Download appendix b

OHSU Knight Cancer Institute
Treatment Protocol
Template Instructions
The protocol template is a tool to facilitate protocol development. It is not intended to supercede
the role of the Principal Investigator in the authoring and scientific development of the protocol.
It contains sample text for protocols submitted to OHSU Knight Cancer Institute.

It is recommended that primary section headings in the protocol template be retained to
facilitate review. If not appropriate for a given study, insert “Not Applicable” after the
section heading, delete unneeded text and sub-headings.

Sample text may be modified as necessary to meet the scientific aims of the study.

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, delete the instructions, italicized text or underlining.
For detailed instructions on developing phase I, II and III Clinical Trials visit this CTEP web site
http://ctep.cancer.gov/handbook/hndbk_4.html
For more detailed templates, visit the National Cancer Institute CTEP web site at
http://ctep.cancer.gov/guidelines/templates.html
Specific templates include: Phase I Single Agent
Phase I Combination
Phase II Single Agent
Phase II Combination
Phase III
For questions about protocol development contact:
Susan Aust, MSPH, CCRP
Protocol Development and Support Specialist
503 494-4108
[email protected]
For questions about protocol submission contact:
Kristin Hackney, MPHA, CCRP
Mail Code CH15R
503-494-6508
[email protected]
For protocol submission to OHSU Knight Cancer Institute, follow instructions on the submission
checklist found on the Knight Clinical Trials Office web page www.ohsucancer.com/crm
Revision: 7/07/2010
i
Oregon Health & Science University
OHSU Knight Cancer Institute
IRB Protocol #:
Other Protocol #:
TITLE: Sample: A Phase 1, 2 or 3 Study of Name Study Agent in Combination with
Name Other Agent(s) in Name Study Disease
Coordinating Center:
Name of Organization (If this is a multi-institution study, only
one organization/institution can be the coordinating center)
Principal Investigator:
Name
Address or Institution
Telephone
Co-Investigators:
Name
Address or Institution
Telephone
Name
Address or Institution
Telephone
If this is a multi-institution study, the protocol title page should include the name of each
participating institution, the investigator responsible for the study at that institution, and his/her
phone #.
Statistician:
(If applicable)
Name
Address or Institution
Telephone
Data Manager /
Study Coordinator:
Name
Address or Institution
Telephone
Final Protocol Date:
month/day/year
Protocol Revision Dates:
month/day/year
Do not delete any revision dates just add new dates.
Revision: 7/07/2010
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SCHEMA
Provide a schema for the study. If preferred, a scientific summary or synopsis may be provided.
Sample Schema
Study title
No Residual Disease > 1.0 cm
Study Drug by 3-Hour Infusion (Day 1)
Other Drug Intraperitoneal (Day 8)
Repeat Every 4 Weeks X 6 Courses
Revision: 7/07/2010
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TABLE OF CONTENTS
SCHEMA
1. OBJECTIVES
2. BACKGROUND
2.1
Study Disease
2.2
Study Agent
2.3
Other Agent(s)
2.4
Rationale
3. PATIENT SELECTION
3.1
Eligibility Criteria
3.2
Exclusion Criteria
4. TREATMENT PLAN
4.1
Agent Administration
4.1.1 Study Agent
4.1.2 Other Agent(s)
4.2
Supportive Care Guidelines
4.3
Duration of Therapy
5. DOSING DELAYS/DOSE MODIFICATIONS
5.1
Study Agent
5.2
Other Agent(s)
6. AGENT FORMULATION AND PROCUREMENT
6.1
Agent Accountability
6.2
Study Agent(s)
6.3
Commercial Agent(s)
7. CORRELATIVE/SPECIAL STUDIES
8. STUDY PROCEDURES AND SCHEDULE OF EVENTS
8.1
Subject Registration
8.2
Baseline Screening
8.3
Study Visits
8.4
Follow-up
8.5
Early Termination
8.6
Schedule of Events
Revision: 7/07/2010
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9. MEASUREMENT OF EFFECT
9.1
Definitions
9.2
Guidelines for Evaluation of Measurable Disease
9.3
Response Criteria
9.4
Confirmatory Measurement/Duration of Response
9.5
Progression-Free Survival
9.6
Response Review
10. ETHICAL AND REGULATORY REQUIREMENTS
10.1 Protocol Review
10.2 Informed Consent
10.3 Changes to Protocol
10.4 Maintenance of Records
10.5 OHSU IRB Reporting of Unanticipated Problems and Adverse Events
10.6 MedWatch Reporting
10.7 Sponsor or Additional Reporting
10.8 OHSU Knight Cancer Institute Data and Safety Monitoring Plan
10.9 Inclusion of Women, Minorities and Children
11. STATISTICAL CONSIDERATIONS
11.1 Study Objectives restate
11.2 Baseline Comparability
11.3 Efficacy Evaluations
11.4 Safety Evaluations
11.5 Sample Size and Power
11.6 Error levels (alpha and beta) in Phase II Studies
REFERENCES
APPENDICES
APPENDIX A
Performance Status Criteria
APPENDIX B
CTCAE
APPENDIX C
Example Case Report Forms
Revision: 7/07/2010
v
1. OBJECTIVES
1.1.
