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
survical 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. 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.
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 Cardiac Function Defined as: Shortening fraction of ≥27% by echocardiogram, or
Ejection fraction of ≥ 50% by gated radionuclide study.
- 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.
