 h post-dose 1
4 Day 3 Pre-dose 9
5 Day 3 2.5 h post-dose 9
6 Day 3 6 h post-dose 9
7 Day 4 6 h post-dose 13
2 ml of blood to be taken in a heparinised tube, centrifuge for 5 min at 2000rpm and 4°C.
Remove plasma and freeze at -20°C.
COMMENTS:
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Samples to be sent by overnight courier, packed on dry ice in an insulated container.
Address for delivery :-
Angelo Paci
Institut de Cancérologie Gustave Roussy
Service de Pharmacologie et d’Analyse du Médicament
Bat ERP, niveau -1
114, rue Camille Desmoulins
94800 VILLEJUIF
FRANCE
Contact numbers:-
Angelo Paci : 00 33 1 42 11 47 30
Fax : 00 33 1 42 11 52 77
e mail : [email protected]
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APPENDIX E : Cyclophosphamide Pharmacokinetics Sampling Sheet
STUDY CENTRE DATE OF STUDY
DATE OF BIRTH INITIALS *
(* first 3 letters of surname, first 2 letters of first name)
STUDY NUMBER TYPE OF CVC
WEIGHT S.A GFR (if available)
Cyclophosphamide Dose (mg)
Cyclophosphamide Infusion Start: ____:___ Finish: ____:___
Samples to be taken for analysis following intravenous administration of cyclophosphamide. Label all tubes with the patient initials, date of study and time of sample or sample number.
Sample number
Time from END of Cyclophosphamide Infusion
Time due
Time taken
1 Pre-treatment
2 End infusion
3 1 h
4 2 h
5 4 h
6 6 h
7 23 h (pre-dose 2)
2 ml of blood to be taken in a heparinised tube, immediately centrifuge for 5 min at 2,000rpm and 4°C. Freeze plasma at -20°C as soon a s possible.
/ /
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HR MB – 5 CSET 2012/xxxxx
12 June 2012 Version 1.0 – Confidential Page 84 of 91
Samples to be sent by overnight courier (Monday to Wednesday) packed on dry ice in an insulated container.
Address for delivery :-
Samples to be sent packed on dry ice in an insulated container to:
Gareth Veal /Julie Errington Contact numbers:-
Northern Institute for Cancer Research Gareth Veal: +44 (0)191 246 4332
Paul O’Gorman Building Julie Errington: +44 (0)191 246 4357
North Terrace Fax: +44 (0)191 222 3452
Newcastle upon Tyne Email : [email protected]
NE2 4AD [email protected]
United Kingdom
HR MB – 5 CSET 2012/xxxxx
12 June 2012 Version 1.0 – Confidential Page 85 of 91
APPENDIX F: CLASSIFICATION CTC-AE (VERSION 4.0)
National Cancer Institute - Common Terminology Criteria for Adverse Events
(NCI-CTCAE, Version 4.0)
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
http://ctep.cancer.gov/
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APPENDIX G: TOXICITY AFTER HIGH DOSE CHEMOTHERAPY ( BEARMAN GRADING)
Grade I Grade II Grade III
Cardiac Mild EKG abnormality, not requiring medical intervention; or noted heart enlargement on CXR with no clinical symptoms
Moderate EKG abnormalities requiring and responding to medical intervention; or requiring continuous monitoring without treatment, or congestive heart failure responsive to digitalis or diuretics.
Severe EKG abnormalities with no or only partial response to medical intervention; or heart failure with no or only minor response to medical intervention; or decrease in voltage by more than 50%.
Bladder Macroscopic haematuria after 2 days from last chemotherapy dose with no subjective symptoms of cystitis and not caused by infection.
Macroscopic haematuria after 7 days from last chemotherapy dose not caused by infection; or haematuria after 2 days with subjective symptoms of cystitis not caused by infection .
Haemorrhagic cystitis with frank blood, necessitating invasive local intervention with installation of sclerosing agents, nephrostomy or other surgical procedure.
Renal Increase in creatinine up to twice the baseline value (usually the last recorded before start of conditioning).
Increase in creatinine above twice baseline but not requiring dialysis.
Requirement of dialysis.
Pulmonary Dyspnoea without CXR changes not caused by infection or congestive heart failure; or CXR showing isolated infiltrate or mild interstitial changes without symptoms not caused by infection or congestive heart failure.
CXR with extensive localised infiltrate or moderate interstitial changes combined with dyspnoea and not caused by infection or CHF; or decrease of PO2 (>10% from baseline) but not requiring mechanical ventilation or >50% O2 on mask and not caused by infection or CHF.
Interstitial changes requiring mechanical ventilatory support or >50% oxygen on mask and not caused by infection or CHF.
Liver Mild hepatic dysfunction with 2.0 mg% � bilirubin 6.0mg%; or weight gain �2.5% and �5% from baseline, of noncardiac origin; or SGOT increase more than 2-fold but less than 5-fold from lowest preconditioning.
Moderate hepatic dysfunction with bilirubin �6mg% �20mg%, or SGOT increase � 5-fold from preconditioning ; or clinical ascites or image documented ascites �100ml, or weight gain �5% from baseline of noncardiac origin.
Severe hepatic dysfunction with bilirubin �20mg%; or hepatic encephalopathy; or ascites compromising respiratory function.
CNS Somnolence but the patient is easily arousable and orientated after arousal.
Somnolence with confusion after arousal, or other new objective CNS symptoms with no loss of consciousness not more easily explained by other medication, bleeding, or CNS infection.
Seizures or coma not explained (documented) by other medication, CNS infection, or bleeding.
Stomatitis Pain and/or ulceration not requiring a continuous IV narcotic drug.
Pain and/or ulceration requiring a continuous IV narcotic drug (morphine drip).
Severe ulceration and/or mucositis requiring preventive intubation; or resulting in documented aspiration pneumonia with or without intubation.
Digestive Watery stools � 500ml but �2,000ml every day not related to infection.
Watery stools �2,000ml every day not related to infection; or macroscopic haemorrhagic stools with no effect on cardiovascular status not caused by infection; or subileus not related to infection.
Ileus requiring nasogastric suction and/or surgery and not related to infection; or haemorrhagic enterocolitis affecting cardiovascular status and requiring transfusion.
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APPENDIX H: STATISTICAL MODEL, SPECIFIC RULES AND OPERATING CHARACTERISTICS OF PHASE I DESIGN
Statistical model : A one-parameter empirical power model will be used to assess the
relation between the dose level and the probability of DLT: )exp(),( αα dpdF = where F(d,α) is
the estimated probability of DLT at dose-level d, pd is the prior probability of DLT at dose
level d, and α is the unknown parameter to be estimated by the model. The vector {p0d}
represent the initial guesses of toxicity probabilities, reflecting the clinicians’ prior belief.
The skeleton of initial guesses of toxicity probabilities {p0d} is numerically calibrated using
the Lee and Cheung approach (ref ClinTrials 2009) and using the getprior function of R,
ensuring good design’s operating characteristics. After discussion with the clinicians, the
delta defining the indifference interval was set at 0.7 (indifference interval: 0.23 to 0.37)
and the prior MTD (MTD0) at the 3rd dose level, meaning that the clinicians believe, a
priori, that the 3rd dose (1500 mg/m²) is probably the MTD. This yields a vector of prior
probabilities {p0k} equal to 0.07, 0.17, 0.30, and 0.44. The clinicians confirmed that it was
in accordance with their initial guesses.
A non-informative prior distribution Normal (0,1.34) has been assigned for α in the
Bayesian computation.
The simulation study below confirmed that the operating characteristics and the behaviour
of the model defined with these parameters were reasonable.
Specific rules:
a. No dose skipping in escalation.
b. No escalation if >1 DLT observed among < 3 patients.
c. If a grade 3 pulmonary toxicity is observed, the corresponding dose level will be
closed.
d. For the first two dose levels, the patients can be recruited with no minimal time
interval between successive inclusions. A safety period of one month will be used
for the first patients at dose levels 3 and 4, that is, a second patient will be treated
at the dose level 3 (or 4) only after the first patient treated at this dose has been
fully observed and no grade 3 pulmonary toxicity occurred.
e. At least two patients fully observed with no DLT are required at a given dose before
dose escalation.
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Operating characteristics:
The operating characteristics of the proposed design were evaluated using the R crmsim
function written by Cheung, and considering five different scenarios (highly toxic,
moderately toxic, similar with prior probabilities, close to the probabilities but a little less
toxic, and little toxic) and with cohort sizes successively equal to 1, 2 or 3. Considering
that approximately 50% of all study patients should enter the phase I part of the trial, we
considered that the phase 1 trial would recruit a total of 24 patients for the simulation
study. The rules a. and b. were implemented in the simulation study.
For each case, 1000 trials were simulated. The Monte Carlo estimation of the percentage
of dose selection, the average number of patients treated at each dose level, the average
number of observed DLTs at each dose level demonstrated that the modified CRM design
can efficiently identify the MTD, with a reasonable probability of overdosing, and expose
few patients to toxicity. Results in terms of the distribution of dose selection were very
similar when the cohort size varied from 1 to 3. The tables below display the results for
cohorts of 1 patient. Additional results are available in appendix X (Plots of the results
according to the cohort size = 1, 2 or 3).
Figure 1: Scenarios studied
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Table 1 : Operating characteristics for five differ ent scenarios for the probability of DLT per dose
The grey row represents the true MTD (proba(DLT) closest to the target of 0.30. Scenario 1 Dose Level Prior Prob
True Proba(DLT)
% of dose selection
Mean no of patients
Mean no of DLTs
80 7% 29% 0.51 12.0 3.5 120 17% 35% 0.33 6.8 2.4 160 30% 45% 0.14 3.7 1.6 200 44% 55% 0.02 1.4 0.8
Expected number of DLTs = 8.3 / trial Scenario 2 Dose Level Prior Prob
True Proba(DLT)
% of dose selection
Mean no of patients
Mean no of DLTs
80 7% 10% 0.06 4.1 0.4 120 17% 27% 0.48 8.9 2.4 160 30% 36% 0.37 7.3 2.6 200 44% 48% 0.09 3.6 1.8
Expected number of DLTs = 7.2 / trial Scenario 3: prior = true proba(DLT) Dose Level Prior Prob
True Proba(DLT)
% of dose selection
Mean no of patients
Mean no of DLTs
80 7% 7% 0.01 2.2 0.1 120 17% 17% 0.22 6.3 1.0 160 30% 30% 0.56 9.4 2.8 200 44% 44% 0.22 6.2 2.7
Expected number of DLTs = 6.7 / trial Scenario 4 Dose Level Prior Prob
True Proba(DLT)
% of dose selection
Mean no of patients
Mean no of DLTs
80 7% 5% 0.00 1.7 0.1 120 17% 12% 0.11 4.5 0.5 160 30% 28% 0.48 8.6 2.4 200 44% 35% 0.41 9.2 3.2
Expected number of DLTs = 6.2 / trial Scenario 5 Dose Level Prior Prob
True Proba(DLT)
% of dose selection
Mean no of patients
Mean no of DLTs
80 7% 1% 0.00 1.1 0.0 120 17% 5% 0.00 1.5 0.1 160 30% 10% 0.05 3.1 0.3 200 44% 20% 0.95 18.2 3.6
Expected number of DLTs = 4.0 / trial
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Examples of behaviour of the step by step design (D L=Dose Level)
Escalation to DL2, if
- 0 DLT / 2 patients DL1
- 1 DLT / > 4 patients DL1
- 2 DLT / > 9 patients DL1
If 0 DLT / 2 (or 3) patients at DL1, then escalation at DL2. Escalation at DL3 if
- 0 DLT / 2 patients DL2
- 1 DLT / > 4 patients DL2
(the model recommends DL3 if 0 DLT / 3 DL1 + 1 DLT / 3 DL2,
but rule b � 4 DL2 requested before escalation)
- 2 DLT / > 8 patients DL2
If 1 DLT / 4 patients at DL1, then escalation at DL2. Escalation at DL3 if
- 0 DLT / 4 patients DL2
- 1 DLT / > 8 patients DL2
Very conservative approach if one DLT occurs at DL1.
