TEMPLATE INSTRUCTIONS

The protocol template is a tool to facilitate rapid protocol
development. It is not intended to supersede the role of the Protocol
Chair in the authoring and scientific development of the protocol. It
contains the "boilerplate" language commonly required in protocols
submitted to CTEP. All sections may be modified as necessary to meet the
scientific aims of the study and development of the protocol.

1\. Each protocol template consists of two parts:

(a) Protocol Submission Worksheet: available at

> <http://ctep.cancer.gov/guidelines/templates.html>. This document
> contains prompts for required administrative information.
>
> \(b\) Main Body and Appendices of the protocol: attached below. This
> document provides standard language plus instructions and prompts for
> information.

2\. The Protocol Submission Worksheet and Protocol Template documents
should be completed, and both documents (including the Appendices)
should be submitted to CTEP 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\. All protocol template instructions and prompts are in *italics*.
Blank space or \_\_\_\_\_\_\_\_ indicates that you should fill in the
appropriate information. **As you complete the information requested,
please delete the italicized text.**

5\. Please redline, highlight or underline new or modified text as this
will facilitate rapid review.

6\. For problems or questions encountered when using these documents
(Protocol Submission Worksheet or Protocol Template), please contact the
CTEP help desk by telephone (301-840-8202), fax (301-948-2242), or
e-mail (<ncictephelp@ctep.nci.nih.gov>).

**NCI Protocol #:** *To be assigned by the NCI. For cooperative group
studies, the NCI will utilize the local group protocol #.*

**Local Protocol #:** *Please insert your local protocol \# for this
study.*

**TITLE:** A Phase 2 Study of [*CTEP IND Agent*]{.underline} in *[Study
Disease]{.underline}*

*Use Simplified Disease Classification (SDC) terminology for study
disease. Please refer to the CTEP web site
(<http://ctep.cancer.gov/guidelines/codes.html#disease>) for a complete
list of SDC disease terms.*

**Coordinating Center:** *Name of Organization (If this is a
multi-institution study, only one organization/institution can be the
coordinating center.)*

**\*Principal Investigator:** *Name*

*Address*

*Address*

*Telephone*

*Fax*

*e-mail address*

**Co-Investigators:** *Name*

*Address*

*Address*

*Telephone*

*Fax*

*e-mail address*

*Name*

*Address*

*Address*

*Telephone*

*Fax*

*e-mail address*

**\**A study can have only one Principal Investigator. The Principal
Investigator must be a physician and is responsible for all study
conduct.*** *Please refer to the Investigator's Handbook on the CTEP
home page for a complete description of the **Principal Investigator's**
responsibilities (<http://ctep.cancer.gov/handbook/index.html>).*

***The Principal Investigator and all physicians responsible for patient
care must have a current FDA form 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 Pharmaceutical Management Branch, CTEP, at (301) 496-5725 or
by e-mail at <PMBRegPend@ctep.nci.nih.gov>. 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 a 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 Cooperative Group
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
<http://www.hc-sc.gc.ca/hpfb-dgpsa/index_e.html>. A copy of the "No
Objection" letter should be forwarded to the Pharmaceutical Management
Branch at (fax) 301-402-0429 when available.

**Statistician:** **Study Coordinator:**

*(if applicable) (if applicable)*

*Name Name*

*Address Address*

*Address Address*

*Telephone Telephone*

*Fax Fax*

*e-mail address e-mail address*

**Responsible Research Nurse: Responsible Data Manager:**

*Name Name*

*Address Address*

*Address Address*

*Telephone Telephone*

*Fax Fax*

*e-mail address e-mail address*

**NCI Supplied Agent**: *[CTEP IND Agent (NSC #; IND #, if
available)]{.underline}*

**Protocol Type / Version \# / Version Date** \_\_*[Type / Version \# /
Version Date]{.underline}*\_\_

*(Protocol types: Original, Revision, or Amendment)*

**SCHEMA**

*Please provide a schema for the study. If preferred, a summary or
synopsis may be provided.*

**TABLE OF CONTENTS**

Page

**SCHEMA** i

**1. OBJECTIVES** 1

1.1 **Primary Objectives**

1.2 **Secondary Objectives**

**2. BACKGROUND** 1

2.1 ***[Study Disease]{.underline}*** 1

2.2 ***[CTEP IND Agent]{.underline}***

2.3 **Rationale**

2.4 **Correlative Studies Background**

**3. PATIENT SELECTION**

3.1 **Eligibility Criteria**

3.2 **Exclusion Criteria**

3.3 **Inclusion of Women and Minorities**

**4. REGISTRATION PROCEDURES**

4.1 **General Guidelines**

4.2 **Registration Process**

**5. TREATMENT PLAN**

5.1 *[**CTEP IND Agent**]{.underline}* **Administration**

5.2 **General Concomitant Medication and Supportive Care Guidelines**

3.  **Duration of Therapy**

4.  **Duration of Follow Up**

5.  **Criteria for Removal from Study**

**6. DOSING DELAYS/DOSE MODIFICATIONS**

**7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS**

7.1 **Comprehensive Adverse Events and Potential Risks List (CAEPR)**

7.2 **Adverse Event Characteristics**

7.3 **Expedited Adverse Event Reporting**

7.4 **Routine Adverse Event Reporting**

5.  **Secondary AML/MDS**

**8. PHARMACEUTICAL INFORMATION**

> 8.1 ***[CTEP IND Agent (NSC#)]{.underline}***
>
> 8.2 **Availability**
>
> 8.3 **Agent Ordering**
>
> 8.4 **Agent Accountability**

**9. CORRELATIVE/SPECIAL STUDIES**

> 9.1 **Laboratory Correlative Studies**
>
> 9.2 **Special Studies**

**10. STUDY CALENDAR**

**11. MEASUREMENT OF EFFECT**

11.1 **Antitumor Effect -- Solid Tumors**

11.2 **Antitumor Effect -- Hematologic Tumors**

11.3 **Other Response Parameters**

**12. DATA REPORTING / REGULATORY CONSIDERATIONS**

1.  **Data Reporting**

12.2 **CTEP Multicenter Guidelines**

12.3 **Cooperative Research and Development Agreement (CRADA)/**

**Clinical Trials Agreement (CTA)**

**13. STATISTICAL CONSIDERATIONS**

**REFERENCES**

**INFORMED CONSENT TEMPLATE FOR CANCER TREATMENT TRIALS**

**APPENDICES**

**APPENDIX A**

Performance Status Criteria

**APPENDIX B**

CTEP Multicenter Guidelines

**1. OBJECTIVES**

1.1. **Primary Objectives**

> *Please insert primary protocol objectives.*

1.2. **Secondary Objectives**

> *Please insert secondary protocol objectives, if pertinent.*

**2. BACKGROUND**

2.1 ***[Study Disease]{.underline}***

> *Please provide background information on the study disease.*

2.2 ***[CTEP IND Agent]{.underline}***

> *Please provide background information on the investigational study
> agent, including the mechanism of action, summaries of nonclinical and
> clinical studies, nonclinical and clinical pharmacokinetics, major
> route of elimination, safety profile, and the rationale for the
> starting dose and regimen chosen. Please include information on the
> metabolism of the investigational study agent in humans and its
> potential for drug interactions, if available.*

2.3 **Rationale**

> *Please provide the background rationale for evaluating this therapy
> in this disease.*

2.4 **Correlative Studies Background**

> *Please provide background information on [each]{.underline} planned
> correlative study including the biologic rationale and hypothesis as
> well as the relevant preclinical and clinical (if available) data.
> Refer to "Guidelines for Correlative Studies in Clinical Trials"
> (<http://ctep.cancer.gov/guidelines/index.html>). If this trial
> includes no correlative studies, this section should be marked "N/A".*

**3. PATIENT SELECTION**

3.1 **Eligibility Criteria**

> 3.1.1 Patients must have histologically or cytologically confirmed
> *[Study Disease]{.underline}. Please specify eligible
> disease(s)/stage(s) using the CTEP Simplified Disease Classification
> (<http://ctep.cancer.gov/guidelines/codes.html#disease>).*
>
> 3.1.2 *Please insert appropriate criteria for the particular patient
> population. Note: Lesions are either measurable or non-measurable
> using the criteria provided in section 11. The term "evaluable" in
> reference to measurability will not be used because it does not
> provide additional meaning or accuracy. Suggested text is provided
> below.*
>
> Patients must have measurable disease, defined as at least one lesion
> that can be accurately measured in at least one dimension (longest
> diameter to be recorded) as [\>]{.underline}20 mm with conventional
> techniques or as [\>]{.underline}10 mm with spiral CT scan. See
> Section 11 for the evaluation of measurable disease.
>
> 3.1.3 *Please state allowable type and amount of prior therapy. Define
> as appropriate any limitations on prior therapy and the time from last
> prior regimen (e.g., no more than 6 cycles of an alkylating agent; no
> more than 450 mg/m^2^ doxorubicin for agents with expected cumulative
> cardiotoxicity). Include separate definitions for duration as needed
> (e.g., at least 4 weeks since prior chemotherapy or radiation therapy,
> 6 weeks if the last regimen included BCNU or mitomycin C). Include
> site/total dose for prior radiation exposure as needed (e.g., no more
> than 3000 cGy to fields including substantial marrow).*
>
> 3.1.4 Age [\>]{.underline}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 *[CTEP IND Agent]{.underline}* in patients \<18 years of age,
> children are excluded from this study but will be eligible for future
> pediatric single-agent trials, if applicable.
>
> 3.1.5 Life expectancy of greater than *[\[#weeks or
> months\]]{.underline}* .
>
> 3.1.6 ECOG performance status 2 (Karnofsky 60%; see Appendix A).
>
> 3.1.7 Patients must have normal organ and marrow function as defined
> below:

-   leukocytes [\>]{.underline}3,000/mcL

-   absolute neutrophil count [\>]{.underline}1,500/mcL

-   platelets [\>]{.underline}100,000/mcL

-   total bilirubin within normal institutional limits

-   AST(SGOT)/ALT(SGPT) 2.5 X institutional upper limit of

normal

-   creatinine within normal institutional limits

OR

-   creatinine clearance [\>]{.underline}60 mL/min/1.73 m^2^ for
    patients with creatinine levels above institutional normal

> 3.1.8 *Please insert other appropriate eligibility criteria.*

3.1.9 *Please use or modify the following paragraph as appropriate.*

> The effects of *[CTEP IND Agent]{.underline}* on the developing human
> fetus at the recommended therapeutic dose are unknown. For this reason
> and because *[Agent Class]{.underline}* are known to be teratogenic,
> women of child-bearing potential and men must agree to use adequate
> contraception (hormonal or barrier method of birth control;
> abstinence) prior to study entry and for the duration of study
> participation. Should a woman become pregnant or suspect she is
> pregnant while participating in this study, she should inform her
> treating physician immediately.
>
> 3.1.10 Ability to understand and the willingness to sign a written
> informed consent document.

