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

  • Clin Cancer Res. 2023 Jul 5;29(13):2385-2393. doi: 10.1158/1078-0432.CCR-22-3321.
Sikander Ailawadhi  1 ,  Zi Chen  #  2 ,  Bo Huang  2 ,  Aneel Paulus  1  3 ,  Mary C Collins  4 ,  Lei Tommy Fu  5 ,  Mingyu Li  5 ,  Mohammad Ahmad  5 ,  Lichuang Men  2 ,  Hengbang Wang  2 ,  Matthew S Davids  4 ,  Eric Liang  5 ,  Divya J Mekala  5 ,  Zhicong He  6 ,  Masa Lasica  7 ,  Costas K Yannakou  8 ,  Ricardo Parrondo  1 ,  Laura Glass  5 ,  Dajun Yang  2  5  9 ,  Asher Chanan-Khan  #  1  10 ,  Yifan Zhai  2  5
Affiliations
  • 1. Division of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida.
  • 2. Ascentage Pharma (Suzhou) Co, Ltd, Suzhou, Jiangsu, China.
  • 3. Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida.
  • 4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 5. Ascentage Pharma Group Inc, Rockville, Maryland.
  • 6. Ascentage Pharma Pty Ltd, Sydney, Australia.
  • 7. Department of Hematology, St Vincent's Hospital Melbourne, Victoria, Australia.
  • 8. Epworth Healthcare, Freemasons Hospital and University of Melbourne, Victoria, Australia.
  • 9. Sun-Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
  • 10. Mayo Clinic Cancer Center, Jacksonville, Florida.
  • # Contributed equally.
PMID: 37074726 DOI: 10.1158/1078-0432.CCR-22-3321
Abstract

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.

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