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

Phase 2

Recruiting

• Conditions: High Grade Glioma; CNS Tumor
• Interventions: Drug: Entrectinib; Drug: Cyclophosphamide; Drug: Etoposide; Drug: Carboplatin; Biological: G-CSF; Biological: Pegfilgrastim; Procedure: Surgery

• Registration Number: NCT06528691
• Lead Sponsor: St. Jude Children's Research Hospital

Brief Summary

This clinical trial tests how well entrectinib works to treat patients less than 3 years of age with NTRK 1/2/3 or ROS1 fused, high grade glioma or other central nervous system (CNS) tumors.

Detailed Description

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.

A gross total resection or significant debulking may become possible if a response to entrectinib is seen. If surgical resection is performed and a gross total resection is achieved, 24 cycles of entrectinib will be completed, including those before and after surgery.

After treatment, patients will be followed for 5 years.

Study Timeline

• Study First Submitted: 2024-07-22
• Study First Submitted QC: 2024-07-25
• Study First Posted: 2024-07-30
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-03
• Last Update Posted: 2025-07-09
• Study Start: 2025-08-01
• Primary Completion: 2027-11
• Study Completion: 2032-11-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 52

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Entrectinib therapy, Cohort 1 and Cohort 2	Pegfilgrastim	Cohort 1: Patients who are younger than 3 years of age diagnosed with NTRK1/2/3- or ROS1-fused high-grade glioma (HGG) will receive therapy as outline in Detailed Description. Cohort 2: Patients who are younger than 3 years of age diagnosed with NTRK1/2/3- or ROS1-fused CNS tumors other than HGG will receive therapy as outline in Detailed Description.
Entrectinib therapy, Cohort 1 and Cohort 2	Surgery	Cohort 1: Patients who are younger than 3 years of age diagnosed with NTRK1/2/3- or ROS1-fused high-grade glioma (HGG) will receive therapy as outline in Detailed Description. Cohort 2: Patients who are younger than 3 years of age diagnosed with NTRK1/2/3- or ROS1-fused CNS tumors other than HGG will receive therapy as outline in Detailed Description.
Entrectinib therapy, Cohort 1 and Cohort 2	G-CSF	Cohort 1: Patients who are younger than 3 years of age diagnosed with NTRK1/2/3- or ROS1-fused high-grade glioma (HGG) will receive therapy as outline in Detailed Description. Cohort 2: Patients who are younger than 3 years of age diagnosed with NTRK1/2/3- or ROS1-fused CNS tumors other than HGG will receive therapy as outline in Detailed Description.
Entrectinib therapy, Cohort 1 and Cohort 2	Entrectinib	Cohort 1: Patients who are younger than 3 years of age diagnosed with NTRK1/2/3- or ROS1-fused high-grade glioma (HGG) will receive therapy as outline in Detailed Description. Cohort 2: Patients who are younger than 3 years of age diagnosed with NTRK1/2/3- or ROS1-fused CNS tumors other than HGG will receive therapy as outline in Detailed Description.
Entrectinib therapy, Cohort 1 and Cohort 2	Etoposide	Cohort 1: Patients who are younger than 3 years of age diagnosed with NTRK1/2/3- or ROS1-fused high-grade glioma (HGG) will receive therapy as outline in Detailed Description. Cohort 2: Patients who are younger than 3 years of age diagnosed with NTRK1/2/3- or ROS1-fused CNS tumors other than HGG will receive therapy as outline in Detailed Description.
Entrectinib therapy, Cohort 1 and Cohort 2	Cyclophosphamide	Cohort 1: Patients who are younger than 3 years of age diagnosed with NTRK1/2/3- or ROS1-fused high-grade glioma (HGG) will receive therapy as outline in Detailed Description. Cohort 2: Patients who are younger than 3 years of age diagnosed with NTRK1/2/3- or ROS1-fused CNS tumors other than HGG will receive therapy as outline in Detailed Description.
Entrectinib therapy, Cohort 1 and Cohort 2	Carboplatin	Cohort 1: Patients who are younger than 3 years of age diagnosed with NTRK1/2/3- or ROS1-fused high-grade glioma (HGG) will receive therapy as outline in Detailed Description. Cohort 2: Patients who are younger than 3 years of age diagnosed with NTRK1/2/3- or ROS1-fused CNS tumors other than HGG will receive therapy as outline in Detailed Description.

Primary Outcome Measures

Name	Time	Method
Overall response rate (ORR) (Cohort 1)	After cycle 4 (each cycle is 28 days).	ORR is defined as the percentage of patients with either partial or complete response assessed at the protocol-defined evaluation timepoint. Overall response will be determined by the central imaging review based on the scheduled evaluations.

Secondary Outcome Measures

Name	Time	Method
Progression free survival (PFS) (Cohort 1)	At 2 and 5 years	PFS is defined as the time from initiation of protocol treatment to first event (progressive disease, death due to any cause), or date last follow-up among those who have not had an event. Described using Kaplan Meier method.
OS (Cohort 2)	At 2 and 5 years	OS is defined as the time from date of diagnosis to date of death due to any cause or date last follow-up. Described using Kaplan Meier method.
Patients who have second surgeries (Cohort 1)	Up to 5 years	Percentage of patients who had second surgeries.
Incidence of adverse events (Cohort 1 and 2)	Up to 5 years	Percentage of adverse events on therapy including Entrectinib, captured using National Cancer Institute Common Terminology Criteria for Adverse Events 5.0.
Duration of response (DOR) (Cohort 1)	Up to 5 years	DOR is defined as time from date of first response (partial or complete) until the date of progression or last follow-up. Described as median time.
Patients who undergo gross-total resection after treatment (Cohort 1)	Up to 5 years	Percentage of patients who underwent a gross-total resection.
Patients who have second surgeries (Cohort 2)	Up to 5 years	Percentage of patients who had second surgeries. \[Time Frame: Up to 5 years\]
Overall survival (OS) (Cohort 1)	At 2 and 5 years	OS is defined as the time from date of diagnosis to date of death due to any cause or date last follow-up. Described using Kaplan Meier method.
ORR (Cohort 2)	After cycle 4 (each cycle is 28 days).	ORR is defined as the percentage of patients with either partial or complete response assessed at the protocol-defined evaluation timepoint. Overall response will be determined by the central imaging review based on the scheduled evaluations.
DOR (Cohort 2)	Up to 5 years	DOR is defined as time from date of first response (partial or complete) until the date of progression or last follow-up. Described as median time.
PFS (Cohort 2)	At 2 and 5 years	PFS is defined as the time from initiation of protocol treatment to first event (progressive disease, death due to any cause), or date last follow-up among those who have not had an event. Described using Kaplan Meier method.
Time from initial diagnostic surgery to screening and enrollment (Cohort 1 and 2)	Up to 5 years	Median time in days from initial surgery to screening and enrollment on study.
Number of patients screened versus enrolled and treated (Cohort 1 and 2)	Up to 5 years	Number of enrolled and treated patients as a percentage of number of patients screened and eligible for study.
Patients who undergo gross-total resection after treatment (Cohort 2)	Up to 5 years	Percentage of patients who underwent a gross-total resection.

Trial Locations

Locations (1)

St. Jude Children's Research Hospital; 🇺🇸 Memphis, Tennessee, United States