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

St. Jude Children's Research Hospital

Status and phase

Enrolling

Phase 2

Conditions

High Grade Glioma

CNS Tumor

Treatments

Biological: G-CSF

Biological: Pegfilgrastim

Drug: Cyclophosphamide

Procedure: Surgery

Drug: Entrectinib

Drug: Carboplatin

Drug: Etoposide

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT06528691

GLOBOTRK

NCI-2024-02977 (Registry Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment

52 estimated patients

Sex

All

Ages

Under 3 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

52 participants in 1 patient group

Entrectinib therapy, Cohort 1 and Cohort 2

Experimental group

Description:

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.