Entrectinib as a Single Agent in Upfront Therapy for Children <3 Years of Age With NTRK1/2/3 or ROS1-FUSED CNS Tumors

Inclusion criteria

• Screening Phase
• Age from birth to age \<3 years at the time of diagnosis (date of surgical resection/biopsy)
• Participant with presumed newly diagnosed tumor in the supratentorial compartment
• Patient must have measurable disease based on RAPNO criteria
• ≤84 days since surgery (resection or biopsy)
• Available tumor tissue for central review
• Parent/guardian has the ability to understand and the willingness to sign a written informed consent document according to institutional guidelines

Exclusion criteria

• Screening Phase
• Previous exposure to cytotoxic chemotherapy or radiotherapy Inclusion Criteria: COHORT 1
• Patients must be \<3 years of age at the time of diagnosis (date of surgical resection/biopsy)
• 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
• Patients must have measurable disease as defined by RAPNO criteria
• Patients are eligible at the time of diagnosis, prior to any exposure to chemotherapy, targeted therapy, immunotherapy, cellular therapy or radiation
• ≤28 days since study screening
• Lansky score ≥50% and a minimum life expectancy of ≥ 12 weeks
• Neurologic deficits must have been stable for at least 7 days prior to study enrollment
• Hemoglobin ≥ 8 g/dL (without transfusion or erythropoietin use within 7 days prior to enrollment)
• Platelet count ≥ 75,000/µL (without transfusion within 7-day period prior to enrollment)
• Absolute neutrophil count \>1,000/µL
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5x the upper limit of normal (ULN)
• Bilirubin ≤ 1.5 x ULN
• 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
• 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%
• Screening and enrollment consents signed
• Willingness and ability to comply with treatment plan, scheduled visits, laboratory tests and other study procedures Inclusion Criteria: COHORT 2
• Patients must be \<3 years of age at the time of diagnosis (date of surgical resection/biopsy)
• CNS tumor other than HGG harboring NTRK1/2/3 or ROS1 gene fusions as determined by central pathology review
• Patients must have measurable disease as defined by RAPNO criteria
• Patients are eligible at the time of diagnosis, prior to any exposure to chemotherapy, targeted therapy, immunotherapy, cellular therapy or radiation
• ≤28 days since study screening
• Lansky score ≥50% and a minimum life expectancy of ≥ 12 weeks
• Neurologic deficits must have been stable for at least 7 days prior to study enrollment.
• Hemoglobin ≥ 8 g/dL (without transfusion or erythropoietin use within 7 days prior to enrollment)
• Platelet count ≥ 75,000/µL (without transfusion within 7-day period prior to enrollment);
• Absolute neutrophil count \>1,000/µL.
• ALT and ALT ≤2.5x the upper limit of normal (ULN)
• Bilirubin ≤ 1.5 x ULN
• 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
• Adequate cardiac function as defined by ECG with QTc ≤ 450 msec and echocardiogram LVEF \>50%
• Screening and enrollment consents signed
• Willingness and ability to comply with treatment plan, scheduled visits, laboratory tests and other study procedures Exclusion Criteria: 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
• History of recent (3 months) symptomatic congestive heart failure
• Known active, uncontrolled infection (bacterial, fungal, or viral)
• Receiving enzyme inducing antiepileptic drugs (EIAEDs)
• Any prior cancer therapy including chemotherapy (excluding Bridging Chemotherapy Cycle), targeted therapy, immunotherapy, cellular therapy, or radiation
• Receiving another investigational agent concurrently
• Surgery within 2 weeks prior to treatment enrollment
• Patients with known hypersensitivity to excipients of the investigational medicinal product
• Active gastrointestinal disease or malabsorption disorder (e.g. Crohn's disease, ulcerative colitis, short-gut syndrome) that would impair drug absorption
• Inability to take medication enterally