Dana–Farber/Harvard Cancer Center



DF/HCC RADIATION PROTOCOL TEMPLATE

Version Date: January 31st, 2020

[Replaces version Date: July 17th, 2015]

INSTRUCTIONS FOR INVESTIGATOR-WRITTEN PROTOCOLS

This template contains DF/HCC recommended language for radiation protocol development. It was derived from federal requirements, NCI guidance documents, DF/HCC policies and operations, and Good Clinical Practice guidelines. The template contains the “boilerplate” language commonly required in protocols submitted to NCI. Content may be modified as necessary to meet the scientific aims of the study and development of the protocol. Much of the formatting is needed for electronic submission of the protocol to NCI or to the FDA and should not be changed.

All protocols submitted to the Office for Human Research Studies (OHRS) must be submitted using the most current template version. Any protocols drafted after this date must be submitted on this current template or at a minimum include all relevant changes found in “Radiation Protocol Template Log” posted on the OHRS website. Review of your protocol may be delayed if it is not submitted on the correct DF/HCC protocol template.

1. Main Body and Appendices of the protocol: attached below. This document provides standard language plus instructions and prompts for information.

2. The Protocol Template documents should be completed, and all documents (including the Appendices) should be submitted for review.

Please note that additional requirements exist for protocol and informed consent documents intended for electronic submission to NCI. For protocol amendments a Summary of Changes should be provided as the first page (page i) of the document, as indicated in the template. The Summary of Changes must provide hyperlinks to the area referenced in the protocol or informed consent document.

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. All Protocol Template instructions and prompts are in blue italics. As you complete the information requested, please delete the blue italicized text.

5. Please note that the Protocol Template has built-in styles for headings levels 1-4 (Level 1 Heading – Level 4 Heading; see image below). Please avoid or limit the use of heading level 4 or more.

[pic]

These heading styles will automatically update the Index and convert to Bookmarks in a final PDF protocol document. Please retain the heading styles.

6. Before updating the Index, please ensure that the Title Page is page 1 of the protocol. For any pages preceding it (i.e., Summary of Changes) use alternative numbering (i, ii, iii, iv, … ).

7. To update the Index in your protocol document:

2007 & 2010 MS Word

a. On the References tab, in the Table of Contents group, click Update Table.

[pic]

b. Click Update entire table.

2003 MS Word

a. Click the index.

b. Press F9.

Please do not edit the Index manually.

8. Do not submit MS Word files that:

• are read-only

• are password protected

• contain macros

• are saved with a file extension other than .doc (Word 2003) or .docx (Word 2007/10)

9. For problems or questions encountered when using this document:

• Contact your Disease Program Leader if questions arise in the creation of the protocol.

• Seek guidance from Biostatistics, Pharmacy, Nursing, etc. as appropriate.

• Direct protocol format issues to the Office for Human Research Studies (OHRS) by email (OHRS@dfci.harvard.edu).

SUMMARY OF CHANGES

Retain this page for all protocol documents intended for electronic submission to NCI. You will need it for subsequent submissions, including amendments. Otherwise this page should be deleted.

For Protocol Amendment # to:

NCI Protocol #:

DF/HCC Protocol #:

NCI Version Date:

Protocol Date:

Please provide a list of changes from the previous NCI approved version of the protocol. The list should identify by page and section each change made to a protocol document with hyperlinks to the section in the protocol document. All changes should be described in a point-by-point format (i.e., Page 3, section 1.2, replace ‘xyz’ and insert ‘abc’). When appropriate, a brief justification for the change should be included.

|# |Section |Page(s) |Change |

|1. | | | |

|2. | | | |

|3. | | | |

|4. | | | |

|5. | | | |

NCI Protocol #: Assigned by the NCI. If not appropriate for this protocol, insert “Not Applicable” or “N/A.”

DF/HCC Protocol #: [YY-###]

Assigned by the Office for Human Research Studies (OHRS) after submission for SRC and IRB review.

TITLE: Full title required. Include phase and drug NSC number(s) if applicable.

Use Simplified Disease Classification (SDC) terminology for study disease. Please refer to the CTEP Web site () for a complete list of SDC disease terms.

Sponsor-Investigator:

Name

Institution

e-mail address

*Principal Investigators (PI): Name

Institution

Address- NCI protocols only

Telephone – NCI protocols only

Fax – NCI protocols only

e-mail address

Name

Institution

Address- NCI protocols only

Telephone – NCI protocols only

Fax – NCI protocols only

e-mail address

Name

Institution

Address- NCI protocols only

Telephone – NCI protocols only

Fax – NCI protocols only

e-mail address

* Note: Each participating site must have a PI who is responsible for study conduct and oversight at their institution. For drug, device, and imaging studies, PIs must be physicians Please refer to the NCI Investigator's Handbook for a complete description of the Principal Investigator's responsibilities ().

The PI and all attending physicians responsible for participant care must have a current Form FDA 1572, Supplemental Investigator Data Form (SIDF), Financial Disclosure Form (FDF), and CV on file with the NCI. Failure to register all appropriate individuals could delay protocol approval. If you are unsure of an investigator's status, please contact the Quality Assurance Office for Clinical Trials by e-mail at QACT@. Please indicate, on the title page, if an Associate Investigator is NOT responsible for patient care and therefore does not require a current 1572, SIDF, FDF, and CV on file.

If this is an NCI multi-institution 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 phone # and e-mail address. (This requirement does not apply to non-NCI studies.)

If this study includes an investigational agent supplied by the NCI Division of Cancer Treatment and Diagnosis and will involve a Canadian institution(s), a Clinical Trials Application (CTA) will need to be submitted to the Canadian Health Products and Food Branch (HPFB) for their participation in the study. A Canadian investigator should be designated to be responsible for preparing and submitting the CTA to the Canadian HPFB for the Canadian institution(s). Procedures and forms for preparing and submitting a CTA to the Canadian HPFB are available at . A copy of the “No Objection” letter should be forwarded to the Pharmaceutical Management Branch at PMBAfterHours@mail. when available.

If this is an NCI study, the protocol title page should include the name of the Responsible Study Coordinator, Research Nurse, and Data Manager along with their institution, phone and fax # and e-mail address. (This requirement does not apply to non-NCI studies.)

Statistician: Study Coordinator:

(if applicable) (if applicable)

Name Name

Institution Institution

Address – NCI protocols only Address

Telephone – NCI protocols only Telephone

Fax – NCI protocols only Fax

e-mail address e-mail address

Responsible Research Nurse: Responsible Data Manager:

(if applicable) (if applicable)

Name Name

Institution Institution

Address Address

Telephone Telephone

Fax Fax

e-mail address e-mail address

Please list all agents and their suppliers in the fields below, including any imaging agents. “Supplier” is defined as the entity that provides the clinical supply of the agent.  If the agent is purchased through commercial sources, then please mark supplier as “commercial”.

NCI-Supplied Agent(s): [Agent Name and NSC #]

Other Agent(s): [Agent Name, NSC # (if applicable), and Supplier]

Below, please describe the IND Status of this study by choosing IND #/Sponsor OR Exemption from IND requirements, making sure to delete the inapplicable field(s).

IND #: [Enter the # of the IND under which this study will be performed. Enter “TBD” if an IND # is not yet available.]

IND Sponsor: [Enter the name of the IND holder. If this study is being conducted under an IND sponsored by NCI, then enter “DCTD, NCI”. If this is solely an imaging study and is to be conducted under a CIP IND, then enter “Cancer Imaging Program, NCI”]

OR

Study Exempt from IND Requirements per 21 CFR 312.2(b).

If an IDE is not applicable to this study, then please delete the following fields (IDE #, IDE Sponsor, Device Name):

IDE #: [Investigational Device Exemption #]

IDE Sponsor:

Device Name: [This can include investigational in vitro diagnostics, which are regulated as devices.]

Protocol Type / Version # / Version Date: [Type* / Version # / Version Date]

*Protocol types: Original, Revision, or Amendment

INDEX

SCHEMA 6

1. Introduction 7

1.1 Study Disease 7

1.2 Rationale 7

2. OBJECTIVES 7

2.1 Study Design 7

2.2 Primary Objectives 7

2.3 Secondary Objectives 7

3. PARTICIPANT SELECTION 7

3.1 Eligibility Criteria 8

3.2 Exclusion Criteria 8

3.3 Inclusion of Women and Minorities 8

4. PRETREATMENT EVALUATIONS/MANAGEMENT 8

5. REGISTRATION PROCEDURES 9

5.1 General Guidelines for DF/HCC Institutions 9

5.2 Registration Process for DF/HCC Institutions 9

5.3 General Guidelines for Other Investigative Sites 9

5.4 Registration Process for Other Investigative Sites 10

6. RADIATION THERAPY 10

6.1 Example only: Dose Specifications: 3D Conformal Radiotherapy (3DCRT) or IMRT 11

6.2 Example only: Technical Factors 11

6.3 Example only: EBRT Localization, Simulation, and Immobilization 11

6.4 Example only: Treatment Planning/Target Volumes 11

6.5 Example only: Critical Structures 12

6.6 Example only: Treatment Verification 12

6.7 Example only: Quality Assurance 13

6.8 Example only: Dose Specifications/Technical Considerations: SBRT/Brachytherapy 14

6.9 Example only: Radiation Quality Assurance Reviews 14

6.10 Example only: Radiation Adverse Events 14

6.11 Example only: Radiation Adverse Event Reporting 14

7. DRUG THERAPY 14

8. SURGERY 15

9. OTHER THERAPIES 15

10. TISSUE/SPECIMEN SUBMISSION 15

11. PARTICIPANT ASSESSMENTS 16

12. DATA COLLECTION 16

13. STATISTICAL CONSIDERATIONS 16

13.1 Study Design/Endpoints 16

13.2 Sample Size, Accrual Rate and Study Duration 19

13.3 Stratification Factors 20

13.4 Interim Monitoring Plan 20

13.5 Analysis of Primary Endpoints 20

13.6 Analysis of Secondary Endpoints 20

13.7 Reporting and Exclusions 21

14. REGULATORY CONSIDERATIONS 21

14.1 Data Safety Monitoring 21

14.2 Multicenter Guidelines 22

14.3 Collaborative Agreements Language 23

15. PUBLICATION PLAN 25

REFERENCES 26

APPENDIX A PERFORMANCE STATUS CRITERIA 27

APPENDIX B MULTICENTER GUIDELINES 28

APPENDIX C BIOASSAY TEMPLATES 30

APPENDIX D STUDY PARAMETERS 31

APPENDIX E ADVERSE EVENT REPORTING REQUIREMENTS 32

SCHEMA

Provide an overall picture of the study design and intervention(s). Be specific enough for reviewers to know what intervention(s) are planned. Include stratification criteria, arm(s) descriptions for radiotherapy and chemotherapy or hormonal therapy (days and/or number of cycles, as applicable), and diagram of therapy sequence (if applicable). Do NOT include any dose or fraction information in this section. If applicable, indicate when advanced imaging will be performed in the study.

Introduction

1 Study Disease

Please provide background information on the history of the disease and current treatment.

2 Rationale

Please provide references to pertinent studies, and the rationale for evaluating this modality/combination therapy in this disease.

OBJECTIVES

This section should clearly state the study hypothesis to be tested and include an adequate plan for answering the hypothesis.

1 Study Design

Briefly describe the general study design.

2 Primary Objectives

Please insert the primary protocol objective(s). DF/HCC recommends careful wording of the primary objective to be limited in scope, clear, detailed and simple to facilitate registration and reporting requirements. Whenever possible a single primary objective is preferable: for example, 5-year Disease Free Survival.

3 Secondary Objectives

Please insert secondary protocol objectives, if pertinent. DF/HCC recommends careful wording of any secondary objectives to be limited in scope, clear, detailed and simple to facilitate registration and reporting requirements. For example, Overall Survival comparing x to y collected every 3 months

PARTICIPANT SELECTION

Clearly specify the population that will be involved. Specific laboratory values required at study entry should not be specified at values that exceed grade 0 toxicity level (active version CTCAE).

Include the following eligibility criteria (as applicable): histology requirements, sites, stage, age requirements, performance status, minimum and/or maximum laboratory values or other relevant evaluations, and informed consent requirements.

Include the following exclusionary criteria: prior treatment requirements and allowances, prior malignancy and disease-free interval (if allowable), and organ function requirements which preclude entry into the study. Describe pre-testing requirements in Section 4 (Pretreatment Evaluations/Management).

Careful consideration should be used in determining eligibility and exclusionary criteria as well as pre-testing requirements. While defining the participants make sure to consider situations where you might subsequently be asking for a deviation to include a participant. For example, if a CT scan from 3 weeks prior to starting therapy would be adequate, do not limit CT scans to having to be within 2 weeks. It is much better to appropriately define the study population prior to initiation of the study than having to amend the protocol subsequently.

1 Eligibility Criteria

Outline the eligibility criteria. As appropriate, sample language for eligibility criteria may be borrowed from the DF/HCC Biomedical Protocol Template, available online in the DF/HCC Clinical Research Support Website (dfhcc.harvard.edu/clinical-research-support/).

