Diseases and Abnormalities at or Before Birth

All Conditions

Heart and Blood Diseases

Neoplasms

Congenital Abnormalities

Arteriovenous Malformations

Hemangioma

Vascular Malformations

Cardiovascular Abnormalities

Vascular Diseases

Neoplasms, Vascular Tissue

Neoplasms by Histologic Type

All Drugs and Chemicals

Antineoplastic Agents

Mitogens

Trametinib

Protein Kinase Inhibitors

Enzyme Inhibitors

Participants will receive oral Trametinib once daily for up to 60 days prior to their elective surgery

Drug is supplied in 2mg and 0.5 mg tablets

Trametinib tablet

Ivan Radovanovic, MD PhD

Ann Mansur, MD

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.

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:

1. 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.
2. 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.
3. is the drug well tolerated in this patient population? This will be determined by following for any side effects of the medication
4. 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.

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.

Pilot Study on Trametinib for Surgical Unruptured AVMs

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

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.

Participants will be followed serially for the presence of adverse events, including their type, severity, and need for dose modifications or interruptions

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)

The blood flow to the AVM will be objectively compared over time after Trametinib dosing with serial quantitative magnetic resonance angiography imaging

The documentation of signaling pathways identified in AVM tissues after Trametinib drug administration

University Health Network, Toronto

Pharmaceutical Solutions

2 mg, orally, on Day 1 of the dosing period

Trametinib pediatric formulation

GSK Clinical Trials

The purpose of this open-label, randomized, 2-treatment, 2-period crossover study with incomplete washout is to evaluate the relative bioavailability of 2mg GSK1120212 pediatric oral solution formulation in comparison to 2mg GSK1120212 tablet formulation, to investigate the safety and tolerability of a single dose of the GSK1120212 pediatric oral solution formulation as compared to a single dose of the GSK1120212 tablet formulation, and to investigate the palatability of the GSK1120212 pediatric oral solution formulation.

Subjects will be assigned to one of two possible treatment sequences according to the randomization code provided to the sites by GSK: a single dose of 2mg GSK1120212 pediatric oral solution formulation then a single dose of 2mg GSK1120212 tablet formulation, or a single dose of 2mg GSK1120212 tablet formulation, then a single dose of 2mg GSK1120212 pediatric oral solution formulation. Administration of GSK1120212 in either sequence will be followed by 7 days of serial blood sampling for pharmacokinetic analysis of plasma GSK1120212. Safety assessments, including assessment of adverse events, clinical laboratory values (hematology, clinical chemistry and urinalysis) and vital signs, will be made throughout the study. After completing the pharmacokinetic assessments for two periods, eligible subjects may transition to MEK114375, an open-label rollover study of GSK1120212.

Relative Bioavailibilty for Pediatric Powder for Suspension (PfOS) Formulation

An Open-Label, Two-Period, Randomized, Crossover Study to Assess the Relative Bioavailability of GSK1120212 Tablet Formulation and the GSK1120212 Pediatric Oral Solution Formulation Following Single-Dose Administration to Adult Subjects With Solid Tumors

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pilot Study on Trametinib for Surgical Unruptured AVMs	NCT06098872	Arteriovenous M...	Trametinib tabl...	18 Years -	University Health Network, Toronto
Pilot Study on Trametinib for Surgical Unruptured AVMs	NCT06098872	Arteriovenous M...	Trametinib tabl...	18 Years -	University Health Network, Toronto
Relative Bioavailibilty for Pediatric Powder for Suspension (PfOS) Formulation	NCT01647659	Cancer	Trametinib tabl... Trametinib pedi...	18 Years -	GlaxoSmithKline

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