Pilot Study on Trametinib for Surgical Unruptured AVMs (OZUHN-017)

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Arteriovenous Malformations
• Intervention / Treatment: Drug: Trametinib tablet

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ivan Radovanovic, MD PhD; Phone Number: 416-603-6207; Email: ivan.radovanovic@uhn.ca
• Study Contact Backup: Name: Ann Mansur, MD; Phone Number: 7371 416-603-5800; Email: ann.mansur@uhn.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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 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
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

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Investigators: Principal Investigator: Ivan Radovanovic, MD PhD, University Health Network, Toronto

Publications and helpful links

General Publications

• Couto JA, Huang AY, Konczyk DJ, Goss JA, Fishman SJ, Mulliken JB, Warman ML, Greene AK. Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation. Am J Hum Genet. 2017 Mar 2;100(3):546-554. doi: 10.1016/j.ajhg.2017.01.018. Epub 2017 Feb 9.
• Wright CJ, McCormack PL. Trametinib: first global approval. Drugs. 2013 Jul;73(11):1245-54. doi: 10.1007/s40265-013-0096-1.
• Lekwuttikarn R, Lim YH, Admani S, Choate KA, Teng JMC. Genotype-Guided Medical Treatment of an Arteriovenous Malformation in a Child. JAMA Dermatol. 2019 Feb 1;155(2):256-257. doi: 10.1001/jamadermatol.2018.4653.
• Mansur A, Radovanovic I. Vascular malformations: An overview of their molecular pathways, detection of mutational profiles and subsequent targets for drug therapy. Front Neurol. 2023 Feb 10;14:1099328. doi: 10.3389/fneur.2023.1099328. eCollection 2023.
• Nikolaev SI, Fish JE, Radovanovic I. Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain. N Engl J Med. 2018 Apr 19;378(16):1561-1562. doi: 10.1056/NEJMc1802190. No abstract available.
• Fish JE, Flores Suarez CP, Boudreau E, Herman AM, Gutierrez MC, Gustafson D, DiStefano PV, Cui M, Chen Z, De Ruiz KB, Schexnayder TS, Ward CS, Radovanovic I, Wythe JD. Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling. Circ Res. 2020 Aug 28;127(6):727-743. doi: 10.1161/CIRCRESAHA.119.316500. Epub 2020 Jun 17.
• Hong T, Yan Y, Li J, Radovanovic I, Ma X, Shao YW, Yu J, Ma Y, Zhang P, Ling F, Huang S, Zhang H, Wang Y. High prevalence of KRAS/BRAF somatic mutations in brain and spinal cord arteriovenous malformations. Brain. 2019 Jan 1;142(1):23-34. doi: 10.1093/brain/awy307.
• Nicholson CL, Flanagan S, Murati M, Boull C, McGough E, Ameduri R, Weigel B, Maguiness S. Successful management of an arteriovenous malformation with trametinib in a patient with capillary-malformation arteriovenous malformation syndrome and cardiac compromise. Pediatr Dermatol. 2022 Mar;39(2):316-319. doi: 10.1111/pde.14912. Epub 2022 Jan 10.
• Edwards EA, Phelps AS, Cooke D, Frieden IJ, Zapala MA, Fullerton HJ, Shimano KA. Monitoring Arteriovenous Malformation Response to Genotype-Targeted Therapy. Pediatrics. 2020 Sep;146(3):e20193206. doi: 10.1542/peds.2019-3206.

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2023
• Primary Completion (Estimated): November 1, 2025
• Study Completion (Estimated): November 1, 2025

Study Registration Dates

• First Submitted: October 17, 2023
• First Submitted That Met QC Criteria: October 17, 2023
• First Posted (Actual): October 25, 2023

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: November 2, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Trametinib; Mitogen-activated-protein-kinase (MEK) inhibitor
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Neoplasms by Histologic Type; Neoplasms; Cardiovascular Abnormalities; Neoplasms, Vascular Tissue; Vascular Malformations; Congenital Abnormalities; Hemangioma; Arteriovenous Malformations; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Trametinib
• Other Study ID Numbers: 23-5463; OZUHN-017 (Other Identifier: Ozmosis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes