ADVL1823: Larotrectinib (LOXO-101, NSC# 788607, IND# 141824) for Previously Untreated TRK Fusion Pediatric Solid Tumors and TRK Fusion Relapsed Pediatric Acute Leukemias

This phase II trial studies the side effects and how well larotrectinib works in treating
patients with previously untreated TRK fusion solid tumors and TRK fusion acute leukemia
that has come back. Larotrectinib may stop the growth of cancer cells with TRK fusions by
blocking the TRK enzymes needed for cell growth.

Inclusion Criteria:

- Patients must be =< 30 years of age at the time of study entry

- COHORT A: Patients must have a histologic diagnosis of infantile fibrosarcoma with
an NTRK1, NTRK2, or NTRK3 fusion identified in a Clinical Laboratory Improvement
Act/College of American Pathologists (CLIA/CAP) certified laboratory. Fusions may be
identified by fluorescence in situ hybridization (FISH) or molecular techniques
(reverse transcriptase-polymerase chain reaction [RT-PCR] using primers flanking the
fusion junction or next generation sequencing). For fusions identified by FISH, an
ETV6 rearrangement is sufficient for eligibility in Cohort A. Identification of the
upstream TRK fusion partner is not required.

- COHORT B: Patients must have a histologic diagnosis of any solid tumor other than
infantile fibrosarcoma, including central nervous system (CNS) tumors but excluding
high grade gliomas. An NTRK1, NTRK2, or NTRK3 fusion must be identified in a
CLIA/CAP certified laboratory. Fusions may be identified by FISH or molecular
techniques (RT-PCR using primers flanking the fusion junction or next generation
sequencing). For fusions identified by FISH, there must be an identified
rearrangement in NTRK1, NTRK2, or NTRK3 (e.g., an ETV6 rearrangement is not
sufficient for eligibility) unless the patient has a diagnosis of congenital
mesoblastic nephroma in which case an ETV6 rearrangement is sufficient for
eligibility. Identification of the upstream TRK fusion partner is not required.

- COHORT C: Patients must have a histologic diagnosis of relapsed or refractory acute
leukemia with an NTRK1, NTRK2, or NTRK3 fusion identified in a CLIA/CAP certified
laboratory. Fusions may be identified by FISH or molecular techniques (RT-PCR using
primers flanking the fusion junction or next generation sequencing). For fusions
identified by FISH, there must be an identified rearrangement in NTRK1, NTRK2, or
NTRK3 (e.g., an ETV6 rearrangement is not sufficient for eligibility).
Identification of the upstream TRK fusion partner is not required.

- SOLID TUMORS (COHORTS A AND B): Patients must have measurable disease. Patients must
have disease that cannot be completely resected without a predicted functional,
neurologic, or significant cosmetic deficit in the opinion of the investigator.

- LEUKEMIA (COHORT C): Patients must have >= 5% blasts in the bone marrow.
Extramedullary disease is permitted.

- Patients must have a Lansky or Karnofsky performance status score of >= 50,
corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1 or 2. Use
Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age.
NOTE: Neurologic deficits in patients with CNS tumors must have been stable for at
least 7 days prior to study enrollment. 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.

- COHORTS A AND B: No prior anti-cancer therapy, including radiotherapy, other than
surgical resection is permitted.

- Patients who experience recurrence after surgery alone and no other anti-cancer
therapy will be eligible.

- If not eligible due to prior anticancer therapy, patients may be eligible for
the larotrectinib arm of Pediatric MATCH (APEC1621A) or treatment with
commercial larotrectinib off study.

- COHORT C: Patients with relapsed leukemia (Cohort C) must have fully recovered from
the acute toxic effects of all prior anti-cancer therapy and must meet the following
minimum duration from prior anti-cancer directed therapy prior to enrollment. If
after the required timeframe, the numerical eligibility criteria are met, e.g. blood
count criteria, the patient is considered to have recovered adequately.

- Cytotoxic chemotherapy or other anti-cancer agents known to be
myelosuppressive. The duration of this interval must be discussed with the
study chair and the study-assigned research coordinator prior to enrollment.

- A waiting period prior to enrollment is not required for patients
receiving standard cytotoxic maintenance chemotherapy (i.e.,
corticosteroid, vincristine, thioguanine [6MP], and/or methotrexate).

- A waiting period is not required for patients receiving a single dose of
intrathecal methotrexate, hydrocortisone, and/or cytarabine within 7 days
prior to enrollment.

- >= 14 days must have elapsed after the completion of other cytotoxic
therapy, with the exception of hydroxyurea, for patients not receiving
standard maintenance therapy. Additionally, patients must have fully
recovered from all acute toxic effects of prior therapy.

- Note: Cytoreduction with hydroxyurea must be discontinued >= 24 hours
prior to the start of protocol therapy.

- Anti-cancer agents not known to be myelosuppressive (e.g., not associated with
reduced platelet or absolute neutrophil [ANC] counts): >= 7 days after the last
dose of agent. The duration of this interval must be discussed with the study
chair and the study-assigned research coordinator prior to enrollment.

- Anti-cancer agents that are antibodies: >= 21 days must have elapsed from
infusion of last dose of antibody, and toxicity related to prior antibody
therapy must be recovered to grade =< 1. There is an exception for blinatumomab
infusions, for which patients must have been off for at least 3 days and all
drug related toxicity must have resolved to grade 2 or lower as outlined in the
inclusion/exclusion criteria.

- Corticosteroids: If used to modify immune adverse events related to prior
therapy, >= 14 days must have elapsed since last dose of corticosteroid. A
waiting period prior to enrollment is not required for patients receiving
corticosteroid for leukemia therapy/cytoreduction.

- Hematopoietic growth factors: >= 14 days after the last dose of a long-acting
growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor.
For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which
adverse events are known to occur. The duration of this interval must be
discussed with the study chair and the study-assigned research coordinator.

- Interleukins, interferons and cytokines (other than hematopoietic growth
factors): >= 21 days after the completion of interleukins, interferon or
cytokines (other than hematopoietic growth factors ).

- Stem cell infusions (with or without total body irradiation [TBI]):

- Allogeneic (non-autologous) bone marrow or stem cell transplant, or any
stem cell infusion including donor lymphocyte infusion (DLI) or boost
infusion: >= 84 days after infusion and no evidence of graft versus host
disease (GVHD).

- Autologous stem cell infusion including boost infusion: >= 42 days.

- Cellular therapy: >= 42 days after the completion of any type of cellular
therapy (e.g., modified T cells, natural killer [NK] cells, dendritic cells,
etc.)

- Radiation therapy (XRT)/external beam irradiation including protons: >= 14 days
after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >=
50% of the pelvis; >= 42 days if other substantial BM radiation.

- Radiopharmaceutical therapy (e.g., radiolabeled antibody): >= 42 days after
systemically administered radiopharmaceutical therapy.

- Patients must not have received prior exposure to TRK inhibitors (including
larotrectinib, LOXO-195, entrectinib, lorlatinib, crizotinib, or lestaurtinib).

- For patients with solid tumors without known bone marrow involvement: Peripheral
absolute neutrophil count (ANC) >= 1000/mm^3 (within 7 days prior to enrollment).

- For patients with solid tumors without known bone marrow involvement: Platelet count
>= 100,000/mm^3 (transfusion independent, defined as not receiving platelet
transfusions for at least 7 days prior to enrollment).

- For patients with solid tumors without known bone marrow involvement: Hemoglobin >=
8.0 g/dL at baseline (within 7 days prior to enrollment) (may receive red blood cell
[RBC] transfusions).

- Patients with solid tumors with known bone marrow metastatic disease will be
eligible for study provided they meet the blood counts above (may receive
transfusions provided they are not known to be refractory to red cell or platelet
transfusions). These patients will not be evaluable for hematologic toxicity.

- For patients with leukemia: Platelet count >= 20,000/mm^3 (within 7 days prior to
enrollment) (may receive platelet transfusions; must not be known to be refractory
to red cell or platelet transfusion).

- For patients with leukemia: Hemoglobin >= 8.0 g/dL at baseline (within 7 days prior
to enrollment) (may receive RBC transfusions; must not be known to be refractory to
red cell or platelet transfusion).

