Dose-escalation of Regorafenib in Advanced Hepatocellular Carcinoma

In patients who are refractory to first-line treatment with sorafenib, regorafenib was tested in the phase III RESORCE study. In this study, a standard dose of 160mg/day was used (in cycles of 4 weeks, with 3 weeks on treatment and 1 week off) until tumor progression or limiting toxicity. Regorafenib was superior to placebo with a significant increase in overall survival and became a sequential treatment option. However, regorafenib is associated with relevant adverse events such as fatigue, hand-foot reaction, diarrhea and hypertension. Such events are more frequent in the first 2 cycles. In the RESORCE trial, 54% of patients had adverse events requiring interruption or dose reduction, and treatment discontinuation was required in 10% of patients. This toxicity profile limits the wide adoption of this drug in clinical practice. Dose escalation strategies for regorafenib have been evaluated in patients with colorectal cancer and have resulted in better tolerability with comparable efficacy. However, there are no prospective studies with alternative doses of regorafenib in patients with advanced HCC. The present protocol (STRAT-aHCC trial) aims to prospectively evaluate the tolerability, quality of life and efficacy of an alternative regimen of regorafenib in patients with advanced HCC. Patients will receive increasing dose of regorafenib in the first 2 treatment cycles (initial dose of 80mg, with weekly increments of 40mg up to 160mg in the first 2 treatment cycles - Figure 1). From the 3rd cycle on, the maximum tolerated dose during the first 2 cycles will be maintained. The maximum tolerated dose will be considered the highest dose in which the patient does not present grade ≥3 adverse events. The primary endpoint is the proportion of evaluable patients completing cycle 4. Radiologic response rate, quality of life, time to progression and overall survival will be evaluated as secondary endpoints. Medical visits will be carried out weekly in the first 2 treatment cycles and every 4 weeks after the 3rd cycle. Laboratory tests will be performed every 2 weeks during the first 2 cycles and every 4 weeks after the 3rd cycle. Response assessment by imaging exams will be performed every 8 weeks. Quality of life assessments will be performed every 4 weeks using the EuroQol EQ-5D-5L7 questionnaire. The planned sample size is 28 patients with an expected duration of 25-30 months.