Initial clinical trial of a selective retinoid X receptor ligand, LGD1069.
OBJECTIVE
The retinoid response is mediated by nuclear receptors, including retinoic acid receptors (RARs) and retinoid "X" receptors (RXRs). All-trans retinoic acid (RA) binds only RARs, while 9-cis RA is an agonist for both RARs and RXRs. Recently, LGD1069 was identified as a highly selective RXR agonist with low affinity for RARs. We undertook a dose-ranging study to examine the safety, clinical tolerance, and pharmacokinetics of LGD1069 in patients with advanced cancer.


METHODS
Fifty-two patients received. LGD1069 administered orally once daily at doses that ranged from 5 to 500 mg/m2 for 1 to 41 weeks. Treatment proceeded from a starting dose of 5 mg/m2. Pharmacokinetic sampling was performed on selected patients on days 1, 15, and 29.


RESULTS
Reversible, asymptomatic increases in liver biochemical tests were the most common dose-limiting adverse effect. Less prominent reactions included leukopenia, hypertriglyceridemia, and hypercalcemia. Characteristic retinoid toxicities, such as cheilitis, headache, and myalgias/arthralgias, were mild or absent. Two patients with cutaneous T-cell lymphoma experienced major antitumor responses. Pharmacokinetic studies obtained in 27 patients at eight dose levels showed that the day 1 area under the plasma concentration-times-time curves (AUCs) were proportional to dose. At all doses studied, the day 1 AUCs were similar to those on days 15 and 29, indicating a lack of induced metabolism.


CONCLUSIONS
LGD1069 is a unique compound that exploits a newly identified pathway of retinoid receptor biology that may be relevant to tumor-cell proliferation and apoptosis. Further investigation of this drug is warranted. Based on the results of this study, a dose of 300 mg/m2 is recommended for single-agent trials.
Miller
V A
VA
Department of Medicine, Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, NY 10021, USA. millerv@mskcc.org
Benedetti
F M
FM
Rigas
J R
JR
Verret
A L
AL
Pfister
D G
DG
Straus
D
D
Kris
M G
MG
Crisp
M
M
Heyman
R
R
Loewen
G R
GR
Truglia
J A
JA
Warrell
R P
RP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D000077610:Bexarotene; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene