Effect of Metformin on Breast Cancer Metabolism
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).
|Study Design:||Endpoint Classification: Pharmacodynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
|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|
- Measure Metformin Induced effects in phosphorylation of S6K, 4E-BP-1 and AMPK via immunohistochemical analysis [ Time Frame: after 14-21 days of daily metforming dosing ] [ Designated as safety issue: No ]
- Measure fatty acid desaturation and deuterated water uptake into fatty acids at baseline and after 2 weeks of metformin. [ Time Frame: Day 14-21 after starting metformin dosing ] [ Designated as safety issue: No ]
- Measure baseline and induced effect of metformin on upstream and downstream members of AMPK family via gene array analysis. [ Time Frame: 14-21 days after start daily metformin dosing ] [ Designated as safety issue: No ]
|Study Start Date:||May 2011|
|Estimated Study Completion Date:||March 2014|
|Estimated Primary Completion Date:||March 2014 (Final data collection date for primary outcome measure)|
Extended release Metformin 1500mg once daily for 14-21 days
Other Name: Glucophage XR
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.
|Contact: Adrian L Harris, MBChB FRCP||+44 (0) 1865 firstname.lastname@example.org|
|Mount Vernon Centre for Cancer Treatment, Rickmansworth Road||Recruiting|
|Northwood, Middlesex, United Kingdom, HA6 2RN|
|Contact: Andreas Makris +44 (0) 1923 844723 email@example.com|
|Principal Investigator: Andreas Makris|
|Dept Oncology, Churchill Hospital, Old Road, Headington||Recruiting|
|Oxford, Oxfordshire, United Kingdom, OX3 7LJ|
|Contact: Simon lord 01865 235302 firstname.lastname@example.org|
|Principal Investigator: Adrian L Harris, BSc DPhil|
|Surgery and Molecular Oncology Ninewells Hospital||Not yet recruiting|
|Dundee, Scotland, United Kingdom, DD1 9SY|
|Contact: Alaister Thompson +44 (0) 1382 632565 email@example.com|
|Principal Investigator: Alistair Thompson|
|Principal Investigator:||Adrian Harris||The University of Oxford|