|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Arteriovenous Malformations that are refractory to standard treatments or for which standard treatment are contra-indicated
|Medical condition in easily understood language
|Diseases [C] - Cardiovascular Diseases [C14]
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|The aim of this clinical study is
1) to confirm the security of trametinib and long-term tolerability in patients with Arteriovenous Malformations (AVM)
2) to evaluate the efficacy of trametinib on signs and symptoms caused by AVMs that are refractory to standard care
whether trametinib treatment can alleviate signs and symptoms caused by AVM
whether trametinib could reduce volume of the malformation (on MRI) on a long-term follow-up
whether patients will see their quality of life improved.
|Secondary objectives of the trial
|Trial contains a sub-study
|Full title, date and version of each sub-study and their related objectives
|In order to better delineate the efficacy of this drug, it could be helpful to know the causative gene responsible for each patient involved in the study. This necessitates a small biopsy of the affected tissue, as the mutation will only be in the tissue. This biopsy is not mandatory as biopsy of AVM is sometimes difficult to perform and could be associated with complications. However, if easily accessible and not damaging for the patient, biopsy will be proposed to adult patients. The biopsy will be put in liquid nitrogen or RNA later solution and stored at -80° and in a FFPE block (if available quantity) at room temperature respectively for the duration of the study (i.e. for 7 years). The samples will be stored in the laboratory of Human Molecular Genetics of Prof Miikka Vikkula, de Duve Institute, Catholic university of Louvain, Brussels 1200, Belgium. An additional informed consent will be signed.
|Principal inclusion criteria
|1. Patients with complex and symptomatic fast-flow vascular malformations that are refractory to standard care such as medical treatment, surgical resection and/or embolization (ineffective or accompanied by major complications) or for wich standard care is contra-indicated.
2. Patients must have adequate bone marrow function: hemoglobine> 10,0 g/dl, neutrophils >1.500/mm³ and platelets > 100.000/mm³.
3. Patients must have the following laboratory values:
o 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)
o Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (or < 5.0 x ULN if hepatic metastases are present)
o 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.
4. Karnofsky score > 50
5. Negative urine pregnancy test in females with a childbearing potential.
6. Sexually active female patients (and female partners of male patients) must use adequate contraceptive measures while on study and for up to 8 weeks after ending treatment.
|Principal exclusion criteria
|1. As AVM can result in impaired cardiac function, congestive heart failure is allowed if stabilized. New York Heart Association functional classification Grade 3-4 congestive heart failure should be excluded from this study, but remains at the discretion of the investigator as trametinib could indirectly improve cardiac function by controlling AVM. Other 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, family history of congenital long or short QT, or known history of QT/QTc prolongation of Torsades de Pointes (TdP) are excluded from this trial.
2. Impairment of Gastro-Intestinal (GI) function or GI disease that may significantly alter the absorption of trametinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea ≥ Grade 2, malabsorption syndrome, or small bowel resection)
3. Known hypersensitivity to drugs or metabolites from similar classes as study treatment.
4. Patient has (an)other concurrent severe and /or uncontrolled medical condition(s) that would, in the investigator’s judgement, contraindicate 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.)
5. Patient with history of Retinal pigment epithelial detachments or Retinal vein occlusion
6. Immunocompromised patients, including known seropositivity for HIV
7. Pregnant or lactating women
|E.5 End points
|Primary end point(s)
|All patients will be seen monthly for the first 3 months and then every three months, in order to evaluate the efficacy and safety of trametinib. Doppler ultrasonography and cardiac echography (Ventriculography) will be performed in baseline and at 6, 12 and 24 months; Magnetic Resonance Imaging (MRI) and arteriography will be performed at baseline, 12 and 24 months.
|Timepoint(s) of evaluation of this end point
|Secondary end point(s)
|At the end of 2 years, the treatment is interrupted and the patient is followed during 5 years. In case of resurgence of symptoms, trametinib could be restarted.
|Timepoint(s) of evaluation of this end point
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|The trial involves multiple Member States
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days