Document Detail

Valproic acid reduces the tolerability of temsirolimus in children and adolescents with solid tumors.
MedLine Citation:
PMID:  23328074     Owner:  NLM     Status:  Publisher    
A pediatric study has established a maximum tolerated dose (MTD) for temsirolimus (Tem) of more than 150 mg/m intravenously/week. A phase I trial was conducted to establish the MTD for Tem in combination with valproic acid (VPA) in children and adolescents with refractory solid tumors. The secondary aims included expression of mammalian target of rapamycin (mTOR) markers on archival tumor tissue; Tem pharmacokinetics; assessment of histone acetylation (HA); and tumor response. Patients were treated with VPA (5 mg/kg orally three times daily) with a target serum level of 75-100 mcg/ml. Tem was started at an initial dose of 60 mg/m/week. Pharmacokinetics and HA measurements were performed during weeks 1 and 5. Two of the first three patients experienced dose-limiting toxicity (grade 3 mucositis). Tem at 35 mg/m/week was found to be tolerable. Peak Tem concentrations were higher in all patients compared with those in previously published reports of single agent Tem. Increases in HA are correlated with VPA levels. All tumor samples expressed mTORC1 and mTORC2. An objective response was observed in one patient (melanoma), whereas transient stable disease was observed in four other patients (spinal cord ependymoma, alveolar soft part sarcoma, medullary thyroid carcinoma, and hepatocellular carcinoma). The MTD of Tem when administered with VPA is considerably lower than when used as a single agent, with mucositis the major dose-limiting toxicity. The combination merits further study and may have activity in melanoma. Attention to drug-drug interactions will be important in future multiagent trials including Tem.
Don W Coulter; Christine Walko; Jai Patel; Billie M Moats-Staats; Andrew McFadden; Scott V Smith; Wasiuddin A Khan; Arlene S Bridges; Allison M Deal; Javier Oesterheld; Ian J Davis; Julie Blatt
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-16
Journal Detail:
Title:  Anti-cancer drugs     Volume:  -     ISSN:  1473-5741     ISO Abbreviation:  Anticancer Drugs     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-18     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9100823     Medline TA:  Anticancer Drugs     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
aDepartment of Pediatrics, Division of Pediatric Endocrinology bDepartment of Pediatrics, Division of Pediatric Hematology Oncology cDepartment of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy Departments of dSurgical Pathology ePathology and Laboratory Medicine fLineberger Comprehensive Cancer Center gBiostatistical Core hDepartment of Genetics iCarolina Center for Genome Science, The University of North Carolina, Chapel Hill jLevine Children's Hospital, Charlotte, North Carolina kDepartment of Pediatrics, Division of Pediatric Hematology Oncology, the University of Nebraska, Lincoln, Nebraska, USA.
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