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A Phase II, Open Label Assessment of Neoadjuvant Intervention With Metformin Against Tumour Expression of Signaling

Phase 2
18 Years
75 Years
Not Enrolling
Prostate Cancer

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Trial Information

A Phase II, Open Label Assessment of Neoadjuvant Intervention With Metformin Against Tumour Expression of Signaling

Prostate cancer is the most commonly diagnosed malignancy in men in North America, with
close to a quarter of a million cases diagnosed in 2007 alone (Joshua et al, 2007). The
activation of the PTEN/ AKT pathway is thought to be of importance in prostatic
carcinogenesis as it correlates with a poor prognosis (Yoshimoto et al, 2007) (Schmitz et
al, 2007). Components of this cellular pathway have pleiotropic targets including the mTOR
complex. In model systems, tumours exhibiting activation of PI3K/AKT kinase are sensitive
to mTOR inhibitors.

Metformin (1,1-dimethylbiguanide hydrochloride) belongs to the biguanide class of oral
hypoglycaemic agents and is a commonly prescribed medication for a number of conditions. It
is the first-line drug of choice for the treatment of type 2 diabetes. Its mechanism of
action is thought to be the primary inhibition of hepatic glucose output through inhibition
of gluconeogenesis. Subsequently, metformin causes a decline in the circulating insulin
level (Hundal et al, 2000).

Metformin causes inhibition of the mTOR complex. The mTOR complex is primarily inhibited
through activation of AMPK (a component of the PTEN/AKT pathway). Metformin causes reduced
hepatic glucose output leading to decreased levels of circulating insulin which causes the
secondary inhibition of the mTOR complex. Metformin has also been shown to inhibit cyclin
D1 expression and retinoblastoma protein (Rb) phosphorylation. Inhibition of Cyclin D1 and
Rb phosphorylation cause inhibition of G1/S phase transition of the cell cycle. This
results in the inhibition of cell proliferation (Matsushime et al, 1994).

This study will investigate the effect of neoadjuvant metformin therapy in the inhibition of
growth and proliferation of prostate cancer cells prior to radical prostatectomy.

Inclusion Criteria:

1. 1. Patients with histologically confirmed prostate cancer involving at least 20% of
at least one unfragmented biopsy core;

2. Over the age of 18 and under the age of 75;

3. Ability to read and understand the consent form, either alone or with the aid of a

4. ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to

5. Patients must have their TRUS biopsy performed at UHN (or at an outside institution
if tissue accession can be arranged) in the last 3 months;

6. Patients must have normal organ and marrow function as defined by the following

1. Absolute neutrophil count greater than or equal to 1,500/uL

2. Platelets greater than or equal to 100,000/uL

3. Total bilirubin less than or equal to 1.5 X institutional ULN

4. AST(SGOT)/ALT(SGPT) less than or equal to 1.5 X institutional ULN

5. Creatinine less than or equal to 1.4 X institutional ULN

Exclusion Criteria:

1. Patients who on initial assessment are found to be on treatment with any drug used
for the treatment of any form of diabetes, or patients that begin treatment for any
form of diabetes during the course of the study;

2. Patients may not be receiving any other investigational, herbal or anticancer agents
while on study;

3. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, congestive heart failure (NYHA Class 3 or greater), cirrhosis with a
Child-Pugh level of B or greater or evidence of cardiac dysfunction, unstable angina
pectoris, cardiac arrhythmia, active peptic ulcer disease, clinically significant
gastrointestinal conditions (e.g. Crohns disease, ulcerative colitis), COPD or
psychiatric illness/social situations that would limit compliance with study

4. Active malignancy at any other site excluding squamous cell or basal cell carcinomas
of the skin

5. Radiotherapy within the past 4 weeks;

6. Patients with a current history of alcohol intake (>2 standard drinks/day) or binge
drinking (5 or more drinks (male), or 4 or more drinks (female)) in one session of
1-3 hours;

7. Past history of lactic acidosis or risk factors for lactic acidosis such as
congestive heart failure (NYHA Class 3 or greater), hypoxia (resting PO2 < 91%) or
renal insufficiency (eGFR < 60 mls/min)

8. Patients taking systemic glucocorticoids or estrogenic compounds.

9. Patients with known hypersensitivity or allergy to metformin or any of its

10. Patients with a history of impaired liver or kidney function.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Difference in Ki67 staining

Outcome Time Frame:


Safety Issue:


Principal Investigator

Anthony Joshua, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

University Health Network, Toronto


Canada: Health Canada

Study ID:




Start Date:

June 2009

Completion Date:

June 2012

Related Keywords:

  • Prostate Cancer
  • Metformin
  • Prostate Cancer
  • Radical Prostatectomy
  • Neoadjuvant Intervention
  • PTEN/AKT Pathway
  • Tumour Expression
  • Ki67 Expression
  • Prostatic Neoplasms