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Phase Study drug(s)Page 1 of 54CC#

PI Name

[Study title]

Protocol Number: CC #

Study Drug:

Version Number:

Version Date:

IND Number:

Principal Investigator (Sponsor-Investigator)

[Name]

University of California San Francisco

[UCSF address]

San Francisco, CA 94

Telephone: 415-

Fax: 415-

E-mail: @medicine.ucsf.edu

Co-Investigators

[Name]

[Name]

[Name]

[Name]

Statistician

[Name]

Clinical Research Coordinator

[Name]

University of California San Francisco

[UCSF address]

San Francisco, CA 94

Telephone: 415-

Fax: 415-

Revision History

[3rd revision, etc] Version [#]

[date]

[2nd revision] Version [#]

[date]

[1st revision] Version [#]

[date]

[Initial Protocol] Version [#]

[date]

Version date: Protocol CC#:

Proprietary and Confidential

The information in this document is considered privileged and confidential, and may not be disclosed to others except to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by Federal and State laws. Persons to whom this information is disclosed should be informed that this information is privileged and confidential and that it should not be further disclosed.

Phase I Study drug(s)Page 1 of 54

Protocol Signature Page

Protocol No.: Version Date:

I agree to follow this protocol version as approved by the UCSF Protocol Review Committee (PRC), Committee on Human Research (CHR), and Data Safety Monitoring Committee (DSMC).

I will conduct the study in accordance with applicable CHR requirements, Federal regulations, and state and local laws to maintain the protection of the rights and welfare of study participants.

I certify that I, and the study staff, have received the requisite training to conduct this research protocol.

I have read and understand the information in the Investigators Brochure (or Manufacturers Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in accordance with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the Statement of Investigator (Form FDA 1572), and with local regulatory requirements. In accordance with the FDA Modernization Act, I will ensure the registration of the trial on the www.clinicaltrials.gov website.

I agree to maintain adequate and accurate records in accordance with CHR policies, Federal, state and local laws and regulations.

UCSF Principal Investigator / Study Chair

Printed Name

Signature

Date

Participating Site(s)

[Name]

[Institution name]

[Address]

Telephone:

E-mail:

[Name]

[Institution name]

[Address]

Telephone:

E-mail:

[Name]

[Institution name]

[Address]

Telephone:

E-mail:

Principal Investigator

Site

Printed Name

Signature

Date

Abstract

[Note: this is intended to be a brief summary of the study, not to exceed 2 pages.]

Title

Patient population

Rationale for Study

[Brief summary of the rationale, as provided in Section 1 Introduction]

Primary Objective

[Identical to the objective(s) described in Section 2 Objectives of the Study - there should only be one primary objective.]

Secondary Objectives

[Identical to the objective(s) described in Section 2.]

Study Design

[Brief summary of Section 3 Study Design, with an abbreviated schema (if possible)]

Number of patients

[As described in Section 3.]

Duration of Therapy

Patients may continue treatment for from the time of study entry.

[Duration of therapy for individual patients, not duration of the study.]

Duration of Follow up

[Duration of follow up for individual patients.]

Duration of study

The study will reach completion weeks/months/years from the time the study opens to accrual.

Study Drugs

[Names, dosage, and brief description of information in Section 4 Study Drugs.]

Safety Assessments

[List safety assessments: dose limiting toxicities, adverse events, clinical laboratory evaluations, vital signs, etc. from Section 9 Statistical Considerations and Evaluations of Results.]

Efficacy Assessments

[List efficacy assessments: overall response rate, response duration, etc. - from Section 9.]

Unique Aspects of this Study

[Optional - This is the first study to evaluate the safety and efficacy of > in patients with >.]

List of Abbreviations

[Review for completeness prior to finalizing protocol all abbreviations mentioned within the protocol must be included; some are provided below, use/modify as needed.]

AE

adverse event

ALP

alkaline phosphatase

ALT

alanine aminotransferase

ANC

absolute neutrophil count

AST

aspartate aminotransferase

ATC

Anatomical Therapeutic Chemical (Classification System)

AUC

area under the curve

BUN

blood urea nitrogen

CBC

complete blood cell (count)

CHR

Committee on Human Research (UCSF IRB)

CR

complete response

CRC

Clinical Research Coordinator

CRF

case report form

CSF

cerebral spinal fluid

CT

computerized tomography

CTCEA

Common Terminology Criteria for Adverse Events

CTEP

Cancer Therapy Evaluation Program

CTMS

Clinical Trial Management System

DFS

disease-free survival

DLT

dose limiting toxicity

DSMC

Data and Safety Monitoring Committee

DSMP

Data and Safety Monitoring Plan

ECOG

Eastern Cooperative Oncology Group

FCBP

female of childbearing potential

FDA

Food and Drug Administration

GCP

Good Clinical Practice

HBeAg

Hepatitis B e antigen

HBV

hepatitis B virus

HCT

hematocrit

HCV

hepatitis C virus

HDFCCC

Helen Diller Family Comprehensive Cancer Center

HGB

hemoglobin

HIV

human immunodeficiency virus

ICH

International Conference on Harmonization

IND

investigational new drug application

IP

investigational product

IRB

Institutional Review Board

iwCLL

International Workshop on Chronic Lymphocytic Leukemia

IV

intravenous

LDH

lactate dehydrogenase

LFT

liver function test

MedDRA

Medical Dictionary for Regulatory Activities

MRI

magnetic resonance imaging

MTD

maximum tolerated dose

NCI

National Cancer Institute

NHL

non-Hodgkins lymphoma

ORR

overall response rate

PD

disease progression

PK

pharmacokinetics

PO

Per os (by mouth, orally)

PR

partial response

PRC

Protocol Review Committee (UCSF)

QOL

Quality of Life

RBC

red blood cell (count)

SD

stable disease

SD

standard deviation

SGOT

serum glutamic oxaloacetic transaminase

SGPT

serum glutamic pyruvic transaminase

ULN

upper limit of normal

WBC

white blood cell (count)

Table of Contents

Protocol Signature Page0

Abstract1

List of Abbreviations2

Table of Contents4

1Introduction7

1.1Background on Indication7

1.2Background on the Compounds7

1.3Rationale for the Proposed Study7

1.4Correlative Studies7

1.4.17

1.4.27

2Objectives of the Study7

2.1Primary7

2.2Secondary7

2.3Exploratory Objectives, Other Assessments7

2.4Endpoints7

2.4.1Primary Endpoints7

2.4.2Secondary Endpoints8

2.4.3Exploratory Endpoints8

3Study Design8

3.1Characteristics8

3.2Number of Subjects8

3.3Eligibility Criteria8

3.3.1Inclusion Criteria8

3.3.2Exclusion Criteria9

3.4Duration of Therapy10

3.5Duration of Follow Up10

3.6Randomization Procedures10

3.7Study Timeline10

3.7.1Primary Completion10

3.7.2Study Completion10

4Study Drugs10

4.1Description, Supply and Storage of Investigational Drugs10

4.1.1Investigational Drug #110

4.1.2Investigational Drug #211

4.2Drug Accountability11

4.3Drug Ordering11

4.4Packaging and Labeling of Study Drugs12

5Treatment Plan12

5.1Dosage and Administration12

5.1.1Other Modality(ies) or Procedures12

5.1.2Dose Limiting Toxicity12

5.1.313

5.2Dose Modifications and Dosing Delays13

5.3Monitoring and Toxicity Management15

5.3.1Other toxicities15

6Study Procedures and Observations16

6.1Schedule of Procedures and Observations16

6.1.1Pretreatment Period16

6.1.2Treatment Period17

6.1.3End-of-Treatment Study Procedures18

6.1.4Post-treatment/Follow Up Visits19

6.1.5Long Term/Survival Follow-up Procedures20

6.1.6Discontinuation of Therapy20

6.2Usage of Concurrent/Concomitant Medications24

6.3Dietary Restrictions24

6.4Prohibited Medications24

7Reporting and Documentation of Results24

7.1Evaluation of Efficacy (or Activity)24

7.224

7.2.124

7.2.2Antitumor Effect Solid Tumors24

7.2.3Antitumor Effect Hematologic Tumors27

7.3Evaluation of Safety27

7.4Definitions of Adverse Events27

7.4.1Adverse Event28

7.4.2Adverse reaction28

7.5Recording of an Adverse Event29

7.6Follow-up of Adverse Events30

7.7Adverse Events Monitoring30

7.8Expedited Reporting30

8Statistical Considerations and Evaluation of Results31

8.1.131

8.1.231

8.2Study Endpoints31

8.2.1Study Design32

8.2.2Randomization32

8.2.3Unblinding Subjects32

8.2.4Stratification Factors32

8.3Determination of Sample Size and Accrual Rate32

8.3.1Sample Size and Power Estimate32

8.3.2Replacement Policy32

8.3.3Accrual estimates32

8.4Interim Analyses and Stopping Rules32

8.5Analyses Plans32

8.5.1Analysis Population32

8.5.2Primary Analysis (or Analysis of Primary Endpoints)32

8.5.3Secondary Analysis (or Analysis of Secondary Endpoints)32

8.5.4Other Analyses/Assessments32

8.6Evaluation of Safety33

8.7Study Results33

9Study Management33

9.1Pre-study Documentation33

9.2Institutional Review Board Approval33

9.3Informed Consent33

9.4Changes in the Protocol34

9.5Handling and Documentation of Clinical Supplies34

9.6Case Report Forms (CRFs)34

9.7Oversight and Monitoring Plan35

9.8Multicenter communication35

9.9Coordinating Center Documentation of Distribution36

9.10Regulatory Documentation36

References37

Appendices38

Appendix 1Performance Status Criteria38

Appendix 2Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study39

Appendix 3UCSF Policy/Procedure for Required Regulatory Documents for a UCSF Investigator-Initiated Oncology Clinical Trials with an Investigator held IND41

Appendix 4Multicenter Institutional Studies43

4.1Data and Safety Monitoring Plan for Multicenter Institutional Study(Phase 2 or 3 Institutional Study)43

Appendix 5Prohibited Medications48

Appendix 6Specimen Collection49

List of Tables

Table 5.1Regimen Description12

Table 5.4Dose Modifications and Dosing Delays13

Dose Modifications and Dosing Delays Tables for Specific Adverse Events13

Table 6.1Schedule of Study Procedures and Assessments21

Table 7.1Response Criteria26

IntroductionBackground on Indication

Background on the Compounds

[This is intended to be a brief summary of Section 4 Study Drugs - provide summary information on each investigational study drug, device, or procedure including the mechanism of action, summaries of non-clinical and clinical studies, non-clinical and clinical pharmacokinetics, major route of elimination, safety profile, and the rationale for the starting dose, and regimen chosen. Include any information on the metabolism of the investigational study drug in humans and its potential for drug interactions, (e.g. via the P450 enzyme system).]

Rationale for the Proposed Study

[Provide background rationale for evaluating this intervention in this disease. Survey current treatment options for patient population and review of clinical outcomes for these treatments. Discuss reasons for conducting this study and briefly summarize study design; described in detail in Section 3 Study Design of this document. This section should connect the disease background with the study drugs under evaluation and provide a brief overview of the study. Indicate why this information is valuable and how it advances knowledge. Identify possible risks and benefits; how risks will be mitigated in the study, and why potential benefits outweigh the risks.]

Correlative Studies

[Provide background information on each planned correlative study including the biological rationale and hypothesis as well as the relevant preclinical and clinical data (if available). For additional information, see FDAs Guidance Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories and CTEPs Guidelines for Correlative Studies in Clinical Trials. If this trial includes no correlative studies, state No correlative studies will be conducted in this study.]

Objectives of the Study

[Provide detailed description of primary and secondary objectives, and describe any other assessments that will be performed in this study. The objectives - to describe, to measure,to compare, to estimate - may be stated in general terms: efficacy, safety, immunogenicity, pharmacokinetics; or specific: dose-response, superiority to placebo. Include the name(s) of the study drug(s) or intervention being evaluated, doses or dose ranges to be studied, dose regimens, etc.]

Primary

[State the primary protocol objective, it should have a corresponding endpoint described in Section 2.4. Objectives of the Study, Endpoints. For example, a typical primary objective for a phase 1 trial is:]

To determine the safety and tolerability of > or combination of > with >

To determine the dose-limiting toxicity (DLT) and maximum tolerated dose for study drug when administered >

Secondary

[State any secondary protocol objectives. Typical secondary objectives for a phase 1 trial may be:]

To describe the pharmacokinetics associated with > when administered >.

To describe any preliminary efficacy of > or combination of > with > in patients with >

Exploratory Objectives, Other Assessments

Endpoints

[Specify primary endpoint to answer primary objective, secondary endpoints to answer secondary objectives, and endpoints for exploratory objectives. This information should be identical to Section 9 Statistical Considerations and Evaluations of Results. A typical endpoint for the primary objective example in 2.1 above would be: DLT will be defined based on the rate of drug-related grade 3-5 adverse events. These will be assessed using the NCI CTCAE v4.0.]

Primary Endpoints

Secondary Endpoints

Exploratory Endpoints

Study DesignCharacteristics

[State a short description of the study, including Phase, type (treatment, prevention, diagnostic, etc.), interventional model (single group, parallel, cross-over, etc.), number of intervention arms, if the study is open label, single-or double blinded, and whether the study is randomized. State the primary outcome that the protocol is designed to evaluate: safety, efficacy, pharmacokinetics, pharmacodynamics.]

Number of Subjects

[State planned number of subjects to be included in the study - take into account screening failures, so that the number of subjects includes the planned number of evaluable patients. If patients are to be replaced, this should also be included in this section.]

Eligibility Criteria

Patients must have baseline evaluations performed prior to the first dose of study drug and must meet all inclusion and exclusion criteria. In addition, the patient must be thoroughly informed about all aspects of the study, including the study visit schedule and required evaluations and all regulatory requirements for informed consent. The written informed consent must be obtained from the patient prior to enrollment. The following criteria apply to all patients enrolled onto the study unless otherwise specified.

Inclusion Criteria

[Create a numbered list of Inclusion and Exclusion Criteria avoid using outline fortmat or sub items, such as 1.a. 1.b., etc.]

1. Patients must have histologically confirmed 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 histologically or cytologically confirmed >

[1. You may specify eligible disease(s)/stage(s) using the CTEP Simplified Disease Classification]

2.

[2. Provide appropriate criteria for the measurement of lesions in this patient population. Lesions are either measurable or non-measurable using the criteria provided in Section 7 Reporting and Documentation of Results. For example, Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral CT scan, MRI, or calipers by clinical exam. See Section 7.2.2.3 for the methods for evaluation of measurable disease.]

OR

[Provide appropriate criteria for diseases other than solid tumors. Criteria for selected hematologic malignancies can be found in the following references: J Clin Oncol 17(4):1244-53, 1999 (non-Hodgkin's lymphoma); J Clin Oncol 8(5):813-19, 1990 (acute myeloid leukemia); and Blood 887(12):4990-97, 1996 (chronic lymphocytic leukemia).]

