Trial in Progress: Phase 1b/2 Study of Alrizomadlin (APG-115), Alone or Combined with 5-Azacitidine (AZA), in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML), Chronic Myelomonocytic Leukemia (CMML), or Myelodysplastic Syndrome (MDS)

Abstract

Background AML, CMML, and MDS are rare and often clinically challenging hematologic malignancies. Alrizomadlin is an investigational, novel, orally active, potent, small-molecule selective inhibitor that destabilizes the MDM2-p53 complex and activates p53-mediated apoptosis in tumor cells with wild-type TP53 and/or MDM2 amplification. This multicenter trial is evaluating alrizomadlin alone or in combination with AZA in patients with AML, CMML, or MDS in order to determine dose-limiting toxicity (DLT), maximum tolerated dose, and recommended phase 2 dose (RP2D). Methods This multicenter study is investigating the safety and tolerability of alrizomadlin as monotherapy (Part 1), and when combined with AZA (Part 2), in adults with histologically confirmed relapsed or refractory AML, CMML, or high-risk MDS for which no available standard treatments are either indicated or likely to elicit a durable response. Part 1 (phase 1) is a standard "3+3"-designed dose escalation in which alrizomadlin is administered orally once daily (QD) on Days 1 to 5 of every 28-day cycle. The starting dose is 100 mg QD, which is then increased to 150, 200, and 250 mg in each subsequent cohort. An additional 3 to 6 patients will be treated at RP2D in the dose expansion phase. In Part 2 (phase 2), alrizomadlin, with a different assigned dose, is combined with AZA 75 mg/m2 subcutaneously on Days 1 to 7 of a 28-day cycle. An additional 12 to 15 patients will be treated with alrizomadlin at the RP2D plus AZA in the dose expansion cohort. The primary outcome measure comprises safety and tolerability, including DLT as well as the severity and frequency of adverse events (AEs) and serious AEs based on NCI CTCAE v5.0. The study is actively enrolling patients, and the overall estimated enrollment is 70 subjects. Internal study identifier: APG115-AU101. ClinicalTrials.gov identifier: NCT04358393.