Bladder Cancer Clinical Trial
Official title:
A Window of Opportunity Study to Evaluate the Role of the Combination of Metformin and Simvastatin as a Neoadjuvant Therapy in Invasive Bladder Cancer
A single arm, single center window of opportunity trial of using a combination of metformin
and simvastatin as a neoadjuvant treatment for patients with invasive bladder cancer who are
to undergo cystectomy. The study will assess the feasibility of conducting window of
opportunity trials in invasive bladder cancer the drug combination's affects on a variety of
important clinicopathologic variables.
The goal is to enroll 44 patients within 18 months. An interim analysis will be conducted at
12 months, and the study will be prematurely closed if fewer than 10 patients have been
enrolled at that time. Patients will be administered 850mg of metformin twice daily along
with 20mg of Simvastatin. Patients will be enrolled following the formal diagnosis of
invasive bladder cancer or at first visit following referral to the London Health Sciences
Center (LHSC). Patient's will receive metformin and simvastatin from the time of enrollment
until the night prior to their operation in the absence of safety or tolerability concerns.
Status | Recruiting |
Enrollment | 44 |
Est. completion date | January 2018 |
Est. primary completion date | January 2018 |
Accepts healthy volunteers | No |
Gender | Both |
Age group | 18 Years to 85 Years |
Eligibility |
Inclusion Criteria 1. Age =18 years and 85=. 2. Patients must have biopsy proven invasive bladder cancer by TURBT, previously untreated prior to TURBT by systemic chemotherapy. 3. Patients must be able to swallow and tolerate oral medication 4. Hemoglobin A1c = 6.5%. 5. Able to comprehend written and verbal study instructions related to study protocol and provide informed consent. 6. Any women with childbearing potential must use a highly effective contraception method, of which include: hormonal contraceptives (e.g. combined oral contraceptives, patch, vaginal ring, injectables, and implants); intrauterine device (IUD) or intrauterine system (IUS); vasectomy and tubal ligation. Exclusion Criteria 1. Patient has been treated for a prior cancer diagnosis with cisplatin-derived chemotherapy regimens or has had pelvic radiation therapy. 2. Previous or current diagnosis of type 1 or 2 diabetes mellitus. 3. Metformin exposure within the previous 12 months. 4. Expected or simultaneous use of sulfonylureas, thiazolidinediones, or insulin. 5. Known metformin allergy or intolerance. 6. Participation in another drug trial either within 30 days prior to study enrollment or during the time when they are on study protocol. 7. Serious cardiovascular disease including myocardial infarction within 6 months, unstable angina, serious cardiac arrythmias excluding atrial fribrillation, or cerebrovascular accident within 6 months prior to screening visit. 8. Abnormal liver function tests: Total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase (ALP) > 1.8 X upper limit of normal 9. Estimated glomerular filtration rate (eGFR) of =40 mL/min. 10. History of other malignancy, except non-muscle invasive bladder cancer, treated non-melanoma skin cancer, stage I melanoma and solid tumors adequately treated, with no persistent evidence of disease for 5 years. 11. Concomitant medical condition predisposing to metformin hydrochloride-associated lactic acidosis; examples include NYHA class III or IV congestive heart failure, history of acidosis and chronic alcohol intake averaging = 4 beverages per day. 12. A history of rhabdomyolysis. 13. The use of medications including niacin and colchicine, as well as strong inhibitors of cytochrome p-450 3A4 (see list in section 4.2). 14. Untreated hypothyroidism. 15. Pregnancy. 16. Breastfeeding |
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Country | Name | City | State |
---|---|---|---|
Canada | London Health Sciences Center; Victoria Hospital | London | Ontario |
Lead Sponsor | Collaborator |
---|---|
London Health Sciences Centre |
Canada,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Bladder tumor proliferation rate | The primary endpoint of this trial will be the assessment of the tumor proliferation rate. This will be investigated through the analysis of the change in Ki67 (cellular marker of cell proliferation) tissue staining between the TURBT tissue samples and the cystectomy tissue. | The participant will be followed for the duration of the pre-surgical preparation period. This is expected to be fewer than 12 weeks | No |
Primary | Feasibility of performing neoadjuvant window of opportunity trials using drugs with potential bioactivity against invasive bladder cancer | This trial is also designed to establish the framework and evaluate the feasibility of performing neoadjuvant window of opportunity trials using drugs with potential bioactivity against invasive bladder cancer at the London Health Sciences Center. The goal is to accrue 44 patients within 18 months to the trial, and the study will be prematurely closed if fewer than 10 patients are recruited within 12 months. | The participant will be followed for the duration of the pre-surgical preparation period. This is expected to be fewer than 12 weeks | No |
Secondary | Toxicity in patients who participate in the treatment regimen of Metformin and Simvastatin therapy | This study will assess the rate of grade 3 or higher toxicity caused by the study drug combination as defined by the CTCAE 4.03. | The participant will be followed for the duration of the pre-surgical preparation period. This is expected to be fewer than 12 weeks | No |
Secondary | Level of apoptosis observed in tumor cells of patients who undergo Metformin and Simvastatin therapy before cystectomy. | Tissue will be analyzed for the change in the marker of apoptosis Terminal deoxynucleotidyl Transferase-mediated dUTP nick end labeling (TUNEL) staining between TURBT and cystectomy tissue samples. | The participant will be followed for the duration of the pre-surgical preparation period. This is expected to be fewer than 12 weeks | No |
Secondary | Impact of Metformin and Simvastatin therapy on the signalling pathways involved in invasive urothelial carcinoma. | Various signalling pathways involved in cell proliferation and metformin response that may be affected by the combination of study drugs will be evaluated by analyzing tissue samples obtained from the patient during TURBT and then cystectomy. These experiments will be done to assess whether the combination of study drugs are able to inhibit the cellular signalling pathways that contribute to cancer cell growth by comparing the signaling levels between pre and post treatment samples. These pathways include PI3K/Akt/mTOR and AMPK. We will also evaluate the effect of the levels of PTEN and p53 on the cell response to therapy. | The participant will be followed for the duration of the pre-surgical preparation period. This is expected to be fewer than 12 weeks | No |
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