Efficacy and Safety of Sirolimus in Vascular Anomalies That Are Refractory to Standard Care

NCT ID: NCT02638389

Last Updated: 2023-02-24

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 250 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-01-25
• Study Completion Date: 2030-04-01

Brief Summary

The phosphatidylinositol 3-kinase (PI3Kinase)/Protein Kinase B (AKT)/mammalian target of rapamycin (mTor) pathway plays a role on the development and the venous/lymphatic vascular organisations.

The investigators want to study the efficacy and the safety of Rapamycin, an mTor inhibitor.

Detailed Description

The complex vascular malformations induce chronical pains and organic dysfunctions causing significant morbidity and mortality. Therefore, the investigators need to establish guidelines in order to treat these pathologies. Standard treatments such as surgery or interventional radiology are of limited efficacy and related to a high level of recurrences as well as complications. Recent preclinical studies have shown the important role of the PI3Kinase/AKT/mTor pathway on the development and the venous/lymphatic vascular organisations suggesting an appealing therapeutic target to treat patients with venous, lympathic or complex vascular malformations.

Investigators will realize a multicentric phase III study enrolling a higher number of patients to statistically evaluate the efficacy and the safety of the Rapamycin, an mTOR inhibitor, in the treatment of children and adults with vascular malformations for which conventional therapies such as surgery or sclerotherapy are ineffective or associated with high risk of important complications. Nearly 250 patients (200 adults and 50 children) will be enrolled in several european centers.

Conditions

Vascular Malformations

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Patients with vascular malformations

Patients with venous, lympathic or complex vascular malformations (KTS, PTEN, etc.) will receive sirolimus after completion of inclusion criteria

Group Type: EXPERIMENTAL

Sirolimus

Intervention Type: DRUG

evaluate the efficacy and safety of sirolimus in these patients

Interventions

Sirolimus

evaluate the efficacy and safety of sirolimus in these patients

Intervention Type: DRUG

Other Intervention Names

Rapamycine

Eligibility Criteria

Inclusion Criteria

• Patients with complex vascular anomalies that are refractory to standard care such as medical treatment, surgical resection and/or sclerotherapy/embolization (ineffective or accompanied by major complications)
• Patients must have adequate medullary function: Hemoglobine> 10,0 g/dl, neutrophils >1500/mm³ and platelets > 100.000/mm³
• Patients must have the following laboratory values:
• Total serum bilirubin ≤ 1.5 x ULN (or totally bilirubin ≤ 3 x ULN with direct bilirubin ≤ 1.5 x ULN in patients with well documented Gilbert Syndrome)
• Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (or < 5.0 x ULN if hepatic metastases are present)
• Serum creatinine 1.5 x ULN. If the serum creatinine is ≥ 1.5 x ULN, then a 24-hour Creatinine Clearance must be conducted and the result must be ≥ 60 mL/min.
• Karnofsky > 50
• Patients have to be able to sign the informed consent
• Women in age of procreation have to be informed that contraceptive methods are mandatory during the study time

Exclusion Criteria

• Any of the following concurrent severe and/or uncontrolled medical conditions, which could compromise participation in the study or interfere with the study results:
• Impaired cardiac function or clinically significant cardiac diseases, including unstable angina pectoris, ventricular arrhythmia, valvular disease with documented compromise in cardiac function, myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function, history of documented congestive heart failure (New York Heart Association functional classification III-IV), documented cardiomyopathy, family history of congenital long or short QT, or known history of QT/QTc prolongation of Torsades de Pointes (TdP)
• Impairment of Gastro-Intestinal (GI) function or GI disease that may significantly alter the absorption of sirolimus (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea ≥ Grade 2, malabsorption syndrome, or small bowel resection)
• Known hypersensitivity to drugs or metabolites from similar classes as study treatment.
• Patient has other concurrent severe and /or uncontrolled medical condition that would,in the investigator's judgment, contraindicated participation in the clinical study (e.g. acute or chronic pancreatitis, liver cirrhosis, active chronic hepatitis, severely impaired lung function with a spirometry ≤ 50% of the normal predicted value and/or O2 saturation ≤ 88% at rest, etc.)
• Immunocompromised patients, including known seropositivity for HIV
• Pregnant or lactating women
• Prior treatment with PI3K and/or mTOR inhibitors

• Minimum Eligible Age: 3 Months
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cliniques universitaires Saint-Luc- Université Catholique de Louvain

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Laurence M Boon, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Cliniques universitaires Saint-Luc- Université Catholique de Louvain

Locations

Cliniques Universitaires Saint-Luc, Université Catholique de Louvain Bruxelles

Brussels, Brussels Capital, Belgium

Site Status: RECRUITING

CHU Caen

Caen, Brittany Region, France

Site Status: RECRUITING

Universitätsklinikum Freiburg

Freiburg im Breisgau, , Germany

Site Status: NOT_YET_RECRUITING

Countries

Belgium; France; Germany

Central Contacts

Laurence M. Boon, MD, PhD

Role: CONTACT

laurence.boon@uclouvain.be

+ 32-2-764 8020

Facility Contacts

Laurence M Boon, MD, PhD

Role: primary

laurence.boon@uclouvain.be

+ 32-2-764 8020

Emmanuel Seront, MD, PhD

Role: backup

emmanuel.seront@uclouvain.be

+ 32-2-764 1992

Anne Dompmartin, MD, PhD

Role: primary

dompmartin-a@chu-caen.fr

Fabien Chaillot

Role: backup

chaillot-f@chu-caen.fr

Jochen Roessler, MD, PhD

Role: primary

jochen.roessler@uniklinik-freiburg.de

References

Seront E, Van Damme A, Legrand C, Bisdorff-Bresson A, Orcel P, Funck-Brentano T, Sevestre MA, Dompmartin A, Quere I, Brouillard P, Revencu N, De Bortoli M, Hammer F, Clapuyt P, Dumitriu D, Vikkula M, Boon LM. Preliminary results of the European multicentric phase III trial regarding sirolimus in slow-flow vascular malformations. JCI Insight. 2023 Nov 8;8(21):e173095. doi: 10.1172/jci.insight.173095.

Reference Type: DERIVED

PMID: 37937645 (View on PubMed)

Other Identifiers

VASE

Identifier Type: -

Identifier Source: org_study_id