FDA Clears IND Application for Ziftomenib in Advanced GI Stromal Tumors

Developers intend to launch a proof-of-concept study assessing ziftomenib/imatinib in patients with GISTs who experience disease progression after imatinib.

The FDA has cleared an investigational new drug (IND) application for ziftomenib as a therapy for patients with advanced gastrointestinal stromal tumors (GISTs), according to a press release from the developer, Kura Oncology, Inc.¹

Developers plan to launch a first-in-human phase 1 trial assessing the investigational menin inhibitor in combination with imatinib (Gleevec) for patients with GISTs in early 2025.

According to the press release, menin inhibitors have exhibited additive therapeutic activity with imatinib in GIST models with sensitivity to imatinib. Based on preclinical findings, administering ziftomenib with imatinib may resensitize patients to imatinib, thereby augmenting response duration. Developers intend to launch a proof-of-concept study assessing ziftomenib/imatinib in patients with GISTs who experience disease progression after imatinib.

“This important milestone represents the first IND clearance of a menin inhibitor to treat GIST, a solid tumor indication with limited treatment options for patients with advanced disease. Although imatinib is utilized in [patients with] frontline GIST, many eventually develop resistance,” Troy Wilson, PhD, JD, president and chief executive officer at Kura Oncology, stated in the press release.1 “We look forward to presenting the preclinical data for the combination at an upcoming scientific meeting and initiating a proof-of-concept clinical study early next year.”

The FDA previously granted breakthrough therapy designation to ziftomenib for patients with relapsed/refractory acute myeloid leukemia (AML) harboring NPM1 mutations in April 2024.² Supporting findings for the breakthrough therapy designation came from the phase 1/2 KOMET-001 trial (NCT04067336). Updated findings from the KOMET-001 trial were presented at the 2023 European Hematology Association Congress (EHA).³

Treatment with ziftomenib at 600 mg elicited a complete remission (CR) rate of 35% across 20 evaluable patients with NPM1-mutated AML. The composite CR rate was 40%, and the overall response rate (ORR) was 45%. Additionally, the median time to first response was 51 days, and treatment yielded a median duration of response (DOR) of 8.2 months (95% CI, 1.0-not evaluable [NE]).

At the time of the analysis, 95% of patients had treatment-emergent adverse effects (TEAEs), which included diarrhea (45%), hypokalemia (40%), and nausea (30%). No patients had treatment-related QTc prolongation. Investigators observed 1 instance of grade 3 differentiation syndrome, which they managed with a mitigation strategy. Data showed no other reports of grade 2 or lower differentiation syndrome.

“We are highly encouraged by FDA’s decision to grant breakthrough therapy designation to ziftomenib, recognizing its potential as an innovative medicine for patients with relapsed/refractory NPM1-mutant AML. NPM1-mutant AML represents approximately 30% of new AML cases annually, and this designation reflects that NPM1-mutant AML is a disease of significant unmet need for which there is no approved targeted therapy as well as the fact that ziftomenib offers potential to demonstrate substantial improvement over available therapies,” Wilson said in a press release at the time of the breakthrough therapy designation.²

In the ongoing, first-in-human, phase 1/2 KOMET-001 trial, investigators are administering ziftomenib at the recommended phase 2 dose of 600 mg once daily. The primary end point of the trial’s phase 2 registration-enabling portion is the CR or CR with partial hematological recovery rate (CRh). The trial’s secondary end points include the duration of CR/CRh, transfusion independence, CR/CRh measurable residual disease (MRD) negativity, and AEs.

Investigators also plan to evaluate ziftomenib as part of the phase 1 KOMET-007 trial (NCT05735184), which is open for enrollment. In this study, patients with newly diagnosed and relapsed/refractory NPM1-mutated or KMT2A-rearranged AML will receive ziftomenib in combination with intensive or non-intensive standard-of-care chemotherapy.

References

1. Kura Oncology announces FDA clearance of IND application for menin inhibitor ziftomenib in advanced gastrointestinal stromal tumors (GIST). News release. Kura Oncology, Inc. August 8, 2024. Accessed August 9, 2024. https://tinyurl.com/2vw6zwjc
2. Kura Oncology receives breakthrough therapy designation for ziftomenib in NPM1-mutant AML. News release. Kura Oncology, Inc. April 22, 2024. Accessed August 9, 2024. https://tinyurl.com/muzr3bye
3. Fathi AT, Wang ES, Issa GC, et al. Activity, tolerability, and resistance profile of the menin inhibitor ziftomenib in adults with relapsed or refractory NPM1-mutated AML. Presented at the 2023 European Hematology Association Congress; June 8-11, 2023; Frankfurt, Germany. Abstract LBA2713.