ANIMATE: A Study of Pre-operative Metformin in Prostate Cancer

Sponsor

University Health Network, Toronto (Other)

Overall Status

Terminated

CT.gov ID

NCT00881725

Collaborator

Jewish General Hospital (Other)

Enrollment

Location

Arm

Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Drug: Metformin	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

24 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jun 1, 2009

Actual Primary Completion Date :

Mar 1, 2011

Actual Study Completion Date :

Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metformin 500mg t.i.d. for 4-12 weeks prior to Radical Prostatectomy	Drug: Metformin 500mg tablets t.i.d. for 4-12 weeks prior to Radical Prostatectomy

Arm

Intervention/Treatment

Experimental: Metformin

500mg t.i.d. for 4-12 weeks prior to Radical Prostatectomy

Drug: Metformin

500mg tablets t.i.d. for 4-12 weeks prior to Radical Prostatectomy

Outcome Measures

Primary Outcome Measures

Difference in Ki67 staining [Pre-Surgery]

Secondary Outcome Measures

Other immunohistochemical assays: IR, IGF-1R, p70S6K, AMPK, MVD, Cleaved caspase 3, PTEN, c-Myc [Pre-Surgery]
Differences in measures of insulin resistance: waist/hip ratio, fasting blood glucose, post-prandial blood glucose, weight [Pre-Surgery, Post-Surgery]
Differences in PSA levels [Pre-Surgery, Post-Surgery]
Incidence of adverse events, serious adverse events, and grade 3-4 toxicities [Pre-Surgery, Post-Surgery]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Inclusion Criteria:

1. Patients with histologically confirmed prostate cancer involving at least 20% of at least one unfragmented biopsy core;
Over the age of 18 and under the age of 75;
Ability to read and understand the consent form, either alone or with the aid of a translator
ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to 60%);
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;
Patients must have normal organ and marrow function as defined by the following criteria:
Absolute neutrophil count greater than or equal to 1,500/uL
Platelets greater than or equal to 100,000/uL
Total bilirubin less than or equal to 1.5 X institutional ULN
AST(SGOT)/ALT(SGPT) less than or equal to 1.5 X institutional ULN
Creatinine less than or equal to 1.4 X institutional ULN

Exclusion Criteria:

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;
Patients may not be receiving any other investigational, herbal or anticancer agents while on study;
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 requirements;
Active malignancy at any other site excluding squamous cell or basal cell carcinomas of the skin
Radiotherapy within the past 4 weeks;
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;
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)
Patients taking systemic glucocorticoids or estrogenic compounds.
Patients with known hypersensitivity or allergy to metformin or any of its excipients.
Patients with a history of impaired liver or kidney function.