2 Exclusion Criteria

Outline the exclusionary criteria. As appropriate, sample language for exclusionary criteria may be borrowed from the DF/HCC Biomedical Protocol Template, available online in the DF/HCC Clinical Research Support Website (dfhcc.harvard.edu/clinical-research-support/).

3 Inclusion of Women and Minorities

Both men and women of all races and ethnic groups are eligible for this trial.

Please alter the above statement as appropriate, if necessary. In accordance with the NIH guidelines on the inclusion of women and minorities as participants in clinical research, the Department of Health and Human Services (HHS) requires that all pilot, phase 1, phase 2, and phase 3 trials must include accrual targets for males, females, and minorities (see Section 13.2, Sample Size, Accrual Rate and Study Duration). The accrual targets should reflect the expected accrual over the life of the study.

The policy states that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification establishes that inclusion is inappropriate with respect to the health of the participants or the purpose of the research.

PRETREATMENT EVALUATIONS/MANAGEMENT

Any mandatory pre-treatment assessment that is considered a requirement of eligibility must appear in Section 3 (Participant Selection). This section should describe any pretreatment criteria needed before the initiation of protocol treatment that do not affect eligibility (e.g., history and physical, diagram or lesion and nodes, mandatory imaging and/or laboratory studies and acceptable interval between study and participant entry, or other relevant assessments such as dental or nutritional evaluations).

REGISTRATION PROCEDURES

This section must be included since this study will be performed within the DF/HCC. Suggested text is provided below which may be modified as necessary. If protocol is limited to DF/HCC institutions, please insert “N/A” directly under headings 5.3 and 5.4 for multi-institutional studies.

1 General Guidelines for DF/HCC Institutions

Institutions will register eligible participants in the Clinical Trials Management System (CTMS) OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not registered to the protocol before protocol therapy begins will be considered ineligible and registration will be denied.

An investigator will confirm eligibility criteria and a member of the study team will complete the protocol-specific eligibility checklist.

Following registration, participants may begin protocol therapy. Issues that would cause treatment delays should be discussed with the Principal Investigator (PI) of the registering site. If a participant does not receive protocol therapy following registration, the subject must be taken off study in the CTMS (OnCore) with an appropriate date and reason entered.

2 Registration Process for DF/HCC Institutions

Applicable DF/HCC Policy REGIST-101 must be followed.

3 General Guidelines for Other Investigative Sites

Eligible participants will be entered on study centrally at the [Coordinating Center] by the Study Coordinator. All sites should call the Study Coordinator [Telephone #] to verify dose level availabilities. The required forms [Name of Form(s)] can be found in Appendix [Appendix #].

Following registration, participants should begin protocol therapy within 5 days. Issues that would cause treatment delays should be discussed with the Sponsor-Investigator. If a participant does not receive protocol therapy following registration, the subject must be taken off study in the CTMS (OnCore) with an appropriate date and reason entered.

4 Registration Process for Other Investigative Sites

To register a participant, the following documents should be completed by the research nurse or data manager and faxed [Fax #] or e-mailed [e-mail address] to the Study Coordinator:

• Copy of [specify which tests or results]

• Signed participant consent form

• HIPAA authorization form

• List any other appropriate forms (e.g., Eligibility Checklist, Registration Form, etc.)

The research nurse or data manager at the participating site will then call [Telephone #] or e-mail [e-mail address] the Study Coordinator to verify eligibility. To complete the registration process, the Coordinator will follow DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol Registration (SOP #: REGIST-101) and register the participant on the protocol. The coordinator will fax or e-mail the participant study number, and if applicable the dose treatment level, to the participating site. The coordinator will also call the research nurse or data manager at the participating site and verbally confirm registration

RADIATION THERAPY

Provide an explicit description of the schedule/requirements for radiation in relationship to any other treatment modalities as well as the treatment sequence.

If radiation therapy will be administered during treatment with another modality, specify whether both modalities MUST or NEED NOT be administered on the same day. If the other modality cannot be given due to toxicity or technical reasons, indicate whether radiation therapy must be held or should proceed.

If radiation therapy will be administered sequentially, either preceding or following another modality, specify the minimum and maximum interval between the preceding modality and the commencement of radiation. When another modality is to follow radiation therapy, specify the minimum and maximum interval between the new treatment and the completion of radiation.

This is the ONLY section of the protocol that should contain dose and fraction information. Explicitly outline the radiation treatment plan. Consider items such as physical factors, localization requirements, imaging modalities to be utilized, target volume, External Beam planning requirements, time/dose definitions and schedule including the maximum and minimum doses in the treatment volume and acceptable variations to the fraction size and total dose, and modifications and toxicity criteria as applicable.

If appropriate, a table may be used to describe the dose and/or dose modification plans.

The text shown below is provided as an example.

Protocol treatment must begin within x weeks after randomization.

1 Example only: Dose Specifications: 3D Conformal Radiotherapy (3DCRT) or IMRT

1. Dose will be normalized such that exactly 98% of the PTV receives the prescription dose and will be scored as per protocol. The maximum allowable dose within the PTV is 107% of the prescribed dose to a volume that is at least x cc. The minimum allowable dose within the PTV is >95% of the prescribed dose to a volume that is at least x cc.

2. Participants treated entirely via EBRT shall receive prescription doses to the PTV (with the above constraints). All attempts should be made to deliver the PTV dose with the above heterogeneity constraints with adherence to the critical structure parameters listed below in Table 1.

See Section 6.5 below for specifics regarding when to implement a dose reduction. The final prescription dose will be reported specifically to the study coordinator and recorded on a patient-by-patient basis.

Table 1. Critical Structure Dose Constraints

Insert table

2 Example only: Technical Factors

3. RT will be delivered with megavoltage equipment at energies ≥6 MV.

4. Stereotactic/ Proton or other equipment as applicable.

3 Example only: EBRT Localization, Simulation, and Immobilization

Simulation will be CT-based in all cases. The use of contrast at the time of simulation is recommended but not required. Participants will be positioned on a flat tabletop with a customized immobilization for stabilization and setup reproducibility. CT images should be acquired at a slice thickness of ≤3 mm. Target volumes (Section 6.4.1) and normal critical structures (Section 6.4.1.5) will be defined in the slices in which they are visualized. The 3DCRT cases must utilize “beam’s eye view” representations to define final beam aperture.

4 Example only: Treatment Planning/Target Volumes

5. The definition of volumes will be in accordance with the ICRU Report #50: Prescribing, Recording, and Reporting Photon Beam Therapy.

1. The Gross Tumor Volume (GTV) is defined by the physician as all known disease as defined by the planning CT.

2. The Clinical Target Volume (CTV) is the GTV plus areas considered to contain microscopic disease, delineated by the treating physician.

3. The Planning Target Volume (PTV) will provide a margin around the CTV to compensate for the variability of treatment set up and internal organ motion. A range of 5-10 mm around the CTV is required to define each respective PTV. Superior and inferior margins (capping) should be 5-10 mm depending on the thickness and spacing of the planning CT scan. Careful consideration should be made when defining the 5-10 mm margin in 3 dimensions.

4. The ICRU Reference Points are to be located in the central part of the PTV and, secondly, on or near the central axis of the beams. Typically these points should be located on the beam axes or at the intersection of the beam axes.

5. Normal Critical Structures to be defined on the treatment planning CT scan will include the following:

All structures will be contoured in their entirety as solid organs. See the ITC web site () to view examples of target and normal tissue contours.

6. The PTV forms the entire target as described. 3D conformal beams will be shaped to include the entire PTV and minimize dose to surrounding critical structures as described. Intensity modulated radiotherapy (IMRT) using inverse planning is permitted with constraints placed to adhere to critical structure dose limitations as defined above.

5 Example only: Critical Structures

Critical structure dose constraints shall remain consistent with Table 1 above. While every effort should be made to deliver prescription doses to the PTV as specified while adhering to these constraints, it is recognized that certain anatomical factors may prevent this.

For purposes of compliance, up to a 5% absolute increase in the volume of critical structure receiving greater than the specified dose will be considered “variation acceptable,” without a protocol deviation. Any increase in critical structure volume greater than 5% receiving more than the specified dose will be considered a “deviation unacceptable”. It is at this point that a dose reduction should be considered.

6 Example only: Treatment Verification

6. First day port films or portal images of each field along with orthogonal isocenter verification films (or images) must be obtained. If modifications are made in field shaping or design, a port film of each modified field along with orthogonal isocenter verification films (or images) is required on the first day’s treatment of that field. Thereafter, weekly verification films or images of orthogonal isocenter views (anterior to posterior and lateral projection) are required.

For IMRT the intensity profiles of each beam must be independently verified and compared to the planned field intensity. Portal films are not required for IMRT but orthogonal verification films are required, just as for 3DCRT. These images are to be archived by the institution for later review if requested by the study chair.

7. Daily on-line target localization (kV or MV imaging with fiducials, trans-abdominal ultrasound, or other) or off-line adaptive approaches to account for interfraction organ motion and setup variability are permitted on this study but not required. The use of image guidance or daily target localization including the specific type implemented must be documented by the treating physician and submitted to study headquarters.

8. Management of Radiation Dose to the Patient from Daily Localization

According to the literature, the estimates of patient dose per imaging study for various imaging systems vary considerably. The doses are in the range of 0.1 cGy BrainLab’s ExacTrac planar kV-systems and can be considered negligible compared with doses from MV portal imaging and kV and MV CT. The doses from helical MV CT scans on a Tomotherapy unit are estimated to be in range from 1 to 3 cGy, similar to doses reported for kV cone beam CT on Elekta Synergy machine. The doses for MV cone beam CT vary from 1 cGy to 10 cGy depending on the field size. Thus, the doses for 3D imaging systems used one time each day are in the range of 0.1 to 10 cGy and can contribute from 0.06 to 6% to a daily dose of 1.8 Gy. As a technique of controlling participant dose, it is recommended that a QA procedure be established at each institution to verify the accuracy of the image registration software on a daily basis. This QA check should

be performed by the therapists operating a particular treatment device and is aimed at reducing the use of repeat imaging to check that the registration software has functioned properly when a shift of participant position is carried out. Additionally, it is not recommended that an institution use a daily imaging technique that delivery greater than 3 cGy/dy to the patient. This limit dictates that repeat imaging on a particular day is held to a minimum when systems that deliver up to 3 cGy per study are used.

7 Example only: Quality Assurance

9. Documentation Requirements

The institution will archive treatment prescription and verification images for later review by the study chair if requested. At least one port film or pretreatment alignment film per field along with the digital reconstructed radiographs (DRRs) from the treatment planning program or, alternatively, a simulation verification radiograph shall be acquired and kept for evaluation if requested except where geometrically impractical.

10. Compliance Criteria

Cases which meet criteria as stated in Section 6.1.1 will be scored as per protocol. The minimum allowable dose within the PTV is >95% of the prescribed dose to a volume that is at least x cc. Cases in which this small volume of at least x cc receives a minimum dose that is 93% or a maximum dose that is >107% and 110% of the prescribed dose will be scored as a deviation unacceptable.

1. Acceptable dose heterogeneity will be as follows: The maximum dose volume of the PTV must not be shared by a normal critical structure. (Section 6.4.1.5). The maximum point dose to normal critical structures outside the PTV including the unspecified tissue should not exceed the prescription dose. The treating physician must carefully consider the tolerance dose/volume to each critical normal structure and unspecified tissue.

8 Example only: Dose Specifications/Technical Considerations: SBRT/Brachytherapy

9 Example only: Radiation Quality Assurance Reviews

The study co-chairs for the respective RT modalities offered in this trial will oversee quality assurance reviews for patients treated in those respective fashions. RT quality assurance reviews will be ongoing and performed remotely. RT quality assurance reviews will be facilitated by study chair.

10 Example only: Radiation Adverse Events

11. All participants will be seen weekly by their treating radiation oncologist while undergoing therapy. Any observations with respect to the following symptoms/side effects will be recorded: \

12. Clinical discretion may be used in managing radiotherapy-related side effects.

11 Example only: Radiation Adverse Event Reporting

See Section 6.10.1 for additional Adverse Events information and Appendix E for Adverse Event Reporting Requirements.

DRUG THERAPY

This section must be clearly written so all medical personnel involved in the treatment of participants can understand and properly follow the drug treatment plan.

When the study includes drug therapy, DF/HCC investigators are required to include the drug-related information outlined in the DF/HCC Biomedical Protocol Template, available online in the DF/HCC Clinical Research Support Website (dfhcc.harvard.edu/clinical-research-support/)Include all sub-sections outlined in Section 5 (Treatment and/or Imaging Plan), Section 6 (Dosing Delays/Dose Modifications) and Section 8 (Pharmaceutical and/or Imaging Agent Information) as they apply to the proposed study.

NOTE: If the specific doses and schedule of agent(s) given as part of a standard treatment for the disease are not important in determining the objectives of the study, this should be clearly stated (e.g. CHOP as per institutional standards). However, this should only be done when the dose and schedule, including modifications, are not important in determining one or more objectives.

