Seamless phase I/II design for novel anticancer agents with competing disease progression.

Molecularly targeted agents and immunotherapies have prolonged administration and complicated toxicity and efficacy profiles requiring longer toxicity observation windows and the inclusion of efficacy information to identify the optimal dose. Methods have been proposed to either jointly model toxicity and efficacy, or for prolonged observation windows. However, it is inappropriate to address these issues individually in the setting of dose-finding because longer toxicity windows increase the risk of patients experiencing disease progression and discontinuing the trial, with progression defining a competing event to toxicity, and progression-free survival being a commonly used efficacy endpoint. No method has been proposed to address this issue in a competing risk framework. We propose a seamless phase I/II design, namely the competing risks continual reassessment method (CR-CRM). Given an observation window, the objective is to recommend doses that minimize the progression probability, among a set of tolerable doses in terms of toxicity risk. In toxicity-centered stage of the design, doses are assigned based on toxicity alone, and in optimization stage of the design, doses are assigned integrating both toxicity and progression information. Design operating characteristics were examined in a simulation study compared with benchmark performances, including sensitivity to time-varying hazards and correlated events. The method performs well in selecting doses with acceptable toxicity risk and minimum progression risk across a wide range of scenarios.