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Phase IIB Trial of Bazedoxifene Plus Conjugated Estrogens

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04821141
Recruitment Status : Not yet recruiting
First Posted : March 29, 2021
Last Update Posted : March 29, 2021
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Carol Fabian, MD, University of Kansas Medical Center

Brief Summary:
Women at risk for development of breast cancer and experiencing vasomotor menopausal symptoms (hot flashes) will be randomized to bazedoxifene (BZA) plus conjugated estrogens (CE) for 6 months versus a wait list control. Two risk factors for development of breast cancer will be studied pre-study and after 6 months: fibroglandular volume (FGV) on mammogram as assessed by Volpara software and proliferation by Ki-67 immunocytochemistry in benign breast tissue acquired by random periareolar fine needle aspiration (RPFNA). Change in biomarkers will be compared between groups.

Condition or disease Intervention/treatment Phase
Risk Reduction Breast Cancer Drug: Bazedoxifene and Conjugated Estrogens Phase 2

Detailed Description:
Phase IIB trial of 6 months of BZA 20 mg +CE 0.45 mg (subsequently designated as BZA+CE) vs a waitlist control. Trial is informed by prior results of a single arm trial that used Duavee® (combination of BZA+CE that is FDA-approved for relief of hot flashes). Since Duavee® is currently not available commercially, the two separate components are used instead. Breast imaging, benign breast tissue by RPFNA, and blood for biomarkers will be obtained at baseline and at 6 months using similar assessment techniques. The primary endpoint is the difference between the BZA+CE and control groups for absolute change from baseline to 6 months in the risk biomarker fibroglandular volume (FGV). Volpara® fully automated assessments overcome the interpretive variance inherent in subjective assessments. Additional endpoints include changes in benign breast epithelial immunolabeling for Ki-67, estrogen receptor alpha (ERα), progesterone receptor (PR), and anterior gradient-2 protein (AGR2); and systemic levels of bioavailable hormones, IGF-1, IGFBP3, and measures of insulin sensitivity. The modifying effects of baseline BMI, visceral adipose, and plasma BZA concentrations on markers will be studied.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomization to immediate 6 months of BZA+CE versus wait list for 6 months followed by option to receive 6 months of BZA+CE.
Masking: None (Open Label)
Masking Description: Only designated biostatistician is aware of randomization assignment until after a subject is enrolled and assigned, Then assignment is unblinded and agents are open-label.
Primary Purpose: Prevention
Official Title: Randomized IIB Study of the Effect of Bazedoxifene Plus Conjugated Estrogens on Breast Imaging and Tissue Biomarkers in Peri or Post-Menopausal Women at Increased Risk for Development of Breast Cancer
Estimated Study Start Date : July 2021
Estimated Primary Completion Date : July 2025
Estimated Study Completion Date : January 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Bazedoxifene plus conjugated estrogens immediately
BZA (20 mg) plus CE (0.45 mg) taken together once daily for 6 months, commencing immediately.
Drug: Bazedoxifene and Conjugated Estrogens
BZA (20 mg) plus CE (0.45 mg) taken together once daily
Other Name: BZA+CE

Bazedoxifene plus conjugated estrogens wait list
No intervention for initial 6 months (wait list), then BZA (20 mg) plus CE (0.45 mg) taken together once daily for 6 months, commencing 6 months after enrollment. Optional on the part of subject.
Drug: Bazedoxifene and Conjugated Estrogens
BZA (20 mg) plus CE (0.45 mg) taken together once daily
Other Name: BZA+CE

Primary Outcome Measures :
  1. Change in FGV [ Time Frame: baseline to 6 months ]
    Change in fibroglandular volume assessed on 3-D digital mammogram by Volpara software.

Secondary Outcome Measures :
  1. Change in proliferation [ Time Frame: baseline to 6 months ]
    change in percent of breast epithelial cells staining positive for Ki-67 by immunocytochemistry

Other Outcome Measures:
  1. Change in blood hormones [ Time Frame: baseline to 6 months ]
    Exploratory analysis of change in levels of hormones (estradiol, progesterone, testosterone, sex hormone binding globulin, etc.) assessed by ELISA or RIA methods at baseline and at 6 months.

  2. change in gene expression [ Time Frame: baselne to 6 months ]
    Exploratory analysis of changes and patterns of change in levels of mRNA assessed by qRT-PCR

Information from the National Library of Medicine

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Ages Eligible for Study:   45 Years to 60 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes

Inclusion Criteria for Baseline Mammogram and RPFNA

Inclusion Criteria:

  • Current vasomotor symptoms (hot-flashes, night sweats or both). These do not need to be frequent or severe, but should occur at least once a week. Women who feel that they would likely need a supplement or be at high risk of withdrawal if they were randomized to waitlist because of vasomotor symptoms are not good candidates for this trial.
  • Menopause status: late menopause transition (have missed 2 periods within past 12 months) or postmenopausal (no periods for 12 months or more) with an intact functional uterus.
  • Intact Functional Uterus: have missed at least 2 periods in the past 12 months in the absence of a Mirena IUD or oral contraceptives which suppress menses.
  • Prior hysterectomy or prior endometrial ablation:

    • Age 45-49, vasomotor symptoms and a FSH ≥ 25 mIU/ml or FSH in the postmenopausal range specified by the local institutional laboratory.
    • Age ≥ 50, vasomotor symptoms only (no requirement for FSH)
  • Must have at least one ovary.
  • BMI: ≤ 35 kg/m2
  • Two breasts without prior therapeutic radiation
  • Chemistry profile showing reasonably normal renal and hepatic function: creatinine <2.0 mg/dL, bilirubin < 2.5 mg/dL, and albumin > 3.4 g/dL within the past 12 months (determination is made at local site).
  • Risk Factors/Level. Moderate risk of developing breast cancer based on having at least one of following:

    • First or second degree relative with breast cancer age 60 or younger;
    • A prior breast biopsy showing proliferative breast disease, including hyperplasia, atypical hyperplasia, or changes designated as lobular carcinoma in situ without evidence of pleomorphism
    • 2 or more prior biopsies regardless of benign histology
    • Women with known gene mutations associated with an increased risk for breast cancer such as ATM, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, STK11, P53, PTEN (Note: BRCA1/2 are excluded as women 45 and over should have undergone risk-reducing bilateral salpingo-oophorectomy).
    • 10-year relative risk of ≥2X that for the average population for age group as calculated by IBIS Breast Cancer Risk Evaluation Tool version 8 (Tyrer-Cuzick) (; or a 5-year Gail Model Risk of ≥2X the average risk woman for age group (as calculated by the NCI Breast Cancer Risk Assessment Tool, Average risk for women in the same age-group is based on the Surveillance, Epidemiology, and End Results (SEER) Program provided by the NCI (
  • Vaginal Hormones: Low dose vaginal hormones, such as Estring(®, Vagifem®, or 0.5 gram or less of conjugated estrogen vaginal cream twice weekly or less often, for vaginal dryness and dyspareunia may be continued at the same dose.
  • Systemic Hormones: If previously on oral contraceptives or hormone replacement, women must be off for 8 weeks or more prior to baseline mammogram and RPFNA.

Exclusion Criteria:

  • Have a predisposition to or prior history of thromboembolism, deep venous thrombosis, pulmonary embolism, stroke, or myocardial infarction
  • Prior bilateral oophorectomy
  • BRCA1/2 deleterious mutation (these women should have both of their ovaries and fallopian tubes removed)
  • Pleomorphic LCIS, DCIS, prior invasive breast, uterine or ovarian cancer (estrogen dependent neoplasia)
  • Current renal or liver disease or clinically significant abnormalities of liver and renal function tests.
  • Women are sufficiently distressed by their vasomotor symptoms, such that they do not believe they would be able to remain on study for 6 months without additional medications if their hot flashes were not relieved.
  • Any other condition or intercurrent illness that in the opinion of the investigator makes the woman a poor candidate for RPFNA or treatment with BZA+CE.
  • Current anticoagulant use (must have discontinued for 3 weeks prior to FNA)
  • Taking oral or transdermal systemic hormones within two months (eight weeks) prior to baseline blood, imaging studies or RPFNA.
  • Taken tamoxifen, raloxifene, or an aromatase inhibitor within 6 months of baseline blood imaging or RPFNA

Inclusion Criteria for Intervention Phase:

  • BIRADs Class I-III mammogram suitable for assessment by Volpara® software, and retention of raw imaging file. This must be performed within 3 months prior to RPFNA. Mammograms read out as Class 0 or IV must be resolved with additional procedures prior to RPFNA or entry on intervention phase.
  • For women with very large breasts: the entire breast must be able to be captured in one view. Women whose breast size require mosaic views will not be eligible.
  • Volpara® determined breast fibroglandular volume as read at site or KUMC must be evaluable on both breasts and total at least 80 cm3
  • Sites with Volpara® assessment capability: If the criteria above are met, the Volpara® clinical report is sent to KUMC (pdf format is acceptable) and the investigator may proceed with RPFNA and additional screening. However, the raw imaging file (DICOM format) must still be received in KUMC central repository prior to stratification and randomization.
  • Sites without Volpara® assessment capability: The raw imaging file (DICOM format) is sent to the KUMC central repository and KUMC notified. KUMC will confirm within 24 hours that the file has been received and whether screening with RPFNA may proceed.
  • RPFNA specimen must be received at KUMC in good condition and cellular enough to provide a minimum of 500 epithelial cells on slide(s); but there is no requirement for a specific value for Ki-67 or cytomorphology.
  • Willing to comply with study procedures.
  • Willing to have fasting blood drawn at baseline and 6 months.
  • Willing to have dual energy x-ray absorptiometry (iDXA) at baseline at KUMC. DXA is optional at other sites.
  • Willing to have a repeat mammogram and RPFNA at 6 months following initiation of study drug. (12-month mammogram for waitlist control only is optional)
  • Willing to provide personal health history, family history of breast and ovarian cancer
  • Willing to undergo a physical exam including weight, height, and waist measurement at baseline and 6-month visit
  • Willing to complete Menopause Quality of Life (MEN-QOL) questionnaire and a hot flash assessment at baseline and 6-month visits
  • Able to understand and willing to sign consent for study participation
  • If less than age 55, and uterus is functionally intact, and menstrual period in past 12 months and husband/partner has not had vasectomy, must be willing to use non-hormonal contraceptive precautions.

Exclusion Criteria for Study Intervention (Randomization)

• Medical: Intercurrent illness which makes potential participant unsuitable for study; development of clinically significant abnormalities of liver or renal functions; or started hormone replacement therapy between mammogram/RPFNA and enrollment on study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04821141

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Contact: Bruce F Kimler, PhD 9132056382
Contact: Amy L Kreutzjans 9139457741

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United States, California
City of Hope Medical Center
Duarte, California, United States, 91010
Principal Investigator: Lisa D Yee, MD         
Principal Investigator: Victoria L Seewaldt, MD         
University of California San Francisco
San Francisco, California, United States, 94115
Principal Investigator: Laura Esserman, MD         
United States, Illinois
Northwestern Medical Center
Chicago, Illinois, United States, 60601
Principal Investigator: Sema Khan, MD         
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
Principal Investigator: Judy Garber, MD         
Sponsors and Collaborators
University of Kansas Medical Center
National Cancer Institute (NCI)
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Principal Investigator: Carol J Fabian, MD University of Kansas Medical Center
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Responsible Party: Carol Fabian, MD, Professor, University of Kansas Medical Center Identifier: NCT04821141    
Other Study ID Numbers: STUDY00146320
R01CA249437-01A1 ( U.S. NIH Grant/Contract )
First Posted: March 29, 2021    Key Record Dates
Last Update Posted: March 29, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Carol Fabian, MD, University of Kansas Medical Center:
breast cancer, menopausal symptoms, hot flashes
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Estrogens, Conjugated (USP)
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Hormone Antagonists
Bone Density Conservation Agents