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Phase 1b Dose Escalation Study of Erlotinib in Combination with Infusional 5-Fluorouracil, Leucovorin, and Oxaliplatin in Patients with Advanced Solid Tumors

Axel-R. Hanauske¹, Jim Cassidy², Javier Sastre³, Claus Bolling¹, Robert J. Jones², Ashok Rakhit⁴, Scott Fettner⁴, Ulrich Brennscheidt^5,, Andrea Feyereislova⁵ and Eduardo Díaz-Rubio³

Authors' Affiliations: ¹ Asklepios Hospital St. Georg, Hamburg, Germany; ² Beatson Oncology Centre, Glasgow, United Kingdom; ³ San Carlos Hospital, Madrid, Spain; ⁴ F. Hoffmann-La Roche, Nutley, New Jersey; and ⁵ F. Hoffmann-La Roche Ltd., Basel, Switzerland

Requests for reprints: Axel-R. Hanauske, Department of Medicine, Asklepios Hospital St. Georg, D-20099 Hamburg, Germany. Phone: 49-40-18-18-85-2281; Fax: 49-40-18-18-85-2137; E-mail: hanauske.ind-synergen{at}t-online.de.

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/m² oxaliplatin, 200 mg/m² leucovorin, 400 mg/m² bolus 5-FU, and 400 mg/m² continuous infusion 5-FU; cohort 2: oxaliplatin increased to 85 mg/m² and 5-FU infusion increased to 600 mg/m²; 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/m² oxaliplatin; 200 mg/m² leucovorin, 400 mg/m² bolus 5-FU, and 600 mg/m² 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.