## [Specific Instructions for the Use of Organ Dysfunction Templates]{.underline}

The goal of an organ dysfunction study is to define the dose of an agent
associated with an acceptable toxicity profile and measurable
pharmacokinetic parameter(s) in patients whose impaired organ function
may alter the absorption and disposition (pharmacokinetics) as well as
the efficacy and safety (pharmacodynamics) of that agent. Ideally, the
pharmacokinetic parameter(s) identified will correlate with the clinical
effects of an agent. The target level of the chosen parameter(s) could
thus serve to guide optimal dosing for a given patient. These organ
dysfunction templates are designed to evaluate toxicity and to measure
pharmacokinetic and pharmacodynamic parameters in each of five cohorts
of patients with varying degrees of organ dysfunction at each dose of
the agent administered.

Investigators planning to conduct studies in cancer patients with
impaired hepatic or renal function should consider the following points:

1.  **FDA Guidance**

> The investigator is advised to refer to the guidance provided by the
> Food and Drug Administration (FDA) on conducting studies in patients
> with organ dysfunction when planning their study. While not
> specifically written for neoplastic diseases, the following documents
> should be consulted:
>
> [Hepatic dysfunction]{.underline}: "Pharmacokinetics in Patients with
> Impaired Hepatic Function: Study Design, Data Analysis, and Impact on
> Dosing and Labeling" (posted 5/20/2003) is available as a Word
> (<http://www.fda.gov/cder/guidance/3625fnl.doc>) or PDF
> (<http://www.fda.gov/cder/guidance/3625fnl.pdf>) document.
>
> [Renal dysfunction]{.underline}: "Pharmacokinetics in Patients with
> Impaired Renal Function: Study Design, Data Analysis, and Impact on
> Dosing and Labeling" (posted 5/14/1998) is available as a PDF document
> (<http://www.fda.gov/cder/guidance/1449fnl.pdf>).

2.  **Extensive PK Sampling**

Investigators planning to conduct studies in these special groups of
patients should be prepared to conduct extensive pharmacokinetic (PK)
sampling for the agent in question as well as its active metabolites to
provide meaningful results that will lead to appropriate dosing
recommendations. Identification of PK parameter(s) that correlate with
an acceptable toxicity profile and which can then guide future dose
recommendations (*e.g.,* AUC when used as the target level for
carboplatin dosing) is a goal of these studies. Because relatively small
patient cohorts are indicated, detailed PK measurements become
especially important. Once the PK parameter(s) and the target level have
been identified in a small study cohort (six patients), an expanded
cohort of 12-15 patients should be treated using the selected
parameter(s) and target level with extensive PK measurements to validate
use of the parameter(s) to guide dosing.

3.  **CYP450 Metabolic Interactions**

> The possibility that enzymatic activity of the CYP450 system may
> affect the agent of interest or its metabolites should be considered
> as well as the effect of concomitant medications. Investigators should
> also consider the possibility that these metabolic products could be
> excreted via an alternative route rather than the known primary route
> of elimination. An example of a table showing potentially
> CYP450-interactive medications is provided in Appendix C of this
> template. The investigator is also advised to consult the annually
> updated Drug Information Handbook (see reference cited at the end of
> Appendix C) for current information.

4.  **Combination Regimens**

If a study using a combination of agents is under consideration, the
investigator is strongly advised to consult with the FDA on an
appropriate design prior to drafting the protocol. Some of the relevant
issues that must be addressed include (1) the choice of regimen and (2)
the need for extensive sampling and PK measurements to isolate and
identify any interactions between the agents administered.

5.  **Data Capture**

Investigators who conduct an organ dysfunction study should plan to make
the raw data from their trial available to the FDA in the final study
report. Data of interest include those data used to estimate hepatic
function and to calculate the Child-Pugh Classification (CPC; hepatic
studies) or data used to estimate the creatinine clearance using the
Cockroft-Gault formula and to estimate the glomerular filtration rate
using the MDRD formula (renal studies). In addition, the final study
report should contain all pharmacokinetic, pharmacodynamic, clinical,
and laboratory data from the trial as well as the case report forms.

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.*

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

**TITLE:** A Phase 1 and Pharmacokinetic Single Agent Study of *[Study
Agent]{.underline}* in Patients with Advanced Malignancies and Varying
Degrees of Renal Dysfunction

**Coordinating Center:** *Name of Organization (For this
multi‑institutional study, only one organization/institution can be the
coordinating center.)*

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

*Address*

*Address*

*Telephone*

*Fax*

*e-mail address*

**Participating Sites/Co‑Investigators:**

+-----------------------------------+-----------------------------------+
| *Name*                            | *Name*                            |
|                                   |                                   |
| *Address*                         | *Address*                         |
|                                   |                                   |
| *Address*                         | *Address*                         |
|                                   |                                   |
| *Telephone*                       | *Telephone*                       |
|                                   |                                   |
| *Fax*                             | *Fax*                             |
|                                   |                                   |
| *e-mail address*                  | *e-mail address*                  |
+-----------------------------------+-----------------------------------+
| *Name*                            | *Name*                            |
|                                   |                                   |
| *Address*                         | *Address*                         |
|                                   |                                   |
| *Address*                         | *Address*                         |
|                                   |                                   |
| *Telephone*                       | *Telephone*                       |
|                                   |                                   |
| *Fax*                             | *Fax*                             |
|                                   |                                   |
| *e-mail address*                  | *e-mail address*                  |
+-----------------------------------+-----------------------------------+
| *Name*                            | *Name*                            |
|                                   |                                   |
| *Address*                         | *Address*                         |
|                                   |                                   |
| *Address*                         | *Address*                         |
|                                   |                                   |
| *Telephone*                       | *Telephone*                       |
|                                   |                                   |
| *Fax*                             | *Fax*                             |
|                                   |                                   |
| *e-mail address*                  | *e-mail address*                  |
+-----------------------------------+-----------------------------------+
| *Name*                            | *Name*                            |
|                                   |                                   |
| *Address*                         | *Address*                         |
|                                   |                                   |
| *Address*                         | *Address*                         |
|                                   |                                   |
| *Telephone*                       | *Telephone*                       |
|                                   |                                   |
| *Fax*                             | *Fax*                             |
|                                   |                                   |
| *e-mail address*                  | *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 web
site 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, by telephone at
301-496-5725 or by email at <PMBRegPend@ctep.nci.nih.gov>. Please
indicate on the title page if a Co-Investigator is NOT responsible for
patient care and therefore does not require a current 1572, SIDF, FDF,
and CV on file.*

**Statistician:** *Name*

*(if applicable) Address*

*Address*

*Telephone*

*Fax*

*e-mail address*

**Responsible Research**

**Nurse:** *Name*

*Address*

*Address*

### Telephone

*Fax*

*e-mail address*

**Organ Dysfunction**

**Working Group**

**Coordinator:** *Name*

*Address*

*Address*

*Telephone*

*Fax*

*e-mail address*

**NCI Supplied Agent**: *[Study Agent (NSC #; IND #)]{.underline}*

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

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

SCHEMA

####### RENAL DYSFUNCTION GROUPS

Patients entering this study will be stratified into five groups or
cohorts (A: normal, B: mild dysfunction, C: moderate dysfunction, D:
severe dysfunction, E: renal dialysis) according to their renal function
based on their estimated body-surface area (BSA)-indexed creatinine
clearance (CrCl) as defined by the following table:

+----------------------+--------+--------+--------+--------+--------+
| **Group**            | *      | *      | *      | *      | *      |
|                      | *Group | *Group | *Group | *Group | *Group |
| #######              | A**    | B**    | C**    | D**    | E**    |
|                      |        |        |        |        |        |
| ##                   | **No   | **     | **Mode | **Se   | **R    |
| ##### Renal Function | rmal** | Mild** | rate** | vere** | enal** |
|                      |        |        |        |        |        |
|                      |        |        |        |        | **Dial |
|                      |        |        |        |        | ysis** |
+----------------------+--------+--------+--------+--------+--------+
| #######              | [\>]{. | 40-59  | 20-39  | \< 20  | Any    |
|                      | underl |        |        |        |        |
| ######               | ine}60 |        |        |        |        |
| # BSA-indexed CrCl\* |        |        |        |        |        |
+----------------------+--------+--------+--------+--------+--------+

\* The BSA-indexed CrCl is determined using the procedure described in
Section 5.1.

####### INVESTIGATIONAL AGENT

*Please state route and schedule of Study Agent administration, and
enter exact doses for each dose level and group in the table below. (For
example, "Agent XXX is given intravenously as a 1-hour infusion on days
1, 3, and 5 of a 21-day cycle.)*

*\_[\_Study Agent]{.underline}*[\_]{.underline} is given
\_*[(route/duration)]{.underline}* on \_\_*[(day/days)\_]{.underline}*
of a \_\_*[(#)-day]{.underline}*\_ cycle.

+-----------+-----------+-----------+-----------+----------+----------+
|           | **Group   | **Group   | **Group   | #######  | #######  |
|           | A**       | B**       | C**       |  Group D |  Group E |
+-----------+-----------+-----------+-----------+----------+----------+
| **Dose**  | **Normal  | **Mild    | *         | **Severe | *        |
|           | renal     | renal     | *Moderate | renal    | *Renal** |
| **Level** | f         | dysf      | renal     | dysf     |          |
|           | unction** | unction** | dys       | unction\ | **d      |
|           |           |           | function\ | (\_**    | ialysis\ |
|           | **(       | **(       | (         | [(*units | (\_**    |
|           | \_**[(*un | \_**[(*un | \_**[(*un | )*]{.und | [(*units |
|           | its)*]{.u | its)*]{.u | its)*]{.u | erline}\ | )*]{.und |
|           | nderline} | nderline} | nderline} | _**)\*** | erline}\ |
|           | \_**)\*** | \_**)\*** | \_**)\*** |          | _**)\*** |
+-----------+-----------+-----------+-----------+----------+----------+
| **Level   |           |           |           |          | \*\*     |
| --1**     |           |           |           |          |          |
+-----------+-----------+-----------+-----------+----------+----------+
| **Level   |           |           |           |          | \*\*     |
| 1**       |           |           |           |          |          |
+-----------+-----------+-----------+-----------+----------+----------+
| **Level   |           |           |           |          | \*\*     |
| 2**       |           |           |           |          |          |
+-----------+-----------+-----------+-----------+----------+----------+
| **Level   |           |           |           |          | \*\*     |
| 3**       |           |           |           |          |          |
+-----------+-----------+-----------+-----------+----------+----------+
| **Level   |           |           |           |          | \*\*     |
| 4**       |           |           |           |          |          |
+-----------+-----------+-----------+-----------+----------+----------+
| *\* Doses |           |           |           |          |          |
| are       |           |           |           |          |          |
| stated as |           |           |           |          |          |
| exact     |           |           |           |          |          |
| dose in   |           |           |           |          |          |
| units     |           |           |           |          |          |
| (e.g.,    |           |           |           |          |          |
| mg/m^2^,  |           |           |           |          |          |
| mcg/kg,   |           |           |           |          |          |
| etc.)     |           |           |           |          |          |
| rather    |           |           |           |          |          |
| than as a |           |           |           |          |          |
| per       |           |           |           |          |          |
| centage.* |           |           |           |          |          |
+-----------+-----------+-----------+-----------+----------+----------+

\*\* (See Section 5.1 for the Group E dosing scheme.)

Note: This schema is not to be used for determining dosage for any
individual patient. For specific dosing information, please refer to
Sections 5 and 6.

TABLE OF CONTENTS

Page

**SCHEMA**

**1. OBJECTIVES**

1.  **Primary Objectives**

2.  **Secondary Objectives**

**2. BACKGROUND**

> **2.1 *[Study Agent]{.underline}***

2.  **Rationale for a Phase 1 Study in Patients with Renal Dysfunction**

3.  **Stratification by Level of Renal Dysfunction**

**3. PATIENT SELECTION**

**3.1 Eligibility Criteria**

**3.2 Exclusion Criteria**

**3.3 Inclusion of Women and Minorities**

**4. REGISTRATION PROCEDURES**

1.  **General Guidelines**

2.  **Registration Process**

**5. TREATMENT PLAN**

**5.1 Stratification by Renal Function**

**5.2 *[Study Agent]{.underline}* Administration**

**5.3 Definition of Dose-Limiting Toxicity**

**5.4 Dose Escalation Scheme**

5.  **Supportive Care Guidelines**

**5.6 Patient Care Considerations**

> **5.7 Duration of Therapy**
>
> **5.8 Duration of Follow Up**
>
> **5.9 Criteria for Removal from Study**

**6. DOSING DELAYS/DOSE MODIFICATIONS**

1.  **Retreatment Criteria**

2.  **Dose Modification Guidelines**

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

1.  **Comprehensive Adverse Events and Potential Risks List**

2.  **Adverse Event Characteristics**

3.  **Expedited Adverse Event Reporting**

4.  **Routine Adverse Event Reporting**

5.  **Secondary AML/MDS**

**8. PHARMACEUTICAL INFORMATION**

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

**9. CORRELATIVE/SPECIAL STUDIES**

> **9.1 Pharmacokinetic Studies**
>
> **9.2 Pharmacodynamic 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**

> **12.1 Data Reporting**
>
> **12.2 Data Monitoring and Safety Plan**

**12.3 CTEP Multicenter Guidelines**

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

**Clinical Trials Agreement (CTA)**

**13. STATISTICAL CONSIDERATIONS**

> **13.1 Study Design**
>
> **13.2 Endpoints**
>
> **13.3 Sample Size/Accrual Rate**
>
> **13.4 Stratification Factors**
>
> **13.5 Analysis of Secondary Endpoints**

**REFERENCES**

**APPENDICES**

**APPENDIX A**

MDRD Formula for Estimation of Glomerular Filtration Rate

**APPENDIX B**

Performance Status Criteria

**APPENDIX C (*Example)***

Drugs Known to be Metabolized by Selected CYP450 Isoenzymes

**APPENDIX D**

CTEP Multicenter Guidelines

**APPENDIX E**

Forms

**1. OBJECTIVES**

1.  **Primary Objectives**

-   To establish the maximum tolerated dose (MTD) and dose-limiting
    toxicity (DLT) of \_\_*[(Study Agent)]{.underline}*\_\_ in groups of
    patients with varying degrees of renal dysfunction (mild, moderate,
    severe, and dialysis) in order to provide appropriate dosing
    recommendations for \_\_*[(Study Agent)]{.underline}*\_\_ in such
    patients.

-   To characterize the pharmacokinetic (PK) and pharmacodynamic
    profiles of \_\_*[(Study Agent)]{.underline}*\_\_in patients with
    varying degrees of renal dysfunction.

> **1.2 Secondary Objectives**

-   To document the non-DLTs associated with administration of
    \_\_*[(Study Agent)]{.underline}*\_ in patients with renal
    dysfunction.

-   To document any antitumor activity associated with *[\_Study
    Agent\_]{.underline}* treatment of patients enrolled on this study.

**2. BACKGROUND**

**2.1 *[Study 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 PK, safety profile, and the
> rationale for the proposed starting doses and dose escalation scheme.
> Please clearly indicate if the liver or kidney is known to be the
> major route of elimination. Please include information on the
> metabolism of the study agent in humans and its potential for renal or
> drug interactions, if available.*

**2.2 Rationale for a Phase 1 Study in Patients with Renal Dysfunction**

> *Please provide the background and rationale for evaluating the study
> agent in patients with renal dysfunction including information such as
> the primary mode of excretion of the agent, its therapeutic index, and
> why this particular patient population has been chosen for study.
> Guidance on PK studies in such patients can be found at*
> <http://www.fda.gov/cder/guidance/1449fnl.pdf>.

**2.3 Stratification by Level of Renal Dysfunction**

> Renal function levels in clinical trials are commonly described in
> terms of creatinine clearance (CrCl) calculated using a formula such
> as Cockcroft-Gault (Cockcroft and Gault, 1976). This formula estimates
> CrCl based on the serum creatinine concentration in a 24-hour urine
> collection plus a single measurement of serum creatinine in addition
> to demographic data. Because this trial is designed to determine
> appropriate dosing of therapeutic agents for patients with cancer who
> have impaired kidney function, the accuracy of the dysfunction
> parameter used for stratification is critical. The stability of this
> measure impacts its accuracy, so this trial will place patients in a
> group or stratum based on two 24-hour urine collections where the CrCl
> values do not differ by more than 25% rather than using the
> Cockcroft-Gault formula. (See Section 5.1 for details of this
> procedure.) In addition, body surface area (BSA) indexing will be used
> to avoid over- or underestimation of renal impairment and because many
> agents are dosed on the basis of BSA.
>
> While the glomerular filtration rate (GFR) is generally accepted as a
> superior overall measure of renal function compared to CrCl, the best
> methods for GFR determination (inulin clearance, ^125^I-iothalamate,
> etc.) are not readily availably or are impractical in the patient care
> setting. However, data from a large trial in patients with renal
> disease (Modification of Diet in Renal Disease; MDRD) were used to
> derive a formula that estimates GFR more accurately than measured CrCl
> or other equations (Levey *et al*., 1999). The "MDRD formula" is
> presented in Appendix A. Although not used in the current study,
> investigators are encouraged to collect the required data on case
> report forms to permit retrospective assessment of this method of
> estimating renal function in cancer patients.

**This trial will use BSA-normalized CrCl (based on two or more 24-hour
urine collections and normalized for body surface area) to stratify
patients rather than renal dysfunction measurements based on the
Cockcroft-Gault formula or GFR.**

**3. PATIENT SELECTION**

> **3.1 Eligibility Criteria**
>
> 3.1.1 *Please select the appropriate text below depending on the agent
> under study and delete the unused text. Patients with hematologic
> malignancies should not be included in the study of an agent where
> myelosuppression is known to be dose limiting.*
>
> Patients must have histologically or cytologically confirmed solid or
> hematologic malignancy that is metastatic or unresectable and for
> which standard curative or palliative measures do not exist or are no
> longer effective.
>
> *OR*
>
> Patients must have a histologically or cytologically confirmed solid
> malignancy or lymphoma that is metastatic or unresectable and for
> which standard curative or palliative measures do not exist or are no
> longer effective.
>
> *OR*
>
> Patients must have histologically or cytologically confirmed advanced
> hematologic malignancy for which standard curative or palliative
> measures do not exist or are no longer effective.
>
> 3.1.2 Age [\>]{.underline}18 years.
>
> 3.1.3 Life expectancy of \>3 months.
>
> 3.1.4 ECOG performance status [\<]{.underline}2 (Karnofsky
> [\>]{.underline}60%, see Appendix B).
>
> 3.1.5 Patients must have acceptable hepatic and marrow function as
> defined below:

\- absolute neutrophil count [\>]{.underline}1.5 x 10^9^/L

\- platelets [\>]{.underline}100 x 10^9^/L

\- total bilirubin within normal institutional limits

> \- AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal.

6.  Patients with abnormal renal function will be eligible and will be
    grouped according to the criteria in Section 5.1. Kidney function
    tests should be repeated within 24 hours prior to starting initial
    therapy.

7.  Patients with gliomas or brain metastases who require
    corticosteroids or anticonvulsants must be on a stable dose of
    corticosteroids and seizure free for 1 month prior to enrollment.
    Patients with known brain metastases should have had brain
    irradiation (whole brain or gamma knife) more than 4 weeks before
    starting the protocol.

8.  Eligibility of patients receiving any medications or substances
    known to affect or with the potential to affect the activity or PK
    of \_*[(Study Agent)]{.underline}*\_ will be determined following
    review of their case by the Principal Investigator and the CTEP
    senior investigators. Efforts should be made to switch patients with
    gliomas or brain metastases who are taking anticonvulsant agents to
    other medications. (A list of medications and substances known or
    with the potential to interact with selected CYP450 isoenzymes is
    provided in Appendix C.)

> 3.1.9 The effects of *[Study Agent]{.underline}* on the developing
> human fetus are unknown. For this reason and because *[Agent
> Class]{.underline}* agents are known to be teratogenic, women of
> childbearing 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, biologic therapy,
> immunotherapy, 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.

2.  Patients must not have had a major surgery within 14 days prior to
    registration/treatment.

3.  Patient may not have received prior therapy with \_\_*[Study
    Agent]{.underline}*\_\_. However, if the patient is otherwise
    eligible, discuss this issue with the Principal Investigator.

4.  Patients may not be receiving any other investigational agents.

> 3.2.5 Patients with unstable or untreated (non-irradiated) 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.
>
> 3.2.6 History of allergic reactions attributed to compounds of similar
> chemical or biologic composition to *[Study Agent]{.underline}* .
>
> 3.2.7 *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
> (number or letter)]{.underline}*\_.
>
> 3.2.8 *Please insert other appropriate agent-specific exclusion
> criteria.*
>
> 3.2.9 Patients may not have active hemolysis.
>
> 3.2.10 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.
>
> 3.2.11 Pregnant women are excluded from this study because *[Study
> 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 *[Study Agent]{.underline}*
> , breastfeeding should be discontinued if the mother is treated with
> *[Study Agent]{.underline}* .
>
> 3.2.12 HIV-positive patients on combination antiretroviral therapy are
> ineligible because of the potential for PK interactions with \_*[Study
> 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. However,
> HIV-positive patients without an AIDS-defining diagnosis who are
> [not]{.underline} receiving agents with the potential for PK
> interactions with \_*[Study Agent]{.underline}*\_ may be eligible.

**3.3 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**

**4.1 General Guidelines**

> Eligible patients will be entered on study centrally at the
> \_\_*[(Coordinating Center)]{.underline}* \_ by the Organ Dysfunction
> Working Group Coordinator. All sites should call the Coordinator
> (\_\_*[Telephone \#]{.underline}*\_\_) to verify dose level
> availabilities. The required forms (Eligibility Screening Worksheet
> and Registration Form) can be found in Appendix F.
>
> Following registration, patients should begin protocol treatment
> within 24 hours. In cases where drug supply is limited and "starter
> supplies" are not available, delays of up to 72 hours are acceptable,
> although treatment within 24 hours is preferable. Other issues that
> would cause treatment delays should be discussed with the Principal
> Investigator. If a patient does not receive protocol therapy, the
> patient's registration on the study may be canceled. The Organ
> Dysfunction Working Group Coordinator should be notified of
> cancellations as soon as possible.
>
> Except in very unusual circumstances, each participating institution
> will order DCTD-supplied investigational agents directly from CTEP.
> Investigational agents may be ordered by a participating site only
> after the initial IRB approval for the site has been forwarded by the
> Coordinating Center to the CTEP PIO (<PIO@ctep.nci.nih.gov>).

**4.2 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 Organ Dysfunction Working Group Coordinator:

-   Eligibility Screening Worksheet

-   Registration Form

-   Copy of required laboratory tests

-   Signed patient consent form

-   HIPAA authorization form (signed by patient).

> 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 the patient a study number

-   assign the patient a dose

-   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**

1.  **Stratification by Renal Function**

> Patients entering this study will be stratified into five groups or
> cohorts (A: normal, B: mild dysfunction, C: moderate dysfunction, D:
> severe dysfunction, E: renal dialysis) according to their renal
> function, as outlined in the following table:

+-----------------+----------+---------+----------+---------+---------+
| **Group**       | **Group  | **Group | **Group  | **      | **Group |
|                 | A**      | B**     | C**      | Group** | E**     |
| #######         |          |         |          |         |         |
|                 |          |         |          | **D**   |         |
| #######         |          |         |          |         |         |
|  Renal Function |          |         |          |         |         |
+-----------------+----------+---------+----------+---------+---------+
|                 | **       | *       | **Mo     | **S     | **Renal |
|                 | Normal** | *Mild** | derate** | evere** | Dia     |
|                 |          |         |          |         | lysis** |
+-----------------+----------+---------+----------+---------+---------+
| BSA-indexed     | [\       | 40-59   | 20-39    | \<20    | Any     |
| CrCl\*          | >]{.unde |         |          |         |         |
|                 | rline}60 |         |          |         |         |
+-----------------+----------+---------+----------+---------+---------+

> \* The body-surface area (BSA)-indexed creatinine clearance (CrCl) is
> calculated using the following equation:
>
> BSA-indexed CrCl = creatinine clearance (mL/min) x (1.73/actual BSA)

-   BSA-indexed CrCl should be calculated at baseline and prior to each
    treatment cycle. To assure that patients have relatively stable
    renal function for the initial part of the protocol, all patients
    must have at least two separate 24-hour urine collections for
    estimation of CrCl with the most recent collection performed within
    1 week of starting therapy. If the two measurements differ by more
    than 25%, a third 24-hour CrCl will be obtained. Stratification will
    be based on the most recent 24-hour CrCl that does not deviate from
    an earlier measurement by more than 25%.

-   In calculating surface areas, actual heights and weights should be
    used; that is, there should be no adjustment to "ideal" weight.
    However, renal dialysis patients should have body surface area
    calculation based on dry weight (*e.g.,* post dialysis).

```{=html}
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```
-   All renal function tests must be completed within 24 hours prior to
    the start of treatment.

-   Group E (renal dialysis): Patients receiving renal dialysis should
    be stratified for dosing purposes to the group (B, C, or D) in which
    their BSA-indexed CrCl matches or is better than the criteria
    defined for non-dialysis patients.

-   Patients whose degree of renal dysfunction changes (becomes worse or
    better) between registration and initiation of protocol therapy may
    be re-assigned to a different dysfunction group and dose level. This
    change should be discussed with the Principal Investigator.

-   Group A (normal): Patients in Group A are included in this study as
    control subjects and will be followed for toxicity; however, the
    definitions of DLT in section 5.3 will not apply and a recommended
    dose will not be defined in these patients.

> **5.2 [\_\_*(Study Agent)*\_]{.underline} Administration**
>
> *Please state the route and schedule of\_ [(Study
> Agent)\_]{.underline} administration. (For example, "Agent XXX is
> given intravenously as a 1-hour infusion on days 1, 3, and 5 of a
> 21-day cycle.")* Treatment will be administered on an
> *[inpatient/outpatient]{.underline}* basis. To allow for renal
> function testing within 24 hours prior to the start of drug
> administration and maximum PK sampling within a standard working week,
> the first dose of \_*[(Study Agent)]{.underline}*\_ should be
> administered on a Tuesday. However, for those institutions with
> resources able to obtain PKs on weekends, treatment may be started on
> other days.
>
> *Please state any special precautions or warnings relevant for agent
> administration (e.g., incompatibility of 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 Nomenclature and Expression.*
>
> The patient's starting dose will be assigned by the Organ Dysfunction
> Working Group Coordinator at the time of registration according to the
> schema and rules outlined in Sections 5.4 (dose escalation scheme) and
> 5.4.1 (dose escalation rules). The dose may be reduced for individual
> patients in subsequent cycles depending on toxicity (Section 6.2).
>
> Reported adverse events (AEs) and potential risks of \_*[(Study
> Agent)]{.underline}* are described in Section 7.1. Appropriate dose
> modifications for \_\_*[(Study Agent)]{.underline}* are described in
> Section 6.2. No investigational or commercial agents or therapies
> other than those described in Section 5.0 (Treatment Plan) may be
> administered with the intent to treat the patient's malignancy.

**5.3 Definition of Dose-Limiting Toxicity**

> Toxicities will be graded according to the NCI Common Terminology
> Criteria for Adverse Events (CTCAE) v3.0. Treatment-related events
> occurring during the first cycle of treatment are considered DLTs.
>
> Elevations of electrolyte, BUN, and creatinine levels will not be
> considered in determination of the DLT unless they are known
> toxicities of \_*[(Study Agent)]{.underline}*. They will be attributed
> to the patient's primary renal failure. However, if sudden changes in
> these parameters occur in a temporal relationship to administration of
> \_*[(Study Agent)]{.underline}*, the changes should be attributed to
> \_*[(Study Agent)]{.underline}* and considered in the determination of
> DLT, MTD, and dosing recommendations.
>
> *Please provide explicit definitions of the type(s), grade(s), and
> duration(s) of all agent-specific dose-limiting adverse event(s)
> below. In addition, certain events will be defined as dose limiting
> for all renal dysfunction studies. Suggested text is provided below.*
>
> The following treatment-related AEs are considered dose limiting for
> all renal dysfunction studies:

-   Any \> grade 3 non-hematologic toxicity (excluding alopecia,
    hypersensitivity, and renal abnormalities)

-   Grade 4 neutropenia, or occurrence of neutropenic fever with ANC \<
    1.5 x 10^9^/L

-   Grade 4 thrombocytopenia

-   Grade 3 nausea and vomiting if it occurs despite maximal (5HT
    antagonist and corticosteroid) antiemetic therapy, and if hydration
    is required for \>24 hours.

-   Grade 3 diarrhea despite patient compliance with loperamide therapy.

-   Renal toxicity

\- Patients in [mild]{.underline} dysfunction group (Group B): increase
of BSA-indexed CrCl from baseline to level defined for the severe group
lasting \> 2 weeks.

\- Patients in [moderate]{.underline} dysfunction group (Group C): 1.5
times increase from baseline BSA-indexed CrCl to level defined for the
severe group, lasting for \>2 weeks

\- Patients in [severe]{.underline} dysfunction group (Group D): 1.5
times increase from baseline BSA-indexed CrCl for \>2 weeks

-   In patients undergoing renal dialysis, laboratory parameters related
    to renal function that are known to worsen between dialysis
    treatments will not be considered as DLTs.

-   Treatment delays of ≥2 weeks due to treatment-related toxicity will
    constitute a DLT.

> Management and dose modifications associated with the above AEs are
> outlined in Section 6.2. Dose escalation will proceed within each
> group according to the rules stated in Section 5.4.
>
> **5.4 Dose Escalation Scheme**
>
> *Please state route and schedule of Study Agent administration, and
> enter exact doses for each dose level and group in the table below.
> (For example, "Agent XXX is given intravenously as a 1-hour infusion
> on days 1, 3, and 5 of a 21-day cycle.)*
>
> *\_\_[Study Agent­]{.underline}\_* is given
> *\_[(route/duration)]{.underline}* on *\_\_[(day/days)\_]{.underline}*
> of a *\_[\_(#)-day]{.underline}\_* cycle.

+---------+-----------+-----------+-----------+-----------+----------+
|         | **[Group  | **[Group  | **[Group  | ##        | #####    |
|         | A]{.und   | B]{.und   | C]{.und   | ##### [Gr | ## [Grou |
|         | erline}** | erline}** | erline}** | oup D]{.u | p E]{.un |
|         |           |           |           | nderline} | derline} |
+---------+-----------+-----------+-----------+-----------+----------+
| *       | **Normal  | **Mild    | *         | **Severe  | **Kidney |
| *Dose** | Renal     | renal     | *Moderate | renal     | d        |
|         | function\ | dys       | renal     | dys       | ialysis\ |
| **      | \_**      | function\ | dys       | function\ | \_**[(*  |
| Level** | [(*units) | \_**      | function\ | \_        | units)*] |
|         | *]{.under | [(*units) | \_        | **[(*unit | {.underl |
|         | line}\_\* | *]{.under | **[(*unit | s)*]{.und | ine}\_\* |
|         |           | line}\_\* | s)*]{.und | erline}\_ |          |
|         |           |           | erline}\_ | **\***    |          |
|         |           |           | **\***    |           |          |
+---------+-----------+-----------+-----------+-----------+----------+
| **Level |           |           |           |           | \*\*     |
| -1**    |           |           |           |           |          |
+---------+-----------+-----------+-----------+-----------+----------+
| **Level |           |           |           |           | \*\*     |
| 1**     |           |           |           |           |          |
+---------+-----------+-----------+-----------+-----------+----------+
| **Level |           |           |           |           | \*\*     |
| 2**     |           |           |           |           |          |
+---------+-----------+-----------+-----------+-----------+----------+
| **Level |           |           |           |           | \*\*     |
| 3**     |           |           |           |           |          |
+---------+-----------+-----------+-----------+-----------+----------+
| **Level |           |           |           |           | \*\*     |
| 4**     |           |           |           |           |          |
+---------+-----------+-----------+-----------+-----------+----------+
| *\*     |           |           |           |           |          |
| Doses   |           |           |           |           |          |
| are     |           |           |           |           |          |
| stated  |           |           |           |           |          |
| as      |           |           |           |           |          |
| exact   |           |           |           |           |          |
| dose in |           |           |           |           |          |
| units   |           |           |           |           |          |
| (e.g.,  |           |           |           |           |          |
| m       |           |           |           |           |          |
| g/m^2^, |           |           |           |           |          |
| mcg/kg, |           |           |           |           |          |
| etc.)   |           |           |           |           |          |
| rather  |           |           |           |           |          |
| than as |           |           |           |           |          |
| a       |           |           |           |           |          |
| perce   |           |           |           |           |          |
| ntage.* |           |           |           |           |          |
+---------+-----------+-----------+-----------+-----------+----------+

\*\* See Section 5.1 for the Group E dosing scheme.

-   See Section 5.1 for definitions of renal dysfunction groups.

-   The first cohort of patients will be treated at dose level 1. Dose
    level --1 is only to be used if dose reduction is necessary.

-   The following modifications to the usual "3&3" dose escalation
    scheme allow for the dosing of new patients in the event that not
    all patients treated at a current dose level are yet evaluable for
    toxicity.

> 5.4.1 Dose Escalation Rules

-   Dose escalation will proceed within each renal dysfunction group
    according to the scheme outlined in Section 5.4. DLT is defined
    above (Section 5.3).

-   Only DLTs that occur during the first cycle of treatment will be
    used to guide dose escalation.

-   Patients are considered evaluable for toxicity when they have
    received the planned dose or duration of therapy and have either 1)
    experienced DLT or 2) been followed for one full cycle without DLT.

> 5.4.2 Dose Escalation Definitions

-   The MTD is the highest dose at which no more than one instance of
    DLT is observed (among 6 patients treated). This is also the
    recommended dose (RD) for further study.

-   L denotes the current dose level in a given renal dysfunction group.
    When patients are active in cycle 1 at two dose levels in the same
    group concurrently, L will denote the lower dose level.

> 5.4.3 Dose Level Sample Size

-   Accrual at each dose level of each renal dysfunction group will
    proceed up to a maximum of 6 patients subject to the following
    rules, provided the MTD has not been determined:

  -------------------------------- --------------------------------------
  No DLT has occurred at dose      Accrual continues at dose level L up
  level L among 1-2 evaluable      to 6 patients.
  patients                         

  No DLT has occurred at dose      Accrual to dose level L is suspended
  level L among 3-4 evaluable      and up to 3 patients may be accrued to
  patients                         level L+1 during this suspension.

  No DLT has occurred at dose      Accrual to dose level L is terminated
  level L among 5 evaluable        and accrual to the next dose level
  patients                         proceeds.

  1 DLT has occurred at dose level 6 patients will be accrued to L.
  L                                

  2 DLTs have occurred at a dose   That dose level exceeds the MTD and no
  level.                           additional patients will be treated at
                                   that dose level or higher.
  -------------------------------- --------------------------------------

-   Patients who are not evaluable for DLT should be replaced, including
    those taking enzyme-inducing anticonvulsant drugs whose PK values
    (increased clearance/decreased AUC) suggest interaction with CYP450
    isoenzymes.

-   Once the MTD has been determined for a given renal dysfunction
    group, a maximum of 12 patients will be accrued to this dose level.

> 5.4.4 Dose Level Assignment
>
> **Before determination of the MTD:**

+---------------+-------------+-----------------+----------------------+
| **\# pts      | **\# pts    | **MTD status**  | **Dose level         |
| evaluable for | with DLT at |                 | assignment for**     |
| toxicity at   | L**         |                 |                      |
| L**           |             |                 | **new patient**      |
+---------------+-------------+-----------------+----------------------+
| \<3           | 0-1         | Not yet defined | L (up to 6 pts)      |
+---------------+-------------+-----------------+----------------------+
|               | [\>]{       | MTD exceeded    | Fill L-1 (to 6 pts)  |
|               | .underline} |                 |                      |
|               | 2           |                 |                      |
+---------------+-------------+-----------------+----------------------+
| 3-4           | 0           | Not yet defined | L+1 (to 3 pts)       |
+---------------+-------------+-----------------+----------------------+
|               | 1           | Not yet defined | L (up to 6 pts)      |
+---------------+-------------+-----------------+----------------------+
|               | [\>]{       | MTD exceeded    | Fill L-1 (to 6 pts)  |
|               | .underline} |                 |                      |
|               | 2           |                 |                      |
+---------------+-------------+-----------------+----------------------+
| 5             | 0           | [               | L+1                  |
|               |             | \<]{.underline} |                      |
|               |             | MTD             |                      |
+---------------+-------------+-----------------+----------------------+
|               | 1           | Not yet defined | L (up to 6 pts)      |
+---------------+-------------+-----------------+----------------------+
|               | [\>]{       | MTD exceeded    | Fill L-1 (to 6 pts)  |
|               | .underline} |                 |                      |
|               | 2           |                 |                      |
+---------------+-------------+-----------------+----------------------+
| 6             | 0-1         | [               | L+1                  |
|               |             | \<]{.underline} |                      |
|               |             | MTD             |                      |
+---------------+-------------+-----------------+----------------------+
|               | [\>]{       | MTD exceeded    | Fill L-1 (to 6 pts)  |
|               | .underline} |                 |                      |
|               | 2           |                 |                      |
+---------------+-------------+-----------------+----------------------+

-   Patients whose degree of renal dysfunction changes (becomes worse or
    better) between registration and initiation of protocol therapy may
    be re-assigned to a different dysfunction group and dose level. This
    change should be discussed with the Principal Investigator and must
    be documented with the Organ Dysfunction Working Group Coordinator.
    (For patients whose degree of renal dysfunction changes after
    initiation of therapy, see Section 6.1.)

-   A maximum of 3 patients may be assigned to L+1 during the suspension
    of accrual to level L (3-4 patients evaluable on L with no observed
    toxicity). When 1 or more patients have been assigned to L+1, the
    following rules apply:

  ------------------ -----------------------------------------------------
  **\# pts with DLT  **Dose level assignment for new patient**
  at L+1**           

  0                  Accrual continues to L+1 up to 3 patients.

  1                  Accrue no additional patients to L+1 until all
                     patients treated at L are evaluable.

  [\>]{.underline} 2 The MTD has been exceeded at L+1.
  ------------------ -----------------------------------------------------

> **After determination of the MTD:**
>
> When the MTD has been determined, it may be expanded to a total of 9
> or 12 patients according to patient availability. Based on the results
> from these additional patients, the MTD may be adjusted as follows:

  ------------------ -----------------------------------------------------
  **\# pts with DLT  **Action**
  at MTD**           

  \< 1/3             The MTD (also the RD) remains the same for this renal
                     dysfunction group.

  [\>]{.underline}   Lower dose levels should be further studied in
  1/3                descending order to re-establish an appropriate MTD.
  ------------------ -----------------------------------------------------

> 5.4.5 Maintaining Consistent Dosing Across the Renal Dysfunction
> Groups
>
> In general, results from each renal dysfunction group will have
> implications for the other groups based upon the assumption that at
> any given dose level, the dysfunction-toxicity response gradient is
> monotonic. In other words, patients in a particular group will not
> tolerate a dose not tolerated by a group with lesser dysfunction and
> conversely, will tolerate a dose tolerated by a group with greater
> dysfunction. When discrepancies arise between observed results and
> this principle, they will be resolved in the direction of conservative
> practice. That is, the lower dose will be recommended for both groups
> if a higher dose is tolerated in a group of greater dysfunction, but
> not in the group of lesser dysfunction. In particular, dose level
> assignments and MTD determination will be made consistent across the
> various renal dysfunction groups as follows:

  ---------------------------------- ------------------------------------
  **Observation for a particular     **Action within other dysfunction
  dysfunction group**                groups**

  MTD has been exceeded at a         Accrual at that dose level or higher
  particular dose level              is terminated for all groups with
                                     greater dysfunction.

  MTD has been established           Accrual at lower dose levels is
  (including results of additional   terminated for all groups with
  patients up to 12) at a particular lesser dysfunction.
  dose level.                        

  MTD has been established           The MTD is determined to be L-1 in
  (including results of additional   both groups, and in both groups,
  patients up to 12) at a particular there may be additional accrual (up
  dose level L while simultaneously, to 12 patients) at dose level L-1,
  the MTD has been exceeded at that  as described in 5.4.4.
  dose level in a group of lesser    
  dysfunction.                       
  ---------------------------------- ------------------------------------

**5.5 Supportive Care Guidelines**

> *Please state guidelines for use of appropriate supportive care
> medications or treatments.*

5.  **Patient Care Considerations**

    1.  Concomitant Medications

-   Patients should be cautioned about the concomitant use of
    cimetidine, trimethoprim, or other agents that interfere with
    creatinine secretion or the creatinine assay.

-   *Please indicate any other medications that should be avoided during
    this evaluation of \_ [(Study Agent)\_]{.underline}* *in patients
    with renal dysfunction.*

-   *For agents known to be metabolized in the liver, please include
    appropriate information regarding the concurrent use of any
    medication or therapy with the potential to affect cytochrome P450
    isoenzymes. Suggested text is provided below. This text should be
    deleted for studies of agents with no known hepatic metabolism.*

> Because many drugs including antineoplastic agents are metabolized by
> the cytochrome P450 system, there is a potential for interaction of
> \_*[Study Agent]{.underline}*\_ with concomitantly administered drugs.
> The case report form (CRF) 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 the P450
> isoenzymes.
>
> 5.6.2 *Please include other nursing guidelines specifically relevant
> for\_ [(Study Agent)\_]{.underline} .*

**5.7 Duration of Therapy**

> In the absence of treatment delays due to adverse events, 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 that render
    the patient unacceptable for further treatment in the judgment of
    the investigator.

**5.8 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.
>
> **5.9** **Criteria for Removal from Study**
>
> Patients will be removed from study when any of the criteria listed in
> Section 5.7 applies. The reason for study removal and the date the
> patient was removed must be documented in the CRF.

**6. DOSE DELAYS / DOSE MODIFICATIONS**

1.  **Retreatment Criteria**

> Prior to retreatment, patients must have recovered the following organ
> function:

-   absolute neutrophil count ≥1.5 x 10^9^/L

-   platelets ≥100 x 10^9^/L

-   total bilirubin within normal institutional limits

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

-   other (including neuropathy) Grade 0-1

> **Laboratory evaluations (renal function tests) must be repeated
> within 24 hours prior to initiation of each cycle of therapy.**
> Patients not fulfilling these criteria should have treatment delayed
> by 1 week to allow for recovery of organ function. Patients who cannot
> be retreated within 2 weeks of the end of the previous cycle should be
> removed from study.
>
> Recovery of baseline renal function is NOT required prior to
> retreatment provided the decline is considered disease related.
> However, patients who have *[Study Agent]{.underline}*-induced
> deterioration of renal function should not be retreated and should be
> removed from the study.
>
> For patients whose renal dysfunction has changed (improved or
> deteriorated) since the last cycle, assignment to a different dose
> level and/or group or cohort may be appropriate following consultation
> with the Principal Investigator. All such changes must be documented
> with the Organ Dysfunction Working Group Coordinator.

1.  **Dose Modification Guidelines**

> The dose of *[\_Study Agent\_]{.underline}* prescribed for cycles
> subsequent to cycle 1 will be determined by the following guidelines
> that integrate the patient's tolerance for the dose received in the
> previous cycle and the current dose level (L) for the patient's renal
> function group at the time of retreatment:

+----------+-------------+--------------+--------------+--------------+
| #        | ##          |              |              |              |
|          |  Worst toxi |              |              |              |
| #        | city in pre |              |              |              |
|          | vious cycle |              |              |              |
+----------+-------------+--------------+--------------+--------------+
|          | **[1 or     | **[1 or more | **[1 or more | **[All       |
|          | more        | of]{.u       | of]{.u       | of]{.u       |
|          | of]{.un     | nderline}:** | nderline}:** | nderline}:** |
|          | derline}:** |              |              |              |
|          |             | **G2         | **G1         | **G0-1       |
|          | **G2        | \            | \            | non-heme     |
|          | \_          | _*[(non-heme | _*[(non-heme | (other)**    |
|          | *[(non-heme | tox)]{.u     | tox)]{.u     |              |
|          | tox)]{      | nderline}*** | nderline}*** | **G0-2       |
|          | .underline} | *\**         | *\**         | heme**       |
|          | ****\**     |              |              |              |
|          |             | **recovered  | **G2         | **No dose    |
|          | *           | to G1 by D   | non-heme     | delay**      |
|          | *persistent | \_*[(cycle   | (other)**    |              |
|          | at D        | l            |              |              |
|          | \_*[(cycle  | ength)]{.und | **G3 heme**  |              |
|          | len         | erline}*\_** |              |              |
|          | gth)]{.unde |              | **Dose delay |              |
|          | rline}*\_** | **G3         | (­[\<]        |              |
|          |             | non-heme     | {.underline} |              |
|          | **G3        | (other)**    | 1 wk)**      |              |
|          | \_          |              |              |              |
|          | (*[non-heme | **G4 heme**  |              |              |
|          | tox)]{.un   |              |              |              |
|          | derline}*** | **Febrile    |              |              |
|          | *\**        | n            |              |              |
|          |             | eutropenia** |              |              |
|          | **G4        |              |              |              |
|          | non-heme    | **Renal      |              |              |
|          | (other)**   | DLT**        |              |              |
|          |             |              |              |              |
|          | **Septic    | **Dose delay |              |              |
|          | shock**     | (­[\<]        |              |              |
|          |             | {.underline} |              |              |
|          | **Dose      | 2 wks)**     |              |              |
|          | delay (\> 2 |              |              |              |
|          | wks)**      |              |              |              |
+----------+-------------+--------------+--------------+--------------+
| #        | Off study   | Administer   | Administer   | Administer   |
|          |             | LOWER of:    | LOWER of:    | LOWER of:    |
| # St     |             |              |              |              |
| able or  |             | Current dose | Current dose | Current dose |
| improved |             | level for    | level for    | level for    |
|          |             | current      | current      | current      |
| **Renal  |             | group        | group        | group        |
| Fu       |             |              |              |              |
| nction** |             | **OR**       | **OR**       | **OR**       |
|          |             |              |              |              |
|          |             | \_\_*[Do     | Same dose as | \_\_*[Do     |
|          |             | se\*\*\_]{.u | previous     | se\*\*\_]{.u |
|          |             | nderline}\_* | cycle        | nderline}\_* |
|          |             | [less]       |              | [more]       |
|          |             | {.underline} |              | {.underline} |
|          |             | than         |              | than         |
|          |             | previous     |              | previous     |
|          |             | cycle        |              | cycle        |
+----------+-------------+--------------+--------------+--------------+
| **Deteri | Off study   | Off study    | Administer   | Administer   |
| orated** |             |              | LOWER of:    | LOWER of:    |
|          |             |              |              |              |
| **Renal  |             |              | Current dose | Current dose |
| Fu       |             |              | level for    | level for    |
| nction** |             |              | current      | current      |
|          |             |              | group        | group        |
| **(1     |             |              |              |              |
| group;   |             |              | **OR**       | **OR**       |
| *e.g*.,  |             |              |              |              |
| from     |             |              | \_\_*[Do     | Same dose as |
| Group B  |             |              | se\*\*\_]{.u | previous     |
| to Group |             |              | nderline}\_* |              |
| C)**     |             |              | [less]       | cycle        |
|          |             |              | {.underline} |              |
|          |             |              | than         |              |
|          |             |              | previous     |              |
|          |             |              | cycle        |              |
+----------+-------------+--------------+--------------+--------------+
| **Deteri | Off study   | Off study    | Off study    | Administer   |
| orated** |             |              |              | LOWER of:    |
|          |             |              |              |              |
| **Renal  |             |              |              | Current dose |
| Fu       |             |              |              | level for    |
| nction** |             |              |              | current      |
|          |             |              |              | group        |
| **(2     |             |              |              |              |
| groups;  |             |              |              | **OR**       |
| *e.g*.,  |             |              |              |              |
| from     |             |              |              | \_\_*[Do     |
| Group B  |             |              |              | se\*\*\_]{.u |
| to Group |             |              |              | nderline}\_* |
| D)**     |             |              |              | [less]       |
|          |             |              |              | {.underline} |
|          |             |              |              | than         |
|          |             |              |              | previous     |
|          |             |              |              | cycle        |
+----------+-------------+--------------+--------------+--------------+

> *\* Please replace "non-heme tox" with the appropriate toxicity
> category (e.g., neurologic, metabolic, etc.) for agents with a known
> non-hematologic DLT (previously determined in patients with normal
> renal function). The term "\_[(non-heme tox)\_]{.underline}\*" under
> the worst toxicity criteria should be deleted for agents with a
> hematologic DLT.*
>
> *\*\* State an exact dose in units (e.g., mg/m^2^, mcg/kg, etc.) by
> which to lower or raise the dose of the previous cycle rather than a
> percentage.*

-   Patients should thus be retreated at the current dose level for the
    renal dysfunction group that they fall into on the day of
    retreatment, unless toxicity in the previous cycle dictates that a
    lower dose be used (see table). The current dose level (L) is
    defined in Section 5.4.2.

-   Collection of pharmacokinetics from patients who change dose level
    and/or renal dysfunction groups between cycles is encouraged but not
    mandatory.

-   No patient should have his/her dose re-escalated following dose
    reduction for toxicity.

-   The Principal Investigator or Study Coordinator should confirm the
    appropriate dose level prior to each cycle.

**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, if
> available, 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/)).

-   **'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).

-   **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.
> **All AEs reported via AdEERS must be copied to the Organ Dysfunction
> Working Group Coordinator (\_\_*[e-mail]{.underline}*\_\_) using the
> copy feature of AdEERS.**
>
> 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 1 Trials

+------+-------+------+------+------+-------+------+-------+--------+
| **P  |       |      |      |      |       |      |       |        |
| hase |       |      |      |      |       |      |       |        |
| 1    |       |      |      |      |       |      |       |        |
| Tria |       |      |      |      |       |      |       |        |
| ls** |       |      |      |      |       |      |       |        |
+------+-------+------+------+------+-------+------+-------+--------+
|      | **    | **G  | **G  | **G  |       | **G  |       | **Gr   |
|      | Grade | rade | rade | rade |       | rade |       | ades** |
|      | 1**   | 2**  | 2**  | 3**  |       | 3**  |       |        |
|      |       |      |      |      |       |      |       | **4 &  |
|      |       |      |      |      |       |      |       | 5^2^** |
+------+-------+------+------+------+-------+------+-------+--------+
|      | **Un  | **U  | **Ex | **   |       | **Ex |       | **     |
|      | expec | nex- | pect | Unex |       | pect |       | Unexpe |
|      | ted** | pect | ed** | pect |       | ed** |       | cted** |
|      |       | ed** |      | ed** |       |      |       |        |
|      | **and |      |      |      |       |      |       | *      |
|      | Expec |      |      |      |       |      |       | *and** |
|      | ted** |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       | **Expe |
|      |       |      |      |      |       |      |       | cted** |
+------+-------+------+------+------+-------+------+-------+--------+
|      |       |      |      | **wi | **wi  | **wi | **wi  |        |
|      |       |      |      | th** | thout | th** | thout |        |
|      |       |      |      |      | Hospi |      | Ho    |        |
|      |       |      |      | **Ho | tali- | **   | spita |        |
|      |       |      |      | spit | zat   | Hosp | li-** |        |
|      |       |      |      | ali- | ion** | ital |       |        |
|      |       |      |      | zati |       | i-** | **zat |        |
|      |       |      |      | on** |       |      | ion** |        |
|      |       |      |      |      |       | **   |       |        |
|      |       |      |      |      |       | zati |       |        |
|      |       |      |      |      |       | on** |       |        |
+------+-------+------+------+------+-------+------+-------+--------+
| *    | Not   | Not  | Not  | 10   | Not   | 10   | Not   | 24     |
| *Unr |       |      |      | Cale |       | Cale |       | -Hour; |
| elat | Req   | Requ | Requ | ndar | Req   | ndar | Req   |        |
| ed** | uired | ired | ired |      | uired |      | uired | 5      |
|      |       |      |      | Days |       | Days |       | Ca     |
| **Un |       |      |      |      |       |      |       | lendar |
| like |       |      |      |      |       |      |       |        |
| ly** |       |      |      |      |       |      |       | Days   |
+------+-------+------+------+------+-------+------+-------+--------+
| **Po | Not   | 10   | Not  | 24-H | 24-   | 10   | Not   | 24     |
| ssib |       | Cale |      | our; | Hour; | Cale |       | -Hour; |
| le** | Req   | ndar | Requ |      |       | ndar | Req   |        |
|      | uired |      | ired | 5    | 5     |      | uired | 5      |
| **Pr |       | Days |      | Cale | Cal   | Days |       | Ca     |
| obab |       |      |      | ndar | endar |      |       | lendar |
| le** |       |      |      |      |       |      |       |        |
|      |       |      |      | Days | Days  |      |       | Days   |
| **De |       |      |      |      |       |      |       |        |
| fini |       |      |      |      |       |      |       |        |
| te** |       |      |      |      |       |      |       |        |
+------+-------+------+------+------+-------+------+-------+--------+
| *    |       |      |      |      |       |      |       |        |
| *^1^ |       |      |      |      |       |      |       |        |
| Adv  |       |      |      |      |       |      |       |        |
| erse |       |      |      |      |       |      |       |        |
| ev   |       |      |      |      |       |      |       |        |
| ents |       |      |      |      |       |      |       |        |
| with |       |      |      |      |       |      |       |        |
| att  |       |      |      |      |       |      |       |        |
| ribu |       |      |      |      |       |      |       |        |
| tion |       |      |      |      |       |      |       |        |
| of   |       |      |      |      |       |      |       |        |
| p    |       |      |      |      |       |      |       |        |
| ossi |       |      |      |      |       |      |       |        |
| ble, |       |      |      |      |       |      |       |        |
| p    |       |      |      |      |       |      |       |        |
| roba |       |      |      |      |       |      |       |        |
| ble, |       |      |      |      |       |      |       |        |
| or   |       |      |      |      |       |      |       |        |
| defi |       |      |      |      |       |      |       |        |
| nite |       |      |      |      |       |      |       |        |
| that |       |      |      |      |       |      |       |        |
| o    |       |      |      |      |       |      |       |        |
| ccur |       |      |      |      |       |      |       |        |
| [    |       |      |      |      |       |      |       |        |
| grea |       |      |      |      |       |      |       |        |
| ter] |       |      |      |      |       |      |       |        |
| {.un |       |      |      |      |       |      |       |        |
| derl |       |      |      |      |       |      |       |        |
| ine} |       |      |      |      |       |      |       |        |
| than |       |      |      |      |       |      |       |        |
| 30   |       |      |      |      |       |      |       |        |
| days |       |      |      |      |       |      |       |        |
| a    |       |      |      |      |       |      |       |        |
| fter |       |      |      |      |       |      |       |        |
| the  |       |      |      |      |       |      |       |        |
| last |       |      |      |      |       |      |       |        |
| dose |       |      |      |      |       |      |       |        |
| of   |       |      |      |      |       |      |       |        |
| t    |       |      |      |      |       |      |       |        |
| reat |       |      |      |      |       |      |       |        |
| ment |       |      |      |      |       |      |       |        |
| with |       |      |      |      |       |      |       |        |
| an   |       |      |      |      |       |      |       |        |
| a    |       |      |      |      |       |      |       |        |
| gent |       |      |      |      |       |      |       |        |
| u    |       |      |      |      |       |      |       |        |
| nder |       |      |      |      |       |      |       |        |
| a    |       |      |      |      |       |      |       |        |
| CTEP |       |      |      |      |       |      |       |        |
| IND  |       |      |      |      |       |      |       |        |
| req  |       |      |      |      |       |      |       |        |
| uire |       |      |      |      |       |      |       |        |
| r    |       |      |      |      |       |      |       |        |
| epor |       |      |      |      |       |      |       |        |
| ting |       |      |      |      |       |      |       |        |
| as   |       |      |      |      |       |      |       |        |
| fo   |       |      |      |      |       |      |       |        |
| llow |       |      |      |      |       |      |       |        |
| s:** |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
| > Ad |       |      |      |      |       |      |       |        |
| EERS |       |      |      |      |       |      |       |        |
| >    |       |      |      |      |       |      |       |        |
|  24- |       |      |      |      |       |      |       |        |
| hour |       |      |      |      |       |      |       |        |
| >    |       |      |      |      |       |      |       |        |
| noti |       |      |      |      |       |      |       |        |
| fica |       |      |      |      |       |      |       |        |
| tion |       |      |      |      |       |      |       |        |
| >    |       |      |      |      |       |      |       |        |
| foll |       |      |      |      |       |      |       |        |
| owed |       |      |      |      |       |      |       |        |
| > by |       |      |      |      |       |      |       |        |
| >    |       |      |      |      |       |      |       |        |
| comp |       |      |      |      |       |      |       |        |
| lete |       |      |      |      |       |      |       |        |
| > re |       |      |      |      |       |      |       |        |
| port |       |      |      |      |       |      |       |        |
| > wi |       |      |      |      |       |      |       |        |
| thin |       |      |      |      |       |      |       |        |
| > 5  |       |      |      |      |       |      |       |        |
| >    |       |      |      |      |       |      |       |        |
| cale |       |      |      |      |       |      |       |        |
| ndar |       |      |      |      |       |      |       |        |
| >    |       |      |      |      |       |      |       |        |
| days |       |      |      |      |       |      |       |        |
| >    |       |      |      |      |       |      |       |        |
| for: |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
| -    |       |      |      |      |       |      |       |        |
|    G |       |      |      |      |       |      |       |        |
| rade |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
|    3 |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
|   un |       |      |      |      |       |      |       |        |
| expe |       |      |      |      |       |      |       |        |
| cted |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
|   ev |       |      |      |      |       |      |       |        |
| ents |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
| with |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
|  hos |       |      |      |      |       |      |       |        |
| pita |       |      |      |      |       |      |       |        |
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|      |       |      |      |      |       |      |       |        |
|   or |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
| prol |       |      |      |      |       |      |       |        |
| onga |       |      |      |      |       |      |       |        |
| tion |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
|   of |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
|  hos |       |      |      |      |       |      |       |        |
| pita |       |      |      |      |       |      |       |        |
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| tion |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
| -    |       |      |      |      |       |      |       |        |
|    G |       |      |      |      |       |      |       |        |
| rade |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
|    4 |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
|   un |       |      |      |      |       |      |       |        |
| expe |       |      |      |      |       |      |       |        |
| cted |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
|   ev |       |      |      |      |       |      |       |        |
| ents |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
| -    |       |      |      |      |       |      |       |        |
|    G |       |      |      |      |       |      |       |        |
| rade |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
|    5 |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
| expe |       |      |      |      |       |      |       |        |
| cted |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
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| ents |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
|  and |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
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| expe |       |      |      |      |       |      |       |        |
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| ents |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
| ^2^  |       |      |      |      |       |      |       |        |
| Alth |       |      |      |      |       |      |       |        |
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| an   |       |      |      |      |       |      |       |        |
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| 24-  |       |      |      |      |       |      |       |        |
| hour |       |      |      |      |       |      |       |        |
| noti |       |      |      |      |       |      |       |        |
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| eath |       |      |      |      |       |      |       |        |
| cle  |       |      |      |      |       |      |       |        |
| arly |       |      |      |      |       |      |       |        |
| rel  |       |      |      |      |       |      |       |        |
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| to   |       |      |      |      |       |      |       |        |
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| sive |       |      |      |      |       |      |       |        |
| dise |       |      |      |      |       |      |       |        |
| ase, |       |      |      |      |       |      |       |        |
| a    |       |      |      |      |       |      |       |        |
| full |       |      |      |      |       |      |       |        |
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| port |       |      |      |      |       |      |       |        |
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| the  |       |      |      |      |       |      |       |        |
| ta   |       |      |      |      |       |      |       |        |
| ble. |       |      |      |      |       |      |       |        |
|      |       |      |      |      |       |      |       |        |
| Dece |       |      |      |      |       |      |       |        |
| mber |       |      |      |      |       |      |       |        |
| 15,  |       |      |      |      |       |      |       |        |
| 2004 |       |      |      |      |       |      |       |        |
+------+-------+------+------+------+-------+------+-------+--------+

> **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:

```{=html}
<!-- -->
```
-   "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 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.

```{=html}
<!-- -->
```
-   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 the
> investigational agent administered in this study can be found in
> Section 7.1.
>
> **8.1 *[Study 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**
>
> *[Study 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 12.4).
>
> **8.3 Agent Ordering**
>
> NCI-supplied agents may be requested by the Principal Investigator (or
> their authorized designees) at each participating institution.
> Investigational agents may be ordered by a participating site only
> after the initial IRB approval for the site has been forwarded by the
> Coordinating Center to the CTEP PIO. Pharmaceutical Management Branch
> (PMB) policy requires that the agent be shipped directly to the
> institution where the patient is to be treated. PMB does not permit
> the transfer of investigational 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**
>
> 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**

> *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.*
>
> **9.1 Pharmacokinetic Studies**
>
> Pharmacokinetic studies will be done on all patients. At the Principal
> Investigator's discretion, this requirement may be waived in case of
> patient hardship, including lack of venous access. In this event,
> patients will be replaced to ensure that adequate PK data are obtained
> for each group (*i.e*., at least 3 patients per group and at least 6
> patients at the MTD level).
>
> All PK measurements for this study will be performed and analyzed by
> \_\_*[Investigator/Institution \_ OR]{.underline} \_\_[Agent
> Manufacturer/Contractor]{.underline}*\_. All data and results will be
> made available to the investigators on this study, to the industrial
> collaborator (if applicable), and to CTEP. The minimum turnaround time
> for PK measurements will be 4 weeks from receipt of samples by the
> analytical laboratory. In patients who experience unexpected serious
> toxicity or patients with gliomas or brain metastases taking
> anticonvulsant drugs, efforts will be made to have analysis available
> in 2 weeks. Availability of PK data is anticipated prior to dose
> escalation to another dose level.
>
> PK sampling will be performed in cycle 1 for all patients. In patients
> with incomplete PK from cycle 1 and in those who change dose level or
> renal dysfunction group between cycles, repeat PK sampling is
> encouraged in subsequent cycles but is not mandatory.
>
> If one or more of the major active metabolites of \_*[(Study
> Agent)]{.underline}*\_ is known to contribute at least 10% of the
> activity or toxicity observed, the PK of that/those metabolite(s)
> should also be measured.
>
> Pharmacokinetic analytical methods are outlined in Section 13.5.
>
> 9.1.1 Specimen Collection / Documentation
>
> Prior to drug administration on day 1 of treatment, an indwelling
> heparin lock should be placed so that serial specimens can be
> collected. At each sampling time, 1 mL of blood will be withdrawn and
> discarded to assure that the solution used to maintain catheter
> patency does not dilute the sample. Even if a patient has a central
> venous catheter, it is preferable for day 1 PK samples to be withdrawn
> through a peripheral heparin lock. However, if the patient objects or
> has problems with peripheral venous access, the central venous
> catheter may be used for PK sampling. In the event that the central
> venous catheter is used, sufficient blood should be withdrawn before
> each PK sample to assure that the solution used to maintain catheter
> patency does not dilute the PK sample. It is important to document
> whether the sample was collected through a heparin lock or central
> venous catheter, especially for day 1 sampling.

##### 

##### *Please provide complete instructions for documentation of sample acquisition including source of samples (i.e., heparin lock or central catheter), as well as the method for labeling each sample with patient's name (or unique identifier), sample date, scheduled sample collection time, and actual sample collection time.* 

> 9.1.2 Pharmacokinetic Sampling Schedule

##### *Please present a schedule for PK sample collection using the table format below. The appropriate number of time points (T1, T2, T3, etc.) and the times of sample collection (D1, D2, D3, etc.; 01:30, 02:00, 02:30, etc.) will be different for each agent. The possibility of impaired clearance rates should be considered in selection of PK sampling intervals.*

+-----------------------+----------------------------------------------+
| **PK Time Point**     | **Day hour:minute (h:m) of collection**      |
|                       |                                              |
|                       | **(24-hour clock)**                          |
+-----------------------+----------------------------------------------+
| T1                    | D1 00:00                                     |
+-----------------------+----------------------------------------------+
|                       |                                              |
+-----------------------+----------------------------------------------+
|                       |                                              |
+-----------------------+----------------------------------------------+
|                       |                                              |
+-----------------------+----------------------------------------------+
|                       |                                              |
+-----------------------+----------------------------------------------+
|                       |                                              |
+-----------------------+----------------------------------------------+
|                       |                                              |
+-----------------------+----------------------------------------------+
|                       |                                              |
+-----------------------+----------------------------------------------+
|                       |                                              |
+-----------------------+----------------------------------------------+

> 9.1.3 Blood Sample Processing Procedures

##### *Please describe methods used to process samples for PK analysis here.*

> 9.1.4 Shipping Instructions

##### *Please provide instructions and all procedures for shipping specimens to the central laboratory including the names of the responsible parties and contact information.*

> **9.2 Pharmacodynamic Studies**
>
> *Please describe all planned pharmacodynamic studies with reference to
> the "Guidelines for Correlative Studies in Clinical Trials" provided
> with the LOI response. Information on endpoint validation including
> background, description of the assay(s) used, materials and methods,
> and assay validation should be provided below or in an appendix.
> Explicit instructions for handling, preserving, and shipping the
> specimens should be provided below. A plan for statistical analysis of
> the results of the correlative study(ies) should be provided in
> Section 13.5, Analysis of Secondary Endpoints. If there are no
> pharmacodynamic studies in this protocol, this section should be
> marked "N/A".*

**10. STUDY CALENDAR**

Schedules shown in Study Calendar below are provided as an example and
should be modified as appropriate.

> Baseline evaluations are to be conducted within 2 weeks prior to start
> 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. For patients
> in stable condition, these evaluations should be repeated within \_
> [XX\_]{.underline} hours of starting a new cycle of therapy. Renal
> function tests should be repeated within 24 hours prior to starting
> initial therapy. Patients should be seen for a physical examination
> every [\_(# weeks)\_]{.underline} .

<table style="width:100%;">
<colgroup>
<col style="width: 22%" />
<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: 5%" />
<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><p>Pre-</p>
<p>Study</p></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><p>Off</p>
<p>Study</p></td>
</tr>
<tr class="even">
<td><em><u>Study Agent<sup>a</sup></u></em></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td></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></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
</tr>
<tr class="even">
<td>Vital signs</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td></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></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
</tr>
<tr class="odd">
<td>Performance Status</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td></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>PT, APTT, INR</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>EKG/EEG (if 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="even">
<td>Adverse event evaluation</td>
<td></td>
<td
colspan="12">X----------------------------------------------------------------------------------------------
X</td>
<td></td>
</tr>
<tr class="odd">
<td>Tumor measurements</td>
<td>X</td>
<td colspan="12">Tumor measurements are repeated every <em><u>#
weeks</u></em> weeks. Documentation (radiologic) must be provided for
patients removed from study for progressive disease.</td>
<td>X<sup>c</sup></td>
</tr>
<tr class="even">
<td>Radiologic evaluation</td>
<td>X</td>
<td colspan="12">Radiologic measurements should be performed every
<em><u># weeks</u></em> weeks.</td>
<td>X<sup>c</sup></td>
</tr>
<tr class="odd">
<td>Pharmacokinetic studies</td>
<td></td>
<td
colspan="12">X<sup>d</sup>----------------------------------------------------------------------------------------------
X<sup>d</sup></td>
<td></td>
</tr>
<tr class="even">
<td colspan="15"><p>a: <em><u>Study Agent</u></em>; Dose as assigned;
<em>route/schedule</em></p>
<p>b: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN,
calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium,
total protein, SGOT[AST], SGPT[ALT], sodium. <strong>Include serum urea
nitrogen; serum creatinine</strong>.</p>
<p>c: Off-study evaluation. <strong>Two consecutive measurements taken 4
weeks apart must be used to document progressive disease if the patient
is removed from study for this reason.</strong></p>
<p>d: Pharmacokinetic samples taken per schedule in Section
9.1.</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 agent- or
> disease-appropriate criteria (e.g., for specific hematologic
> malignancies, supportive care agents, etc.) with references, and all
> solid tumor criteria should be deleted.*
>
> Although response is not the primary endpoint of this trial, patients
> with measurable disease will be assessed by standard criteria. For the
> purposes of this study, patients should be reevaluated every *[\# of
> weeks]{.underline}* weeks. In addition to a baseline scan,
> confirmatory scans will also be obtained *[\# of weeks]{.underline}*
> weeks following initial documentation of an objective response.

11.1 **Antitumor Effect -- Solid Tumors**

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.*
>
> 11.2 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**

**12.1 Data Reporting**

> This study will be monitored by CTMS. Data will be submitted to CTMS
> at least once every 2 weeks on the NCI/DCTD case report form or the
> electronic case report form (ACES). CTEP will arrange for a bi-weekly
> toxicity report to be generated by Theradex, and this report will be
> provided to the Principal Investigator, all Co-Investigators, and the
> Organ Dysfunction Working Group Coordinator for the purpose of
> monitoring and coordination of this multicenter trial.
>
> The final study report should contain all raw data collected during
> the trial including the case report forms as well as all clinical,
> laboratory, pharmacokinetic, and pharmacodynamic data collected. This
> report will be made available to the FDA as well as all members of the
> Organ Dysfunction Working Group.

**12.2 Data Monitoring and Safety Plan**

> A mandatory conference call will take place every other week on
> \_*[(day of week)]{.underline}*\_ at \_*[(time of day)]{.underline}*\_
> (Eastern Time) unless unforeseen events require postponement or
> cancellation. The call will update participants on the current status
> of the trial and will include investigators from all participating
> centers, CTEP, and representatives from \_*[(Agent
> Manufacturer)]{.underline}*\_. At this time, any serious toxicities
> encountered will be discussed and appropriate action taken, and issues
> relating to the protocol, treatment, management, or other matters of
> importance that arise during the conduct of the study will be
> discussed. Between these regularly scheduled conference calls, unusual
> toxicities may be discussed among the Principal Investigator and CTEP
> senior investigators; however, all participants will routinely be
> updated on such calls via e-mail.

**12.3 CTEP Multicenter Guidelines**

> This protocol complies with the requirements of the CTEP Multicenter
> Guidelines. The specific responsibilities of the Principal
> Investigator and the Coordinating Center (Organ Dysfunction Working
> Group Coordinator) and the procedures for auditing are presented in
> Appendix D.
>
> **12.4 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.

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```
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**

> This phase 1 trial will use a design involving five parallel groups of
> patients with different degrees of renal dysfunction.

-   The dose escalation rules used in this study, as detailed in Section
    5.4.1, are adapted from the standard up-and-down "3&3" design, and
    maintain the basic principles of that design. The design has been
    modified for this organ dysfunction study to eliminate waiting
    periods between dose levels as the clinical stability of patients
    with impaired renal function is frequently limited, and it is thus
    unreasonable to delay therapy for 2-3 weeks in this patient
    population. The disadvantage of this approach is that it may
    increase the number of patients who receive a dose that is
    subsequently found to be above the recommended dose level. However,
    the benefit is expected to outweigh this risk as this population of
    patients is small, has few or no standard therapeutic options, and
    these patients usually have a limited timeframe during which therapy
    can be safely administered.

-   Although dose-finding will be carried out independently for each of
    the renal dysfunction groups, an ancillary constraint is imposed:
    the dose recommended for a group with greater renal dysfunction
    cannot be greater than that for a group with a lesser dysfunction.
    Section 5.4 describes how this constraint will be applied. While it
    is conceivable that patients with greater renal dysfunction might
    tolerate the study drug better than those with lesser dysfunction,
    it is considered very unlikely. Furthermore, the highest dose to be
    explored is no greater than the recommended dose for patients with
    normal renal function. Thus, the ancillary constraint can do no
    harm; it is intended to compensate in part for patient heterogeneity
    and yield more accurate final recommended doses than possible with
    independent dose escalation in the four renal dysfunction groups.

-   A maximum of 12 patients (1 per participating institution) will be
    entered into group A (normal renal function). Patients in group A
    are included in this study to obtain PK data in the same manner as
    for the patients with renal dysfunction. This group will also be
    followed for toxicity, but the definitions of recommended dose that
    are specific to patients with renal dysfunction will not be used.

-   In order to define levels of renal impairment at which dose
    modifications of \_\_*[(Study Agent)]{.underline}*\_ are required,
    data will be combined across renal dysfunction groups to evaluate
    the association between \_[\_*(most common/most severe
    toxicity)­­­*]{.underline}*\_\_\_*, dose, and BSA-indexed GFR level(s).
    The outcome variable, \_[\_*(most common/most severe
    toxicity)­­­*]{.underline}*\_\_\_*, will be modeled as a function of
    dose and BSA-indexed CrCl using multivariate linear regression.
    Higher order terms of the predictor variables and interactions will
    be included if there is evidence of non-linear and/or non-additive
    associations. The regression parameter estimates from this model may
    then be used to identify the maximum dose which would not adversely
    impact \_[\_*(most common/most severe
    toxicity)­­­*]{.underline}*\_\_\_* levels (*e.g*., *state specific
    level such as ANC \<1000)* for a patient with a given kidney
    function profile.

-   Toxicity will be graded according to the NCI CTCAE v3.0 and
    relationship to the study drug; results will be tabulated by renal
    dysfunction group. All patients who receive any amount of
    \_\_*[(Study Agent)]{.underline}*\_ will be evaluable for toxicity,
    but patients who receive other than the prescribed dose and do not
    experience a DLT will be considered inevaluable for DLT. Patients
    who are not evaluable for DLT will be replaced.

-   The PK variables described in Section 13.5 will be tabulated and
    descriptive statistics calculated for each group. Geometric means
    and coefficients of variation will be presented for C~max~ and
    AUC(INF) for each group.

> **13.2 Endpoints**
>
> The primary endpoints of this study are as follows:

-   Determination of the MTD and DLT of \_\_*[(Study
    Agent)]{.underline}*\_\_ in groups of patients with varying degrees
    of renal dysfunction (mild, moderate, severe, and renal dialysis) in
    order to provide appropriate dosing recommendations for \_\_*[(Study
    Agent)]{.underline}*\_\_ in such patients.

> Toxicity will be graded according to the NCI CTCAE v3.0. The MTD for
> each renal dysfunction group will be defined based on the toxicities
> observed during the first cycle \_[(# days)]{.underline}\_ of
> treatment.

-   Determination of the level(s) of renal dysfunction parameters at
    which alterations in the pharmacokinetics of *[\_\_(Study
    Agent)\_]{.underline}* are observed.

> **13.3 Sample Size/Accrual Rate**
>
> *Please specify the planned sample size and accrual rate (e.g.,
> patients/month)*.
>
> A minimum of 2 and a maximum of 12 patients will be accrued in each
> group at each dose level, with 12 patients entered at the recommended
> dose level in each group. Thus, Group A will accrue 12 patients, while
> Groups B-E will accrue approximately 15-30 patients each for a total
> accrual of 72-132 patients. The trial is expected to accrue patients
> at a rate of approximately 5 patients per month. Group A will be
> limited to 12 patients, who can be accrued rapidly.

**13.4 Stratification Factors**

> Patients will be stratified according to level of renal dysfunction as
> described in Section 5.1. Dose escalation and determination of the MTD
> will be carried out separately for each stratum.
>
> *Please specify any planned patient stratification factors. Indicate
> whether dose escalation and MTD determination will be done for each
> stratum individually.*

**13.5 Analysis of Secondary Endpoints**

> *If secondary endpoints are included in this study, please specify how
> they will be analyzed. In particular, brief descriptions should be
> given of analyses of pharmacokinetic, biologic, and correlative
> laboratory endpoints.*
>
> *If responses are reported as a secondary endpoint, the following
> criteria should be used. Every report should contain all patients
> included in the study. For the response calculation, the report should
> contain at least a section with all eligible patients. Another section
> of the report may detail the response rate for evaluable patients
