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
{"title":"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。","authors":"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","doi":"10.1093/noajnl/vdae150","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Lisavanbulin (BAL101553) is a small, lipophilic, oral microtubule destabilizer with promising antitumoral activity observed in preclinical glioblastoma (GBM) models.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>Lisavanbulin in combination with RT was considered safe up to the highest predefined oral dose level of 15 mg daily.</p>","PeriodicalId":94157,"journal":{"name":"Neuro-oncology advances","volume":null,"pages":null},"PeriodicalIF":3.7000,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450402/pdf/","citationCount":"0","resultStr":"{\"title\":\"Lisavanbulin (BAL101553), a novel microtubule inhibitor, plus radiation in patients with newly diagnosed, MGMT promoter unmethylated glioblastoma.\",\"authors\":\"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\",\"doi\":\"10.1093/noajnl/vdae150\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Lisavanbulin (BAL101553) is a small, lipophilic, oral microtubule destabilizer with promising antitumoral activity observed in preclinical glioblastoma (GBM) models.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>Lisavanbulin in combination with RT was considered safe up to the highest predefined oral dose level of 15 mg daily.</p>\",\"PeriodicalId\":94157,\"journal\":{\"name\":\"Neuro-oncology advances\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2024-08-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450402/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neuro-oncology advances\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1093/noajnl/vdae150\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuro-oncology advances","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/noajnl/vdae150","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
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.