Nivolumab in Combination with Trametinib with or without Dabrafenib for the Treatment of Newly Diagnosed, Progressive or Recurrent Low Grade or High Grade Childhood Gliomas

Inclusion Criteria

• COHORT A: 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 ** Note: LGG diagnoses may include, but are not limited to: low-grade gliomas (ganglioglioma, pilocytic astrocytoma, pleomorphic xanthoastrocytoma, pilomyxoid astrocytoma, fibrillary astrocytoma, diffuse astrocytoma, low-grade glioma NOS; for those diagnosed since World Health Organization [WHO] 2021 classification was released: diffuse low-grade glioma, MAPK pathway-altered) ** Note: HGG diagnoses may include, but are not limited to: anaplastic astrocytoma, glioblastoma, diffuse midline glioma, anaplastic pleomorphic xanthoastrocytoma, anaplastic ganglioglioma; for those diagnosed since WHO 2021 classification was released: diffuse pediatric-type high-grade glioma, H3-wild type (WT) and isocitrate dehydrogenase (IDH)-WT, infant-type hemispheric glioma, high-grade astrocytoma with piloid features
• COHORT A: Patients with KIAA1549-BRAF fusions must have fusion confirmed by genetic testing or fluorescence in situ hybridization (FISH)
• COHORT A: Patients with NF1-associated glioma or NF1-altered glioma must have histologically confirmed disease
• COHORT A: Patients with transforming glioma must have demonstration of ATRX and/or p16 loss by IHC OR homozygous CKD2a deletion by FISH or next generation sequencing (NGS) in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory
• COHORT A: Patients must be ≥ 1 and ≤ 26 years of age at the time of enrollment
• COHORT A: Patients must have a performance status of Karnofsky ≥ 50% for patients > 16 years old and Lansky ≥ 50% for patients ≤ 16 years old
• COHORT A: Leukocytes (white blood cells [WBC]) ≥ 3,000/mcL
• COHORT A: Absolute neutrophil count (ANC) ≥ 75,000/mcL
• COHORT A: Hemoglobin (Hgb) ≥ 7 g/dL (transfusions allowed)
• COHORT A: Platelets (PLT) ≥ 75,000/mcL (transfusions allowed)
• COHORT A: Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
• COHORT A: Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) ≤ 3 x institutional ULN
• COHORT A: Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x institutional ULN
• COHORT A: Albumin ≥ 2 g/dL
• COHORT A: Creatinine based on age/sex assigned at birth as follows: * Male ** Age 1 ≤ 3 years: ≤ 0.7mg/dL ** Age 4 ≤ 13 years: ≤ 0.8mg/dL ** Age 11 ≤ 13 years: ≤ 1.2mg/dL ** Age 14 ≤ 16 years: ≤ 1.5mg/dL ** Age ≥ 17 years: ≤ 1.7mg/dL * Female Age 1 ≤ 3 years: ≤ 0.7mg/dL ** Age 4 ≤ 13 years: ≤ 0.8mg/dL ** Age 11 ≤ 13 years: ≤ 1.2mg/dL ** Age 14 ≤ 16 years: ≤ 1.4mg/dL ** Age ≥ 17 years: ≤ 1.4mg/dL
• COHORT A: Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70mL/min/1.73m^2 * eGFR is estimated GFR calculated by the abbreviated Modification of Diet in Renal Disease (MDRD) equation * Threshold creatinine values based on Schwartz formula for estimating GFR utilizing child length and status data published by the Centers for Disease Control and Prevention (CDC)
• COHORT A: 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 5 months following completion of therapy * Should a POCBP become pregnant or suspect they are pregnant while they or their partner are participating in this study, they should inform their treating physician immediately. PWSPRC treated or enrolled in this study must also agree to use adequate contraception from time of informed consent, for the duration of study participation, and 4 months after completion of treatment * Note: A POCBP is any person with an egg-producing reproductive tract (regardless of gender, sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: ** Has not undergone a hysterectomy or bilateral oophorectomy ** Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months)
• COHORT A: POCBP must have a negative pregnancy test prior to registration * Note: If a urine pregnancy test is positive or cannot be confirmed negative, a serum pregnancy test will be required
• COHORT A: Patients or their parents/legally authorized representatives (LARs) must have the ability to understand and the willingness to sign a written informed consent document. Written informed consent/assent must be signed prior to registration * Note: A subject will not be registered until they and/or their parents/LARs have signed an informed consent/assent. Furthermore, consent/assent should be obtained prior to the initiation of any clinical procedures of assessments performed for the purpose of determining protocol eligibility, which would not otherwise be consistent with the institution’s standards of clinical practice
• COHORT A: 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
• COHORT A: 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
• COHORT A: Patients must have the ability to swallow, retain, and absorb oral medication
• COHORT A: Patients that received standard of care (SOC) chemotherapy and other SOC tyrosine kinase inhibitor (TKI) or anticancer therapeutics must have a washout period of 21 days for chemotherapy, 28 days for bevacizumab, and two half-lives for all other anticancer agents. Patient should have recovered from all adverse events of these therapies to grade 1 or less * Note: A wash out period is not required for prior MAPK inhibitor therapy including but not limited to dabrafenib, trametinib, tovorafenib, etc
• COHORT A: Patients must have measurable disease at time of registration per Response Assessment in Neuro-Oncology (RANO) 2.0 criteria
• COHORT A; LGG ONLY: Patients must have received a prior BRAF inhibitor (first or second generation), mitogen-activated protein kinase (MEK) inhibitor, or a combination
• COHORT A; LGG ONLY: Patients must have recovered from acute treatment-related toxicities (defined as < grade 1, excludes alopecia) prior to entering this study
• COHORT A; HGG ONLY: Patients must have received prior radiotherapy ≥ 12 weeks prior to enrollment
• COHORT A; HGG ONLY: Patients must have recovered from acute treatment-related toxicities (defined as ≤ grade 1, excludes alopecia) prior to entering this study
• COHORT A; HGG ONLY: NF1 patients with transforming gliomas and high-grade gliomas are eligible regardless of prior systemic therapy
• COHORT B: Patients with histologically confirmed diagnosis of pediatric low-grade glioma harboring 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
• COHORT B: Patients must be ≥ 1 and ≤ 26 years of age at the time of enrollment
• COHORT B: BRAFV600 mutation status must be confirmed with genetic testing or positive IHC testing
• COHORT B: Patients must have a performance status of Karnofsky ≥ 50% for patients > 16 years old and Lansky ≥ 50% for patients ≤ 16 years old
• COHORT B: Leukocytes (WBC) ≥ 3,000/mcL
• COHORT B: Absolute neutrophil count (ANC) ≥ 75,000/mcL
• COHORT B: Hemoglobin (Hgb) ≥ 7 g/dL (transfusions allowed)
• COHORT B: Platelets (PLT) ≥ 75,000/mcL (transfusions allowed)
• COHORT B: Total bilirubin ≤ 1.5 x Institutional upper limit of normal (ULN)
• COHORT B: AST (SGOT) ≤ 3 x institutional ULN
• COHORT B: ALT (SGPT) ≤ 3 x institutional ULN
• COHORT B: Albumin ≥ 2 g/dL
• COHORT B: Creatinine based on age/sex assigned at birth as follows: * Male ** Age 1 ≤ 3 years: ≤ 0.7mg/dL ** Age 4 ≤ 13 years: ≤ 0.8mg/dL ** Age 11 ≤ 13 years: ≤ 1.2mg/dL ** Age 14 ≤ 16 years: ≤ 1.5mg/dL ** Age ≥ 17 years: ≤ 1.7mg/dL * Female Age 1 ≤ 3 years: ≤ 0.7mg/dL ** Age 4 ≤ 13 years: ≤ 0.8mg/dL ** Age 11 ≤ 13 years: ≤ 1.2mg/dL ** Age 14 ≤ 16 years: ≤ 1.4mg/dL ** Age ≥ 17 years: ≤ 1.4mg/dL
• COHORT B: Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73m^2 * eGFR is estimated GFR calculated by the abbreviated MDRD equation * Threshold creatinine values based on Schwartz formula for estimating GFR utilizing child length and status data published by the CDC
• COHORT B: 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 5 months following completion of therapy * Should a POCBP become pregnant or suspect they are pregnant while they or their partner are participating in this study, they should inform their treating physician immediately. PWSPRC treated or enrolled in this study must also agree to use adequate contraception from time of informed consent, for the duration of study participation, and 4 months after completion of treatment * Note: A POCBP is any person with an egg-producing reproductive tract (regardless of gender, sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: ** Has not undergone a hysterectomy or bilateral oophorectomy ** Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months)
• COHORT B: POCBP must have a negative pregnancy test prior to registration * Note: If a urine pregnancy test is positive or cannot be confirmed negative, a serum pregnancy test will be required
• COHORT B: Patients or their parents/LARs must have the ability to understand and the willingness to sign a written informed consent document. Written informed consent/assent must be signed prior to registration * Note: A subject will not be registered until they and/or their parents/LARs have signed an informed consent/assent. Furthermore, consent/assent should be obtained prior to the initiation of any clinical procedures of assessments performed for the purpose of determining protocol eligibility, which would not otherwise be consistent with the institution’s standards of clinical practice
• COHORT B: 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
• COHORT B: 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
• COHORT B: Patients must be able to swallow, retain, and absorb oral medication
• COHORT B: Patients that received standard of care (SOC) chemotherapy and other SOC TKI or anticancer therapeutics must have a washout period of 21 days for chemotherapy, 28 days for bevacizumab, and two half-lives for all other SOC anticancer agents or devices. Patient should have recovered from all adverse events of these therapies to grade 1 or less * Note: A wash out period is not required for prior MAPK inhibitor therapy including but not limited to dabrafenib, trametinib, tovorafenib, etc.
