What is the mechanism of action of this treatment?

The most common treatments for Anaplastic Astrocytoma include targeted therapies such as BRAF and MEK inhibitors, exemplified by dabrafenib and trametinib. These drugs work by blocking the activity of the BRAF V600E mutation and the MEK enzyme, respectively, which are involved in the MAPK/ERK signaling pathway that promotes tumor cell growth and survival. By inhibiting these targets, the treatments can reduce tumor proliferation and potentially shrink the tumor. This is particularly important for Anaplastic Astrocytoma patients as these tumors are aggressive and often resistant to conventional therapies, making targeted treatments a promising option to improve outcomes.

What side effects are associated with this type of intervention?

Common side effects of BRAF and MEK inhibitors, such as Dabrafenib and Trametinib, include fever, fatigue, nausea, diarrhea, rash, and joint pain. More serious side effects can include heart problems, eye issues, liver problems, and increased risk of bleeding. These treatments can also cause secondary skin cancers and severe skin reactions. Patients should be closely monitored for these side effects during treatment.

What prior FDA approvals exist?

The FDA has approved several treatments for Anaplastic Astrocytoma, though specific approvals for BRAF and MEK inhibitors like Dabrafenib and Trametinib are more commonly associated with other types of tumors, such as melanoma. For Anaplastic Astrocytoma, traditional treatments include surgery, radiation, and chemotherapy agents like temozolomide. While BRAF and MEK inhibitors are being studied in clinical trials for their efficacy in treating high-grade gliomas with BRAF V600 mutations, they are not yet standard FDA-approved treatments for Anaplastic Astrocytoma.

What other types of research exist?

Promising novel alternatives for Anaplastic Astrocytoma patients include: 1) Immune checkpoint inhibitors such as pembrolizumab and nivolumab, especially in cases with hypermutation or mismatch repair deficiency. 2) Tumor-Treating Fields (TTF) combined with temozolomide, which has shown improved survival rates. 3) Targeted therapies like Depatux-M (an EGFR-targeted antibody-drug conjugate) for EGFR-amplified tumors. 4) Combination therapies involving bevacizumab and everolimus, which have shown efficacy in recurrent high-grade gliomas.

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Dabrafenib + Trametinib After Radiation for Brain Cancer

Phase 2

Recruiting

Led By Rishi R Lulla

Research Sponsored by National Cancer Institute (NCI)

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Newly diagnosed high-grade glioma with BRAF^V600-mutation

Results for H3 K27M by immunohistochemistry (IHC) or sequencing

Must not have

History of allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib, trametinib, and their excipients

Patients with intrinsic brainstem or primary spinal cord tumors will be excluded

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 5 years

Awards & highlights

No Placebo-Only Group

Summary

This trial studies how well dabrafenib and trametinib work after radiation therapy in children and young adults with a specific type of brain tumor. These drugs help stop tumor growth by blocking signals that tell the cells to multiply. Dabrafenib has been developed and tested extensively for a specific type of skin cancer, showing effectiveness both alone and when used with trametinib.

Who is the study for?

This trial is for children and young adults aged between 1 to 21 years with newly-diagnosed high-grade glioma that has a specific genetic change (BRAF V600 mutation). They must not have had any previous tumor-directed therapy other than surgery or corticosteroids, should be in good health otherwise, and able to follow the study procedures. Pregnant or breastfeeding females are ineligible, as well as those with certain medical conditions like uncontrolled heart disease.

What is being tested?

The trial tests how well dabrafenib combined with trametinib works after radiation therapy in patients with BRAF V600-mutant high-grade glioma. Dabrafenib targets the BRAF enzyme while trametinib targets MEK; both enzymes are involved in tumor cell growth. The goal is to see if this combination improves outcomes compared to past treatments.

What are the potential side effects?

Potential side effects include allergic reactions similar to those from compounds related to dabrafenib and trametinib, issues affecting drug absorption due to gastrointestinal diseases, liver problems from hepatitis B/C infections, increased risk of cardiac events such as heart attacks or angina, vision problems like retinal vein occlusion or central serous retinopathy.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My brain tumor is newly diagnosed, high-grade, and has a BRAF V600 mutation.

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My tumor tested positive for H3 K27M mutation.

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I can take care of myself but may not be able to do active work.

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My spinal fluid test was negative for cancer cells.

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I am suspected to have a new high-grade glioma without spread.

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My liver enzyme (SGPT/ALT) levels are within the required range for the study.

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I have a high-grade brain tumor (grade III or IV).

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My diagnosis of a high-grade brain tumor has been confirmed by tissue examination.

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I am 25 years old or younger.

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My treatment will start within 31 days after my final cancer surgery.

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I am between 3 and 25 years old.

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My kidney function, based on my age and gender, is within the required range.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have no allergies to dabrafenib, trametinib, or similar medications.

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I do not have a tumor in my brainstem or spinal cord.

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I am not pregnant or have confirmed it with a negative pregnancy test.

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I have interstitial lung disease or pneumonitis.

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I have a heart condition that could make participating in the study unsafe.

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I have not had any treatment for my brain tumor except surgery or steroids.

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I do not have a GI condition that affects drug absorption.

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I am not pregnant.

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I have been treated with specific cancer drugs like dabrafenib, trametinib, or an ERK inhibitor.

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My cancer has not spread to my brain or spinal cord.

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I have had cancer with a RAS mutation.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 5 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Event-free survival (EFS) for stratum 1

Secondary study objectives

Event-free survival (EFS) for stratum 2 and stratum 3

Incidence of adverse events

Overall survival (OS) for stratum 1, stratum 2, and stratum 3

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (radiation therapy, dabrafenib, trametinib)Experimental Treatment6 Interventions

Patients undergo standardized local RT 5 days a week (Monday-Friday) for 6-7 weeks. Four weeks after completion of RT, patients receive dabrafenib mesylate PO BID and trametinib dimethyl sulfoxide PO QD on days 1-28 of each cycle. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo MRI at baseline, on day 1 of cycles 1, 3, 5, 7, 11, 14, 17, 20, and 23 while on treatment, then at time of relapse, every 3 months for year 1, every 4 months for year 2, every 6 months for year 3, and annually for years 4-5. Patients may also undergo lumbar puncture for CSF testing during treatment. Patients also undergo collection of blood on study.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Biospecimen Collection

2004

Completed Phase 3

~2020

Dabrafenib Mesylate

2014

Completed Phase 2

~10

Lumbar Puncture

2016

Completed Phase 3

~510

Magnetic Resonance Imaging

2017

Completed Phase 3

~1160

Radiation Therapy

2017

Completed Phase 3

~7250

Trametinib Dimethyl Sulfoxide

2014

Completed Phase 2

~10

0 / 23Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Anaplastic Astrocytoma include targeted therapies such as BRAF and MEK inhibitors, exemplified by dabrafenib and trametinib. These drugs work by blocking the activity of the BRAF V600E mutation and the MEK enzyme, respectively, which are involved in the MAPK/ERK signaling pathway that promotes tumor cell growth and survival. By inhibiting these targets, the treatments can reduce tumor proliferation and potentially shrink the tumor. This is particularly important for Anaplastic Astrocytoma patients as these tumors are aggressive and often resistant to conventional therapies, making targeted treatments a promising option to improve outcomes.