Trial record 1 of 1 for:    NCT01905046
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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 2016 by Alliance for Clinical Trials in Oncology
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier:
NCT01905046
First received: July 16, 2013
Last updated: June 6, 2016
Last verified: June 2016
  Purpose

The purpose of this research study is to test whether metformin, a drug commonly used to treat diabetes, is able to get rid of atypia (early cell changes that are thought to be a marker of breast cancer risk) in women at increased risk for breast cancer. There will be testing for the presence of atypia in the breast after metformin is given to see if it can get rid of atypia. The study will compare the effects, good and/or bad, of metformin or placebo on atypia to find out which is better.

Note: The standard drug used for the "breast cancer prevention" is tamoxifen. If the patient is eligible to take tamoxifen, he/she must be offered tamoxifen prevention as part of clinical care. Metformin and tamoxifen are not similar and function differently. This study is not investigating the use of tamoxifen. Metformin is not approved for preventing breast cancer, but is currently being tested to determine if it can prevent 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 (24 month optional for placebo group for patients who remain on 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, 12 and 24 months) and following therapy (ie, 36 and 48 months). [ 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

RPFNA samples will be collected and submitted to the laboratory to determine eligibility. Patients will receive metformin 850 mg PO daily for 4 weeks then metformin 850 mg PO BID for months 2-12. At approximately 12 months, patients will undergo RPFNA and all patients will be unblinded.

Patients will continue metformin 850 mg PO BID for months 13-24. Patients will undergo RPFNA at 24 months. Follow up visits will be performed at 36 and 48 months after the start of treatment.

Drug: metformin hydrochloride
given PO
Other Names:
  • 1,1 - dimethylbiguanide hydrochloride
  • 657-24-9
  • N, N - dimethylimidodicarbonimidic diamide monohydrochloride
Placebo Comparator: Arm II: placebo +/- metformin hydrochloride

RPFNA samples will be collected and submitted to the laboratory to determine eligibility. Patients will receive placebo 850 mg PO daily for 4 weeks then placebo 850 mg PO BID for months 2-12. At approximately 12 months, patients will undergo RPFNA and all patients will be unblinded.

Patients may opt to crossover to metformin and receive metformin 850 mg PO daily for 4 weeks then 850 mg PO BID for months 14-24 or discontinue protocol treatment. Patients will undergo RPFNA at 24 months. For paitents that discontinue protocol treatment, RPFNA is optional.

Follow up visits will be performed at 36 and 48 months after the start of treatment.

Drug: metformin hydrochloride
given PO
Other Names:
  • 1,1 - dimethylbiguanide hydrochloride
  • 657-24-9
  • N, N - dimethylimidodicarbonimidic diamide monohydrochloride
Other: placebo
given PO
Other Name: PLCB

Detailed Description:

A total of 400 premenopausal women (200 per arm) will be pre-registered, among which 300 patients with atypia (Masood Score 14-17) on random periareolar fine needle aspiration (RPFNA) at baseline are expected to be randomized between Metformin and placebo control arm. It is expected that the accrual rate will be 5 to 10 patients per month and that accrual will be completed about 4 years after study activation. The randomization will be stratified for known BRCA mutation (BRCA1 or BRCA2 mutation vs. no mutation), prior excisional biopsy (atypical epithelial hyperplasia, atypical lobular hyperplasia, flat epithelial hyperplasia vs. DCIS vs. LCIS), and baseline fasting insulin > 2x ULN vs. ≤ 2x ULN.

The primary and secondary objectives are described below.

Primary Objective:

• Test for the presence or absence of cytological atypia in RPFNA bilateral aspirates after 12 and 24 months (24 month is optional for placebo-only group for patients who remain on placebo arm and will not receive metformin) for women receiving metformin versus placebo control. The presence of cytological atypia means any atypia in any RPFNA specimen.

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 after 12 months for both arms, and 24 months (24 month is optional for placebo-only group for patients who remain on placebo arm and will not receive metformin, and mandatory for crossover patients) for women receiving metformin 850 mg PO BID (metformin group).
  • Compare Masood Cytology Score values at 0 and 12 months 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) at month 12 and month 24 (month 24 optional for placebo-only group; for patients who remain on placebo arm and will not receive metformin) RPFNA.
  • Determine the change in percent breast density from prior to the initiation of metformin or placebo treatment through therapy (ie, at 12 and 24 months), and following therapy (ie, 36 and 48 months).

Follow up visits will be performed at 36 and 48 months after the start of treatment.

  Eligibility

Ages Eligible for Study:   25 Years to 55 Years   (Adult)
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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 BRCA1 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. 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.
  5. Must be non-pregnant and non-lactating for at least one year prior to pre-registration.
  6. If currently menstruating, subjects must use a reliable method of birth control.
  7. Willing to provide RPFNA and blood samples for correlative research purposes.
  8. Women with core biopsy or excisional biopsy containing DCIS, LCIS or atypia are eligible for this study.
  9. Women eligible to take tamoxifen must be offered tamoxifen prevention as part of their clinical care and have refused tamoxifen treatment.

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. Previous 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.
  14. Women who have taken metformin within the past 90 days.
  15. Patients with hemoglobin alc > 6.3 or who are being actively treated for diabetes.

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 ≤ 1.4 mg/dL
    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. A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal for at least 12 consecutive months (ie, has had menses at any time in the preceding 12 consectuve imonths).
  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 ClinicalTrials.gov identifier: NCT01905046

Contacts
Contact: Victoria Seewaldt, MD (626) 471-7321

Locations
United States, California
City of Hope Comprehensive Cancer Center Recruiting
Duarte, California, United States, 91010
Contact: Victoria Seewaldt, MD    626-471-7321      
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Sandhya Pruthi, MD    507-538-0289      
United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Jessica Young, MD    716-845-2918      
Columbia University-Herbert Irving Cancer Center Recruiting
New York, New York, United States, 10032
Contact: Katherine Crew, MD    212-305-1732      
United States, Ohio
The Christ Hospital Recruiting
Cincinnati, Ohio, United States, 45219
Contact: Jennifer Manders, MD    513-585-1496      
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Lisa Yee, MD    614-293-6654      
United States, South Carolina
Greenville Health System Cancer Institute-Easley Recruiting
Easley, South Carolina, United States, 29640
Contact: Jeffrey Giguere, MD    864-241-6251      
Greenville Memorial Hospital Recruiting
Greenville, South Carolina, United States, 29605
Contact: Jeffrey Giguere, MD    864-241-6251      
Greenville Health System Cancer Institute-Eastside Recruiting
Greenville, South Carolina, United States, 29615
Contact: Jeffrey Giguere, MD    864-241-6251      
Greenville Health System Cancer Institute-Faris Recruiting
Greenville, South Carolina, United States, 29605
Contact: Jeffrey Giguere, MD    864-241-6251      
Greenville Health System Cancer Institute-Greer Recruiting
Greer, South Carolina, United States, 29650
Contact: Jeffrey Giguere, MD    864-241-6251      
Greenville Health System Cancer Institute-Seneca Recruiting
Seneca, South Carolina, United States, 29672
Contact: Jeffrey Giguere, MD    864-241-6251      
Greenville Health System Cancer Institute-Spartanburg Recruiting
Spartanburg, South Carolina, United States, 29307
Contact: Jeffrey Giguere, MD    864-241-6251      
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Therese Bevers, MD    713-745-8048      
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)
Investigators
Study Chair: Victoria Seewaldt, MD Beckman Research Institute
  More Information

Responsible Party: Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier: NCT01905046     History of Changes
Other Study ID Numbers: A211102  U10CA031946  NCI-2013-00995 
Study First Received: July 16, 2013
Last Updated: June 6, 2016
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Carcinoma
Hyperplasia
Breast Neoplasms
Carcinoma in Situ
Carcinoma, Ductal, Breast
Carcinoma, Intraductal, Noninfiltrating
Carcinoma, Lobular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Pathologic Processes
Neoplasms by Site
Breast Diseases
Skin Diseases
Carcinoma, Ductal
Adenocarcinoma
Neoplasms, Ductal, Lobular, and Medullary
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 21, 2016