Cobimetinib for Arteriovenous Malformations

Overseen By D'Ann Pierce, BSN

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Arkansas

Must not be taking: CYP3A4 inducers/inhibitors

Disqualifiers: Active infection, Uncontrolled hypertension, 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

Approved in 5 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 tests a drug called cobimetinib (Cotellic) to determine its safety and effectiveness for treating extracranial arteriovenous malformations (AVMs), which are abnormal connections between arteries and veins outside the brain. Participants will take cobimetinib daily for 21 days, followed by a 7-day break, in a repeating cycle for up to a year. Suitable candidates are those with measurable extracranial AVMs and available tissue samples from a biopsy. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important advancements in AVM treatment.

Will I have to stop taking my current medications?

The trial requires you to stop taking strong inducers or inhibitors of CYP3A4, such as certain antibiotics and herbal supplements, at least 14 days before starting the study. If you are on any chemotherapy, immunotherapy, or targeted therapy, you must have completed it and recovered from any side effects at least 28 days before joining the trial.

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

Research shows that cobimetinib is generally well-tolerated by patients. Studies have found that over 80% of patients with blood vessel tumors and malformations consider targeted treatments like cobimetinib safe and effective. Common side effects include diarrhea, tiredness, and swelling, typical for this kind of medication. The FDA has already approved cobimetinib for other uses, supporting its safety. However, individual experiences can differ, so discussing all possible side effects with a healthcare provider is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for arteriovenous malformations, which often involve invasive procedures like surgery or embolization, Cobimetinib offers a non-invasive oral medication option. Cobimetinib works by specifically targeting and inhibiting a protein involved in cell growth, which is a novel approach for this condition. Researchers are excited about Cobimetinib because it represents a potentially safer and more targeted therapy, reducing reliance on surgery and potentially improving outcomes with fewer side effects.

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

Research has shown that cobimetinib may help treat certain conditions by targeting specific cell pathways. For instance, when combined with vemurafenib, it significantly improved tumor response in patients with metastatic melanoma, a type of skin cancer. In this trial, researchers are investigating cobimetinib for its potential to treat extracranial arteriovenous malformations (AVM). Cobimetinib acts as a MEK inhibitor, blocking signals that cancer cells need to grow, which suggests it might be effective. Animal studies with similar drugs have successfully slowed AVM progression and improved blood flow. These findings suggest that cobimetinib could help manage AVMs by targeting similar pathways. ^{1 2 4 6 7}

Who Is on the Research Team?

Joana M Mack, MD

Principal Investigator

University of Arkansas for Medical Sciences, Arkansas Children's Hospital

Kevin J Bielamowicz, MD,

Principal Investigator

University of Arkansas for Medical Sciences, Arkansas Children's Hospital

Are You a Good Fit for This Trial?

This trial is for people aged 2-80 with extracranial arteriovenous malformations (AVMs). Participants must be able to take oral medication, have a certain level of physical functioning, and normal organ function. Women who can get pregnant must use two forms of birth control and provide negative pregnancy tests. People with active cancer, severe allergies to cobimetinib components, recent infections or surgeries, heart problems, HIV, CNS hemorrhage history or those on certain medications are excluded.

Inclusion Criteria

I agree not to donate eggs or sperm during and for 3 months after the study.

I have an AVM outside the brain with measurable size and can provide a previous biopsy report or will undergo a biopsy.

Your platelet count should be at least 75 x 10^9 per liter of blood, and you should not have received a blood transfusion in the past 7 days.

Exclusion Criteria

I have been diagnosed with chronic HIV.

I haven't taken strong CYP3A4 drugs in the last 14 days.

I am currently pregnant or breastfeeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cobimetinib for 21 days followed by 7 days off in a 28-day cycle, repeated for 12 cycles

12 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cobimetinib

Trial Overview The COBI-AVM study is testing the safety and effectiveness of cobimetinib in treating AVMs located outside the brain. It's an open-label trial where all participants know they're receiving the drug. The goal is to see how well it works and what side effects occur when used for this condition.

How Is the Trial Designed?

