Phase Ia/b Multicenter Study of BPM31510IV Targeting Mitochondrial Metabolism/Warburg Effect as Monotherapy and Combination Chemotherapy in Solid Tumor Patients.

purposeBPM31510IV, a highly bioavailable intravenously administered coenzyme Q10 (CoQ10) formulation, was evaluated in a phase Ia/Ib study as monotherapy and in combination with chemotherapy in patients with advanced solid tumors. PATIENTS AND

methodsUsing a 3 + 3 design, patients received twice-weekly intravenous infusions of BPM31510IV monotherapy (arm 1) or combined with gemcitabine, 5-fluorouracil/leucovorin, or docetaxel (arm 2); crossover between arms was permitted. Tumor response was assessed by RECIST1.1. Pharmacokinetic and multiomics pharmacodynamic (PD) analyses were performed on plasma and core biopsy samples.

resultsA total of 97 patients were enrolled, 33 in arm 1 and 71 in arm 2 (seven patients crossed from arm 1 to arm 2). The MTD was 171 mg/kg for BPM31510IV monotherapy or with 5-fluorouracil/leucovorin and 110 mg/kg with gemcitabine or docetaxel. Four dose-limiting toxicities occurred (two in monotherapy; two in combination with chemotherapy). Most adverse events were coagulation-related, occurring in 96% of patients (grade ≥3 in 4%). Pharmacokinetics showed dose-proportional increases in CoQ10 levels to supraphysiologic concentrations (>200×). In arm 1, there was one (3%) partial response (PR), with stable disease (SD) reported in eight (24%) patients. In arm 2, there was one (1%) PR, with SD reported in 25 (35%) patients. Fluorodeoxyglucose-PET imaging and PD data suggest a change in tumor metabolism from glycolysis to oxidative phosphorylation.

conclusionsBPM31510IV as monotherapy and in combination with chemotherapy was safe, with preliminary evidence of antitumor activity. High plasma CoQ10 levels were achieved, inducing PD responses consistent with mitochondrial metabolic changes. These findings support continued clinical development of BPM31510IV. SIGNIFICANCE: BPM31510IV is a lipid nanodispersion of oxidized CoQ10 that alters the Warburg effect and displays anticancer activity. BPM31510IV seems to synergize with chemotherapy to induce cancer cell apoptosis, likely through mitochondrial priming. An initial phase I monotherapy study demonstrated that BPM31510IV is well tolerated in patients with advanced solid tumors. Based on these observations, the safety and preliminary antitumor activity of BPM31510IV were further explored in a phase Ia/Ib study in combination with chemotherapy. Results indicated that BPM31510IV monotherapy and BPM31510IV combined with chemotherapy are well tolerated, demonstrating preliminary evidence of antitumor activity and inducing physiologic and molecular changes consistent with altered mitochondrial metabolism. The most common adverse events were changes in coagulation parameters. Overall, this study provides valuable MTD and surrogate efficacy data that support the continued clinical development of BPM31510IV.