Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Cancer Research and Clinical Oncology
Published in: Journal of Cancer Research and Clinical Oncology 12/2008

01-12-2008 | Original Paper

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

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

Published in: Journal of Cancer Research and Clinical Oncology | Issue 12/2008

Login to get access

Abstract

Purpose

Preclinical models showed TAC-101 (4-[3,5-bis(trimethylsilyl) benzamide] benzoic acid), an oral synthetic retinoid, has anti-tumor activity in hepatocellular carcinoma (HCC). A phase I/II study was performed in advanced HCC patients (pts).

Patients and methods

Thirty-three patients were enrolled. During Phase I, pts received 40 mg daily for 14 days q3 weeks; 2 of 5 patients developed DLT so dose was reduced to 20 mg/day. Twenty-eight patients received 20 mg/day.

Results

No pt had a CR or PR, but 12 of 21 (57%) had SD. Two pts (9.5%) had late PR after discontinuing TAC-101. Median survival (MS) for all 28 pts treated with 20 mg/day was 12.7 months (95% CI 8.8–22.7); MS for 21 evaluable pts was 19.2 months (95% CI 10.4–27.6).

Conclusions

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.
Literature
Abou-Alfa GK, Schwartz L, Ricci S et al (2006) Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 24(26):4293–4300PubMedCrossRef
Abrams RA, Pajak TF, Haulk TL, Flam M, Asbell SO (1998) Survival results among patients with alpha-fetoprotein-positive, unresectable hepatocellular carcinoma: analysis of three sequential treatments of the RTOG and Johns Hopkins Oncology Center. Cancer J Sci Am 4(3):178–184PubMed
Barbare JC, Bouche O, Bonnetain F et al (2005) Randomized controlled trial of tamoxifen in advanced hepatocellular carcinoma. J Clin Oncol 23(19):4338–4346PubMedCrossRef
Boige V, Taieb J, Hebbar M et al (2006) Irinotecan as first-line chemotherapy in patients with advanced hepatocellular carcinoma: a multicenter phase II study with dose adjustment according to baseline serum bilirubin level. Eur J Cancer 42(4):456–459PubMedCrossRef
Bruserud O, Gjertsen BT (2000) New strategies for the treatment of acute myelogenous leukemia: differentiation induction-present use and future possibilities. Stem Cells 18:157–165PubMedCrossRef
Dimery IW, Hong WK, Lee JJ et al (1997) Phase I trial of alpha-tocopherol effects on 13-cis-retinoic acid toxicity. Ann Oncol 8(1):85–89PubMedCrossRef
Eferl R, Ricci R, Kenner L et al (2003) Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53. Cell 112(2):181–192PubMedCrossRef
El-Serag HB, Davila JA, Petersen NJ, McGlynn KA (2003) The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med 139(10):817–823PubMed
El-Serag HB, Mason AC (1999) Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 340(310):745–750PubMedCrossRef
Fuchs CS, Clark JW, Ryan DP et al (2002) A phase II trial of gemcitabine in patients with advanced hepatocellular carcinoma. Cancer 94(12):3186–3191PubMedCrossRef
Fujimoto K, Hosotani R, Doi R et al (1999) Induction of cell-cycle arrest and apoptosis by a novel retinobenzoic-acid derivative, TAC-101, in human pancreatic-cancer cells. Int J Cancer 81(4):637–644PubMedCrossRef
Gish RG, Porta C, Lazar L et al (2007) Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol 25(21):3069–3075PubMedCrossRef
Guan Z, Wang Y, Maoleekoonpairoj S et al (2003) Prospective randomised phase II study of gemcitabine at standard or fixed dose rate schedule in unresectable hepatocellular carcinoma. Br J Cancer 89(10):1865–1869PubMedCrossRef
Guo L, Guo Y, Xiao S, Shi X (2005) Protein kinase p-JNK is correlated with the activation of AP-1 and its associated Jun family proteins in hepatocellular carcinoma. Life Sci 77(15):1869–1878PubMedCrossRef
Hashimoto Y, Kagechika H, Kawachi E et al (1996) Evaluation of differentiation-inducing activity of retinoids on human leukemia cell lines HL-60 and NB4. Biol Pharm Bull 19:1322–1328PubMed
Hasumi A, Matsui H, Sugioka A et al (2000) Precancerous conditions of biliary tract cancer in patients with pancreaticobiliary maljunction: reappraisal of nationwide survey in Japan. J Hepatobiliary Pancreat Surg 7(6):551–555PubMedCrossRef
Ikeda M, Okusaka T, Ueno H, Takezako Y, Morizane C (2005) A phase II trial of continuous infusion of 5-fluorouracil, mitoxantrone, and cisplatin for metastatic hepatocellular carcinoma. Cancer 103(4):756–762PubMedCrossRef
Kato H, Nakamura M, Muramatsu M, Orito E, Ueda R, Mizokami M (2004) Spontaneous regression of hepatocellular carcinoma: two case reports and a literature review. Hepatol Res 29(3):180–190PubMedCrossRef
Kim WR, Brown RS Jr, Terrault NA, El-Serag H (2002) Burden of liver disease in the United States: summary of a workshop. Hepatology 36(1):227–242PubMedCrossRef
Lee J, Park JO, Kim WS et al (2004) Phase II study of doxorubicin and cisplatin in patients with metastatic hepatocellular carcinoma. Cancer Chemother Pharmacol 54(5):385–390PubMedCrossRef
Lee SJ, Ohashi Y, Sakurai H, Saiki I (2003) TAC-101 inhibits intrahepatic metastasis of orthotopically implanted murine hepatocellular carcinoma. Cancer Lett 198(2):169–177PubMedCrossRef
Leung CS, Tang CN, Fung KH, Li MK (2002a) A retrospective review of transcatheter hepatic arterial embolisation for ruptured hepatocellular carcinoma. J R Coll Surg Edinb 47(5):685–688PubMed
Leung TW, Tang AM, Zee B et al (2002b) Factors predicting response and survival in 149 patients with unresectable hepatocellular carcinoma treated by combination cisplatin, interferon-alpha, doxorubicin and 5-fluorouracil chemotherapy. Cancer 94(2):421–427PubMedCrossRef
Lin F, Xiao D, Kolluri SK, Zhang X (2000) Unique anti-activator protein-1 activity of retinoic acid receptor beta. Cancer Res 60(12):3271–3280PubMed
Lippman SM (1997) Head and neck chemoprevention: recent advances. Cancer Control 4(2):128–135PubMed
Lippman SM, Benner SE, Hong WK (1993a) Chemoprevention strategies in lung carcinogenesis. Chest 103(1 Suppl):15S–19SPubMedCrossRef
Lippman SM, Benner SE, Hong WK (1993b) Retinoids in chemoprevention of head and neck carcinogenesis. Prev Med 22(5):693–700PubMedCrossRef
Lippman SM, Garewal H, Meyskens FL Jr (1989) Retinoids as potential chemopreventive agents in squamous cell carcinoma of the head and neck. Prev Med 18:740–48PubMedCrossRef
Llovet JM, Bruix J (2000) Prospective validation of the Cancer of the Liver Italian Program (CLIP) score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma. Hepatology 32(3):679–680PubMedCrossRef
Llovet JM, Ricci S, Mazzaferro V et al (2007) Sorafenib improves survival in advanced Hepatocellular Carcinoma (HCC): results of a Phase III randomized placebo-controlled trials (SHARP trial). American Society of Clinical Oncology Annual Meeting, Chicago
Lotan R (1997) Retinoids and chemoprevention of aerodigestive tract cancers. Cancer Metastasis Rev 16(3–4):349–356PubMedCrossRef
Matsushima-Nishiwaki R, Okuno M, Takano Y, Kojima S, Friedman SL, Moriwaki H (2003) Molecular mechanism for growth suppression of human hepatocellular carcinoma cells by acyclic retinoid. Carcinogenesis 24(8):1353–1359PubMedCrossRef
Matthews CP, Colburn NH, Young MR (2007) AP-1 a target for cancer prevention. Curr Cancer Drug Targets 7(4):317–324PubMedCrossRef
Mechta-Grigoriou F, Gerald D, Yaniv M (2001) The mammalian Jun proteins: redundancy and specificity. Oncogene 20(19):2378–2389PubMedCrossRef
Meyskens FL Jr, Jacobson J, Nguyen B, Weiss GR, Gandara DR, MacDonald JS (1998) Phase II trial of oral beta-all trans-retinoic acid in hepatocellular carcinoma (SWOG 9157). Invest New Drugs 16(2):171–173PubMedCrossRef
Minagawa N, Nakayama Y, Inoue Y et al (2004) 4-[3, 5-Bis(trimethylsilyl) benzamido] benzoic acid inhibits angiogenesis in colon cancer through reduced expression of vascular endothelial growth factor. Oncol Res 14(9):407–414PubMed
