PMID- 9626460
OWN - NLM
STAT- MEDLINE
DCOM- 19980827
LR  - 20181201
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 4
IP  - 6
DP  - 1998 Jun
TI  - Phase I study of 9-cis-retinoic acid (ALRT1057 capsules) in adults with advanced 
      cancer.
PG  - 1437-42
AB  - 9-cis-Retinoic acid (9-cis-RA) and all-trans-RA (ATRA) are naturally occurring 
      hormones. The nuclear receptors that mediate the effects of retinoids are the 
      retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). ATRA binds 
      RAR with high affinity but does not bind to RXR, whereas 9-cis-RA, an isomer of 
      ATRA, is a ligand that binds and transactivates both RARs and RXRs. The goals of 
      this study were to determine the safety, tolerability, pharmacokinetics, and 
      metabolic profile of 9-cis-RA in advanced cancer patients. Forty-one patients 
      received oral 9-cis-RA (ALRT1057; Panretin capsules) at doses ranging from 5-140 
      mg/m2/day. Twenty-six patients were treated once daily with up to 140 mg/m2; a 
      subsequent cohort of 15 patients were treated twice daily (b.i.d.) at 100-140 
      mg/m2/day (50, 60, and 70 mg/m2 b.i.d.) to evaluate a b.i.d. dosing regimen. 
      Headache was the most frequent adverse event and was dose limiting in 3 of 41 
      patients. Skin toxicity was the next most common toxicity and was seen in 11 of 
      41 patients; it was typically mild and limited to skin dryness and erythema. 
      Other toxicities included conjunctivitis, flushing, diarrhea, transaminitis, 
      hypercalcemia, and asymptomatic hypertryglyceridemia. Toxicities were typically 
      dose related, occurred primarily above 83 mg/m2/day, and were not ameliorated by 
      b.i.d. dosing. No tumor responses were observed. The mean day 1 area under the 
      plasma concentration-time curve and peak plasma concentration values were 
      dose-proportional over all dose levels, whereas day 15 area under the plasma 
      concentration-time curve and peak plasma concentration values were nonlinear 
      above 83 mg/m2/day, suggesting that 9-cis-RA induced its own metabolism at doses 
      equal to and above 140 mg/m2/day. 9-cis-RA is a retinoid receptor pan agonist 
      with a more favorable pharmacokinetic and toxicity profile than that observed 
      with previously studied retinoids and merits further investigation.
FAU - Rizvi, N A
AU  - Rizvi NA
AD  - Department of Medicine, Lombardi Cancer Center, Georgetown University Medical 
      Center, Washington, D.C. 20007, USA.
FAU - Marshall, J L
AU  - Marshall JL
FAU - Ness, E
AU  - Ness E
FAU - Yoe, J
AU  - Yoe J
FAU - Gill, G M
AU  - Gill GM
FAU - Truglia, J A
AU  - Truglia JA
FAU - Loewen, G R
AU  - Loewen GR
FAU - Jaunakais, D
AU  - Jaunakais D
FAU - Ulm, E H
AU  - Ulm EH
FAU - Hawkins, M J
AU  - Hawkins MJ
LA  - eng
PT  - Clinical Trial
PT  - Clinical Trial, Phase I
PT  - Journal Article
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Capsules)
RN  - 1UA8E65KDZ (Alitretinoin)
RN  - 5688UTC01R (Tretinoin)
SB  - IM
MH  - Administration, Oral
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Alitretinoin
MH  - Antineoplastic Agents/administration & dosage/*pharmacokinetics/*toxicity
MH  - Capsules
MH  - Drug Administration Schedule
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/*drug therapy
MH  - Tretinoin/administration & dosage/*pharmacokinetics/*toxicity
EDAT- 1998/06/17 00:00
MHDA- 1998/06/17 00:01
CRDT- 1998/06/17 00:00
PHST- 1998/06/17 00:00 [pubmed]
PHST- 1998/06/17 00:01 [medline]
PHST- 1998/06/17 00:00 [entrez]
PST - ppublish
SO  - Clin Cancer Res. 1998 Jun;4(6):1437-42.