Data from Novel BCL-2 Inhibitor Lisaftoclax in Relapsed or Refractory Chronic Lymphocytic Leukemia and Other Hematologic Malignancies: First-in-Human Open-Label Trial
Year: 2024
Type: other
Abstract: Purpose: This global phase 1 trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective BCL-2 inhibitor, in patients with relapsed or refractory chronic or small lymphocytic leukemia (R/R CLL/SLL) and other hematologic malignancies (HMs). Patients and Methods: Maximum tolerated dose (MTD) and recommended phase 2 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 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.
Authors: Sikander Ailawadhi, Zi Chen, Bo Huang, Aneel Paulus, Mary C. Collins, Lei (Tommy). Fu, Mingyu Li, Mohammad Ahmad, Lichuang Men, Hengbang Wang, Matthew S. Davids, Eric Liang, Divya J. Mekala, Zhicong He, Masa Lasica, Costas K. Yannakou, Ricardo Parrondo, Laura Glass, Dajun Yang, Asher Chanan-Khan, Yifan Zhai
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4402817970