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

摘要： 卡波西样血管内皮瘤（KHE）是一种非常罕见的危及生命的肿瘤， 与Kasabach-Merritt现象相关，包括严重的血小板减少症， 低纤维蛋白原血症导致出血的显著风险，相关死亡率高达 百分之二十到三十尽管潜在并发症的严重性，我们缺乏统一的指导方针， 治疗和对这些肿瘤的儿童和年轻人的治疗反应。KHE患者有 接受过多种侵袭性药物方案治疗，但未对缓解进行前瞻性评价，或 安全为代价的最近，一项共识声明认为长春新碱是复杂的 KHE我们在研究SIR-DA-0901“一项2期临床研究”中治疗了这些患者的一个子集。 评估mTOR抑制剂西罗莫司治疗复杂性高血压的疗效和安全性的试验 血管异常”（FDA批准号5 RO 1FD 003712 -04）。虽然人数不多，但反应 具有极好的耐受性，非常有前景。有临床前和临床数据 支持血管生长中PI 3激酶/AKT/mTOR通路的基本调节功能 和组织，为复杂血管畸形患者提供了治疗靶点。 我们目前的协议进一步支持这一数据。本试验的总体目标是客观评估 西罗莫司与长春新碱治疗高危KHE患者的疗效比较。我们 采用自适应统计设计，拟定一项由8家临床试验机构参与的多中心II期试验。 研究将分两个阶段进行。其中第一个是初始诱导阶段，其中长春新碱 类固醇将与西罗莫司和类固醇进行比较。诱导阶段的反应将是 评估为至血液学缓解的时间。在诱导阶段结束时，如果存在以下情况，则可以发生交叉 就是没有回应尽管患者预计将完成分配的2个月诱导治疗， 如果医生和患者可以在2个月期间结束之前停止治疗， 研究PI认为这符合患者安全和健康的最佳利益。第二部分是维护 这一阶段将持续一年。将继续收集安全性和疗效数据， 对于失去反应的患者，可以随时交叉治疗。维护中的正式响应将是 根据研究SIR-DA-0901，通过影像学研究、功能评估和生活质量进行评价。 目前的治疗方法非常有限，因此迫切需要新的治疗方法来治疗这种毁灭性的疾病。 疾病根据我们的初步数据，西罗莫司治疗KHE有很好的理由 因此，迫切需要进行II期试验，以确定这种疗法是否会成为新的治疗方法。 KHE患者的护理标准。

Abstract: 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, we lack 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. Recently a consensus statement deemed vincristine the standard of practice for complicated KHE. We have treated a subset of these patients on study SIR-DA-0901, "A Phase 2 Study- Clinical Trial Assessing Efficacy and Safety of the mTOR Inhibitor Sirolimus in the Treatment of Complicated Vascular Anomalies" (FDA Grant# 5RO1FD003712-04). Although the numbers are small, the response has been extremely promising with excellent tolerability. There is pre-clinical and clinical data supporting the essential regulatory function of the PI3 kinase/AKT/mTOR pathway in vascular growth and organization which suggests a therapeutic target for patients with complicated vascular anomalies. Our present protocol further supports this data. The overall goal of this trial is to objectively assess the efficacy of sirolimus compared to vincristine for the treatment of patients with high risk KHE. We propose a multi-center, phase II trial with participation from 8 sites using an adaptive statistical design. 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. Although patients are expected to finish their assigned 2-month induction therapy, a patient may switch off the therapy prior to the end of the 2 months period if the physician and the study PI deem it is in the best interest of the patient's safety and well-being. 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 SIR-DA-0901. Present therapies are very limited and so new therapies are desperately needed for this devastating disease. Based on our preliminary data, there is a very good rationale for sirolimus therapy in KHE patients and so a phase II trial is urgently needed to determine if this therapy is to become the new standard of care for KHE patients.