Matthew S Davids, Asher Chanan-Khan, Sikander Ailawadhi, Vladimir Ivanov, Ganna Usenko, Larysa Nogaieva, Iryna Kryachock, Ivan Muzhychuk, Tetiana Perekhrestenko, Olena Kyselova, Alexander Myasnikov, Les Lukavetskyy, Olga Uspenskaya, Paula Marlton, Andrei Proydakov, Elena Borisenkova, Allison Winter, Tanya Siddiqi, Tamila Lysa, Bulat Bakirov, Nashat Gabrail, Vinod Ganju, Tatyana Konstantinova, Olga Samoilova, Olena Karpenko, Iurii Osipov, Boyd Mudenda, Tommy Fu, Zi Chen, Zhiyan Liang, Divya J Mekala, Mingyu Li, Laura Glass, Mohammad Ahmad, Asit De, Vallari Shah, Hengbang Wang, Robert E Winkler, Dajun Yang, Yifan Zhai
{"title":"基于lisaftoclax （APG-2575）治疗慢性淋巴细胞白血病患者的安全性、耐受性和药代动力学：1b/2期研究","authors":"Matthew S Davids, Asher Chanan-Khan, Sikander Ailawadhi, Vladimir Ivanov, Ganna Usenko, Larysa Nogaieva, Iryna Kryachock, Ivan Muzhychuk, Tetiana Perekhrestenko, Olena Kyselova, Alexander Myasnikov, Les Lukavetskyy, Olga Uspenskaya, Paula Marlton, Andrei Proydakov, Elena Borisenkova, Allison Winter, Tanya Siddiqi, Tamila Lysa, Bulat Bakirov, Nashat Gabrail, Vinod Ganju, Tatyana Konstantinova, Olga Samoilova, Olena Karpenko, Iurii Osipov, Boyd Mudenda, Tommy Fu, Zi Chen, Zhiyan Liang, Divya J Mekala, Mingyu Li, Laura Glass, Mohammad Ahmad, Asit De, Vallari Shah, Hengbang Wang, Robert E Winkler, Dajun Yang, Yifan Zhai","doi":"10.1016/j.medj.2025.100885","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Despite recent chronic lymphocytic leukemia (CLL) treatment advances, resistance and intolerance are challenges. Lisaftoclax is a selective, small-molecule oral BCL-2 inhibitor.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Funding: </strong>Ascentage Pharma Group Corp Ltd. (Hong Kong).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100885"},"PeriodicalIF":11.8000,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Safety, tolerability, and pharmacokinetics of lisaftoclax (APG-2575)-based therapy in patients with chronic lymphocytic leukemia: Phase 1b/2 study.\",\"authors\":\"Matthew S Davids, Asher Chanan-Khan, Sikander Ailawadhi, Vladimir Ivanov, Ganna Usenko, Larysa Nogaieva, Iryna Kryachock, Ivan Muzhychuk, Tetiana Perekhrestenko, Olena Kyselova, Alexander Myasnikov, Les Lukavetskyy, Olga Uspenskaya, Paula Marlton, Andrei Proydakov, Elena Borisenkova, Allison Winter, Tanya Siddiqi, Tamila Lysa, Bulat Bakirov, Nashat Gabrail, Vinod Ganju, Tatyana Konstantinova, Olga Samoilova, Olena Karpenko, Iurii Osipov, Boyd Mudenda, Tommy Fu, Zi Chen, Zhiyan Liang, Divya J Mekala, Mingyu Li, Laura Glass, Mohammad Ahmad, Asit De, Vallari Shah, Hengbang Wang, Robert E Winkler, Dajun Yang, Yifan Zhai\",\"doi\":\"10.1016/j.medj.2025.100885\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Despite recent chronic lymphocytic leukemia (CLL) treatment advances, resistance and intolerance are challenges. Lisaftoclax is a selective, small-molecule oral BCL-2 inhibitor.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>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. 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Safety, tolerability, and pharmacokinetics of lisaftoclax (APG-2575)-based therapy in patients with chronic lymphocytic leukemia: Phase 1b/2 study.
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).
期刊介绍：
Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically.
Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.
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