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

Overview

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.

Detailed description

The investigator has hypothesized adding IVC to carbo/gem NAC will enhance pathological downstaging and improve QOL. The patients eligible for this study (cisplatin ineligible or declined with MIBC) typically proceed straight to cystectomy within 12 weeks of initial diagnosis.

In this study, participants will receive two cycles of gemcitabine/carboplatin, along with IVC and then proceed to cystectomy.

Interventions

• Drug Intravenous ascorbic acid/vitamin C
  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

Primary outcome measures

• Post treatment pathological staging [Time frame: Approximately 10 to 12 weeks]

Secondary outcome measures (3)

• To assess Quality of life (QOL) [Time frame: Approximately 10 to 16 weeks]
• To measure Disease Free Survival (DFS) [Time frame: Approximately 2 years]
• To measure Disease Specific Survival (DSS) [Time frame: Approximately 2 years]

Eligibility criteria

Inclusion criteria

• 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.

Exclusion criteria

• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 2 centers

• Holden Comprehensive Cancer Center - The University of Iowa — Iowa City
• The University of Kansas Cancer Center — Kansas City

Publications

• 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
• 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
• 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
• 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
• 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 PMID 22917984
• 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
• 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
• 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

Identifiers

NCT: NCT06493370 · IIT-2024-IVC GC MIBC

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