Cited by 242Glioma Diagnosis and TreatmentCancer, Hypoxia, and MetabolismNeuroprotection in Cerebral Ischemia

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

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Dunbar, E. M., Coats, B. S., Shroads, A. L., Langaee, T., Lew, A., Forder, J. R., Shuster, J. J., Wagner, D. A., Stacpoole, P. W.·2014·Investigational New Drugs

DOI 10.1007/s10637-013-0047-4PMC PMC4455946

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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. 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.

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Authors: Dunbar, E. M., Coats, B. S., Shroads, A. L., Langaee, T., Lew, A., Forder, J. R., Shuster, J. J., Wagner, D. A., & Stacpoole, P. W.
Affiliations: University of Florida Health (US)
University of Florida (US)
Metabolic Solutions (US)
Corresponding author: Stacpoole, P. W.
ORCID: Langaee, T.
Shuster, J. J.
Wagner, D. A.
Stacpoole, P. W.
Venue: Investigational New Drugs
Publisher: Springer Science and Business Media LLC
Published: 2013-12-03
Volume: 32
Issue: 3
Pages: 452-464
ISSN: 0167-6997 (ISSN-L)
1573-0646
DOI: 10.1007/s10637-013-0047-4
PMC: PMC4455946
OpenAlex: W2017529554
Cited by: 241
References: 50
Citations by year: 2026: 30 · 2025: 18 · 2024: 17 · 2023: 15 · 2022: 16 · 2021: 18 · 2020: 18 · 2019: 29 · 2018: 20 · 2017: 17 · 2016: 15 · 2015: 19 · 2014: 9
FWCI: 7.06
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Investigational New Drugs (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (UL1TR000064)
National Center for Advancing Translational Sciences
Topics: Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Neuroscience › Neurology › Neuroprotection in Cerebral Ischemia
Keywords: dichloroacetate, glioma, brain metastases, dose-limiting toxicity, drug safety and tolerability, mitochondrial oxidative metabolism
MeSH terms: Acetone, Adult, Aged, Alanine Transaminase, Antineoplastic Agents, Aspartate Aminotransferases, Brain Neoplasms, Breath Tests, Dichloroacetic Acid, Female, Glutathione Transferase, Haplotypes, Humans, Male, Maleates, Middle Aged, Pyruvic Acid

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