3.2 **Exclusion Criteria**

> 3.2.1 Patients who have had chemotherapy or radiotherapy within 4
> weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the
> study or those who have not recovered from adverse events due to
> agents administered more than 4 weeks earlier.
>
> 3.2.2 Patients may not be receiving any other investigational agents.
>
> 3.2.3 Patients with known brain metastases should 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.
>
> 3.2.4 History of allergic reactions attributed to compounds of similar
> chemical or biologic composition to *[CTEP IND Agent]{.underline}* .
>
> 3.2.5 *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. Examples
> of such agents or substances include those that interact through the
> CYP450 isoenzyme system or other sources of drug interactions (e.g.,
> P-glycoprotein). Specifically excluded substances may be listed below,
> stated in Section 8 (Pharmaceutical Information), or presented as an
> appendix. If appropriate, the following text concerning CYP450
> interactions may be used or modified.*
>
> Patients receiving any medications or substances that are inhibitors
> or inducers of \_*[specify CYP450 enzyme(s)]{.underline}*\_ are
> ineligible. Lists including medications and substances known or with
> the potential to interact with the \_*[specified CYP450
> enzyme(s)]{.underline}*\_isoenzymes are provided in \_*[Appendix
> (#/letter)]{.underline}*\_.
>
> 3.2.6 *Please insert other appropriate agent-specific exclusion
> criteria.*
>
> 3.2.7 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.
>
> 3.2.8 *The investigator(s) must state a medical or scientific reason
> if pregnant or nursing patients will be excluded from the study. The
> full text of the Policies, Guidelines, and Procedures pertinent to
> this requirement is available on the CTEP web site
> (<http://ctep.cancer.gov/guidelines/pregnant.html>). Suggested text is
> provided below:*
>
> Pregnant women are excluded from this study because *[CTEP IND
> Agent]{.underline}* is *[a/an Agent Class]{.underline}* 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 *[CTEP IND
> Agent]{.underline}* , breastfeeding should be discontinued if the
> mother is treated with *[CTEP IND Agent]{.underline}* .
>
> 3.2.9 *The investigator(s) must state a medical or scientific reason
> if patients who are cancer survivors or those who are HIV-positive
> will be excluded from the study. The full text of the Policies,
> Guidelines, and Procedures pertinent to this requirement is available
> on the CTEP web site (<http://ctep.cancer.gov/guidelines/hiv.html>).
> Suggested text is provided below:*
>
> HIV-positive patients on combination antiretroviral therapy are
> ineligible because of the potential for pharmacokinetic interactions
> with *[\_\_CTEP IND]{.underline}* *[Agent]{.underline}*\_\_. In
> addition, these patients are at increased risk of lethal infections
> when treated with marrow-suppressive therapy. Appropriate studies will
> be undertaken in patients receiving combination antiretroviral therapy
> when indicated.

3.  **Inclusion of Women and Minorities**

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

4.  **REGISTRATION PROCEDURES**

> *This section should be marked "N/A" if this study is being performed
> within a single institution. For multi-institutional studies,
> suggested text is provided below which may be modified as necessary.
> Appropriate forms for the study (e.g., Eligibility Screening
> Worksheet, Registration Form) should be developed and included with
> the protocol. These forms must be used by all participating
> institutions.*

1.  **General Guidelines**

> Eligible patients will be entered on study centrally at the
> \_\_*[(Coordinating Center)]{.underline}* by the Study Coordinator.
> All sites should call the Study Coordinator \_\_\_*[(Telephone
> #)\_]{.underline}*\_ to verify agent availability. The required forms
> \_*[\[Name of Form(s)\]]{.underline}* can be found in Appendix
> [\_(*Appendix #)\_*]{.underline}.
>
> Following registration, patients should begin protocol treatment
> within 72 hours. Issues that would cause treatment delays should be
> discussed with the Principal Investigator. If a patient does not
> receive protocol therapy following registration, the patient's
> registration on the study may be canceled. The Study Coordinator
> should be notified of cancellations as soon as possible.
>
> 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.nih.gov>) except for Group studies.

2.  **Registration Process**

> To register a patient, the following documents should be completed by
> the research nurse or data manager and faxed \_ *[(Fax \#
> )]{.underline}* or e-mailed *[\_(e-mail address)\_]{.underline}* to
> the Study Coordinator:

-   Copy of required laboratory tests

-   Signed patient consent form

-   HIPAA authorization form

-   *Other appropriate forms (e.g., Eligibility Screening Worksheet,
    Registration Form).*

> The research nurse or data manager at the participating site will then
> call \_*[(Telephone #)]{.underline}*\_ or e-mail ­*[(e-mail
> address)]{.underline}* the Study Coordinator to verify eligibility. To
> complete the registration process, the Coordinator will

-   assign a patient study number

-   register the patient on the study

-   fax or e-mail the patient study number and dose to the participating
    site

-   call the research nurse or data manager at the participating site
    and verbally confirm registration.

**5. TREATMENT PLAN**

5.1 ***[CTEP IND Agent]{.underline}* Administration**

> Treatment will be administered on an
> *[inpatient/outpatient]{.underline}* basis. Reported adverse events
> and potential risks are described in Section 7. Appropriate dose
> modifications for *[CTEP IND Agent]{.underline}* are described in
> Section 6. No investigational or commercial agents or therapies other
> than those described below may be administered with the intent to
> treat the patient's malignancy.
>
> *Please describe the regimen and state any special precautions or
> warnings relevant for investigational study agent administration
> (e.g., incompatibility of the agent with commonly used intravenous
> solutions, necessity of administering agent with food, premedications,
> etc.). Please refer to the CTEP web site
> (<http://ctep.cancer.gov/guidelines/nomenclature.html>) for Guidelines
> for Treatment Regimen Expression and Nomenclature.*

5.2 **General Concomitant Medication and Supportive Care Guidelines**

> *Please state guidelines for use of concomitant medications or any
> additional appropriate supportive care medications or treatments. The
> potential for interaction with the cytochrome P450 system should be
> addressed if applicable. Please use or modify the following paragraph
> as appropriate.*
>
> Because there is a potential for interaction of \_\_*[CTEP IND
> Agent]{.underline}*\_ with other concomitantly administered drugs
> through the cytochrome P450 system, the case report form must capture
> the concurrent use of all other drugs, over-the-counter medications,
> or alternative therapies. The Principal Investigator should be alerted
> if the patient is taking any agent known to affect or with the
> potential to affect selected CYP450 isoenzymes.

5.3 **Duration of Therapy**

> In the absence of treatment delays due to adverse event(s), treatment
> may continue for [*\[# cycles\]*]{.underline} or until one of the
> following criteria applies:

-   Disease progression,

-   Intercurrent illness that prevents further administration of
    treatment,

-   Unacceptable adverse event(s),

-   Patient decides to withdraw from the study, or

-   General or specific changes in the patient's condition render the
    patient unacceptable for further treatment in the judgment of the
    investigator.

    4.  **Duration of Follow Up**

> Patients will be followed for \_\_*[weeks]{.underline}*\_\_ after
> removal from study or until death, whichever occurs first. Patients
> removed from study for unacceptable adverse events will be followed
> until resolution or stabilization of the adverse event.
>
> 5.5 **Criteria for Removal from Study**
>
> *Patients will be removed from study when any of the criteria listed
> in Section 5.3 applies. The reason for study removal and the date the
> patient was removed must be documented in the Case Report Form.*

**6. DOSING DELAYS/DOSE MODIFICATIONS**

> *Treatment plans should explicitly identify when treatment (typically
> dosage) modifications are appropriate. Treatment modifications/dosing
> delays and the factors predicating treatment modification should be
> explicit and clear. If dose modifications or treatment delays are
> anticipated, please provide a dose de-escalation schema. The following
> format for an orally available agent is provided as an example and may
> be used or modified as appropriate:*

+----------------------------------+-----------------------------------+
| **Dose Level**                   | **\_*[Agent Name]{.underline}\_*  |
|                                  | Dose**                            |
+----------------------------------+-----------------------------------+
| -2                               | *XX mg, schedule*                 |
|                                  |                                   |
|                                  | *(# tablets, size)*               |
+----------------------------------+-----------------------------------+
| -1                               | *XX mg, schedule*                 |
|                                  |                                   |
|                                  | *(# tablets, size)*               |
+----------------------------------+-----------------------------------+
| 0                                | *XX mg, schedule*                 |
|                                  |                                   |
|                                  | *(# tablets, size)*               |
+----------------------------------+-----------------------------------+

> ***Note:** All treatment modifications must be expressed as a specific
> dose or amount rather than as a percentage of the starting or previous
> dose.*

**7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS**

> Adverse event (AE) monitoring and reporting is a routine part of every
> clinical trial. The following list of AEs (Section 7.1) and the
> characteristics of an observed AE (Section 7.2) will determine whether
> the event requires expedited (via AdEERS) reporting **in addition** to
> routine reporting.
>
> 7.1 **Comprehensive Adverse Events and Potential Risks List (CAEPR)**
>
> The Comprehensive Adverse Event and Potential Risks list (CAEPR)
> provides a single, complete list of reported and/or potential adverse
> events (AE) associated with an agent using a uniform presentation of
> events by body system. In addition to the comprehensive list, a
> [subset,]{.underline} the Agent Specific Adverse Event List (ASAEL),
> appears in a separate column and is identified with ***bold*** and
> ***italicized*** text. This [subset]{.underline} of AEs (the ASAEL)
> contains events that are considered 'expected' for expedited reporting
> purposes only. Refer to the "CTEP, NCI Guidelines: Adverse Event
> Reporting Requirements"
> (<http://ctep.cancer.gov/reporting/adeers.html>) for further
> clarification. The CAEPR may not provide frequency data; if not, refer
> to the Investigator's Brochure for this information.

The Comprehensive Adverse Events and Potential Risks (CAEPR) list will
be provided with the LOI approval letter. Please insert the CAEPR here.

> 7.2 **Adverse Event Characteristics**

-   **CTCAE term (AE description) and grade:** The descriptions and
    grading scales found in the revised NCI Common Terminology Criteria
    for Adverse Events (CTCAE) version 3.0 will be utilized for AE
    reporting. All appropriate treatment areas should have access to a
    copy of the CTCAE version 3.0. A copy of the CTCAE version 3.0 can
    be downloaded from the CTEP web site
    ([http://ctep.cancer.gov](http://ctep.cancer.gov/)).

```{=html}
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```
-   **"Expectedness"**: AEs can be 'Unexpected' or 'Expected' (see
    Section 7.1 above) for expedited reporting purposes only. 'Expected'
    AEs (the ASAEL) are ***bold and italicized*** in the CAEPR (Section
    7.1.1).

-   **Attribution** of the AE:

    -   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.

> 7.3 **Expedited Adverse Event Reporting**
>
> 7.3.1 Expedited AE reporting for this study must use AdEERS (Adverse
> Event Expedited Reporting System), accessed via the CTEP home page
> ([http://ctep.cancer.gov](http://ctep.cancer.gov/)). The reporting
> procedures to be followed are presented in the "CTEP, NCI Guidelines:
> Adverse Event Reporting Requirements" which can be downloaded from the
> CTEP home page
> ([[http://ctep.cancer.gov]{.underline}](http://ctep.cancer.gov/reporting/adeers.html)).
> These requirements are briefly outlined in the table below (Section
> 7.3.3).
>
> In the rare occurrence when Internet connectivity is lost, an AE
> report may be submitted using CTEP\'s Adverse Event Expedited
> Report-Single Agent or Multiple Agent paper template (available at
> [http://ctep.cancer.gov](http://ctep.cancer.gov/)) and faxed to
> 301-230-0159. A 24-hour notification is to be made to CTEP by
> telephone at 301-897-7497, only when Internet connectivity is
> disrupted. Once Internet connectivity is restored, an AE report
> submitted on a paper template or a 24-hour notification phoned in must
> be entered electronically into AdEERS by the original submitter at the
> site.
>
> 7.3.2 *The following text is required for multi-institutional studies
> only and may be deleted for single institution studies.*
>
> AdEERS is programmed for automatic electronic distribution of reports
> to the following individuals: Study Coordinator of the Lead
> Organization, Principal Investigator, and the local treating
> physician. AdEERS provides a copy feature for other e-mail recipients.
>
> 7.3.3 **[Expedited Reporting Guidelines]{.underline}** -- AdEERS
> Reporting Requirements for Adverse Events that occur within 30 Days^1^
> of the Last Dose of the Investigational Agent on Phase 2 and 3 Trials

<table style="width:100%;">
<colgroup>
<col style="width: 9%" />
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 10%" />
<col style="width: 10%" />
<col style="width: 10%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="10"><strong>Phase 2 and 3 Trials</strong></td>
</tr>
<tr class="even">
<td rowspan="3"></td>
<td><strong>Grade 1</strong></td>
<td><strong>Grade 2</strong></td>
<td><strong>Grade 2</strong></td>
<td colspan="2"><strong>Grade 3</strong></td>
<td colspan="2"><strong>Grade 3</strong></td>
<td><p><strong>Grades</strong></p>
<p><strong>4 &amp; 5<sup>2</sup></strong></p></td>
<td><p><strong>Grades</strong></p>
<p><strong>4 &amp; 5<sup>2</sup></strong></p></td>
</tr>
<tr class="odd">
<td rowspan="2"><p><strong>Unexpected</strong></p>
<p><strong>and Expected</strong></p></td>
<td rowspan="2"><strong>Unex-pected</strong></td>
<td rowspan="2"><strong>Expected</strong></td>
<td colspan="2"><strong>Unexpected</strong></td>
<td colspan="2"><strong>Expected</strong></td>
<td rowspan="2"><p><strong>Unex-</strong></p>
<p><strong>pected</strong></p></td>
<td rowspan="2"><strong>Expected</strong></td>
</tr>
<tr class="even">
<td><p><strong>with</strong></p>
<p><strong>Hospitali-zation</strong></p></td>
<td><strong>without Hospitali- zation</strong></td>
<td><p><strong>with</strong></p>
<p><strong>Hospitali-</strong></p>
<p><strong>zation</strong></p></td>
<td><p><strong>without Hospitali-</strong></p>
<p><strong>zation</strong></p></td>
</tr>
<tr class="odd">
<td><p><strong>Unrelated</strong></p>
<p><strong>Unlikely</strong></p></td>
<td><p>Not</p>
<p>Required</p></td>
<td><p>Not</p>
<p>Required</p></td>
<td><p>Not</p>
<p>Required</p></td>
<td><p>10 Calendar</p>
<p>Days</p></td>
<td><p>Not</p>
<p>Required</p></td>
<td><p>10 Calendar</p>
<p>Days</p></td>
<td><p>Not</p>
<p>Required</p></td>
<td><p>10</p>
<p>Calendar</p>
<p>Days</p></td>
<td><p>10</p>
<p>Calendar</p>
<p>Days</p></td>
</tr>
<tr class="even">
<td><p><strong>Possible</strong></p>
<p><strong>Probable</strong></p>
<p><strong>Definite</strong></p></td>
<td><p>Not</p>
<p>Required</p></td>
<td><p>10 Calendar</p>
<p>Days</p></td>
<td><p>Not</p>
<p>Required</p></td>
<td><p>10 Calendar</p>
<p>Days</p></td>
<td><p>10 Calendar</p>
<p>Days</p></td>
<td><p>10 Calendar</p>
<p>Days</p></td>
<td><p>Not</p>
<p>Required</p></td>
<td><p>24-Hour;</p>
<p>5 Calendar</p>
<p>Days</p></td>
<td><p>10</p>
<p>Calendar</p>
<p>Days</p></td>
</tr>
<tr class="odd">
<td colspan="10"><p><strong><sup>1</sup> Adverse events with attribution
of possible, probable, or definite that occur <u>greater</u> than 30
days after the last dose of treatment with an agent under a CTEP IND
require reporting as follows:</strong></p>
<blockquote>
<p>AdEERS 24-hour notification followed by complete report within 5
calendar days for:</p>
</blockquote>
<ul>
<li><p>Grade 4 and Grade 5 unexpected events</p></li>
</ul>
<p>AdEERS 10 calendar day report:</p>
<ul>
<li><p>Grade 3 unexpected events with hospitalization or prolongation of
hospitalization</p></li>
<li><p>Grade 5 expected events</p></li>
</ul>
<p><sup>2</sup> Although an AdEERS 24-hour notification is not required
for death clearly related to progressive disease, a full report is
required as outlined in the table.</p>
<p>December 15, 2004</p></td>
</tr>
</tbody>
</table>

**Note: All deaths on study require both routine and expedited reporting
regardless of causality. Attribution to treatment or other cause must be
provided.**

-   Expedited AE reporting timelines defined:

    -   "24 hours; 5 calendar days" -- The investigator must initially
        report the AE via AdEERS within [24 hours]{.underline} of
        learning of the event followed by a complete AdEERS report
        within [5 calendar days]{.underline} of the initial 24-hour
        report.

    -   "10 calendar days" - A complete AdEERS report on the AE must be
        submitted within [10 calendar days]{.underline} of the
        investigator learning of the event.

-   Any medical event equivalent to CTCAE grade 3, 4, or 5 that
    precipitates hospitalization (or prolongation of existing
    hospitalization) must be reported regardless of attribution and
    designation as expected or unexpected with the exception of any
    events identified as protocol-specific expedited adverse event
    reporting exclusions.

-   Any event that results in persistent or significant
    disabilities/incapacities, congenital anomalies, or birth defects
    must be reported via AdEERS if the event occurs following treatment
    with an agent under a CTEP IND.

-   Use the NCI protocol number and the protocol-specific patient ID
    assigned during trial registration on all reports.

> 7.3.4 [Protocol-Specific Expedited Adverse Event Reporting
> Exclusions]{.underline}

-   [For this protocol only]{.underline}, certain AEs/grades are
    exceptions to the Expedited Reporting Guidelines and [do not require
    expedited reporting ( *i.e*., AdEERS)]{.underline}. The following
    AEs must be reported through the routine reporting mechanism
    (Section 7.4):

  ------------ --------------- ----------- -------------------- ----------------- ------------------
  **CTCAE      **Adverse       **Grade**   **Hospitalization/   **Attribution**   **Comments**
  Category**   Event**                     Prolongation of                        
                                           Hospitalization**                      

                                                                                  

                                                                                  

                                                                                  

                                                                                  

                                                                                  
  ------------ --------------- ----------- -------------------- ----------------- ------------------

> 7.4 **Routine Adverse Event Reporting**
>
> All Adverse Events **must** be reported in routine study data
> submissions. **AEs reported through AdEERS must [also]{.underline} be
> reported in routine study data submissions.**
>
> 7.5 **Secondary AML/MDS**
>
> Investigators are required to report cases of secondary AML/MDS
> occurring on or following treatment on NCI-sponsored chemotherapy
> protocols using the [NCI/CTEP Secondary AML/MDS Report
> Form.]{.underline} This form can be downloaded from the CTEP web site
> ([http://ctep.cancer.gov](http://ctep.cancer.gov/reporting/index.html)).
> Refer to the "CTEP, NCI Guidelines: Adverse Event Reporting
> Requirements" (available at
> [[http://ctep.cancer.gov]{.underline}](http://ctep.cancer.gov/reporting/adeers.html))
> for additional information about secondary AML/MDS reporting.

**8. PHARMACEUTICAL INFORMATION**

> A list of the adverse events and potential risks associated with
> \_*[CTEP IND Agent]{.underline}*\_ can be found in Section 7.1.

**8.1 *[CTEP IND Agent (NSC #)]{.underline}***

> ***Confidential** pharmaceutical information for investigational study
> agents supplied by NCI will be provided as an attachment to the
> approved Letter of Intent (LOI) response and should be inserted here.*

**8.2 Availability**

> *[CTEP IND Agent]{.underline}* is an investigational agent supplied to
> investigators by the Division of Cancer Treatment and Diagnosis
> (DCTD), NCI.
>
> *If the study agent is provided by the NCI under a Collaborative
> Agreement with the agent manufacturer, the text below must be included
> in the protocol. Information on the study agent's Collaborative
> Agreement status will be provided in the approved LOI response
> letter.*
>
> [*Study Agent*]{.underline} is provided to the NCI under a
> Collaborative Agreement between [*Agent Manufacturer*]{.underline} and
> the DCTD, NCI (see Section 12.3).
>
> **8.3 Agent Ordering**
>
> NCI supplied agents may be requested by the Principal Investigator (or
> their authorized designee) at each participating institution.
> Pharmaceutical Management Branch (PMB) policy requires that agent be
> shipped directly to the institution where the patient is to be
> treated. PMB does not permit the transfer of agents between
> institutions (unless prior approval from PMB is obtained.) The CTEP
> assigned protocol number must be used for ordering all CTEP supplied
> investigational agents. The responsible investigator at each
> participating institution must be registered with CTEP, DCTD through
> an annual submission of FDA form 1572 (Statement of Investigator),
> Curriculum Vitae, Supplemental Investigator Data Form (IDF), and
> Financial Disclosure Form (FDF). If there are several participating
> investigators at one institution, CTEP supplied investigational agents
> for the study should be ordered under the name of one lead
> investigator at that institution.
>
> Agent may be requested by completing a Clinical Drug Request (NIH-986)
> and mailing it to the Pharmaceutical Management Branch, DCTD, NCI,
> 9000 Rockville Pike, EPN Room 7149, Bethesda, MD 20892-7422 or faxing
> it to (301) 480-4612. For questions call (301) 496-5725.
>
> **8.4 Agent Accountability**
>
> [Agent Inventory Records]{.underline} -- The investigator, or a
> responsible party designated by the investigator, must maintain a
> careful record of the inventory and disposition of all agents received
> from DCTD using the NCI Drug Accountability Record Form (DARF). (See
> the CTEP home page at
> [http://ctep.cancer.gov](http://ctep.cancer.gov/) for the Procedures
> for Drug Accountability and Storage and to obtain a copy of the DARF
> and Clinical Drug Request form.)

**9. CORRELATIVE/SPECIAL STUDIES**

> *Please briefly describe all planned correlative studies with
> reference to the "Guidelines for Correlative Studies in Clinical
> Trials" provided with the LOI response and available on the CTEP web
> site (<http://ctep.cancer.gov/guidelines/index.html>). **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 patients 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
> (<http://ctep.cancer.gov/forms/index.html> ). 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 is
> shown below and may be used or modified as required. If this trial
> does not include correlative or special studies, this section should
> be marked "N/A" and all instructions as well as the text below
> deleted.*
>
> 9.1 **Laboratory Correlative Studies**
>
> 9.1.1 [(*Title -- Laboratory Correlative Study #1*)]{.underline}
>
> 9.1.1.1 Collection of Specimen(s)
>
> 9.1.1.2 Handling of Specimens(s)
>
> 9.1.1.3 Shipping of Specimen(s)
>
> 9.1.1.4 Site(s) Performing Correlative Study
>
> 9.1.2 [(*Title -- Laboratory Correlative Study #2*)]{.underline}
>
> 9.1.2.1 Collection of Specimen(s)
>
> 9.1.2.2 Handling of Specimens(s)
>
> 9.1.2.3 Shipping of Specimen(s)
>
> 9.1.2.4 Site(s) Performing Correlative Study
>
> 9.2 **Special Studies**
>
> 9.2.1 [(*Title -- Special Correlative Study #1*)]{.underline}
>
> 9.2.1.1 Outcome Measure
>
> 9.2.1.2 Assessment
>
> 9.2.1.2.1 Method of Assessment
>
> 9.2.1.2.2 Timing of Assessment
>
> 9.2.1.3 Data Recording
>
> 9.2.1.3.1 Method of Recording
>
> 9.2.1.3.2 Timing of Recording

**10. STUDY CALENDAR**

> ***Schedules shown in the Study Calendar below are provided as an
> example and should be modified as appropriate.***
>
> Baseline evaluations are to be conducted within 1 week prior to
> administration of protocol therapy. Scans and x-rays must be done 4
> weeks prior to the start of therapy. In the event that the patient's
> condition is deteriorating, laboratory evaluations should be repeated
> within 48 hours prior to initiation of the next cycle of therapy.

<table>
<colgroup>
<col style="width: 23%" />
<col style="width: 6%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 5%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 10%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td>Pre-Study</td>
<td><p>Wk</p>
<p>1</p></td>
<td><p>Wk</p>
<p>2</p></td>
<td><p>Wk</p>
<p>3</p></td>
<td><p>Wk</p>
<p>4</p></td>
<td><p>Wk</p>
<p>5</p></td>
<td><p>Wk</p>
<p>6</p></td>
<td><p>Wk</p>
<p>7</p></td>
<td><p>Wk</p>
<p>8</p></td>
<td><p>Wk</p>
<p>9</p></td>
<td><p>Wk</p>
<p>10</p></td>
<td><p>Wk</p>
<p>11</p></td>
<td><p>Wk</p>
<p>12</p></td>
<td>Off Study<sup>d</sup></td>
</tr>
<tr class="even">
<td><em><u>CTEP IND Agent</u></em><sup>a</sup></td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Informed consent</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Demographics</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Medical history</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Concurrent meds</td>
<td>X</td>
<td
colspan="12">X----------------------------------------------------------------------------------------------X</td>
<td></td>
</tr>
<tr class="odd">
<td>Physical exam</td>
<td>X</td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
</tr>
<tr class="even">
<td>Vital signs</td>
<td>X</td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
</tr>
<tr class="odd">
<td>Height</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Weight</td>
<td>X</td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
</tr>
<tr class="odd">
<td>Performance status</td>
<td>X</td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
</tr>
<tr class="even">
<td>CBC w/diff, plts</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Serum chemistry<sup>b</sup></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>EKG (as indicated)</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Adverse event evaluation</td>
<td></td>
<td colspan="12">X
--------------------------------------------------------------------------------------------X</td>
<td>X</td>
</tr>
<tr class="even">
<td>Tumor measurements</td>
<td>X</td>
<td colspan="12">Tumor measurements are repeated every <u><em>[#
weeks]</em></u> weeks. Documentation (radiologic) must be provided for
patients removed from study for progressive disease.</td>
<td>X<sup>d</sup></td>
</tr>
<tr class="odd">
<td>Radiologic evaluation</td>
<td>X</td>
<td colspan="12">Radiologic measurements should be performed every
<u><em>[# weeks]</em></u> weeks.</td>
<td>X<sup>d</sup></td>
</tr>
<tr class="even">
<td>B-HCG</td>
<td>X<sup>c</sup></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Other tests, as appropriate</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Other correlative studies</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="15"><p>a: <em><u>CTEP IND Agent</u></em>: Dose as assigned;
route/schedule.</p>
<p>b: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN,
calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium,
total protein, SGOT[AST], SGPT[ALT], sodium.</p>
<p>c: Serum pregnancy test (women of childbearing potential).</p>
<p>d: Off-study evaluation.</p></td>
</tr>
</tbody>
</table>

**11. MEASUREMENT OF EFFECT**

*Please provide response criteria. If the criteria for solid tumors
below are not applicable, the investigator(s) should provide
disease-appropriate criteria (e.g., for specific hematologic
malignancies) with references, and all solid tumor criteria should be
deleted.*

11.1 **Antitumor Effect -- Solid Tumors**

For the purposes of this study, patients should be re-evaluated for
response every [*\[# of weeks\]*]{.underline} weeks. In addition to a
baseline scan, confirmatory scans should also be obtained *[\[# of
weeks\]]{.underline}* (not less than 4) weeks following initial
documentation of objective response.

Response and progression will be evaluated in this study using the new
international criteria proposed by the Response Evaluation Criteria in
Solid Tumors (RECIST) Committee \[*JNCI* 92(3):205-216, 2000\]. Changes
in only the largest diameter (unidimensional measurement) of the tumor
lesions are used in the RECIST criteria.

> 11.1.1 **Definitions**
>
> *Please use or modify the following text as appropriate.*
>
> [Evaluable for toxicity]{.underline}. All patients will be evaluable
> for toxicity from the time of their first treatment with \_[*\[Agent
> Name*\]\_]{.underline}.
>
> [Evaluable for objective response.]{.underline} Only those patients
> who have measurable disease present at baseline, have received at
> least one cycle of therapy, and have had their disease re-evaluated
> will be considered evaluable for response. These patients will have
> their response classified according to the definitions stated below.
> (Note: Patients who exhibit objective disease progression prior to the
> end of cycle 1 will also be considered evaluable.)
>
> 11.1.2 **Disease Parameters**
>
> [Measurable disease]{.underline}. Measurable lesions are defined as
> those that can be accurately measured in at least one dimension
> (longest diameter to be recorded) as [\>]{.underline}20 mm with
> conventional techniques (CT, MRI, x-ray) or as [\>]{.underline}10 mm
> with spiral CT scan. All tumor measurements must be recorded in
> [millimeters]{.underline} (or decimal fractions of centimeters).

Note: Tumor lesions that are situated in a previously irradiated area
might or might not be considered measurable. *If the investigator thinks
it appropriate to include them, the conditions under which such lesions
should be considered must be defined in the protocol*.

> [Non-measurable disease]{.underline}. All other lesions (or sites of
> disease), including small lesions (longest diameter \<20 mm with
> conventional techniques or \<10 mm using spiral CT scan), are
> considered non-measurable disease. Bone lesions, leptomeningeal
> disease, ascites, pleural/pericardial effusions, lymphangitis
> cutis/pulmonis, inflammatory breast disease, abdominal masses (not
> followed by CT or MRI), and cystic lesions are all non-measurable.
>
> [Target lesions.]{.underline} All measurable lesions up to a maximum
> of 5 lesions per organ and 10 lesions in total, representative of all
> involved organs, should be identified as **target lesions** and
> recorded and measured at baseline. Target lesions should be selected
> on the basis of their size (lesions with the longest diameter) and
> their suitability for accurate repeated measurements (either by
> imaging techniques or clinically). A sum of the longest diameter (LD)
> for all target lesions will be calculated and reported as the baseline
> sum LD. The baseline sum LD will be used as reference by which to
> characterize the objective tumor response.
>
> [Non-target lesions]{.underline}. All other lesions (or sites of
> disease) including any measurable lesions over and above the 10 target
> lesions should be identified as **non-target lesions** and should also
> be recorded at baseline. Measurements of these lesions are not
> required, but the presence or absence of each should be noted
> throughout follow-up.

11.1.3 **Methods for Evaluation of Measurable Disease**

All measurements should be taken and recorded in metric notation using a
ruler or calipers. All baseline evaluations should be performed as
closely as possible to the beginning of treatment and never more than 4
weeks before the beginning of the treatment.

The same method of assessment and the same technique should be used to
characterize each identified and reported lesion at baseline and during
follow-up. Imaging-based evaluation is preferred to evaluation by
clinical examination when both methods have been used to assess the
antitumor effect of a treatment.

[Clinical lesions]{.underline} Clinical lesions will only be considered
measurable when they are superficial (e.g., skin nodules and palpable
lymph nodes). In the case of skin lesions, documentation by color
photography, including a ruler to estimate the size of the lesion, is
recommended.

[Chest x-ray]{.underline} Lesions on chest x-ray are acceptable as
measurable lesions when they are clearly defined and surrounded by
aerated lung. However, CT is preferable.

[Conventional CT and MRI]{.underline} These techniques should be
performed with cuts of 10 mm or less in slice thickness contiguously.
Spiral CT should be performed using a 5 mm contiguous reconstruction
algorithm. This applies to tumors of the chest, abdomen, and pelvis.
Head and neck tumors and those of extremities usually require specific
protocols.

[Ultrasound (US)]{.underline} When the primary endpoint of the study is
objective response evaluation, US should not be used to measure tumor
lesions. It is, however, a possible alternative to clinical measurements
of superficial palpable lymph nodes, subcutaneous lesions, and thyroid
nodules. US might also be useful to confirm the complete disappearance
of superficial lesions usually assessed by clinical examination.

> [Endoscopy, Laparoscopy]{.underline} The utilization of these
> techniques for objective tumor evaluation has not yet been fully and
> widely validated. Their uses in this specific context require
> sophisticated equipment and a high level of expertise that may only be
> available in some centers. Therefore, the utilization of such
> techniques for objective tumor response should be restricted to
> validation purposes in reference centers. However, such techniques may
> be useful to confirm complete pathological response when biopsies are
> obtained.
>
> [Tumor markers]{.underline} Tumor markers alone cannot be used to
> assess response. If markers are initially above the upper normal
> limit, they must normalize for a patient to be considered in complete
> clinical response. Specific additional criteria for standardized usage
> of prostate-specific antigen (PSA) and CA-125 response in support of
> clinical trials are being developed.
>
> [Cytology, Histology]{.underline} These techniques can be used to
> differentiate between partial responses (PR) and complete responses
> (CR) in rare cases (e.g., residual lesions in tumor types, such as
> germ cell tumors, where known residual benign tumors can remain).
>
> The cytological confirmation of the neoplastic origin of any effusion
> that appears or worsens during treatment when the measurable tumor has
> met criteria for response or stable disease is mandatory to
> differentiate between response or stable disease (an effusion may be a
> side effect of the treatment) and progressive disease.

11.1.4 **Response Criteria**

11.1.4.1 **Evaluation of Target Lesions**

> [Complete Response (CR)]{.underline}: Disappearance of all target
> lesions
>
> [Partial Response (PR)]{.underline}: At least a 30% decrease in the
> sum of the longest diameter (LD) of target lesions, taking as
> reference the baseline sum LD
>
> [Progressive Disease (PD)]{.underline}: At least a 20% increase in the
> sum of the LD of target lesions, taking as reference the smallest sum
> LD recorded since the treatment started or the appearance of one or
> more new lesions

[Stable Disease (SD)]{.underline}: Neither sufficient shrinkage to
qualify for PR nor sufficient increase to qualify for PD, taking as
reference the smallest sum LD since the treatment started

11.1.4.2 **Evaluation of Non-Target Lesions**

[Complete Response (CR)]{.underline}: Disappearance of all non-target
lesions and normalization of tumor marker level

Note: If tumor markers are initially above the upper normal limit, they
must normalize for a patient to be considered in complete clinical
response.

[Incomplete Response/]{.underline}

[Stable Disease (SD)]{.underline}: Persistence of one or more non-target
lesion(s) and/or maintenance of tumor marker level above the normal
limits

[Progressive Disease (PD)]{.underline}: Appearance of one or more new
lesions and/or unequivocal progression of existing non-target lesions

Although a clear progression of "non-target" lesions only is
exceptional, the opinion of the treating physician should prevail in
such circumstances, and the progression status should be confirmed at a
later time by the review panel (or Principal Investigator).

11.1.4.3 **Evaluation of Best Overall Response**

The best overall response is the best response recorded from the start
of the treatment until disease progression/recurrence (taking as
reference for progressive disease the smallest measurements recorded
since the treatment started). The patient\'s best response assignment
will depend on the achievement of both measurement and confirmation
criteria.

+----------+------------+---------+---------+------------------------+
| **Target | **         | **New   | **      | **Best Response for    |
| L        | Non-Target | Le      | Overall | this Category Also     |
