MAPK Inhibitors + Anti-PD1 Therapy for Brain Tumors
Recruiting in Palo Alto (17 mi)
+2 other locations
Overseen ByAshley Plant-Fox, MD
Age: < 65
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Ann & Robert H Lurie Children's Hospital of Chicago
No Placebo Group
Breakthrough Therapy
Trial Summary
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.
Is the drug combination of Dabrafenib, Nivolumab, and Trametinib promising for treating brain tumors?Yes, the combination of Dabrafenib, Nivolumab, and Trametinib shows promise for treating brain tumors. Research indicates that using these drugs together can lead to significant tumor shrinkage and stable disease in some cases. This combination targets specific mutations in brain tumors and has shown encouraging results in patients who did not respond to other treatments.245811
What data supports the idea that MAPK Inhibitors + Anti-PD1 Therapy for Brain Tumors is an effective treatment?The available research shows that using MAPK inhibitors like dabrafenib and trametinib, combined with anti-PD1 therapy, has been effective in treating brain tumors with the BRAF V600E mutation. For example, a study reported dramatic clinical and radiographic responses in adults with high-grade gliomas, a type of brain tumor. Another study found substantial clinical responses in primary brain cancers treated with this combination, along with a reduction in skin-related side effects. These findings suggest that this treatment can be effective for certain brain tumors, especially those with specific genetic mutations.357911
Do I need to stop my current medications to join the trial?The trial protocol does not specify if you must stop all current medications, but there is a 21-day washout period for chemotherapeutic agents, a washout period of two half-lives for targeted agents, and a 4-week washout for antibody therapies. You must stop taking herbal preparations and cannabis products 7 days before enrollment. If you are on dexamethasone, the dose must be stable or decreasing for at least 1 week before enrollment.
What safety data exists for MAPK inhibitors and anti-PD1 therapy in brain tumors?The combination of dabrafenib and trametinib has been evaluated for safety in various studies. In a phase 2 trial for BRAFV600E-mutant gliomas, the safety of dabrafenib plus trametinib was assessed. In melanoma studies, continuous MAPK pathway inhibition with anti-PD1 therapy showed high response rates but also a high frequency of treatment-related adverse events. In non-small cell lung cancer, dabrafenib plus trametinib was well tolerated, with common adverse events including pyrexia, nausea, and fatigue. In metastatic melanoma, the combination was well tolerated with no new safety signals identified, even in patients with brain metastases. Overall, the combination therapy has shown a manageable safety profile across different cancer types.1691011
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 can do most activities but may need help.
My organs and bone marrow are functioning well.
My child has a high-grade glioma with a BRAFV600 mutation.
I am between 1 and 26 years old.
I agree to use birth control during and for 30 days after the study, and if I can become pregnant, I have a negative pregnancy test.
My high-grade glioma has grown after radiation or is larger than 1cm.
Exclusion Criteria
I am allergic to medications similar to dabrafenib, trametinib, or nivolumab.
I have never stopped taking BRAF or MEK inhibitors due to side effects.
I have not had major surgery in the last 28 days or minor surgery in the last 7 days.
My cancer has spread to other parts of my body.
I have been treated with both MAPK inhibitor and checkpoint blockade therapy.
I am currently using herbal or cannabis products.
I do not have active pancreatitis, recent pancreatitis, or lung disease.
I have an active HIV, Hepatitis B, or Hepatitis C infection.
Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: Trametinib combined with nivolumab (Cohort A)Experimental Treatment1 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 Treatment1 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
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Children's National HospitalWashington DC, United States
Ann & Robert H. Lurie Children's Hospital of ChicagoChicago, IL
Memorial Sloan Kettering Cancer CenterNew York, NY
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Who is running the clinical trial?
Ann & Robert H Lurie Children's Hospital of ChicagoLead Sponsor
References
Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. [2022]Dabrafenib is an inhibitor of BRAF kinase that is selective for mutant BRAF. We aimed to assess its safety and tolerability and to establish a recommended phase 2 dose in patients with incurable solid tumours, especially those with melanoma and untreated, asymptomatic brain metastases.
Overcoming resistance to single-agent therapy for oncogenic BRAF gene fusions via combinatorial targeting of MAPK and PI3K/mTOR signaling pathways. [2019]Pediatric low-grade gliomas (PLGGs) are frequently associated with activating BRAF gene fusions, such as KIAA1549-BRAF, that aberrantly drive the mitogen activated protein kinase (MAPK) pathway. Although RAF inhibitors (RAFi) have been proven effective in BRAF-V600E mutant tumors, we have previously shown how the KIAA1549-BRAF fusion can be paradoxically activated by RAFi. While newer classes of RAFi, such as PLX8394, have now been shown to inhibit MAPK activation by KIAA1549-BRAF, we sought to identify alternative MAPK pathway targeting strategies using clinically relevant MEK inhibitors (MEKi), along with potential escape mechanisms of acquired resistance to single-agent MAPK pathway therapies. We demonstrate effectiveness of multiple MEKi against diverse BRAF-fusions with novel N-terminal partners, with trametinib being the most potent. However, resistance to MEKi or PLX8394 develops via increased RTK expression causing activation of PI3K/mTOR pathway in BRAF-fusion expressing resistant clones. To circumvent acquired resistance, we show potency of combinatorial targeting with trametinib and everolimus, an mTOR inhibitor (mTORi) against multiple BRAF-fusions. While single-agent mTORi and MEKi PLGG clinical trials are underway, our study provides preclinical rationales for using MEKi and mTORi combinatorial therapy to stave off or prevent emergent drug-resistance in BRAF-fusion driven PLGGs.
Rapid Clinical and Radiographic Response With Combined Dabrafenib and Trametinib in Adults With BRAF-Mutated High-Grade Glioma. [2019]BRAF V600E mutations have been successfully treated with targeted therapy in melanoma, non-small cell lung cancer, and thyroid cancer. Interestingly, these mutations have also been identified in a subset of pediatric and adult brain tumors, with several cases reportedly responding to targeted therapy. However, these reports have been limited to single-agent BRAF inhibitor therapy and recurrent disease. Herein, we report dramatic clinical and radiographic responses to combination dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in 2 adults with high-grade gliomas (HGGs), with 1 patient treated in the first-line setting. These observations, together with prior case reports, advocate for routine screening of BRAF point mutations in adult HGGs, and suggest that treatment with dual-targeted therapy, even in newly diagnosed cases, is safe and effective.
Concurrent BRAF/MEK Inhibitors in BRAF V600-Mutant High-Grade Primary Brain Tumors. [2019]BRAF V600 mutations are being identified in patients with primary brain tumors more often as molecular testing becomes widely available. Targeted treatment with BRAF inhibitors has been attempted in individual cases with some responses, whereas others showed no response or developed resistance. Preclinical work suggests that gliomas could be more responsive to the concurrent use of BRAF and MEK inhibition for MAP kinase pathway suppression. This report presents 2 cases of malignant brain tumors with BRAF V600E mutations that were resistant to radiation and temozolomide, and reports on their response to targeted treatment with the BRAF and MEK inhibitors dabrafenib and trametinib. One patient with an anaplastic pleomorphic xanthoastrocytoma experienced a partial response for 14 months, demonstrated by progressive tumor shrinkage and clinical improvement; however, this was followed by clinical and radiographic progression. The patient with glioblastoma continued to have stable disease after 16 months of treatment. These cases are encouraging in a disease that urgently needs new treatments. Further work is necessary to understand response rates, duration, and survival in primary brain tumors.
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]BRAF V600E is a common oncogenic driver in a variety of primary brain tumors. Dual inhibitor therapy using dabrafenib (a selective oral inhibitor of several mutated forms of BRAF kinase) and trametinib (a reversible inhibitor of MEK1 and MEK2) has been used successfully for treatment of metastatic melanoma, anaplastic thyroid cancer, and other tumor types, but has been reported in only a few patients with primary brain tumors and none with pleomorphic xanthoastrocytoma. Here, the authors report on the substantial clinical response and reduction in cutaneous toxicity in a case series of BRAF V600E primary brain cancers treated with dual BRAF/MEK inhibitor therapy.
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]In clinical trials, dabrafenib plus trametinib improved overall survival (OS) compared with single-agent BRAF inhibitors (BRAFi) in patients with BRAF V600-mutant unresectable or metastatic melanoma. We investigated dabrafenib plus trametinib therapy in a compassionate-use setting [Named Patient Program (NPP); DESCRIBE II]. A retrospective chart review of patients with BRAF V600-mutated unresectable stage III/IV melanoma receiving dabrafenib plus trametinib as compassionate use was conducted. Treatment patterns and duration, clinical outcomes, and tolerability were evaluated. Of 271 patients, 92.6% had stage IV melanoma, including 36.5% with brain metastases. Overall, 162 patients (59.8%) were BRAFi naive and 171 (63.1%) received first-line dabrafenib plus trametinib. Among BRAFi-naive patients, the overall response rate (ORR) was 67.3%, median OS (mOS) was 20.0 months, and median progression-free survival (mPFS) was 7.5 months. In BRAFi-naive patients with known brain metastases (n = 62), ORR was 61.3%, mOS was 15.5 months, and mPFS was 6.2 months. Eighty-four patients received BRAFi monotherapy for >30 days and switched to dabrafenib plus trametinib prior to progression. Of these 84 patients, 63 had known disease status at the time of switch, and 22 improved with the combination therapy. No new safety signals were identified, and dabrafenib plus trametinib was well tolerated. Dabrafenib plus trametinib showed substantial clinical activity in NPP patients with BRAF V600-mutated unresectable or metastatic melanoma. Analysis of treatment patterns demonstrated the effectiveness of the combination in patients with brain metastases and across lines of therapy with a well tolerated and manageable safety profile.
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]BRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM). In a large phase IIIb, single-arm, open-label, multicenter French study, we assessed safety, response to treatment, progression-free survival (PFS) and factors associated with progression, and stratified the population into risk groups.
Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy. [2022]Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by BrafV600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by KrasG12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γhi, and CD8+ cytotoxic and proliferative (versus CD4+ regulatory) T cells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust T cell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.
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]Label="BACKGROUND">Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAFV600E mutation-positive high-grade glioma and low-grade glioma.
BRAF Inhibitors in Non-Small Cell Lung Cancer. [2022]RAF family proteins are serine-threonine kinases that play a central role in the MAPK pathway which is involved in embryogenesis, cell differentiation, cell proliferation and death. Deregulation of this pathway is found in up to 30% of all human cancers and BRAF mutations can be identified in 1.5-3.5% of NSCLC patients. Following the positive results obtained through the combination of BRAF and MEK inhibitors in BRAF-mutant melanoma, the same combination was prospectively assessed in BRAF-mutant NSCLC. In cohort B of the BRF113928 trial, 57 pretreated NSCLC patients were treated with dabrafenib plus trametinib: an ORR of 68.4%, a disease control rate of 80.7%, a median PFS of 10.2 months and a median OS of 18.2 months were observed. Similar results were reported in the first-line setting (cohort C), with an ORR of 63.9%, a DCR of 75% and a median PFS and OS of 10.2 and 17.3 months, respectively. The combination was well tolerated: the main adverse events were pyrexia (64%), nausea (56%), diarrhoea (56%), fatigue (36%), oedema (36%) and vomiting (33%). These positive results led to the approval of the combination of dabrafenib and trametinib for the treatment of BRAF V600E metastatic NSCLC patients regardless of previous therapy. Ongoing research should better define the role of new generation RAF inhibitors for patients with acquired resistance, the activity of chemo-immunotherapy or the combination of TKIs with chemotherapy or with immunotherapy in patients with BRAF-mutated cancers.
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]Label="BACKGROUND">Continuous combination of MAPK pathway inhibition (MAPKi) and anti-programmed death-(ligand) 1 (PD-(L)1) showed high response rates, but only limited improvement in progression-free survival (PFS) at the cost of a high frequency of treatment-related adverse events (TRAE) in patients with BRAFV600-mutated melanoma. Short-term MAPKi induces T-cell infiltration in patients and is synergistic with anti-programmed death-1 (PD-1) in a preclinical melanoma mouse model. The aim of this phase 2b trial was to identify an optimal regimen of short-term MAPKi with dabrafenib plus trametinib in combination with pembrolizumab.