Metformin Hydrochloride in Patients With Atypical Hyperplasia or In Situ Breast Cancer to Placebo in Decreasing Atypical Cells in Patients With Atypical Hyperplasia or in Situ Breast Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2015 by Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology Identifier:
First received: July 16, 2013
Last updated: June 12, 2015
Last verified: June 2015
This randomized phase III trial studies metformin hydrochloride to see how well it works compared to placebo in decreasing atypical cells in patients with atypical hyperplasia or in situ breast cancer.

Condition Intervention Phase
Atypical Ductal Breast Hyperplasia
BRCA1 Mutation Carrier
BRCA2 Mutation Carrier
Ductal Breast Carcinoma in Situ
Lobular Breast Carcinoma in Situ
Drug: metformin hydrochloride
Other: placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Prevention
Official Title: Testing for Atypia in Random Periareolar Fine Needle Aspiration (RPFNA) Cytology After 12 Months Metformin (1,1-Dimethylbiguanide Hydrochloride) Chemoprevention Versus Placebo Control in Premenopausal Women

Resource links provided by NLM:

Further study details as provided by Alliance for Clinical Trials in Oncology:

Primary Outcome Measures:
  • Test for the presence or absence of atypia in RPFNA after 12 months and 24 months. Month 24 is optional for the placebo group for those patients who remain on the placebo arm and will not receive metformin (Metformin versus placebo control). [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Test for the Masood Score and the presence of atypia or disapperance of atypia in RPFNA after 12 months (for both arms) and 24 months for Metformin arm. [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
  • Test the reproducibility of RPPM in duplicate RPPM determination from single bilateral RPFNA specimen. [ Time Frame: Up to 12 months ] [ Designated as safety issue: No ]
  • Determine the change in percent breast density from prior to the initiation of metformin or placebo treatment through therapy (ie, Months 12 and 24) and following therapy (Months 36 and 48). [ Time Frame: Baseline up to 48 months ] [ Designated as safety issue: No ]
  • Compare Masood Cytology Score value at 0, 12 and 24 months in right and left breast from the same individual in the metformin and non-metformin group. [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
  • Correlate baseline RPPM values with presence of atypia at Month 12 and Month 24. [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 400
Study Start Date: August 2013
Estimated Primary Completion Date: January 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I: metformin hydrochloride
Patients will receive metformin hydrochloride tablet 850 mg PO BID for 24 months on Arm I, which includes a 4-week ramp up of 850 mg PO QD.
Drug: metformin hydrochloride
given PO
Other Names:
  • 1,1 - dimethylbiguanide hydrochloride
  • 657-24-9
  • N, N - dimethylimidodicarbonimidic diamide monohydrochloride
Placebo Comparator: Arm II: placebo
Patients receive placebo tablet PO QD BID for 12 months which includes a 4-week ramp up of 850 mg PO QD. Patients initially randomized to the placebo group (Arm II) may crossover to the metformin group (Arm I) for months 13-24.
Other: placebo
given PO
Other Name: PLCB

Detailed Description:

Patients are randomized to 1 of 2 treatment groups. Patients will receive metformin hydrochloride 850 mg by mouth (PO) twice daily (BID) for 24 months on Arm I, which includes a 4-week ramp up of 850 mg PO QD. Patients will receive placebo 850 mg PO BID for 12 months on Arm II, which includes a 4-week ramp up of 850 mg PO QD. Patients initially randomized to the placebo (Arm II) may crossover to the metformin hydrochloride treatment group (Arm I) for months 13-24. The primary and secondary objectives are described below.

Primary Objective:

• Test for the presence or absence of cytological atypia in random periareolar fine needle aspiration (RPFNA) bilateral aspirates for women receiving metformin versus placebo control.

Secondary Objectives:

  • Use the Masood Cytology Index Score to test for the presence of cytological atypia or disappearance of cytological atypia in RPFNA bilateral aspirates.
  • Compare Masood Cytology Score values in the right and left breasts from the same individual in the metformin and placebo groups.
  • Test the reproducibility of reverse phase protein microarray (RPPM) in duplicate RPPM determinations from individual RPFNA specimens.
  • Correlate baseline RPPM values with presence of atypia (as measured by Masood Cytology Index Score).
  • Determine the change in percent breast density.

After completion of study treatment, patients are followed up for 2 years.


Ages Eligible for Study:   25 Years to 55 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Pre-Registration Inclusion Criteria:

  1. Must be at increased risk for breast cancer, defined as at least one of the following four criteria:

    • Having had a prior biopsy demonstrating atypical hyperplasia, lobular carcinoma in situ (LCIS), or ductal carcinoma in situ (DCIS)
    • A Gail Model Risk of ≥1.66% over 5 years
    • A strong family history of breast and/or ovarian cancer as defined in the study protocol.
    • Known breast cancer (BRCA)1 or BRCA2 mutation carrier providing that the woman has:

      • Met with a genetic counselor to review genetic testing results, and
      • Has been offered the opportunity to undergo prophylactic mastectomy and oophorectomy
  2. Pre-menopausal women as defined as four menstrual cycles within the last six months prior to pre-registration. Women with less than 4 menses within 6 months prior to pre-registration or women who have had a hysterectomy with ovaries intact will be considered premenopausal if follicle-stimulating hormone (FSH) level is < 20. Women who are using hormonal contraceptives that cause amenorrhea (e.g. injectable and extended oral contraceptives, Hormone-containing contraceptive ring, or hormone-containing intrauterine device) will be considered eligible if they had a minimum of 4 menstrual cycles within the last six months prior to starting on the contraceptive.
  3. Digital mammogram within 180 days prior to pre-registration.
  4. Mammographic density ≥ 25% or mammogram evaluated by a radiologist as scattered fibro glandular density.
  5. Mammograms must be read as not suspicious for breast cancer (American College of Rheumatology [ACR] class I-III). Subjects with a class IV mammogram may be enrolled once they have been evaluated by a breast surgeon and there is no evidence of invasive malignancy.
  6. Must be non-pregnant and non-lactating for at least one year prior to pre-registration.
  7. If currently menstruating, subjects must use a reliable method of birth control.
  8. Willing to provide RPFNA and blood samples for correlative research purposes.
  9. Women with core biopsy or excisional biopsy containing DCIS, LCIS or atypia are eligible for this study.
  10. Women eligible to take tamoxifen must be offered tamoxifen prevention as part of their clinical care and have refused tamoxifen treatment.
  11. Age 25-55 years.

Pre-registration Exclusion Criteria:

  1. Other active malignancy ≤ 5 years prior to pre-registration. EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix. NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment, i.e., other hormonal therapy, for their cancer.
  2. Body mass index (BMI) < 25.
  3. Receiving warfarin.
  4. Bilateral breast implants or autologous breast flap reconstruction.
  5. Active diagnosis of alcoholism.
  6. Contraindication to metformin prevention such as acute hypersensitivity or allergic reaction to metformin.
  7. Receiving tamoxifen or raloxifene.
  8. Administration of any investigational agent ≤ 30 days prior to pre-registration.
  9. Radiation to both breasts.
  10. Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
  11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  12. Receiving pyrimethamine, cimetidine, rifampin or cephalexin.
  13. Women who have a core biopsy or excisional biopsy containing invasive cancer.

Registration/Randomization Inclusion Criteria:

  1. Qualifying cytological atypia in RPFNA, Masood score of 14-17.
  2. Required laboratory values obtained no more than 30 days prior to registration/randomization.

    1. Hemoglobin ≥ 9 g/dL.
    2. Absolute neutrophil count (ANC) ≥ 1500/mm^3.
    3. Platelet count ≥ 75,000/mm^3.
    4. Creatinine ≤ 1.5 mg/dL or creatinine clearance (CrCl) >= 30 mL/min.
    5. Total bilirubin ≤ 3.0 mg/dL.
    6. Aspartate trasaminase (AST) ≤ 3 x upper limit of normal (ULN).
    7. Alanine transaminase (ALT) ≤ 3 x ULN.
  3. Negative pregnancy test done ≤ 7 days prior to registration /randomization, for women of childbearing potential only.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01905046

Contact: Victoria Seewaldt, M.D. 919 668-2454

United States, Texas
Doctor's Hospital of Laredo Recruiting
Laredo, Texas, United States, 78045
Contact: Gary Unzeitig, MD    956-726-3691      
United States, Wisconsin
University of Wisconsin Hospital and Clinics Recruiting
Madison, Wisconsin, United States, 53792
Contact: Lee Wilke, MD    608-265-5852      
Sponsors and Collaborators
Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
Study Chair: Victoria Seewaldt, M.D. Duke University School of Medicine - Department of Pharmacology and Cancer Biology
  More Information

Responsible Party: Alliance for Clinical Trials in Oncology Identifier: NCT01905046     History of Changes
Other Study ID Numbers: A211102  U10CA031946  NCI-2013-00995 
Study First Received: July 16, 2013
Last Updated: June 12, 2015
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Breast Neoplasms
Carcinoma in Situ
Carcinoma, Ductal, Breast
Carcinoma, Intraductal, Noninfiltrating
Carcinoma, Lobular
Breast Diseases
Carcinoma, Ductal
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Ductal, Lobular, and Medullary
Neoplasms, Glandular and Epithelial
Pathologic Processes
Skin Diseases
Hypoglycemic Agents
Physiological Effects of Drugs processed this record on May 26, 2016