Clinical lymphoma, myeloma & leukemia · 2023
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.
Клиническое исследование II фазыКлиническое исследование I фазыСтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Patel Manish R, Donnellan William, Byrne Michael, Asch Adam S, Zeidan Amer M, Baer Maria R, Fathi Amir T, Kuykendall Andrew T, Zheng Fred, Walker Chris, Cheng Lulu, Marando Cindy, Savona Michael R
Аннотация
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.
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.