Miyagawa N, Homma T, Kagechika H, Shudo K, Nagai H (2003) Effect of synthetic retinoid, TAC-101, on experimental autoimmune disease. Pharmacology 67(1):21–31PubMedCrossRef
Miyaguchi T, Nomata K, Noguchi M et al (2001) TAC-101, a novel retinobenzoic-acid derivative, enhances gap junctional intercellular communication among renal epithelial cells treated with renal carcinogens. Anticancer Res 21:4025–4030PubMed
Mok TS, Leung TW, Lee SD et al (1999) A multi-centre randomized phase II study of nolatrexed versus doxorubicin in treatment of Chinese patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 44(4):307–311PubMedCrossRef
Murakami K, Wierzba K, Sani M et al (1998a) TAC-101, a benzoic acid derivative, inhibits liver metastasis of human gastrointestinal cancer and prolongs the life-span. Clin Exp Metastasis 16:323–331PubMedCrossRef
Murakami K, Matsuura T, Sano M et al (1998b) 4-[3, 5-Bis(trimethylsilyl) benzamido] benzoic acid (TAC-101) inhibits the intrahepatic spread of hepatocellular carcinoma and prolongs the life-span of tumor-bearing animals. Clin Exp Metastasis 16(7):633–643PubMedCrossRef
Murakami K, Yamaura T, Suda K et al (1999) TAC-101 (4-[3, 5-bis(trimethylsilyl) benzamido]benzoic acid) inhibits spontaneous mediastinal lymph node metastasis produced by orthotopic implantation of Lewis lung carcinoma. Jpn J Cancer Res 90(11):1254–1261PubMed
Muto Y, Moriwaki H, Ninomiya M et al (1996) Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med 334(24):1561–1567PubMedCrossRef
Muto Y, Moriwaki H, Saito A (1999) Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. N Engl J Med 340(13):1046–1047PubMedCrossRef
Ohtani H, Yamazaki O, Matsuyama M et al (2005) Spontaneous regression of hepatocellular carcinoma: report of a case. Surg Today 35(12):1081–1086PubMedCrossRef
Oikawa T (1998) Control of tumor-related angiogenesis. Hum Cell 11:201–206PubMed
Oikawa T, Murakami K, Sano M, Shibata J, Wierzba K, Yamada Y (2001) A potential use of a synthetic retinoid TAC-101 as an orally active agent that blocks angiogenesis in liver metastases of human stomach cancer cells. Jpn J Cancer Res 92(11):1225–1234PubMed
Papadimitrakopoulou VA, Hong WK (1997) Retinoids in head and neck chemoprevention. Proc Soc Exp Biol Med 216(2):283–290PubMed
Parkin DM, Pisani P, Ferlay J (1999a) Estimates of the worldwide incidence of 25 major cancers in 1990. Int J Cancer 80(6):827–841PubMedCrossRef
Patt YZ, Hassan MM, Lozano RD et al (2005) Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial. Cancer 103(4):749–755PubMedCrossRef
Philip PA, Mahoney MR, Allmer C et al (2005) Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol 23(27):6657–6663PubMedCrossRef
Posey J, Johnson P, Mok T, Hirmand M, Dahlberg S, Kwei L, Leung T (2005) Results of a phase 2/3 open-label, randomized trial of T138067 versus doxorubicin (DOX) in chemotherapy-naive, unresectable hepatocelular carcinoma (HC). 2005 ASCO Annual Meeting, Orlando, FL, USA
Rizvi NA, Marshall JL, Ness E et al (2002) Initial clinical trial of oral TAC-101, a novel retinoic acid receptor-alpha selective retinoid, in patients with advanced cancer. J Clin Oncol 20(16):3522–3532PubMedCrossRef
Sako T, Nakayama Y, Minagawa N et al (2005) 4-[3, 5-Bis(trimethylsily) benzamido] benzoic acid (TAC-101) induces apoptosis in colon cancer partially through the induction of Fas expression. In Vivo 19:125–132PubMed
Sankaranarayanan, Mathew RB (1996) Retinoids as cancer-preventive agents. IARC Sci Publ (139):47–59
Sano K, Takayama T, Murakami K, Saiki I, Makuuchi M (2003) Overexpression of retinoic acid receptor alpha in hepatocellular carcinoma. Clin Cancer Res 9(10 Pt 1):3679–3683PubMed
Satake K, Takagi E, Ishii A et al (2003) Anti-tumor effect of vitamin A and D on head and neck squamous cell carcinoma. Auris Nasus Larynx 30(4):403–412PubMedCrossRef
Shudo K, Kagechika H, Yamazaki N et al (2004) A synthetic retinoid Am80 (tamibarotene) rescues the memory deficit caused by scopolamine in a passive avoidance paradigm. Biol Pharm Bull 27:1887–1889PubMedCrossRef
Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10(1):1–10PubMedCrossRef
Suzuki N, Aoki D, Oie S et al (2004) A novel retinoid, 4-[3, 5-bis (trimethylsilyl) venzamido] benzoic acid (TAC-101), induces apoptosis of human ocarian carcinoma cells and shows potential as a new antitumor agent for clear cell adneocarcinoma. Gynecol Oncol 94:643–649PubMedCrossRef
Takai K, Okuno M, Yasuda I et al (2005) Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. Updated analysis of the long-term follow-up data. Intervirology 48(1):39–45PubMedCrossRef
Ventegodt S, Morad M, Hyam E, Merrick J (2004) Clinical holistic medicine: induction of spontaneous remission of cancer by recovery of the human character and the purpose of life (the life mission). Sci World J 4:362–377
Wang ZY, Sun GL, Lu JX, Gu LJ, Huang ME, Chen SR (1990) Treatment of acute promyelocytic leukemia with all-trans retinoic acid in China. Nouv Rev Fr Hematol 32(1):34–36PubMed
Yasuda I, Shiratori Y, Adachi S et al (2002) Acyclic retinoid induces partial differentiation, down-regulates telomerase reverse transcriptase mRNA expression and telomerase activity, and induces apoptosis in human hepatoma-derived cell lines. J Hepatol 36(5):660–671PubMedCrossRef
Yeo W, Mok TS, Zee B et al (2005) A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst 97(20):1532–1538PubMedCrossRef
Yoshimura K, Uchida G, Okazaki M et al (2003) Differential expression of heparin-binding EGF-like growth factor (HB-EGF) mRNA in normal human keratinocytes induced by a variety of natural and synthetic retinoids. Exp Cell Res 12(S2):28–34
Yuen MF, Wu PC, Lai VC, Lau JY, Lai CL (2001) Expression of c-Myc, c-Fos, and c-jun in hepatocellular carcinoma. Cancer 91(1):106–112PubMedCrossRef
Zhang JW, Wang JY, Chen SJ, Chen Z (2000) Mechanisms of all-trans retinoic acid-induced differentiation of acute promyelocytic leukemia cells. J Biosci 25(3):275–284PubMedCrossRef
Zhu AX, Blaszkowsky LS, Ryan DP et al (2006) Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol 24(12):1898–1903PubMedCrossRef
Metadata
Title
A phase I/II trial of TAC-101, an oral synthetic retinoid, in patients with advanced hepatocellular carcinoma
Authors
Kimberly B. Higginbotham
Richard Lozano
Thomas Brown
Yehuda Z. Patt
Takashi Arima
James L. Abbruzzese
Melanie B. Thomas
Publication date
01-12-2008
Publisher
Springer-Verlag
Published in
Journal of Cancer Research and Clinical Oncology / Issue 12/2008
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-008-0406-2

Other articles of this Issue 12/2008

Journal of Cancer Research and Clinical Oncology 12/2008 Go to the issue

Original Paper

Oral versus intravenous ibandronic acid: a comparison of treatment options for metastatic bone disease

Original Paper

Hepatocellular carcinoma presenting with bone metastasis: clinical characteristics and prognostic factors

Original Paper

A novel EGFR mutation D1012H and polymorphism at exon 25 in Japanese lung cancer

Original Paper

Clinical identification of colorectal cancer patients benefiting from adjuvant uracil–tegafur (UFT): a randomized controlled trial

Original Paper

Novel treatment of ovarian cancer cell lines with Imatinib mesylate combined with Paclitaxel and Carboplatin leads to receptor-mediated antiproliferative effects

Original Paper

Evaluation of quality of life in patients with previously untreated advanced prostate cancer receiving maximum androgen blockade therapy or LHRHa monotherapy: a multicenter, randomized, double-blind, comparative study
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits