ABSTRACT

Treatment of glioblastoma xenografts with chloroquine results in macroautophagy/autophagy inhibition, resulting in a reduction of tumor hypoxia and sensitization to radiation. Preclinical data show that EGFRvIII-expressing glioblastoma may benefit most from chloroquine because of autophagy dependency. This study is the first to explore the safety, pharmacokinetics and maximum tolerated dose of chloroquine in combination with radiotherapy and concurrent daily temozolomide in patients with a newly diagnosed glioblastoma. This study is a single-center, open-label, dose-finding phase I trial. Patients received oral chloroquine daily starting one week before the course of chemoradiation (temozolomide 75 mg/m²/d) until the end of radiotherapy (59.4 Gy/33 fractions). Thirteen patients were included in the study (n = 6: 200 mg, n = 3: 300 mg, n = 4: 400 mg chloroquine). A total of 44 adverse events, possibly related to chloroquine, were registered including electrocardiogram QTc prolongation, irreversible blurred vision and nausea/vomiting resulting in cessation of temozolomide or delay of adjuvant cycles. The maximum tolerated dose was 200 mg chloroquine. Median overall survival was 16 months (range 2–32). Median survival was 11.5 months for EGFRvIII- patients and 20 months for EGFRvIII+ patients. A daily dose of 200 mg chloroquine was determined to be the maximum tolerated dose when combined with radiotherapy and concurrent temozolomide for newly diagnosed glioblastoma. Favorable toxicity and promising overall survival support further clinical studies.

Abbreviations: AE: adverse events; CQ: chloroquine; DLT: dose-limiting toxicities; EGFR: epidermal growth factor receptor; GBM: glioblastoma; HCQ: hydroxychloroquine; IDH1/2: isocitrate dehydrogenase (NADP(+)) 1/2; MTD: maximum tolerated dose; CTC: National Cancer Institute Common Toxicity Criteria; MGMT: O-6-methylguanine-DNA methyltransferase; OS: overall survival; po qd: per os quaque die; SAE: serious adverse events; TMZ: temozolomide; WHO: World Health Organization

摘要

用氯喹治疗胶质母细胞瘤异种移植物会导致巨自噬/自噬抑制，从而减少肿瘤缺氧和对辐射的敏感性。临床前数据表明，由于自噬依赖性，表达EGFRvIII的胶质母细胞瘤可能从氯喹中获益最多。本研究首次探讨了氯喹联合放疗和每日同时使用替莫唑胺治疗新诊断的胶质母细胞瘤患者的安全性、药代动力学和最大耐受剂量。本研究是一项单中心、开放标签、剂量探索的 I 期试验。患者在放化疗前一周开始每天口服氯喹（替莫唑胺 75 mg/m ²/d) 直到放疗结束（59.4 Gy/33 次）。该研究包括 13 名患者（n = 6：200 mg，n = 3：300 mg，n = 4：400 mg 氯喹）。共记录了 44 起可能与氯喹有关的不良事件，包括心电图 QTc 延长、不可逆的视力模糊和恶心/呕吐，导致替莫唑胺停止或辅助治疗周期延迟。最大耐受剂量为 200 mg 氯喹。中位总生存期为 16 个月（范围 2-32）。EGFRvIII患者的中位生存期为 11.5 个月，EGFRvIII患者的中位生存期为 20 个月+ 患者。当与放射治疗和并发替莫唑胺联合用于新诊断的胶质母细胞瘤时，每日 200 mg 氯喹的剂量被确定为最大耐受剂量。有利的毒性和有希望的总生存期支持进一步的临床研究。

缩写： AE：不良事件；CQ：氯喹；DLT：剂量限制性毒性；EGFR：表皮生长因子受体；GBM：胶质母细胞瘤；HCQ：羟氯喹；IDH1/2：异柠檬酸脱氢酶(NADP(+)) 1/2；MTD：最大耐受​​剂量；CTC：国家癌症研究所常见毒性标准；MGMT：O-6-甲基鸟嘌呤-DNA甲基转移酶；OS：总生存期；po qd: per os quaque die; SAE：严重不良事件；TMZ：替莫唑胺；世界卫生组织：世界卫生组织