MIRROS: Planning a Phase 3 Trial with Time-to-Event Endpoint, a Cure Proportion, and a Futility Interim Analysis Using Response

• Activity Number: 135 - The Use of Baseline Covariates and Early Read-Outs in Adaptive and Group Sequential Designs: Worth the Effort?
• Type: Topic Contributed
• Date/Time: Monday, August 8, 2022 : 10:30 AM to 12:20 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Kaspar Rufibach* and Dominik Heinzmann and Annabelle Monnet
• Companies: F. Hoffmann-La Roche and F. Hoffmann-La Roche and F. Hoffmann-La Roche
• Keywords: acute myeloid leukemia; cure proportion; futility interim analysis; integrate phase 2; intermediate endpoint; randomized clinical trial

Abstract

At the time of planning the MIRROS trial, 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 was 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 patient needs to become eligible for a bone marrow transplant, through 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 response. To evaluate the operating characteristics of the interim analysis a mechanistic simulation model was developed connecting response, the odds for transplantation, and OS in responders and non-respon