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

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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.