abbreviation list - university of kansas medical … protocol template 8 2014... · web viewstable...

Study Title

PRINCIPAL INVESTIGATORPI NameAddress

Office PhoneFax

Email address

Study Drug:

IND Number:

IND Holder Name:

Initial Version:

Modification Date:

CONFIDENTIALThis material is the property of the University of Kansas Cancer Center. Do not disclose or use

except as authorized in writing by the study sponsor.

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LIST OF KEY PERSONNEL

PRINCIPAL INVESTIGATOR

SUB-INVESTIGATOR(S)

BIOSTATISTICIAN

COLLABORATORS

Version Date Insert Date of 34

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Signature Page

The signature below constitutes the approval of this protocol and the attachments, and provides the necessary assurances that this trial will be conducted according to all stipulations of the protocol, including all statements regarding confidentiality, and according to local legal and regulatory requirements and applicable U.S. federal regulations and ICH guidelines.

Principal Investigator (PI) Name: _____________________________

PI Signature: _____________________________

Date: ____________________

Biostatistician Name:

Biostatistician Signature:

Date: ____________________

(Consider adding additional signoffs for research staff (nurse/coordinators) or routing page)


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TABLE OF CONTENTSABBREVIATION LIST................................................................................................................................. 6STUDY SCHEMA........................................................................................................................................ 8STUDY SUMMARY..................................................................................................................................... 81.0 BACKGROUND AND RATIONALE...................................................................................................9

1.1 DISEASE BACKGROUND..................................................................................................................... 91.2 STUDY AGENT(S) BACKGROUND AND ASSOCIATED KNOWN TOXICITIES...............................................91.3 OTHER AGENTS................................................................................................................................ 91.4 RATIONALE....................................................................................................................................... 91.5 CORRELATIVE STUDIES..................................................................................................................... 9

2.0 STUDY OBJECTIVES........................................................................................................................ 92.1 PRIMARY OBJECTIVES.....................................................................................................................102.2 SECONDARY OBJECTIVES................................................................................................................102.3 EXPLORATORY OBJECTIVES............................................................................................................102.4 ENDPOINTS..................................................................................................................................... 10

3.0 PATIENT ELIGIBILITY..................................................................................................................... 103.1 INCLUSION CRITERIA....................................................................................................................... 103.2 EXCLUSION CRITERIA...................................................................................................................... 11

4.0 TREATMENT PLAN.........................................................................................................................114.1 TREATMENT DOSAGE AND ADMINISTRATION.....................................................................................114.2 TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS...................................................................134.3 CONCOMITANT MEDICATIONS/TREATMENTS......................................................................................154.4 OTHER MODALITIES OR PROCEDURES.............................................................................................154.5 DURATION OF THERAPY..................................................................................................................154.6 DURATION OF FOLLOW UP..............................................................................................................154.7 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY.........................................................................164.8 PATIENT REPLACEMENT.................................................................................................................. 16

5.0 STUDY PROCEDURES....................................................................................................................165.1 SCREENING/BASELINE PROCEDURES...............................................................................................165.2 PROCEDURES DURING TREATMENT.................................................................................................175.3 FOLLOW-UP PROCEDURES..............................................................................................................185.4 SCHEDULE OF EVENTS....................................................................................................................185.5 REMOVAL OF SUBJECTS FROM STUDY TREATMENT AND STUDY........................................................18

6.0 ADVERSE EVENTS......................................................................................................................... 186.1 DEFINITIONS................................................................................................................................... 196.2 REPORTING REQUIREMENTS FOR ADVERSE EVENTS.........................................................................21

7.0 DRUG INFORMATION..................................................................................................................... 237.1 AGENT XXX................................................................................................................................... 23

8.0 CORRELATIVES/SPECIAL STUDIES.............................................................................................248.1 SAMPLE COLLECTION GUIDELINES...................................................................................................248.2 ASSAY METHODOLOGY....................................................................................................................248.3 SPECIMEN BANKING........................................................................................................................ 24

9.0 MEASUREMENT OF EFFECT.........................................................................................................259.1 ANTITUMOR EFFECT- SOLID TUMORS...............................................................................................259.2 ANTITUMOR EFFECT- HEMATOLOGIC TUMORS..................................................................................29


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9.3 SAFETY/TOLERABILITY.....................................................................................................................29

10.0 DATA AND SAFETY MONITORING............................................................................................2910.1 OVERSIGHT AND MONITORING PLAN............................................................................................2910.2 REVIEW AND OVERSIGHT REQUIREMENTS....................................................................................29

11.0 REGULATORY CONSIDERATIONS...........................................................................................3011.1 PROTOCOL REVIEW AND AMENDMENTS.......................................................................................3011.2 INFORMED CONSENT.................................................................................................................. 3011.3 ETHICS AND GOOD CLINICAL PRACTICE (GCP)............................................................................31

12.0 STUDY MANAGEMENT...............................................................................................................3112.1 INVESTIGATOR FILES AND RETENTION OF DOCUMENTS.................................................................3112.2 CASE REPORT FORMS................................................................................................................3112.3 STUDY MONITORING...................................................................................................................32

13.0 STATISTICAL CONSIDERATIONS.............................................................................................3213.1 STUDY DESIGN/STUDY ENDPOINTS.............................................................................................3213.2 SAMPLE SIZE AND ACCRUAL.......................................................................................................3213.3 DATA ANALYSES PLANS..............................................................................................................32

14.0 REFERENCES............................................................................................................................. 3315.0 APPENDICES.............................................................................................................................. 33

APPENDIX A. PERFORMANCE STATUS.......................................................................................................33APPENDIX B. CYP450 ENZYMES.............................................................................................................33APPENDIX C. QUALITY OF LIFE QUESTIONNAIRES.....................................................................................33APPENDIX D. MODIFIED CRITERIA FOR HEMATOLOGIC ADVERSE EVENTS...................................................33APPENDIX E. PATIENT PILL DIARY............................................................................................................33


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ABBREVIATION LIST

AE Adverse EventALC Absolute Lymphocyte CountALT Alanine AminotransferaseAST Aspartate AminotransferaseBUN Blood Urea NitrogenCBC Complete Blood CountCMP Comprehensive Metabolic PanelCR Complete ResponseCRP C-Reactive ProteinCT Computed TomographyCTCAE Common Terminology Criteria for Adverse EventsDC Dendritic CellDLT Dose-Limiting ToxicityDSMB Data and Safety Monitoring BoardELISPOT Enzyme-Linked Immunosorbent SpotFACS Fluorescence Activated Cell SortingFU Follow-Up VisitIFN InterferonHSC Human Subjects CommitteeICF Informed Consent FormIRB Institutional Review BoardIL-2 Interleukin-2KU University of KansasKUCC University of Kansas Cancer CenterLD Longest DiameterMDSC Myeloid-Derived Suppressor Cells MHC Major Histocompatibility ComplexMRI Magnetic Resonance ImagingMTD Maximum Tolerated DoseNCI National Cancer InstituteNK Natural KillerORR Overall Response RateOS Overall SurvivalPBMC Peripheral Blood Mononuclear CellPD Progressive DiseasePET Positron Emission TomographyPFS Progression Free SurvivalPI Principal InvestigatorPMN Polymorphonuclearp.o. Per Os/By Mouth/OrallyPR Partial ResponsePrn As NeededPT Prothrombin TimeQA Quality AssuranceRECIST Response Evaluation Criteria in Solid TumorsSAE Serious Adverse EventSD Stable Disease


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TAMs Tumor Associated MacrophagesTCM Central Memory T cellTEM Effector Memory T cellTh1 T-Helper Type 1Th2 T-Helper Type 2TILs Tumor Infiltrating LymphocytesTNF Tumor Necrosis FactorTregs Regulatory T CellsWBC White Blood Cells


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STUDY SCHEMA The schema should represent your study design, along with corresponding descriptive text, as applicable. For example:

STUDY SUMMARYTitle Full title of protocol

Short Title Shortened title (can match this to title used at ClinicalTrials.gov)

Phase Clinical study phase (e.g., Phase 1, 2, 3 or 4)

Methodology Design attributes such as single blind, double blind or open label; randomized, placebo or active placebo control; cross-over design, etc.

Study Duration Estimated duration for the main protocol (e.g., from start of screening to last subject processed and finishing the study)

Study Center(s) Single-center or multi-center; if multi-center, note number of projected centers to be involved

Objectives Brief statement of primary study objectives

Number of Subjects Number of subjects projected for the entire study (e.g., not for simply one site, rather for all sites combined) and the anticipated accrual rate

Diagnosis and Main Inclusion Criteria

Note the main clinical disease state under study and the key inclusion criteria (i.e., not the entire list that will appear later in the protocol, rather only the key inclusion criteria)

Study Product(s), Dose, Route, Regimen

Study drug name(s) (generic name, though can also state marketed name if name-brand used in the study) and/or description of non-drug therapy (i.e., radiation, surgery, etc.); include dose, route and regimen

Duration of Administration Total duration of drug product administration (including any open-label lead-in, if applicable)

Reference Therapy Note if there is a standard reference therapy against which the study product is being compared, or if the reference is a placebo

Interim Monitoring Note if there is interim monitoring for safety, futility, or superiority. Specify when those analyses will be done and if a DSMB is involved.

Statistical Methodology A very brief description of the main elements of the statistical methodology to be used in the study (as few lines as possible)


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1.0 BACKGROUND AND RATIONALE

1.1 Disease BackgroundPlease provide disease background information particularly relevant to your study. Questions to be addressed may include the current standard of care and any relevant treatment issues or controversies. Please justify why an investigational therapy or approach is warranted.

1.2 Study Agent(s) Background and Associated Known ToxicitiesPlease provide relevant background information about the study agent(s) that you are planning to use in the study and known toxicities. The following briefly explains what is required in this section:

A summary of findings from non-clinical in vitro/in vivo studies that have potential clinical significance including information on mechanism of action, pharmacokinetics and safety. This is particularly important for investigational agents, and may not be necessary for commercially available drugs, and/or drugs with sufficient clinical data.

A summary from relevant clinical studies, with focus on those that provide background for your study. Please include important safety information, the rationale for the starting dose(s), information on clinical pharmacokinetics, and major route(s) of elimination. If available, please include information on the metabolism of the agent(s) in humans and address any potential for drug interactions.

1.3 Other AgentsThis section may be required if your study focuses on either an investigational agent in combination with commercially available products, or if your primary objective focuses on only one of several commercial agents included in the study. If needed, please provide background information on other agent(s) and/or treatments in this study that are not described in Section 1.2 including rationale for including them in this study, their mechanism of action, information to support safety issues and the rationale for the proposed starting dose scheme, if applicable. For commercially available agents, detailed information on adverse events and potential risks should be deferred till Section 7.0 (Drug Information).

1.4 RationaleDiscuss reasoning behind conducting the study and your study design. Include justification of your study endpoints. This section should link the disease background with the study agent(s) under evaluation. Include study population rationale, particularly if focusing on a subset within the disease population (e.g., relapsed or elderly subjects).

1.5 Correlative StudiesIf applicable, please provide the background information on the planned correlative study(ies) including the biological rationale and hypothesis.

2.0 STUDY OBJECTIVESThere should be one primary objective with a single endpoint. Typically, the sample size justification is based solely on the primary objective. If there are multiple primary objectives or multiple endpoints for the primary objective, adjustments will need to be made to the sample size justification to account for an inflated Type I error.


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2.1 Primary Objectives2.1.1 To…

2.2 Secondary Objectives 2.2.1 To…

2.2.2 To…

2.3 Exploratory Objectives2.3.1 To…

2.4 Endpoints

Primary Endpoint:

Secondary Endpoints:

3.0 SUBJECT ELIGIBILITY

3.1 Inclusion CriteriaSubjects must meet all of the inclusion criteria to participate in this study.

3.1.1 Ability to understand and the willingness to sign a written Informed Consent Form.

3.1.2 Diagnosis/disease status.

3.1.3 Allowable type and amount of prior therapy.

3.1.4 Age ≥ 18 years.

3.1.5 Performance Status # (Appendix A.).

3.1.6 Adequate organ and marrow function as defined below:

- leukocytes ≥ 3,000/mcL- absolute neutrophil count ≥ 1,500/mcL- platelets ≥ 100,000/mcl- total bilirubin within normal institutional limits- AST(SGOT)/ALT(SPGT) ≤ 2.5 X institutional upper limit of normal- creatinine within normal institutional limits

3.1.7 Women of child-bearing potential and men with partners of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days following completion of therapy. Should a woman or partner become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician and the investigator immediately.

3.1.7.1 A woman of child-bearing potential is any female (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by


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choice) who meets the following criteria:

Has not undergone a hysterectomy or bilateral oophorectomy; or

Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)

3.1.8 Other study-specific criteria.

3.2 Exclusion CriteriaSubjects meeting any of the exclusion criteria at baseline will be excluded from study participation.

3.2.1 Current or anticipated use of other investigational agents.

3.2.2 Subject has received chemotherapy or radiotherapy within 4 weeks prior to entering the study or has not recovered from adverse events due to agents administered more than 4 weeks earlier.

3.2.3 Subject has known brain metastases. Presence of brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

3.2.4 Current use or anticipated need for treatment with any medications or substances that are inhibitors or inducers of _specify CYP450 enzyme(s). Lists including medications and substances known or with the potential to interact with the _specified CYP450 enzyme(s)_isoenzymes are provided in _Appendix (#/letter)_.

3.2.5 History of allergic reactions attributed to compounds of similar chemical or biologic composition to Study Agent(s) or other agents used in study.

3.2.6 Study-specific exclusion criteria

3.2.7 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

3.2.8 Pregnant or nursing. There is a potential for congenital abnormalities and for this regimen to harm nursing infants.

4.0 TREATMENT PLAN

4.1 Treatment Dosage and AdministrationFor complicated studies (e.g., multiple treatment phases), please first provide a summary of the entire treatment plan. This should be a few sentences, which provide a “snapshot” of the treatment plan. Details will be described below.


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Please provide a full description of the treatment and how it will be administered (inpatient/outpatient basis). Include a description of any definite required or recommended/suggested supportive care medications.

See the example below for how the planned treatment regimen may be presented. Please provide separate regimen descriptions for different treatment groups of subjects as necessary.

REGIMEN DESCRIPTION

AgentPremedications;Precautions Dose Route Schedule

Cycle Length

Agent X Premedicate with DRUG for 3 days prior to Agent X.

300 mg/m2 in500 cc NS

IV over 2 hours before Agent Y

Days 1-3, week 1

4 weeks (28 days)

Agent Y Avoid exposure to cold (food, liquids, air) for 24 hrs after each dose.

150 mg/m2 in250 cc D5W

IV 1 hr after completion of Agent Y; separate IV line required

Days 1-3, week 1

Agent Z Take with food. 50 mg tablet PO in the a.m. Daily, wks 1 & 2

For phase I dose-escalation studies: Please state the starting dose of the study agent/drug and describe the dose escalation scheme and treatment regimen. Use exact dose rather than percentages. Please describe the number of subjects to be treated at each level and how a decision about dose escalation or expansion of cohort sizes will be made. If there are multiple agents being used in the study, include dose levels for each agent. Please note that escalation of only one drug at each dose level is recommended.

Please use the following table as a guideline to describe the dose escalation scheme:

Dose-Escalation ScheduleDose Level Dose of the Study Agent(s)* Minimum

Number of Subjects

Level -1 3Level 1 3Level 2 3Level 3 3Level 4 3*Doses are stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) rather than as a percentage

There are numerous variations of the “Standard 3+3” design. Please detail the particular dose escalation and de-escalation algorithm to be used. Any non-3+3 Phase I designs should include operating characteristics detailing, for a variety of toxicity profile scenarios, the probability of stopping without finding the MTD, the probability of selecting a dose level as the MTD, the average number of subjects treated and the average number of DLTs expected. For example, if the true toxicity rate is 5%, 10%, 30% and 80% for the 4 dose levels of the study drug, the probability of finding an MTD is XX%, the probability of selecting dose level 3 as the MTD is YY%, on average the MTD is determined after ZZ subjects, and on average WW experience a DLT.


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Dose-Limiting Toxicity (DLT) and Maximally Tolerated Dose (MTD):Please provide explicit definition of type(s), grade(s) and duration of adverse event (s) that will be considered dose-limiting, or provide definitions of other endpoints that will be used to determine dose escalations if applicable. Please note any definite exclusions from the DLT definition (e.g., if a rule states any grade 3/4 hematologic toxicity is a DLT but this EXCLUDES lymphopenia of any grade.)

Please give the specific timeframe for DLT evaluation (e.g., after 1st cycle of therapy, any time during treatment, etc.). Please also describe how you will determine the MTD, and if applicable, the recommended phase 2 dose (these will likely be one and the same). Be sure to include not only the criteria, but the minimum number of subjects required (e.g. highest dose level in which at least 6 subjects have been fully evaluated and less than 33% of subjects experienced a DLT). Ensure this section is consistent with the statistical section of your protocol.

Please state any special precautions or warnings relevant for agent administration (e.g., incompatibility of agent with commonly used intravenous solutions, necessity of administering agent with food, pre-medications, hydration, whether any monitoring of vital signs during or shortly after treatment is required, etc.). If treatment will be self-administered (i.e. oral drug or self-injection), please reference any subject tools that will be implemented (study medication diary, subcutaneous injection instruction sheets, etc); please also state how missed (or vomited) doses should be handled.

4.2 Toxicities and Dosing Delays/Dose ModificationsAny subject who receives treatment on this protocol will be evaluable for toxicity. Each subject will be assessed for the development of toxicity according to the Schedule of Events table (Insert Appropriate Section Number). Toxicity will be assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0x. Dose adjustments should be made according to the system showing the greatest degree of toxicity.

Treatment plans should explicitly identify when treatment (typically dosage) modifications are appropriate. Treatment modifications/dosing delays and the factors predicating treatment modification should be explicit and clear. For phase I studies, there should be consistency between toxicities which mandate dose reductions, and those events which are considered a DLT. If dose modifications or treatment delays are anticipated, please provide a dose de-escalation schema. If there are multiple agents being used in the study, provide a detailed description of toxicity grades and method of dose modification for each agent separately. In the event that more than one study agent could be responsible for a given toxicity, please address in which order each agent should be modified/delayed and provide justification (if available). You may also want to refer reader to the appropriate section in the protocol that contains more detailed information on the potential adverse events and risks associated with each agent (either in Section 1.2,1.3 or Section 7.0). All treatment modifications should be expressed as a specific dose or amount rather than as a percentage of the starting or previous dose. Please also address how many missed days of treatment or missed cycles warrants removal of the subject from the study. If subjects may remain on study after missed days or cycles, please specify when treatment under study may resume, whether permission to continue is needed and how to obtain that permission.

You may also want to consider breaking out your dose modification schema for hematological versus non-hematological criteria. For hematological toxicity, please address guidance on use of growth factor(s). Use of a table format is recommended if applicable. The following tables are provided as examples and should be modified as appropriate:


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Example 1 Hematological Toxicities

Hematological Toxicity Dose Reductions for Agent A

ANC1 Platelets Action

≥ 1,500/L 100,000/ L None.

1000-1499/L 75,000-99,000/ L -1st Occurrence: Hold current dose until ANC ≥ 1,500/L and platelets ≥ 100,000/L. Do not replace missed doses. Restart next treatment at TBD dose.-2nd Occurrence: Hold current dose until ANC ≥ 1,500/L and platelets ≥ 100,000/L. Do not replace missed doses. Restart next treatment at TBD dose.-3rd Occurrence: Hold current dose until ANC ≥ 1,500/L and platelets ≥ 100,000/L. Do not replace missed doses. Restart next treatment at TBD dose.-4th Occurrence: Discontinue protocol therapy.

