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: 9316339
• 负责人: Andrew Jacob Brenner
• 金额: $ 40万
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316339
• 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）： 胶质母细胞瘤是成年人中最常见和最具侵略性的原发性恶性脑肿瘤。每年诊断出大约13,000例GBM病例，历史1年和5年生存率分别为34.6％和4.75％。虽然与替莫唑胺的伴随性化学疗法仍然是初始治疗的护理标准，但所有患者最终都需要打捞疗法和靶向血管内皮生长因子（VEGF）途径的血管生成抑制剂在这种情况下都是标准的。该申请提出了一项前瞻性开放标签的2阶段研究，将33例胶质母细胞瘤患者的Bevacizumab与贝伐单抗一起以670mg/m2的形式组合为670mg/m2。贝伐单抗将以10mg/kg的身份作为确定的护理标准管理。 TH-302是细胞毒素，Bromo-偶然磷酰胺芥末（BR-IPM）的硝基咪唑前药。当暴露于低氧条件时，通过细胞内还原酶降低了前药的氮咪唑位点，导致BR-IPM释放。然后，BR-IPM可以充当DNA交联剂。研究人员报告说，体外的细胞毒性和克隆生成试验表明，在常氧条件下TH-302的活性很小，但在低氧条件下具有高度的细胞毒性。患者将进行磁共振成像（MRI），直到疾病进展。主要终点将是中值无进展生存期（PFS），其总生存率（OS）和安全性的次要终点。与历史控制相比，将通过对数秩分析来评估生存的显着性。该研究的具体目的是：1）建立Th-302在贝伐单抗上进展的胶质母细胞瘤患者中的功效，2）2）表征低氧体积，脑血流量和氧气萃取分数（OEF）在患者中，在与TH-302治疗的患者中，与TH-302的治疗以及3）相关的分子抗药性和3）bevaculisabe bevaculabise tumox abbise tumox abbise tumox abbise bevaculab abb novoxizab abb novoox abb abk abk tumox abb。肿瘤反应，进展时间和患者存活。