title: Initial clinical trial of a selective retinoid X receptor ligand, LGD1069.
abstract: OBJECTIVE
  The retinoid response is mediated by nuclear receptors, including retinoic acid receptors (RARs) and retinoid "X" receptors (RXRs). All-trans retinoic acid (RA) binds only RARs, while 9-cis RA is an agonist for both RARs and RXRs. Recently, LGD1069 was identified as a highly selective RXR agonist with low affinity for RARs. We undertook a dose-ranging study to examine the safety, clinical tolerance, and pharmacokinetics of LGD1069 in patients with advanced cancer.
  
  
  METHODS
  Fifty-two patients received. LGD1069 administered orally once daily at doses that ranged from 5 to 500 mg/m2 for 1 to 41 weeks. Treatment proceeded from a starting dose of 5 mg/m2. Pharmacokinetic sampling was performed on selected patients on days 1, 15, and 29.
  
  
  RESULTS
  Reversible, asymptomatic increases in liver biochemical tests were the most common dose-limiting adverse effect. Less prominent reactions included leukopenia, hypertriglyceridemia, and hypercalcemia. Characteristic retinoid toxicities, such as cheilitis, headache, and myalgias/arthralgias, were mild or absent. Two patients with cutaneous T-cell lymphoma experienced major antitumor responses. Pharmacokinetic studies obtained in 27 patients at eight dose levels showed that the day 1 area under the plasma concentration-times-time curves (AUCs) were proportional to dose. At all doses studied, the day 1 AUCs were similar to those on days 15 and 29, indicating a lack of induced metabolism.
  
  
  CONCLUSIONS
  LGD1069 is a unique compound that exploits a newly identified pathway of retinoid receptor biology that may be relevant to tumor-cell proliferation and apoptosis. Further investigation of this drug is warranted. Based on the results of this study, a dose of 300 mg/m2 is recommended for single-agent trials.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, NY 10021, USA. millerv@mskcc.org
authors.forename: V A
authors.initials: VA
authors.lastname: Miller
authors.forename: F M
authors.initials: FM
authors.lastname: Benedetti
authors.forename: J R
authors.initials: JR
authors.lastname: Rigas
authors.forename: A L
authors.initials: AL
authors.lastname: Verret
authors.forename: D G
authors.initials: DG
authors.lastname: Pfister
authors.forename: D
authors.initials: D
authors.lastname: Straus
authors.forename: M G
authors.initials: MG
authors.lastname: Kris
authors.forename: M
authors.initials: M
authors.lastname: Crisp
authors.forename: R
authors.initials: R
authors.lastname: Heyman
authors.forename: G R
authors.initials: GR
authors.lastname: Loewen
authors.forename: J A
authors.initials: JA
authors.lastname: Truglia
authors.forename: R P
authors.initials: RP
authors.lastname: Warrell
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D000077610:Bexarotene; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D016588:Anticarcinogenic Agents; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene