Paper Details

ABSTRACT

Introduction: The standard treatment for newly diagnosed (ND) older/unfit AML remains azacitidine and venetoclax (AZA/VEN), however outcomes remain poor, especially in high-risk subgroups. Mipletamig is a novel CD123 x CD3 bispecific T-cell engager that demonstrated promising activity in a Phase 1 dose escalation and expansion trial, establishing weekly dosing up to 60 mcg as safe and efficacious in monotherapy and combination therapies. We present a clinical update from the ongoing Phase 1b dose optimization trial of mipletamig in combination with AZA/VEN in ND CD123+ AML (RAINIER, APVO436-5201 (NCT 05303076)).

Methods: ND patients (pts) with CD123+ AML aged 75 years or older or with comorbidities are included. Prior hypomethylating agent therapy is excluded. Mipletamig/AZA/VEN triplet therapy starts on cycle 1 day 1 (C1D1) of a 28-day cycle. In cycle 1, each cohort receives 4 priming doses of mipletamig on days 1, 3, 5, and 8, followed by the cohort assigned weekly dose on days 15 and 22, which continued weekly during cycle 2 and beyond. Target dose level is infused over 4 hours after completion of priming. 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. The primary endpoint of safety is assessed using a Bayesian optimal interval (BOIN) design across 7 dosing cohorts to determine the RP2D of mipletamig with AZA/VEN. Pts were evaluable for target dose limiting toxicity (DLT) if they received at least 1 dose of mipletamig at the target dose level (C1D15).

Results: As of data cut of July 17, 2026, 45 pts received at least one dose of mipletamig. Thirty-four pts were evaluable at C1D28 for DLT and response assessment. Of evaluable pts, median age was 73 years (range 58-87) and 12 pts had mutated TP53. Pts were evaluable in the following cohorts: Cohort 1, n=3, 9 mcg; Cohort 2, n=6, 18 mcg; Cohort 3, n=6, 27mcg; Cohort 4, n=6, 41mcg; Cohort 5, n=6, 61mcg; Cohort 5 backfill, n=1, 61mcg; Cohort 6, n=6, 91mcg. Twenty-three were adverse-risk, 7 intermediate, and 4 favorable-risk. Eleven enrolled pts received at least one mipletamig dose but did not complete C1D15 for various reasons, including infusion related reactions (IRRs); therefore, the original priming dose regimen was adjusted from 1mcg to 0.5mcg (22 hours), 1.5mcg to 0.75mcg (8 hours), 4mcg to 3mcg (8 hours), 8mcg to 6mcg (8 hours), on Days 1, 3, 5, and 8, respectively. There were 3 priming dose DLTs in earlier cohorts, before priming adjustment: 2 pts had G4 AST/ALT elevation, 1 pt had G3 IRR with NSTEMI. No target dose DLTs have been observed. All 34 pts experienced >1 treatment related adverse event (TRAE), with the most frequent TRAEs being IRR (n=25; G3: n=7, G4: n=0), AST/ALT elevations (n=11; G3-4: n=8), platelet count decrease (n=8; G3-4: n=8), and chills (n=7; G3-4: n=0). One pt in cohort 6 (91 mcg) experienced G2 CRS. Although IRRs were frequent during priming, adjustments to priming dose and infusion time substantially reduced IRR events, such that in Cohort 6 only 1 IRR occurred during 24 priming dose administrations. Among 34 evaluable pts, 20 achieved complete remission (CR: 59%). Additionally, 4, 1, and 2 pts achieved CRi, CRh, and MLFS, respectively, for a composite CR (CR/CRh/CRi) and overall response rate (ORR) (CR/CRh/CRi/MLFS) = 74% and 79%, respectively. Ten (83%) of 12 pts with mutated TP53 achieved ORR. Of 27 pts who achieved an ORR (CR, CRi, CRh, MLFS), 20 had MRD status reported based on local lab testing; of those, 11 achieved MRD negativity (55%). Further, 6 pts in remission proceeded to allogeneic transplant.

Conclusions: Preliminary results from this dose-optimization study indicate mipletamig is well tolerated and safe in combination with AZA/VEN in ND older/unfit CD123+ AML pts. A high response rate has been observed, including a 55% MRD negative rate based on local lab testing across treated cohorts. These findings support the hypothesis of potentially enhanced efficacy for Phase 2 development. The observation that 10 of 12 pts with highly resistant mutated TP53 responded represents an attractive signal for further exploration. The study is actively enrolling with an adjusted priming regimen successfully mitigating early IRRs as well as preventing CRS to a substantial degree. Higher dose level/expansion results will be presented at the congress with updated clinical data.