Study design and patients
We conducted a single arm, open-label, single center phase II trial to evaluate the efficacy of a sequential S-1 and CPA regimen for MBC. Women aged 20–75 years old with a histological diagnosis of MBC were considered eligible for the study. Eligibility required a measurable tumor based on the RECIST criteria; an Eastern Cooperative Oncology Group performance status of 0 or 1; a body surface area >1.25; expected survival >3 months; adequate organ function defined as a leukocyte count 3,500–12,000/mm3 (or neutrophil count >2000/mm3), platelet count >100,000/mm3, hemoglobin >9 g/dl, serum ALT and AST level less than the upper level of normal in each institution × 2.5, serum total bilirubin <1.5 mg/dl, and serum creatinine <1.2 mg/dl (or creatinine clearance >50 ml/min); and the resolution of all toxicities from prior therapy. All patients provided written informed consent to participate in this study. The sample size was estimated to be approximately 40 patients, without any calculations based on statistical assumptions.
The exclusion criteria included symptomatic central nervous system metastases, active systemic infectious disease, clinically significant cardiovascular impairment, serious concomitant illness, pregnancy, breast feeding, a history of other cancers with a disease-free interval of ≤5 years, patients who had received trastuzumab-containing therapy within the prior 4 weeks, those who were receiving 5-FU-containing therapy, flucytosine, or pentostatin, and those who had recurrent disease within 1 year after having received 5-FU-containing therapy or CPA. From November 2007 to December 2018, a total of 36 patients were enrolled in this study. The demographic characteristics of the patients are summarized in Table 1. The study was carried out at Gunma University, Japan. The study protocol was approved by our Ethics Committee.
Treatment procedure
According to the RDs determined by our phase I study (18), S-1 80 mg/m2/day divided twice a day orally for 14 consecutive days, and then CPA 100 mg/m2/day divided twice a day orally for 14 consecutive days in a repeating 4-week cycle (S-1 for 2 weeks, CPA for 2 weeks). This regimen was continued until the occurrence of (1) progressive disease (PD) as assessed by the investigator using RECIST criteria, or (2) the appearance of unmanageable toxicity, or (3) the patient's withdrawal of consent. Any concomitant medication could be given at the discretion of the investigator if it was considered necessary for the patient's welfare and was not expected to interfere with the evaluation of the study treatment. Other antitumor therapies were not permitted.
Assessments
The primary endpoint was the antitumor activity of the sequential S-1 and CPA therapy as assessed by the overall response rate (ORR) based on the RECIST criteria. The secondary endpoints included the patients' overall survival (OS) and progression-free survival (PFS), the clinical benefit rate (CBR), and the regimen's safety. Routine tumor assessments based on the RECIST criteria were performed 1 month after the first dose and then every month during the treatment period. The ORR was defined as the proportion of patients with a complete response (CR) or a partial response (PR) among all patients. The CBR was defined as the proportion of patients with a CR or PR or stable disease (SD) continuing >4 weeks (28 days). CR and PR required confirmation at ≥4 weeks after first being reported. The Kaplan-Meier approach was used to estimate the median PFS and OS values.
Treatment-related adverse events were evaluated according to the Common Terminology Criteria for Adverse Events, ver. 3.0 and 4.0. There was a protocol amendment that changed the evaluation from version 3 to 4 in the middle of the trial. The incidence of adverse events was calculated according to grade. Hematology and biochemistry assessments, physical examinations, and periodic measurements of vital signs were performed before the start of each treatment cycle.