Kura Oncology has announced the dosing of first patients in KOMET-015, a Phase 1 clinical trial evaluating ziftomenib in combination with imatinib for patients with advanced gastrointestinal stromal tumors (GIST) who have experienced imatinib failure.
The open-label, dose-escalation trial will assess the safety, tolerability, and preliminary antitumor activity of the combination therapy in adults with documented disease progression while on or after treatment with imatinib. This marks the first clinical trial evaluating a menin inhibitor with standard-of-care treatments for GIST.
"Approximately 4,000 to 6,000 new cases of GIST are diagnosed each year in the U.S., and advanced GIST patients have limited treatment options," said Mollie Leoni, M.D., Chief Medical Officer of Kura Oncology. "Our preclinical data demonstrate the combination of ziftomenib and imatinib provides robust and durable antitumor activity in both imatinib-sensitive and imatinib-resistant GIST patient-derived xenograft models."
Novel Mechanism of Action Addresses Treatment Resistance
GIST represents the most common form of sarcoma, characterized as KIT-dependent solid tumors. While imatinib serves as the frontline standard of care, approximately 60% of patients develop resistance within two years due to acquired secondary KIT mutations.
The preclinical data suggests the combination of ziftomenib and imatinib works through a synthetic lethal mechanism. Ziftomenib epigenetically targets vulnerabilities in GIST tumors that are actively induced even by ineffective tyrosine kinase inhibitor (TKI) treatments. This approach could potentially delay or overcome resistance in these patients.
"Until now, most approaches to treating gastrointestinal stromal tumors rely on targeted KIT inhibition via tyrosine kinase inhibitors such as imatinib, however most patients eventually progress due to acquired secondary KIT mutations highlighting the need for new treatment options," explained Shreyaskumar Patel, M.D., Center Medical Director, Sarcoma Center, at The University of Texas MD Anderson Cancer Center.
Trial Design and Objectives
The KOMET-015 Phase 1a/1b trial will initially focus on dose escalation, followed by planned expansion cohorts to further assess safety, tolerability, and clinical activity. Primary objectives include safety evaluation and determination of the recommended Phase 2 dose.
Key secondary endpoints include:
- Clinical benefit
- Overall response rate (ORR)
- Progression-free survival (PFS)
- Duration of response
- Overall survival (OS)
"This study is an important step in developing new combination treatments to potentially improve outcomes for patients with advanced gastrointestinal stromal tumors, a disease indication for which new therapeutic options are needed," said Mrinal Gounder, M.D., Sarcoma Oncologist & Early Phase Drug Development Specialist at Memorial Sloan Kettering Cancer Center.
Building on Previous Success
Ziftomenib is a once-daily, oral investigational menin inhibitor that has already shown promising results in other indications. In April 2024, it received Breakthrough Therapy Designation from the FDA for the treatment of relapsed/refractory NPM1-mutant acute myeloid leukemia (AML).
The expansion into GIST represents Kura Oncology's commitment to exploring the full therapeutic potential of menin inhibitors across different cancer types. The company has already completed enrollment in a Phase 2 registration-directed trial of ziftomenib in R/R NPM1-m AML and has submitted a New Drug Application for this indication in the second quarter of 2025.
Current Treatment Landscape
While tyrosine kinase inhibitors like sunitinib target imatinib-resistant genotypes and are approved for later-line treatment, response rates and long-term outcomes remain modest. The KOMET-015 trial aims to address this significant unmet need by potentially transforming the treatment paradigm for GIST patients.
For patients interested in learning more about the KOMET-015 trial, information is available on www.clinicaltrials.gov under the identifier NCT06655246.
About Ziftomenib
Ziftomenib is a potent and selective oral menin inhibitor currently in development for the treatment of genetically defined AML and GIST patients with high unmet need. It is designed to be taken once daily and has shown promising results in previous clinical trials.
In November 2024, Kura entered into a global strategic collaboration agreement with Kyowa Kirin Co., Ltd. to develop and commercialize ziftomenib for AML and other hematologic malignancies, further validating the potential of this investigational therapy.
