Ubidecarenone

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Niven R. Narain - One of the best experts on this subject based on the ideXlab platform.

  • Phase II trial of BPM31510-IV plus gemcitabine in advanced pancreatic ductal adenocarcinomas (PDAC).
    Journal of Clinical Oncology, 2020
    Co-Authors: Madappa N. Kundranda, David Propper, Paul S. Ritch, James Strauss, Manuel Hidalgo, Roopinder Gillmore, Rangaprasad Sarangarajan, Niven R. Narain, Michael A. Kiebish, Leonardo O. Rodrigues
    Abstract:

    723Background: BPM31510-IV is an Ubidecarenone (CoQ10) drug-lipid conjugate nanodispersion targeting metabolic machinery in cancer, shifting bioenergetics from lactate dependency towards mitochondr...

  • Proteomic profiling identifies molecular basis of adverse event to BPM31510 exposure: Rationale for comprehensive molecular pharmacodynamics (PD) in phase I clinical trial design
    Annals of Oncology, 2019
    Co-Authors: Vivek Subbiah, Michael A. Kiebish, Leonardo O. Rodrigues, David S. Hong, Gregory M Miller, Lixia Zhang, Ralph Zinner, Granger, Vijetha Vemulapalli, Niven R. Narain
    Abstract:

    Abstract Background BPM31510-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. Methods Patients 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 96 h or 144 h 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. Results A 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. Conclusions BPM31510-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 identification NCT01957735. Legal entity responsible for the study BERG LLC. Funding BERG LLC. Disclosure E. 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.

  • A phase I molecular adaptive clinical study to evaluate safety and tolerability of BPM31510-IV in advanced solid tumors: Final study results.
    Journal of Clinical Oncology, 2018
    Co-Authors: Niven R. Narain, Michael A. Kiebish, Leonardo O. Rodrigues, Vivek Subbiah, David S. Hong, David Lucius, Viatcheslav R. Akmaev, Gregory M Miller, Eric Milliman, Lixia Zhang
    Abstract:

    2541Background: BPM31510-IV is an Ubidecarenone (CoQ10) containing IV nanodispersion targeting metabolic machinery in cancer, shifting bioenergetics from lactate dependency towards mitochondrial Ox...

  • Abstract 4067: BPM31510, a clinical stage metabolic modulator demonstrates therapeutic efficacy in anin vivoC6 rat glioma model and synergizes with temozolomide
    Cancer Research, 2017
    Co-Authors: Stephane Gesta, Michael A. Kiebish, Vivek K Vishnudas, Tulin Dadali, Milton Merchant, Anne R. Diers, Semma Nagpal, Joaquin Jiminez, Niven R. Narain
    Abstract:

    BPM31510, a parenteral nanodispersion of Ubidecarenone that is in clinical testing for solid tumors, effectuates an anti-cancer effect in highly metabolic cancers by eliciting an anti-Warburg effect. Intraperitoneal (i.p.) administration of BPM31510 reverses paraplegia in a rat CNS leukemia model demonstrating the bioavailability of the drug to the central nervous system. The study describes data demonstrating the therapeutic utility of BPM31510 in glioblastoma multiforme (GBM). BPM31510 decreased cell proliferation rates in patient derived GBM cell lines compared to temozolamide (TMZ), pretreatment with BPM31510 followed by TMZ challenge was associated with significant synergy in reducing cell proliferation compared to monotherapy. In a C6 glioma allograft rat model treatment with BPM31510 alone (n=30/group) (i.p., 50mg/kg, b.i.d) increased overall survival compared to untreated control group. BPM31510 in combination with procarbazine (oral, 60mg/kg; d 8, 21) and vincristine (IV, 1.4mg/kg; d 8, 29) significantly improved overall survival compared to BPM31510 alone or chemotherapy. Furthermore, long term survival was achieved in four of twenty rats with C6 gliomas receiving BPM31510 doses between 10 and 50 mg/kg compared with none treated with either vehicle or irradiation (P Citation Format: Stephane Gesta, Semma Nagpal, Tulin Dadali, Milton Merchant, Taichang Jan, Anne R. Diers, Michael Kiebish, Joaquin Jiminez, Vivek K. Vishnudas, Niven R. Narain, Rangaprasad Sarangarajan, Lawrence Recht. BPM31510, a clinical stage metabolic modulator demonstrates therapeutic efficacy in an in vivo C6 rat glioma model and synergizes with temozolomide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4067. doi:10.1158/1538-7445.AM2017-4067

  • Abstract 5576: BPM 31510, a clinical stage candidate demonstrates potent anti-tumor effect in an immune-competent syngeneic pancreatic cancer model
    Cancer Research, 2017
    Co-Authors: Shiva Kazerounian, Rangaprasad Sarangarajan, Vivek K Vishnudas, Tulin Dadali, Anne R. Diers, Stephane Gesta, Aishwarya Sarma, Nidhi Gaur, Maria D. Nastke, Niven R. Narain
    Abstract:

    BPM 31510, a clinical stage nanodispersion of Ubidecarenone, demonstrates anti-tumor effects by eliciting an anti-Warburg metabolic switch in cancer. Previous studies in an immune compromised PaCa2 xenograft model has unequivocally demonstrated significant efficacy of BPM 31510 on tumor volume and survival. The fundamental property of BPM 31510 to influence mitochondrial bioenergetics and the recognized interplay between T cell metabolism and maturation prompted investigation into the effects of BPM 31510 on T lymphocyte functions in eliciting anti-cancer effects. In this study BPM 31510 selectively influenced activation and maturation of T cells in murine peripheral blood mononuclear cells (PBMCs). Moreover, in addition to determining changes in the CD3+ population, changes in surface expression of PD-1 and CTLA4 along with the IFN-γ secretion were examined. Murine cancer cell lines exposed to BPM 31510 were associated with variable sensitivity with highly metabolic tumor types being most sensitive. Next, the anti-cancer activity of BPM 31510 in an in vivo immunocompetent syngeneic Pan02 rodent model was investigated. Murine Pan02 pancreatic cancer cells were implanted subcutaneously into C57BL/6 mice. Tumors with mean volume of 80 mm3 were treated twice a day with vehicle control or BPM 31510 at 25, 50, 100 mg/kg, administered intraperitoneal. Tumor volumes were measured every 4 days. At day 21 post treatment, tumors were harvested and analyzed for the level of infiltrating immune cells by immunofluorescent staining with CD8+ for T cells and F4/80 for tumor macrophages. These results demonstrate a dose-dependent reduction in tumor volume following 21 days of BPM 31510 treatment. In summary, BPM 31510 exerts potent anti-tumor effects through its dual function of modulating tumor cell metabolism and potentially influencing immune check-point to improve overall survival outcomes. Citation Format: Shiva Kazerounian, Aishwarya Sarma, Nidhi Gaur, Maria D. Nastke, Tulin Dadali, Anne R. Diers, Stephane Gesta, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Niven R. Narain. BPM 31510, a clinical stage candidate demonstrates potent anti-tumor effect in an immune-competent syngeneic pancreatic cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5576. doi:10.1158/1538-7445.AM2017-5576

Janice Stevens - One of the best experts on this subject based on the ideXlab platform.

  • bayesian ai to delineate molecular signatures of patient susceptibility to potential hematologic events in a phase i study of bpm31510 Ubidecarenone in solid tumors
    Journal of Clinical Oncology, 2017
    Co-Authors: Rangaprasad Sarangarajan, Michael A. Kiebish, Leonardo O. Rodrigues, Vivek Subbiah, David S. Hong, Gregory M Miller, Vivek K Vishnudas, Eric M Grund, Hedy Dion, Janice Stevens
    Abstract:

    e14042Background: BPM 31510 is a Ubidecarenone containing nanodispersion elicits anticancer effect by switching cancer cells energy generation from glycolysis to mitochondrial OXPHOS; i.e. reverses...

