Camelot-2: A phase 3 randomized, double-blind, placebo-controlled, study of bleximenib, venetoclax and azacitidine for the treatment of participants with newly diagnosed Acute Myeloid Leukemia harboring KMT2A rearrangements or NPM1 mutations, who are ineligible for intensive chemotherapy

Abstract

Abstract Background and Significance Newly diagnosed (ND) acute myeloid leukemia (AML) with KMT2A rearrangement (KMT2Ar)is associated with poor treatment outcomes. While NPM1 mutated (NPM1m) AML is generally associated with favorable risk, patients aged ≥65 years with NPM1m have worse outcomes. Older or ‘unfit’ patients have limited tolerance to intensive chemotherapy (IC) and are typically treated with hypomethylating agents, such as azacitidine (AZA), plus venetoclax (VEN). Bleximenib is a menin inhibitor designed to target KMT2Ar and NPM1m AML. By potently and selectively disrupting KMT2Afrom binding to menin, bleximenib induces leukemia cell differentiation and cell death. No menin inhibitors are approved for patients with ND KMT2Ar or NPM1m AML ineligible for IC. Investigational use of bleximenib as both a monotherapy and in combination with standard of care (SoC) anti-leukemic treatments is supported by preclinical evidence and preliminary clinical data. In the Phase 1 ALE1002 study (NCT05453903), high rates of response were observed at the bleximenib recommended Phase 2 dose of 100 mg BID in combination with VEN + AZA in participants with ND KMT2Ar or NPM1m AML. The safety profile of bleximenib in combination with VEN + AZA was consistent with the VEN + AZA backbone, with no drug-drug interactions observed or QTc prolongation signal identified. With the implementation of safety mitigation measures, low rates of differentiation syndrome were observed. cAMeLot-2 (EU CT number 2024-520154-38; NCT06852222) is a Phase 3, randomized, double-blind, placebo-controlled, global multicenter studythatwill evaluate efficacy and safety of bleximenib with VEN + AZA in adults with ND KMT2Ar or NPM1m AML who are ineligible for IC. Study Design and Methods Eligible participants are ≥18 years with ND KMT2Aror NPM1m AML (≥10% blasts per 2022 International Consensus Classification criteria), considered ineligible for IC (based on: [a] ≥75 years and ineligible per physician's discretion, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2, or [b] ≥18 to <75 years with ≥1 of the following comorbidities: ECOG PS of 2; severe cardiac or pulmonary disorder; renal impairment; comorbidity that, in the investigator's opinion, makes the participant unsuitable for intensive chemotherapy). Exclusion criteria include acute promyelocytic leukemia, known active leukemic involvement of the central nervous system, prior solid organ transplantation, and any significant cardiac disorder ≤6 months prior to randomization. 600 participants will be randomized to bleximenib 100 mg BID or placebo, both in combination with VEN + AZA. Treatment will be administered on a 28-day cycle and continued until progression or unacceptable toxicity.Primary endpoints are CR rate and overall survival (OS). Secondary endpoints include event-free survival (EFS), duration of CR, time to CR, rate of CR without measurable residual disease (CRMRD-), transfusion independence, allogeneic stem cell transplantation rate, incidence of adverse events, clinical laboratory parameter abnormalities, and serum concentration of bleximenib.