Trametinib for Arteriovenous Malformations

(OZUHN-017 Trial)

Overseen By Ann Mansur, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must be taking: Trametinib

Must not be taking: Anticoagulants, MEK inhibitors

Disqualifiers: Pregnancy, Coagulopathy, Liver failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 8-9 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether the medication Trametinib (also known as Mekinist) can improve the structure of abnormal blood vessel tangles, known as arteriovenous malformations (AVMs), before surgery. AVMs can cause issues like bleeding and pain, often requiring surgical removal for safety. The trial aims to determine if taking Trametinib for up to 60 days before surgery can facilitate easier removal of AVMs. Individuals with an unruptured AVM who are planning surgery might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

If you are taking anticoagulants, you will need to stop them 7 days before starting Trametinib. The protocol does not specify about other medications, so it's best to discuss with the study team.

Is there any evidence suggesting that Trametinib is likely to be safe for humans?

Research shows that trametinib may help treat arteriovenous malformations (AVMs). Studies have found that trametinib can be used safely in both children and adults with AVMs. For instance, one study reported that trametinib was well-tolerated in a child with an AVM caused by a specific genetic mutation. Another study demonstrated its short-term safety for treating early-stage AVMs. While more research is needed, these findings suggest that trametinib could be a safe option for some people with AVMs. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for AVM?

Unlike standard treatments for arteriovenous malformations (AVMs), which often involve invasive procedures like surgery or embolization, Trametinib offers a different approach. Trametinib is a targeted therapy that blocks a specific protein in the body called MEK, which is part of a pathway that can cause cells to grow uncontrollably. This mechanism could potentially reduce the size of AVMs before surgery, making them easier to manage. Researchers are excited because Trametinib's oral form provides a non-invasive treatment option that might complement or even reduce the need for traditional surgical interventions.

What evidence suggests that Trametinib might be an effective treatment for arteriovenous malformations?

Studies have shown promising results for Trametinib in treating arteriovenous malformations (AVMs). In earlier research, patients demonstrated improvements in both symptoms and medical scans, indicating their AVMs improved. Another study found that Trametinib reduced AVM size and blood flow, which are crucial for managing this condition. Reports indicate Trametinib has been effective for patients unresponsive to other treatments, suggesting it may be a viable option for difficult cases. In this trial, participants will take oral Trametinib once daily for up to 60 days before their elective surgery. Overall, these findings support Trametinib's potential to positively impact AVM treatment. ^{1 2 3 4 5}

Who Is on the Research Team?

Ivan Radovanovic, MD PhD

Principal Investigator

University Health Network, Toronto

Are You a Good Fit for This Trial?

Adults over 18 with an unruptured arteriovenous malformation (AVM) graded ≤6, who are scheduled for surgery at University Health Network. They must not have taken investigational drugs within the last 4 weeks or certain therapies recently and should be able to take oral medication. Participants need to agree to use two forms of contraception if they can have children.

Inclusion Criteria

I have an unruptured AVM that is Grade 6 or less, confirmed by MRI, CTA, or angiogram.

I finished any biologic therapy at least 14 days before joining the study.

Patients of childbearing potential and fertile men who are sexually active must agree to utilize two forms of contraception throughout the study as determined by their physician, and for 16 weeks following the last dose of medication

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Treatment

Participants receive oral Trametinib once daily for 60 days prior to their planned surgery

8-9 weeks

3 visits (in-person) at days 15, 30, and 60

Follow-up

Participants are monitored for safety and effectiveness after treatment, including adverse events and changes in AVM structure

4 weeks

1 visit (in-person) within 1 week of surgery and up to 30 days after final dose

Surgery and Analysis

Surgery is performed, and a part of the AVM is analyzed to assess the effect of Trametinib at the cellular level

What Are the Treatments Tested in This Trial?

Interventions

• Trametinib

Trial Overview The study is testing whether Trametinib tablets, taken before surgery, can improve AVM structure in patients. It's a pilot study which means it's preliminary research to gather initial data on the drug's effects on AVM prior to surgical removal.

How Is the Trial Designed?

Group I: Experimental: Oral Trametinib Experimental Treatment 1 Intervention

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

Trametinib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Mekinist for:

• Melanoma
• Non-small cell lung cancer

Approved in United States as Mekinist for:

• Melanoma
• Non-small cell lung cancer
• Thyroid cancer

Approved in Canada as Mekinist for:

• Melanoma
• Non-small cell lung cancer

Approved in Japan as Mekinist for:

• Melanoma

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Published Research Related to This Trial

Trametinib is an effective oral MEK inhibitor specifically targeting MEK1 and MEK2, approved in the US for treating unresectable or metastatic malignant melanoma with specific BRAF mutations, demonstrating its antineoplastic activity.

The drug is currently undergoing extensive clinical development for various cancers, including phase III trials in combination with dabrafenib for melanoma and phase II trials for pancreatic cancer and non-small cell lung cancer, indicating its potential for broader therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trametinib: first global approval. Wright, CJ., McCormack, PL.[2023]

In a phase 3 trial involving 36 patients with untreated BRAF V600-mutant metastatic melanoma, the combination of spartalizumab, dabrafenib, and trametinib resulted in a high objective response rate of 78%, with 44% achieving complete responses.

While the treatment showed promising efficacy, 72% of patients experienced severe treatment-related adverse events, and 17% had to permanently discontinue the therapy due to these side effects, highlighting the need for careful monitoring and management of adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i. Dummer, R., Lebbé, C., Atkinson, V., et al.[2022]

Combination therapy with the BRAF V600E inhibitor dabrafenib and the MEK inhibitor trametinib significantly improves progression-free survival in patients with BRAF V600-positive metastatic melanoma, but it is associated with serious side effects, including an increased risk of hemorrhagic events.

This case report highlights the occurrence of intracranial hemorrhage in a patient undergoing this combination therapy, emphasizing the need for vigilance in monitoring neurological symptoms in patients receiving these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of intracranial hemorrhage caused by combined dabrafenib and trametinib therapy for metastatic melanoma. Lee, le M., Feun, L., Tan, Y.[2022]

Trametinib, when used alone, was found to be tolerable in Japanese patients with advanced solid tumors, with a maximum tolerated dose not reached up to 3.0 mg daily and some patients showing stable disease or partial response.

However, combining trametinib with gemcitabine resulted in serious safety concerns, including interstitial lung disease in 3 out of 5 patients, highlighting a higher risk associated with this combination therapy compared to trametinib alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I/Ib study of trametinib (GSK1120212) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors. Kasuga, A., Nakagawa, K., Nagashima, F., et al.[2022]

Trametinib, a MEK1/MEK2 inhibitor, demonstrated selective activity against RAS-mutated myeloid malignancies, with overall response rates of 20% in patients with NRAS or KRAS mutations, indicating its potential as a targeted therapy.

The treatment was generally well tolerated, with manageable side effects such as diarrhea and rash, and the recommended dose was established at 2 mg daily, suggesting a favorable safety profile for further clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies. Borthakur, G., Popplewell, L., Boyiadzis, M., et al.[2022]

Trametinib, a MEK inhibitor approved for treating metastatic melanoma with a BRAF V600E mutation, effectively blocks cell proliferation and improves survival in patients, but emerging evidence suggests it may cause significant cardiotoxicity.

A case study of a patient treated with trametinib revealed a decline in heart function, with ejection fraction dropping from 55-60% to 40% within two months, highlighting the need for further research on the drug's potential cardiac side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular Effects of the MEK Inhibitor, Trametinib: A Case Report, Literature Review, and Consideration of Mechanism. Banks, M., Crowell, K., Proctor, A., et al.[2022]

Trametinib, when combined with dabrafenib, significantly prolongs median survival by about 8 months compared to vemurafenib alone in patients with metastatic or inoperable melanoma, based on a study of 704 patients.

While trametinib can enhance treatment efficacy, it also carries serious adverse effects, including life-threatening conditions like heart failure and gastrointestinal perforation, making it essential for patients to weigh the benefits against the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trametinib (MEKINIST°) Metastatic or inoperable BRAF V600-positive melanoma: a few extra months of life. [2019]

The pediatric oral solution of trametinib showed improved bioavailability compared to the tablet formulation, with significant increases in key pharmacokinetic measures such as Cmax and AUC, indicating it may be more effective in delivering the drug to patients.

The safety profile of the trametinib pediatric oral solution was consistent with existing data, with no serious adverse events leading to withdrawal from the study, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relative bioavailability of pediatric oral solution and tablet formulations of trametinib in adult patients with solid tumors. Cox, DS., Allred, A., Zhou, Y., et al.[2018]

In a study of 14 pediatric patients with recurrent low-grade glioma or high-grade CNS tumors, 64% were progression-free while receiving trametinib, indicating promising efficacy for this MEK inhibitor in treating MAP kinase pathway mutations.

While trametinib showed potential benefits, including partial responses and improved clinical symptoms in some patients, adverse events were common, particularly in those receiving combination therapy, highlighting the need for careful monitoring and further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trametinib-based Treatment of Pediatric CNS Tumors: A Single Institutional Experience. Paul, MR., Pehlivan, KC., Milburn, M., et al.[2021]

Citations

1. jaad.org jaad.org/article/S0190-9622(25)02486-7/fulltext

Trametinib treatment for early-stage extracranial ... The results of this study revealed clinical and radiological improvements in early-stage eAVM patients after trametinib chemotherapy. In ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.3096

Monocentric pilot trial of trametinib in severe extracranial ... This trial aimed to assess trametinib safety and efficacy in adult patients with stage III AVM refractory to conventional therapy, causing deformities, pain, ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7186908/

Genotype-Guided Successful Treatment of an Arteriovenous ... Main Outcome:​​ Tramitinib was effective in reducing the size of and blood flow to the arteriovenous malformation.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04258046

Study Details | NCT04258046 | Trametinib in the Treatment ... The purpose of this study is to assess the safety and efficacy of Trametinib in children and adults with Extracranial Arteriovenous Malformation (AVM).

5. sciencedirect.com sciencedirect.com/science/article/pii/S2096691123000493

MEK inhibitors for the treatment of extracranial ... Two clinical cases demonstrated the potential efficacy of trametinib in treating AVMs. In 2018, Ramrada et al. reported the case of a child with a poor response ...