Entrectinib as a Single Agent in Upfront Therapy for Children <3 Years of Age With NTRK1/2/3 or ROS1-FUSED CNS Tumors
- Conditions
- Interventions
- 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
...
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 52
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
- ≤42 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
Screening Phase
- Previous exposure to cytotoxic chemotherapy or radiotherapy
Inclusion Criteria: COHORT 1
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Patients must be <3 years of age at the time of diagnosis (date of surgical resection/biopsy)
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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
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Patients must have measurable disease as defined by RAPNO criteria
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Patients are eligible at the time of diagnosis, prior to any exposure to chemotherapy, targeted therapy, immunotherapy, cellular therapy or radiation
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≤28 days since study screening
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Lansky score ≥50% and a minimum life expectancy of ≥ 12 weeks
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Neurologic deficits must have been stable for at least 7 days prior to study enrollment
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Hemoglobin ≥ 8 g/dL (without transfusion or erythropoietin use within 7 days prior to enrollment)
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Platelet count ≥ 75,000/µL (without transfusion within 7-day period prior to enrollment)
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Absolute neutrophil count >1,000/µL
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Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5x the upper limit of normal (ULN)
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Bilirubin ≤ 1.5 x ULN
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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
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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%
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Screening and enrollment consents signed
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Willingness and ability to comply with treatment plan, scheduled visits, laboratory tests and other study procedures
Inclusion Criteria: COHORT 2
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Patients must be <3 years of age at the time of diagnosis (date of surgical resection/biopsy)
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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.
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.
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.
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. \[Time Frame: Up to 5 years\]
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.
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.
Patients who undergo gross-total resection after treatment (Cohort 2) Up to 5 years Percentage of patients who underwent a gross-total resection.
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.
Trial Locations
- Locations (1)
St. Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States