ral neuropathy > grade 1 at time of study initiation, pregnancy, other invasive cancers within the last two years, cancer treatment within 28 days of first DCA dose, active CNS metastases, malabsorption syndromes, or medications that may interact with DCA. This study was approved by the Institutional Review Board at the University of California Los Angeles, and all patients provided written informed consent documentation prior to enrollment. The study was monitored by the Jonsson Comprehensive Cancer Center Data Safety and order Aglafoline Monitoring Board. Study design This single arm, phase II, open-labeled study was designed to observe the role of oral DCA therapy in the management of stage IIIB/IV NSCLC and metastatic breast cancer. 29 patients were planned for the NSCLC cohort. As part of a Simon 2-Stage design, the breast cancer cohort was to enroll 18 patients with expansion to 43 patients if 3 responses were J Cancer Res Clin Oncol. Author manuscript; available in PMC 2015 March 01. Garon et al. Page 4 seen among the first 18 patients. The primary endpoint was response rate. Secondary endpoints included safety/tolerability, progression free survival and overall survival. The analysis described in the manuscript is descriptive based on the low number of patients enrolled. Treatment Based on dosage data determined by a glioblastoma trial performed by Michelakis et al in 2010, as well as trials published with DCA as a therapy for patients with congenital mitochondria diseases, a dose of 6.25 mg/kg orally twice daily was chosen. DCA was purchased from a 
commercial chemical supplier. Each dose was administered with food. Patients were continued on treatment until radiographic progression, clinical progression, unacceptable toxicity, withdrawal of consent, or death. One dose reduction to 3.25 mg/kg twice daily was allowed in the setting of grade 2 adverse events after resolution to grade 1. Study Assessments Safety–Safety assessments occurred within 28 days of therapy and on day 1, 8, 15, 29, and every 28 days thereafter as well as at the end of study. Assessments included: history and physical examination, vital signs, blood counts with differential, adverse events graded according to NCI-CTCAE version 3.0, concomitant medications, and standard hematology and chemistry tests. During the study, a requirement for a baseline MRI of the brain with contrast was added. CT scan of the chest and upper abdomen with contrast was required within 28 days of enrollment, and tumor response was evaluated radiographically using PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19843186 the RECIST 1.0 every 8 weeks.Data were compared to untreated controls. Cells were counted using a Z1 Coulter Particle Counter on day 1 and day 6 with percent growth inhibition defined as 100 . Experiments were performed in duplicate. Error bars represent standard error for each experiment. Nonlinear curve fitting to data points was performed using the Proc NLIN function in SAS for Windows version 9.2 using a basic four-parameter sigmoid model. IC50 were interpolated from the resulting curves. Measurement of oxygen consumption rates post 48hr DCA treatment Cellular oxygen consumption rates were measured in 4 cell lines using a water-jacketed anaerobic chamber fitted with a fiber optic oxygen sensor. The fiber optic probe was calibrated with 15mM sodium hydrosulfite corresponding to 0% oxygen, and cell culture media corresponding to 20.9% oxygen. In vitro combination proliferation assays For combination in vitro proliferation assays, the same
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