Phase I study of weekly oxaliplatin plus irinotecan in previously treated patients with metastatic colorectal cancer.
BACKGROUND
In vitro synergy between Oxal (oxaliplatin) and CPT-11 (irinotecan) has been reported. Oxaliplatin exerts its antineoplastic activity through the formation of platinum-DNA adducts. Resistance to oxaliplatin is through repair of these adducts, which is inhibited by irinotecan.


METHODS
Oxaliplatin and irinotecan were administered weekly for 4 weeks followed by a 2-week rest period. The dose of oxaliplatin was escalated first, starting at 30 mg/m(2). Once a dose of 60 mg/m(2) was attained, the weekly dose of irinotecan was escalated, from 40 mg/m(2) to 85 mg/m(2). A total of 49 previously treated patients with metastatic colorectal cancer were entered in order to establish the maximum tolerated dose. Pharmacokinetics of oxaliplatin and irinotecan were analyzed.


RESULTS
Forty-nine patients were evaluable for toxicity. The recommended phase II doses for this combination are oxaliplatin 60 mg/m(2) and irinotecan 50 mg/m(2), weekly x 4 q 6 weeks. Diarrhea was the most common dose-limiting toxicity. No pharmacological interactions were noted between oxaliplatin and irinotecan. Twelve of the 47 evaluable patients (26%) achieved a partial response.


CONCLUSIONS
Weekly combination of oxaliplatin and irinotecan appears to be a well tolerated and active regimen in patients previously treated for metastatic colorectal cancer. Further investigations of this regimen are warranted.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. kemenyn@mskcc.org
N
N
Kemeny
W
W
Tong
M
M
Gonen
J
J
Stockman
C
C
Di Lauro
J
J
Teitcher
P
P
White
C
C
Price
L
L
Saltz
S
S
Sharma
M A
MA
Graham
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D011336:Probability; D011379:Prognosis; D011725:Pyridines / Q000008:administration & dosage*; D018570:Risk Assessment; D016879:Salvage Therapy; D016019:Survival Analysis; D016896:Treatment Outcome
D009944:Organoplatinum Compounds; D011725:Pyridines; C431073:oxiplatin; D000077146:Irinotecan; D002166:Camptothecin