500-999/L 50,000-74,000/ L -1st Occurrence: Hold current dose until ANC ≥ 1,500/L and platelets ≥ 100,000/L. Do not replace missed doses. Restart next treatment at TBD dose. -2nd Occurrence: Hold current dose until ANC ≥ 1,500/L and platelets ≥ 100,000/L. Do not replace missed doses. Restart next treatment at TBD dose.-3rd Occurrence: Discontinue protocol therapy.

<500/L <50,000/ L -1st Occurrence: Hold current dose until ANC ≥ 1,500/L and platelets ≥ 100,000/L. Restart next treatment at TBD dose.-2nd Occurrence: Discontinue protocol therapy.

1Note: G-CSF (filgrastim) may be added for low ANC on day of treatment BEFORE a dose reduction is instituted at treating physician’s discretions. Neulasta® (pegfilgrastim) is NOT allowed.

Example 2 Non-hematological Toxicities: Modifications for several agents at once may be presented. Any exceptions should be further explained in the text of the protocol.

Non-hematological Toxicity Dose ReductionsNCI CTC Grade Agent A Agent B Agent C0-2 No change from No change from No change from


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original starting dose (Note any exceptions here and address in text)

original starting dose(Note any exceptions here and address in text)

original starting dose (Note any exceptions here and address in text)

3 Hold until resolved to < Grade 2, then reduce to TBD dose

Hold until resolved to < Grade 2, then reduce to TBD dose


Second episode of grade 3 or 4 toxicity




Third episode of grade 3 or 4 toxicity

Remove subject from trial



Example 3 Non-hematological Toxicities: Each agent to be modified may have a separate table.

Example of non-hematological Toxicity Dose ReductionsEvent ActionName of ToxicityGrade 1-2 NoneGrade 3 Insert dose modification. May want to

specify if first allow attempt at control, e.g., with anti-emetics prior to dose modification

Grade 4Name of Separate ToxicityGrade 1-2Grade 3

4.3 Concomitant Medications/TreatmentsPlease list all relevant concomitant drugs and/or treatments that are prohibited. This section should be consistent with the medications restrictions in the inclusion/exclusion criteria. If any medications may be used, but only with caution, please address that in this section.

4.4 Other Modalities or ProceduresIf applicable, please provide a detailed description of any other modalities (e.g., surgery, radiotherapy) or procedures (e.g., hematopoietic stem cell transplantation) used in the protocol treatment. Please distinguish between those modalities that comprise standard of care, and those under investigation within your protocol.


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4.5 Duration of TherapyThis section should unambiguously define the “end of protocol therapy.” For example: “In the absence of treatment delays due to adverse events, treatment may continue for TBD or until:

Disease progression Inter-current illness that prevents further administration of treatment Unacceptable adverse event(s) Death Subject decision to withdraw from the study, OR General or specific changes in the subject’s condition which render the subject

unacceptable for further treatment in the judgment of the investigator”.

4.6 Duration of Follow-UpInclude information regarding follow-up, for example, “Subjects will be followed for TBD after removal from treatment or until death, whichever occurs first. Subjects removed from treatment for unacceptable adverse events will be followed until resolution or stabilization of the adverse event”. For Phase I studies, subjects are usually “off study" at 30 days from last treatment. Follow-up in Phase II studies will vary (e.g., 2 to 5 or even 10 years or more) depending on whether subjects are followed for a survival endpoint. Please think this through carefully as following subjects until death may require considerable resources, and may not be necessary. Please also state the nature and frequency of follow-up (e.g., visits every 3 months, by phone call every 6 months, etc.). Please include time windows for visits (e.g., +/- 3 days, +/- 1 month, etc.).

4.7 Removal of Subjects from Protocol TherapySubjects will be removed from therapy when any of the criteria listed in Section 5.5 apply. Notify the Principal Investigator, and document the reason for study removal and the date the subject was removed in the Case Report Form. The subject should be followed-up per protocol. The way in which removed subjects will be handled in the statistical analysis should be clearly stated (e.g. Subjects who are removed from protocol therapy due to disease progression or toxicity will be counted as a treatment failure in the efficacy analysis).

4.8 Subject ReplacementPlease include guidelines describing when and how enrolled subject may be replaced in the study. For example, “Three subjects within a dose level must be observed for one cycle (28 days) before accrual to the next higher dose level may begin. If a subject is withdrawn from the study prior to completing 22 days of therapy without experiencing a DLT prior to withdrawal, an additional subject may be added to that dose level. Subjects missing 7 or more doses due to toxicity will not be replaced since these subjects will be considered to have experienced a DLT.”

5.0 STUDY PROCEDURES

5.1 Screening/Baseline ProceduresAssessments performed exclusively to determine eligibility for this study will be done only after obtaining Informed Consent. Assessments performed for clinical indications (not exclusively to determine study eligibility) may be used for baseline values even if the studies were done before Informed Consent was obtained.


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All screening procedures must be performed within # days prior to registration unless otherwise stated (for labs, usually within 14 days, other procedures, within 30 days). The screening procedures include:

5.1.1 Informed Consent5.1.2 Medical history

Complete medical, surgical and oncology history as well as history of infections are obtained at screening. Any changes from Screening (e.g. worsening severity or abnormal findings) are considered to be adverse events (AEs).

5.1.3 DemographicsDemographic profile will include date of birth, gender, race, ethnicity and zip code.

5.1.4 Review subject eligibility criteriaReview of eligibility criteria as described in Section 3.0 to ensure subject qualification for study entry.

5.1.5 Review previous and concomitant medicationsAll prior medication taken by the subject within 30 days before starting the study is to be recorded. At minimum, the start year of the medication should also be recorded. Concomitant medications taken by the subject during the study are to be recorded up until 30 days after last study dose. If a reportable adverse event (see Section 6.0) occurs within 30 days after last study dose, recording of concomitant medications should continue until resolution of the adverse event.

5.1.6 Physical exam including vital signs, height and weightVital signs (temperature, pulse, respirations, blood pressure), height, weight, and assessment of all major body systems

5.1.7 Performance statusPerformance status evaluated prior to study entry and possibly during study. Specific criteria for assessing performance status can be found in Appendix A.

5.1.8 Adverse event assessmentBaseline assessment of subject status for determining adverse events. See Section 6.0 for Adverse Event monitoring and reporting.

5.1.9 HematologyDescribe what will be measured. Example: “Hematology to include hemoglobin (Hgb), platelets, total white blood cell count (WBC) and differential.”

5.1.10 Serum chemistriesDescribe what will be measured. Example “Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, ALT, AST, BUN, creatinine, electrolytes (sodium, potassium, calcium, chloride, bicarbonate), glucose, and total bilirubin. Additional chemistries: lactate dehydrogenase (LDH), phosphate, lipase, and amylase.”

5.1.11 Blood draw for correlative studiesSee Section 8.0 for details.


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5.1.12 Pregnancy test (for women of child bearing potential)See Section 3.1 for definition.

5.1.13 Tumor assessmentDescribe type of assessments to be performed (and recommendation to use same method at subsequent assessments)

5.1.14 Other Describe…

5.2 Procedures During Treatment5.2.1 Prior to Each Treatment Cycle: add treatment window (e.g., 0-2 days prior to

treatment)

Physical exam, vital signs Hematology Serum chemistries

5.2.2 Day 1

Procedure

5.2.3 30 days after treatment termination

1. Define treatment termination exactly: when an AE begins which ends treatment or when the decision to stop treatment is made or when the last study drug was taken

2. Add a visit window (e.g. +/- 2 days)

Physical exam, vital signs Hematology Serum chemistries

5.3 Follow-up ProceduresSubjects will be followed every <time frame> after completion of (or early withdrawal from) study treatment until when.

List of procedures

5.4 Schedule of EventsInsert table

5.5 Removal of Subjects from Study Treatment and StudySubjects can be taken off the study treatment and/or study at any time at their own request, or they may be withdrawn at the discretion of the investigator for safety, behavioral or administrative reasons. The reason(s) for discontinuation will be documented and may include:


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5.5.1 Subject voluntarily withdraws from treatment (follow-up permitted);

5.5.2 Subject withdraws consent (termination of treatment and follow-up);

5.5.3 Subject is unable to comply with protocol requirements;

5.5.4 Subject demonstrates disease progression (unless continued treatment with study drug is deemed appropriate at the discretion of the investigator);

5.5.5 Subject experiences toxicity that makes continuation in the protocol unsafe;

5.5.6 Treating physician judges continuation on the study would not be in the subject’s best interest;

5.5.7 Subject becomes pregnant (pregnancy to be reported along same timelines as a serious adverse event; see Section 6.0);

5.5.8 Development of second malignancy (except for basal cell carcinoma or squamous cell carcinoma of the skin) that requires treatment, which would interfere with this study;

5.5.9 Lost to follow-up.

If a research subject cannot be located to document survival after 3 attempts by mail and/or telephone, the subject may be considered “lost to follow-up” All attempts to contact the subject must be documented.

6.0 ADVERSE EVENTSText below in italics is verbatim from “Guidance for Industry and Investigators. Safety Reporting Requirements for INDs and BA/BE Studies”, issued December 2012 by U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, and Center for Biologics Evaluation and Research. The guidance may be retrieved from:

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM227351.pdf?source=govdelivery.

6.1 Definitions6.1.1 Adverse Event [21 CFR 312.32(a)]

An adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.

An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, and does not imply any judgment about causality. An adverse event can arise with any use of the drug (e.g., off-label use, use in combination with another drug) and with any route of administration, formulation, or dose, including an overdose.

This study will use the descriptions and grading scales from Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) for hematologic and non-hematologic toxicities. Detailed information may be found on the Cancer Therapy


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Evaluation Program (CTEP) website: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm

Information for adverse events, whether reported by the subject, directly observed, or detected by physical examination, laboratory test or other means, will be collected, recorded, followed and reported in the CRF as described in the following sections.

Adverse events experienced by subjects will be collected and reported from time of screening, throughout the study, and within 30 days of the last dose of protocol therapy. Subjects who experience an ongoing adverse event related to a study procedure and/or study medication beyond 30 days will continue to be contacted by a member of the study team until the event is resolved, stabilized, or determined to be irreversible by the principal investigator. Study subjects should also be instructed to report any new serious post-study event(s) that might reasonably be related to participation in this study.

Medical conditions/diseases, or cancer related symptoms present before starting study treatment are considered adverse events only if they worsen after initial screening. Adverse clinical events occurring before starting study drug but after signing the Informed Consent form are to be recorded on the Medical History/Current Medical Conditions CRF. All cancer-related symptoms that have occurred in the last 30 days prior to start of study drug must also be recorded on this CRF. Abnormal laboratory values or test results constitute adverse events only if they induce clinical signs or symptoms, or require therapy. In this case they will be recorded on the Adverse Events CRF, along with the associated signs, symptoms or diagnosis.As far as possible, each adverse event will also be described by: its duration (start and end dates), grading of severity, its relationship to the study drug, the action(s) taken, outcome.

6.1.2 Suspected Adverse Reaction [21 CFR 312.32(a)]

Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.

Suspected adverse reactions are the subset of all adverse events for which there is a reasonable possibility that the drug caused the event. Inherent in this definition, and in the requirement to report suspected adverse reactions, is the need for the sponsor to evaluate the available evidence and make a judgment about the likelihood that the drug actually caused the adverse event.

Factors to be considered in assessing the relationship of the adverse event to study drug include:


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The temporal sequence from study drug administration: The event should occur after the study drug is given. The length of time from study drug exposure to event should be evaluated in the clinical context of the event.

Recovery on discontinuation (de-challenge), recurrence on reintroduction (re-challenge): Subject’s response after drug discontinuation (de-challenge) or subject’s response after study drug re-introduction (re-challenge) should be considered in the view of the usual clinical course of the event in question.

Underlying, concomitant, intercurrent diseases: Each report should be evaluated in the context of the natural history and course of the disease being treated and any other disease the subject may have.

Concomitant medication or treatment: The other drugs the subject is taking or the treatment the subject receives should be examined to determine whether any of them may be suspected to cause the event in question.

The pharmacology and pharmacokinetics of the study drug: The pharmacokinetic properties (absorption, distribution, metabolism and excretion) of the test drug(s), coupled with the individual subject’s pharmacodynamics should be considered.

Attribution is the relationship between an adverse event or serious adverse event and the study treatment. Attribution will be assigned as follows:

Unrelated - The AE is clearly NOT related to the study treatment. Unlikely - The AE is doubtfully related to the study treatment. Possible – The AE may be related to the study treatment. Probable – The AE is likely related to the study treatment. Definite – The AE is clearly related to the study treatment.

6.1.3 Unexpected [21 CFR 312.32(a)]

An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application… "Unexpected," as used in this definition, also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the Particular drug under investigation.

This definition relies entirely on a listing of the adverse events or suspected adverse reactions in the investigator brochure…as the basis for determining whether newly acquired information generated from clinical trials or reported from other sources is unexpected. This means that events not listed for the Particular drug under investigation in the investigator brochure are considered “unexpected” and those listed are considered “expected.” When new adverse event information is received, it is the sponsor’s responsibility to determine whether the event is “unexpected” for safety reporting purposes.


