Phase 2 Study of TH-302 for the Treatment of Glioblastoma

TH-302 治疗胶质母细胞瘤的 2 期研究

• 批准号: 9108161
• 负责人: Andrew Jacob Brenner
• 金额: $ 39.94万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9108161
• 关键词: Phase; Study; TH; 302; Treatment

DESCRIPTION (provided by applicant): Glioblastoma is the most common and most aggressive of the primary malignant brain tumors in adults. Annually there are approximately 13,000 cases of GBM diagnosed, with historical 1 year and 5 year survival rates of 34.6% and 4.75% respectively. While concomitant chemoradiotherapy with temozolomide remains the standard of care for initial treatment, all patients eventually require salvage therapy and angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) pathway are standard in this setting. This application proposes a prospective, open-label, phase 2 study combining TH-302 at 670mg/m2 given every 2 weeks with bevacizumab in 33 patients with glioblastoma. Bevacizumab will be administered at 10mg/kg as established standard of care. TH-302 is a nitroimidazole prodrug of the cytotoxin, bromo-isophosphoramide mustard (Br-IPM). When exposed to hypoxic conditions, TH-302 is reduced at the nitroimadazole site of the prodrug by intracellular reductases leading to the release of Br-IPM. Br-IPM can then act as a DNA crosslinking agent. The investigators report that in vitro cytotoxicity and clonogenic assays indicate that TH-302 has little activity under normoxic conditions but is highly cytotoxic under hypoxic conditions. Patients will be followed by magnetic resonance imaging (MRI) until disease progression. The primary endpoint will be median progression free survival (PFS), with secondary end points of overall survival (OS) and safety. Significance in survival will be assessed by log-rank analysis with comparison to historical controls. The specific aims of the study are to: 1) establish the efficacy of TH-302 in glioblastoma patients progressing on bevacizumab, 2) characterize hypoxic volume, cerebral blood flow, and oxygen extraction fraction (OEF) in patients undergoing treatment with TH-302, and 3) correlate changes in known molecular markers of bevacizumab de novo resistance, acquired resistance, and tumor hypoxia with tumor response, time to progression, and patient survival.

描述（由申请人提供）： 胶质母细胞瘤是成人中最常见和最具侵袭性的原发性恶性脑肿瘤。每年约有13，000例GBM确诊病例，历史1年和5年生存率分别为34.6%和4.75%。虽然伴随替莫唑胺的放化疗仍然是初始治疗的标准治疗，但所有患者最终都需要挽救治疗，靶向血管内皮生长因子（VEGF）通路的血管生成抑制剂是这种情况下的标准治疗。本申请提出了一项前瞻性、开放标签、2期研究，在33例胶质母细胞瘤患者中联合使用TH-302 670 mg/m2，每2周一次与贝伐单抗。贝伐珠单抗将以10 mg/kg的剂量给药，作为既定的标准治疗。TH-302是细胞毒素溴代异磷酰胺芥（Br-IPM）的硝基咪唑前药。当暴露于缺氧条件时，TH-302在前药的硝基咪唑位点被细胞内还原酶还原，导致Br-IPM的释放。Br-IPM可以作为DNA交联剂。研究人员报告说，体外细胞毒性和克隆形成试验表明，TH-302在常氧条件下几乎没有活性，但在缺氧条件下具有高度细胞毒性。患者将接受磁共振成像（MRI）随访，直至疾病进展。主要终点为中位无进展生存期（PFS），次要终点为总生存期（OS）和安全性。将通过与历史对照比较的对数秩分析评估生存期的显著性。这项研究的具体目标是：1）确定TH-302在贝伐单抗治疗进展的胶质母细胞瘤患者中的功效，2）表征经历TH-302治疗的患者中的缺氧体积、脑血流量和氧提取分数（OEF），和3）将贝伐单抗从头抗性、获得性抗性和肿瘤缺氧的已知分子标志物的变化与肿瘤应答相关联，进展时间和患者存活率。