Biomarker-Based Phase IIB Trial of (Bazedoxifene-Conjugated Estrogen) to Reduce Risk for Breast Cancer

基于生物标志物的 IIB 期试验（巴多昔芬结合雌激素）可降低乳腺癌风险

• 批准号: 10579173
• 负责人: CAROL J. FABIAN
• 金额: $ 83.26万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-26 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579173
• 关键词: Age; Agonist; Agreement; Benign; Biological Availability; Biological Markers; Blinded; Blood; Body fat; Breast; Breast Cancer Risk Factor; Chemoprevention; Clinical Trials; Cognition; Complex; Computer software; Conjugated Estrogens; Development; Digital Mammography; Eligibility Determination; Encapsulated; Endocrine; Enrollment; Estrogen Antagonists; Estrogen Receptors; Estrogens; FDA approved; Fasting; Fine needle aspiration biopsy; Fright; Gene Expression; Genes; High Risk Woman; Hormones; Hot flushes; IGFBP3 gene; Incidence; Inflammation; Inflammatory; Institution; Insulin Resistance; Insulin-Like Growth Factor I; Intervention; Malignant Neoplasms; Mammary Gland Parenchyma; Mammography; Marketing; Measures; Messenger RNA; Osteoporosis prevention; Outcome Assessment; Outcome Measure; Patient Outcomes Assessments; Perimenopause; Pharmaceutical Preparations; Phase; Phosphoproteins; Pilot Projects; Placebo Control; Placebos; Plasma; Postmenopause; Premature Menopause; Prevention trial; Progesterone; Progesterone Receptors; Proliferating; Property; Protein Array; Proteins; Quality of life; Randomized; Risk; Risk Reduction; Sample Size; Serum; Sex Hormone-Binding Globulin; Site; TRANCE protein; Testosterone; Tissue Banks; Tissues; Tumor necrosis factor receptor 11b; Uterus; Visceral fat; Woman; angiogenesis; bone; cell motility; cytokine; digital; immunocytochemistry; malignant breast neoplasm; men; open label; predicting response; primary endpoint; receptor; response biomarker; secondary endpoint; side effect; transcriptome sequencing; tumor; vasomotor symptoms

ABSTRACT Few risk-eligible women agree to standard endocrine interventions for breast cancer risk reduction due to fear of side effects combined with incomplete efficacy and lack of a reliable marker of response. Worry about initiation or worsening vasomotor symptoms is a common barrier. The Tissue Selective Estrogen Complex of bazedoxifene (BZA) 20 mg and conjugated estrogen (CE) 0.45 mg marketed as Duavee® is FDA-approved for relief of hot flashes and prevention of osteoporosis. Duavee® is promising for breast cancer risk reduction given the estrogen antagonist effects in the breast and uterus, and estrogen agonist properties in bone. The bazedoxifene component does not antagonize CE's favorable effects on vasomotor symptoms despite anti- tumor efficacy observed for the combination. In our pilot, 6 months of Duavee® given to symptomatic women at increased risk for breast cancer alleviated hot flashes and favorably modulated risk biomarkers of mammographic fibroglandular volume (Volpara™ fully automated assessments), benign breast tissue proliferation (Ki-67), and serum progesterone, IGF-1, and bioavailable testosterone. A phase IIB multi- institutional trial of 6 months of Duavee® vs placebo is proposed in high-risk women with vasomotor symptoms. Blood, mammogram, and benign breast tissue, and anthropomorphic and quality of life measures will be obtained at baseline. Subjects will be stratified by enrollment site, fibroglandular volume, and Ki-67; and randomized to blinded Duavee® or matched placebo for 6 months, followed by repeat assessments. The primary endpoint is change in mammographic fibroglandular volume. Secondary endpoints are change in benign breast tissue Ki-67, estrogen and progesterone receptor protein, ER and PgR target gene expression (RT-qPCR), serum IGF-1: IGFBP3, bioavailable hormones, the ratio of soluble receptor activator of nuclear factor kappa-Β ligand (sRANKL) to osteoprotegerin, and patient reported outcome measures related to vasomotor symptoms, quality of life, and cognition. Reverse phase protein array and RNA-seq are performed on benign tissue to aid in elucidation of mechanisms of action. The possible influence of BZA levels, body fat, visceral fat, insulin resistance, and inflammatory cytokines on biomarker modulation will be examined. Favorable biomarker modulation would provide evidence that Duavee® is likely to reduce risk for breast cancer and establish potential markers to predict response in a Phase III chemoprevention trial.

抽象的 很少有风险符合风险的妇女同意由于担心而降低乳腺癌风险的标准内分泌干预措施 副作用结合了不完全的效率和缺乏可靠的响应标记。担心 引发或令人担忧的血管舒缩症状是常见的障碍。组织选择性雌激素复合物的 Bazedoxifene（BZA）20毫克和共轭雌激素（CE）0.45 mg销售，Duavee®已被FDA批准为FDA 缓解潮热和预防骨质疏松症。 Duavee®有望减少乳腺癌风险 鉴于雌激素拮抗剂在乳房和子宫中的作用，以及骨骼中的雌激素激动剂特性。 Bazedoxifene成分不会拮抗CE对血管舒缩符号的有利影响。 观察到组合的肿瘤效率。在我们的飞行员中，有症状女性的6个月的Duavee® 乳腺癌的风险增加，可缓解潮热，并受到调制的风险生物标志物 乳房X线纤维界体积（Volpara™全自动评估），良性乳腺组织 增殖（KI-67），血清孕酮，IGF-1和生物利用睾丸激素。 IIB期多 在具有血管舒适的高风险女性中，提出了6个月Duavee®与安慰剂的机构试验 症状。血液，乳房X线照片和良性乳房组织以及拟人化和生活质量测量 将在基线时获得。受试者将按入学地点，纤维界体积和KI-67进行分层；和 随机分配至盲人Duavee®或匹配的安慰剂6个月，然后进行重复评估。这 主要终点是乳房X线纤维界体积的变化。次要终点是更改 良性乳腺组织KI-67，雌激素和孕酮受体蛋白，ER和PGR靶基因表达 （RT-QPCR），血清IGF-1：IGFBP3，生物可用恐怖，核受体激活剂的比率 因子Kappa-β配体（Srankl）到骨蛋白蛋白蛋白，患者报告了与 血管运动症状，生活质量和认知。进行反相蛋白阵列和RNA-Seq 在良性组织上有助于阐明作用机理。 BZA水平，体内脂肪的可能影响 将检查内脏脂肪，胰岛素抵抗和炎性细胞因子在生物标志物调节中。 有利的生物标志物调制将提供证据表明Duavee®可能会降低乳腺癌的风险 并建立潜在的标记以预测III期化学预防试验中的反应。

项目成果

A novel Bayesian adaptive design incorporating both primary and secondary endpoints for randomized IIB chemoprevention study of women at increased risk for breast cancer.

• DOI: 10.1186/s13063-022-06930-5
• 发表时间: 2022-12-05
• 期刊: TRIALS
• 影响因子: 2.5
• 作者: Gajewski, Byron J. J.;Kimler, Bruce F. F.;Koestler, Devin C. C.;Mudaranthakam, Dinesh Pal;Young, Kate;Fabian, Carol J. J.
• 通讯作者: Fabian, Carol J. J.