Trial in Progress: A Multicenter, Open Label, Randomized, Phase 2 Study of Venetoclax and Azacitidine Plus Cusatuzumab Versus Venetoclax and Azacitidine Alone in Newly Diagnosed AML Patients Who Are Not Candidates for Intensive Therapy

Background and Significance: Acute myeloid leukemia (AML) is an aggressive, biologically heterogeneous hematopoietic stem cell neoplasm with historically dismal outcomes in patients unable to receive intensive chemotherapy. Based on the pivotal phase 3 VIALE-A study (DiNardo et. al. NEJM, 2020), the combination of venetoclax (Ven), a selective oral BCL-2 inhibitor, with azacitidine (Aza) was approved for the treatment of newly diagnosed AML in adults 75 years or older, or adults ³18 years with comorbidities precluding intensive induction chemotherapy. Overall survival (OS) in VIALE-A was 14.7 months for Ven-Aza vs 9.6 months for placebo-Aza. Among patients with a poor cytogenetic risk the median OS was 7.6 months. Cusatuzumab (Cusa) is a monoclonal antibody with high affinity to human CD70, a cell surface protein expressed on a variety of cancers with limited expression in normal tissues other than activated immune cells. Cusa blocks CD70/CD27 signaling, leading to inhibition of leukemia stem cell proliferation and reduction in leukemic blast cells and exerts direct Fc-mediated, effector functions such as enhanced antibody-dependent cellular cytotoxicity. A Phase 1/2 study (NCT03030612) and a Phase 2 study (NCT04023526) combining Cusa and Aza were conducted in patients with AML unable to tolerate intensive chemotherapy. The combination was generally well-tolerated, with most treatment-emergent adverse events consistent with those expected for hypomethylating agents and there was no obvious dose dependency for toxicities. Manageable infusion-related reactions related to Cusa were noted (Pabst et al. Haematologica, 2023). Subsequently, a single arm Phase 1b study of Cusa combined with Ven and Aza (VAC) for patients with AML was performed (NCT04150887). CR for VAC was 47.6%, CR + CRh + CRi 81.0% and MLFS 11.9% in 42 evaluable patients. Among responders, 47% were MRD negative (Roboz et al, Blood 2021, 138: 369). Overall, the study results showed promising efficacy and safety and support the further development of VAC induction for newly diagnosed patients with AML.

Study Design and Methods: OV-AML-1231 is a randomized, open-label, multicenter, multinational, Phase 2 trial to evaluate the efficacy and safety of VAC compared to VA in patients with newly diagnosed AML ineligible for intensive chemotherapy (NCT06384261) that started accrual in July 2024. The planned enrollment is 120 newly diagnosed AML patients, randomized 2:1 to VAC (80 patients) and VA (40 patients). Participants will receive standard of care VA or Cusa 20 mg/kg administered by intravenous infusion on Day 3 and Day 17 of 28-day cycles in combination with VA. The trial population will be enriched for patients with adverse cytogenetic and molecular risk features. The primary end point is OS. Secondary endpoints include event-free survival, response rates including CR, CR+CRh, and rates of MRD negativity. Planned exploratory studies include defining differential responses of AML genetically subgroups to the two treatment arms. Key eligibility criteria include age of 18 years or older and a confirmed diagnosis of previously untreated AML. Eligible patients will include those 75 years of age or older or patients with at least one of the following coexisting conditions: ECOG performance status of 2 or 3, history of congestive heart failure requiring treatment or ejection fraction ≤50% or chronic stable angina, diffusion capacity of the lungs for carbon monoxide (DLCO) ≤65% or forced expiratory volume in the first second (FEV1) ≤65%. Patients with prior exposure to hypomethylating agents are excluded.

This ongoing, multicenter, randomized study may inform new frontline low-intensity therapeutic options for newly diagnosed AML patients with high-risk biological features.