A phase I/II trial of TAC-101, an oral synthetic retinoid, in patients with advanced hepatocellular carcinoma

Higginbotham, Kimberly; Lozano, Richard D.; Brown, Thomas; Patt, Yehuda Z.; Arima, Takashi; Abbruzzese, James L.; Thomas, Melanie B.

doi:10.1007/s00432-008-0406-2

Cited by 22 publications

(12 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(7,8) Higginbotham et al reported the results of pharmacokinetic studies of TAC-101 in patients with advanced hepatocellular carcinoma treated in the United States. (8) The mean pharmacokinetic parameters (t max , 4.3 h; C max , 242 ng/mL; AUC 0-24 , 3067.6 ng h/mL; AUC inf , 4241.1 ng h/mL) obtained for a dose of 20 mg were generally consistent with our data in Japanese patients. The slightly lower C max and AUCs values in the American study might be attributed to general differences in body size between Caucasians and Japanese.…”

Section: Discussionmentioning

confidence: 99%

“…The results for efficacy in this study were also similar to those in the study performed in the United States. (8) Unfortunately, tumor shrinkage was not evident, and the median TTP seemed to be unfavorable on the basis of MST. However, we believe that further evaluations are warranted, because the mechanisms of action of TAC-101 and other retinoids are considered cytostatic as opposed to cytotoxic, and the TTP in this study may be comparable to those in studies of sorafenib (2.8-5.5 months).…”

Section: Discussionmentioning

confidence: 99%

“…Median progression free survival (PFS) and overall survival (OS) were 3.4 months and 19.2 months, respectively. (8) We report the results of the first phase I study of TAC-101 in Japanese patients with HCC. Our major goals were to evaluate safe dose levels, tolerability, pharmacokinetics, and efficacy.…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

Okusaka¹,

Ueno²,

Ikeda

et al. 2012

Cancer Science

View full text Add to dashboard Cite

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)

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Okusaka¹,

Ueno²,

Ikeda

et al. 2012

Cancer Science

View full text Add to dashboard Cite

show abstract

“…Another possible target in endocrine therapy is the retinoid X receptor (RXRα), which is malfunctioning in HCC due to phosphorylation by the Ras-MAPK signaling pathway [16]. A recent phase I/II study of an oral synthetic retinoid (TAC-101) has reported good tolerability and a significant disease stabilization effect in 12 out of 21 patients [17]. However, because of the limited number of reports, further investigation is needed to warrant endocrine therapy for HCC.…”

Section: Systemic Therapy For Hccmentioning

confidence: 99%

Surgical Strategy for Liver Cancers in the Era of Effective Chemotherapy

Shindoh

Kaseb²,

Vauthey³

2013

Liver Cancer

View full text Add to dashboard Cite

Systemic chemotherapy is the only option for advanced and/or disseminated disease in patients with hepatocellular carcinoma (HCC). For decades, various systemic therapies have been explored for the treatment of advanced HCC. Nevertheless, no satisfactory results have been obtained in cytotoxic chemotherapy so far. However, with the recent introduction of effective chemotherapy agents including sorafenib, the role of systemic therapy for the treatment of HCC is changing. The goals of systemic therapy include prolongation of survival with stabilization of disease progression and, in selected patients, downsizing of primarily unresectable tumors. In the era of effective chemotherapy, patients with advanced HCC should be managed with individualized approaches to optimize outcome.

show abstract

“…PTK787 (Vatalanib) [143] , AZD2171 (Cediranib) [144] , SU6668 (TSU-68) [145] ) under investigation in advanced HCC; however, they are beyond the scope of this article and are reviewed elsewhere [101,110,146,147] . Other novel strategies apart from monoclonal antibodies and tyrosine kinase inhibitors include the retinoid compound TAC101 [148] , the cell cycle inhibitor flavopiridol [149] , the proteasome inhibitor bortezomib [150] , and histone deacetylase inhibitors for targeting epigenetic alterations. Some of them are already in phase I-II clinical trials.…”

Section: Additional Agents Under Investigationmentioning

confidence: 99%

Systemic Therapies in Hepatocellular Carcinoma

Wörns

Weinmann

Schuchmann

et al. 2009

Dig Dis

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors worldwide in the human population. Due to late diagnosis and/or advanced underlying liver cirrhosis, only limited treatment options with marginal clinical benefit are available in up to 70% of patients. During the last decades, no effective conventional cytotoxic systemic therapy was available contributing to the dismal prognosis in patients with advanced disease. However, a better knowledge of molecular hepatocarcinogenesis provides today the opportunity for targeted therapy. Positive data from the pivotal phase III SHARP trial assessing the efficacy and safety of the multikinase inhibitor sorafenib broadened the horizon for patients with advanced disease. After years of therapeutic nihilism, sorafenib was the first agent to demonstrate a statistically significant improvement in overall survival for patients with advanced HCC. This article reviews the historical perspective of systemic therapy in HCC and provides a brief overview of molecular hepatocarcinogenesis and potential targets in HCC. Most promising molecular targeted agents tested within clinical trials in advanced HCC are summarized, with a special attention to sorafenib, sunitinib, bevacizumab, and erlotinib.

show abstract

A phase I/II trial of TAC-101, an oral synthetic retinoid, in patients with advanced hepatocellular carcinoma

Abstract: 20 mg of TAC- was well tolerated. Significant disease stabilization (12/21 pts, 57%), 2 late PRs, and prolonged MS (19.2 months) suggest that TAC-101 provides meaningful patient benefit.

Cited by 22 publications

References 61 publications

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

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

Surgical Strategy for Liver Cancers in the Era of Effective Chemotherapy

Systemic Therapies in Hepatocellular Carcinoma

Contact Info

Product

Resources

About