An open-label phase I/II study of tamibarotene in patients with advanced hepatocellular carcinoma

Tamibarotene is a synthetic retinoid expected to inhibit tumor-cell proliferation and to induce apoptosis by selective interaction with retinoic acid receptor α/β. We conducted an open-label phase I/II study to determine the maximum tolerated dose (MTD) and recommended dose (RD), and to evaluate the pharmacokinetics, efficacy, and safety profiles for advanced hepatocellular carcinoma (HCC).

Patients with histologically confirmed, measurable, unresectable HCC of Child-Pugh classification A or B and with no effective systemic or local therapies were eligible. In phase I, patients were assigned based on the 3 + 3 dose escalation criteria to receive tamibarotene at 8, 12, and 16 mg/day. The RD determined in phase I was employed for phase II. The planned sample size in phase II was 25, including the RD-treated patients in phase I.

Thirty-six patients were enrolled. No patients experienced dose-limiting toxicity (DLT) at 8 mg/day. However, two out of six patients experienced the DLTs at 12 mg/day: one experienced thrombosis in a limb vein and pulmonary artery, and the other experienced an increase of γ-GTP. The MTD and RD were determined as 12 and 8 mg/day, respectively. In phase II, one patient achieved partial response, and seven achieved stable disease. The disease control rate was 32 % (95 % CI: 15.0-53.5). The following drug-related serious adverse events were reported: thrombosis in a limb vein, pulmonary artery, and portal vein; interstitial lung disease; and vomiting.

Tamibarotene demonstrated the inhibition of tumor cell growth in advanced HCC with acceptable tolerance.