A Phase 1 Dose Escalation Study of Milademetan in Combination with 5-Azacitidine (AZA) in Patients with Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Background: The tumor suppressor p53, encoded by the TP53 gene, is negatively regulated by murine double minute 2 (MDM2), an E3 ubiquitin ligase. Deregulation of MDM2 results in the degradation of p53, leading to cessation of the protein's multiple tumor-suppressive functions, including the induction of apoptosis and reactivation of aberrantly silenced genes. Although TP53 is not frequently mutated in AML, p53 pathway dysfunction is prevalent, with MDM2 overexpression being frequently observed. Disrupting MDM2's negative regulatory effect to reactivate functional p53 is a promising strategy for the treatment of AML. Milademetan (DS-3032b) is a small-molecule MDM2 inhibitor that disrupts the p53-MDM2 interaction and has demonstrated single-agent activity in preclinical and clinical studies of AML. Survival rates are poor for patients with relapsed/refractory (R/R) AML or high-risk MDS which underpins the rationale for combination treatments to build on the efficacy of available agents. AZA, a hypomethylating agent, is part of the standard of care for AML and MDS. Reactivation of p53-inducible genes with milademetan combined with hypomethylation and direct cytotoxicity with AZA has shown activity in preclinical models of AML. Study Design and Methods: This open-label, 2-part, multicenter, phase 1 dose-escalation and -expansion study (NCT02319369) evaluates milademetan in combination with AZA in patients with R/R AML or high-risk MDS. Key inclusion criteria comprise a diagnosis of R/R AML or high-risk MDS; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2; and adequate renal, hepatic, and clotting functions. Additional inclusion criteria for newly diagnosed patients is ineligibility for intensive induction chemotherapy due to advanced age (≥ 75 years), congestive heart failure, or ECOG PS of 3 that is not related to leukemia. Key exclusion criteria include acute promyelocytic leukemia, central nervous system leukemia, unresolved toxicity from previous anticancer therapy, mean QTcF interval >450 ms for males or >470 ms for females, or prior treatment with an MDM2 inhibitor. During part 1 (dose escalation), patients with R/R AML or high-risk MDS receive single-agent milademetan (part 1; completed) or milademetan in combination with AZA at different dose schedules (part 1A; ongoing). Milademetan is administered as a single agent on days 1-21 of each 28-day cycle (21/28 schedule) at a starting dose of 60 mg and escalating to 90, 120, 160, and 210 mg. Less frequent dosing schedules will also be evaluated, starting with the maximum tolerated dose (MTD) determined from the 21/28 schedule. In part 1A, AZA will be administered at 75 mg/m2 subcutaneously or intravenously on days 1-7 of each 28-day cycle, with milademetan treatment on days 5-14 or 8-14. The primary objectives of part 1 are to assess safety and tolerability, determine the MTD of single-agent milademetan and in combination with AZA, and identify the recommended dose for expansion (RDE) for milademetan plus AZA. During part 2 (dose expansion), 3 cohorts of patients with either (1) R/R AML, (2) newly diagnosed AML, or (3) high-risk MDS will receive milademetan in combination with AZA at the RDE. The primary objectives of part 2 are to confirm safety and tolerability, evaluate response to combination treatment, and identify a recommended phase 2 dose. Pharmacokinetics and pharmacodynamics of milademetan as a single agent and in combination with AZA will be evaluated in both parts. Approximately 80 patients are planned to be enrolled in part 1, and up to 40 patients are planned to be enrolled for each cohort in part 2. This study is currently recruiting in the United States. Disclosures DiNardo: agios: Consultancy, Honoraria; medimmune: Honoraria; celgene: Consultancy, Honoraria; syros: Honoraria; jazz: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria. Olin:Spectrum: Research Funding; Revolution Medicine: Consultancy; Mirati Therapeutics: Research Funding; Genentech: Consultancy, Research Funding; Astellas: Research Funding; Ignyta: Research Funding; Jazz Pharmaceuticals: Consultancy; Novartis: Research Funding; Astrazeneca: Research Funding; Daiichi Sankyo: Research Funding; Clovis: Research Funding. Ishizawa:Daiichi Sankyo: Patents & Royalties: Joint submission with Daiichi Sankyo for a PTC patent titled "Predictive Gene Signature in Acute Myeloid Leukemia for Therapy with the MDM2 Inhibitor DS-3032b," United States, 62/245667, 10/23/2015, Filed. Sumi:Daiichi Sankyo, Inc.: Employment. Xie:Daiichi Sankyo, Inc.: Employment. Kato:Daiichi Sankyo, Inc.: Employment; Celgene: Employment, Equity Ownership. Kumar:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Andreeff:NIH/NCI: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Equity Ownership; Breast Cancer Research Foundation: Research Funding; CPRIT: Research Funding; BiolineRx: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy.