title: Initial clinical trial of oral TAC-101, a novel retinoic acid receptor-alpha selective retinoid, in patients with advanced cancer.
abstract: OBJECTIVE
  The goals of this study were to determine the safety, toxicity, and pharmacokinetics of TAC-101, a novel synthetic retinoic acid receptor-alpha (RAR-alpha) selective retinoid, in patients with advanced cancer.
  
  
  METHODS
  Twenty-nine patients at two centers received oral TAC-101 at doses ranging from 12 to 34 mg/m(2)/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/m(2). However, seven of 21 patients experienced venous thromboembolic events (VTEs) during TAC-101 treatment. Eight additional patients who received 34 mg/m(2) 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/m(2)/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.
  
  
  CONCLUSIONS
  This is the first human clinical study with TAC-101, a RAR-alpha selective retinoid. Musculoskeletal toxicity and hypertriglyceridemia were observed characteristics of previously studied retinoids. The recommended phase II dose is 24 mg/m(2) with this treatment schedule. Alternative treatment schedules and prospective evaluation of thrombotic risk will be investigated in subsequent studies.
authors.affiliation: Developmental Therapeutics Program, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC, USA. rizvin@mskcc.org
authors.forename: Naiyer A
authors.initials: NA
authors.lastname: Rizvi
authors.forename: John L
authors.initials: JL
authors.lastname: Marshall
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ness
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hawkins
authors.forename: Craig
authors.initials: C
authors.lastname: Kessler
authors.forename: Helena
authors.initials: H
authors.lastname: Jacobs
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Brenckman
authors.forename: Jin S
authors.initials: JS
authors.lastname: Lee
authors.forename: William
authors.initials: W
authors.lastname: Petros
authors.forename: Waun K
authors.initials: WK
authors.lastname: Hong
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Kurie
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001565:Benzoates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D013923:Thromboembolism / Q000097:blood / Q000139:chemically induced; D014297:Trimethylsilyl Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; C112689:TAC 101; D014297:Trimethylsilyl Compounds