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

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
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
  • ≤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
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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
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Study & Design

Study Type
INTERVENTIONAL
Study Design
SINGLE_GROUP
Arm && Interventions
GroupInterventionDescription
Entrectinib therapy, Cohort 1 and Cohort 2PegfilgrastimCohort 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 2SurgeryCohort 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 2G-CSFCohort 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 2EntrectinibCohort 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 2EtoposideCohort 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 2CyclophosphamideCohort 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 2CarboplatinCohort 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
NameTimeMethod
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
NameTimeMethod
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

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