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

NCT06493370 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: IIT-2024-IVC GC MIBC
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Bladder Cancer

Outcome Measures

Primary Outcomes (1)

• Post treatment pathological staging

  To assess pathologic downstaging rate in MIBC cisplatin-ineligible patients when IVC is added to a gemcitabine/carboplatin NAC regimen. Pre and Post treatment specimen pathology results evaluated per American Joint Committee on Cancer (AJCC) staging guidelines.

  Approximately 10 to 12 weeks

Secondary Outcomes (3)

• To assess Quality of life (QOL)

  Approximately 10 to 16 weeks

• To measure Disease Free Survival (DFS)

  Approximately 2 years

• To measure Disease Specific Survival (DSS)

  Approximately 2 years

Other Outcomes (1)

• Cellular outcome markers, IVC uptake, IVC specific mechanism markers, Cell death, Cell proliferation

  During surgery

Study Arms (1)

Intravenous ascorbic acid/vitamin C

EXPERIMENTAL

2 Cycles Carboplatin Day 1 and Gemcitabine Days 1 and 8 (NAC) \+ Intravenous Vitamin C Days 1-28

Drug: Intravenous ascorbic acid/vitamin C

Interventions

Intravenous ascorbic acid/vitamin C DRUG

A dose escalation regimen will be initiated for each participant at a single dose of 25 g, titrated to up target peak plasma concentration. Once established, IVC will be administered intravenously 2 times per week for the remaining cycles

Intravenous ascorbic acid/vitamin C

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ability of participant to understand this study, and participant willingness to sign a written informed consent
• Consent to participate in biorepository protocol number GUB-BCR-001, KU IRB Approved HSC # STUDY00141546
• Males and females age ≥ 18 years
• ECOG Performance Status (PS) 0 - 2
• Women of childbearing potential must have a negative serum pregnancy test 72 hours prior to initiating treatment.
• Diagnosis/disease status Cisplatin-ineligible or declined muscle invasive bladder cancer. Cisplatin ineligibility will be defined based on Galsky criteria: CTCAE ver. 5.0 Grade 2 or greater peripheral neuropathy; CTCAE ver. 5.0 Grade 2 or greater hearing loss; Creatinine clearance estimated or calculated \< 60 ml/min; NYHA class II or greater congestive heart failure
• Adequate organ function, defined as follows: Absolute Neutrophil Count \>1.5K/UL. (NOTE: Patients with established diagnosis of benign neutropenia are eligible to participate with ANC between 1000-1500 based on discretion of the treating physician.); Platelets \>100K/UL; Hemoglobin ≥ 9 g/dL; Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation; Total bilirubin ≤ 2.0 x ULN; Aspartate aminotransferase (AST \[SGOT\]) and alanine aminotransferase (ALT \[SGPT\]) ≤ 2.5 x ULN unless liver metastases are present, in which case they must be ≤ 5 x ULN; Normal Glucose-6-phosphate dehydrogenase (G6PD) status
• Women of child-bearing potential (WOCBP) and men with partners of child-bearing potential must agree not to donate sperm (men), to practice sexual abstinence or to use the forms of contraception listed in Child-Bearing Potential/Pregnancy section for the duration of study participation and for WOMEN: 6 months after EOT, MEN: 3 months after EOT following completion of therapy.

You may not qualify if:

• Simultaneously enrolled in any therapeutic clinical trial
• Current or anticipating use of other anti-neoplastic or investigational agents while participating in this study
• Diagnosed with a psychiatric illness or is in a social situation that would limit compliance with study requirements
• Is pregnant or breastfeeding. There is a potential for congenital abnormalities and for this regimen to harm breast feeding infants
• Women of childbearing age expecting to conceive children while receiving study treatment and for 6 months after the last dose of study treatment. Men expecting to conceive children while receiving study treatment and for 3 months after the last dose of study treatment
• Has a severe known allergic reaction to any excipient contained in the study drug formulation
• Active Grade 3 or 4 (per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0109) viral, bacterial, or fungal infection within 2 weeks prior to the first dose of study treatment.
• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, as determined per treating physician.
• Histology of pure adenocarcinoma, pure squamous cell carcinoma, or pure small cell carcinoma in the TURBT sample
• Current consumption of tobacco products, patients may be asked to quit for 2 weeks prior to enrollment
• If tobacco use is suspected at any point during the trial, cotinine level will be obtained
• History of G6PD deficiency
• History of oxalate renal calculi - per discretion of treating physician

Sponsors & Collaborators

• University of Kansas Medical Center: lead

Study Sites (2)

Holden Comprehensive Cancer Center - The University of Iowa

Iowa City, Iowa, 52242, United States

NOT YET RECRUITING

The University of Kansas Cancer Center

Kansas City, Kansas, 66160, United States

RECRUITING

Related Publications (36)

• Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10. doi: 10.1016/0197-2456(89)90015-9.

  PMID: 2702835 BACKGROUND

• Kamat AM, Hahn NM, Efstathiou JA, Lerner SP, Malmstrom PU, Choi W, Guo CC, Lotan Y, Kassouf W. Bladder cancer. Lancet. 2016 Dec 3;388(10061):2796-2810. doi: 10.1016/S0140-6736(16)30512-8. Epub 2016 Jun 23.

  PMID: 27345655 BACKGROUND

• Hermans TJN, Voskuilen CS, van der Heijden MS, Schmitz-Drager BJ, Kassouf W, Seiler R, Kamat AM, Grivas P, Kiltie AE, Black PC, van Rhijn BWG. Neoadjuvant treatment for muscle-invasive bladder cancer: The past, the present, and the future. Urol Oncol. 2018 Sep;36(9):413-422. doi: 10.1016/j.urolonc.2017.10.014. Epub 2017 Nov 8.

  PMID: 29128420 BACKGROUND

• Carles J, Nogue M, Domenech M, Perez C, Saigi E, Villadiego K, Guasch I, Ibeas R. Carboplatin-gemcitabine treatment of patients with transitional cell carcinoma of the bladder and impaired renal function. Oncology. 2000 Jun;59(1):24-7. doi: 10.1159/000012132.

  PMID: 10895062 BACKGROUND

• Sternberg CN, Bellmunt J, Sonpavde G, Siefker-Radtke AO, Stadler WM, Bajorin DF, Dreicer R, George DJ, Milowsky MI, Theodorescu D, Vaughn DJ, Galsky MD, Soloway MS, Quinn DI; International Consultation on Urologic Disease-European Association of Urology Consultation on Bladder Cancer 2012. ICUD-EAU International Consultation on Bladder Cancer 2012: Chemotherapy for urothelial carcinoma-neoadjuvant and adjuvant settings. Eur Urol. 2013 Jan;63(1):58-66. doi: 10.1016/j.eururo.2012.08.010. Epub 2012 Aug 14.

  PMID: 22917984 BACKGROUND

• Ma Y, Chapman J, Levine M, Polireddy K, Drisko J, Chen Q. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci Transl Med. 2014 Feb 5;6(222):222ra18. doi: 10.1126/scitranslmed.3007154.

  PMID: 24500406 BACKGROUND

• Polireddy K, Dong R, Reed G, Yu J, Chen P, Williamson S, Violet PC, Pessetto Z, Godwin AK, Fan F, Levine M, Drisko JA, Chen Q. High Dose Parenteral Ascorbate Inhibited Pancreatic Cancer Growth and Metastasis: Mechanisms and a Phase I/IIa study. Sci Rep. 2017 Dec 7;7(1):17188. doi: 10.1038/s41598-017-17568-8.

  PMID: 29215048 BACKGROUND

• Espey MG, Chen P, Chalmers B, Drisko J, Sun AY, Levine M, Chen Q. Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer. Free Radic Biol Med. 2011 Jun 1;50(11):1610-9. doi: 10.1016/j.freeradbiomed.2011.03.007. Epub 2011 Mar 12.

  PMID: 21402145 BACKGROUND

• Du J, Martin SM, Levine M, Wagner BA, Buettner GR, Wang SH, Taghiyev AF, Du C, Knudson CM, Cullen JJ. Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. Clin Cancer Res. 2010 Jan 15;16(2):509-20. doi: 10.1158/1078-0432.CCR-09-1713. Epub 2010 Jan 12.

  PMID: 20068072 BACKGROUND

• Yun J, Mullarky E, Lu C, Bosch KN, Kavalier A, Rivera K, Roper J, Chio II, Giannopoulou EG, Rago C, Muley A, Asara JM, Paik J, Elemento O, Chen Z, Pappin DJ, Dow LE, Papadopoulos N, Gross SS, Cantley LC. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science. 2015 Dec 11;350(6266):1391-6. doi: 10.1126/science.aaa5004. Epub 2015 Nov 5.

  PMID: 26541605 BACKGROUND

• Pollard HB, Levine MA, Eidelman O, Pollard M. Pharmacological ascorbic acid suppresses syngeneic tumor growth and metastases in hormone-refractory prostate cancer. In Vivo. 2010 May-Jun;24(3):249-55.

  PMID: 20554995 BACKGROUND

• Monti DA, Mitchell E, Bazzan AJ, Littman S, Zabrecky G, Yeo CJ, Pillai MV, Newberg AB, Deshmukh S, Levine M. Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. PLoS One. 2012;7(1):e29794. doi: 10.1371/journal.pone.0029794. Epub 2012 Jan 17.

  PMID: 22272248 BACKGROUND

• Welsh JL, Wagner BA, van't Erve TJ, Zehr PS, Berg DJ, Halfdanarson TR, Yee NS, Bodeker KL, Du J, Roberts LJ 2nd, Drisko J, Levine M, Buettner GR, Cullen JJ. Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. Cancer Chemother Pharmacol. 2013 Mar;71(3):765-75. doi: 10.1007/s00280-013-2070-8. Epub 2013 Feb 5.

  PMID: 23381814 BACKGROUND

• Gilloteaux J, Jamison JM, Neal DR, Loukas M, Doberzstyn T, Summers JL. Cell damage and death by autoschizis in human bladder (RT4) carcinoma cells resulting from treatment with ascorbate and menadione. Ultrastruct Pathol. 2010 May;34(3):140-60. doi: 10.3109/01913121003662304.

  PMID: 20455663 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.

  PMID: 16157892 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.

  PMID: 17502596 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.

  PMID: 18678913 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.

  PMID: 28810149 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.

  PMID: 20511723 BACKGROUND

• Miller DM, Buettner GR, Aust SD. Transition metals as catalysts of "autoxidation" reactions. Free Radic Biol Med. 1990;8(1):95-108. doi: 10.1016/0891-5849(90)90148-c.

  PMID: 2182396 BACKGROUND

• Levine M, Conry-Cantilena C, Wang Y, Welch RW, Washko PW, Dhariwal KR, Park JB, Lazarev A, Graumlich JF, King J, Cantilena LR. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3704-9. doi: 10.1073/pnas.93.8.3704.

  PMID: 8623000 BACKGROUND

• Levine M, Wang Y, Padayatty SJ, Morrow J. A new recommended dietary allowance of vitamin C for healthy young women. Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9842-6. doi: 10.1073/pnas.171318198.

  PMID: 11504949 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.

  PMID: 35750958 BACKGROUND

• Lv H, Wang C, Fang T, Li T, Lv G, Han Q, Yang W, Wang H. Vitamin C preferentially kills cancer stem cells in hepatocellular carcinoma via SVCT-2. NPJ Precis Oncol. 2018 Jan 8;2(1):1. doi: 10.1038/s41698-017-0044-8. eCollection 2018.

  PMID: 29872720 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.

  PMID: 37137343 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.