Insert primary protocol objectives.
1.2.
Insert secondary protocol objectives, if pertinent.
2. BACKGROUND
2.1
Study Disease
Provide background information on the study disease.
2.2
Study Agent
Provide background information on the investigational study agent, including information to support
safety issues and the rationale for the starting dose chosen.
2.3
Other Agent(s)
Provide background information on other agent(s) and/or treatments in study, including information
to support safety issues and the rationale for the starting dose chosen, if applicable.
2.4
Rationale
Provide the background and rationale for evaluating this combination therapy in this disease.
3. PATIENT SELECTION
3.1
Eligibility Criteria
3.1.1 Patients must have histologically or cytologically confirmed Study Disease Specify eligible
disease(s)/stage(s) using International Medical Terminology (IMT) terms
(http://ctep.cancer.gov/guidelines/codes.html# imt).
3.1.2 Insert appropriate criteria for the extent of disease
3.1.3
State allowable type and amount of prior therapy
3.1.4 Age >18 years. Both men and women and members of all races and ethnic groups will be
included. Edit as appropriate
3.1.5 Life expectancy of greater than
# weeks or months
3.1.6 ECOG performance status < insert number
3.1.7
Patients must have normal organ and marrow function as defined below: Edit as appropriate
- leukocytes
>3,000/L
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-
absolute neutrophil count
platelets
total bilirubin
AST(SGOT)/ALT(SGPT)
creatinine
>1,500/L
>100,000/L
within normal institutional limits
<2.5 X institutional upper limit of normal
within normal institutional limits
OR
-
creatinine clearance
>60 mL/min/1.73 m2 for patients with creatinine levels
above institutional normal
3.1.8
Insert other appropriate eligibility criteria
3.1.9
Willing to use adequate contraception for the duration of study participation, If applicable
3.1.10 Ability to understand and the willingness to sign a written informed consent document
3.2
Exclusion Criteria
3.2.1
Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered
from adverse events due to agents administered more than 4 weeks earlier. Edit as
appropriate
3.2.2
Patients may not have received any other investigational agents within the last 30 days.
3.2.3
Optional: Patients with known metastases
3.2.4
History of allergic reactions attributed to compounds of similar chemical or biologic
composition to Study Agent or other agents used in the study
3.2.5
Insert appropriate agent-specific exclusion criteria.
3.2.6
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.
3.2.7
The investigator(s) must state a medical or scientific reason if pregnant or nursing patients
or patients who are cancer survivors or those who are HIV-positive will be excluded from the
study. Samples statements:
Pregnant or lactating women are excluded from this study because of possible risk to the
fetus or infant.
Known HIV-positive patients are excluded from the study because of possible risk of lethal
infection when treated with marrow suppressive therapy.
4. TREATMENT PLAN
4.1
Agent Administration
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Treatment will be administered on an inpatient/outpatient basis. No investigational or commercial
agents or therapies other than those described below may be administered with the intent to treat the
patient's malignancy.
4.1.1 Study Agent
Describe regimen and 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.)
Include a detailed dose escalation schedule if applicable.
4.1.2 Other Agent(s)
Please provide agent administration information for other agent(s) used.
4.2
Supportive Care Guidelines
State guidelines for use of appropriate supportive care medications or treatments.
4.3
Duration of Therapy
In the absence of treatment delays due to adverse events, treatment may continue for (# cycles)
or until one of the following criteria applies:
Disease progression,
Intercurrent illness that prevents further administration of treatment,
Unacceptable adverse events(s),
Patient decides to withdraw from the study, or
General or specific changes in the patient's condition render the patient unacceptable for further
treatment in the judgment of the investigator.
5. DOSING DELAYS/DOSE MODIFICATIONS
Treatment plans should explicitly identify when treatment (typically dosage) modifications are
appropriate. Treatment modifications and the factors predicating treatment modification should be
explicit and clear. If dose modifications are anticipated, please provide a dose de-escalation schema
with treatment modifications expressed as a specific dose or amount rather than as a percentage of the
starting or previous dose.
5.1 Study Agent(s)
Discuss the dose modifications/treatment delays for the investigational agent used in this study.
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5.2 Other Agent(s)
Discuss the dose modifications/treatment delays for other agent(s) used in this study.
6. AGENT FORMULATION AND PROCUREMENT
6.1
Agent Accountability
The Investigator, or a responsible party designated by the Investigator, must maintain a careful
record of the inventory and disposition of the study agent.
6.2
Study Agent(s)
Availability: Study Agent is supplied to investigators by describe or state that the agent is
commercially available.
Product description: Include the available dosage forms, ingredients, and packaging, as
appropriate.
Solution preparation (how the dose is to be prepared): Include reconstitution directions and
directions for further dilution, if appropriate. State Not applicable if agent is not solution or does
not require preparation.
Storage requirements: Include the requirements for the original dosage form, reconstituted
solution, and final diluted product, as applicable.
Stability: Include the stability of the original dosage form, reconstituted solution, and final diluted
product, as applicable.
Route of administration: Include a description of the method to be used and the rate of
administration, if applicable. For example, continuous intravenous infusion over 24 hours, short
intravenous infusion over 30 to 60 minutes, intravenous bolus, etc. Describe any precautions
required for safe administration.
Expected adverse events: Include a comprehensive list of all known risks and any potential risks
(such as the toxicities seen with another agent of the same class or risks seen in animals
administered this agent).
6.3
Commercial Agent(s)
A separate pharmaceutical section is needed for each commercially available agent containing at
least the following information, available in the manufacturer's current package insert:
Product description: Include any dosage form(s), ingredients, and packaging applicable to the
protocol. Also state the agent's supplier or state that it is commercially available.
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9
Solution preparation (how the dose is to be prepared): Investigators may refer the reader to the
package insert for 'standard' preparation instructions. If the agent is to be prepared in a 'nonstandard' or protocol-specific fashion, the reconstitution directions and instructions for further
dilution must be included. Appropriate storage and stability information should be included to
support the method of preparation. State Not applicable if agent is not solution or does not require
preparation.
Route of administration: Include a description of the method to be used and the rate of
administration, if applicable. For example, continuous intravenous infusion over 24 hours, short
intravenous infusion over 30 to 60 minutes, intravenous bolus, etc. Describe any precautions
required for safe administration.
Expected adverse events: Include a comprehensive list of all known risks.
7.
CORRELATIVE/SPECIAL STUDIES
Optional: Insert Not applicable or describe all planned correlative studies.
8.
STUDY PROCEDURES AND SCHEDULE OF EVENTS
Subject Registration
procedure for consent
list procedures for registration
Describe detailed procedure for randomization and blinding if applicable.
Baseline Screening
list procedures screening
Baseline screening evaluations are to be conducted within # weeks prior to start of
protocol therapy. Scans and x-rays must be done  weeks prior to the start of therapy.
Study Visits
list procedures for study visits
Toxicities and adverse experiences will be assessed at each visit using the
Toxicity Criteria for Adverse Events v3.0 (CTCAE, see
appendix B).
Follow-up
8.4.1 list procedures for follow-up
Early Termination
Provide Criteria for early termination the following are examples.
8.5.1 Voluntary patient withdrawal
8.5.2 Investigator’s decision that is in the patient’s best interest to withdrawal
8.5.3 If the patient becomes pregnant
8.5.4 Noncompliance
8.5.5 Significant protocol violation
8.5.6 For any reason, at the Sponsor or Investigators discretion
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NCI Common
8.6
Schedule of Events
Schedules shown in the Study Calendar below are provided as an example and should be modified as
appropriate.
PreStudy
Wk
1
Study Agent
A
Other Agent(s)
B
Wk
2
Wk
3
Wk
4
Wk
5
Wk
6
A
B
B
Wk
7
Wk
8
Wk
9
A
B
B
Wk
10
Wk
11
Wk
12
Off
c
Study
A
B
B
B
Informed consent
X
Demographics
X
Medical history
X
Concurrent meds
X
Physical exam
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
X
CBC w/diff, plts
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Serum chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EKG (as indicated)
X
Adverse event evaluation
X-------------------------------------------------------------------------------------------------X
X-------------------------------------------------------------------------------------------------X
X
Tumor measurements
X
Tumor measurements are repeated every [# weeks] weeks. Documentation
(radiologic) must be provided for patients removed from study for progressive disease.
c
X
Radiologic evaluation
X
Radiologic measurements should be performed every
c
X
B-HCG
b
X
[# weeks] weeks.
Other tests, as appropriate
Other correlative studies
A:
B:
a:
b:
c:
Study Agent: Dose as assigned; administration schedule
Other Agent(s): Dose as assigned; administration schedule
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT
[AST], SGPT [ALT], sodium.
Serum pregnancy test (women of childbearing potential).
Off-study evaluation. Two consecutive measurements taken 4 weeks apart must be used to document progressive disease if the patient is removed from
study for this reason.
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9. MEASUREMENT OF EFFECT
Provide response criteria. If the criteria for solid tumors below are not applicable, the investigator(s)
should provide disease-appropriate criteria (e.g., for specific hematologic malignancies) with references,
and all solid tumor criteria should be deleted.
For the purposes of this study, patients should be reevaluated for response every [# of weeks] weeks. In
addition to a baseline scan, confirmatory scans should also be obtained [# of weeks](not less than 4)
weeks following initial documentation of objective response.
9.1.
Definitions
Sample if RECIST is being used: 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. Note: Lesions are either
measurable or non-measurable using the criteria provided below. The term “evaluable” in reference
to measurability will not be used because it does not provide additional meaning or accuracy.
Delete the following of not applicable
9.1.1 Measurable disease
Measurable lesions are defined as those that can be accurately measured in at least one
dimension (longest diameter to be recorded) as >20 mm with conventional techniques (CT,
MRI, x-ray) or as >10 mm with spiral CT scan. All tumor measurements must be recorded in
millimeters (or decimal fractions of centimeters).
9.1.2
Non-measurable disease
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.
9.1.3
Target lesions
All measurable lesions up to a maximum of five 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.
9.1.4 Non-target lesions
All other lesions (or sites of disease) should be identified as non-target lesions and should
also be recorded at baseline. Non-target lesions include measurable lesions that exceed the
maximum numbers per organ or total of all involved organs as well as non-measurable
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12
lesions. Measurements of these lesions are not required but the presence or absence of each
should be noted throughout follow-up.
9.2
Guidelines 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.
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.
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. 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. 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. 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). 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. 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 can be useful to confirm complete
pathological response when biopsies are obtained.
Tumor markers. 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. These techniques can be used to differentiate between partial responses (PR)
Enter date of protocol version
13
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.
9.3
Response Criteria
9.3.1 Evaluation of target lesions
Complete Response (CR):
Disappearance of all target lesions
Partial Response (PR):
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):
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):
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
9.3.2 Evaluation of non-target lesions
Complete Response (CR):
Incomplete Response/
Stable Disease (SD):
Progressive Disease (PD):
Disappearance of all non-target lesions and normalization of
tumor marker level
Persistence of one or more non-target lesion(s) and/or
maintenance of tumor marker level above the normal limits
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, in such
circumstances the opinion of the treating physician should prevail, and the progression status
should be confirmed at a later time by the review panel (or study chair). Note: If tumor
markers are initially above the upper normal limit, they must normalize for a patient to be
considered in complete clinical response.
9.3.3 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 (see section
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9.3.1).
Enter date of protocol version
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Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Incomplete
response/SD
No
PR
PR
Non-PD
No
PR
SD
Non-PD
No
SD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Note:
Patients with a global deterioration of health status requiring discontinuation of treatment
without objective evidence of disease progression at that time should be classified as having
“symptomatic deterioration.” Every effort should be made to document the objective
progression, even after discontinuation of treatment.
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.
When the evaluation of complete response depends on this determination, it is recommended that
the residual lesion be investigated (fine needle aspirate/biopsy) before confirming the complete
response status.
9.4
Confirmatory Measurement/Duration of Response
9.4.1 Confirmation
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by
repeat assessments that should be performed [# weeks, no less than 4] after the criteria for
response are first met. In the case of SD, follow-up measurements must have met the SD
criteria at least once after study entry at a minimum interval of [# weeks, not less than 6-8
weeks] (see section 9.3.3).
9.4.2
Duration of overall response
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.
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9.4.3
Duration of Stable Disease
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.
9.5
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.
Uncontrolled trials using PFS as a primary endpoint should be considered on a case by case basis.
The methodology to be applied should be thoroughly described in the protocol.
9.6
Review
For trials where the response rate is the primary endpoint, it is strongly recommended that all
responses be reviewed by an expert(s) independent of the study at the study’s completion.
Simultaneous review of the patients’ files and radiological images is the best approach.
Note: When a review of the radiological images is to take place, it is also recommended that
images be free of marks that might obscure the lesions or bias the evaluation of the
reviewer(s).
10. ETHICAL AND REGULATORY REQUIREMENTS
10.1
Protocol Review
The protocol and informed consent form for this study must be reviewed and approved in writing by
the OHSU Knight Cancer Institute (CI) Clinical Research Review Committee (CRRC) and
appropriate Institutional Review Board (IRB) prior to any patient being registered on this study.
10.2
Informed Consent
Written informed consent will be obtained from all patients, or the legally authorized representative
of the patient, participating in this trial, as stated in the Informed Consent section of the case of
Federal Regulations, Title 21, Part 50. If a patients signature cannot be obtained, and for all patients
under the age of 18, the investigator must ensure that the informed consent is signed by the patients
legally authorized representative. Documentation of the consent process and a copy of the signed
consent shall be maintained in the patient’s medical record.
10.3
Changes to Protocol
Any modification of this protocol must be documented in the form of a protocol revision or
amendment signed by the principal investigator and approved by the CRRC and IRB, before the
revision or amendment may be implemented. The only circumstance in which the amendment may
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17
be initiated without regulatory approval is for a change necessary to eliminate an apparent and
immediate hazard to the patient. In that event, the investigator must notify the CRRC and IRB in
writing within 10 working days after the implementation. Investigators holding the IND must notify
FDA of substantive changes to the protocol.
10.4
Maintenance of Records
If the investigator relocates or for any reason withdraws from the study, the study records must be
transferred to an agreed upon designee, such as another institution, another investigator, or to OHSU
Knight Cancer Institute Clinical Research Management. Records must be maintained according to
sponsor or FDA requirements. State requirements specific to this protocol.
10.5
OHSU IRB Reporting of Unanticipated Problems and Adverse Events
Unanticipated Problems (UP) and Adverse Events (AE) will be reported to IRB according to the
policies, procedures and guidelines posted on the OHSU IRB web site
http://www.ohsu.edu/research/rda/irb/policies.shtml.
Fatal and life-threatening UP will be reported to OHSU IRB within 7 days of notification of the
event. All other UP reports will be submitted to OHSU IRB no later than 15 days of occurrence or
notification of the event. Copies of the report documents will be kept in the study regulatory binder.
UP and AE reports are submitted through OHSU e-IRB and will be reviewed by OHSU Knight
Cancer Institute and IRB. Monthly accumulative reports will be reviewed by a DSMC Oncologist
and forwarded to the CRRC.
10.6
MedWatch Reporting
For this investigator-initiated study, the investigator is considered the sponsor. The
investigator/sponsor is required to report adverse experiences to the FDA through the MedWatch
reporting program, even if the trial involves a commercially available agent. Adverse experiences to
be reported include any unexpected (not listed in the package label), serious adverse experiences
with a suspected association to the study drug.
These adverse experiences will be reported using a MedWatch form 3500 for voluntary reporting.
MedWatch forms. Instructions are available at www.fda.gov/medwatch . MedWatch reports can be
submitted online at https://www.accessdata.fda.gov/scripts/medwatch/
When the serious adverse event is reported to the FDA, copies of the MedWatch 3500 form and
supporting materials will be submitted to the OHSU IRB and the OHSU Drug Information Service.
A copy of the MedWatch 3500 form and supporting materials will be kept on file in the study
regulatory binder.
10.7 Sponsor or additional reporting requirements. Insert FDA reporting requirements if
IND.
10.8
OHSU Knight Cancer Institute Data and Safety Monitoring Plan
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PI holds the
In addition to complete study and pharmacy files, complete records must be maintained on each
patient treated on this protocol. OHSU Knight Cancer Institute (CI), CRM shared resource is
responsible for ensuring that all member investigators and affiliate investigators conduct clinical
research studies in compliance with local IRB standards, FDA regulations and NIH policies. The
Data and Safety Monitoring Committee (DSMC) is responsible for conducting Quality Assurance
audits on CI approved protocols according to the Data and Safety Monitoring Plan policies and
procedures http://ohsucancer.com/crm
Locally initiated studies will be audited by an OHSU Knight CI DSMC audit team. Newly approved
studies may be audited anytime after enrollment. Each OHSU Knight CI approved treatment
protocol will be audited on an annual basis.
10.9
Inclusion of Women, Minorities and Children
10.9.1
Inclusion of Women and Minorities
No OHSU Knight Cancer Institute study will focus on any particular gender, racial or ethnic subset.
No subject will be excluded from the study on the basis of gender, racial or ethnic origin. Male,
female and minority volunteers will be recruited for this study from the general population and
approximately 50% men and 50% women will be studied.
State either: The projected gender, racial, and ethnic composition of the study will represent that of the state
of Oregon. Or: The projected gender, racial and ethnic composition of the study will include
because the disease
.
If the disease being studied does not affect both genders or all races and ethnicities equally (e.g., cervical
cancer only affects women and Black males are more likely than White males to have prostate cancer), then
this information needs to be stated and taken into account when calculating the projected enrollment. If the
prevalence of the disease being studied is consistent across race, ethnicity and gender, then table 1 figures can
be used to calculate projected enrollments in Table 2. The OHSU General Clinical Research Center has links
to various sources of statistics on their webpage at www.ohsu.edu/gcrc. If a different source is used in
calculating projected enrollments, that source should be cited below Table 2.
Table 1: Population Demographics - Oregon (%)
Sex/Gender
Ethnic Category
Females
Males
Total
Hispanic or Latino
8.0
Not Hispanic or Latino
92.0
Ethnic Category: Total of all subjects*
100*
Racial Category
American Indian or Alaskan Native
1.3
Asian
3.0
Black or African American
1.6
Native Hawaiian or other Pacific Islander
0.2
White
86.6
More than one race
3.1
Unknown/Other
4.2
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Sex/Gender
Ethnic Category
Females
Males
Total
100*
Racial Category: Total of all subjects*
TOTALS
50.4
Source: Adapted from U.S. Census Bureau, 2000
49.6
100*
*Totals may not equal 100 due to rounding.
Complete Table 2. The numbers within Table 2 should reflect the anticipated recruitment of subjects.
Each subject should be entered into the table twice: once under an ethnic category and once under
a racial category. Do not inter “0” for any gender or minority category unless there is a protocol
reason to exclude them. If the calculation is less that 1, enter 0-1.
Table 2: Projected Accrual for the Present Study (enter actual estimates, not percentages).
Sex/Gender
Ethnic Category
Females
Males
Unknown
Total
Hispanic or Latino
Not Hispanic or Latino
Unknown
*
Ethnic Category: Total of all subjects*
Racial Category
American Indian or Alaskan Native
Asian
Black or African American
Native Hawaiian or other Pacific Islander
White
More than one race
Unknown
*
Racial Category: Total of all subjects*
Source: Investigator projections based on ______________________________________________*Totals must agree.
10.9.2 Inclusion of Children
In accordance with NIH guidelines on the inclusion of children as participants in research involving human
subjects, children under the age of 18 years must be included in all human subjects research, conducted or
supported by the NIH, unless there are clear and compelling reasons not to include them. Therefore, proposals
for research involving human subjects must include a description of plans for the inclusion of children
Include the appropriate following statement:
This protocol includes children.
OR
This protocol does not include children for the following reason: (Acceptable reasons for the
exclusion of children from clinical research may be one or more of the following) 1. the number of
children with this type of cancer is limited or 2. no dosing or adverse event data are currently
available on the use of Study Agent in combination with Other Agent(s) in patients <18 years of
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age, therefore, children are excluded from this study but will be eligible for future pediatric phase 2
combination trials.
1. STATISTICAL CONSIDERATIONS
This section should be developed in coordination with the biostatistician available to you at OHSU Knight
Cancer Institute.
11.1 Study Objectives
11.1.1 Primary Objective: restate
11.1.2 Secondary Objective: restate
11.2
Baseline Comparability
11.3
Efficacy Evaluations
11.4
Safety Evaluations
11.5
Sample Size and Power
11.6
Error Levels (alpha and beta) in Phase II studies
REFERENCES
Please provide the citations for all publications referenced in the text.
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APPENDIX A
Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
100
0
Normal activity. Fully active, able
to carry on all pre-disease
performance without restriction.
1
2
3
4
5
Symptoms, but ambulatory.
Restricted in physically strenuous
activity, but ambulatory and able
to carry out work of a light or
sedentary nature (e.g., light
housework, office work).
In bed <50% of the time.
Ambulatory and capable of all
self-care, but unable to carry out
any work activities. Up and about
more than 50% of waking hours.
In bed >50% of the time. Capable
of only limited self-care, confined
to bed or chair more than 50% of
waking hours.
100% bedridden. Completely
disabled. Cannot carry on any
self-care. Totally confined to bed
or chair.
Dead.
90
Description
Normal, no complaints, no evidence
of disease.
Able to carry on normal activity;
minor signs or symptoms of disease.
80
Normal activity with effort; some
signs or symptoms of disease.
70
Cares for self, unable to carry on
normal activity or to do active work.
60
50
40
30
20
10
0
A-1
Requires occasional assistance, but
is able to care for most of his/her
needs.
Requires considerable assistance and
frequent medical care.
Disabled, requires special care and
assistance.
Severely disabled, hospitalization
indicated. Death not imminent.
Very sick, hospitalization indicated.
Death not imminent.
Moribund, fatal processes
progressing rapidly.
Dead.
APPENDIX B
Common Terminology Criteria for Adverse Events v3.0 (CTCAE)
Toxicities and adverse events will be assessed using the NCI Common Toxicity Criteria for Adverse Events
v3.0 (CTCAE). Since CTEP has standardized the CTCAE, the NCI does not require the inclusion of the
CTCAE within the protocol document. A copy can be downloaded from the CTEP home page
http://ctep.cancer.gov/reporting/ctc.html
APPENDIX C
Sample case report forms