Safety, Efficacy, Pharmacokinetic (PK) and Biomarker Analyses of BCL2 Inhibitor Venetoclax (Ven) Plus MDM2 Inhibitor Idasanutlin (idasa) in Patients (pts) with Relapsed or Refractory (R/R) AML: A Phase Ib, Non-Randomized, Open-Label Study

▪ Introduction Effective therapies for R/R AML remain limited. MEK or MDM2 inhibition can downregulate MCL1, overcoming resistance to BCL2 inhibition. Preclinical synergy was seen when combining BCL2 inhibitor Ven with MEK inhibitor cobimetinib (cobi) or MDM2 inhibitor idasa (Han et al. ASH 2016; Pan et al. Cancer Cell 2017), supporting clinical evaluation in AML. Preliminary data in a Phase Ib dose-escalation study (NCT02670044) evaluating Ven+cobi/idasa in R/R AML suggested both combinations were tolerable (Daver et al. ASH 2017). However, Ven+cobi was closed due to limited clinical activity. Here we present data for additional pts, longer follow-up and biomarker analyses for Ven+idasa. Methods This ongoing, open-label, multicenter study evaluates safety, tolerability and efficacy of Ven+idasa in R/R AML or secondary AML previously treated for an antecedent hematologic disease. Pts >60 yrs of age and ineligible for cytotoxic therapy/allogeneic stem cell transplant were enrolled. A 2-dimensional dose escalation was used to establish the maximum tolerated dose: pts received doses of Ven orally (PO) daily (400mg or 600mg) + idasa PO daily on Days 1-5 (150mg, 200mg, or 400mg) in 28-day cycles. Plasma samples were taken for PK analysis at Cycles 1 and 2 Days 1 and 5, and Cycle 4 Day 1. BCL2, BCLxL and MCL1 status and minimal residual disease (MRD) were assayed centrally at Covance Laboratories using multicolor flow cytometry. Mutation (mut) sequencing was performed by Foundation Medicine using FoundationOne Heme at screening and from last bone marrow collected on study. Results As of April 6 2018, 34 pts received Ven+idasa across all dose cohorts (Table 1). Median age: 74 (range 64-93) yrs; median prior therapies: 1 (range 1-4); ECOG performance status 2: 18%; refractory: 56%; secondary AML: 53%; adverse cytogenetics: 27%. Pre-therapy mut data were available for 32 pts; most common muts were RUNX1 14 (41%), ASXL1 11 (32%), SRSF2 11 (32%). Other significant pre-therapy muts: TP53 6 (18%), IDH2 7 (21%), IDH1 1 (3%), FLT3 4 (13%). The most common adverse events (AEs) were diarrhea (88%) and nausea (71%); the most common grade (Gr) ≥3 AEs were neutropenia (32%), febrile neutropenia (32%), thrombocytopenia (29%; Table 2). After 2 cases of Gr 3 diarrhea in the Ven 600mg cohorts, mandatory prophylaxis was implemented; no further cases of Gr ≥3 diarrhea were seen in the following 10 pts. Laboratory tumor lysis syndrome occurred in 3 pts (9%); none required treatment