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Poster display

1619 - Phase I/II pharmacokinetics/pharmacodynamics study of irinotecan and S-1 for recurrent/metastatic breast cancer in patients with select UGT1A1 genotypes (the JBCRG-M01 study)


10 Oct 2016


Poster display


Shigehira Saji


Annals of Oncology (2016) 27 (6): 68-99. 10.1093/annonc/mdw365


S. Saji1, H. Ishiguro2, S. Nomura3, H. Iwata4, S. Tanaka5, T. Ueno6, M. Onoue7, T. Yamanaka8, Y. Sasaki9, M. Toi5

Author affiliations

  • 1 Department Of Medical Oncology, Fukushima Medical University, 960-1295 - Fukushima/JP
  • 2 Department Of Target Therapy Oncology, Kyoto University-Graduate school of medicine, Kyoto/JP
  • 3 Biostatistics Division, Center For Research Administration And Support, National Cancer Center Hospital East, 277-8577 - Kashiwa/JP
  • 4 Department Of Breast Oncology, Aichi Cancer Center Hospital, 464-8681 - Nagoya/JP
  • 5 Department Of Breast Surgery, Kyoto University-Graduate school of medicine, Kyoto/JP
  • 6 Department Of Breast Surgery, Kyorin university Hospital, Mitaka/JP
  • 7 Department Of Pharmacy, Kitano Hospital, Osaka/JP
  • 8 Department Of Biostatistics, Yokohama City University, Yokohama/JP
  • 9 Division Of Medical Oncology, Showa University, School of Medicine, Tokyo/JP


Abstract 1619


S-1 (combination of tegafur, gimeracil, and oteracil) and irinotecan (CPT) have different mechanisms of action. Combined therapy of S-1 and CPT is an attractive option for anthracycline and taxane-refractory breast cancer.


Patients with advanced HER2-negative breast cancer previously treated with anthracycline and taxane and with measurable lesions were eligible for the trial. Those with brain metastases and homozygous for UGT1A1*6 or *28 or compound heterozygous (*6/*28) were excluded. A 3 + 3 dose escalation design was used in phase I (Level 1: CPT 80 mg/m2 on days 1 and 8, and S-1 80 mg/m2 on days 1-14, every 3 weeks; Level 2: CPT 100 mg/m2 and S-1 80 mg/m2). The objectives were to determine the recommended dose (RD) for the phase II (primary for phase I) study, response rate (RR, primary for phase II), progression-free survival (PFS), and safety in relation to UGT1A1. Pharmacokinetics (PK) of CPT and circulating endothelial cells (CEC) as pharmacodynamics (PD) of S-1 were analysed.


Thirty-seven patients (13 for phase I, 24 for phase II) were enrolled. One patient at level 1 developed grade (G) 3 non-haematological toxicity and another at level 2 developed G4 neutropenia; therefore, level 2 was used as the RD. Common adverse events and their rates in the UGT1A1 wt/wt and wt/*6 or *28 heterozygous groups were diarrhoea, 25% and 46%; vomiting, 17% and 9%; anorexia, 25% and 9%; and fatigue, 25% and 9% respectively. As shown in Table 1 and supported by PK data, PFS seemed better for the UGT1A1 wt/*6 or *28 group compared to that for the wt/wt group. There also seemed to be an association between clinical benefit and suppression of CD34+ CEC by S-1 (Wilcoxon p = 0.047).

Efficacy results of Level 2 patients (n = 29, 6 for phase I and 23 for phase II)

Wild/Wild (n = 15) Wild/*6 or *28 (n = 14)
Response Rate 1 (7%) 3 (21%) -
Clinical Benefit Rate 4 (27%) 5 (36%) -
Median PFS (month) 8.3 12.3 HR = 0.47 (p = 0.0600)
Median OS (month) 17.4 23.1 HR = 0.74 (p = 0.5607)


A combination of CPT and S-1 is effective in patients having recurrent/metastatic breast cancer, and further study of the underlying pharmacogenomics/PK/PD is warranted.

Clinical trial identification

UMIN 000000517

Legal entity responsible for the study

Masakazu Toi




S. Saji: Lecture fee from Taiho Pharmaceutical Co. Ltd. S. Nomura: Receiving personal fees from Japan Breast Cancer Research Group.Y. Sasaki: Financial interest with Taiho Pharmaceutical Co. Ltd.

All other authors have declared no conflicts of interest.

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