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Protocol Template for Phase I studies

Instructions for use:

1. This protocol template is designed for use in Duke PI-initiated Phase I studies.

2. When preparing Phase I protocol submissions in eIRB, separate documents for the research summary and protocol are required. The protocol synopsis (see Section 3) is designed to mimic the IRB Research Summary Template, so this content may be exported or saved separately as the IRB Research Summary.

3. The ultimate goal of this template is to structure and format it in a manner that is consistent with DCI, Cancer Protocol Committee, and DUHS IRB requirements for research summaries and protocols. This pilot version of the template has been released primarily to solicit feedback from PIs and study teams. At this time, this draft may not have language that fully reflects the requirements of the DCI, Cancer Protocol Committee, and/or DUHS IRB. However, PIs and study teams may use this draft to guide development of their protocols. It is expected that PIs will customize certain standard elements to accurately convey the intent, needs, and conduct of each unique protocol. When the protocol has been finished, upload a separate research summary into eIRB section “06. Research Summary & Abstract” and the completed protocol into eIRB section “07. Full Protocol”.

4. This template has been formatted to permit quick navigation to the various sections of the protocol. To access the navigation panel, click on the “View” tab in MS Word, click on “Navigation Pane”, and the Navigation Pane should appear to the left of this document. Select the desired section to jump to that section.

5. Text written in black font indicates required elements of the protocol. These should not be removed or changed. Doing so can result in alteration of the template formatting, while also eliminating required elements of the protocol.

6. Section additions are permitted. To create additional sections, copy a similar section from the template and paste it into the location desired. Doing so will preserve the formatting of that particular section, and therefore automatically update the navigation pane. The Table of Contents must be updated manually. To do this, click on the “References” tab of MS Word, and then click “Update Table”.

7. Text written in blue font indicates instructions or fields that require input. All instructions address the specific requirements of the DCI, Cancer Protocol Committee, and DUHS IRB. If a given field is not relevant, do not delete the section or leave it blank. Instead, indicate “none” or “not applicable”. This helps the CPC understand that the section has been considered and has been left empty intentionally.

8. Text written in red font indicates suggested language which meets the requirements of the DCI, Cancer Protocol Committee, and DUHS IRB.

9. When completing each section, it is not sufficient to cite or reference information that appears in eIRB. The protocol should be considered a “master” document, and all relevant information should be included in the protocol. Thus, the protocol should serve as a one-stop resource for any study team members to learn how to conduct the protocol accurately and thoroughly.

PT-PhIDEE v04.30.12

10. Prior to submission of this protocol, delete the instructions page(s) and ensure that all text is changed to black font. Failure to do so will result in delays in completion of protocol review.

Feedback and suggestions for improvement of the protocol template:

1. All feedback and suggestions should be directed to Ashley Godfrey ([email protected]).

PT-PhIDEE v04.30.14

A Phase I Study

Insert Title HereIndicate type (Phase I), design (blinded/unblinded, single-arm,

placebo-controlled), multicenter?, the investigational drug, and subject population (adult, cancer type, newly

diagnosed/refractory)

Sponsor: PI – Duke Cancer InstituteFunding Source: Please provideProtocol Source: PI - Duke Cancer InstituteDuke IRB#: Pro000XXXXXIND# 000000

Principal Investigator Can add other staff here if desiredName, degree

AddressAddress

TelephoneFax

Email address

Co-Principal Investigator(s)Name, degreeEmail address

StatisticianName, degreeEmail address

Original version: Date

Amended version 1: Date

CONFIDENTIALThe information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is

required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.

PT-PhIDEE v04.30.14

Pro000XXXXX: Short Protocol TitleVersion: Date

1 TABLE OF CONTENTS2 LIST OF ABBREVIATIONS..................................................................................................63 PROTOCOL SYNOPSIS AND RESEARCH SUMMARY...................................................7

3.1 Purpose..............................................................................................................................73.2 Background and Significance...........................................................................................73.3 Design and Procedure.......................................................................................................73.4 Selection of Subjects.........................................................................................................83.5 Duration of Study..............................................................................................................83.6 Data Analysis and Statistical Considerations....................................................................8

4 STUDY SCHEMA..................................................................................................................95 BACKGROUND AND SIGNIFICANCE.............................................................................10

5.1 Study Disease..................................................................................................................105.2 Study Agent.....................................................................................................................10

5.2.1 Pre-clinical experience.............................................................................................10

5.2.2 Clinical experience...................................................................................................105.3 Study Purpose/Rationale.................................................................................................10

6 OBJECTIVES AND ENDPOINTS.......................................................................................117 INVESTIGATIONAL PLAN................................................................................................12

7.1 Study Design...................................................................................................................127.1.1 Dose Escalation and Expansion...............................................................................12

7.1.2 Definition of Dose-Limiting Toxicity (DLT)...............................................................12

7.1.3 Dose Modification....................................................................................................12

7.1.4 Safety Considerations..............................................................................................13

7.1.5 Missed Doses...........................................................................................................13

7.1.6 Concomitant Medications.......................................................................................13

7.1.7 Study Drug Blinding.................................................................................................137.2 Rationale for Selection of Dose, Regimen, and Treatment Duration.............................137.3 Rationale for Correlative Studies....................................................................................137.4 Definition of Evaluable Subjects, On Study, and End of Study.....................................137.5 Early Study Termination.................................................................................................13

8 STUDY DRUG......................................................................................................................148.1 Names, Classification, and Mechanism of Action..........................................................14

PT-PhIDEE v04.30.14 Duke Cancer Institute Page 2 of 32CONFIDENTIAL


8.2 Packaging and Labeling..................................................................................................148.3 Supply, Receipt, and Storage..........................................................................................148.4 Dispensing and Preparation............................................................................................148.5 Compliance and Accountability......................................................................................148.6 Disposal and Destruction................................................................................................14

9 SUBJECT ELIGIBILITY......................................................................................................159.1 Inclusion Criteria.............................................................................................................159.2 Exclusion Criteria...........................................................................................................15

10 SCREENING AND ON-STUDY TESTS AND PROCEDURES........................................1610.1 Screening Examination................................................................................................1610.2 Run-In Period..............................................................................................................1710.3 Treatment Period.........................................................................................................1710.4 End of Treatment.........................................................................................................1710.5 Follow-up Period.........................................................................................................1710.6 End of Study................................................................................................................1710.7 Early Withdrawal of Subject(s)...................................................................................17

10.7.1 Criteria for Early Withdrawal...............................................................................17

10.7.2 Follow-up Requirements for Early Withdrawal...................................................17

10.7.3 Replacement of Early Withdrawal(s)...................................................................1710.8 Study Assessments......................................................................................................18

10.8.1 Medical History....................................................................................................18

10.8.2 Physical Exam.......................................................................................................18

10.8.3 Correlative Assessments......................................................................................1811 SAFETY MONITORING AND REPORTING....................................................................19

11.1 Adverse Events............................................................................................................19

11.1.1 AEs of Special Interest..........................................................................................19

11.1.2 Reporting of AEs...................................................................................................1911.2 Serious Adverse Events...............................................................................................19

11.2.1 Reporting of SAEs.................................................................................................2011.3 Emergency Unblinding of Investigational Treatment.................................................2011.4 Other Reportable Information.....................................................................................2011.5 Special Warnings and Precautions..............................................................................2011.6 Safety Oversight Committee (SOC)............................................................................2011.7 External Data and Safety Monitoring Board (DSMB)................................................20



12 QUALITY CONTROL AND QUALITY ASSURANCE....................................................2112.1 Monitoring...................................................................................................................2112.2 Audits..........................................................................................................................2112.3 Data Management and Processing..............................................................................21

12.3.1 Case Report Forms (CRFs)....................................................................................21

12.3.2 Data Management Procedures and Data Verification.........................................22

12.3.3 Study Closure.......................................................................................................2213 STATISTICAL METHODS AND DATA ANALYSIS.......................................................23

13.1 Analysis Sets...............................................................................................................2313.2 Patient Demographics and Other Baseline Characteristics.........................................2313.3 Treatments...................................................................................................................2313.4 Primary Objective........................................................................................................23

13.4.1 Variable................................................................................................................23

13.4.2 Statistical Hypothesis, Model, and Method of Analysis......................................23

13.4.3 Handling of missing values, censoring, and discontinuations.............................2313.5 Secondary Objectives..................................................................................................24

13.5.1 Key Secondary Objective......................................................................................24

13.5.2 Other Secondary Objectives................................................................................2413.6 Exploratory Objectives................................................................................................24

13.6.1 Key Exploratory Objective....................................................................................24

13.6.2 Other Exploratory Objectives...............................................................................2413.7 Interim Analysis..........................................................................................................2413.8 Sample Size Calculation..............................................................................................24

14 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS..............................................2514.1 Regulatory and Ethical Compliance............................................................................2514.2 DUHS Institutional Review Board and DCI Cancer Protocol Committee.................2514.3 Informed Consent........................................................................................................2514.4 Study Documentation..................................................................................................2514.5 Privacy, Confidentiality, and Data Storage.................................................................2614.6 Data and Safety Monitoring........................................................................................2714.7 Protocol Amendments.................................................................................................2714.8 Records Retention.......................................................................................................27

15 REFERENCES......................................................................................................................2816 APPENDICES.......................................................................................................................29



2 LIST OF ABBREVIATIONSUse this list as a starting point for abbreviations used in your protocol.

AE Adverse EventALT Alanine AminotransferaseALC Absolute Lymphocyte CountAST Aspartate AminotransferaseBUN Blood Urea NitrogenCBC Complete Blood CountCMP Comprehensive Metabolic PanelCR Complete ResponseCT Computed TomographyCTCAE Common Terminology Criteria for Adverse EventsDLT Dose Limiting ToxicityDSMB Data and Safety Monitoring BoardECOG Eastern Cooperative Oncology GroupH&P History & Physical ExamHRPP Human Research Protections ProgramIV (or iv) IntravenouslyMTD Maximum Tolerated DoseNCI National Cancer InstituteORR Overall Response RateOS Overall SurvivalPBMCs Peripheral Blood Mononuclear CellsPD Progressive DiseasePFS Progression Free Survivalp.o. per os/by mouth/orallyPR Partial ResponseSAE Serious Adverse EventSD Stable DiseaseSGOT Serum Glutamic Oxaloacetic TransaminaseSPGT Serum Glutamic Pyruvic TransaminaseWBC White Blood Cells



3 PROTOCOL SYNOPSIS AND RESEARCH SUMMARYThis section is designed to be compatible with the DUHS IRB research summary template. Thus, this section can be saved separately and uploaded as the research summary in the eIRB submission.

