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 centre 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
Centre (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.
- Bladder tumour proliferation rate
- Feasibility of performing neoadjuvant window of opportunity trials using drugs with potential bioactivity against invasive bladder cancer
- Toxicity in patients who participate in the treatment regimen of Metformin and Simvastatin therapy
- Level of apoptosis observed in tumour cells of patients who undergo Metformin and Simvastatin therapy before cystectomy.
- Impact of Metformin and Simvastatin therapy on the signalling pathways involved in invasive urothelial carcinoma.
This is a single centre window of opportunity trial. A total of 44 patients with a diagnosis
of invasive bladder cancer diagnosed by pathologic evaluation of transurethral resection of
bladder tumour (TURBT) specimens and meeting all eligibility criteria will be enrolled in the
study. Study participants will receive Metformin 850mg twice daily and simvastatin 20mg once
daily until the night before of their scheduled cystectomy, which is a time period which
will last approximately 12 weeks or less. Pre-treatment TURBT tissue samples and the
Cystectomy post-therapy tissue samples will be analyzed and compared. Samples will be
analyzed for cell proliferation markers and to determine whether or not the combination of
metformin and simvastatin is able to produce a synergistic effect that will result in the
decrease of the growth of these aggressive cancer cells. The anticipated recruitment period
will be approximately 18 months. Participants in this study will be asked to attend the
following clinic visits for this study:
During this visit, the study doctor will conduct a physical exam and take vital signs as
well as height and weight measurements. Blood will also be drawn for analysis and research
purposes. Females that are of child bearing potential will have a pregnancy test to confirm
that they are not pregnant. Pregnant women will be removed from the study. We will also be
collecting blood samples.
Clinic Visits Participants will have follow-up clinic visits or phone interviews scheduled
every 4 weeks until the time of their surgery. At least 1 visit will be in person before
surgery. At these times they will have blood drawn for analysis, have their medication
reviewed, and confirm that they are taking the medication in adherence with the study
Day of Surgery On the day of surgery, the participants will have their height and weight
measured, have blood drawn for analysis and research purposes, and drug compliance will be
This is a feasibility study, and an interim analysis of enrollment is planned at 12 months
after the first patient is enrolled. The trial will be prematurely closed if it fails to
enroll 10 patients by the 12 month time point. A preliminary pathological analysis will be
performed following the completion of 12 months from the time of study initiation.
In the event that the enrolled patient underwent a TURBT for diagnosis prior to referral,
either tissue will be obtained from the peripheral centre where the TURBT was performed or
they will be consented for repeat TURBT, or withdrawn from the study.
Based upon the documentation at the time of TURBT, an attempt will be made, where possible,
to obtain tissue sections from the same tumour contained in the cystectomy sections. Where
this is not possible, representative slides will be obtained from another tumour, if
Study Objectives The aim of this study is to evaluate feasibility of window of opportunity
neoadjuvant trials for invasive bladder cancer in our centre, and to determine the effect of
the combination of metformin and simvastatin on clinicopathologic markers of drug activity
in our patient cohort.
Primary Objectives - Feasibility and Tumour Proliferation Rate The primary endpoint of this
trial will be the assessment of the tumour proliferation rate. This will be investigated
through the analysis of the change in Ki67 tissue staining between the TURBT tissue samples
and the cystectomy tissue.
Marker of cell proliferation;
- Ki67 staining
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 Centre. The
goal is to accrue 44 patients within 18 months to the trial. A midterm analysis at 12
months will be performed, at which time the trial will be prematurely closed if there
have been fewer than 10 patients enrolled.
- Feasibility - goal to accrue 44 patients in 18 months.
Secondary Objectives This study will assess the rate of grade 3 or higher toxicity as
defined by the CTCAE 4.03 (Common Terminology Criteria for Adverse Events). If 41 patients
are enrolled and complete the study, the study will have an 85% power at an of 0.05 to
detect if the toxicity rate is >20% with an assumed baseline of ≤5%.
The following parameters will be investigated through the analysis of any differences
in their tissue staining between the TURBT tissue samples and the cystectomy tissue.
This should aid in the delineation of any therapeutic effects of the combination of
metformin and simvastatin therapy on urothelial carcinoma (UC).
Marker of Apoptosis;
Terminal deoxynucleotidyl Transferase-mediated deoxy uridine triphosphate (dUTP) nick
end labeling (TUNEL) staining
Phosphoinositide-3 kinase/protein kinase B/mammalian target of rapamycin
(PI3K/Akt/mTOR) pathway readouts;
- p-mTOR staining
- p-Akt staining
Metformin stimulates activation;
- phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK)
The following parameters will be investigated through the analysis of their tissue
staining in the cystectomy sample, as they are assumed to be dependent on the
underlying tumour biology and will not be affected by metformin therapy:
PI3K/Akt/mTOR pathway regulator, frequently mutated in UC, could affect metformin
- Phosphatase and tensin homolog (PTEN) staining
Cell cycle regulator, frequently inactivated in invasive UC, affects metformin
Tertiary Endpoints The following parameters will be investigated through the analysis of any
differences in either their values between the time of enrollment and the day of surgery or
differences in the frequency between the treatment and control groups.
Between time of enrollment and date of surgery;
- Serum Insulin
- Fasting glucose levels
- Body mass index
- Changes in serum prostate specific antigen (PSA)
Clinical Marker of efficacy, has been shown to affect prognosis:
- Pathologic T0 rate at cystectomy vs. historical rates
Potential Novel Biomarkers:
- Number of circulating tumour cells or tumour microparticles before and after treatment
The following additional stratification analyses of the data will be performed in order
to assess our results in light of prior research findings:
Stratification of Pathologic Markers;
- Stratification of pAKT and Survivin expression levels by the presence or absence of
Stratification of TUNEL and Ki67 by the status of p53 staining
Stratification of pathologic markers by the use or absence of administration of
View this trial on ClinicalTrials.gov