Pilot Study on Trametinib for Surgical Unruptured AVMs

NCT06098872 | Unknown Phase 2 DMC FDA Drug

• 2 other identifiers: 23-5463OZUHN-017
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Arteriovenous Malformations

Keywords

Trametinib; Mitogen-activated-protein-kinase (MEK) inhibitor

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Safety of Trametinib in surgical AVM population

  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

  screening, day 15, 30, and 60

• Change from baseline in AVM blood flow

  screening, day 60 or 5 days after final dose (whichever comes first)

• Effect of Trametinib on AVM pathobiology

  time of surgery

Study Arms (1)

Experimental: Oral Trametinib

EXPERIMENTAL

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

Drug: Trametinib tablet

Interventions

Trametinib tablet DRUG

Drug is supplied in 2mg and 0.5 mg tablets

Experimental: Oral Trametinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University Health Network, Toronto: lead

Study Sites (1)

University Health Network

Toronto, Ontario, Canada

RECRUITING

Related Publications (9)

• 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.

  PMID: 36846125 BACKGROUND

• 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.

  PMID: 29669234 BACKGROUND

• 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.

  PMID: 32552404 BACKGROUND

• 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.

  PMID: 30544177 BACKGROUND

• 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.

  PMID: 35014097 BACKGROUND

• 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.

  PMID: 30566190 BACKGROUND

• 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.

  PMID: 32859736 BACKGROUND

• Wright CJ, McCormack PL. Trametinib: first global approval. Drugs. 2013 Jul;73(11):1245-54. doi: 10.1007/s40265-013-0096-1.

  PMID: 23846731 BACKGROUND

• 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.

  PMID: 28190454 BACKGROUND

MeSH Terms

Conditions

Arteriovenous Malformations

Interventions

trametinib

Condition Hierarchy (Ancestors)

Vascular Malformations; Cardiovascular Abnormalities; Cardiovascular Diseases; Vascular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Ivan Radovanovic, MD PhD

  University Health Network, Toronto

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ivan Radovanovic, MD PhD

CONTACT

416-603-6207; ivan.radovanovic@uhn.ca

Ann Mansur, MD

CONTACT

416-603-5800; ann.mansur@uhn.ca

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: October 17, 2023
• First Posted: October 25, 2023
• Study Start: January 30, 2024
• Primary Completion: November 1, 2025
• Study Completion: November 1, 2025
• Last Updated: May 30, 2024

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)