Ph 2 Multicenter study of seliciclib for Cushing Disease IND 120,848 (10/10/2017)

seliciclib 治疗库欣病的 2 期多中心研究 IND 120,848 (10/10/2017)

• 批准号: 10003845
• 负责人: SHLOMO MELMED
• 金额: $ 46.78万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10003845
• 关键词: Ph; Multicenter; study; seliciclib; Cushing

PROJECT SUMMARY The proposed phase 2 multicenter study will evaluate the small molecule selective CDK2/cyclin E inhibitor seliciclib in patients with Cushing disease. This rare disease, with an estimated prevalence in the United States of approximately 20,000 cases, results from an adrenocorticotrophic hormone (ACTH)-secreting pituitary corticotroph adenoma and predisposes patients to serious morbidities and increased mortality, mostly due to cardiovascular complications. The current multimodal standard of care of surgical, radiotherapeutic, and medical treatments for this endogenous hypercortisolism is usually not sufficient to control disease, and can lead to serious sequelae. There is a clear unmet need for a medical therapy that directly suppresses pituitary corticotroph ACTH secretion and normalizes cortisol levels in patients with this rare disease. Preclinical discoveries led to identification of seliciclib (R-roscovitine), which directly targets processes promoting ACTH overproduction and the consequent hypercortisolism that underlies the excess morbidity and mortality associated with Cushing disease. Preliminary data from an NIH-funded pilot phase 2 study indicate efficacy of oral seliciclib without conferring adrenal side effects seen with current medications used for this disease. The proposed expanded phase 2 multicenter trial has an adaptive design and will evaluate the safety and efficacy of two of three doses/schedules of seliciclib in patients with de novo or recurrent Cushing disease. Up to 30 subjects will be recruited, consented, and enrolled in consecutive dose cohorts through a collaborative effort among all five major specialty pituitary centers in greater Los Angeles. Results of this trial will lay the foundation for additional trials of this novel, highly targeted agent for treatment of this rare disease.

项目摘要 拟定的II期多中心研究将评估小分子选择性CDK 2/细胞周期蛋白E抑制剂seliciclib 在库欣病患者中。这种罕见的疾病，估计在美国的患病率为 大约20，000例，由促肾上腺皮质激素（ACTH）分泌的垂体促肾上腺皮质激素细胞引起 腺瘤，使患者容易发生严重的发病率和死亡率增加，主要是由于心血管疾病， 并发症目前的外科、放射治疗和内科治疗的多模式护理标准 内源性皮质醇增多症通常不足以控制疾病，并可导致严重的后遗症。有一个 对直接抑制垂体促肾上腺皮质激素ACTH分泌的药物治疗的明确未满足的需求， 使这种罕见疾病患者的皮质醇水平正常化。 临床前发现导致seliciclib（R-roscovitine）的鉴定，其直接靶向过程 促进促肾上腺皮质激素过度产生和随之而来的皮质醇增多症，这是过度发病率的基础， 与库欣病相关的死亡率。来自NIH资助的试验性2期研究的初步数据表明疗效 口服seliciclib而不产生目前用于这种疾病的药物所见的肾上腺副作用。的 拟定的扩展2期多中心试验具有适应性设计，将评价两种药物的安全性和有效性。 在新发或复发性库欣病患者中，seliciclib的三种剂量/方案。最多30名受试者将 通过所有五个主要剂量队列之间的协作，招募、同意并入组连续剂量队列 大洛杉矶的专业垂体中心这项试验的结果将为进一步的试验奠定基础， 这种新型的，高度靶向的药物用于治疗这种罕见的疾病。

项目成果

Treatment of Cushing Disease With Pituitary-Targeting Seliciclib.

使用靶向垂体的 Seliciclib 治疗库欣病。

• DOI: 10.1210/clinem/dgac588
• 发表时间: 2023
• 期刊: The Journal of clinical endocrinology and metabolism
• 作者: Liu,Ning-Ai;Ben-Shlomo,Anat;Carmichael,JohnD;Wang,Christina;Swerdloff,RonaldS;Heaney,AnthonyP;Barkhoudarian,Garni;Kelly,Daniel;Noureddin,Mazen;Lu,Lin;Desai,Manish;Stolyarov,Yana;Yuen,Kevin;Mamelak,AdamN;Mirocha,James;Tigh
• 通讯作者: Tigh