A Phase I Study Investigating the Combination of the Ziftomenib, Venetoclax and Azacitidine (ZiVA) in Pediatric Relapsed and Refractory Acute Leukemias

Background and Significance: KMT2A-rearanged (KMT2A-r) and NPM1-mutated (NPM1-m) leukemia cells exist in an arrested, undifferentiated state mediated by the KMT2A-menin complex. Ziftomenib, an oral inhibitor of the KMT2A-menin interaction, has shown efficacy in adults. KMT2A-rearanged leukemias exhibit upregulation of the BCL-2 gene, and venetoclax has shown synergistic effects with standard treatments in preclinical models. The combination of ziftomenib with venetoclax also demonstrated synergistic activity in NPM1-m leukemia models, in which ziftomenib primarily targeted CD34+CD38+ cells, while venetoclax targeted CD34+CD38- cells (earlier progenitors). Only the combination treatment effectively eliminated both bulk and CD34+CD38+/CD34+CD38- stem/progenitor cells. Given this promising preclinical data and the prevalence of these leukemias in pediatric patients we have created an open label, Phase I trial (NCT06397027) to determine the safety/tolerability of ziftomenib in combination with venetoclax and the hypomethylating agent azacitidine for relapsed or refractory pediatric patients with acute leukemias with KMT2A-r, NPM1-m or NUP98-r. An almost all-oral regimen would also facilitate delivery of care, save time for patients by minimizing infusions, in addition to lower healthcare costs from decreased utilization of recourses. Study Design and Methods: ZiVA (NCI-2024-03798, NCT06397027) is a Phase I open-label, single site, single-arm trial to determine the safety/tolerability of ziftomenib in combination with azacitidine 75 mg/m2 days 1 through 5 and venetoclax 400mg/m2 (or dose equivalent) days 1 through 14 for relapsed or refractory pediatric patients aged 2 to 21 years with acute leukemias with KMT2A-r, NPM1-m, or NUP98-r. Daily ziftomenib will be dosed continually starting on day 8 of cycle 1 to potentially allow cytoreduction and reduce risk of differentiation syndrome. Treatment cycles will be 28 days with the option to use ziftomenib monotherapy leading up to stem cell transplant and also as maintenance following transplant once criteria have been met. Patients will need adequate cardiac, hepatic, and renal function and an ECOG performance status of ≤ 2. The use of hydroxyurea or cytarabine for patients with rapidly proliferative disease during screening is allowed. Outside of hydroxyurea and cytarabine, there will be a chemotherapy washout prior to enrollment. Patients with clinically active CNS disease or active infections will be excluded. The primary objective will be to determine the safety, tolerability, and recommended Phase II dose (RP2D) of ziftomenib in combination with venetoclax and azacitidine. The secondary objective is to determine the preliminary assessment of efficacy by overall response, including complete remission (CR), CR with partial hematological recovery, CR with incomplete blood count recovery, morphological leukemia-free state and partial remission, overall survival, event-free survival and duration of response. The exploratory objective is to evaluate molecular and cellular markers that may be predictive of antitumor activity and/or resistance and to investigate relationships between PK/exposure and clinical outcomes (e.g., safety/tolerability, efficacy). The sample size for the trial is based on the dose-escalation rules and number of dose levels evaluated, A sample size of 12 patients is planned for the dose escalation. Once a RP2D been defined by the Bayesian Optimal Interval design, we will open a dose expansion cohort of 10 patients at that dose level to further evaluate safety and efficacy. On the basis of the BOIN design of a 3-patient cohort, there will be 3 reserved slots for ages 2 to <6 years old and three reserved slots for ages 6 to <12 years old. If there are unanticipated toxicities, additional slots will be added in an amendment for the particular age. In this Phase I study, we will investigate the potential of the combination of ziftomenib with azacitidine and venetoclax to improve response rate and prolong survival in relapsed and refractory pediatric leukemia.