Intravenous Ascorbate Plus Gemcitabine/Carboplatin: A Novel and Cost-Effective Alternative With Evident Efficacy in Patients With Muscle Invasive Bladder Cancer

Summary

This is a phase II, single arm, Simon two-stage design, trial, enrolling patients with cisplatin ineligible MIBC and/or those patients who decline cisplatin based NAC. Assess rates of pathologic downstaging and quality of life in MIBC cisplatin-ineligible/declined patients when IVC is added to gemcitabine-carboplatin NAC.

Timeline

Start

2025-01-16

Primary completion

2028-12-01

Completion

2030-12-01

Publications

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• Background Chen Q, Espey MG, Krishna MC, Mitchell JB, Corpe CP, Buettner GR, Shacter E, Levine M. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13604-9. doi: 10.1073/pnas.0506390102. Epub 2005 Sep 12.
• Background Chen Q, Espey MG, Sun AY, Lee JH, Krishna MC, Shacter E, Choyke PL, Pooput C, Kirk KL, Buettner GR, Levine M. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci U S A. 2007 May 22;104(21):8749-54. doi: 10.1073/pnas.0702854104. Epub 2007 May 14.
• Background Chen Q, Espey MG, Sun AY, Pooput C, Kirk KL, Krishna MC, Khosh DB, Drisko J, Levine M. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11105-9. doi: 10.1073/pnas.0804226105. Epub 2008 Aug 4.
• Background Schoenfeld JD, Sibenaller ZA, Mapuskar KA, Wagner BA, Cramer-Morales KL, Furqan M, Sandhu S, Carlisle TL, Smith MC, Abu Hejleh T, Berg DJ, Zhang J, Keech J, Parekh KR, Bhatia S, Monga V, Bodeker KL, Ahmann L, Vollstedt S, Brown H, Kauffman EPS, Schall ME, Hohl RJ, Clamon GH, Greenlee JD, Howard MA, Schultz MK, Smith BJ, Riley DP, Domann FE, Cullen JJ, Buettner GR, Buatti JM, Spitz DR, Allen BG. O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer Cell. 2017 Aug 14;32(2):268. doi: 10.1016/j.ccell.2017.07.008. No abstract available.
• Background Deubzer B, Mayer F, Kuci Z, Niewisch M, Merkel G, Handgretinger R, Bruchelt G. H(2)O(2)-mediated cytotoxicity of pharmacologic ascorbate concentrations to neuroblastoma cells: potential role of lactate and ferritin. Cell Physiol Biochem. 2010;25(6):767-74. doi: 10.1159/000315098. Epub 2010 May 18.
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• Background Chen P, Reed G, Jiang J, Wang Y, Sunega J, Dong R, Ma Y, Esparham A, Ferrell R, Levine M, Drisko J, Chen Q. Pharmacokinetic Evaluation of Intravenous Vitamin C: A Classic Pharmacokinetic Study. Clin Pharmacokinet. 2022 Sep;61(9):1237-1249. doi: 10.1007/s40262-022-01142-1. Epub 2022 Jun 25.
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• Background Carroll RS, Du J, O'Leary BR, Steers G, Goswami PC, Buettner GR, Cullen JJ. Pharmacological ascorbate induces sustained mitochondrial dysfunction. Free Radic Biol Med. 2023 Aug 1;204:108-117. doi: 10.1016/j.freeradbiomed.2023.04.023. Epub 2023 May 1.
• Background Alexander MS, Wilkes JG, Schroeder SR, Buettner GR, Wagner BA, Du J, Gibson-Corley K, O'Leary BR, Spitz DR, Buatti JM, Berg DJ, Bodeker KL, Vollstedt S, Brown HA, Allen BG, Cullen JJ. Pharmacologic Ascorbate Reduces Radiation-Induced Normal Tissue Toxicity and Enhances Tumor Radiosensitization in Pancreatic Cancer. Cancer Res. 2018 Dec 15;78(24):6838-6851. doi: 10.1158/0008-5472.CAN-18-1680. Epub 2018 Sep 25.
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• Background Narain TA, Tosh JM, Gautam G, Talwar HS, Panwar VK, Mittal A, Mandal AK. Neoadjuvant Therapy for Cisplatin Ineligible Muscle Invasive Bladder Cancer Patients: A Review of Available Evidence. Urology. 2021 Aug;154:8-15. doi: 10.1016/j.urology.2021.03.010. Epub 2021 Mar 26.
• Background Jain RK, Sonpavde G. Neoadjuvant therapy for muscle-invasive bladder cancer. Expert Rev Anticancer Ther. 2020 Jul;20(7):603-614. doi: 10.1080/14737140.2020.1784011. Epub 2020 Jun 30.
• Background Sadeghi S, Groshen SG, Tsao-Wei DD, Parikh R, Mortazavi A, Dorff TB, Kefauver C, Hoimes C, Doyle L, Quinn DI, Newman E, Lara PN Jr. Phase II California Cancer Consortium Trial of Gemcitabine-Eribulin Combination in Cisplatin-Ineligible Patients With Metastatic Urothelial Carcinoma: Final Report (NCI-9653). J Clin Oncol. 2019 Oct 10;37(29):2682-2688. doi: 10.1200/JCO.19.00861. Epub 2019 Aug 7.
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Drugs

Indications