A Study to Compare Vincristine to Sirolimus for Treatment of High Risk Vascular Tumors
In this research study we want to learn more about which treatment works better for patients diagnosed with a vascular tumor called Kaposiform Hemangioendothelioma (KHE) or other high risk vascular tumors such as Tufted Angioma (TA). In these tumors, the blood cells that help your blood clot called platelets become trapped in the tumor causing swelling, pain, and bruising. Vascular tumors can be life threatening. There are few medical treatments that will work to shrink the vascular tumor. Some doctors will use steroids and vincristine to try and shrink vascular tumors.
In this research study, the study doctor will compare two different drugs to see which one will work better to help shrink your vascular tumor. One of the drugs is vincristine. Vincristine is approved by the Food and Drug Administration (FDA) to treat people with cancer. Vincristine is used to stop the abnormal cells from growing such as cells that make up blood vessels.
The other drug to be used in this study is sirolimus. Sirolimus is currently approved by the Food and Drug Administration (FDA) to prevent transplanted organ rejection. Sirolimus is not approved by the FDA for treatment of vascular abnormalities and is considered experimental. Sirolimus belongs to a class of drugs call 'mTOR inhibitors'. mTOR (mammilian target of rapamycin) helps cells to grow and may also help blood vessels to grow in a more normal fashion. Sirolimus is currently being tested in patients with vascular tumors and cancer. In vascular tumors, we hope sirolimus will stop the blood vessel growth.
Funding Source: FDA - OOPD (Office of Orphan Products Development)
|Kaposiform Hemangioendothelioma (KHE) Kasabach-Merritt Syndrome Tufted Angioma||Drug: Vincristine Drug: Sirolimus||Phase 2|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||A Randomized Phase 2 Study of Vincristine Versus Sirolimus to Treat High Risk Kaposiform Hemangioendothelioma (KHE).|
- Change in hematologic parameters [ Time Frame: 2 months ]Hematologic parameters are defined as a platelet count greater than 50,000/uL (or a 2 times increase in platelet count compared to baseline) and a fibrinogen level greater than 100mg/dl.
- Number of Serious and Non-Serious Adverse Events [ Time Frame: 2 months; 12 months ]Serious and non-serious adverse events will be recorded for all participants and graded using CTCAE v4.0 (Common Toxicity Criteria for Adverse Effects). Adverse event rates will be calculated for both sirolimus and vincristine.
- Evaluation of Disease Response - Maintenance [ Time Frame: 6 months; 12 months ]Disease evaluation will be measured using a combination of quality of life assessments, clinical parameters, and radiologic images.
- Number of serious and non serious adverse events - Maintenance [ Time Frame: 6 months; 12 months ]Serious adverse events and adverse events will be graded according to CTCAE v4.0. Adverse event rates will be calculated for both sirolimus and vincristine.
- Change in the serum levels of KHE biomarkers [ Time Frame: Baseline, 2 months, 6 months, and 12 months ]The following KHE biomarkers will be evaluated vascular endothelial growth factor A, C, and D (VEGF-A, C, D_, IL-8 (interleukin), Pleiotrophin, IGF-1 (insulin-like growth factor), endothelin-1, thrombospondin and angiopoietin 1 and 2.
- Identify genetic variants in drug metabolism enzymes. [ Time Frame: Baseline ]Single nucleotide polymorphism array analysis to obtain genetic information on variants in drug metabolism enzymes that affect sirolimus and vincristine metabolism.
|Actual Study Start Date:||June 14, 2017|
|Estimated Study Completion Date:||December 2026|
|Estimated Primary Completion Date:||June 2021 (Final data collection date for primary outcome measure)|
Active Comparator: Vincristine
Induction phase: participants assigned to vincristine will receive vincristine weekly at a dose of 0.05mg/kd/dose IV (for participants less than 10kg) or a dose of 1.5 mg/m2/dose (for participants greater than 10kg).
Maintenance: if participants continue to receive vincristine weekly for 2 months, every 2 weeks for 5 months and every 3 weeks for 5 months.
Vincristine dose dependent upon weight. Weekly for 2 weeks (Induction); Weekly 2 months; every 2 weeks for next 5 months; every 3 weeks for 5 months (Maintenance)
Sirolimus will be administered at a dose of 0.8mg/m2/dose twice a day on a continuous dosing schedule throughout the trial for participants randomized to Sirolimus or for participants who fail vincristine may cross-over to the sirolimus arm.
Sirolimus trough levels will be maintained between 10-15 ng/ml.
Continuous dosing to maintain trough level of 10-15ng/ml.
Other Name: Rapamune
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. Presently, vincristine is considered the standard of practice. We have treated a subset of these patients on study SIR-DA-0901 (FDA Grant# 5RO1FD003712-01). This study is a phase II trial assessing the efficacy and safety of sirolimus for the treatment of complicated vascular anomalies. 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. 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.
Hypothesis: Sirolimus treatment for children and young adults with Kaposiform hemangioendotheliomas will be more effective than vincristine, assessed by time to response in an induction period and provide equivalent safety parameters.
Study Rationale We propose a multi-center, phase II trial with participation from 8 sites. 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 during maintenance and there will be cross over at any time for patients who lose their response following induction. Failure will be defined as worsening of hematological parameters on two separate laboratory evaluations at any time during maintenance or if they meet the definition of progressive disease following response assessments. 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 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.
Our secondary aims will be addressing biomarker analysis. There are limited studies describing the biology of these tumors. Per study SIR-DA-0901 there is some preliminary data indicating the importance of VEGF-C and other upregulated markers in the mTor pathway. This needs to be further investigated especially in KHE patients. Furthermore there are no clear objective measurements to determine response data.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02110069
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02110069
|Contact: Denise Adams, MDemail@example.com|
|Contact: Yvonne Sheldon, RN, BSNfirstname.lastname@example.org|
|United States, California|
|Lucille Packard Children's Hospital Stanford||Recruiting|
|Palo Alto, California, United States, 94304|
|Contact: Michael Jeng, MD 650-723-5535 email@example.com|
|United States, Georgia|
|Emory Children's Healthcare of Atlanta||Recruiting|
|Atlanta, Georgia, United States, 30322|
|Contact: Michael Briones, MD 401-785-1641 firstname.lastname@example.org|
|United States, Maryland|
|Baltimore, Maryland, United States, 21287|
|Contact: Clifford Takemoto 410-955-6132 email@example.com|
|United States, Massachusetts|
|Boston Children's Hospital||Recruiting|
|Boston, Massachusetts, United States, 02115|
|Contact: Denise Adams, MD 617-919-1761 firstname.lastname@example.org|
|Contact: Yvonne Sheldon, RN, BSN 617-919-6299 email@example.com|
|Principal Investigator: Denise Adams, MD|
|United States, Ohio|
|Cincinnati Children's Hospital Medical Center||Recruiting|
|Cincinnati, Ohio, United States, 45229|
|Contact: Adrienne M Hammill, MD, PhD 513-803-3184 firstname.lastname@example.org|
|United States, Texas|
|Texas Children's Hospital||Recruiting|
|Houston, Texas, United States, 77094|
|Contact: Ionela Iacobas, MD 832-824-4819 email@example.com|
|Principal Investigator:||Denise Adams, MD||Boston Children’s Hospital|