Effect of Metformin on Breast Cancer Metabolism

Breast Cancer Clinical Trial

Official title:

A Phase 2 Single Arm Study to Examine the Effects of Metformin on Cancer Metabolism in Patients With Early Stage Breast Cancer Receiving Neoadjuvant Chemotherapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01266486
• Other study ID #: EP-TSC-647
• Status: Completed
• Phase: Phase 2
• First received: December 23, 2010
• Last updated: July 1, 2014
• Start date: May 2011
• Est. completion date: May 2014

Study information

• Verified date: July 2014
• Source: Oxford University Hospitals NHS Trust
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Research Ethics CommitteeUnited Kingdom: National Health Service
• Study type: Interventional

Clinical Trial Summary

Metformin, a drug that has been used since the 1950's in the treatment of diabetes, has recently generated great interest in its anticancer effects based on in vitro, in vivo and clinical studies. This study assesses the pharmacodynamic effects of metformin on breast cancer metabolism.

The trial design is based on a 2 centre study 'Early Antiangiogenic Response to Bevacizumab in Primary Breast Cancer' that is about to successfully complete recruitment in Oxford and Mount Vernon hospitals. The study takes advantage of the 2 week window between the first clinic visit and commencement of neoadjuvant chemotherapy. Metformin will be given to patients for at least 2 weeks prior to neoadjuvant chemotherapy with a set of 3 breast core biopsies, a PET-CT scan and blood tests carried out before and after this 2 week period of treatment. Patients will also receive a drink of heavy (deuterated) water, a safe and stable isotope commonly used in clinical lipid metabolism studies, the evening prior to both sets of core biopsies. Having completed the first 2 weeks of metformin patients will have the option of continuing metformin until completion of chemotherapy, at the discretion of the trial physician.

The core biopsies will then be used to assess for changes in:

• immunohistochemical staining;

• gene profiles;

• uptake of heavy water into tumour fatty acids using mass spectrometry techniques.

The aim is to identify potential biomarkers of response to metformin (and other future cancer metabolism drugs).

Description:

Metformin is a safe and well tolerated drug that has been widely used in the treatment of diabetes for over 50 years. There is now growing evidence from in vitro laboratory and animal work that metformin has anticancer properties. In addition a retrospective clinical study in a diabetic population has demonstrated evidence of markedly increased pathological response rates (a typically robust surrogate clinical endpoint of efficacy) to pre-surgical chemotherapy in early breast cancer for patients that were also taking metformin as part of their diabetes treatment.

There are several studies of metformin in cancer patients ongoing or being developed worldwide These are predominantly in relatively unselected cancer populations and with clinical outcomes as endpoints. However this study is the only study currently planned which will carry out a substantial assessment of pharmacodynamic endpoints. It is important that this study is carried out at an early stage in the development of metformin as a potential cancer therapy in order to ensure that future large scale studies are properly informed.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 41
• Est. completion date: May 2014
• Est. primary completion date: May 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Women with histology proven locally advanced breast cancer (LABC) or tumours >3 cm in diameter.

• ECOG performance status 0-1.

• Age =18 years.

• No prior treatment for breast cancer and scheduled to commence neoadjuvant chemotherapy in <3 weeks time.

• Have given written informed consent and are capable of cooperating with protocol.

• Adequate bone marrow, renal and liver function.

Exclusion Criteria:

• Radiotherapy, major surgery, significant traumatic injury, endocrine therapy, immunotherapy, chemotherapy or experimental therapy during four weeks prior to starting or during trial.

• Pregnancy or breast feeding

• History of type 1 or type 2 diabetes.

• Serum glucose greater than 7.0 mMol/L.

• Treatment with metformin in the past year.

• Estimated glomerular filtration rate (eGFR) <45ml/min.

• Acute or chronic metabolic acidosis

• Known hypersensitivity to metformin

• Other psychological, social or medical condition, physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results.

Study Design

Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Metformin
Extended release Metformin 1500mg once daily for 14-21 days

Locations

Country	Name	City	State
United Kingdom	Surgery and Molecular Oncology Ninewells Hospital	Dundee	Scotland
United Kingdom	Mount Vernon Centre for Cancer Treatment, Rickmansworth Road	Northwood	Middlesex
United Kingdom	Dept Oncology, Churchill Hospital, Old Road, Headington	Oxford	Oxfordshire

Sponsors (2)

Lead Sponsor	Collaborator
Oxford University Hospitals NHS Trust	Cancer Research UK

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Measure Metformin Induced effects in phosphorylation of S6K, 4E-BP-1 and AMPK via immunohistochemical analysis		after 14-21 days of daily metforming dosing	No
Secondary	Measure fatty acid desaturation and deuterated water uptake into fatty acids at baseline and after 2 weeks of metformin.		Day 14-21 after starting metformin dosing	No
Secondary	Measure baseline and induced effect of metformin on upstream and downstream members of AMPK family via gene array analysis.		14-21 days after start daily metformin dosing	No