(Note A Letter of Intent should be submitted and

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(Note A Letter of Intent should be submitted and Powered By Docstoc
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              THE ROBERT H. LURIE COMPREHENSIVE CANCER CENTER

                                 Protocol Development Template

NOTE: A Letter of Intent (LOI) must be submitted and approved by the Clinical Protocol
Scientific Review and Monitoring Committee of the Cancer Center prior to developing and
submitting an investigator-initiated protocol. (LOI templates, instructions are available at:
http://www.cro.lurie.northwestern.edu/Administrative/; “New Protocol Submission Procedures”,
“Forms: View or Download”.)

After LOI approval is obtained, a completed CRO New Protocol Submission form, signed by the
Disease Section Leader, must be submitted to CPSRMC coordinator along with:

    o a paper copy and/or electronic copy of the protocol
    o an electronic copy of the model consent
    o a print out of the lay abstract

Protocols should be submitted electronically via email to a-stephens@northwestern.edu or with
an IBM compatible disk in Word Perfect 6.0 or MS Word 6.0 or higher format. Set all margins
at one inch.

The consent form should be submitted as a separate document, not as an appendix to the
protocol, since consents require frequent revisions by the IRB. For guidelines regarding the
study consent, please see templates posted at the OPRS website:
http://www.northwestern.edu/research/OPRS/irb/consent.html

   If extra blood samples or tumor specimens are to be obtained for research purposes only, this
    must be stated in either the primary study consent form or in a secondary study consent form.

   If extra tissue or blood sampling for future research (e.g. specimen banking or any additional
    testing not directly related to main study Objectives), then a separate “Optional” consent
    form is strongly recommended.

Information on writing the lay abstract can be obtained at:
http://www.cro.lurie.northwestern.edu/ The lay abstract is a non-technically written, protocol
description that is available to the public. Since the technical version of a protocol is usually not
accessible to the general public, the intent of the public version of the protocol abstract is to
describe the study in terms the layman can understand.


This instructional cover page should be deleted from final protocol, along with all italicized
                         sections throughout the protocol template.




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                               PROTOCOL TITLE HERE
              (when completed, go back and delete instructions in parentheses)


PRINCIPAL INVESTIGATOR:                      Name
                                             Address
                                             Phone #
                                             Fax #
                                             Email


CO-INVESTIGATORS:                            Name
(include chair for each modality of treatment, if applicable)


STATISTICIAN:                                Name

(The first draft of any in-house study should be given to Alfred Rademaker, Ph.D. or Borko
Jovanovic, Ph.D., Biostatistics Core Facility, prior to submitting to the CRO.)


FUNDING AGENCY (if applicable):             Name
[Please note: The funding agency is not necessarily a study sponsor (sponsor = responsible.]

IND number (holder’s last name):
(if applicable)


                                   Northwestern University
                         Robert H. Lurie Comprehensive Cancer Center
                                   Clinical Research Office
                              676 N. St. Clair Street, Suite 1200
                                      Chicago, IL 60611




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TABLE OF CONTENTS (on a separate page)
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SCHEMA                     (on a separate page - must be consistent with treatment plan)
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1.0        INTRODUCTION - BACKGROUND AND RATIONALE (include references)


2.0        OBJECTIVES - Primary endpoints of study, listed and numbered individually.


3.0        SELECTION OF PATIENTS - ELIGIBILITY CRITERIA (List criteria for
           eligibility only rather than breaking into eligibility and ineligibility criteria. Should
           include: )

          Diagnosis required: “Histologically confirmed ...”

          Extent or stage of disease required

          Whether disease must be measurable or can be non-measurable using the criteria
           provided in section 9. The term “evaluable” in reference to measurability will not be
           used because it does not provide additional meaning or accuracy. Suggested text is
           provided below in quotes:

           “Patients must have measurable disease, defined as at least one lesion that can be
           accurately measured in at least one dimension (longest diameter to be recorded) as >20
           mm with conventional techniques or as >10 mm with spiral CT scan. See section 6.0 for
           the evaluation of measurable disease (RECIST).”

           For diseases other than solid tumors, please insert appropriate criteria. 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).