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6.1.4 Serious [21 CFR 312.32(a)]

An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the investigator or sponsor, it results in any of the following outcomes: Death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or patient and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

6.1.5 Life-threatening

An adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of either the investigator or sponsor, its occurrence places the patient or patient at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death.

6.2 Reporting Requirements for Adverse Events6.2.1 Submitting Serious Adverse Events Reports to IRB

For serious adverse events, the clinical research site will follow local IRB policies and procedures.

6.2.2 Study Investigator Notification of Adverse Events

All expected and unexpected serious adverse events occurring after the subject has signed the Informed Consent and has started protocol treatment must be reported to the study principal investigator within 24 hours of becoming aware of the event:

PI Name:Office Phone: Fax:

6.2.3 DSMC Notification of SAEs

Note: If there is an institutional (cancer center) conflict of interest and an external DSMB is required, this section will be revised as such.

All expected and unexpected serious adverse events occurring after the subject has signed the Informed Consent and has started protocol treatment must be reported by phone or email to the KUCC DSMC within 24 hours of becoming aware of the event to:

KUCC DSMCPhone: 913-588-4791Fax: 913-945-8111Email: [email protected]


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A follow-up written report in the form of a MEDWATCH Form FDA 3500A is required within 5 days. (If the protocol’s funding sponsor has a specific SAE reporting form, replace this sentence with the title of that form)

6.2.4 Recording Adverse Events and Documentation in VELOS

All expected and unexpected adverse events and serious adverse events occurring after the patient has signed the Informed Consent and has started protocol treatment must be fully recorded in the subject’s case record form.

All AEs and SAEs regardless of causality must be entered in the KU implementation of eVELOS, called the Comprehensive Research Information System (CRIS). All SAEs regardless of causality must be entered into CRIS within 24 hours. Unexpected and expected adverse events must be entered within 5 days and include: new unexpected adverse events; worsening baseline conditions; clinically significant laboratory findings; disease-related signs and symptoms that were not present at baseline, and any event of findings that the Investigator feels is clinically significant.

Documentation must be supported by an entry in the subject’s file. A laboratory test abnormality considered clinically relevant, e.g., causing the subject to withdraw from the study, requiring treatment or causing apparent clinical manifestations, or judged relevant by the investigator, should be reported as an adverse event. Each event should be described in detail along with start and stop dates, severity, relationship to investigational product, action taken and outcome.

6.2.5 Reporting of Unexpected, Related SAEs for Concomitant Medications

For concomitant medications, all unexpected, related serious adverse experiences will be forwarded to the product manufacturer by the investigator using the Voluntary MEDWATCH Form FDA 3500.

6.2.6 Summary of Expedited Serious Adverse Event Reporting

Relationship to Study

Drug

KUCC DSMC IRB PI Velos

Unexpected SAE

Related* 24 hrs

Follow local IRB reporting requirements

24 hrs 24 hrs

Unexpected SAE

Not-related* 24 hrs 24 hrs 24 hrs

Expected SAE

Related* 24 hrs 24 hrs 24 hrs

Expected SAE

Not-related* 24 hrs 24 hrs 24 hrs

*24 hour e-mail notification: send to [email protected] and [email protected]

7.0 DRUG INFORMATION


mailto:[email protected]

mailto:[email protected]

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7.1 Agent XXXPlease refer to Investigator’s Brochure for more comprehensive information.

Other names for the drug(s):

Classification - type of agent:

Mode of action:

Storage and stability:

Preparation:

Route of administration for this study:

Incompatibilities:

Availability: (e.g., “commercially available”, “provided by sponsor”; specify if provided free of charge as this has implications for the consent form.)

Side effects: A brief summary of the adverse events most likely to occur in this study and associated with this agent should be inserted here.

Nursing implications:

7.1.1 Return and Retention of Study DrugIf remaining drug is to be destroyed, please state “Remaining drug is to be destroyed, according to University of Kansas Cancer Center Investigational Drug Services destruction policy.” (or other appropriate instructions.Otherwise, please include address and sponsor/Pharma/collaborator contact for the drug return and destruction policy.

7.1.2 Drug Accountability/Subject ComplianceFor oral or self-administered investigational agents: Please include, if applicable, plans for subject’s compliance with the study agent, e.g., questionnaire, subject diary, pill diary, etc. Other sections may be required/requested by sponsor.

Example:

“Records of study medications used, dosages administered, and intervals between visits will be kept during the study. Subjects will be asked to fill out a pill diary and bring with them for review after each cycle of study treatment.Drug accountability will be noted at the completion of the trial. Subjects will be asked to return all unused medication at the end of the study. Drug compliance will be calculated based on documentation of study drug dispensed vs. study drug returned.”

8.0 CORRELATIVES/SPECIAL STUDIES


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The goal of the planned laboratory correlative studies is to… Indicate if submission of samples for correlative studies is mandatory/optional…

8.1 Sample Collection GuidelinesWhat kind samples will be collected using what. Samples will be labeled with the subject’s de-identified study number and collection date and delivered for analysis to:

<Insert Location/Address>

Specify instructions for preparation and shipment (types of tubes, spun, frozen, on wet/dry ice or at room temperature, sent by overnight mail or batched, etc.) Please add any restrictions on specimen receiving times (e.g., after hours, weekends, holidays).

Samples will be collected at the following time points (+/- window): (Within 28 days) prior to study treatment. ETC…

8.2 Assay Methodology

8.3 Specimen Banking<if applicable>Subject samples collected for this study will be retained at where. {describe what kind of security is involved}. Specimens will be stored indefinitely or until they are used up. If future use is denied or withdrawn by the subject (submitted in writing to the investigator), best efforts will be made to stop any additional studies and to destroy the specimens.

Name will be responsible for reviewing and approving requests for clinical specimen from potential research collaborators outside of the University of Kansas. Collaborators will be required to complete an agreement (a Material Transfer Agreement or recharge agreement) that states specimens will only be released for use in disclosed research. Any data obtained from the use of clinical specimens will be the property of the University of Kansas for publication and any licensing agreement will be strictly adhered to.

{also need to include how clinical annotation data will be linked to sample, where and how secure storage of linking data will be kept (paper or electronic, offices, servers?), how will de-identification of specimens and annotations be performed, what future uses are envisioned (would these include studies of inherited disease susceptibility markers that could create risk to subjects/families if inadvertently disclosed)}

The specimens, DNA, and their derivatives may have significant therapeutic or commercial value. The Informed Consent form contains this information and informs the subject that there is the potential for financial gain by the University of Kansas, the investigator or a collaborating researcher or entity.

The following information obtained from the subject's medical record may be provided to research collaborators when specimens are made available:

Diagnosis Collection time in relation to study treatment Clinical outcome – if available


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Demographic data

9.0 MEASUREMENT OF EFFECT

9.1 Antitumor Effect- Solid TumorsDefine/describe the criteria to be utilized (iwCLL, RANO, RECIST, other) and, if necessary, provide the justification.

If using RECIST, state:Response and progression will be evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 92(3):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST v1.1 criteria.

9.1.1 DefinitionsEvaluable for toxicity. All subjects will be evaluable for toxicity from the time of their first treatment with study drug.

Evaluable for objective response. Only those subjects who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These subjects will have their response classified according to the definitions stated below. (Note: Subjects who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.)

9.1.2 Disease ParametersIf using RECIST, state:Measurable disease. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques (CT, MRI, x-ray, PET scan) or as >10 mm with spiral CT scan. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).

Note: Previously irradiated lesions are non-measurable except in cases of documented progression of the lesion since the completion of radiation therapy.

Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <20 mm with conventional techniques or <10 mm using spiral CT scan), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all non-measurable.

Target lesions. All measurable lesions up to a maximum of 3 lesions per organ and 6 lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the


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baseline sum LD. The baseline sum LD will be used as reference by which to characterize the objective tumor response.

Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 6 target lesions should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, but the presence or absence of each should be noted throughout follow-up.

9.1.3 Methods for Evaluation of Measurable DiseaseAll measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 28 days before the beginning of the treatment.

The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination when both methods have been used to assess the antitumor effect of a treatment.

Provide each method and note timeframe for when each will be done (e.g., every 6 weeks, every 2 cycles, etc.). Examples include:

Conventional CT and MRI. These techniques should be performed with cuts of 10 mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm. This applies to tumors of the chest, abdomen, and pelvis.

Cytology, Histology. These techniques can be used to differentiate between partial responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain).

The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease.

9.1.4 Response CriteriaIf using RECIST, state:

9.1.4.1 Evaluation of Target Lesions

Complete Response (CR): Disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions.

Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. There can be no appearance of new lesions.


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Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions.

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.

9.1.4.2 Evaluation of Non-Target Lesions

Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level.

Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.

Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions

9.1.4.3 Evaluation of Best Overall Response

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The subject's best response assignment will depend on the achievement of both measurement and confirmation criteria.

Target Lesions

Non-Target

Lesions

New Lesions Overall Response

Best Response for this Category

Also Requires:

CR CR No CR >4 wks. confirmation

CR Non-CR/Non-PD

No PR>4 wks.

confirmationPR Non-PD No PRSD Non-PD No SD documented at

least once >4 wks. from baseline

PD Any Yes or No PDno prior SD, PR or CR

Any PD* Yes or No PDAny Any Yes PD

* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression.

Note: Subjects with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as “symptomatic deterioration”. Every effort should be made to document the objective progression even after discontinuation of treatment.


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Note: If subjects respond to treatment and are able to have their disease resected, the subject’s response will be assessed prior to the surgery.

9.1.5 Duration of ResponseDuration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).

The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.

Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started.

9.1.6 Progression-Free SurvivalProgression-free survival (PFS) is defined as the duration of time from start of treatment until objective tumor progression or death. Subjects who do not experience objective tumor progression or death during the evaluation period, or are lost to follow-up, will be censored on the date they were last known to be alive and without objective tumor progression.

9.1.7 Time to ProgressionTime to progression is defined as the duration of time from start of treatment until objective tumor progression. Subjects who do not experience objective tumor progression during the evaluation period will be censored on the date of death, lost to follow-up, or were last known to be without objective tumor progression.

9.1.8 Overall SurvivalOverall survival is defined as the duration of time from start of treatment to death. Subjects who do not experience death during the evaluation period, or are lost to follow-up, will be censored on the date they were last known to be alive.

9.2 Antitumor Effect- Hematologic TumorsPlease provide appropriate criteria for evaluation of response and methods of measurement.

Example:

Responses will document surrogate clinical activity and will also be reported consistent with iwCLL 2008 guidelines (see Appendix #/letter).

Baseline disease assessments will occur as indicated in Section 5.1. Final Response assessment will be assessed per iw-CLL criteria with clinical CRs confirmed by bone marrow biopsy and CT scan should be performed if previously abnormal. The primary efficacy point is response assessed following 3 cycles of treatment.


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9.2.1 Primary Efficacy/ Response assessment Clinical response following 3 cycles of treatment. If patient is clinically in CR (without or with cytopenias) peripheral blood should be assessed for clonal lymphocytes.

9.2.2 Final Response AssessmentFinal response will occur two months following completion of study treatment. It is acknowledged that to meet iwCLL Guidelines for response in CLL, a response assessment must be performed 2 months from end of therapy to document responses including a bone marrow to confirm CR and a CT scan may be indicated or recommended. Therefore, those subjects that clinically appear to be in CR will have a bone marrow and possibly a CT scan to confirm complete responses at least 3 months after all treatment.

9.3 Safety/tolerabilityAnalyses will be performed for all subjects having received at least one dose of study drug. The study will use the CTCAE version 4.0x (http://ctep.cancer.gov/reporting/ctc.html) for reporting of non-hematologic adverse events and modified criteria for hematologic adverse events (Appendix #/letter). Include a description of any interim assessments for safety and associated early stopping criteria as appropriate. These assessments and criteria are inherent in typical Phase I designs and do not need to be reiterated here.

10.0 DATA AND SAFETY MONITORING

10.1 Oversight and Monitoring PlanThe DSMC of the KUCC is responsible for monitoring subject safety for this trial. The DSMC is responsible for: Review of all clinical trials conducted by the KUCC for progress and safety Review of all adverse events requiring expedited reporting as defined in the protocol Submission of recommendations for corrective action to the PI and the Deputy Director

of the KUCC or designee Notification of external sites participating in multi-institution clinical trials coordinated by

the KUCC of adverse events requiring expedited reporting and subsequent committee recommendations for study modifications.

10.2 Review and Oversight Requirementsa) Serious Adverse Event Serious adverse events that require expedited reporting will be reviewed by the DSMC Chair or designee who will determine if immediate action is required. If determined to be necessary by the DSMB, all participating sites will be notified of the event and of any resulting action within one working day of this determination.

b) Review of Adverse Event Rates Once per month, adverse event rates will be monitored by the QA Coordinator. If any study has had 2 or more of the same SAE reported within one month, or more than 6 of the same SAE in 6 months, the DSMC will review summaries of SAEs, and discuss events in detail with the PI. The DSMC chair or designee determines whether further action is required. The QA Coordinator ensures that collaborating investigators and IRBs for all participating sites are notified of any resulting action.


http://ctep.cancer.gov/

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c) Study Safety and Progress – Quarterly Review(Protocol can also be reviewed semi-annually if that is deemed appropriate for adequate safety by the PI and the IRB)An overall assessment of toxicities as described in the protocol is reviewed at quarterly DSMC meetings. This review enables DSMC members to assess whether significant risks are occurring that would warrant study suspension/closure or protocol amendment.

