Metronomic capecitabine (cape) and cyclophosphamide (CTX) for refractory metastatic colorectal cancer (mCRC): Results of a phase II trial.

Abstract

e14577 Background: The protracted exposure to low doses of cytotoxics according to metronomic schedules reported encouraging results in the treatment of different malignancies. In a recent trial from our group, the association of a single standard dose of CTX followed by metronomic UFT and CTX with celecoxib showed a very favourable safety profile and promising activity in a cohort of heavily pre-treated patients (pts) with gastrointestinal tumors (Allegrini, 2012). The aim of the present trial was to prospectively evaluate the activity of metronomic cape and CTX in a population of refractory mCRC pts. Methods: Pts with documented diagnosis of CRC, progressed during or within 3 mos from the last administration of standard therapies, were eligible. They received cape 800 mg PO bid and CTX 50 mg PO once daily. Treatment was administered continuously until disease progression. Primary endpoint was 2 mos-progression free rate (2m-PFR). Hypothesizing a 2m-PFR of 10% for refractory mCRC pts with no therapeutic options, metronomic cape plus CTX would have been judged promising for an estimated increase from 10 to 35% in 2m-PFR. According to the Fleming single-stage design, setting α and β errors 0.05 and 0.10, 25 evaluable pts were required. The null hypothesis would have been rejected if at least 6 pts were progression free at 2 mos. Results: Between June 2011 and June 2012, 26 pts were enrolled. Main characteristics were: M/F 19/7; median age: 71 yrs; single/multiple sites of metastases: 2/24, KRAS wt/mut: 18/8, BRAFwt/mut 25/1. 16 (62%) pts had received at least 3 previous lines of chemotherapy. Five pts were progression free at 2 mos, for a 2m-PFR of 19%. At a median follow up of 14.4 mos, median PFS and OS were 2.1 and 6.0 mos. No chemo-related G3/4 adverse events were reported. Conclusions: Metronomic cape and CTX demonstrated low clinical activity in heavily pretreated mCRC. Ongoing pharmacokinetic and dynamic analyses might provide additional data to interpret results and further insights into the antiangiogenic properties of this metronomic combination. Clinical effects of metronomic cape and CTX are under investigation in earlier settings and in association with other antiangiogenic agents.