          Prior therapies permitted and/or not allowed

          Performance Status required (please use ECOG scale)

          Required laboratory parameters and time limits (usually 14 days for blood tests and
           chemistries, 4-6 weeks for x-rays and scans)

          Age > 18 years (or as appropriate; no upper age limit is permitted by the NCI except for
           BMT studies)



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          If applicable, please include a statement that women who are pregnant or lactating are
           not eligible for study treatment.

          If applicable, please include a statement that women of childbearing potential and
           sexually active males must commit to the use of effective contraception while on study.

          All patients must have given signed, informed consent prior to registration on study.


4.0        PATIENT REGISTRATION (standard section for experimental treatment protocols)

Note: A patient must not start protocol treatment prior to registration.

           4.1 Obtain the following documents:
                   patient signed and witnessed informed consent form
                   pathology report (to confirm diagnosis)
                   completed Patient Registration Form (provided by sponsor institution).

           4.2 Call or page the QA Officer at (312) 695-1355 (phone) between 8:30 a.m. and 5:00
               p.m. to alert that a patient is ready to be enrolled.

           4.3 Fax registration documents (see section 4.1 or section 11.0) to (312) 695-1352 (fax).

           4.4 Once eligibility is confirmed, the patient will be registered to the study and a subject
               I.D. number will be faxed, emailed, or given over the phone. Registration then will
               be complete and patient may begin study treatment.

                 If a patient must be entered on study after hours, the investigator must fax the
                 completed registration documents (see 4.1) and absolutely no exceptions to eligibility
                 criteria to (312) 695-1352. A study number will be assigned on the next working day.

           4.5 In addition to the above, please… (if there are other instructions, such as laboratory
               or pathology specimens to be handled prior to treatment, reference these items here).
                                                   OR

4.0    PATIENT REGISTRATION (alternative registration section for non-treatment
protocols)

           4.1      Obtain the patient's informed consent and complete the Patient Registration Form.

           4.2      Registered patients will be tracked by patient log. This log will be submitted to
                    the CRO on a periodic basis (quarterly, at minimum) until study closure and will
                    include:

                       Subject name (or initials)


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                     Registration number (will be assigned by CRO, if not required for study)
                     Date of registration
                     Date of birth
                     Sex
                     Race


5.0        TREATMENT PLAN

           Administration

              Route of administration (e.g. IV bolus, IV infusion, oral, IM injection)
              Administration time (e.g. “over ___ minutes” or “hours”; “3X per day at mealtime”)
              Days of Administration (e.g. days 1-5, 8 and 10)

              Treatment intervals (how often, e.g. q 3 weeks, daily for 28 days, etc.)

              Total duration of treatment [for a maximum of ___ cycles or until progression, or
               (other specified time)].

           (Sample: IV infusion over 2 hours on days 1 and 5 q 3 weeks for a maximum of 4 cycles,
           where 3 weeks = 1 cycle.)

           Dose Modifications

          Give instructions for dose modifications using NCI Common Toxicity Criteria Version
           2.0 for grading toxicities.

          Specify at what time points and how toxicity is to be assessed - whether by nadir counts
           or counts on day 1 of each cycle.

          Give instructions for dose modification for each study drug and each modality (XRT) as
           applicable.

          Supportive Care Guidelines (include in Treatment Plan if necessary to the protocol.
           Unless required for research purposes, these should be guidelines only to allow
           flexibility)

           Duration of Therapy

          Give conditions given for taking patient off study – e.g., if grade 4 _________, patient
           should go off study; or, if treatment is held x times for toxicity, patient must go off study.

          Does the study state whether it requires long-term follow-up or not?



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          If the study does require patients to be followed after active study treatment is over, does
           the protocol state for how long patients will be followed (e.g. until disease recurrence,
           until disease progression, until death)? NOTE: Any long-term follow-up should also be
           specified in the consent template.


6.0        RESPONSE ASSESSMENT

          Define categories of response (i.e. what exactly constitutes a complete response, partial
           response, stable disease and progression?)

          Specify how much therapy a patient must receive in order to be evaluable for response:

           For the purposes of this study, patients should be re-evaluated 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.

