PHASE IIB TRIAL OF NEOADJUVANT ORAL TAMOXIFEN VERSUS TRANSDERMAL 4-HYDROXYTAMOXIFEN IN WOMEN WITH DCIS OF THE BREAST

新辅助口服他莫昔芬与透皮 4-羟基他莫昔芬治疗乳腺癌女性患者的 IIB 期试验

基本信息

批准号：
10018597
负责人：
SEEMA KHAN
金额：
$ 60.17万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2021-07-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10018597
关键词：
4-Hydroxy-Tamoxifen Affinity Back Biological Assay Biological Markers Breast Breast Cancer Cell Breast Cancer Prevention Trial Breast Cancer Risk Factor Cancer Cell Growth Core Biopsy Development Diagnosis Diagnostic Double-Blind Method Enrollment Estradiol Estrogen Antagonists Estrogen Receptor alpha Excision Factor IX Factor VIII Formulation GSTM1 gene Gel Insulin-Like Growth Factor I Isomerism Label Lesion MYBL2 gene Mammary Gland Parenchyma Mammary Neoplasms Menopausal Status Methods Neoadjuvant Therapy Noninfiltrating Intraductal Carcinoma Operative Surgical Procedures Oral PTGS2 gene Participant Patients Phase Placebos Plasma Plasma Proteins Preventive Progesterone Protein S Protocols documentation Questionnaires Randomized Reaction Recurrence Residual state Reverse Transcriptase Polymerase Chain Reaction Risk Risk Reduction SHBG gene STK6 gene Sampling Site Skin Symptoms Tamoxifen Therapeutic Topical application Toxic effect United States Woman Work arm breast density cyclin B1 estrogenic expectation follow-up high risk indexing macrophage malignant breast neoplasm preservation primary endpoint response survivin von Willebrand Factor

项目摘要

Tamoxifen (TAM) has been proven to reduce risk of both local recurrence and new primary breast cancer in women with DCIS, providing both preventive and therapeutic benefit. Oral TAM also has proven risk reduction value for women at increased risk for breast cancer, numbering over a million women in the United States alone. However, tamoxifen acceptance by DCIS and high-risk patients has been lower than expected, mainly because of toxicity concerns. A potential solution is the development of delivery methods that preserve efficacy through targeted local delivery to the breast, but minimize toxicity because of low systemic exposure. A potential alternative to oral tamoxifen is suggested by studies going back to the 1980s, which showed that 4-OHT, the monohydroxy metabolite of oral tamoxifen, has a far greater affinity for the estrogen receptor α (ER) and is more effective than TAM in suppressing breast cancer cell growth. Pre-surgical studies indicate that the anti-proliferative activity of 4-OHT gel at 1, 2, and 4 mg/day in invasive breast tumors and DCIS is similar to that of oral TAM at 20 mg/day. 4-OHT is a potent antiestrogenic metabolite of oral TAM, an agent with an unparalleled record of therapeutic and preventive breast cancer efficacy. This randomized, double-blind, placebo-controlled neoadjuvant trial of 0.228% 4-hydroxy-tamoxifen (4-OHT) gel vs. oral tamoxifen (TAM) 20 mg daily will enroll 100 women with a core needle biopsy diagnosis of ER positive DCIS, regardless of grade, with 1:1 randomization to oral TAM and 4-OHT gel. The 4-OHT group will apply active gel 2 mg daily to each breast for a minimum of 24 and a maximum of 28 weeks and take oral placebo. The TAM group will take 20 mg TAM orally daily and apply gel placebo. The primary endpoint is Ki67 labeling index in the DCIS core compared to the surgical sample, with the expectation that the reduction in this parameter will be equivalent in the two groups. Therefore, this statement of work outlines the requirements for the study, including (but not limited to) participant accrual, agent administration and patient follow-up as well as associated biomarker analyses. This statement of work includes protocol activities to screen 150 participants and enroll 100 on trial stratified by menopausal status and site of enrollment.

他莫昔芬（TAM）已被证明可以降低DCI女性的局部复发和新的原发性乳腺癌的风险，从而提供预防和治疗益处。口服TAM还证明，妇女的乳腺癌风险增加，仅在美国就有超过一百万妇女。但是，DCIS和高危患者接受的他莫昔芬的接受程度低于预期，这主要是由于毒性问题。潜在的解决方案是开发通过针对性的局部递送到乳房来保留有效性的输送方法，但由于全身暴露率低，可最大程度地减少毒性。通过研究可以追溯到1980年代，提出了一种潜在的口服他莫昔芬的替代方法，该研究表明4-OHT是口服他莫昔芬的单羟基代谢产物，对雌激素受体α（ER）具有更大的亲和力，并且比TAM在抑制乳腺癌细胞生长方面更有效。术前研究表明，在浸润性乳腺肿瘤和DCIS中，4-OHT凝胶在1、2和4 mg/天的抗增殖活性与以20 mg/天的口服TAM相似。 4-OHT是一种潜在的口服TAM的抗雌激素代谢产物，该代谢物具有无与伦比的治疗记录和预防性乳腺癌效率。 This randomized, double-blind, placebo-controlled neoadjuvant trial of 0.228% 4-hydroxy-tamoxifen (4-OHT) gel vs. oral tamoxifen (TAM) 20 mg daily will enroll 100 women with a core needle biopsy diagnostic of ER positive DCIS, regardless of grade, with 1:1 randomiization to oral TAM and 4-OHT gel. 4-OHT组将每天将活性凝胶2毫克涂在每个乳房中，至少为24周，最多28周，并服用口服安慰剂。 TAM组每天要服用20毫克TAM，并涂上凝胶安慰剂。与手术样本相比，DCIS核心中的Ki67标记指数的主要终点是，预计该参数的降低在两组中将是等效的。因此，这项工作陈述概述了研究的要求，包括（但不限于）参与成立，代理给药和患者随访以及相关的生物标志物分析。这项工作声明包括屏幕150名参与者的协议活动，并通过更年期状态和入学地点分层的试验进行了100次招募。