  • Effect of BPM31510 on radiosensitivity of temozolomide-resistant glioblastoma cell model and survival in in vivo C6 glioma rat model supporting phase I clinical investigation in GBM.
    Journal of Clinical Oncology, 2017
    Co-Authors: Seema Nagpal, Vivek K Vishnudas, Janice Stevens, Tulin Dadali, Taichang Jang, Milton Merchant, Anne R. Diers, Stephane Gesta, Megan Wilson, Michael A. Kiebish
    Abstract:

    e13509Background: Glioblastoma (GB) is characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an Ubidecarenone containing lipid nanodispersion effectuates a switch in cancer energy sourcing from glycolysis towards mitochondrial OXPHOS, i.e. reverses Warburg effect, providing rationale for its potential utility in treatment of GB. The current study investigated utility of BPM31510 alone and in combination with temozolomide. Methods: In vitro (U251-MG human GB cell line) and in vivo (C6 glioma rat model) preclinical models of GB were used to assess the anti-cancer activity of BPM 31510 alone (100 mg/kg/d) and combination with TMZ/bevacizumab (BEV). In addition, an in vitro model of acquired TMZ chemo-resistance was established by progressive adaptation of parental U251-MG cells to increasing doses of TMZ. Parental and resistant subclones (TMZ-R) were used to define activity of BPM31510 in the TMZ-refractory setting. Results: In vitro r...

  • abstract ct315 phase i study of bpm 31510 Ubidecarenone in patients with advanced solid tumors
    Cancer Research, 2015
    Co-Authors: Manish A Shah, Rangaprasad Sarangarajan, Niven R. Narain, Michael A. Kiebish, Leonardo O. Rodrigues, Viatcheslav R. Akmaev, Vivek K Vishnudas, Peter Paul Yu, Susan Brouwer, Janice Stevens
    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

  • phase 1 study of bpm 31510 Ubidecarenone in patients with advanced solid tumors st use of multiomics platform to evaluate reversal of warburg effect
    Journal of Clinical Oncology, 2015
    Co-Authors: Ralph Zinner, Rangaprasad Sarangarajan, Niven R. Narain, Michael A. Kiebish, Leonardo O. Rodrigues, Vivek K Vishnudas, Peter Paul Yu, Susan Brouwer, Viacheslav R Akmaev, Janice Stevens
    Abstract:

    2539 Background: BPM 31510 is a 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 indicate BPM 31510 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 BPM 31510 at a 4-days (d) 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 ST. Pts in the monotherapy arm received IV BPM 31510 for 4 d in continuous infusion in 28-d cycles. Pts in the combination arms were primed for 3 wks and then started in a weekly dosing (either gemcitabine, 5-FU or docetaxel) after the BPM 31510 infusion in a 6-wk cycle. Doses were escalated in a 3+3 schema. Phase I endp...

Rangaprasad Sarangarajan - One of the best experts on this subject based on the ideXlab platform.

  • Phase II trial of BPM31510-IV plus gemcitabine in advanced pancreatic ductal adenocarcinomas (PDAC).
    Journal of Clinical Oncology, 2020
    Co-Authors: Madappa N. Kundranda, David Propper, Paul S. Ritch, James Strauss, Manuel Hidalgo, Roopinder Gillmore, Rangaprasad Sarangarajan, Niven R. Narain, Michael A. Kiebish, Leonardo O. Rodrigues
    Abstract:

    723Background: BPM31510-IV is an Ubidecarenone (CoQ10) drug-lipid conjugate nanodispersion targeting metabolic machinery in cancer, shifting bioenergetics from lactate dependency towards mitochondr...

  • Abstract 5576: BPM 31510, a clinical stage candidate demonstrates potent anti-tumor effect in an immune-competent syngeneic pancreatic cancer model
    Cancer Research, 2017
    Co-Authors: Shiva Kazerounian, Rangaprasad Sarangarajan, Vivek K Vishnudas, Tulin Dadali, Anne R. Diers, Stephane Gesta, Aishwarya Sarma, Nidhi Gaur, Maria D. Nastke, Niven R. Narain
    Abstract:

