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

• Published in: Investigational new drugs Vol. 32; no. 3; pp. 452 - 464
• Main 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.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-06-2014; Springer; Springer Nature B.V
• Subjects: Acetone - analogs & derivatives; Acetone - urine; Acids; Adult; Aged; Alanine Transaminase - blood; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Aspartate Aminotransferases - blood; Biochemistry; Biological and medical sciences; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Breath Tests; Cancer therapies; Dehydrogenases; Dichloroacetic Acid - administration & dosage; Dichloroacetic Acid - adverse effects; Dichloroacetic Acid - blood; Dichloroacetic Acid - pharmacokinetics; Drug dosages; Enzymes; Female; Glucose; Glutathione Transferase - genetics; Haplotypes; Humans; Kinases; Male; Maleates - urine; Medical schools; Medical sciences; Medicine; Medicine & Public Health; Metabolism; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nervous system; Neurology; Oncology; Oxidation; Patients; Pharmaceuticals; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacovigilance; Phase I Studies; Phosphorylation; Product safety; Pyruvic Acid - metabolism; R&D; Research & development; Toxicity; Tumors; Tumors of the nervous system. Phacomatoses; United States > US; Dichloroacetate; Malignant (high grade) glioma; Pyruvate dehydrogenase kinase; Pyruvate dehydrogenase complex; Phase 1 trial; Warburg effect; Human; Nervous system diseases; Relapse; Pyruvate kinase; Enzyme; Transferases; Brain cancer; Pyruvate dehydrogenase (lipoamide); Malignant tumor; Cerebral disorder; High grade; Malignant glioma; Central nervous system disease; Phase I trial; Adult; Oxidoreductases; Cancer; High malignancy
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-013-0047-4

Summary
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.