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Acolbifene in Preventing Cancer in Premenopausal Women at High Risk of Breast Cancer

Primary Purpose

Breast Cancer

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
acolbifene hydrochloride
Sponsored by
University of Kansas Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Breast Cancer

Eligibility Criteria

30 Years - 55 Years (Adult)FemaleAccepts Healthy Volunteers

Inclusion Criteria:

  • Gail risk >= 1.7% and/or relative risk >= 3 times that for 5-year age group
  • Premenopausal
  • More than 6 months since initiating or discontinuing oral contraceptives
  • At increased risk for breast cancer, as indicated by >= 1 of the following risk factors:
  • BRCA1/2 mutation characterized as deleterious or of uncertain significance
  • Prior atypical ductal hyperplasia, ductal carcinoma in situ, or lobular carcinoma in situ
  • Prior random periareolar fine needle aspiration (RPFNA) showing atypical hyperplasia
  • Family history consistent with hereditary breast cancer, as indicated by 1 of the following criteria:

    • >= 4 relatives with breast cancer
    • >= 2 relatives diagnosed with breast cancer at ≤ 50 years of age
    • Breast and ovarian cancer diagnosed in same relative
  • No suspicion for breast cancer on baseline mammogram performed between days 1-10 of menstrual cycle within 3 months prior to screening baseline RPFNA
  • Exhibits hyperplasia with or without atypia (Masood score >= 14) with >= 500 cells AND Ki-67 positivity >= 2% by RPFNA performed within 6 months prior to initiation of study drug
  • Estimated visual mammographic breast density category >= 5% on mammogram performed within 6 months prior to initiation of study drug
  • Has regular menstrual cycles (between 21 and 35 days) unless using extended regimen oral contraceptives or a contraceptive device (e.g., Mirena IUD) Values for metabolic profile and blood count within normal limits
  • Absolute granulocyte count > 1,000/mm^3
  • Platelets > 100,000/mm^3
  • Hemoglobin > 10 g/dL
  • Bilirubin < 2.0 mg/dL
  • AST < 2 times upper limit of normal (ULN)
  • Albumin > 3.0 g/dL
  • Creatinine < 1.5 mg/dL
  • Alkaline phosphatase < 2 times ULN
  • Concurrent hormonal contraceptives allowed provided patient remains on the same hormonal regimen from 3 months prior to baseline aspiration until the completion of study treatment
  • Fertile patients must use effective contraception during and for 3 months after completion of study treatment
  • Willing to ingest recommended dose of calcium and vitamin D for premenopausal bone health (1,200 mg calcium and 800 IU vitamin D daily)
  • Negative pregnancy test prior to receiving study agent

Exclusion Criteria

  • pregnant or nursing
  • nursing within the past 6 months
  • Known osteoporosis or severe osteopenia (T-score -2 or worse by DEXA)
  • History of symptomatic endometriosis with pelvic pain, poorly controlled migraines, or hot flashes
  • History of deep venous thrombosis
  • History of allergic reactions attributed to compounds of similar chemical or biological composition to the study agent
  • Other condition or concurrent illness that, in the opinion of the investigator, would make the patient a poor candidate for RPFNA
  • Less than 1 year since prior use of aromatase inhibitors (e.g., anastrozole, exemestane, or letrozole) or selective estrogen receptor modulators (e.g., tamoxifen citrate, raloxifene, or arzoxifene hydrochloride)
  • Other concurrent chemopreventive agents
  • Concurrent anticoagulants
  • Other concurrent investigational agents
  • Bilateral breast implants

Sites / Locations

  • University of Kansas Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Prevention (acolbifene hydrochloride)

Arm Description

Patients receive oral acolbifene hydrochloride once daily for 6 months in the absence of unacceptable toxicity.

Outcomes

Primary Outcome Measures

Change in the Percentage of Breast Epithelial Cells Expressing Ki-67, From Baseline to 6 Months
Change in proliferation as measured by Ki-67 immunocytochemical expression in breast epithelial cells obtained by random periareolar fine needle aspiration at baseline and at 6 months.

Secondary Outcome Measures

Change in Mammographic Breast Density
Change in mammographic density from baseline to 6 months, The Percent Breast Density is estimated using the Cumulus computer-assisted program to define a region that is at greater density than the remainder of the breast.
Change in Serum Estradiol Concentration
Change in serum concentration of estradiol from baseline to 6 months
Change in Serum Concentration of Bioavailable Estradiol
Change in serum concentration of bioavailable estradiol (adjusted for concentration of Sex Hormone Binding Globulin), from baseline to 6 months
Change in Serum Concentration of Testosterone
Change in serum concentration of Testosterone from baseline to 6 months
Reports of Hot Flashes as Assessed by the Loprinzi Hot Flash Scoring System
Problems with hot flashes were assessed by average number per day and intensity.
Reports of Muscle/Joint Complaints as Assessed by the Validated HAQ II Questionnaire
The Health Assessment Questionnaire II (HAQ-II) measures interference in daily activities from arthralgias and joint pain. Range 0 - 4. A higher score indicates greater (i.e., "worse") interference.

Full Information

First Posted
February 26, 2009
Last Updated
January 15, 2018
Sponsor
University of Kansas Medical Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00853996
Brief Title
Acolbifene in Preventing Cancer in Premenopausal Women at High Risk of Breast Cancer
Official Title
Phase II Study of Acolbifene in Pre-Menopausal Women at High Risk for Breast Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
January 2018
Overall Recruitment Status
Completed
Study Start Date
February 2009 (undefined)
Primary Completion Date
December 2010 (Actual)
Study Completion Date
December 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Kansas Medical Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This phase II trial is studying how well acolbifene works in preventing cancer in premenopausal women at high risk of breast cancer. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of acolbifene may stop cancer from growing or coming back.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the effect of six months of acolbifene 20 mg/day on Ki-67 in high risk premenopausal women with baseline hyperplasia +/- atypia and Ki-67 positivity of >= 2%.. SECONDARY OBJECTIVES: I. To determine the effect of six months of acolbifene 20 mg/day on mammographic breast density in high risk premenopausal women. II. To determine the effect of six months of acolbifene 20 mg/day on serum levels of follicular phase bioavailable estradiol, and luteal phase progesterone, testosterone, and fasting IGF-1/IGFBP-3. III. To determine the effect of six months of acolbifene 20 mg/day on epithelial cell cytomorphology and molecular markers such as ER, PgR, and pS2. IV. To determine the effect of six months of acolbifene on markers of cardiovascular risk (C-reactive protein, functional AntiThrombin III, and fasting lipid profile) and bone turnover markers associated with bone mineral density gain or loss (serum osteocalcin and N-telopeptide crosslinks). V. To assess any increase in reported hot flashes, menstrual cycle irregularities, pelvic pain, musculoskeletal complaints, and fatigue from baseline. OUTLINE: Patients receive oral acolbifene hydrochloride once daily for 6 months in the absence of unacceptable toxicity. Patients undergo symptom assessment (hot flashes, menstrual abnormalities, pelvic pain, muscle and joint pain, and fatigue) at baseline, 6-8 weeks, monthly for 6 months, and then at 2 weeks after completion of study treatment. Patients undergo random periareolar fine needle aspiration between days 1-10 of menstrual cycle at baseline and at 6 months. Patients also undergo blood sample collection between days 1-10 and days 20-24 of menstrual cycle at baseline and at 6 months. Samples taken between days 1-10 of menstrual cycle are analyzed for Ki-67 expression, cytomorphology, molecular markers (estrogen receptor, progesterone receptor, and pS2 expression), and bioavailable estradiol levels. Samples taken between days 20-24 of menstrual cycle are analyzed for progesterone, testosterone, IGF-1, IGFBP-3, lipid profile, bone-turnover markers (osteocalcin and N-telopeptide crosslinks), C-reactive protein, and functional antithrombin III. After completion of study treatment, patients are followed at 2 weeks.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
25 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Prevention (acolbifene hydrochloride)
Arm Type
Experimental
Arm Description
Patients receive oral acolbifene hydrochloride once daily for 6 months in the absence of unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
acolbifene hydrochloride
Other Intervention Name(s)
EM-652.HCL, SCH 57068.HCl
Intervention Description
Given orally
Primary Outcome Measure Information:
Title
Change in the Percentage of Breast Epithelial Cells Expressing Ki-67, From Baseline to 6 Months
Description
Change in proliferation as measured by Ki-67 immunocytochemical expression in breast epithelial cells obtained by random periareolar fine needle aspiration at baseline and at 6 months.
Time Frame
Baseline to 6 months
Secondary Outcome Measure Information:
Title
Change in Mammographic Breast Density
Description
Change in mammographic density from baseline to 6 months, The Percent Breast Density is estimated using the Cumulus computer-assisted program to define a region that is at greater density than the remainder of the breast.
Time Frame
Baseline to 6 months
Title
Change in Serum Estradiol Concentration
Description
Change in serum concentration of estradiol from baseline to 6 months
Time Frame
Baseline to 6 months
Title
Change in Serum Concentration of Bioavailable Estradiol
Description
Change in serum concentration of bioavailable estradiol (adjusted for concentration of Sex Hormone Binding Globulin), from baseline to 6 months
Time Frame
Baseline to 6 months
Title
Change in Serum Concentration of Testosterone
Description
Change in serum concentration of Testosterone from baseline to 6 months
Time Frame
Baseline to 6 months
Title
Reports of Hot Flashes as Assessed by the Loprinzi Hot Flash Scoring System
Description
Problems with hot flashes were assessed by average number per day and intensity.
Time Frame
Baseline to up to 2 weeks post-treatment
Title
Reports of Muscle/Joint Complaints as Assessed by the Validated HAQ II Questionnaire
Description
The Health Assessment Questionnaire II (HAQ-II) measures interference in daily activities from arthralgias and joint pain. Range 0 - 4. A higher score indicates greater (i.e., "worse") interference.
Time Frame
Baseline to up to 2 weeks post-treatment

