Effect of Metformin on Breast Cancer Metabolism

NCT01266486 | Completed Phase 2

• 1 other identifier: EP-TSC-647
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 3

Brief 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).

Conditions

Breast Cancer

Keywords

Breast cancer; Pharmacodynamics; AMPK; PET Scan

Outcome Measures

Primary Outcomes (1)

• Measure Metformin Induced effects in phosphorylation of S6K, 4E-BP-1 and AMPK via immunohistochemical analysis

  after 14-21 days of daily metforming dosing

Secondary Outcomes (2)

• 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

• 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

Study Arms (1)

Metformin

EXPERIMENTAL

Drug: Metformin

Interventions

Metformin DRUG

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

Also known as: Glucophage XR

Metformin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Oxford University Hospitals NHS Trust: lead
• Cancer Research UK: collaborator

Study Sites (3)

Mount Vernon Centre for Cancer Treatment, Rickmansworth Road

Northwood, Middlesex, HA6 2RN, United Kingdom

Location

Dept Oncology, Churchill Hospital, Old Road, Headington

Oxford, Oxfordshire, OX3 7LJ, United Kingdom

Location

Surgery and Molecular Oncology Ninewells Hospital

Dundee, Scotland, DD1 9SY, United Kingdom

Location

Related Publications (3)

• Ralli GP, Carter RD, McGowan DR, Cheng WC, Liu D, Teoh EJ, Patel N, Gleeson F, Harris AL, Lord SR, Buffa FM, Fenwick JD. Radiogenomic analysis of primary breast cancer reveals [18F]-fluorodeoxglucose dynamic flux-constants are positively associated with immune pathways and outperform static uptake measures in associating with glucose metabolism. Breast Cancer Res. 2022 May 17;24(1):34. doi: 10.1186/s13058-022-01529-9.

  PMID: 35581637 DERIVED

• Lord SR, Collins JM, Cheng WC, Haider S, Wigfield S, Gaude E, Fielding BA, Pinnick KE, Harjes U, Segaran A, Jha P, Hoefler G, Pollak MN, Thompson AM, Roy PG, English R, Adams RF, Frezza C, Buffa FM, Karpe F, Harris AL. Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin. Br J Cancer. 2020 Jan;122(2):258-265. doi: 10.1038/s41416-019-0665-5. Epub 2019 Dec 10.

  PMID: 31819193 DERIVED

• Lord SR, Cheng WC, Liu D, Gaude E, Haider S, Metcalf T, Patel N, Teoh EJ, Gleeson F, Bradley K, Wigfield S, Zois C, McGowan DR, Ah-See ML, Thompson AM, Sharma A, Bidaut L, Pollak M, Roy PG, Karpe F, James T, English R, Adams RF, Campo L, Ayers L, Snell C, Roxanis I, Frezza C, Fenwick JD, Buffa FM, Harris AL. Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer. Cell Metab. 2018 Nov 6;28(5):679-688.e4. doi: 10.1016/j.cmet.2018.08.021. Epub 2018 Sep 20.

  PMID: 30244975 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Metformin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Adrian Harris

  The University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: QA Coordinator, Cancer Centre

Study Record Dates

• First Submitted: December 23, 2010
• First Posted: December 24, 2010
• Study Start: May 1, 2011
• Primary Completion: May 1, 2014
• Study Completion: May 1, 2014
• Last Updated: July 2, 2014

Record last verified: 2014-07

Locations

GB (3)