A phase I/II pharmacokinetics/pharmacodynamics study of irinotecan combined with S−1 for recurrent/metastatic breast cancer in patients with selected UGT1A1 genotypes (the JBCRG‐M01 study)

S‐1 and irinotecan combination is attractive for breast cancer refractory to anthracyclines and taxanes. Patients with advanced human epidermal growth factor receptor 2 (HER2)‐negative breast cancer previously treated with anthracyclines and taxanes were eligible. Patients with brain metastases and homozygous for UGT1A1 *6 or *28 or compound heterozygous (*6/*28) were excluded. A dose‐escalation design was chosen for the phase I portion (level 1: irinotecan 80 mg/m(2) days 1–8 and S‐1 80 mg/m(2) days 1–14 every 3 weeks; level 2: irinotecan 100 mg/m(2) and S‐1 80 mg/m(2)). Study objectives included determination of the recommended dose for phase II, response rate, progression‐free survival (PFS), and safety. Pharmacokinetics and CD34(+) circulating endothelial cells (CECs) as pharmacodynamics were also analyzed. Thirty‐seven patients were included. One patient at each level developed dose‐limiting toxicities; therefore, level 2 was the recommended dose for phase II. Diarrhea was more common in patients possessing a *6 or *28 allele compared with wild‐type homozygous patients (46% and 25%). Among 29 patients treated at level 2, PFS was longer for UGT1A1 wt/*6 and wt/*28 patients than for wt/wt patients (12 vs. 8 months, P = 0.06). PFS was significantly longer in patients with a larger‐than‐median SN‐38 area under the curve (AUC) than in those with a smaller AUC (P = 0.039). There was an association between clinical benefit and reduction in baseline CD34(+) CECs by S‐1 (P = 0.047). The combination of irinotecan and S‐1 is effective and warrants further investigation.