• COHORT B; LGG ONLY: Patients must have received a prior BRAF inhibitor (first or second generation), MEK inhibitor, or a combination
• COHORT B; LGG ONLY: Patients must have recovered from acute treatment-related toxicities (defined as < grade 1, excludes alopecia) prior to entering this study
• COHORT B; HGG ONLY: Patients must have received prior radiotherapy > 12 weeks prior to enrollment
• COHORT B; HGG ONLY: Patients must have recovered from acute treatment-related toxicities (defined as < grade 1, excludes alopecia) prior to entering this study
• COHORT B; HGG ONLY: NF1 patients with transforming gliomas and high-grade gliomas are eligible regardless of prior systemic therapy
• COHORTS A AND B; LGG ONLY: Patients must have received prior MAPK inhibitor monotherapy * Note: Information regarding response must be available (PR, CR, stable disease, and DOR)
• COHORTS A AND B; HGG ONLY: Patients must have received prior radiation therapy
• COHORTS A AND B; HGG ONLY: 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

Exclusion Criteria

• Patients with disseminated disease
• Patients who have had prior radiation therapy < 12 weeks prior to registration
• Patients who are receiving any other investigational agents
• Patients who have a history of allergic reactions attributed to compounds of similar chemical or biological composition to dabrafenib, trametinib, or nivolumab
• Patients who have received MAPK inhibitor and checkpoint blockade combination therapy. For immune checkpoint inhibitors, the washout period is 42 days
• Patients who previously discontinued BRAF inhibitor (type 1 inhibitor or dimer inhibitor, such as, DAY101), MEK inhibitor, or the combination because of grade 3 or higher toxicity or clinically significant grade 2 toxicity requiring discontinuation of therapy are not eligible
• Patients with the following: * Known autoimmune disorders * Immune disorders * Immunodeficiencies * Note: Autoimmune disorders include but are not limited to rheumatoid or juvenile idiopathic arthritis, systemic lupus erythematosus, juvenile dermatomyositis, Addison’s disease, autoimmune hepatitis, Crohn’s disease, multiple sclerosis, Hashimoto’s thyroiditis, and scleroderma. Patients with autoimmune disease with external/environmental triggers are also excluded * Note: exceptions to this criterion include vitiligo, resolved asthma/atopy, Sjogren’s syndrome, and hypothyroidism that is stable with hormone replacement
• Patients with active pancreatitis or history of pancreatitis within the last 3 months
• Patients who: * Require oxygen * Require continuous positive airway pressure (CPAP)/biphasic positive airway pressure (BiPap) * Require mechanical ventilation * Have active respiratory infections * Have been treated for a respiratory infection in which they required oxygen support within the last 7 days * Have chronic lung disease (not including asthma) * Patients with baseline oxygen (O2) saturation < 92% on room air
• Patients with the following: * Any known active infections (within the last 7 days prior to enrollment) * Previous fungal infection within the last month * Active serious viral infections including influenza, cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, herpes zoster, hepatitis A/B/C, herpes simplex virus 1/2 ** Note: Patients at high risk for tuberculosis (TB) should have a purified protein derivative (PPD) placed or quantiferon gold serum testing done prior to enrollment. Patients who are positive for TB are excluded
• Patients with active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis requiring treatment with systemic steroids
• Patients who have a known active human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection are ineligible. Patient must have documented evidence of negative tests for the presence of HIV, hepatitis B surface antigen, and hepatitis C (anti-hepatitis C virus [HCV] antibody OR hepatitis [Hep] C RNA-qualitative)
• Patients who have received a major surgical procedure ≤ 28 days of beginning study treatment, or minor surgical procedures (including ventriculoperitoneal [VP] shunt placement or stereotactic biopsy of the tumor) ≤ 7 days are not eligible * Note: There is no waiting period for port-a-cath or other central venous access placement. There is no waiting period for gastrostomy tube (G-tube) placement
• Patients who are taking herbal preparations. These medications include but are not limited to St. John’s wort, kava, ephedra (ma hung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Cannabis products of any type are not allowed throughout the study. Patients should stop using these herbal medications or cannabis products 7 days prior to enrollment
• Patients who are pregnant. Patients of childbearing potential must have a negative serum or urine pregnancy test. (If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.)
• Patients who are lactating (unless they have agreed to not breastfeed). Breastfeeding patients are excluded from this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies
• Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic, or other organ dysfunction), that in the opinion of the investigator would compromise the patient’s ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results
• Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen for this trial
• Patients with bulky tumor on imaging are ineligible. Bulky tumor is defined as: * Tumor with any evidence of clinically significant uncal herniation or midline shift * Tumor with diameter of > 5cm in one dimension on T2/FLAIR except for those patients with newly diagnosed HGG treated following irradiation without signs of tumor progression. For the latter group, a maximum diameter of contrast enhancing solid or necrotic tumor and of T2/FLAIR abnormality will be 5 cm and 8 cm, respectively * Tumor that in the opinion of the site investigator, shows significant mass effect * Metastatic disease: Patients with ≤ 5 separate foci of metastatic disease not causing mass effect on adjacent parenchyma and each measuring less than 0.5 cm in maximum diameter will be eligible for this arm of the study. Patients with leptomeningeal disease are eligible * Multi-focal disease (patients with multi-focal parenchymal disease will be eligible if the sum of the product of the maximum perpendicular diameters of all measurable non-contiguous lesions is less than 16 cm2 based on the T2/FLAIR abnormality)