Phase I study of mFOLFOX-6, bevacizumab, and mTOR inhibitor RAD001 as first-line treatment of metastatic colorectal cancer

600 Background: This study was designed to determine the dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), and efficacy of the mTOR inhibitor RAD001 in combination with mFOLFOX-6 and bevacizumab in metastatic colorectal cancer. Methods: Twenty patients with previously untreated metastatic colorectal cancer received mFOLFOX-6, bevacizumab and RAD001 using a standard three patient cohort dose escalation schema. Seventeen of the twenty patients were evaluable with a median age of 52 (ten females and seven males). RAD001 was administered orally at escalating doses of 2.5 mg, 5 mg and 10 mg daily. mFOLFOX-6 and bevacizumab were administered in standard fashion. Results: The most common grade 3/4 hematological adverse events (AEs) were neutropenia (59%), leucopenia (29%) and thrombocytopenia (12%). The most common grade 3 non-hematological AEs were diarrhea (24%) and hypokalemia (18%). One dose-limiting toxicity was noted at 10 mg/day due to grade 3 anorexia, grade 3 diarrhea, and grade 3 hypokalemia. Grade 1 mucositis was noted in 12% of patients and grade 2 mucositis was noted in 47% of patients. There was no grade 3/4 mucositis. Fourteen patients are evaluable for efficacy. The RR is 86% including 2 CRs, 7 PRs, and 3 SDs. Conclusions: RAD001 in combination with mFOLFOX6 and bevacizumab is well-tolerated at a dose of 10 mg/day. The regimen appears to be effective. Evidence of anti-tumor activity correlated with mutation status (k-ras, BRAF, PIK3CA) and PTEN deletion status will be presented.