3.1 Purpose

Provide a simple description of the scope of the research.Example 1: This research protocol seeks to describe Stage IV breast cancer patient outcomes following

treatment with various drugs.Example 2: Establish mechanisms that regulate Bcl-2 family proteins in response to metabolic stress to

promote apoptosis to T-ALL therapies.

Primary Objectives:1. State the primary objective

a. Note: Objectives should clearly identify the variable(s) and the endpoint measure(s).b. In reference to Example 1 above:

i. To compare the effect of Drug X, Y, and Z on overall survival in Stage IV breast cancer patients.

c. In reference to Example 2 above:i. Test whether the percentage of cells surviving at 3 days is higher for treated cells than

untreated cells.2. State other primary objectives, if any

Secondary Objectives:1. State secondary objective2. State other secondary objectives, if any

Hypotheses1. Indicate whether this protocol is hypothesis-generating, hypothesis-supporting, or hypothesis-testing.2. If hypothesis-supporting or testing, then clearly describe the hypothesis.

a. For example:i. Drug X improves overall survival more effectively than Drugs Y and Z in Stage IV breast

cancer patients.

3.2 Background and Significance

This section should minimally describe the following:1. The study agent.2. The disease population.3. The clinically unmet need.4. Why the stated objectives of the research are important.5. The rationale for performing this research.6. Citations for existing literature that supports the rationale for performing this research.7. Unpublished data, if any, that supports the conduct of this research.8. How research in this protocol is different from existing research or literature.9. How conclusions derived from this research will be used. For example:

A. To inform patients and doctors about prior outcomes?B. To drive development of a prospective clinical trial?



3.3 Design and Procedure

Provide a brief overview of research design and study procedures.

3.4 Selection of Subjects

List all inclusion/exclusion criteria, which will likely minimally include:1. Disease type (and method of confirmation)2. Disease stage (and method of confirmation)3. Age

3.5 Duration of StudyState how long the study will last and how long participants will be in study (including all follow-up).

3.6 Data Analysis and Statistical Considerations

This section should be developed and completed with the assistance of a biostatistician. For protocols that clearly align with a DCI clinical research group, the clinical research group’s “embedded” biostatistician should be used (see below). For other protocols, the CPC strongly suggests that the PI contact the DTMI biostatistics core (or other resource) to consult a biostatistician.

DCI Clinical Research Group Embedded Statistician Melanoma Bercedis Peterson Sarcoma Bercedis Peterson Genitourinary Susan Halabi/Lan Lan Heme Malignancies/BMT/Cell Therapy Lan Lan/Zhiguo Li/Sin-Ho Jung (SPORE) Lung Xiaofei Wang Gastrointestinal/Phase I Donna Niedzwicki/Herbert Pang Brain Jim Herndon Radiation Oncology Bercedis Peterson Breast Bercedis Peterson Gynecology Lan Lan Head & Neck Bercedis Peterson


https://www.cancer.duke.edu/cru/cpc












https://www.dtmi.duke.edu/for-researchers/quantitative-resources/biostatistics-core



4 STUDY SCHEMA

Provide a schema which diagrams the basic study design along with descriptive text. An example follows:



5 BACKGROUND AND SIGNIFICANCE

5.1 Study Disease

Provide background information about the disease. This section should encompass the following:

1. Disease incidence, prevalence, and mortality2. The current standard of care3. Explanation of how/why the current standard of care is inadequate4. Any relevant treatment issues or controversies5. Current knowledge on the molecular, genetic, and cellular basis of the disease

- This is particularly important for studies involving targeted agents

5.2 Study Agent

Provide background information about the study agent. This section should encompass the following:

1. Type of agent (small molecule, TKI, antibody, cellular therapy, etc.)2. Agent mechanism of action3. Rationale for use of study agent in this particular disease context

Note: If this protocol involves an investigational combination of agents, then this section should describe experience with each agent individually but focus primarily on experience with the combination.

5.2.1 Pre-clinical experience

Describe the pre-clinical experience with efficacy, toxicity, pharmacokinetics, mutagenicity, etc.- Cell-free in vitro biochemical data- Cell-based in vitro data- Animal model-based data- Unpublished data should be included here

5.2.2 Clinical experience

Describe the clinical experience with safety, efficacy, toxicity, pharmacokinetics, etc.- Knowledge from prior and current clinical trials

5.3 Study Purpose/Rationale

Justify the purpose of this study. This section should encompass the following:

1. Experience with other agents, especially those that (a) are similar in function/mechanism or (b) are being used in similar disease contexts.2. Explanation of how/why the current standard of care is inadequate3. Any relevant treatment issues or controversies4. Description of how the study agent is different from current treatment paradigms, and how this difference might help meet an unmet medical need.



6 OBJECTIVES AND ENDPOINTS

Provide a concise summary of objectives and related endpoints. This might best be conveyed in table format as exemplified below. Note: Objectives should be carefully considered because designation as primary, secondary, or exploratory will affect how much effort study teams must devote to compliance with Clinicaltrials.gov reporting requirements.

Objective Endpoint AnalysisPrimary Evaluate safety and determine MTD

of Agent X in refractory cancer patients

Frequency of AEs, SAEs, DLTs; Clinical lab values; Vital sign measurements.

See Section X.X.X.XXX

Key Secondary Assess ORR after Agent X treatment Frequency of response (≥ minor response) 6 months after Agent X treatment


Other Secondary Evaluate PFS after Agent X treatment Proportion with stable disease 6 months after Agent X treatment


Other Secondary Characterize single-dose PK profile of Agent X therapy

PK parameters, including Cmax, Tmax, AUC, t1/2, and accumulation ratio.


Exploratory Explore association of baseline YFP levels and disease response to Agent X

Correlation of YFP expression in serum and plasma cells and ORR at 6 months


Exploratory Investigate potential immunogenicity of Agent X

Anti-Agent X antibody levels in serum after single-dose Agent X treatment


Exploratory Explore association of genomic signatures and disease response to Agent X

Correlation between genomic signature from tumor tissue and PFS at 6 months




7 INVESTIGATIONAL PLAN

7.1 Study Design

Provide a brief overview of the study design. This section should minimally indicate the following:

1. Specifics about study type (phase, number of arms, blinded/unblinded, etc.)2. Design (i.e. standard 3+3, modified 3+3 with accelerated titration, etc.) and supporting rationale3. Interim analyses, if applicable4. Dosage range5. Eligible subject population (i.e. disease type)6. Number of subjects7. Number of centers (if applicable, specify all sites)8. Treatment duration (i.e. specified as cycles and months/years)9. Supportive treatments (i.e. Vitamin D)10. Samples or tissues collected for clinical labs and/or correlative studies, if applicable

7.1.1 Dose Escalation and ExpansionDescribe in detail the dose escalation scheme (and dose expansion phase, if applicable). This information is often summarized clearly and concisely in table format, as exemplified below:

Dose Escalation and Expansion

Cohort Dose Level # Subjects Schema1 0.5 mg 1 Dose escalation: “Accelerated Titration” phase:

If no DLT, then escalate to next dose.If 1 DLT of Grade 2 or greater toxicity, add 2 additional subjects and switch to Standard 3+3 with Modified Fibonacci dose escalation

2 1.5 mg 13 4.5 mg 14 10.0 mg 15 20.0 mg 3 Dose escalation: “Standard 3+3 with Modified Fibonacci design” phase:

If 1 DLT, expand to 6 subjects.If ≤ 1/6 DLT, then escalate dose.If 2/3 or or 2/6 DLT or more, stop escalation.

6 30.0 mg 37 40.0 mg 38 45.0 mg 39 TBD 20 Dose expansion at MTD

TBD = to be determined; DLT = dose limiting toxicity; MTD = maximum tolerated dose

7.1.2 Definition of Dose-Limiting Toxicity (DLT)Toxicities will be graded according to the NCI CTCAE version 4.0 criteria. DLTs will be defined as any of the following events that are at least (possibly, probably, or definitely) attributable to Agent X during dose escalation.

7.1.2.1 Non-hematologic:Define events that constitute DLTs here.

7.1.2.2 Hematologic:Define events that constitute DLTs here.

7.1.2.3 Other Considerations:Describe other situations which may constitute a DLT.



7.1.3 Dose Modification

7.1.3.1 Non-hematologic:Describe the dose modification scheme for non-hematologic toxicities. For investigational combinations, specify what agent dosages will be reduced or held constant.

7.1.3.2 Hematologic:Describe the dose modification scheme for hematologic toxicities. For investigational combinations, specify what agent dosages will be reduced or held constant.

7.1.3.3 Other considerations:Describe the dose modification scheme for other situations as needed. For investigational combinations, specify what agent dosages will be reduced or held constant.

7.1.4 Safety ConsiderationsDescribe any special considerations or monitoring activities for adverse events that are particularly associated with the study agent.

7.1.5 Missed DosesDescribe how missed doses will be handled, and how subsequent doses should be administered.

7.1.6 Concomitant MedicationsIndicate the management plan for concomitant medications that are required, permitted, and prohibited.

7.1.7 Study Drug BlindingIf applicable, describe the blinding procedure and the person(s) who will be responsible for overseeing the blinding process. If blinding applies to the protocol, the following additional language is suggested: Emergency unblinding procedures are described in 11.3.

7.2 Rationale for Selection of Dose, Regimen, and Treatment Duration

Provide relevant information from pre-clinical and clinical experience which justifies the doses, regimens, and treatment duration used in this protocol.

7.3 Rationale for Correlative Studies

Describe what correlative studies will be performed. Provide justification for each correlative study approach and selection of specific biomarkers, if applicable.

7.4 Definition of Evaluable Subjects, On Study, and End of Study

Define “evaluable” subject, on study, and end of study.

7.5 Early Study Termination

This study can be terminated at any time for any reason by the PI-sponsor. If this occurs, all subjects on study should be notified as soon as possible. Additional procedures and/or follow up should occur in accordance with Section 10.7, which describes procedures and process for prematurely withdrawn patients.



8 STUDY DRUG

8.1 Names, Classification, and Mechanism of Action

Provide alternate names, type of study drug class, and mechanism of study drug action..

8.2 Packaging and Labeling

If applicable, provide packaging and labeling information.

8.3 Supply, Receipt, and Storage

Provide information about supply, receipt, and storage. If ICS is used, this information should be consistent with ICS policy and practice.

8.4 Dispensing and Preparation

Provide information about dispensing and preparation. If ICS is used, this information should be consistent with ICS policy and practice.

8.5 Compliance and Accountability

Describe how compliance with drug usage and accountability will be tracked and documented.

8.6 Disposal and Destruction

Describe how and where unused drug will be destroyed, as well as who will be responsible for performing and documenting such activities.



9 SUBJECT ELIGIBILITY

9.1 Inclusion Criteria

Provide inclusion criteria. If applicable, provide rationale for criterion.

9.2 Exclusion Criteria

Provide exclusion criteria. If applicable, provide rationale for criterion.



10 SCREENING AND ON-STUDY TESTS AND PROCEDURES

In a short paragraph summary, provide a brief overview of the tests and procedures that occur during the screening phase, treatment phase, maintenance phase, and follow-up phase of the protocol. Then, provide a more detailed “schedule of events”, as exemplified below.

SeeSection

Phase Screen Treatment Maintenance EOT Follow-upVisit Number 1 2 3 4 5 6 7 8 9 10 11 12,14 13,15 16 17Cycle Duration 30 days 30 days 30 days 1 day 1 dayCycle 1 2 3, 4 5 6Day of Cycle -30 1 2 8 15 29 1 2 8 15 29 1 15 1 1

General EvaluationsInformed ConsentEligibility CriteriaMedical HistoryTreatment HistoryPhysical ExamHeight, Weight, BSAVital SignsNeurologic ExamPerformance StatusConcomitant MedicationsAdverse Events

Laboratory EvaluationsCBC with PlateletsSerum ChemistryUric AcidLDHCoagulation TestsUrinalysisSerum Pregnancy TestUrine Pregnancy Test

Disease EvaluationsBone Marrow Aspirate/BiopsySerum Ig/ProteinUrine ProteinMRICT ScanSurvival StatusBlood collection for PK

Correlative EvaluationsTumor Tissue Collection

TreatmentAgent XRequired Concomitant

10.1 Screening Examination

The screening examination will take place between Day X and Y. An informed consent must be signed by the patient before any screening procedure takes place. Subject data to be collected at the Screening Examination includes (indicate all data here).

Provide details about data that must be collected and where it will be recorded in the event of a screen failure.



10.2 Run-In Period

If applicable, describe subject treatment during the run-in period.

10.3 Treatment Period

Describe subject treatment during the treatment period. This section may include information about frequency of study drug administration, cycle duration, etc.

10.4 End of Treatment

Describe the End of Treatment visit and the study assessments and administrative requirements of this visit.

10.5 Follow-up Period

Define the follow-up period, and describe study activity during this time.

10.6 End of Study

Define the end of study. Indicate how subjects lost to follow-up will be handled, and how such incidents will be documented. Also, indicate when data lock will occur.

10.7 Early Withdrawal of Subject(s)

10.7.1 Criteria for Early Withdrawal

Subjects may voluntarily withdraw from the study at any time. The PI may also withdraw a subject from the study at any time based on his/her discretion. Reasons for PI-initiated withdrawal may include, but is not limited to the following:

- Adverse events- Abnormal laboratory values- Abnormal test procedure results- Protocol deviation- Administrative issues- Disease progression- Pregnancy

10.7.2 Follow-up Requirements for Early Withdrawal

Detail the study assessments and administrative needs of the Premature Withdrawal visit. Also, describe the follow up duration and tests/procedures that must occur after a subject is removed from the study.

10.7.3 Replacement of Early Withdrawal(s)

Describe whether subjects who prematurely withdraw will be replaced.



10.8 Study Assessments

10.8.1 Medical History

Describe how medical history assessments will be conducted and what data will be recorded.

10.8.2 Physical Exam

Describe details of physical exam and data to be recorded.

To add more assessments, copy paste the “10.8.2 Physical Exam” header along with this text. Then, paste it in the line below this paragraph. Then, change the header and text to reflect the additional assessment. Since copy/pasting will preserve formatting, the new header should appear in the Navigation Pane of MS Word.

10.8.3 Correlative Assessments

Describe how biomarker and/or pharmacogenetic assessments will be performed and sampled.. Information about sample collection procedure, whether correlative assessments are optional vs. not optional, and how samples will be stored, processed, labeled, shipped, and destroyed should be provided here.



11 SAFETY MONITORING AND REPORTING

The PI is responsible for the identification and documentation of adverse events and serious adverse events, as defined below. At each study visit, the PI or designee must assess, through non-suggestive inquiries of the subject or evaluation of study assessments, whether an AE or SAE has occurred.

If the DCI Safety Team will be used to track and report AEs and SAEs, indicate that here. Clearly describe what aspects of AE/SAE tracking and reporting that the DCI Safety Team will be responsible for, and provide contact information.

11.1 Adverse Events

An adverse event (AE) is any untoward medical occurrence in a subject receiving study drug and which does not necessarily have a causal relationship with this treatment. For this protocol, the definition of AE also includes worsening of any pre-existing medical condition. An AE can therefore be any unfavorable and unintended or worsening sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not related to use of the study drug. Abnormal laboratory findings without clinical significance (based on the PI’s judgment) should not be recorded as AEs. But laboratory value changes that require therapy or adjustment in prior therapy are considered adverse events.

From the time the subject signs the informed consent form through the End of Study visit (as defined in Section 10.6), all AEs must be recorded in the subject medical record and adverse events case report form.

AEs will be assessed according to the CTCAE version 4.0. If CTCAE grading does not exist for an AE, the severity of the AE will be graded as mild (1), moderate (2), severe (3), life-threatening (4), or fatal (5).

Attribution of AEs will be indicated as follows:- Definite: The AE is clearly related to the study drug- Probably: The AE is likely related to the study drug- Possible: The AE may be related to the study drug- Unlikely: The AE is doubtfully related to the study drug- Unrelated: The AE is clearly NOT related to the study drug

11.1.1 AEs of Special Interest

Indicate if there are AEs of particular concern or emphasis.

11.1.2 Reporting of AEs

Indicate any reporting requirements for AEs here.

11.2 Serious Adverse Events

An AE is considered “serious” if in the opinion of the investigator it is one of the following outcomes:

- Fatal- Life-threatening- Constitutes a congenital anomaly or birth defect- A medically significant condition (defined as an event that compromises subject safety or may

require medical or surgical intervention to prevent one of the three outcomes above).



- Requires inpatient hospitalization or prolongation of existing hospitalization- Results in persistent or significant incapacity or substantial disruption to conduct normal life

functions.

11.2.1 Reporting of SAEs

Indicate any reporting requirements for SAEs here, and address the specific reporting process and timeframes for expedited reporting.

11.3 Emergency Unblinding of Investigational Treatment

If applicable, describe the unblinding process and who will be responsible for managing this process. Emergency contact information (i.e. 24/7 access phone number or email) should be provided here.

11.4 Other Reportable Information

Describe other events that require reporting, and whether they should be handled as AEs or SAEs. Examples of such events include overdose, pregnancy, and other complications resulting from study activities.

11.5 Special Warnings and Precautions

Describe other events that require reporting, and whether they should be handled as AEs or SAEs. Examples of such events include overdose, pregnancy, and other complications resulting from study activities.

11.6 Safety Oversight Committee (SOC)

The Duke Cancer Institute SOC is responsible for annual data and safety monitoring of DUHS sponsor-investigator phase I and II, therapeutic interventional studies that do not have an independent Data Safety Monitoring Board (DSMB). The primary focus of the SOC is review of safety data, toxicities and new information that may affect subject safety or efficacy. Annual safety reviews includes but may not be limited to review of safety data, enrollment status, stopping rules if applicable, accrual, toxicities, reference literature, and interim analyses as provided by the sponsor-investigator. The SOC in concert with the DCI Monitoring Team (see Section 12.1 for Monitoring Team description) oversees the conduct of DUHS cancer-related, sponsor-investigator greater-than-minimal-risk intervention studies that do not have an external monitoring plan, ensuring subject safety and that the protocol is conducted, recorded and reported in accordance with the protocol, standing operating procedures (SOPs), Good Clinical Practice (GCP), and applicable regulatory requirements.

11.7 External Data and Safety Monitoring Board (DSMB)

If the PI or DCI has a potential conflict of interest with conduct of this protocol, the protocol may require additional oversight beyond or in place of the SOC in the form of an external DSMB. If a potential conflict of interest exists, the PI should contact Ross McKinney, M.D. at the Duke Research Integrity Office to develop a conflict of interest management plan for the protocol. The plan should describe who will comprise the external DSMB, how frequently it will meet, what it will review, and the criteria it will use to determine whether it is safe to proceed with the protocol.



12 QUALITY CONTROL AND QUALITY ASSURANCE

12.1 Monitoring

The Duke Cancer Institute (DCI) Monitoring Team will conduct monitoring visits to ensure subject safety and to ensure that the protocol is conducted, recorded, and reported in accordance with the protocol, standard operating procedures, good clinical practice, and applicable regulatory requirements. As specified in the DCI Data and Safety Monitoring Plan, the DCI Monitoring Team will conduct routine monitoring after the third subject is enrolled, followed by annual monitoring of 1 – 3 subjects until the study is closed to enrollment and subjects are no longer receiving study interventions that are more than minimal risk.

Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of serious and/or unexpected toxicities, or other concerns and may be initiated upon request of DUHS and DCI leadership, the DCI Cancer Protocol Committee, the Safety Oversight Committee (SOC), the sponsor, the Principal Investigator, or the IRB. All study documents must be made available upon request to the DCI Monitoring Team and other authorized regulatory authorities, including but not limited to the National Institute of Health, National Cancer Institute, and the FDA. Every reasonable effort will be made to maintain confidentiality during study monitoring.

If this is a multi-site study, budgeting and monitoring arrangements will need to be customized. Please contact Vijaya Chadaram, the DCI Monitoring Team lead, to obtain more information and to develop a protocol-specific external site monitoring plan.

12.2 Audits

The Duke School of Medicine Clinical Trials Quality Assurance (CTQA) office may conduct confidential audits to evaluate compliance with the protocol and the principles of GCP. The PI agrees to allow the CTQA auditor(s) direct access to all relevant documents and to allocate his/her time and the time of the study team to the CTQA auditor(s) in order to discuss findings and any relevant issues.

CTQA audits are designed to protect the rights and well-being of human research subjects. CTQA audits may be routine or directed (for cause). Routine audits are selected based upon risk metrics generally geared towards high subject enrollment, studies with limited oversight or monitoring, Investigator initiated Investigational Drugs or Devices, federally-funded studies, high degree of risk (based upon adverse events, type of study, or vulnerable populations), Phase I studies, or studies that involve Medicare populations. Directed audits occur at the directive of the IRB or an authorized Institutional Official.

CTQA audits examine research studies/clinical trials methodology, processes and systems to assess whether the research is conducted according to the protocol approved by the DUHS IRB. The primary purpose of the audit/review is to verify that the standards for safety of human subjects in clinical trials and the quality of data produced by the clinical trial research are met. The audit/review will serve as a quality assurance measure, internal to the institution. Additional goals of such audits are to detect both random and systemic errors occurring during the conduct of clinical research and to emphasize “best practices” in the research/clinical trials environment.

12.3 Data Management and Processing

12.3.1 Case Report Forms (CRFs)



The CRF (please indicate whether a paper or electronic CRF will be used) will be the primary data collection document for the study. The CRFs will be updated in a timely manner following acquisition of new source data. Only approved study staff (please specify names and/or titles of authorized individuals as stated in key personnel), are permitted to make entries, changes, or corrections in the CRF.

If paper CRF…Errors will crossed out with a single line, and this line will not obscure the original entry. Changes or corrections will be dated, initialed, and explained (if necessary). The PI or authorized key personnel will maintain a record of the changes and corrections.

If electronic CRF…An audit trail will be maintained automatically by the electronic CRF management system (please indicate what eCRF management system is being used). Designated personnel will complete user training, as required or appropriate per regulations.

12.3.2 Data Management Procedures and Data Verification

Designated personnel using the electronic CRF will have access based on their specific roles in the protocol. Please specify them here.

Completeness of entered data will be checked automatically by the eCRF system, and users will be alerted to the presence of data inconsistencies. Additionally, the data manager and (specify individual) will cross-reference the data to verify accuracy. Missing or implausible data will be highlighted for the PI requiring appropriate responses (i.e. confirmation of data, correction of data, completion or confirmation that data is not available, etc.).

The database will be reviewed and discussed prior to database closure, and will be closed only after resolution of all remaining queries. An audit trail will be kept of all subsequent changes to the data.

12.3.3 Study Closure

Following completion of the studies, the PI will be responsible for ensuring the following activities:

- Data clarification and/or resolution- Accounting, reconciliation, and destruction/return of used and unused study drugs- Review of site study records for completeness- Shipment of all remaining laboratory samples to the designated laboratories



13 STATISTICAL METHODS AND DATA ANALYSIS

All statistical analysis will be performed under the direction of the statistician designated in key personnel. Any data analysis carried out independently by the investigator must be approved by the statistician before publication or presentation.

This section should be developed and completed with the assistance of a biostatistician. For protocols that clearly align with a DCI clinical research group, the clinical research group’s “embedded” biostatistician (see below) should be contacted for assistance in development of a statistical analysis plan. For other protocols, the CPC strongly suggests that the PI contact the DTMI biostatistics core (or other resource) to consult a biostatistician.

DCI Clinical Research Group Embedded Statistician Melanoma Bercedis Peterson Sarcoma Bercedis Peterson Genitourinary Susan Halabi/Lan Lan Heme Malignancies/BMT/Cell Therapy Lan Lan/Zhiguo Li/Sin-Ho Jung (SPORE) Lung Xiaofei Wang Gastrointestinal/Phase I Donna Niedzwicki/Herbert Pang Brain Jim Herndon Radiation Oncology Bercedis Peterson Breast Bercedis Peterson Gynecology Lan Lan Head & Neck Bercedis Peterson

13.1 Analysis Sets

Define the analysis sets here.

13.2 Patient Demographics and Other Baseline Characteristics

Indicate analysis plan for these matters here.

13.3 Treatments

Indicate how treatments (i.e. dose and duration) will be summarized/analyzed.

13.4 Primary Objective

Refer to Section 6 for the primary objective and endpoint. Briefly restate the primary objective here.

13.4.1 Variable

Describe the variable

13.4.2 Statistical Hypothesis, Model, and Method of Analysis

Provide description here.
















13.4.3 Handling of missing values, censoring, and discontinuations

Provide description here.

13.5 Secondary Objectives

Refer to Section 6 for the secondary objectives and endpoints. Briefly restate the secondary objective here.

13.5.1 Key Secondary Objective

Describe analysis plan here.

13.5.2 Other Secondary Objectives


13.6 Exploratory Objectives

Refer to Section 6 for the exploratory objectives and endpoints. Briefly restate the exploratory objective here.

13.6.1 Key Exploratory Objective


13.6.2 Other Exploratory Objectives


13.7 Interim Analysis

Describe process here.

13.8 Sample Size Calculation

Describe calculations here.



14 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS

14.1 Regulatory and Ethical Compliance

This protocol was designed and will be conducted and reported in accordance with the International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, the Declaration of Helsinki, and applicable federal, state, and local regulations.

14.2 DUHS Institutional Review Board and DCI Cancer Protocol Committee

The protocol, informed consent form, advertising material, and additional protocol-related documents must be submitted to the DUHS Institutional Review Board (IRB) and DCI Cancer Protocol Committee (CPC) for review. The study may be initiated only after the Principal Investigator has received written and dated approval from the CPC and IRB.

The Principal Investigator must submit and obtain approval from the IRB for all subsequent protocol amendments and changes to the informed consent form. The CPC should be informed about any protocol amendments that potentially affect research design or data analysis (i.e. amendments affecting subject population, inclusion/exclusion criteria, agent administration, statistical analysis, etc.).

The Principal Investigator must obtain protocol re-approval from the IRB within 1 year of the most recent IRB approval. The Principal Investigator must also obtain protocol re-approval from the CPC within 1 year of the most recent IRB approval, for as long as the protocol remains open to subject enrollment.

14.3 Informed Consent

The informed consent form must be written in a manner that is understandable to the subject population. Prior to its use, the informed consent form must be approved by the IRB.

The Principal Investigator or authorized key personnel will discuss with the potential subject the purpose of the research, methods, potential risks and benefits, subject concerns, and other study-related matters. This discussion will occur in a location that ensures subject privacy and in a manner that minimizes the possibility of coercion. Appropriate accommodations will be made available for potential subjects who cannot read or understand English or are visually impaired. Potential subjects will have the opportunity to contact the Principal investigator or authorized key personnel with questions, and will be given as much time as needed to make an informed decision about participation in the study.

Before conducting any study-specific procedures, the Principal Investigator must obtain written informed consent from the subject or a legally acceptable representative. The original informed consent form will be stored with the subject’s study records, and a copy of the informed consent form will be provided to the subject. The Principal Investigator is responsible for asking the subject whether the subject wishes to notify his/her primary care physician about participation in the study. If the subject agrees to such notification, the Principal Investigator will inform the subject’s primary care physician about the subject’s participation in the clinical study.

14.4 Study Documentation

Study documentation includes but is not limited to source documents, case report forms (CRFs), monitoring logs, appointment schedules, study team correspondence with sponsors or regulatory bodies/committees, and regulatory documents that can be found in the DCI-mandated “Regulatory Binder”, which includes but is



not limited to signed protocol and amendments, approved and signed informed consent forms, FDA Form 1572, CAP and CLIA laboratory certifications, and clinical supplies receipts and distribution records.

Source documents are original records that contain source data, which is all information in original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source documents include but are not limited to hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial. When possible, the original record should be retained as the source document. However, a photocopy is acceptable provided that it is a clear, legible, and an exact duplication of the original document.

A case report form (CRF) (please indicate whether a paper or electronic CRF will be used) will be the primary data collection document for the study. The CRFs will be updated within two weeks of acquisition of new source data. Only approved staff (please specify names and/or titles of authorized individuals as stated in key personnel), are permitted to make entries, changes, or corrections in the CRF. For paper CRFs, errors will crossed out with a single line, and this line will not obscure the original entry. Changes or corrections will be dated, initialed, and explained (if necessary). The Principal Investigator or authorized key personnel will maintain a record of the changes and corrections. For electronic CRFs, an audit trail will be maintained by the electronic CRF management system (please indicate what eCRF management system is being used).

14.5 Privacy, Confidentiality, and Data Storage

The Principal Investigator will ensure that subject privacy and confidentiality of the subject’s data will be maintained. Research Data Security Plans (RDSPs) will be approved by the appropriate institutional Site Based Research group.

To protect privacy, every reasonable effort will be made to prevent undue access to subjects during the course of the study. Prospective participants will be consented in an exam room where it is just the research staff, the patient and his family, if desired. For all future visits, interactions with research staff (study doctor and study coordinators) regarding research activities will take place in a private exam room. All research related interactions with the participant will be conducted by qualified research staff who are directly involved in the conduct of the research study.

To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock and key accessible only by the research staff. Subjects will be identified only by a unique study number and subject initials. Electronic records of subject data will be maintained using a dedicated database (required: please specify database application, i.e. Microsoft Excel, Microsoft Access, eResearch, Oracle Clinical, Redcap, etc.), which is housed in an encrypted and password-protected (required: please specify storage device, i.e. laptop computer, desktop computer, DCI file server). Access to electronic databases will be limited to (please specify). Subject data may be stored temporarily on encrypted and password-protected portable memory devices such as flash drives and external hard drives, but only when absolutely necessary. Data stored on portable memory devices will be de-identified. Subject data will be deleted from the portable memory device at the earliest opportunity. The security and viability of the IT infrastructure will be managed by the DCI and/or Duke Medicine.

Upon completion of the study, research records will be archived and handled per DUHS HRPP policy.

Subject names or identifiers will not be used in reports, presentations at scientific meetings, or publications in scientific journals.



14.6 Data and Safety Monitoring

Data and Safety Monitoring will be performed in accordance with the DCI Data and Safety Monitoring Plan. For a more detailed description of the DSMP for this protocol, refer to Section 11 (Sections 11.6 and 11.7 in particular) and Section 12.

14.7 Protocol Amendments

All protocol amendments must be initiated by the Principal Investigator and approved by the IRB prior to implementation. IRB approval is not required for protocol changes that occur to protect the safety of a subject from an immediate hazard. However, the Principal Investigator must inform the IRB and all other applicable regulatory agencies of such action immediately.

Though not yet required, the CPC should be informed about any protocol amendments that potentially affect research design or data analysis (i.e. amendments affecting subject population, inclusion/exclusion criteria, agent administration, etc.).

14.8 Records Retention

The Principal Investigator will maintain study-related records for the longer of a period of:

- at least two years after the date on which a New Drug Application is approved by the FDA (if an IND is involved)

- at least two years after formal withdrawal of the IND associated with this protocol (if an IND is involved)- at least six years after study completion (Duke policy)



15 REFERENCES



16 APPENDICES


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