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
30 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Gail risk >= 1.7% and/or relative risk >= 3 times that for 5-year age group Premenopausal More than 6 months since initiating or discontinuing oral contraceptives At increased risk for breast cancer, as indicated by >= 1 of the following risk factors: BRCA1/2 mutation characterized as deleterious or of uncertain significance Prior atypical ductal hyperplasia, ductal carcinoma in situ, or lobular carcinoma in situ Prior random periareolar fine needle aspiration (RPFNA) showing atypical hyperplasia Family history consistent with hereditary breast cancer, as indicated by 1 of the following criteria: >= 4 relatives with breast cancer >= 2 relatives diagnosed with breast cancer at ≤ 50 years of age Breast and ovarian cancer diagnosed in same relative No suspicion for breast cancer on baseline mammogram performed between days 1-10 of menstrual cycle within 3 months prior to screening baseline RPFNA Exhibits hyperplasia with or without atypia (Masood score >= 14) with >= 500 cells AND Ki-67 positivity >= 2% by RPFNA performed within 6 months prior to initiation of study drug Estimated visual mammographic breast density category >= 5% on mammogram performed within 6 months prior to initiation of study drug Has regular menstrual cycles (between 21 and 35 days) unless using extended regimen oral contraceptives or a contraceptive device (e.g., Mirena IUD) Values for metabolic profile and blood count within normal limits Absolute granulocyte count > 1,000/mm^3 Platelets > 100,000/mm^3 Hemoglobin > 10 g/dL Bilirubin < 2.0 mg/dL AST < 2 times upper limit of normal (ULN) Albumin > 3.0 g/dL Creatinine < 1.5 mg/dL Alkaline phosphatase < 2 times ULN Concurrent hormonal contraceptives allowed provided patient remains on the same hormonal regimen from 3 months prior to baseline aspiration until the completion of study treatment Fertile patients must use effective contraception during and for 3 months after completion of study treatment Willing to ingest recommended dose of calcium and vitamin D for premenopausal bone health (1,200 mg calcium and 800 IU vitamin D daily) Negative pregnancy test prior to receiving study agent Exclusion Criteria pregnant or nursing nursing within the past 6 months Known osteoporosis or severe osteopenia (T-score -2 or worse by DEXA) History of symptomatic endometriosis with pelvic pain, poorly controlled migraines, or hot flashes History of deep venous thrombosis History of allergic reactions attributed to compounds of similar chemical or biological composition to the study agent Other condition or concurrent illness that, in the opinion of the investigator, would make the patient a poor candidate for RPFNA Less than 1 year since prior use of aromatase inhibitors (e.g., anastrozole, exemestane, or letrozole) or selective estrogen receptor modulators (e.g., tamoxifen citrate, raloxifene, or arzoxifene hydrochloride) Other concurrent chemopreventive agents Concurrent anticoagulants Other concurrent investigational agents Bilateral breast implants
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Carol Fabian
Organizational Affiliation
University of Kansas Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Kansas Medical Center
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Individual data will not be shared; only summary assessments.

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Acolbifene in Preventing Cancer in Premenopausal Women at High Risk of Breast Cancer

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