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

IF 11.8 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Med Pub Date : 2025-10-17 DOI:10.1016/j.medj.2025.100885

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

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引用次数: 0

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).

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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

背景：尽管近年来慢性淋巴细胞白血病（CLL）的治疗取得了进展，但耐药和不耐受是一个挑战。Lisaftoclax是一种选择性小分子口服BCL-2抑制剂。方法：Lisaftoclax以初始每日剂量递增（5-7天取决于目标剂量）给药，随后作为单药每日给药，加上6个28天周期的利妥昔单抗或连续阿卡拉布替尼（ClinicalTrials.gov: NCT04215809）。主要终点包括安全性/耐受性（1b期和2期）和有效性（2期），而药代动力学特征是次要终点。结果：176例患者中，154例（87.5%）为复发/难治性CLL， 22例（12.5%）为首次治疗CLL。5例（2.8%）出现肿瘤溶解综合征（TLS）（2例临床，3例实验室）。任何级别的治疗不良事件（teae）包括中性粒细胞减少症67例（38.1%），腹泻或贫血51例（29.0%），COVID-19 63例（35.8%）。中性粒细胞减少症患者53例（30.1%），血小板减少症患者15例（8.5%）发生≥3级细胞减少症。没有发生与治疗相关的中断或死亡。利沙托劳单药治疗的总有效率（ORR）为67.4%(29/43)，利沙托劳-利妥昔单抗治疗的总有效率为84.6%(33/39)，利沙托劳-阿卡拉布替尼治疗的总有效率为97.7%（85/87）。在lisaftoclax-acalabrutinib队列中，包括22名未接受治疗的患者和65名复发/难治性患者，其中14名患者先前有venetoclax暴露。这些患者的ORR为92.9% (13/14)；这些患者中100%（8/8）是布鲁顿酪氨酸激酶抑制剂（BTKi）新手，83.3%（5/6）有BTKi暴露史，64.3%（9/14）是venetoclax难治性患者。利妥昔单抗或阿卡鲁替尼没有改变利沙托克的药代动力学特征。结论：连续使用利沙托劳或联合利妥昔单抗或阿卡鲁替尼治疗，每天增加5-7天（至400或800 mg）耐受性良好，CLL患者无明显的临床药代动力学相互作用。资金来源：升腾医药集团有限公司（香港）。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Med MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

17.70

自引率

0.60%

发文量

102

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.