Background: Acute myeloid leukemia (AML) accounts for approximately 70-75% of all adult patients diagnosed with acute leukemia. Nucleophosmin 1 mutations occur in 20-30% of AML patients. KMT2A rearrangement occurs in ~5% of AML patients. NUP98 rearrangements occurs in ~1% of AML patients. With the standard 7+3 induction regimen for young and fit AML and venetoclax plus hypomethylating agents for older and unfit AML patients harboring these aberrations, the complete remission rates ranged from 45-75%. Menin is a scaffolding protein that interacts with aberrant NPM1/KMT2A/NUP98 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, allowing blasts differentiation. Menin inhibitor revumenib combined with venetoclax and azacitidine have shown complete remission (CR) rate of 88.4% in newly diagnosed AML patients harboring these aberrations.

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. 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.

Study design: This study (NCT06746519) is a phase 1/2, multicenter, open-label study, which is divided into 2 phases. Phase 1 dose escalation part has three cohorts, which will enroll 90 patients to evaluate safety and tolerance of zefamenib combined with intensive chemotherapy or venetoclax/azacitidine in patients with untreated or relapsed/refractory (R/R) AML patients with specific mutations (KMT2A/NUP98rearrangements or NPM1 mutation). Patients will be allocated into 3 cohorts based on their disease status quo. Each cohort will use 3+3 dose escalation model. Phase 2 expansion part will enroll 30-45 patients and be conducted at the selected dose level to further evaluate the safety and tolerability of zefamenib combined with intensive chemotherapy or venetoclax/azacitidine, as well as preliminary efficacy in AML subjects with specific mutations (KMT2A/NUP98rearrangements or NPM1 mutation). This phase 1/2 study aims to evaluate the efficacy, safety, pharmacokinetics (PK), and efficacy of zefamenib with intensive chemotherapy or targeted agents (venetoclax/azacitidine) in Chinese AML patients.

Key eligibility criteria include patients diagnosed with untreated (cohorts A/B in phase 1 and cohorts D/E in phase 2) or relapsed/refractory AML (cohort C in phase 1 and cohort F in phase 2) according to the World Health Organization 2022 criteria, who had confirmed NPM1 mutation with ELN intermediate risk or KMT2A/NUP98 rearrangements. Cohort A and D will enroll untreated AML patients, who will receive zefamenib combined with standard 7+3 chemotherapy for induction and zefamenib combined with high dose cytarabine for consolidation. Cohort B and D will enroll untreated AML patients, who will receive zefamenib combined with venetoclax/azacitidine for induction and consolidation. Cohort C and F will enroll R/R AML patients failed zefamenib monotherapy or screened failure to the zefamenib monotherapy, who will receive zefamenib combined with venetoclax/azacitidine for induction and consolidation.

The primary endpoint is to evaluate the safety and tolerability of zefamenib in combination with intensive chemotherapy or venetoclax/azacitidine at the end of cycle 1. Key secondary endpoints include peak concentration and Auc of zefamenib, rate of CR, CR+CRh+CRi, objective response rate (CR+CRh+CRi+PR+MLFS), duration of response, event free survival, relapse free survival and overall survival. Exploratory endpoint include MRD negative remission rate and pharmacodynamics.

This study will be the first to clarify the feasibility of zefamenib with intensive chemotherapy or targeted agents in the frontline treatment of AML patients or the efficacy and safety of zefamenib with targeted agents in R/R AML patients harboring NPM1 mutation or KMT2A/NUP98 rearrangements. Results of this study will provide ideas and evidence to improve the prognosis of Chinese AML patients with these genetic aberrations.

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2025
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