Abstract
e15115 Background: The PI3K/AKT/mTOR pathway is frequently dysregulated in colorectal cancer (Cancer Res 2005;65:11227). In a phase I study in patients with advanced solid tumors, everolimus an oral mTOR inhibitor demonstrated clinical benefit including a partial response in pts with colorectal cancer (J Clin Oncol 2008;26:1603–10; J Clin Oncol 2008; 26:1588–95). Methods: This open-label, multicenter phase I study uses a Bayesian logistic model to identify feasible doses of everolimus + irinotecan + cetuximab. Adult pts with mCRC progressing despite prior 5-FU/oxaliplatin (FOLFOX) or capecitabine/oxaliplatin (XELOX) plus bevacizumab (if standard practice) were treated using a sequential dose escalation scheme (Table). Dose decisions were driven by the probability of dose-limiting toxicity (DLT) in the first 2 cycles. Dose level decisions were based on maximizing the probability that end-of-cycle-2 DLT rate would be within the targeted toxicity interval (20% to <35%) and minimizing the risk of over-dosing (< 5% risk of unacceptable toxicity and < 25% risk of excessive/unacceptable toxicity). Results: 18 pts were treated from April ‘07 to August ‘08, 5 pts at dose level A1 and 13 pts at dose level B1. Two DLTs (G3 rash on cycle 2 day 1 lasting > 7 days and G3 mucositis on cycle 1 day 14 lasting > 7 days, 1 pt each) were reported in 4 evaluable pts at dose level A1. No DLTs were reported in 7 evaluable patients at dose level B1. Conclusions: At dose level B1 everolimus in combination with irinotecan and cetuximab was generally well tolerated. The study was stopped due to changes in clinical practice based on emerging data indicating that cetuximab has limited efficacy in mCRC patients with KRAS mutations and that efficacy data favors daily RAD001 over weekly dosing. Patients in this study were treated with cetuximab irrespective of KRAS status. [Table: see text] [Table: see text]
Published Version
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