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows (within 7 days
prior to enrollment):

- 1 month to < 6 months (male 0.4 mg/dL, female 0.4 mg/dL)

- 6 months to < 1 year (male 0.5 mg/dL, female 0.5 mg/dL)

- 1 to < 2 years (male 0.6 mg/dL, female 0.6 mg/dL)

- 2 to < 6 years (male 0.8 mg/dL, female 0.8 mg/dL)

- 6 to < 10 years (male 1 mg/dL, female 1 mg/dL)

- 10 to < 13 years (male 1.2 mg/dL, female 1.2 mg/dL)

- 13 to < 16 years (male 1.5 mg/dL, female 1.4 mg/dL)

- >= 16 years (male 1.7 mg/dL, female 1.4 mg/dL)

- For patients < 1 month of age, serum creatinine levels must be < 1.5 x the
treating institution's creatinine upper limit of normal (ULN) for patients
< 1 month of age or the creatinine clearance or radioisotope GFR must be
>= 70 mL/min/1.73 m^2.

- Patients with solid tumors: Bilirubin (sum of conjugated + unconjugated) =< 1.5 x
upper limit of normal (ULN) for age (within 7 days prior to enrollment). After
approval of the study chair or designee, infants with a higher total bilirubin due
to physiologic or breast milk jaundice are eligible if the conjugated (direct)
bilirubin is =< 2 mg/dL.

- Patients with solid tumors: Serum glutamate pyruvate transaminase (SGPT) (alanine
aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment). For the
purpose of this study, the ULN for SGPT is 45 U/L.

- Patients with solid tumors: Serum albumin >= 2 g/dL (within 7 days prior to
enrollment).

- Patients with leukemias: Conjugated (direct) bilirubin =< 1.5 x upper limit of
normal (ULN) for age (within 7 days prior to enrollment).

- Patients with leukemias: SGPT (ALT) =< 225 U/L (within 7 days prior to enrollment).
For the purpose of this study, the ULN for SGPT is 45 U/L.

- Patients with leukemias: Serum albumin >= 2 g/dL (within 7 days prior to
enrollment).

- Patients with seizure disorder may be enrolled if on a stable antiepileptic regimen
for >= 14 days and well controlled.

- Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE]
version [v] 5) except tendon reflex decreased resulting from prior therapy must be
=< grade 2.

- All patients and/or their parents or legal guardians must sign a written informed
consent.

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met.

Exclusion Criteria:

- Pregnant or breast-feeding women will not be entered on this study due to risks of
fetal and teratogenic adverse events as seen in animal/human studies, OR because
there is yet no available information regarding human fetal or teratogenic
toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Female
patients of reproductive potential may not participate unless they have agreed to
use a highly effective contraceptive method for the duration of study therapy and
for at least one month after the final dose of larotrectinib. Males of reproductive
potential with a non-pregnant female partner of child-bearing potential must use a
highly effective contraception for the duration of the study and for at least one
month after the final dose of larotrectinib. Because of the unknown risk of
larotrectinib in nursing infants, nursing women should discontinue breastfeeding
during treatment with larotrectinib and for 3 days following the final dose.

- Patients with solid tumors, including CNS tumors, requiring corticosteroids who have
not been on a stable or decreasing dose of corticosteroid for at least 7 days prior
to enrollment are not eligible. Patients with leukemia may receive systemic
corticosteroids for cytoreduction up to 24 hours prior to the start of protocol
therapy. If used to modify immune adverse events related to prior therapy, >= 14
days must have elapsed since last dose of corticosteroid.

- Patients who are currently receiving another investigational drug are not eligible.

- Patients who are currently receiving other anti-cancer agents are not eligible
[except leukemia patients receiving corticosteroids or hydroxyurea, which may be
continued until 24 hours prior to start of protocol therapy]. Patients with leukemia
should receive a single dose of intrathecal cytarabine, hydrocortisone, and/or
methotrexate within 7 days prior to Day 1 of Cycle 1 at the time of the baseline
lumbar puncture.

- Patients who are receiving cyclosporine, tacrolimus or other agents to prevent
graft-versus-host disease post bone marrow transplant are not eligible for this
trial.

- Patients currently receiving a strong CYP3A4 inducer or inhibitor are not eligible.
Strong inducers or inhibitors of CYP3A4 should be avoided from 14 days prior to
enrollment to the end of the study. Note: CYP3A4 inducing anti-epileptic drugs and
dexamethasone for CNS tumors or metastases, on a stable dose, are allowed.

- Patients with malabsorption syndrome or other conditions that significantly limit
enteral absorption are not eligible.

- Patients who are unable to swallow capsules or liquid and do not have gastric access
via a nasogastric or gastrostomy tube are not eligible.

- Patients who have an uncontrolled infection are not eligible.

- Patients who have received prior solid organ transplantation are not eligible.

- 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.

- Patients with high grade gliomas (HGG) are not eligible.