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 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. 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.

Low Dose Bexarotene Treatment Rescues Dopamine Neurons and Restores Behavioral Function in Models of Parkinson’s Disease

“…24,25,29,34 For example, there is a clear dose dependence of hyperlipidemia in patients, 24,25 and based on this relationship, doses within the range we estimate Figure 2. Efficacy of bexarotene in restoring dopamine cells and behavior in 6-OHDA lesioned rats.…”

Results of a Phase II trial of oral bexarotene (Targretin) combined with interferon alfa‐2b (Intron‐A) for patients with cutaneous T‐cell lymphoma

“…The toxicity profile of bexarotene is favorable as compared with isotretinoin and etretinate. 23,24 In the present study, 3 of 7 responses occurred with bexarotene alone at Week 8. However, a higher response rate with bexarotene alone might have been seen if the period of monotherapy had been extended beyond 8 weeks before the addition of interferon alfa.…”

Aerosolized Bexarotene Inhibits Lung Tumorigenesis without Increasing Plasma Triglyceride and Cholesterol Levels in Mice

“…Bexarotene is presently undergoing human phase II and phase III trials in lung cancer and is the first RXR-selective ligand to be tested in humans (17,18). It is well tolerated in these trials over a wide dose range (17,19).…”