Clinical trial NCT01266486: Effect of Metformin on Breast Cancer Metabolism
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: Breast cancer
Pharmacodynamics
AMPK
PET Scan
Lead sponsor: Oxford University Hospitals NHS Trust
Sponsor class: OTHER
Collaborators: name: Cancer Research UK
First posted: 2010-12-24
Enrollment: 41
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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).

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Measure Metformin Induced effects in phosphorylation of S6K, 4E-BP-1 and AMPK via immunohistochemical analysis
timeFrame: after 14-21 days of daily metforming dosing
Secondary outcomes:
measure: Measure fatty acid desaturation and deuterated water uptake into fatty acids at baseline and after 2 weeks of metformin.
timeFrame: Day 14-21 after starting metformin dosing
measure: Measure baseline and induced effect of metformin on upstream and downstream members of AMPK family via gene array analysis.
timeFrame: 14-21 days after start daily metformin dosing
Other outcomes:
Locations:
city: Northwood
country: United Kingdom
facility: Mount Vernon Centre for Cancer Treatment, Rickmansworth Road
state: Middlesex
city: Oxford
country: United Kingdom
facility: Dept Oncology, Churchill Hospital, Old Road, Headington
state: Oxfordshire
city: Dundee
country: United Kingdom
facility: Surgery and Molecular Oncology Ninewells Hospital
state: Scotland
Study officials:
affiliation: The University of Oxford
name: Adrian Harris
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.