TEMPLATE INSTRUCTIONS



PROTOCOL TEMPLATE INSTRUCTIONS

The protocol template is a tool to facilitate protocol development. It is not intended to supersede the role of the Principal Investigator in the authoring and scientific development of the protocol. It contains the “boilerplate” language commonly required to be submitted to the WVUCI PRMC, NIH and external funding agencies. Content may be modified as necessary to meet the scientific aims of the study and development of the protocol.

The BLUE text is meant to provide instructions and examples, please delete the BLUE instructions and examples and replace them with protocol specific designs.

1. The main body and appendices of the protocol are attached below. This document provides standard language plus instructions and prompts for information.

2. The Protocol and Informed Consent Template documents should be completed, and all documents (including the Appendices) should be submitted to the PRMC or other protocol review committee for review.

3. All sections in the Protocol Template should be retained to facilitate rapid review. If not appropriate for a given study, please insert “Not Applicable” after the section number and delete unneeded text.

4. Please note that the Protocol Template has built-in styles for Heading Levels 1-3, Level 5 for the Appendix and Normal for body of text. (see image below).

These heading styles will automatically update the Table of Contents (TOC) and convert to Bookmarks in a final PDF protocol document. Please retain the heading styles.

5. To update the TOC in your protocol document:

• Right click somewhere in the table of contents, the entire TOC should be highlighted gray

• Click on Update Field

• Choose Update entire table

• Click OK

Please do not edit the TOC manually.

STUDY NUMBER: WVUXXXXXX

Number will be assigned by Cancer Center at time of PRMC Submission

Protocol Version Date:

STUDY TITLE: Full study title here (600 characters maximum)

PRINCIPAL INVESTIGATOR: A study can only have one Principal Investigator. Principle Investigators much be faculty members.

The Co-PI(s) refer to the physician(s) who will lead the study at non-lead institution(s).

Example: Joint Protocol with Institution Lead

PRINCIPAL INVESTIGATOR: Name of Physician, MD

Department

West Virginia University Cancer Institute

Mary Babb Randolph Cancer Center

1 Medical Center Drive

Morgantown, WV 26506

Telephone including area code

Email address

CO-PI: (if joint protocol) Name of Physician, MD

Department

Institution

Institution address

Telephone including area code

Email address

List co-investigators alphabetically by site in the following order:

Lead Institution

Joint Institution

*If this is a multi-institutional study, the protocol title page should include the name of each participating institution, the investigator responsible for the study at that institution, and his/her telephone # and e-mail address.

CO- INVESTIGATOR: Name of Physician, MD

Department

West Virginia University Cancer Institute

Mary Babb Randolph Cancer Center

1 Medical Center Drive

Morgantown, WV 26506

Telephone including area code

Email address

STATISTICIAN: Name of Statistician, degree

Name of Institution

Street Address

City, State, Zip code

Telephone including area code

Email address

STUDY COORDINATOR: Name of Lead Study Coordinator

Name of Institution

Street Address

City, State, Zip code

Telephone including area code

Email address

SPONSOR: WVU Cancer Institute Mary Babb Randolph Cancer Center / WV Clinical and Translational Institute

SUPPORT/FUNDING: List any support/grants or any funding source (partial or full) here

SUPPLIED AGENT(S): Name of supplied agents and supplier, if applicable

IND #: If applicable

OTHER AGENT(S): Name of other agents

SUMMARY OF CHANGES

Please provide a list of changes from the previous approved version of the protocol starting at IRB approval. This table will remain blank until initial IRB approval. The list shall be a brief overview. When appropriate, a brief justification for the change should be included. This is a running list for the life of the study.

|Protocol Date |Section |Change |

| | |Initial IRB approval |

| | |Summarize changes to first protocol amendment |

| | | |

| | | |

| | | |

STUDY SCHEMA

Please provide a visual schema for the study.

If preferred, a summary or synopsis may be provided.

Protocol Synopsis:

|Protocol Number/Title |Assigned protocol number/Title |

|Study Phase |Study phase |

|Brief Background/Rationale |Include: |

| |Why doing this study on this population with this drug. |

| |Incidence/burden |

|Primary Objective |Primary Endpoint(s) |

| |Endpoints: how it will be measured and at what time point. Do not use “end of study” or |

| |“at progression”. |

|Secondary Objective(s) |Secondary Endpoint(s) |

|Exploratory Objective(s) |Exploratory Endpoints (s) |

| |This is where exploratory research endpoints will go. For example, gathering preliminary|

| |data |

|Correlative Objective(s) |Correlative Endpoint(s) |

| |This is where correlative study objectives will go. Pharmacokinetics, Pharmacodynamics, |

| |and biomarkers, etc. |

|Sample Size |Number expected to accrue |

| |Age, gender |

|Disease sites/Conditions |ICD terminology |

|Interventions |Agent X, route, dose, cycle length, number of cycles |

| |Agent Y, route, dose, cycle length, number of cycles |

Abbreviations

|MBRCC |Mary Babb Randolph Cancer Center |

|CRF |Case Report Form |

|CTRU |Clinical Trials Research Unit |

|DSTC |Data Safety Toxicity Committee |

|FDA |Food and Drug Administration |

|ICF |Informed Consent Form |

|IRB |Institutional Review Board |

|PRMC |Protocol Review and Monitoring Committee |

|SOC |Standard of Care |

|WVUCI |West Virginia University Cancer Institute |

| |Please update table with relevant abbreviations used in the protocol |

| | |

| | |

| | |

TABLE OF CONTENTS

1. OBJECTIVE 6

1.1. Primary Objective 6

1.2. Secondary Objective(s) 6

1.3. Correlative Objective(s) 6

2. BACKGROUND 6

2.1. Background of Study Disease 6

2.2. Name and Description of Investigational Agent X 6

2.3. Name and Description of Investigational Agent Y 7

2.4. Name and description of Other Agent(s) (if applicable) 7

2.5. Rationale 7

2.6. Background and rationale of correlative studies 7

3. STUDY DESIGN 7

3.1. Study design including dose escalation / cohorts 7

3.2. Number of Subjects 7

3.3. Replacement of Subjects 8

3.4. Expected Duration of Treatment and Subject Participation 8

4. SUBJECT SELECTION AND REGISTRATION 8

4.1. Inclusion Criteria 9

4.2 Exclusion Criteria 10

4.3 Inclusion of Women and Minorities 11

4.2. Registration 11

5. TREATMENT PLAN AND/OR IMAGING PLAN 12

5.1. Name of Investigational Agent Administration 13

5.2. Phase I Dose Escalation 13

5.3. Definition of Dose-Limiting Toxicity 14

5.4. Name of Standard of Care (SOC) Agent(s) Administration 14

5.5. Name of Other Modality(s) or Procedures 14

5.6. General Concomitant Medications and Supportive Care Guidelines 15

5.7. Duration of Therapy 15

5.8. Duration of Follow Up 16

5.9. Criteria for Removal from Study 16

6. DOSE DELAYS/DOSE MODIFICATIONS 16

7. ADVERSE EVENTS 17

7.1. Definitions 17

7.2. Adverse Event Evaluation 19

7.3. Adverse Event Reporting Procedures 21

7.4. Serious Adverse Event Reporting Procedures 21

7.5. SAEs and OnCore 21

7.6. Data Safety and Toxicity Committee 22

7.7. Data and Safety Monitoring Plan (DSMP) 22

8. PHARMAPEUTICAL OR IMAGING INFORMATION 22

8.1. Investigational Agents 22

8.2. Commercial Agent 24

9. CORRELATIVE AND SPECIAL STUDIES 25

9.1. Name of Exploratory or Correlative study #1 26

9.2. Name of Exploratory or Correlative study#2 28

10. STUDY PARAMETERS AND CALENDAR 28

10.1. Study Parameters 28

10.2. Study Calendar 31

11. MEASUREMENT OF EFFECT 35

11.1. Antitumor Effect – Solid Tumors 35

11.2. Response Criteria 39

11.3. Antitumor Effect – Hematologic Tumors 42

11.4. Other Response Parameters 42

12. DATA REPORTING / REGULATORY CONSIDERATIONS 42

12.1. Data Reporting 43

12.2. Regulatory Considerations 43

13. STATISTICAL CONSIDERATIONS 45

13.1. Study Design/Endpoints 45

13.2. Sample Size/Accrual Rate 45

13.3. Stratification Factors 46

13.4. Analysis of Secondary Endpoints 46

13.5. Methods for Analysis 46

13.6. Safety Analysis 46

13.7. REFERENCES 47

14. APPENDICES 48

Appendix 1 48

OBJECTIVE

Describe the overall objectives and purpose of the study, keeping in mind that objectives must be measurable.

Records to be kept should capture the measurement. Study parameters (calendar) should indicate when captured.

1 Primary Objective

It is preferable to have only one primary objective and primary endpoint. What scientific question are you trying to answer?

2 Secondary Objective(s)

3 Correlative Objective(s)

BACKGROUND

1 Background of Study Disease

Please provide background, incidence, and treatment information on the study disease.

Please be specific in the title for disease specific studies.

Example: “Advanced Biliary Cancers” versus “Advanced Cancers”

2 Name and Description of Investigational Agent X

1 Preclinical Data

Provide background and brief information for agent X. Include any animal studies, the explanation of the mechanism of action, and any preclinical data about the agent or treatment.

2 Clinical Data

Summarize the available clinical study data with relevance to the protocol under development. If none is available, include a statement that there is no available clinical research data to date on the investigational product.

3 Clinical Pharmacokinetics (if applicable)

Add metabolism, molecular formula and classification information here if available.

3 Name and Description of Investigational Agent Y

Note: Section is repeated for each investigational agent as applicable to protocol.

1 Preclinical Data

2 Clinical Data

3 Clinical Pharmacokinetics

4 Name and description of Other Agent(s) (if applicable)

Please provide background information on other agent(s) and/or treatments in this study, including information to support safety issues and the rationale for the proposed starting dose and dose escalation scheme, if applicable.

1 Preclinical Data

2 Clinical data

3 Clinical Pharmacokinetics

5 Rationale

Please provide the background and rationale for evaluating this (combination) therapy in this disease. Include the rationale for the proposed starting doses and dose escalation scheme as well as route of administration and dosage period.

6 Background and rationale of correlative studies

Please provide the background and rationale for correlative studies and exploratory endpoints.

STUDY DESIGN

Please provide an overview of the study design and the rationale for this type of design.

1 Study design including dose escalation / cohorts

This section should include: the type of trial design of the study, stages, cohort information, how subjects will be randomized and if there are plans to use a placebo.

2 Number of Subjects

Provide the number of subjects that will be included in the study using a sentence format.

Example: Approximately 50 subjects will be enrolled in this trial.

Example if more than one phase: Approximately 50 subjects will be enrolled in this trial. Approximately 15 will be enrolled in the phase I part and 35 in the phase II part.

3 Replacement of Subjects

The replacement of subjects is protocol specific and needs to be tailored to the trial.

Example: If Oral Drug is to be taken 21 out of 21 days and this is not met:

Example: If a subject does not take at least 17 doses in the first cycle, the subject will be replaced because he/she has not taken enough drug to confirm safety at that dose level.

4 Expected Duration of Treatment and Subject Participation

Please provide a brief summary of the length of treatment period, plus the length of follow up period and any study windows that are applicable. Please provide length of each cycle, minimum and maximum number of cycles. If treatment can continue until disease progression (i.e. no maximum number of cycles), please indicate here. If clinical benefit is not likely until after a certain number of cycles, specify that here.

Treatment duration may be modified per section ___.

SUBJECT SELECTION AND REGISTRATION

Each of the criteria in the sections that follow must be met in order for a subject to be considered eligible for this study. Use the eligibility criteria to confirm a subject’s eligibility.

Patient’s Name _______________________________________________________

Medical Record # ____________________________________________________

Research Nurse /

Study Coordinator Signature:____________________________ Date __________

Treating Physician [Print] ______________________________________________

Treating Physician Signature:

__________________________________________ Date _______________

1 Inclusion Criteria

Inclusion Criteria must describe the subject population that you want to include in the study.

Create a numbered list of criteria applicable to the protocol that subjects must meet to be eligible for study enrollment.

Subjects must meet all of the following inclusion criteria to be eligible for enrollment:

Below are common examples: Edit per protocol

____ 4.1.1 Subjects must have histologically or cytologically confirmed Name of Disease.

Please specify eligible disease(s)/stage(s)/prognostic score(s) as well as if staging is pathological or clinical.

___ 4.1.2 Subjects must have received (no, no more than X) prior therapies for this disease.

**If applicable, provide guidance on what constitutes a prior line of therapy, how to count prior lines of therapy and breaks in therapy.

____ 4.1.3 Age >18 years. Please state reason for age restriction.

If applicable, the following text can be used;

“Because no dosing or adverse event data are currently available on the use of ______ in combination with _______ in subjects ≤18 years of age, children are excluded from this study.”

____ 4.1.4 Performance status _____ [See Appendix __].

Choose one method (not both):

Example: ECOG Performance status ≤ 2

Example: Karnofsky Performance status ≥ 60%

____ 4.1.5 Subjects must have normal organ and marrow function as defined below: Add time frame if applicable.

Please review for relevance to the specific study and modify.

Example:

• Hemoglobin ≥ 10.0 g/dl

• Leukocytes ≥ 3,000/mcL

• Absolute neutrophil count ≥ 1,500/mcL

• Platelet count ≥ 100,000/mcL

• Total bilirubin within normal institutional limits

• AST (SGOT) ≤ 2.5 X institutional upper limit of normal

• ALT (SGPT) ≤ 2.5 X institutional upper limit of normal

• Serum Creatinine within normal institutional limits

____ 4.1.6 Please insert other appropriate eligibility criteria.

____ 4.1.7 Subjects must have the ability to understand and the willingness to sign a written informed consent document.

4.2 Exclusion Criteria

Exclusion Criteria must describe the subject population that you do NOT want to include in the study.

Create a numbered list of criteria applicable to the protocol that would exclude a subject from study enrollment.

The presence of any of the following will exclude a subject from study enrollment.

Below are common examples: Edit per protocol or see further examples hyperlinked above.

____ 4.2.1 Prior treatment toxicities resolved to ≤ Grade X according to NCI CTCAE Version 5.0 (list exceptions, e.g. alopecia, neuropathy, etc).

____ 4.2.2 Subjects receiving any other investigational agents.

____ 4.2.3 To be included if applicable to protocol. Suggested text is provided below:

Subjects with untreated brain metastases/CNS disease will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

____ 4.2.4 History of allergic reactions attributed to compounds of similar chemical or biologic composition to Agent X or other agents used in this study.

Please state appropriate exclusion criteria relating to concomitant medications or substances that have the potential to affect the activity or pharmacokinetics of the study agent(s).

____ 4.2.5 Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

The investigator must state a medical or scientific reason if pregnant or nursing subjects will be excluded from the study.

Suggested text is provided below:

____ 4.2.6 Pregnant or breastfeeding are excluded from this study because Agent X is Name of Agent Class agent with the potential for teratogenic or abortifacient effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with Agent X, breastfeeding should be discontinued if the mother is treated with Agent X. These potential risks may also apply to other agents used in this study.

____ 4.2.7 Insert other appropriate agent-specific exclusion criteria.

4.3 Inclusion of Women and Minorities

Make sure you include the appropriate verbiage for the subject population.

Both men and women of all races and ethnic groups are eligible for this trial. It is the policy of the West Virginia University Cancer Institute to strive for gender and minority patient participation that represents the population of West Virginia in all clinical investigations. Between January 2017 and December 2017, 248 patients were enrolled onto clinical trials at the West Virginia University Cancer Institute.  Of these patients 62% percent were female and 3% percent were members of minority ethnic groups.  It is anticipated that a similar or greater proportion of patients on this study will be female and/or members of ethnic minorities. It is important to recognize that according to the 2014 US Census Bureau (available at ) that the State of West Virginia minority ethnic group (e.g., not limited to African American and Hispanic) population is 3.6% Black (national average 13.2%) and 1.5% Hispanic (national average 17.4%).  The majority of Black West Virginians live in the central and southern part of the state and Gilmer County is the only county in WV whose Black population approaches the national average.

4 Registration

At the point of registration, the study coordinator will complete registration in the OnCore database, including demographic, consent and on-study information.

The patient will be assigned a unique sequence number for the study prior to the initiation of the study treatment.

For those subjects who are consented, but not enrolled, the reason for exclusion must be recorded.

All source documents that support eligibility, signed informed consent/HIPAA and signed eligibility checklist must be available for review and verification by the quality coordinator prior to starting therapy.

If the trial is randomized the method of randomization should be stated as well as the proportion of subjects that will be accrued to each dose level.

Example: Subjects will be assigned to either [Name of Study Agent] or [Name of Study Agent + Name of Study Agent] based on the randomization lists prepared by the WVU WVUCI Biostatistics Core. Randomization will be stratified by: EXAMPLES: performance status (0-1 vs. 2) and smoking status (ever vs. never lifetime). This is a 1:1 randomization.

TREATMENT PLAN AND/OR IMAGING PLAN

Describe the treatment regimen planned. If there are different cohorts, label each cohort and appropriate treatment schedule:

• Pre-medications allowed/required/suggested (if applicable)

• Agent(s)

• Dose(s)

• Route of administration

• Treatment schedule

• Treatment duration

Please provide separate regimen descriptions for different treatment groups of subjects as necessary.

The investigator must include the following statement if treatment is required to be administered only on an inpatient basis: Treatment must be administered only on an inpatient basis.

Appropriate dose modifications for Name of Investigational Agent(s) and Name of Other Agent(s) are described in Section 7.0.

Reported adverse events and potential risks of Name of Investigational Agent(s) and Name of Other Agent(s) are described in Section 7.0.

No investigational or commercial agents or therapies other than those described below may be administered with the intent to treat the subject's malignancy.

1 Name of Investigational Agent Administration

In addition to a dosing schema, please add a narrative description of the investigational agent administration.

Investigational Agent Administration

Example:

Subjects will receive Agent X ___ mg/m2 on Days 1-3 of each (28 day) cycle. Agent X will be administered IV over 2 hours.

Example:

Subjects will receive Agent Y ___ mg/m2 by IV on Day 1 of each 21-day cycle. Prior to each treatment, pre-hydrate with at least 1000 ml normal saline and use diuretics per institutional guidelines.

Example:

Subjects will receive Agent Z ____mg/m2 by IV on days 1, 2, and 3 of each 21-day cycle.

Please add subsequent sections for additional investigational agents.

2 Phase I Dose Escalation

(if applicable)

Dose escalation will proceed within each cohort according to the following scheme. Dose-limiting toxicity (DLT) is defined in section 6.3.

|Number of Subjects with DLT at a Given Dose Level|Escalation Decision Rule |

|0 out of 3 |Enter 3 subjects at the next dose level. |

|1 out of 3 |Enter 3 more subjects at this dose level. |

| |If 0 of these 3 subjects 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 subjects will be entered at the next lowest dose level if only|

| |3 subjects were treated previously at that dose. |

|>2 |Dose escalation will be stopped. This dose level will be declared the |

| |maximally administered dose (highest dose administered). Three (3) |

| |additional subjects will be entered at the next lowest dose level if only|

| |3 subjects were treated previously at that dose. |

| ................
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