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

他莫昔芬（TAM）已被证明可以降低DCIS女性局部复发和新发原发性乳腺癌的风险，提供预防和治疗益处。口服TAM也被证明对乳腺癌风险增加的女性具有降低风险的价值，仅在美国就有超过100万女性。然而，DCIS和高危患者对他莫昔芬的接受程度低于预期，主要是因为毒性问题。一个潜在的解决方案是开发通过靶向局部递送到乳房来保持功效的递送方法，但由于全身暴露较低而使毒性最小化。追溯到20世纪80年代的研究提出了口服他莫昔芬的潜在替代品，该研究表明，口服他莫昔芬的单羟基代谢产物4-OHT对雌激素受体α（ER）具有更大的亲和力，并且在抑制乳腺癌细胞生长方面比TAM更有效。术前研究表明，在浸润性乳腺肿瘤和DCIS中，1、2和4 mg/天的4-OHT凝胶的抗增殖活性与20 mg/天的口服TAM相似。4-OHT是口服TAM的有效抗雌激素代谢物，口服TAM是一种具有无与伦比的治疗和预防乳腺癌功效的药物。 这项随机、双盲、安慰剂对照的新辅助治疗试验比较了0.228% 4-羟基-他莫昔芬（4-OHT）凝胶与口服他莫昔芬（TAM）每日20 mg，将入组100名经芯针活检诊断为ER阳性DCIS的女性，无论级别如何，1：1随机分配至口服TAM和4-OHT凝胶组。4-OHT组将在每个乳房上每天涂抹活性凝胶2 mg，最少24周，最多28周，并口服安慰剂。TAM组每日口服TAM 20 mg，并应用凝胶安慰剂。主要终点是与手术样本相比，DCIS核心样本中的Ki 67标记指数，预计两组中该参数的降低程度相同。 因此，本工作说明书概述了研究要求，包括（但不限于）受试者招募、药物给药和患者随访以及相关生物标志物分析。本工作说明书包括筛选150名受试者并招募100名受试者参加试验的方案活动，按绝经状态和招募部位分层。

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.