Phase 1/2 Study of the Pan-PIM Kinase Inhibitor INCB053914 Alone or in Combination With Standard-of-Care Agents in Patients With Advanced Hematologic Malignancies.

Autor: Patel MR; Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL. Electronic address: mpatel@flcancer.com., Donnellan W; Tennessee Oncology, PLLC, Chattanooga, TN., Byrne M; Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN., Asch AS; Stephenson Cancer Center, Oklahoma University, Oklahoma City, OK., Zeidan AM; Yale University and Yale Cancer Center, New Haven, CT., Baer MR; University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD., Fathi AT; Massachusetts General Hospital, Harvard Medical School, Boston, MA., Kuykendall AT; Moffitt Cancer Center, FL., Zheng F; Incyte Corporation, Wilmington, DE., Walker C; Incyte Corporation, Wilmington, DE., Cheng L; Incyte Corporation, Wilmington, DE., Marando C; Incyte Corporation, Wilmington, DE., Savona MR; Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN.
Jazyk: angličtina
Zdroj: Clinical lymphoma, myeloma & leukemia [Clin Lymphoma Myeloma Leuk] 2023 Sep; Vol. 23 (9), pp. 674-686. Date of Electronic Publication: 2023 May 15.
DOI: 10.1016/j.clml.2023.05.002
Abstrakt: Background: The Proviral Integration site of Moloney murine leukemia virus (PIM) kinases are implicated in tumorigenesis; the pan-PIM kinase inhibitor, INCB053914, demonstrated antitumor activity in hematologic malignancy preclinical models.
Patients and Methods: This phase 1/2 study evaluated oral INCB053914 alone or combined with standard-of-care agents for advanced hematologic malignancies (NCT02587598). In Parts 1/2 (monotherapy), patients (≥18 years) had acute leukemia, high-risk myelodysplastic syndrome (MDS), MDS/myeloproliferative neoplasm, myelofibrosis (MF), multiple myeloma, or lymphoproliferative neoplasms. In Parts 3/4 (combination therapy), patients had relapsed/refractory or newly diagnosed (≥65 years, unfit for intensive chemotherapy) acute myeloid leukemia (AML) or MF with suboptimal ruxolitinib response.
Results: Parts 1/2 (n = 58): 6 patients experienced dose-limiting toxicities (DLTs), most commonly aspartate aminotransferase/alanine aminotransferase-elevated (AST/ALT; each n = 4). Fifty-seven patients (98.3%) had treatment-emergent adverse events (TEAEs), most commonly ALT-elevated and fatigue (36.2% each); 48 (82.8%) had grade ≥3 TEAEs, most commonly anemia (31.0%); 8 (13.8%) had grade ≥3 ALT/AST-elevated TEAEs. Parts 3/4 (n = 39): for INCB053914 + cytarabine (AML; n = 6), 2 patients experienced DLTs (grade 3 maculopapular rash, n = 1; grade 3 ALT-elevated and grade 4 hypophosphatemia, n = 1); for INCB053914 + azacitidine (AML; n = 16), 1 patient experienced a DLT (grade 3 maculopapular rash). Two complete responses were observed (1 with incomplete count recovery). For INCB053914 + ruxolitinib (MF; n = 17), no DLTs occurred; 3 patients achieved best reduction of >25% spleen volume at week 12 or 24.
Conclusion: INCB053914 was generally well tolerated as monotherapy and in combinations; TEAEs were most commonly ALT/AST-elevated. Limited responses were observed with combinations. Future studies are needed to identify rational, effective combination strategies.
(Copyright © 2023. Published by Elsevier Inc.)
Databáze: MEDLINE
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