Phase I study of gefitinib plus FOLFIRI in previously untreated patients with metastatic colorectal cancer.
BACKGROUND
In this study, the maximum tolerated dose and toxicity profile of FOLFIRI (infusional fluorouracil [5-FU]/leucovorin/irinotecan) plus gefitinib (an oral inhibitor of the epidermal growth factor receptor) were evaluated as first-line therapy in patients with metastatic colorectal cancer.


METHODS
Sixteen patients participated in this study. Oral gefitinib was administered at 250 mg or 500 mg daily in 2 dose-escalation cohorts. FOLFIRI was administered without dose escalation on a 14-day cycle with treatment on day 1 with irinotecan 180 mg/m2, leucovorin 200 mg/m2, and 5-FU 400 mg/m2 bolus, followed by 5-FU 2400 mg/m2 continuous infusion over 46 hours.


RESULTS
The maximum tolerated dose of gefitinib was 250 mg, with diarrhea and neutropenia noted as the principal dose-limiting toxicities. Dose reductions in 5-FU and irinotecan were required in 4 patients because of diarrhea and 1 patient because of neutropenia. A partial response was observed in 25% of patients, and 56% had stable disease for > 12 weeks, corresponding to a disease control rate of 81%.


CONCLUSIONS
These findings suggest that gefitinib can be safely combined with FOLFIRI as first-line treatment of metastatic CRC and support the safety of further investigations of EGFR tyrosine kinase inhibitors with multiagent chemotherapy in this patient population.
Wolpin
Brian M
BM
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Clark
Jeffrey W
JW
Meyerhardt
Jeffrey A
JA
Earle
Craig C
CC
Ryan
David P
DP
Enzinger
Peter C
PC
Zhu
Andrew X
AX
Blaszkowsky
Lawrence
L
Battu
Subha
S
Fuchs
Charles S
CS
D000230:Adenocarcinoma / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D066246:ErbB Receptors; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D000077156:Gefitinib; D006801:Humans; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D002955:Leucovorin; D000077156:Gefitinib; D005472:Fluorouracil; D002166:Camptothecin