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

Sponsor

Nationwide Children's Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT04655404

Collaborator

(none)

Enrollment

Locations

Arm

55.8

Anticipated Duration (Months)

0.8

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
High Grade Glioma Diffuse Intrinsic Pontine Glioma	Drug: Larotrectinib Procedure: Larotrectinib surgical	Early Phase 1

Detailed Description

In this pilot study, we will assess the disease control rate (Continued Complete Response-CCR, Complete Response-CR, Partial Response-PR and Stable Disease-SD) as well as survival rate (overall survival- OS and progression free survival- PFS) in children with newly diagnosed HGG with TRK fusion who receive 2 cycles of larotrectinib monotherapy administered orally, twice daily, at 100 mg/m2 continuously on a 28-day cycle schedule. After 2 monotherapy cycles of larotrectinib, patients with CCR or CR will continue to receive larotrectinib maintenance therapy as monotherapy for a total of 12 cycles. Continuation of treatment beyond 12 cycles, and up to 24 cycles, may be considered for patients on Larotrectinib monotherapy if they are receiving clinical benefit from the study, at the discretion of the treating physician.

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

15 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Pilot and Surgical Study of Larotrectinib for Treatment of Children With Newly-Diagnosed High-Grade Glioma With NTRK Fusion

Actual Study Start Date :

Apr 8, 2021

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Dec 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Larotrectinib Larotrectinib will be administered orally, twice daily, at 100 mg/m2 continuously on a 28-day cycle schedule.	Drug: Larotrectinib Larotrectinib monotherapy x2 cycles followed by disease evaluation Other Names: Larotrectinib with or without chemotherapy backbone Procedure: Larotrectinib surgical Surgical cohort: Larotrectinib x 3-5 days prior to definitive surgery

Arm

Intervention/Treatment

Experimental: Larotrectinib

Larotrectinib will be administered orally, twice daily, at 100 mg/m2 continuously on a 28-day cycle schedule.

Drug: Larotrectinib

Larotrectinib monotherapy x2 cycles followed by disease evaluation

Other Names:

Larotrectinib with or without chemotherapy backbone

Procedure: Larotrectinib surgical

Surgical cohort: Larotrectinib x 3-5 days prior to definitive surgery

Outcome Measures

Primary Outcome Measures

Disease control rate [24 months]
To assess the disease control rate of larotrectinib in young children with newly-diagnosed high-grade glioma with NTRK fusion after 2 cycles of larotrectinib monotherapy
Incidence of Treatment- Emergent Adverse Events (Safety) of larotrectinib [24 months]
To assess the safety of larotrectinib when given in combination with chemotherapy or post-focal radiation therapy, assessed by CTCAE v5.0
Measurement of Are Under the Curve (AUC) of larotrectinib [24 months]
To characterize the area under the plasma concentration versus time curve (AUC) of larotrectinib in surgical patients through the measurement of blood pharmacokinetics
Dose-response relationship of larotrectinib [24 months]
To characterize the dose-response relationship of larotrectinib in surgical patients through the measurement of blood pharmacodynamics

Secondary Outcome Measures

Response rate [24 months]
To assess the objective response rate (ORR) (Complete Response [CR] and Partial Response [PR]) of larotrectinib in children with newly-diagnosed high-grade glioma with NTRK fusion after 2 cycles of larotrectinib monotherapy.
Survival rate [60 months]
To assess overall (OS) and progression-free survivals (PFS) of children with high-grade gliomas treated with a larotrectinib-containing regimen at 1, 3 and 5 years defined as date of death or earliest date of failure.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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.
Prior Therapy: Patients must not have received any prior anti-cancer chemotherapy. Prior use of corticosteroids are allowed (see below Exclusion Criteria)
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.

Exclusion Criteria:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Colorado	Aurora	Colorado	United States	80045
2	Children's National Medical Center	Washington	District of Columbia	United States	20010
3	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
4	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
5	Duke University Health System	Durham	North Carolina	United States	27708
6	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
7	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
8	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
9	Texas Children's Hospital	Houston	Texas	United States	77030
10	Seattle Children's Hospital	Seattle	Washington	United States	98105
11	Sydney Children's Hospital	Randwick	New South Wales	Australia	2031
12	Queensland Children's Hospital	South Brisbane	Queensland	Australia	4101
13	Perth Children's Hospital	Perth	Western Australia	Australia	6000
14	The Hospital for Sick Children (SickKids)	Toronto	Ontario	Canada	M5G1X8
15	Montreal Children's Hospital	Montréal	Quebec	Canada	H4A3J1
16	Hopp Children's Cancer Center at NCT Heidelberg (KiTZ)	Heidelberg	Baden-Württemberg	Germany	69120
17	Princess Máxima Center	Utrecht		Netherlands	3720
18	Great Ormond Street Hospital	London		United Kingdom	WC1N 3JH

Sponsors and Collaborators

Nationwide Children's Hospital

Investigators

Study Chair: Susan Chi, MD, Dana Farber/ Boston Children's Cancer and Blood Disorders Center
Study Chair: Maryam Fouladi, Nationwide Children's Hospital