          Provide criteria for assessing response for the following categories, depending on what
           is permitted in the protocol:
                  ____ - measurable disease (use RECIST)
                  ____ - non-measurable disease ( if permitted per protocol)
                  ____ - leukemia/lymphoma assessment criteria

OR, if using RECIST, use as below:

6.1 Definitions

           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.

           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.

           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 (PET, 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).

           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)


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           are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites,
           pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease,
           abdominal masses (not followed by CT or MRI) and cystic lesions are all non-measurable

           Target Lesions. 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.

           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 lesions. Measurements of these lesions are not required,
           but the presence or absence of each should be noted throughout follow-up.

6.2 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


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           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) 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.

6.3 Response Criteria

           6.3.1   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.


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           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

           6.3.2   Evaluation of non-target lesions

           Complete Response (CR): Disappearance of all non-target lesions and normalization of
           tumor marker level

           Incomplete Response/Stable Disease (SD): Persistence of one or more non-target
           lesion(s) or/and maintenance of tumor marker level above the normal limits

           Progressive Disease (PD): 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.

           6.3.3   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 6.4).

           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.

6.4 Confirmatory Measurement/Duration of Response

           6.4.1   Confirmation




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           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].

           6.4.2   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.

           6.4.3   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.

           6.4.4   Progression Free Survival

           Include this section if time to progression or progression-free (PFS) survival are to be
           used.

           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.

           6.4.5   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.

           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).


7.0        STUDY PARAMETERS (Table format required)




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          All required lab tests, scans and measurements, ancillary labs, etc. should be included in
           chart format so that the intervals at which they are required are clear. Be sure that the
           table includes any tests necessary to fulfill objectives of the study.

          Be sure that all labs, scans, and/or procedures required in eligibility section are listed
           here. Specify which chemistry panel is to be done (e.g. “Comprehensive Chemistry
           Panel, “Renal Chemistry Panel,”). Specify differential and/or platelets, if needed with
           CBC.

          Do not include non-standard tests unless specifically needed – e.g., SGPT, PT/PTT

          Be sure that intervals for labs/tests are reasonable.

          Give time limits for pre-study tests -- usually 2 weeks for hematology and chemistries and
           4-6 weeks for CXR, ECG, scans, etc.


8.0    DRUG FORMULATION AND PROCUREMENT (each section is required for each
study drug):

          Other names for the drug(s):

          Classification - type of agent:

          Mode of action:

          Storage and stability:

          Protocol dose: (if a drug is given at different doses at different points in the treatment
           cycle, all doses should be indicated.)

          Preparation:

          Route of administration for this study:

          Incompatibilities:

          Availability: (e.g. “commercially available”, “provided by sponsor”; specify if provided
           free of charge as this has implications for the consent form.)

          Side effects:

          Nursing implications:




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9.0        STATISTICAL CONSIDERATIONS (This section should be written and/or reviewed
           by a statistician prior to submission)

          Proposed sample size:

          Proposed time period for accrual:

          Early stopping procedures

          How will data be analyzed and by whom (Northwestern vs. any other site):


Reporting and Exclusions

Evaluation of toxicity. All patients will be evaluable for toxicity from the time of their first
treatment with [Study Agent].

Evaluation of Response. All patients included in the study must be assessed for response to
treatment, even if there are major protocol treatment deviations or if they are ineligible. Each
patient will be assigned one of the following categories: 1) complete response, 2) partial
response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable,
insufficient data). [Note: By arbitrary convention, category 9 usually designates the “unknown”
status of any type of data in a clinical database.]

All of the patients who met the eligibility criteria 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 for response rate should also
be provided.


10.0       ADVERSE EVENT REPORTING

Adverse event reporting procedures will vary depending on the nature of the protocol (e.g.
studies involving an IND/FDA notification, studies involving pharmaceutical company
notification, etc.) Please discuss this section with other involved agencies (e.g. supporting


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pharmaceutical companies, FDA, etc.) for specific protocol requirements.


11.0 RECORDS TO BE KEPT (may be used as listed here or edited to reflect protocol
requirements)

       11.1 In addition to the regular hospital chart, a separate patient folder will be kept which
            includes:

                  11.1.1 The patient's signed, dated informed consent document.
                  11.1.2 Pathologic documentation of the study disease.
                  11.1.3 The completed Patient Registration Form and all other study forms.

           11.2 Patient Registration (see section 4.0): BEFORE a patient can be treated on study,
               please submit the following items (fax number below) to confirm patient eligibility
               and receive subject registration number:

                  11.2.1 Completed Patient Registration Form.
                  11.2.2 Signed, dated informed consent document.
                  11.2.3 Pathology Report (histologic confirmation of disease.)

                         Robert H. Lurie Comprehensive Cancer Center
                         Clinical Research Office
                         ATTN: QA Coordinator
                         676 N. St. Clair Street, Suite 1200
                         Chicago, Illinois 60611
                         Fax: (312) 695-1352
                         Phone: (312) 695-1355

           11.3   Once subject is confirmed and enrolled to the study, the following study forms
                  should be submitted to the QA Coordinator at the above address via mail
                  according to the schedule below:

                  11.31 Baseline: Flow Sheet reflecting pretreatment test results and Measurement
                        Form showing baseline measurement (measurable disease patients) or
                        evaluation (non-measurable disease only): after Cycle 1.

                  11.32 During Treatment: While a patient is on study, forms are to be submitted
                        to the CRO according to the following schedule:

                         11.32.1 Flow Sheets, Interim Toxicity Forms and Interim Treatment
                                 Summary Forms: after each cycle of therapy or monthly,
                                 whichever is less frequent.      Flow sheets must include
                                 chemotherapy dosage, treatment dates, toxicities according to the
                                 NCI Common Toxicity Criteria Version 3.0, and results of all


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                                      tests required in the Study Parameter section.

                           11.32.2 Measurement Forms: monthly or after each lesion measurement
                                   or evaluation, whichever is less frequent. Measurement forms
                                   must give serial measurements or evaluations as required by
                                   protocol to assess disease response to therapy.

                  11.33 Off-Study: A final Treatment Summary Form and a Toxicity Summary
                        Form are to be submitted when a patient progresses, dies, or goes off study
                        for any other reason.

                           11.33.1 Follow-Up Form is submitted as required per protocol: at the
                                   time a patient goes off study, and every 3 months for 2 years
                                   following the end of study treatment.

                           11.33.2 Death must be reported using the Follow-Up Form.


12.0 PATHOLOGY REQUIREMENTS

Specify the type of pathology report required - e.g., for advanced disease protocol, is biopsy
proof of recurrent or metastatic disease required or only the path from initial diagnosis?

For special laboratory/pathology samples:

Identify personnel who will process the samples:

Give specific instructions for preparation and shipment (types of tubes, spun, frozen, on wet/dry
ice or at room temperature, sent by overnight mail or batched, etc.) Please add any restrictions
on specimen receiving times (e.g. after hours, weekends, holidays).

Give name and address of person to whom samples are to be sent and name of phone number of
contact person to consult with questions prior to shipping.


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13.0 REFERENCES (start on a separate page)
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14.0       APPENDICES

14.1       For Phase I and Phase II trials (as of July, 2001):

A copy of the Data Safety and Monitoring Plan must be included as an appendix in all


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Investigator-Initiated phase I or phase II clinical trials. Please include either a full copy of the
plan or a reference to the plan as below:


Data and Safety Monitoring Plan

This trial will be conducted in accordance with the Data and Safety Monitoring Plan of the
Robert H. Lurie Comprehensive Cancer Center, a copy of which can be found at:

http://www.cro.lurie.northwestern.edu/Administrative/



14.2       For patient administered drug:

           Patient diaries for drug administration and recording of side effects should be provided
           with the protocol. Use of diaries should be mentioned in the consent. A template is
           available at the CRO. Please contact Isabel Melendez (i-melendez@northwestern.edu).


14.3       For patient self-injections:

           Patient instruction sheets for self-injection, to be provided at the time of patient teaching,
           should be included when submitting the protocol for review. The instruction sheet should
           also be mentioned in the consent.



14.4       For questionnaires or quality of life assessment tools:

           Study questionnaires should be provided with the protocol and mentioned in the consent
           along with how long it will take (approximately) to complete the tool(s) each time.




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