First Patient Dosed in Trial of Ziftomenib for Advanced GIST

The first patient has been dosed in a phase 1 trial investigating ziftomenib plus Gleevec (imatinib) in advanced gastrointestinal stromal tumors (GIST) following progression with Gleevec, according to a news release from Kura Oncology.

In addition, the company announced that the combination has shown robust and durable antitumor activity in Gleevec-sensitive and Gleevec-resistant GIST in preclinical models.

“Building on compelling clinical activity of ziftomenib in patients with NPM1-mutant and KMT2A-rearranged [acute myeloid leukemia], we are committed to evaluating the full therapeutic potential of menin inhibitors for the treatment of cancer,” Dr. Mollie Leoni, chief medical officer of Kura Oncology, said in the news release.

She continued, “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. Our preclinical data demonstrate the combination of ziftomenib and [Gleevec] provides robust and durable antitumor activity in both Gleevec-sensitive (1L) and [Gleevec]-resistant (2L/3L) GIST patient-derived xenograft models, and we look forward to seeing whether the combination offers potential to transform the treatment paradigm.”

In preclinical studies, data show the combination has antitumor activity via a synthetic lethal mechanism, as ziftomenib epigenetically targets a GIST tumor weakness caused by ineffective tyrosine kinase inhibitors. Sixty percent of patients develop resistance to Gleevec, the frontline standard of care for GIST, within two years, and ziftomenib may help delay or overcome that resistance.

The phase 1a/1b, open-label, dose-escalation KOMET-015 trial is evaluating the safety, tolerability and early antitumor activity of ziftomenib plus Gleevec in adults with GIST whose disease progressed during or after Gleevec treatment. After the dose-escalation portion, expansion cohorts will assess safety, tolerability and clinical activity. Primary objectives include evaluating safety and tolerability and identifying the recommended phase 2 dose. Secondary end points include clinical benefit, overall response rate, progression-free survival, duration of response and overall survival.

“This study is an important step in developing new combination treatments to potentially improve outcomes for patients with advanced GIST, a disease indication for which new therapeutic options are needed,” Dr. Mrinal Gounder, sarcoma oncologist & early phase drug development specialist at Memorial Sloan Kettering Cancer Center, said in the news release. “KOMET-015 builds upon the promising preclinical data observed with ziftomenib in combination with Gleevec in GIST models and we look forward to evaluating the investigational drug candidate and its potential to transform the treatment landscape.”

Currently, no other clinical trials are studying a menin inhibitor combined with standard treatments for GIST.

Ziftomenib, an investigational oral menin inhibitor taken once daily, is in development for genetically defined acute myeloid leukemia and gastrointestinal stromal tumor. In April 2024, the Food and Drug Administration granted breakthrough therapy designation to ziftomenib for the treatment of relapsed or refractory NPM1-mutant acute myeloid leukemia, based on findings from Kura Oncology’s KOMET-001 trial.

“Until now, most approaches to treating GIST rely on targeted KIT inhibition via tyrosine kinase inhibitors such as Gleevec, however most patients eventually progress due to acquired secondary KIT mutations highlighting the need for new treatment options,” Dr. Shreyaskumar Patel, center medical director, Sarcoma Center, at The University of Texas MD Anderson Cancer Center, said in the news release. “We are highly encouraged by the substantial preclinical data generated to date supporting the combination for ziftomenib in combination with KIT inhibitors in advanced GIST, and the dosing of the first patients marks an important milestone to address the meaningful unmet need for these patients.”

For more information regarding the KOMET-015 trial, please visit www.clinicaltrials.gov using the identifier: NCT06655246.

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