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

Официальное название

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)

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Entrectinib
  Given orally (PO) or enterally
• Препарат Cyclophosphamide
  Given intravenous (IV)
• Препарат Etoposide
  Given IV
• Препарат Carboplatin
  Given IV
• Биопрепарат G-CSF
  Given subcutaneous (SQ) or IV
• Биопрепарат Pegfilgrastim
  Given SQ as part of recommended Bridging Therapy instead of G-CSF.
• Процедура Surgery
  A gross total resection or significant debulking may become possible if a response to entrectinib is seen.

Первичные конечные точки

• Overall response rate (ORR) (Cohort 1) [Срок оценки: After cycle 4 (each cycle is 28 days).]

Вторичные конечные точки (12)

• Progression free survival (PFS) (Cohort 1) [Срок оценки: At 2 and 5 years]
• Overall survival (OS) (Cohort 1) [Срок оценки: At 2 and 5 years]
• Duration of response (DOR) (Cohort 1) [Срок оценки: Up to 5 years]
• Patients who have second surgeries (Cohort 1) [Срок оценки: Up to 5 years]
• Patients who undergo gross-total resection after treatment (Cohort 1) [Срок оценки: Up to 5 years]
• ORR (Cohort 2) [Срок оценки: After cycle 4 (each cycle is 28 days).]
• PFS (Cohort 2) [Срок оценки: At 2 and 5 years]
• OS (Cohort 2) [Срок оценки: At 2 and 5 years]
• DOR (Cohort 2) [Срок оценки: Up to 5 years]
• Patients who have second surgeries (Cohort 2) [Срок оценки: Up to 5 years]
• Patients who undergo gross-total resection after treatment (Cohort 2) [Срок оценки: Up to 5 years]
• Incidence of adverse events (Cohort 1 and 2) [Срок оценки: Up to 5 years]

Критерии участия

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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Бразилия · 3 центра

• Hospital de Câncer de Barretos — Barretos
• GRAACC Hospital (Grupo de Apoio ao Adolescente e à Criança com Câncer) — São Paulo
• Hospital Santa Marcelina — São Paulo

США · 1 центр

• St. Jude Children's Research Hospital — Memphis

Иордания · 1 центр

• King Hussein Cancer Center — Amman

Перу · 1 центр

• Instituto Nacional de Enfermedades Neoplásicas — Lima

Публикации

• 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. PMID 41213248

Идентификаторы

NCT: NCT06528691 · GLOBOTRK · NCI-2024-02977

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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