Novel BCL-2 Inhibitor Lisaftoclax in Relapsed or Refractory Chronic Lymphocytic Leukemia and Other Hematologic Malignancies: First-in-Human Open-Label Trial.

Autor:	Ailawadhi S; Division of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida., Chen Z; Ascentage Pharma (Suzhou) Co, Ltd, Suzhou, Jiangsu, China., Huang B; Ascentage Pharma (Suzhou) Co, Ltd, Suzhou, Jiangsu, China., Paulus A; Division of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida.; Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida., Collins MC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Fu LT; Ascentage Pharma Group Inc, Rockville, Maryland., Li M; Ascentage Pharma Group Inc, Rockville, Maryland., Ahmad M; Ascentage Pharma Group Inc, Rockville, Maryland., Men L; Ascentage Pharma (Suzhou) Co, Ltd, Suzhou, Jiangsu, China., Wang H; Ascentage Pharma (Suzhou) Co, Ltd, Suzhou, Jiangsu, China., Davids MS; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Liang E; Ascentage Pharma Group Inc, Rockville, Maryland., Mekala DJ; Ascentage Pharma Group Inc, Rockville, Maryland., He Z; Ascentage Pharma Pty Ltd, Sydney, Australia., Lasica M; Department of Hematology, St Vincent's Hospital Melbourne, Victoria, Australia., Yannakou CK; Epworth Healthcare, Freemasons Hospital and University of Melbourne, Victoria, Australia., Parrondo R; Division of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida., Glass L; Ascentage Pharma Group Inc, Rockville, Maryland., Yang D; Ascentage Pharma (Suzhou) Co, Ltd, Suzhou, Jiangsu, China.; Ascentage Pharma Group Inc, Rockville, Maryland.; Sun-Yat-sen University Cancer Center, Guangzhou, Guangdong, China., Chanan-Khan A; Division of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida.; Mayo Clinic Cancer Center, Jacksonville, Florida., Zhai Y; Ascentage Pharma (Suzhou) Co, Ltd, Suzhou, Jiangsu, China.; Ascentage Pharma Group Inc, Rockville, Maryland.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2023 Jul 05; Vol. 29 (13), pp. 2385-2393.
DOI:	10.1158/1078-0432.CCR-22-3321
Abstrakt:	Purpose: This global phase I trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective B-cell lymphoma 2 (BCL-2) inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL) and other hematologic malignancies (HMs). Patients and Methods: Maximum tolerated dose (MTD) and recommended phase II dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored. Results: Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%), fatigue (34.6%), nausea (30.8%), anemia and thrombocytopenia (28.8% each), neutropenia (26.9%), constipation (25.0%), vomiting (23.1%), headache (21.2%), peripheral edema and hypokalemia (17.3% each), and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%), thrombocytopenia (13.5%), and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6-43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response rate of 63.6% and median time to response of 2 (range, 2-8) cycles. Conclusions: Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose ramp-up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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