Trial #NCT01905046
Atypical Ductal Breast Hyperplasia Clinical Trials

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

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
Study ID: A211102; Secondary ID: U10CA031946; Source: Alliance for Clinical Trials in Oncology
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Determine whether experimental treatments or new ways of using known therapies are safe and effective under controlled environments.
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Status Not yet recruiting
Country n/a
Study type Interventional
Enrollment 400
Start date August 2013
Completion date
Phase Phase 3
Sponsor Alliance for Clinical Trials in Oncology
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.
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.
Gender: Female
Age: 25 Years - 55 Years
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.
Primary outcome
  • 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
Secondary outcome
  • 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
  • Correlate baseline RPPM values with presence of atypia at Month 12 and Month 24.
    Time frame: Up to 24 months
  • 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
  • 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
  • Test the reproducibility of RPPM in duplicate RPPM determination from single bilateral RPFNA specimen.
    Time frame: Up to 12 months
  • Victoria Seewaldt, M.D.; Duke University School of Medicine - Department of Pharmacology and Cancer Biology (Study Chair)
Location Country Status
  • Alliance for Clinical Trials in Oncology - (Lead Sponsor)
  • National Cancer Institute (NCI) - Collaborator

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