Purpose: Erlotinib (Tarceva) is a potent epidermal growth factor receptor (HER1) inhibitor. Infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX) is a standard therapy for colorectal cancer. This trial assessed the maximum tolerated dose (MTD), safety, preliminary efficacy, and pharmacokinetics of erlotinib combined with FOLFOX. Experimental Design: Patients with advanced solid tumors were sequentially enrolled into three cohorts (cohort 1: 100 mg/d erlotinib, 65 mg/m 2

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... tin, 200 mg/m 2 leucovorin, 400 mg/m 2 bolus 5-FU, and 400 mg/m 2 continuous infusion 5-FU; cohort 2: oxaliplatin increased to 85 mg/m 2 and 5-FU infusion increased to 600 mg/m 2 ; and cohort 3: erlotinib increased to 150 mg/d). Results:Thirty-two patients were enrolled (23 with colorectal cancer): no dose-limiting toxicities (DLT) were observed in cohort 1. In cohort 2, two of nine patients experienced a DLT (both diarrhea). In cohort 3, two of nine patients had a DLT (diarrhea and staphylococcal septicemia). Cohort 3 determined the MTD cohort and expanded to 17 patients in total. The most common adverse events were diarrhea, nausea, stomatitis, and rash (primarily mild/moderate). No pharmacokinetics interactions were observed. One patient (colorectal cancer) had a complete response, seven patients had a partial response, and nine had stable disease. Conclusions: The MTD was defined as follows: 150 mg/d erlotinib, 85 mg/m 2 oxaliplatin; 200 mg/m 2 leucovorin, 400 mg/m 2 bolus 5-FU, and 600 mg/m 2 infusion 5-FU. At the MTD, the combination was well tolerated and showed antitumor activity, warranting further investigation in patients with advanced colorectal cancer and other solid tumors.