Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors

Invest New Drugs. 2014 Jun;32(3):452-64. doi: 10.1007/s10637-013-0047-4. Epub 2013 Dec 3.


Background: Recurrent malignant brain tumors (RMBTs) carry a poor prognosis. Dichloroacetate (DCA) activates mitochondrial oxidative metabolism and has shown activity against several human cancers.

Design: We conducted an open-label study of oral DCA in 15 adults with recurrent WHO grade III - IV gliomas or metastases from a primary cancer outside the central nervous system. The primary objective was detection of a dose limiting toxicity for RMBTs at 4 weeks of treatment, defined as any grade 4 or 5 toxicity, or grade 3 toxicity directly attributable to DCA, based on the National Cancer Institute's Common Toxicity Criteria for Adverse Events, version 4.0. Secondary objectives involved safety, tolerability and hypothesis-generating data on disease status. Dosing was based on haplotype variation in glutathione transferase zeta 1/maleylacetoacetate isomerase (GSTZ1/MAAI), which participates in DCA and tyrosine catabolism.

Results: Eight patients completed at least 1 four week cycle. During this time, no dose-limiting toxicities occurred. No patient withdrew because of lack of tolerance to DCA, although 2 subjects experienced grade 0-1 distal parasthesias that led to elective withdrawal and/or dose-adjustment. All subjects completing at least 1 four week cycle remained clinically stable during this time and remained on DCA for an average of 75.5 days (range 26-312).

Conclusions: Chronic, oral DCA is feasible and well-tolerated in patients with recurrent malignant gliomas and other tumors metastatic to the brain using the dose range established for metabolic diseases. The importance of genetic-based dosing is confirmed and should be incorporated into future trials of chronic DCA administration.

Trial registration: NCT01111097.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetone / analogs & derivatives
  • Acetone / urine
  • Adult
  • Aged
  • Alanine Transaminase / blood
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics
  • Aspartate Aminotransferases / blood
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism
  • Breath Tests
  • Dichloroacetic Acid / administration & dosage*
  • Dichloroacetic Acid / adverse effects
  • Dichloroacetic Acid / blood
  • Dichloroacetic Acid / pharmacokinetics
  • Female
  • Glutathione Transferase / genetics
  • Haplotypes
  • Humans
  • Male
  • Maleates / urine
  • Middle Aged
  • Pyruvic Acid / metabolism


  • Antineoplastic Agents
  • Maleates
  • maleylacetone
  • Acetone
  • Pyruvic Acid
  • Dichloroacetic Acid
  • GSTZ1 protein, human
  • Glutathione Transferase
  • Aspartate Aminotransferases
  • Alanine Transaminase

Associated data