8075 Background: mTOR inhibition may overcome PI3K/AKT pathway mediated resistance to anti-EGFR therapy. We performed a phase I study to determine the dose-limiting toxicity (DLT) of ridaforolimus, an investigational oral mTOR inhibitor, in combination with the anti-EGFR antibody cetuximab. Methods: Patients with advanced NSCLC, colorectal cancer, and head and neck cancer that progressed after at least 1 prior regimen for metastatic disease were eligible. ECOG performance status 0-1. Patients with previously treated brain metastases that were stable for >3 months were eligible. Wild-type K-RAS was required in colon cancer. All patients received cetuximab 400 mg/m2 week 1 followed by 250 mg/m2 weekly. Three dose levels of ridaforolimus were planned: 20mg, 30mg, and 40mg daily, 5 days each week, on a 28-day cycle. Results: 12 patients were entered with NSCLC (n=7), colon cancer (n=4), and head and neck cancer (n=1). The median age was 58 (42-69). The median number of prior regimens for metastatic disease, by disease type, was NSCLC (n=3), colorectal (n=4), head & neck (n=4). Three patients completed the first dose level without DLT. Two of 3 patients at dose level 2 had dose-limiting mucositis. The first dose level was then expanded with six additional patients with NSCLC without any further dose-limiting toxicities. The recommended phase II dose of ridaforolimus is 20 mg daily, 5 days a week, in combination with cetuximab. Response and prolonged stable disease was demonstrated in NSCLC. Conclusions: The DLT of the combination of ridaforolimus and cetuximab is mucositis. The activity observed in heavily pretreated patients with NSCLC suggests that the combination of an mTOR inhibitor with an EGFR antibody merits further investigation in NSCLC. Clinical trial information: NCT01212627.
Phase I Study of Oral S-1 and Concurrent Radiotherapy in Patients with Head and Neck Cancer