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

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.

Study Overview

• Status: Recruiting
• Conditions: High Grade Glioma; CNS Tumor
• Intervention / Treatment: Drug: Carboplatin; Drug: Etoposide; Drug: Entrectinib; Drug: Cyclophosphamide; Biological: G-CSF; Biological: Pegfilgrastim; Procedure: Surgery

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 Type: Interventional
• Enrollment (Estimated): 52
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Tabatha E. Doyle, RN; Phone Number: 901-595-2544; Email: tabatha.doyle@stjude.org
• Study Contact Backup: Name: Daniel Moreira, MD, MEd; Phone Number: 901-585-1911; Email: daniel.moreira@stjude.org

Study Locations

• Brazil
  • São Paulo, Brazil, 08270-070
    • Recruiting
    • Hospital Santa Marcelina
    • Principal Investigator: Sidnei Epelman, MD
    • Contact: Sidnei Epelman, MD; Phone Number: +55 11 2522-2472; Email: epelman@inctrbrasil.org
  • São Paulo, Brazil, 04039-001
    • Recruiting
    • GRAACC Hospital (Grupo de Apoio ao Adolescente e à Criança com Câncer)
    • Contact: Andrea M. Cappellano, MD; Phone Number: +55 11 5080-8400; Email: andreacappellano@graacc.org.br
    • Principal Investigator: Andrea M. Cappellano, MD
  • São Paulo
    • Barretos, São Paulo, Brazil, 14784400
      • Recruiting
      • Hospital de Cancer de Barretos
      • Contact: Thais J. Vampre, MD; Phone Number: 17 3321-6647; Email: thaisjunq79@gmail.com
      • Principal Investigator: Thais J. Vampre, MD
• Jordan
  • Amman, Jordan, 11941
    • Recruiting
    • King Hussein Cancer Center
    • Contact: Nisreen Amayiri, MD; Phone Number: 6376 (962 6) 5300460; Email: namayiri@khcc.jo
    • Principal Investigator: Nisreen Amayiri, MD
• Peru
  • Lima, Peru
    • Recruiting
    • Instituto Nacional de Enfermedades Neoplasicas
    • Contact: Rosdali Coronado, MD; Phone Number: +51 991765893; Email: rosdali.diaz.c@upch.pe
    • Principal Investigator: Rosdali Coronado, MD
• United States
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • Recruiting
      • St. Jude Children's Research Hospital
      • Contact: Tabatha E. Doyle, RN; Phone Number: 901-595-2544; Email: tabatha.doyle@stjude.org
      • Principal Investigator: Daniel Moreira, MD, MEd
      • Contact: Email: GLOBOTRK@stjude.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Entrectinib therapy, Cohort 1 and Cohort 2; 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.

Drug: Carboplatin; Given IV; Other Names: Paraplatin®; Drug: Etoposide; Given IV; Other Names: VP-16; Drug: Entrectinib; Given orally (PO) or enterally; Other Names: Rozlytrek; Drug: Cyclophosphamide; Given intravenous (IV); Other Names: Cytoxan®; Biological: G-CSF; Given subcutaneous (SQ) or IV; Other Names: Filgrastim; Biological: Pegfilgrastim; Given SQ as part of recommended Bridging Therapy instead of G-CSF.; Other Names: Neulasta; Procedure: Surgery; A gross total resection or significant debulking may become possible if a response to entrectinib is seen.; Other Names: Surgical resection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR) (Cohort 1)	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.	After cycle 4 (each cycle is 28 days).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS) (Cohort 1)	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.	At 2 and 5 years
Overall survival (OS) (Cohort 1)	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.	At 2 and 5 years
Duration of response (DOR) (Cohort 1)	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.	Up to 5 years
Patients who have second surgeries (Cohort 1)	Percentage of patients who had second surgeries.	Up to 5 years
Patients who undergo gross-total resection after treatment (Cohort 1)	Percentage of patients who underwent a gross-total resection.	Up to 5 years
ORR (Cohort 2)	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.	After cycle 4 (each cycle is 28 days).
PFS (Cohort 2)	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.	At 2 and 5 years
OS (Cohort 2)	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.	At 2 and 5 years
DOR (Cohort 2)	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.	Up to 5 years
Patients who have second surgeries (Cohort 2)	Percentage of patients who had second surgeries. [Time Frame: Up to 5 years]	Up to 5 years
Patients who undergo gross-total resection after treatment (Cohort 2)	Percentage of patients who underwent a gross-total resection.	Up to 5 years
Incidence of adverse events (Cohort 1 and 2)	Percentage of adverse events on therapy including Entrectinib, captured using National Cancer Institute Common Terminology Criteria for Adverse Events 5.0.	Up to 5 years
Number of patients screened versus enrolled and treated (Cohort 1 and 2)	Number of enrolled and treated patients as a percentage of number of patients screened and eligible for study.	Up to 5 years
Time from initial diagnostic surgery to screening and enrollment (Cohort 1 and 2)	Median time in days from initial surgery to screening and enrollment on study.	Up to 5 years

Collaborators and Investigators

• Sponsor: St. Jude Children's Research Hospital
• Collaborators: Hoffmann-La Roche
• Investigators: Principal Investigator: Daniel Moreira, MD, MEd, St. Jude Children's Research Hospital

Publications and helpful links

General Publications

• Bagchi A, Chiang J, Pinto S, Dhanda S, Gajjar A. Infant-Type Hemispheric Gliomas: A Review of Clinical, Radiologic, Histopathologic, and Molecular Features. J Natl Compr Canc Netw. 2025 Nov;23(11):e257064. doi: 10.6004/jnccn.2025.7064.

Helpful Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2026
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): November 1, 2032

Study Registration Dates

• First Submitted: July 22, 2024
• First Submitted That Met QC Criteria: July 25, 2024
• First Posted (Actual): July 30, 2024

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Children; CNS Tumors; High Grade Glioma with NTRK1/2/3 gene fusion; High Grade Glioma with ROS1 gene fusion; CNS tumor other than HGG harboring NTRK1/2/3 gene fusion; CNS tumor other than HGG harboring ROS1 gene fusion
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Glioma; Central Nervous System Neoplasms; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Biological Factors; Carbohydrates; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glucosides; Glycosides; Coordination Complexes; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Intercellular Signaling Peptides and Proteins; Glycoproteins; Glycoconjugates; Colony-Stimulating Factors; Hematopoietic Cell Growth Factors; Cytokines; Cyclophosphamide; Etoposide; Carboplatin; Surgical Procedures, Operative; Granulocyte Colony-Stimulating Factor; Filgrastim; entrectinib; pegfilgrastim
• Other Study ID Numbers: GLOBOTRK; NCI-2024-02977 (Registry Identifier: NCI Clinical Trial Registration Program)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.
• IPD Sharing Time Frame: Data will be made available at the time of article publication.
• IPD Sharing Access Criteria: Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No