A phase 1 trial of imatinib, bevacizumab, and metronomic cyclophosphamide in advanced colorectal cancer

作者：Kelley R K; Hwang J; Magbanua M J M; Watt L; Beumer J H; Christner S M; Baruchel S; Wu B; Fong L; Yeh B M; Moore A P; Ko A H; Korn W M; Rajpal S; Park J W; Tempero M A; Venook A P; Bergsland E K^*

来源：British Journal of Cancer, 2013, 109(7): 1725-1734.

DOI：10.1038/bjc.2013.553

Background: 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).
Methods: Patients with refractory stage IV CRC were treated with bevacizumab 5mgkg(-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.
Results: Thirty-five patients were enrolled. Maximum-tolerated doses were cyclophosphamide 50mg q.d., imatinib 400mg q.d., and bevacizumab 5mg 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.
Conclusion: 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.

• 出版日期2013-10-1