缺氧激活依氟鸟氨酸治疗复发性贝伐珠单抗耐药性胶质母细胞瘤：I 期手术研究。
Hypoxia-activated evofosfamide for treatment of recurrent bevacizumab-refractory glioblastoma: a phase I surgical study.
机构信息
University of Texas Health San Antonio Cancer Center, San Antonio, Texas.
University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas.
出版信息
Neuro Oncol. 2018 Aug 2;20(9):1231-1239. doi: 10.1093/neuonc/noy015.
BACKGROUND
Anti-angiogenic therapy is known to induce a greater degree of hypoxia, including in glioblastoma (GBM). Evofosfamide (Evo) is a hypoxia-activated prodrug which is reduced, leading to the release of the alkylating agent bromo-isophosphoramide mustard. We assessed the safety, tolerability, preliminary efficacy, and biomarkers of Evo plus bevacizumab (Bev) in Bev-refractory GBM.
METHODS
Twenty-eight patients with Bev-refractory GBM were enrolled in a dose escalation study receiving from 240 mg/m2 (cohort 1) to 670 mg/m2 (cohort 4) of Evo every 2 weeks in combination with Bev. Patients deemed surgical candidates underwent a single dose of Evo or placebo with pimonidazole immediately prior to surgery for biomarker evaluation, followed by dose escalation upon recovery. Assessments included adverse events, response, and survival.
RESULTS
Evo plus Bev was well tolerated up to and including the maximum dose of 670 mg/m2, which was determined to be the recommended phase II dose. Overall response rate was 17.4%, with disease control (complete response, partial response, and stable disease) observed in 14 (60.9%) of the 23 patients. The ratio of enhancement to non-enhancement was significant on log-rank analysis with time to progression (P = 0.023), with patients having a ratio of less than 0.37 showing a median progression-free survival of 98 days versus 56 days for those with more enhancement.
CONCLUSIONS
Evo plus Bev was well tolerated in patients with Bev-refractory GBM, with preliminary evidence of activity that merits further investigation.
背景
抗血管生成疗法会导致更严重的缺氧，包括在胶质母细胞瘤（GBM）中。依氟鸟氨酸（Evo）是一种缺氧激活的前药，会被还原，导致烷基化剂溴异磷酰胺 mustard 的释放。我们评估了 Evo 联合贝伐珠单抗（Bev）在 Bev 耐药性 GBM 中的安全性、耐受性、初步疗效和生物标志物。
方法
28 例 Bev 耐药性 GBM 患者入组了一项剂量递增研究，每 2 周接受 240 mg/m2（队列 1）至 670 mg/m2（队列 4）的 Evo 联合 Bev。认为有手术适应证的患者在手术前单次给予 Evo 或安慰剂联合 pimonidazole 进行生物标志物评估，然后在恢复后进行剂量递增。评估包括不良事件、反应和生存。
结果
Evo 联合 Bev 耐受良好，最高剂量可达 670 mg/m2，这被确定为推荐的 II 期剂量。总体缓解率为 17.4%，23 例患者中有 14 例（60.9%）观察到疾病控制（完全缓解、部分缓解和稳定疾病）。进展时间的对数秩分析显示增强与非增强的比值具有显著意义（P=0.023），比值小于 0.37 的患者中位无进展生存期为 98 天，而比值大于 0.37 的患者中位无进展生存期为 56 天。
结论
Evo 联合 Bev 在 Bev 耐药性 GBM 患者中耐受良好，初步证据表明有活性，值得进一步研究。
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