Author Affiliation: Department of Medical Oncology
and Hematology, Princess Margaret Hospital and University of Toronto, Toronto,
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.
Chen EX, Tannock IF. Risks and Benefits of Phase 1 Clinical Trials Evaluating New Anticancer Agents: A Case for More Innovation. JAMA. 2004;292(17):2150–2151. doi:https://doi.org/10.1001/jama.292.17.2150
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