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

PRIMARY OBJECTIVE

* To determine the overall response rate of entrectinib when used as first line therapy in patients who are younger than 3 years of age with NTRK1/2/3- or ROS1-fused high-grade glioma (HGG) (Cohort 1).

SECONDARY OBJECTIVES

* To estimate the 2-year and 5-year progression free survival (PFS) and overall survival (OS) in patients who are younger than 3 years of age with NTRK1/2/3- or ROS1-fused HGG treated with entrectinib as first line therapy (Cohort 1). * To estimate the duration of response (DOR) in patients who are younger than 3 years of age with NTRK1/2/3- or ROS1-fused HGG treated with entrectinib as first line therapy (Cohort 1). * To evaluate the fraction of patients with NTRK1/2/3- or ROS1-fused HGG treated who have second surgeries and a gross-total resection after treatment with entrectinib is achieved, overall and by country and hospital (Cohort 1). * To describe the overall response rate of entrectinib when used as first line therapy in patients who are younger than 3 years of age with NTRK1/2/3- or ROS1-fused CNS tumors other than HGG (Cohort 2). * To estimate the 2-year and 5-year PFS and OS in patients who are younger than 3 years of age with NTRK1/2/3- or ROS1-fused CNS tumors other than HGG treated with entrectinib as first line therapy (Cohort 2). * To estimate the duration of response (DOR) in patients who are younger than 3 years of age with NTRK1/2/3- or ROS1-fused CNS tumors other than HGG treated with entrectinib as first line therapy (Cohort 2). * To evaluate the fraction of patients with NTRK1/2/3- or ROS1-fused CNS tumors other than HGG who have second surgeries and a gross-total resection after treatment with entrectinib is achieved, overall and by country and hospital (Cohort 2). * To describe toxicities experienced by patients younger than 3 years of age treated with entrectinib (Cohort 1 and 2). * To evaluate number of patients that are screened for the study and eligible versus enrolled and treated with entrectinib (Cohort 1 and 2). * To measure the time intervals (days) from time of initial diagnostic surgery to screening and enrollment in this study (Cohort 1 and 2).

The trial will have 2 cohorts: Cohort 1: patients diagnosed with NTRK1/2/3- or ROS1-fused high-grade glioma (HGG) and Cohort 2: patients diagnosed with NTRK1/2/3- or ROS1-fused CNS tumors other than HGG.

Patients receive entrectinib enterally once daily (QD) on days 1-28 of each cycle. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients requiring bridging therapy prior to starting entrectinib may receive cyclophosphamide intravenously (IV) over 1 hour on day 1, etoposide IV over 1 hour on day 1 and 2, carboplatin IV over 1 hour on day 2, filgrastim subcutaneously (SC) or IV or pegfilgrastim SC on day 3.