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

描述(由申请人提供)： 胶质母细胞瘤是成人最常见、最具侵袭性的原发恶性脑肿瘤。每年约有1.3万例GBM确诊，历史1年和5年生存率分别为34.6%和4.75%。虽然配合替莫唑胺的放化疗仍然是最初治疗的标准治疗，但所有患者最终都需要抢救治疗，而针对血管内皮生长因子(VEGF)途径的血管生成抑制剂在这种情况下是标准的。这项申请提出了一项前瞻性、开放标签的2期研究，将TH-302以670 mg/m2的剂量与贝伐单抗联合应用于33例胶质母细胞瘤患者。贝伐单抗的剂量为10毫克/公斤，这是既定的治疗标准。TH-302是一种细胞毒素溴异磷酰胺芥末(BR-IPM)的硝基咪唑前药。当暴露在低氧条件下时，TH-302通过细胞内还原酶在前药的硝基咪唑位置被还原，导致BR-IPM的释放。然后，BR-IPM可以作为DNA交联剂。研究人员报道，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，但在低氧条件下具有高度的细胞毒性。患者将接受磁共振成像(MRI)检查，直到病情进展。主要终点将是中位无进展生存期(PFS)，次要终点是总体生存率(OS)和安全性。生存的重要性将通过与历史对照比较的对数等级分析来评估。这项研究的具体目的是：1)确定TH-302对接受贝伐单抗治疗的胶质母细胞瘤患者的疗效；2)表征接受TH-302治疗的患者的缺氧量、脑血流量和氧摄取分数(OEF)；3)将贝伐单抗新生耐药、获得性耐药和肿瘤缺氧等已知分子标志物的变化与肿瘤反应、进展时间和患者生存相关联。

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.