PMID- 9053506
OWN - NLM
STAT- MEDLINE
DCOM- 19970310
LR  - 20220330
IS  - 0732-183X (Print)
IS  - 0732-183X (Linking)
VI  - 15
IP  - 2
DP  - 1997 Feb
TI  - Initial clinical trial of a selective retinoid X receptor ligand, LGD1069.
PG  - 790-5
AB  - PURPOSE: 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. PATIENTS AND 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. CONCLUSION: 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.
FAU - Miller, V A
AU  - Miller VA
AD  - Department of Medicine, Memorial Sloan-Kettering Cancer Center and Cornell 
      University Medical College, New York, NY 10021, USA. millerv@mskcc.org
FAU - Benedetti, F M
AU  - Benedetti FM
FAU - Rigas, J R
AU  - Rigas JR
FAU - Verret, A L
AU  - Verret AL
FAU - Pfister, D G
AU  - Pfister DG
FAU - Straus, D
AU  - Straus D
FAU - Kris, M G
AU  - Kris MG
FAU - Crisp, M
AU  - Crisp M
FAU - Heyman, R
AU  - Heyman R
FAU - Loewen, G R
AU  - Loewen GR
FAU - Truglia, J A
AU  - Truglia JA
FAU - Warrell, R P Jr
AU  - Warrell RP Jr
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - 0 (Anticarcinogenic Agents)
RN  - 0 (Tetrahydronaphthalenes)
RN  - A61RXM4375 (Bexarotene)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Anticarcinogenic Agents/administration & dosage/adverse 
      effects/pharmacokinetics/*pharmacology
MH  - Area Under Curve
MH  - Bexarotene
MH  - Drug Administration Schedule
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/*blood/drug therapy
MH  - Tetrahydronaphthalenes/administration & dosage/adverse 
      effects/pharmacokinetics/*pharmacology
EDAT- 1997/02/01 00:00
MHDA- 2001/03/28 10:01
CRDT- 1997/02/01 00:00
PHST- 1997/02/01 00:00 [pubmed]
PHST- 2001/03/28 10:01 [medline]
PHST- 1997/02/01 00:00 [entrez]
AID - 10.1200/JCO.1997.15.2.790 [doi]
PST - ppublish
SO  - J Clin Oncol. 1997 Feb;15(2):790-5. doi: 10.1200/JCO.1997.15.2.790.