| esions** | Lesions**  | sions** | Res     | Requires:**            |
|          |            |         | ponse** |                        |
+----------+------------+---------+---------+------------------------+
| CR       | CR         | No      | CR      | [\>]{.underline}4 wks. |
|          |            |         |         | confirmation           |
+----------+------------+---------+---------+------------------------+
| CR       | Non        | No      | PR      | [\>]{.underline}4 wks. |
|          | -CR/Non-PD |         |         | confirmation           |
+----------+------------+---------+---------+------------------------+
| PR       | Non-PD     | No      | PR      |                        |
+----------+------------+---------+---------+------------------------+
| SD       | Non-PD     | No      | SD      | documented at least    |
|          |            |         |         | once [\>]{.underline}4 |
|          |            |         |         | wks. from baseline     |
+----------+------------+---------+---------+------------------------+
| PD       | Any        | Yes or  | PD      | no prior SD, PR or CR  |
|          |            | No      |         |                        |
+----------+------------+---------+---------+------------------------+
| Any      | PD\*       | Yes or  | PD      |                        |
|          |            | No      |         |                        |
+----------+------------+---------+---------+------------------------+
| Any      | Any        | Yes     | PD      |                        |
+----------+------------+---------+---------+------------------------+
| \* In    |            |         |         |                        |
| exc      |            |         |         |                        |
| eptional |            |         |         |                        |
| circum   |            |         |         |                        |
| stances, |            |         |         |                        |
| une      |            |         |         |                        |
| quivocal |            |         |         |                        |
| pro      |            |         |         |                        |
| gression |            |         |         |                        |
| in       |            |         |         |                        |
| no       |            |         |         |                        |
| n-target |            |         |         |                        |
| lesions  |            |         |         |                        |
| may be   |            |         |         |                        |
| accepted |            |         |         |                        |
| as       |            |         |         |                        |
| disease  |            |         |         |                        |
| prog     |            |         |         |                        |
| ression. |            |         |         |                        |
|          |            |         |         |                        |
| [No      |            |         |         |                        |
| te]{.und |            |         |         |                        |
| erline}: |            |         |         |                        |
| Patients |            |         |         |                        |
| with a   |            |         |         |                        |
| global   |            |         |         |                        |
| deter    |            |         |         |                        |
| ioration |            |         |         |                        |
| of       |            |         |         |                        |
| health   |            |         |         |                        |
| status   |            |         |         |                        |
| r        |            |         |         |                        |
| equiring |            |         |         |                        |
| discont  |            |         |         |                        |
| inuation |            |         |         |                        |
| of       |            |         |         |                        |
| t        |            |         |         |                        |
| reatment |            |         |         |                        |
| without  |            |         |         |                        |
| o        |            |         |         |                        |
| bjective |            |         |         |                        |
| evidence |            |         |         |                        |
| of       |            |         |         |                        |
| disease  |            |         |         |                        |
| pro      |            |         |         |                        |
| gression |            |         |         |                        |
| at that  |            |         |         |                        |
| time     |            |         |         |                        |
| should   |            |         |         |                        |
| be       |            |         |         |                        |
| reported |            |         |         |                        |
| as       |            |         |         |                        |
| "*sym    |            |         |         |                        |
| ptomatic |            |         |         |                        |
| deterior |            |         |         |                        |
| ation"*. |            |         |         |                        |
| Every    |            |         |         |                        |
| effort   |            |         |         |                        |
| should   |            |         |         |                        |
| be made  |            |         |         |                        |
| to       |            |         |         |                        |
| document |            |         |         |                        |
| the      |            |         |         |                        |
| o        |            |         |         |                        |
| bjective |            |         |         |                        |
| pro      |            |         |         |                        |
| gression |            |         |         |                        |
| even     |            |         |         |                        |
| after    |            |         |         |                        |
| discont  |            |         |         |                        |
| inuation |            |         |         |                        |
| of       |            |         |         |                        |
| tr       |            |         |         |                        |
| eatment. |            |         |         |                        |
+----------+------------+---------+---------+------------------------+

> 11.1.5 **Duration of Response**
>
> [Duration of overall response]{.underline}: The duration of overall
> response is measured from the time measurement criteria are met for CR
> or PR (whichever is first recorded) until the first date that
> recurrent or progressive disease is objectively documented (taking as
> reference for progressive disease the smallest measurements recorded
> since the treatment started).
>
> The duration of overall CR is measured from the time measurement
> criteria are first met for CR until the first date that recurrent
> disease is objectively documented.
>
> [Duration of stable disease]{.underline}: Stable disease is measured
> from the start of the treatment until the criteria for progression are
> met, taking as reference the smallest measurements recorded since the
> treatment started.
>
> 11.1.6 **Progression-Free Survival**
>
> *Include this section if time to progression or progression-free
> survival (PFS) are to be used. PFS is defined as the duration of time
> from start of treatment to time of progression.*
>
> 11.1.7 **Response Review**
>
> *For trials where the response rate is the primary endpoint, it is
> strongly recommended that all responses be reviewed by an expert(s)
> independent of the study at the study's completion. Simultaneous
> review of the patients' files and radiological images is the best
> approach.*

**11.2 Antitumor Effect -- Hematologic Tumors**

Please provide appropriate criteria for evaluation of response and
methods of measurement.

**11.3 Other Response Parameters**

Other endpoints and the criteria for their measurement should be entered
below or reference should be made to the protocol section where these
criteria may be found.

**12. DATA REPORTING / REGULATORY CONSIDERATIONS**

> Adverse event lists, guidelines, and instructions for AE reporting can
> be found in Section 7.0 (Adverse Events: List and Reporting
> Requirements).
>
> 12.1 **Data Reporting**
>
> 12.1.1 [Method]{.underline}
>
> This study will be monitored by the Clinical Data Update System (CDUS)
> version 3.0. Cumulative CDUS data will be submitted quarterly to CTEP
> by electronic means. Reports are due January 31, April 30, July 31,
> and October 31. Instructions for submitting data using the CDUS can be
> found on the CTEP web site
> ([http://ctep.cancer.gov](http://ctep.cancer.gov/)). **Note**:
> **[All]{.underline}** adverse events that have occurred on the study,
> including those reported through AdEERS, must be reported via CDUS.

2.  [Responsibility for Submissions]{.underline}

> Suggested text is provided below which can be modified as necessary.
> If this study is being performed within a single institution, this
> section should be marked "N/A" and the text below deleted.
>
> Study participants are responsible for submitting CDUS data and/or
> data forms to the Coordinating Center quarterly by \_[(date for Q1
> data)]{.underline}\_, \_[(date for Q2 data)]{.underline}\_, \_[(date
> for Q3 data)]{.underline}\_, and \_[(date for Q4 data)]{.underline}\_
> to allow time for Coordinating Center compilation, Principal
> Investigator review, and timely submission to CTEP (see Section
> 12.1.1.). For trials monitored by CTMS, the monthly data submission to
> CTEP from Theradex should be copied to the Coordinating Center.
>
> The Coordinating Center is responsible for compiling and submitting
> CDUS data to CTEP for all participants and for providing the data to
> the Principal Investigator for review.
>
> 12.2 **CTEP Multicenter Guidelines**

Suggested text is provided below which can be modified as necessary. If
this study is being performed within a single institution, this section
should be marked "N/A" and the text below deleted.

This protocol will adhere to the policies and requirements of the CTEP
Multicenter Guidelines. The specific responsibilities of the Principal
Investigator and the Coordinating Center (Study Coordinator) and the
procedures for auditing are presented in Appendix B.

-   The Principal 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
    individual IRBs for action as required.

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-   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.nih.gov>) except for Group studies.

> 12.3 **Cooperative Research and Development Agreement (CRADA)/Clinical
> Trials Agreement (CTA)**
>
> *If the investigational study agent is provided by CTEP under a
> Collaborative Agreement \[Cooperative Research and Development
> Agreement (CRADA), Clinical Trials Agreement (CTA), or Clinical Supply
> Agreement (CSA)\] with the manufacturer, this section must be included
> in the protocol. Information on the investigational study agent's
> CRADA/CTA/CSA status will be provided in the approved LOI response. If
> no Collaborative Agreement (CRADA, CTA, or CSA) 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
> ACollaborator(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@ (http:// ctep.cancer.gov/industry) 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 investigational 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
> patient or patient's family member participating on the study, the
> individual should sign a confidentiality agreement. A suitable model
> agreement can be downloaded from:
> [http://ctep.cancer.gov](http://ctep.cancer.gov/).
>
> 2\. For a clinical protocol where there is an investigational Agent
> used in combination with (an)other investigational 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 NIH, 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 investigational 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 investigational
> Agent.

3.  Clinical Trial Data and Results and Raw Data developed under a
    Collaborative Agreement will be made available exclusively to
    Collaborator(s), the NCI, and the FDA, as appropriate and unless
    additional disclosure is required by law or court order.
    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:
>
> Regulatory Affairs Branch, CTEP, DCTD, NCI
>
> Executive Plaza North, Suite 7111
>
> Bethesda, Maryland 20892
>
> FAX 301-402-1584
>
> Email: <anshers@mail.nih.gov>
>
> 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.

**13. STATISTICAL CONSIDERATIONS**

13.1 **Study Design/Endpoints**

> *Please specify the study design and primary endpoints. The design
> should provide for early termination for sufficiently discouraging
> results (e.g., by use of a 2-stage design). For the primary endpoint,
> indicate the "promising range", the range of true values sufficiently
