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

10 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug Trametinib for treating arteriovenous malformations?

Trametinib has shown effectiveness in treating certain types of brain tumors in children, with some patients experiencing tumor shrinkage or stable disease. It is also used in combination with another drug to improve survival in patients with a specific type of skin cancer, suggesting its potential in treating other conditions. ^{1 2 3 4 5}

Is trametinib safe for use in humans?

Trametinib has been studied in various clinical trials and is generally considered safe for use in humans, although it can cause side effects. Common side effects include skin issues, mouth sores, fever, and fatigue, and more serious side effects can occur, especially when used in combination with other drugs. In some studies, a significant number of patients experienced treatment-related adverse events, leading to dose adjustments or discontinuation. ^{2 3 5 6 7}

How is the drug trametinib unique for treating arteriovenous malformations?

Trametinib is unique because it is an oral drug that inhibits MEK1 and MEK2, proteins involved in cell growth, which is different from other treatments for arteriovenous malformations that may not target these specific pathways. This mechanism is primarily used in cancer treatments, making its application to arteriovenous malformations novel. ^{2 3 7 8 9}

What is the purpose of this trial?

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.

Research Team

Ivan Radovanovic, MD PhD

Principal Investigator

University Health Network, Toronto

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

A case of intracranial hemorrhage caused by combined dabrafenib and trametinib therapy for metastatic melanoma. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Relative bioavailability of pediatric oral solution and tablet formulations of trametinib in adult patients with solid tumors. [2018]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Trametinib: first global approval. [2023]

4. France pubmed.ncbi.nlm.nih.gov

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

5. United States pubmed.ncbi.nlm.nih.gov

Trametinib-based Treatment of Pediatric CNS Tumors: A Single Institutional Experience. [2021]

6. United States 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. [2022]

7. United States 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. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Cardiovascular Effects of the MEK Inhibitor, Trametinib: A Case Report, Literature Review, and Consideration of Mechanism. [2022]