Initial clinical trial of the retinoid receptor pan agonist 9-cis retinoic acid Journal Article
| Authors: | Miller, V. A.; Rigas, J. R.; Benedetti, F. M.; Verret, A. L.; Tong, W. P.; Kris, M. G.; Gill, G. M.; Loewen, G. R.; Truglia, J. A.; Ulm, E. H.; Warrell, R. P. Jr |
| Article Title: | Initial clinical trial of the retinoid receptor pan agonist 9-cis retinoic acid |
| Abstract: | The retinoid response is mediated by families of nuclear receptors, the retinoic acid receptors (RARs), and the retinoid X receptors. All-trans 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 the safety, clinical tolerance, and pharmacokinetics of 9-cis RA in patients with advanced cancer. Thirty-four patients received once daily p.o. doses of 9 cis RA (administered as LGD1057) ranging from 5 to 230 mg/m2 for 3 weeks. Pharmacokinetic studies were performed on 28 patients at seven dose levels, 9-cis RA was generally well tolerated. Headache was the most common dose-limiting adverse effect. Other prominent reactions included facial flushing, myalgia, dyspnea, hypertriglyceridemia, and hypercalcemia. Relative to other retinoids, mucocutaneous reactions were mild. Two major antitumor responses were observed. Pharmacokinetic analysis revealed that the day 1 area under the plasma concentration x time curves (AUCs) were proportional to the dose. Up through doses of 140 mg/m2, 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 may be relevant to turner cell proliferation and differentiation. We recommend a dose of 140 mg/m2 for single-agent trials utilizing a once-daily schedule of administration. |
| Keywords: | adult; clinical article; aged; middle aged; unclassified drug; clinical trial; advanced cancer; side effect; antineoplastic agents; neoplasms; myalgia; hypercalcemia; transcription factors; dyspnea; flushing; headache; alitretinoin; drug blood level; phase 1 clinical trial; hypertriglyceridemia; oral drug administration; retinoic acid receptor; tretinoin; receptors, retinoic acid; retinoid x receptors; humans; human; male; female; priority journal; article; retinoic acid receptor agonist |
| Journal Title: | Clinical Cancer Research |
| Volume: | 2 |
| Issue: | 3 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 1996-03-01 |
| Start Page: | 471 |
| End Page: | 475 |
| Language: | English |
| PUBMED: | 9816192 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 22 November 2017 -- Source: Scopus |
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