A hybrid phase I‐II/III clinical trial design allowing dose re‐optimization in phase III

Conventionally, evaluation of a new drug, A, is done in three phases. Phase I is based on toxicity to determine a “maximum tolerable dose” (MTD) of A, phase II is conducted to decide whether A at the MTD is promising in terms of response probability, and if so a large randomized phase III trial is conducted to compare A to a control treatment, C, usually based on survival time or progression free survival time. It is widely recognized that this paradigm has many flaws. A recent approach combines the first two phases by conducting a phase I‐II trial, which chooses an optimal dose based on both efficacy and toxicity, and evaluation of A at the selected optimal phase I‐II dose then is done in a phase III trial. This paper proposes a new design paradigm, motivated by the possibility that the optimal phase I‐II dose may not maximize mean survival time with A. We propose a hybridized design, which we call phase I‐II/III, that combines phase I‐II and phase III by allowing the chosen optimal phase I‐II dose of A to be re‐optimized based on survival time data from phase I‐II patients and the first portion of phase III. The phase I‐II/III design uses adaptive randomization in phase I‐II, and relies on a mixture model for the survival time distribution as a function of efficacy, toxicity, and dose. A simulation study is presented to evaluate the phase I‐II/III design and compare it to the usual approach that does not re‐optimize the dose of A in phase III.