Symptoms and General Pathology

All Conditions

Diseases and Abnormalities at or Before Birth

Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Infections

Rare Diseases

Syndrome

Congenital Abnormalities

Hemangioendothelioma

Vascular Malformations

Hemangioma

Kasabach-Merritt Syndrome

Neoplasms, Vascular Tissue

Vascular Neoplasms

Sarcoma

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Neoplasms by Histologic Type

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Thrombocytopenia

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Kaposiform Hemangioendothelioma

Tufted Angioma

Hemangioma Thrombocytopenia Syndrome

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Antineoplastic Agents

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Vincristine

Sirolimus

Benzocaine

Temsirolimus

MTOR Inhibitors

Tubulin Modulators

Antimitotic Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Immunosuppressive Agents

Immunologic Factors

Tannic Acid

Induction phase: participants assigned to vincristine will receive vincristine weekly at a dose of 0.05mg/kg/dose IV (for participants less than 10kg) or a dose of 1.5 mg/m2/dose (for participants greater than 10kg) for 2 months.

Maintenance: if participants continue to receive vincristine weekly for 2 months, every 2 weeks for 5 months and every 3 weeks for 5 months.

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.

Vincristine dose dependent upon weight. Weekly for 2 months (Induction); Weekly 2 months; every 2 weeks for next 5 months; every 3 weeks for 5 months (Maintenance)

Continuous dosing to maintain trough level of 10-15ng/ml.

Denise Adams, MD

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 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.

A Study to Compare Vincristine to Sirolimus for Treatment of High Risk Vascular Tumors

A Randomized Phase 2 Study of Vincristine Versus Sirolimus to Treat High Risk Kaposiform Hemangioendothelioma (KHE).

Hematologic parameters are defined as a platelet count greater than 100,000/uL (or a 2 times increase in platelet count compared to baseline) and a fibrinogen level greater than 150mg/dl.

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.

Disease evaluation will be measured using a combination of quality of life assessments, clinical parameters, and radiologic images.

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.

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.

Single nucleotide polymorphism array analysis to obtain genetic information on variants in drug metabolism enzymes that affect sirolimus and vincristine metabolism.

Pfizer

Boston Children's Hospital

Associate Professor

Induction phase: participants assigned to vincristine will receive vincristine weekly at a dose of 0.05mg/kg/dose IV (for participants less than 10kg) or a dose of 1.5 mg/m2/dose (for participants greater than 10kg) for 2 months.

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: Vincristine dose dependent upon weight. Weekly for 2 months (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.

Sirolimus: Continuous dosing to maintain trough level of 10-15ng/ml.

Total

Age, Categorical

There was no analysis as study was closed early

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Number of participants with platelet count & fibrinogen levels

no analysis was performed as study was closed early

Dr. Denise M. Adans

no analysis was performed due to study being closed for low enrollment

Change in Hematologic Parameters

study was closed early due to slow enrollment

Number of Serious and Non-Serious Adverse Events

Evaluation of Disease Response - Maintenance

no data analyzed as study was closed early

Number of Serious and Non Serious Adverse Events - Maintenance

no analysis performed as study was closed early

Change in the Serum Levels of KHE Biomarkers

study closed early due to slow enrollment

Identify Genetic Variants in Drug Metabolism Enzymes.

Overall Study

Lymphangioma

Lymphatic Abnormalities

Lymphangiectasis

Lymphatic Diseases

Cardiovascular Abnormalities

Lymphatic Malformations

Microcystic Lymphatic Malformation

Lymphangiomatosis

sirolimus

Denise M Adams, MD

The purpose of this study is to determine if the use of sirolimus in the treatment of children and young adults with complicated vascular anomalies will prove to be safe and provide objective response resulting in improved clinical status and quality of life.

Funding Source - FDA OOPD (Food and Drug Administration - Office of Orphan Products Development)

Patients with vascular anomalies (VA) have a spectrum of diseases that can be broadly classified into vascular tumors and malformations. Complicated vascular anomalies can cause disfigurement, chronic pain, and organ dysfunction with significant morbidity and mortality. Despite the severity of potential complications, we lack uniform guidelines for the treatment and response to treatment of children and young adults with these diseases. There are pre-clinical and clinical data supporting the essential regulatory function of the PI3K/Akt/mTOR pathway in vascular growth and organization, and suggest a therapeutic target for patients with complicated vascular anomalies. The overall goal of this trial is to objectively determine the effectiveness and safety of the mTOR inhibitor Rapamycin\* in the treatment of children and young adults diagnosed with complicated vascular anomalies. We propose a Phase 2 trial with the diagnostic, therapeutic and response criteria experimentally determined in this study used as a framework for future Phase 3 clinical trials.

Safety and Efficacy Study of Sirolimus in Complicated Vascular Anomalies

A Phase 2 Study - Clinical Trial Assessing Efficacy and Safety of the mTOR Inhibitor Sirolimus in the Treatment of Complicated Vascular Anomalies

Children's Hospital Medical Center, Cincinnati

Pharmaceutical Solutions

Protein Kinase Inhibitors

Enzyme Inhibitors

Drop 5 ml of sirolimus oral solution and 5 g of dressing into the mixed bottle. Apply mixed gel of topical sirolimus to affected area. Use it twice a day for 6 months.

Oral dose of sirolimus is calculated according to body surface area. Take it twice a day for 6 months. Maintain the blood concentration of sirolimus at 5-15ng/ml.

We compare topical and oral use of sirolimus in the treatment of superficial complicted vascular anomalies. In experimental group, we administrate percutaneous sirolimus. Drop 5 ml of sirolimus oral solution and 5 g of dressing into the mixed bottle. Apply mixed gel of topical sirolimus to affected area. Use it twice a day for 6 months.

Percutaneous sirolimus

We compare topical and oral use of sirolimus in the treatment of superficial complicted vascular anomalies. In active comparator group, we administrate oral sirolimus. Oral dose of sirolimus is calculated according to body surface area. Take it twice a day for 6 months. Maintain the blood concentration of sirolimus at 5-15ng/ml.

Oral sirolimus

Kai Li, MD, PhD

Weili Yan, MD,PhD

Ying Gong, MD,PhD

Wei Yao, MD, PhD

Zuopeng Wang, MD,PhD

Yingjing Ding, MD

Hanlei Yan, MD

In this study, we investigate the safety and efficacy of topical sirolimus in the treatment of superficial complicated vascular anomolies.

Vascular anomaly is a kind of rare disease. According to histology, biological behavior and clinical manifestations, it can be divided into two categories: vascular tumor and vascular malformation.

mTOR inhibitors are proved with the properties of anti-proliferation and anti-angiogenesis. Therefore, they have been used in the treatment of vascular anomalies. Sirolimus, by its ability to prevent downstream protein synthesis and subsequent cell proliferation and angiogenesis, has become a novel and effective treatment. However, after the children reach complete response, there may still be skin manifestations that affect the appearance and cause psychological shadows. Therefore, intervention is required.

Studies have reported that topical sirolimus is effective in treating Kaposiform Hemangioendothelioma (KHE). It is absorbed through the skin, avoiding the first pass elimination effect of the liver. Fewer adverse reactions have been observed. In this study, we investigate the efficacy and safety of percutaneous administration of sirolimus in the treatment of superficial complicated vascular anomalies.

Percutaneous Administration of Sirolimus in the Treatment of Superficial Complicated Vascular Anomalies

Percutaneous Administration of Sirolimus in the Treatment of Superficial Complicated Vascular Anomalies: a Randomized Controlled Trial

Achauer BM et al. made the four-level standard as follows. Grade I: tumor size and skin lesion color regression ≤ 25%; grade II: tumor size and skin lesion color regression 25%-50%; grade III: tumor size and skin lesion color regression 50-75%; grade IV: tumor size and skin lesion color regression ≥75%. After 6 months of treatment, the pzrticipant will be evaluated. Grade I will be viewed as invalid. Grade II and grade III will be viewed as effective, and grade IV will be viewed as very effective. Those in grade Ⅱ, Ⅲ or Ⅳ will be calculated in effectiveness rate.

Measured by ultrosonic doppler flowmetery at follow-up

Adverse events will be reported according to Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE v4.0). Incidence of complications such as oral ulcers, abnormal liver enzymes, infections will be recorded. It is defined as occurring if individual subject has any of the above complications during the 6-month intervention

Platelet count is one of the major indicators of response to treatment. It is supposed to be greater than 100×10\^9/L.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study to Compare Vincristine to Sirolimus for Treatment of High Risk Vascular Tumors	NCT02110069	Kaposiform Hema... Kasabach-Merrit... Tufted Angioma	Vincristine Sirolimus	- 31 Years	Boston Children's Hospital
Safety and Efficacy Study of Sirolimus in Complicated Vascular Anomalies	NCT00975819	Kaposiform Hema... Tufted Angioma Capillary Venou... Venous Lymphati... Microcystic Lym... Mucocutaneous L... Capillary Lymph... PTEN Overgrowth... Lymphangiectasi...	sirolimus	- 31 Years	Children's Hospital Medical Center, Cincinnati
Percutaneous Administration of Sirolimus in the Treatment of Superficial Complicated Vascular Anomalies	NCT04921722	Kaposiform Hema... Tufted Angioma Superficial Vas... Superficial Lym...	Percutaneous si... Oral sirolimus	0 Years - 18 Years	Children's Hospital of Fudan University
Safety and Efficacy Study of Sirolimus in Complicated Vascular Anomalies	NCT00975819	Kaposiform Hema... Tufted Angioma Capillary Venou... Venous Lymphati... Microcystic Lym... Mucocutaneous L... Capillary Lymph... PTEN Overgrowth... Lymphangiectasi...	sirolimus	- 31 Years	Children's Hospital Medical Center, Cincinnati
Percutaneous Administration of Sirolimus in the Treatment of Superficial Complicated Vascular Anomalies	NCT04921722	Kaposiform Hema... Tufted Angioma Superficial Vas... Superficial Lym...	Percutaneous si... Oral sirolimus	0 Years - 18 Years	Children's Hospital of Fudan University

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