Phase I clinical and pharmacokinetic study of oxaliplatin, irinotecan and capecitabine.
OBJECTIVE
To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of the combination of weekly oxaliplatin x 4, weekly irinotecan x 4 and capecitabine Monday through Friday for 4 weeks of every 6 week cycle in patients with solid tumors; to determine the pharmacokinetic profile of these agents in this combination; to observe patients for clinical anti-tumor response.


METHODS
Twenty-two patients with metastatic solid tumors received oxaliplatin 60 mg/m(2) weekly x 4, irinotecan beginning at a dose of 40 mg/m(2) weekly x 4, and capecitabine Monday through Friday for 4 weeks of every 6 week cycle, initially at 1,000 mg twice daily (bid).


RESULTS
The MTD was oxaliplatin 60 mg/m(2) weekly x 4, irinotecan 50 mg/m(2) weekly x 4 and capecitabine 450 mg bid Monday through Friday for 4 weeks of every 6 week cycle. One of six patients at this dose level developed DLT of nausea, vomiting, and diarrhea. Among patients treated with a constant capecitabine dose of 450 mg bid, there was a higher mean AUC of 5-FU in women than in men (mean +/- SD: 892 +/- 287 nM h vs. 537 +/- 182 nM h; Mann-Whitney two-tailed, P = 0.02). There was one complete response in a patient with gastric cancer.


CONCLUSIONS
The novel schedule of weekly oxaliplatin, weekly irinotecan, and capecitabine Monday through Friday, all administered for 4 weeks of every 6 week cycle, evaluated in this phase I trial is well-tolerated and demonstrated activity in a patient with gastric cancer.
Krishnamurthi
Smitha S
SS
Developmental Therapeutics Program, Case Comprehensive Cancer Center, Cleveland, OH, USA. ssk7@case.edu
Brell
Joanna M
JM
Hoppel
Charles L
CL
Egorin
Merrill J
MJ
Weaver
Karen C
KC
Li
Xiaolin
X
Ingalls
Stephen T
ST
Zuhowski
Eleanor G
EG
Schluchter
Mark D
MD
Dowlati
Afshin
A
Cooney
Matthew M
MM
Gibbons
Joseph
J
Overmoyer
Beth A
BA
Ivy
S Percy
SP
Remick
Scot C
SC
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin
D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069287:Capecitabine; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin