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.

Public Health Relevance

Kaposiform Hemangioendotheliomas (KHE) are tumors of blood vessels and lymphatic vessels that are extremely rare;the majority occurring in children less than 3 years of age. They cause a Phenomenon called Kasabach-Merritt Phenomenon with is associated with extremely low platelets (thrombocytopenia) and other low clotting proteins (hypofibrinogenemia) that can result in a significant risk of bleeding and a death rate of as high as 20 - 30%. Not much is known about the biology of these tumors but there is some evidence that a certain pathway that regulates vascular growth and organization may be involved (Pl3 kinase/AKT/mTOR pathway). If we can block this pathway we may be able to use a medication to help these patients. There is a medication called Sirolimus that blocks this pathway and we have recently shown effectiveness of this medication in some patients with KHE tumors. We need larger numbers of patients though to prove that it is more effective than what is considered the standard of practice (vincristine and chemotherapy agent). This trial will enable us to prove which medication works better so we can obtain approval to treat patients with KHE with this medication and improve their quality of life.

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Cincinnati Children's Hospital Medical Center
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