title: A Phase I study of LGD1069 in adults with advanced cancer.
abstract: LGD1069 [Targretin; 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphtalenyl) propenyl] benzoic acid] is a novel synthetic retinoid X receptor-selective retinoid that has been recently identified. The goals of this study were to determine the safety, toxicity, pharmacokinetics (PKs), and metabolic profile of LGD1069 in advanced cancer patients. Sixty patients received oral LGD1069 at doses ranging from 5-1000 mg/m2/day with PK sampling performed on days 1 and 15. No dose-limiting toxicities (DLTs) were observed up to the 500 mg/m2/day dose level. DLT observed at and above 650 mg/m2/day included skin desquamation, hyperbilirubinemia, transaminase elevation, leukopenia, and diarrhea. Asymptomatic, dose-related alterations in lipid and thyroid metabolism were also observed. DLTs frequently observed with retinoic acid receptor-selective retinoids and pan agonists, including headache, mucocutaneous toxicity, and hypercalcemia, were not dose-limiting with LGD1069. Day 1 LGD1069 Cmax and area under the curve values increased dose-proportionately up to 800 mg/m2/day. Repeat-dose (day 15) area under the curve values varied between 25 and 105% of day 1 values. Although no objective tumor responses were observed, tumor progression may have been substantially arrested or delayed in non-small cell lung cancer (5 of 16) and in head and neck cancer (1 of 5), as well as other tumor types. At the higher dose levels, the molar concentration of LGD1069 was up to 10-fold higher than observed with other retinoids, yet toxicity was minimal. LGD1069 is an retinoid X receptor-selective retinoid agonist with a more favorable PK and toxicity profile than previously studied retinoids and merits further investigation as a chemopreventive and anticancer agent. On the basis of this Phase I trial, the recommended Phase II dose is 500 mg/m2/day.
authors.affiliation: Department of Medicine, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Rizvi
authors.forename: J L
authors.initials: JL
authors.lastname: Marshall
authors.forename: W
authors.initials: W
authors.lastname: Dahut
authors.forename: E
authors.initials: E
authors.lastname: Ness
authors.forename: J A
authors.initials: JA
authors.lastname: Truglia
authors.forename: G
authors.initials: G
authors.lastname: Loewen
authors.forename: G M
authors.initials: GM
authors.lastname: Gill
authors.forename: E H
authors.initials: EH
authors.lastname: Ulm
authors.forename: R
authors.initials: R
authors.lastname: Geiser
authors.forename: D
authors.initials: D
authors.lastname: Jaunakais
authors.forename: M J
authors.initials: MJ
authors.lastname: Hawkins
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016588:Anticarcinogenic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077610:Bexarotene; D005260:Female; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D016588:Anticarcinogenic Agents; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene