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Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer

Primary Purpose

Breast Cancer, Hereditary Breast/Ovarian Cancer (brca1, brca2)

Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
arzoxifene hydrochloride
tamoxifen citrate
placebo
Sponsored by
The Cleveland Clinic
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Breast Cancer focused on measuring hereditary breast/ovarian cancer (BRCA1, BRCA2), breast cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

DISEASE CHARACTERISTICS: Estimated probability of carrying a BRCA1 or BRCA2 mutation ≥ 10% AND meets one of the following criteria: Participants must have first-degree relatives (FDRs)* or second-degree relatives (SDRs)* (with an intervening male relative) with breast or ovarian cancer who satisfy one of the following criteria: High-risk breast/ovarian cancer (non-Jewish families) One FDR ≤ 40 years old** diagnosed with breast cancer At least two FDRs or SDRs diagnosed with breast cancer at ≤ 50 years old OR had bilateral breast cancer One FDR or one SDR diagnosed with breast cancer at ≤ 50 years old OR had bilateral breast cancer AND one FDR or SDR diagnosed with ovarian cancer Three FDRs and/or SDRs diagnosed with breast or ovarian cancer (at least one in case of ovarian cancer) Two FDRs and/or SDRs diagnosed with ovarian cancer One male FDR or SDR diagnosed with breast cancer and one FDR or SDR (male or female) diagnosed with breast or ovarian cancer Moderate-risk breast /ovarian cancer (non-Jewish families) Two FDRs diagnosed with breast cancer with one ≤ 50 years old and/or both < 60 years old One FDR and one SDR (mother or sister and maternal aunt or maternal grandmother) diagnosed with breast cancer if the sum of their ages is ≥ 118 years One FDR and one SDR (mother or sister and paternal aunt or paternal grandmother) diagnosed with breast cancer if the sum of their ages is ≥ 78 years Two SDRs (both maternal or both paternal) diagnosed with breast cancer if the sum of their ages is ≤ 98 years One FDR with ovarian cancer High-risk breast/ovarian cancer (Jewish families ) At least one FDR or SDR diagnosed with breast cancer at ≤ 50 years old At least one FDR or SDR diagnosed with ovarian cancer At least one FDR or SDR diagnosed with breast cancer at any age AND one FDR or SDR diagnosed with breast and/or ovarian cancer At least one male FDR or SDR diagnosed with breast cancer NOTE: *FDRs are parents, siblings, and children of the participant; SDRs are aunts, uncles, grandparents, grandchildren, nieces, nephews, or half siblings of the participant NOTE: **Age is approximated to the earliest age possible (e.g., a relative diagnosed in their 40's should be considered 40) Patterns of cancer cases must all be on the maternal or paternal side of the family Participants not meeting any of the above FDR or SDR criteria may provide medical documentation stating that they, a FDR, or a SDR carry BRCA1 or BRCA2 mutations Participants with a prior history of breast cancer are eligible provided they have a remaining breast that has not been irradiated, all therapy for breast cancer was completed more than 2 years ago, and they are premenopausal No ovarian cyst during screening No more than 12 months since prior Pap smear with normal cytological results OR human papilloma virus negative if atypical squamous cells of uncertain significance (ASCUS) present No higher degrees of atypia beyond ASCUS on Pap smear No known history of osteoporosis (bone mineral density > 1.5 standard deviations below young adult norms) Hormone receptor status Not specified PATIENT CHARACTERISTICS: Menopausal status Premenopausal, as defined by 1 of the following: Last menstrual period < 6 months ago Less than 45 years old AND underwent partial hysterectomy OR follicle-stimulating hormone within institutional pre-menopausal range within the past 3 months Sex Female Performance status ECOG 0-1 Life expectancy More than 2 years Hematopoietic WBC ≥ 3,000/mm^3 Platelet count ≥ 125,000/mm^3 Hemoglobin ≥ 10 g/dL Hepatic Bilirubin ≤ 1.5 mg/dL AST < 2 times upper limit of normal (ULN) Albumin ≥ 3.0 g/dL PT/PTT ≤ 1.25 times ULN Renal Creatinine ≤ 1.5 mg/dL OR Creatinine clearance ≥ 60 mL/min Cardiovascular No history of deep venous thrombosis Pulmonary No history of pulmonary embolism Other Not pregnant or nursing Negative pregnancy test Fertile participants must use effective barrier-method contraception during and for 3 months after completion of study treatment No other malignancy within the past 2 years except curatively treated basal cell or squamous cell skin cancer or cervical cancer ≤ stage I No known addiction Not undergoing treatment for an illicit drug addiction Willing and able to undergo required study procedures (e.g., research-related breast biopsies) PRIOR CONCURRENT THERAPY: Chemotherapy More than 2 years since prior chemotherapy Endocrine Therapy At least 3 months since prior oral contraceptives or intramuscular progestational agent At least 3 months since prior luteinizing-hormone releasing hormone (LHRH) agonists or antagonists if agent was administered daily or monthly At least 6 months since prior LHRH agonists or antagonists if agent was administered every 3 months At least 6 months since prior antiestrogens (e.g., tamoxifen, toremifene, and raloxifene) No concurrent progestational or contraceptive agents Radiotherapy See Disease Characteristics More than 2 years since prior radiotherapy Surgery No prior prophylactic bilateral mastectomy Other No concurrent cholestyramine No concurrent routine warfarin, bromocriptine, or phenobarbital No other concurrent investigational agents

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm Type

    Experimental

    Experimental

    Placebo Comparator

    Arm Label

    Arm I

    Arm II

    Arm III

    Arm Description

    Participants receive oral tamoxifen once daily for 6 months in the absence of disease progression or unacceptable toxicity. After the completion of 6 months of treatment, participants are offered the opportunity to continue treatment for an additional 6 months.

    Participants receive oral arzoxifene once daily for 6 months in the absence of disease progression or unacceptable toxicity. After the completion of 6 months of treatment, participants are offered the opportunity to continue treatment for an additional 6 months.

    Participants receive an oral placebo once daily once daily for 6 months in the absence of disease progression or unacceptable toxicity. After the completion of 6 months of treatment, participants are offered treatment with arzoxifene for an additional 6 months.

    Outcomes

    Primary Outcome Measures

    Ki67 in breast tissue of enrolled patients
    The primary endpoint was changed in Ki67 in breast tissue of enrolled patients

    Secondary Outcome Measures

    Toxicity

    Full Information

    First Posted
    November 11, 2005
    Last Updated
    April 11, 2011
    Sponsor
    The Cleveland Clinic
    Collaborators
    National Cancer Institute (NCI)
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00253539
    Brief Title
    Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
    Official Title
    A Phase II Study of a Selective Estrogen Receptor Modulator (LY353381) vs. Tamoxifen vs. Placebo in Premenopausal Women With and Increased Risk for Breast Cancer
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    April 2011
    Overall Recruitment Status
    Completed
    Study Start Date
    January 2002 (undefined)
    Primary Completion Date
    April 2005 (Actual)
    Study Completion Date
    April 2005 (Actual)

    3. Sponsor/Collaborators

    Name of the Sponsor
    The Cleveland Clinic
    Collaborators
    National Cancer Institute (NCI)

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    RATIONALE: Chemoprevention is the use of certain drugs to keep cancer from forming, growing, or coming back. Estrogen can cause the growth of breast cancer cells. Hormone therapy using arzoxifene or tamoxifen may prevent breast cancer by lowering the amount of estrogen the body makes. The use of arzoxifene or tamoxifen may keep breast cancer from forming in women at high risk for breast cancer. PURPOSE: This randomized phase II trial is studying arzoxifene to see how well it works compared to tamoxifen or a placebo in preventing breast cancer in premenopausal women at high risk for breast cancer.
    Detailed Description
    OBJECTIVES: Compare the effect of arzoxifene vs tamoxifen vs placebo on surrogate endpoints biomarkers, especially systemic insulin-like growth factor levels, in women at high risk for breast cancer. Compare the toxic effects, biologic effects, clinical pharmacology, and pharmacodynamics of these drugs in these participants. Determine the effect of these drugs on surrogate endpoint biomarkers in participants with BRCA1 and BRCA2 mutations. Determine the feasibility of a chemoprevention study in participants with a strong family history of breast cancer. OUTLINE: This is a randomized, placebo-controlled, double-blind study. Participants are randomized to 1 of 3 treatment arms. Arm I: Participants receive oral tamoxifen once daily. Arm II: Participants receive oral arzoxifene once daily. Arm III: Participants receive an oral placebo once daily. In all arms, treatment continues for 6 months in the absence of disease progression or unacceptable toxicity. After the completion of 6 months of treatment, participants are offered the opportunity to continue treatment with their assigned study drug for an additional 6 months. Participants randomized to receive placebo are offered treatment with arzoxifene for an additional 6 months. After completion of study treatment, participants are followed annually. PROJECTED ACCRUAL: A total of 120 participants will be accrued for this study.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Breast Cancer, Hereditary Breast/Ovarian Cancer (brca1, brca2)
    Keywords
    hereditary breast/ovarian cancer (BRCA1, BRCA2), breast cancer

    7. Study Design

    Primary Purpose
    Prevention
    Study Phase
    Phase 2
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantInvestigator
    Allocation
    Randomized
    Enrollment
    3 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Arm I
    Arm Type
    Experimental
    Arm Description
    Participants receive oral tamoxifen once daily for 6 months in the absence of disease progression or unacceptable toxicity. After the completion of 6 months of treatment, participants are offered the opportunity to continue treatment for an additional 6 months.
    Arm Title
    Arm II
    Arm Type
    Experimental
    Arm Description
    Participants receive oral arzoxifene once daily for 6 months in the absence of disease progression or unacceptable toxicity. After the completion of 6 months of treatment, participants are offered the opportunity to continue treatment for an additional 6 months.
    Arm Title
    Arm III
    Arm Type
    Placebo Comparator
    Arm Description
    Participants receive an oral placebo once daily once daily for 6 months in the absence of disease progression or unacceptable toxicity. After the completion of 6 months of treatment, participants are offered treatment with arzoxifene for an additional 6 months.
    Intervention Type
    Drug
    Intervention Name(s)
    arzoxifene hydrochloride
    Intervention Description
    Given orally
    Intervention Type
    Drug
    Intervention Name(s)
    tamoxifen citrate
    Intervention Description
    Given orally
    Intervention Type
    Other
    Intervention Name(s)
    placebo
    Intervention Description
    Given orally
    Primary Outcome Measure Information:
    Title
    Ki67 in breast tissue of enrolled patients
    Description
    The primary endpoint was changed in Ki67 in breast tissue of enrolled patients
    Secondary Outcome Measure Information:
    Title
    Toxicity

    10. Eligibility

    Sex
    Female
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    DISEASE CHARACTERISTICS: Estimated probability of carrying a BRCA1 or BRCA2 mutation ≥ 10% AND meets one of the following criteria: Participants must have first-degree relatives (FDRs)* or second-degree relatives (SDRs)* (with an intervening male relative) with breast or ovarian cancer who satisfy one of the following criteria: High-risk breast/ovarian cancer (non-Jewish families) One FDR ≤ 40 years old** diagnosed with breast cancer At least two FDRs or SDRs diagnosed with breast cancer at ≤ 50 years old OR had bilateral breast cancer One FDR or one SDR diagnosed with breast cancer at ≤ 50 years old OR had bilateral breast cancer AND one FDR or SDR diagnosed with ovarian cancer Three FDRs and/or SDRs diagnosed with breast or ovarian cancer (at least one in case of ovarian cancer) Two FDRs and/or SDRs diagnosed with ovarian cancer One male FDR or SDR diagnosed with breast cancer and one FDR or SDR (male or female) diagnosed with breast or ovarian cancer Moderate-risk breast /ovarian cancer (non-Jewish families) Two FDRs diagnosed with breast cancer with one ≤ 50 years old and/or both < 60 years old One FDR and one SDR (mother or sister and maternal aunt or maternal grandmother) diagnosed with breast cancer if the sum of their ages is ≥ 118 years One FDR and one SDR (mother or sister and paternal aunt or paternal grandmother) diagnosed with breast cancer if the sum of their ages is ≥ 78 years Two SDRs (both maternal or both paternal) diagnosed with breast cancer if the sum of their ages is ≤ 98 years One FDR with ovarian cancer High-risk breast/ovarian cancer (Jewish families ) At least one FDR or SDR diagnosed with breast cancer at ≤ 50 years old At least one FDR or SDR diagnosed with ovarian cancer At least one FDR or SDR diagnosed with breast cancer at any age AND one FDR or SDR diagnosed with breast and/or ovarian cancer At least one male FDR or SDR diagnosed with breast cancer NOTE: *FDRs are parents, siblings, and children of the participant; SDRs are aunts, uncles, grandparents, grandchildren, nieces, nephews, or half siblings of the participant NOTE: **Age is approximated to the earliest age possible (e.g., a relative diagnosed in their 40's should be considered 40) Patterns of cancer cases must all be on the maternal or paternal side of the family Participants not meeting any of the above FDR or SDR criteria may provide medical documentation stating that they, a FDR, or a SDR carry BRCA1 or BRCA2 mutations Participants with a prior history of breast cancer are eligible provided they have a remaining breast that has not been irradiated, all therapy for breast cancer was completed more than 2 years ago, and they are premenopausal No ovarian cyst during screening No more than 12 months since prior Pap smear with normal cytological results OR human papilloma virus negative if atypical squamous cells of uncertain significance (ASCUS) present No higher degrees of atypia beyond ASCUS on Pap smear No known history of osteoporosis (bone mineral density > 1.5 standard deviations below young adult norms) Hormone receptor status Not specified PATIENT CHARACTERISTICS: Menopausal status Premenopausal, as defined by 1 of the following: Last menstrual period < 6 months ago Less than 45 years old AND underwent partial hysterectomy OR follicle-stimulating hormone within institutional pre-menopausal range within the past 3 months Sex Female Performance status ECOG 0-1 Life expectancy More than 2 years Hematopoietic WBC ≥ 3,000/mm^3 Platelet count ≥ 125,000/mm^3 Hemoglobin ≥ 10 g/dL Hepatic Bilirubin ≤ 1.5 mg/dL AST < 2 times upper limit of normal (ULN) Albumin ≥ 3.0 g/dL PT/PTT ≤ 1.25 times ULN Renal Creatinine ≤ 1.5 mg/dL OR Creatinine clearance ≥ 60 mL/min Cardiovascular No history of deep venous thrombosis Pulmonary No history of pulmonary embolism Other Not pregnant or nursing Negative pregnancy test Fertile participants must use effective barrier-method contraception during and for 3 months after completion of study treatment No other malignancy within the past 2 years except curatively treated basal cell or squamous cell skin cancer or cervical cancer ≤ stage I No known addiction Not undergoing treatment for an illicit drug addiction Willing and able to undergo required study procedures (e.g., research-related breast biopsies) PRIOR CONCURRENT THERAPY: Chemotherapy More than 2 years since prior chemotherapy Endocrine Therapy At least 3 months since prior oral contraceptives or intramuscular progestational agent At least 3 months since prior luteinizing-hormone releasing hormone (LHRH) agonists or antagonists if agent was administered daily or monthly At least 6 months since prior LHRH agonists or antagonists if agent was administered every 3 months At least 6 months since prior antiestrogens (e.g., tamoxifen, toremifene, and raloxifene) No concurrent progestational or contraceptive agents Radiotherapy See Disease Characteristics More than 2 years since prior radiotherapy Surgery No prior prophylactic bilateral mastectomy Other No concurrent cholestyramine No concurrent routine warfarin, bromocriptine, or phenobarbital No other concurrent investigational agents
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    George T. Budd, MD
    Organizational Affiliation
    The Cleveland Clinic
    Official's Role
    Study Chair

    12. IPD Sharing Statement

    Learn more about this trial

    Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer

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