title: Valproic acid reduces the tolerability of temsirolimus in children and adolescents with solid tumors.
abstract: 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.
authors: Department of Pediatrics, Division of Pediatric Endocrinology, University of North Carolina, Chapel Hill, NC 27599-7236, USA.
authors: Don W
authors: DW
authors: Coulter
authors: Christine
authors: C
authors: Walko
authors: Jai
authors: J
authors: Patel
authors: Billie M
authors: BM
authors: Moats-Staats
authors: Andrew
authors: A
authors: McFadden
authors: Scott V
authors: SV
authors: Smith
authors: Wasiuddin A
authors: WA
authors: Khan
authors: Arlene S
authors: AS
authors: Bridges
authors: Allison M
authors: AM
authors: Deal
authors: Javier
authors: J
authors: Oesterheld
authors: Ian J
authors: IJ
authors: Davis
authors: Julie
authors: J
authors: Blatt
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004155:Diphenhydramine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D003875:Drug Eruptions / Q000209:etiology* / Q000517:prevention & control; D057239:Early Termination of Clinical Trials; D005221:Fatigue / Q000139:chemically induced*; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000494:pharmacology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D052016:Mucositis / Q000139:chemically induced*; D009369:Neoplasms / Q000188:drug therapy*; D010146:Pain / Q000139:chemically induced; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D014635:Valproic Acid / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000494:pharmacology
chemical_list: D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid; C401859:temsirolimus; D004155:Diphenhydramine; D020123:Sirolimus