Diseases and Abnormalities at or Before Birth

All Conditions

Heart and Blood Diseases

Neoplasms

Skin and Connective Tissue Diseases

Congenital Abnormalities

Vascular Malformations

Hemangioma

Hemangioma, Capillary

Port-Wine Stain

Neoplasms, Vascular Tissue

Neoplasms by Histologic Type

Cardiovascular Abnormalities

DNA will be extracted from cheek cell or blood samples from parents and child having hemangioma.

Cheek cell samples or blood sample (4mL)

DNA will be extracted from cheek cell or blood samples of parents and child with a vascular anomaly.

Cheek cell sample or blood sample (4mL)

Beth Drolet, MD

The purpose of this study is to determine if there are genes that are common in children with infantile hemangioma. This information will allow physicians to improve care for patients who have been diagnosed with this disease and to provide their parents with more complete information regarding the cause of this disease. This research is being done because many unanswered questions remain regarding children with infantile hemangioma. There are very few medications to treat infants with hemangiomas.

WHAT IS INVOLVED IN THE RESEARCH STUDY?

* Buccal smear (cheek cells) or small blood sample (4 mL or 1 teaspoon) from child being seen in the Dermatology clinic having infantile hemangioma or vascular anomaly
* Buccal smear (cheek cells) or small blood sample (4 mL or 1 teaspoon) from parents of child

If you and your child agree to be in this study, the following will happen:

1. Informed consent and permission to use or disclose your/your child's health information for research purposes will be obtained by Dr. Drolet, the principal investigator, or her research team. You will receive a copy of this consent form.
2. A buccal swab or blood sample will be obtained from you and your child; buccal sampling involves rubbing the inside of your cheek and removing cells to perform a genetic test called "Genomewide Association (GWA).

We expect you and your child to be involved in this study until you and your child have the genetic testing performed.

Buccal smear (cheek cells)or small blood sample (4 mL or one teaspoon)

Genetic Basis of Hemangiomas

Children's Hospital and Health System Foundation, Wisconsin

Medical College of Wisconsin

Professor and Vice Chairman of Pediatric Dermatology

Blood and Lymph Conditions

Rare Diseases

Arteriovenous Malformations

Lymphangioma

Lymphatic Abnormalities

Skin Diseases

Skin Diseases, Vascular

Vascular Diseases

Lymphatic Diseases

Lymphatic Malformations

PIK3CA-related Overgrowth Spectrum

Cystic Hygroma

Dermatologic Agents

All Drugs and Chemicals

Gastrointestinal Agents

Coal Tar

Lactitol

Slow-flow vascular malformations with identified causative variants in the phosphoinositide 3-kinase (PI3K) signalling pathway will receive alpelisib (provided by Novartis Pharmaceuticals), an oral alpha-specific PI3-kinase inhibitor for a total duration of 48 weeks as monotherapy, followed by 24 weeks of follow-up.

Fast-flow vascular malformations with identified causative variants in the RAS-MEK-ERK signalling pathway will receive mirdametinib (provided by SpringWorks Therapeutics, Inc.), an investigational oral MEK inhibitor for a total duration of 48 weeks as monotherapy, followed by 24 weeks of follow-up.

Alpelisib

Mirdametinib

Michelle de Silva, PhD

Tony Penington, MBBS, FRACS

Stephen Luen, MBChB, FRACP

Anthony Penington, MBBS, FRACS, MD(res), Grad Dip

Michelle de Silva, BSc(Hons), PhD, MGenCouns

Tony Penington, MBBS, FRACS.

Stephen Luen, MBChB, FRACP.

Lydia Pathmanathan, MBBS, FRACP.

Recent studies have demonstrated that growth of vascular malformations can be driven by genetic variants in one of 2 signalling pathways. Targeted drugs specific to these pathways have been developed and shown to be effective in treating cancer. This study will describe the effectiveness of (i) 48 weeks of alpelisib therapy for participants with slow-flow vascular malformations and a gene mutation in one of these signalling pathways (module 1) and (ii) 48 weeks of mirdametinib therapy for participants with fast-flow vascular malformations and a gene mutations in the other signalling pathway (module 2).

TARGET-VM is a modular open-label, signal seeking, phase II trial of targeted therapies for patients with vascular malformations. Patients with vascular malformations which are refractory to standard therapies, or in whom standard therapy is not appropriate, are potentially eligible for the clinical trial. Vascular malformations will be classified as slow-flow or fast-flow lesions using established clinical criteria. Genetic testing to identify causative variants in genes affecting the phosphoinositide 3-kinase (PI3K) signalling pathway for slow-flow vascular malformations or the Mitogen-Activated Protein Kinase (MAPK) signalling pathway for fast-flow vascular malformations must be performed using research protocols or commercial testing assays that are external to this clinical trial.

The study consists of individual modules, each evaluating the clinical efficacy of 48 weeks of targeted therapy. The treatment modules are:

1. Module 1 - Treatment for slow-flow vascular malformations Eligible patients with slow-flow vascular malformations with an identified causative variant in the PI3K signalling pathway will receive alpelisib, an oral alpha-specific PI3-kinase inhibitor for a total duration of 48 weeks as monotherapy (treatment period), followed by 24 weeks of follow-up (follow-up period).
2. Module 2 - Treatment for fast-flow vascular malformations Eligible patients with fast-flow vascular malformations with an identified causative variant in the MAPK signalling pathway will receive mirdametinib, an investigational oral MEK inhibitor for a total duration of 48 weeks as monotherapy (treatment period), followed by 24 weeks of follow-up (follow-up period).

TARGET-VM will be conducted only in Victoria, Australia.

i) Participants with slow-flow vascular malformations with an eligible gene mutation will receive 48 weeks of treatment with open-label alpelisib.

ii) Participants with fast-flow vascular malformations with an eligible gene mutation will receive 48 weeks of treatment with open-label mirdametinib

A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations

A Modular Open Label, Signal Seeking, Phase II Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations (TARGET-VM)

From 6 months post analysis and article publication, the following will be made available long-term for use by future researchers from a recognised research institution whose proposed use of the data has been ethically reviewed and approved by an independent committee and who accept The Murdoch Children's Research Institute's (MCRI) conditions for access:

* Individual participant data that underlie the results reported in this article after de-identification
* Trial protocol, Statistical Analysis Plan, PICF The Sponsor-Investigator will be the long-term custodian after the archive period has finished.

Vascular malformations present with a range of different symptoms. Therefore, there is no single outcome measure that can capture the effectiveness of a systemic treatment across different patients. Thus for this study, an individualised primary outcome for each patient informed by their symptoms will be used, termed the Vascular Malformation Patient Specific Outcome Measure (VM-PSOM). The study "Outcome Committee" will define an individualised primary outcome for each patient informed by their symptoms and vascular malformation features prior to starting trial treatments. The VM-PSOM endpoint will therefore define a binary outcome for each patients (achieved or failed to reach the threshold improvement in the chosen measure).

VM-PSOM response at the 168 day follow-up visit assessment compared with the 48 week (end-of-treatment) VM-PSOM.

Objective response rate by volumetric MRI assessment comparing 48 week (end-of-treatment) MRI with baseline MRI. MRI scan will only be performed in patients where their vascular malformation is feasibly evaluable by MRI scan. Objective response is defined as ≥ 20% reduction from index date in the sum of measurable target lesion volume by volumetric analysis on MRI.

The mean scores in the OVAMA (Outcome measures for VAscular MAlformations) questionnaire will be calculated and analysed at specified time points. This is a set of questions developed specifically to measure symptom burden from vascular malformations. These questions are open-ended to allow the subject to describe how they feel. The questions are more tightly structured to allow comparison of answers to other people with vascular malformations. The questions have been designed in a way to determine if symptoms are getting better over time.

The mean scores in the OVAMA (Outcome measures for VAscular MAlformations) questionnaire will be calculated and analysed at specified time points.

Peter MacCallum Cancer Centre, Australia

Royal Children's Hospital

Murdoch Childrens Research Institute

Symptoms and General Pathology

Infections

Syndrome

Hemangioendothelioma

Kasabach-Merritt Syndrome

Vascular Neoplasms

Sarcoma

Sarcoma, Kaposi

Communicable Diseases

Herpesviridae Infections

Virus Diseases

DNA Virus Infections

Neoplasms, Connective and Soft Tissue

Thrombocytopenia

Blood Platelet Disorders

Hematologic Diseases

Cytopenia

Kaposiform Hemangioendothelioma

Tufted Angioma

Hemangioma Thrombocytopenia Syndrome

Soft Tissue Sarcoma

Antineoplastic Agents

Anti-Infective Agents

Central Nervous System Depressants

Other Dietary Supplements

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

Musculoskeletal Diseases

Nervous System Diseases

Nevus, Pigmented

Klippel-Trenaunay-Weber Syndrome

Nevus

Osteolysis

Osteolysis, Essential

Sturge-Weber Syndrome

Angiomatosis

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

Ulcer

Skin Abnormalities

Pharmaceutical Solutions

Anti-Arrhythmia Agents

Antihypertensive Agents

Adrenergic beta-Antagonists

Timolol

Mupirocin

Adrenergic Agents

Adrenergic Antagonists

Neurotransmitter Agents

Enzyme Inhibitors

Half of enrolled subjects will receive topical Timolol

Half of enrolled subjects will receive Mupirocin

Dose-based escalation schedule for topical application:

4-8 kg: Day 0-7: 1 drop every other day; Day 7-14: 1 drop daily; Day 14 - Day 60: 1 drop twice per day

8-12 kg: Day 07: 1 drop daily; Day 7-14: 1 drop twice per day; Day 14 - Day 60: 2 drops twice per day

Timolol 0.5% Gel Forming Solution (GFS)

Topical application twice per day for 60 days

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Genetic Basis of Hemangiomas	NCT00466375	Hemangioma, Vas...	Cheek cell samp... Cheek cell samp...	-	Medical College of Wisconsin
A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations	NCT05983159	Slow-Flow Vascu... Fast-Flow Vascu... Vascular Malfor... Venous Malforma... Lymphatic Malfo... Lymphatic Malfo... Lymphangioma Arteriovenous M... Venous Malforma... Cystic Hygroma Vascular Anomal... Vascular Anomal... PI3K Gene Mutat... MAP2K1 Gene Mut... PIK3CA-related ... Arteriovenous M... KRAS G12C KRAS G12D	Alpelisib Mirdametinib	2 Years -	Murdoch Childrens Research Institute
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
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
A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations	NCT05983159	Slow-Flow Vascu... Fast-Flow Vascu... Vascular Malfor... Venous Malforma... Lymphatic Malfo... Lymphatic Malfo... Lymphangioma Arteriovenous M... Venous Malforma... Cystic Hygroma Vascular Anomal... Vascular Anomal... PI3K Gene Mutat... MAP2K1 Gene Mut... PIK3CA-related ... Arteriovenous M... KRAS G12C KRAS G12D	Alpelisib Mirdametinib	2 Years -	Murdoch Childrens Research Institute
Timolol Option for Ulcerated Hemangiomas (TOUCH Trial)	NCT01408056	Infantile Heman...	Timolol 0.5% Ge... Mupirocin 2% Oi...	1 Month - 8 Months	Children's Hospital of Philadelphia
Genetic Basis of Hemangiomas	NCT00466375	Hemangioma, Vas...	Cheek cell samp... Cheek cell samp...	-	Medical College of Wisconsin
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

Spots Global Cancer Trial Database for vascular anomaly