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| Investigator's Handbook A Manual for Participants in Clinical Trials of Investigational Agents Sponsored by DCTD, NCI
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The following three sections explain CTEP policies for each phase of clinical investigation with experimental agents. For each phase we outline our scientific objectives as a sponsor of investigational agents. We also describe which physicians are eligible to study and administer investigational agents. These two aspects of agent use--study and administration--are formally quite separate issues. In general, eligibility to study NCI investigational agents has been restricted to institutions and physicians approved by peer review; these individuals may include grantees, contractors, Cooperative Group members, physicians affiliated with approved cancer centers, and recipients of investigator-initiated clinical research project grants (RO1, PO1). The application of this general rule to each phase of agent development is explained in detail. Except in certain explicitly defined circumstances outlined in the following sections, the administration of experimental agents is restricted to these investigators.
We also describe how investigators may obtain information about individual investigational agents and CTEP plans for their development.
4. Phase I
5. Phase II
6. Phase III
4.1 Scientific Policies of CTEP
CTEP prospectively plans the Phase 1 development of each agent. Selection of schedules for clinical trials is based on experimental data (see Section 4.1.4 for details). Generally, each schedule is examined in not more than two studies. From the results of the Phase 1 and clinical pharmacology studies, CTEP and its collaborating investigators decide which schedule is to be taken into Phase 2. If the need exists, a second schedule may later be examined comparatively in selected tumors to define the therapeutic index better.
Phase 1 trials determine a safe dose for Phase 2 trials and define acute effects on normal tissues. In addition, these trials examine the agent's pharmacology and may reveal evidence of antitumor activity. Therapeutic intent is always present in Phase 1 trials; indeed, anticancer agents are not tested in patients unless preclinical activity studies have already demonstrated evidence of significant activity in laboratory models.
Animal toxicology studies carried out prior to Phase 1 trials provide the investigator with
These data provide the investigator with clues that help focus clinical observation of the patient. The dose is increased gradually by some defined procedure until a level is found that produces limiting but tolerable adverse events and/or clear signs of therapeutic activity. Phase I trials define acute effects that occur with a relatively high frequency on normal tissues.
Continued careful observation during Phase 2 and 3 trials is essential to identify less frequent acute adverse effects, as well as cumulative and chronic adverse events.
Patients eligible for Phase 1 must have confirmed malignant disease that is not satisfactorily treated by conventional forms of therapy or for which there is no standard treatment. Initial patients should have normal organ function, in order that the investigator may reliably distinguish agent effects from disease effects. When there is impairment of a major organ, agent treatment may produce increased adverse effects because of decreased clearance or additive injury to the organ. Since most cancer agents will ultimately be used in some patients having impairment of major organ function (particularly cardiac, hepatic, and renal), it is reasonable to explore their use in such patients through Phase 1 trials explicitly designed to determine safe doses and pharmacology in these settings. CTEP will usually sponsor such trials selectively after the initial trials in patients with normal organ function. After successful completion of Phase 1 trials in adults with normal and abnormal physiology, other types of studies are initiated. These studies include those in pediatric populations, elderly patients, and (if hematotoxicity is dose-limiting) combination studies with hematopoietic growth factors. Such attempts are aimed at identifying a family of Maximally Tolerated Doses (MTDs) for each agent.
Typically, Phase 1 studies are performed in both women and men. If gender-specific pharmacologic differences exist, these differences must be characterized.
The number of separate schedules studied in Phase 1 is determined by several factors, including evidence of schedule dependence in experimental in vivo systems; pharmacokinetics, mechanism of action, if known; and existing clinical data with similar compounds suggesting superiority of a particular schedule. Agents that are highly schedule-dependent in preclinical models are usually brought into Phase 1 on the putatively optimal schedule.
Because the correlation between schedule dependence in preclinical models and in the clinic is not firmly established, however, some agents may be candidates for a broader array of schedules. DCTD is prospectively evaluating the ability of experimental models to predict the schedule dependence of efficacy, adverse effects, and pharmacokinetics. For agents showing no particular schedule dependence in models, two extremes of schedules (e.g., single bolus dose per course and 5-day continuous infusion) are sometimes examined.
The starting dose of a Phase 1 trial, as derived from preclinical toxicology, is 1/10 of the MTD in the most sensitive species tested.
Doses are generally escalated according to a scheme in which the initial increments are large and decrease rapidly as biologic effects become evident. Often, a modified Fibonacci plan is employed. However, when the goal is to escalate to a biologically effective dose as rapidly as possible, it may be justified to employ successive dose doubling until Grade 3 adverse events or two instances of a Grade 2 adverse event are seen. The exact schema may be affected by the steepness of the dose toxicity curve in animal models or, for trials of combinations of agents, the steepness of the single-agent dose toxicity curves. In all cases, the goal is to arrive at the recommended Phase 2 dose with the fewest number of escalations consistent with patient safety; this approach minimizes the number of patients receiving biologically inactive doses. The DCTD is actively evaluating other methods of dose escalation, based on the use of blood level data (see Section 4.1.7 below) and the accelerated titration designs for Phase 1 clinical trials at http://linus.nci.nih.gov/~brb/Methodologic.htm.
When there is sufficient concern about anticipated adverse events, a minimum of three patients not previously treated with the new agent should be entered at each dose level. In these cases, escalation to the next level should not occur until the safety of the current level has been established, which may require that at least three patients will have been observed for the entire course interval (e.g., 3 - 5 weeks). For many trials, however, escalation can proceed with one or two patients per level, provided no Grade 3 or repeated Grade 2 adverse events have yet been seen in the study. Intra-patient dose escalation should be considered for use wherever it is deemed safe. At least six patients should be treated at the recommended dose. The incidence of dose limiting toxicity acceptable for a recommended dose should be specified in the protocol (e.g., <33%).
The role of pharmacokinetics in Phase 1 is now receiving increasing emphasis, with specific focus on the possible use of such data to guide dose escalation. Human data on the pharmacokinetics of a parent compound and active metabolites, taken together with similar preclinical data in vivo, will be extensively analyzed over the next several years of Phase 1 trials to identify new approaches to dose escalations. This work is being coordinated by the Blood Level Working Group, composed of investigators from the DCTD and FDA. Investigators developing Phase I trials should consider pharmacokinetic determinations an integral part of a Phase 1 study. Because this may be limited by the availability of suitable methodologies, investigators should check with the Investigational Drug Branch (IDB) staff physician before writing a protocol.
4.2 Who Is Eligible to Study Phase 1 Agents
4.2.1 Contractors
Important resources for Phase 1 trials are institutions awarded cooperative agreement grants or contracts for these studies. Principal investigators are selected through competitive peer review in response to periodic solicitations from DCTD (Note 1). These contracts are usually awarded for 5 years.
Note 1:
When NCI seeks offerors for a contract, it issues a Request for Proposal (RFP). Notices of the availability of RFPs are published in the "NIH Guide to Grants and Contracts," which is widely distributed to universities in the U.S. They are also announced in the Commerce Business Daily, which announces all U.S. Government contract solicitations.
Qualified investigators with peer-reviewed expertise in the conduct of early clinical trials are also eligible to conduct Phase 1 trials. Investigators are usually selected because of unique expertise or research experience relevant to the agent or the availability of certain patient populations or laboratory facilities to perform special studies. In all cases, such investigators must have demonstrated competence to conduct a Phase 1 study with anticancer agents.
Selection of Phase 1 investigators is a competitive process, with preference given to those with greatest expertise, ability to correlate clinical and laboratory biologic studies, and ability to complete a high-quality study as rapidly as possible. However, this competitive process is an open one, and all appropriate individuals are welcome.
Ad hoc Phase I investigators must fulfill all CTEP requirements for trials conduct, as defined in this section, and for reporting of data as described in Section 10.
4.3 Which Organizations Can Conduct Phase I Studies
Phase 1 trials will generally be conducted by single institutions. Multicenter trials with a new single agent whose adverse event profile is not yet known will not be approved, with the exception of pediatric Phase 1 studies (see Appendix III, Policy Statement: The Conduct of Phase 1 Trials in Children).
4.4 Who Is Eligible to Administer Phase 1 Agents
All Phase 1 agents will be administered only at the institutions listed on the cover page of the approved protocol and will be administered under the supervision of the protocol chair. These agents should not be sent to referring physicians, except with written permission of CTEP. Any part of the treatment that will be administered at a site other than the study center must be indicated in the protocol.
4.5 How to Obtain Information About Phase 1 Agents
This document contains all relevant information about the agent, including animal screening, preclinical toxicology, detailed pharmaceutical data, pharmacology and mechanism of action. CTEP has an Investigator's Brochure for each investigational agent it sponsors. These are routinely provided to investigators who are approved to conduct a clinical trial of the agent at the time the LOI is approved and when the Investigator's Brochure is updated. When necessary, investigators with approved LOIs or protocols may obtain the Investigator's Brochure from the address listed in Appendix IV.
Each DCTD investigational agent is assigned to an IDB staff physician, who coordinates its clinical development. Phase 1 investigators are advised to discuss a proposal with this physician before writing a formal protocol. IDB strongly encourages investigators to submit an LOI for Phase 1 trials (see Section 5.6 below). Relevant telephone numbers and addresses can be found in Appendix IV.
Phase 1 investigators should carefully read the following sections that are relevant to issues arising with Phase 1 agents:
| Table of Contents |
Part A 1 2 3 |
Part B 4 5 6 |
Part C 7 8 9 10 11 |
Part D 12 13 14 15 16 |
Part E 17 18 19 |
Appendices |
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