3.

[3. State allowable type and amount of prior therapy. Define any limitations on prior therapy and the time from last prior regimen (e.g., no more than 6 cycles of an alkylating drug; no more than 450 mg/m2 doxorubicin for drugs with expected cumulative cardiotoxicity). Include separate definitions for duration as needed (e.g., at least 4 weeks since prior chemotherapy or radiation therapy, 6 weeks if the last regimen included BCNU or mitomycin C). Include site/total dose for prior radiation exposure as needed (e.g., no more than 3000 cGy to fields including substantial marrow).]

4. Age >18 years

5.

[5. State any age and/or gender/race-ethnic restrictions.]

6.

[6. State allowable type and amount of prior therapy.]

7.

[7. State any life expectancy restrictions.]

8.

[8. State whether ECOG or Karnofsky Performance Status will be employed (see Appendix 1).]

9.

[9. State requirements for organ and marrow function, examples provided below:]

Adequate bone marrow function:

leukocytes

>3,000/mcL

absolute neutrophil count

>1,500/mcL

platelets

>100,000/mcL

Adequate hepatic function:

total bilirubin

within normal institutional limits

total bilirubin

within normal institutional limits

AST(SGOT)

on the developing human fetus are unknown. For this reason and because > as well as other therapeutic drugs used in this trial are known to be teratogenic [if drugs in this study are known to be teratogenic, edit as necessary], women of child-bearing potential and men must agree to use adequate contraception: > prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and > months/weeks after completion of study drug administration.

[10. State any requirements for pregnancy testing or birth control. For approved products, review package insert and follow the stated recommendations.]

11. Ability to understand a written informed consent document, and the willingness to sign it

12.

[12. State any other appropriate inclusion criteria for this study.]

Exclusion Criteria

1.

[1. State therapy restrictions, for example: Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to drugs administered more than 4 weeks earlier.]

2.

[2. State restrictions regarding use of other investigational drugs]

3.

[3. State exclusion requirements due to co-morbid disease or concurrent illness, for example: Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.]

4.

[4. State requirements regarding history of allergic reactions attributed to compounds of similar chemical or biologic composition to investigational drug or device.]

5. Patients receiving any medications or substances that are inhibitors or inducers of CYP450 enzyme(s) are ineligible. Lists including medications and substances known or with the potential to interact with the specified CYP450 enzyme(s) isoenzymes are provided in Appendix >.

[5. State exclusion criteria relating to concomitant medications or substances that have the potential to affect the activity or pharmacokinetics of the study drug. Examples of drugs 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 in Section 6.2 Usage of Concurrent/Concomitant Medications and/or presented as an appendix. The above text (CYP450 interactions) may be used or modified.]

6. Pregnant women are excluded from this study because > is a/an > drug 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 > breastfeeding should be discontinued if the mother is treated with >.

If more than one study drug is administered:These potential risks may also apply to other drugs used in this study.

[6. State the medical or scientific reason if pregnant or nursing patients will be excluded from the study. See CTEPs Guidelines Regarding the Inclusion of Pregnant and Breast-Feeding Women on Cancer Clinical Treatment Trials. Also, refer to the manufacturers package insert or Investigator Brochure for the study drugs that will be used. Some manufacturers may have their own language they want included in the protocol. The above text may be used or modififed.]

7. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with >. 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.

[7. State the medical or scientific reason if patients who are cancer survivors or those who are HIV-positive will be excluded from the study. Refer to CTEPs Guidelines Regarding the Inclusion of Cancer Survivors and HIV-Positive Individuals on Clinical Trials. The above text may be used or modified.]

8.

[8. Insert any other drug-specific exclusion criteria.]

Duration of Therapy

[3.4 This section should define the length of time an individual patient may remain in the study (not the length of the study itself) and the circumstances under which protocol therapy will end.]

In the absence of treatment delays due to adverse events, treatment may continue for > or until:

Disease progression

Inter-current illness that prevents further administration of treatment

Unacceptable adverse event(s)

Patients decides to withdraw from the study

Significant patient non-compliance with protocol

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

Duration of Follow Up

Patients will be followed for 30 days after completion of treatment or removal from study, or until death, whichever occurs first. Patients removed from study for unacceptable treatment related adverse event(s) will be followed until resolution or stabilization of all treatment related adverse events to Grade 2 or lower.

[For any early phase study if changing 30 day follow-up, please discuss with Dr. Munster prior to making that change]

Randomization Procedures

[If patients are randomized, describe how, including any blocking or adaptive methods, and who will set it up. Report the individuals will be blinded to the randomization status.]

Study Timeline

Primary Completion

[Estimate the length of time it will take for the study to reach Primary Completion from the time the study opens to accrual to the date that the final subject is expected to be examined or receive an intervention for the purposes of final collection of data for the primary outcome. For example, The study will reach primary completion 24 months from the time the study opens to accrual.]

Study Completion

[Estimate the length of time it will take for the study to reach Study Completion from the time the study opens to accrual to the final date on which data are expected to be collected. For Example, The study will reach study completion 36 months from the time the study opens to accrual.]

Study DrugsDescription, Supply and Storage of Investigational DrugsInvestigational Drug #1

[Refer to the package insert(s) for complete information.]

> is available in > capsules/tablets for oral administration.

Classification

Mechanism of Action

Metabolism

Contraindications

Availability

Storage and handling

Drug #1 is stored at >.

[Example: 25C (77F)]

Side Effects

Complete and updated adverse event information is available in the Investigational Drug Brochure and/or product package insert. [if an IB and/or package insert are available]

Investigational Drug #2

> is available in > /mL solution in a single use-vial for intravenous administration.

Classification

Mechanism of Action

Metabolism

Contraindications

Availability

Storage and handling

Drug #2 >.

[Example: Drug #2 in the single-use vial is stable at 2C-8C (36F-46F). Solutions diluted for infusion may be stored at 2C-8C (36F-46F) for 24 hours.]

Side Effects

Drug Accountability

The Investigational Pharmacist will manage drug accountability records.

Drug Ordering

UCSF will obtain > directly from pharmaceutical company as study supply.

[OR - explain how study drug will be provided as study supply.]

Packaging and Labeling of Study Drugs

Drugs will be packaged and labeled per UCSF institutional standards, adhering to applicable local and federal laws.

[Include additional manufacturer information.]

Treatment Plan

Dosage and Administration

Treatment will be administered on an (inpatient/outpatient) basis.

[Describe dosage and administration for this study. Describe the regimen (drug, dose, route, and schedule) and state any special precautions or warnings relevant for investigational study drug administration (e.g., incompatibility of the drug with commonly used intravenous solutions, necessity of administering drug with food, how to round a dose of oral drug to available tablet/capsule strengths, premedications etc.), and describe in detail any prophylactic or supportive care regimens required for study drug(s) administration. See CTEPs Guidelines for Treatment Regimens, Expression and Nomenclature for guidance on expressing chemotherapy dosage schedules and treatment regimens. Provide separate regimen descriptions for different treatment groups of patients.

The following table is an example of how planned treatment regimen may be presented:]

Table 5.1Regimen Description

Study Drug

Premedication; precautions

Dose

Route

Schedule

Cycle Length

Study Drug 1

Pre-medicate with for > days prior to Study Drug 1

100 mg

Oral

Days 1-3 week 1

4 weeks (28 days)

Study Drug 2

Avoid exposure to cold (food, liquids, air) for 24 hr after each dose

300 mg/m2

Intravenous

Days 1-3 week 1

Study Drug 3

Take with food

50 mg tablet

Oral

Daily, weeks 1 and 2

Footnotes

[For orally or self-administered drugs, provide a method for assessing compliance with treatment, for example: The patient will be requested to maintain a medication diary of each dose of medication. The medication diary will be returned to clinic staff at the end of each >. The use of a diary should also be included in the schedule of procedures and study assessments, In Section 6 Study Procedures and Observations.]

Other Modality(ies) or Procedures

[Provide a detailed description of any other modalities (e.g., surgery, radiotherapy) or procedures (e.g., hematopoietic stem cell transplantation) used in the protocol treatment, not as study assessments. . If this study involves no other modalities or procedures, state, No other modalities will be used in this study. Study assessments are defined in Section.]

Dose Limiting Toxicity

Dose limiting toxicity (DLT) will be defined as > which are attributable to the study treatment during the first 28 days of therapy (Cycle 1). The dose limiting toxicity will be based on the tolerability observed during of treatment/observation. The maximum tolerated dose of will be that dose at which fewer than one-third of patients experience a dose limiting toxicity. If multiple toxicities are seen, the presence of dose limiting toxicity should be based on the most severe toxicity experienced.

The dose limiting toxicity will be defined as any grade 3 or grade 4 toxicity lasting longer than days despite > which occurs during of treatment and observation with and , and which is attributable to the study drug(s). In addition, any grade 3 or 4 toxicity will be a dose-limiting toxicity with the exclusion of grade 3 .

Grade 3 or 4 will be treated with . Grade 3 or 4 will be treated with . [repeat as necessary]

State the definition of the major potential toxicity and type, and how it will be managed and for how long. State how it will be graded and at what point the patient will be removed from study for dose-limiting toxicity related to . Describe DLT attribution, if necessary]

Describe any grading relative to supportive care, such as any nausea grade 3, or nausea that persists despite optimal supportive care; mouth sores, diarrhea, etc.]

Dose Modifications and Dosing Delays

[Identify when treatment (typically dosage) modifications are appropriate. Treatment modifications/dosing delays and the factors predicating treatment modification should be explicit and clear. State how an individual patients dose might be modified or delayed because of side effects. If dose modifications or treatment delays are anticipated, provide a dose de-escalation schema. The following table for an orally available drug is an example use/modify as needed:]

Table 5.2Dose Modifications and Dosing Delays

Dose Level

Dose of Study Drug

-1

1

2

3

Footnotes

Treatment or visit delays for public holidays or weather conditions do not constitute a protocol violation.

[All treatment modifications must be expressed as a specific dose or amount rather than as a percentage of the starting or previous dose. Dose modifications/treatment delays for study drug(s) may be presented separately or together. Table format is recommended.

Below are dose modification tables for the following AEs: nausea, vomiting, diarrhea, neutropenia, and thrombocytopenia; and a template (blank) dose modification table. Note that if a patient experiences several adverse events and there are conflicting recommendations, the investigator should use the recommended dose adjustment that reduces the dose to the lowest level.]

The following dose modification rules will be used with respect to potential toxicity. Toxicity will be assessed according to the NCI Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0).

Dose Modifications and Dosing Delays Tables for Specific Adverse Events 3

Adverse Event: Nausea

Grade of Event

Management/Next Dose for


Grade 1

No change in dose

No change in dose

Grade 2

Hold until Grade 1

Resume at same dose level

Hold until Grade 1


Grade 3

Hold* until two dose reductions should go off protocol therapy

Adverse Event: Vomiting

Grade of Event



Grade 1

No change in dose

No change in dose

Grade 2

Hold until Grade 1


Hold until Grade 1


Grade 3


Adverse Event: Diarrhea

Grade of Event



Grade 1

No change in dose

No change in dose

Grade 2

Hold until Grade 1


Hold until Grade 1


Grade 3


Adverse Event: Neutropenia

Grade of Event



Grade 1

No change in dose

No change in dose

Grade 2

Hold until Grade 1


Hold until Grade 1


Grade 3

Hold* until 2 weeks should go off protocol therapy

**Patients requiring >two dose reductions should go off protocol therapy

Adverse Event: Thrombocytopenia

Grade of Event



Grade 1

No change in dose

No change in dose

Grade 2

Hold until Grade 1


Hold until Grade 1


Grade 3

Hold* until 2 weeks should go off protocol therapy

**Patients requiring >two dose reductions should go off protocol therapy

Adverse Event:

Grade of Event



Grade 1

Grade 2

Grade 3

Grade 4

>

*Footnote any relevant guidelines regarding how long a delay in therapy is allowed before patients should go off protocol therapy

**Footnote any relevant guidelines regarding how many dose reductions are allowed before patients should go off protocol therapy

Monitoring and Toxicity Management

Each patient receiving in combination with will be evaluable for safety. The safety parameters include all laboratory tests and hematological abnormalities, physical findings, >and spontaneous reports of adverse events reported to the investigator by patients.

Each patient will be assessed periodically for the development of any toxicity as outlined in Section 6 Study Procedures and Observations. Toxicity will be assessed according to the NCI CTCAE v4.0. Dose adjustments will be made according to the system showing the greatest degree of toxicity.

We will monitor for >.

Acute toxicity will be managed by >. Further management will depend upon the judgment of the clinician and may include >.

Patients will also be monitored for >. This will be monitored by >.

Other toxicities

Cardiovascular toxicity

A major potential toxicity with > is > which will also be graded on the basis of the NCI CTCAE v4.0 scale

Hematologic Toxicities

>

Viral Infection

>

Gastrointestinal toxicity

>

>

>

Study Procedures and ObservationsSchedule of Procedures and Observations

The study-specific assessments are detailed in this section and outlined in Section 6 Schedule of Study Procedures and Assessments. Screening assessments must be performed within days prior to the first dose of investigational product. Any results falling outside of the reference ranges may be repeated at the discretion of the investigator. All on-study visit procedures are allowed a window of > days unless otherwise noted. Treatment or visit delays for public holidays or weather conditions do not constitute a protocol violation.

A written, signed, informed consent form (ICF) and a Health Insurance Portability and Accountability Act (HIPAA) authorization must be obtained before any study-specific assessments are initiated. A copy of the signed ICF will be given to the subject and a copy will be filed in the medical record. The original will be kept on file with the study records.

All patients who are consented will be registered in OnCore, the UCSF Helen Diller Family Comprehensive Cancer Center Clinical Trial Management System (CTMS). The system is password protected and meets HIPAA requirements.

Pretreatment Period

Screening Assessments

The Screening procedures and assessments must be completed within > of the Day 1 Visit.

[or first day of study drug/infusion].

Physical examination

Vital signs

Complete medical history

Baseline conditions assessment

Documentation of disease assessment (disease-specific staging criteria)

Performance status (ECOG, KPS, etc.)

Measureable disease

[Disease assessment / Measurable Disease / Imaging: these are listed as different items as required for OnCore calendar/CRF/billing configuration: edit these procedures accordingly for your study]

History of prior treatments and any residual toxicity relating to prior treatment

Baseline medications taken within > days of Day 1

Sample of tumor tissue [describe details of sample required, if a biopsy is needed if no previous tumor tissue is available or adequate for study]

Hematology labs (other than CBC w/ Diff)

Complete blood count (CBC) with differential and platelet count

Blood chemistry assessment, including:

Alkaline phosphatase, aspartate aminotransferase/alanine aminotransferase (ALT/AST), total bilirubin, calcium, phosphorus, blood urea nitrogen (BUN), creatinine, total protein, albumin, fasting glucose, potassium, sodium, chloride, bicarbonate, uric acid, lactate dehydrogenase (LDH), fasting lipid panel (low-density lipoprotein [LDL], total cholesterol, triglycerides)

Thyroid function tests: thyroid-stimulating hormone (TSH), free thyroxine (FT4)

Coagulation assessment, including prothrombin time, partial thromboplastin time, international normalized ratio (PT/PTT/INR)

Tumor marker assessments [such as CAE, AFP, CA19-9, CA 125, etc.]

