A Phase 1 Study to Evaluate the Safety, Pharmacokinetics (PK) and Pharmacodynamics (PD) of Lisaftoclax (APG-2575), a Novel BCL-2 Inhibitor (BCL-2i), in Patients (pts) with Certain Relapsed or Refractory (R/R) Hematologic Malignancies (HMs)

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.3730-3730
• Main Authors: Sun, Mingyuan, Qi, Junyuan, Chen, Zi, Zhang, Hongli, Song, Yongping, Shen, Aizong, Liu, Huilan, Huang, Jianying, Zhou, Fuling, Jin, Jie, Lu, Ming, Ahmad, Mohammad, Men, Lichuang, Cen, Wan, Yang, Dajun, Wang, Jianxiang, Zhai, Yifan
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-152235

Background: Many B-cell malignancies evade apoptosis by overexpressing BCL-2 proteins. Studies of the BCL-2i venetoclax have demonstrated activity in certain HMs but show that venetoclax requires a slow dose ramp-up over several weeks to reduce the risk of tumor lysis syndrome (TLS), which may warrant frequent or intensive laboratory monitoring. Cases of severe neutropenia with venetoclax treatment have also been reported. Lisaftoclax is a novel, potent, selective BCL-2i that is active against HMs and offers a potential advantage of a daily clinical ramp-up (rather than weekly) to the target dose over a few days. Methods: This Chinese, multicenter, open-label, single-agent, phase 1 trial is evaluating the safety (including dose-limiting toxicity [DLT] and maximum tolerated dose [MTD]), efficacy, PK, and PD of lisaftoclax in adults with histologically confirmed diagnoses of R/R chronic lymphocytic leukemia (CLL) or non-Hodgkin's lymphoma. Eligibility criteria include an ECOG performance score of 0-1 (in dose escalation) or 0-2 (in dose expansion); life expectancy ≥ 3 months; and adequate bone marrow, renal, and liver function. Lisaftoclax was orally administered once daily in 4-week cycles across multiple dose cohorts. Results: As July 27, 2021, 31 pts had been enrolled and treated with lisaftoclax at doses ranging from 20 to 800 mg. Pts had a median (range) of 4 (1-14) prior lines of treatment and diagnoses of CLL/SLL (n = 9), mantle cell lymphoma (MCL; n = 6), marginal zone lymphoma (MZL; n = 3), follicular lymphoma (n = 8), diffuse large B-cell lymphoma (n = 2), lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (n = 1), angioimmunoblastic T-cell lymphoma (n = 1) or mycosis fungoides (MF; n = 1). DLT, MTD, and laboratory/clinical TLS have not been observed at doses up to 800 mg. The recommended phase 2 dose (RP2D) is 600 mg. Lisaftoclax was generally well tolerated. Treatment-related adverse events (TRAEs) were reported in 28 pts (87.5%), most of which were grade 1 to 2. Any grade TRAEs in > 10% of pts include thrombocytopenia (34.4%), neutropenia (21.9%), leukopenia (21.9%), anemia (28.1%), hyperuricemia (15.6%), hyperphosphatemia (12.5%), hypertriglyceridemia (12.5%), and diarrhea (15.6%). Grade 3-4 TRAEs were reported in 7 pts (21.9%), including thrombocytopenia (18.8%), neutropenia (12.5%), leukopenia (9.4%), and anemia (6.3%). Serious TRAEs occurred in 1 pt and included anemia and thrombocytopenia (in 3.1% each). With a median (range) treatmen