Trametinib in the Treatment of Complicated Extracranial Arterial Venous Malformation

Arterial Disease Clinical Trial

Official title:

Phase II Clinical Trial of MEK Inhibitor Trametinib in the Treatment of Complicated Extracranial Arterial Venous Malformation (VM)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04258046
• Other study ID #: 53105
• Status: Recruiting
• Phase: Phase 2
• Start date: December 1, 2020
• Est. completion date: December 31, 2024

Study information

• Verified date: June 2023
• Source: Stanford University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Arteriovenous malformation (AVM) is a congenital vascular anomaly that progresses throughout life and causes complications including tissue destruction due to rapid overgrowth, bleeding, functional deficits, severe deformity and cardiac failure. Unfortunately, traditional managements have transient benefits with more than 90 recurrence rate within a year. Therefore, there is a significant unmet medical need. The purpose of this study is to assess the safety and efficacy of Trametinib in children and adults with Extracranial Arteriovenous Malformation (AVM).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 60 Years

Eligibility

Inclusion Criteria:

• Patient must be = 12 years and = 60 years
• Confirmed diagnosis of complicated extracranial AVMs made by a physician who is familiar with this condition.
• Genetic testing for mutations within MAP2K1 or remaining RAS/MAPK pathway is preferred but not mandatory
• Patient is able to swallow and/or retain oral medication via G tube
• All clinical and laboratory studies to determine eligibility will be performed within six weeks prior to enrollment unless otherwise indicated.
• Patients who have undergone surgical resection or interventional radiology procedures (sclerotherapy) of their AVM are eligible if they meet all inclusion criteria after these procedures
• At least 4 weeks from undergoing any major surgery
• Patients with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary.
• Myelosuppressive chemotherapy: None within 4 weeks of entry into this study.
• At least 14 days since the completion of therapy with a biologic. For agents that have known adverse events occurring beyond 14 days after administration, this period must be extended beyond the time during which adverse events are known to occur. These patients must be discussed among PI and other investigators on a case-by-case basis.
• Patients must not have received an investigational drug within the prior 4 weeks.
• Not within 6 months prior to entering study if AVM is within field of radiation

Exclusion Criteria:

• AVM due to germline mutation such as PTEN
• Prior MEK inhibitor therapy or have allergy or contraindication to MEK inhibitor
• Unable to swallow PO drugs or administer the drug via G tube
• Patients who have undergone major surgery = 4 weeks prior to starting study treatment or who have not recovered from side effects of such procedure
• Patients with evidence of or history of cardiovascular risk
• Patients with retinal vein occlusion, hemorrhage or have a history of such conditions.
• Patients who are currently on other immunosuppressive medication(s)
• Patients who have an uncontrolled infection
• Unstable health status that may interfere with completing study
• Unable to travel to clinic as requested
• Patients unwilling or unable to comply with the protocol, or who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
• Females of child-bearing potential must be willing to practice acceptable methods of birth control.
• Additionally, females of childbearing potential must have a negative serum pregnancy test result from 7 days prior to the initiation of the medication to 3 months after the final administration of the medication. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method during the period when they are receiving the study drug and for 3 months thereafter.

Related Conditions & MeSH terms

• Arterial Disease
• Congenital Abnormalities
• Venous Malformation

Intervention

Drug:
• Trametinib tablet
Drug is supplied in 0.5 mg and 2 mg tablets

Locations

Country	Name	City	State
United States	Pediatric Dermatology Clinic at Stanford Children's Hospital	Palo Alto	California

Sponsors (2)

Lead Sponsor	Collaborator
Stanford University	Boston Children's Hospital

Country where clinical trial is conducted

United States, 

References & Publications (10)

Adams DM, Trenor CC 3rd, Hammill AM, Vinks AA, Patel MN, Chaudry G, Wentzel MS, Mobberley-Schuman PS, Campbell LM, Brookbank C, Gupta A, Chute C, Eile J, McKenna J, Merrow AC, Fei L, Hornung L, Seid M, Dasgupta AR, Dickie BH, Elluru RG, Lucky AW, Weiss B, Azizkhan RG. Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies. Pediatrics. 2016 Feb;137(2):e20153257. doi: 10.1542/peds.2015-3257. Epub 2016 Jan 18. — View Citation

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. — View Citation

Goss JA, Konczyk DJ, Smits PJ, Kozakewich HPW, Alomari AI, Al-Ibraheemi A, Taghinia AH, Dickie BH, Adams DM, Fishman SJ, Mulliken JB, Warman ML, Greene AK. Intramuscular fast-flow vascular anomaly contains somatic MAP2K1 and KRAS mutations. Angiogenesis. 2019 Nov;22(4):547-552. doi: 10.1007/s10456-019-09678-w. Epub 2019 Sep 5. — View Citation

Green JS, Norris DA, Wisell J. Novel cutaneous effects of combination chemotherapy with BRAF and MEK inhibitors: a report of two cases. Br J Dermatol. 2013 Jul;169(1):172-6. doi: 10.1111/bjd.12279. — View Citation

Hashemzadeh S, Ramezani F, Rafii-Tabar H. Study of Molecular Mechanism of the Interaction Between MEK1/2 and Trametinib with Docking and Molecular Dynamic Simulation. Interdiscip Sci. 2019 Mar;11(1):115-124. doi: 10.1007/s12539-018-0305-4. Epub 2018 Nov 21. — View Citation

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. — View Citation

Liu AS, Mulliken JB, Zurakowski D, Fishman SJ, Greene AK. Extracranial arteriovenous malformations: natural progression and recurrence after treatment. Plast Reconstr Surg. 2010 Apr;125(4):1185-1194. doi: 10.1097/PRS.0b013e3181d18070. — View Citation

Steiner JE, Drolet BA. Classification of Vascular Anomalies: An Update. Semin Intervent Radiol. 2017 Sep;34(3):225-232. doi: 10.1055/s-0037-1604295. Epub 2017 Sep 11. — View Citation

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

Zeiser R, Andrlova H, Meiss F. Trametinib (GSK1120212). Recent Results Cancer Res. 2018;211:91-100. doi: 10.1007/978-3-319-91442-8_7. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease response rate by investigator assessment at Month 6	Combining a composite of radiographic, clinical, functional impairment, and quality of life measures.	Month 6
Secondary	Change from baseline in MRI Volumetric Scan Measurement of Targeted Disease Area		Month 6
Secondary	Change from baseline in MRI Volumetric Scan Measurement of Targeted Disease Area		Month 12
Secondary	Disease response rate by investigator assessment at Month 12	Combining a composite of radiographic, clinical, functional impairment, and quality of life measures.	Month 12