Abstract
BackgroundBPM31510-IV is a ubidecarenone (CoQ10) containing IV nanodispersion evaluated for safety and tolerability alone or in combination with chemotherapy in a phase 1 solid tumor study. In addition to clinical monitoring, an extensive pre- and post-treatment PD sampling was evaluated to generate comprehensive multi-omic profiles enabling post-hoc analysis of drug exposure to molecular analytes and pathways identifying the mechanism(s) driving clinical endpoints. MethodsPatients relapsed/refractory to standard therapy were enrolled either in the monotherapy arm with BPM31510 alone or in combination arms with gemcitabine, 5-FU or docetaxel. BPM31510-IV was administered as 96h or 144h continuous infusion. Endpoints included assessment of DLT, MTD, safety & tolerability, PK and assessment of tumor response evaluated at cycle 1 (28 days) and then after every 2 cycles. An 18 point PD sampling in Cycle 1 and 8 point sampling in Cycle 2 to collect plasma and buffy coat and optional tumor core biopsy (pre- and post-treatment) was obtained for comprehensive multi-omic profiling. ResultsA total of 104 patients were enrolled (33 monotherapy, 71 combination therapy) and included in the Safety Population; 99% patients receiving ≥ 1 treatment with BPM31510 experienced a TEAE. The most frequently (> 50% patients) experienced TEAEs were coagulation related including prolonged Prothrombin Time (PT), elevated INR and/or prolonged PTT and managed by administration of Vitamin K. Analysis of molecular proteomic datasets from the patients identified significant changes in levels of proteins directly or indirectly involved in the Complement and Coagulation Cascade (KEGG analysis: 37 proteins, q=2.51-44). Specifically, changes in the levels of vitamin K dependent coagulation factors (Prothrombin, Protein S, Complement C6 and others) were identified, suggestive of effect of BPM31510 on coagulation cascade. ConclusionsBPM31510-IV is well tolerated alone and in combination with chemotherapeutic agents. Proteomic profile based insights on Mechanism of Action (MOA) and adverse events will be used in Phase 2/3 clinical development. Clinical trial identificationNCT01957735. Legal entity responsible for the studyBERG LLC. FundingBERG LLC. DisclosureE. Granger: Leadership role, Full / Part-time employment, Officer / Board of Directors: BERG, LLC. M. Kiebish: Leadership role, Full / Part-time employment: BERG, LLC. G. Miller: Full / Part-time employment: BERG, LLC. L. Zhang: Full / Part-time employment: BERG, LLC. V. Vemulapalli: Full / Part-time employment: BERG, LLC. L. Rodrigues: Leadership role, Full / Part-time employment: BERG, LLC. N. Narain: Leadership role, Full / Part-time employment, Officer / Board of Directors: BERG, LLC. R. Sarangarajan: Leadership role, Full / Part-time employment: BERG, LLC. All other authors have declared no conflicts of interest.
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