Bladder Cancer
Conditions
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.
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
DRUGIntravenous 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
Sponsors
University of Kansas Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Post treatment pathological staging | Approximately 10 to 12 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To assess Quality of life (QOL) | Approximately 10 to 16 weeks | Overall change in participant-reported quality of life outcomes. Fact-Bladder (FACT-BI) Quality of life questionnaire as measurement tool. |
| To measure Disease Free Survival (DFS) | Approximately 2 years | Disease free survival rate (DFS) among participants |
| To measure Disease Specific Survival (DSS) | Approximately 2 years | Disease specific survival rate among participants |
Other
| Measure | Time frame | Description |
|---|---|---|
| Cellular outcome markers, IVC uptake, IVC specific mechanism markers, Cell death, Cell proliferation | During surgery | Tumor samples will be collected at timepoints as listed in the protocol study procedures and schedule of events table for evaluation of generally used cellular outcome markers, as well as markers for IVC specific mechanism, via the IRB approved BCa tumor bank (Taylor PI). Acetylated tubulin levels and transferrin receptor levels in tumor samples will be detected as IVC related markers. SLC23A2 (SVCT2, vitamin C tissue receptor) will be assessed for drug uptake. TUNEL staining will be used as a measure of cell death and Ki67 as a measure of cell proliferation. Circulating tumor DNA (ctDNA) will be assessed in serum as an additional marker of treatment efficacy and recurrence. In addition, single-cell sequencing will be used to define changes in specific tissue populations at TUR and RC to evaluate both biomarkers of response and potential mechanisms associated with IVC treatment. To monitor inflammation, urinary cytokines will be assessed via multiplex ELISA at RC (post-treatment). |
Countries
United States
Contacts
Primary ContactKUCC Navigation
Backup ContactFaith Rahman
Outcome results
None listed