> only. However, a response rate analysis based on a subset of patients
> must explain which patients were excluded and for which reasons. It is
> preferred that 95% confidence limits are given.*

**REFERENCES**

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

Cockcroft, D.W. and M.H. Gault. (1976). Prediction of creatinine
clearance from serum creatinine. *Nephron* 16:31-41.

Levey A.S., J.P. Bosch, J.B. Lewis, *et al*. (1999). A more accurate
method to estimate glomerular filtration rate from serum creatinine: A
new prediction equation. Modification of Diet in Renal Disease Study
Group. *Ann Intern Med* 130:461-470.

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/>

-   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**
*\[Type/stage/presentation of cancer being studied is briefly described
here. For example: "Colon cancer that has spread and has not responded
to one treatment."\]* **and your kidneys do not function normally.**

Why is this study being done?

**The purpose of this study is to test the safety of**
*\[drug/intervention\]* **at different dose levels in patients with
cancer who have different degrees of abnormal kidney function.**

*\[Complete and include the following sentence if appropriate.\]*
**\[***Agent name***\] is an investigational or experimental anti-cancer
agent that has not yet been approved by the Food and Drug Administration
for use in patients with cancer whose kidneys do not function
normally.**

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.**

-   *\[List tests and procedures as appropriate, including blood
    collection for pharmacokinetic analyses. Use bulleted format.\]*

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

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** *\[drugs or intervention\]* **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. Side effects of supportive
    medications should not be listed unless they are mandated by the
    study.*

-   *The possibility that unanticipated (or currently unknown) adverse
    events could occur because this is a new or untested agent should be
    noted.*

-   *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 are 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, will be presented in Section 7.1.2. 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 the safety of** *\[procedures,
drugs, interventions, devices\]* **in patients with cancer who have
abnormal kidney function. 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**

-   **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 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 \[[the NCI or other study sponsor, as
appropriate]{.underline}\]. 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."\]*

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).** *\[\*Only applies to sites using the CIRB.\]*

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

MDRD Formula for Estimation of Glomerular Filtration Rate

Renal function levels in clinical trials are commonly described in terms
of creatinine clearance (CrCl) calculated using a formula such as
Cockcroft-Gault (Cockcroft and Gault, 1976). This formula estimates CrCl
based on the serum creatinine concentration in a 24-hour urine
collection plus a single measurement of serum creatinine in addition to
demographic data. The drawbacks of the method include the inconvenience
of the 24-hour urine collection and its estimation of CrCl rather than
glomerular filtration rate (GFR), generally accepted as the best overall
index of renal function. Moreover, methods based on creatinine levels in
urine overestimate GFR because both secreted and filtered creatinine are
measured. The GFR correlates more closely with the renal excretion of
many drugs than does CrCl, but the "gold standard" methods for GFR
measurement are impractical or unavailable in the clinical setting.

In a large study (n = 1628) in patients with chronic renal disease,
baseline data were collected on a variety of parameters including
measured GFR (^125^I-iothalamate), CrCl (24-hour urine collection plus a
single measurement of serum creatinine), serum albumin, serum urea
nitrogen, and demographic data (Levey *et al.*, 1999). Statistical
analysis was used to develop an equation (MDRD formula) that uses these
clinical and demographic data to calculate a GFR that correlates closely
with the measured GFR. The formula also provides an estimation of GFR
that is normalized for body surface area (BSA). Although use of BSA
indexing is not universally accepted in expressions of renal function
such as CrCl or GFR, it seems reasonable when drug dosing is frequently
based on BSA (Murray and Ratain 2003). If an unadjusted GFR is desired,
the MDRD-derived estimate of GFR can be readily recalculated.

The formula for estimation of GFR shown below was developed and
validated during the analysis of the Modification of Diet in Renal
Disease (MDRD) Study (Levey *et al.*, 1999). To simplify the apparent
difficulty of the calculations, a "GFR calculator" can be found at
<http://www.hdcn.com/calcf/gfr.htm> as well as at other web sites.

> GFR (*mL/min/1.73m^2^*) = 170 X \[Pcr\] ^−0.999^ X \[age\] ^−0.176^ X
> \[0.762 if patient is
>
> female\] X \[1.18 if patient is Black\] X \[SUN\] ^−0.17^ X \[Alb\]
> ^+0.318^
>
> Where: Pcr = plasma creatinine (mg/dL)
>
> SUN = serum urea nitrogen (mg/dL)
>
> Alb = serum albumin (g/dL)

-   The estimated GFR should be calculated at baseline and prior to each
    treatment cycle.

-   Use actual body weight in calculating body surface area. Renal
    dialysis patients should have body surface area calculation based on
    dry weight (*e.g.,* post dialysis).

Cockcroft, D.W. and M.H. Gault. (1976). Prediction of creatinine
clearance from serum creatinine. *Nephron* 16:31-41.

Levey A.S., J.P. Bosch, J.B. Lewis, *et al*. (1999). A more accurate
method to estimate glomerular filtration rate from serum creatinine: A
new prediction equation. Modification of Diet in Renal Disease Study
Group. *Ann Intern Med* 130:461-470.

Murray P.T. and M.J. Ratain. (2003). Estimation of the glomerular
filtration rate in cancer patients: a new formula for new drugs. *J Clin
Oncol* 21(14):2633-2635.

APPENDIX B

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 C (*Example)***

**Drugs Known to be Metabolized by Selected CYP450 Isoenzymes**

+------------+-----------+-----------+-----------+------------+-------+
| **CYP3A4** |           |           |           |            |       |
+------------+-----------+-----------+-----------+------------+-------+
| **SU       |           | **INH     |           | **         |       |
| BSTRATES** |           | IBITORS** |           | INDUCERS** |       |
+------------+-----------+-----------+-----------+------------+-------+
| **Generic  | **Trade   | **Generic | **Trade   | **Generic  | **    |
| Name**     | Name**    | Name**    | Name**    | Name**     | Trade |
|            |           |           |           |            | N     |
|            |           |           |           |            | ame** |
+------------+-----------+-----------+-----------+------------+-------+
| Anti-ne    | Taxotere  | Anti-arr  | C         | Aminogl    | Cyt   |
| oplastics: |           | hythmics: | ordarone, | utethimide | adren |
| *e.g.*     | Iressa    | *e.g*.    | Pacerone  |            |       |
|            |           |           |           |            |       |
| Docetaxel  | Camptosar | A         | Cardizem, |            |       |
|            |           | miodarone | Dilacor   |            |       |
| Gefitinib  |           |           | XR        |            |       |
|            |           | Diltiazem |           |            |       |
| Irinotecan |           |           | C         |            |       |
|            |           | Quinidine | ardioquin |            |       |
+------------+-----------+-----------+-----------+------------+-------+
| An         | Agenerase | Ant       | Agenerase | An         | Ri    |
| ti-virals: |           | i-virals: |           | tibiotics: | fadin |
| *e.g.*     | Rifadin   | *e.g*.    | Crixivan  | *e.g.*     |       |
|            |           |           |           |            | Myco  |
| Amprenivir |           | A         | Viracept  | Rifabutin  | butin |
|            |           | mprenavir |           |            |       |
| Rifampin   |           |           | Norvir    | Rifampin   |       |
|            |           | Indinavir |           |            |       |
|            |           |           |           |            |       |
|            |           | N         |           |            |       |
|            |           | elfinavir |           |            |       |
|            |           |           |           |            |       |
|            |           | Ritonavir |           |            |       |
+------------+-----------+-----------+-----------+------------+-------+
| An         | Valium    | C         | Tagamet   | Antico     | Teg   |
| xiolytics: |           | imetadine |           | nvulsants: | retol |
| *e.g.*     | Zoloft    |           |           | *e.g*.     |       |
|            |           |           |           |            | Dil   |
| Diazepam   |           |           |           | Car        | antin |
|            |           |           |           | bamazapine |       |
| Sertraline |           |           |           |            | Nem   |
|            |           |           |           | Phenytoin  | butal |
|            |           |           |           |            |       |
|            |           |           |           | Pen        | Lu    |
|            |           |           |           | tobarbital | minal |
|            |           |           |           |            |       |
|            |           |           |           | Phe        |       |
|            |           |           |           | nobarbital |       |
+------------+-----------+-----------+-----------+------------+-------+
| Cy         | S         | Cyc       | S         | *Hypericum | St.   |
| closporine | andimmune | losporine | andimmune | p          | J     |
|            |           |           |           | erforatum* | ohn's |
|            |           |           |           | (2)        | Wort  |
+------------+-----------+-----------+-----------+------------+-------+
| Anti-i     | E         | Ant       | Cipro,    |            |       |
| nfectives: | rythrocin | ibiotics: | Ciloxan   |            |       |
| *e.g.*     |           | *e.g*.    |           |            |       |
|            | Sumycin   |           | Biaxin    |            |       |
| Er         |           | Cipr      |           |            |       |
| ythromycin |           | ofloxacin | Adoxa,    |            |       |
|            |           |           | Periostat |            |       |
| Te         |           | Clari     |           |            |       |
| tracycline |           | thromycin | Penetrex  |            |       |
|            |           |           |           |            |       |
|            |           | Do        | Nydrazid, |            |       |
|            |           | xycycline | INH       |            |       |
|            |           |           |           |            |       |
|            |           | Enoxacin  | Ketek     |            |       |
|            |           |           |           |            |       |
|            |           | Isoniazid |           |            |       |
|            |           |           |           |            |       |
|            |           | Teli      |           |            |       |
|            |           | thromycin |           |            |       |
+------------+-----------+-----------+-----------+------------+-------+
| Steroids:  | Premarin  | Imatinib  | Gleevec   |            |       |
| *e.g.*     |           |           |           |            |       |
|            | Climara   |           |           |            |       |
| Estrogens, |           |           |           |            |       |
| conjugated | Crinone   |           |           |            |       |
|            |           |           |           |            |       |
| Estradiol  |           |           |           |            |       |
|            |           |           |           |            |       |
| Pr         |           |           |           |            |       |
| ogesterone |           |           |           |            |       |
+------------+-----------+-----------+-----------+------------+-------+
| H          | Haldol    | Ha        | Haldol    |            |       |
| aloperidol |           | loperidol |           |            |       |
+------------+-----------+-----------+-----------+------------+-------+
| Card       | Cr        | D         | Cataflam, |            |       |
| iovascular | ystodigin | iclofenac | Voltaren  |            |       |
| agents:    |           |           |           |            |       |
| *e.g.*     | C         |           |           |            |       |
|            | ardioquin |           |           |            |       |
| Digitoxin  |           |           |           |            |       |
|            |           |           |           |            |       |
| Quinidine  |           |           |           |            |       |
+------------+-----------+-----------+-----------+------------+-------+
| Anti-hype  | Cardene   | Vaso      | Cardene   |            |       |
| rtensives: |           | dilators: |           |            |       |
| *e.g.*     | Calan,    | *e.g.*    | Calan,    |            |       |
|            | C         |           | C         |            |       |
| N          | hronovera | Ni        | hronovera |            |       |
| icardipine |           | cardipine |           |            |       |
|            |           |           |           |            |       |
| Verapamil  |           | Verapamil |           |            |       |
+------------+-----------+-----------+-----------+------------+-------+
| An         | Xylocaine | Ane       | Xylocaine |            |       |
| esthetics: |           | sthetics: |           |            |       |
| *e.g.*     | Diprivan  | *e.g*.    | Diprivan  |            |       |
|            |           |           |           |            |       |
| Ketamine   |           | Lidocaine |           |            |       |
|            |           |           |           |            |       |
| Lidocaine  |           | Propofol  |           |            |       |
+------------+-----------+-----------+-----------+------------+-------+
| Nefazodone | Serzone   | Anti-dep  | Serzone   |            |       |
|            |           | ressants: |           |            |       |
|            |           | *e.g.*    | Zoloft    |            |       |
|            |           |           |           |            |       |
|            |           | N         |           |            |       |
|            |           | efazodone |           |            |       |
|            |           |           |           |            |       |
|            |           | S         |           |            |       |
|            |           | ertraline |           |            |       |
+------------+-----------+-----------+-----------+------------+-------+
| Cocaine    |           | Anti      | Sporanox  |            |       |
|            |           | -fungals: |           |            |       |
|            |           | *e.g.*    | Nizoral   |            |       |
|            |           |           |           |            |       |
|            |           | Itr       | Lotrimin, |            |       |
|            |           | aconazole | Monistat  |            |       |
|            |           |           |           |            |       |
|            |           | Ket       |           |            |       |
|            |           | oconazole |           |            |       |
|            |           |           |           |            |       |
|            |           | M         |           |            |       |
|            |           | iconazole |           |            |       |
+------------+-----------+-----------+-----------+------------+-------+
| Ke         | Nizoral   | Caffeine  |           |            |       |
| toconazole |           |           |           |            |       |
+------------+-----------+-----------+-----------+------------+-------+
| Sildenafil | Viagra    | G         |           |            |       |
|            |           | rapefruit |           |            |       |
|            |           | juice (1) |           |            |       |
+------------+-----------+-----------+-----------+------------+-------+
| Albuterol  | Ventolin  |           |           |            |       |
+------------+-----------+-----------+-----------+------------+-------+
| Car        | Tegretol  |           |           |            |       |
| bamazapine |           |           |           |            |       |
+------------+-----------+-----------+-----------+------------+-------+
| Lovastatin | Mevacor   |           |           |            |       |
+------------+-----------+-----------+-----------+------------+-------+

When drugs classified as 'substrates' are co-administered with *[(Study
Agent)]{.underline}*, there is the potential for higher concentrations
of the 'substrate'. When *[(Study Agent)]{.underline}* is
co-administered with compounds classified as 'inhibitors', increased
plasma concentrations of *[(Study Agent)]{.underline}* is the potential
outcome. The coadministration of 'inducers' would potentially lower
plasma *[(Study Agent)]{.underline}* concentrations.

**Comprehensive List of Drugs That May Have Potential Interactions**

+---------------+-----------------+----------------+-----------------+
| ##### CYP 3   |                 |                |                 |
| A4 Substrates |                 |                |                 |
+---------------+-----------------+----------------+-----------------+
| Albuterol     | Docetaxel       | Ketoconazole   | Quetiapine      |
|               |                 |                |                 |
| Alfentanil    | Doxepin         | Lansoprazole   | Quinidine       |
|               |                 |                |                 |
| Alprazolam    | Doxorubicin     | Letrozole      | Rabeprazole     |
|               |                 |                |                 |
| Amlodipine    | Doxycycline     | Levomethadyl   | Repaglinide     |
|               |                 | acetate        |                 |
| Amprenavir    | Efavirenz       |                | Rifabutin       |
|               |                 | hydrochloride  |                 |
| Aprepitant    | Eletriptan      |                | Rifampin        |
|               |                 | Levonorgestrel |                 |
| Aripiprazole  | Enalapril       |                | Ritonavir       |
|               |                 | Lidocaine      |                 |
| Atazanavir    | Eplerenone      |                | Saquinavir      |
|               |                 | Losartan       |                 |
| Atorvastatin  | Ergoloid        |                | Sertraline      |
|               | mesylates       | Lovastatin     |                 |
| Benzphetamine |                 |                | Sibutramine     |
|               | Ergonovine      | Medro          |                 |
| Bisoprolol    |                 | xyprogesterone | Sildenafil      |
|               | Ergotamine      | Mefloquine     |                 |
| Bortezomib    |                 |                | Simvastatin     |
|               | Erythromycin    | Mestranol      |                 |
| Bosentan      |                 |                | Sirolimus       |
|               | Escitalopram    | Methadone      |                 |
| Bromazepam    |                 |                | Sufentanil      |
|               | Estradiol       | Me             |                 |
| Bromocriptine |                 | thylergonovine | Tacrolimus      |
|               | Estrogens,      |                |                 |
| Buprenorphine | conj.,          | Methysergide   | Tamoxifen       |
|               | synthetic       |                |                 |
| Buspirone     |                 | Miconazole     | Tamsulosin      |
|               | Estrogens,      |                |                 |
| Busulfan      | conj., equine   | Midazolam      | Telithromycin   |
|               |                 |                |                 |
| Carbamazapine | Estrogens,      | Miglustat      | Teniposide      |
|               | conj.,          |                |                 |
| Cerivastatin  | esterified      | Mirtazapine    | Terbinafine     |
|               |                 |                |                 |
| Chl           | Estrone         | Modafinil      | Tetracycline    |
| ordiazepoxide |                 |                |                 |
|               | Estropipate     | Montelukast    | Theophylline    |
| Chloroquine   |                 |                |                 |
|               | Ethinyl         | Moricizine     | Tiagabine       |
| Chl           | estradiol       |                |                 |
| orpheniramine |                 | Nateglinide    | Ticlopidine     |
|               | Ethosuximide    |                |                 |
| Cisapride     |                 | Nefazodone     | Tolterodine     |
|               | Etoposide       |                |                 |
| Citalopram    |                 | Nelfinavir     | Toremifene      |
|               | Felbamate       |                |                 |
| C             |                 | Nevirapine     | Trazodone       |
| larithromycin | Felodipine      |                |                 |
|               |                 | Nicardipine    | Triazolam       |
| Clobazam      | Fentanyl        |                |                 |
|               |                 | Nifedipine     | Trimethoprim    |
| Clonazepam    | Flurazepam      |                |                 |
|               |                 | Nimodipine     | Trimipramine    |
| Clorazepate   | Flutamide       |                |                 |
|               |                 | Nisoldipine    | Troleandomycin  |
| Cocaine       | Fosamprenavir   |                |                 |
|               |                 | Nitrendipine   | Vardenafil      |
| Colchicine    | Fulvestrant     |                |                 |
|               |                 | Norethindrone  | Venlafaxine     |
| Cyc           | Gefitinib       |                |                 |
| lophosphamide |                 | Norgestrel     | Verapamil       |
|               | Halofantrine    |                |                 |
| Cyclosporine  |                 | Ondansetron    | Vinblastine     |
|               | Haloperidol     |                |                 |
| Dantrolene    |                 | Paclitaxel     | Vincristine     |
|               | Ifosfamide      |                |                 |
| Dapsone       |                 | Pergolide      | Vinorelbine     |
|               | Imatinib        |                |                 |
| Delavirdine   |                 | Phencyclidine  | Zolpidem        |
|               | Indinavir       |                |                 |
| Diazepam      |                 | Pimozide       | Zonisamide      |
|               | Irinotecan      |                |                 |
| Digitoxin     |                 | Pioglitazone   | Zopiclone       |
|               | Isosorbide      |                |                 |
| Dihy          | dinitrate       | Primaquine     |                 |
| droergotamine |                 |                |                 |
|               | Isosorbide      | Progesterone   |                 |
| Diltiazem     | mononitrate     |                |                 |
|               |                 |                |                 |
| Disopyramide  | Isradipine      |                |                 |
|               |                 |                |                 |
|               | Itraconazole    |                |                 |
|               |                 |                |                 |
|               | Ketamine        |                |                 |
+---------------+-----------------+----------------+-----------------+

+-----------------+----------------+-----------------+----------------+
| ##### CY        |                |                 |                |
| P3A4 Inhibitors |                |                 |                |
+-----------------+----------------+-----------------+----------------+
| Acetominophen   | Diltiazem      | Lovastatin      | Progesterone   |
|                 |                |                 |                |
| Acetazolamide   | Disulfiram     | Mefloquine      | Propofol       |
|                 |                |                 |                |
| Amioderone      | Docetaxel      | Mestranol       | Propoxyphene   |
|                 |                |                 |                |
| Amlodipine      | Doxorubicin    | Methadone       | Quinidine      |
|                 |                |                 |                |
| Amprenavir      | Doxycycline    | Methimazole     | Quinine        |
|                 |                |                 |                |
| Anastrozole     | Drospirenone   | Methoxsalen     | Quinupristin   |
|                 |                |                 |                |
| Aprepitant      | Efavirenz      | Met             | Rabeprazole    |
|                 |                | hylprednisolone |                |
| Atazanavir      | Enoxacin       |                 | Risperidone    |
|                 |                | Metronidazole   |                |
| Atorvastatin    | Entacapone     |                 | Ritonavir      |
|                 |                | Miconazole      |                |
| Azelastine      | Ergotamine     |                 | Saquinavir     |
|                 |                | Midazolam       |                |
| Azithromycin    | Erythromycin   |                 | Selegiline     |
|                 |                | Mifepristone    |                |
| Betamethasone   | Ethinyl        |                 | Sertraline     |
|                 | estradiol      | Mirtazapine     |                |
| Bortezomib      |                |                 | Sildenafil     |
|                 | Etoposide      | Mitoxantrone    |                |
| Bromocriptine   |                |                 | Sirolimus      |
|                 | Felodipine     | Modafinil       |                |
| Caffiene        |                |                 | Sulconazole    |
|                 | Fentanyl       | Nefazodone      |                |
| Cerivastatin    |                |                 | Tacrolimus     |
|                 | Fluconazole    | Nelfinavir      |                |
| Chloramphenicol |                |                 | Tamoxifen      |
|                 | Fluoxetine     | Nevirapine      |                |
| Chlorzoxazone   |                |                 | Telithromycin  |
|                 | Fluvastatin    | Nicardipine     |                |
| Cimetadine      |                |                 | Teniposide     |
|                 | Fluvoxamine    | Nifedipine      |                |
| Ciprofloxacin   |                |                 | Testosterone   |
|                 | Fosamprenavir  | Nisoldipine     |                |
| Cisapride       |                |                 | Tetracycline   |
|                 | Glyburide      | Nitrendipine    |                |
| Clarithromycin  |                |                 | Ticlopidine    |
|                 | Grapefruit     | Nizatidine      |                |
| Clemastine      | juice          |                 | T              |
|                 |                | Norfloxacin     | ranylcypromine |
| Clofazimine     | Haloperidol    |                 |                |
|                 |                | Olanzapine      | Trazodone      |
| Clotrimazole    | Hydralazine    |                 |                |
|                 |                | Omeprazole      | Troleandomycin |
| Clozapine       | Ifosfamide     |                 |                |
|                 |                | Orphenadrine    | Valproic acid  |
| Cocaine         | Imatinib       |                 |                |
|                 |                | Oxybutynin      | Venlafaxine    |
| C               | Indinavir      |                 |                |
| yclophosphamide |                | Paroxetine      | Verapimil      |
|                 | Irbesartan     |                 |                |
| Cyclosporine    |                | Pentamidine     | Vinblastine    |
|                 | Isoniazid      |                 |                |
| Danazol         |                | Pergolide       | Vincristine    |
|                 | Isradapine     |                 |                |
| Delavirdine     |                | Phencyclidine   | Vinorelbine    |
|                 | Itraconazole   |                 |                |
| Desipramine     |                | Pilocarpine     | Zafirlukast    |
|                 | Ketoconazole   |                 |                |
| Dexmedetomidine |                | Pimozide        | Ziprasidone    |
|                 | Lansoprazole   |                 |                |
| Diazepam        |                | Pravastatin     |                |
|                 | Lidocaine      |                 |                |
| Diclofenac      |                | Prednisolone    |                |
|                 | Lomustine      |                 |                |
| Di              |                | Primaquine      |                |
| hydroergotamine | Losartan       |                 |                |
+-----------------+----------------+-----------------+----------------+

+-----------------+----------------+-----------------+----------------+
| #####           |                |                 |                |
| CYP3A4 Inducers |                |                 |                |
+-----------------+----------------+-----------------+----------------+
| Am              | Nevirapine     | Phenytoin       | Rifapentine    |
| inoglutethimide |                |                 |                |
|                 | Oxcarbazepine  | Primidone       |                |
| Carbamazapine   |                |                 |                |
|                 | Pentobarbital  | Rifabutin       |                |
| Fosphenytoin    |                |                 |                |
|                 | Phenobarbital  | Rifampin        |                |
| St. John's wort |                |                 |                |
+-----------------+----------------+-----------------+----------------+

> (Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In: Lacy
> CF, Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook
> 12^TH^ ed. Hudson, OH; LexiComp Inc. 2004: 1619-1631.)
>
> \(1\) Malhorta *et al*. (2000). Clin Pharmacol Ther. 69:14-23
>
> \(2\) Mathijssen *et al*. (2002). J Natl Cancer Inst. 94:1247-1249
>
> Frye *et al*. (2004). Clin Pharmacol Ther. 76:323-329

**APPENDIX D**

**CTEP MULTICENTER GUIDELINES**

**[Responsibility of the Principal Investigator]{.underline}**

-   The Principal Investigator will be the single liaison with the CTEP
    Protocol and Information Office (PIO). The Principal Investigator 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
    Principal Investigator. There will be only one version of the
    protocol, and each participating institution will use that document.
    The Principal Investigator is responsible for assuring that all
    participating institutions are using the correct version of the
    protocol.

-   The Principal Investigator 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 Principal Investigator.

-   The Principal Investigator is responsible for the timely review of
    AEs to assure safety of the patients.

-   The Principal Investigator 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 Protections (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 assurance (formerly 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 Principal Investigator.

-   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. **For this study,
    participating institutions will report expedited AEs directly to
    CTEP via AdEERS (see Section 7) with a copy to the Coordinating
    Center.** The Coordinating Center will submit AE reports to the
    Principal Investigator for timely review.

**[Audit Procedures]{.underline}**

-   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:

-   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.

**[Agent Ordering]{.underline}**

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

###### APPENDIX E

**FORMS**

#######  Model Eligibility Screening Worksheet

#######  Registration Form

**A Phase 1 and Pharmacokinetic Single Agent Study of \_\_*[Study
Agent]{.underline}*\_\_in Patients**

**with Advanced Malignancies and Varying Degrees of Renal Dysfunction**

**Physician of record: Site Co-Investigator:**

NCI Investigator Number: NCI Investigator Number:

Institution Name: Participating Site (Institution):

NCI Site Code: NCI Site Code:

Address: Address:

Phone: ( ) Phone: ( )

Fax: ( ) Fax: ( )

E-mail: E-mail:

**......*Patient Initials (First, Middle, Last) .......Patient Date of
Birth (mm/dd/yyyy)***

**PATIENT DISEASE**

Primary Disease Site Stage of Disease

Disease Grade Histology

**ELIGIBILITY CHECKLIST**

 No  *Yes* 1. Patient has a histologically or cytologically confirmed
solid or hematologic malignancy that is metastatic or unresectable and
for which standard curative or palliative measures do not exist or are
no longer effective.

 No  *Yes* 2. Patient is [\>]{.underline} 18 years of age.

 No  *Yes* 3. Life expectancy is greater than 3 months.

 No  *Yes* 4. Patient's performance status (ECOG scale) is
[\<]{.underline} 2 (Karnofsky [\>]{.underline} 60%)

 No  *Yes* 5. Patient has acceptable marrow and renal function as
defined below:

\- ANC [\>]{.underline} 1.5 x 10^9^/L

-   platelet count [\>]{.underline} 100 x 10^9^/L

-   total bilirubin within normal institutional limits

-   AST (SGOT)/ALT (SGPT) [\<]{.underline}2.5 X institutional upper
    limit of normal

 No  *Yes* 6. Patient is free of unstable or untreated
(non-irradiated) brain metastases.

 *No*  Yes 7. Does patient have a history of allergic reactions to
compounds of similar chemical or biologic composition to *[Study
Agent?]{.underline}*\_

 *No*  Yes 8. Does patient have any intercurrent illness including
(but not limited to) the following:

-   ongoing or active infection

-   symptomatic congestive heart failure

-   unstable angina pectoris

-   cardiac arrhythmia

-   psychiatric illness/social situations that would limit compliance
    with study requirements?

 *No*  Yes 9. Is patient pregnant?

 No  *Yes* 10. Does patient agree to use adequate means to prevent
pregnancy while participating in the study (applies to both male and
female patients)?

 *No*  Yes 11. Has patient received chemotherapy or radiotherapy
within 4 weeks of study entry (6 weeks for nitrosoureas or mitomycin C)
and/or has patient not yet recovered from the adverse effects of earlier
treatment?

 *No*  Yes 12. Has patient undergone major surgery within 14 days
prior to registration?

 *No*  Yes 13. Has patient received prior therapy with [\_\_*Study
Agent*\_\_]{.underline}?

 *No*  Yes 14. Is patient receiving concurrent therapy with any other
investigational agent?

 *No*  Yes 15. Is patient receiving any medications or substances
known to affect or with the potential to affect the activity or
pharmacokinetics of [\_*Study Agen*]{.underline}*t*\_? (Refer to
Appendix C.)

 *No*  Yes 16. Does patient have active hemolysis?

 *No*  Yes 17. Is patient HIV positive and receiving combination
anti-retroviral therapy?

 *No*  Yes 18. *Please insert questions appropriate to agent-specific
exclusion criteria.*

**RENAL FUNCTION**

[Plasma creatinine]{.underline} mg/dL [Creatinine clearance]{.underline}
mL/min

(CrCl)

Date measured: Date measured:

(mm/dd/yyyy) (mm/dd/yyyy)

[Calculated BSA-indexed CrCl]{.underline}: mL/min x 1.73 m^2^/actual BSA
**(VALUE USED FOR STRATIFICATION)**

[Serum albumin]{.underline} g/dL [Serum urea nitrogen]{.underline} mg/dL

Date measured Date measured:

(mm/dd/yyyy) (mm/dd/yyyy)

[Calculated BSA-indexed GFR:]{.underline} mL/min/1.73 m^2^

(using MDRD formula)

**COMMENTS:**

**ELIGIBILITY:**  Patient satisfies all eligibility criteria.

>  Patient is not formally eligible, but may be admitted to the study
> because (state reason)\*:

\* **Coordinator must document and date exceptions to eligibility in the
record.**

**A Phase 1 and Pharmacokinetic Single Agent Study of \_\_*[Study
Agent]{.underline}*\_\_in Patients**

**with Advanced Malignancies and Varying Degrees of Renal Dysfunction**

CTEP-assigned Protocol Number Coordinating Center (Local) Protocol
Number

Coordinating Center Name Coordinating Center Code

Participating Institution Name Participating Institution Code

Patient Study ID, Coordinating Center Patient Study ID, Participating
Institution

Patient Medical Record Number

Physician of Record

# 

# 

# Protocol Administration

IRB/REB Approval Date Person Completing Form, Last Name

^MM\ DD\ YYYY^ Person Completing Form, First Name

Date Informed Consent Signed Person Completing Form, Phone (\_\_\_\_)

^MM\ DD\ YYYY^ Person Completing Form, Fax (\_\_\_\_)

Projected Start Date of Treatment Person Completing Form, E-mail

^MM\ DD\ YYYY^

Date of Registration

^MM\ DD\ YYYY^

**Patient Demographics / Pre-Treatment Characteristics**

Patient Name, Last Patient Name, First Patient Name, Middle

*(initials acceptable) (initials acceptable)* *(initials acceptable)*

Patient Birth Date Patient Gender  *Male*  *Female*

^MM\ DD\ YYYY^

Patient Race/Ethnicity  *White*  *Black or African American*

***(check all that apply)***  *Native Hawaiian or Other Pacific
Islander*  *Asian*

 *American Indian or Alaska Native*  *Unknown*

Patient Ethnicity  *Hispanic or Latino*

***(check one)***  *Non-Hispanic*

 *Unknown*

Patient Social Security Number *(USA only)*

Patient's ZIP Code *(USA)* Country of Residence *(if not USA)*

Patient Height (cm) Patient Weight (kg) Body Surface Area (m^2^)

Performance Status ***(check one)*** Method of Payment ***(check one)**
(U.S. only)*

 *0 = Fully active, able to carry on all pre-disease performance* 
*Private*  *Military Sponsored*

*without restriction (Karnofsky 90 - 100)*  *Medicare* *(including
CHAMPUS or TRICARE)*

 *1 = Restricted in physically strenuous activity*  *Medicare/Private*
 *Veterans Sponsored*

*but ambulatory (K 70 - 80)*

 *2 = Ambulatory and capable of all selfcare but*  *Medicaid*  *Self
pay (no insurance)*

*unable to carry out any work activities (K 50 - 60)*  *Medicaid &
Medicare*  *No means of payment*

*(no insurance)*

 *3 = Capable of only limited selfcare, confined to bed or chair more*
 *Military or Veterans*  *Other*

*than 50% of waking hours (K 30 - 40)* *Sponsored NOS*  *Unknown*

 *4 = Completely disabled (K 10 -- 20)*

Date Signed Informed Consent Obtained:

MM DD YYYY

**Certification of Eligibility** **Protocol Design**

In the opinion of the investigator\
is the patient eligible?

 *Yes*  *No*

*(if No, the patient should not be registered)*

**Initial Patient Consent for Specimen Use**

Patient's Initial Consent given for specimen use for research on the
patient\'s cancer?  *Yes*  *No*

Patient's Initial Consent given for specimen use for research unrelated
to the patient\'s cancer?  *Yes*  *No*

Patient's Initial Consent given for further contact regarding specimen?
 *Yes*  *No*

Date of Consent for Specimen Use

^MM\ DD\ YYYY^