INITIAL CLINICAL-TRIAL OF THE RETINOID RECEPTOR PAN AGONIST 9-CIS RETINOIC ACID

The retinoid response is mediated by families of nuclear receptors, th e retinoic acid receptors (RARs), and the retinoid X receptors. All-tr ans retinoic acid (RA) binds only RARs and induces its own metabolism. In contrast, 9-cis RA is a newly identified agonist for both RARs and retinoid X receptors. We undertook a dose-ranging study to examine th e safety, clinical tolerance, and pharmacokinetics of 9-cis RA in pati ents with advanced cancer. Thirty-four patients received once daily p. o. doses of 9-cis RA (administered as LGD1057) ranging from 5 to 230 m g/m(2) for 4 weeks. Pharmacokinetic studies were performed on 28 patie nts at seven dose levels. 9-cis RA was generally well tolerated. Heada che was the most common dose-limiting adverse effect. Other prominent reactions included facial flushing, myalgia, dyspnea, hypertriglycerid emia, and hypercalcemia. Relative to other retinoids, mucocutaneous re actions were mild. No major antitumor responses were observed. Pharmac okinetic analysis revealed that the day 1 area under the plasma concen tration x time curves (AUCs) were proportional to the dose. Up through doses of 140 mg/m(2), the day 1 AUCs were similar to those on days 15 and 29. At higher doses, however, AUCs tended to decline with repeat dosing. 9-cis RA is a novel compound that exploits a newly identified pathway of retinoid receptor biology that mag be relevant to tumor cel l proliferation and differentiation. We recommend a dose of 140 mg/m(2 ) for single-agent trials utilizing a once-daily schedule of administr ation.