Abstract CT315: Phase I study of BPM 31510 (ubidecarenone) in patients with advanced solid tumors
Authors: Shah Manish A. , Yu Peter , Narain Niven , Sarangarajan Rangaprasad , Kiebish Michael , Vishnudas Vivek , Sun Yezhou , Rodrigues Leonardo , Akmaev Viatcheslav R. , Brouwer Susan , Stevens Janice , Benaim Ely , Zinner Ralph 
Published: August 2015

Abstract
Background: BPM 31510 is a novel small molecule that targets the metabolic machinery of the cancer microenvironment to create a hallmark shift from lactate dependency towards mitochondrial oxidative phosphorylation, reversing the Warburg effect. Preclinical data indicates Ubidecarenone causes this shift resulting in tumor regression and enhances the antitumor activity in combination with chemotherapy agents in a priming schedule. This is the first clinical study to evaluate the BPM 31510 at a 4-days continuous infusion in four arms; as a single agent, and in combination with Gemcitabine, 5-FU or Docetaxel. Methods: Eligible patients (pts) (aged ≥18 y) had previously treated relapsed/refractory solid tumors. Pts in the monotherapy arm received IV BPM 31510 for 4 days in continuous infusion in 28-d cycles. Patients in the combination arms were primed for 3 weeks with BPM 31510 and then started in a weekly dosing (either gemcitabine, 5-FU or docetaxel) after the BPM 31510 infusion in a 6-week cycle. Doses were escalated in a 3+3 schema. Phase I endpoints were safety, pharmacokinetics (PK) and Multi-Omics based pharmacodynamics (PD). Dose limiting toxicities (DLTs) are determined using Cycle 1 safety data. Tumor response is evaluated at week 2 and every 4 -6 weeks. Results: As of 01 Dec 2014, 56 pts with advanced solid tumors have been enrolled. Pts have been treated at 3 dose levels up to 137 mg/kg of BPM 31510. No DLTs or study treatment-related SAEs have been reported. The MTD has not yet been established. The most frequently reported related AEs in all 4 arms were grade 1-2 INR prolongation that was resolved after Vitamin K administration. Pre-load of pts with Vitamin K have resolved these events. No bleeding reported. Grade 1-2 thrombocytopenia has been seen in the Gemcitabine arm requiring dose modification. Preliminary PK data indicated linear distribution. Tmax and Cmax are associated with the end of the infusion. Twelve out of twenty five patients (48%) that are evaluable for efficacy after cycle 2 showed various responses including: tumor reductions, decrease FDG, arrested tumor progression, stable disease, decrease in tumor markers, clinical improvements reflected on QOL. Conclusions: Emerging data from this study suggest that BPM 31510 is well tolerated in monotherapy or in combination with chemotherapy agents. Early anti-tumor activity is seen. Dose-escalation on a 6-day infusion schedule is ongoing to determine the recommended phase II dose.
Citation Format: Manish A. Shah, Peter Yu, Niven Narain, Rangaprasad Sarangarajan, Michael Kiebish, Vivek Vishnudas, Yezhou Sun, Leonardo Rodrigues, Viatcheslav R. Akmaev, Susan Brouwer, Janice Stevens, Ely Benaim, Ralph Zinner. Phase I study of BPM 31510 (ubidecarenone) in patients with advanced solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT315. doi:10.1158/1538-7445.AM2015-CT315