Group I: Investigational Drug Experimental Treatment 1 Intervention

Cobimetinib will be administered at a maximal dose of 60 mg daily for 21 days on, then 7 days off, in a 28-Day treatment cycle for 12 cycles (approximately 12 months). Cobimetinib should be taken once daily at approximately the same time each day, and no later than 4 hours after the scheduled time. Cobimetinib can be taken with or without a meal. Cobimetinib tablets should never be chewed, cut, or crushed. Therapy may continue for up to 12 cycles provided the subject meets the criteria for starting subsequent cycles and does not meet any of the criteria for cobimetinib discontinuation. At least 7 days off cobimetinib (within +7 days) is required prior to starting a new treatment cycle.

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

Approved in European Union as Cotellic for:

• Melanoma

Approved in United States as Cotellic for:

• Melanoma

Approved in Canada as Cotellic for:

• Melanoma

Approved in Switzerland as Cotellic for:

• Melanoma

Approved in Japan as Cotellic for:

• Melanoma

Who Is Running the Clinical Trial?

University of Arkansas

Lead Sponsor

Trials

500

Recruited

153,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

The Brain Vascular Malformation Consortium (BVMC) is a collaborative effort involving multiple institutions aimed at improving research and treatment for brain vascular malformations, which currently lack specific therapies and validated biomarkers.

The BVMC is developing biomarkers for disease progression and severity while enhancing patient recruitment through partnerships with Patient Support Organizations, which will help advance new treatment strategies for conditions like Sturge-Weber Syndrome and hereditary hemorrhagic telangiectasia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain Vascular Malformation Consortium: Overview, Progress and Future Directions. Akers, AL., Ball, KL., Clancy, M., et al.[2021]

Cobimetinib, a MEK1/2 inhibitor, was found to be generally well tolerated in a study involving 97 patients with advanced solid tumors, with the maximum tolerated doses established at 60 mg on a 21/7 schedule and 100 mg on a 14/14 schedule.

The treatment showed promising anti-tumor activity, particularly in melanoma patients with the BRAF(V600E) mutation, resulting in one unconfirmed complete response and six confirmed partial responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors. Rosen, LS., LoRusso, P., Ma, WW., et al.[2019]

In a real-world study involving 95 patients with metastatic BRAF V600 mutated melanoma, the median overall survival (OS) was significantly higher for patients without brain metastases (21.6 months) compared to those with brain metastases (7.4 months).

The safety profile of cobimetinib/vemurafenib was consistent with previous studies, with high rates of adverse events (83.3% in patients without brain metastases and 87.8% in those with brain metastases), but no new safety concerns were identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness, safety and utilization of cobimetinib and vemurafenib in patients with BRAF V600 mutant melanoma with and without cerebral metastasis under real-world conditions in Germany: the non-interventional study coveNIS. Kähler, KC., Debus, D., Schley, G., et al.[2023]

In the coBRIM phase III trial involving 495 patients with advanced BRAF-mutated melanoma, the combination of cobimetinib and vemurafenib significantly improved progression-free survival and overall survival compared to vemurafenib alone.

While nearly all patients experienced adverse events (AEs), the majority were manageable and occurred mostly within the first treatment cycle, with a higher incidence of severe AEs in the combination group (75% vs. 61%), indicating the need for careful monitoring and potential dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study. Dréno, B., Ribas, A., Larkin, J., et al.[2022]

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]

Inherited and somatic mutations in key signaling pathways related to vascular and lymphatic malformations have been identified, which can guide the development of targeted therapies.

The study suggests that existing cancer drugs that target these signaling pathways may be repurposed for treating vascular anomalies, marking the beginning of a new era in personalized medicine for these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic Basis and Therapies for Vascular Anomalies. Queisser, A., Seront, E., Boon, LM., et al.[2021]

Vascular malformations of the brain (VMB) can lead to serious complications like hemorrhages and strokes, but many cases remain asymptomatic until advanced stages, highlighting the need for early detection.

Recent advancements in high-throughput omics technologies have improved our understanding of VMBs, leading to the identification of potential biomarkers and therapeutic targets that could enhance clinical management and treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular Biomarkers and Drug Targets in Brain Arteriovenous and Cavernous Malformations: Where Are We? Venugopal, V., Sumi, S.[2022]

Cobimetinib, when combined with vemurafenib, significantly improves tumor response rates and progression-free survival in metastatic melanoma patients with BRAF V600 mutations compared to vemurafenib alone.

