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. 2025 Oct 17:100885.
doi: 10.1016/j.medj.2025.100885. Online ahead of print.

Safety, tolerability, and pharmacokinetics of lisaftoclax (APG-2575)-based therapy in patients with chronic lymphocytic leukemia: Phase 1b/2 study

Matthew S Davids  1 , Asher Chanan-Khan  2 , Sikander Ailawadhi  2 , Vladimir Ivanov  3 , Ganna Usenko  4 , Larysa Nogaieva  5 , Iryna Kryachock  6 , Ivan Muzhychuk  7 , Tetiana Perekhrestenko  8 , Olena Kyselova  9 , Alexander Myasnikov  10 , Les Lukavetskyy  11 , Olga Uspenskaya  12 , Paula Marlton  13 , Andrei Proydakov  14 , Elena Borisenkova  15 , Allison Winter  16 , Tanya Siddiqi  17 , Tamila Lysa  18 , Bulat Bakirov  19 , Nashat Gabrail  20 , Vinod Ganju  21 , Tatyana Konstantinova  22 , Olga Samoilova  23 , Olena Karpenko  9 , Iurii Osipov  3 , Boyd Mudenda  24 , Tommy Fu  25 , Zi Chen  26 , Zhiyan Liang  25 , Divya J Mekala  25 , Mingyu Li  25 , Laura Glass  25 , Mohammad Ahmad  25 , Asit De  25 , Vallari Shah  25 , Hengbang Wang  26 , Robert E Winkler  25 , Dajun Yang  27 , Yifan Zhai  28
Affiliations

Safety, tolerability, and pharmacokinetics of lisaftoclax (APG-2575)-based therapy in patients with chronic lymphocytic leukemia: Phase 1b/2 study

Matthew S Davids et al. Med. .

Abstract

Background: Despite recent chronic lymphocytic leukemia (CLL) treatment advances, resistance and intolerance are challenges. Lisaftoclax is a selective, small-molecule oral BCL-2 inhibitor.

Methods: Lisaftoclax was administered with initial daily dose ramp-up (5-7 days depending on the target dose), followed by daily dosing as monotherapy, plus six 28-day cycles of rituximab or continuous acalabrutinib (ClinicalTrials.gov: NCT04215809). The primary endpoints comprised safety/tolerability (phases 1b and 2) and efficacy (phase 2), while the pharmacokinetic profile was a secondary endpoint.

Findings: Of 176 patients, 154 (87.5%) had relapsed/refractory and 22 (12.5%) treatment-naive CLL. Five patients (2.8%) experienced tumor lysis syndrome (TLS) (2 clinical and 3 laboratory). Any-grade treatment-emergent adverse events (TEAEs) included neutropenia in 67 patients (38.1%), diarrhea or anemia in 51 (29.0%), and COVID-19 in 63 (35.8%). Grade ≥3 cytopenias occurred in 53 patients (30.1%) with neutropenia and 15 (8.5%) with thrombocytopenia. No treatment-related discontinuations or deaths occurred. The overall response rate (ORR) was 67.4% (29/43) with lisaftoclax monotherapy, 84.6% (33/39) with lisaftoclax-rituximab, and 97.7% (85/87) with lisaftoclax-acalabrutinib. In the lisaftoclax-acalabrutinib cohort, this included 22 patients who were treatment naive and 65 relapsed/refractory, among whom 14 patients had prior venetoclax exposure. In these patients, the ORR was 92.9% (13/14); 100% (8/8) of these patients were Bruton tyrosine kinase inhibitor (BTKi) naive, 83.3% (5/6) had prior BTKi exposure, and 64.3% (9/14) were venetoclax refractory. Rituximab or acalabrutinib did not alter the pharmacokinetic profile of lisaftoclax.

Conclusions: Daily ramp-up over 5-7 days (to 400 or 800 mg) with continuous treatment with lisaftoclax alone or plus rituximab or acalabrutinib was well tolerated and led to responses in patients with CLL without clinically significant pharmacokinetic interactions.

Funding: Ascentage Pharma Group Corp Ltd. (Hong Kong).

Keywords: B cell lymphoma 2; Bruton tyrosine kinase; Translation to patients; chronic lymphocytic leukemia; efficacy; pharmacokinetics; safety; small lymphocytic lymphoma.

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Conflict of interest statement

Declaration of interests M.S.D. has received research funding from Ascentage Pharma Group Inc., MEI Pharma, and Novartis and consulting fees from AbbVie, Ascentage Pharma Group Inc., AstraZeneca, BeiGene (now BeOne), Bristol-Meyers Squibb, Eli Lilly, Galapagos, Genentech, Genmab, Janssen, Merck, MEI Pharma, Nuvalent, and Schroedinger. A.C.-K. has received grant and other support from BeiGene, Ascentage Pharma Group Inc., and AbbVie and consulting fees from/or participated in board membership roles with Cellectar, Starton, and Ascentage Pharma Group Inc. S.A. has received consulting fees from GSK, Sanofi, BMS, Takeda, BeiGene, Pharmacyclics, Amgen, Janssen, Regeneron, Cellectar, and Pfizer and research funding to institution (as a clinical trial investigator) from GSK, BMS, Pharmacyclics, Amgen, Janssen, Cellectar, AbbVie, and Ascentage Pharma Group Inc. V.I. has participated as a principal investigator in clinical trials sponsored by AbbVie, Ascentage Pharma Group Inc., Astellas, MSD, Takeda, and Biocad; has participated in a Russian speaker bureau for Pfizer, Rosh, Novartis, and Biocad; and has received consulting fees from Biocad. G.U. has received consulting fees from AbbVie, Acerta, Ascentage Pharma Group Inc., AstraZeneca, Celgene, Il-Yang, Janssen, and Pfizer. P.M. has no research funding (Ascentage Pharma Group Inc. sponsored this trial); has participated as an advisory board speaker in the last 2 years for Astellas, Janssen, BeiGene, AstraZeneca, Otsuka, AbbVie, Menarini, and Pfizer. A.W. has received consulting fees from BeiGene, BTG Pharmaceuticals, AstraZeneca, and ADC Therapeutics. T.S. has received research funding from BMS; has participated in advisory boards for AstraZeneca, BMS, BeiGene, Celgene, AbbVie, and Gilead; and has participated in a speaker bureau for AstraZeneca. B.M., T.F., Z.C., Z.L., D.M., M.L., L.G., M.A., A.D., V.S., and H.W. are employed by Ascentage Pharma Group Inc. or Ascentage Pharma (Suzhou) Co., Ltd. and hold stock in Ascentage Pharma Group International. D.Y. is employed by Ascentage Pharma (Suzhou) Co., Ltd. and Ascentage Pharma Group Inc. and holds leadership positions in these companies and Ascentage Pharma Group International. Y.Z. is employed by Ascentage Pharma Group Inc. and Guangzhou Healthquest Pharma Co., Ltd. and holds leadership positions in these companies. Y.Z. and D.Y. hold stock in Ascentage Pharma Group International and are coinventors on two patent applications related to this study (US-11491167-B2, “Combination product of Bcl-2 inhibitor and chemotherapeutic agent and use thereof in the prevention and/or treatment of diseases” [granted], and WO2020024826A1, “Synergistic antitumor effect of bcl-2 inhibitor combined with rituximab and/or bendamustine or bcl-2 inhibitor combined with chop” [pending]).

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