Clinical trial designs for cytostatic agents: Are new approaches needed?

Preclinical data suggest that some new anticancer agents directed at novel targets demonstrate tumor growth inhibition but not tumor shrinkage. Such c ytostatic agents may offer clinical benefits for patients in the absence of tumor shrinkage. In addition, lower doses of some of these agents may be j ust as effective as higher doses, implying that toxicity may not be an idea l end point for dose finding. Because of these factors, the sequence and de sign of traditional phase I, II, and III trials used for cytotoxic agents ( which typically shrink tumors and in a dose-dependent manner) may not be ap propriate for cytostatic agents. This article discusses options for modifyi ng trial designs to accommodate cytostatic agents. Examples are given where there options have been tried or are currently being tried. Recommendation s given for choosing among the trial designs depend on what is known precli nically about the agents (eg, does one have a validated and reproducible bi ologic end point that can be used to guide a dose escalation?), what is kno wn about the patient population being studied (eg, does one have a well-doc umented historical progression-free survival rate at 1 year for comparison with the experience of the new agent?), and the numbers of agents and patie nts available for participation in trials. Planned and ongoing trials will test the utility of some of these new approaches. J Clin Oncol 19:265-272. This is a United States government work. There are no restrictions on its u se.