Trametinib for Arterial Venous Malformation

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Stanford University

Must not be taking: Immunosuppressives, MEK inhibitors

Disqualifiers: Cardiovascular risk, Retinal conditions, 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: Unknown

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the use of Trametinib, an oral medication, to determine its safety and effectiveness in treating arteriovenous malformations (AVMs). AVMs are abnormal blood vessel connections that can lead to serious health issues. Current treatments for AVMs often lack long-term effectiveness, highlighting the need for better options. Suitable candidates for this trial are individuals aged 12 to 60 with a confirmed diagnosis of complicated AVMs outside the brain or spine. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group, providing an opportunity to contribute to advancements in AVM treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot be on immunosuppressive medications or have had recent chemotherapy, biologic therapy, or investigational drugs. It's best to discuss your current medications with the trial team.

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

Research has shown that trametinib is usually well-tolerated by people with arteriovenous malformations (AVM). In several studies, patients taking trametinib reported few serious side effects. For instance, one study included all participants in the safety review and described the treatment as well-tolerated. Another study reported successful treatment in a child with AVM, noting that trametinib was both effective and well-tolerated.

These findings suggest that trametinib could be a safe option for treating AVM, although individual experiences may differ. It's important for patients to talk with healthcare providers to understand the potential risks and benefits. ^{1 2 3 4 5}

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

Trametinib is unique because it targets a specific pathway involved in the formation of arterial venous malformations (AVMs), which are complex tangles of abnormal blood vessels connecting arteries and veins. Unlike traditional methods such as surgery or embolization, which focus on physically removing or blocking the malformation, trametinib works at a molecular level by inhibiting the MEK enzyme. This targeted approach might reduce the size and symptoms of AVMs with potentially fewer side effects and risks compared to invasive procedures. Researchers are excited about trametinib because it offers a non-surgical option that could provide relief for patients who are not candidates for existing treatments.

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

Research shows that Trametinib, which participants in this trial will receive, may help treat arteriovenous malformations (AVMs), unusual connections between arteries and veins. In one study, patients experienced a significant drop in blood flow to their AVMs, with more than a 75% reduction after six months of treatment. Another case demonstrated that Trametinib worked well and was safe for a child with an AVM caused by a specific genetic change. Additionally, it has been used successfully in adults with severe AVMs that didn't improve with other treatments, helping to reduce pain and physical changes. These findings suggest that Trametinib could be a helpful option for managing AVMs, especially when other treatments fail. ^{1 2 3 4 5}

Who Is on the Research Team?

Joyce Teng, MD, PhD, FAAD

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

This trial is for individuals aged 12-60 with a confirmed diagnosis of complicated extracranial AVMs. They must be able to take oral medication and have not received certain treatments like biologics, major surgery, or investigational drugs within specific time frames before enrollment. Women of childbearing potential must agree to use birth control.

Inclusion Criteria

Confirmed diagnosis of complicated extracranial AVMs made by a physician who is familiar with this condition

I am taking steroids for hormone deficiencies as needed.

I haven't had chemotherapy that lowers my blood cell counts in the last 4 weeks.

Exclusion Criteria

I have previously taken or am allergic to MEK inhibitor therapy.

I have AVM caused by a genetic change.

I am currently taking medication that suppresses my immune system.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral trametinib once daily to assess safety and efficacy in treating Extracranial Arteriovenous Malformation

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Trametinib

Trial Overview The study tests the safety and effectiveness of Trametinib tablets in treating Extracranial Arteriovenous Malformation (AVM), which can cause severe complications. The goal is to find a better treatment option than current therapies that often result in high recurrence rates.

How Is the Trial Designed?

Group I: Oral Trametinib Experimental Treatment 1 Intervention

Patients will receive oral trametinib once daily

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?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Boston Children's Hospital

Collaborator

Trials

801

Recruited

5,584,000+

Published Research Related to This Trial

A patient with a KRAS mutant arteriovenous malformation (AVM) associated with Cobb syndrome was treated with the mitogen-activated protein kinase inhibitor trametinib, showing promising results.

After 6 months of treatment, there was a significant therapeutic response, with over a 75% reduction in arterial inflow to the AVM, indicating the potential efficacy of trametinib for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring Arteriovenous Malformation Response to Genotype-Targeted Therapy. Edwards, EA., Phelps, AS., Cooke, D., et al.[2020]

A mouse model with activated KRAS in vascular endothelial cells showed significant mortality and varying severity of arteriovenous malformations, with only 31.5% of pups surviving to postnatal day 14, highlighting the serious impact of KRAS mutations on vascular development.

Treatment with the MEK inhibitor trametinib improved survival rates to 76.9% by postnatal day 16 and helped normalize vessel morphology, suggesting it could be a promising therapy for KRAS-induced vascular malformations in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trametinib as a promising therapeutic option in alleviating vascular defects in an endothelial KRAS-induced mouse model. Nguyen, HL., Boon, LM., Vikkula, M.[2023]

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]

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]

Dabrafenib and trametinib, both targeting the MAPK pathway, have shown significant efficacy in treating BRAF-mutant metastatic melanoma, with dabrafenib achieving a 59% objective response rate and improved progression-free survival compared to traditional chemotherapy.

The combination of dabrafenib and trametinib resulted in higher response rates and longer median progression-free survival than dabrafenib alone, while also presenting less cutaneous toxicity, making it a promising treatment option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib and trametinib, alone and in combination for BRAF-mutant metastatic melanoma. Menzies, AM., Long, GV.[2022]

Citations

1. 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).

2. sciencedirect.com sciencedirect.com/science/article/pii/S0190962225024867

Trametinib treatment for early-stage extracranial ... In this study, we used the quantitative data of abnormal PAV detected by ultrasound as the primary outcome for evaluating hemodynamics.

3. 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, ...

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

Genotype-Guided Successful Treatment of an Arteriovenous ... Tramitinib can be an effective and well-tolerated treatment for a child with an extracranial arteriovenous malformation due to a MAP2K1 mutation.

5. publications.aap.org publications.aap.org/pediatrics/article/146/3/e20193206/36699/Monitoring-Arteriovenous-Malformation-Response-to

Monitoring Arteriovenous Malformation Response to ... Treatment with trametinib resulted in a substantial decrease in blood flow to the AVM, with a >75% reduction in arterial inflow after 6 months ...