Gefitinib in combination with oxaliplatin and 5-fluorouracil in irinotecan-refractory patients with colorectal cancer: a phase I study of the Arbeits gemeinschaft Internistische Onkologie (AIO).
BACKGROUND
The aim of the study was to establish the recommended dose and to evaluate the safety of gefitinib plus FUFOX regimen in irinotecan-refractory colorectal carcinoma (CRC).


METHODS
Patients with advanced CRC progressing on fluoropyrimidine/irinotecan-based chemotherapy and with an ECOG performance level 0-2 were enrolled. Four dose levels with sequential dose escalation of oral gefitinib and FUFOX were tested. Each cycle consisted of 5 weeks with gefitinib given daily to weekly FUFOX x4 to be repeated at day 36.


RESULTS
Eighteen patients were enrolled. No dose-limiting toxicity (DLT) was observed at the dose levels L1-L3. At L4 diarrhea was the major DLT requiring treatment interruption in 3 patients. Other grade 3/4 toxicities were observed with skin rash, paresthesia, anemia, and nausea/vomiting (n = 1 each). Grade 1/2 toxicities consisted of diarrhea (n = 9), mucositis (8), skin rash (10), paresthesia (10), nausea (7) as well as leukopenia (2) and fever (1). Clinical benefit was seen in 11 of 16 evaluable patients (69%): 4 patients showed partial response (25%), 7 stable disease (44%). Median time to progression was 219 days (range 50-387 days).


CONCLUSIONS
Gefitinib at a dose of 250 mg daily in combination with weekly 5-fluorouracil at 2,000 mg/m(2) or gefitinib at a dose of 500 mg daily with 5-fluorouracil at 1,600 mg/m(2) plus oxaliplatin has an acceptable safety profile.
Hartmann
Jorg Thomas
JT
Abteilung Onkologie/Hämatologie/Immunologie/Rheumatologie/Pulmologie, Südwestdeutsches Tumorzentrum -Comprehensive Cancer Center Tübingen, Eberhard-Karls-Universität Tübingen, Germany. joerg.hartmann@med.uni-tuebingen.de
Pintoffl
Jan Peter
JP
Kröning
Hendrik
H
Bokemeyer
Carsten
C
Holtmann
Martin
M
Höhler
Thomas
T
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D000077156:Gefitinib; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008452:Maximum Allowable Concentration; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D011799:Quinazolines / Q000008:administration & dosage; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors; D016896:Treatment Outcome
D009944:Organoplatinum Compounds; D011799:Quinazolines; D000077150:Oxaliplatin; D000077146:Irinotecan; D002955:Leucovorin; D000077156:Gefitinib; D005472:Fluorouracil; D002166:Camptothecin