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Metformin and Simvastatin Use in Bladder Cancer

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ClinicalTrials.gov Identifier: NCT02360618
Recruitment Status : Recruiting
First Posted : February 10, 2015
Last Update Posted : July 11, 2016
Sponsor:
Information provided by (Responsible Party):
Dr. Jonathan Izawa, London Health Sciences Centre

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Bladder Cancer Drug: Metformin Drug: Simvastatin Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 44 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : October 2015
Estimated Primary Completion Date : January 2018
Estimated Study Completion Date : January 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

Arm Intervention/treatment
Experimental: Metformin and Simvastatin Treatment
Patients in this group will receive 850 mg of Metformin and 20 mg of Simvastatin daily from the time they are enrolled in the study until the day before their surgery (approximately 12 weeks), in the absence of any safety or tolerability concerns.
Drug: Metformin
See Group Description
Other Name: No other names

Drug: Simvastatin
See Group Description
Other Name: No other names




Primary Outcome Measures :
  1. Bladder tumor proliferation rate [ Time Frame: The participant will be followed for the duration of the pre-surgical preparation period. This is expected to be fewer than 12 weeks ]
    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.

  2. Feasibility of performing neoadjuvant window of opportunity trials using drugs with potential bioactivity against invasive bladder cancer [ Time Frame: The participant will be followed for the duration of the pre-surgical preparation period. This is expected to be fewer than 12 weeks ]
    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.


Secondary Outcome Measures :
  1. Toxicity in patients who participate in the treatment regimen of Metformin and Simvastatin therapy [ Time Frame: The participant will be followed for the duration of the pre-surgical preparation period. This is expected to be fewer than 12 weeks ]
    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.

  2. Level of apoptosis observed in tumor cells of patients who undergo Metformin and Simvastatin therapy before cystectomy. [ Time Frame: The participant will be followed for the duration of the pre-surgical preparation period. This is expected to be fewer than 12 weeks ]
    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.

  3. Impact of Metformin and Simvastatin therapy on the signalling pathways involved in invasive urothelial carcinoma. [ Time Frame: The participant will be followed for the duration of the pre-surgical preparation period. This is expected to be fewer than 12 weeks ]
    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.



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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02360618


Contacts
Contact: Jonathan Izawa, MD 519-685-8500 ext 58551 jonathan.izawa@lhsc.on.ca
Contact: Catherine Hildebrand, PhD 519-685-8500 ext 53535 Catherine.Hildebrand@lhsc.on.ca

Locations
Canada, Ontario
London Health Sciences Center; Victoria Hospital Recruiting
London, Ontario, Canada, N6A 5W9
Contact: Jonathan Izawa, MD         
Sponsors and Collaborators
London Health Sciences Centre
Investigators
Principal Investigator: Jonathan Izawa, MD London Health Sciences Centre

Responsible Party: Dr. Jonathan Izawa, Urologic Surgeon, London Health Sciences Centre
ClinicalTrials.gov Identifier: NCT02360618     History of Changes
Other Study ID Numbers: MS_1
First Posted: February 10, 2015    Key Record Dates
Last Update Posted: July 11, 2016
Last Verified: July 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Dr. Jonathan Izawa, London Health Sciences Centre:
Bladder Cancer
Metformin
Simvastatin
Combination Therapy

Additional relevant MeSH terms:
Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Metformin
Simvastatin
Hypoglycemic Agents
Physiological Effects of Drugs
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors