Investigational New Drugs

, Volume 32, Issue 3, pp 452–464 | Cite as

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

  • E. M. Dunbar
  • B. S. Coats
  • A. L. Shroads
  • T. Langaee
  • A. Lew
  • J. R. Forder
  • J. J. Shuster
  • D. A. Wagner
  • P. W. StacpooleEmail author


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.


Dichloroacetate Malignant (high grade) glioma Warburg effect Pyruvate dehydrogenase complex Pyruvate dehydrogenase kinase Phase 1 trial 



We are grateful to the DSMB members for their dedication to this trial and to Ms. Candace Caputo for editorial assistance.


This study was funded by Reliable Cancer Therapies, Brussels, Belgium, the Ocala Royal Dames Foundation, Ocala, FL, the Preston A. Wells, Jr., Center for Brain Tumor Therapy and a National Institutes of Health Clinical and Translational Science Award UL1 TR000064.

Conflict of interest disclosures

PWS holds investigator INDs for DCA. DAW is President, Metabolic Solutions, Inc.

Authors’ contributions

EMD, JJS and PWS developed the study design; EMD and BSC screened and enrolled subjects; EMD, PWS and BSC evaluated and treated patients; TL performed and interpreted the genotyping; ALS conducted mass spectrometric analyses; EMD, BSC and PWS analyzed routine clinical and imaging data; JRF and EMD analyzed exploratory imaging data; JJS reviewed interim safety data, PWS and DAW designed the breath test procedures; BSC conducted the pyruvate breath test; DAW analyzed 13CO2 breath samples; EMD, PWS and DAW wrote the manuscript.


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • E. M. Dunbar
    • 1
    • 2
  • B. S. Coats
    • 3
  • A. L. Shroads
    • 3
  • T. Langaee
    • 7
  • A. Lew
    • 3
  • J. R. Forder
    • 4
  • J. J. Shuster
    • 6
  • D. A. Wagner
    • 8
  • P. W. Stacpoole
    • 3
    • 5
    Email author
  1. 1.Department of Neurosurgery, JHMHC, College of MedicineUniversity of FloridaGainesvilleUSA
  2. 2.Piedmont Hospital Brain Tumor CenterAtlantaUSA
  3. 3.Department of Medicine, JHMHC, College of MedicineUniversity of FloridaGainesvilleUSA
  4. 4.Department of Radiology, JHMHC, College of MedicineUniversity of FloridaGainesvilleUSA
  5. 5.Department of Biochemistry and Molecular Biology, JHMHC, College of MedicineUniversity of FloridaGainesvilleUSA
  6. 6.Department of Health Outcomes and Policy, JHMHC, College of MedicineUniversity of FloridaGainesvilleUSA
  7. 7.Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, JHMHC, College of PharmacyUniversity of FloridaGainesvilleUSA
  8. 8.Metabolic Solutions, Inc.NashuaUSA

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