MAPK Inhibitors + Anti-PD1 Therapy for Brain Tumors

Recruiting at 2 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

Trial Summary

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.

What data supports the effectiveness of the drug combination Dabrafenib, Trametinib, and Nivolumab for brain tumors?

Research shows that the combination of Dabrafenib and Trametinib has been effective in treating BRAF V600E-mutated brain tumors, with reports of significant clinical and radiographic responses. Additionally, combining MAPK inhibitors with anti-PD1 therapy, like Nivolumab, has shown promise in enhancing immune response in melanoma, suggesting potential benefits for brain tumors as well. ^{1 2 3 4 5}

Is the combination of MAPK inhibitors and anti-PD1 therapy safe for humans?

The combination of dabrafenib and trametinib, which are MAPK inhibitors, has been generally well tolerated in patients with various cancers, including melanoma and non-small cell lung cancer. Common side effects include fever, nausea, diarrhea, fatigue, and vomiting, but no new safety concerns have been identified in these studies. ^{1 4 6 7 8}

How is the drug combination of Dabrafenib, Nivolumab, and Trametinib unique for treating brain tumors?

This drug combination is unique because it targets the MAPK pathway with Dabrafenib and Trametinib, while also using Nivolumab to enhance the immune system's ability to fight cancer. This approach is particularly promising for brain tumors with BRAF V600 mutations, as it combines targeted therapy with immune checkpoint inhibition to potentially overcome resistance and improve treatment outcomes. ^{1 3 9 10 11}

What is the purpose of this trial?

Pediatric gliomas harboring BRAF-alterations, commonly BRAFV600 mutation or KIAA1549-BRAF fusion, are currently treated with either chemotherapy or mitogen activated protein kinase (MAPK) inhibitors, such as, dabrafenib and/or trametinib. Unfortunately, some BRAF-altered gliomas can progress or have rebound growth after discontinuation of therapy. Data from BRAFV600E-mutant melanoma has shown potential synergy between MAPK inhibition and anti-programmed cell death 1 (anti-PD1) checkpoint blockade. Anti-PD1 therapy, such as, nivolumab can block the PD1 receptor on T cells, a marker of T cell exhaustion, allowing a continued or more robust anti-tumor immune response. Here, investigators will combine MAPK inhibition with anti-PD1 therapy in recurrent, refractory low grade BRAF-altered glioma and newly diagnosed or recurrent BRAF-altered or NF-altered high grade glioma.

Research Team

Ashley Plant-Fox, MD

Principal Investigator

Ann & Robert H Lurie Children's Hospital of Chicago

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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]

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]

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]

References

1. England 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. [2023]

2. England 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. [2021]

3. 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]

4. England 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. [2022]

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

Rapid Clinical and Radiographic Response With Combined Dabrafenib and Trametinib in Adults With BRAF-Mutated High-Grade Glioma. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

BRAF Inhibitors in Non-Small Cell Lung Cancer. [2022]

7. England 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). [2023]

8. England pubmed.ncbi.nlm.nih.gov

Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. [2022]

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

Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy. [2022]

10. United States 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. [2019]

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

Concurrent BRAF/MEK Inhibitors in BRAF V600-Mutant High-Grade Primary Brain Tumors. [2019]