Immune parameter assessments [such as immunoglobulins, etc]

Serum Hepatitis assessment, including Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody (HBsAb), Hepatitis B core antibody (HBcAb), Hepatitis C virus RNA

Urinalysis

Serum or urine pregnancy test within > prior to the start of study drug

Imaging (CT or MRI) of > for tumor/lesion assessment

Electrocardiogram (ECG)

Cardiac assessment (ECHO, MUGA, etc.)

Bone scan

Specimen Collection for Banking (blood, tissue, etc.)

Biopsy

Questionnaires

[NOTE: Please provide a window for scans, e.g: Only to be performed if X weeks since the last scan. Adjust time frame window for completing scans appropriately most scans need a 28-day window, while other procedures such as labs and ECG/EKG need about 7 days to complete. Modify the procedures and assessments list as needed]

Treatment PeriodStudy Procedures, Cycle 1, Day 1


Vital signs

Performance status

Evaluation of adverse events

Concomitant medications

CBC with differential and platelet count



Alkaline phosphatase, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting glucose, potassium, sodium, chloride, bicarbonate, uric acid, LDH, fasting lipid panel (LDL, total cholesterol, triglycerides)

Thyroid Function Tests: TSH, FT4

Coagulation assessment, including PT/PTT/INR



Urinalysis

Serum or urine pregnancy test



Bone scan

PK/PD/PG

Questionnaires

Study Procedures Cycle >, Day >

These procedures must be completed within > of Day >.

Evaluation of clinical response or deterioration


Vital signs

Performance status



Hematology assessment, including CBC with differential and platelet count


Alkaline phosphatase, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting glucose, potassium, sodium, chloride, bicarbonate, uric acid, LDH, fasting lipid panel, TSH, FT4




Urinalysis




Cardiac Assessments (ECHO, MUGA, etc)

Bone scan

PK/PD/PG

Biopsy

End-of-Treatment Study Procedures

To be completed within 30 days of the last dose of study drug.



Vital signs

Performance Status



Hematology assessment, including CBC with differential and platelet count


Alkaline phosphatase, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting glucose, potassium, sodium, chloride, bicarbonate, uric acid, LDH, fasting lipid panel, TSH, FT4




Urinalysis




Bone scan

PK/PD/PG

Questionnaires

Post-treatment/Follow Up Visits

Patients will be followed > for up to > after enrollment or until disease progression. The following procedures will be performed at the Follow Up Visit(s):



Vital signs

Performance Status



CBC with differential and platelet count



Alkaline phosphatase, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting glucose, potassium, sodium, chloride, bicarbonate, uric acid, LDH, fasting lipid panel

Thyroid Function Tests: TSH, FT4




Urinalysis


Imaging (CT or MRI) > (scans would only be completed in follow-up for patients whose disease has not yet progressed since entering the study)


Cardiac assessment (ECHO, MUGA, etc)

Bone scan

Long Term/Survival Follow-up ProceduresDiscontinuation of Therapy

The Investigator will withdraw a patient whenever continued participation is no longer in the patients best interests. Reasons for withdrawing a patient include, but are not limited to, disease progression, the occurrence of an adverse event or an concurrent illness, a patients request to end participation, a patients non-compliance or simply significant uncertainty on the part of the Investigator that continued participation is prudent. There may also be administrative reasons to terminate participation, such as concern about a patients compliance with the prescribed treatment regimen.

Phase II Study drug(s)Page 24 of 61

Table 4.1Schedule of Study Procedures and Assessments

[This table works as required for OnCore calendar/CRF/billing configuration

List assessments and procedures in the same order as listed in previous section text and list similar types of procedures together (e.g. labs, imaging, exams). Use/modify schedule table as needed

+/- #: if the window is the same # of days for each cycle & visit, one footnote may be added to describe and text in each column may be deleted

PLEASE NOTE: The CRISS Team (OnCore) will review this schedule for accuracy & CRF creation]

Period/

Procedure

Screening

Cycle 1

Cycle 2 and future Cycles

End of Treatment visit

Follow-up visits

Study Day/Visit Day

-# to 0(+/- #)

1(+/- #)

8(+/- #)

15(+/- #)

22(+/- #)

29(+/- #)

1(+/- #)

8(+/- #)

15(+/- #)

22(+/- #)

29(+/- #)

#(+/- #)

FU #(+/- #)

Informed consent

X

Baseline conditions 1

X

AE assessment

X

X

X

X

X

X

X

X

X

X

X

X


X

X

X

X

X

X

X

X

X

X

X

X

Specimen Collection or Optional Specimen Banking

Treatment/Drug Administration

>

>

Clinical procedures

Physical exam

Vital signs

Medical history

Disease assessment 2

Performance status

Measurable disease

Biopsy

Questionnaire

>

Laboratory procedures

CBC w/ Diff 3

Hematology

Blood chemistry 4

Thyroid Function Tests

Coagulation 5

Tumor markers 6

Immune parameters 7

Hepatitis 8

Study Labs

Serum sample PK

Urinalysis

Pregnancy test (HCG)

Imaging procedures

Imaging (CT or MRI) 9

Cardiac Assessment (ECHO, MUGA)

ECG/EKG

Bone scan

1 Baseline conditions assessment per DSMC policy (Baseline Conditions VI Form)

2 Disease-specific staging criteria (for CRF purposes, e.g: GU Assessment, BR Disease Eval, AML-MDS Summary, etc.)

3 Including CBC with differential and platelet count

4 Including alkaline phosphatase, ALT/AST, total bilirubin, calcium, phosphorus, (BUN), creatinine, total protein, albumin, fasting glucose, potassium, sodium, chloride, bicarbonate, uric acid, LDH, fasting lipid panel (LDL, total cholesterol, triglycerides),

5 Including PT/PTT/INR

6 Including CAE, AFP, CA19-9, CA 125, etc

7 Immune parameter assessments

8 Including HBsAg, HBsAb, HBcAb, Hep C RNA

9 Restaging will occur q x cycle

[Please provide a window for assessments when applicable]

Version date:Protocol CC#:


Usage of Concurrent/Concomitant Medications

[Complete this section as required for the particular study and drug interactions concerns, for example consider:

Temperature elevations & treatment

Growth Factors

Anti-diarrheals

Antiemetics

Drugs such as lorazepam, prochlorperazine, or serotonin antagonists may be used if clinically indicated.

Antihistamines

Topical Steroid Creams

Anticoagulants]

[Include any specific reasons for this indication or treatment.]

Dietary Restrictions

Prohibited Medications

[Include any prohibited medications that are specific to the drugs in this study. A standard list of prohibited medications is provided in Appendix 5.]

Reporting and Documentation of Results

[This section may vary significantly among studies, some sample text is provided.]

Evaluation of Efficacy (or Activity)

Antitumor Effect Solid Tumors

Response and progression in this study will be evaluated 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 v1.1 criteria (or International Workshop on Chronic Lymphocytic Leukemia [IWCLL]).

Definitions

Evaluable for toxicity

All patients will be evaluable for toxicity from the time of their first treatment with the study drug.

Evaluable for objective response

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.)

Disease Parameters

Measurable disease

Measurable disease is defined as lesions (or tumors) that can be accurately measured in at least one dimension (longest diameter to be recorded) with a minimum size of 10mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice thickness and a minimum of 10mm), 10mm caliper measurement by clinical exam (when superficial), and/or 20mm by chest X-ray (if clearly defined and surrounded by aerated lung).

All tumor measurements will be recorded in millimeters or decimal fractions of centimeters. Previously irradiated lesions are considered non-measurable except in cases of documented progression of the lesion since the completion of radiation therapy.

Target lesions

All measurable lesions up to a maximum of 5 lesions total (and a maximum of two lesions per organ) representative of all involved organs should be identified as target lesions and recorded and measured at baseline. Target lesions will 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

All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as non-target lesions and should also be recorded at baseline. It is possible to record multiple non-target lesions involving the same organ as a single item on the case record form (e.g. multiple enlarged pelvic lymph nodes or multiple liver metastases). Bone lesions may be measureable if 1 cm on MRI. Measurements of these lesions are not required, but the presence or absence of each will be noted throughout follow-up.

Non-measurable disease (Tumor Markers)

Non-measurable disease is all other lesions (or sites of disease), including small lesions (longest diameter day.

pharmacokinetics and correlative studies assessments[drug name]

pharmacokinetics[drug name]

Under the supervision of Drs. Yong Huang and Leslie Floren, vemurafenib analysis will be performed at UCSF.

sampling and shipping information[drug name]

Draw 2 mL into a 5 mL EDTA (K3) coated tube

Invert the tube gently several times to avoid clotting

Place the tube into an ice bath at approximately 4C during the sampling period

Within 30 min after collection, centrifuge the tube at 3-5C for 15 min at 1500 to 2000g

Transfer the plasma into uniquely labeled 2ML SMART SCAN TUBES from Thermo (Reference for rack/48 tubes: Nr. AB1411 or Reference for only 100 tubes: AB-1389) and frozen immediately over solid carbon dioxide (dry ice) or in a freezer at approximately -70C or below.

Ship to:

[contact name]

[company name & address]

[contact phone]

Email:

Correlative studies assessments

Portions of all new tumor biopsy specimens will be immediately immersed in formalin and subsequently embedded in paraffin and additional tissue will be flash-frozen and stored at -70 C until the time of analysis

The primary contact for acquisition and processing of these specimens at UCSF is:

[contact name]

[UCSF address/location]

[contact phone]

Email:
