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November 3, 2004

Risks and Benefits of Phase 1 Clinical Trials Evaluating New Anticancer Agents: A Case for More Innovation

Author Affiliations

Author Affiliation: Department of Medical Oncology and Hematology, Princess Margaret Hospital and University of Toronto, Toronto, Ontario.

JAMA. 2004;292(17):2150-2151. doi:10.1001/jama.292.17.2150

The development of new anticancer agents follows a well-established paradigm that progresses sequentially from phase 1 through phase 3 clinical trials. Phase 1 clinical trials are first in human studies of investigational agents and enroll patients with advanced or refractory disease for whom no standard options exist. The starting dose is usually about one tenth of the lethal dose in animals that have been used for preclinical studies of toxicity. Cohorts of 3 to 6 patients are treated at each dose level, and the dose escalation in most studies involves higher escalation steps with decreasing relative increments.1 Dose escalation within the same patient is not permitted in most studies because of the desire to evaluate patients for cumulative or delayed toxicity at lower doses. The primary objectives of phase 1 studies are to evaluate the safety and tolerability of new agents and to recommend doses and schedules for phase 2 studies of efficacy. Phase 2 studies are usually limited to patients with a specific type of cancer and the usual outcome measure is tumor response (ie, for solid tumors, reduction in tumor volume). New drugs that demonstrate reasonable levels of efficacy are then selected for evaluation in large randomized phase 3 trials in which they are compared (either alone or in combination) with the current standard treatment, using outcomes that reflect patient benefit.