SURGERY

If the study includes surgery, please specify details for staging procedures, therapeutic procedures, flaps and drainage, surgical quality control review procedures, and any requirements that will be considered “unacceptable deviations.”

If surgery precedes registration, specify the maximum interval between surgery, registration and commencement of protocol therapy. If the interval affects eligibility, this must be clearly stated in the eligibility section (see Section 3: Participant Selection).

If surgery will be performed subsequent to another study modality, specify the maximum and minimum interval between the end of therapy and surgery.

If the surgery involves a site where “staged surgery” is commonly used (i.e., resection of the tumor is performed in more than one sequential procedure), indicate whether multiple sequential procedures ARE or ARE NOT acceptable. Include the timing intervals (registration, start of study treatment) from the first or last procedure.

Examples of “staged surgery”:

Head & Neck – neck dissection performed subsequent to resection at the primary site

Breast – Re-resection of margins

OTHER THERAPIES

Please describe any preventive and supportive non-protocol treatment that will be permitted and not permitted during the course of the study. Clearly specify whether and under what conditions such treatment may be administered.

TISSUE/SPECIMEN SUBMISSION

Please briefly describe all planned correlative studies and indicate whether they are mandatory or optional. For additional information refer to the “Guidelines for Correlative Studies in Clinical Trials” available on the CTEP Web site (). Explicit instructions for handling, preserving, and shipping the specimens should be provided below. Information on endpoint validation including additional background (as needed), description of the assay(s) used, materials and methods, and assay validation should be provided in an appendix. A plan for statistical analysis of the results of the correlative study(ies) should be provided in Section 13.4, Analysis of Secondary Endpoints.

If development of diagnostic assays to identify participants who might benefit from a molecularly targeted therapy is planned, validation in a central reference laboratory, tissue banking, and standardization of procedures is of high importance. If samples will be shipped to a central laboratory for processing and analysis, responsible parties and contact information should be provided below in addition to instructions for handling, preserving, and shipping the specimens.

A correlative study title using meaningful descriptive text should be provided for each planned correlative study using the Protocol Submission Worksheet found on the CTEP Web site (). These titles will facilitate documentation of contributions to basic science in the context of the clinical trial.

A suggested format for presentation of the required information may be borrowed from the DF/HCC Biomedical Protocol Template, available online in the DF/HCC Clinical Research Support Website (dfhcc.harvard.edu/clinical-research-support/).If this trial does not include correlative or special studies, this section should be marked “N/A.”

PARTICIPANT ASSESSMENTS

Provide the requirements for each assessment (e.g., primary tumor, nodal disease status, presence of metastatic diseases and radiation effects. Include the studies to be done and the follow-up times (can be graphically indicated in table form). Response criteria must also be listed. If participants will be followed for survival or recurrence, clearly define the follow-up period.

DATA COLLECTION

Provide a list of all data items due, including treatment planning information, forms, pathology material and the specified times. It is preferable to display the information in tabular form, with the left hand column indicating the data item and the right hand indicating the time it is due after commencement of treatment.

STATISTICAL CONSIDERATIONS

The statistical section should clearly outline how the data will be evaluated in relation to each objective and MUST be written in conjunction with a statistician. Contact the Biostatistics Core for the statistician associated with your disease site or study population ().

1 Study Design/Endpoints

For Pilot Studies: Preliminary Study

• Specify the objectives and endpoints (e.g., feasibility, pharmacodynamics, etc.).

• Specify the maximum total accrual (often no larger than 10 participants and almost never larger than 20 participants).

• Provide a justification of the sample size. Invocation of the term “pilot study” does not exempt the investigator from justifying their choice of sample size.

• Provide statistical considerations whenever possible.

• Specify the statistical methods that will be used in the data analyses.

• Explain how data and tests will be interpreted.

• Explain how the information gathered from the pilot study will be used to design and optimize subsequent clinical trials.

For Phase I Study: Evaluation of Toxicity

• Specify the study design and primary endpoints.

• Include information on how toxicity will be graded and reported, and state that all participants who receive any amount of the study drug will be evaluable for toxicity.

• State the toxicities that are dose-limiting (DLT).

• Define the maximum tolerated dose (MTD), the dose below that which produced an unacceptable rate of DLT, and state if this will be the dose used for further testing in Phase II studies.

• Explicitly describe the escalation scheme: the number of participants at each dose, a minimum suspension time between doses, and a decision rule for dose escalation, de-escalation, or further exploration of a dose given observed toxicity.

• Specify the various possible values of the true toxicity rate, the chance of observing toxic events, and hence of escalating or de-escalating, at a given dose.

• If an additional group of participants (usually fewer than 15) is to be treated at the MTD once it has been determined, state how many participants will be included in this expansion cohort and the maximum width of a 90% exact confidence interval for the true but unknown toxicity rate.

• Specify the maximum total accrual (approximately 15-30 participants), the accrual rate and anticipated time to study completion even though the study completion depends on observed toxicity and the need to suspend accrual after each dose.

For Phase II Study: Treatment Efficacy

• Specify the primary endpoint that should reflect the first stated objective of the study. The primary objective may be to “investigate”, “estimate”, or “describe” the endpoints of interest. The verbs “determine” and “establish” should be avoided, as such goals are not consistent with the exploratory nature of a Phase II study. Other goals include determination of feasibility of administering a treatment, classification of toxicity, etc.

• Specify the study design, that is, whether participants will be accrued in one stage, two or more stages, or some other formal sequential design.

• Explicitly state any early stopping rules. If a multistage design is used, criteria for moving onto subsequent stages of accrual, and for determining if the treatment is promising after the final stage of accrual must be outlined.

• State the planned total sample size, the expected accrual rate and accrual period, and the expected duration of follow-up. The statistical considerations section must include a justification for the proposed sample size and the design parameters. It is not appropriate to suggest that a Phase II study will continue to accrue beyond its specified accrual goal.

• State whether the total sample size should be adjusted to allow for participants who never begin protocol therapy, ineligibility, inevaluability, participant drop out, and/or pathology exclusions.

• If a Phase III investigation is planned, contingent upon the outcome of the Phase II study, this should be explicitly stated in the protocol.

• Specify which outcomes (e.g., how many responses) will be regarded as indicating inactivity, and which will indicate efficacy, that is, the null and alternative hypotheses. These results should be based on literature or prior work and cited in the background section. Also, explicitly state the overall Type I error rate, and the power. Since the goal of a Phase II study is to determine whether or not to proceed with further testing, the probability of warranting further testing when the null hypothesis is actually true should be limited. Generally, Phase II designs use a 10% one-sided type I error and have at least 90% power.

• The accrual goal is between 17 and 50 participants total in single arm trials or per arm in randomized phase II trials. If the study involves randomization, also state the randomization process and any stratification factors.

For Phase III Study: Comparative Study

• State the primary objective and provide a precise definition of the primary endpoint.

• Specify the projected accrual rates, total sample size (or maximum sample size in the case of sequential trials), and projected length of accrual and follow-up after termination of accrual. The accrual rate for a particular study should be estimated from other studies previously conducted by DF/HCC with the same disease (sub) types.

• Adjust the total sample size according to the expected rate of ineligibility, exclusion based on central pathology review, and drop out.

• Describe the randomization process and any stratification factors.

• Specify the type I error rates. Superiority trials should have type I error rates < 0.05. For one-sided tests, type I errors of 0.025 are recommended. Equivalence or non-inferiority trials may have larger type I errors.

• Specify the alternative hypothesis of interest and the power. The alternative hypothesis used for sample size should represent the minimum treatment difference required to change clinical practice.

• Sample sizes must be sufficiently large to have at least 80% (85-90% if feasible) power to detect a clinically meaningful alternative to no treatment difference, in a reasonable time frame. In diseases where many cases may be accrued quickly, 90% power is recommended. Equivalence/non-inferiority trials may be designed with powers of 90-95%.

• State which participants will be included in the primary analysis. The primary efficacy analysis should be based on the intention to treat (ITT) principle, which groups participants based on assigned treatment, regardless of the treatment actually received.

• Clearly state the test (e.g., log rank) to be used for the primary analysis, including details such as stratification and whether the test is one-sided or two-sided. Any assumptions such as a proportional hazards model or a cure rate model made in calculating power should also be mentioned.

• Clearly describe the sequential monitoring plan, including planned total information, how analysis times will be determined, how critical values for rejecting the null will be determined, and if appropriate, describe rules for stopping in favor of the null hypothesis. If no interim analyses are planned, a justification should be given.

• Explicitly state any early stopping rules.

• Discuss the power for each endpoint to be analyzed. Usually this includes survival, even when it is not the primary endpoint.

2 Sample Size, Accrual Rate and Study Duration

Please specify the planned sample size, justify the accrual rate (e.g., participants/year) and state the follow-up after termination of accrual if applicable. The end of the study should be defined, i.e., the time at which all protocol specified time points have passed and/or follow-up data are sufficiently mature for analysis. For example, for a response endpoint, “A total of 20 evaluable participants will be accrued within one year. Up to an additional 6 months of follow-up will be required on the last participant accrued to observe the participant’s response after the 6th cycle of protocol therapy, for a total study duration of 1.5 years.” Or for a survival endpoint, “The study duration will be 4 years; 2 years of accrual, and 2 years of follow-up on the last participant enrolled.”

In accordance with the NIH guidelines on the inclusion of women and minorities as participants in clinical research, the Department of Health and Human Services (HHS) requires that all pilot, phase 1, phase 2, and phase 3 trials must include accrual targets for males, females, and minorities. The accrual targets should reflect the expected accrual over the life of the study.

The policy states that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification establishes that inclusion is inappropriate with respect to the health of the participants or the purpose of the research.

The NCI suggests that the accrual targets be based on data from similar trials completed by your organization during the previous 5 years. It is hoped that the accrual targets will resemble the gender, ethnic, and racial composition of the U.S. population as closely as possible. Please see the Protocol Submission Worksheet () for a complete description of ethnic and racial categories and a sample table (which is also provided below).

Enter actual estimates, whole numbers only (percentages, fractions, or decimals are not acceptable). The totals provided for each Ethnic/gender or Ethnic/total combination must match those given for each Race/gender or Race/total combination (i.e., A1 must match A2, B1 must match B2, and C1 must match C2).

|Accrual Targets |

|Ethnic Category |Sex/Gender |

| |Females | |Males | |Total |

|Hispanic or Latino | |+| |=| |

|Not Hispanic or Latino | |+| |=| |

|Ethnic Category: Total of all subjects | (A1) |+| (B1) |=| (C1) |

|Racial Category | |

|American Indian or Alaskan Native | |+| |=| |

|Asian | |+| |=| |

|Black or African American | |+| |=| |

|Native Hawaiian or other Pacific Islander | |+| |=| |

|White | |+| |=| |

|Racial Category: Total of all subjects | (A2) |+| (B2) |=| (C2) |

| |(A1 = A2) | |(B1 = B2) | |(C1 = C2) |

3 Stratification Factors

Please specify any planned participant stratification factors. If this is a Phase I study, indicate whether dose escalation and MTD determination will be done for each stratum individually. If it is a Phase II or Phase III study, indicate whether interim monitoring and efficacy determination will be done for each stratum individually.

4 Interim Monitoring Plan

If previously specified above, simply refer to that section. If not specified above, specify any safety, efficacy, or futility monitoring rules. If applicable, include a table of the time points and monitoring boundary(ies). State the action(s) to be taken if a monitoring boundary is crossed, i.e., who the reviewing bodies are, and the options for actions to be taken to address the crossed boundary.

5 Analysis of Primary Endpoints

If previously specified above, simply refer to that section. If not specified above, describe in detail the statistical methodology to be used to address the study’s primary aim. Define the participant cohort to be analyzed, state the primary endpoint, and explain how the results will be interpreted.

6 Analysis of Secondary Endpoints

If secondary endpoints are included in this study, please specify how they will be analyzed. In particular, brief descriptions should be given of analyses of pharmacokinetic, biologic, and correlative laboratory endpoints. If the analysis is inferential and not descriptive, the power for each endpoint to be analyzed should be discussed.

A typical secondary objective is the association between the biologic, biochemical, or pathological endpoint and the clinical endpoint. Phase III studies often have multiple endpoints, such as time to disease progression and survival.

Quality of Life (QOL) is sometimes a secondary endpoint of interest. Selection of instruments should be justified from scientific and psychometric perspectives and instrument validation and experience in previous studies should be described. Instruments should be age appropriate. Scoring of instruments should be included. Timing of the administration of the QOL instrument(s) should be discussed and windows for completion of instruments should be provided. Statistical considerations should include: justification for the sample size, power statements, clinical significance of the effect size that can be detected, variability of the instrument(s), expected compliance rate, method of analysis (e.g., longitudinal), and a clear outline of how missing data will be handled.

Some secondary aims are exploratory, and it may not be necessary to provide details on power and effect sizes.

7 Reporting and Exclusions

Precisely define the analysis population for the various endpoints and subset analyses. Participants who never start protocol therapy are usually excluded (“inevaluable”) from most analyses in Phase I and Phase II studies.

13. Evaluation of Toxicity

Define “evaluable.” For example: All participants will be evaluable for toxicity from the time of their first treatment.

14. Evaluation of the Primary Efficacy Endpoint

Analyses should be intent-to-treat unless justification can be provided for not doing so. Specifically, all eligible participants included in the study must be assessed for response/outcome to therapy, even if there are major protocol therapy deviations.

Subanalyses may then be performed on the basis of a subset of participants, excluding those for whom major protocol deviations have been identified (e.g., early death due to other reasons, early discontinuation of treatment, major protocol violations, etc.). However, these subanalyses may not serve as the basis for drawing conclusions concerning treatment efficacy, and the reasons for excluding participants from the analysis should be clearly reported. If applicable to the endpoint, the 95% confidence intervals should also be provided.

REGULATORY CONSIDERATIONS

1 Data Safety Monitoring

Each protocol is subject to safety review and oversight from a source independent of the study team. Text describing DF/HCC oversight committees is provided below and should be used or modified as necessary. For studies utilizing non-DF/HCC oversight committees, this section should include the name of the entity, number of members and roles (e.g., clinicians, statisticians, ethicists, etc.), frequency of meetings, types of information that will be analyzed, how the data will be supplied, number of types of interim analyses that will be conducted, and how the entity will record and report its findings and recommendations.

Use this text for High Risk Pilot, Phase I or non-randomized Phase II studies:

The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and accrual data from this study. The committee is composed of clinical specialists with experience in oncology and who have no direct relationship with the study. Information that raises any questions about participant safety will be addressed with the Sponsor-Investigator and study team.

The DSMC generally reviews each protocol up to four times a year or more often if required to review toxicity and accrual data. Information to be provided to the committee may include: up-to-date participant accrual; current dose level information; DLT information; all grade 2 or higher unexpected adverse events that have been reported across all sites; summary of all deaths occurring with 30 days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths while being treated and during active follow-up; any response information; audit results, and a summary provided by the study team. Other information (e.g. scans, laboratory values) will be provided upon request.

Use this text for Phase III or randomized Phase II studies:

The DF/HCC Data and Safety Monitoring Board (DSMB) will review and monitor study progress, toxicity, safety and other data from this study. The board is chaired by a medical oncologist from outside of DF/HCC and has external and internal representation. Information that raises any questions about participant safety or protocol performance will be addressed by the Sponsor-Investigator, statistician and study team. Should any major concerns arise, the DSMB will offer recommendations regarding whether or not to suspend the study.

The DSMB will meet twice a year to review accrual, toxicity, response and reporting information. Information to be provided to the DSMB may include: participant accrual; treatment regimen information; all adverse events and serious adverse events reported across all sites by category; summary of any deaths on study; audit results; and a summary provided by the study team. Other information (e.g. scans, laboratory values) will be provided upon request.

2 Multicenter Guidelines

Suggested text is provided below which may be modified as necessary. This language is for investigator-sponsored multi-center studies where a DF/HCC PI is the sponsor, and external (non-DF/HCC) sites will participate in the research. If this study is being performed within only DF/HCC or DF/PCC institutions (e.g., MGH, BIDMC), this section should be deleted.

Use this text for all Multicenter Trials:

This protocol will adhere to DF/HCC Policy MULTI-100 and the requirements of the DF/HCC Multi-Center Data and Safety Monitoring Plan. The specific responsibilities of the Sponsor-Investigator, Coordinating Center, and External Sites and the procedures for auditing are presented in Appendix B.

Include this text for CTEP Multicenter Trials:

In addition, this protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines. The specific responsibilities of the Sponsor-Investigator and the Coordinating Center (Study Coordinator) and the procedures for auditing are presented in Appendix B.

• The Sponsor-Investigator/Coordinating Center is responsible for distributing all IND Action Letters or Safety Reports received from CTEP to all participating institutions for submission to their IRB of record for action as required.

• Except in very unusual circumstances, each participating institution will order DCTD-supplied agents directly from CTEP. Agents may be ordered by a participating site only after the initial IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO (PIO@ctep.nci.) except for Group studies.

3 Collaborative Agreements Language

If a study agent is provided by CTEP under a Collaborative Agreement [Cooperative Research and Development Agreement (CRADA), Clinical Trials Agreement (CTA), Agent-CRADA or Clinical Supply Agreement (CSA)] with the Pharmaceutical Company, this section must be included in the protocol. Information on the study agent’s Agreement status will be provided in the approved LOI response. If no Collaborative Agreement applies to the investigational study agent, this section should be marked “N/A” and the text below deleted.

The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to Collaborator”

() contained within the terms of award, apply to the use of the Agent(s) in this study:

1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the investigators. The protocol documents for studies utilizing Agents contain confidential information and should not be shared or distributed without the permission of the NCI. If a copy of this protocol is requested by a study participant or participant’s family member, the individual should sign a confidentiality agreement. A suitable model agreement can be downloaded from: .

2. For a clinical protocol where there is an investigational Agent used in combination with (an)other Agent(s), each the subject of different Collaborative Agreements, the access to and use of data by each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be referred to as "Multi-Party Data”):

a. NCI will provide all Collaborators with prior written notice regarding the existence and nature of any agreements governing their collaboration with NCI, the design of the proposed combination protocol, and the existence of any obligations that would tend to restrict NCI's participation in the proposed combination protocol.

b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain regulatory approval or commercialize its own Agent.

c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree in writing prior to the commencement of the trials that it will use the Multi-Party Data solely for development, regulatory approval, and commercialization of its own Agent.

3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional disclosure is required by law or court order as described in the IP Option to Collaborator (). Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed consistent with all applicable federal statutes and regulations for the protection of human subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164.

4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact them.

5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial.

6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the Group office for Cooperative Group studies or by the principal investigator for non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and comment prior to submission for publication. Collaborator(s) will have 30 days from the date of receipt for review. Collaborator shall have the right to request that publication be delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected. Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or publication in the proceedings. Press releases and other media presentations must also be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press release/ media presentation should be sent to:

Email: ncicteppubs@mail.

The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ proprietary information.

PUBLICATION PLAN

This section should specify the method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or the study is terminated early. At a minimum, this section should include information on the intent to publish. Suggested text is provided below and should be modified as necessary.

The results should be made public within 24 months of reaching the end of the study. The end of the study is the time point at which the last data items are to be reported, or after the outcome data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors. A full report of the outcomes should be made public no later than three (3) years after the end of the study.

REFERENCES

Please provide the citations for all publications referenced in the text. Publications should be recent and organized in the format required by major journals.

APPENDIX A PERFORMANCE STATUS CRITERIA

|ECOG Performance Status Scale |Karnofsky Performance Scale |

|Grade |Descriptions |Percent |Description |

|0 |Normal activity. Fully active, able to carry on all|100 |Normal, no complaints, no evidence of disease. |

| |pre-disease performance without restriction. | | |

| | |90 |Able to carry on normal activity; minor signs or |

| | | |symptoms of disease. |

|1 |Symptoms, but ambulatory. Restricted in physically |80 |Normal activity with effort; some signs or symptoms of|

| |strenuous activity, but ambulatory and able to carry| |disease. |

| |out work of a light or sedentary nature (e.g., light| | |

| |housework, office work). | | |

| | |70 |Cares for self, unable to carry on normal activity or |

| | | |to do active work. |

|2 |In bed 50% of the time. Capable of only limited |40 |Disabled, requires special care and assistance. |

| |self-care, confined to bed or chair more than 50% of| | |

| |waking hours. | | |

| | |30 |Severely disabled, hospitalization indicated. Death |

| | | |not imminent. |

|4 |100% bedridden. Completely disabled. Cannot carry |20 |Very sick, hospitalization indicated. Death not |

| |on any self-care. Totally confined to bed or chair.| |imminent. |

| | |10 |Moribund, fatal processes progressing rapidly. |

|5 |Dead. |0 |Dead. |

APPENDIX B MULTICENTER GUIDELINES

If this is a non-CTEP multi-institution study (i.e. includes research sites external to DF/HCC or DF/PCC institutions), insert the protocol-specific DF/HCC Multi-center Data and Safety Monitoring Plan. If this is a CTEP multi-institution study, include the CTEP Multicenter Guidelines and insert the protocol-specific DF/HCC Multi-center Data and Safety Monitoring Plan.

Provided below is text specific to the CTEP Multicenter Guidelines.

If an institution wishes to collaborate with other participating institutions in performing a CTEP sponsored research protocol, then the following guidelines must be followed.

Responsibility of the Protocol Chair

• The Protocol Chair will be the single liaison with the CTEP Protocol and Information Office (PIO). The Protocol Chair is responsible for the coordination, development, submission, and approval of the protocol as well as its subsequent amendments. The protocol must not be rewritten or modified by anyone other than the Protocol Chair. There will be only one version of the protocol, and each participating institution will use that document. The Protocol Chair is responsible for assuring that all participating institutions are using the correct version of the protocol.

• The Protocol Chair is responsible for the overall conduct of the study at all participating institutions and for monitoring its progress. All reporting requirements to CTEP are the responsibility of the Protocol Chair.

• The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure safety of the patients.

• The Protocol Chair will be responsible for the review of and timely submission of data for study analysis.

Responsibilities of the Coordinating Center

• Each participating institution will have an appropriate assurance on file with the Office for Human Research Protection (OHRP), NIH. The Coordinating Center is responsible for assuring that each participating institution has an OHRP assurance and must maintain copies of IRB approvals from each participating site.

• Prior to the activation of the protocol at each participating institution, an OHRP form 310 (documentation of IRB approval) must be submitted to the CTEP PIO.

• The Coordinating Center is responsible for central participant registration. The Coordinating Center is responsible for assuring that IRB approval has been obtained at each participating site prior to the first participant registration from that site.

• The Coordinating Center is responsible for the preparation of all submitted data for review by the Protocol Chair.

• The Coordinating Center will maintain documentation of AE reports. There are two options for AE reporting: (1) participating institutions may report directly to CTEP with a copy to the Coordinating Center, or (2) participating institutions report to the Coordinating Center who in turn reports to CTEP. The Coordinating Center will submit AE reports to the Protocol Chair for timely review.

• Audits may be accomplished in one of two ways: (1) source documents and research records for selected participants are brought from participating sites to the Coordinating Center for audit, or (2) selected participant records may be audited on-site at participating sites. If the NCI chooses to have an audit at the Coordinating Center, then the Coordinating Center is responsible for having all source documents, research records, all IRB approval documents, NCI Drug Accountability Record forms, participant registration lists, response assessments scans, x-rays, etc. available for the audit.

Inclusion of Multicenter Guidelines in the Protocol

• The protocol must include the following minimum information:

➢ The title page must include the name and address of each participating institution and the name, telephone number and e-mail address of the responsible investigator at each participating institution.

➢ The Coordinating Center must be designated on the title page.

➢ Central registration of participants is required. The procedures for registration must be stated in the protocol.

➢ Data collection forms should be of a common format. Sample forms should be submitted with the protocol. The frequency and timing of data submission forms to the Coordinating Center should be stated.

➢ Describe how AEs will be reported from the participating institutions, either directly to CTEP or through the Coordinating Center.

➢ Describe how Safety Reports and Action Letters from CTEP will be distributed to participating institutions.

Agent Ordering

• Except in very unusual circumstances, each participating institution will order DCTD-supplied investigational agents directly from CTEP. Investigational agents may be ordered by a participating site only after the initial IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO.

APPENDIX C BIOASSAY TEMPLATES

Please include all applicable bioassays.

APPENDIX D STUDY PARAMETERS

Please provide a detailed study timeline that describes the procedures to be performed at each visit. A table format is recommended, with footnotes to clarify which criteria are required to determine eligibility. If appropriate, include a statement to allow for flexibility of the timing of protocol-specified procedures in order to avoid protocol deviations.

The schedule and text shown below are provided as an example.

|Assessments |Pre-Study |Weekly Visit During Radiation |Follow-Up (1) |

| | |Therapy | |

|Informed Consent and Registration |X | | |

|History/physical |X | |X |

|Performance Status |X | |X |

|Neurological Exam |X |X | |

|CBC (WBC, HGB, PLT |X (2) | | |

|MRI of affected region |X (3) | |X |

|Toxicity Assessment | |X |X |

1) Follow up schedule: initial evaluation at 6 weeks after completion of radiation therapy, than at 6 months and every 6 months thereafter for four years, then annually to year 10. Visits can be scheduled + 6 weeks from the due date.

2) Baseline labs are to be done within 4 weeks of study registration.

3) Baseline imaging is to be done within 6 weeks of study registration.

APPENDIX E ADVERSE EVENT REPORTING REQUIREMENTS

Federal requirements require that investigators report adverse events and reactions in a timely manner. Please outline the adverse event reporting requirements for this study. As appropriate, sample language for adverse event reporting may be borrowed from the DF/HCC Biomedical Protocol Template, available online in the DF/HCC Clinical Research Support Website (dfhcc.harvard.edu/clinical-research-support/).Sample text should be modified or deleted as necessary.

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