A Study to Test the Safety and Efficacy of the Drug Larotrectinib for the Treatment of Tumors With NTRK-fusion in Children

The primary objectives are to determine the safety and efficacy of oral larotrectinib in
pediatric patients with advanced solid or primary central nervous system (CNS) tumors.

The secondary objectives comprise e.g. the determination of the pharmacokinetic properties,
the maximum tolerated dose/ recommended dose and the tumor-type specific efficacy of
larotrectinib. In addition, pain status and health-related quality of life of the pediatric
patients will be assessed.

Inclusion Criteria:

- Phase 1:

- Dose escalation: Birth through 21 years of age at C1D1 with a locally advanced or
metastatic solid tumor or primary CNS tumor that has relapsed, progressed or was
nonresponsive to available therapies and for which no standard or available
systemic curative therapy exists; OR Infants from birth and older with a
diagnosis of malignancy and with a documented NTRK fusion that has progressed or
was nonresponsive to available therapies, and for which no standard or available
curative therapy exists; OR Patients with locally advanced infantile fibrosarcoma
who would require, in the opinion of the investigator, disfiguring surgery or
limb amputation to achieve a complete surgical resection. Phase I dose escalation
cohorts are closed to enrollment.

- Dose expansion: In addition to the above stated inclusion criteria, patients must
have a malignancy with a documented NTRK gene fusion with the exception of
patients with infantile fibrosarcoma, congenital mesoblastic nephroma or
secretory breast cancer. Patients with infantile fibrosarcoma, congenital
mesoblastic nephroma or secretory breast cancer may enroll into this cohort with
documentation of an ETV6 rearrangement by FISH or RT-PCR or a documented NTRK
fusion by next generation sequencing.

- Phase 2:

- Infants from birth and older at C1D1 with a locally advanced or metastatic
infantile fibrosarcoma, patients with locally advanced infantile fibrosarcoma who
would require, in the opinion of the investigator, disfiguring surgery or limb
amputation to achieve a complete surgical resection; OR Birth through 21 years of
age at C1D1 with a locally advanced or metastatic solid tumor or primary CNS
tumor that has relapsed, progressed or was nonresponsive to available therapies
and for which no standard or available systemic curative therapy exists with a
documented NTRK gene fusion (or in the case of infantile fibrosarcoma, congenital
mesoblastic nephroma or secretory breast cancer with documented ETV6
rearrangement by FISH or RT-PCR or a documented NTRK fusion by next generation
sequencing) (identified through molecular assays as routinely performed at CLIA
or other similarly certified laboratories). Patients with NTRK-fusion positive
benign tumors are also eligible; OR Potential patients older than 21 years of age
with a tumor diagnosis with histology typical of a pediatric patient and an NTRK
fusion may be considered for enrollment following discussion between the local
site Investigator and the Sponsor's Medical Monitor.

- Patients with primary CNS tumors or cerebral metastasis

- Karnofsky (those 16 years and older) or Lansky (those younger than 16 years)
performance score of at least 50.

- Adequate hematologic function

- Adequate hepatic and renal function

Exclusion Criteria:

- Major surgery within 14 days (2 weeks) prior to C1D1

- Clinically significant active cardiovascular disease or history of myocardial
infarction within 6 months prior to C1D1, ongoing cardiomyopathy; current prolonged
QTc interval > 480 milliseconds

- Active uncontrolled systemic bacterial, viral, or fungal infection

- Current treatment with a strong CYP3A4 inhibitor or inducer. Enzyme-inducing
anti-epileptic drugs (EIAEDs) and dexamethasone for CNS tumors or metastases, on a
stable dose, are allowed.

- Phase 2 only:

- Prior progression while receiving approved or investigational tyrosine kinase
inhibitors targeting TRK, including entrectinib, crizotinib and lestaurtanib.
Patients who received a TRK inhibitor for less than 28 days of treatment and
discontinued because of intolerance remain eligible.