A Pilot Study of Larotrectinib for Newly-Diagnosed High-Grade Glioma With NTRK Fusion
NCT ID: NCT04655404
Last Updated: 2025-12-26
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
EARLY_PHASE1
15 participants
INTERVENTIONAL
2021-04-08
2036-12-01
Brief Summary
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The study will also evaluate the safety of larotrectinib when given with chemotherapy in your children; as well as the safety larotrectinib when given post-focal radiation therapy.
Detailed Description
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Patients ≤ 48 months with PR or SD after 2 cycles of larotrectinib will go on to receive combination therapy with standard backbone chemotherapy (BABYPOG or HIT-SKK). Patients \> 48 months of age (or patients ≥ 36 months of age, or patients with DIPG \>18 months of age, at the discretion of the local investigator) will receive focal radiation therapy. A surgical cohort study will be explored whereby patients who have had a tumor biopsy/partial resection at their local institution and are planned to subsequently undergo definitive resection will receive 3-5 days (6-10 doses) of larotrectinib pre-surgery.
The study design of this trial requires 15 patients evaluable for disease control and for safety/ toxicity of larotrectinib as monotherapy. The surgical cohort will enroll up to 4 patients and will count towards the total 15 evaluable patients. A minimum of 6 patients will be evaluable for safety toxicity of larotrectinib in combination with standard-of-care chemotherapy or radiotherapy.
Conditions
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Keywords
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Study Design
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NON_RANDOMIZED
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Surgical Cohort
Larotrectinib administered PO, BID @100 mg/m2 3-5 days prior to definitive surgery, followed by Larotrectinib administered PO, BID @100 mg/m2 on a 28-day cycle schedule.
Larotrectinib
1. Larotrectinib monotherapy x2 cycles followed by disease evaluation
2. Larotrectinib with or without chemotherapy backbone
Larotrectinib surgical
1. Surgical cohort: Larotrectinib x 3-5 days prior to definitive surgery followed by Larotrectinib monotherapy x2 cycles followed by disease evaluation
2. Larotrectinib with or without chemotherapy backbone
Feasibility Cohort
Larotrectinib administered PO, BID @100 mg/m2 on a 28-day cycle schedule.
Larotrectinib
1. Larotrectinib monotherapy x2 cycles followed by disease evaluation
2. Larotrectinib with or without chemotherapy backbone
Interventions
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Larotrectinib
1. Larotrectinib monotherapy x2 cycles followed by disease evaluation
2. Larotrectinib with or without chemotherapy backbone
Larotrectinib surgical
1. Surgical cohort: Larotrectinib x 3-5 days prior to definitive surgery followed by Larotrectinib monotherapy x2 cycles followed by disease evaluation
2. Larotrectinib with or without chemotherapy backbone
Eligibility Criteria
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Inclusion Criteria
* Diagnosis: Patients with newly-diagnosed high-grade (HGG), including diffuse intrinsic pontine gliomas (DIPG), whose tumors are documented in a CLIA/CAP certified lab (or clinically equivalent method considered standard in non-US sites) to harbor an NTRK fusion alteration by FISH, PCR, or next generation sequencing are eligible. Patients must have had histologically verified high-grade glioma such as anaplastic astrocytoma, glioblastoma, or H3 K27-mutant diffuse midline glioma verified at a CONNECT site.
For sites that do not have CLIA-certified equivalent (certified laboratory) to assess NTRK fusion, testing will be conducted centrally at NCH. NTRK testing will be performed by NGS using targeted RNA-sequencing (Archer Solid Tumor analysis) Please submit 10 unstained sections on charged slides at 10uM thickness, or 10 scrolls cut at 10uM thickness, along with submission of an H\&E slide. Formalin-fixed paraffin embedded (FFPE) tissue block and FFPE tissue scroll specimens must contain minimum of 25% tumor Snap-frozen tissue specimens are also acceptable and they must contain a minimum of 10% tumor. Please note that turn-around time for this test is up to 21 days.
* Disease Status: Patients with disseminated DIPG or HGG are eligible only if the patient is to receive chemotherapy only, i.e. no craniospinal RT is intended to be given. MRI of spine must be performed if disseminated disease is suspected clinically by the treating physicians. Patients with primary spinal tumors are eligible only if the patient is to receive either chemotherapy or focal radiation therapy, i.e. no craniospinal RT is intended to be given. Patients with leptomeningeal disease only, with no definitive identifiable primary tumor, and documented NTRK fusion, must be discussed with the Study Chair on a case-by-case basis.
* Surgical Cohort ONLY: Patients with newly-diagnosed HGG with NTRK fusions who have undergone prior biopsy and for whom further resection is indicated for a more definitive surgery at an enrolling site will be eligible to enroll onto the surgical study. DIPG patients are not eligible for the surgical cohort.
* Performance Level: Karnofsky ≥ 50% for patients \> 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age (See Appendix I). Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
Exclusion Criteria
Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) Hemoglobin \>8 g/dL (may receive transfusions)
\- Adequate Renal Function Defined as: Serum creatinine within normal institutional limits, or Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2
\- Adequate Liver Function Defined as: Total bilirubin ≤ 2.5 × institutional upper limit of normal AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal
\- Adequate Pulmonary Function Defined as: Pulse oximetry \> 94% on room air if there is clinical indication for determination (e.g. dyspnea at rest).
\- Adequate Neurologic Function Defined as: Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled. See Section 5.5.2 and Appendix III for EIAED guidelines.
\- Informed Consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
* Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered on this study due to unknown risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.
* Concomitant Medications Investigational Drugs: Patients who have previously received or are currently receiving another investigational drug are not eligible.
Anti-cancer Agents: Patients who have previously received or are currently receiving other anti-cancer agents, including chemotherapy, immunotherapy, monoclonal antibodies, biologic or targeted therapy, are not eligible
* Infection: Patients must not have any active, uncontrolled systemic bacterial, viral or fungal infection.
* Patients who have received prior solid organ transplantation are not eligible.
* Patients must not have malabsorption syndrome or other condition affecting oral absorption.
* Patients must not be receiving any treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor or inducer. (See Appendix III.) Strong inducers or inhibitors of CYP3A4 should be avoided from 7 days prior to enrollment to the end of the study.
* Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
21 Years
ALL
No
Sponsors
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Nationwide Children's Hospital
OTHER
Responsible Party
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Principal Investigators
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Susan Chi, MD
Role: STUDY_CHAIR
Dana Farber/ Boston Children's Cancer and Blood Disorders Center
Maryam Fouladi, MD
Role: STUDY_CHAIR
Nationwide Children's Hospital
Locations
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Children's Hospital Colorado
Aurora, Colorado, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Duke University Health System
Durham, North Carolina, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
Nationwide Children's Hospital
Columbus, Ohio, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Texas Children's Hospital
Houston, Texas, United States
Seattle Children's Hospital
Seattle, Washington, United States
Sydney Children's Hospital
Randwick, New South Wales, Australia
Queensland Children's Hospital
South Brisbane, Queensland, Australia
Perth Children's Hospital
Perth, Western Australia, Australia
The Hospital for Sick Children (SickKids)
Toronto, Ontario, Canada
Montreal Children's Hospital
Montreal, Quebec, Canada
Hopp Children's Cancer Center at NCT Heidelberg (KiTZ)
Heidelberg, Baden-Wurttemberg, Germany
University Medical Center Augsburg
Augsburg, , Germany
University Hospital Berlin
Berlin, , Germany
University Hospital Koln
Cologne, , Germany
University Medical Center Gottingen
Göttingen, , Germany
Starship Children's Hospital
Auckland, Grafton, New Zealand
Countries
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Central Contacts
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Facility Contacts
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Holly Lindsay, MD
Role: primary
Eugene Hwang, MD
Role: primary
Ashley Plant, MD
Role: primary
Susan Chi, MD
Role: primary
David Ashley, MBBS, PhD
Role: primary
Peter de Blank, MD
Role: primary
Maryam Fouladi, MD
Role: primary
Michael J Fisher, MD
Role: primary
Patricia Baxter, MD
Role: primary
Sarah Leary, MD
Role: primary
David Ziegler, MBBS
Role: primary
Tim Hassall, MBBS
Role: primary
Nick Gottardo, MBChB
Role: primary
Eric Bouffet, MD
Role: primary
Genevieve Legault, MD
Role: primary
Olaf Witt, MD
Role: primary
Michael Fruhwald, MD
Role: primary
Pablo Hernaiz Driever, MD
Role: primary
Matthias Fischer, MD
Role: primary
C. Kramm, MD
Role: primary
Sarah Hunter, MB ChB
Role: primary
Other Identifiers
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CONNECT1903
Identifier Type: -
Identifier Source: org_study_id