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

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ClinicalTrials.gov Identifier: NCT02638389
Recruitment Status : Recruiting
First Posted : December 23, 2015
Last Update Posted : June 14, 2017
Sponsor:
Information provided by (Responsible Party):
Cliniques universitaires Saint-Luc- Université Catholique de Louvain

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.


Condition or disease Intervention/treatment Phase
Vascular Malformations Drug: Sirolimus Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 250 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase III Multicentric Study Evaluating the Efficacy and Safety of Sirolimus in Vascular Anomalies That Are Refractory to Standard Care
Study Start Date : November 2015
Estimated Primary Completion Date : October 2018
Estimated Study Completion Date : October 2025


Arm Intervention/treatment
Experimental: Patients with vascular malformations
Patients with venous, lympathic or complex vascular malformations (KTS, PTEN, etc.) will receive sirolimus after completion of inclusion criteria
Drug: Sirolimus
evaluate the efficacy and safety of sirolimus in these patients
Other Name: Rapamycine




Primary Outcome Measures :
  1. Self-assesment (or parent assesment), using visual anagogic scale (0-10) of efficacy of sirolimus [ Time Frame: every 3 months, up to 2-year period. ]
    • Global treatment efficacy
    • Pain
    • Local complications/symptoms (bleeding, skin tension, esthetic and functional impairment)


Secondary Outcome Measures :
  1. Number of enrolled patients with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: every month during the first three months and then every three months for a 2-year-treatment period ]
  2. Self assessment of quality of life change induced by sirolimus [ Time Frame: every 3 months, up to 2-year period. ]
    Measured by quality of life questionnaire (adapted to MOS SF-36 survey).

  3. Volumetric changes of the malformation on sirolimus, based on magnetic resonance imaging (MRI) 12 months after sirolimus onset. [ Time Frame: At 12 month ]
    Relative change of volume of the vascular malformation between the baseline MRI (before sirolimus onset) and the 12-month MRI (during sirolimus treatment)

  4. Efficacy of sirolimus [ Time Frame: every three months, up to 2-year period ]
    Change in plasma levels fibrinogen and/ or D-dimers, reflecting improvement in an abnormal intravascular coagulation consumption

  5. Efficacy of sirolimus measured on digital photographs [ Time Frame: every three months, up to 2-year period ]
    Qualitative assessment of efficacy on digital photographs



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Ages Eligible for Study:   3 Months to 70 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02638389


Contacts
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Contact: Laurence M. Boon, MD, PhD + 32-2-764 8020 laurence.boon@uclouvain.be

Locations
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Belgium
Cliniques Universitaires Saint-Luc, Université Catholique de Louvain Bruxelles Recruiting
Bruxelles, Région de Bruxelles-Capitale, Belgium, 1200
Contact: Laurence M Boon, MD, PhD    + 32-2-764 8020    laurence.boon@uclouvain.be   
Contact: Emmanuel Seront, MD, PhD    + 32-2-764 1992    emmanuel.seront@uclouvain.be   
France
CHU Caen Recruiting
Caen, Bretagne, France, 14000
Contact: Anne Dompmartin, MD, PhD       dompmartin-a@chu-caen.fr   
Contact: Fabien Chaillot       chaillot-f@chu-caen.fr   
Sub-Investigator: Annouk Bisdorff Bresson, MD         
Principal Investigator: Isabelle Quere, MD, PhD         
Principal Investigator: Philippe Orcel, MD, PhD         
Principal Investigator: Marie-Antoinette Sevestre, MD, PhD         
Principal Investigator: Anne Dompmartin, MD, PhD         
Germany
Universitätsklinikum Freiburg Not yet recruiting
Freiburg, Germany, 79106
Contact: Jochen Roessler, MD, PhD       jochen.roessler@uniklinik-freiburg.de   
Principal Investigator: Jochen Roessler, MD, PhD         
Sponsors and Collaborators
Cliniques universitaires Saint-Luc- Université Catholique de Louvain
Investigators
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Principal Investigator: Laurence M Boon, MD, PhD Cliniques universitaires Saint-Luc

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Responsible Party: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
ClinicalTrials.gov Identifier: NCT02638389     History of Changes
Other Study ID Numbers: VASE
First Posted: December 23, 2015    Key Record Dates
Last Update Posted: June 14, 2017
Last Verified: June 2017

Additional relevant MeSH terms:
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Vascular Malformations
Congenital Abnormalities
Cardiovascular Abnormalities
Cardiovascular Diseases
Sirolimus
Everolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs