A Pilot Study Evaluating the Toxicity and Clinical Benefit of Mitogen-activated Protein Kinase (MAPK) Pathway Inhibition Combined With Programmed Cell Death-1 Checkpoint Blockade (Anti-PD1) for the Treatment of BRAF-altered Pediatric Gliomas
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.
⁃ Cohort A Only:
• Patients with histologically confirmed diagnosis of pediatric high- or low-grade glioma harboring a KIAA1549-BRAF fusion: Low-grade glioma that is recurrent or progressive OR High-grade glioma that is newly diagnosed or recurrent OR
• Patients with NF1-associated gliomas or NF1-altered glioma: Low-grade glioma that is recurrent or progressive OR High-grade glioma that is newly diagnosed or recurrent OR Transforming glioma that is newly diagnosed or recurrent
⁃ Cohort B Only:
• Patients with histologically confirmed diagnosis of pediatric low-grade glioma harboring a BRAFV600 mutation that is recurrent or progressive OR
• Patients with histologically confirmed diagnosis of non-brainstem pediatric high-grade glioma harboring BRAFV600 mutation that is newly diagnosed, recurrent, or progressive
⁃ All Cohorts:
• Patients must be ≥1 and ≤26 years of age at the time of enrollment.
• Patients must have a performance status of Karnofsky \>50% for patients \>16 years old and Lansky \>50% for patients \<16 years old.
• Patients must have adequate organ and bone marrow function
• The effects of dabrafenib, trametinib, and nivolumab on the developing human fetus are unknown. For this reason, patients of childbearing potential (POCBP) and patients with sperm-producing reproductive capacity (PWSPRC) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from time of informed consent for the duration of study participation and for 30 days following completion of therapy. POCBP must have a negative pregnancy test.
• Patients with neurological deficits that are stable for a minimum of 1 week prior to enrollment are eligible.
⁃ Note: A baseline detailed neurological exam should clearly document the neurological status of the patient at the time of enrollment on the study.
⁃ \- Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment. Total dexamethasone dose at time of enrollment must be less than or equal to 2 mg/day total or 0.5 mg/kg/day, whichever is smaller.
⁃ LGG Only
• Patients must have received a prior BRAF inhibitor (first or second generation), MEK inhibitor, or a combination. The response to this therapy must be known and information provided at study enrollment.
• Patients must have recovered from acute treatment-related toxicities (defined as \<Grade 1, excludes alopecia) prior to entering this study.
⁃ HGG Only
• Patients must have received prior radiotherapy \>12 weeks prior to enrollment.
• Patients must have recovered from acute treatment-related toxicities (defined as \<Grade 1, excludes alopecia) prior to entering this study.
• NF1 patients with transforming gliomas and high-grade gliomas are eligible regardless of prior systemic therapy.
• Patients who have received prior radiation therapy must have experienced progression post-radiation OR have measurable disease defined as residual tumor \>1cm in at least one dimension