Abstract

Background

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.

Methods

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.

Results

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).

Conclusions

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.

中文翻译：

---

贝伐单抗联合或不联合伏立诺他治疗成人胶质母细胞瘤的贝叶斯适应性随机II期多中心试验

摘要

背景

贝伐单抗具有抗复发性胶质母细胞瘤（GBM）的活性。但是，获得对该药的耐药性会导致肿瘤复发。我们假设伏立诺他是一种具有抗血管生成作用的组蛋白脱乙酰基酶（HDAC）抑制剂，可预防对贝伐单抗的获得性耐药。

方法

这项多中心II期临床试验采用贝叶斯适应性设计，将复发性GBM的患者随机分为贝伐单抗或贝伐单抗加伏立诺他治疗，其主要终点为无进展生存期（PFS），次要终点为总体生存期（OS）和临床结局评估（MD） Anderson症状清单脑肿瘤模块[MDASI-BT]）。符合条件的患者为成年人（≥18岁），在事先接受放射治疗后经组织学确诊为GBM复发，器官功能良好，KPS≥60，并且既无贝伐单抗或HDAC抑制剂。

结果

入组90例患者（贝伐单抗+伏立诺他：49例，贝伐单抗：41例），其中74例可评估PFS（贝伐单抗+伏立诺他：44例，贝伐单抗：30例）。PFS中位数（3.7 vs 3.9 mo，P  = 0.94，危险比[HR] 0.63 [95％CI：0.38，1.06，P  = 0.08]），OS中位数（7.8 vs 9.3 mo，P  = 0.64，HR 0.93 [95％ CI：0.5、1.6，P  = 0.79] ，两组之间的临床获益相似。85名可评估患者的毒性（≥3级）包括高血压（n =  37），神经系统改变（n =  2），厌食症（n =  2），感染（n =  9），伤口裂开（n =  2），深静脉血栓形成/肺栓塞（n = 2）和结肠穿孔（n =  1）。

结论

与单独使用贝伐珠单抗相比，贝伐单抗联合伏立诺他治疗并没有改善PFS或OS或临床获益，也没有成人GBM复发患者的临床获益。该试验是首次在原发性脑肿瘤患者中通过自适应随机化和贝叶斯连续监测测试贝叶斯自适应设计，并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。