Phase I pharmacokinetic study of chronomodulated dose-intensified combination of capecitabine and oxaliplatin (XELOX) in metastatic colorectal cancer.
OBJECTIVE
To evaluate the maximum tolerated dose (MTD) and pharmacokinetic profile of a chronomodulated, dose-intensified regimen of capecitabine in combination with oxaliplatin (XELOX) in metastatic colorectal cancer (mCRC).


METHODS
Patients (N = 18) with 0 or 1 line of prior chemotherapy received oxaliplatin 100 mg/m(2) on day 1 from 1400 to 1800 hours with escalating dose levels of capecitabine (2,500, 3,000, 3,500, 4,000, 4,500, and 5,000 mg) once daily taken at 2400 hours on days 1-5. Each cycle lasted 14 days.


RESULTS
The MTD of capecitabine was 4,500 mg. Transaminitis and anemia were the commonest non-hematologic and hematologic toxicities, respectively. Toxicities were generally mild, with only five occurrences of grade 3 toxicity and none of grade 4. There were no dose-limiting toxicities, defined as specific grade 3 or 4 toxicities occurring in the first two cycles of treatment. The objective response rate was 33.3 %, and median overall survival was 16.3 months (95 % CI: 11.2-18.2 months). The maximum plasma concentration (C(max)) and area under plasma concentration-time curve from time 0 to infinity (AUC([0-∞])) of the capecitabine metabolites in our fixed-dosing chronomodulated regimen were comparable to values seen with comparably dose-intense regimens but associated with significantly reduced toxicity.


CONCLUSIONS
Chronomodulated dose-intensified XELOX facilitates delivery of dose-intense treatment in mCRC with a favorable therapeutic index that is promising.
Department of Medical Oncology, National Cancer Centre, 11 Hospital Drive, Singapore 169610, Singapore.
Mohamad
M
Farid
Balram
B
Chowbay
Xiangai
X
Chen
Sze Huey
SH
Tan
Saminathan
S
Ramasamy
Wen Hsin
WH
Koo
Han Chong
HC
Toh
Su Pin
SP
Choo
Simon Yew Kuang
SY
Ong
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077150:Oxaliplatin; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil