11/11/02 Revisions to the following sections:
15.1 Monitoring, 15.5Women and Minority Statement, 16.0 Adverse Event Reporting and Appendix I: CTC M. McMahon 4-6349 PHASE I: MASTER PROTOCOL TEMPLATE TITLE OF PROTOCOL CENTERED IN BOLD CAPS Sponsor: Name of sponsor Address Name Address or University Telephone # Name(s ) Address or University Telephone # Name Address or University Telephone # Name(s) Address or University Telephone # Fax # List dates of revision in chronological order Month DD, 20XX Principal Investigator: Co-Investigator(s): Biostatistician: Data Management/ Study Coordinator: Revision: TABLE OF CONTENTS 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 18.1 18.2 18.3 18.4 18.5 18.6 18.7 18.8 18.9 18.10 ABSTRACT BACKGROUND / RATIONALE OBJECTIVES ELIGIBILITY CRITERIA PATIENT REGISTRATION TREATMENT PLAN TOXICITIES AND DOSE MODIFICATIONS STUDY PROCEDURES AND SCHEDULE OF EVENTS CRITERIA FOR EVALUATION PHARMACEUTICAL / BIOLOGICAL / CHEMICAL INFORMATION BIOSTATISTICAL CONSIDERATIONS DATA FORMS AND SUBMISSION SCHEDULE SPECIAL COMPANION STUDIES SPECIAL INSTRUCTIONS ETHICAL AND REGULATORY CONSIDERATIONS ADVERSE EVENTS REFERENCES APPENDICES Appendix I: Appendix II: Appendix III: Appendix IV: Appendix V: Appendix VI: Appendix VII: Appendix VIII: Appendix IX: Appendix X: Toxicity Criteria Schedule of Events Performance Criteria Scales Source Documentation Staging Criteria ADR Reporting form for Investigational New Drugs ADR Reporting form for Commercial Drugs Acceptable Limits for Laboratory Tests Informed Patient Consent Randomized codes, Fibonacci dose escalation scheme details, etc. 1.0 2.0 2.1 2.1.1 2.1.2 2.1.3 2.1.4 2.2 2.2.1 2.2.1.1 2.2.1.2 2.2.1.3 2.2.2 2.2.2.1 2.2.2.2 2.2.2.3 ABSTRACT BACKGROUND / RATIONALE Introductory information Please reference this section appropriately. Natural History Nature of Disease and Characteristics of Diagnosis Treatment and Current Response Rates Brief Epidemiological Data, i.e.-incidence and prevalence rates Description of investigational drug / biotherapy / treatment or biological system Drug / Biotherapy / Treatment Pharmacology Pharmacokinetics Dosing Biological System Molecular Biology Cellular Biology Measurements 2.3 Preliminary Results Review prior pre-clinical experimental results, preliminary clinical results with toxicity experience, any relevant unpublished results, prior studies or on-going trials to support hypotheses or rationale being tested. 2.4 Rationale for Combined Therapeutic Agents New agents should not be combined with other drugs until it has shown reproducible evidence of activity in at least two single-agent trials in one clinical circumstance. 2.5 Combination Therapies Description of combination therapies. Rationale must be clear and well documented based on laboratory evidence relevant to the clinical circumstance. 2.5.1 Evidence of single-agent activity 2.5.2 Laboratory evidence of synergistic activity based on mechanism of action 2.5.3 Evidence of alteration in pharmacodynamics or pharmacokinetics 2.6 Summary Summarize rationale for this study. 3.0 OBJECTIVES The purpose and objectives of a study are related to the phase of clinical testing. Phase I cancer studies consist of initial testing of an agent in humans with confirmed malignancy. The primary objective is safety evaluation and establishing approximate patient tolerance for acute and usually multiple dosing. In addition, these trials examine pharmacology and may yield preliminary efficacy data. Therapeutic intent is always present in Phase I trials. 3.1 Primary Objectives List primary questions and response variables--the outcomes to be measured during study. Clearly and briefly define the study goals, e.g., to determine the maximum tolerated dose of a single drug, ___, in conjunction with ___ and ___in patients with metastatic breast cancer refractory to conventional therapy. 3.2 Secondary Objectives Secondary questions and response variables, e.g., "to assess the toxicities of ____ and ____ in patients undergoing peripheral blood stem cell transplantation for multiple myeloma." 3.3 4.0 Other Subgroup Hypotheses ELIGIBILITY CRITERIA Some Phase I trials are explicitly designed to determine safe doses and pharmacology in patients with significant organ impairment. Define acceptable level of organ functioning and any exceptions if applicable. 4.1 Inclusion Criteria. Define the study population. Provided are examples listed as separate points. 4.1.1 Tumor type: site and stage of cancer 4.1.2 Clinical status: out-patient or in-patient at the time of enrollment 4.1.3 Unequivocal diagnostic criteria, may include duration of diagnosis 4.1.4 Performance status (ECOG=50% decrease in estimated area of evaluable, but non-measurable, tumor mass, as agreed upon by two independent observers, not to include pleural effusions. 9.1.7 Stable: Does not qualify for complete response, partial response or progression. All measurable and evaluable sites and lesions must be assessed. 9.1.8 Progressive Disease: 25% increase or an increase of 10 cm2 (whichever is smaller) in the sum of products of measurable lesions over smallest sum observed (over baseline if no decrease), OR appearance of any lesion which had disappeared, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to deteriorating condition (unless deterioration is clearly unrelated to this cancer). For scan only bone disease, increased uptake does not constitute clear worsening and new lesions are required for progression. Worsening of existing non-evaluable disease does not constitute progression. Exceptions: 1) in cases for which initial flare reaction is possible (hypercalcemia, increased bone pain, erythema of skin lesions), either symptoms must persist beyond four weeks or there must be additional evidence of progression; 2) lesions which appear to increase in size due to presence of necrotic tissue will not be considered to have progressed. 9.1.9 Unknown: Progression has not been documented and one or more measurable or evaluable lesions or sites have not been assessed. 9.2 Non-Evaluable Disease Note that non-evaluable disease does not affect objective status except in determination of CR (must be absent), and in determination of progression (if NEW sites of non-evaluable disease develop). 9.3 Best Response This will be calculated from the serial evaluation of objective status. For patients with all disease sites assessed every three to six weeks, two objective determinations of CR, will be required for a best response of CR; two of PR or better, but not qualifying for CR, will be required for PR; two of stable or better, but not qualifying as PR or CR, will be required for stable; and patients with objective status of progression on or before the second evaluation (second AFTER the prestudy evaluation) will have a best response of increasing disease. 9.4 Rate of Response Definitions related to adequate trial, including differentiation between evaluable toxicity vs. evaluable response, and/or fully vs. partially evaluable. Define the duration of response and time of disease progression or time of treatment failure. 9.5 Response / Outcomes Methodology Describe the method of determining outcomes/response, e.g., pain scale, survival time, incidence of infection. Append criteria as Appendix III: Performance Criteria Scales. 10.0 PHARMACEUTICAL / BIOLOGICAL / CHEMICAL INFORMATION Provide a description of drugs used in the study. Each drug listed must be presented in alphabetical order. For all drugs disclosed, each of the sections outlined below must be included. Please find enclosed a list of commonly used preventative therapies used in cancer treatment. This document can be found under therapy.doc on your diskette. In addition, the Clinical Drug Brochure contains all relevant information regarding these aspects. If the drug is investigational, please include the name, address and telephone number of supplier. 10.1 Drug Name Other Names Classification Mode of Action Storage, Stability, Appearance and Shelf-Life Metabolism Preparation Incompatibilities 1
Availability Side Effects (please list by system, i.e. Hematologic, Neurological, Gastrointestinal, etc.) Nursing Implications 10.2 Drug Accountability and Ordering Please add. 10.2.1 Study article accountability will be recorded by procedures mandated by the National Institutes of Health (NIH) and the National Cancer Institute (NCI) using the Investigational Drug Accountability Record. These proceedings include ordering, disposing and the dispensation of investigational drug. For a copy of this handbook, please contact the CRO. 10.2.2 Describe who will be responsible for maintaining drug utilization / disposition records: Name, address and phone number. 11.0 BIOSTATISTICAL APPROACHES This section should be developed in coordination with the biostatistician available to you at the Oregon Cancer Center. Please direct your call to the CRO. 11.1 Study Objectives 11.1.1 Restate Primary Objectives 11.1.2 Restate Secondary Objectives 11.2 11.3 11.4 11.5 11.6 Baseline Comparability Efficacy Evaluations Safety Evaluations Sample Size and Power Toxicity Evaluations The number of patients studied per dose level should be discussed in Section 6.0: Treatment Plan 12.0 12.1 DATA FORMS AND SUBMISSION SCHEDULE Please add. Individual Patient Data For each patient on trial, data are recorded on a Cancer Therapy Evaluation Program (CTEP) case report form. This form is specific for Phase I/II pharrmacokinetic trials. All information specified in the protocol should be recorded on this form. It must be maintained prospectively. These forms are submitted biweekly to the CTMS of CTEP. The biweekly submission should include case report forms on patients actively on study and all new patients entered since the last update. At the end of each course, the investigator should indicate which medical events in the patients course were in his/her judgment drug induced. All evaluations regarding toxicity should be reported according to the CTEP toxicity criteria scale. This is a standard format which has been adopted by all CTEP Phase I investigators. 1
These reporting requirements apply to all Phase I trials of drugs newly entering clinical trials, including both adult and pediatric studies. Investigators will receive a full report of their study form the CTMS each month. They should review the printout for accuracy and report any discrepancies to CTMS. The CTMS provides CTEP with summary information on all trials in the data base with each drug. Investigators may, if they wish, receive this summary information for any drug they are studying. The CTMS analyzes the data from phase I trials for timeliness of submission and completeness and provides monthly reports of this analysis to CTEP investigators. 12.2 Please add. Because of the limited efficacy and toxicity data available for this investigational drug/biotherapy, it is important that data reporting forms or data is down loaded into the Oregon Cancer Center database on schedule. Preliminary results may be used to amend the protocol in an effort to ensure that the therapy provided is in the patients' best interest. 12.3 Study Documentation Provide required study documentation and define any special record formats to be used. Append section as Appendix IV: Source Documentation 12.4 Management of Study Data 12.4.1 Please add. Record maintenance will be upheld by name the study coordinator or data manager in the department or division of. Data accumulated from this study will be forwarded either by completed source documents and/or sent via the networked OCC database to the Oregon Cancer Center Data Manager on a monthly basis unless otherwise informed. List the Guardian of records: name, address, phone, facsimile number. 13.0 SPECIAL COMPANION STUDIES 13.1 Provide protocol number and title for any companion protocols, e.g. tumor or other tissue acquisition protocols for adjunct lab study, if applicable. 13.2 14.0 Describe rationale for any companion or adjunct studies, if applicable. SPECIAL INSTRUCTIONS Describe special samples, shared resources or other procedures including pathology review, etc. if applicable. For in-house protocols, areas of responsibility are defined. 15.0 ETHICAL AND REGULATORY CONSIDERATIONS Please add the entire section with modifications to section 15.6, Early Termination Criteria. 15.1 Monitoring Obligations OHSU Cancer Institute Data and Safety Monitoring Plan In addition to complete study and pharmacy files, complete records must be maintained on each patient treated on this protocol. OHSU Cancer Institute (OHSU CI), Clinical Research 1 Management (CRM) shared resource is responsible for ensuring that all member investigators and affiliate investigators conduct clinical research studies in compliance with local IRB standards, FDA regulations and NIH policies. The Data and Safety Monitoring Committee (DSMC) is responsible for conducting Quality Assurance audits on OHSU CI approved protocols according to the Data and Safety Monitoring Plan policies and procedures. Locally initiated studies will be audited by an OHSU CI DSMC audit team. Newly approved studies may be audited anytime after enrollment. Each OHSU CI approved protocol will be audited on an annual basis. The Quality Assurance audit process provides assurance that the reported data accurately reflects the data in the primary patient record. Central Coordination of Multicenter Studies OHSU central coordination of multi-center studies is the responsibility of the principal investigator. Coordinating Center (CC) activities are to include central registration recorded in the CRM database and central reporting of serious adverse events (SAEs.) The CC will prepare Quarterly Summary Reports of SAEs from all centers. The report will include the enrollment numbers. The Quarterly Summary Report will be submitted to CRM, OHSU IRB and each individual site's IRB. It is the responsibility of each site's principal investigator to ensure that the study is conducted in compliance with local IRB standards, FDA regulations and NIH policies. Data and Safety Monitoring at each site will be conducted according to their institution's policies and procedures. 15.1.2 Institutional Review Board (IRB) The protocol and informed consent form for this study must be approved in writing by the appropriate Institutional Review Board (IRB) prior to any patient being registered on this study. Institutional Review-IRB: This study must be approved by the appropriate Institutional Review Board as defined by Federal Regulatory Guidelines (Federal Register Volume 46, No. 17, January 27, 1982, part 56) and the Office for Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). Obligations of Investigators: All adverse events occurring during the study, whether or not attributed to the investigational drug / biotherapy, observed by the investigator or reported by the patient must be reported as specified in Section 16.0. 15.2 Informed Consent Written informed consent will be obtained from all patients, or the legally authorized representative of the patient, participating in this trial, as stated in the Informed Consent section of the case of Federal Regulations, Title 21, Part 50. If a patients signature cannot be obtained, and for all patients under the age of 18, the investigator must ensure that the informed consent is signed by the patients legally authorized representative. The original shall be maintained in the patients record. 1
The principles of informed consent are described by Federal Regulatory Guidelines, (Federal Register Volume 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). They must be followed to be in compliance with FDA and OPRR regulations for the conduct and monitoring of clinical investigations. 15.3 Changes to Protocol 15.3.1 Amendments Changes in any portion of this protocol that affect patient safety or that alter efficacy parameters, must be documented in the form of an amendment and signed by the appropriate study personnel, including clinical scientist, statistician and the investigator, and be approved by the CRRC and IRB, before the amendment may be implemented. The CRRC and IRB chairpersons may approve minor changes, or may designate one or more regulatory members to approve it. The only circumstance in which the amendment may be initiated without regulatory approval is for a change necessary to eliminate an apparent and immediate hazard to the patient. In that event, the investigator must notify the CRRC and IRB in writing within 10 working days after the implementation. 15.3.2 Administrative Changes Clarification or interpretation of the study protocol or changes in the methods of statistical analysis may be documented in the form of an administrative change. Administrative changes do not require the investigators signature nor CRRC or IRB approval. Administrative changes will be transmitted to the investigator and be provided to the CRRC and IRB for completeness. 15.4 Maintenance of Records The Investigator must maintain all study records for fifteen years. If the investigator relocates or for any reason withdraws from the study, the study records may be transferred to an agreeable designee, such as another institution, another investigator, or to the Oregon Cancer Center CRO. The investigator will obtain written consent from the CRRC and IRB before disposing of any study records. 15.5 Inclusion of Women And Minorities No OHSU Cancer Institute study will focus on any particular racial or ethnic subset. No subject will be excluded from the study on the basis of racial or ethnic origin. Male, female and minority volunteers will be recruited for this study from the general population and approximately 50% men and 50% women will be studied. The racial and ethnic composition of the study should represent that of the state of Oregon (see Table 1). If the prevalence of the disease being studied is consistent across race, ethnicity and gender, then these figures can be used to calculate projected enrollments in Table 2. If the disease being studied does not affect both genders or all races and ethnicities equally (e.g., cervical cancer only affects women and Black males are more likely than White males to have prostate cancer), then this information should be taken into account when calculating the projected enrollment. The OHSU General Clinical Research Center has links to various sources of statistics on their webpage at www.ohsu.edu/gcrc. If a different source is used in calculating projected enrollments, that source should be cited below Table 2. Table 1: Population Demographics - Oregon (%) 1
Ethnic Category
Females Hispanic or Latino Not Hispanic or Latino Ethnic Category: Total of all subjects* Sex/Gender
Males Total 8.0 92.0 100* Racial Category
American Indian or Alaskan Native Asian Black or African American Native Hawaiian or other Pacific Islander White More than one race Unknown/Other Racial Category: Total of all subjects* TOTALS 1.3 3.0 1.6 0.2 86.6 3.1 4.2 100* 50.4 49.6 100* Source: Adapted from U.S. Census Bureau, 2000 *Totals may not equal 100 due to rounding. Principal Investigators submitting proposals to the OHSU Cancer Institute must complete Table 2. The numbers within Table 2 should reflect the anticipated recruitment of subjects according to gender, race and ethnicity. Each subject should be entered into the table twice: once under an ethnic category and once under a racial category. Table 2: Projected Accrual for the Present Study (enter actual estimates, not percentages).
