Novel BCL-2 Inhibitor Lisaftoclax in Relapsed or Refractory Chronic Lymphocytic Leukemia and Other Hematologic Malignancies: First-in-Human Open-Label Trial
Mené sur 52 patients atteints d'une leucémie lymphoïde chronique récidivante ou réfractaire ou d'un autre cancer hématologique, cet essai de phase I détermine la dose maximale tolérée du lisaftoclax (un inhibiteur sélectif de BCL-2) et analyse ses caractéristiques pharmacodynamiques et pharmacocinétiques
Résumé en anglais
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.
