Pilot Study on Trametinib for Surgical Unruptured AVMs

Study Overview
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Brief Summary
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Arteriovenous malformation (AVM) is a tangle of abnormal vessels that can progress through life and cause significant bleeding, deformity, pain, and deficits in day-to-day activities. Surgery is a common treatment option for patients with AVMs where the goal is to safely remove the entire AVM without causing complications. While any surgery has its potential risks, most of the potential modifiable risk factors relate to the AVM's structure, such as the AVM size or presence of high risk structural features seen on scans. The purpose of this pilot study is to see whether taking an oral medication called Trametinib can improve upon the AVM structure in adult patients before their scheduled surgery.

Detailed Description
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The goal of this pilot clinical trial is to see whether an oral medication called Trametinib can be given to patients with arteriovenous malformations (AVMs) of the brain and body before surgery in order to make the AVM structure less risky for surgery. The main questions it aims to answer are: does taking Trametinib make the structure of the AVM less risky for surgery? This will determined by comparing the size and structure of the AVM on repeat scans before and after taking the drug. does taking Trametinib reduce the blood flow to the AVM? This will be determined by quantifying the blood flow to the AVM with quantitative magnetic resonance imaging software. is the drug well tolerated in this patient population? This will be determined by following for any side effects of the medication how does the drug do what it is supposed to do clinically by looking at its effect at the cell level? This will be determined by taking a piece of the AVM that is removed at the time of surgery and running experiments in the lab to compare its structure and behaviour to other AVMs that were not treated with this medication. Participants will first undergo screening tests to ensure they are candidates for the medication. They will take oral Trametinib once daily for a total of 60 days prior to their planned surgery. They will be monitored for side effects at days 15, 30 and 60. They will undergo routine scans prior to starting the drug and then again within 5 days of their last dose to see any changes made to the AVM structure after taking the drug. Lastly, at the time of surgery, a part of the AVM removed will be sent to our research lab to see what the drug is doing at the cell level to result in the changes we can see on the scans.

Official Title
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Pilot Study on the Efficacy of MEK1/MEK2 Inhibitor Trametinib in Patients With Surgical Unruptured Arteriovenous Malformations

Conditions
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Arteriovenous Malformations

Intervention / Treatment
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* Drug: Trametinib tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years. Confirmed diagnosis of an unruptured AVM Spetzler-Martin Lawton Young Grade equal to or less than 6 on magnetic resonance imaging (MRI), CT-angiogram (CTA) or angiogram, and clinical exam by a physician who is familiar with this condition at any time in patient's medical history. Planned surgical resection of AVM at University Health Network within the acceptable window defined by the study calendar (i.e. after the indicated study drug dosing period and approximate week-long follow up). Patients must not have received an investigational drug within the 4 weeks prior to study enrolment. Patients who have previously received biologic therapy treatment must have completed therapy at least 14 days prior to study enrolment. Patients who have previously received myelosuppressive chemotherapy must have completed therapy at least 28 days prior to study enrolment. Patients on anticoagulants must have stopped treatment within 7 days of starting Trametinib. Patient is able to swallow oral medication and/or retain oral medication via G tube. Patients of childbearing potential (as assessed by their local Investigator) and fertile men who are sexually active must agree to the use of 2 forms of contraception (as discussed with the overseeing physician) throughout the period of study treatment and for 16 weeks after last dose of study drug. They are not allowed to donate ova or sperm for up to 16 weeks after the last dose of study drug. Exclusion Criteria: AVM due to known germline mutation such as phosphatase and tensin homolog (PTEN) or known history of familial AVM syndromes. Received prior map kinase (MEK) inhibitor therapy. Known allergy or contraindication to MEK inhibitor treatment. Patients who have undergone major surgery, as defined by the overseeing Investigator, within 28 days prior to study enrolment or who have not recovered from side effects of such a procedure. Patients that are currently pregnant or breastfeeding. A known history of coagulopathy and/or current use of anticoagulant therapy. International normalized ratio (INR) > 1.5 within 7 days of enrolment. Left ventricular ejection fraction (LVEF) <50%, or any ECG abnormalities within 7 days of enrolment. Retinal vein occlusion, serous retinopathy or glaucoma diagnosed within 1 month of enrolment. Diagnosis of significant liver failure (Child-Pugh score 2+) within 7 days of enrolment. Rhabdomyolysis (creatinine kinase (CK) >5x ULN) within 7 days of enrolment. Patients with known risk factors for gastrointestinal perforation (prior perforation, diverticulitis, metastases to the gastrointestinal tract and concomitant use of medications with a recognized risk of gastrointestinal perforation Positive covid-19 polymerase chain reaction (PCR) test within 7 days of enrolment. Patient is unwilling or unable to comply with study requirements. Unstable health status that may interfere with completing the study, as assessed by the overseeing Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is an open-label pilot study assessing the potential efficacy of Trametinib in improving AVM angioarchitecture for patients who are already planned to undergo surgical resection as part of their standard of care.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: Oral Trametinib<br>Participants will receive oral Trametinib once daily for up to 60 days prior to their elective surgery | Drug: Trametinib tablet<br>* Drug is supplied in 2mg and 0.5 mg tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiological response by independent central review at day 60 or 5 days after last dose, whichever comes first | as defined by one or more of the following: (1) at least 20% reduction in the volume of the AVM confirmed on repeat imaging, (2) resolution of angiographic weak points, or (3) resolution of AVM induced parenchymal changes by independent central review. | screening, Day 60 or 5 days after last dose (whichever comes first) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of Trametinib in surgical AVM population | Participants will be followed serially for the presence of adverse events, including their type, severity, and need for dose modifications or interruptions | screening, Day 15, 30, 60, within 1 week of surgery and up to 30 days after final dose | 
| Change from baseline in symptomatology and functional performance | Participants will be followed serially for any changes in self-reported clinical symptoms or signs, and for any changes in functional outcome with the modified Rankin Scale (mRS) (scale from 0 to 6, with increasing score representing worse functional status) | screening, day 15, 30, and 60 | 
| Change from baseline in AVM blood flow | The blood flow to the AVM will be objectively compared over time after Trametinib dosing with serial quantitative magnetic resonance angiography imaging | screening, day 60 or 5 days after final dose (whichever comes first) | 
| Effect of Trametinib on AVM pathobiology | The documentation of signaling pathways identified in AVM tissues after Trametinib drug administration | time of surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trametinib, Mitogen-activated-protein-kinase (MEK) inhibitor