A Phase 3 trial with cure proportion, and some thoughts on NPH


With median overall survival (OS) of about six months and no approved drug for more than forty years, the unmet medical need in acute myeloid leukemia is dramatic. Idasanutlin is a MDM2 antagonist that can effectively displace p53 from MDM2 to restore p53 function, leading to cell cycle arrest and apoptosis of cancer cells. Planning the Phase 3 trial MIRROS comparing Idasanutlin + standard of care against the standard of care presented with the following challenges: (1) To survive AML a patients needs to become eligible for a bone marrow transplant, trough achieving a complete response (CR) after induction therapy. Planning the trial using overall survival as primary endpoint thus needs to account for a cure proportion in both, the treatment and control arm. (2) MIRROS was planned based on Phase 1 data only. To mitigate the risk of directly moving to Phase 3, a futility interim was built in the design, using gates on the odds ratio for. The interim analysis was built-in the design using a mechanistic simulation model, making assumptions on response proportions, proportion of transplant survivors, and OS in these various groups. The talk describes the design in detail, discusses sample size planning, operating characteristics of the futility interim analysis, and will touch upon how we plan to report the results. We conclude with sharing feedback from US and European Health Authorities on the design.