    BPM 31510, a clinical stage nanodispersion of Ubidecarenone, demonstrates anti-tumor effects by eliciting an anti-Warburg metabolic switch in cancer. Previous studies in an immune compromised PaCa2 xenograft model has unequivocally demonstrated significant efficacy of BPM 31510 on tumor volume and survival. The fundamental property of BPM 31510 to influence mitochondrial bioenergetics and the recognized interplay between T cell metabolism and maturation prompted investigation into the effects of BPM 31510 on T lymphocyte functions in eliciting anti-cancer effects. In this study BPM 31510 selectively influenced activation and maturation of T cells in murine peripheral blood mononuclear cells (PBMCs). Moreover, in addition to determining changes in the CD3+ population, changes in surface expression of PD-1 and CTLA4 along with the IFN-γ secretion were examined. Murine cancer cell lines exposed to BPM 31510 were associated with variable sensitivity with highly metabolic tumor types being most sensitive. Next, the anti-cancer activity of BPM 31510 in an in vivo immunocompetent syngeneic Pan02 rodent model was investigated. Murine Pan02 pancreatic cancer cells were implanted subcutaneously into C57BL/6 mice. Tumors with mean volume of 80 mm3 were treated twice a day with vehicle control or BPM 31510 at 25, 50, 100 mg/kg, administered intraperitoneal. Tumor volumes were measured every 4 days. At day 21 post treatment, tumors were harvested and analyzed for the level of infiltrating immune cells by immunofluorescent staining with CD8+ for T cells and F4/80 for tumor macrophages. These results demonstrate a dose-dependent reduction in tumor volume following 21 days of BPM 31510 treatment. In summary, BPM 31510 exerts potent anti-tumor effects through its dual function of modulating tumor cell metabolism and potentially influencing immune check-point to improve overall survival outcomes. Citation Format: Shiva Kazerounian, Aishwarya Sarma, Nidhi Gaur, Maria D. Nastke, Tulin Dadali, Anne R. Diers, Stephane Gesta, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Niven R. Narain. BPM 31510, a clinical stage candidate demonstrates potent anti-tumor effect in an immune-competent syngeneic pancreatic cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5576. doi:10.1158/1538-7445.AM2017-5576

  • Abstract 1680: BPM31510, an anti-cancer agent selectively causes activation and proliferation of T cells, demonstrating potential utility in an immune-oncology setting
    Cancer Research, 2017
    Co-Authors: Maria D. Nastke, Niven R. Narain, Vivek K Vishnudas, Anne R. Diers, Stephane Gesta, Nidhi Gaur, Louisa Dowal, Samantha Fowler, Rangaprasad Sarangarajan
    Abstract:

    BPM 31510, a clinical stage, nanodispersion of Ubidecarenone has a unique mechanism of action that effectuates an anti-Warburg switch in cancer cell metabolism and activation of apoptosis. Given the observed central role of BPM 31510 in regulating mitochondrial function in cancer cells, it is of great interest to investigate the ability of BPM 31510 to modulate immune cells and their functionality. Therefore, the effects of BPM 31510 on peripheral blood mononuclear cells (PBMCs) were investigated to elucidate the immuno-metabolic mechanism of BPM 31510. Healthy donor PBMCs activated with PHA or PWM was used as model system, and the effect of BPM 31510 on immune cells viability was determined using flow cytometry. In addition, the effect of BPM31510 on immune cell function was evaluated by measuring a panel cytokines released in these cells, using a quantitative ELISA platform from Meso Scale Discovery. Results: BPM 31510 has been shown in previous studies to effectively induce apoptosis on a variety of cancer cell lines while sparing normal cells. Interestingly, increasing concentrations of BPM31510 lead to an increased frequency of viable CD3+ cells. Further phenotypic analysis revealed that cytotoxic T cells (CD8+/CD3+) and T helper cells (CD4+/CD3+), as well as NKT cells (CD56+/CD3+) contributed to the observed increase in T cells frequency. On the other hand, B cells (CD19+), NK cells (CD56+/CD3-), and the monocytes (CD14+) showed a decrease in frequency, an effect reflected also by a reduction in viability with increasing BPM 31510 concentrations. Cytokine analysis indicated that effector cytokines IL-2, IFN-γ, and TNF- α were secreted at significantly higher levels with increasing concentration of BPM 31510. Interestingly, IL-10 level, an immuno-regulatory cytokine, was strongly decreased in the supernatant of PBMCs treated with BPM31510. Taken together, we demonstrated that BPM 31510 has a direct effect on immune cells and their functionality. Although BPM 31510 induced apoptosis of cancer cells, our data indicate that it supports cell proliferation of T cells, and effector function of adaptive immune cells, likely by providing a higher energy supply for effector T cells. Subsequently, a higher activation state of effector T cells may result in increased levels of cytotoxic effector molecules (perforin, granzymes, Fas ligand) and macrophage activating effector molecules (IFN-γ, IL-2, TNF-α) which supports and attracts other immune cells like NK cells to the tumor. Citation Format: Maria-D Nastke, Nidhi Gaur, Louisa Dowal, Samantha Fowler, Anne Diers, Stephane Gesta, Vivek K. Vishnudas, Niven R. Narain, Rangaprasad Sarangarajan. BPM31510, an anti-cancer agent selectively causes activation and proliferation of T cells, demonstrating potential utility in an immune-oncology setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1680. doi:10.1158/1538-7445.AM2017-1680

  • bayesian ai to delineate molecular signatures of patient susceptibility to potential hematologic events in a phase i study of bpm31510 Ubidecarenone in solid tumors
    Journal of Clinical Oncology, 2017
    Co-Authors: Rangaprasad Sarangarajan, Michael A. Kiebish, Leonardo O. Rodrigues, Vivek Subbiah, David S. Hong, Gregory M Miller, Vivek K Vishnudas, Eric M Grund, Hedy Dion, Janice Stevens
    Abstract:

    e14042Background: BPM 31510 is a Ubidecarenone containing nanodispersion elicits anticancer effect by switching cancer cells energy generation from glycolysis to mitochondrial OXPHOS; i.e. reverses...

  • abstract ct315 phase i study of bpm 31510 Ubidecarenone in patients with advanced solid tumors
    Cancer Research, 2015
    Co-Authors: Manish A Shah, Rangaprasad Sarangarajan, Niven R. Narain, Michael A. Kiebish, Leonardo O. Rodrigues, Viatcheslav R. Akmaev, Vivek K Vishnudas, Peter Paul Yu, Susan Brouwer, Janice Stevens
    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

Vivek K Vishnudas - One of the best experts on this subject based on the ideXlab platform.

  • Abstract 5576: BPM 31510, a clinical stage candidate demonstrates potent anti-tumor effect in an immune-competent syngeneic pancreatic cancer model
    Cancer Research, 2017
    Co-Authors: Shiva Kazerounian, Rangaprasad Sarangarajan, Vivek K Vishnudas, Tulin Dadali, Anne R. Diers, Stephane Gesta, Aishwarya Sarma, Nidhi Gaur, Maria D. Nastke, Niven R. Narain
    Abstract:

    BPM 31510, a clinical stage nanodispersion of Ubidecarenone, demonstrates anti-tumor effects by eliciting an anti-Warburg metabolic switch in cancer. Previous studies in an immune compromised PaCa2 xenograft model has unequivocally demonstrated significant efficacy of BPM 31510 on tumor volume and survival. The fundamental property of BPM 31510 to influence mitochondrial bioenergetics and the recognized interplay between T cell metabolism and maturation prompted investigation into the effects of BPM 31510 on T lymphocyte functions in eliciting anti-cancer effects. In this study BPM 31510 selectively influenced activation and maturation of T cells in murine peripheral blood mononuclear cells (PBMCs). Moreover, in addition to determining changes in the CD3+ population, changes in surface expression of PD-1 and CTLA4 along with the IFN-γ secretion were examined. Murine cancer cell lines exposed to BPM 31510 were associated with variable sensitivity with highly metabolic tumor types being most sensitive. Next, the anti-cancer activity of BPM 31510 in an in vivo immunocompetent syngeneic Pan02 rodent model was investigated. Murine Pan02 pancreatic cancer cells were implanted subcutaneously into C57BL/6 mice. Tumors with mean volume of 80 mm3 were treated twice a day with vehicle control or BPM 31510 at 25, 50, 100 mg/kg, administered intraperitoneal. Tumor volumes were measured every 4 days. At day 21 post treatment, tumors were harvested and analyzed for the level of infiltrating immune cells by immunofluorescent staining with CD8+ for T cells and F4/80 for tumor macrophages. These results demonstrate a dose-dependent reduction in tumor volume following 21 days of BPM 31510 treatment. In summary, BPM 31510 exerts potent anti-tumor effects through its dual function of modulating tumor cell metabolism and potentially influencing immune check-point to improve overall survival outcomes. Citation Format: Shiva Kazerounian, Aishwarya Sarma, Nidhi Gaur, Maria D. Nastke, Tulin Dadali, Anne R. Diers, Stephane Gesta, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Niven R. Narain. BPM 31510, a clinical stage candidate demonstrates potent anti-tumor effect in an immune-competent syngeneic pancreatic cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5576. doi:10.1158/1538-7445.AM2017-5576

  • Abstract 4067: BPM31510, a clinical stage metabolic modulator demonstrates therapeutic efficacy in anin vivoC6 rat glioma model and synergizes with temozolomide
    Cancer Research, 2017
    Co-Authors: Stephane Gesta, Michael A. Kiebish, Vivek K Vishnudas, Tulin Dadali, Milton Merchant, Anne R. Diers, Semma Nagpal, Joaquin Jiminez, Niven R. Narain
    Abstract:

    BPM31510, a parenteral nanodispersion of Ubidecarenone that is in clinical testing for solid tumors, effectuates an anti-cancer effect in highly metabolic cancers by eliciting an anti-Warburg effect. Intraperitoneal (i.p.) administration of BPM31510 reverses paraplegia in a rat CNS leukemia model demonstrating the bioavailability of the drug to the central nervous system. The study describes data demonstrating the therapeutic utility of BPM31510 in glioblastoma multiforme (GBM). BPM31510 decreased cell proliferation rates in patient derived GBM cell lines compared to temozolamide (TMZ), pretreatment with BPM31510 followed by TMZ challenge was associated with significant synergy in reducing cell proliferation compared to monotherapy. In a C6 glioma allograft rat model treatment with BPM31510 alone (n=30/group) (i.p., 50mg/kg, b.i.d) increased overall survival compared to untreated control group. BPM31510 in combination with procarbazine (oral, 60mg/kg; d 8, 21) and vincristine (IV, 1.4mg/kg; d 8, 29) significantly improved overall survival compared to BPM31510 alone or chemotherapy. Furthermore, long term survival was achieved in four of twenty rats with C6 gliomas receiving BPM31510 doses between 10 and 50 mg/kg compared with none treated with either vehicle or irradiation (P Citation Format: Stephane Gesta, Semma Nagpal, Tulin Dadali, Milton Merchant, Taichang Jan, Anne R. Diers, Michael Kiebish, Joaquin Jiminez, Vivek K. Vishnudas, Niven R. Narain, Rangaprasad Sarangarajan, Lawrence Recht. BPM31510, a clinical stage metabolic modulator demonstrates therapeutic efficacy in an in vivo C6 rat glioma model and synergizes with temozolomide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4067. doi:10.1158/1538-7445.AM2017-4067

  • Abstract 1680: BPM31510, an anti-cancer agent selectively causes activation and proliferation of T cells, demonstrating potential utility in an immune-oncology setting
    Cancer Research, 2017
    Co-Authors: Maria D. Nastke, Niven R. Narain, Vivek K Vishnudas, Anne R. Diers, Stephane Gesta, Nidhi Gaur, Louisa Dowal, Samantha Fowler, Rangaprasad Sarangarajan
    Abstract:

    BPM 31510, a clinical stage, nanodispersion of Ubidecarenone has a unique mechanism of action that effectuates an anti-Warburg switch in cancer cell metabolism and activation of apoptosis. Given the observed central role of BPM 31510 in regulating mitochondrial function in cancer cells, it is of great interest to investigate the ability of BPM 31510 to modulate immune cells and their functionality. Therefore, the effects of BPM 31510 on peripheral blood mononuclear cells (PBMCs) were investigated to elucidate the immuno-metabolic mechanism of BPM 31510. Healthy donor PBMCs activated with PHA or PWM was used as model system, and the effect of BPM 31510 on immune cells viability was determined using flow cytometry. In addition, the effect of BPM31510 on immune cell function was evaluated by measuring a panel cytokines released in these cells, using a quantitative ELISA platform from Meso Scale Discovery. Results: BPM 31510 has been shown in previous studies to effectively induce apoptosis on a variety of cancer cell lines while sparing normal cells. Interestingly, increasing concentrations of BPM31510 lead to an increased frequency of viable CD3+ cells. Further phenotypic analysis revealed that cytotoxic T cells (CD8+/CD3+) and T helper cells (CD4+/CD3+), as well as NKT cells (CD56+/CD3+) contributed to the observed increase in T cells frequency. On the other hand, B cells (CD19+), NK cells (CD56+/CD3-), and the monocytes (CD14+) showed a decrease in frequency, an effect reflected also by a reduction in viability with increasing BPM 31510 concentrations. Cytokine analysis indicated that effector cytokines IL-2, IFN-γ, and TNF- α were secreted at significantly higher levels with increasing concentration of BPM 31510. Interestingly, IL-10 level, an immuno-regulatory cytokine, was strongly decreased in the supernatant of PBMCs treated with BPM31510. Taken together, we demonstrated that BPM 31510 has a direct effect on immune cells and their functionality. Although BPM 31510 induced apoptosis of cancer cells, our data indicate that it supports cell proliferation of T cells, and effector function of adaptive immune cells, likely by providing a higher energy supply for effector T cells. Subsequently, a higher activation state of effector T cells may result in increased levels of cytotoxic effector molecules (perforin, granzymes, Fas ligand) and macrophage activating effector molecules (IFN-γ, IL-2, TNF-α) which supports and attracts other immune cells like NK cells to the tumor. Citation Format: Maria-D Nastke, Nidhi Gaur, Louisa Dowal, Samantha Fowler, Anne Diers, Stephane Gesta, Vivek K. Vishnudas, Niven R. Narain, Rangaprasad Sarangarajan. BPM31510, an anti-cancer agent selectively causes activation and proliferation of T cells, demonstrating potential utility in an immune-oncology setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1680. doi:10.1158/1538-7445.AM2017-1680

  • bayesian ai to delineate molecular signatures of patient susceptibility to potential hematologic events in a phase i study of bpm31510 Ubidecarenone in solid tumors
    Journal of Clinical Oncology, 2017
    Co-Authors: Rangaprasad Sarangarajan, Michael A. Kiebish, Leonardo O. Rodrigues, Vivek Subbiah, David S. Hong, Gregory M Miller, Vivek K Vishnudas, Eric M Grund, Hedy Dion, Janice Stevens
    Abstract:

    e14042Background: BPM 31510 is a Ubidecarenone containing nanodispersion elicits anticancer effect by switching cancer cells energy generation from glycolysis to mitochondrial OXPHOS; i.e. reverses...

  • Effect of BPM31510 on radiosensitivity of temozolomide-resistant glioblastoma cell model and survival in in vivo C6 glioma rat model supporting phase I clinical investigation in GBM.
    Journal of Clinical Oncology, 2017
    Co-Authors: Seema Nagpal, Vivek K Vishnudas, Janice Stevens, Tulin Dadali, Taichang Jang, Milton Merchant, Anne R. Diers, Stephane Gesta, Megan Wilson, Michael A. Kiebish
    Abstract:

    e13509Background: Glioblastoma (GB) is characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an Ubidecarenone containing lipid nanodispersion effectuates a switch in cancer energy sourcing from glycolysis towards mitochondrial OXPHOS, i.e. reverses Warburg effect, providing rationale for its potential utility in treatment of GB. The current study investigated utility of BPM31510 alone and in combination with temozolomide. Methods: In vitro (U251-MG human GB cell line) and in vivo (C6 glioma rat model) preclinical models of GB were used to assess the anti-cancer activity of BPM 31510 alone (100 mg/kg/d) and combination with TMZ/bevacizumab (BEV). In addition, an in vitro model of acquired TMZ chemo-resistance was established by progressive adaptation of parental U251-MG cells to increasing doses of TMZ. Parental and resistant subclones (TMZ-R) were used to define activity of BPM31510 in the TMZ-refractory setting. Results: In vitro r...

Michael A. Kiebish - One of the best experts on this subject based on the ideXlab platform.

  • Phase II trial of BPM31510-IV plus gemcitabine in advanced pancreatic ductal adenocarcinomas (PDAC).
    Journal of Clinical Oncology, 2020
    Co-Authors: Madappa N. Kundranda, David Propper, Paul S. Ritch, James Strauss, Manuel Hidalgo, Roopinder Gillmore, Rangaprasad Sarangarajan, Niven R. Narain, Michael A. Kiebish, Leonardo O. Rodrigues
    Abstract:

    723Background: BPM31510-IV is an Ubidecarenone (CoQ10) drug-lipid conjugate nanodispersion targeting metabolic machinery in cancer, shifting bioenergetics from lactate dependency towards mitochondr...

