Entrectinib for the Treatment of Patients Less Than 3 Years of Age with NTRK1/2/3 or ROS1 Fused High Grade Glioma or Other Central Nervous System Tumor

Inclusion Criteria

• SCREENING PHASE: Age from birth to age < 3 years at the time of diagnosis (date of surgical resection/biopsy)
• SCREENING PHASE: Participant with presumed newly diagnosed tumor in the supratentorial compartment
• SCREENING PHASE: Patient must have measurable disease based on RAPNO criteria
• SCREENING PHASE: ≤ 84 days since surgery (resection or biopsy)
• SCREENING PHASE: Available tumor tissue for central review
• SCREENING PHASE: Parent/guardian has the ability to understand and the willingness to sign a written informed consent document according to institutional guidelines
• COHORT 1: Patients must be < 3 years of age at the time of diagnosis (date of surgical resection/biopsy)
• COHORT 1: High-grade glioma (World Health Organization [WHO] grade III or IV) harboring NTRK1/2/3 or ROS1 gene fusions as determined by central pathology review
• COHORT 1: Patients must have measurable disease as defined by RAPNO criteria
• COHORT 1: Patients are eligible at the time of diagnosis, prior to any exposure to chemotherapy, targeted therapy, immunotherapy, cellular therapy or radiation
• COHORT 1: ≤ 28 days since study screening
• COHORT 1: Lansky score ≥ 50% and a minimum life expectancy of ≥ 12 weeks
• COHORT 1: Neurologic deficits must have been stable for at least 7 days prior to study enrollment
• COHORT 1: Hemoglobin ≥ 8 g/dL (without transfusion or erythropoietin use within 7 days prior to enrollment)
• COHORT 1: Platelet count ≥ 75,000/µL (without transfusion within 7-day period prior to enrollment)
• COHORT 1: Absolute neutrophil count >1,000/µL
• COHORT 1: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x the upper limit of normal (ULN)
• COHORT 1: Bilirubin ≤ 1.5 x ULN
• COHORT 1: Adequate renal function as defined by the following age-based serum creatinine concentrations: * 0 to < 1 year: 0.5 mg/dL * 1 to < 2 years: 0.6 mg/dL * 2 to 3 years: 0.8 mg/dL
• COHORT 1: Adequate cardiac function as defined by electrocardiogram (ECG) with Fridericia's corrected QT interval (QTc) ≤ 450 msec and echocardiogram left ventricular ejection fraction (LVEF) > 50%
• COHORT 1: Screening and enrollment consents signed
• COHORT 1: Willingness and ability to comply with treatment plan, scheduled visits, laboratory tests and other study procedures
• COHORT 2: Patients must be < 3 years of age at the time of diagnosis (date of surgical resection/biopsy)
• COHORT 2: CNS tumor other than HGG harboring NTRK1/2/3 or ROS1 gene fusions as determined by central pathology review
• COHORT 2: Patients must have measurable disease as defined by RAPNO criteria
• COHORT 2: Patients are eligible at the time of diagnosis, prior to any exposure to chemotherapy, targeted therapy, immunotherapy, cellular therapy or radiation
• COHORT 2: ≤ 28 days since study screening
• COHORT 2: Lansky score ≥ 50% and a minimum life expectancy of ≥ 12 weeks
• COHORT 2: Neurologic deficits must have been stable for at least 7 days prior to study enrollment
• COHORT 2: Hemoglobin ≥ 8 g/dL (without transfusion or erythropoietin use within 7 days prior to enrollment)
• COHORT 2: Platelet count ≥ 75,000/µL (without transfusion within 7-day period prior to enrollment)
• COHORT 2: Absolute neutrophil count >1,000/µL
• COHORT 2: ALT and ALT ≤ 2.5x the upper limit of normal (ULN)
• COHORT 2: Bilirubin ≤ 1.5 x ULN
• COHORT 2: Adequate renal function as defined by the following age-based serum creatinine concentrations: * 0 to < 1 year: 0.5 mg/dL * 1 to < 2 years: 0.6 mg/dL * 2 to 3 years: 0.8 mg/dL
• COHORT 2: Adequate cardiac function as defined by ECG with QTc ≤ 450 msec and echocardiogram LVEF >50%
• COHORT 2: Screening and enrollment consents signed
• COHORT 2: Willingness and ability to comply with treatment plan, scheduled visits, laboratory tests and other study procedures

Exclusion Criteria

• SCREENING PHASE: Previous exposure to cytotoxic chemotherapy or radiotherapy
• COHORT 1 AND 2: Clinically significant medical disorder that could compromise the ability to tolerate study therapy or would interfere with the study procedures or results history
• COHORT 1 AND 2: History of recent (3 months) symptomatic congestive heart failure
• COHORT 1 AND 2: Known active, uncontrolled infection (bacterial, fungal, or viral)
• COHORT 1 AND 2: Receiving enzyme inducing antiepileptic drugs (EIAEDs)
• COHORT 1 AND 2: Any prior cancer therapy including chemotherapy (excluding bridging chemotherapy cycle), targeted therapy, immunotherapy, cellular therapy, or radiation
• COHORT 1 AND 2: Receiving another investigational agent concurrently
• COHORT 1 AND 2: Surgery within 2 weeks prior to treatment enrollment
• COHORT 1 AND 2: Patients with known hypersensitivity to excipients of the investigational medicinal product
• COHORT 1 AND 2: Active gastrointestinal disease or malabsorption disorder (e.g. Crohn’s disease, ulcerative colitis, short-gut syndrome) that would impair drug absorption
• COHORT 1 AND 2: Inability to take medication enterally