Dabrafenib + Trametinib After Radiation for Brain Cancer

Recruiting at 137 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

58 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

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.

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.

What safety data exists for Dabrafenib + Trametinib after radiation for brain cancer?

The provided research does not directly address the safety data for Dabrafenib + Trametinib after radiation for brain cancer. However, it includes studies on the safety and toxicity of various radiotherapy techniques, such as stereotactic radiotherapy (SRT), intensity-modulated radiotherapy (IMRT), and image-guided radiotherapy (IGRT), in different cancer treatments. These studies highlight the importance of advanced radiotherapy techniques in reducing toxicity, but specific safety data for the combination of Dabrafenib and Trametinib with radiation therapy for brain cancer is not covered in the provided abstracts. ^{1 2 3 4 5}

Is the combination of Dabrafenib, Trametinib, and various forms of radiotherapy generally safe for humans?

Research shows that advanced radiotherapy techniques like intensity-modulated radiotherapy (IMRT) and stereotactic body radiation therapy (SBRT) are generally safe, with some risk of gastrointestinal and genitourinary side effects. These techniques have been used safely in treating various cancers, including prostate and cervical cancer. ^{1 2 3 4 5}

Is Radiation Therapy a promising treatment for brain cancer when used with Dabrafenib and Trametinib?

Radiation Therapy, when combined with the drugs Dabrafenib and Trametinib, shows promise for treating brain cancer. This combination has been effective in treating other cancers with similar mutations, and early studies suggest it could work well for brain tumors too. ^{6 7 8 9 10}

How is the treatment of Dabrafenib + Trametinib after radiation therapy unique for brain cancer?

This treatment combines radiation therapy with two drugs, Dabrafenib and Trametinib, which target specific mutations (BRAF V600E) in brain tumors. This approach is unique because it combines targeted drug therapy with radiation, potentially enhancing effectiveness against certain brain cancers with specific genetic mutations. ^{6 7 8 9 10}

What data supports the idea that Dabrafenib + Trametinib After Radiation for Brain Cancer is an effective treatment?

The available research does not provide specific data on the effectiveness of Dabrafenib + Trametinib after radiation for brain cancer. The studies focus on different radiotherapy techniques and their advancements, but they do not directly address the combination of Dabrafenib and Trametinib with radiation for brain cancer. Therefore, we cannot conclude its effectiveness based on the provided information. ^{2 11 12 13 14}

What data supports the effectiveness of the treatment Dabrafenib + Trametinib after radiation for brain cancer?

Research shows that advanced radiotherapy techniques like intensity-modulated radiotherapy (IMRT) and stereotactic radiosurgery can improve outcomes for brain tumors by precisely targeting cancer cells while sparing healthy tissue. These methods are part of the treatment plan in the trial, suggesting potential effectiveness in combination with Dabrafenib and Trametinib. ^{2 11 12 13 14}

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

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]

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]

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 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]

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]

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]

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 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]

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 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 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]

Citations

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

Early clinical outcomes for 3 radiation techniques for brain metastases: focal versus whole-brain. [2016]

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

Intensity-modulated stereotactic radiotherapy vs. stereotactic conformal radiotherapy for the treatment of meningioma located predominantly in the skull base. [2022]

3. United States 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. [2021]

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

Improving radiotherapy for brain tumors. [2005]

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

Radiotherapy for brain tumors. [2019]

6. France pubmed.ncbi.nlm.nih.gov

Toxicity and time lapse between immunotherapy and stereotactic radiotherapy of brain metastases. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Impact of advanced radiotherapy techniques and dose intensification on toxicity of salvage radiotherapy after radical prostatectomy. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Radiotherapy of Cervical Cancer. [2017]

9. England pubmed.ncbi.nlm.nih.gov

Current use of stereotactic body radiation therapy for low and intermediate risk prostate cancer: A National Cancer Database Analysis. [2021]

10. Ireland pubmed.ncbi.nlm.nih.gov

Phase I study of trametinib in combination with whole brain radiation therapy for brain metastases. [2023]

11. Singapore 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. [2023]

12. United States 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. [2023]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Treatment related toxicities with combination BRAF and MEK inhibitor therapy in resected stage III melanoma. [2022]

14. England 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. [2022]