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Clinical Trial Design for Target-Based Therapy

Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA

Correspondence: Elizabeth Fox, M.D., Pediatric Oncology Branch, CCR, NCI, Building 10/Room 13C103, 10 Center Drive, MSC 1920, Bethesda, Maryland 20892-1920, USA. Telephone: 301-402-6641; Fax: 301-480-8871; e-mail: foxb{at}mail.nih.gov

Anticancer drug discovery has shifted from an empiric random screening directed approach to a more rational and mechanistic, target-based approach, which reflects our rapidly expanding knowledge of the pathogenesis of a variety of forms of cancer at the molecular level, providing new targets for drug discovery and development. The clinical development of target-based anticancer drugs will require fundamental changes to the traditional clinical trial design and end points that have been used for conventional cytotoxic drugs. In the phase I and II settings, traditional end points (toxicity and response) may not be suitable for more selective, cytostatic target-based agents, and these end points may be replaced by biological or pharmacokinetic end points to define the optimal doses and the therapeutic effects of these drugs on their targets. For phase III trials, measurable clinical benefit will continue to be the primary end point. As our understanding of the complex pathways and networks controlling cell signaling, proliferation, and cell death expands, we must learn how and when to use agents to target specific steps in malignant transformation and proliferation, and we must adapt clinical trial design to test the clinical utility of this promising new class of anticancer drugs.

Key Words. Clinical trials • Drug development • Pharmacokinetics • Pharmacodynamics • Molecular targets

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