MCC Protocol #: / FDA IND #:
Principal Investigator/Study Chair/Coordinating Center/Sponsor-Investigator: / IND Sponsor:
Subinvestigator/Responsible Investigator: / Subinvestigator/Responsible Investigator:
Subinvestigator/Responsible Investigator: / Subinvestigator/Responsible Investigator:
Subinvestigator/Responsible Investigator: / Subinvestigator/Responsible Investigator:
Subinvestigator/Responsible Investigator: / Subinvestigator / Responsible Investigator:
Biostatistician: / Responsible Research Nurse:
Funding Sponsor: / Funding Sponsor:
Investigational Agent(s):
Version #: / Version Date:
Protocol Summary
Title:Protocol Number:
IND Sponsor:
Principal Investigator /Study Chair/Coordinating Center/Sponsor-Investigator:
Study Sites:
Clinical Trial Phase:
Study Disease:
Main Eligibility Criteria:
Primary Objectives:
Secondary Objectives:
Endpoints:
Study Design:
Study Agent/Intervention Description:
Number of Subjects:
Subject Participation Duration:
Estimated Time to Complete Enrollment:
Statistical Methodology:
SCHEMA
Revision History
Revision history is presented in reverse order so that the information pertaining to the most current version of the protocol is presented first in this section.
Version 1, Version Date MM/DD/YYYY
Initial submission of the protocol.
TABLE OF CONTENTS
Protocol Summary 2
SCHEMA 3
Revision History 4
TABLE OF CONTENTS 5
List of Abbreviations 7
1 background 8
1.1 Study Disease 8
1.2 Investigational Agent(s) 8
1.3 Other Agents 8
1.4 Correlative Studies Background 8
2 objectives 8
2.1 Primary Objectives 8
2.2 Secondary Objectives 8
3 STUDY DESIGN 8
3.1 General Description 8
3.2 Primary Endpoint(s) 9
3.3 Secondary Endpoint(s) 9
4 patient selection 9
4.1 Inclusion Criteria 9
4.2 Exclusion Criteria 9
5 study entry and withdrawal procedures 9
5.1 Study Entry Procedures 9
5.2 Study Withdrawal Procedures 9
6 Treatment plan 10
6.1 Baseline Tests and Procedures 10
6.2 Investigational Agent Administration 10
6.3 Definition of DLT and MTD 10
6.4 Additional Treatment Modalities 11
6.5 General Concomitant Medication and Supportive Care Guidelines 11
6.6 Duration of Therapy 11
6.7 Monitoring Subject Compliance 11
6.8 Follow-Up Period 11
7 dosing delays/dose modifications 11
8 adverse events: Definitions and reporting requirements 12
8.1 Definitions 12
8.2 Known AEs List 14
8.3 Time Period and Grade of AE Capture 14
8.4 Procedures for Recording AEs, SAEs, and UPs 14
8.5 Routine Reporting Procedures for AEs 14
8.6 Expedited Reporting Procedures for SAEs, SARs, UPs, and DLTs 14
9 pharmaceutical information 16
9.1 Agent #1 16
10 measurement of effect 17
10.1 Anti-tumor Effect 17
10.2 Other Response Parameters 17
11 correlative studies/Special Studies 18
11.1 Laboratory Correlative #1 18
11.2 Laboratory Correlative #2 18
11.3 Shipping Instructions 18
12 study calendar 18
13 statistical considerations 18
13.1 Study Design and Analysis 18
13.2 Sample Size/Accrual Rates 18
13.3 Stratification Factors 18
13.4 Analysis of Secondary Endpoints 18
14 Data and Safety Monitoring Plan (DSMP) 18
14.1 Study Team 18
14.2 Audit Committee 19
14.3 DSMB 19
15 regulatory compliance and ethics 19
15.1 Ethical Standard 19
15.2 Regulatory Compliance 19
15.3 Institutional Review Board 19
15.4 Informed Consent Process 19
15.5 Subject Confidentiality and Access to Source Documents/Data 20
16 data handling and record keeping 20
16.1 Data Management Responsibilities 20
16.2 Source Documents 21
16.3 Case Report Forms (or other appropriate title to reflect the study-specific manner in which protocol-specific data will be recorded) 21
16.4 Study Record Retention 21
17 references 22
18 appendix 1. Insert title here. 23
19 informed consent template 24
MCC Protocol #: 1 Version #:
IND #: Version Date: MM/DD/YYY
List of Abbreviations
1 background
1.1 Study Disease
1.2 Investigational Agent(s)
1.2.1 Preclinical Data
1.2.2 Clinical Data
1.2.3 Known and Potential Risks and Benefits
1.2.4 Rationale
1.3 Other Agents
1.4 Correlative Studies Background
2 objectives
2.1 Primary Objectives
2.2 Secondary Objectives
3 STUDY DESIGN
3.1 General Description
3.2 Primary Endpoint(s)
3.2.1
3.3 Secondary Endpoint(s)
3.3.1
4 patient selection
4.1 Inclusion Criteria
A potential subject must meet all of the following inclusion criteria to be eligible to participate in the study.
