Trial in progress: A phase II study of ziftomenib monotherapy in unfit patients with newly diagnosed Acute Myeloid Leukemia with NPM1 mutation or KMT2A rearrangement

Abstract Background and Significance: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, with a median age of 69 years at diagnosis. As AML primarily affects older adults, treatment options can be limited by a patient's age and comorbidities. While the standard treatment for less intensive induction in AML consists of venetoclax and azacitidine, some patients are too frail for this regimen and may benefit from targeted therapies in the frontline setting. Currently, the only targeted treatment approved as a single agent in the frontline setting is ivosidenib for patients aged 75 years and older with IDH1-mutated AML, based on an open-label, single arm study. Recently, menin inhibitors are being explored for treatment of AML dependent on HOX overexpression, including AML with KMT2A-rearrangement (KMT2A-r) or NPM1 mutations (NPM1-m). Ziftomenib is a potent, highly selective, oral, investigational menin inhibitor that has shown clinical activity as a single agent in the relapsed/refractory setting. In a phase 1b study in relapsed or refractory AML, 25% of patients with KMT2A-r or NPM1-m AML treated with ziftomenib 600 mg had complete remission or complete remission with partial hematologic recovery (CR/CRh). Here, we plan to explore ziftomenib monotherapy in the frontline setting in unfit patients with KMT2A-r AML, NPM1-m AML, and AML with mutations sensitive to menin inhibition. Study Design and Methods: This is a phase II, multi-center open-label trial to assess the clinical activity of single-agent ziftomenib as frontline treatment in patients with KMT2A-r and NPM1-m AML not eligible for other therapy (NCT06930352). Enrollment is planned to begin in the fall of 2025. Eligible patients will include adults over age 75 years, or younger patients with ECOG performance status of 2-3, impaired organ function, those benefiting from continuation of therapeutic anticoagulation, and those with a history of severe infection. Patients requiring dual antiplatelet therapy or those with mean QTcF >480 milliseconds, active central nervous system disease, or uncontrolled infection are excluded. All enrolled patients will receive oral ziftomenib 600 mg once daily with continuous 28-day cycles and are eligible to continue if clinical benefit is seen. If patients proceed to allogeneic stem cell transplantation, they may be eligible to continue ziftomenib maintenance. The primary endpoint will be CR/CRh after three cycles of treatment, assessed separately in the KMT2A-r and NPM1-m cohorts. Secondary endpoints will evaluate other response metrics, rates of transfusion independence, adverse events, and quality-of-life measures. An exploratory arm may be considered for other mutations that may be sensitive to menin inhibition. A total of 60 patients will be enrolled for the primary efficacy analysis (35 in the KMT2A-r arm, 25 in the NPM1-m arm). In an effort to safeguard patients and mitigate the risk of menin-inhibition associated differentiation syndrome, a safety run-in will be used for the KMT2A-r cohort using a modified 3+3 design. For both arms, Simon's two-stage minimax design will be used. For the first stage of the KMT2A-r cohort, 18 patients will be enrolled including those from that dose level at the safety run-in. If at least 3 patients achieve CR/CRh of these 18 patients, an additional 11 patients will be enrolled. For the NPM1-m cohort, if 2 patients achieve CR/CRh of an initial 10 patients, then 12 additional patients will be enrolled.