新型微管抑制剂 Lisavanbulin (BAL101553) 加放射治疗新诊断的 MGMT 启动子未甲基化胶质母细胞瘤患者。

IF 3.7 Q1 CLINICAL NEUROLOGY Neuro-oncology advances Pub Date : 2024-08-28 eCollection Date: 2024-01-01 DOI:10.1093/noajnl/vdae150
Matthias Holdhoff, Xiaobu Ye, Roy E Strowd, Burt Nabors, Tobias Walbert, Frank S Lieberman, Stephen J Bagley, John B Fiveash, Joy D Fisher, Serena Desideri, Trisha Surakus, Marc Engelhardt, Thomas Kaindl, Heidi A Lane, Karine Litherland, Stuart A Grossman, Lawrence R Kleinberg
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引用次数: 0

摘要

背景:利沙万bulin(BAL101553)是一种小型、亲脂性、口服微管破坏剂,在临床前胶质母细胞瘤(GBM)模型中具有良好的抗肿瘤活性:这项多中心 1 期研究旨在确定新诊断的 MGMT 启动子未甲基化 GBM(uGBM)患者口服利沙班bulin 与标准 RT(60 Gy/30 分次)联合治疗的 MTD,但不包括替莫唑胺。剂量升级采用改良的 3 + 3 设计。次要目标包括估计OS和PFS以及药代动力学分析:26例uGBM患者(中位年龄63岁,42.3%为男性,61.5%为全切,中位Karnofsky表现状态80)入组;2例肿瘤有IDH1突变。利沙万球蛋白的预定剂量水平为4毫克(5例)、6毫克(5例)、8毫克(7例)、12毫克(5例)和15毫克(4例)。最初的起始剂量为 8 毫克。由于第一例患者出现 4 级无菌性脑膜脑炎,剂量降至 4 毫克。剂量继续增加并持续到 15 毫克,在 12 毫克时观察到 2 级精神错乱和记忆障碍的剂量限制毒性。随着利沙万bulin口服剂量从4毫克增加到15毫克,阿凡布林暴露量以相对剂量比例的方式增加:利沙万bulin与RT联用被认为在最高预定口服剂量水平(每天15毫克)以下是安全的。
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Lisavanbulin (BAL101553), a novel microtubule inhibitor, plus radiation in patients with newly diagnosed, MGMT promoter unmethylated glioblastoma.

Background: Lisavanbulin (BAL101553) is a small, lipophilic, oral microtubule destabilizer with promising antitumoral activity observed in preclinical glioblastoma (GBM) models.

Methods: 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.

Results: 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.

Conclusions: Lisavanbulin in combination with RT was considered safe up to the highest predefined oral dose level of 15 mg daily.

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