Clinical Trials /

Metformin Hydrochloride in Preventing Breast Cancer in Patients With Atypical Hyperplasia or In Situ Breast Cancer

NCT01905046

Description:

This randomized phase III trial studies metformin hydrochloride to see how well it works compared to placebo in preventing breast cancer in patients with atypical hyperplasia or in situ breast cancer. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of metformin hydrochloride may prevent breast cancer.

Related Conditions:
  • Breast Lobular Carcinoma In Situ
  • Ductal Carcinoma In Situ
  • Hereditary Breast and Ovarian Cancer Syndrome
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Metformin Hydrochloride in Preventing Breast Cancer in Patients With Atypical Hyperplasia or In Situ Breast Cancer
  • 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

Clinical Trial IDs

  • ORG STUDY ID: A211102
  • SECONDARY ID: U10CA031946
  • SECONDARY ID: NCI-2013-00995
  • NCT ID: NCT01905046

Conditions

  • Atypical Ductal Breast Hyperplasia
  • BRCA1 Mutation Carrier
  • BRCA2 Mutation Carrier
  • Ductal Breast Carcinoma in Situ
  • Lobular Breast Carcinoma in Situ

Interventions

DrugSynonymsArms
metformin hydrochloride1,1 - dimethylbiguanide hydrochloride, 657-24-9, N, N - dimethylimidodicarbonimidic diamide monohydrochlorideArm I: metformin hydrochloride

Purpose

This randomized phase III trial studies metformin hydrochloride to see how well it works compared to placebo in preventing breast cancer in patients with atypical hyperplasia or in situ breast cancer. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of metformin hydrochloride may prevent breast cancer.

Detailed Description

      I. Test for the presence or absence of cytological atypia (as measured by a Masood Cytology
      Index Score of 14-17) in unilateral or bilateral random periareolar fine needle aspiration
      (RPFNA) 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 [metformin hydrochloride])
      for women receiving metformin versus placebo control. The presence of cytological atypia
      means any atypia in any RPFNA specimen.

      SECONDARY OBJECTIVES:

      I. Use the Masood Cytology Index Score to test for the presence of cytological atypia or
      disappearance of cytological atypia in RPFNA 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 orally (PO) twice daily (BID) (metformin group).

      II. Compare Masood Cytology Score values at 0 and 12 months in right and left breasts (if
      both breasts were aspirated) from the same individual in the metformin and placebo group.

      III. Test the reproducibility of reverse phase protein microarray (RPPM) in duplicate RPPM
      determinations from individual RPFNA specimens.

      IV. 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.

      TERTIARY OBJECTIVES:

      I. Test whether metformin alters RPFNA or blood biomarkers associated with breast cancer
      risk.

      II. Test whether metformin alters markers associated with obesity and insulin resistance.

      III. Test other exploratory measures in RPFNA and serum including metformin levels and
      estrogen/progesterone.

      IV. Banking: As part of ongoing research for Alliance Cancer Control studies, banking
      residual blood and RPFNA products for future studies.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I: metformin hydrochlorideExperimentalPatients receive metformin hydrochloride PO QD or BID for 24 months. 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.
  • metformin hydrochloride
Arm II: placeboPlacebo ComparatorPatients receive placebo PO QD or BID for 12 months. Patients may crossover to Arm I for months 13-24.

    Eligibility Criteria

            -  PRE-REGISTRATION-INCLUSION CRITERIA
    
              -  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 which is defined as at
                      least one of the following:
    
                        -  One first-degree relative with breast cancer before the age of 50 years
    
                        -  One first degree relative with bilateral breast cancer
    
                        -  Two or more first-degree relatives with breast cancer
    
                        -  One first degree relative and two or more second or third degree relatives
                           with breast cancer
    
                        -  One first-degree relative with breast cancer and one or more relatives with
                           ovarian cancer
    
                        -  Two second or third degree relatives with either breast cancer and one or
                           more with ovarian cancer
    
                        -  One second or third degree relative with breast cancer and two or more with
                           ovarian cancer
    
                        -  Three or more second or third degree relatives with breast cancer
    
                   -  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
    
              -  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
    
              -  Digital mammogram within 365 days prior to pre-registration
    
              -  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
    
              -  Must be non-pregnant and non-lactating for at least one year prior to pre-registration
    
              -  If currently menstruating, subjects must use a reliable method of birth control
    
              -  Willing to provide RPFNA and blood samples for correlative research purposes
    
              -  REGISTRATION/RANDOMIZATION INCLUSION CRITERIA:
    
              -  Qualifying cytological atypia in RPFNA, Masood score of 14-17; the qualifying RPFNA
                 (of one or both breasts) must be send to Dr. Seewaldt's laboratory for cytological
                 scoring and proteomic analysis; score results must be received from Dr. Seewaldt's lab
                 prior to patient registration/randomization; test must be done =< 90 days prior to
                 registration/randomization
    
                 * Note: Only the contralateral breast can be aspirated in women with DCIS and those
                 undergoing surgery for an atypical lesion; the decision to aspirate the contralateral
                 breast is at the discretion of the woman's surgeon
    
              -  Hemoglobin >= 9 g/dL
    
              -  Absolute neutrophil count (ANC) >= 1500/mm^3
    
              -  Platelet count >= 75,000/mm^3
    
              -  Creatinine =< 1.4 mg/dL
    
              -  Total bilirubin =< 3.0 mg/dL
    
              -  Aspartate transaminase (AST) =< 3 x upper limit of normal (ULN)
    
              -  Alanine transaminase (ALT) =< 3 x ULN
    
              -  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 (i.e., has had menses at any time in
                 the preceding 12 consecutive months)
    
              -  Women eligible to take tamoxifen must be offered tamoxifen prevention as part of their
                 clinical care and have refused tamoxifen treatment
    
            Exclusion Criteria
    
              -  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 or prior malignancy, they must not be receiving other specific treatment,
                 i.e., other hormonal therapy, for their cancer
    
              -  Body mass index (BMI) < 25
    
              -  Receiving Warfarin
    
              -  Bilateral breast implants or autologous breast flap reconstruction
    
              -  Active diagnosis of alcoholism
    
              -  Contraindication to metformin prevention such as acute hypersensitivity or allergic
                 reaction to metformin
    
              -  Currently receiving tamoxifen or raloxifene
    
              -  Administration of any investigational agent =< 30 days prior to pre-registration
    
              -  Previous radiation to both breasts
    
              -  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
    
              -  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
    
              -  Receiving pyrimethamine, cimetidine, rifampin or cephalexin
    
              -  Women who have a core biopsy or excisional biopsy containing invasive cancer
    
              -  Women who have taken metformin within the past 90 days
    
              -  Patients with hemoglobin a1c > 6.3 or who are being actively treated for diabetes
          
    Maximum Eligible Age:55 Years
    Minimum Eligible Age:25 Years
    Eligible Gender:Female
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Test for the presence or absence of cytological atypia in unilateral or bilateral RPFNA 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).
    Time Frame:Up to 24 months
    Safety Issue:
    Description:

    Secondary Outcome Measures

    Measure: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
    Safety Issue:
    Description:
    Measure:Compare Masood Cytology Score value at 0 and 12 in right and left breast from the same individual in the metformin and non-metformin group.
    Time Frame:Up to 24 months
    Safety Issue:
    Description:
    Measure:Test the reproducibility of RPPM in duplicate RPPM determinations from individual RPFNA specimens.
    Time Frame:Up to 12 months
    Safety Issue:
    Description:
    Measure:Correlate baseline RPPM values with presence of atypia at Month 12 and Month 24.
    Time Frame:Up to 24 months
    Safety Issue:
    Description:

    Details

    Phase:Phase 3
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Alliance for Clinical Trials in Oncology

    Last Updated