Dose-finding phase I and pharmacokinetic study of capecitabine (Xeloda) in combination with epirubicin and cyclophosphamide (CEX) in patients with inoperable or metastatic breast cancer.
OBJECTIVE
The present study aimed to identify the recommended dose (RD) of capecitabine, epirubicin and cyclophosphamide (CEX) combination treatment for inoperable or metastatic breast cancer and to assess response rate, tolerability and pharmacokinetics in Japanese patients.


METHODS
Patients received 3-week cycles of fixed-dose intravenous cyclophosphamide (600 mg/m(2), day 1), intravenous epirubicin (75-100 mg/m(2), day 1) and oral capecitabine (628-900 mg/m(2) twice daily, days 1-14). Dose escalation/deescalation decisions for consecutive cohorts were made using the continual reassessment method (CRM). RD was defined as dose level closest to that causing dose-limiting toxicity (DLT) in 33% of patients.


RESULTS
Among the 17 patients enrolled, 3 experienced DLT (hand-foot syndrome, anorexia, mucositis; all grade 3) and 3 (18%) febrile neutropenia. Based on CRM calculation, mean DLT occurrence probabilities (90% confidence intervals in parentheses) for levels 2, 3 and 4 were 21% (8-42%), 35% (17-56%) and 56% (38-71%), respectively. Level 3 was thus chosen as the RD. Combination treatment did not affect pharmacokinetic parameters of capecitabine, epirubicin or their metabolites. Objective responses were achieved by 7 patients (41%), including partial responses in 4 of 6 patients (67%) receiving the RD.


CONCLUSIONS
CEX represents a well-tolerated regimen, and RD for Japanese patients was determined to be capecitabine 900 mg/m(2) twice daily in combination with epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2) using the CRM.
Saji
Shigehira
S
Department of Surgery and Breast Oncology, Division of Clinical Trials and Research, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.
Toi
Masakazu
M
Morita
Satoshi
S
Iwata
Hiroji
H
Ito
Yoshinori
Y
Ohno
Shinji
S
Kobayashi
Tadashi
T
Hozumi
Yasuo
Y
Sakamoto
Junichi
J
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000069287:Capecitabine; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000493:pharmacokinetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D015251:Epirubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D008875:Middle Aged
D003841:Deoxycytidine; D015251:Epirubicin; D000069287:Capecitabine; D003520:Cyclophosphamide; D005472:Fluorouracil