Using Trametinib to Improve Surgery Outcomes for Unruptured AVMs

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

This study is testing if the medication Trametinib can improve surgery outcomes for adults with unruptured arteriovenous malformations (AVMs) by changing the AVM structure and reducing blood flow before their surgery.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 10 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University Health Network, Toronto (Academic / other)
• Drugs / interventions: Trametinib, chemotherapy
• Locations: 1 site (Toronto, Ontario)
• Trial ID: NCT06098872 on ClinicalTrials.gov

What this trial studies

This pilot clinical trial investigates the use of Trametinib, an oral medication, in adult patients with unruptured arteriovenous malformations (AVMs) prior to surgical intervention. The study aims to determine if Trametinib can enhance the AVM structure, reduce blood flow, and improve surgical safety by comparing imaging results before and after treatment. Participants will take the medication daily for 60 days and will be monitored for side effects and changes in AVM characteristics through routine scans and lab analyses of removed tissue. The findings could provide insights into the drug's efficacy and tolerability in this patient population.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with a confirmed diagnosis of unruptured AVMs scheduled for surgical resection.

Not a fit: Patients with ruptured AVMs or those who have received investigational drugs or certain therapies recently may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could lead to safer surgical outcomes for patients with AVMs by improving the structural characteristics of the malformations.

How similar studies have performed: While the use of Trametinib in this context is novel, similar studies involving MEK inhibitors have shown promise in other conditions, suggesting potential for success.

Eligibility criteria

Inclusion Criteria:

1. Age ≥18 years.
2. 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.
3. 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).
4. Patients must not have received an investigational drug within the 4 weeks prior to study enrolment.
5. Patients who have previously received biologic therapy treatment must have completed therapy at least 14 days prior to study enrolment.
6. Patients who have previously received myelosuppressive chemotherapy must have completed therapy at least 28 days prior to study enrolment.
7. Patients on anticoagulants must have stopped treatment within 7 days of starting Trametinib.
8. Patient is able to swallow oral medication and/or retain oral medication via G tube.
9. 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:

1. AVM due to known germline mutation such as phosphatase and tensin homolog (PTEN) or known history of familial AVM syndromes.
2. Received prior map kinase (MEK) inhibitor therapy.
3. Known allergy or contraindication to MEK inhibitor treatment.
4. 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.
5. Patients that are currently pregnant or breastfeeding.
6. A known history of coagulopathy and/or current use of anticoagulant therapy.
7. International normalized ratio (INR) \> 1.5 within 7 days of enrolment.
8. Left ventricular ejection fraction (LVEF) \<50%, or any ECG abnormalities within 7 days of enrolment.
9. Retinal vein occlusion, serous retinopathy or glaucoma diagnosed within 1 month of enrolment.
10. Diagnosis of significant liver failure (Child-Pugh score 2+) within 7 days of enrolment.
11. Rhabdomyolysis (creatinine kinase (CK) \>5x ULN) within 7 days of enrolment.
12. 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
13. Positive covid-19 polymerase chain reaction (PCR) test within 7 days of enrolment.
14. Patient is unwilling or unable to comply with study requirements.
15. Unstable health status that may interfere with completing the study, as assessed by the overseeing Investigator.

Where this trial is running

Toronto, Ontario

• University Health Network — Toronto, Ontario, Canada (Recruiting)

Study contacts

• Principal investigator: Ivan Radovanovic, MD PhD — University Health Network, Toronto
• Study coordinator: Ivan Radovanovic, MD PhD

Conditions Arteriovenous Malformations; Trametinib; Mitogen-activated-protein-kinase inhibitor