Neoplasms

All Conditions

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Blood and Lymph Conditions

Rare Diseases

Hemangioendothelioma

Sarcoma

Sarcoma, Kaposi

Syndrome

Kasabach-Merritt Syndrome

Hemangioma

Neoplasms, Vascular Tissue

Neoplasms by Histologic Type

Communicable Diseases

Herpesviridae Infections

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Neoplasms, Connective and Soft Tissue

Thrombocytopenia

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Kaposiform Hemangioendothelioma

Soft Tissue Sarcoma

Hemangioma Thrombocytopenia Syndrome

Anti-Infective Agents

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Sirolimus

Temsirolimus

MTOR Inhibitors

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Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Immunosuppressive Agents

Immunologic Factors

Sirolimus The plasma trough concentration of sirolimus is maintained within the range of 5-8 ng/ml by adjusting sirolimus dose, for 1 year.

Sirolimus The plasma trough concentration of sirolimus is maintained within the range of 10-15 ng/ml by adjusting sirolimus dose, for 1 year.

Yi Ji, MD, PhD

The purpose of this study is to compare the efficacy and safety of different concentration gradients of sirolimus in the treatment of Kaposiform hemangioendothelioma.

Kaposiform hemangioendothelioma (KHE) is a rare aggressive vascular neoplasm that occurs predominantly in infancy or early childhood, with an incidence of approximately 0.71/100,000. Currently, sirolimus is a promising treatment modality for KHE. Most scholars consider sirolimus blood concentration of 5-15 ng/ml to be an effective therapeutic concentration.

However, long-term higher dose sirolimus treatment can cause some common complications such as oral mucositis which affects the quality of life of the patient. Finer control of the plasma concentration of sirolimus may contribute to the efficacy of treatment and reduce the incidence of complications. Therefore, we conducted this study to see if low-dose sirolimus is beneficial to the prognosis of patients.

Efficacy and Safety of Different Concentrations of Sirolimus in the Treatment of Kaposiform Hemangioendothelioma.

Efficacy and Safety of High- vs Low-Dose Sirolimus in Patients With Kaposiform Hemangioendothelioma: A Trial Protocol

Objective response was defined as ≥20% reduction in KHE volume compared to that at baseline.

The primary endpoint was classified as follow:

* Complete involution: 100% resolution of the measured KHE;
* Nearly complete involution was defined as decrease of ≥75% and \<100%;
* Partial involution was defined as decrease of ≥20% and \<75%;
* No change was defined as \<20% increase and \<20% decrease in the volumes of KHE lesions;
* Further growth was defined as ≥20% increase in the volume of index KHE compared with the baseline volume measured. Lesion responses were overall lesion response rate and good lesion response rate.

Overall lesion response comprised complete, nearly complete and partial involutions.

Good lesion response comprised complete and nearly complete involutions.

Pediatric Quality of Life Inventory (PedsQLTM) 4.0 Genetic Core Infant Scales (\<2 years) or Pediatric Quality of Life Inventory (PedsQLTM) 4.0 Genetic Core Scales (2-18 years) were used.

Disease sequelae (e.g., chronic pain, lymphedema and decreased ROM) were assessed by site investigators at month 12. The site investigators assessed patients' extremity swelling (if any), general physical activity and exercise levels. The diagnosis of lymphedema was based on physical examination (e.g., Stemmer's sign) and lymphoscintigraphic findings.

Frequency of adverse events (e.g. gastrointestinal disorders, blood and lymphatic system disorders, metabolic disorders or other abnormal laboratory results, skin disorders and general disorders, etc.) collected by investigator and reported by parents. All adverse events were collected and graded according to Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0). The causality of the adverse event was determined by the multidisciplinary staff and was classified as definitively not related, probably not related, possibly related, probably related, or definitively related. Any dose reductions, interruptions, or cessations enacted at the discretion of the investigators were recorded.

West China Hospital

Clinical Professor

Diseases and Abnormalities at or Before Birth

Heart and Blood Diseases

Musculoskeletal Diseases

Nervous System Diseases

Congenital Abnormalities

Vascular Malformations

Nevus, Pigmented

Klippel-Trenaunay-Weber Syndrome

Nevus

Osteolysis

Osteolysis, Essential

Sturge-Weber Syndrome

Cardiovascular Abnormalities

Angiomatosis

Vascular Diseases

Bone Diseases

Bone Diseases, Developmental

Bone Resorption

Klippel-Trenaunay Syndrome

Parkes Weber Syndrome

Weber Syndrome

CLOVES Syndrome

Lymphangiomatosis

Kaposiform Lymphangiomatosis

Gorham's Disease

Endothelial Growth Factors

Mitogens

Timothy LeCras, PhD

Megan Metcalf

Adrienne Hammill, MD, PhD

The study will use blood (serum and plasma) and tissue obtained from participants undergoing prescribed surgical resection of vascular anomalies of interest proposed in this study. The study will also use blood (serum and plasma) and tissue collected and stored in a tissue bank maintained by the Department of Hematology/Oncology.

While vascular anomalies are rare diseases, they can be life-threatening and devastating to affected children and their families. Advances in diagnosis, monitoring and therapies will be significantly improved if non-invasive biomarkers that are sensitive and specific can be identified. Obtaining a tissue biopsy to help in diagnosis can actually worsen the disease and so identification of specific blood biomarkers is highly desirable. Studies will measure angiogenic factors in serum and plasma samples at baseline and on therapy. Tissue removed during surgical resection or blood removed prior to sclerotherapy will be used to obtain cells and tissue for the assessment of where biomarkers are coming from and to identify disease-causing pathways for new therapeutic targeting.

Identification of Biomarkers for Patients With Vascular Anomalies

Lymphangiomatosis and Gorham's Disease Alliance (LGDA)

Klippel Trenaunay (KT) Support Group

CLOVES Syndrome Community Support Group

Children's Hospital Medical Center, Cincinnati

Lymphangioma

Lymphatic Abnormalities

Lymphatic Diseases

Lymphatic Malformations

Microcystic Lymphatic Malformation

Tufted Angioma

Pharmaceutical Solutions

Central Nervous System Depressants

Other Dietary Supplements

Benzocaine

Protein Kinase Inhibitors

Enzyme Inhibitors

Tannic Acid

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.

Children's Hospital of Fudan University

After at least 2 years of remission of KHE, the participant receives sirolimus as usual. The serum concentration is supposed to be 5-7 ng/ml. If the effect or side effects of sirolimus require discontinuation, it is allowed to modify intervention, and if so, the patient stays in the maintenance group.

After at least 2 years of remission of KHE, the discontinuation measurement should be guided by the clinician with the following principles:

1. 10% monthly reduction of the previous dose at most.
2. At least 5 half-lives between each reduction (2 weeks).
3. Blood concentration should be monitored monthly. Adjustment can be suggested according to the linear relationship between the dose and the blood concentration.
4. At least 6 months for the duration of guided discontinuation.
5. Regular assessments and evaluations should be done.

If the condition relapses or worsens during this process, dose of sirolimus should be adjusted to the previously effective dose. After a 3-month stabilization phase, 5% monthly reduction of the previous dose could be considered.

After at least 2 years of remission of KHE, we compare guided discontinuation with maintenance treatment in pediatric patients with KHE.

This randomized controlled trial aims to compare guided discontinuation with maintenance treatment of sirolimus in pediatric patients with KHE.

Kaposiform Hemangioendothelioma (KHE) is a rare vascular tumor that occurs in infants and children. KHE is characterized by sheets of spindle cells with an infiltrative pattern in the dermis, subcutaneous fat, and muscle. It is locally aggressive and can cause Kasabach-Merritt phenomenon, a serious life-threatening coagulopathy characterized by profound thrombocytopenia and hypofibrinogenemia. Sirolimus, one of the mTOR inhibitors, has become a new and very effective treatment, which is especially reliable for KHE with KMP and has acceptable side effects. However, there is yet no strong evidence on the best practice of treatment length of sirolimus. This randomized controlled trial aims to compare guided discontinuation with maintenance treatment in pediatric patients with KHE in order to provide a basis for the optimal treatment duration of sirolimus, as well as the clinical characteristics of pediatric patients who can safely reduce the dose till withdrawal.

Only the outcome assessors are blinded, neither clinicians nor patients, because they should be attentive of the risk of relapse in the discontinuation group. Also, it seems unethical if researchers were not to discover the group of patients in the maintenance group who can discontinue sirolimus without relapsing. Clinicians should be given the possibility to adjust dose and ensure the benefits of patients. Therefore, this trial only includes assessors blinding.

Guided Discontinuation Versus Maintenance Treatment of Sirolimus in Pediatric Patients With Kaposiform Hemangioendothelioma

Guided Discontinuation Versus Maintenance Treatment of Sirolimus in Pediatric Patients With Kaposiform Hemangioendothelioma: a Randomized Controlled Trial

This outcome is a binary variable. The primary outcome measure will be analyzed with binary logistic regression to estimate the odds ratio between the two groups.

At two or three years' follow-up, the participant may be on remission, but still taking sirolimus. The condition is a binary variable and the dose of sirolimus is a continuous variable.

At two or three years' follow-up, the participant may suffer from relapse of KHE and still takes sirolimus. The period of time to the relapse will be recorded as a time variable, and the cox regression survival analysis model will be used.The dose of sirolimus is a continuous variable. Whether this variable is normally distributed will be checked.

The primary outcome is a binary variable. The primary outcome measure will be analyzed with binary logistic regression to estimate the odds ratio between the two groups.

At one year's follow-up, the participant may be on remission, but still taking sirolimus. The condition is a binary variable and the dose of sirolimus is a continuous variable.

At one year's follow-up, the participant may suffer from relapse of KHE and still takes sirolimus. The period of time to the first relapse will be recorded as a time variable, and the cox regression survival analysis model will be used.The dose of sirolimus is a continuous variable. Whether this variable is normally distributed will be checked.

The outcome 4 will be described. 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. The blood concentration of sirolimus will be adjusted accordingly.

Platelet count is one of the major indicators of response to treatment and will be used in a prognosis model to predict the clinical characteristics of patients with benefits. It is supposed to be greater than 100×10\^9/L.

Fibrinogen level will be used in a prognosis model to predict the clinical characteristics of patients with benefits. It is supposed to be at 2-4g/L.

Tumor volume will be used in a prognosis model to predict the clinical characteristics of patients with benefits. The size of the tumor is supposed to shrink according to imaging evaluation. The tumor is supposed to be softer by palpation.

Complaints are subjective feelings. Whether there is pain, swelling, lameness or skin color change will be recorded as binary variables and used in a prognosis model to predict the clinical characteristics of patients with benefits.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Efficacy and Safety of Different Concentrations of Sirolimus in the Treatment of Kaposiform Hemangioendothelioma.	NCT04775173	Kaposiform Hema...	Sirolimus	1 Day - 14 Years	West China Hospital
Identification of Biomarkers for Patients With Vascular Anomalies	NCT03001180	Vascular Anomal... Generalized Lym... Kaposiform Hema... Kaposiform Lymp... Gorham-Stout Di... Klippel Trenaun... Congenital Lipo...		1 Day -	Children's Hospital Medical Center, Cincinnati
Efficacy and Safety of Different Concentrations of Sirolimus in the Treatment of Kaposiform Hemangioendothelioma.	NCT04775173	Kaposiform Hema...	Sirolimus	1 Day - 14 Years	West China Hospital
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
Guided Discontinuation Versus Maintenance Treatment of Sirolimus in Pediatric Patients With Kaposiform Hemangioendothelioma	NCT04448873	Kaposiform Hema... Kasabach-Merrit...	Sirolimus	- 12 Years	Children's Hospital of Fudan University
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
Identification of Biomarkers for Patients With Vascular Anomalies	NCT03001180	Vascular Anomal... Generalized Lym... Kaposiform Hema... Kaposiform Lymp... Gorham-Stout Di... Klippel Trenaun... Congenital Lipo...		1 Day -	Children's Hospital Medical Center, Cincinnati

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