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Initial Clinical Trial of a High-affinity Retinoic Acid Receptor Ligand (LGD1550)¹

Developmental Chemotherapy [S. L. S., B. J. B., R. H., R. P. W.], Thoracic Oncology [V. A. M.], and the Head and Neck/Genitourinary Oncology Services [D. G. P.], Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, New York 10021, and Ligand Pharmaceuticals, Inc., San Diego, California 92128 [B. A. P., S. A. A., A. C.]

Retinoids mediate their biological response by binding to specific nuclear receptors, including retinoic acid receptors and/or retinoid X receptors. LGD1550 is a high-affinity ligand for all three retinoic acid receptors (, ß, and isoforms) and a potent inhibitor of AP-1, a protein that is closely linked with trophic responses and malignant transformation. We conducted a dose ranging study to evaluate the pharmacokinetics, safety, clinical tolerance, and potential efficacy of this drug in patients with advanced cancer. Twenty-seven patients received oral doses of LGD1550 once per day at doses ranging from 20–400 µg/m². Skin toxicity was the dose-limiting reaction at the 400 µg/m² daily dose level. Less prominent reactions included nausea and headache. No major antitumor effects were observed. Pharmacokinetic studies in 15 patients at five dose levels showed that the peak plasma concentration (C_max) and areas under the plasma concentration-time curve on day 1 were dose-proportional and were similar to values obtained on days 15, 29, and 84. Unlike other retinoids, LGD1550 did not induce its own metabolism, and there was little evidence of drug accumulation. The 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 µg/m² are relatively well tolerated. Additional clinical explorations are warranted, especially in patients with cancers of the prostate, thyroid, head and neck, and cervix.

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