  • Proteomic profiling identifies molecular basis of adverse event to BPM31510 exposure: Rationale for comprehensive molecular pharmacodynamics (PD) in phase I clinical trial design
    Annals of Oncology, 2019
    Co-Authors: Vivek Subbiah, Michael A. Kiebish, Leonardo O. Rodrigues, David S. Hong, Gregory M Miller, Lixia Zhang, Ralph Zinner, Granger, Vijetha Vemulapalli, Niven R. Narain
    Abstract:

    Abstract Background BPM31510-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. Methods Patients 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 96 h or 144 h 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. Results A 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. Conclusions BPM31510-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 identification NCT01957735. Legal entity responsible for the study BERG LLC. Funding BERG LLC. Disclosure E. 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.

  • A phase I molecular adaptive clinical study to evaluate safety and tolerability of BPM31510-IV in advanced solid tumors: Final study results.
    Journal of Clinical Oncology, 2018
    Co-Authors: Niven R. Narain, Michael A. Kiebish, Leonardo O. Rodrigues, Vivek Subbiah, David S. Hong, David Lucius, Viatcheslav R. Akmaev, Gregory M Miller, Eric Milliman, Lixia Zhang
    Abstract:

    2541Background: BPM31510-IV is an Ubidecarenone (CoQ10) containing IV nanodispersion targeting metabolic machinery in cancer, shifting bioenergetics from lactate dependency towards mitochondrial Ox...

  • Abstract 4067: BPM31510, a clinical stage metabolic modulator demonstrates therapeutic efficacy in anin vivoC6 rat glioma model and synergizes with temozolomide
    Cancer Research, 2017
    Co-Authors: Stephane Gesta, Michael A. Kiebish, Vivek K Vishnudas, Tulin Dadali, Milton Merchant, Anne R. Diers, Semma Nagpal, Joaquin Jiminez, Niven R. Narain
    Abstract:

    BPM31510, a parenteral nanodispersion of Ubidecarenone that is in clinical testing for solid tumors, effectuates an anti-cancer effect in highly metabolic cancers by eliciting an anti-Warburg effect. Intraperitoneal (i.p.) administration of BPM31510 reverses paraplegia in a rat CNS leukemia model demonstrating the bioavailability of the drug to the central nervous system. The study describes data demonstrating the therapeutic utility of BPM31510 in glioblastoma multiforme (GBM). BPM31510 decreased cell proliferation rates in patient derived GBM cell lines compared to temozolamide (TMZ), pretreatment with BPM31510 followed by TMZ challenge was associated with significant synergy in reducing cell proliferation compared to monotherapy. In a C6 glioma allograft rat model treatment with BPM31510 alone (n=30/group) (i.p., 50mg/kg, b.i.d) increased overall survival compared to untreated control group. BPM31510 in combination with procarbazine (oral, 60mg/kg; d 8, 21) and vincristine (IV, 1.4mg/kg; d 8, 29) significantly improved overall survival compared to BPM31510 alone or chemotherapy. Furthermore, long term survival was achieved in four of twenty rats with C6 gliomas receiving BPM31510 doses between 10 and 50 mg/kg compared with none treated with either vehicle or irradiation (P Citation Format: Stephane Gesta, Semma Nagpal, Tulin Dadali, Milton Merchant, Taichang Jan, Anne R. Diers, Michael Kiebish, Joaquin Jiminez, Vivek K. Vishnudas, Niven R. Narain, Rangaprasad Sarangarajan, Lawrence Recht. BPM31510, a clinical stage metabolic modulator demonstrates therapeutic efficacy in an in vivo C6 rat glioma model and synergizes with temozolomide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4067. doi:10.1158/1538-7445.AM2017-4067

  • bayesian ai to delineate molecular signatures of patient susceptibility to potential hematologic events in a phase i study of bpm31510 Ubidecarenone in solid tumors
    Journal of Clinical Oncology, 2017
    Co-Authors: Rangaprasad Sarangarajan, Michael A. Kiebish, Leonardo O. Rodrigues, Vivek Subbiah, David S. Hong, Gregory M Miller, Vivek K Vishnudas, Eric M Grund, Hedy Dion, Janice Stevens
    Abstract:

    e14042Background: BPM 31510 is a Ubidecarenone containing nanodispersion elicits anticancer effect by switching cancer cells energy generation from glycolysis to mitochondrial OXPHOS; i.e. reverses...

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