MIRROS: An ongoing randomized phase 3 trial of idasanutlin + ARA-C in patients with relapsed or refractory acute myeloid leukemia.

Abstract

TPS7063 Background: The prognosis for patients (pts) with relapsed or refractory (R/R) acute myeloid leukemia (AML) is poor, with 3-year overall survival rates ~10–30% after intensive chemotherapy-based approaches. Despite the advent of targeted therapies, considerable unmet medical need remains in this population. Idasanutlin (RG7388; RO5503781) is an orally available small molecule that binds to the murine double minute 2 (MDM2) protein and blocks MDM2 interaction with p53. This stabilizes and activates p53 and facilitates cell cycle arrest and apoptosis, preventing tumor growth. A phase 1b study of idasanutlin + ARA-C in pts with R/R AML, irrespective of TP53 mutation status (NCT01773408), has shown a composite complete remission (CR) rate (CR plus CR with incomplete platelet or hematologic recovery) of 29% (Martinelli et al. 2016). Methods: MIRROS (NCT02545283; WO29519) is an international, phase 3, double-blind, randomized study comparing idasanutlin (300 mg bid) + ARA-C (1 g/m2 qd) days 1–5 versus placebo + ARA-C in 440 pts with first or second R/R AML, with or without TP53 mutation. The primary endpoint is overall survival in pts with wild-type (WT) TP53. Secondary endpoints include CR, overall remission rates, event-free survival (EFS) and percentages of pts undergoing hematopoietic stem cell transplantation. MIRROS integrates phase 2 trial methodology into the phase 3 design by incorporating an interim analysis (IA) in 120 pts with WT TP53, using a high bar on the odds ratio for durable CR and EFS to assess for futility. Stop/go gating criteria for safety were also implemented. The IA was performed by an independent data monitoring committee and study continuation criteria were successfully met in mid-2017. This innovative strategy has allowed acceleration of the idasanutlin development program while maintaining a robust trial design. As of December 31 2018, 351 pts had been enrolled. The MIRROS study is ongoing and its results will inform the potential role of idasanutlin and MDM2 inhibition in the treatment of R/R AML. Clinical trial information: NCT02545283; WO29519.