Department of Medicine, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero Street, Box 1700, San Francisco, CA 94143, USA.
Br J Cancer. 2013 Oct 1;109(7):1725-34. doi: 10.1038/bjc.2013.553. Epub 2013 Sep 10.
This phase 1 clinical trial was conducted to determine the safety, maximum-tolerated dose (MTD), and pharmacokinetics of imatinib, bevacizumab, and metronomic cyclophosphamide in patients with advanced colorectal cancer (CRC).
Patients with refractory stage IV CRC were treated with bevacizumab 5 mg kg(-1) i.v. every 2 weeks (fixed dose) plus oral cyclophosphamide q.d. and imatinib q.d. or b.i.d. in 28-day cycles with 3+3 dose escalation. Response was assessed every two cycles. Pharmacokinetics of imatinib and cyclophosphamide and circulating tumour, endothelial, and immune cell subsets were measured.
Thirty-five patients were enrolled. Maximum-tolerated doses were cyclophosphamide 50 mg q.d., imatinib 400 mg q.d., and bevacizumab 5 mg kg(-1) i.v. every 2 weeks. Dose-limiting toxicities (DLTs) included nausea/vomiting, neutropaenia, hyponatraemia, fistula, and haematuria. The DLT window required expansion to 42 days (1.5 cycles) to capture delayed toxicities. Imatinib exposure increased insignificantly after adding cyclophosphamide. Seven patients (20%) experienced stable disease for >6 months. Circulating tumour, endothelial, or immune cells were not associated with progression-free survival.
The combination of metronomic cyclophosphamide, imatinib, and bevacizumab is safe and tolerable without significant drug interactions. A subset of patients experienced prolonged stable disease independent of dose level.
本Ⅰ期临床试验旨在确定晚期结直肠癌（CRC）患者中伊马替尼、贝伐珠单抗和环磷酰胺节拍方案的安全性、最大耐受剂量（MTD）和药代动力学。
采用贝伐珠单抗 5mg/kg 静脉输注每 2 周 1 次（固定剂量）联合环磷酰胺 q.d.和伊马替尼 q.d.或 b.i.d.方案治疗难治性Ⅳ期 CRC 患者，28 天为 1 个周期，3+3 剂量递增。每 2 个周期评估 1 次疗效。检测伊马替尼和环磷酰胺的药代动力学以及循环肿瘤、内皮和免疫细胞亚群。
共入组 35 例患者。最大耐受剂量为环磷酰胺 50mg q.d.、伊马替尼 400mg q.d.和贝伐珠单抗 5mg/kg 静脉输注每 2 周 1 次。剂量限制性毒性（DLT）包括恶心/呕吐、中性粒细胞减少症、低钠血症、瘘管和血尿。需要将 DLT 窗口扩展至 42 天（1.5 个周期）以捕捉延迟毒性。联合环磷酰胺后伊马替尼的暴露量增加不显著。7 例（20%）患者疾病稳定>6 个月。循环肿瘤、内皮或免疫细胞与无进展生存期无关。
节拍方案中环磷酰胺、伊马替尼和贝伐珠单抗联合应用安全且耐受良好，无明显药物相互作用。部分患者在不依赖剂量水平的情况下出现延长的疾病稳定。
