Phase IIB Trial of Bazedoxifene Plus Conjugated Estrogens

• ClinicalTrials.gov Identifier: NCT04821141
• Recruitment Status: Recruiting
• First Posted: March 29, 2021
• Last Update Posted: February 6, 2023
• Sponsor: University of Kansas Medical Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Carol Fabian, MD, University of Kansas Medical Center

Tracking Information

• First Submitted Date: March 18, 2021
• First Posted Date: March 29, 2021
• Last Update Posted Date: February 6, 2023
• Actual Study Start Date: December 14, 2021
• Estimated Primary Completion Date: August 1, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 25, 2021)

Change in FGV [ Time Frame: baseline to 6 months ]

Change in fibroglandular volume assessed on 3-D digital mammogram by Volpara software.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 25, 2021)

Change in proliferation [ Time Frame: baseline to 6 months ]

change in percent of breast epithelial cells staining positive for Ki-67 by immunocytochemistry

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: March 25, 2021)

• 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.
• 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

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Phase IIB Trial of Bazedoxifene Plus Conjugated Estrogens
• 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
• 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.
• 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.
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

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

Condition

• Risk Reduction
• Breast Cancer

Intervention

Drug: Bazedoxifene and Conjugated Estrogens

BZA (20 mg) plus CE (0.45 mg) taken together once daily

Other Name: BZA+CE

Study Arms

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

• Publications *: Fabian CJ, Nye L, Powers KR, Nydegger JL, Kreutzjans AL, Phillips TA, Metheny T, Winblad O, Zalles CM, Hagan CR, Goodman ML, Gajewski BJ, Koestler DC, Chalise P, Kimler BF. Effect of Bazedoxifene and Conjugated Estrogen (Duavee) on Breast Cancer Risk Biomarkers in High-Risk Women: A Pilot Study. Cancer Prev Res (Phila). 2019 Oct;12(10):711-720. doi: 10.1158/1940-6207.CAPR-19-0315. Epub 2019 Aug 16.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 25, 2021): 120
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 31, 2026
• Estimated Primary Completion Date: August 1, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria for Baseline Mammogram and RPFNA

Women age 45 - 60.

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.

Women must be in one of the four menopausal status categories, as defined below.

Category 1: Clinically Postmenopausal. Age 45-60 with an intact uterus and no periods in past 12 months. Amenorrhea is not thought to be due to endometrial ablation, Mirena IUD or other menses suppressing contraceptives. No pre-study FSH is required.

Category 2: Late menopause transition. Age 45-60 with an intact uterus and no periods in past 2 months immediately preceding eligibility testing; but has not been amenorrheic for 12 months. Amenorrhea not thought to be due to endometrial ablation, Mirena IUD or other menses suppressing contraceptives. No pre-study FSH is required.

Category 3: Menopause status cannot be determined by menstrual history; age ≥50. Age 50-60 and prior hysterectomy, prior endometrial ablation with subsequent lack of periods, or menses suppression due to Mirena IUD or other types of contraceptives. No pre-study FSH is required.

Category 4: Menopausal status cannot be accurately determined by menstrual history; age 45-49. Age 45-49 and prior hysterectomy, prior endometrial ablation with subsequent lack of periods, or menses suppression due to Mirena IUD or other types of contraceptives. A pre-study FSH is required and must be ≥25 mIU/ml or in postmenopausal range by institutional laboratory standard.

Must have at least one ovary.

BMI: ≤ 35 kg/m2

At least one breast without prior therapeutic radiation that can be assessed by Volpara® software.

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.

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) (http://www.ems-trials.org/riskevaluator/); 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, http://www.cancer.gov/bcrisktoolmobile). Average risk for women in the same age-group is based on the Surveillance, Epidemiology, and End Results (SEER) Program provided by the NCI (http://srab.cancer.gov/devcan/).

Vaginal Hormones: Low dose vaginal hormones, such as Estring(®, Vagifem®, Imvexy®, 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 systemic hormone replacement such as pills, transdermal patches, oral troches, or injections, must be off for 8 weeks or more prior to baseline mammogram and RPFNA.

Exclusion Criteria for Screening

Conditions:

• 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
• 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.
• Known hypoparathyroidism or recent history of triglycerides > 300 mg/dl.
• 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.

Medications

• 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. (Note that continued use of vaginal low dose hormonal preparations for dyspareunia is allowed if the woman had been on for at least 2 weeks prior to baseline testing)
• 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. 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 for at least one breast and average at least 30 cm3 per breast (i.e., 30 cm3 if only one breast evaluable; 60 cm3 if both breasts evaluable).

RPFNA specimen must be received at KUMC in good condition with cellular integrity and evidence of ductal/lobular epithelial cells on Thinprep® slides; but there is no requirement for a specific cell number, 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 and 6 months (at KUMC only).
• 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 limited physical exam including evaluation of heart, lungs, abdomen and liver, and breast exam, plus 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.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 45 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Bruce F Kimler, PhD; 9132056382; bkimler@kumc.edu

Contact: Carol J Fabian, MD; 9135887791; cfabian@kumc.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04821141
• Other Study ID Numbers: STUDY00146320; R01CA249437-01A1 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Carol Fabian, MD, University of Kansas Medical Center
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Kansas Medical Center
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Carol J Fabian, MD; University of Kansas Medical Center

• PRS Account: University of Kansas Medical Center
• Verification Date: February 2023