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.
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.
