A Manual for Participants in Clinical Trials of Investigational Agents ...

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Animal toxicology studies conducted prior to phase 1 trials provide the investigator with • estimates of a starting dose for clinical trials • prediction of the agent’s likely effects (desired and adverse) on normal tissues These studies provide investigators with information that helps focus clinical observation of the patient. The phase 1 dose is increased gradually by defined procedures until a level is found that • produces limiting but tolerable adverse events, or • finds pharmacodynamic (PD) evidence of target effect, and/or • finds clear signs of therapeutic activity. Phase 1 studies may have multiple endpoints, including determination of a biologically effective dose, but usually increase doses to some level of normal tissue toxicity. Phase 1 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. 4.1.3 Patient Selection Patients eligible for phase 1 trials must have confirmed malignant disease that is not effectively treated by conventional forms of therapy or for which there is no standard treatment. Initially, patients should have normal organ function so the investigator may reliably distinguish agent effects from disease effects. In the presence of major organ impairment, drug treatment may increase adverse effects due to decreased clearance or additive injury to the organ. Since most anticancer 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. CTEP sponsors specific phase 1 trials explicitly designed to determine safe and tolerable doses in patients who have organ impairment and to determine potential toxicities (see Section 4.1.10). CTEP usually supports 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, CTEP initiates other types of studies. These studies include those in pediatric populations and elderly patients. Such attempts are aimed at identifying a range of maximally tolerated doses (MTDs) or biologically effective dose for each agent. Typically, phase 1 studies are performed in both women and men. If gender-specific pharmacologic differences exist, these differences must be demonstrated and characterized. In some situations, pharmacogenomic differences in drug metabolism or target effects may alter toxicity or efficacy of the agent in different ethnic populations, requiring separate analyses of drug effects in these ethnic groups. 4.1.4 Schedule Selection Several factors determine the number of separate schedules studied in phase 1 trials. These include 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 trials on the putative optimal schedule. Section 4 - Investigator’s Manual 2009 12
Because the correlation between schedule dependence in preclinical models and 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 activity, adverse effects, and pharmacokinetics. For agents showing no particular schedule dependence in preclinical models, two extremes of schedules (e.g., single bolus dose per course and 5-day continuous infusion) are sometimes examined. 4.1.5 Starting Dose The starting dose of a phase 1 trial is based on preclinical toxicology studies. Numerous formulas to calculate a starting dose exist, for example, a fraction of the MTD in the most sensitive species tested or the no adverse effect level (NOAEL). Investigators would discuss their rationale for the proposed starting dose with CTEP. 4.1.6 Dose Escalation Doses are generally escalated according to a schema in which incremental increases in dose decrease as biologic activity becomes evident. Often, a modified Fibonacci plan is employed. However, when the goal is to escalate to a biologically effective dose as rapidly as possible, a number of accelerated titration, continual reassessment method, and other designs allow rapid dose escalation in the absence of limiting toxicity. A frequent phase I design employs successive dose doubling until a Grade 3 adverse event 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. CTEP is actively evaluating other methods of dose escalation, based on the use of pharmacodynamic markers to determine target effects, and the accelerated titration designs for phase 1 clinical trials found 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. This may require observation of at least three patients 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 phase 2 dose. The incidence of dose limiting toxicity acceptable for a recommended dose should be specified in the protocol (e.g.,
Page 1 and 2: A Manual for Clinical Investigators
Page 3 and 4: 7.1.3 Purpose .....................
Page 5 and 6: 13.4 Responsibilities of Clinical S
Page 7 and 8: 1 Introduction This manual explains
Page 9 and 10: drugs and biologics rests with the
Page 11 and 12: costs might include additional labo
Page 13 and 14: 3 The Clinical Trial Site and the I
Page 15 and 16: CTEP's site visit monitoring progra
Page 17: 4 Phase 1 Trials The Development of
Page 21 and 22: for organ dysfunction studies. The
Page 23 and 24: efore writing a formal LOI. IDB sta
Page 25 and 26: CTEP has based its guidelines conce
Page 27 and 28: 5.1.4 Randomized Phase 2 Studies A
Page 29 and 30: • Physician members of CCOPs for
Page 31 and 32: 6 Phase 3 Trials 6.1 Scientific Pol
Page 33 and 34: completed by the Cooperative Group
Page 35 and 36: clinical trial participation to all
Page 37 and 38: proposer that the submission will n
Page 39 and 40: at the FDA, and for the listing of
Page 41 and 42: expected adverse events that the pa
Page 43 and 44: • How dose modifications will be
Page 45 and 46: consent forms. However, the informe
Page 47 and 48: Investigators’ failure to submit
Page 49 and 50: espond to this re-review in the sam
Page 51 and 52: 9 Ordering Investigational Agents f
Page 53 and 54: the local oncologist(s) must regist
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Page 57 and 58: investigator send an additional cop
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Page 61 and 62: CTEP has devised a detailed policy
Page 63 and 64: 13 Affiliate Investigators The part
Page 65 and 66: 13.4.3 Cancer Centers The Cancer Ce
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• Agents are stored in various pl
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16 Monitoring and Quality Assurance
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16.5 Components of the Quality Assu
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Also, please note that medical reco
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• Even if the agent has been repo
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Appendix I NCI-Cooperative Group-In
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Phase 0 trials do not replace phase
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phase 2 trials enroll 20-30 patient
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the study should be ordered under t
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Appendix IV Key Contact Information
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Appendix V Informed Consent Checkli
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2. Describe risks as outlined in th
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CLINICAL SITE: An institution, coop
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RAB: Regulatory Affairs Branch, htt
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• Agent preparations must be perf
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Procedure for Acute Exposure or Spi
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Appendix VIII National Cancer Insti
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7) Investigational Drug Accountabil
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• Write treatment instructions cl
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• For agent admixtures that can b
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