Ethnic Category
Females Hispanic or Latino Not Hispanic or Latino Unknown Ethnic Category: Total of all subjects* Males Sex/Gender
Unknown Total * Racial Category
American Indian or Alaskan Native Asian Black or African American Native Hawaiian or other Pacific Islander White More than one race Unknown 1
Ethnic Category
Females Racial Category: Total of all subjects* Males Sex/Gender
Unknown Total * *These totals must agree. Source: Adapted from U.S. Census Bureau, 2000 1.0 Inclusion of Children In accordance with NIH guidelines on the inclusion of children as participants in research involving human subjects, children under the age of 18 years must be included in all human subjects research, conducted or supported by the NIH, unless there are clear and compelling reasons not to include them. Therefore, proposals for research involving human subjects must include a description of plans for the inclusion of children Include one of these statements This protocol includes children. OR This protocol does not include children for the following reason: Enter reason here [Acceptable reasons for the exclusion of children from clinical research may be based on section 4b of the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects on the basis that the number of children with cancer is limited and because the majority are already accessed by a nationwide pediatric cancer research 15.6 Early Termination Criteria for early termination. Provided are examples listed as separate points. Disclosure of study termination will be made to the CRRC and IRB. 15.6.1 Voluntary patient withdrawal 15.6.2 Investigators decision that is in the patients best interest to withdrawal 15.6.3 Occurrence of a serious adverse event 15.6.4 If the patient becomes pregnant 15.6.5 If, in the opinion of the Investigator, laboratory values become abnormal to a clinically significant degree during the course of the study 15.6.6 Noncompliance 15.6.7 Significant protocol violation 15.6.8 For any reason, at the Sponsor or Investigators discretion 16.0 ADVERSE EVENTS OHSU IRB Reporting 1
The OHSU IRB defines an SAE as an event that is fatal, life-threatening, permanently disabling, requires inpatient hospitalization, is a congenital anomaly, the development of a new cancer, or an overdose. Reports must also contain any unexpected adverse experience that has not been previously observed in the Investigators Brochure whether or not it is serious. All deaths must be reported for intervention studies, regardless of cause of death. Fatal and life-threatening events will be reported to the IRB by email within 24 hours of notification of the event, indicating that a full report will follow. All SAE reports will be submitted no later than 10 days of occurrence or notification of the event using the VA/OHSU IRB SAE report form: http://www.ohsu.edu/ra/rso/irb/irbforms.htm SAE reports and supporting documents will be sent to: Clinical Research Management OHSU Cancer Institute, HRC 145 Oregon Health & Science University 3181 SW Sam Jackson Park Road Portland, OR 97201-3098 The SAE report will be reviewed and signed by a DSMC Oncologist. The SAE report will then be forwarded to IRB. Copies of the serious adverse event report will be kept on file in the Clinical Research Management office and in the study regulatory binder. MedWatch Reporting For this investigator-initiated study, the investigator is considered the sponsor. The investigator/sponsor is required to report adverse events to the FDA through the MedWatch reporting program, even if the trial involves a commercially available agent. Adverse events to be reported include any unexpected (not listed in the package label), life-threatening or fatal adverse event with an attribution of related. These adverse events will be reported to the FDA within 10 working days using a MedWatch form 3500 for voluntary reporting. MedWatch forms and instructions are available at www.fda.gov/medwatch MedWatch reports can be submitted online at https://www.accessdata.fda.gov/scripts/medwatch/ After the serious adverse event is reported to the FDA, copies of the MedWatch 3500 form and supporting materials will be submitted to the OHSU IRB with the OHSU/VA SAE report form and the OHSU Drug Information Service: Mailcode CR 9-4 or fax: 494-1096. A copy of the MedWatch 3500 form and supporting materials will be kept on file in the Clinical Research Management office and in the study regulatory binder. DEFINITIONS: The following terms are defined by the Food and Drug Administration, HHS 21 CFR 312.32: "Associated with the use of the drug" means that there is a reasonable possibility that the experience may have been caused by the drug. "Serious adverse experience" means any experience that suggests a significant hazard, contraindication, side effect, or precaution. With respect to human clinical experience, a serious adverse drug experience 1
includes any experience that is fatal or life-threatening, is permanently disabling, requires inpatient hospitalization, or is a congenital anomaly, cancer, or overdose. "Unexpected adverse experience" means any adverse experience that is not identified in nature, severity, or frequency in the current investigator brochure; or, if an investigator brochure is not required, that is not identified in nature, severity, or frequency in the risk information described in the general investigational plan or elsewhere in the current application, as amended. "Life-threatening" means that the patient was, in the view of the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more serious form, might have caused death. If Investigator hold the IND or for NIH CTEP protocols add special instructions. 17.0 REFERENCES List all references used to support protocol. 18.0 18.1 18.2 18.3 18.4 18.5 APPENDICES Appendix I: Appendix II: Appendix III: Appendix IV: Appendix V: Toxicity Criteria Schedule of Events Performance Criteria Scales Source Documents Staging Criteria 18.6 Appendix VI: Adverse Drug Reaction (ADR) Reporting form for Investigational New Drugs (1571). Please obtain from CRO. 18.7 Appendix VII: Adverse Drug Reaction (ADR) Reporting form for Commercial Drugs (3500). Please obtain from CRO. 18.8 18.9 Appendix VIII: Appendix IX: Acceptable Limits for Screening Laboratory Tests Informed Patient Consent 1 APPENDIX I - TOXICITY CRITERIA Toxicities and adverse events will be assessed using the NCI Common Toxicity Criteria (CTC) Version 2.0. Since CTEP has standardized the CTC, the NCI does not require the inclusion of the CTC within the protocol document. A copy can be downloaded from the CTEP home page http://ctep.info.nih.gov APPENDIX II: SCHEDULE OF EVENTS Sample
EVALUATION MONTHS 1 - 6 STUDY DISCONTINUATION Pre-Screen Evaluation & Procedures Informed Consent Inclusion / Exclusion Criteria Physical Exam Sitting Vital Signs Serum hCG CBC Chemistry Panel Adverse Events Concomitant Medications Screen Weekly Visits Monthly Visits Follow-Up Premature Discontinuation x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x 1 APPENDIX III - KARNOFSKY AND ECOG PERFORMANCE CRITERIA KARNOFSKY ACTIVITY Normal, no complaints SCORE % 100 ECOG GRADE ACTIVITY Fully active, able to carry on all predisease activities without restrictions Normal, only minor 90 0 signs/symptoms -----------------------------------------------------------------------------------------------------------------Normal activity, but 80 No physically strenuous requires effort activity, but ambulatory 1 and able to carry out light Unable to do active 70 or sedentary work (eg., work, but able to care office work, light house for self work -----------------------------------------------------------------------------------------------------------------Able to care for most 60 Ambulatory/capable of all needs, requires self-care, unable to occasional help perform any work activities 2 Up and about more than Requires frequent 50 50% of waking hours medical help and considerable assistance -----------------------------------------------------------------------------------------------------------------Disabled, needs special 40 Capable of only limited care and assistance 3 self-care, confined to bed needs hospitalization, death not imminent ------------------------------------------------------------------------------------------------------------------ 2 Very sick, hospitalized, 20 Completely disabled, active support needed 4 totally confined to bed or -----------------------------------------------------------------------------------------------------------------Dead 0 0 Dead