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Design performance according to the cohort size
Percentage of dose selection
Average number of patients treated at each
dose level
Average number of observed DLTs at each
dose level
Sce
nario
1
Percentage of dose selection according to cohort size, m
0
0.2
0.4
0.6
0.8
1
500 1000 1500 2000
Dose level
Pe
rce
nta
ge o
f se
lect
ion m=1
m=2m=3
Percentage of dose selection according to cohort size, m
0
0.2
0.4
0.6
0.8
1
500 1000 1500 2000
Dose level
Pe
rce
nta
ge o
f se
lect
ion m=1
m=2m=3
Percentage of dose selection according to cohort size, m
0
0.2
0.4
0.6
0.8
1
500 1000 1500 2000
Dose level
Pe
rce
nta
ge o
f se
lect
ion m=1
m=2m=3
Sce
nario
2
Percentage of dose selection according to cohort size, m
0
0.2
0.4
0.6
0.8
1
500 1000 1500 2000
Dose level
Pe
rce
nta
ge o
f se
lect
ion m=1
m=2m=3
Percentage of dose selection according to cohort size, m
0
0.2
0.4
0.6
0.8
1
500 1000 1500 2000
Dose level
Pe
rce
nta
ge o
f se
lect
ion m=1
m=2m=3
Number of DLTsaccording to cohort size, m
0
1
2
3
4
5
500 1000 1500 2000
Dose level
Nu
mb
er o
f DL
Ts
m=1m=2m=3
Sce
nario
3
Number of DLTsaccording to cohort size, m
0
1
2
3
4
5
500 1000 1500 2000
Dose level
Nu
mb
er o
f DL
Ts
m=1m=2m=3
Number of DLTsaccording to cohort size, m
0
1
2
3
4
5
500 1000 1500 2000
Dose level
Nu
mb
er o
f DL
Ts
m=1m=2m=3
Number of DLTsaccording to cohort size, m
0
1
2
3
4
5
500 1000 1500 2000
Dose level
Nu
mb
er o
f DL
Ts
m=1m=2m=3
Sce
nario
4
Number of DLTsaccording to cohort size, m
0
1
2
3
4
5
500 1000 1500 2000
Dose level
Nu
mb
er o
f DL
Ts
m=1m=2m=3
Number of DLTsaccording to cohort size, m
0
1
2
3
4
5
500 1000 1500 2000
Dose level
Nu
mb
er o
f DL
Ts
m=1m=2m=3
Number of DLTs according to cohort size, m
0
1
2
3
4
5
500 1000 1500 2000
Dose level
Nu
mb
er o
f DL
Ts
m=1m=2m=3
Sce
nario
5
Percentage of dose selection according to cohort size, m
0
0.2
0.4
0.6
0.8
1
500 1000 1500 2000
Dose level
Pe
rce
nta
ge o
f se
lect
ion m=1m=2m=3
Dose allocation in the trialaccording to cohort size, m
0
5
10
15
20
500 1000 1500 2000
Dose level
Num
ber o
f pat
ient
s
m=1m=2m=3
Number of DLTsaccording to cohort size, m
0
1
2
3
4
5
500 1000 1500 2000
Dose level
Nu
mb
er o
f DL
Ts
m=1m=2m=3
80 120 160 200 80 120 160 200 80 120 160 200
80 120 160 200 80 120 160 200 80 120 160 200
80 120 160 200 80 120 160 200 80 120 160 200
80 120 160 200 80 120 160 200 80 120 160 200
80 120 160 200 80 120 160 200 80 120 160 200