Holdhoff Matthias, Ye Xiaobu, Strowd Roy E, Nabors Burt, Walbert Tobias, Lieberman Frank S, Bagley Stephen J, Fiveash John B, Fisher Joy D, Desideri Serena, Surakus Trisha, Engelhardt Marc, Kaindl Thomas, Lane Heidi A, Litherland Karine, Grossman Stuart A, Kleinberg Lawrence R
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Neurooncol Adv. 2024 Aug 28;6(1):vdae150. doi: 10.1093/noajnl/vdae150. eCollection 2024 Jan-Dec.
Lisavanbulin (BAL101553) is a small, lipophilic, oral microtubule destabilizer with promising antitumoral activity observed in preclinical glioblastoma (GBM) models.
This multicenter phase 1 study sought to determine the MTD of oral Lisavanbulin in combination with standard RT (60 Gy/30 fractions) but without temozolomide in patients with newly diagnosed MGMT promoter unmethylated GBM (uGBM). Dose escalation followed a modified 3 + 3 design. Secondary objectives included estimation of OS and PFS and pharmacokinetic analysis.
Twenty-six patients with uGBM (median age, 63 years, 42.3% male, 61.5% with gross total resection, median Karnofsky performance status 80) were enrolled; 2 tumors had an IDH1 mutation. Predefined dose levels of Lisavanbulin, administered daily concomitantly with RT, were: 4 mg (5 pts), 6 mg (5 pts), 8 mg (7 pts), 12 mg (5 pts), and 15 mg (4 pts). The initial starting dose was 8 mg. Due to grade 4 aseptic meningoencephalitis in the first patient, the dose was decreased to 4 mg. Dose escalation resumed and continued to 15 mg with dose-limiting toxicities of grade 2 confusion and memory impairment observed at 12 mg. Avanbulin exposures increased in a relatively dose-proportional manner with increasing oral dose of Lisavanbulin from 4 to 15 mg.
Lisavanbulin in combination with RT was considered safe up to the highest predefined oral dose level of 15 mg daily.
利沙万布林（BAL101553）是一种小分子亲脂性口服微管解聚剂，在临床前胶质母细胞瘤（GBM）模型中显示出有前景的抗肿瘤活性。
这项多中心1期研究旨在确定口服利沙万布林联合标准放疗（60 Gy/30次分割）但不联合替莫唑胺，用于新诊断的O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）启动子未甲基化胶质母细胞瘤（uGBM）患者的最大耐受剂量（MTD）。剂量递增遵循改良的3+3设计。次要目标包括总生存期（OS）和无进展生存期（PFS）的评估以及药代动力学分析。
纳入了26例uGBM患者（中位年龄63岁，42.3%为男性，61.5%为肉眼全切，中位卡氏评分80）；2例肿瘤存在异柠檬酸脱氢酶1（IDH1）突变。利沙万布林的预定义剂量水平为每日与放疗同时给药，分别为：4 mg（5例）、6 mg（5例）、8 mg（7例）、12 mg（5例）和15 mg（4例）。初始起始剂量为8 mg。由于首例患者出现4级无菌性脑膜脑炎，剂量降至4 mg。剂量递增恢复并持续至15 mg，在12 mg时观察到2级意识模糊和记忆障碍等剂量限制性毒性。随着利沙万布林口服剂量从4 mg增加到15 mg，阿万布林的暴露量以相对剂量成正比的方式增加。
利沙万布林联合放疗在每日最高预定义口服剂量水平15 mg时被认为安全。
