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首页> 美国卫生研究院文献>Neuro-Oncology >AT-12PHASE 1/2 STUDY OF TH-302 INVESTIGATIONAL HYPOXIA-ACTIVATED PRODRUG AND BEVACIZUMAB IN PATIENTS WITH BEVACIZUMAB-REFRACTORY RECURRENT GLIOBLASTOMA
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AT-12PHASE 1/2 STUDY OF TH-302 INVESTIGATIONAL HYPOXIA-ACTIVATED PRODRUG AND BEVACIZUMAB IN PATIENTS WITH BEVACIZUMAB-REFRACTORY RECURRENT GLIOBLASTOMA

机译：耐贝伐单抗递归性胶质母细胞瘤患者TH-302研究性低氧激活的药物和贝伐单抗的AT-12PHASE 1/2研究

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BACKGROUND: Hypoxia is implicated in the pathogenesis of glioblastoma multiforme (GBM), and greater hypoxic burden is associated with poorer outcomes in GBM. Treatment with bevacizumab (BEV) may increase intratumoral hypoxia. An ongoing phase 1/2 study () investigates safety and activity of TH-302, an investigational hypoxia-activated prodrug, combined with BEV in patients with BEV-refractory GBM. METHODS: Single center, dose-escalation, prospective study with 2:1 randomization to TH-302 single dose of 575 mg/m2 or placebo administered pre-surgery (cohorts 1-3 only), followed by post-surgery combination therapy of BEV at 10 mg/kg and TH-302 dose escalated 240-670 mg/m2 every 2 weeks (4-week cycle) until disease progression. Following the first 5 patients in cohort 3, patients were allowed to proceed directly to TH-302/BEV combination therapy without surgery. RESULTS: Twenty three patients have been enrolled: 14 randomized in presurgery cohorts 1-3 with 9 proceeding to TH-302/BEV after surgery and 9 additional patients proceeding directly to TH-302/BEV. No grade 4 adverse events (AEs) were observed. Three grade 3 AEs in 3 patients were observed: skin ulceration at 340 mg/m2, thrombocytopenia at 670 mg/m2, and oral mucositis at 670 mg/m2. Primary TH-302-related toxicities were mucosal, but not dose limiting: rectal mucositis in 1/4 patients at 480 mg/m2 and 6/8 patients at 670 mg/m2 (all grade 1 or 2). Oral mucositis was limited. Best tumor responses in 18 evaluable patients: 1 complete response, 3 partial responses, and 9 stable disease. Median progression-free survival (PFS) was 3.1 mos (95% CI: 2.0 to 4.0 mos) and 4-month PFS was 26% (95% CI: 4% to 47%). CONCLUSIONS: The recommended phase 2 dose of TH-302 is 670 mg/m2 when combined with BEV. These preliminary data suggest potential activity of TH-302/BEV in GBM patients with poor prognosis. Dose expansion at 670 mg/m2 of TH-302 is ongoing.
机译：背景：缺氧与多形性胶质母细胞瘤（GBM）的发病机理有关，缺氧负荷增加与GBM的不良预后相关。贝伐单抗（BEV）治疗可能会增加肿瘤内缺氧。正在进行的1/2期研究（）研究了低氧激活的前药TH-302联合BEV在BEV难治性GBM患者中的安全性和活性。方法：单中心，剂量递增，前瞻性研究，对TH-302单剂量575 mg / m 2 或安慰剂在手术前（仅针对队列1-3）进行2：1随机分组，然后进行术后BEV 10 mg / kg和TH-302剂量的联合治疗每2周（4周周期）将240-670 mg / m 2 升高至疾病进展。在第3组中的前5名患者之后，患者无需手术即可直接进行TH-302 / BEV联合治疗。结果：23名患者入组：术前队列1-3中有14例随机分组，其中9例在手术后进行TH-302 / BEV，另外9例直接进行TH-302 / BEV。没有观察到4级不良事件（AE）。在3例患者中观察到3种3级AE：皮肤溃疡为340 mg / m 2 ，血小板减少症为670 mg / m 2 和口腔粘膜炎为670 mg / m < sup> 2 。与TH-302相关的主要毒性为粘膜毒性，但无剂量限制：直肠粘膜炎的1/4患者480 mg / m 2 和6/8患者的670 mg / m 2 < / sup>（所有1级或2级）。口腔粘膜炎有限。 18位可评估患者的最佳肿瘤反应：1例完全缓解，3例部分缓解和9例稳定疾病。中位无进展生存期（PFS）为3.1 mos（95％CI：2.0至4.0 mos），而4个月PFS为26％（95％CI：4％至47％）。结论：与BEV联合使用时，TH-302的第2阶段推荐剂量为670 mg / m 2 。这些初步数据表明，TH-302 / BEV在预后不良的GBM患者中具有潜在的活性。正在进行TH-302的670 mg / m 2 剂量扩展。

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