Corresponding author: Markus Hutterer, MD, Department of Neurology and Wilhelm-Sander NeuroOncology Unit, University of Regensburg Medical School, Franz Josef Strauß-Allee 11, D-93053 Regensburg, Germany.
Neuro Oncol. 2014 Jan;16(1):92-102. doi: 10.1093/neuonc/not161. Epub 2013 Dec 4.
Due to the redundancy of molecular pathways simultaneously involved in glioblastoma growth and angiogenesis, therapeutic approaches intervening at multiple levels seem particularly appealing.
This prospective, multicenter, single-arm phase II trial was designed to evaluate the antitumor activity of sunitinib, an oral small-molecule inhibitor of several receptor tyrosine kinases, in patients with first recurrence of primary glioblastoma using a continuous once-daily dosing regimen. Patients received a starting dose of sunitinib 37.5 mg, followed by a maintenance dose between 12.5 mg and 50 mg depending on drug tolerability. The primary endpoint was a 6-month progression-free survival (PFS) rate. Secondary endpoints included median PFS, overall survival (OS), safety/toxicity, quality of life, and translational studies on the expression of sunitinib target molecules.
Forty participants were included in this study, and no objective responses were detected. PFS6 was 12.5%, median PFS 2.2 months, and median OS 9.2 months. Five participants (12.5%) showed prolonged stable disease ≥6 months with a median PFS of 16.0 months (range, 6.4-41.4 mo) and a median OS of 46.9 months (range, 21.2-49.2 mo) for this subgroup. c-KIT expression in vascular endothelial cells (n = 14 participants) was associated with improved PFS. The most common toxicities were fatigue/asthenia, mucositis/dermatitis, dysesthesias, gastrointestinal symptoms, cognitive impairment, leukoctopenia, and thrombocytopenia. Two participants (5%) terminated treatment due to toxicity.
Continuous daily sunitinib showed minimal antiglioblastoma activity and substantial toxicity when given at higher doses. High endothelial c-KIT expression may define a subgroup of patients who will benefit from sunitinib treatment by achieving prolonged PFS. ClinicalTrials.gov Identifier: NCT00535379.
由于涉及胶质母细胞瘤生长和血管生成的分子途径存在冗余，因此干预多个水平的治疗方法似乎特别有吸引力。
这项前瞻性、多中心、单臂 II 期试验旨在评估舒尼替尼在原发性胶质母细胞瘤首次复发患者中的抗肿瘤活性，采用连续每日一次的给药方案。患者起始剂量为舒尼替尼 37.5mg，然后根据药物耐受性维持在 12.5mg 至 50mg 之间。主要终点是 6 个月无进展生存期（PFS）率。次要终点包括中位 PFS、总生存期（OS）、安全性/毒性、生活质量以及舒尼替尼靶分子表达的转化研究。
本研究纳入了 40 名参与者，未检测到客观反应。PFS6 为 12.5%，中位 PFS 为 2.2 个月，中位 OS 为 9.2 个月。5 名患者（12.5%）表现出延长的稳定疾病≥6 个月，中位 PFS 为 16.0 个月（范围为 6.4-41.4mo），中位 OS 为 46.9 个月（范围为 21.2-49.2mo）。血管内皮细胞中 c-KIT 的表达与改善的 PFS 相关。最常见的毒性包括疲劳/乏力、黏膜炎/皮炎、感觉异常、胃肠道症状、认知障碍、白细胞减少和血小板减少。两名患者（5%）因毒性而终止治疗。
当以较高剂量给药时，连续每日舒尼替尼表现出最小的抗胶质母细胞瘤活性和显著的毒性。高内皮 c-KIT 的表达可能定义了一个亚组患者，他们将通过实现延长的 PFS 从舒尼替尼治疗中获益。临床试验注册号：NCT00535379。
