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

项目总结 拟议的第二阶段多中心研究将评估小分子选择性CDK2/细胞周期蛋白E抑制剂seliclib 在库欣病患者中。这种罕见的疾病在美国的流行率估计为 大约20,000例，由一种分泌促肾上腺皮质激素(ACTH)的垂体促肾上腺皮质激素所致 腺瘤，使患者易患严重疾病并增加死亡率，主要由心血管疾病引起 并发症。目前手术、放射治疗和内科治疗的多模式护理标准 内源性皮质醇过多通常不足以控制疾病，并可能导致严重的后遗症。有一个 明确未得到满足的药物治疗需求，直接抑制垂体促肾上腺皮质激素分泌和 使这种罕见疾病患者的皮质醇水平正常化。 临床前的发现导致了塞利昔布(R-罗斯科维汀)的发现，它直接针对过程 促进ACTH的过度生产和随之而来的皮质醇增多，这是过度发病率和 与库欣病相关的死亡率。美国国立卫生研究院资助的第二阶段试点研究的初步数据表明 口服塞利西利，不会引起肾上腺副作用，与目前用于治疗这种疾病的药物一样。这个 拟议的扩展2期多中心试验采用了适应性设计，并将评估两种方案的安全性和有效性 对初发或复发性库欣病患者服用三种剂量/时间表的塞利西利。多达30名受试者将 通过所有五个主要组织之间的协作努力，被招募、同意并加入连续剂量队列 大洛杉矶的专科脑下垂体中心。这项试验的结果将为进一步的试验奠定基础 这种治疗这种罕见疾病的新的、高度靶向的药物。

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.