title: Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors.
abstract: BACKGROUND
  Recurrent malignant brain tumors (RMBTs) carry a poor prognosis. Dichloroacetate (DCA) activates mitochondrial oxidative metabolism and has shown activity against several human cancers.
  
  
  METHODS
  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.
authors.affiliation: Department of Neurosurgery, JHMHC, College of Medicine, University of Florida, PO Box 100265, Gainesville, FL, 32610-0265, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Dunbar
authors.forename: B S
authors.initials: BS
authors.lastname: Coats
authors.forename: A L
authors.initials: AL
authors.lastname: Shroads
authors.forename: T
authors.initials: T
authors.lastname: Langaee
authors.forename: A
authors.initials: A
authors.lastname: Lew
authors.forename: J R
authors.initials: JR
authors.lastname: Forder
authors.forename: J J
authors.initials: JJ
authors.lastname: Shuster
authors.forename: D A
authors.initials: DA
authors.lastname: Wagner
authors.forename: P W
authors.initials: PW
authors.lastname: Stacpoole
mesh_terms: D000096:Acetone / Q000031:analogs & derivatives / Q000652:urine; D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D001219:Aspartate Aminotransferases / Q000097:blood; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D001944:Breath Tests; D003999:Dichloroacetic Acid / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008297:Male; D008298:Maleates / Q000652:urine; D008875:Middle Aged; D019289:Pyruvic Acid / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D008298:Maleates; C460372:maleylacetone; D000096:Acetone; D019289:Pyruvic Acid; D003999:Dichloroacetic Acid; C407705:GSTZ1 protein, human; D005982:Glutathione Transferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase