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A phase 1 study of the irreversible FLT3 inhibitor FF-10101 in relapsed or refractory acute myeloid leukemia

Year: 2024
Type: article
Study design: Clinical Trial
Abstract: ABSTRACT: FLT3 tyrosine kinase inhibitors (TKIs) have clinical efficacy for patients with FLT3-mutated AML (acute myeloid leukemia), but their impact is limited by resistance in the setting of monotherapy and by tolerability problems when used in combination therapies. FF-10101 is a novel compound that covalently binds to a cysteine residue near the active site of FLT3, irreversibly inhibiting receptor signaling. It is effective against most FLT3 activating mutations, and, unlike other inhibitors, is minimally vulnerable to resistance induced by FLT3 ligand. We conducted a phase 1 dose escalation study of oral FF-10101 in patients with relapsed and/or refractory AML, the majority of whom harbored FLT3-activating mutations and/or had prior exposure to FLT3 inhibitors. Fifty-four participants enrolled in cohorts receiving doses ranging from 10 to 225 mg per day and 50 to 100 mg twice daily (BID). The dose limiting toxicities were diarrhea and QT prolongation. Among 40 response-evaluable participants, the composite complete response rate was 10%, and the overall response rate (including partial responses) was 12.5%, including patients who had progressed on gilteritinib. Overall, 56% of participants had prior exposure to FLT3 inhibitors. The recommended phase 2 dose was 75 mg BID. FF-10101 potentially represents a next-generation advance in the management of FLT3-mutated AML. This trial was registered at www.ClinicalTrials.gov as #NCT03194685.
DOI: 10.1182/bloodadvances.2023010619
Authors: Mark Levis, Alexander Perl, Gary Schiller, Amir T. Fathi, Gail Roboz, Eunice S. Wang, Jessica Altman, Trivikram Rajkhowa, Makoto Ando, Takeaki Suzuki, Ruth Ann Subach, Gary Maier, Timothy Madden, Mary Johansen, Kin Cheung, Michael Kurman, Catherine Smith
Institutions: Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Abramson Cancer Center, University of Pennsylvania, University of California, Los Angeles, Harvard University, Massachusetts General Hospital, NewYork–Presbyterian Hospital, Weill Cornell Medicine, Weill Cornell Medical Center, Roswell Park Comprehensive Cancer Center, Northwestern University, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Fujifilm (Japan), Fujifilm (United States), University of California, San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center
Language: English
Subfield: Hematology
Field: Medicine
Open Access status: gold
Estimated APC paid: $3,000
Funders: Bristol-Myers Squibb, Pfizer, Celgene, Revolution Medicines, Astellas Pharma, Genentech, Japan Science and Technology Agency, FUJIFILM Pharmaceuticals U.S.A.
OpenAlex ID: W4392949219
FWCI: 6.403
Cites: 45
Cited by: 24
Related to: 10