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

长春新碱与西罗莫司治疗高危卡波西样血管内皮瘤的 2 期研究

• 批准号: 8749326
• 负责人: Denise Martin Adams
• 金额: $ 25.84万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8749326
• 关键词: Phase; Study; Vincristine; vs.; Sirolimus

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.

抽象的： 卡波西样血管内皮瘤（KHE）是极其罕见的危及生命的肿瘤，可通过 与卡萨巴赫-梅里特现象有关，包括严重的血小板减少症和 低纤维蛋白原血症会导致严重的出血风险，相关死亡率高达 20%到30%。尽管潜在并发症很严重，但我们缺乏统一的指导方针 患有这些肿瘤的儿童和年轻人的治疗和治疗反应。 KHE 患者有 接受过多种侵袭性药物治疗但未对反应进行前瞻性评估或 安全。最近的共识声明认为长春新碱是治疗复杂疾病的实践标准 KHE。我们在研究 SIR-DA-0901“2 期研究 - 临床 mTOR 抑制剂西罗莫司治疗并发症的疗效和安全性试验评估 血管异常”（FDA 拨款# 5RO1FD003712-04）。虽然数字很小，但反应 具有出色的耐受性，极具前景。有临床前和临床数据 支持 PI3 激酶/AKT/mTOR 通路在血管生长中的基本调节功能 和组织，为患有复杂血管异常的患者提出治疗目标。 我们目前的协议进一步支持该数据。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 提出一项由 8 个中心参与的多中心 II 期试验，采用自适应统计设计。 该研究将分为两个阶段。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 评估为血液学反应的时间。在诱导阶段结束时，如果存在，则可能会发生交叉 是无法响应。尽管患者预计会完成指定的 2 个月诱导治疗， 如果医生和治疗人员同意，患者可以在 2 个月期限结束之前停止治疗 研究 PI 认为这符合患者安全和福祉的最佳利益。第 2 部分是维护 阶段，为期 1 年。将持续收集安全性和有效性数据，并将 对于失去反应的患者可以随时进行交叉。维护中的正式响应将是 根据 SIR-DA-0901 研究，通过影像学研究、功能评估和生活质量进行评估。 目前的疗法非常有限，因此迫切需要新的疗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 期试验来确定这种疗法是否会成为新的疗法 KHE 患者的护理标准。