Phase I study of sorafenib in combination with uracil-tegafur in patients with unresectable advanced hepatocellular carcinoma in Japan

Aim/Background

Our goal was to evaluate the frequency of dose-limiting toxicity and determine the recommended dose of sorafenib administered in combination with uracil-tegafur (UFT) to patients with unresectable advanced hepatocellular carcinoma (HCC).Our goal was to evaluate the frequency of dose-limiting toxicity and determine the recommended dose of sorafenib administered in combination with uracil-tegafur (UFT) to patients with unresectable advanced hepatocellular carcinoma (HCC).

Methods

Patients with unresectable advanced HCC were treated with sorafenib plus UFT by 3 + 3 design. Dose levels were as follows: level 1, 200 mg sorafenib twice daily (400 mg/day) and 100 mg UFT 3 times daily (300 mg/day); level 2, 400 mg sorafenib twice daily (800 mg/day) and 100 mg UFT three times daily (300 mg/day); and level 3, 400 mg sorafenib (800 mg/day) and 200 mg UFT twice daily (400 mg/day). A cycle was 28 days in duration and there were 3 cycles in total.

Results

Eleven patients with unresectable advanced HCC were enrolled in our study. Median patient age was 69 years (range, 56–82). Eight (73%) patients had hepatitis C viral infection. Dose-limiting toxicities including grade 3 erythema multiforme (skin rash) and dehydration occurred at dose level 2. Therefore, the maximum tolerated dose of sorafenib was 400 mg/day (level 1). The most common grade 3 or 4 drug-related adverse reactions included neutropenia (9%), increased levels of lipase (9%), decreased levels of phosphate (9%), fatigue (9%), dehydration (9%), hypertension (9%), skin rash (9%), and hand-foot skin reaction (9%).

Conclusions

The recommended dose of sorafenib in combination with UFT (300 mg/day) was determined to be 200 mg twice daily (400 mg/day) for patients with unresectable advanced HCC.

Clinical trial identification

Disclosure

Y. Maehara: partly supported by research funding from Bayer Yakuhin, Ltd. All other authors have declared no conflicts of interest.