A phase I study of capecitabine and a modulatory dose of irinotecan in metastatic breast cancer.

PURPOSE: There is a need for chemotherapy regimens active against anthracycline- and taxane-refractory breast cancer. Data from preclinical and pilot studies performed at Roswell Park Cancer Institute (RPCI) suggested that when irinotecan (IRN) is given with 5-fluorouracil (5-FU) efficacy is affected by the sequence of drug administration. Pretreatment with IRN 24 h before 5-FU increased the number of tumor cells in S-phase and the antitumor activity in a preclinical system. These data provided the rationale for the evaluation of IRN and capecitabine, a 5-FU prodrug, sequentially administered in patients with metastatic breast cancer. The main objective of the study was to determine the MTD and identify dose-limiting toxicities (DLTs) of capecitabine and IRN. Additionally, the degree of accumulation of cells in S-phase in tumor biopsies obtained at 24 h after the first dose of IRN was measured in consenting patients. PATIENTS AND METHODS: Metastatic breast cancer patients who experienced disease progression after at least one (taxane or anthracycline based) chemotherapy regimen and an expected survival of at least 3 months and ECOG performance status 0-2 were eligible. Twelve patients were enrolled and treated. The starting doses were IRN 80 mg/m(2) given over 90 min on days 1, 8, 22, 29, and capecitabine 1,500 mg/m(2)/day given days 2-15 and 23-36. Evaluation for response was performed after the first cycle. Sequential tumor biopsies were performed on five patients.
RESULTS: The first three patients treated exhibited modulation in cyclin A index on tumor biopsy as defined by the study, defining the modulatory dose of IRN as 80 mg/m(2). Overall, 4/5 biopsies showed modulation. Dose Limiting Toxicities (DLTs) were assessed during the first cycle of therapy. Two DLTs (Grade 3 nausea vomiting and dehydration; grade 3 pneumonia, hypoxia, hypotension) were seen at dose level 2 of capecitabine (2,000 mg/m(2)/day) and the first cohort was expanded. There were no DLTs for patients treated at DL 1. No grade 3-4 toxicities occurred at DL 1. Seven patients were evaluable for response following one cycle of treatment (partial response 1, stable disease 4, progressive disease 2) Of the five inevaluable patients, two experienced DLT, one received 50% of the planned capecitabine dose, one progressed prior to evaluation, and one withdrew consent.
CONCLUSION: IRN 80 mg/m(2) days 1, 8, 22, 29 in combination with capecitabine 1,500 mg/m(2)/day in divided dose days 2-15 and 23-36 has an acceptable toxicity profile and resulted in modulation of S-phase in 4/5 specimens examined. Further studies of the activity of this combination and modulatory effect of IRN are warranted.