The design of clinical trials for new molecularly targeted compounds: progress and new initiatives.
ABSTRACT Investigators involved in the development of cancer therapeutics are testing new trial designs and endpoints in order to accommodate the perceived challenges in defining appropriate doses and schedules for further testing. Many new agents with specific molecular targets have entered clinical development or are being considered for development. While some of the agents have both toxicity and antitumour efficacy apparent at clinically achievable doses, thus the use of traditional algorithms is appropriate, others have significant clinical activity at doses considerably lower than the maximum tolerated dose. New initiatives in clinical trial design, both phase I and phase II may allow the development of appropriate plans for the development of these new molecularly targeted agents. Measures of target effect (tissue or imaging) are now commonly included in early trials of new targeted compounds, in an attempt to demonstrate proof of principle as well as guide dose selection. Phase II trial designs including novel correlative, imaging and clinical endpoints are being tested. Alternate endpoints such as progression or time to progression are being increasingly considered, and novel designs such as randomized discontinuation designs, multinomial designs and growth modulation indices are being prospectively tested. Progress in this area of early trial design are reviewed.
Nature Medicine 09/2006; 12(8):895-904. · 22.46 Impact Factor
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ABSTRACT: In recent years, we have witnessed growing interest in the methodology of clinical trials with molecular-targeted agents. In phase I studies, alternative end points to toxicity have been proposed to define the optimal biological dose: the identification of a 'target effect', the measurement of 'surrogates' for biological activity and the assessment of drug plasma levels. However, these end points are not routinely incorporated into the study design and have rarely formed the primary basis for dose selection. In phase II studies, response rate remains the preferred end point in the early evaluation of new drugs. However, this approach might lead to rejection of potentially useful drugs when significant tumor shrinkage cannot be demonstrated. Therefore, a number of alternative end points have been proposed for agents that are not expected to cause a major tumor regression: time to progression, progression-free survival, overall survival, early progression rate and growth modulation index. In phase III trials, where efficacy in terms of survival remains the most important goal of the research, the major issues are the adequate selection of patients and the optimal clinical setting of evaluation of drugs. In conclusion, many important questions regarding the methodology of clinical research with target-based agents remain open and need to be defined by research in the near future.Annals of Oncology 07/2006; 17 Suppl 7:vii128-31. · 6.43 Impact Factor