Diseases and Abnormalities at or Before Birth

All Conditions

Neoplasms

Blood and Lymph Conditions

Rare Diseases

Congenital Abnormalities

Lymphangioma

Lymphatic Abnormalities

Neoplasms by Histologic Type

Lymphatic Diseases

Lymphatic Malformations

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Sirolimus

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Immunosuppressive Agents

Immunologic Factors

Participants will get Sirolimus (1.5-2 2mg/m2) weekly for 6 months.

Stephnie Munie, BS

Stephanie Munie, BS

Chelsea Shope, MSCR

In current practice, options for venous and lymphatic malformations remain limited. Recently an oral medication, sirolimus, has been found to benefit patients when taken once or twice a day for several months. Unfortunately there are many side effects associated with this medication, some of which can be severe including, neutropenia, oral ulcerations, and lab abnormalities. The purpose of this study is to determine if once weekly dosed sirolimus will be effective for the treatment of venous and lymphatic malformations. Additionally, the study will evaluate patient satisfaction and identify adverse effects. Participants will be on the medication for 6 months with an option to continue after this time period.

Weekly Sirolimus Therapy

Weekly Sirolimus Therapy for the Treatment of Venous and Lymphatic Malformations

Will be measuring the size of the lesions (mm) at each patient visit

Will be evaluating clinical photographs of lesions at each patient visit

Patient will complete side effect questionnaires at each visit

Patient will complete quality of life questionnaire at each visit

Standard of care laboratory results (CBC, CMP, triglycerides) will be monitored

Medical University of South Carolina

Principal Investigator

Heart and Blood Diseases

Skin and Connective Tissue Diseases

Arteriovenous Malformations

Skin Diseases

Vascular Malformations

Skin Diseases, Vascular

Hemangioma

Cardiovascular Abnormalities

Vascular Diseases

Neoplasms, Vascular Tissue

PIK3CA-related Overgrowth Spectrum

Cystic Hygroma

Dermatologic Agents

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

VT30 is a PI3K-inhibitor prodrug, formulated as a topical gel and dispensed from a metered dose pump; administration is once or twice daily, applied to target-treatment area(s) on the skin. One pump action dispenses 250 µL of gel, intended to treat an area of 140 cm2.

VT30 gel is intended as a topical treatment of cutaneous VMs, LMs, or VLMs that driven by inappropriate PI3K activation. In the skin, VT30 is rapidly metabolized to VT10, an active drug form, and is intended to sufficiently permeate the stratum corneum and achieve target engagement. It is expected that VT30 will lead to amelioration of the signs and symptoms of cutaneous VMs, LMs and/or VLMs.

VT30

Michael Henderson

VT30-101 is a 2-part first-in-human trial of topically administered VT30 to subjects with cutaneous venous malformations, lymphatic malformations, or mixed venolymphatic malformations associated with PIK3CA or TEK mutations.

Part 1 is a 4-week treatment, open-label, 4-sequence, escalating repeat-application cohort study, with intra-subject and inter-cohort dose escalation.

Part 2 is a 12-week treatment, randomized, placebo-controlled, double-blind, safety and exploratory efficacy study. Part 2 will be initiated only after the successful completion of Part 1 with results that demonstrate the general safety and tolerability of topically applied VT30. Up to 12 subjects who complete Part 1 may be enrolled into Part 2 of the study.

The primary objective is to evaluate the safety and tolerability of VT30. The study will also determine the dose and regimen of VT30 to be carried into Part 2 of the protocol. Other aims include documenting plasma drug levels of VT30 and VT10 and, on an exploratory basis, examining pharmacologic target engagement and change in potential efficacy readouts.

VT30-101 is designed as a Phase 1/2, first-in-human study of topically administered VT30 to subjects with cutaneous venous malformations (VMs), lymphatic malformations (LMs), or mixed venolymphatic malformations (VLMs) associated with phosphatidylinositol 3-kinase catalytic alpha polypeptide (PIK3CA) or tyrosine receptor kinase (TEK) mutations. Capillary involvement and/or extension of the lesion into subcutaneous tissues is permitted.

The study will occur in 2 parts, and in both study parts, subjects will participate in a Screening Period (up to 6 weeks) before beginning the indicated Treatment Period.

Part 1 will be an open-label, 4-sequence, escalating repeat-application study comprised of up to 4 cohorts (3 subjects per cohort, with 3 up to 6 in Cohort 4, or the final Part 1 cohort). In each cohort, subjects will be given topical VT30 for a 4-week Treatment Period. Subjects will begin treatment with the designated dose on Day 1. After 2 weeks, the Investigator will examine the treated surface area and determine if the formulation is tolerated such that the subject may apply the next dose strength of VT30 gel for the remaining duration of the Treatment Period.

Specifically, the following gel dose strengths (concentrations) are planned for Cohorts 1 through 3 in Part 1:

* Cohort 1: initiate dosing with 0.12% (w/w) gel and progress to 0.6% (w/w) gel for the final 2 weeks of the Part 1 Treatment Period (if the lower dose is tolerated)
* Cohort 2: initiate dosing with 0.6% (w/w) gel and progress to 1.2% (w/w) gel for the final 2 weeks of the Part 1 Treatment Period (if the lower dose is tolerated)
* Cohort 3: initiate dosing with 1.2% (w/w) gel and progress to 2.3% (w/w) gel for the final 2 weeks of the Part 1 Treatment Period (if the lower dose is tolerated)

A Safety Review Committee (SRC), with sponsor, investigator and independent medical representation, will provide oversight and guidance for study conduct. After 3 subjects have been dosed for at least 21 days in any of the first three Part 1 cohorts, the SRC may request additional data, approve initiation of the subsequent cohort, or mandate that additional subjects to be enrolled at either the higher or lower dose within the cohort.

After 9 subjects in Cohorts 1 through 3 (3 subjects per cohort) have completed the 4-week Treatment Period, the SRC will determine if additional subjects should be assigned to Cohort 4 (or the final Part 1 cohort) to receive the MTD (maximum tolerated dose) or MFD (maximum feasible dose) strength of VT30. Subjects in Cohort 4 will receive the designated dose strength and regimen of VT30 for a full 4 weeks.

Following the completion of Cohort 4 in Part 1, the SRC will determine whether to authorize initiation of Part 2 and will confirm the dose level and regimen to be administered in Part 2.

Part 2 will be a randomized, placebo-controlled, double-blind study containing 36 subjects assigned in a 2:1 ratio to receive either VT30 or placebo. Up to 12 subjects who complete Part 1 may enroll in Part 2, provided they meet all Part 2-specific inclusion criteria with no applicable exclusions.

After the first 12 subjects in Part 2 have completed 4 weeks of treatment, the SRC will conduct a review of blinded safety data to confirm no revisions or changes are needed to the protocol. Subsequent reviews may also be conducted to ensure continued acceptable safety and tolerability.

After subjects complete their designated Treatment Period (in Part 1 or Part 2), they will participate in a 4-week post treatment Follow-up Period.

Part 1: Open-label, 4-sequence, escalating repeat-application cohort study, with intra-subject and inter-cohort dose escalation to determine safety and tolerability, and maximum feasible dose/maximum tolerable dose Part 2: Randomized, placebo-controlled, double-blind, safety and exploratory efficacy study

First in Human Trial of Topical VT30 in Pts With Venous/Lymphatic Malformations Assoc With PIK3CA or TEK Gene Mutations

Open-Label, Intra Subject, Dose Escalation (Part 1) Followed by Randomized, Double Blind, Placebo Controlled (Part 2) Trial of Topical VT30 in Pts With Venous, Lymphatic or Mixed Malformations Associated With PIK3CA or TEK Genetic Mutations

As assessed by treated lesion tissue levels of phosphoproteins, as an indicator of local target engagement

Assessed by subjects' self-reporting their pain, related to the treated lesion, on a Numerical Rating Scale

Assessed by change in appearance of the treated lesion

Assessed by subject-reported difficulty managing bleeding, oozing, or discharge from the treated lesion

Composite of adverse events and changes in physical exam findings, vital signs, lab tests, and electrocardiogram evaluations

The MTD or MFD strength will be determined based on results from Part 1, and will inform the dose strength to be used in Part 2

Plasma levels of VT30 and VT10 will be assessed following topical administration of VT30 to determine level of systemic exposure

Venthera, Inc., a BridgeBio company

Symptoms and General Pathology

Digestive System Diseases

Syndrome

Blister

Nevus, Pigmented

Nevus

Gastrointestinal Neoplasms

Digestive System Neoplasms

Skin Neoplasms

Nevus, Blue

Melanoma

Nevi and Melanomas

Gastrointestinal Diseases

Blue Rubber Bleb Nevus Syndrome

Temsirolimus

MTOR Inhibitors

For children: rapamycin, 1 mg per square meter of body surface area a day, orally, for at least 6 months For adults: rapamycin, 2 mg a day, orally, for at least 6 months

Rapamycin

Jiaolin Zhou, MD

A prospective, nonrandomized, open-label, single-arm clinical trial to study efficacy of rapamycin (sirolimus) in the treatment of Blue Rubber Bleb Nevus Syndrome, hereditary or sporadic venous malformation

Blue rubber bleb nevus syndrome (BRBNS) and venous malformation are mainly caused by somatic mutation of TEK and PIK3CA, which activates the PI3K/AKT signaling pathway. As an important protein kinase downstream of the PI3K/AKT pathway, mTOR can serve as a potential therapeutic target for BRBNS. Experiments of mice have shown that rapamycin inhibited the progression of venous malformation lesions. There are a few human cases reported using rapamycin treatment. The investigator's study is designed to be a prospective, nonrandomized, open-label, single-arm clinical trial to investigate its efficacy and safety.

Efficacy of Rapamycin (Sirolimus) in the Treatment of BRBNS, Hereditary or Sporadic Venous Malformation

Efficacy of Rapamycin (Sirolimus) in the Treatment of Blue Rubber Bleb Nevus Syndrome, Hereditary or Sporadic Venous Malformation

lesion load (cm2) = A + B + C. A = sum of the product of maximum diameter and maximum height of the largest 3 lesions shown by chest, abdomen and pelvis MRI or small bowel CT reconstruction (in cm2) B = sum of the product of maximum diameter and maximum height of the largest 3 lesions shown by digestive endoscope (in cm2) C = sum of the product of maximum diameter and maximum height of the largest 3 lesions shown by ultrasound (in cm2) Remarks: 1. If it is impossible to evaluate 3 or more lesions, results of the actual number of lesions should be taken as valid; 2. Lesions evaluated should be correspondent before and after treatment. If the lesion is difficult to assess after treatment, it should be ruled out from the assessment.

The value indicates the amount of gastrointestinal bleeding.

The value indicates the amount of gastrointestinal bleeding

The value indicates the extent of local coagulation caused by Venous Malformation lesions.

Air Force General Hospital of the PLA

Chinese Academy of Medical Sciences

Peking Union Medical College Hospital

Musculoskeletal Diseases

Nervous System Diseases

Megalencephaly

Klippel-Trenaunay-Weber Syndrome

Sturge-Weber Syndrome

Angiomatosis

Craniofacial Abnormalities

Musculoskeletal Abnormalities

Malformations of Cortical Development

Nervous System Malformations

Klippel-Trenaunay Syndrome

Parkes Weber Syndrome

Weber Syndrome

CLOVES Syndrome

The investigators will collect demographic, clinical, biological and imaging characteristics of patients with PROS.

national registry

Guillaume GC Canaud, MD,PHD

Nadia NB BAHI-BUISSON, MD,PHD

Guillaume Canaud, MD, PHD

Nadia Bahi-Buisson, MD, PHD

Guillaume Canaud, MD,PHD

Overgrowth syndromes are rare genetic disorders defined by tissue hypertrophy that can be either localized or generalized, affecting both latitudinal and longitudinal growth. The genes involved in overgrowth syndromes are not well characterized but mostly concern the PIK3CA/AKT/mTOR pathway, a major actor of cell growth and proliferation. The mutations are not inherited but occurs during embryogenesis leading to somatic mosaicism. Owing to the variability of the clinical presentation, their exact prevalence is yet unknown. In order to answer this question, the investigators team create here the first French national registry on overgrowth syndromes.

Biopsies and tissues removed during surgical procedures will be stored in the Department of Pathology of Hôpital Necker-Enfants Malades (authorization CODECOH n° DC-2020-3940 de la Plateforme de Resource Biologique de l'Hôpital Necker-Enfants Malades).

DNA, PBMC and plasma from patients will be stored for further studies. Samples will be stored at the au Centre de Ressources Biologiques de la Structure Fédérative de Recherche Necker (autorisation CODECOH n° DC-2020-3940 du CRB Necker, supervised by Dr. Marie-Alexandra ALYANAKIAN).

National Evaluation of Patients With PIK3CA-Related Overgrowth Spectrum (PROS)

Evaluation Nationale Des Enfants et Adultes Avec Syndromes d'Hypercroissance Dysharmonieuse National Evaluation of Patients With PIK3CA-Related Overgrowth Spectrum (PROS)

Clinical and molecular characterization of patients with overgrowth syndromes will be performed.

An estimation of the prevalence of overgrowth syndromes in France will be done

A biobank will be created with biological samples (plasma) collected for research and residual biological samples from patient cares (treatment/diagnosis)

An analysis of care trajectories will be performed. These data will be collected from health insurance databases for patients with overgrowth syndromes.

SDNS data will be used to estimate care costs per year for patients with overgrowth syndrome.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Weekly Sirolimus Therapy	NCT04861064	Venous Malforma... Lymphatic Malfo...	Sirolimus	2 Years -	Medical University of South Carolina
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
First in Human Trial of Topical VT30 in Pts With Venous/Lymphatic Malformations Assoc With PIK3CA or TEK Gene Mutations	NCT04409145	Venous Malforma... Lymphatic Malfo... Venolymphatic M...	VT30	18 Years - 60 Years	Venthera, Inc., a BridgeBio company
Efficacy of Rapamycin (Sirolimus) in the Treatment of BRBNS, Hereditary or Sporadic Venous Malformation	NCT03767660	Blue Rubber Ble... Venous Malforma...	Rapamycin	-	Peking Union Medical College Hospital
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
National Evaluation of Patients With PIK3CA-Related Overgrowth Spectrum (PROS)	NCT05563831	PIK3CA-related ... CLOVES Syndrome Klippel Trenaun... Megalencephaly MCAP Macrodactyly Vascular Malfor... Lymphatic Malfo... Venous Malforma...	national regist...	-	Institut National de la Santé Et de la Recherche Médicale, France

Spots Global Cancer Trial Database for venous malformation