While this combination therapy shows enhanced efficacy, it may also present higher toxicity compared to other treatments like dabrafenib and trametinib, indicating a need for careful management and potential combination with immune therapies for better long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cobimetinib and vemurafenib for the treatment of melanoma. Boespflug, A., Thomas, L.[2019]

In a study of 185 patients with advanced melanoma treated with cobimetinib and vemurafenib, the median overall survival was 16.1 months, indicating the effectiveness of this combination therapy in a real-world setting.

The safety profile was consistent with previous studies, with serious adverse events like increased CPK and retinal detachment occurring in 3% of patients, suggesting that while the treatment is effective, monitoring for these side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival in adult patients with BRAFV600 mutation-positive advanced melanoma: a noninterventional ambispective study of patients with cobimetinib combined with vemurafenib during the French early access program: MELANIS study. Meyer, N., Pérol, D., Duval-Modeste, AB., et al.[2023]

In the coBRIM trial, patients with BRAF (V600) mutation-positive unresectable or metastatic melanoma who received cobimetinib in combination with vemurafenib experienced significantly longer progression-free survival compared to those treated with vemurafenib alone.

The combination treatment also resulted in a higher overall response rate and prolonged overall survival, while maintaining a manageable safety profile, making it a valuable treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cobimetinib Plus Vemurafenib: A Review in BRAF (V600) Mutation-Positive Unresectable or Metastatic Melanoma. Keating, GM.[2019]

The maximum tolerated dose (MTD) of vandetanib when combined with fractionated stereotactic radiosurgery (SRS) for patients with recurrent malignant gliomas was determined to be 100 mg daily, as this dose resulted in less than 33% of patients experiencing dose-limiting toxicities.

In a study involving 10 patients, 6 showed a radiographic response to treatment, indicating potential efficacy of the combination therapy, although further evaluation is needed to confirm safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I dose escalation trial of vandetanib with fractionated radiosurgery in patients with recurrent malignant gliomas. Fields, EC., Damek, D., Gaspar, LE., et al.[2022]

The VEGF signaling pathway is crucial for angiogenesis, and the development of targeted anti-angiogenic drugs has significantly improved cancer treatment outcomes.

However, these drugs, including bevacizumab, sorafenib, and sunitinib, can cause serious skin-related side effects that affect patients' overall well-being, highlighting the need for awareness and management strategies among healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cutaneous manifestations of anti-angiogenic therapy in oncology: Review with focus on VEGF inhibitors. Ishak, RS., Aad, SA., Kyei, A., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05125471

Study Details | NCT05125471 | Cobimetinib In Extracranial ... The purpose of this open-label study is to evaluate the safety and efficacy of cobimetinib in extracranial AVM. Detailed Description. After being informed of ...

2. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT05125471?term=Cobimetinib&draw=2&rank=9

Cobimetinib In Extracranial Arteriovenous Malformations ... The purpose of this open-label study is to evaluate the safety and efficacy of cobimetinib in extracranial AVM. Detailed Description. After being informed of ...

3. withpower.com withpower.com/trial/phase-3-hemangioma-2022-ebd14

Cobimetinib for Arteriovenous Malformations Cobimetinib, when combined with vemurafenib, significantly improves tumor response rates and progression-free survival in metastatic melanoma patients with BRAF ...

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

MEK inhibitors for the treatment of extracranial ... The use of selective MEK1/2 inhibitors, such as trametinib, in animal models can effectively inhibit AVM progression, improve blood flow, and achieve ...

5. app.trialscreen.org app.trialscreen.org/trials/phase-2-arteriovenous-malformations-extracranial-cobimetinib-cobi-avm-trial-nct05125471

Cobimetinib In Extracranial Arteriovenous Malformations ... Evaluating the safety and effectiveness of cobimetinib in treating extracranial arteriovenous malformations. Check your eligibility. Share study information

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2022/206192s005lbl.pdf

COTELLIC (cobimetinib) - accessdata.fda.gov Effect of Cobimetinib on Transporters: In vitro data suggest that cobimetinib at clinically relevant concentrations does not inhibit P-gp, BCRP, OATP1B1 ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11665586/

Targeted medical therapies for vascular anomalies - PMC This prospective trial demonstrated efficacy and safety in more than 80% of patients with vascular tumors and malformations and started a new ...