Phase I study of a novel capecitabine schedule based on the Norton-Simon mathematical model in patients with metastatic breast cancer.
OBJECTIVE
This study was conducted to determine, in patients with advanced-stage breast cancer, the maximum tolerated dose (MTD) of capecitabine administered orally for 7 days followed by a 7-day rest (7/7), a schedule based on a mathematical method for the optimization of anticancer drug scheduling.


METHODS
Eligible patients had measurable, metastatic breast cancer. There was no limit to number of prior treatments. A standard, three-patients-per-cohort dose-escalation scheme used flat-dose capecitabine beginning at 1,500 mg orally twice daily (bid) on a 7/7 schedule. Each cohort was monitored for 28 days before escalation to the next cohort to assess for delayed toxicity. Response was evaluated radiographically every 12 weeks; toxicity was assessed every 2 weeks.


RESULTS
Twenty-one patients were treated on study. The most frequently reported treatment-related grade 2/3 adverse events were hand-foot syndrome (29%), leukopenia/neutropenia (24%), and fatigue (19%). Grade 3 toxicity was transient and easily managed. Three patients experienced grade 3 hand-foot syndrome; one of these patients had grade 3 diarrhea. There were no grade 4 events. The MTD of capecitabine 7/7 is 2,000 mg twice daily.


CONCLUSIONS
As predicted by mathematical modeling, capecitabine dosing for 7 days followed by a 7-day rest is well tolerated. Efficacy of this schedule is being determined in a phase II clinical trial in patients with advanced breast cancer.
Traina
Tiffany A
TA
Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA. trainat@mskcc.org
Theodoulou
Maria
M
Feigin
Kimberly
K
Patil
Sujata
S
Tan
K Lee
KL
Edwards
Charles
C
Dugan
Ute
U
Norton
Larry
L
Hudis
Clifford
C
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy*; D000069287:Capecitabine; D002277:Carcinoma / Q000188:drug therapy* / Q000556:secondary*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D005533:Foot Dermatoses / Q000139:chemically induced; D006229:Hand Dermatoses / Q000139:chemically induced; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000556:secondary; D008207:Lymphatic Metastasis; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008954:Models, Biological; D011355:Prodrugs / Q000008:administration & dosage* / Q000633:toxicity; D012983:Soft Tissue Neoplasms / Q000556:secondary; D013899:Thoracic Neoplasms / Q000556:secondary
D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil