Initial clinical trial of a high-affinity retinoic acid receptor ligand (LGD1550)

Retinoids mediate their biological response by binding to specific nuclear receptors, including retinoic acid receptors and/or retinoid X receptors, L GD1550 is a high-affinity ligand for all three retinoic acid receptors (alp ha, beta, and gamma isoforms) and a potent inhibitor of AP-1, a protein tha t is closely linked with trophic responses and malignant trans formation. W e conducted a dose ranging study to evaluate the pharmacokinetics, safety, clinical tolerance, and potential efficacy of this drug in patients with ad vanced cancer. Twenty-seven patients received oral doses of LGD1550 once pe r day at doses ranging from 20-400 mu g/m(2). Skin toxicity was the dose-li miting reaction at the 400 mu g/m(2) daily dose level. Less prominent react ions included nausea and headache. No major antitumor effects were observed . Pharmacokinetic studies in 15 patients at five dose levels showed that th e peak plasma concentration (C-max) and areas under the plasma concentratio n-time curve on day 1 were dose-proportional and were similar to values obt ained on days 15, 29, and 84. Unlike other retinoids, LGD1550 did not induc e its own metabolism, and there was little evidence of drug accumulation. T he t(1/2) was approximately 5 h after both the initial and repeated doses. We conclude that once-daily doses of LGD1550 of up to 300 mu g/m(2) are rel atively well tolerated. Additional clinical explorations are warranted, esp ecially in patients with cancers of the prostate, thyroid, head and neck, a nd cervix.