AML-143 Trial in Progress: Phase Ib/II Study of Siremadlin in Combination With Venetoclax + Azacitidine in Patients With Acute Myeloid Leukemia (AML) Who Are Ineligible for Intensive Chemotherapy (IC)

Context: Treatments for AML patients unfit for IC are limited. Venetoclax+hypomethylating agents (HMAs) demonstrated improved survival; however, relapse rates are high, and most patients remain measurable residual disease (MRD) positive. Siremadlin is a selective inhibitor of the tumor protein 53 (p53)-murine double minute-2 (MDM2) interaction. AML patients treated with siremadlin experienced a tolerable safety profile and preliminary antitumor activity in a Phase I study (NCT02143635). Initial results from a Phase lb study exploring siremadlin+venetoclax showed promising antileukemic activity in patients with relapsed/refractory AML (NCT03940352). Objective: To describe the study design of a Phase lb/II study assessing the safety and efficacy of siremadlin+venetoclax+azacitidine in AML patients unfit for IC (NCT05155709). Design: The study will consist of a safety run-in (part 1) and an expansion phase (part 2). Patients: Adult AML patients unfit for IC due to age (≥75 years) or comorbidities are eligible. Patients with TP53 mutation or del17p are excluded. Two subpopulations will be evaluated: patients with prior suboptimal response (no CR, CRh, CRi, or morphologic leukemia-free state) after 2-4 cycles of first-line venetoclax+azacitidine (Arm 1) and patients with newly diagnosed AML with high-risk features that confer a low likelihood of response to venetoclax+HMAs (adverse genetic risk stratification per European Leukemia Network, 2017; Arm 2). Interventions: Safety run-in/part 1: siremadlin 20 or 30 mg from Day (D)1 to D5 in each 28-day cycle with venetoclax+azacitidine. Arm 1: patients will continue receiving their tolerated venetoclax+azacitidine doses prior to study enrollment. Arm 2: venetoclax will be increased over 3 days to a target daily dose of 400 mg and azacitidine (75 mg/m²) from D1-D7 or from D1-D5, and D8+D9. Upon confirmation of the recommended dose for expansion (RDE) for each arm, enrollment for the expansion phase/part 2 will open; patients will be treated with siremadlin at the RDE in combination with venetoclax+azacitidine. Main Outcome Measures: Primary endpoints: incidence of dose-limiting toxicities (Arms 1 and 2 separately) and CR rate (Arm 1). Secondary endpoints: safety and tolerability; CR rate (Arm 2); CR/CRh and CR/CRi rates, duration of CR, CRi, and CRh; OS; early mortality; MRD; pharmacokinetics.