Phase 2 KOMET-001 Trial of Ziftomenib Begins Dosing Patients With NPM1-Mutant AML

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In phase 1 of the KOMET-001 trial, ziftomenib showed a 30% complete response rate in patients with NPM1-mutant acute myeloid leukemia treated at a dose of 600 mg. This is now the recommended phase 2 dose for the phase 2 portion of the study.

About the Phase 2 KOMET-001 Trial

Trial Name: A Phase 1/2 First in Human Study of the Menin-MLL(KMT2A) Inhibitor KO-539 in Patients With Relapsed or Refractory Acute Myeloid Leukemia

ClinicalTrials.gov Identifier: NCT04067336

Sponsor: Kura Oncology, Inc.

Recruitment Contact: Clinical Operations, 617 588 3755, KO-MEN-001@kuraoncology.com

Completion Date: September 30, 2025

The phase 2 KOMET-001 trial (NCT04067336) has dosed its first patients with NPM1-mutant relapsed or refractory acute myeloid leukemia (AML) with the Menin inhibitor ziftomenib, according to Kura Oncology, Inc.1

Ziftomenib is an oral investigational drug designed as a highly potent and selective inhibitor of the menin/KMT2A interaction. The agent leads to the downregulation of HOXA9 and MEIS1, and increased differentiation.

At the data cutoff of October 24, 2022, the phase 1 clinical trial of ziftomenib showed a 30% complete response (CR) rate among 20 patients with NPM1-mutant AML who were treated with the agent at a dose of 600 mg. Ziftomenib also displayed a favorable safety profile and had encouraging tolerability at this 600 mg dose level.

“The dosing of the first patients in the phase 2 of Kura Oncology’s KOMET-001 trial is a significant milestone for the AML patient community, especially for those with relapsed/refractory NPM1-mutant AML, an area of unmet need for which there are currently no FDA-approved targeted therapies. Recent data presented at the 2022 American Society of Hematology Annual Meeting have demonstrated encouraging activity and safety of ziftomenib, underscoring the potential for this investigational therapy, creating an environment of excitement and hope for the patients and the trial.” Eunice Wang, MD, chief of the Leukemia Service at Roswell Park Comprehensive Cancer Center, told Targeted OncologyTM.

In phase 1a, the dose escalation portion of the study, ziftomenib was evaluated in an all-comer population at doses escalating from 50 mg (n = 1) to 100 mg (n = 1) to 200 mg (n = 6) to 400 mg (n = 5) to 600 mg (n = 5) to 800 mg (n = 11) to 1000 mg (n = 1). They evaluated the safety, tolerability, pharmacokinetics (PK), and early evidence of antitumor activity. Based on the positive findings from the 600 mg dose level of ziftomenib, this is the recommended phase 2 dose that will be examined.

Additional findings from phase 1 showed there to be no grade 3 or higher treatment-emergent adverse effects (AEs) in the patients harboring NPM1 mutations at either dose level. Among patients with KMT2A-rearranged disease given ziftomenib at a dose of 200 mg (n = 13) 30.8% experienced differentiation syndrome (DS) vs 25.0% of those with KMT2A-rearranged disease given the agent at 600 mg (n = 16). At the 600 mg dose 12.5% of patients also had febrile neutropenia.

Among patients with NPM1-mutated disease treated at the 600-mg dose, 20% experienced DS. Five percent of DS cases in these patients were grade 3 or higher in severity. Additionally, DS was observed in 38.5% and 37.5% of those with KMT2A-rearranged disease treated at the 200-mg and 600-mg doses, respectively. Grade 3 or higher DS was seen in 30.8% and 25.0% of these cases, respectively.

Now in phase 2 of the study, investigators are assessing the primary end points of CR or complete response with hematologic recovery (CRh), as well as the secondary end points of clinical benefit, safety, and tolerability.2

Phase 2 of the study is a registration-directed trial evaluating patients aged 18 years and older with AML who have a documented NPM1 mutation, are ECOG performance status of 0 to 2, and a life expectancy of 2 months or more. Patients are required to have adequate liver and kidney function, and peripheral white blood cell counts ≤ 30,000/μL. Additionally, patients are allowed to have received hydroxyurea to control and maintain white blood cell count prior to enrollment.

While ziftomenib is being evaluated as a monotherapy in patients with NPM1-mutant AML, the company plans to start 2 more trials, KOMET-007 and KOMET-008, to evaluate ziftomenib in combination with current standards of care across multiple patient populations, including NPM1-mutant and KMT2A-rearranged AML.

The trial is actively recruiting patients and is expected to enroll a total of 85 patients across various sites in the United States and Europe. The estimated study completion date is September 30, 2025.

"Although an NPM1 mutation is generally associated with a more favorable prognosis and is considered favorable risk by ELN 2017 and ELN 2022 risk stratification, relapse is NOT uncommon, especially in patients with concomitant FLT3 ITD mutations. We observed complete remissions with single agent ziftomenib, even with concomitant FLT3 or IDH mutations. I believe single agent ziftomenib will provide an attractive option for older patients, not eligible for intensive therapy, with NPM1 mutated AML. We have observed durable mutations in some of our phase I patients treated with the single agent. The true benefit of this agent may not be seen until we complete combination studies with intensive chemotherapy, less intensive chemotherapy and other inhibitors. The study of these combinations will launch in the near future. Ultimately, I believe we will incorporate ziftomenib and other menin inhibitors in first line therapy for NPM1-mutated AML," Harry Erba, MD, PhD, leukemia program director at Duke Cancer Institute in North Carolina and chair of the SWOG Leukemia Committee, told Targeted OncologyTM.

REFERENCES:
Kura oncology announces first patients dosed in phase 2 registration-directed trial of ziftomenib in NPM1-mutant acute myeloid leukemia. News release. Kura Oncology. February 9, 2023. Accessed February 9, 2023. https://yhoo.it/3JVKaE9
First in human study of ziftomenib in relapsed or refractory acute myeloid leukemia. ClinicalTrials.gov. Updated February 9, 2023. Accessed February 9, 2023. https://www.clinicaltrials.gov/ct2/show/NCT04067336
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