Phase I/Randomized Phase II Study of Second Line Therapy With Irinotecan + Cetuximab +/- RAD001 for Colorectal Cancer

The addition of RAD001, an mTOR inhibitor, to irinotecan and anti-EGFR antibody cetuximab may increase efficacy for patients with metastatic colorectal cancer who progressed on prior chemotherapy. This approach is biologically directed to overall target the cancer cell at multiple levels, and potentially preventing chemotherapy and EGFR-therapy resistance.

OUTLINE: This is a multi-center study. PHASE I: * UGT1A1 \*28 7/7 genotype IS NOT present * Cetuximab 250 mg/m2 IV days 1, 8, and 15 * Irinotecan 125 mg/m2 IV days 1 and 8 * RAD001 PO QD (dose determined at the time of registration; subjects will remain at this dose level until treatment discontinuation) PHASE II: * Randomization based on UGT1A1 \*28 7/7 Genotype or Prior Irinotecan Exposure ARM A: * Cetuximab 250 mg/m2 IV days 1, 8, and 15 * Irinotecan 125 mg/m2 IV days 1 and 8 AT TIME OF PROGRESSIVE DISEASE, ARM A TREATMENT WILL CROSSOVER: * Cetuximab 250 mg/m2 IV days 1, 8, and 15 * Irinotecan 125 mg/m2 IV days 1 and 8 * RAD001 PO QD (maximum tolerated dose) ARM B: * Cetuximab 250 mg/m2 IV days 1, 8, and 15 * Irinotecan 125 mg/m2 IV days 1 and 8 * RAD001 PO QD (maximum tolerated dose) AT TIME OF PROGRESSIVE DISEASE, ARM B TREATMENT WILL BE DISCONTINUED ECOG performance status 0-2 Life Expectancy: Not specified Hematopoietic: * Absolute neutrophil count (ANC) ≥ 1,500 mm3 * Platelets ≥ 100,000 mm3 * Hemoglobin (Hgb) ≥ 9 g/dL * White blood cell count (WBC) ≥ 2,000 mm3 * INR \< 1.5 x upper limit of normal (ULN) if not on anticoagulation (if on anticoagulation must have an in-range INR (usually between 2 and 3) on a stable dose of warfarin) * PTT \< 1.5 x ULN Hepatic: * Bilirubin ≤ 1.5 x ULN * Aspartate aminotransferase (AST, SGOT) ≤ 2.5 x ULN * Alanine aminotransferase (ALT, SGPT) ≤ 2.5 x ULN * Albumin ≥ 3.0 g/dL Renal: * Calculated creatinine clearance of ≥ 60 cc/min using the Cockcroft-Gault formula Cardiovascular: * No uncontrolled cardiac arrhythmia requiring medication, transient ischemic attack (TIA), or cerebrovascular accident (CVA) within 6 months prior to being registered for protocol therapy * No uncontrolled congestive heart failure, myocardial infarction, or unstable angina within 6 months prior to being registered for protocol therapy Pulmonary: * No severely impaired lung function as demonstrated by pulse O2 saturation ≤ 90% at rest on room air, or pulmonary function test FEV1 ≤ 2L * No history of prior chronic lung infection such as tuberculosis, atypical tuberculosis, or histoplasmosis as evidenced by a chest CT or x-ray within 21 days prior to being registered for protocol therapy