Valproic acid (VPA) in patients with refractory advanced cancer: a dose escalating phase I clinical trial

Br J Cancer. 2007 Jul 16;97(2):177-82. doi: 10.1038/sj.bjc.6603851. Epub 2007 Jun 19.


Altered histone deacetylase (HDAC) activity has been identified in several types of cancer. This study was designed to determine the safety and maximum tolerated dose (MTD) of valproic acid (VPA) as an HDAC inhibitor in cancer patients. Twenty-six pre-treated patients with progressing solid tumours were enrolled in dose-escalating three-patient cohorts, starting at a dose of VPA 30 mg kg(-1) day(-1). VPA was administered as an 1-h infusion daily for 5 consecutive days in a 21-day cycle. Neurocognitive impairment dominated the toxicity profile, with grade 3 or 4 neurological side effects occurring in 8 out of 26 patients. No grade 3 or 4 haematological toxicity was observed. The MTD of infusional VPA was 60 mg kg(-1) day(-1). Biomonitoring of peripheral blood lymphocytes demonstrated the induction of histone hyperacetylation in the majority of patients and downmodulation of HDAC2. Pharmacokinetic studies showed increased mean and maximum serum VPA concentrations >120 and >250 mg l(-1), respectively, in the 90 and 120 mg kg(-1) cohorts, correlating well with the incidence of dose-limiting toxicity (DLT). Neurotoxicity was the main DLT of infusional VPA, doses up to 60 mg kg(-1) day(-1) for 5 consecutive days are well tolerated and show detectable biological activity. Further investigations are warranted to evaluate the effectivity of VPA alone and in combination with other cytotoxic drugs.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / therapeutic use
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Histone Deacetylase 2
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / analysis
  • Humans
  • Lymphocytes / enzymology
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms / drug therapy*
  • Repressor Proteins / analysis
  • Repressor Proteins / antagonists & inhibitors*
  • Valproic Acid / administration & dosage*
  • Valproic Acid / adverse effects*
  • Valproic Acid / therapeutic use


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Repressor Proteins
  • Valproic Acid
  • Histone Deacetylase 2
  • Histone Deacetylases