Phase I trial of capecitabine plus everolimus (RAD001) in patients with previously treated metastatic gastric cancer
Everolimus is a novel inhibitor of the mammalian target of rapamycin pathway, which is aberrantly activated in cancer cell. We conducted a phase I study of capecitabine plus everolimus (RAD001) in refractory gastric cancer patients. Patients with metastatic gastric cancer and progression after prior chemotherapy were eligible. Four dose levels were planned as follows: Level 1, 5 mg bid/day of everolimus (D1-D21) and 500 mg/m2 bid/day of capecitabine (D1-14); Level 2, 5 mg bid/day of everolimus (D1-D21) and 750 mg/m2 bid/day of capecitabine (D1-14); Level 3, 5 mg bid/day of everolimus (D1-D21) and 1000 mg/m2 bid/day of capecitabine (D1-14); and Level 4, 10 mg bid/day of everolimus (D1-D21) and 1000 mg/m2 bid/day of capecitabine (D1-14). Treatment was repeated every 3 weeks until disease progression, patient refusal, or any serious adverse event. Fifteen patients were enrolled in this study between November 2009 and April 2010. Fifteen patients were enrolled (median age, 50 years; men, 9). Six patients had received two previous chemotherapy regimens; six patients had three previous chemotherapy regimens before the study treatment. Thus, the majority of patients were heavily pretreated. The dose-limiting toxicities were grade 3 infection, grade 3 mucositis, and grade 3 hyperglycemia and hyponatremia. After a median follow-up duration of 5.6 months (range, 2.3–8.1 months), median PFS was 1.8 months (95% CI, 0.8–2.8 months). The maximum best change observed was a 28.7% decrease in sum of longest diameters when compared with baseline. The combination of capecitabine and everolimus showed satisfactory toxicity profile and modest clinical benefit in patients with refractory gastric cancer. The recommended dose of capecitabine and everolimus was 650 mg/m2 twice daily and 5 mg twice daily, respectively.