A Phase III Randomized Trial of Metformin vs Placebo in Early Stage Breast Cancer

Breast Cancer Clinical Trial

Official title:

A Phase III Randomized Trial of Metformin Versus Placebo on Recurrence and Survival in Early Stage Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01101438
• Other study ID #: MA32
• Secondary ID: U10CA077202CAN-N
• Status: Completed
• Phase: Phase 3
• Start date: August 13, 2010
• Est. completion date: August 18, 2023

Study information

• Verified date: August 2023
• Source: Canadian Cancer Trials Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is looking at whether Metformin, an agent that is commonly used to treat diabetes, can decrease or affect the ability of breast cancer cells to grow and whether Metformin will work with other therapies to keep cancer from recurring. Health Canada has not approved the sale or use of Metformin to treat breast cancer, although they have approved its use in this clinical trial. Although Metformin is approved by the FDA for the treatment of diabetes, its use in breast cancer is considered investigational.

Description:

This is a multicenter study. Patients are stratified according to hormone-receptor status (estrogen receptor- and/or progesterone receptor- positive vs both receptors negative), body mass index (≤ 30 vs > 30 kg/m²), HER2 status (positive vs negative), and prior chemotherapy (any vs none). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral metformin hydrochloride twice daily (once daily in weeks 1-4). Treatment continues for up to 5 years in the absence of disease progression or unacceptable toxicity.

• Arm II: Patients receive oral placebo twice daily (once daily in weeks 1-4). Treatment continues for up to 5 years in the absence of disease progression or unacceptable toxicity.

Blood and tumor samples are collected periodically for correlative studies.

Patients may complete quality-of-life, physical activity, and diet questionnaires at baseline and at 6, 12, 24, 36, 48, and 60 months. (Sub-set of patients).

After completion of study treatment, patients are followed annually.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3649
• Est. completion date: August 18, 2023
• Est. primary completion date: September 21, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 74 Years

Eligibility

Eligibility Criteria:

• Subjects must have histologically confirmed invasive breast cancer and be enrolled in the trial within 12 months after the first histologic diagnosis of invasive breast cancer. A core biopsy interpreted as invasive cancer meets this criterion; otherwise, the date of first histologic diagnosis will be the date of first surgical procedure that identifies invasive cancer (biopsy, lumpectomy or mastectomy). Neoadjuvant subjects should have no evidence of clinical T4 disease prior to chemotherapy and surgery. Bilateral breast carcinoma is allowed provided diagnoses are synchronous - that is, within 3 months of one another - and at least one of the two breast carcinomas meet the eligibility criteria and neither violates the eligibility criteria.

• All subjects (both adjuvant and neo-adjuvant) must have sentinel lymph node biopsy and/or axillary lymph node dissection.

Sentinel lymph node biopsy alone is allowed in the following instances:

1. sentinel lymph node biopsy is negative: pN0

2. sentinel lymph node biopsy is positive for isolated tumour cells only: pN0 (i+)

3. * clinically node negative, T1-2 tumours with sentinel lymph node biopsy positive in = 2 lymph nodes without extra-capsular extension or matted nodes and undergoing breast conserving surgery and tangential whole breast irradiation (* excludes subjects treated with neo-adjuvant systemic therapy)

Definitive surgery and/or chemotherapy have been completed at least 4 weeks prior to randomization. Surgical margins must be clear of invasive carcinoma. If there is microscopic residual ductal in situ disease present at lumpectomy or total mastectomy margins, further excision is highly recommended. If further excision is not undertaken, the subject may still be entered on study, provided that in addition to breast or chest wall irradiation, a boost to the tumour bed is delivered. In situ lobular disease at the margin is acceptable.

Adjuvant subjects with the following pT pN combinations are eligible:

• pT1c, pN0 AND negative estrogen and progesterone receptors AND HER2 negative OR

• pT2N0 and at least one of the following tumour characteristics: histologic grade 3, lymphovascular invasion, negative estrogen and progesterone receptors, HER2 positive, Oncotype Dx recurrence score = 25 (or if Oncotype Dx recurrence score is not available, Ki67 > 14%) OR

• Subjects with pT3, pN0 OR

• Subjects with pT1-3, pN1-3

The eligibility of neo-adjuvant subjects is assessed on the basis of cTNM. The same eligible TNM combinations apply.

• HER2 status must be known. (Positive = 3+ over-expression by IHC in > 30% of invasive tumour cells OR HER2 gene amplification by FISH/CISH > 6 HER2 gene copies per nucleus, OR a FISH/CISH ratio: HER2 gene copies to chromosome 17 signals of = 2.2. All other results will be considered negative).

• Patients must have had a bilateral mammogram within 12 months prior to randomization, unless the initial surgery was a total mastectomy, in which case only a mammogram of the remaining breast is required. (Subjects with bilateral total mastectomies and no mammogram within 12 months prior to randomization must, instead, have a physical examination of the chest wall to ensure there is no residual or recurrent disease at the time of randomization. The date of this examination is used in place of the mammogram date on the eligibility checklist.)

• Investigations, including chest X-ray or CT chest, bone scan (with radiographs of suspicious areas) and abdominal ultrasound or liver scan or CT abdomen have been performed between the first histologic diagnosis and the time of randomization.

• Chest X-Ray, 2 view (or Chest CT) is mandatory

• Bone scans (with x-rays of abnormal areas) are required only if there are signs or symptoms of metastatic disease

• Abdominal imaging is required only if there are signs or symptoms of metastatic disease

• Hematology investigations (WBC, Granulocytes, Platelets, Hemoglobin) have been completed within 28 days prior to randomization and results are available.

• Biochemistry investigations have been completed within 28 days prior to randomization and values are within the parameters required by the protocol.

AST < 1.8 X ULN; ALT < 1.8 X ULN; Alkaline Phosphatase < 2 X ULN; Serum Creatinine < 115 µmol/L (1.3mg/dL) Serum Bilirubin < institution ULN (except for subjects with Gilbert's Disease who are eligible despite elevated serum bilirubin level)

• ECOG Performance Status of 0,1 or 2 (at baseline evaluation visit within 28 days prior to randomization).

• Age = 18 and < 75 and life expectancy of at least 5 years (18 years of age was used as a cut-off due to the lack of data indicating that breast cancer is a health issue in the < 18 years age group and metformin safety in pediatric patients has not been confirmed. Age > 80 carries increased risk of lactic acidosis and study intervention is for 5 years).

• Subjects must be accessible for treatment and follow-up. Investigators must assure themselves the subjects randomized on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.

• In accordance with NCIC CTG policy, protocol treatment is to begin within 10 working days of patient randomization.

• Subject consent must be obtained according to local Institutional and/or University Human Experimentation Committee requirements. It will be the responsibility of the local participating investigators to obtain the necessary local clearance, and to indicate in writing to the NCIC CTG Study Coordinator that such clearance has been obtained, before the trial can commence in that centre. Because of differing requirements, a standard consent form for the trial will not be provided but a sample form is given. A copy of the initial full board REB approval and approved consent form must be sent to the central office. The patient must sign the consent form prior to randomization or registration. Please note that the consent form for this study must contain a statement which gives permission for the NCIC CTG and monitoring agencies to review patient records (see Section 16 for further details).

For the first 888 eligible English or French-speaking subjects only (sub-set enrollment completed 2011NOV04):

• Subject is able (i.e. sufficiently fluent) and willing to complete the Quality of Life (EORTC QLQ C-30 and Trial Specific Checklist) in English or French. The baseline assessment must already have been completed at the time of enrollment. Inability (illiteracy in English or French, loss of sight or other equivalent reason) to complete questionnaires will not make the patient ineligible for the study; however, ability but unwillingness to complete the questionnaires will make the patient ineligible. (Once the target number of 888 subjects is achieved, this criterion will no longer need to be fulfilled.) [See Appendix VI]. Sub-set enrollment completed 2011NOV04.

• English-speaking subjects who have completed the Quality of Life Questionnaire who are able (i.e. sufficiently fluent) and willing to complete Nurses Health Study II Physical Activity Questionnaire and Block Alive Screener in English. The baseline assessment must already have been completed at the time of enrollment. Inability (illiteracy in English, loss of sight or other equivalent reason) to complete questionnaires will not make the patient ineligible for the study; however, ability but unwillingness to complete the questionnaires will make the patient ineligible. (This component of the study will close at the same time as the Quality Of Life sub-study.) Closed to new patient enrollment as of 2011NOV04.

Ineligibility Criteria:

• Subjects with a history of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for = 5 years.

• Subjects with locally recurrent or metastatic breast carcinoma. (Subjects with prior invasive breast cancer at any time are not eligible. Subjects with prior DCIS only in either breast are eligible provided the DCIS has been curatively treated including surgery, radiotherapy and/or Tamoxifen).

• Subjects whose axillary node status is unknown.

• Known diabetes (type 1 or 2) or baseline fasting glucose > 7.0 mmol/L (126 mg/dL). (Sampled and assayed according to local institution's procedures.)

• Known hypersensitivity or intolerance to metformin.

• Any condition associated with increased risk of metformin-associated lactic acidosis (e.g. congestive heart failure defined as New York Heart Association {NYHA} Class III or IV functional status [see Appendix IX], history of acidosis of any type; habitual * Currently taking metformin, sulfonylureas, thiazolidinediones or insulin for any reason.

• Current or planned pregnancy or lactation in women of child-bearing potential. Men should not father a child. (An effective method of birth control should be used while on study treatment which could include abstinence, IUD, condoms or other barrier methods of birth control because the safety of metformin in pregnancy or in male fertility has not been established).

• Concurrent or planned participation in randomized trials of weight loss or exercise interventions or trials targeting insulin, IGF-1 or their receptors, or involving P13K inhibitors (at the time of randomization)*.

• These interventions would interfere with the primary endpoint. (Also, in general, double randomizations in breast cancer trials for MA.32 patients are permitted only if the patient meets all the eligibility criteria for MA.32 and the sponsor of the previous trial has no objection to the patient also being enrolled in MA.32).

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• metformin hydrochloride
Given orally

