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DF/HCC BIOMEDICAL PROTOCOL TEMPLATE
Version Date: June 9, 2023
[Replaces version Date: June 1, 2022]
INSTRUCTIONS FOR INVESTIGATOR-WRITTEN PROTOCOLS
This template contains DF/HCC recommended language for protocol development. It was derived from federal requirements, NCI/CTEP guidance documents, DF/HCC policies and procedures, and Good Clinical Practice guidelines. The template contains the “boilerplate” language commonly required in protocols submitted to CTEP. Content may be modified as necessary to meet the scientific aims of the study and development of the protocol. Much of the formatting is needed for electronic submission of the protocol to CTEP or to the FDA and should not be changed.
All protocols submitted to the Office for Human Research Studies (OHRS) must be submitted using the most current template version. Any protocols drafted after this date must be submitted on this current template. Review of your protocol may be delayed if it is not submitted on the correct DF/HCC protocol template.
1. Main Body and Appendices of the protocol: attached below. This document provides standard language plus instructions and prompts for information.
2. The Protocol Template documents should be completed, and all documents (including the Appendices) should be submitted for review.
Please note that additional requirements exist for protocol and informed consent documents intended for electronic submission to CTEP. For protocol amendments a Summary of Changes should be provided as the first page (page i) of the document, as indicated in the template. The Summary of Changes must provide hyperlinks to the area referenced in the protocol or informed consent document.
3. All sections in the Protocol Template should be retained to facilitate rapid review. If not appropriate for a given study, please insert “Not Applicable” after the section number and delete unneeded text. Depending on the phase of the study and whether it is a single-agent or combination agent study, include sections as follows:
• No highlighting – for all protocols
• Yellow highlighting – for phase 1 protocols
• Green highlighting – for phase 2 protocols
• Blue highlighting – for combination agent protocols
• Pink highlighting – for advanced imaging protocols
4. All Protocol Template instructions and prompts are in blue italics. As you complete the information requested, please delete the italicized text.
5. Please note that the Protocol Template has built-in styles for headings levels 1-4 (Level 1 Heading – Level 4 Heading; see image below). Please avoid or limit the use of heading level 4 or more.
[pic]
These heading styles will automatically update the Table of Contents (TOC) and convert to Bookmarks in a final PDF protocol document. Please retain the heading styles.
6. Before updating the TOC, please ensure that the Title Page is page 1 of the protocol. For any pages preceding it (i.e., Summary of Changes) use alternative numbering (i, ii, iii, iv, …).
7. To update the TOC in your protocol document:
2007 & 2010 MS Word
a. On the References tab, in the Table of Contents group, click Update Table.
[pic]
b. Click Update entire table.
2003 MS Word
a. Click the table of contents.
b. Press F9.
Please do not edit the TOC manually.
8. Do not submit MS Word files that:
• are read-only
• are password protected
• contain macros
• are saved with a file extension other than .doc (Word 2003) or .docx (Word 2007/10)
9. For problems or questions encountered when using this document:
• Contact your Disease Program Leader if questions arise in the creation of the protocol.
• Seek guidance from Biostatistics, Pharmacy, Nursing, etc. as appropriate.
• Direct protocol format issues to the Office for Human Research Studies (OHRS) by email (OHRS@dfci.harvard.edu).
10. As investigators address inclusions, exclusions, and the population being studied, every effort should be made to make clinical trials as inclusive and broad in eligibility as possible. Any exclusion should be directly relevant to the trial, study question, or agent being studied, and all study visits should be streamlined to minimize unnecessary visits, promote patient convenience. Methodology for the recruitment and retention of patients should be addressed, with the overall goal of making a trial representative of the population with the condition.
SUMMARY OF CHANGES
Retain this page for all protocol documents intended for electronic submission to CTEP. You will need it for subsequent submissions, including amendments. Otherwise this page should be deleted.
For Protocol Amendment # to:
NCI Protocol #:
DF/HCC Protocol #:
NCI Version Date:
Protocol Date:
Please provide a list of changes from the previous CTEP approved version of the protocol. The list should identify by page and section each change made to a protocol document with hyperlinks to the section in the protocol document. All changes should be described in a point-by-point format (i.e., Page 3, section 1.2, replace ‘xyz’ and insert ‘abc’). When appropriate, a brief justification for the change should be included.
|# |Section |Page(s) |Change |
|1. | | | |
|2. | | | |
|3. | | | |
|4. | | | |
|5. | | | |
NCI Protocol #: Assigned by the NCI. If not appropriate for this protocol, insert “Not Applicable” or “N/A.”
DF/HCC Protocol #: [YY-###]
Assigned by the Office for Human Research Studies (OHRS) after submission for SRC and IRB review.
TITLE: A Phase 1 Study of or A Phase 2 Study of [CTEP and/or CIP IND Agent or other IND Agent] in Combination with [Other Agent(s)] in [Solid Tumors/Study Disease]
Full title required.
Use Simplified Disease Classification (SDC) terminology for study disease. Please refer to the CTEP Web site () for a complete list of SDC disease terms.
Sponsor-Investigator:
Name
Institution
e-mail address
*Principal Investigators (PI):
Name
Institution
Address- CTEP protocols only
Telephone – CTEP protocols only
Fax – CTEP protocols only
e-mail address
Name
Institution
Address – CTEP protocols only
Telephone – CTEP protocols only
Fax – CTEP protocols only
e-mail address
Name
Institution
Address – CTEP protocols only
Telephone – CTEP protocols only
Fax – CTEP protocols only
e-mail address
*Note: Each participating site must have a PI who is responsible for study conduct and oversight at their institution. For drug, device, and imaging studies, PIs must be physicians. Please refer to the Investigator's Handbook on the CTEP Web site for a complete description of the Principal Investigator's responsibilities ().
The PI and all attending physicians responsible for participant care must be currently registered with the NCI. Failure to register all appropriate individuals could delay protocol approval. If you are unsure of an investigator's status, please contact the Office of Data Quality (ODQ) at ODQEducation@dfci.harvard.edu . Please indicate, on the title page, if an Associate Investigator is NOT responsible for patient care and therefore does not require NCI registration.
If this is a CTEP Multi-Center 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 # and e-mail address. (This requirement does not apply to non-CTEP studies.)
If this study includes an investigational agent supplied by the NCI Division of Cancer Treatment and Diagnosis and will involve a Canadian institution(s), a Clinical Trials Application (CTA) will need to be submitted to the Canadian Health Products and Food Branch (HPFB) for their participation in the study. A Canadian investigator should be designated to be responsible for preparing and submitting the CTA to the Canadian HPFB for the Canadian institution(s). Procedures and forms for preparing and submitting a CTA to the Canadian HPFB are available at . A copy of the “No Objection” letter should be forwarded to the Pharmaceutical Management Branch at PMBAfterHours@mail. when available.
If this is a CTEP study, the protocol title page should include the name of the Responsible Study Coordinator, Research Nurse, and Data Manager along with their institution, phone and fax # and e-mail address. (This requirement does not apply to non-CTEP studies.)
Statistician: Study Coordinator:
(if applicable) (if applicable)
Name Name
Institution Institution
Address – CTEP protocols only Address
Telephone – CTEP protocols only Telephone
Fax – CTEP protocols only Fax
e-mail address e-mail address
Responsible Research Nurse: Responsible Data Manager:
(if applicable) (if applicable)
Name Name
Institution Institution
Address Address
Telephone Telephone
Fax Fax
e-mail address e-mail address
Please list all agents and their suppliers in the fields below, including any imaging agents. “Supplier” is defined as the entity that provides the clinical supply of the agent. If the agent is purchased through commercial sources, then please mark supplier as “commercial”.
NCI-Supplied Agent(s): [Agent Name and NSC #]
Other Agent(s): [Agent Name, NSC # (if applicable), and Supplier]
Below, please describe the IND Status of this study by choosing IND #/Sponsor OR Exemption from IND requirements, making sure to delete the inapplicable field(s).
IND #: [Enter the # of the IND under which this study will be performed. Enter “TBD” if an IND # is not yet available.]
IND Sponsor: [Enter the name of the IND holder. If this study is being conducted under an IND sponsored by CTEP, then enter “DCTD, NCI”. If this is solely an imaging study and is to be conducted under a CIP IND, then enter “Cancer Imaging Program, NCI”]
OR
Study Exempt from IND Requirements per 21 CFR 312.2(b).
If an IDE is not applicable to this study, then please delete the following fields (IDE #, IDE Sponsor, Device Name):
IDE #: [Investigational Device Exemption #]
IDE Sponsor:
Device Name: [This can include investigational in vitro diagnostics, which are regulated as devices.]
Protocol Type / Version # / Version Date: [Type* / Version # / Version Date]
*Protocol types: Original, Revision, or Amendment
SCHEMA
Provide an overall picture of the study design and treatment. Include the major decision points and all possible research treatments. Do NOT include any dose information. If applicable, indicate when advanced imaging will be performed in the study.
Example: Phase I Dose Escalation trial
Example: Randomized trial
|Diseases: | Stratify R|[pic] |Treatment |
|STS - Soft Tissues Sarcoma OGS - |A | |ARM A: DOX/DTIC |
|Osteogenic Sarcoma RMS - |OGS N | |q 3 wk x 4 |
|Rhabdomyosarcoma ES - Ewings Sarcoma | | | |
|Drugs: |RMS D | | |
|DOX - Doxorubicin DTIC - Darcabazine |ES O | |ARM B: DOX/DTIC/IFF |
|IFF – Ifosfamide |OTHER M | |q 3 wk x 4 |
| |I | | |
| |Z | | |
| |E | | |
TABLE OF CONTENTS
SCHEMA 4
1. OBJECTIVES 8
1.1 Study Design 9
1.1 Primary Objectives 9
1.2 Secondary Objectives 10
2. BACKGROUND 10
2.1 Study Disease(s) 10
2.2 IND Agent(s) 10
2.3 Other Agent(s) 11
2.4 Rationale 11
2.5 Correlative Studies Background 11
3. PARTICIPANT SELECTION 11
3.1 Eligibility Criteria 12
3.2 Exclusion Criteria 15
3.3 Inclusion of Women and Minorities 16
4 REGISTRATION And Randomization PROCEDURES Please Remove “And Randomization” if the trial is not randomized. 17
4.1 General Guidelines for DF/HCC Institutions 17
4.1 Registration Process for DF/HCC Institutions 18
4.2 General Guidelines for Other Investigative Sites 18
4.3 Registration Process for Other Investigative Sites 18
5. TREATMENT AND/OR IMAGING PLAN 18
5.1. Treatment Regimen 18
5.2. Pre-Treatment Criteria 22
5.3. Agent Administration 22
5.4. For phase 1 protocols only: Definition of Dose-Limiting Toxicity (DLT) 24
5.5. General Concomitant Medication and Supportive Care Guidelines 25
5.6. Criteria for Taking a Participant Off Protocol Therapy 25
5.7. Duration of Follow Up 26
5.8. Criteria for Taking a Participant Off Study 26
6. DOSING DELAYS/DOSE MODIFICATIONS 26
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 30
7.1. For CTEP protocols only: Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 30
7.2. For CTEP protocols only: Adverse Event Characteristics 31
7.3. For CTEP protocols only: Expedited Adverse Event Reporting 32
7.4. For CTEP protocols only: Routine Adverse Event Reporting 37
7.5. For CTEP protocols only: Secondary Malignancy 37
7.6. For CTEP protocols only: Second Malignancy 37
7.7. For non-CTEP protocols only: Expected Toxicities 38
7.8. For non-CTEP protocols only: Adverse Event Characteristics 38
7.9. For non-CTEP protocols only: Adverse Event Reporting 38
7.10. Reporting to the Food and Drug Administration (FDA) 40
7.11. Reporting to the NIH Office of Biotechnology Activities (OBA) 40
7.12. Reporting to the Institutional Biosafety Committee (IBC) 40
7.13. Reporting to Hospital Risk Management 41
7.14. For non-CTEP protocols only: Routine Adverse Event Reporting 41
8. PHARMACEUTICAL and/or IMAGING AGENT INFORMATION 41
8.1. IND Agent #1 41
8.2. IND Agent #2 45
8.3. Other Agent #1 45
8.4. Other Agent #2 45
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 45
9.1. Biomarker Studies 46
9.2. For IDE protocols only: Investigational Device Information 47
9.3. Laboratory Correlative Studies 47
9.4. Special Studies 47
10. STUDY CALENDAR 47
11. MEASUREMENT OF EFFECT 51
11.1. Antitumor Effect – Solid Tumors 51
11.2. Antitumor Effect – Hematologic Tumors 59
11.3. Other Response Parameters 59
12. DATA REPORTING / REGULATORY REQUIREMENTS 59
12.1. Data Reporting 59
12.2. Data Safety Monitoring 60
12.3. Multi-Center Guidelines 61
12.4. Collaborative Agreements Language 62
13. STATISTICAL CONSIDERATIONS 64
13.1. Study Design/Endpoints 64
13.2. Sample Size, Accrual Rate and Study Duration 67
13.3. Stratification Factors 68
13.4. Interim Monitoring Plan 68
13.5. Analysis of Primary Endpoints 68
13.6. Analysis of Secondary Endpoints 68
13.7. Reporting and Exclusions 69
14. PUBLICATION PLAN 69
REFERENCES 71
APPENDIX A PERFORMANCE STATUS CRITERIA 72
APPENDIX B MULTI-CENTER GUIDELINES 73
APPENDIX C INFORMATION ON POSSIBLE DRUG INTERACTIONS 75
APPENDIX D BIOASSAY TEMPLATES 79
OBJECTIVES
This section should state the study hypothesis to be tested in the research project.
The study design should describe an adequate plan for answering the hypothesis. The objective should correspond to the phase of the study and Quality of Life objectives should be included when applicable.
NA- No Phase: Trials without a Drug or Biologic (for example, studies involving devices or behavioral interventions) Describe the hypothesis being tested. For drug or biologic interventions, please designate a numerical phase I-IV per 21 CFR 312.21 or 21 CFR 312.85.
Early Phase I: Exploratory
Exploratory studies involve very limited human exposure, with no therapeutic or diagnostic intent (e.g., screening studies, microdose studies). These trials are not designed to establish efficacy or toxicity, but to obtain preliminary data to support the rationale for a subsequent clinical trial. These studies are typically designed to assess feasibility, to define and/or refine the target population, to develop and test the feasibility of obtaining surrogate endpoints, to quickly test the safety of a drug for which there is single agent safety data but which is being used for the first time in combination with a drug that should have no synergistic effects with the agent, to establish measures of safety and efficacy, to establish preliminary estimates of variances, correlations, and/or differences, to evaluate total costs or timelines of doing an experiment, to determine sample recruitment strategies, and to address design and methodological issues for clinical trials. The expected results are intended to translate clinical questions into statistical hypotheses and ultimately to optimize the design of the eventual full-scale clinical trial. The sample size may not be adequate to even detect large differences; however, the data should provide a basis for providing sample size estimation for future clinical trials. Usually exploratory studies are no larger than 10 participants and almost never larger than 20 participants. To determine the sample size, consult a statistician. For more information, please see: FDA guidance on Exploratory IND Studies
Phase I: Evaluation of Toxicity
The primary objective of a Phase I study is to identify a maximum tolerated dose (MTD) for a given dose/schedule and to explore the quantitative (frequency, duration) and qualitative (organ specific) nature of acceptable and unacceptable toxicities. Preliminary information on efficacy may also be obtained.
These studies are concerned with evaluating toxicity and are often the first test of a drug or drug combination in humans. A few participants are entered at a pre-planned dose and accrual is suspended for a review of toxicity. The dose is escalated for the next group of participants if an unacceptable rate of dose limiting toxicity (DLT) is not seen. The dose below that which produced an unacceptable rate of DLT is designated as the MTD, and this dose is used for further testing in Phase II studies. Since a small number of participants (typically 3-6) are treated at each dose level during the dose escalation, the design of a Phase I study will often specify that an additional group of participants (usually fewer than 15) be treated at the MTD once it has been determined. Usually Phase I studies require a total accrual of approximately 15-30 participants. The study design should be worked out with a statistician.
Phase II: Treatment Efficacy
The objective of a Phase II clinical trial in oncology is to assess whether there is adequate anti-tumor activity of a new treatment regimen to pursue further testing, and to describe any associated adverse reactions (toxicities) with a larger sample size than in Phase I trials. The primary endpoint in a Phase II trial is typically response, e.g. shrinkage of the tumor or change in biochemical marker(s), but other endpoints (imaging, biological, and disease progression) are possible as primary or secondary endpoints.
These studies are designed to evaluate the safety and efficacy of a drug that has passed through Phase I testing with acceptable levels of toxicity. Careful monitoring of participants is required since both response and toxicity assessments are necessary. Usually Phase II studies require an accrual of 20-50 participants. A statistician should determine the appropriate number of participants.
Phase III: Comparative Study
The most important objective of Phase III clinical trials in oncology is the randomized comparison of treatments or interventions. Typically, one or more new treatments that have been shown to have anti-tumor activity in Phase II trials are compared to the standard treatment, which could include no treatment or a placebo, depending on the disease. The main endpoint of Phase III trials is usually overall survival and/or disease-free or progression-free survival (DFS or PFS). Different disease programs have different standard endpoints. For most solid tumors, response in advanced stage disease is commonly defined using the RECIST criteria (). These studies usually require greater than 100 participants. A statistician should determine the final accrual figure.
1 Study Design
Briefly describe the general study design.
2 Primary Objectives
Please insert the primary protocol objective(s). Please specify advanced imaging Primary Objective if applicable. Whenever possible, a single primary objective is preferable.
Each objective should include the specific measurement and a description of the metric that will be used. For example, “safety,” “tolerability,” and “feasibility” measures must include the specific metric that will be used to make the assessment (e.g., number of participants experiencing adverse events). “What” and “How” the outcome will be measured needs to be clearly stated.
DF/HCC recommends careful wording of objectives to facilitate registration and reporting requirements. For more information, see Outcome Measures:
3 Secondary Objectives
Please insert secondary protocol objectives, if pertinent. Please specify advanced imaging Secondary/Exploratory Objective if applicable.
Each objective should include the specific measurement and a description of the metric that will be used. For example, “safety,” “tolerability,” and “feasibility” measures must include the specific metric that will be used to make the assessment (e.g., number of participants experiencing adverse events). “What” and “How” the outcome will be measured needs to be clearly stated.
DF/HCC recommends careful wording of objectives to facilitate registration and reporting requirements. For more information, see Outcome Measures:
We strongly encourage inclusion of primary and/or secondary objectives that address questions most relevant for diverse populations.
BACKGROUND
1 Study Disease(s) and Populations Affected by the Disease
Please provide background information on the study disease(s). Please include a description of the epidemiology of the disease, including known demographic characteristics of the target population, or subpopulations, who are likely to have access to the product or treatment regimen under an IND or with FDA approval.
If you choose to use county level Massachusetts data for your epidemiology, these registry data are available to investigators to demonstrate the local epidemiology of the cancer of interest. Investigators may choose to describe both national and local statistics when they describe the burden of disease. (Please see ).
2 IND Agent(s)
Please provide background information below on the IND agents (whether CTEP and/or CIP IND study agent(s) or other IND agent(s)), including information to support safety issues and the rationale for the proposed starting dose, dose escalation scheme, and regimen chosen. Please also provide information on the mechanism of action, summaries of nonclinical and clinical studies, nonclinical and clinical pharmacokinetics, and major route of elimination, safety profile. If available, please include information on the metabolism of the study agent in humans and its potential for drug interactions, if any interactions (e.g., via the P450 enzyme system). If protocol is a single IND agent study, please insert background information directly under heading 2.2 and remove subheadings 2.2.1, 2.2.2, etc., for multiple IND agent studies.
Please include information regarding the rationale for advanced imaging as appropriate; include information on the pharmacology, toxicology, and previous human imaging studies from the current Investigator’s Brochure as applicable. For complete information, please refer to the current Investigator’s Brochure: [Insert title, version and date of NCI/CIP IB]. Contact CIP regulatory staff at NCICIPINDAGENTS@mail. for the current Investigator’s Brochure.
1. IND Agent #1
2. IND Agent #2
3 Other Agent(s)
Please provide background information on other agent(s) and/or treatments in this study, including information to support safety issues and the rationale for the proposed starting dose and dose escalation scheme, if applicable. If there are no agent(s) in this study, this section should be deleted.
NOTE: If the specific doses and schedule of other agent(s) given as part of a standard treatment for the disease are not important in determining the objectives of the study, this should be clearly stated (e.g., CHOP as per institutional standards). However, this should only be done when the dose and schedule, including modifications, are not important in determining one or more objectives.
4 Rationale
Please provide the background and rationale for evaluating this therapy/combination therapy/advanced imaging in this disease.
5 Correlative Studies Background
Please provide background information on each planned correlative study including the biologic rationale and hypothesis as well as the relevant preclinical and clinical (if available) data. Refer to “Guidelines for Correlative Studies in Clinical Trials” (). If this trial includes no correlative studies, this section should be marked “N/A”.
Consider correlative studies relevant to diverse patient backgrounds and how this will be accounted for in analytic plans and applicability.
PARTICIPANT SELECTION
Clearly outline the criteria participants must meet to be eligible for or excluded from study enrollment (e.g., histologic confirmation of disease, stage, measurability, baseline staging requirements, prior therapy requirements and allowances, age and life expectancy, performance status, adequate organ function, other appropriate eligibility or exclusionary criteria, and informed consent requirements. Describe pre-testing requirements in Section 10 (Study Calendar).
Careful consideration should be used in determining eligibility and exclusionary criteria as well as pre-testing requirements. While defining the participants make sure to consider situations where you might subsequently be asking for a deviation to include a participant. For example, if a CT scan from 3 weeks prior to starting therapy would be adequate, do not limit CT scans to having to be within 2 weeks. It is much better to appropriately define the study population prior to initiation of the study than having to amend the protocol subsequently.
Note: The following timeframes are in accordance with good clinical practice.
Non-BMT: Laboratory tests required for eligibility must be completed within 14 days prior to the date of registration. Baseline measurements must be documented from tests within 14 days of the date of registration for protocols requiring measurable disease. Diagnostic tests, such as MRIs and CT scans, must be performed within 30 days of the date of registration.
BMT: Eligibility test for subjects on BMT protocols must be completed within 42 days of registration, unless otherwise stated.
Eligibility criteria should be as open and broad as possible, with exclusions directly relevant to the research question or safety concerns. A strong rationale for exclusions should be provided (e.g., if an agent being investigated cannot be safely given with renal insufficiency, renal exclusions are appropriate. However, renal exclusions without rationale will be scrutinized).
Headings 3.1, 3.2 and 3.3 contain sample text provided by CTEP and DF/HCC. Please modify the text to meet the specific needs of the proposed study.
1 Eligibility Criteria
Generally, eligibility should be as broad as possible within safety parameters. Exclusions should be scientifically or ethically justified (FDA Guidance Nov. 2020).
Note for all protocols: If study has an integral biomarker to determine eligibility to study or specific treatment arms, then the relevant eligibility criteria must be stated (e.g., Presence of [specific gene mutations and variants]).
3. For phase 1 protocols: Participants must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective.
OR
Participants must have histologically or cytologically confirmed [Study Disease]
Please specify eligible disease(s)/stage(s) using the CTEP Simplified Disease Classification ().
Note: Radiological evaluation should occur within approximately 30 days prior to enrollment initiation. Studies using progression-free survival (PFS) as an endpoint will require a stricter window for radiological evaluation.
4. For phase 2 protocols: Please insert appropriate criteria for the particular participant population. Note: Lesions are either measurable or non-measurable using the criteria provided in section 11. 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.
Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. See Section 12 (Measurement of Effect) for the evaluation of measurable disease.
OR
Please insert appropriate criteria for diseases other than solid tumors. Criteria for selected hematologic malignancies can be found in the following references: J Clin Oncol 17(4):1244-53, 1999 (non-Hodgkin's lymphoma); J Clin Oncol 8(5):813-19, 1990 (acute myeloid leukemia); and Blood 887(12):4990-97, 1996 (chronic lymphocytic leukemia).
5. Please state allowable type and amount of prior therapy. Define as appropriate any limitations on prior therapy and the time from last prior regimen (e.g., no more than 6 cycles of an alkylating agent; no more than 450 mg/m2 doxorubicin for agents with expected cumulative cardiotoxicity). Include separate definitions for duration as needed (e.g., at least 4 weeks since prior chemotherapy or radiation therapy, 6 weeks if the last regimen included BCNU or mitomycin C). Include site/total dose for prior radiation exposure as needed (e.g., no more than 3000 cGy to fields including substantial marrow).
6. Age ≥18 years. Please state reasons for any age restrictions. In line with NIH “Inclusion Across the Lifespan” policies, we recommend no upper age limit for trials designed for adult participants unless a strong rationale is provided.
Because no dosing or adverse event data are currently available on the use of [CTEP and/or CIP IND Agent] in combination with [other agents] in participants Grade 1) with the exception of alopecia. [if appropriate only]
18. Participants who are receiving any other investigational agents for this condition (if appropriate only).
19. The investigator(s) must state a medical or scientific reason if participants who have brain metastases will be excluded from the study.
20. History of allergic reactions attributed to compounds of similar chemical or biologic composition to [CTEP and/or CIP IND Agent(s) or other IND agent] or other agents used in study.
21. Please state appropriate exclusion criteria relating to concomitant medications or substances that have the potential to affect the activity or pharmacokinetics of the study agent(s). Examples of such agents or substances include those that interact through the CYP450 isoenzyme system or other sources of drug interactions (e.g., P-glycoprotein). Specifically excluded substances may be listed below, stated in Section 8 (Pharmaceutical Information), and presented as an appendix. If appropriate, the following text concerning CYP450 interactions may be used or modified.
Participants receiving any medications or substances that are inhibitors or inducers of [specify CYP450 enzyme(s)] are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product. [Appendix C is a sample participant information sheet that can be tailored to this specific protocol and presented to the participant.]
22. The investigator(s) must state a medical or scientific reason if pregnant or nursing women will be excluded from the study. The full text of the Policies, Guidelines, and Procedures pertinent to this requirement is available on the CTEP website (). Suggested text is provided below:
Pregnant women are excluded from this study because [CTEP and/or CIP IND Agent] is [a/an Agent Class] agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with [CTEP and/or CIP IND Agent], breastfeeding should be discontinued if the mother is treated with [CTEP and/or CIP IND Agent]. These potential risks may also apply to other agents used in this study.
23. The investigator(s) must state a medical or scientific reason if participants who are cancer survivors will be excluded from the study. The full text of the Policies, Guidelines, and Procedures pertinent to this requirement is available on the CTEP website ().
24. Please insert other appropriate agent-specific exclusion criteria. For example, participant must be able to swallow pills.
3 Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.
Please alter the above statement as appropriate, if necessary.
NIH policy requires that women and members of minority groups and their subpopulations be included in all NIH-supported biomedical and behavioral research projects involving NIH-defined clinical research unless a clear and compelling rationale and justification establishes to the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. Exclusion under other circumstances designated by the Director, NIH, upon the recommendation of an IC Director based on a compelling rationale and justification. Cost is not an acceptable reason for exclusion except when the study would duplicate data from other sources. Women of childbearing potential should not be routinely excluded from participation in clinical research. Please see .
Please also include, or justify excluding, participants with disabilities, those at the extremes of weight, and those whose preferred language is not English. The IRB will assist with decisions regarding the use of an interpreter with a short form and addendum (which are available in many languages) along with an English language informed consent document; and where appropriate, to strongly consider translation of the ICF into one or more other languages.
Please summarize the demographic makeup of the population with the disease and address plans for inclusion of diverse populations/ ways the investigator will ensure that the trial population is representative of the population with the disease.
REGISTRATION And Randomization PROCEDURES Please Remove “And Randomization” if the trial is not randomized.
This section must be included since this study will be performed within the DF/HCC. Suggested text is provided below which may be modified as necessary. If protocol is limited to DF/HCC institutions, please insert “N/A” directly under headings 4.3 and 4.4 for Multi-Center studies.
1 General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or intervention. Any participant not registered to the protocol before protocol-specific therapy or intervention begins will be considered ineligible and registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the protocol-specific eligibility checklist.
Remove the following paragraph if the trial is not randomized.
The eligibility checklist(s) and all pages of the consent form(s) will be emailed to ODQ at ODQ@dfci.harvard.edu. The ODQ will (a) review the eligibility checklist, (b) register the participant on the protocol, and (c) randomize the participant.
Remove the following paragraph if the trial is not randomized.
Randomization can only occur during ODQ business hours (8:30am - 5pm Eastern Time, Monday through Friday excluding holidays).
Remove the following paragraph if the trial is not randomized.
An email confirmation of the registration and/or randomization will be sent to the study coordinator(s) from the registering site, treating investigator and registering person immediately following the registration and/or randomization.
Following registration, participants may begin protocol-specific therapy and/or intervention. Issues that would cause treatment delays should be discussed with the Principal Investigator (PI) of the registering site. If the subject does not receive protocol therapy following registration, the subject must be taken off study in the CTMS (OnCore) with an appropriate date and reason entered.
2 Registration Process for DF/HCC Institutions
Applicable DF/HCC policy (REGIST-101) must be followed.
3 General Guidelines for Other Investigative Sites
Eligible participants will be entered on study centrally at the [Coordinating Center] by the Study Coordinator. All sites should call the Study Coordinator [Telephone #] to verify dose level availabilities. The required forms [Name of Form(s)] can be found in Appendix [Appendix #].
Following registration, participants should begin protocol therapy within 5 days.* Issues that would cause treatment delays should be discussed with the Sponsor-Investigator. If the subject does not receive protocol therapy following registration, the subject must be taken off study in the CTMS (OnCore) with an appropriate date and reason entered.
[*Note: This can be edited for leukemia protocols where treatment should be started as rapidly as possible.]
4 Registration Process for Other Investigative Sites
To register a participant, the following documents should be completed by the participating site and faxed [Fax #] or e-mailed [e-mail address] to the Study Coordinator:
• Copy of [specify which tests or results]
• Signed participant consent form
• HIPAA authorization form
• List any other appropriate forms (e.g., Eligibility Checklist, Registration Form, etc.)
The participating site will then call [Telephone #] or e-mail [e-mail address] the Study Coordinator to verify eligibility. The Study Coordinator will follow DF/HCC policy (REGIST-101) and register the participant on the protocol. The Study Coordinator will fax or e-mail the participant study number, and if applicable the dose treatment level, to the participating site. The Study Coordinator will also contact the participating site and verbally confirm registration
TREATMENT AND/OR IMAGING PLAN
This section should be clearly written so all medical personnel involved in the treatment of participants can understand and properly follow the treatment plan. This is the ONLY section of the protocol that should contain dosage information.
Please renumber sections as necessary depending on which sections are included for phase 1 or 2, single-agent or combination, or imaging protocols.
