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Clinical Trial
, 17 (3), 381-388

A Phase I Study of Combination Therapy With Sorafenib and 5-Fluorouracil in Patients With Advanced Hepatocellular Carcinoma

Clinical Trial

A Phase I Study of Combination Therapy With Sorafenib and 5-Fluorouracil in Patients With Advanced Hepatocellular Carcinoma

Takuya Sho et al. Drugs R D.


Background and aims: Sorafenib is the first molecular targeted drug approved for the treatment of advanced hepatocellular carcinoma (HCC) and is a potent small molecule inhibitor of multiple kinases. Combination therapy with sorafenib and other cytotoxic agents for HCC may result in additive anticancer activity. The purpose of this phase I study was to investigate the safety and tolerability of combination therapy with sorafenib and 5-fluorouracil (5-FU) and to determine the optimum dose of 5-FU for a phase II trial.

Methods: This phase I study used a conventional 3 + 3 dose-escalation design. The primary endpoint was to determine the maximum tolerated dose (MTD) of 5-FU in combination with sorafenib and to determine the recommended dosage (RD) for phase II. The secondary endpoints evaluated were toxicity and the tumor response rate. All patients received 800 mg of sorafenib daily and three different dosages of 5-FU (250, 350, and 450 mg/m2/day) for 20 days by intravenous infusion in 1 month as one cycle.

Results: Twelve patients with advanced HCC were evaluated. The MTD of 5-FU in combination with sorafenib was 450 mg/m2/day, and 350 mg/m2/day was selected as the RD for a phase II study. Thrombocytopenia, stomatitis, and hand-foot skin reaction were observed as grade 3 adverse events. Nine patients achieved stable disease (75%), and three patients (25%) were judged to have progressive disease. The disease control rate was 75%.

Conclusions: Combination therapy with sorafenib and 5-FU appears to be well tolerated and may have the potential to be an option for advanced HCC.

Conflict of interest statement

Conflict of interest

Professor Naoya Sakamoto received lecture fees from Bristol Myers Squibb and Pharmaceutical K.K, and endowments from MSD K. K and Chugai Pharmaceutical Co., Ltd, and a research grant from Gilead Sciences, Inc. Dr Kenichi Morikawa received a research grant from Gilead Sciences. Inc. Dr Goki Suda received a research grant from Bristol Myers Squibb. Takuya Sho, Mitsuru Nakanishi, Masatsugu Ohara, Naoki Kawagishi, Jun Ito, Machiko Umemura, Takaaki Izumi, Masato Nakai, Koji Ogawa, Makoto Chuma, Takashi Meguro, Michio Nakamura, Atsushi Nagasaka, Hiromasa Horimoto, and Yoshiya Yamamoto declare that they have no conflict of interest.

Financial support

This work was supported by Bayer Holding Ltd Japan as an endowment.

Trial registration number

This study was registered at the UMIN Clinical Trials Registry as UMIN000004313.


Fig. 1
Fig. 1
A 3 + 3 dose-escalation study design. Continuous sorafenib 800 mg/day and 3 planned dose levels of 5-FU (250, 350, and 450 mg/m2/day) for 20 days (day 1–5, 8–12, 15–19, and 22–26) by intravenous infusion in 1 month as one cycle. 5-FU 5-fluorouracil
Fig. 2
Fig. 2
A 74-year-old man diagnosed with moderately differentiated HCC. a Multiple lung metastases of HCC are observed before combination treatment on chest CT. b After one cycle, multiple metastases of HCC are enlarged and diagnosed as progressive disease on chest CT. c Six months after treatment, multiple metastases of HCC show partial response on chest CT. CT computed tomography, HCC hepatocellular carcinoma

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