Phase I study of trifluridine/tipiracil (TAS-102) plus irinotecan in combination with bevacizumab as a second-line therapy for patients with metastatic colorectal cancer.

Purpose: This phase I trial is to determine the recommended dose of the TAS-102, irinotecan plus bevacizumab regimen and assess its safety and efficacy in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin treatment.

Methods: A 3 + 3 designed dose escalation was performed. Patients were administered TAS-102 (30-35 mg/m² twice daily on days 1-5) and irinotecan (150-165 mg/m² on day 1) combined with a fixed dose of bevacizumab (5 mg/kg on day 1) every two weeks. The primary endpoint was the determination of the recommended phase II dose.

Results: Eighteen patients were enrolled: 6 at the Level 1 (TAS-102 30 mg/m² twice daily, irinotecan 150 mg/m² plus bevacizumab 5 mg/kg), six at the Level 2 (TAS-102 35 mg/m² twice daily, irinotecan 150 mg/m² plus bevacizumab 5 mg/kg), and six at the Level 3 (TAS-102 30 mg/m² twice daily, irinotecan 165 mg/m² plus bevacizumab 5 mg/kg). Five dose-limiting toxicities occurred: one observed at Level 1 (thrombocytopenia), two at Level 2 (neutropenia and diarrhea), and two at Level 3 (fatigue and neutropenia). The RP2D was established as TAS-102 30 mg/m² twice daily and irinotecan 150 mg/m² plus bevacizumab 5 mg/kg. The most frequent grade 3/4 treatment-related adverse events were neutropenia (33.3%), diarrhea (16.7%), and thrombocytopenia (11.1%). No treatment-related death occurred. Two patients (11.1%) experienced partial responses and 14 (77.8%) had stable disease.

Conclusion: The regimen of TAS-102, irinotecan, and bevacizumab is tolerable with antitumor activity for metastatic colorectal cancer patients refractory to first-line fluoropyrimidines and oxaliplatin treatment.