> promising to justify further testing of the agent (e.g., **true**
> response rate of at least 20%). Likewise, for the primary endpoint
> indicate the "discouraging" range, a range of values sufficiently
> discouraging to justify no further testing of the agent (e.g.,
> **true** response rate no greater than 5%). Define the decision rule
> for declaring the agent promising based on the **observed value** of
> the primary endpoint. Give the probability of a positive result, given
> that the true value falls within the promising range, and the
> probability of a negative result (along with the probability of early
> negative termination), given that the true value falls within the
> discouraging range.*

13.2 **Sample Size/Accrual Rate**

> *Please specify the planned sample size and accrual rate (e.g.,
> patients/month).*

13.3 **Stratification Factors**

> *Please specify any planned patient stratification factors. Indicate
> whether interim monitoring and efficacy determination will be done for
> each stratum individually.*

13.4 **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.*

5.  **Reporting and Exclusions**

> 13.5.1 **Evaluation of toxicity.** All patients will be evaluable for
> toxicity from the time of their first treatment with *[\[CTEP IND
> Agent\]]{.underline}* .
>
> 13.5.2 **Evaluation of response.** All patients included in the study
> must be assessed for response to treatment, even if there are major
> protocol treatment deviations or if they are ineligible. Each patient
> will be assigned one of the following categories: 1) complete
> response, 2) partial response, 3) stable disease, 4) progressive
> disease, 5) early death from malignant disease, 6) early death from
> toxicity, 7) early death because of other cause, or 9) unknown (not
> assessable, insufficient data). \[Note: By arbitrary convention,
> category 9 usually designates the "unknown" status of any type of data
> in a clinical database.\]
>
> All of the patients who met the eligibility criteria (with the
> possible exception of those who received no study medication) should
> be included in the main analysis of the response rate. Patients in
> response categories 4-9 should be considered to have a treatment
> failure (disease progression). Thus, an incorrect treatment schedule
> or drug administration does not result in exclusion from the analysis
> of the response rate. Precise definitions for categories 4-9 will be
> protocol specific.
>
> All conclusions should be based on all eligible patients. Subanalyses
> may then be performed on the basis of a subset of patients, 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 patients from the analysis
> should be clearly reported. The 95% confidence intervals should also
> be provided.

**REFERENCES**

*Please provide the citations for all publications referenced in the
text.*

Informed Consent Template for Cancer Treatment Trials

**\* NOTES FOR INFORMED CONSENT AUTHORS:**

-   Model text suggested for use in the informed consent form is in
    **bold**. It is recommended that the **bold** text be retained when
    adapting the template to a specific protocol.

-   Instructions and examples for informed consent authors are in
    *\[italics\]*.

-   A blank line, \_\_\_\_\_\_\_\_\_\_, indicates that the local
    investigator should provide the appropriate information before the
    document is reviewed with the prospective research participant.

-   The term 'study doctor' has been used throughout the template
    because the Principal Investigator of a cancer treatment trial is a
    physician. If this template is used for a trial where the Principal
    Investigator is not a physician, another appropriate term should be
    used instead of 'study doctor'.

-   The template date in the header is for reference to this template
    only and should not be included in the informed consent form given
    to the prospective research participant.

**\* NOTES FOR LOCAL INVESTIGATORS:**

-   The goal of the informed consent process is to provide people with
    sufficient information for making informed choices. The informed
    consent form provides a summary of the clinical study and the
    individual\'s rights as a research participant. It serves as a
    starting point for the necessary exchange of information between the
    investigator and potential research participant. This template for
    the informed consent form is only one part of the larger process of
    informed consent. For more information about informed consent,
    review the \"Recommendations for the Development of Informed Consent
    Documents for Cancer Clinical Trials\" prepared by the Comprehensive
    Working Group on Informed Consent in Cancer Clinical Trials for the
    National Cancer Institute. The web site address for this document is
    <http://cancer.gov/clinicaltrials/understanding/simplification-of-informed-consent-docs>/

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-   A blank line, \_\_\_\_\_\_\_\_\_\_, indicates that the local
    investigator should provide the appropriate information before the
    document is reviewed with the prospective research participant.

-   Suggestion for Local Investigators: An NCI pamphlet explaining
    clinical trials is available for your patients. The pamphlet is
    entitled: \"If You Have Cancer...What You Should Know about Clinical
    Trials\". This pamphlet may be ordered on the NCI Web site at
    *<http://cissecure.nci.nih.gov/ncipubs/details.asp?pid=1035>* or
    call 1-800-4**-** CANCER (1-800-422-6237) to request a free copy.

-   Optional feature for Local Investigators: Reference and attach drug
    sheets, pharmaceutical information for the public, or other material
    on risks. Check with your local IRB regarding review of additional
    materials.

**\* These notes for authors and investigators are instructional and
should not be included in the informed consent form given to the
prospective research participant.**

Study Title *\[Title must be exactly the same as the title of the
protocol document.\]*

**This is a clinical trial, a type of research study. Your study doctor
will explain the clinical trial to you. Clinical trials include only
people who choose to take part. Please take your time to make your
decision about taking part. You may discuss your decision with your
friends and family. You can also discuss it with your health care team.
If you have any questions, you can ask your study doctor for more
explanation.**

**You are being asked to take part in this study because you have**
*\[Type/stage/presentation of cancer being studied is briefly described
here. For example: "Colon cancer that has spread and has not responded
to one treatment".\]*

Why is this study being done?

**The purpose of this study is to....** *\[Limit explanation to why
study is being done. Include a brief explanation of the mechanism of
action of the study agent in lay language and why an agent with this
mechanism is being studied in this kind of cancer. Explain in 1-3
sentences. An example is provided.\]*

*\[Example: Phase 2 study\]*

*Find out what effects, good and/or bad, \[drug/intervention\] has on
you and your \[specify type/stage/presentation of\] cancer. This
\[drug\] acts by preventing the growth of new blood vessels in tumors.
Because tumors need new blood vessels to grow and spread, \[drug\] may
stop blood vessel growth and spread of your \[specify
type/stage/presentation\] cancer.*

*\[Complete and include the following sentence if appropriate.\]*
**\[***Agent name***\] is an investigational or experimental anti-cancer
agent that has not been approved by the Food and Drug Administration for
use in this \[***type/stage/presentation of cancer***\].**

How many people will take part in the study?

**About** *\[state total accrual goal here\]* **people will take part in
this study.** *\[If appropriate, a short description about cohorts can
be given here. For example: "At the beginning of the study, (enter
number of first cohort) patients will be treated with a low dose of the
drug. If this dose does not cause bad side effects, it will slowly be
made higher as new patients take part in the study. A total of (enter
maximum number) patients are the most that would be able to enter the
study".*

What will happen if I take part in this research study?

\[List tests and procedures and their frequency under the categories
below. Include whether a patient will be at home, in the hospital, or in
an outpatient setting.\]

**Before you begin the study ...**

**You will need to have the following exams, tests or procedures to find
out if you can be in the study. These exams, tests or procedures are
part of regular cancer care and may be done even if you do not join the
study. If you have had some of them recently, they may not need to be
repeated. This will be up to your study doctor.**

-   *\[List tests and procedures as appropriate. Use bulleted format.\]*

**During the study ...**

**If the exams, tests and procedures show that you can be in the study,
and you choose to take part, then you will need the following tests and
procedures. They are part of regular cancer care.**

-   *\[List tests and procedures as appropriate. Use bulleted format.\]*

**You will need these tests and procedures that are part of regular
cancer care. They are being done more often because you are in this
study.**

-   *\[List tests and procedures as appropriate. Use bulleted format.
    Omit this section if no tests or procedures are being done more
    often than usual.\]*

**You will need these tests and procedures that are either being tested
in this study or being done to see how the study is affecting your
body.**

-   *\[List tests and procedures as appropriate. Use bulleted format.
    Omit this section if no tests or procedures are being tested in this
    study or required for safety monitoring.\]*

*\[For randomized studies:\]* **You will be \"randomized\" into one of
the study groups described below. Randomization means that you are put
into a group by chance. A computer program will place you in one of the
study groups. Neither you nor your doctor can choose the group you will
be in. You will have an** *\[equal/one in three/etc.\]* **chance of
being placed in any group.**

> **If you are in group 1 (often called \"Arm A\") *...*** *\[Explain
> what will happen for this group with clear indication of which
> interventions depart from routine care.\]*
>
> **If you are in group 2 (often called \"Arm B\")...** *\[Explain what
> will happen for this group with clear indication of which
> interventions depart from routine care.\]*
>
> *\[For studies with more than two groups, an explanatory paragraph
> containing the same type of information should be included for each
> group.\]*

**When I am finished taking *\[drugs or intervention\]...****\[Explain
the follow-up tests, procedures, exams, etc. required, including the
timing of each and whether they are part of standard cancer care or part
of standard care but being performed more often than usual or being
tested in this study. Define the length of follow-up.\]*

*\[Optional Feature: In addition to the mandatory narrative explanation
found in the preceding text, a simplified calendar (study chart) or
schema (study plan) may be inserted here. The schema from the protocol
should not be used as it is too complex, however a simplified version of
the schema is encouraged. Instructions for reading the calendar or
schema should be included. See examples.\]*

# Study Chart *\[Example\]*

**You will receive** \[drug(s) or intervention\] **every** \[insert
appropriate number of days or weeks\] **in this study. This** \[insert
appropriate number of days or weeks\] **period of time is called a
cycle. The cycle will be repeated** \[insert appropriate number\]
**times. Each cycle is numbered in order. The chart below shows what
will happen to you during Cycle 1 and future treatment cycles as
explained previously. The left-hand column shows the day in the cycle
and the right-hand column tells you what to do on that day.**

###### **Cycle 1**

######### Day What you do

+---------+------------------------------------------------------------+---+
| ­Two     | -   Get routine blood tests.                               |   |
| days    |                                                            |   |
| before  |                                                            |   |
| s       |                                                            |   |
| tarting |                                                            |   |
| study   |                                                            |   |
+---------+------------------------------------------------------------+---+
| Day     | -   Check-in to \_\_\_\_\_\_\_\_\_\_\_\_\_ the evening     |   |
| before  |     before starting study.                                 |   |
| s       |                                                            |   |
| tarting |                                                            |   |
| study   |                                                            |   |
+---------+------------------------------------------------------------+---+
| Day 1   | -   Begin taking \_\_\_\_\_\_ once a day. Keep taking      |   |
|         |     \_\_\_\_\_ until the end of study, unless told to stop |   |
|         |     by your health care team.                              |   |
+---------+------------------------------------------------------------+---+
| Day 2   | -   Leave \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ and go to where   |   |
|         |     you are staying.                                       |   |
+---------+------------------------------------------------------------+---+
| Day 8   | -   Get routine blood tests.                               |   |
+---------+------------------------------------------------------------+---+
| Day 15  | -   Get routine blood tests.                               |   |
+---------+------------------------------------------------------------+---+
| Day 22  | -   Get routine blood tests.                               |   |
+---------+------------------------------------------------------------+---+
| Day 28  | -   Get routine blood tests and exams.                     |   |
|         |                                                            |   |
|         | -   Get 2^nd^ chest x-ray for research purposes.           |   |
+---------+------------------------------------------------------------+---+
| Day 29  | -   Return to your doctor's office at \_\_\_\_\_\_\_       |   |
|         |     *\[insert appointment time\]* for your next exam and   |   |
|         |     to begin the next cycle.                               |   |
+---------+------------------------------------------------------------+---+

##   {#section .unnumbered}

## Future cycles {#future-cycles .unnumbered}

######### Day What you do {#day-what-you-do-1 .unnumbered}

+----------+-----------------------------------------------------------+
| Days     | -   Keep taking \_\_\_\_\_ once a day if you have no bad  |
| 1-28     |     side effects and cancer is not getting worse. Call    |
|          |     the doctor at \_\_\_\_\_\_\_\_\_\_\_\_\_ *\[insert    |
|          |     phone number\]* if you do not know what to do.        |
|          |                                                           |
|          | -   Get routine blood tests each week (more if your       |
|          |     doctor tells you to).                                 |
|          |                                                           |
|          | -   Get routine blood tests and exams every cycle (more   |
|          |     if your doctor tells you to).                         |
|          |                                                           |
|          | -   Get routine X-rays, CT scans, or MRIs every other     |
|          |     cycle (more if your doctor tells you to).             |
+----------+-----------------------------------------------------------+
| Day 29   | -   Return to your doctor's office at \_\_\_\_\_\_\_      |
|          |     *\[insert appointment time\]* for your next exam and  |
|          |     to begin the next cycle.                              |
+----------+-----------------------------------------------------------+

# Study Plan *\[Example\]*

Another way to find out what will happen to you during the study is to
read the chart below. Start reading at the top and read down the list,
following the lines and arrows.

How long will I be in the study?

**You will be asked to take** *\[drugs or intervention\]* **for**
*(months, weeks/until a certain event).* **After you are finished
taking** *\[drugs or intervention\]*, **the study doctor will ask you to
visit the office for follow-up exams for at least** *\[indicate time
frames and requirements of follow-up. When appropriate, state that the
study will involve long-term follow-up and specify time frames and
requirements of long-term follow-up. For example, "We would like to keep
track of your medical condition for the rest of your life. We would like
to do this by calling you on the telephone once a year to see how you
are doing. Keeping in touch with you and checking on your condition
every year helps us look at the long-term effects of the study."\]*

#### Can I stop being in the study?

**Yes. You can decide to stop at any time. Tell the study doctor if you
are thinking about stopping or decide to stop. He or she will tell you
how to stop safely.**

**It is important to tell the study doctor if you are thinking about
stopping so any risks from the** *\[drugs or intervention\]* **can be
evaluated by your doctor. Another reason to tell your doctor that you
are thinking about stopping is to discuss what follow up care and
testing could be most helpful for you.**

The study doctor may stop you from taking part in this study at any time
if he/she believes it is in your best interest; if you do not follow the
study rules; or if the study is stopped.

What side effects or risks can I expect from being in the study?

**You may have side effects while on the study. Everyone taking part in
the study will be watched carefully for any side effects. However,
doctors don't know all the side effects that may happen. Side effects
may be mild or very serious. Your health care team may give you
medicines to help lessen side effects. Many side effects go away soon
after you stop taking the** *\[drug(s) or intervention\]***. In some
cases, side effects can be serious, long lasting, or may never go
away.** *\[The next sentence should be included if appropriate.* **There
also is a risk of death.***\]*

*You should talk to your study doctor about any side effects that you
have while taking part in the study.*

**Risks and side effects related to the** *\[procedures, drugs,
interventions, devices\]* **include those which are:**

**[Likely]{.underline}**

-   
-   
-   
-   

**[Less Likely]{.underline}**

-   
-   
-   
-   

**[Rare but serious]{.underline}**

-   
-   
-   
-   

*\[Notes for consent form authors regarding the presentation of risks
and side effects:*

-   *Using a bulleted format, list risks and side effects related to the
    investigational aspects of the trial using layman's terms. Side
    effects of supportive medications should not be listed unless they
    are mandated by the study.*

-   *If available, the CAEPR (Comprehensive Adverse Events and Potential
    Risks) document should be used to determine the risks and side
    effects that should be included in the consent. These side effects
    should be presented in layman's terms. Consent form authors should
    contact <AdEERSMD@tech-res.com> to obtain a CAEPR (if available) for
    the study agent.*

-   *List by regimen the physical and nonphysical risks and side effects
    of participating in the study in three categories: 1.\" likely\"; 2.
    \"less likely"; 3. "rare but serious\".*

-   *There is no standard definition of \" likely\" and \"less likely".
    As a guideline, "likely" can be viewed as occurring in greater than
    20% of patients and "less likely" in less than or equal to 20% of
    patients. However, this categorization should be adapted to specific
    study agents by the principal investigator.*

-   *In the "likely" and "less likely" categories, identify those side
    effects that may be 'serious'. 'Serious' is defined as side effects
    that may require hospitalization or may be irreversible, long-term,
    life threatening or fatal.*

-   *Side effects that occur in less than 2-3% of patients do not have
    to be listed unless they are serious, and should then appear in the
    "rare but serious" category.*

-   *Physical and nonphysical risks and side effects should include such
    things as the inability to work. Whenever possible, describe side
    effects by how they make a patient feel, for example, "Loss of red
    blood cells, also called anemia, can cause tiredness, weakness and
    shortness of breath."*

-   *For some investigational drugs/interventions/devices there may be
    side effects that have been noted during treatment however not
    enough data is available to determine if the side effect is related
    to the drug/intervention/device. Because some local IRBs request to
    be informed of these possible side effects, this information, when
    available, is provided to the study chair. Inclusion of this
    information in the informed consent document is not mandatory.
    However, if included, these side effects should be listed under a
    separate category titled "Side effects reported by patients, but not
    proven to be caused by (drug/intervention/device)". Side effects in
    this category do not have to be labeled as "likely", "less likely"
    or "rare but serious" and should not be repeated here if they appear
    in a previous category. Similar to the other categories, these side
    effects should be listed in a bulleted format.\]*

**Reproductive risks: You should not become pregnant or father a baby
while on this study because the drugs in this study can affect an unborn
baby. Women should not breastfeed a baby while on this study. It is
important you understand that you need to use birth control while on
this study. Check with your study doctor about what kind of birth
control methods to use and how long to use them. Some methods might not
be approved for use in this study.** *\[Include a statement about
possible sterility when appropriate. For example, "Some of the drugs
used in the study may make you unable to have children in the future."
If appropriate include a statement that pregnancy testing may be
required.\]*

**For more information about risks and side effects, ask your study
doctor.**

Are there benefits to taking part in the study?

**Taking part in this study may or may not make your health better.
While doctors hope** *\[procedures, drugs, interventions, devices\]*
**will be more useful against cancer compared to the usual treatment,
there is no proof of this yet. We do know that the information from this
study will help doctors learn more about** *\[procedures, drugs,
interventions, devices\]* **as a treatment for cancer. This information
could help future cancer patients.**

What other choices do I have if I do not take part in this study?

Your other choices may include:

-   **Getting treatment or care for your cancer without being in a
    study**

-   **Taking part in another study**

-   **Getting no treatment**

*\[Additional bullets should include, when appropriate, alternative
specific procedures or treatments.\]*

-   *\[For studies involving end-stage cancer, add the following
    paragraph as an additional bullet.\]* **Getting comfort care, also
    called palliative care. This type of care helps reduce pain,
    tiredness, appetite problems and other problems caused by the
    cancer. It does not treat the cancer directly, but instead tries to
    improve how you feel. Comfort care tries to keep you as active and
    comfortable as possible.**

**Talk to your doctor about your choices before you decide if you will
take part in this study.**

Will my medical information be kept private?

We will do our best to make sure that the personal information in your
medical record will be kept private. However, we cannot guarantee total
privacy. Your personal information may be given out if required by law.
If information from this study is published or presented at scientific
meetings, your name and other personal information will not be used.

**Organizations that may look at and/or copy your medical records for
research, quality assurance, and data analysis include:**

-   *\[List relevant organizations like study sponsor(s), local IRB,
    etc.\]*

-   **The National Cancer Institute (NCI) and other government agencies,
    like the Food and Drug Administration (FDA), involved in keeping
    research safe for people**

-   *\[Pharmaceutical Collaborator/Agent Manufacturer\].*

*\[Note to Local Investigators: The NCI has recommended that HIPAA
regulations be addressed by the local institution. The regulations may
or may not be included in the informed consent form depending on local
institutional policy.\]*

What are the costs of taking part in this study?

You and/or your health plan/ insurance company will need to pay for some
or all of the costs of treating your cancer in this study. Some health
plans will not pay these costs for people taking part in studies. Check
with your health plan or insurance company to find out what they will
pay for. Taking part in this study may or may not cost your insurance
company more than the cost of getting regular cancer treatment.

*\[If applicable, inform the patient of any tests, procedures or agents
for which there is no charge. The explanation, when applicable, should
clearly state that there are charges resulting from performance of the
test or drug administration that will be billed to the patient and/or
health plan. For example, "The study agent, [,]{.underline} will be
provided free of charge by the Division of Cancer Treatment and
Diagnosis, NCI, while you are participating in this study. However, if
you should need to take the study agent much longer than is usual, it is
possible that the supply of free study agent that has been supplied to
the NCI could run out. If this happens, your study doctor will discuss
with you how to obtain additional drug from the manufacturer and you may
be asked to pay for it. However, you or your health plan may need to pay
for costs of the supplies and personnel who give you the (drug)."\].*

You will not be paid for taking part in this study.

*For more information on clinical trials and insurance coverage, you can
visit the National Cancer Institute's Web site at
<http://cancer.gov/clinicaltrials/understanding/insurance-coverage> .
You can print a copy of the "Clinical Trials and Insurance Coverage"
information from this Web site.*

*Another way to get the information is to call 1-800-4-CANCER
(1-800-422-6237) and ask them to send you a free copy.*

What happens if I am injured because I took part in this study?

**It is important that you tell your study doctor,
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_** *\[investigator's name(s)\],*
**if you feel that you have been injured because of taking part in this
study. You can tell the doctor in person or call him/her at
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_** *\[telephone number\].*

You will get medical treatment if you are injured as a result of taking
part in this study. You and/or your health plan will be charged for this
treatment. The study will not pay for medical treatment.

What are my rights if I take part in this study?

Taking part in this study is your choice. You may choose either to take
part or not to take part in the study. If you decide to take part in
this study, you may leave the study at any time. No matter what decision
you make, there will be no penalty to you and you will not lose any of
your regular benefits. Leaving the study will not affect your medical
care. You can still get your medical care from our institution.

We will tell you about new information or changes in the study that may
affect your health or your willingness to continue in the study.

**In the case of injury resulting from this study, you do not lose any
of your legal rights to seek payment by signing this form.**

Who can answer my questions about the study?

**You can talk to your study doctor about any questions or concerns you
have about this study. Contact your study doctor
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_** *\[name(s)\]* **at
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_** *\[telephone number\].*

For questions about your rights while taking part in this study, call
the \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **\[name of
center\]** Institutional Review Board (a group of people who review the
research to protect your rights) at \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
**(telephone number). \[Note to Local Investigator: Contact information
for patient representatives or other individuals in a local institution
who are not on the IRB or research team but take calls regarding
clinical trial questions can be listed here.\]**

**\*You may also call the Operations Office of the NCI Central
Institutional Review Board (CIRB) at 888-657-3711 (from the continental
US only).** *\[\*Only applies to sites using the CIRB.\]*

**Please note: This section of the informed consent form is about
additional research studies that are being done with people who are
taking part in the main study. You may take part in these additional
studies if you want to. You can still be a part of the main study even
if you say 'no' to taking part in any of these additional studies.**

**You can say "yes" or "no" to each of the following studies. Please
mark your choice for each study.**

*\[Insert information about companion studies here. Provide yes/no
options at each decision point. The following studies are included as
examples therefore are written with italicized font. Any text provided
for patients should use the same non-italicized font as used for the
rest of the informed consent document.\]*

*\[Example: Quality of Life study\]*

######## *Quality of Life Study*

*We want to know your view of how your life has been affected by cancer
and its treatment. This "Quality of life" study looks at how you are
feeling physically and emotionally during your cancer treatment. It also
looks at how you are able to carry out your day-to-day activities.*

*This information will help doctors better understand how patients feel
during treatments and what effects the medicines are having. In the
future, this information may help patients and doctors as they decide
which medicines to use to treat cancer*.

*You will be asked to complete 3 questionnaires: one on your first
visit, one 6 months later, and the last one 12 months after your first
visit. It takes about 15 minutes to fill out each questionnaire.*

*If any questions make you feel uncomfortable, you may skip those
questions and not give an answer.*

*If you decide to take part in this study, the only thing you will be
asked to do is fill out the three questionnaires. You may change your
mind about completing the questionnaires at any time.*

*Just like in the main study, we will do our best to make sure that your
personal information will be kept private.*

*Please circle your answer.*

> *I choose to take part in the Quality of Life Study. I agree to fill
> out the three Quality of Life Questionnaires.*
>
> *YES NO*

*\[Example: Use of Tissue for Research\]*

*\[The following example of tissue consent has been taken from the NCI
Cancer Diagnosis Program's model tissue consent form found at the
following url*

***<http://www.cancerdiagnosis.nci.nih.gov/specimens/model.pdf> \]***

*Consent Form for Use of Tissue for Research*

***About Using Tissue for Research***

*You are going to have a biopsy (or surgery) to see if you have cancer.
Your doctor will remove some body tissue to do some tests. The results
of these tests will be given to you by your doctor and will be used to
plan your care.*

*We would like to keep some of the tissue that is left over for future
research. If you agree, this tissue will be kept and may be used in
research to learn more about cancer and other diseases. Please read the
information sheet called \"How is Tissue Used for Research\" to learn
more about tissue research.*

*Your tissue may be helpful for research whether you do or do not have
cancer. The research that may be done with your tissue is not designed
specifically to help you. It might help people who have cancer and other
diseases in the future.*

*Reports about research done with your tissue will not be given to you
or your doctor. These reports will not be put in your health record. The
research will not have an effect on your care.*

***Things to Think About***

*The choice to let us keep the left over tissue for future research is
up to you. No matter what you decide to do, it will not affect your
care.*

*If you decide now that your tissue can be kept for research, you can
change your mind at any time. Just contact us and let us know that you
do not want us to use your tissue. Then any tissue that remains will no
longer be used for research.*

*In the future, people who do research may need to know more about your
health. While the xyz may give them reports about your health, it will
not give them your name, address, phone number, or any other information
that will let the researchers know who you are.*

*Sometimes tissue is used for genetic research (about diseases that are
passed on in families). Even if your tissue is used for this kind of
research, the results will not be put in your health records.*

*Your tissue will be used only for research and will not be sold. The
research done with your tissue may help to develop new products in the
future.*

***Benefits***

*The benefits of research using tissue include learning more about what
causes cancer and other diseases, how to prevent them, and how to treat
them.*

***Risks***

*The greatest risk to you is the release of information from your health
records. We will do our best to make sure that your personal information
will be kept private. The chance that this information will be given to
someone else is very small.*

***Making Your Choice***

*Please read each sentence below and think about your choice. After
reading each sentence, circle \"Yes\" or \"No\". If you have any
questions, please talk to your doctor or nurse, or call our research
review board at IRB\'s phone number.*

*No matter what you decide to do, it will not affect your care.*

*1. My tissue may be kept for use in research to learn about, prevent,
or treat cancer.*

  -------------------------------------- --------------------------------
  *Yes*                                  *No*

  -------------------------------------- --------------------------------

*2. My tissue may be kept for use in research to learn about, prevent or
treat other health problems (for example: diabetes, Alzheimer\'s
disease, or heart disease).*

  -------------------------------------- --------------------------------
  *Yes*                                  *No*

  -------------------------------------- --------------------------------

*3. Someone may contact me in the future to ask me to take part in more
research.*

  ----------------------------------------- -----------------------------
  *Yes*                                     *No*

  ----------------------------------------- -----------------------------

Where can I get more information?

**You may call the National Cancer Institute\'s Cancer Information
Service at:**

> **1-800-4-CANCER (1-800-422-6237)** or **TTY: 1-800-332-8615**

**You may also visit the NCI Web site at**
[**http://cancer.gov/**](http://cancer.gov/)

-   **For NCI's clinical trials information, go to:
    <http://cancer.gov/clinicaltrials/>**

-   **For NCI's general information about cancer, go to
    <http://cancer.gov/cancerinfo/>**

**You will get a copy of this form. If you want more information about
this study, ask your study doctor.**

Signature

**I have been given a copy of all \_\_\_\_\_** *\[insert total of number
of pages\]* **pages of this form. I have read it or it has been read to
me. I understand the information and have had my questions answered. I
agree to take part in this study.**

######### Participant \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

**Date
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

APPENDIX A

**Performance Status Criteria**

  ------------- -------------------------- ------------- ----------------------------
  **ECOG                                   **Karnofsky   
  Performance                              Performance   
  Status                                   Scale**       
  Scale**                                                

  Grade         Descriptions               Percent       Description

  0             Normal activity. Fully     100           Normal, no complaints, no
                active, able to carry on                 evidence of disease.
                all pre-disease                          
                performance without                      
                restriction.                             

                                           90            Able to carry on normal
                                                         activity; minor signs or
                                                         symptoms of disease.

  1             Symptoms, but ambulatory.  80            Normal activity with effort;
                Restricted in physically                 some signs or symptoms of
                strenuous activity, but                  disease.
                ambulatory and able to                   
                carry 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.  60            Requires occasional
                Ambulatory and capable of                assistance, but is able to
                all self-care, but unable                care for most of his/her
                to carry out any work                    needs.
                activities. Up and about                 
                more than 50% of waking                  
                hours.                                   

                                           50            Requires considerable
                                                         assistance and frequent
                                                         medical care.

  3             In bed \>50% of the time.  40            Disabled, requires special
                Capable of only limited                  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 20            Very sick, hospitalization
                disabled. Cannot carry on                indicated. Death not
                any self-care. Totally                   imminent.
                confined to bed or chair.                

                                           10            Moribund, fatal processes
                                                         progressing rapidly.

  5             Dead.                      0             Dead.
  ------------- -------------------------- ------------- ----------------------------

# APPENDIX B

## 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]{.underline}

-   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]{.underline}

-   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 patient
    registration. The Coordinating Center is responsible for assuring
    that IRB approval has been obtained at each participating site prior
    to the first patient 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 report 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 patients are brought from
    participating sites to the Coordinating Center for audit, or (2)
    selected patient 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, patient registration lists,
    response assessments scans, x-rays, etc. available for the audit.

> [Inclusion of Multicenter Guidelines in the Protocol]{.underline}

-   The protocol must include the following minimum information:

```{=html}
<!-- -->
```
-   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 patients 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]{.underline}

-   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.