1 Treatment Regimen
For all protocols, clearly define the cycle length. Provide a statement regarding the treatment setting and reference the protocol sections that outline expected toxicities and potential risks for the agent(s) used in the study, as well as appropriate dose modifications. Suggested text is provided below and should be modified as necessary.
[Agent(s)] will be administered every 4 weeks, with 28 consecutive days defined as a treatment cycle. Treatment will be administered on an [inpatient/outpatient] basis. Reported adverse events and potential risks are described in Section 7. Appropriate dose modifications are described in Section 6. No investigational or commercial agents or therapies other than those described below may be administered with the intent to treat the participant's malignancy.
Please describe the treatment plan. Describe any other investigational or commercial agents or therapies that may be used to treat the participant’s malignancy.
For phase 1 dose-escalation protocols: State the starting dose of each agent and describe the dose escalation scheme and treatment regimen. Use exact doses rather than percentages. If appropriate, a table may be used to describe the regimen; see examples below for phase 1 single-agent and combination protocols. Please refer to the CTEP Web site () for Guidelines for Treatment Regimen Nomenclature and Expression.
NOTE: If the dosing schedule contains negative dose levels, the starting dose must be level 0.
Example for phase 1 single-agent protocols:
|Dose Escalation Schedule |
|Dose Level |Dose of [IND Agent]* |
|Level 1 – Starting Dose | |
|Level 2 | |
|Level 3 | |
|Level 4 | |
|Level 5 | |
|*Doses are stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) rather than as a percentage. |
Examples for phase 1 combination protocols:
|Dose Escalation Schedule |
|Dose Level |Dose* |
| |[Agent X] |[Agent Y] |[Agent Z] |
| |(units) |(units) |(units) |
|Level 1- Starting Dose | | | |
|Level 2 | | | |
|Level 3 | | | |
|Level 4 | | | |
|Level 5 | | | |
|*Doses are stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) rather than as a percentage. |
|Regimen Description |
|Agent |Premedications; |Dose |Route*** |Schedule |Cycle Length |
| |Precautions | | | | |
|[Agent X] |Premedicate with |** in 500 cc NS |IV over 2 hours before |Days 1-3, week 1 |28 days |
| |dexamethasone | |[Agent Y], +/- 10 min | |(4 weeks) |
| |for 3 days prior to [Agent| | | | |
| |X] | | | | |
|[Agent Y] |Avoid exposure to cold |** in 250 cc D5W|IV 1 hr after completion |Days 1-3, week 1 | |
| |(food, liquids, air) for | |of Agent A through | | |
| |24 hr after each dose. | |separate IV line, +/- 10 | | |
| | | |min | | |
|[Agent Z] |Take with food. |** tablet |PO in the a.m. |Daily, weeks 1 and| |
| | | | |2 | |
|**Doses as appropriate for assigned dose level and stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) rather than as a percentage. |
|*** Specify route of administration (e.g., IVB, IVP, IVCI, PO, intra-arterial, peritoneal, intrathecal, intracavity, etc.) and duration |
|(e.g., IVP over ten seconds), including any allowable time windows (+/- minutes). |
For phase 2 protocols: Please describe the regimen (agent, dose, route, and schedule) and state any special precautions or warnings relevant for investigational study agent administration (e.g., incompatibility of the agent with commonly used intravenous solutions, necessity of administering agent with food, how to round a dose of oral agent to available tablet/capsule strengths, premedications etc.). Please refer to the CTEP Web site () for Guidelines for Treatment Regimen Expression and Nomenclature.
NOTE: For orally administered agents, a method for assessing compliance with treatment should be included, e.g., “The participant will be requested to maintain a medication diary of each dose of medication. The medication diary will be returned to clinic staff at the end of each cycle.”
For protocols with varying treatment cycles: Please define each cycle individually and label which cycle is being addressed.
For randomized arms: Address each arm separately and identify which arm is being addressed.
For Phase 1 dose escalation methods determined by information generated during the trial:
(1) Provide a clear description of how each dose level will be determined. Suggested text for the definition of an alternative dose determination method and the corresponding references are provided below and should be modified as necessary.
The design for the study is an adaptation of the continuous reassessment method (CRM) of dosing, which is based on the concept of maximizing the number of participants at the best current estimation of the maximum tolerated dose (MTD) given the previous observations. (See below for references.) The CRM is expected to locate the MTD efficiently. The CRM attempts to estimate the target MTD from a continuum of doses, whereas a fixed design merely selects a dose from a discrete series. If the true target dose is not among the choices set out in advance by fixed designs, they can only approximate it. A CRM based design uses a statistical model for dose and toxicity by including the accumulating data to guide selection of the next dose. Simulations and literature have shown that compared to the conventional fixed 3+3 design, the CRM typically requires fewer participants to find the MTD, does not greatly overshoot the MTD (that is, participants are not expected to be treated with dangerously high doses), and does not greatly underestimate the MTD. This design also minimized the exposure of Phase I participants to lower, potentially inefficacious doses.
References:
Schoffski P, Riggert S, Fumoleau P, et al. Phase I trial of intravenous aviscumine (rViscumin) in patients with solid tumors: a study of the European Organization for Research and Treatment of Cancer New Drug Development Group. Annals of Oncology 2004: 15(12):1816-1824.
O’Quigley J, Zohar S. Experimental designs for phase I and phase I/II dose-finding studies. British Journal of Cancer 2006: 94:609-613.
(2) Describe the dosing schedule in narrative and tabular form. Dosing tables must contain percentages rather than provisional or sample doses. For example:
The starting dose level will be 0.9 mg/m2 per infusion. The dose for subsequent dose levels will be determined according to the treatment-related adverse events observed during the first 2 cycles in the previous dose level, as follow:
|Maximum number of grades of toxicity above baseline observed in the |% increase of dose for dose level |
|previous DL during the first 2 cycles | |
|0 |100% |
|1 |50% |
|2-4 |33% |
(3) When using an alternative dose determination method where the dose is not pre-specified for the next dosing level, an Alert Page stating the next dose level must be submitted to the DF/HCC Office for Human Research Studies (OHRS), for posting to the Oncology Protocol System (OncPro), prior to agent administration in the next participant or cohort.
2 Pre-Treatment Criteria
As appropriate, outline any hematologic and non-hematologic pre-treatment criteria (e.g., platelets must be > ..., LFT < ..., any non-heme toxicities must return to baseline or to < Grade ..., etc.) that are important to the participant’s involvement with the study beginning with Cycle 1, Day 1(C1D1) and for each subsequent dose or cycle. Procedures should address Day 1 concerns as related to treatment (e.g., whether C1D1 results need to meet eligibility parameters to start treatment or whether results of D1 labs need to be reviewed before treatment).
1. Cycle 1, Day 1
2. Subsequent Cycles
3 Agent Administration
Use the full name of any agent(s) consistently throughout the protocol document. For example, if the first reference to an agent is Cytoxan do not switch to cyclophosphomide later in the protocol. Doses should be written with a leading zero before the decimal point (0.5 mg). Do not use a terminal zero after the decimal point. Use 1mg rather than 1.0 mg. Avoid the use of slash marks to separate doses. Be consistent with dosage information. Chose one unit of measurement and use it consistently throughout the protocol. For example: 1.2 grams OR 1,200 milligrams, dose/kg OR dose/m2, etc.
As applicable, describe in detail the following parameters for each agent used as part of the protocol therapy:
Administration – Include the dose, dosing schedule, route/mode of administration, and the treatment period. Indicate if the agent is a vesicant or irritant. If an FDA approved agent is part of the treatment regimen, specify whether administration is per institutional standard/package insert or investigator discretion. If IVCI up and down times need to be captured, specify the need and make provisions in data capture to account for these times being recorded.
Dosing – Include the daily dose and dosing time points with allowable time window (e.g., drug taken 6 hours apart, +/- 15 minutes). Any additional factors to be used in making dose calculations, such as ideal body weight and body surface area, should be delineated and any formulas for the calculations should be provided here or in an appendix. State under what circumstances the dose should be recalculated and what parameters should be followed (e.g., per dose, per cycle or do not recalculate). It is preferable to calculate doses based on same-day weight/BSA measurement.
Drug, Tubing and Filtration – Specify whether any special IV tubing and/or filtration are necessary. State the type of tubing and/or the type and size of filter needed.
Hydration – Specify whether pre-treatment, treatment or post-treatment hydration is required or recommended. Include the type of solution and any additives, volume, rate and schedule.
Special Equipment – Indicate whether a special infusion pump or overfills will be required.
Observation period – State the length of observation during and/or following the infusion with any allowable time windows (+/- minutes).
Protocol specific procedures – Describe timing and frequency with which vital signs should be monitored or ECGs and PKs should be obtained. Indicate allowable time windows (+/- minutes) as appropriate (e.g., ECGs, PKs, vital signs, +/- 10 minutes).
Infusion Reactions – Indicate what symptoms should be monitored for and what interventions should be taken. For example slow the infusion, administer hypersensitivity medications, etc.
Oral Agents – Include any instructions regarding administration with or without food and any dietary considerations. Indicate whether the agent may be crushed, chewed or dissolved. Specify whether doses should be retaken or skipped if missed or vomited. NOTE: If an oral or self-administered agent is part of the protocol treatment, supply a drug diary in an appendix.
Order of Administration - If more than one agent is given, specify the order in which each agent will need to be administered.
Caregiver Precautions - Describe in detail the need for caregivers to follow any specific precautions (e.g. should not be dispensed by a pregnant woman, wear gloves, use caution when cleaning up vomited matter).
3. CTEP and/or CIP IND Agent(s), or other IND agent
4. Other Agent(s)
5. Other Modality(ies) or Procedures
Please provide a detailed description of any other modalities (e.g., surgery, radiotherapy) or procedures (e.g., hematopoietic stem cell transplantation) used in the protocol treatment. If this study involves no other modalities or procedures, this section should be marked “N/A”.
6. Investigational Imaging Agent Administration
Please describe the imaging agent regimen (agent, dose, route, schedule, and timing relative to imaging, special precautions or procedures, required pre-administration lab parameters [e.g., blood glucose]) for imaging agent administration.
Please provide the following sections:
Image Acquisition Details:
Image Analysis Details:
Image Interpretation Details (including whether there will be local and/or central review, etc.):
Imaging Related Procedures:
4 For phase 1 protocols only: Definition of Dose-Limiting Toxicity (DLT)
Please provide explicit definitions of the type(s), grade(s), and duration(s) of adverse events that will be considered dose-limiting toxicity(ies), or provide definitions of other endpoints that will be used to determine dose escalations. Define the DLT determination period (e.g., toxicity during Cycle 1 only).
Management and dose modifications associated with the above adverse events are outlined in Section 6.
Dose escalation will proceed within each cohort according to the following scheme. Dose-limiting toxicity (DLT) is defined above. An accelerated titration design of the investigator's choice may be substituted. An example can be found on the following Web site ().
|Number of Participants with DLT at a Given Dose Level |Escalation Decision Rule |
|0 out of 3 |Enter 3 participants at the next dose level. |
|>2 |Dose escalation will be stopped. This dose level will be declared the maximally |
| |administered dose (highest dose administered). Three (3) additional participants |
| |will be entered at the next lowest dose level if only 3 participants were treated |
| |previously at that dose. |
|1 out of 3 |Enter at least 3 more participants at this dose level. |
| |If 0 of these 3 participants experience DLT, proceed to the next dose level. |
| |If 1 or more of this group suffer DLT, then dose escalation is stopped, and this |
| |dose is declared the maximally administered dose. Three (3) additional |
| |participants will be entered at the next lowest dose level if only 3 participants |
| |were treated previously at that dose. |
|≤1 out of 6 at highest dose level below the maximally |This is generally the recommended phase 2 dose. At least 6 participants must be |
|administered dose |entered at the recommended phase 2 dose. |
5 General Concomitant Medication and Supportive Care Guidelines
Please state guidelines for use of concomitant medications, appropriate supportive care medications or treatments (e.g. growth factors, steroids, anti-emetics, etc.) and any prohibited medications that may or may not be used. The potential for interaction with the cytochrome P450 system should be addressed if applicable. Please use or modify the following paragraph as appropriate.
Because there is a potential for interaction of [CTEP and/or CIP IND Agent(s) or other IND agent] with other concomitantly administered drugs through the cytochrome P450 system, the case report form must capture the concurrent use of all other drugs, over-the-counter medications, or alternative therapies. The PI should be alerted if the participant is taking any agent known to affect or with the potential to affect selected CYP450 isoenzymes. Appendix C presents guidelines for identifying medications/substances that could potentially interact with the study agent(s).
6 Criteria for Taking a Participant Off Protocol Therapy
Please describe the planned duration of therapy and define the treatment stopping points. Suggested text is provided below and should be modified as necessary.
Duration of therapy will depend on individual response, evidence of disease progression and tolerance. In the absence of treatment delays due to adverse event(s), 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 event(s)
• Participant demonstrates an inability or unwillingness to comply with the oral medication regimen and/or documentation requirements
• Participant decides to withdraw from the protocol therapy
• General or specific changes in the participant's condition render the participant unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply. The reason for removal from protocol therapy, and the date the participant was removed, must be documented in the case report form (CRF). Alternative care options will be discussed with the participant.
When a participant is removed from protocol therapy and/or is off of the study, the participant’s status must be updated in OnCore in accordance with REGIST-OP-1.
7 Duration of Follow Up
Please define participant care following completion of the study or the achievement of a response. Describe how follow up will be accomplished with respect to out-of-state participants. Suggested text is provided below and should be modified as necessary.
Participants will be followed for [# of weeks] after removal from protocol therapy or until death, whichever occurs first. Participants removed from protocol therapy for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.
8 Criteria for Taking a Participant Off Study
Please describe the criteria and procedures for removing participants from the study. Suggested text is provided below and should be modified as necessary.
Participants will be removed from study when any of the following criteria apply:
• Lost to follow-up
• Withdrawal of consent for data submission
• Death
The reason for taking a participant off study, and the date the participant was removed, must be documented in the case report form (CRF). In addition, the study team will ensure the participant’s status is updated in OnCore in accordance with REGIST-OP-1.
DOSING DELAYS/DOSE MODIFICATIONS
A suggested introduction to Section 6 is provided below and may be used and modified as necessary.
Dose delays and modifications will be made as indicated in the following table(s). The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose modifications. A copy of the CTCAE version 5.0can be downloaded from the CTEP website
.
Treatment plans should explicitly identify when treatment (typically dose) modifications are appropriate. Treatment modifications/dosing delays and the factors predicating treatment modification should be explicit and clear.
This section should include instructions for local and systemic management of acute toxicity or overdose and whether management is specific (i.e., if antidote is known - specify type and dosage), systemic, or supportive. Include recommendations for supportive care when toxicity necessitates withdrawal from the study. If applicable, describe the management plan if severe toxicities are encountered more than once. For example, define what level of toxicity would lead to temporary or permanent withdrawal of the participant or suspension of the study. Ensure to refer to the same criteria (e.g., CTCAE v 5.0) for assessing, recording and managing adverse events.
Provide clear and detailed instructions for modifying and/or delaying the dose or changing the treatment in any way in the case of an adverse event. Outline the requirements for reduction (dose, schedule, suspension or termination). As applicable, the methodology should address the following:
• The grade the toxicity should resolve to in order to be able to resume treatment (e.g., baseline, Grade 1, etc.).
• The number of dose reductions allowed.
• The maximum amount of time that the agent can be held without withdrawing the participant from the study (e.g., 7 days, 14 days, etc.).
• For an oral agent, ensure that reduced doses match the available formulations (i.e., tablet size, etc.).
• If more than one agent or treatment modality is involved, specify when to hold each therapy. Indicate whether holding one means holding the other(s).
• Whether dose reductions are permanent or dose(s) can be re-escalated if certain conditions are met.
• Intra-participant dose escalation
• For phase I studies, describe criteria to treat a DLT and criteria to treat the toxicity after the DLT period.
If dose modifications or treatment delays are anticipated, please provide a dose de-escalation schema. The following format for an orally available agent is provided as an example and should be modified as appropriate for the protocol:
|Dose Level |[Agent Name] Dose |
|-2 |XX mg, schedule |
|-1 |XX mg, schedule |
|0 |XX mg, schedule |
|+1 |XX mg, schedule |
|+2 |XX mg, schedule |
|+3 |XX mg, schedule |
Note: All treatment modifications must be expressed as a specific dose or amount rather than as a percentage of the starting or previous dose (e.g., AUC dosing reductions must be by AUC dose levels).
For combination studies, dose modifications/treatment delays for [CTEP and/or CIP IND Agent(s) or other IND agent] and [Other Agent(s)] may be presented separately or together, as appropriate. Use of a table format is recommended if applicable.
Below are dose modification tables for the following adverse events: nausea, vomiting, diarrhea, neutropenia, and thrombocytopenia. Please use as appropriate. In addition, for your convenience, a blank dose modification table has been provided. Note in the text that if a participant experiences several adverse events and there are conflicting recommendations, the investigator should use the recommended dose adjustment that reduces the dose to the lowest level.
|Nausea |Management/Next Dose for [Agent Name] |Management/Next Dose for [Agent Name] |
|≤ Grade 1 |No change in dose |No change in dose |
|Grade 2 |Hold until ≤ Grade 1. Resume at same dose level. |Hold until ≤ Grade 1. Resume at same dose level. |
|Grade 3 |Hold* until < Grade 2. Resume at one dose level |Hold* until < Grade 2. Resume at one dose level |
| |lower, if indicated.** |lower, if indicated.** |
|Grade 4 |Off protocol therapy |Off protocol therapy |
|*Participants requiring a delay of >2 weeks should go off protocol therapy. |
|**Participants requiring > two dose reductions should go off protocol therapy. |
|Recommended management: antiemetics. |
|Vomiting |Management/Next Dose for [Agent Name] |Management/Next Dose for [Agent Name] |
|≤ Grade 1 |No change in dose |No change in dose |
|Grade 2 |Hold until ≤ Grade 1. Resume at same dose level. |Hold until ≤ Grade 1. Resume at same dose level. |
|Grade 3 |Hold* until < Grade 2. Resume at one dose level |Hold* until < Grade 2. Resume at one dose level |
| |lower, if indicated.** |lower, if indicated.** |
|Grade 4 |Off protocol therapy |Off protocol therapy |
|*Participants requiring a delay of >2 weeks should go off protocol therapy. |
|**Participants requiring > two dose reductions should go off protocol therapy. |
|Recommended management: antiemetics. |
|Diarrhea |Management/Next Dose for [Agent Name] |Management/Next Dose for [Agent Name] |
|≤ Grade 1 |No change in dose |No change in dose |
|Grade 2 |Hold until ≤ Grade 1. Resume at same dose level. |Hold until ≤ Grade 1. Resume at same dose level. |
|Grade 3 |Hold* until < Grade 2. Resume at one dose level |Hold* until < Grade 2. Resume at one dose level |
| |lower, if indicated.** |lower, if indicated.** |
|Grade 4 |Off protocol therapy |Off protocol therapy |
|*Participants requiring a delay of >2 weeks should go off protocol therapy. |
|**Participants requiring > two dose reductions should go off protocol therapy. |
|Recommended management: Loperamide antidiarrheal therapy |
|Dosage schedule: 4 mg at first onset, followed by 2 mg with each loose motion until diarrhea-free for 12 hours (maximum dosage: 16 mg/24 |
|hours) |
|Adjunct anti-diarrheal therapy is permitted and should be recorded when used. |
|Neutropenia |Management/Next Dose for [Agent Name] |Management/Next Dose for [Agent Name] |
|≤ Grade 1 |No change in dose |No change in dose |
|Grade 2 |Hold until ≤ Grade 1. Resume at same dose level. |Hold until ≤ Grade 1. Resume at same dose level. |
|Grade 3 |Hold* until < Grade 2. Resume at one dose level |Hold* until < Grade 2. Resume at one dose level |
| |lower, if indicated.** |lower, if indicated.** |
|Grade 4 |Off protocol therapy |Off protocol therapy |
|*Participants requiring a delay of >2 weeks should go off protocol therapy. |
|**Participants requiring > two dose reductions should go off protocol therapy. |
|Insert any recommended management guidelines, if appropriate. |
|Thrombocytopenia |Management/Next Dose for [Agent Name] |Management/Next Dose for [Agent Name] |
|≤ Grade 1 |No change in dose |No change in dose |
|Grade 2 |Hold until ≤ Grade 1. Resume at same dose level. |Hold until ≤ Grade 1. Resume at same dose level. |
|Grade 3 |Hold* until < Grade 2. Resume at one dose level |Hold* until < Grade 2. Resume at one dose level |
| |lower, if indicated.** |lower, if indicated.** |
|Grade 4 |Off protocol therapy |Off protocol therapy |
|*Participants requiring a delay of >2 weeks should go off protocol therapy. |
|**Participants requiring > two dose reductions should go off protocol therapy. |
|Insert any recommended management guidelines, if appropriate. |
Example of Dose Modification Table:
|Event |Management/Next Dose for [Agent Name] |Management/Next Dose for [Agent Name] |
|≤ Grade 1 |Insert appropriate management guidelines in this |Insert appropriate management guidelines in this |
| |column. |column. |
|Grade 2 | | |
|Grade 3 | | |
|Grade 4 | | |
|*Footnote any relevant guidelines regarding how long a delay in therapy is allowed before participants should go off protocol therapy |
|**Footnote any relevant guidelines regarding how many dose reductions are allowed before participants should go off protocol therapy. |
|Insert any recommended management guidelines, if appropriate. |
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following list of reported and/or potential AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine whether the event requires expedited reporting in addition to routine reporting.
Suggested text is provided below and should be modified or deleted as necessary. Delete the sections specific to CTEP protocols when not applicable to this study.
1 For CTEP protocols only: Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs)
The Comprehensive Adverse Event and Potential Risks (CAEPR) list for CTEP-supplied agent(s) will be provided with the LOI approval letter. Sections provided below should be used or deleted as necessary. Adjust the heading levels as appropriate (e.g., if this template is being used for a single-agent protocol, the subsections below can be deleted, and the CAEPR for that agent inserted directly under heading 7.1).
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset of AEs, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. The SPEER is a list of events that are protocol-specific exceptions to expedited reporting to NCI via AdEERS (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' for further clarification.
The CAEPR may not provide frequency data; if not, refer to the Investigator’s Brochure for this information.
NOTE: The highest grade currently reported is noted in parentheses next to the AE in the SPEER. Report ONLY AEs higher than this grade expeditiously via AdEERS. If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required.
7. CAEPRs for CTEP IND Agent(s)
1. CAEPR for [CTEP IND Agent #1]
The Comprehensive Adverse Events and Potential Risks (CAEPR) list will be provided with the LOI approval letter. Please insert the CAEPR here.
2. CAEPR for [CTEP IND Agent #2]
The Comprehensive Adverse Events and Potential Risks (CAEPR) list will be provided with the LOI approval letter. Please insert the CAEPR here.
8. Adverse Event List(s) for [Other Investigational Agent(s)]
Agent not supplied by CTEP: Please include a comprehensive list of all reported adverse events and any potential risks (such as the toxicities seen with another agent of the same class or risks seen in animals administered this agent) as provided by the manufacturer.
9. Adverse Event List(s) for Commercial Agent(s)
For each commercial agent, please provide a list of those adverse events most likely to occur on this study, and refer the reader to the package insert(s) for the comprehensive list of adverse events.
10. CAEPR for [CIP IND Agent #1)]
The Comprehensive Adverse Events and Potential Risks (CAEPR) list will be provided with the LOI approval letter. Please insert the CAEPR here.
For each CIP and/or commercial image agent, please provide a list of those adverse events most likely to occur on this study, and refer the reader to the Investigator’s Brochure and/or package insert(s) for the comprehensive list of adverse events.
11. Adverse Event List(s) for CIP (e.g. Study-Specific) Commercial Imaging Agents
For each CIP study-specific commercial imaging agent, please provide a list of those adverse events most likely to occur on this study, and refer the reader to the Investigator’s Brochure and/or package insert(s) for the comprehensive list of adverse events.
2 For CTEP protocols only: Adverse Event Characteristics
• CTCAE term (AE description) and grade: The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site .
• For expedited reporting purposes only:
- AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the SPEER column, Section 7.1.1) should be reported through AdEERS only if the grade is above the grade provided in the SPEER.
- Other AEs for the protocol that do not require expedited reporting are outlined in section 7.3.4.
• Attribution of the AE:
- Definite – The AE is clearly related to the study treatment.
- Probable – The AE is likely related to the study treatment.
- Possible – The AE may be related to the study treatment.
- Unlikely – The AE is doubtfully related to the study treatment.
- Unrelated – The AE is clearly NOT related to the study treatment.
3 For CTEP protocols only: Expedited Adverse Event Reporting
12. Expedited AE reporting for this study must use AdEERS (Adverse Event Expedited Reporting System), accessed via the CTEP Web site (). The reporting procedures to be followed are presented in the “NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP Web site (). These requirements are briefly outlined in the tables below (Section 7.3.3).
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to CTEP by telephone at 301-897-7497. Once Internet connectivity is restored, the 24-hour notification phoned in must be entered electronically into AdEERS by the original submitter at the site.
13. The following text is required for Multi-Center studies only and may be deleted for single institution studies.
AdEERS is programmed for automatic electronic distribution of reports to the following individuals: Study Coordinator of the Lead Organization, Principal Investigator, and the local treating physician. AdEERS provides a copy feature for other e-mail recipients.
14. Expedited Reporting Guidelines
Use the NCI protocol number and the protocol-specific participant ID assigned during trial registration on all reports.
Note: A death on study requires both routine and expedited reporting regardless of causality, unless as noted below. Attribution to treatment or other cause must be provided.
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (Progressive Disease)” under the system organ class (SOC) of the same name. Evidence that the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor growth or progression: clinical deterioration associated with a disease process) should be submitted.
Phase 0 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention1, 2
|FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) |
|NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are considered related to|
|the investigational agent(s)/intervention (21 CFR 312.64) |
|An adverse event is considered serious if it results in ANY of the following outcomes: |
|Death |
|A life-threatening adverse event |
|An adverse event results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours |
|A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions |
|A congenital anomaly/birth defect. |
|Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious |
|when, based upon 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 (FDA, 21 CFR 312.32; ICH E2A and ICH E6). |
|ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via AdEERS within the timeframes detailed |
|in the table below. |
|Grade 1 and 2 Timeframes |Grade 3-5 Timeframes |
|10 Calendar Days |24-Hour 5 Calendar Days |
|Expedited AE reporting timelines are defined as: |
|“24-Hour; 5 Calendar Days” - The AE must initially be reported via AdEERS within 24 hours of learning of the AE, followed by a complete |
|expedited report within 5 calendar days of the initial 24-hour report. |
|“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of learning of the AE. |
|1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention require reporting |
|as follows: |
|Expedited 24-hour notification followed by complete report within 5 calendar days for ALL Grade 4 and 5 AEs and Grade 3 AEs with at least a|
|possible attribution. |
|2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the nearest |
|whole day, after the agent/intervention was last administered. Footnote “1” above applies after this reporting period. |
|Effective Date: May 5, 2011 |
Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention 1, 2
|FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) |
|NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are considered related |
|to the investigational agent(s)/intervention (21 CFR 312.64) |
|An adverse event is considered serious if it results in ANY of the following outcomes: |
|Death |
|A life-threatening adverse event |
|An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours |
|A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions |
|A congenital anomaly/birth defect. |
|Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious |
|when, based upon 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. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). |
|ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via AdEERS within the timeframes detailed|
|in the table below. |
|Hospitalization |Grade 1 and Grade 2 Timeframes |Grade 3-5 |
| | |Timeframes |
|Resulting in |10 Calendar Days |24-Hour 5 Calendar Days |
|Hospitalization | | |
|≥ 24 hrs | | |
|Not resulting in |Not required | |
|Hospitalization | | |
|≥ 24 hrs | | |
|NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol Exceptions to |
|Expedited Reporting (SPEER) portion of the CAEPR. |
|Expedited AE reporting timelines are defined as: |
|“24-Hour; 5 Calendar Days” - The AE must initially be reported via AdEERS within 24 hours of learning of the AE, followed by a complete |
|expedited report within 5 calendar days of the initial 24-hour report. |
|“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of learning of the AE. |
|1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have an |
|attribution of possible, probable, or definite require reporting as follows: |
|Expedited 24-hour notification followed by complete report within 5 calendar days for: |
|All Grade 3, 4, and Grade 5 AEs |
|Expedited 10 calendar day reports for: |
|Grade 2 AEs resulting in hospitalization or prolongation of hospitalization |
|2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the nearest |
|whole day, after the agent/intervention was last administered. Footnote “1” above applies after this reporting period. |
|Effective Date: May 5, 2011 |
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention1, 2
|FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) |
|NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are considered related |
|to the investigational agent(s)/intervention (21 CFR 312.64) |
|An adverse event is considered serious if it results in ANY of the following outcomes: |
|Death |
|A life-threatening adverse event |
|An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours |
|A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions |
|A congenital anomaly/birth defect. |
|Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious |
|when, based upon 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. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). |
|ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via AdEERS within the timeframes detailed|
|in the table below. |
|Hospitalization |Grade 1 Timeframes |Grade 2 Timeframes |Grade 3 Timeframes |Grade 4 & 5 Timeframes |
|Resulting in |10 Calendar Days |24-Hour 5 Calendar |
|Hospitalization | |Days |
|≥ 24 hrs | | |
|Not resulting in |Not required |10 Calendar Days | |
|Hospitalization | | | |
|≥ 24 hrs | | | |
|NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol Exceptions to |
|Expedited Reporting (SPEER) portion of the CAEPR |
|Expedited AE reporting timelines are defined as: |
|“24-Hour; 5 Calendar Days” - The AE must initially be reported via AdEERS within 24 hours of learning of the AE, followed by a complete |
|expedited report within 5 calendar days of the initial 24-hour report. |
|“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of learning of the AE. |
|1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have an |
|attribution of possible, probable, or definite require reporting as follows: |
|Expedited 24-hour notification followed by complete report within 5 calendar days for: |
|All Grade 4, and Grade 5 AEs |
|Expedited 10 calendar day reports for: |
|Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization |
|Grade 3 adverse events |
|2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the nearest |
|whole day, after the agent/intervention was last administered. Footnote “1” above applies after this reporting period. |
|Effective Date: May 5, 2011 |
FOR USE IN CIP STUDIES INVOLVING COMMERCIAL (NON-IND/IDE) AGENTS ONLY
CIP Commercial Agent Studies: Expedited Reporting Requirements for Adverse Events that Occur in a CIP Non-IND/IDE trial within 30 Days of the Last Administration of a Commercial Imaging Agent 1, 2
|FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) |
|NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are considered related |
|to the investigational agent(s)/intervention (21 CFR 312.64) |
|An adverse event is considered serious if it results in ANY of the following outcomes: |
|Death |
|A life-threatening adverse event |
|An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours |
|A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions |
|A congenital anomaly/birth defect. |
|Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious |
|when, based upon 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. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). |
|ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via AdEERS within the timeframes detailed|
|in the table below. |
|Hospitalization |Grade 1 Timeframes |Grade 2 Timeframes |Grade 3 Timeframes |Grade 4 & 5 Timeframes|
|Resulting in |10 Calendar Days |24-Hour 5 Calendar |
|Hospitalization | |Days |
|≥ 24 hrs | | |
|Not resulting in |Not required |10 Calendar Days | |
|Hospitalization | | | |
|≥ 24 hrs | | | |
|NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol Exceptions to |
|Expedited Reporting (SPEER) portion of the CAEPR |
|Expedited AE reporting timelines are defined as: |
|“24-Hour; 5 Calendar Days” - The AE must initially be reported via AdEERS within 24 hours of learning of the AE, followed by a complete |
|expedited report within 5 calendar days of the initial 24-hour report. |
|“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of learning of the AE. |
|1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have an |
|attribution of possible, probable, or definite require reporting as follows: |
|Expedited 24-hour notification followed by complete report within 5 calendar days for: |
|All Grade 4, and Grade 5 AEs |
|Expedited 10 calendar day reports for: |
|Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization Grade 3 adverse events |
|2 For studies using PET or SPECT agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the nearest whole|
|day, after the agent/intervention was last administered. Footnote “1” above applies after this reporting period. |
|Effective Date: May 5, 2011 |
15. For CTEP protocols only: Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions
For this protocol only, the AEs/grades listed below do not require expedited reporting via AdEERS. However, they still must be reported through the routine reporting mechanism (Section 7.4).
|CTCAE SOC |Adverse Event |Grade |Hospitalization/ |Attribution |Comments |
| | | |Prolongation of | | |
| | | |Hospitalization | | |
| | | | | | |
| | | | | | |
| | | | | | |
| | | | | | |
| | | | | | |
For protocols including advanced imaging, please insert information as to the window of time and all other parameters that will determine eligibility of events for AE reporting. For example, for studies using PET and SPECT, or MR, the AE reporting period is limited to:
• [PET & SPECT = 10 radioactive half-lives rounded UP to the nearest whole day]
• [MR = 30 days]
4 For CTEP protocols only: Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions. AEs reported through AdEERS must also be reported in routine study data submissions.
5 For CTEP protocols only: Secondary Malignancy
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered a metastasis of the initial neoplasm.
CTEP requires all secondary malignancies that occur following treatment with an agent under an NCI IND/IDE be reported via AdEERS. Three options are available to describe the event:
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])
• Myelodysplastic syndrome (MDS)
• Treatment-related secondary malignancy
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported via the routine reporting mechanisms outlined in each protocol.
6 For CTEP protocols only: Second Malignancy
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a metastasis from the initial malignancy). Second malignancies require ONLY routine reporting via CDUS unless otherwise specified.
7 For non-CTEP protocols only: Expected Toxicities
Outline the reported toxicities. Indicate the nature (i.e., local or systemic) and timing of the toxicity if known (e.g., leucopenia onset 10 days, thrombocytopenia onset 10-15 days, etc.).
16. Adverse Events List(s)
1. Adverse Event List(s) for [IND Agent #1]
Please include a comprehensive list of all reported adverse events and any potential risks (such as the toxicities seen with another agent of the same class or risks seen in animals administered this agent) as provided by the manufacturer.
2. Adverse Event List(s) for Other Agent(s)
For any other agent, please provide a list of those adverse events most likely to occur on this study, and refer the reader to the package insert(s) for the comprehensive list of adverse events.
8 For non-CTEP protocols only: Adverse Event Characteristics
• CTCAE term (AE description) and grade: The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site .
• For expedited reporting purposes only:
- AEs for the agent(s) that are listed above should be reported only if the adverse event varies in nature, intensity or frequency from the expected toxicity information which is provided.
- Other AEs for the protocol that do not require expedited reporting are outlined in the next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-Specific Expedited Adverse Event Reporting Exclusions.
• Attribution of the AE:
- Definite – The AE is clearly related to the study treatment.
- Probable – The AE is likely related to the study treatment.
- Possible – The AE may be related to the study treatment.
- Unlikely – The AE is doubtfully related to the study treatment.
- Unrelated – The AE is clearly NOT related to the study treatment.
9 For non-CTEP protocols only: Adverse Event Reporting
17. In the event of an unanticipated problem or life-threatening complications treating investigators must immediately notify the PI.
18. Investigators must report to the PI any adverse event (AE) that occurs after the initial dose of study treatment, during treatment, or within 30 days of the last dose of treatment on the local institutional SAE form.
19. Adverse Event Reporting Guidelines
All participating sites will report AEs to the Sponsor-Investigator per DF/HCC requirements, and the IRB of record for each site as applicable per IRB policies. The table below indicates which events must be reported to the DF/HCC Sponsor-Investigator.
| |DF/HCC Reportable Adverse Events(AEs) |
| | |
| | |
|Attribution | |
| |Gr. 2 & 3 AE |Gr. 2 & 3 AE |Gr. 4 AE Expected |Gr. 4 AE |Gr. 5 AE Expected or |
| |Expected |Unexpected | |Unexpected |Unexpected |
|Unrelated |Not required |Not required |5 calendar days# |5 calendar days |24 hours* |
|Unlikely | | | | | |
|Possible | | | | | |
|Probable |Not required |5 calendar days |5 calendar days# |5 calendar days |24 hours* |
|Definite | | | | | |
|# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. |
|* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last intervention, events |
|must be reported within 1 business day of learning of the event. |
20. Protocol-Specific Adverse Event Reporting Exclusions
For this protocol only, the AEs/grades listed below do not require expedited reporting to the DF/HCC Sponsor-Investigator. However, they still must be recorded through the routine reporting mechanism (i.e. case report forms).
|CTCAE SOC |Adverse Event |Grade |Hospitalization/ |Attribution |Comments |
| | | |Prolongation of | | |
| | | |Hospitalization | | |
| | | | | | |
| | | | | | |
| | | | | | |
| | | | | | |
| | | | | | |
10 Reporting to the Food and Drug Administration (FDA)
Include this section and text for investigator-held IDE and IND studies, including gene transfer. If this is not an investigator-held IDE or IND study, this section and text should be deleted.
The Sponsor-Investigator will be responsible for all communications with the FDA. The Sponsor-Investigator will report to the FDA, regardless of the site of occurrence, any serious adverse event that meets the FDA’s criteria for expedited reporting following the reporting requirements and timelines set by the FDA.
11 Reporting to the NIH Office of Biotechnology Activities (OBA)
Include this section and text for gene transfer studies. If this is not a gene transfer study, this section and text should be deleted.
The Sponsor-Investigator, will be responsible for all communications with the OBA. The Sponsor-Investigator will report to the OBA, regardless of the site of occurrence, any serious adverse event that meets the OBA’s criteria for expedited reporting following the reporting requirements and timelines set by the OBA.
12 Reporting to the Institutional Biosafety Committee (IBC)
Include this section and text for gene transfer studies. If this is not a gene transfer study, this section and text should be deleted.
Participating investigators will register and report on research protocols involving biohazards (i.e., recombinant DNA or infectious agents) according to the reporting requirements set by their respective IBC.
13 Reporting to Hospital Risk Management
Include this section and text for all studies (i.e., CTEP protocols and non-CTEP protocols).
Participating investigators will report to their local Risk Management office any participant safety reports, sentinel events or unanticipated problems that require reporting per institutional policy.
14 For non-CTEP protocols only: Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the PI on the toxicity case report forms. AEs reported through expedited processes (e.g., reported to the IRB, FDA, etc.) must also be reported in routine study data submissions.
PHARMACEUTICAL and/or IMAGING AGENT INFORMATION
A list of the adverse events and potential risks associated with the investigational or other agents administered in this study can be found in Section 7.1.
A separate pharmaceutical section is needed for each agent (investigational or other) included in the protocol therapy regarding Description, Form, Storage and Stability, Compatibility, Handling, Availability, Preparation, Administration, Ordering, Accountability, and Destruction and Return. Refer to the appropriate pharmaceutical data sheet, Investigator’s Brochure or package insert for agent information. Pharmaceutical information for CTEP-supplied agents may be found in the attachment to the approved Letter of Intent (LOI) response. For CIP agents, include reference to the current Investigator’s Brochure, and include appropriate Dosimetry, Quality Assurance, Quality Control, and Storage information from the Investigator’s Brochure and/or supplier.
1 IND Agent #1
21. Description
Describe the agent scientifically, including the molecular and chemical structure as well as the molecular weight. Include the agent’s NSC # (if applicable), chemical name, and other names. For example the investigational agent Flavopiridol:
The chemical name is: (-)-cis-2-(2-chorophnyl-5,7-dihydroxy-8-(4R-3S-hydroxy-1-methyl) piperidinyl-4H-1benzopyran-4-one,hydrochloride. Flavopiridol is also known as HMR 1275 and is a synthetic flavone. The molecular formula is C21H20CINO3 HCL. The molecular weight is 438.29.
Provide basic pharmacokinetic information including mechanism of clearance, plasma t ½ and relevant drug interactions.
22. Form
Describe the available dose form(s) to be used in the proposed study. Extraneous information (e.g., information about tablets when the agent will only be given IV) should NOT be included as it may lead to error. Include the color and appearance of the agent, how it is supplied (e.g., powder or liquid form, etc.), and the packaging (e.g., vial, ampule, tablet, etc.). Include instructions for rounding doses as it relates to tablets or capsule size availability, as applicable. Also state the agent’s manufacturer and/or supplier. For a non-IND agent, there may be more than one manufacturer/supplier. If this is the case, the term “various manufacturers” may be used. The package insert of the online resources MicroMedex or Lexicomp may be helpful in determining the manufacturer(s). DFCI, MGH & BWH (Partners) nursing and physicians can access MicroMedex through the Partners Applications menu under Clinical References. BIDMC nursing and physicians can access MicroMedex through the BIDMC home portal. BCH nursing and physicians can access Lexicomp through the BCH electronic medical record.
23. Storage and Stability
Include the storage requirements (e.g., room temperature, freezer, etc.) and the stability of the original dosage form, reconstituted solution and final diluted product, as applicable.
24. Compatibility
Provide any relevant information about reconstitution or mixing of the agent with specific diluents as well as any information about an agent’s incompatibility with other adjunctive therapies. If the protocol therapy involves more than one agent, provide compatibility information for the co-administration of the other agent(s).
25. Handling
Describe any considerations about the agent that would affect handling, including the need for utilizing chemotherapeutic handling precautions or any special equipment (i.e., water baths, vortex mixers, etc.). Sample text is provided below for an agent requiring chemotherapy precautions:
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the environment, should undertake the preparation, handling, and safe disposal of the chemotherapeutic agent in a self-contained and protective environment.
26. Availability
Indicate how the agent will be distributed to investigators. State the agent’s supplier or state that it is commercially available. In the case of a commercially supplied agent clearly state whether it will or will NOT be provided free of charge for this study.
If a commercially available agent has more than one manufacturer and it is not known which one will be used, this should be stated as “available from various manufacturers.” The package insert or the on-line resources MicroMedex or Lexicomp may be helpful in determining the manufacturer(s). DFCI, MGH & BWH (Partners) nursing and physicians can access MicroMedex through the Partners Applications menu under Clinical References. BIDMC nursing and physicians can access MicroMedex through the BIDMC home portal. BCH nursing and physicians can access Lexicomp through the BCH electronic medical record.
If the study agent is provided by the NCI under a Collaborative Agreement with the agent manufacturer, the text below must be included in the protocol. Information on the study agent’s Collaborative Agreement status will be provided in the approved LOI response letter.
[Agent] is provided to the NCI under a Collaborative Agreement between the Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.4).
27. Preparation
Describe how the dose is to be prepared. Include instructions about compatible diluents, reconstitution directions, concentration ranges, directions for further dilution, and any other information necessary to prepare the agent.
28. Administration
Describe 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, etc. Specify whether any special IV tubing and/or filtration are necessary. State the type of tubing and/or the type and size of filter needed.
NOTE: These instructions must be consistent with protocol section 5: TREATMENT AND/OR IMAGING PLAN.
29. Ordering
Describe how the agent will be obtained. If the agent is commercially available, check with the site Director of Pharmacy and/or the site research pharmacy to ensure that the agent is in stock. If the agent is not stocked, ensure that the agent can be ordered before the protocol is activated. If the agent is under an IND, ensure that the pharmacy will be able to receive and store the agent. The IRB should be kept informed of who will supply the agent (i.e., NCI or a pharmaceutical company) so that any regulatory responsibilities can be met in a timely fashion.
NOTE: Generally investigative sites will order their own agent regardless of the supplier (i.e., NCI or a pharmaceutical company).
If the agent will be supplied by CTEP, the following text must be included in this section.
NCI-supplied agents may be requested by the Principal Investigator (or their authorized designee) at each participating institution. Pharmaceutical Management Branch (PMB) policy requires that agent be shipped directly to the institution where the patient is to be treated. PMB does not permit the transfer of agents between institutions (unless prior approval from PMB is obtained). The CTEP-assigned protocol number must be used for ordering all CTEP-supplied investigational agents. The responsible investigator at each participating institution must be registered with CTEP, DCTD through an annual submission of Form FDA 1572 (Statement of Investigator), Curriculum Vitae, Supplemental Investigator Data Form (SIDF), and Financial Disclosure Form (FDF). If there are several participating investigators at one institution, CTEP-supplied investigational agents for the study should be ordered under the name of one lead investigator at that institution.
Active CTEP-registered investigators and investigator-designated shipping designees and ordering designees can submit agent requests through the PMB Online Agent Order Processing (OAOP) application (). Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account () and the maintenance of an “active” account status and a “current” password. For questions about drug orders, transfers, returns, or accountability, call (240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET) or email PMBAfterHours@mail. anytime.
For CIP IND Agents, insert the following text (and delete text above):
The CIP regulatory staff will inform the commercial radiopharmac(y/ies) that your NCI protocol is authorized to use the IND agent under NCI’s IND. The IND agent can then be purchased from a NCI CIP AUTHORIZED commercial vendor under the NCI IND. The vendor must be specifically authorized within the NCI IND. The investigator or appropriate investigator-designee will order subject doses of the IND agent for this specific trial. The investigational radiopharmaceutical will be shipped to the site by the day the participant is to be injected, taking into account varying radioactive half-lives for different radioactive imaging agents.
30. Accountability
Provide information on the agent inventory records. Suggested text is provided below and may be modified as necessary.
The investigator, or a responsible party designated by the investigator, should maintain a careful record of the inventory and disposition of the agent using the NCI Drug Accountability Record Form (DARF) or another comparable drug accountability form. (See the NCI Investigator’s Handbook for Procedures for Drug Accountability and Storage.)
31. Destruction and Return
Describe how unused supplies of the agent will be destroyed or returned. Indicate the disposition of any expired supplies of the agent. The DF/HCC Research Pharmacies strongly suggest that the disposition of unused or expired agents not be left until the completion of the study.
2 IND Agent #2
If there are no other investigational agent(s) in this study, this section and the instructions should be deleted.
3 Other Agent #1
Insert a subsection regarding Description, Form, Storage and Stability, Compatibility, Handling, Availability, Preparation, Administration, Ordering, Accountability, and Destruction and Return. If there are no other agent(s) in this study, this section and the instructions should be deleted.
For imaging agents, include reference to the current Investigator’s Brochure, and include appropriate Dosimetry, Quality Assurance, Quality Control, and Storage information from the Investigator’s Brochure and/or supplier.
4 Other Agent #2
If there are no other agent(s) in this study, this section and the instructions should be deleted.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
Please briefly describe all planned correlative studies and indicate whether they are mandatory or optional. For additional information refer to the “Guidelines for Correlative Studies in Clinical Trials” available on the CTEP Web site (). Explicit instructions for handling, preserving, and shipping the specimens should be provided below. Information on endpoint validation including additional background (as needed), description of the assay(s) used, materials and methods, and assay validation should be provided in an appendix. A plan for statistical analysis of the results of the correlative study(ies) should be provided in Section 13.4, Analysis of Secondary Endpoints.
If development of diagnostic assays to identify participants who might benefit from a molecularly targeted therapy is planned, validation in a central reference laboratory, tissue banking, and standardization of procedures is of high importance. If samples will be shipped to a central laboratory for processing and analysis, responsible parties and contact information should be provided below in addition to instructions for handling, preserving, and shipping the specimens.
A correlative study title using meaningful descriptive text should be provided for each planned correlative study using the Protocol Submission Worksheet found on the CTEP Web site (). These titles will facilitate documentation of contributions to basic science in the context of the clinical trial.
A suggested format for presentation of the required information is shown below and may be used or modified as required. If this trial does not include correlative or special studies, this section should be marked “N/A” and all instructions as well as the text below deleted.
1 Biomarker Studies
If the protocol includes any biomarker studies using in situ hybridization (ISH) and/or immunohistochemistry (IHC) techniques, refer to the “ISH Biomarker Template” and/or the “IHC Marker Template” for guidance. These templates can be downloaded from the CTEP website ().
Biomarker studies should be summarized in this section. Please specify whether these studies are “integral,” “integrated,” or “ancillary/exploratory,” as defined by Dancey et al. (“Guidelines for the Development and Incorporation of Biomarker Studies in Early Clinical Trials of Novel Agents.” Clin Cancer Res. 2010; 16:1745-55.). For example, an “integral” bioassay is one that is necessary for the trial to proceed, i.e., the outcome determines participant disposition. Note especially that if integral markers are to be used to make individual participant decisions, then CLIA regulations will apply ().
The description for all proposed biomarker studies, if applicable, should include specific information, as outlined below.
1. Provide a hypothesis and rationale for biomarker utility and a description of the impact on therapeutic agent development based on the following considerations:
a. Biological and/or mechanistic rationale with data to support relationship between biomarker and agent effects
b. Intended use within the proposed study
c. Preclinical in vitro and in vivo, and clinical results, if applicable
2. Describe the assay method’s validity and appropriateness for the study
3. Describe the investigator’s experience and competence with the proposed assays
4. Provide the data supporting the degree of biomarker “fit for purpose” and clinical qualification
5. Justify the number of participants and specimens:
a. To demonstrate feasibility
b. To demonstrate that studies are likely to produce interpretable and meaningful results
6. Give thoughtful consideration to the risk to the participant of obtaining samples, specimens, or data for biomarker studies in the context of data on biomarker validity and degree of clinical qualification
2 For IDE protocols only: Investigational Device Information
If an investigational device requiring an IDE is to be used in this trial, please provide the IDE#, IDE title, and the IDE sponsor. This section should be deleted if no investigational devices requiring an IDE are used.
3 Laboratory Correlative Studies
Include the following collection/processing details when developing this section: (a) amount and type of specimen collected; (b) number, size, and type of tubes or cryovials used for collection; and (c) processing instructions.
32. Title – Laboratory Correlative Study #1
1. Collection of Specimen(s)
2. Handling of Specimens(s)
3. Shipping of Specimen(s)
4. Site(s) Performing Correlative Study
33. Title – Laboratory Correlative Study #2
1. Collection of Specimen(s)
2. Handling of Specimens(s)
3. Shipping of Specimen(s)
4. Site(s) Performing Correlative Study
4 Special Studies
34. Title – Special Correlative Study #1
1. Outcome Measure
2. Method of Assessment
3. Timing of Assessment
4. Method of Data Recording
5. Timing of Data Recording
STUDY CALENDAR
Provide a detailed study timeline that describes the procedures and treatments to be performed at each visit. Schedules shown in the Study Calendar below are provided as an example and must be modified for each protocol. A table format is required, with footnotes to clarify which criteria are required to determine eligibility. Ensure that the data table is consistent with the written information within the protocol sections. If appropriate, include a statement to allow for flexibility of the timing of protocol-specified procedures in order to avoid protocol deviations and/or violations.
The EDC Timepoints column needs to be completed for investigator sponsored protocols where you are requesting forms to be built in InForm, RedCap or another EDC tool. It will be used to design the electronic case report forms for the study and must be finalized by the study team (including both the PI and Biostatistician) prior to OHRS submission. If this study will not be using InForm, RedCap or another EDC tool please remove the EDC Timepoints column.
In this column, specify the timepoints in which data will be captured. If flexibility is needed to capture an assessment that could be done at any point throughout the study, make that known when documenting the timepoints. For example, the Bone Marrow assessment below is required at “Baseline and Off Treatment - If a Bone Marrow Assessment is performed during any Cycle or Follow-Up visits, it must be captured in InForm.”
The following are common examples of assessments that are not necessary for data analysis and therefore do not need to be captured in the EDC Timepoints column: pregnancy tests and standard-of-care assessments.
Baseline evaluations are to be conducted within X days/weeks/months prior to start of protocol therapy. Scans and x-rays must be done ................
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