Valproic acid reduces the tolerability of temsirolimus in children and adolescents with solid tumors

Donald 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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)415-421
Number of pages7
JournalAnti-Cancer Drugs
Volume24
Issue number4
DOIs
StatePublished - Apr 1 2013

Fingerprint

Valproic Acid
Neoplasms
Maximum Tolerated Dose
Acetylation
Histones
Mucositis
Melanoma
Alveolar Soft Part Sarcoma
Pharmacokinetics
temsirolimus
Ependymoma
Sirolimus
Drug Interactions
Hepatocellular Carcinoma
Spinal Cord
Pediatrics
Serum

Keywords

  • pediatrics
  • phase I
  • solid tumors
  • temsirolimus
  • valproic

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Valproic acid reduces the tolerability of temsirolimus in children and adolescents with solid tumors. / Coulter, Donald W; Walko, Christine; Patel, Jai; Moats-Staats, Billie M.; Mcfadden, Andrew; Smith, Scott V.; Khan, Wasiuddin A.; Bridges, Arlene S.; Deal, Allison M.; Oesterheld, Javier; Davis, Ian J.; Blatt, Julie.

In: Anti-Cancer Drugs, Vol. 24, No. 4, 01.04.2013, p. 415-421.

Research output: Contribution to journalArticle

Coulter, DW, Walko, C, Patel, J, Moats-Staats, BM, Mcfadden, A, Smith, SV, Khan, WA, Bridges, AS, Deal, AM, Oesterheld, J, Davis, IJ & Blatt, J 2013, 'Valproic acid reduces the tolerability of temsirolimus in children and adolescents with solid tumors', Anti-Cancer Drugs, vol. 24, no. 4, pp. 415-421. https://doi.org/10.1097/CAD.0b013e32835dc7c5
Coulter, Donald W ; Walko, Christine ; Patel, Jai ; Moats-Staats, Billie M. ; Mcfadden, Andrew ; Smith, Scott V. ; Khan, Wasiuddin A. ; Bridges, Arlene S. ; Deal, Allison M. ; Oesterheld, Javier ; Davis, Ian J. ; Blatt, Julie. / Valproic acid reduces the tolerability of temsirolimus in children and adolescents with solid tumors. In: Anti-Cancer Drugs. 2013 ; Vol. 24, No. 4. pp. 415-421.
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