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

• DOI: 10.1007/s10637-013-0047-4
• Publication Date: 2013-12-02T08:17:57Z
• Authors: E. M. Dunbar; B. S. Coats; A. L. Shroads; T. Langaee; A. Lew; J. R. Forder; J. J. Shuster; D. A. Wagner; P. W. Stacpoole
• Keywords: Adult; Male; 0303 health sciences; Dichloroacetic Acid; Brain Neoplasms; Maleates; Alanine Transaminase; Antineoplastic Agents; Middle Aged; 3. Good health; Acetone; 03 medical and health sciences; Breath Tests; Haplotypes; Pyruvic Acid; Humans; Female; Aspartate Aminotransferases; Aged; Glutathione Transferase

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