Download Components of a Phase II Cancer Center Protocol

THE UNIVERSITY OF MICHIGAN
COMPREHENSIVE CANCER CENTER
Components of a Phase II Cancer Center Protocol
Following is a summary of the sections which comprise a University of Michigan Cancer Center
Phase II protocol, listed in the order in which they appear along with a brief description of the
information contained in each section. It is recommended that this format be used for all Cancer
Center Phase II investigator-initiated protocols. Complete each section as applicable. Other
sections may not be applicable for a specific protocol.
TITLE PAGE
Includes protocol number assigned by Clinical Trials Office (CTO), title of protocol, Principal
Investigator, co-Investigators, and study coordinator(s).
TABLE OF CONTENTS
Includes reference to all sections and appendices.
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1
OBJECTIVE(S)
Purpose of study and brief outline of therapy to be evaluated.
2
BACKGROUND
Justification for conducting study and results of similar studies or pilot data.
Scientific background and basis for hypothesis(es) to be tested.
3
DRUG INFORMATION
Description of drugs used in study (in alphabetical order).
4
STAGING CRITERIA
Criteria by which patients will be staged (if applicable).
5
ELIGIBILITY CRITERIA
Specific inclusion/exclusion requirements which must be met.
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STRATIFICATION/DESCRIPTIVE FACTOR/RANDOMIZATION SCHEME
Pretreatment patient characteristics that are balanced across treatment arms or
used to determine initial doses (stratification). Descriptive factors are patient
characteristics that do not affect treatment assignments. If there is no
randomization, “randomization scheme” is deleted.
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TREATMENT PLAN
Describes therapy and should include:
1) treatment doses/schedule,
2) any dose adjustments for 1st course of therapy, and
3) duration of therapy.
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TOXICITIES TO BE MONITORED/DOSAGE MODIFICATIONS
Dose adjustments for each drug (increases/decreases/delaying and/or withholding
therapy) related to toxicity after initiation of therapy. Also, outlines modifications
due to toxicities from other therapies, such as surgery and radiotherapy.
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STUDY PARAMETERS/CALENDAR
List of all parameters and required intervals for repeating tests, also include
therapy and intervals at which it is to be given (can also include timeline for data
collection forms submission).
SCHEMA
Abbreviated description of protocol (“Treatment at a Glance”).
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RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST)
QUICK REFERENCE
10.1
Eligibility
Only patients with measurable disease at baseline should be included in
protocols where objective tumor response is the primary endpoint.
Measurable disease - the presence of at least one measurable
lesion. If the measurable disease is restricted to a solitary lesion, its
neoplastic nature should be confirmed by cytology/histology.
Measurable lesions - lesions that can be accurately measured in at
least one dimension with longest diameter 20 mm using
conventional techniques or 10 mm with spiral CT scan.
Non-measurable lesions - all other lesions, including small lesions
(longest diameter <20 mm with conventional techniques or <10 mm
with spiral CT scan), i.e., bone lesions, leptomeningeal disease,
ascites, pleural/pericardial effusion, inflammatory breast disease,
lymphangitis cutis/pulmonis, cystic lesions, and also abdominal
masses that are not confirmed and followed by imaging techniques.
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.
Clinical lesions will only be considered measurable when they are
superficial (e.g., skin nodules and palpable lymph nodes). For the case of
skin lesions, documentation by color photography, including a ruler to
estimate the size of the lesion, is recommended.
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10.2
Methods of Measurement
CT and MRI are the best currently available and reproducible methods to
measure target lesions selected for response assessment. Conventional CT
and MRI 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.
Lesions on chest X-ray are acceptable as measurable lesions when they are
clearly defined and surrounded by aerated lung. However, CT is
preferable.
When the primary endpoint of the study is objective response evaluation,
ultrasound (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.
The utilization of endoscopy and laparoscopy 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 specialized centers. However, such
techniques can be useful in confirming complete pathological response
when biopsies are obtained.
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 when all lesions have
disappeared.
Cytology and histology can be used to differentiate between PR and CR in
rare cases (e.g., after treatment to differentiate between residual benign
lesions and residual malignant lesions in tumor types such as germ cell
tumors).
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10.3
Baseline documentation of “Target” and “Non-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.
All other lesions (or sites of disease) 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.
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10.4
Response Criteria
EVALUATION OF TARGET LESIONS
Complete
Disappearance of all target lesions
Response (CR):
Partial Response
(PR):
Progressive
Disease (PD):
Stable Disease
(SD):
At least a 30% decrease in the sum of the LD of
target lesions, taking as reference the baseline sum
LD
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
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
EVALUATION OF NON-TARGET LESIONS
Complete
Disappearance of all non-target lesions and
Response (CR):
normalization of tumor marker level
Incomplete
Persistence of one or more non-target lesion(s)
Response/
or/and maintenance of tumor marker level above
Stable Disease
the normal limits
(SD):
Progressive
Disease (PD):
Appearance of one or more new lesions and/or
unequivocal progression of existing non-target
lesions (1)
(1) 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 later on by
the review panel (or study chair).
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10.5
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
PD the smallest measurements recorded since the treatment started). In
general, the patient's best response assignment will depend on the
achievement of both measurement and confirmation criteria.
Target lesions
CR
CR
PR
SD
PD
Any
Any
Non-Target
lesions
CR
Incomplete
response/SD
Non-PD
Non-PD
Any
PD
Any
New Lesions
Overall response
No
No
CR
PR
No
No
Yes or No
Yes or No
Yes
PR
SD
PD
PD
PD
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) to confirm the complete
response status.
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10.6
Confirmation
The main goal of confirmation of objective response is to avoid
overestimating the response rate observed. In cases where confirmation of
response is not feasible, it should be made clear when reporting the
outcome of such studies that the responses are not confirmed.
To be assigned a status of PR or CR, changes in tumor measurements must
be confirmed by repeat assessments that should be performed no less than
4 weeks after the criteria for response are first met. Longer intervals as
determined by the study protocol may also be appropriate.
In the case of SD, follow-up measurements must have met the SD criteria
at least once after study entry at a minimum interval (in general, not less
than 6-8 weeks) that is defined in the study protocol.
10.7
Duration of overall response
The duration of overall response is measured from the time measurement
criteria are met for CR or PR (whichever status is recorded first) until the
first date that recurrence or PD is objectively documented, taking as
reference for PD the smallest measurements recorded since the treatment
started.
10.8
Duration of stable disease
SD is measured from the start of the treatment until the criteria for disease
progression are met, taking as reference the smallest measurements
recorded since the treatment started.
The clinical relevance of the duration of SD varies for different tumor
types and grades. Therefore, it is highly recommended that the protocol
specify the minimal time interval required between two measurements for
determination of SD. This time interval should take into account the
expected clinical benefit that such a status may bring to the population
under study.
10.9
Response review
For trials where the response rate is the primary endpoint it is strongly
recommended that all responses be reviewed by an expert(s) independent
of the study at the study’s completion. Simultaneous review of the
patients’ files and radiological images is the best approach.
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10.10 Reporting of results
All patients included in the study must be assessed for response to
treatment, even if there are major protocol treatment deviations or if they
are ineligible. Each patient will be assigned one of the following
categories: 1) complete response, 2) partial response, 3) stable disease, 4)
progressive disease, 5) early death from malignant disease, 6) early death
from toxicity, 7) early death because of other cause, or 9) unknown (not
assessable, insufficient data).
All of the patients who met the eligibility criteria should be included in the
main analysis of the response rate. Patients in response categories 4-9
should be considered as failing to respond to treatment (disease
progression). Thus, an incorrect treatment schedule or drug administration
does not result in exclusion from the analysis of the response rate. Precise
definitions for categories 4-9 will be protocol specific.
All conclusions should be based on all eligible patients.
Subanalyses may then be performed on the basis of a subset of patients,
excluding those for whom major protocol deviations have been identified
(e.g., early death due to other reasons, early discontinuation of treatment,
major protocol violations, etc.). However, these subanalyses may not
serve as the basis for drawing conclusions concerning treatment efficacy,
and the reasons for excluding patients from the analysis should be clearly
reported.
The 95% confidence intervals should be provided.
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REPORTING ADVERSE EVENTS
11.1
Adverse events (AE’s) will use the descriptions and grading scales found
in the revised National Cancer Institute (NCI) Common Toxicity Criteria
(CTC).
A copy of the CTC version 2.0 can be downloaded from the CTEP home
page:
http://ctep.info.nih.gov/reporting/ctc.html
CTC v.2.0 can also be found as a PDF file on the Cancer Center Intranet
Clinical Trials Office page:
http://www.cancer.med.umich.edu/i/cto.htm
11.2
Definition of an AE
a. Serious adverse event: Any adverse experience occurring at
any dose that results in any of the following outcomes: Death, a
life-threatening adverse drug experience, inpatient hospitalization
or prolongation of existing hospitalization, a persistent or
significant disability/incapacity, or a congenital anomaly/birth
defect. Important medical events that may not result in death, be
life-threatening, or require hospitalization may be considered a
serious adverse drug experience when, based upon appropriate
medical judgment, they may jeopardize the patient or subject and
may require medical or surgical intervention to prevent one of the
outcomes listed in this definition.
At the University of Michigan Comprehensive Cancer Center
CTC grades III-V are categorized as serious adverse events.
b. Unexpected adverse event: Any adverse experience, the
specificity or severity of which is not consistent with the current
investigator brochure; or, if an investigator brochure is not required
or available, the specificity or severity of which is not consistent
with the risk information described in the general investigational
plan or elsewhere in the current application, as amended. (In
addition to this definition, the IRBMED (Medical Institutional
Review Board) will interpret any adverse event not included in the
informed consent document as a risk as “unexpected”.)
c. Expected (known) adverse event: An adverse event, which has
been reported in the Investigator’s Brochure. (In addition to this
definition, the IRBMED will consider an adverse event as
“expected,” only if it is included in the informed consent document
as a risk.)
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d. Adverse event definitely associated with an investigational
drug: An adverse event which has a timely relationship to the
administration of the investigational drug/agent, follows a known
pattern of response, for which no alternative cause is present.
e. Adverse event probably associated with an investigational drug:
An adverse event, which has a timely relationship to the
administration of the investigational drug/agent, follows a known
pattern of response, but for which a potential alternative cause may
be present.
f. Adverse event possibly associated with an investigational drug:
An adverse event, which has a timely relationship to the
administration of the investigational drug/agent, follows no known
pattern of response, but a potential alternative cause does not exist.
g. Adverse event unrelated to an investigational drug: An adverse
event, for which there is evidence that it is definitely related to a
cause other than the investigational drug/agent. In general, there is
no timely relationship to the administration of the investigational
drug/agent, or if there is a timely relationship, the event does not
follow a known pattern of response, and there is an alternative
cause.
11.3
Reporting Procedures
11.3.1 Serious adverse Events (SAE’s) that are unexpected and/or
definitely, probably or possibly related to protocol therapy will
have written report sent to
1. Principal Investigator of the study: Fax #
2. Data Manager (Name), Clinical Trials Office:
Fax # (734)-936-9582
The Clinical Trials Office (CTO) staff will coordinate the reporting
process between the Investigator and the IRBMED as well as other
applicable reporting agencies (FDA, CTEP, NIH, OBA, industry).
Copies of all related correspondence and reporting documents will
be maintained in the regulatory file.
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11.3.2 Deaths or life-threatening adverse events (regardless of
relatedness) will be reported to the University of Michigan
Medical Institutional Review Board (IRBMED) immediately,
phone # (734) 763-4768, fax # (734) 763-9603 with formal written
notification within 7 days of the event. Formal notification
includes the FDA and or sponsor AE reporting forms attached to
the completed IRBMED reporting AE form.
(IRBMED reporting form templates can be downloaded from the IRBMED
website located at: http://www.med.umich.edu/irbmed/Appguide)
11.3.3 Reporting requirements for AEs are dependent on the Phase of the
trial, grade, attribution and whether the event is expected or
unexpected as determined by the NCI Specific Expected Adverse
Event List, IRB approved protocol and/or Investigator’s Brochure.
11.3.4 Adverse events which are serious (but not life threatening or not
resulting in death) have a causal relation to the research (possibly,
probably, or definitely related), and are unexpected must be
reported to the IRBMED immediately by phone or email; followed
by a written report within 7 days of the event.
11.3.5 If the adverse event requires modification of the study protocol
and informed consent they should be provided to the IRBMED
with the report of the adverse event.
11.3.6 Consent revisions for sponsored research studies must receive
sponsor approval prior to submission to the IRBMED. In the event
that the study is sponsored by NCI, the Principal Investigator must
obtain IRB approval of the consent prior to submission to NCI.
11.3.7 All adverse events occurring in the study, whether or not attributed
to study drug, should be included in the investigator’s annual IND
report to the FDA for those studies being performed under an
investigator IND.
11.3.8 All adverse events will be noted in the case report forms.
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ADVERSE EVENT REPORTING TO THE UNIVERSITY OF MICHIGAN IRBMED
(This guidance table is not to be used in place of IRBMED Procedures, it is intended as a guide
to the investigator when writing a protocol).
If discrepancies occur All IRBMED procedures in the reporting of adverse events
SUPERCEED this guidance table.
EVENT
Fatal Event/Grade V Toxicity
Occurring within 30 days of last
study intervention
Fatal Event/Grade V Toxicity
Occurring after 30 days of last study
intervention
Life Threatening Event/Grade III
Toxicity, Grade IV Toxicity,
Serious Adverse Event
Serious Adverse Event/Grade III
Toxicity
EXPECTED
Within 7 days if possibly, probably or definitely related.
Within 7 days regardless of relatedness
Do not report
Grade II Toxicity
Do not report
Grade I Toxicity
Do not report
MedWatch, Sponsor, or DSM
report in which serious issues were
found.
DSM Reports
MedWatch Reports
Sponsor Reports
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UNEXPECTED
Immediately by phone or email; followed by an AE Form within 7 days
regardless of relatedness
Immediately by phone or email;
followed by an AE Form within 7
days if possibly, probably, or
definitely related.
Within 15 days if possibly,
probably, or definitely related.
Prior to or concurrent with
submission of Scheduled
Continuation Application when
frequency is different than expected
in consent or protocol.
Within 15 days of PI receipt
Prior to or concurrent with
submission of Scheduled
Continuation Application.
Prior to or concurrent with
submission of Scheduled
Continuation Application.
Prior to or concurrent with
submission of Scheduled
Continuation Application.
Within 15 days of receipt
Within 15 days of receipt
Within 15 days of receipt
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FOR PROTOCOLS THAT ARE UNDER AN NCI SPONSORED IND
ONLY:
GUIDELINES FOR REPORTING OF SERIOUS ADVERSE EVENTS
TABLE A: Expedited Reporting for Phase 2 and Phase 3 Studies
UNEXPECTED EVENT
GRADES 2-3
Attribution of Possible,
Probable or Definite
Expedited report within 10
working days.
(Grade 1 - Adverse Event
Expedited Reporting NOT
required.)
EXPECTED EVENT
GRADES 4 and 5
Regardless of Attribution
GRADES 1-3
Report by phone to IDB within
24 hrs (301-230-2330).
Expedited report to follow
within 10 working days.
Adverse Event
Expedited Reporting
NOT required.
GRADES 4 and 5
Regardless of Attribution
Expedited report, including
Grade 5 Aplasia in leukemia
patients, within 10 working
days.
This includes all deaths within
30 days of the last dose of
treatment with an
investigational agent
regardless of attribution.
This includes all deaths within
30 days of the last dose of
treatment with an
investigational agent regardless
of attribution.
Any late death attributed to the
agent (possible, probable, or
definite) should be reported
within 10 working days.
Any late death attributed to the
agent (possible, probable, or
definite) should be reported
within 10 working days.
Grade 5: Death on treatment
or within 30 days of protocol
treatment.
Grade 4 Myelosuppression or
other Grade 4 events that do not
required expedited reporting
will be specified in the
protocol.
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DATA AND SAFETY MONITORING
12.1
Scheduled meetings will occur every month or more frequently depending
on the activity of the protocol. These meetings will include the protocol
investigators and data managers involved with the conduct of the protocol.
12.2
During these meetings the investigators will discuss matters related to:
1. safety of protocol participants (AE reporting)
2. validity and integrity of the data
3. enrollment rate relative to expectation, characteristics of
participants
4. retention of participants, adherence to protocol (potential or real
protocol violations)
5. data completeness
12.3
Data and Safety Monitoring Reports of these regular meetings will be kept
on file in the Cancer Center CTO. The data manager assigned to the trial
will be responsible for completing the report. The reports will be signed
by the principle investigator or by one of the Co-PI. (see Appendix 2 for
DSM report)
12.4
The University of Michigan Comprehensive Cancer Center’s PRC
Executive Committee will meet on a monthly basis to review the prior
months SAEs and Data and Safety Monitoring study specific reports that
have been filed.
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STATISTICAL CONSIDERATIONS
Identification of a plan for answering objectives, including endpoint definitions,
patient accrual objectives, and estimated duration of study. This section may be
developed in coordination with the Biostatistics Unit of the Cancer Center.
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REGISTRATION GUIDELINES
Describe how to register a patient (if necessary).
After approval for registration has been given by (one of) the Study
Coordinator(s), the CTO supplies appropriate consents and other forms. When
the consent has been signed, it is returned to the CTO along with appropriate
patient information. Eligibility is verified and only then is the patient registered.
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DATA FORMS, SUBMISSION AND DISTRIBUTION INFORMATION
Data Submission Schedule
Identifies required forms to be completed and submitted, intervals at which forms
must be submitted, location to which forms are submitted and number of copies.
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SPECIFIC INSTRUCTIONS
Used to describe special samples, cores or other procedures (including pathology
review) if used in the protocol. For in-house protocols, defines areas of
responsibility.
UMCC Coordinator Responsibilities
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APPENDIX 1
ELIGIBILITY CHECKLIST
Checklist giving criteria for inclusion/exclusion of patients.
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APPENDIX 2
PROTOCOL SPECIFIC DATA AND SAFETY MONITORING REPORT
To insure that the most up-to-date Protocol Specific Data and Safety Monitoring Report is used
please refer to the following link on the internal Comprehensive Cancer Center Intranet site.
http://www.cancer.med.umich.edu/i/cto.htm
Select:
Protocol Specific Data and Safety Monitoring Report (note: this will open in a second browser window)
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