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

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing Trametinib, a medication that may help treat arteriovenous malformation (AVM), a condition where blood vessels grow abnormally. The study focuses on children and adults with AVM because current treatments often fail, with symptoms returning quickly. Trametinib works by blocking proteins that cause abnormal blood vessel growth.

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.

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

Research shows that Trametinib, a drug that targets specific cell pathways, improved survival and reduced abnormal blood vessel size in a mouse model of arteriovenous malformations. Additionally, in a patient case, Trametinib significantly decreased blood flow to the malformation, suggesting it could be effective in treating these conditions. ^{1 2 3 4 5}

Is trametinib safe for humans?

Trametinib has been used in humans for various cancers, and while it can have serious side effects like heart problems, bleeding, and lung issues, it is generally considered safe when monitored by healthcare professionals. In studies, some patients experienced side effects like skin issues, fever, and fatigue, but these were often manageable. ^{6 7 8 9 10}

How does the drug Trametinib work for arteriovenous malformations?

Trametinib is unique because it targets specific genetic mutations (KRAS and MAP2K1) involved in arteriovenous malformations, which are not addressed by traditional treatments like surgery or radiation. It works by inhibiting the RAS/MAPK pathway, reducing abnormal blood vessel growth and improving symptoms. ^{1 2 3 5 11}

Research Team

Joyce Teng, MD, PhD, FAAD

Principal Investigator

Stanford University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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, 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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Trametinib as a promising therapeutic option in alleviating vascular defects in an endothelial KRAS-induced mouse model. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Vascular malformations: An overview of their molecular pathways, detection of mutational profiles and subsequent targets for drug therapy. [2023]

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

Monitoring Arteriovenous Malformation Response to Genotype-Targeted Therapy. [2020]

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

Somatic PIK3CA mutations as a driver of sporadic venous malformations. [2018]

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

Endothelial MAP2K1 mutations in arteriovenous malformation activate the RAS/MAPK pathway. [2021]

6. 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]

7. France pubmed.ncbi.nlm.nih.gov

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

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

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

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

Trametinib: first global approval. [2023]

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

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

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

Successful management of an arteriovenous malformation with trametinib in a patient with capillary-malformation arteriovenous malformation syndrome and cardiac compromise. [2022]