A Pilot Study of Larotrectinib for Newly-Diagnosed High-Grade Glioma With NTRK Fusion

NCT04655404 | Recruiting Early Phase 1 DMC FDA Drug

• 1 other identifier: CONNECT1903
• Study Type: interventional
• Target: 15
• Locations: 5 countries
• Sites: 21

Brief Summary

This is a pilot study that will evaluate disease status in children that have been newly diagnosed high-grade glioma with TRK fusion. The evaluation will occur after 2 cycles of the medication (Larotrectinib) have been given. 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.

Conditions

High Grade Glioma; Diffuse Intrinsic Pontine Glioma

Keywords

NTRK gene fusion; BABYPOG; HIT-SKK; Larotrectinib

Outcome Measures

Primary Outcomes (4)

• Disease control rate

  To assess the disease control rate (Complete Response \[CR\], Continued Complete Response \[CCR\], Partial Response \[PR\] and Stable Disease \[SD\]) of larotrectinib in young children newly diagnosed with HGG carrying NTRK fusion after 2 cycles of larotrectinib monotherapy.

  At the end of Cycle 2 (each cycle is 28 days)

• Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

  To assess the safety and tolerability of larotrectinib given in combination with chemotherapy or post-focal radiation therapy in young children newly diagnosed with HGG carrying NTRK fusion. This will be achieved by calculating the number of participants with, as well as frequency and severity of, larotrectinib-related Adverse Events as assessed by CTCAE v5.0.

  From Day 1 of treatment through 30 days following end of protocol treatment

• Maximum Plasma Concentration [Cmax] of larotrectinib

  To characterize the plasma pharmacokinetics (PK) of larotrectinib in children newly diagnosed with HGG carrying NTRK fusions who undergo a second definitive resection. This will be achieved by measuring the Maximum Plasma Concentration (Cmax) of larotrectinib in blood (plasma) samples collected at pre-dose (day -5), pre-surgery (day -1) and during surgery.

  Days 1 through 5 of surgical cycle

• Tumor Concentration of larotrectinib

  To characterize the tumor pharmacokinetics (PK) of larotrectinib in children newly diagnosed with HGG carrying NTRK fusions who undergo a second definitive resection by measuring the concentration of larotrectinib in tumor tissue collected on day 5 of surgical cycle

  Day 5 of surgical surgical cycle

Secondary Outcomes (2)

• Objective response rate (ORR)

  At the end of Cycle 2 (each cycle is 28 days)

• Survival rate

  From date of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months

Study Arms (2)

Feasibility Cohort

EXPERIMENTAL

Larotrectinib administered PO, BID @100 mg/m2 on a 28-day cycle schedule.

Drug: Larotrectinib

Surgical Cohort

EXPERIMENTAL

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.

Drug: Larotrectinib; Procedure: Larotrectinib surgical

Interventions

Larotrectinib DRUG

1. Larotrectinib monotherapy x2 cycles followed by disease evaluation 2. Larotrectinib with or without chemotherapy backbone

Feasibility Cohort; Surgical Cohort

Larotrectinib surgical PROCEDURE

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

Surgical Cohort

Eligibility Criteria

• Age: Up to 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age: Patients ≤ 21 years of age (birth to 21 years of age) at the time of study enrollment will be eligible.
• 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.

You may not qualify if:

• Organ Function Requirements: Adequate Bone Marrow Function Defined as:
• 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.

Sponsors & Collaborators

• Nationwide Children's Hospital: lead

Study Sites (21)

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

RECRUITING

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

RECRUITING

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

WITHDRAWN

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

RECRUITING

Duke University Health System

Durham, North Carolina, 27708, United States

RECRUITING

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

RECRUITING

Nationwide Children's Hospital

Columbus, Ohio, 43235, United States

RECRUITING

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

Texas Children's Hospital

Houston, Texas, 77030, United States

RECRUITING

Seattle Children's Hospital

Seattle, Washington, 98105, United States

RECRUITING

Sydney Children's Hospital

Randwick, New South Wales, 2031, Australia

RECRUITING

Queensland Children's Hospital

South Brisbane, Queensland, 4101, Australia

RECRUITING

Perth Children's Hospital

Perth, Western Australia, 6000, Australia

RECRUITING

The Hospital for Sick Children (SickKids)

Toronto, Ontario, M5G1X8, Canada

RECRUITING

Montreal Children's Hospital

Montreal, Quebec, H4A3J1, Canada

RECRUITING

Hopp Children's Cancer Center at NCT Heidelberg (KiTZ)

Heidelberg, Baden-Wurttemberg, 69120, Germany

RECRUITING

University Medical Center Augsburg

Augsburg, Germany

RECRUITING

University Hospital Berlin

Berlin, Germany

RECRUITING

University Hospital Koln

Cologne, Germany

RECRUITING

University Medical Center Gottingen

Göttingen, Germany

RECRUITING

Starship Children's Hospital

Auckland, Grafton, 1023, New Zealand

RECRUITING

MeSH Terms

Conditions

Glioma; Diffuse Intrinsic Pontine Glioma

Interventions

larotrectinib

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Brain Stem Neoplasms; Infratentorial Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Susan Chi, MD

  Dana Farber/ Boston Children's Cancer and Blood Disorders Center

  STUDY CHAIR

• Maryam Fouladi, MD

  Nationwide Children's Hospital

  STUDY CHAIR

Central Study Contacts

Kelsey H Troyer, PhD

CONTACT

16147223284; kelsey.troyer@nationwidechildrens.org

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Feasibility and surgical cohorts

Study Record Dates

• First Submitted: November 9, 2020
• First Posted: December 7, 2020
• Study Start: April 8, 2021
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2036
• Last Updated: March 18, 2026

Record last verified: 2026-03

Locations

US (10); DE (5); AU (3); NZ (1); CA (2)