A Pilot Study of Larotrectinib for Newly-Diagnosed High-Grade Glioma With NTRK Fusion
Trial statusRecruiting
Trial phaseEarly Phase 1
Trial typeInterventional
Biological sexAll
AgeUp to 21
SponsorNationwide Children's Hospital
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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.
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.
Disqualifiers
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.
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.
Trial design
Design model
Single group
Treatments tested in this trial
Larotrectinib
Drug1. Larotrectinib monotherapy x2 cycles followed by disease evaluation 2. Larotrectinib with or without chemotherapy backbone
Larotrectinib surgical
Procedure/Surgery1. 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
Treatment groups
15 Participants
are divided into 2 treatment groupsGroup A: Feasibility CohortExperimental treatment 1 intervention
Group B: Surgical CohortExperimental treatment 2 interventions
Trial outcomes
Primary outcomes
1
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.
Time frame
At the end of Cycle 2 (each cycle is 28 days)2
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.
Time frame
From Day 1 of treatment through 30 days following end of protocol treatment3
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.
Time frame
Days 1 through 5 of surgical cycle4
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
Time frame
Day 5 of surgical surgical cycleSecondary outcomes
1
Objective response rate (ORR)
To assess the objective response rate (ORR) (Complete Response \[CR\] and Partial Response \[PR\]) of larotrectinib in children newly-diagnosed with HGG carrying NTRK fusion after 2 cycles of larotrectinib monotherapy.
Time frame
At the end of Cycle 2 (each cycle is 28 days)2
Survival rate
To assess overall (OS) and progression-free survivals (PFS) of children newly diagnosed with HGG carrying NTRK fusion treated with a larotrectinib-containing regimen at 1, 3 and 5 years and compared to historical data from BABYPOG and HIT-SKK.
Time frame
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 monthsSponsors and contacts
Click on the lead sponsor to view all of their trials.
Source ClinicalTrials.gov