  PMID: 30254147 BACKGROUND

• Furqan M, Abu-Hejleh T, Stephens LM, Hartwig SM, Mott SL, Pulliam CF, Petronek M, Henrich JB, Fath MA, Houtman JC, Varga SM, Bodeker KL, Bossler AD, Bellizzi AM, Zhang J, Monga V, Mani H, Ivanovic M, Smith BJ, Byrne MM, Zeitler W, Wagner BA, Buettner GR, Cullen JJ, Buatti JM, Spitz DR, Allen BG. Pharmacological ascorbate improves the response to platinum-based chemotherapy in advanced stage non-small cell lung cancer. Redox Biol. 2022 Jul;53:102318. doi: 10.1016/j.redox.2022.102318. Epub 2022 Apr 20.

  PMID: 35525024 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.

  PMID: 33775784 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.

  PMID: 32546025 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.

  PMID: 31390274 BACKGROUND

• Dogliotti L, Carteni G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. doi: 10.1016/j.eururo.2006.12.029. Epub 2006 Dec 26.

  PMID: 17207911 BACKGROUND

• Bellmunt J, Ribas A, Eres N, Albanell J, Almanza C, Bermejo B, Sole LA, Baselga J. Carboplatin-based versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma. Cancer. 1997 Nov 15;80(10):1966-72. doi: 10.1002/(sici)1097-0142(19971115)80:103.0.co;2-w.

  PMID: 9366300 BACKGROUND

• Petrioli R, Frediani B, Manganelli A, Barbanti G, De Capua B, De Lauretis A, Salvestrini F, Mondillo S, Francini G. Comparison between a cisplatin-containing regimen and a carboplatin-containing regimen for recurrent or metastatic bladder cancer patients. A randomized phase II study. Cancer. 1996 Jan 15;77(2):344-51. doi: 10.1002/(SICI)1097-0142(19960115)77:23.0.CO;2-1.

  PMID: 8625244 BACKGROUND

• Einerhand SMH, van Dijk N, van Dorp J, de Feijter JM, van Montfoort ML, van de Kamp MW, Schaake EE, Boellaard TN, Hendricksen K, van der Heijden MS, van Rhijn BWG. Survival after neoadjuvant/induction combination immunotherapy vs combination platinum-based chemotherapy for locally advanced (Stage III) urothelial cancer. Int J Cancer. 2022 Dec 1;151(11):2004-2011. doi: 10.1002/ijc.34125. Epub 2022 Jun 10.

  PMID: 35603905 BACKGROUND

• Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A, Wesley RA, Levine M. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004 Apr 6;140(7):533-7. doi: 10.7326/0003-4819-140-7-200404060-00010.

  PMID: 15068981 BACKGROUND

• Padayatty SJ, Sun AY, Chen Q, Espey MG, Drisko J, Levine M. Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS One. 2010 Jul 7;5(7):e11414. doi: 10.1371/journal.pone.0011414.

  PMID: 20628650 BACKGROUND

Related Links

• National Institute of Health/National Cancer Institute - Cancer Therapy Evaluation Program (CTEP). Common Terminology Criteria for Adverse Events (CTCAE).

MeSH Terms

Conditions

Urinary Bladder Neoplasms

Condition Hierarchy (Ancestors)

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Central Study Contacts

KUCC Navigation

CONTACT

913-588-3671; kucc_navigation@kumc.edu

Faith Rahman

CONTACT

913-588-2502; frahman2@kumc.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Basic Urologic Research

Model Details: This phase 2 study is not randomized or blinded. All eligible participants will be enrolled to avoid bias and be evaluated for adverse events. Due to the small sample size, patients who do not complete neo-adjuvant therapy will be evaluated for toxicity but maybe replaced for efficacy analysis.

Study Record Dates

• First Submitted: June 26, 2024
• First Posted: July 10, 2024
• Study Start: January 16, 2025
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2030
• Last Updated: February 20, 2025

Record last verified: 2024-07

Locations

US (2)