MAPK Inhibitors + Anti-PD1 Therapy for Brain Tumors

Recruiting at 3 trial locations

Overseen By Monica Newmark

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Ann & Robert H Lurie Children's Hospital of Chicago

Must be taking: BRAF inhibitors, MEK inhibitors

Must not be taking: Herbal medications, Cannabis products

Disqualifiers: Autoimmune disorders, Immunodeficiencies, Pancreatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 28

Duration: 1 year

27 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new approach to treating brain tumors in young people by combining two therapies: MAPK inhibitors and anti-PD1 therapy. Researchers aim to determine if this combination can combat tumors with specific BRAF gene changes, which may cause treatments to fail or tumors to recur. The trial includes two groups: one tests trametinib (a MAPK inhibitor) with nivolumab (an anti-PD1 therapy), while the other adds dabrafenib (another MAPK inhibitor) to the mix. It seeks patients with certain gliomas (a type of brain tumor) that have specific BRAF gene changes or are linked to NF1, whose condition has progressed or returned. As a Phase 1, Phase 2 trial, this study focuses on understanding the treatment's effects in people and measuring its initial effectiveness, offering patients a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial requires a 21-day washout period (time without taking certain medications) for all chemotherapeutic agents, a washout period of two half-lives for any targeted agents like MAPK inhibitors, and a 4-week washout period for any antibody therapies. Additionally, you must stop taking any herbal preparations or cannabis products 7 days before enrollment.

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

A previous study found dabrafenib and trametinib safe for children with certain brain tumors. These treatments block signals that help tumors grow. The FDA has approved this combination for children with specific low-grade gliomas, indicating it is generally well-tolerated.

Research has also examined nivolumab, a treatment that helps the immune system fight cancer. Studies have shown that nivolumab can be safely used with trametinib.

While serious side effects can occur, they are uncommon. Most patients experience mild to moderate issues, such as tiredness or skin rash. These findings suggest the treatments are reasonably safe for many patients considering a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for pediatric gliomas because they explore innovative combinations that target specific genetic mutations. Unlike traditional chemotherapy and radiation, which broadly attack cancer cells, these therapies use MAPK inhibitors like dabrafenib and trametinib alongside nivolumab, an immune checkpoint inhibitor. This combination not only targets the BRAF mutation found in some gliomas but also helps the immune system recognize and fight cancer cells more effectively. By focusing on these precise mechanisms, researchers hope to improve outcomes and reduce side effects compared to conventional treatments.

What evidence suggests that this trial's treatments could be effective for brain tumors?

This trial will evaluate the effectiveness of different drug combinations for treating certain brain tumors. In Cohort A, participants will receive a combination of trametinib and nivolumab. Research has shown that trametinib with nivolumab improves treatment efficacy, making it a promising option for children with gliomas. In Cohort B, participants will receive a combination of dabrafenib, trametinib, and nivolumab. Studies have found that using dabrafenib and trametinib together is more effective and safer than traditional chemotherapy, particularly in shrinking tumors and preventing their growth. These combined treatments have also led to longer-lasting improvements in patients with similar genetic changes. This evidence supports using these drug combinations to effectively target and manage difficult brain tumors. ^{3 6 7 8 9}

Who Is on the Research Team?

Ashley Plant-Fox, MD

Principal Investigator

Ann & Robert H Lurie Children's Hospital of Chicago

Are You a Good Fit for This Trial?

This trial is for children with low-grade gliomas or high-grade gliomas that have specific genetic changes (BRAF-alterations). It's aimed at those whose tumors have grown despite previous treatments or are newly diagnosed. Patients must be able to perform daily activities with minimal assistance.

Inclusion Criteria

I am a child with a specific brain tumor type that is either new, getting worse, or has come back.

I can do most activities but may need help.

I have recovered from any serious side effects of my previous cancer treatments.

Exclusion Criteria

Patients with autoimmune disorders, immune disorders, immunodeficiencies, Crohn's disease, ulcerative colitis, or other inflammatory bowel disease

I am allergic to medications similar to dabrafenib, trametinib, or nivolumab.

I have never stopped taking BRAF or MEK inhibitors due to side effects.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive combination therapy with trametinib, nivolumab, and optionally dabrafenib for up to 1 year or 13 cycles

1 year

Cycle length is every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Dabrafenib
• Nivolumab
• Trametinib

Trial Overview The study tests combining MAPK inhibitors (Dabrafenib and Trametinib) with an anti-PD1 therapy (Nivolumab) in pediatric patients. The goal is to see if this combination can better control tumor growth compared to current treatments.

How Is the Trial Designed?

Group I: Trametinib combined with nivolumab (Cohort A) Experimental Treatment 1 Intervention

Patients with histologically confirmed diagnosis of pediatric high- or low-grade glioma harboring a KIAA1549-BRAF fusion. Patients with NF1-associated gliomas or NF1-altered glioma. Patients in Cohort A will receive trametinib and nivolumab combination therapy. Trametinib will be administered at 0.025 mg/kg/dose orally once daily. Nivolumab will be administered at 6 mg/kg/dose intravenously every 4 weeks. Cycle length will be every 28 days. Treatment will include 1 year or 13 cycles of combination therapy, whichever comes first. For patients with high grade glioma, therapy can be continued beyond the 13 cycles if they are deemed to have clinical benefit from the therapy. Patients will be followed for up to 5 years to evaluate clinical endpoints.

Group II: Dabrafenib + trametinib combined with nivolumab (Cohort B) Experimental Treatment 1 Intervention

Patients with histologically confirmed diagnosis of pediatric low-grade glioma harboring a BRAFV600 mutation that is recurrent or progressive or non-brainstem pediatric high-grade glioma harbor ng BRAFV600 mutation that is newly diagnosed, recurrent, or progressive. Cohort B will receive trametinib, nivolumab dabrafenib combination therapy. Trametinib will be administered at 0.025 mg/kg/dose orally once daily. Nivolumab will be administered at 6 mg/kg/dose intravenously every 4 weeks. Dabrafenib will be administered at a dose of 5.25 mg/kg/day orally divided into two doses, which shall be taken 12 hours apart. Cycle length will be every 28 days. Treatment will include 1 year or 13 cycles of combination therapy, whichever comes first. For patients with high grade glioma, therapy can be continued beyond the 13 cycles if they are deemed to have clinical benefit from the therapy. Patients will be followed for up to 5 years to evaluate clinical endpoints.

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

Approved in European Union as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation
• Adjuvant treatment of melanoma with a BRAF V600 mutation

Approved in United States as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600E mutation
• Adjuvant treatment of melanoma with a BRAF V600E or V600K mutation
• Metastatic non-small cell lung cancer with a BRAF V600E mutation

Approved in Canada as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation
• Adjuvant treatment of melanoma with a BRAF V600 mutation

Approved in Japan as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Who Is Running the Clinical Trial?

Ann & Robert H Lurie Children's Hospital of Chicago

Lead Sponsor

Trials

275

Recruited

5,182,000+

Published Research Related to This Trial

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]

Two cases of malignant brain tumors with BRAF V600E mutations showed promising responses to targeted treatment with BRAF and MEK inhibitors, dabrafenib and trametinib, despite previous resistance to radiation and temozolomide.

One patient had a partial response lasting 14 months, while the other maintained stable disease for 16 months, highlighting the potential of this combination therapy in treating aggressive brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent BRAF/MEK Inhibitors in BRAF V600-Mutant High-Grade Primary Brain Tumors. Schreck, KC., Guajardo, A., Lin, DDM., et al.[2019]

Dabrafenib, a selective BRAF kinase inhibitor, was found to be safe and well-tolerated in a phase 1 trial involving 184 patients with incurable solid tumors, with a recommended phase 2 dose established at 150 mg twice daily.

The treatment showed significant efficacy, particularly in patients with Val600 BRAF-mutant melanoma, where 69% of patients experienced a response, and notable reductions in brain metastases were observed in 90% of patients with untreated brain lesions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Falchook, GS., Long, GV., Kurzrock, R., et al.[2022]

Combining PD-1/L1 inhibitors with MAPK-targeted therapies can enhance treatment effectiveness against melanoma and other cancers by improving immune responses, particularly when PD-1/L1 therapy is administered first.

In mouse models, this sequencing not only boosts the immune system's ability to fight tumors but also significantly reduces the spread of melanoma to the brain, leading to better survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy. Wang, Y., Liu, S., Yang, Z., et al.[2022]

MEK inhibitors (MEKi), particularly trametinib, have shown effectiveness against pediatric low-grade gliomas (PLGGs) driven by various BRAF fusions, including KIAA1549-BRAF, which is important since traditional RAF inhibitors can paradoxically activate these fusions.

To combat resistance that develops from increased RTK expression activating the PI3K/mTOR pathway, combining trametinib with everolimus (an mTOR inhibitor) may provide a more effective treatment strategy for BRAF-fusion driven PLGGs, offering a promising approach to prevent drug resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overcoming resistance to single-agent therapy for oncogenic BRAF gene fusions via combinatorial targeting of MAPK and PI3K/mTOR signaling pathways. Jain, P., Silva, A., Han, HJ., et al.[2019]

In a clinical trial involving 57 pretreated NSCLC patients, the combination of dabrafenib and trametinib showed a high overall response rate (ORR) of 68.4% and a median overall survival (OS) of 18.2 months, indicating its efficacy in treating BRAF V600E mutant non-small cell lung cancer.

The treatment was well tolerated, with manageable side effects such as pyrexia and nausea, leading to its approval for BRAF V600E metastatic NSCLC patients, regardless of prior therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BRAF Inhibitors in Non-Small Cell Lung Cancer. Sforza, V., Palumbo, G., Cascetta, P., et al.[2022]

In a compassionate-use setting involving 271 patients with BRAF V600-mutant unresectable or metastatic melanoma, the combination of dabrafenib and trametinib demonstrated a high overall response rate of 67.3% and a median overall survival of 20.0 months for BRAFi-naive patients.

