Phase 2 Study of Vincristine vs. Sirolimus for the Treatment of High Risk Kaposiform Hemangioendothelioma

描述(由申请人提供)： 卡波西样血管内皮瘤(KHE)是一种极其罕见的危及生命的肿瘤，它可与严重的血小板减少和低纤维蛋白原血症的Kasabach-Merritt现象有关，导致严重的出血风险和高达20%~30%的相关死亡率。尽管潜在并发症很严重，但对于患有这些肿瘤的儿童和年轻人的治疗和治疗反应，缺乏统一的指导方针。KHE患者已经接受了多种积极的药物方案治疗，但没有进行前瞻性的反应或安全性评估。目前，长春新碱被认为是实践的标准。这些患者中的一部分已在SIR-DA-0901研究中接受治疗，这是一项第二阶段试验，评估西罗莫司治疗复杂血管异常的有效性和安全性。虽然人数很少，但对治疗的反应和耐受性似乎是有希望的。有临床前和临床数据支持磷脂酰肌醇-3-激酶/AKT/哺乳动物雷帕霉素靶标(PI3/AKT/mTOR)通路在血管生长和组织中的基本调节功能，这为复杂血管畸形患者提供了一个治疗靶点。本协议还支持该数据。本试验的总体目标是客观评价西罗莫司与长春新碱治疗50例高危KHE患者的疗效。提出了一项多中心、有8个站点参与的第二阶段试验。这项研究将分为两个阶段。其中第一个阶段是最初的诱导阶段，长春新碱和类固醇将与西罗莫司进行比较。 和类固醇。诱导阶段的反应将被评估为血液学反应的时间。在诱导阶段结束时，如果没有响应，则可能发生交叉。第二部分是维护阶段，为期一年。将收集持续的安全性和有效性数据，并将在任何时候为失去反应的患者进行交叉。根据研究SIRDA-0901，将通过成像研究、功能评估和生活质量评估来评估维护中的正式反应。任何时候的失败将被定义为在两个独立的实验室评估中的血液学参数恶化。

DESCRIPTION (provided by applicant): Kaposiform hemangioendotheliomas (KHE) are extremely rare life threatening tumors, which can be associated with Kasabach-Merritt phenomenon consisting of profound thrombocytopenia and hypofibrinogenemia, causing a significant risk of bleeding and an associated mortality rate as high as 20% to 30%. Despite the severity of potential complications, there is a lack of uniform guidelines for the treatment and response to treatment of children and young adults with these tumors. KHE patients have been treated with a multitude of aggressive drug regimens without prospective evaluation of response or safety. Presently, vincristine is considered the standard of practice. A subset of these patients has been treated on study SIR-DA-0901, a Phase 2 trial assessing the efficacy and safety of sirolimus for the treatment of complicated vascular anomalies. Although the numbers are small, the response and tolerability to treatment have appeared promising. There are pre-clinical and clinical data supporting the essential regulatory function of the phosphoinositide-3-kinase/AKT/mammalian target of rapamycin (PI3 kinase/AKT/mTOR) pathway in vascular growth and organization which suggests a therapeutic target for patients with complicated vascular anomalies. The present protocol further supports this data. The overall goal of this trial is to objectively assess the efficacy of sirolimus compard to vincristine for the treatment of 50 patients with high risk KHE. A multi-center, Phase 2 trial with participation from 8 sites is proposed. The study will consist of two phases. The first of these is an initial induction phase in which vincristine and steroids will be compared to sirolimus and steroids. Response in the induction phase will be assessed as time to hematologic response. At the end of induction phase, cross-over can occur if there is failure to respond. Part 2 is a maintenance phase which will be 1 year in length. Continued safety and efficacy data will be collected, and there will be cross-over at any time for patients who lose their response. Formal response in maintenance will be evaluated by imaging studies, functional assessment, and quality of life as per study SIRDA- 0901. Failure at any time will be defined as worsening of hematologic parameters on two separate laboratory evaluations.