Phase 1/2, multi-center, open-label clinical study to evaluate the safety, pharmacokinetics, and efficacy of zefamenib in patients with relapsed/refractory acute leukemia

Abstract Background: Acute leukemia is the most common hematological malignancy, mainly including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Nucleophosmin 1 mutations (mNPM1) occur in 20%-30% of AML patients. Patients with mNPM1 have a 5-year survival rate of ~50%, with a median overall survival (OS) of 6.1-7.3 months in relapsed/refractory (R/R) patients. The gene rearrangement of the lysine methyltransferase 2A (KMT2Ar) occurs in ~10% of acute leukemia patients. Patients with a KMT2A rearrangement have a 5-year survival rate of ~20%-25%, with a median OS 2.4-6 months in R/R patients. Menin is a scaffolding protein that interacts with aberrant NPM1 or KMT2A to upregulate the HOXA/MEIS1 pathway, resulting in leukemogenesis. Menin inhibitors are a new class of targeted therapy that inhibit the interaction of menin and KMT2A, thus allowing differentiation of blasts. Zefamenib is a potent small molecule inhibitor targeting menin. In mouse studies, zefamenib has been shown to significantly reduce the tumor burden and reduce the proliferation of leukemia cell in peripheral blood, bone marrow, and spleen. Zefamenib has also demonstrated anti-leukemia efficacy and safety in relapsed/refractory acute leukemia patients in a phase 1 dose escalation/dose optimization study; results were presented at ASH in 2024. Of the 28 patients with mNMP1 or KMT2Ar treated with the RP2D of 600 mg BID, the overall response rate and CR/CRh rate was 89.3% and 57.1%, respectively. No patient had a dose-limiting toxicity, and the toxicity profile was acceptable with 2 pts with grade 1 QT prolongation and 2 pts with grade 2 differentiation syndrome. This study is currently enrolling in the phase 2 portion and is designed to evaluate the efficacy, safety, pharmacokinetics (PK), and efficacy of zefamenib in Chinese patients with relapsed/refractory acute leukemia. Study Design and Methods: This study (NCT06052813) is a phase 2, multicenter, open-label study of zefamenib monotherapy in Chinese patients with relapsed/refractory acute leukemias who have either a KMT2A or or an NPM1 gene mutation. Key eligibility criteria include patients diagnosed with relapsed/refractory acute leukemia (including AML, ALL, and mixed lineage leukemia, excluding acute promyelocytic leukemia) according to the World Health Organization 2022 criteria, bone marrow morphological changes (blasts/immature cells ≥5%), confirmed NPM1 gene mutation or KMT2A or NUP98 rearrangement, and meet one of the following four conditions: (i) primary refractory disease; (ii) first relapse and duration of first response ≤12 months; (iii) relapsed/refractory disease after 2 or more lines of therapy; (iv) relapse after allogeneic hematopoietic stem cell transplantation. Zefamenib will be administered twice daily for 28-day treatment cycles until disease progression/recurrence, intolerable toxicity, loss to follow-up, withdrawal of informed consent, death, or the investigator's judgment to terminate the study drug, whichever occurs first. The primary objective of the phase 2 dose expansion phase is to evaluate the efficacy of zefamenib in 30-48 patients using the RP2D dose obtained in phase 1. The patients will be divided into 3 cohorts (10-16 patients per cohort): (A) patients with AML with NPM1 mutations; (B) patients with AML with KMT2A rearrangements; and (C) other patients, including patients with relapsed/refractory ALL or mixed lineage leukemia with KMT2A rearrangement; patients with AML with NUP98 rearrangement; patients with AML or ALL with other types of gene alterations that meet protocol requirements. The primary endpoint for the phase 2 dose expansion phase CRc (CR+CRh+CRi). Key secondary endpoints include CR, CR+CRh, objective response rate, MRD negative remission rate, duration of response, duration of CR+CRh, duration of CRc, EFS, OS, cumulative relapse rate, cumulative mortality, safety, and pharmacokinetics. Based on the phase 1 results of this study, a global phase 2 study assessing the efficacy and safety of zefamenib monotherapy in acute leukemias with NUP98r, HOXA9r, or mNPM1 will be started in Q2 2026.