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

IGF::OT::IGF IIB 期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试验

• 批准号: 9369106
• 负责人: SEEMA KHAN
• 金额: $ 63.02万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9369106
• 关键词: 4-Hydroxy-Tamoxifen; Affinity; Back; Biological Assay; Biological Markers; Breast; Breast Cancer Cell; Breast Cancer Prevention Trial; Cancer Cell Growth; Core Biopsy; Development; Diagnosis; Diagnostic; Double-Blind Method; Enrollment; Estradiol; Estrogen Antagonists; Estrogen Receptor alpha; Excision; Factor VIII; Formulation; GSTM1 gene; Gel; Inferior; 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; Placebo Control; 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; base; breast density; cyclin B1; estrogenic; expectation; follow-up; high risk; indexing; macrophage; malignant breast neoplasm; response; survivin; von Willebrand Factor

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()已被证明可以降低患有DCIS的妇女的局部复发和新的原发乳腺癌的风险，提供预防和治疗益处。口服也证明了乳腺癌风险增加的女性的风险降低价值，仅在美国就有100多万女性。然而，DCIS和高危患者对他莫昔芬的接受度低于预期，主要是因为毒性方面的考虑。一个潜在的解决方案是开发一种给药方法，通过有针对性的局部给药来保持疗效，但由于全身暴露较低，毒性最小。早在20世纪80年代的研究表明，口服他莫昔芬的单羟基代谢物4-羟色胺与雌激素受体α(ER)有更强的亲和力，在抑制乳腺癌细胞生长方面比更有效。术前研究表明，4-羟色胺凝胶1、2、4 mg/d对乳腺浸润性肿瘤和导管内癌的抗增殖活性与口服20 mg/d相似。4-羟色胺是口服的一种有效的抗雌激素代谢物，该药在治疗和预防乳腺癌方面有着无与伦比的记录。 这项0.228%4-羟基三苯氧胺(4-OHT)凝胶与口服他莫昔芬()每天20毫克的随机、双盲、安慰剂对照新辅助试验将招募100名经核心针刺活检诊断为ER阳性DCI的妇女，不分级别，1：1随机分为口服和4-OHT凝胶。4-OHT组将每天在每个乳房上涂抹活性凝胶2毫克，持续最少24周，最多28周，并服用口服安慰剂。组每日口服20 mg，外用凝胶安慰剂。与手术样本相比，主要终点是DCIS核心中的Ki67标记指数，预期这一参数的减少在两组中将是相同的。 因此，这份工作说明书概述了这项研究的要求，包括(但不限于)参与者应计、制剂管理和患者随访以及相关的生物标记物分析。该工作说明书包括按更年期状态和登记地点分层筛选150名参与者和招募100名受试者的礼仪活动。