Other:
• placebo
Given orally

Locations

Country	Name	City	State
Canada	BCCA - Abbotsford Centre	Abbotsford	British Columbia
Canada	Cambridge Memorial Hospital	Cambridge	Ontario
Canada	PEI Cancer Treatment Centre,Queen Elizabeth Hospital	Charlottetown	Prince Edward Island
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	Hopital Charles LeMoyne	Greenfield Park	Quebec
Canada	Juravinski Cancer Centre at Hamilton Health Sciences	Hamilton	Ontario
Canada	BCCA - Cancer Centre for the Southern Interior	Kelowna	British Columbia
Canada	Cancer Centre of Southeastern Ontario at Kingston	Kingston	Ontario
Canada	Grand River Regional Cancer Centre	Kitchener	Ontario
Canada	Hopital de la Cite-de-la-Sante	Laval	Quebec
Canada	London Regional Cancer Program	London	Ontario
Canada	Credit Valley Hospital	Mississauga	Ontario
Canada	The Moncton Hospital	Moncton	New Brunswick
Canada	The Vitalite Health Network - Dr. Leon Richard	Moncton	New Brunswick
Canada	CHUM - Hotel Dieu du Montreal	Montreal	Quebec
Canada	Hopital Maisonneuve-Rosemont	Montreal	Quebec
Canada	McGill University - Dept. Oncology	Montreal	Quebec
Canada	Stronach Regional Health Centre at Southlake	Newmarket	Ontario
Canada	Lakeridge Health Oshawa	Oshawa	Ontario
Canada	Ottawa Health Research Institute - General Division	Ottawa	Ontario
Canada	CHA-Hopital Du St-Sacrement	Quebec City	Quebec
Canada	CHUQ-Pavillon Hotel-Dieu de Quebec	Quebec City	Quebec
Canada	Allan Blair Cancer Centre	Regina	Saskatchewan
Canada	Atlantic Health Sciences Corporation	Saint John	New Brunswick
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
Canada	Algoma District Cancer Program	Sault Ste. Marie	Ontario
Canada	Niagara Health System	St. Catharines	Ontario
Canada	Dr. H. Bliss Murphy Cancer Centre	St. John's	Newfoundland and Labrador
Canada	Northeast Cancer Center Health Sciences	Sudbury	Ontario
Canada	BCCA - Fraser Valley Cancer Centre	Surrey	British Columbia
Canada	Thunder Bay Regional Health Science Centre	Thunder Bay	Ontario
Canada	Mount Sinai Hospital	Toronto	Ontario
Canada	Odette Cancer Centre	Toronto	Ontario
Canada	St. Michael's Hospital	Toronto	Ontario
Canada	Toronto East General Hospital	Toronto	Ontario
Canada	Trillium Health Centre - West Toronto	Toronto	Ontario
Canada	Univ. Health Network-Princess Margaret Hospital	Toronto	Ontario
Canada	BCCA - Vancouver Cancer Centre	Vancouver	British Columbia
Canada	BCCA - Vancouver Island Cancer Centre	Victoria	British Columbia
Canada	Windsor Regional Cancer Centre	Windsor	Ontario
Canada	CancerCare Manitoba	Winnipeg	Manitoba
Switzerland	Switzerland-Chur (Ratisches Kantons- und Regionalspital)	Chur
Switzerland	Brustzentrum Thurgau, Spital Thurgau AG	Frauenfeld
Switzerland	Fondazione Oncologia Lago Maggiore, FOLM	Locarno
Switzerland	Switzerland-Luzern (Kantonsspital Luzern)	Luzern 16
Switzerland	Switzerland - Oncology Institute of Southern Switzerland (IOSI)	Mendrisio
Switzerland	Switzerland - Olten (Kantonsspital) affiliate-3101	Olten
Switzerland	Switzerland - ZeTup St.Gallen	St. Gallen
Switzerland	Switzerland - Brust-Zentrum, Zurich	Zurich
United Kingdom	Sandwell and West Birmingham Hospitals NHS Trust	Birmingham
United Kingdom	Brighton and Sussex University Hospitals NHS Trust	Brighton	East Sussex
United Kingdom	North Bristol NHS Trust	Bristol	Southmead
United Kingdom	Velindre Cancer Centre	Cardiff	Whitchurch
United Kingdom	Ninewells Hospital	Dundee	University Of Dundee
United Kingdom	University Hospital Birmingham NHS Foundation Trust	Edgbaston	Birmingham
United Kingdom	Edinburgh Cancer Centre, Western General Hospital	Edinburgh	Crewe Road South
United Kingdom	Medway NHS Foundation Trust	Gillingham	Kent
United Kingdom	Withybush General Hospital	Haverfordwest	Pembrokeshire
United Kingdom	St George's Healthcare NHS Trust	London	Tooting
United Kingdom	Kent Centre for Oncology	Maidstone	Kent
United Kingdom	The Christie NHS Foundation Trust	Manchester	Withington
United Kingdom	South Tees Hospitals NHS Foundation Trust	Middlesborough	Marton Road
United Kingdom	East and North Hertfordshire NHS Trust	Middlesex	Rickmansworth Road
United Kingdom	Singleton Hospital	Swansea	Sketty Lane
United States	Akron City Hospital	Akron	Ohio
United States	Akron General Medical Center	Akron	Ohio
United States	Phoebe Putney Memorial Hospital	Albany	Georgia
United States	Presbyterian Kaseman Hospital	Albuquerque	New Mexico
United States	University of New Mexico	Albuquerque	New Mexico
United States	McFarland Clinic	Ames	Iowa
United States	Providence Alaska Medical Center	Anchorage	Alaska
United States	AnMed Health Cancer Center	Anderson	South Carolina
United States	University of Michigan Health System-Cancer Center	Ann Arbor	Michigan
United States	Kaiser Permanente-Deer Valley Medical Center	Antioch	California
United States	Mission Hospitals Inc	Asheville	North Carolina
United States	Rush - Copley Medical Center	Aurora	Illinois
United States	University of Colorado Cancer Center - Anschutz Cancer Pavilion	Aurora	Colorado
United States	University Medical Center Brackenridge	Austin	Texas
United States	Johns Hopkins University	Baltimore	Maryland
United States	Mercy Medical Center	Baltimore	Maryland
United States	University of Maryland Greenebaum Cancer Center	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Mary Bird Perkins Cancer Center	Baton Rouge	Louisiana
United States	Battle Creek Health System	Battle Creek	Michigan
United States	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California
United States	Mountainview Medical	Berlin	Vermont
United States	Suburban Hospital	Bethesda	Maryland
United States	Medcenter One Health Systems	Bismarck	North Dakota
United States	Mid Dakota Clinic	Bismarck	North Dakota
United States	Boca Raton Regional Hospital	Boca Raton	Florida
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Albert Einstein College of Medicine	Bronx	New York
United States	Montefiore Medical Center	Bronx	New York
United States	The North Division of Montefiore Medical Center	Bronx	New York
United States	Coney Island Hospital	Brooklyn	New York
United States	Maimonides Medical Center	Brooklyn	New York
United States	State University of New York Downstate Medical Center	Brooklyn	New York
United States	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Lahey Clinic Medical Center	Burlington	Massachusetts
United States	University of Vermont	Burlington	Vermont
United States	Aultman Health Foundation	Canton	Ohio
United States	Oncology Associates at Mercy Medical Center	Cedar Rapids	Iowa
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Presbyterian Hospital	Charlotte	North Carolina
United States	Martha Jefferson Hospital	Charlottesville	Virginia
United States	Saint Luke's Hospital	Chesterfield	Missouri
United States	John H Stroger Jr Hospital of Cook County	Chicago	Illinois
United States	Mount Sinai Hospital Medical Center	Chicago	Illinois
United States	Resurrection Healthcare	Chicago	Illinois
United States	Swedish Covenant Hospital	Chicago	Illinois
United States	University of Chicago	Chicago	Illinois
United States	Enloe Medical Center	Chico	California
United States	Case Western Reserve University	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	MetroHealth Medical Center	Cleveland	Ohio
United States	Memorial Hospital Colorado Springs	Colorado Springs	Colorado
United States	Ohio State University Medical Center	Columbus	Ohio
United States	New Hampshire Oncology-Hematology PA	Concord	New Hampshire
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	Heartland Oncology and Hematology LLP	Council Bluffs	Iowa
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Kaiser Permanente-Franklin	Denver	Colorado
United States	Wayne State University	Detroit	Michigan
United States	Duluth Clinic CCOP	Duluth	Minnesota
United States	Hematology Oncology Associates of Central New York PC	East Syracuse	New York
United States	Marshfield Clinic Cancer Care at Regional Cancer Center	Eau Claire	Wisconsin
United States	Fairview-Southdale Hospital	Edina	Minnesota
United States	Elkhart Clinic	Elkhart	Indiana
United States	Michiana Hematology Oncology PC-Elkhart	Elkhart	Indiana
United States	Elmhurst Memorial Hospital	Elmhurst	Illinois
United States	Evanston CCOP-NorthShore University HealthSystem	Evanston	Illinois
United States	Saint Francis Hospital	Evanston	Illinois
United States	Fairbanks Memorial Hospital	Fairbanks	Alaska
United States	Sanford Clinic North-Fargo	Fargo	North Dakota
United States	Sanford Medical Center-Fargo	Fargo	North Dakota
United States	University of Connecticut	Farmington	Connecticut
United States	McLeod Regional Medical Center	Florence	South Carolina
United States	Central Wisconsin Cancer Program	Fond Du Lac	Wisconsin
United States	Front Range Cancer Specialists	Fort Collins	Colorado
United States	Poudre Valley Hospital	Fort Collins	Colorado
United States	Frederick Memorial Hospital	Frederick	Maryland
United States	Unity Hospital	Fridley	Minnesota
United States	Northeast Georgia Medical Center	Gainesville	Georgia
United States	Glendale Memorial Hospital and Health Center	Glendale	California
United States	Addison Gilbert Hospital	Gloucester	Massachusetts
United States	Wayne Memorial Hospital	Goldsboro	North Carolina
United States	Altru Cancer Center	Grand Forks	North Dakota
United States	Grand Rapids Clinical Oncology Program	Grand Rapids	Michigan
United States	Saint Mary's Health Care	Grand Rapids	Michigan
United States	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan
United States	Aurora BayCare Medical Center	Green Bay	Wisconsin
United States	Saint Vincent Hospital	Green Bay	Wisconsin
United States	Greenwich Hospital	Greenwich	Connecticut
United States	Hartford Hospital	Hartford	Connecticut
United States	Ingalls Memorial Hospital	Harvey	Illinois
United States	Kaiser Permanente, Hayward	Hayward	California
United States	Margaret R Pardee Memorial Hospital	Hendersonville	North Carolina
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	High Point Regional Hospital	High Point	North Carolina
United States	Kaiser Permanente Moanalua Medical Center	Honolulu	Hawaii
United States	University of Hawaii	Honolulu	Hawaii
United States	New Hampshire Oncology Hematology Associates	Hooksett	New Hampshire
United States	Edwards Comprehensive Cancer Center	Huntington	West Virginia
United States	Indiana University Hospital/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Good Samaritan Hospital	Kearney	Nebraska
United States	Kettering Medical Center	Kettering	Ohio
United States	Kinston Medical Specialists PA	Kinston	North Carolina
United States	University of Tennessee - Knoxville	Knoxville	Tennessee
United States	Howard Regional Healthcare System	Kokomo	Indiana
United States	Gundersen Lutheran Health System/CCOP	La Crosse	Wisconsin
United States	Moores University of California San Diego Cancer Center	La Jolla	California
United States	LRGHealthcare-Lakes Region General Hospital	Laconia	New Hampshire
United States	Monter Cancer Center	Lake Success	New York
United States	The Watson Clinic	Lakeland	Florida
United States	Lancaster General Hospital	Lancaster	Pennsylvania
United States	Doctor's Hospital of Laredo	Laredo	Texas
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	Central Baptist Hospital	Lexington	Kentucky
United States	Lincoln Medical Education Foundation Cancer Resource Center	Lincoln	Nebraska
United States	Saint Barnabas Medical Center	Livingston	New Jersey
United States	The Dana-Farber Cancer Institute at Londonderry	Londonderry	New Hampshire
United States	Long Beach Memorial Medical Center-Todd Cancer Institute	Long Beach	California
United States	Saint John Medical Center	Longview	Washington
United States	University of California at Los Angeles (UCLA )	Los Angeles	California
United States	University of Southern California	Los Angeles	California
United States	Lowell General Hospital	Lowell	Massachusetts
United States	Lynchburg Hematology-Oncology Clinic	Lynchburg	Virginia
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	North Shore University Hospital	Manhasset	New York
United States	North Shore University Hospital CCOP	Manhasset	New York
United States	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota
United States	Saint John's Hospital - Healtheast	Maplewood	Minnesota
United States	Marshfield Clinic	Marshfield	Wisconsin
United States	Fremont - Rideout Cancer Center	Marysville	California
United States	Loyola University Medical Center	Maywood	Illinois
United States	Columbia Saint Mary's Hospital - Ozaukee	Mequon	Wisconsin
United States	Mount Sinai Medical Center CCOP	Miami Beach	Florida
United States	Saint Anthony Memorial Health Center	Michigan City	Indiana
United States	Columbia Saint Mary's Water Tower Medical Commons	Milwaukee	Wisconsin
United States	Wheaton Franciscan Healthcare - Saint Joseph	Milwaukee	Wisconsin
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Trinity Cancer Care Center	Minot	North Dakota
United States	Michiana Hematology Oncology PC-Mishawaka	Mishawaka	Indiana
United States	Trinity Medical Center	Moline	Illinois
United States	West Virginia University	Morgantown	West Virginia
United States	Fox Chase Cancer Center at Virtua Memorial Hospital of Burlington County	Mount Holly	New Jersey
United States	Mount Kisco Medical Group	Mount Kisco	New York
United States	Mount Kisco Medical Group at Northern Westchester Hospital	Mount Kisco	New York
United States	Mercy Health Partners-Mercy Campus	Muskegon	Michigan
United States	Vanderbilt Breast Center at One Hundred Oaks	Nashville	Tennessee
United States	Vanderbilt University	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	Long Island Jewish Medical Center	New Hyde Park	New York
United States	Beth Israel Medical Center	New York	New York
United States	Columbia University Medical Center	New York	New York
United States	Mount Sinai Medical Center	New York	New York
United States	New York University Langone Medical Center	New York	New York
United States	Saint Luke's Roosevelt Hospital Center - Saint Luke's Division	New York	New York
United States	Michiana Hematology Oncology PC-Niles	Niles	Michigan
United States	Bay Area Tumor Institution CCOP	Oakland	California
United States	Kaiser Permanente-Oakland	Oakland	California
United States	Methodist Estabrook Cancer Center	Omaha	Nebraska
United States	Missouri Valley Cancer Consortium CCOP	Omaha	Nebraska
United States	University of California Medical Center At Irvine-Orange Campus	Orange	California
United States	Florida Hospital	Orlando	Florida
United States	Ottumwa Regional Health Center	Ottumwa	Iowa
United States	Owensboro Mercy Medical Center	Owensboro	Kentucky
United States	Paoli Memorial Hospital	Paoli	Pennsylvania
United States	Singing River Hospital	Pascagoula	Mississippi
United States	Memorial Hospital of Rhode Island	Pawtucket	Rhode Island
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Illinois Oncology Research Association CCOP	Peoria	Illinois
United States	Albert Einstein Medical Center	Philadelphia	Pennsylvania
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Pennsylvania Hospital	Philadelphia	Pennsylvania
United States	Phoenixville Hospital	Phoenixville	Pennsylvania
United States	FirstHealth of the Carolinas-Moore Regional Hosiptal	Pinehurst	North Carolina
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Michiana Hematology Oncology PC-Plymouth	Plymouth	Indiana
United States	Pomona Valley Hospital Medical Center	Pomona	California
United States	Columbia River Oncology Program	Portland	Oregon
United States	Kaiser Permanente	Portland	Oregon
United States	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Kansas City CCOP	Prairie Village	Kansas
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Women and Infants Hospital	Providence	Rhode Island
United States	Rex Cancer Center	Raleigh	North Carolina
United States	Rapid City Regional Hospital	Rapid City	South Dakota
United States	Saint Joseph Medical Center	Reading	Pennsylvania
United States	Kaiser Permanente-Redwood City	Redwood City	California
United States	Kaiser Permanente-Richmond	Richmond	California
United States	Valley Hospital	Ridgewood	New Jersey
United States	North Memorial Medical Health Center	Robbinsdale	Minnesota
United States	Mayo Clinic	Rochester	Minnesota
United States	Rochester General Hospital	Rochester	New York
United States	Kaiser Permanente-Roseville	Roseville	California
United States	William Beaumont Hospital	Royal Oak	Michigan
United States	Kaiser Permanente - Sacramento	Sacramento	California
United States	Kaiser Permanente-South Sacramento	Sacramento	California
United States	University of California Davis-Cancer Center	Sacramento	California
United States	CentraCare Clinic	Saint Cloud	Minnesota
United States	Marie Yeager Cancer Center	Saint Joseph	Michigan
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	Saint John's Mercy Medical Center	Saint Louis	Missouri
United States	Saint Louis-Cape Girardeau CCOP	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Metro-Minnesota CCOP	Saint Louis Park	Minnesota
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	University of Texas Health Science Center	San Antonio	Texas
United States	Kaiser Permanente	San Diego	California
United States	Kaiser Permanente-Mission	San Diego	California
United States	Kaiser Permanente-San Francisco	San Francisco	California
United States	University of California San Francisco Medical Center-Mount Zion	San Francisco	California
United States	Kaiser Permanente-Santa Teresa-San Jose	San Jose	California
United States	Kaiser Permanente-San Rafael	San Rafael	California
United States	Kaiser Permanente Medical Center - Santa Clara	Santa Clara	California
United States	Kaiser Permanente-Santa Rosa	Santa Rosa	California
United States	Mayo Clinic in Arizona	Scottsdale	Arizona
United States	Pinnacle Oncology Associates	Scottsdale	Arizona
United States	Group Health Cooperative	Seattle	Washington
United States	Pacific Medical Center-First Hill	Seattle	Washington
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	University of Washington Medical Center	Seattle	Washington
United States	Virginia Mason CCOP	Seattle	Washington
United States	Siouxland Hematology Oncology Associates	Sioux City	Iowa
United States	Avera Cancer Institute	Sioux Falls	South Dakota
United States	Sanford Clinic	Sioux Falls	South Dakota
United States	Michiana Hematology Oncology PC-South Bend	South Bend	Indiana
United States	Kaiser Permanente-South San Francisco	South San Francisco	California
United States	Spartanburg Regional Medical Center	Spartanburg	South Carolina
United States	Rockwood Clinic	Spokane	Washington
United States	Cox Medical Center	Springfield	Missouri
United States	Memorial Medical Center	Springfield	Illinois
United States	Saint John's Hospital	Springfield	Missouri
United States	Stamford Hospital	Stamford	Connecticut
United States	Stanford University	Stanford	California
United States	Mount Nittany Medical Center	State College	Pennsylvania
United States	Kaiser Permanente-Stockton	Stockton	California
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	Aurora Medical Center in Summit	Summit	Wisconsin
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Northwest CCOP	Tacoma	Washington
United States	Moffitt Cancer Center and Research Institute	Tampa	Florida
United States	Connecticut Oncology and Hematology LLP	Torrington	Connecticut
United States	Munson Medical Center	Traverse City	Michigan
United States	Tahoe Forest Cancer Center	Truckee	California
United States	Arizona Cancer Center at University Medical Center North	Tucson	Arizona
United States	University of Arizona Health Sciences Center	Tucson	Arizona
United States	Carle Foundation - Carle Cancer Center	Urbana	Illinois
United States	Kaiser Permanente Medical Center-Vacaville	Vacaville	California
United States	South Georgia Medical Center	Valdosta	Georgia
United States	Kaiser Permanente-Vallejo	Vallejo	California
United States	Providence Saint Mary Regional Cancer Center	Walla Walla	Washington
United States	John Muir Medical Center	Walnut Creek	California
United States	Kaiser Permanente-Walnut Creek	Walnut Creek	California
United States	Georgetown University Hospital	Washington	District of Columbia
United States	Sibley Memorial Hospital	Washington	District of Columbia
United States	Washington Hospital Center	Washington	District of Columbia
United States	Wenatchee Valley Medical Center	Wenatchee	Washington
United States	Chester County Hospital	West Chester	Pennsylvania
United States	Marshfield Clinic - Weston Center	Weston	Wisconsin
United States	Michiana Hematology Oncology-PC Westville	Westville	Indiana
United States	Wheeling Hospital	Wheeling	West Virginia
United States	Wichita CCOP	Wichita	Kansas
United States	Rice Memorial Hospital	Willmar	Minnesota
United States	Forsyth Memorial Hospital	Winston-Salem	North Carolina
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	Minnesota Oncology and Hematology PA-Woodbury	Woodbury	Minnesota
United States	Saint Vincent Hospital - Fallon Clinic	Worcester	Massachusetts
United States	Lankenau Hospital	Wynnewood	Pennsylvania
United States	Metro Health Hospital	Wyoming	Michigan
United States	North Star Lodge Cancer Center at Yakima Valley Memorial Hospital	Yakima	Washington
United States	York Hospital	York	Maine

Sponsors (4)

Lead Sponsor	Collaborator
Canadian Cancer Trials Group	ETOP IBCSG Partners Foundation, ICR-CTSU, National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada,  Switzerland,  United Kingdom, 

References & Publications (2)

Goodwin PJ, Chen BE, Gelmon KA, Whelan TJ, Ennis M, Lemieux J, Ligibel JA, Hershman DL, Mayer IA, Hobday TJ, Bliss JM, Rastogi P, Rabaglio-Poretti M, Mukherjee SD, Mackey JR, Abramson VG, Oja C, Wesolowski R, Thompson AM, Rea DW, Stos PM, Shepherd LE, Sta — View Citation

Goodwin PJ, Parulekar WR, Gelmon KA, Shepherd LE, Ligibel JA, Hershman DL, Rastogi P, Mayer IA, Hobday TJ, Lemieux J, Thompson AM, Pritchard KI, Whelan TJ, Mukherjee SD, Chalchal HI, Oja CD, Tonkin KS, Bernstein V, Chen BE, Stambolic V. Effect of metformin vs placebo on and metabolic factors in NCIC CTG MA.32. J Natl Cancer Inst. 2015 Mar 4;107(3):djv006. doi: 10.1093/jnci/djv006. Print 2015 Mar. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Invasive Disease-free Survival in Hormone Receptor (ER and PgR) Positive Sub-groups	Invasive disease-free survival (IDFS) is defined as percentage of patients without documented development of ipsilateral and contralateral invasive breast tumour, local/regional invasive recurrence, distant recurrence, death from any causes. If a subject has not had invasive disease or died at the time of data cut-off for this final analysis, IDFS was censored on the date of last follow-up.	5 years
Primary	Invasive Disease-free Survival	Invasive disease-free survival (IDFS) is defined as the percent of patients without documented development of ipsilateral and contralateral invasive breast tumour, local/regional invasive recurrence, distant recurrence, death from any causes. If a subject has not had invasive disease or died at the time of data cut-off for this final analysis, IDFS was censored on the date of last follow-up.	5 years
Secondary	Overall Survival	Number of patients who died from any causes.	10 years
Secondary	Distant Relapse-free Survival	Distant Relapse Free Survival (DRFS) is defined as the percentage of patients without any documented distant recurrence, death from breast cancer, death from a non breast cancer cause or death from an unknown cause. If a subject has not had distant DRFS event nor died at the time of data cut-off for this analysis, DRFS will be censored on the date of last disease assessment.	5 years
Secondary	Breast Cancer-specific Mortality	Patients who died from breast cancer	10 years