Phase 1b dose escalation study of erlotinib in combination with infusional 5-Fluorouracil, leucovorin, and oxaliplatin in patients with advanced solid tumors.
OBJECTIVE
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.


METHODS
Patients with advanced solid tumors were sequentially enrolled into three cohorts (cohort 1: 100 mg/d erlotinib, 65 mg/m(2) oxaliplatin, 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.
Hanauske
Axel-R
AR
Department of Medicine, Asklepios Hospital St. Georg, D-20099 Hamburg, Germany. hanauske.ind-synergen@t-online.de
Cassidy
Jim
J
Sastre
Javier
J
Bolling
Claus
C
Jones
Robert J
RJ
Rakhit
Ashok
A
Fettner
Scott
S
Brennscheidt
Ulrich
U
Feyereislova
Andrea
A
Díaz-Rubio
Eduardo
E
D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D000069347:Erlotinib Hydrochloride; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D000077150:Oxaliplatin; D011799:Quinazolines / Q000008:administration & dosage*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D011799:Quinazolines; D000077150:Oxaliplatin; D000069347:Erlotinib Hydrochloride; D002955:Leucovorin; D005472:Fluorouracil