Phase I dose-escalation of trifluridine/tipiracil in combination with oxaliplatin in patients with metastatic colorectal cancer

Abstract Background and objectives Pre-clinical data have shown that combining trifluridine/tipiracil with oxaliplatin enhances anti-tumour activity compared with either monotherapy. A phase I dose-escalation study was conducted to determine the maximum tolerated dose (MTD), recommended dose (RD) for phase II and pharmacokinetic profile of this combination in patients with metastatic colorectal cancer (mCRC) who had progressed after at least 1 prior line of treatment. Methods Using a 3 + 3 design, patients received escalating trifluridine/tipiracil doses from 25, then 30 and to 35 mg/m 2 twice daily, days 1–5, q14 days, together with a fixed dose of 85 mg/m 2 of oxaliplatin day 1, q14 days. An intermediate cohort with a lower oxaliplatin dose (65 mg/m 2 ) was also investigated. After MTD determination, additional patients were treated to define the RD. Results Twenty-four patients were enrolled. One dose-limiting toxicity of grade 3 febrile neutropenia was observed at the highest dose level, which was established as the MTD and subsequently the RD. The most common drug-related adverse events (AEs) were asthenia, nausea, diarrhoea, peripheral neuropathy, neutropenia, decreased appetite, thrombocytopenia, vomiting, anaemia and peripheral sensory neuropathy. Most drug-related AEs (93.0%) were of grade 1–2. Pharmacokinetic parameters of trifluridine/tipiracil were not influenced by oxaliplatin co-administration. Best overall responses at the RD (n = 14) included 1 patient with partial response (7.1%) and 7 patients with stable disease (50.0%). Conclusion The combination of trifluridine/tipiracil and oxaliplatin in patients with mCRC has a manageable safety profile with some efficacy. The RD is 35 mg/m 2 of trifluridine/tipiracil twice daily, days 1–5, q14 days and 85 mg/m 2 of oxaliplatin day 1, q14 Clinicaltrials.gov number NCT02848443 .