Phase I trial of capecitabine plus everolimus (RAD001) in patients with previously treated metastatic gastric cancer

Purpose: 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. Methods: 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. Results: 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. Conclusions: 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.