Dabrafenib + Trametinib After Radiation for Brain Cancer

Not currently recruiting at 146 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Chemotherapy, Immunotherapy, Antidepressants, others

Disqualifiers: Metastatic disease, Cardiac disease, 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 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 8

Duration: Up to 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of combining dabrafenib and trametinib, both targeted cancer therapies, after radiation therapy in treating children and young adults with high-grade glioma that has the BRAF V600 mutation. The study investigates whether these drugs, which block enzymes essential for tumor growth, outperform previous treatments. Ideal participants are those recently diagnosed with this brain cancer and without metastatic disease. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you have a seizure disorder, you can participate if your seizures are well controlled with non-enzyme inducing anticonvulsants. It's best to discuss your specific medications with the trial team.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that patients with a seizure disorder can participate if their seizures are well controlled on non-enzyme inducing anticonvulsants, which suggests some medications may be allowed. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of dabrafenib and trametinib holds promise for treating brain tumors. Patients with metastatic brain melanoma have generally tolerated this treatment well, with manageable side effects. In children with glioma, this treatment proved safer than standard chemotherapy. For some glioma patients, the combination also demonstrated consistent safety, with many responding well to the therapy. These findings suggest that dabrafenib and trametinib are generally well-tolerated, though side effects may still occur. Always discuss potential risks with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for brain cancer?

Researchers are excited about combining dabrafenib and trametinib with radiation therapy for brain cancer because these drugs target specific proteins involved in cancer growth. Most brain cancer treatments rely on surgery, radiation, and chemotherapy, but dabrafenib and trametinib work by inhibiting the BRAF and MEK proteins, which are often mutated in cancer cells. This targeted approach can potentially slow down cancer progression more effectively and with fewer side effects compared to traditional chemotherapy. Additionally, this combination therapy is taken orally, which could offer a more convenient alternative to the intravenous administration of standard chemotherapy drugs.

What evidence suggests that dabrafenib and trametinib after radiation therapy might be an effective treatment for high-grade glioma?

Research has shown that the combination of dabrafenib and trametinib, which participants in this trial will receive after radiation therapy, may help treat brain tumors with a BRAF V600 mutation. In clinical trials, about 33% of patients with aggressive brain tumors responded well to this treatment. For melanoma that has spread to the brain, the response rates were also significant, indicating that this treatment might work well for tumors with similar mutations. Additionally, earlier studies found that patients experienced an average of 6.10 months without disease progression. These results suggest that this drug combination could be effective for patients with BRAF V600-mutant aggressive brain tumors following radiation therapy. ^{1 5 6 7 8}

Who Is on the Research Team?

Rishi R Lulla

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

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.

Inclusion Criteria

My tumor tested positive for H3 K27M mutation.

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

My spinal fluid test was negative for cancer cells.

Exclusion Criteria

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

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

I have a history or current issue with specific eye conditions (RVO or CSR) or risk factors for them.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation Therapy

Patients undergo standardized local radiation therapy 5 days a week (Monday-Friday) for 6-7 weeks

6-7 weeks

5 visits per week (in-person)

Treatment

Patients receive dabrafenib mesylate orally twice daily and trametinib dimethyl sulfoxide once daily on days 1-28 of each cycle. Treatment repeats every 28 days for up to 24 cycles

Up to 24 months

Regular visits for MRI and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, with MRI and other assessments

Up to 5 years

Every 3 months for year 1, every 4 months for year 2, every 6 months for year 3, then annually for years 4-5

What Are the Treatments Tested in This Trial?

Interventions

• Dabrafenib, Trametinib
• Radiation Therapy

Trial Overview

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.

How Is the Trial Designed?

Group I: Treatment (radiation therapy, dabrafenib, trametinib) Experimental Treatment 6 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.

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

Approved in European Union as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in United States as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Canada as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Japan as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in China as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Switzerland as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The use of stereotactic body radiation therapy (SBRT) for low and intermediate risk prostate cancer increased dramatically from 0.9% in 2004 to 19.5% in 2015, indicating growing acceptance of this treatment method.

SBRT has been shown to have a favorable toxicity profile and efficacy, leading to a significant decline in conventional fractionation treatments, which dropped from 96.3% to 75.8% during the same period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current use of stereotactic body radiation therapy for low and intermediate risk prostate cancer: A National Cancer Database Analysis. Malouff, TD., Stross, WC., Seneviratne, DS., et al.[2021]

In a study of 92 patients with brain metastases, low-dose whole brain radiation therapy (WBRT) combined with simultaneous integrated boost (SIB) achieved a local brain control rate of 72%, which was higher than conventional WBRT (56%) and comparable to stereotactic IMRT (78%).

The SIB technique also demonstrated a high distant brain control rate of 92%, indicating its effectiveness in preventing new brain metastases, while showing a low incidence of toxicity, with only one case of radionecrosis reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early clinical outcomes for 3 radiation techniques for brain metastases: focal versus whole-brain. Vargo, JA., Plants, BA., Mihailidis, DN., et al.[2016]

Intensity-modulated stereotactic radiotherapy (IMSRT) provides better conformity and coverage for planning target volumes (PTV) compared to stereotactic conformal radiotherapy (SCRT), especially for irregular and multifocal lesions, based on a study of 10 patients.

IMSRT also offers improved sparing of organs at risk (OAR), resulting in lower doses to these critical areas, although it may increase the volume of normal tissue receiving a low dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensity-modulated stereotactic radiotherapy vs. stereotactic conformal radiotherapy for the treatment of meningioma located predominantly in the skull base. Baumert, BG., Norton, IA., Davis, JB.[2022]

Intensity-modulated radiotherapy (IMRT) for cervical cancer has been shown to reduce gastrointestinal toxicity while allowing for higher doses of radiation to be targeted at tumors, improving treatment safety.

Individualized, image-guided brachytherapy enhances the precision of high-dose radiation delivery, adapting to the tumor's specific shape and size, which may lead to better tumor control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiotherapy of Cervical Cancer. Vordermark, D.[2017]

Radiation oncologists are exploring various innovative approaches, such as interstitial implants and stereotactic radiosurgery, to enhance cure rates for primary brain tumors while aiming to reduce long-term side effects.

These new radiation techniques must be integrated into a comprehensive treatment plan that includes other therapies to effectively manage primary malignant brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving radiotherapy for brain tumors. Woo, SY., Maor, MH.[2005]

Recent advances in radiotherapy for brain tumors include technologies like radiosurgery and intensity-modulated radiotherapy, which enhance treatment precision and effectiveness.

New molecular discoveries, such as radiation-induced promoters and various radiosensitizers, may improve the radiation response and allow for targeted genetic changes in tumor tissues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiotherapy for brain tumors. Mehta, MP., Tomé, WA., Olivera, GH.[2019]

In a real-world study of 20 patients with resected stage III BRAF-mutant melanoma, 90% experienced treatment-related toxicities requiring at least one interruption, highlighting the need for careful monitoring during therapy.

The most common adverse events included recurrent fever and chills (85%) and liver abnormalities (50%), with 65% of patients permanently discontinuing treatment due to these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment related toxicities with combination BRAF and MEK inhibitor therapy in resected stage III melanoma. Homan, M., Warrier, G., Lao, CD., et al.[2022]

In a study of 379 patients with non-metastatic Stage III-IV head and neck squamous cell cancer, IMRT with simultaneous integrated boost (IMRT+SIB) showed similar effectiveness in local control and survival rates compared to traditional 3D conformal radiotherapy (3D-CRT) and sequential IMRT (IMRTseq).

IMRT+SIB significantly reduced acute toxicity, with lower rates of severe mucositis, dermatitis, and the need for feeding tubes during treatment, suggesting it is a safer option for patients undergoing chemoradiation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of 3D confromal radiotherapy and intensity modulated radiotherapy with or without simultaneous integrated boost during concurrent chemoradiation for locally advanced head and neck cancers. Spiotto, MT., Weichselbaum, RR.[2021]

In a study of 59 patients with brain metastases from non-small-cell lung cancer and melanoma, the timing between immunotherapy and stereotactic radiotherapy (SRT) did not significantly affect the local control of tumors or the incidence of severe toxicities.

The main predictor of toxicity was tumor volume, with only 5.1% of patients experiencing grade 3 or higher toxicities, indicating that SRT combined with immunotherapy is generally safe regardless of the timing of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and time lapse between immunotherapy and stereotactic radiotherapy of brain metastases. Cabanie, C., Biau, J., Durando, X., et al.[2021]

A 61-year-old man with BRAF V600E-mutated lung adenocarcinoma experienced cerebral infarction after treatment with dabrafenib and trametinib, highlighting a potential risk associated with this therapy.

Despite being considered safe in previous trials, this case suggests that clinicians should monitor for signs of cerebral infarction during treatment, especially in patients with complications like disseminated intravascular coagulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cerebral infarction after treatment with dabrafenib plus trametinib for BRAF-V600E-positive non-small cell lung cancer: A case report. Taniguchi, Y., Tamiya, A., Yanagisawa, A., et al.[2023]

In a case series of 4 patients with BRAF V600E primary brain tumors, dual therapy with dabrafenib and trametinib led to near-complete or complete clinical responses in three patients after 8 weeks, demonstrating significant efficacy.

The combination therapy not only showed greater effectiveness than dabrafenib alone but also helped reduce skin-related side effects, such as keratosis, highlighting its potential to improve patient tolerability during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual BRAF/MEK therapy in BRAF V600E-mutated primary brain tumors: a case series showing dramatic clinical and radiographic responses and a reduction in cutaneous toxicity. Bernstein, A., Mrowczynski, OD., Greene, A., et al.[2023]

In a study of 421 patients undergoing salvage radiotherapy (SRT) after prostate surgery, the use of advanced techniques like intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) significantly reduced the incidence of late gastrointestinal (GI) toxicities to 4.8%.

However, increasing the radiation dose to 68 Gy or more was linked to a higher risk of genitourinary (GU) toxicities, indicating that while advanced techniques can help minimize some side effects, higher doses may still pose risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of advanced radiotherapy techniques and dose intensification on toxicity of salvage radiotherapy after radical prostatectomy. Tomita, N., Uchiyama, K., Mizuno, T., et al.[2021]

In a phase I clinical trial involving 10 patients with brain metastases, trametinib combined with whole brain radiation therapy (WBRT) was found to be highly toxic, with a maximum tolerated dose (MTD) of less than 1.5 mg due to significant side effects like thrombocytopenia and diarrhea.

The study indicated that 89% of patients completed the therapy as planned, but the trial was closed early due to a shift in treatment practices towards stereotactic radiosurgery (SRS), highlighting the need for further research on the safety of trametinib in combination with SRS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of trametinib in combination with whole brain radiation therapy for brain metastases. Palmer, JD., Prasad, RN., Fabian, D., et al.[2023]

In a study of 36 patients with BRAF V600E-mutant anaplastic thyroid cancer, the combination of dabrafenib and trametinib showed a significant overall response rate of 56%, with three patients achieving complete responses.

The treatment demonstrated manageable safety, with no new adverse effects identified, and improved median progression-free survival of 6.7 months and overall survival of 14.5 months, indicating it is a promising option for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study. Subbiah, V., Kreitman, RJ., Wainberg, ZA., et al.[2022]

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New Treatment Approved for Certain Glioma Patients

Using a measure called “Overall Response Rate (ORR),” trials found that 33% of high-grade glioma patients responded to the combination, while 50 ...

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Dabrafenib plus trametinib resulted in significantly more responses, longer progression-free survival, and a better safety profile than standard chemotherapy ...