Bazedoxifene + Conjugated Estrogens for Breast Cancer Risk Reduction

Recruiting at 4 trial locations

Overseen By Laura Esserman, MD

Age: 18 - 65

Sex: Female

Trial Phase: Phase 2

Sponsor: University of Kansas Medical Center

Must not be taking: Anticoagulants, Systemic hormones, Tamoxifen

Disqualifiers: Thromboembolism, BRCA1/2 mutation, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

Duration: 6 months

120 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

If you are currently taking oral contraceptives or systemic hormone replacement therapies, you must stop them at least 8 weeks before starting the trial. However, you can continue using low-dose vaginal hormones for vaginal dryness if you've been on them for at least 2 weeks before the trial.

Is Bazedoxifene + Conjugated Estrogens safe for humans?

Bazedoxifene combined with conjugated estrogens has been studied in several trials and is generally considered safe for treating menopausal symptoms and preserving bone health. It has been shown to have cardiovascular safety and does not increase the risk of uterine bleeding or breast pain, which are common with other hormone therapies. ^{1 2 3 4 5}

How is the drug Bazedoxifene + Conjugated Estrogens unique for breast cancer risk reduction?

Bazedoxifene + Conjugated Estrogens is unique because it combines a selective estrogen receptor modulator (Bazedoxifene) with estrogens to reduce breast cancer risk by minimizing estrogen's stimulatory effects on breast tissue, unlike traditional hormone therapies that often include progestins. ^{3 4 6 7 8}

What is the purpose of this trial?

This trial tests a combination of two medications, bazedoxifene and conjugated estrogens, in women at risk for breast cancer who also have menopausal hot flashes. The treatment aims to reduce these symptoms and possibly lower cancer risk. Researchers will compare changes in breast tissue and hormone levels over several months between those taking the medication and those who are not. Bazedoxifene paired with conjugated estrogens is the first combination approved by the FDA for treating menopausal symptoms.

Research Team

Carol J Fabian, MD

Principal Investigator

University of Kansas Medical Center

Eligibility Criteria

Women aged 45-64 with moderate risk of breast cancer, experiencing menopausal hot flashes at least weekly, and not currently on certain hormone treatments or having specific health conditions. Participants must have a BMI ≤ 38 kg/m2 and at least one breast assessable by Volpara software without prior radiation.

Inclusion Criteria

My kidney and liver tests are within normal ranges.

Must be in one of the four menopausal status categories

I am a woman aged 45-60, or 61-64 with a recent mammogram showing dense breast tissue.

Exclusion Criteria

Sufficiently distressed by vasomotor symptoms that they do not believe they would be able to remain on study for 6 months without additional medications

My breast condition is identified as pleomorphic LCIS.

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

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive BZA (20 mg) plus CE (0.45 mg) daily for 6 months

6 months

Baseline and 6-month visits for imaging and biomarker assessments

Waitlist Control

Participants are on a waitlist for 6 months before starting treatment

6 months

Follow-up

Participants are monitored for changes in biomarkers and safety after treatment

4 weeks

Treatment Details

Interventions

• Bazedoxifene
• Conjugated Estrogens

Trial Overview The trial is testing if Bazedoxifene plus Conjugated Estrogens can reduce the risk of developing breast cancer in women with vasomotor symptoms. It measures changes in fibroglandular volume and cell proliferation over six months against a control group.

Participant Groups

Group I: Bazedoxifene plus conjugated estrogens wait list Experimental Treatment 1 Intervention

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.

Group II: Bazedoxifene plus conjugated estrogens immediately Experimental Treatment 1 Intervention

BZA (20 mg) plus CE (0.45 mg) taken together once daily for 6 months, commencing immediately.

Bazedoxifene is already approved in United States, European Union for the following indications:

Approved in United States as Duavee for:

• Moderate to severe vasomotor symptoms associated with menopause
• Prevention of postmenopausal osteoporosis

Approved in European Union as Duavive for:

• Treatment of estrogen deficiency symptoms in postmenopausal women with an intact uterus
• Prevention of osteoporosis in postmenopausal women at high risk of future fractures

Who Is Running the Clinical Trial?

University of Kansas Medical Center

Lead Sponsor

Trials

527

Recruited

181,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

A pooled analysis of five phase-3 trials involving 4868 healthy, non-hysterectomized postmenopausal women showed that conjugated estrogens/bazedoxifene (CE/BZA) has an acceptable cardiovascular safety profile, with low rates of venous thromboembolic events (VTEs) and comparable rates of stroke and coronary heart disease (CHD) to placebo.

The incidence of VTEs was very low across different doses of CE/BZA, with rates of 0.3 to 0.7 per 1000 woman-years, indicating that CE/BZA is a safe option for managing menopausal symptoms without significantly increasing cardiovascular risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular safety of conjugated estrogens plus bazedoxifene: meta-analysis of the SMART trials. Komm, BS., Thompson, JR., Mirkin, S.[2015]

In a 1-year study involving 1061 non-hysterectomized postmenopausal women, Bazedoxifene/conjugated estrogens (BZA/CE) demonstrated no cases of endometrial hyperplasia at the lower dose and only a small incidence at the higher dose, indicating strong endometrial safety.

BZA/CE significantly improved bone mineral density (BMD) in the lumbar spine and total hip compared to placebo, while also showing a favorable safety profile with low rates of bleeding and breast tenderness, making it a promising option for managing menopausal symptoms and preventing osteoporosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of bazedoxifene/conjugated estrogens on endometrial safety and bone in postmenopausal women. Mirkin, S., Komm, BS., Pan, K., et al.[2013]

Conjugated estrogen/bazedoxifene (CE/BZA) is a new progestin-free therapy for postmenopausal health that effectively manages vasomotor symptoms and helps prevent bone loss, based on results from five Phase III SMART trials.

CE/BZA works by using bazedoxifene to inhibit the proliferative effects of estrogen on the uterus and breast, which reduces side effects like uterine bleeding and breast pain commonly associated with progestin-containing therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conjugated estrogen/bazedoxifene tablets for the treatment of moderate-to-severe vasomotor symptoms associated with menopause. Mirkin, S., Komm, B., Pickar, JH.[2016]

Duavive, a combination of conjugated oestrogens and bazedoxifene acetate, is effective for treating estrogen deficiency symptoms in postmenopausal women who cannot use progestogen therapy, highlighting its targeted approach for this specific patient group.

Since its approval by the European Medicines Agency in 2014 and launch in the UK in 2016, Duavive has been reviewed for both efficacy and safety, establishing its role in managing menopausal symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bazedoxifene for HRT? [2017]

In a 12-week study involving 664 nonhysterectomized postmenopausal women, conjugated estrogens/bazedoxifene (CE/BZA) significantly improved sexual functioning and lubrication, especially in women who reported pain with intercourse as their most bothersome symptom.

CE/BZA also showed positive effects on vaginal cell counts and overall treatment satisfaction, indicating its efficacy in addressing moderate to severe menopausal symptoms and enhancing quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Most bothersome symptom in women with genitourinary syndrome of menopause as a moderator of treatment effects. Pinkerton, JV., Bushmakin, AG., Abraham, L., et al.[2018]

Bazedoxifene acetate is an effective oral treatment for preventing and treating osteoporosis in postmenopausal women, showing positive effects on bone health without stimulating breast or uterine tissue.

In combination with conjugated estrogens, bazedoxifene improves bone mineral density and reduces fracture risk while also alleviating menopausal symptoms, making it a promising option for women at high risk of osteoporosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bazedoxifene: a new selective estrogen receptor modulator for the treatment of postmenopausal osteoporosis. Kung, AW., Chu, EY., Xu, L.[2012]

Bazedoxifene acetate is an investigational oral drug that effectively prevents bone loss and reduces vertebral fracture risk in postmenopausal women, without affecting the endometrium or breast tissue.

When combined with conjugated estrogens, bazedoxifene shows promise in improving menopausal symptoms while providing skeletal benefits, making it a potential treatment for postmenopausal osteoporosis and related symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bazedoxifene and bazedoxifene combined with conjugated estrogens for the management of postmenopausal osteoporosis. Lewiecki, EM.[2019]

In a 20-month study involving 95 ovariectomized cynomolgus macaques, the combination of bazedoxifene acetate (BZA) and conjugated equine estrogens (CEE) significantly reduced breast tissue proliferation and density compared to CEE alone, suggesting a potential for lower breast cancer risk.

BZA acted as an estrogen antagonist in the breast, effectively blocking the effects of CEE on estrogen receptor activity and gene expression related to cell proliferation, indicating that BZA could be a safer alternative to traditional estrogen and progestin therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of bazedoxifene acetate with and without conjugated equine estrogens on the breast of postmenopausal monkeys. Ethun, KF., Wood, CE., Register, TC., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Cardiovascular safety of conjugated estrogens plus bazedoxifene: meta-analysis of the SMART trials. [2015]

2. England pubmed.ncbi.nlm.nih.gov

Effects of bazedoxifene/conjugated estrogens on endometrial safety and bone in postmenopausal women. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Conjugated estrogen/bazedoxifene tablets for the treatment of moderate-to-severe vasomotor symptoms associated with menopause. [2016]

4. England pubmed.ncbi.nlm.nih.gov

Bazedoxifene for HRT? [2017]

5. United States pubmed.ncbi.nlm.nih.gov

Most bothersome symptom in women with genitourinary syndrome of menopause as a moderator of treatment effects. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Bazedoxifene: a new selective estrogen receptor modulator for the treatment of postmenopausal osteoporosis. [2012]

7. England pubmed.ncbi.nlm.nih.gov

Bazedoxifene and bazedoxifene combined with conjugated estrogens for the management of postmenopausal osteoporosis. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Effects of bazedoxifene acetate with and without conjugated equine estrogens on the breast of postmenopausal monkeys. [2021]