The effectiveness of reintroduction of oxaliplatin for metastatic colorectal cancer (mCRC) refractory to both oxaliplatin and irinotecan was previously reported in a single arm, open-label phase II study (RE-OPEN, Suenaga, 2015). We conducted a phase I study to determine the maximum tolerated dose (MTD) and the safety of oxalipatin plus trifluridine/tipiracil (FTD/TPI, also known as TAS-102) in patients with refractory mCRC (UMIN000015764).
Three dosages of intravenous oxaliplatin (50, 65 and 85 mg/m2) on days 1 and 15 and a fixed dose of FTD/TPI 35 mg/m2 bid on days 1–5, 15–19 every 4 weeks were investigated in patients with refractory mCRC by using a 3 + 3 design. Eligible patients had received prior oxaliplatin-based treatment that achieved a response or stable disease followed by confirmed disease progression at least 6 months before entering the study.
12 patients were enrolled in the study. Characteristics of patients were as follows: median age, 62 (range, 47–68) years; male/female, 6/6; ECOG PS 0, 75%; number of prior regimens ≥3, 33.3%; and median oxaliplatin-free interval, 24.3 (range, 6.2–71.4) months. 3 of 6 patients of the oxaliplatin 85mg/m2 cohort had dose-limiting toxicities (DLTs): treatment delay on 2nd cycle ≥8 days due to grade ≥2 neutropenia or grade 2 AST/ALT increased. No DLTs were observed in the other cohorts. The median number of treatment cycles was 3 (range, 1–9): 9 patients continued the treatment until disease progression; and 3 patients discontinued due to toxicity or patient’s refusal. In safety, grade ≥3 adverse events were neutropenia (n = 3), thrombocytopenia (n = 1), anorexia (n = 1) and nausea (n = 1). There was no evidence of allergic reaction to oxaliplatin and severe peripheral sensory neuropathy.
According to the results of this phase I study, a combination of trifluridine/tipiracil 35 mg/m2 bid on days 1–5, 15–19 and oxaliplatin 85 mg/m2 on days 1 and 15 every 4 weeks could be a candidate for recommended dose of the trifluridine/tipiracil+oxaliplatin regimen in patients with refractory mCRC.
Clinical trial identification
UMIN000015764 (release date, 1/12/2014).
Legal entity responsible for the study
Cancer Institute Hospital of the Japanese Foundation for Cancer Research.
Japanese Foundation for Cancer Research.
All authors have declared no conflicts of interest.