4.1.1
4.1.2 Ability to understand and the willingness to sign a written informed consent document.
4.2 Exclusion Criteria
A potential subject who meets any of the following exclusion criteria is ineligible to participate in the study.
4.2.1
5 study entry and withdrawal procedures
5.1 Study Entry Procedures
5.1.1 Required Pre-Registration Screening Tests and Procedures
Refer to section 11, STUDY CALENDAR, for the screening tests and procedures that are required prior to registration, and for the timing of these events relative to the start of treatment. (sample language)
5.1.2 Registration Process
5.2 Study Withdrawal Procedures
5.2.1 A patient may decide to withdraw from the study at any time.
5.2.2 A patient may be removed from treatment for one of the following criteria: (The 2 broad categories are as follows, although the first is frequently made more specific as indicated below.)
5.2.2.1 If in the opinion of the treating physician, it is in the best interest of the patient to do so. (This is a generic statement that some investigators prefer. You may want to include more specific criteria such as (i) unwillingness or inability of the patient to comply with the protocol requirements; (ii) disease progression; (iii) intercurrent illness that prevents further administration of treatment; (iv) unacceptable adverse events (AE[s]); and (v) general or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator.)
5.2.2.2 Sponsor’s decision to discontinue the study.
5.2.3 The reason for withdraw from the study and the date the patient was removed from the study must be documented in the case report form (eCRF/CRF [choose one]).
6 Treatment plan
6.1 Baseline Tests and Procedures
6.2 Investigational Agent Administration
6.3 Definition of DLT and MTD
Management and dose modifications associated with the above AEs are outlined in section 7, DOSING DELAYS/Dose modifications.
Dose escalation will proceed within each cohort according to the following scheme. DLT is defined above.
Number of Patients with DLT at a Given Dose Level / Escalation Decision Rule0 out of 3 / Enter 3 patients at the next dose level.
2 / Dose escalation will be stopped. This dose level will be declared the maximally administered dose (highest dose administered). Three (3) additional patients will be entered at the next lowest dose level if only 3 patients were treated previously at that dose.
1 out of 3 / Enter at least 3 more patients at this dose level.
· If 0 of these 3 patients experience DLT, proceed to the next dose level.
· If 1 or more of this group suffer DLT, then dose escalation is stopped, and this dose is declared the maximally administered dose. Three (3) additional patients will be entered at the next lowest dose level if only 3 patients were treated previously at that dose.
1 out of 6 at highest dose level below the maximally administered dose / This is generally the recommended phase 2 dose. At least 6 patients must be entered at the recommended phase 2 dose.
6.4 Additional Treatment Modalities
6.5 General Concomitant Medication and Supportive Care Guidelines
6.6 Duration of Therapy
6.7 Monitoring Subject Compliance
6.8 Follow-Up Period
Patients will be followed for # weeks/months/years after removal from the study treatment or until death, whichever occurs first. Patients removed from the study treatment for unacceptable AEs will be followed until resolution or stabilization of the adverse event.
7 dosing delays/dose modifications
8 adverse events: Definitions and reporting requirements
8.1 Definitions
8.1.1 Adverse Event (AE)
AE means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.
8.1.2 Suspected Adverse Reaction (SAR)
Any AE for which there is a reasonable possibility that the drug caused the AE. “Reasonable possibility” means that there is evidence to suggest a causal relationship between the drug and the AE.
An AE with an attribution of possible, probable, or definite (see section 8.3.3 below) is a SAR.
8.1.3 Serious AE (SAE) or Serious SAR (SSAR)
An AE or SAR 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 AE (An AE or SAR is consider “life-threatening” if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an AE or SAR that, had it occurred in a more severe form, might have caused death.),
· 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 subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.4 Unexpected SAR
A SAR 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, as amended.
· “Unexpected” as used in this definition, also refers to SARs 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.
8.1.5 Unanticipated Problem (UP)
Unanticipated problems include any incident, experience, or outcome that meets all of the following criteria:
· unexpected (in terms of nature, severity, frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied;
· related or possibly related to participation in the research (possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and
· suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.
8.1.6 AE Description and Grade
The descriptions and grading scales found in the revised Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.
8.1.7 AE Expectedness
AEs can be ‘Unexpected’ or ‘Expected’.
Expected AEs are listed in section 8.2 below.
