Phase II study of weekly low-dose everolimus plus weekly 24-hour infusions of cisplatin and high-dose 5-fluorouracil and leucovorin for first-line treatment in patients with advanced gastric cancers.

Abstract

86 Background: Cisplatin-HDFL, consisting of weekly 24-hour infusions of cisplatin and high-dose 5-fluorouracil (5-FU) and leucovorin (LV), is an effective and low-toxicity regimen for patients with advanced gastric cancer (GC) in Taiwan (J Clin Oncol. 1994;12(4):875; J Clin Oncol. 2006;24(18S):A14063). Everolimus (RAD001), a derivative of rapamycin, is an orally bioavailable mTOR inhibitor. We have demonstrated that low-dose everolimus (0.5-5.0 nM) sensitizes cytotoxic effects of cisplatin and 5-FU in GC cells (Proc Am Assoc Cancer Res. 2007;48:A4043). Methods: Patients who had pathologically confirmed chemonaive advanced GC, at least 1 measurable lesion, a fasting serum triglyceride level > 70 mg/dl, ECOG PS 0-2, and adequate organ functions were treated with everolimus 10 mg po on days 1, 8, and 15 concurrently with the initiation of chemotherapy; cisplatin 35 mg/m2 iv 24h infusion on days 1 and 8; 5-FU 2,000 mg/m2 and LV 300 mg/m2 (HDFL) iv 24h infusion on days 1, 8, and 15, in a every 28-day cycle. Response assessment was performed every 2 cycles. The primary endpoint was confirmed objective response rate (RR) by RECIST. Results: Between March 2008 and July 2010, 24 patients (M:11, F:13) with a median age of 53 (range: 33-69) were evaluable for response. The overall RR was 50% (95% CI: 29-71%) with 12 partial responders. Among a total of 162 cycles (median: 7, range: 1-13) given, grade (Gr) 3/4 toxicities included neutropenia (4.3%), infection (2.5%), nausea (3.1%) and vomiting (3.1%). Gr 1/2 nausea, vomiting, stomatitis, and diarrhea developed in 19.2%, 15.4%, 14.8%, and 5.5% of cycles, respectively. Skin rash and hand-foot syndrome were mild. One patient developed reversible HDFL-related hyperammonemic encephalopathy. Median progression-free survival was 8.4 months (range: 1.3-15.4+) and median overall survival was 14.8 months (range: 4.0-21.6+). Conclusions: Weekly low-dose everolimus plus weekly cisplatin-HDFL is an effective first-line regimen for patients with advanced GC. Addition of weekly low-dose everolimus to infusional cisplatin-HDFL did not add gastrointestinal toxicities. No significant financial relationships to disclose.