A Phase 1/2 Study of the Oral TRK Inhibitor larotrectinib in Pediatric patients with Advanced Solid or Primary Central Nervous System Tumors

Inclusion Criteria
1. Phase 1: 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
The Phase 1 dose escalation cohorts are closed to enrollment.
Phase 1 dose expansion: In addition to the above stated Inclusion Criteria,
patients eligible for enrollment onto this cohort must have a malignancy with a
documented NTRK gene fusion.,
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, with
documented ETV6 rearrangement (or NTRK3 rearrangement after discussion with the
Sponsor) by FISH or RT-PCR or a documented NTRK fusion by e.g. NGS.
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 with a documented NTRK gene fusion with the exception
of patients with IFS (Infantile FibroSarcoma), CMN (Congenital Mesoblastic
Nephroma tumors) or SBC (Secretory Breast Cancer), they may enroll into this
cohort with documentation of an ETV6 rearrangement by FISH or RT-PCR.
Documented NTRK fusion by NGS (Next Generation Sequencing) shall be identified
through molecular assays as routinely performed at CLIA or other
similarly-certified laboratories. If CLIA or similar certification of the
laboratory performing the molecular assay is not confirmed at the time of
consent patients may be included after discussion with the Sponsor. Patients
with NTRK-fusion positive benign tumors are also eligible.
or:
(including Expansion Phase) 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.,
2. Patients with primary CNS tumors or cerebral metastasis:
a) Must be neurologically stable based on stable neurologic exam for 7 days
prior to enrollment.
b) Must have not required increasing doses of steroids within the 7 days prior
to study entry to manage CNS symptoms
c) Phase 2 only: Imaging study must be performed within 28 days of C1D1 while
on stable dose steroid medication (if needed) for at least 7 days immediately
before the imaging study., 3. Histologic verification of malignancy at original
diagnosis or relapse, except in patients with intrinsic brain stem tumors,
optic pathway gliomas, or patients with pineal tumors and elevations of
cerebral spinal fluid (CSF) or serum tumor markers including alpha-fetoprotein
or beta-human chorionic gonadotropin (HCG)., 4. Evaluable and/or measurable
disease
a) Phase 1: Subjects must have evaluable and/or measurable disease as defined
by RECIST, RANO or INRC.
b) Phase 2: Subjects with a solid or CNS tumor must have at least one
measurable lesion as defined by RECIST, version 1.1, RANO or INRC. , 5.
Karnofsky (those 16 years and older) or Lansky (those younger than 16 years)
performance score of at least 50., 6. Patients must have fully recovered from
the acute toxic effects of all prior anti-cancer chemotherapy.
a) Myelosuppressive chemotherapy: At least 21 days after the last dose of
myelosuppressive chemotherapy (42 days if prior nitrosourea)
b) Investigational agent or anticancer therapy other than chemotherapy: Not
within 2 weeks prior to planned start of larotrectinib or 5 half-lives,
whichever is shorter. Full recovery of clinically significant toxicities from
that therapy must be evident.
c) Hematopoietic growth factors: At least 14 days after the last dose of a
long-acting growth factor (e.g., Neulasta) or 7 days for short-acting growth
factor
d) Immunotherapy: At least 42 days after the completion of any type of
immunotherapy (except for steroids), e.g., immune checkpoint inhibitors and
tumor vaccines
e) X-ray therapy (XRT): At least 14 days after local palliative XRT (small
port); >=At least 42 days must have elapsed if other substantial bone marrow
(BM) radiation, including prior radio iodized metaiodobenzylguanidine
(131I-MIBG) therapy.
f) Stem cell infusion without total body irradiation (TBI): No evidence of
active graft versus host disease and at least 56 days must have elapsed after
transplant or stem cell infusion., 7. An archival tumor tissue sample must be
available. If archival tumor tissue sample is not available, a fresh biopsy
(at a primary or at one metastatic site) should be performed. , 8. For patients
without known bone marrow involvement:
a) Absolute neutrophil count (ANC) >=1.0 * 109/L and
b) Platelet count >=100.0 * 109/L (transfusion allowed)
c) Hemoglobin >=8.0 g/dL (transfusions allowed), 9. Patients with bone marrow
involvement will not be evaluable for hematologic DLT and can enroll with:
a) ANC >=0.75 * 109/L and
b) Platelet count >=50.0 * 109/L (transfusions allowed)
c) Hemoglobin >=8.0 g/dL (transfusions allowed), 10. Adequate hepatic and renal
function, defined as:
a) Bilirubin (sum of conjugated + unconjugated) <=2.5 * upper limit of normal
(ULN) for age (patients with documented Gilbert*s Disease may be enrolled with
Sponsor approval)
b) SGPT (ALT) <=2.5 * upper limit of normal.
c) Estimated glomerular filtration rate >=30 mL/min/1.73 m2 based on local
institutional practice for determination, or a minimum serum creatinine as
presented in Section 4.1,
11. Ability to comply with outpatient treatment, laboratory monitoring, and
required clinic visits for the duration of study participation.,
12. Willingness of male and female patients with reproductive potential to use
double effective birth control methods, defined as one used by the patient and
another by his/her partner, for the duration of treatment and for 1 month
following study completion., For male patients with a non-pregnant female
partner of child-bearing potential and woman of child bearing potential one of
the following highly effective birth control methods with a failure rate of
less than 1% per year when used consistently and correctly are recommended:
a) Combined estrogen and progestogen containing hormonal contraception
associated with inhibition of ovulation given orally, intravaginally, or
transdermally
b) Progestogen-only hormonal contraception associated with inhibition of
ovulation given orally, by injection, or by implant
c) Intrauterine device (IUD)
d) Intrauterine hormone-releasing system (IUS)
e) Bilateral tubal occlusion
f) Vasectomized partner
g) Sexual abstinence: considered a highly effective method only if defined as
refraining from heterosexual intercourse during an entire period of risk
associated with the study treatment. The reliability of sexual abstinence will
be evaluated in relation to the duration of the study and to the usual
lifestyle of the patient.
Birth control methods unacceptable for this clinical trial are:
a) Periodic abstinence (calendar, symptothermal, or post-ovulation methods)
b) Withdrawal (coitus interruptus)
c) Spermacide only
d) Lactational amenorrhea method,
13. Ability to swallow capsules, liquid or gastric access via a naso- or
gastric tube,
14. Parent/g

Patients meeting any of the following criteria are to be excluded from study
participation:
1. Major surgery within 14 days (2 weeks) prior to C1D1., 2. Clinically
significant active cardiovascular disease or history of myocardial infarction
within 6 months prior to C1D1; ongoing cardiomyopathy; or current prolonged QT
interval corrected for heart rate (QTc) interval >480 milliseconds., 3. Active
uncontrolled systemic bacterial, viral, or fungal infection., 4. Malabsorption
syndrome or other condition affecting oral absorption., 5. Current treatment
with a strong cytochrome P450 3A4 (CYP3A4) inhibitor or inducer other than
those allowed per Section 6.3.2., 6. Pregnancy or lactation., 7. Phase 2 only:
Prior progression while receiving approved or investigational tyrosine kinase
inhibitors targeting TRK, including entrectinib, crizotinib and lestaurtanib.
Patients who received a tropomyosin-related kinase (TRK) inhibitor for less
than 28 days of treatment and discontinued because of intolerance remain
eligible.