Unexpected AEs are those AEs occurring in one or more subjects participating in the research protocol, the nature, severity, or frequency of which is not consistent with either:
· The known or foreseeable risk of AEs associated with the procedures involved in the research that are described in (a) the protocol-related document, such as the IRB-approved research protocol, any applicable investigator brochure, and the current IRB-approved informed consent document, and other relevant sources of information, such as product labeling and package inserts; or
· The expected natural progression of any underlying disease, disorder, or condition of the subject(s) experiencing the AE and the subject’s predisposing risk factor profile for the AE.
8.1.8 AE Attribution
· Definite – The AE is clearly related to the study treatment.
· Probable – The AE is likely related to the study treatment.
· Possible – The AE may be related to the study treatment.
· Unlikely – The AE is doubtfully related to the study treatment.
· Unrelated – The AE is clearly NOT related to the study treatment.
8.2 Known AEs List
8.3 Time Period and Grade of AE Capture
8.4 Procedures for Recording AEs, SAEs, and UPs
8.5 Routine Reporting Procedures for AEs
8.6 Expedited Reporting Procedures for SAEs, SARs, UPs, and DLTs
The following table should be used for phase 1 trials with DLT reporting requirements:
Expedited Reporting Requirements (Events, Report Recipients, and Time Frames)SAEs / UPs / SARs / DLTs
Sponsor/
Sponsor-Investigator1 / Sponsor/
Sponsor-Investigator1 / FDA3 / ___ CRA/CRN or other as specified4
Principal Investigator/Study Chair/Coordinating Center1 / Principal Investigator/Study Chair/Coordinating Center1 / Other5
Other5 / DSMB1 / Other5
IRB2
Other5
1 Report event within 5 business days of becoming aware of the occurrence.
2 VCU only study: Each UP must be reported to the VCU IRB within 5 business days of becoming aware of the occurrence. The report must be prepared using the “VCU IRB PROMPT REPORTING FORM,” found on the VCU IRB Forms Page.
or
For multi-institutional studies: VCU Investigators: Each UP, including those occurring at non-VCU sites, must be reported to the VCU IRB within 5 business days of becoming aware of the occurrence. The report must be prepared using the “VCU IRB PROMPT REPORTING FORM,” found on the VCU IRB Forms Page.
Non-VCU Investigators: Participating sites other than VCU should report AEs and UPs to their respective IRBs according to their local institutional guidelines.
3 The sponsor OR sponsor-investigator (select one) will report to the FDA any:
· SARs that are both serious and unexpected within 15 days of determining that the information is reportable.
· clinically important increase in the rate of SSARs within 15 days of determining that the information is reportable.
· unexpected fatal or life-threatening SARs within 7 days of receipt of the information.
4 Report event within 1 business day of becoming aware of the occurrence. Receipt of reports is confirmed. If confirmation is not received within one working day, the coordinating center should be called by telephone (804- - ).
5 Used for any required reporting to other entities (such as a collaborating company, when that entity/company is not an FDA-defined Sponsor). This section should be deleted if not needed..
Sponsor/Sponsor-Investigator / Principal Investigator/Study Chair/Coordinating Center
Massey Cancer Center DSMB
FAX: 804-828-5406
E-mail: / CRA/CRN or other as specified
Other
The following table should be used for protocols that do not have DLT reporting requirements.
Expedited Reporting Requirements (Events, Report Recipients, and Time Frames)SAEs / UPs / SARs
Sponsor/
Sponsor-Investigator1 / Sponsor/
Sponsor-Investigator1 / FDA3
Principal Investigator/Study Chair/Coordinating Center1 / Principal Investigator/Study Chair/Coordinating Center1 / Other4
Other4 / DSMB1
IRB2
Other4
1 Report event within 5 business days of becoming aware of the occurrence.
2 VCU only study: Each UP must be reported to the VCU IRB within 5 business days of becoming aware of the occurrence. The report must be prepared using the “VCU IRB PROMPT REPORTING FORM,” found on the VCU IRB Forms Page.
or
For multi-institutional studies: VCU Investigators: Each UP, including those occurring at non-VCU sites, must be reported to the VCU IRB within 5 business days of becoming aware of the occurrence. The report must be prepared using the “VCU IRB PROMPT REPORTING FORM,” found on the VCU IRB Forms Page.
Non-VCU Investigators: Participating sites other than VCU should report AEs and UPs to their respective IRBs according to their local institutional guidelines.
3 The sponsor OR sponsor-investigator (select one) will report to the FDA any:
· SARs that are both serious and unexpected within 15 days of determining that the information is reportable.
· clinically important increase in the rate of SSARs within 15 days of determining that the information is reportable.
· unexpected fatal or life-threatening SARs within 7 days of receipt of the information.
4 Used for any required reporting to other entities (such as a collaborating company, when that entity/company is not an FDA-defined Sponsor). This section should be deleted if not needed..
Sponsor/Sponsor-Investigator / Principal Investigator/Study Chair/Coordinating Center
Massey Cancer Center DSMB
FAX: 804-828-5406
E-mail: / Other
9 pharmaceutical information