Phase I/II dose-escalation study of pemetrexed plus irinotecan in patients with advanced colorectal cancer.
BACKGROUND
Pemetrexed and irinotecan have demonstrated antitumor activity as single agents in lung, pancreatic, breast, and colorectal cancer (CRC). The distinct mechanisms of action and patterns of resistance displayed by pemetrexed and irinotecan make them attractive agents for combination therapy.


METHODS
This phase I/II, nonrandomized, open-labeled, single-arm study was composed of 3 segments. The initial phase II portion of the study enrolled 23 patients with advanced CRC who had received 1 previous dose of 5-fluorouracil (5-FU)-based chemotherapy for advanced disease. Because of poorer than anticipated efficacy, a phase I dose-escalation study using vitamin supplementation (n = 12) was added to the original protocol. The phase II dose-escalation portion of the study enrolled 36 patients (64% with previous oxaliplatin-based therapy) who received pemetrexed 500 mg/m2 followed by irinotecan 300 mg/m2 on day 1, every 21 days.


RESULTS
For the 35 evaluable patients in the phase II dose-escalation study, the objective response rate was 11.4% (95% confidence interval, 3.2%-26.7%); there was 1 patient with a complete response, 3 with partial responses, and 17 with stable disease. Three of four responders had received previous oxaliplatin-based combination therapy. Grade 3/4 hematologic toxicities included leukopenia (5.6%), anemia (2.8%), and thrombocytopenia (2.8%). Grade 3/4 nonhematologic toxicities included diarrhea (11.1%), increased aminotransferase levels (8.3%), nausea (8.3%), febrile neutropenia (5.6%), vomiting (5.6%), and reduced creatinine clearance (2.8%).


CONCLUSIONS
Pemetrexed plus irinotecan appears to be at least as active as FOLFIRI (leucovorin/5-FU/irinotecan) for second-line therapy of CRC following 5-FU-based combination chemotherapy. Further studies are warranted.
Hochster
Howard
H
Cancer Institute, New York University Medical Center, 160 East 34th Street, 9th Floor, New York, NY 10016, USA. howard.hochster@nyumc.org
Kettner
Erika
E
Kroning
Hendrik
H
Becker
Klaus
K
Lordick
Florian
F
Ramanathan
Ramesh K
RK
Macdonald
John
J
Hong
Shengyan
S
John
William
W
Schmoll
Hans-Joachim
HJ
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000068437:Pemetrexed; D013997:Time Factors; D016896:Treatment Outcome; D014815:Vitamins / Q000627:therapeutic use
D005971:Glutamates; D014815:Vitamins; D000068437:Pemetrexed; D006147:Guanine; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin