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Initial Clinical Trial of Oral TAC-101, a Novel Retinoic Acid Receptor-Alpha Selective Retinoid, in Patients With Advanced Cancer

From the Developmental Therapeutics Program, Lombardi Cancer Center, Georgetown University Medical Center, and Washington Hospital Center, Washington, DC; Department of Thoracic/Head and Neck Medical Oncology, M.D. Anderson Cancer Center, University of Texas, Houston, TX; West Virginia University Health Science Center, Morgantown, WV; and Inveresk Research, Research Triangle Park, NC.

Address reprint requests to Naiyer Rizvi, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; email: rizvin{at}mskcc.org

PURPOSE: The goals of this study were to determine the safety, toxicity, and pharmacokinetics of TAC-101, a novel synthetic retinoic acid receptor-alpha (RAR-) selective retinoid, in patients with advanced cancer.

PATIENTS AND METHODS: Twenty-nine patients at two centers received oral TAC-101 at doses ranging from 12 to 34 mg/m²/d. Pharmacokinetic sampling was performed on days 1 and 28.

RESULTS: The most frequent toxicities were myalgia/arthralgia, fatigue, and triglyceridemia. No dose-limiting toxicities were observed within the first 28 days up to 28 mg/m². However, seven of 21 patients experienced venous thromboembolic events (VTEs) during TAC-101 treatment. Eight additional patients who received 34 mg/m² were treated after a hypercoagulable work-up to exclude potential risk factors for VTE, and two of eight patients subsequently experienced VTEs. The maximum tolerated dose was exceeded at 34 mg/m²/d within the first 28 days, with one grade 3 hypertriglyceridemia, two grade 3 myalgia/arthralgia, and one grade 3 fatigue. One patient with advanced non–small-cell lung cancer had a complete response. No other responses were observed. No autoinduction of metabolism was observed with dosing over 28 days.

CONCLUSION: This is the first human clinical study with TAC-101, a RAR- selective retinoid. Musculoskeletal toxicity and hypertriglyceridemia were observed characteristics of previously studied retinoids. The recommended phase II dose is 24 mg/m² with this treatment schedule. Alternative treatment schedules and prospective evaluation of thrombotic risk will be investigated in subsequent studies.

W.K.H. is a consultant for Taiho Pharmaceutical.

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