All DSMC reports, including those recommending continuation of the study, are forwarded to the KUMC Human Subjects Committee (KUMC IRB). Any DSMC recommendations for modifications to the trial are forwarded to the Deputy Director of KUCC or their designee. The PI is notified of this recommendation in order that he/she may alert all investigators about the potential action. At this time the PI may submit to the Deputy Director of KUCC or their designee additional information that could affect the Committee’s decision. The Deputy Director of the KUCC or their designee will notify the PI if he/she concurs with the DSMC’s recommendation, including suspension or closure. The PI will notify all investigators involved with the study, the IRB, the sponsor and the funding agency and provide written documentation of these notifications to the DSMC.

11.0 REGULATORY CONSIDERATIONS

11.1 Protocol Review and AmendmentsThis protocol, the proposed Informed Consent and all forms of participant information related to the study (e.g., advertisements used to recruit participants) and any other necessary documents must be submitted, reviewed and approved by a properly constituted IRB governing each study location.

Any changes made to the protocol must be submitted as amendments and must be approved by the IRB prior to implementation. Any changes in study conduct must be reported to the IRB. The Principal Investigator will disseminate protocol amendment information to all participating investigators. All decisions of the IRB concerning the conduct of the study must be made in writing.

11.2 Informed ConsentAll participants must be provided a consent form describing this study and providing sufficient information for participants to make an informed decision about their participation in this study. The formal consent of a participant, using the IRB approved consent form, must be obtained before the participant is involved in any study-related procedure. The consent form must be signed and dated by the participant or the participant’s legally authorized representative, and by the person obtaining the consent. The participant must be given a copy of the signed and dated consent document. The original signed copy of the consent document must be retained in the medical record or research file.

11.3 Ethics and Good Clinical Practice (GCP)This study is to be conducted according to the following considerations, which represent good and sound research practice:


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1. ICH Consolidated Good Clinical Practice: Guidelines (E6) www.fda.gov/cder/guidance/iche6.htm

2. US Code of Federal Regulations (CFR) governing clinical study conduct and ethical principles that have their origin in the Declaration of Helsinki

- Title 21 Part 11 – Electronic Records; Electronic Signatures www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html

- Title 21 Part 50 – Protection of Human Patients www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html

- Title 21 Part 54 – Financial Disclosure by Clinical Investigators www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html

- Title 21 Part 56 – Institutional Review Boards www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html

- Title 21 Part 312 – Investigational New Drug Application www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html

3. State laws4. Institutional research policies and procedures

http://www2.kumc.edu/researchcompliance/hscpolicies.htm

It is understood that deviations from the protocol should be avoided, except when necessary to eliminate an immediate hazard to a research participant. In such case, the deviation must be reported to the IRB according to the local reporting policy.

12.0 STUDY MANAGEMENT

12.1 Investigator Files and Retention of DocumentsThe investigator must prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the study for each research participant. This information enables the study to be fully documented and the study data to be subsequently verified. Original source documents supporting entries in the case report forms include but are not limited to hospital records and clinic charts, laboratory and pharmacy records, ECG, signed ICFs, subject diaries and pathology reports. All study-related documents must be retained for the maximum period required by applicable federal regulations and guidelines or institutional policies.

12.2 Case Report FormsCase report forms (CRFs) will be completed for each subject enrolled. All CRFs will be complete and accurate. The medical chart and any other clinical worksheets, procedural reports, etc. are the source of verification of the data captured into the study database.

12.3 Study MonitoringThe study will be monitored at appropriate intervals to assure compliance to GCP and to assess the data quality and study integrity. The frequency of monitoring may vary depending on enrollment rate and the quality of data collected.

The investigator and staff are expected to cooperate and provide all relevant study documentation in detail at each site visit on request for review. The study monitor will have direct access to source data for data verification. Data verification will be conducted by comparing the data entered into the CRFs with source data.


http://www2.kumc.edu/researchcompliance/hscpolicies.htm

http://www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html





http://www.fda.gov/cder/guidance/iche6.htm

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Any interim monitoring for efficacy (futility or superiority) should be included here. Please include the details of when the checks occur, the endpoint and criteria used at eachcheck, and when and what action will be taken as a result. Please specify if enrollment will be suspended until efficacy can be evaluated at the interim time point, or if enrollment will continue. Any operating characteristics associated with interim monitoring rules should be included here. For example, if the observed response rate is X%, under the proposed rule the probability of stopping the study early for futility at time point Y would be Z%. A series of scenarios should be provided.

13.0 STATISTICAL CONSIDERATIONS

13.1 Study Design/Study EndpointsPlease specify the study design. State clearly key design aspects, such as, is the study retrospective or prospective, blinded, randomized, single or multi-centered, etc. Define all study endpoints.

If there are stopping rules for either safety or efficacy, describe the reasoning behind them, and how they might cause a suspension of study enrollment until a safety review has been convened. Examples of findings that might trigger a safety review are the number of SAEs overall, the number of occurrences of a particular type of SAE, severe AEs/reactions, or increased frequency of events.

13.2 Sample Size and AccrualJustification for the number of subjects to be used in the study must be given. Please state precisely what the statistical power and sample size considerations are for the proposed study, and which objective they address. (It should be the primary objective.) The total sample size, the total accrual, the expected accrual rate, and all relevant assumptions should be stated explicitly. How these numbers were calculated, including the software/version used in the calculations should be included. A reviewer should be able to duplicate the calculations given the information provided.

13.3 Data Analyses PlansPlease describe in detail how each objective (particularly the primary objective) will be addressed by a particular data analysis plan. This is where the details of each data analysis plan (for each objective) are given – stating what statistical methods will be used, and under which assumptions. Every objective and every study endpoint should have a plan associated with it. Further details concerning safety and/or pharmacokinetics, may be given here as well. It is a protocol violation to conduct statistical data analysis that is not described in the protocol. If further analysis is desired, an amendment to the protocol is required prior to the analysis being done.

14.0 REFERENCESList all protocol references.


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15.0 APPENDICES

Appendix A. Performance Status

Appendix B. CYP450 Enzymes

Appendix C. Quality of Life Questionnaires

Appendix D. Modified Criteria for Hematologic Adverse Events

Appendix E. Subject Pill Diary
