Phase I study of TAC‐101, an oral synthetic retinoid, in Japanese patients with advanced hepatocellular carcinoma

Abstract

Preclinical models have shown that TAC‐101 (4‐[3,5‐bis(trimethylsilyl) benzamide] benzoic acid), an oral synthetic retinoid, has antitumor activity in hepatocellular carcinoma (HCC). We conducted a phase I study in Japanese patients with advanced HCC to examine the pharmacokinetics, recommended dose, safety, and efficacy of TAC‐101. The administered dose of TAC‐101 was 10 mg/day in four patients (level 1), 20 mg/day in six (level 2), and 30 mg/day in three (level 3). There was no dose‐limiting toxicity at level 1. Only one patient each had dose‐limiting toxicity at level 2 (grade 2 fatigue, recovery requiring eight or more consecutive days of rest) and at level 3 (grade 3 splenic vein thrombosis). Level 3 (30 mg/day) was considered the maximum tolerated dose and 20 mg/day the recommended dose by a panel of medical experts, placing maximum emphasis on safety. The most frequent adverse events were fatigue, headache, and dermal symptoms such as rash. Pharmacokinetic parameters in Japanese patients with HCC were similar to those in patients in the United States, most of whom were Caucasian. Although no patient had a complete or partial response, the disease control rate was 38.5%. In conclusion, the recommended dose of TAC‐101 for patients with HCC is 20 mg/day. TAC‐101 had an acceptable toxicity profile, warranting further evaluation in clinical trials. (Cancer Sci, doi: 10.1111/j.1349‐7006.2012.02334.x, 2012)

Hepatocellular Carcinoma: Molecular Mechanisms and Targeted Therapies

“…Two superiority trials compared sorafenib with radioembolization, SARAH and SIRveniB, in locally advanced HCC, and they were also reported at EASL2017 and ASCO 2017; however, these trials failed to meet their primary endpoints, with one criticism being the difficulty in performing clinical-trials of first-line HCC while using OS as the endpoint. A phase I study with TAC-101, an oral synthetic retinoid, with Japanese HCC patients showed positive anti-tumor activity with a satisfactory toxicity profile [57]. There is an ongoing phase III (NCT00756782) study that combines TAC-101 and transcathetar arterial chemoembolization (TACE) vs. TACE alone in Japanese HCC patients [58].…”

Retinoic Acid Actions through Mammalian Nuclear Receptors

“…Treatment of osteosarcoma and chondrosarcoma cell lines with all-trans RA has shown reversible growth inhibition and simultaneously blocking of colony formation. , Retinoids have recently entered different phases of clinical trials for the treatment of solid tumors. , These molecules include TAC-101 (Taiho Pharmaceuticals, Japan, and tazarotene (Allergen, USA).…”

“…260,261 Retinoids have recently entered different phases of clinical trials for the treatment of solid tumors. 262,263 These molecules include TAC-101 (Taiho Pharmaceuticals, Japan, and tazarotene (Allergen, USA).…”

Vitamin A, Cancer Treatment and Prevention: The New Role of Cellular Retinol Binding Proteins

“…4-HPR has activity against tumours by generating reactive oxygen species [ 76 , 87 , 88 ], increasing dihydroceramide production [ 87 , 89 – 91 ] and natural killer cell activity [ 92 , 93 ] and inhibiting angiogenesis [ 89 , 94 ]. TAC-101 has shown efficacy in inhibiting liver tumour growth in particular of hepatocellular carcinoma [ 95 , 96 ]. Synthetic retinoids, approved from FDA for dermatological purposes, have a potential antitumour activity.…”