Division of Neuro-Oncoology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
Neuro-Oncology Branch, National Institute of Health, Bethesda, Maryland.
Neuro Oncol. 2020 Oct 14;22(10):1505-1515. doi: 10.1093/neuonc/noaa062.
Bevacizumab has promising activity against recurrent glioblastoma (GBM). However, acquired resistance to this agent results in tumor recurrence. We hypothesized that vorinostat, a histone deacetylase (HDAC) inhibitor with anti-angiogenic effects, would prevent acquired resistance to bevacizumab.
This multicenter phase II trial used a Bayesian adaptive design to randomize patients with recurrent GBM to bevacizumab alone or bevacizumab plus vorinostat with the primary endpoint of progression-free survival (PFS) and secondary endpoints of overall survival (OS) and clinical outcomes assessment (MD Anderson Symptom Inventory Brain Tumor module [MDASI-BT]). Eligible patients were adults (≥18 y) with histologically confirmed GBM recurrent after prior radiation therapy, with adequate organ function, KPS ≥60, and no prior bevacizumab or HDAC inhibitors.
Ninety patients (bevacizumab + vorinostat: 49, bevacizumab: 41) were enrolled, of whom 74 were evaluable for PFS (bevacizumab + vorinostat: 44, bevacizumab: 30). Median PFS (3.7 vs 3.9 mo, P = 0.94, hazard ratio [HR] 0.63 [95% CI: 0.38, 1.06, P = 0.08]), median OS (7.8 vs 9.3 mo, P = 0.64, HR 0.93 [95% CI: 0.5, 1.6, P = 0.79]) and clinical benefit were similar between the 2 arms. Toxicity (grade ≥3) in 85 evaluable patients included hypertension (n = 37), neurological changes (n = 2), anorexia (n = 2), infections (n = 9), wound dehiscence (n = 2), deep vein thrombosis/pulmonary embolism (n = 2), and colonic perforation (n = 1).
Bevacizumab combined with vorinostat did not yield improvement in PFS or OS or clinical benefit compared with bevacizumab alone or a clinical benefit in adults with recurrent GBM. This trial is the first to test a Bayesian adaptive design with adaptive randomization and Bayesian continuous monitoring in patients with primary brain tumor and demonstrates the feasibility of using complex Bayesian adaptive design in a multicenter setting.
贝伐单抗对复发性胶质母细胞瘤（GBM）具有良好的活性。然而，该药物的获得性耐药会导致肿瘤复发。我们假设组蛋白去乙酰化酶（HDAC）抑制剂伏立诺他具有抗血管生成作用，可预防贝伐单抗的获得性耐药。
这项多中心 II 期试验采用贝叶斯自适应设计，将复发性 GBM 患者随机分为贝伐单抗单药组或贝伐单抗联合伏立诺他组，主要终点为无进展生存期（PFS），次要终点为总生存期（OS）和临床疗效评估（MD 安德森症状量表脑肿瘤模块[MDASI-BT]）。纳入标准为：年龄≥18 岁，经放疗后复发的组织学证实的 GBM，器官功能良好，KPS≥60，且无贝伐单抗或 HDAC 抑制剂治疗史。
共纳入 90 例患者（贝伐单抗联合伏立诺他组 49 例，贝伐单抗组 41 例），其中 74 例患者可评估 PFS（贝伐单抗联合伏立诺他组 44 例，贝伐单抗组 30 例）。PFS（3.7 个月 vs 3.9 个月，P=0.94，HR 0.63[95%CI：0.38，1.06，P=0.08]）、OS（7.8 个月 vs 9.3 个月，P=0.64，HR 0.93[95%CI：0.5，1.6，P=0.79]）和临床获益在两组间无显著差异。85 例可评估毒性（≥3 级）的患者中，发生高血压（n=37）、神经功能改变（n=2）、厌食（n=2）、感染（n=9）、伤口裂开（n=2）、深静脉血栓/肺栓塞（n=2）和结肠穿孔（n=1）。
与贝伐单抗单药治疗相比，贝伐单抗联合伏立诺他并未改善复发性 GBM 患者的 PFS、OS 或临床获益，也未能在成人复发性 GBM 患者中体现出临床获益。该试验首次采用贝叶斯自适应设计，对原发性脑肿瘤患者进行适应性随机分组和贝叶斯连续监测，证明了在多中心环境中使用复杂贝叶斯自适应设计的可行性。