The treatment was well tolerated with no new safety concerns, showing significant clinical activity even in patients with brain metastases, indicating its effectiveness across different treatment lines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus trametinib is effective in the treatment of BRAF V600-mutated metastatic melanoma patients: analysis of patients from the dabrafenib plus trametinib Named Patient Program (DESCRIBE II). Atkinson, V., Sandhu, S., Hospers, G., et al.[2023]

Combination therapy using dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) showed dramatic clinical and radiographic responses in two adults with high-grade gliomas, indicating a promising treatment approach.

The study suggests that routine screening for BRAF V600E mutations in adult high-grade gliomas is beneficial, as dual-targeted therapy may be safe and effective even for newly diagnosed patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid Clinical and Radiographic Response With Combined Dabrafenib and Trametinib in Adults With BRAF-Mutated High-Grade Glioma. Johanns, TM., Ferguson, CJ., Grierson, PM., et al.[2019]

Dabrafenib plus trametinib demonstrated significant efficacy in treating BRAFV600E mutation-positive high-grade glioma, with a 33% objective response rate in 45 patients, including complete and partial responses.

In the low-grade glioma cohort, the treatment showed even higher efficacy, with a 69% objective response rate in 13 patients, indicating that this combination therapy could be a promising option for patients with these types of tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. Wen, PY., Stein, A., van den Bent, M., et al.[2022]

In a large study of 856 patients with advanced BRAF V600-mutant melanoma, the combination of dabrafenib and trametinib showed a median progression-free survival (PFS) of 8.02 months, indicating its efficacy in this patient population.

Factors such as elevated lactate dehydrogenase (LDH), poor Eastern Cooperative Oncology Group Performance Status (ECOG PS), and the presence of brain metastasis were associated with shorter PFS, highlighting the importance of these factors in predicting treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, safety and factors associated with disease progression in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: An open label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib. Saiag, P., Robert, C., Grob, JJ., et al.[2021]

In a phase 2b trial involving 33 patients with BRAFV600E/K-mutant advanced melanoma, the combination of pembrolizumab with intermittent dabrafenib and trametinib showed promising efficacy, with a notable increase in objective response rates compared to pembrolizumab alone, particularly at week 18 where cohort 4 reached a 50% response rate.

The study indicated that intermittent treatment with dabrafenib and trametinib resulted in a more tolerable safety profile, with lower rates of severe treatment-related adverse events (TRAE) compared to continuous therapy, suggesting a better balance between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IMPemBra: a phase 2 study comparing pembrolizumab with intermittent/short-term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation. Rozeman, EA., Versluis, JM., Sikorska, K., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10809164/

Dabrafenib plus Trametinib: A breakthrough in pediatric low ... Dabrafenib and trametinib are targeted therapies that are recently approved by Food and Drug Administration for pediatric patients with pLGG ...

2. cancer.gov cancer.gov/news-events/cancer-currents-blog/2022/glioma-brain-cancer-dabrafenib-trametinib

Dabrafenib–Trametinib Combo Better than Chemo for Glioma The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) was safer and better than standard chemotherapy at shrinking tumors and keeping them at bay.

3. onclive.com onclive.com/view/longterm-and-brain-mets-data-demonstrate-strong-dabrafenibtrametinib-efficacy-in-melanoma

Long-Term and Brain Mets Data Demonstrate Strong ... Favorable long-term phase II results of the combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) in patients with BRAF V600-mutant ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02224781

Study Details | NCT02224781 | Dabrafenib and Trametinib ... This phase III trial studies how well initial treatment with ipilimumab and nivolumab followed by dabrafenib and trametinib works and compares it to initial ...

5. cancernetwork.com cancernetwork.com/view/nivolumab-ipilimumab---dabrafenib-and-trametinib-improved-survival-for-braf-metastatic-melanoma

Nivolumab/Ipilimumab +/- Dabrafenib and Trametinib ... The combination of nivolumab and ipilimumab followed by treatment with dabrafenib and trametinib, if necessary, resulted in greater overall survival at 2 years.

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2025-03278

Nivolumab in Combination with Trametinib with or without ... To evaluate the safety and tolerability of dabrafenib mesylate (dabrafenib) and trametinib in combination with nivolumab for the treatment of pediatric glioma.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12133646/

The safety and efficacy of dabrafenib plus trametinib for ... ... safety and efficacy of dabrafenib plus trametinib treatment for patients with metastatic brain tumors. The pooled 1-year OS rate of 45% [95 ...

8. ema.europa.eu ema.europa.eu/en/documents/rmp/tafinlar-epar-risk-management-plan_en.pdf

Dabrafenib EU Safety Risk Management Plan trametinib. Rationale and study objectives: This study will facilitate data collection of the long-term outcomes of pediatric subjects who have been treated ...

9. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-dabrafenib-trametinib-pediatric-patients-low-grade-glioma-braf-v600e-mutation

FDA approves dabrafenib with trametinib for pediatric ... FDA approves dabrafenib with trametinib for pediatric patients with low-grade glioma with a BRAF V600E mutation. Resources for Information ...