A dose optimization phase 1b/2 study evaluating mipletamig (formerly APVO436), a novel bispecific CD123 x CD3 ADAPTIRÒ molecule in combination therapy for the treatment of frontline acute myeloid leukemia (AML) in patients unfit for intensive chemotherapy

Abstract Introduction Despite azacitidine and venetoclax (AZA/VEN) being a new standard treatment for newly diagnosed older/unfit AML, overall outcomes remain poor. Mipletamig is a novel CD123 x CD3 bispecific molecule that showed promising activity in a Phase 1 dose escalation/expansion trial, including combination and monotherapy cohorts, at a safe and efficacious dose of 18 mcg weekly. We present preliminary results of the Phase 1b dose optimization trial using mipletamig with AZA/VEN in newly diagnosed (ND) CD123+ AML pts (RAINIER, APVO436-5201 (NCT 05303076)). Methods Patients (Pts/Pt) with primary or secondary AML (arising from MDS or CMML) are included. Prior hypomethylating agent therapy is excluded. Mipletamig/AZA/VEN triplet therapy starts on cycle 1 day 1 (C1D1) in a 28-day cycle. In cycle 1, each cohort receives 4 priming doses, administered by 4-hour intravenous (IV) infusion of mipletamig (1, 2, 4, and 8 mcg) on days 1, 3, 5, and 8, respectively, followed by the cohort assigned weekly dose on days 15 and 22, which continued weekly during cycle 2 and beyond. Escalating mipletamig target doses are planned across 7 sequential dose levels (9 mcg-137mcg). VEN duration is 21 days/cycle and AZA (75 mg/m2) 7 days/cycle. Responses are assessed using 2022 ELN criteria. Reduction in AZA/VEN dosing duration is allowed for pts in morphologic complete remission (CR), as is the interruption of all 3 drugs between cycles for count recovery. Priming and target dose levels are subject to modification based on safety observations, using a Bayesian optimal interval (BOIN) design across all 7 dosing cohorts. The primary endpoint is safety and determining the optimal recommended phase 2 dose(s) of mipletamig in combination with AZA/VEN for ND AML. Pts had to have received at least 1 dose of mipletamig at the target dose level (C1D15) to be evaluable for target dose DLT and response assessment. Pts withdrawn prior to C1D15 were evaluable for safety and priming dose DLT assessment. Results A total of 13 pts were enrolled with a data cut of July 18, 2025, nine pts with a median age of 72 years (range 58-87) and ECOG 0-2 were evaluable for target dose limiting toxicity (DLT) and response across 2 Cohorts: Cohort 1, n=3, 9 mcg; Cohort 2, n=6, 18 mcg.Of these 9, 6 were ELN adverse risk, 2 intermediate, and 1 favorable.Four enrolled pts received at least one mipletamig dose but did not complete C1D15 and were not evaluable (1 pt withdrew consent, 1 pt died from unrelated causes, 1 pt withdrawn based on PI discretion, 1 pt experienced a priming dose DLT of Grade 4 AST elevation leading to reduction in priming doses for subsequent study patients).The reduced priming dose regimen is 0.5 mcg, 1.5 mcg, 3 mcg, and 6 mcg on Days 1, 3, 5, and 8, respectively. There was 1 priming dose DLT and no target dose DLTs. All 13 enrolled pts had at least one TEAE. The most frequent non-hematological TEAEs were infusion related reactions (IRR) in 9 pts; constipation, cough, AST and ALT elevations each in 6 pts; Hypoxia, Hypotension and Nausea each in 5 pts. Twenty-five treatment-related AEs occurred in 9 pts with the most frequent being IRR in 9 pts and increased AST, ALT and QTc prolongation in 2 pts each. Most IRRs were Grade (G) 1-2 and manageable. Related G3/G4 AEs were reported in 2 pts as ALT and AST elevations and in 1 pt each as QTc prolongation, IRR, neutropenia and platelet count decreased. No pts experienced cytokine release syndrome (CRS). A total of 7 of 9 evaluable pts (78%) achieved a complete remission (CR), one (11%) partial remission (PR), and one (11%) was refractory. Five of the 7 CR pts achieved MRD negative status. Of 4 pts that had TP53 mutations, 2 achieved CR, one achieved PR and one was refractory. One of the TP53 gene-mutated pts became MRD negative and has maintained the CR for > 8 months (study treatment ongoing). Conclusions Preliminary results from the study indicate that mipletamig is well tolerated and safe as a combination agent with AZA/VEN in untreated AML pts. Anti-leukemic activity is notable and particularly encouraging at the two lowest target dose levels of mipletamig (9 mcg and 18 mcg), with high rates of full CR and MRD-negativity and consistent with signals seen on the prior Phase 1 study. CRS has not been detected with the addition of the new priming dose schedule, while manageable IRRs were observed during that phase. The study is actively enrolling, and higher dose level results will be presented at the congress.