Initial clinical trial of a selective retinoid X receptor ligand, LGD1069 Journal Article


Authors: Miller, V. A.; Benedetti, F. M.; Rigas, J. R.; Verret, A. L.; Pfister, D. G.; Straus, D.; Kris, M. G.; Crisp, M.; Heyman, R.; Loewen, G. R.; Truglia, J. A.; Warrell Jr, R. P.
Article Title: Initial clinical trial of a selective retinoid X receptor ligand, LGD1069
Abstract: Purpose: 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 PARs and RXRs. Recently, LGD1069 was identified as a highly selective RXR agonist with low affinity for PARs. We undertook a dose- ranging study to examine the safety, clinical tolerance, and pharmacokinetics of LGD1069 in patients with advanced cancer. Patients and 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. Conclusion: 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.
Keywords: adult; cancer chemotherapy; aged; aged, 80 and over; middle aged; major clinical study; clinical trial; advanced cancer; neoplasms; leukopenia; myalgia; drug administration schedule; hypercalcemia; antineoplastic activity; arthralgia; transcription regulation; anticarcinogenic agents; area under curve; headache; receptor affinity; dose calculation; ligand binding; hypertriglyceridemia; cheilitis; bexarotene; tetrahydronaphthalenes; retinoid x receptor; humans; human; male; female; priority journal; article
Journal Title: Journal of Clinical Oncology
Volume: 15
Issue: 2
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 1997-02-01
Start Page: 790
End Page: 795
Language: English
PUBMED: 9053506
PROVIDER: scopus
DOI: 10.1200/JCO.1997.15.2.790
DOI/URL:
Notes: Article -- Export Date: 17 March 2017 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Vincent Miller
    262 Miller
  2. David G Pfister
    247 Pfister
  3. David J Straus
    205 Straus
  4. Mark Kris
    598 Kris
  5. Raymond P Warrell
    105 Warrell