Larotrectinib in Treating Patients With Previously Untreated TRK Fusion Solid Tumors and TRK Fusion Relapsed Acute Leukemia
Larotrectinib in Treating Patients With Previously Untreated TRK Fusion Solid Tumors and TRK Fusion Relapsed Acute Leukemia
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.
PRIMARY OBJECTIVE:

 I. To determine the objective response rate (ORR) of children with infantile fibrosarcoma
 (IFS) treated with neoadjuvant larotrectinib prior to local control.

 SECONDARY OBJECTIVES:

 I. To determine event-free survival (EFS), overall survival (OS), and duration of response
 (DoR) of children with IFS treated with neoadjuvant larotrectinib prior to local control.

 II. To determine the ORR, EFS, OS, and DoR of children with newly diagnosed TRK fusion solid
 tumors other than IFS treated with neoadjuvant larotrectinib prior to local control.

 III. To describe the toxicity of larotrectinib in children with solid tumors and acute
 leukemia.

 IV. To determine the percentage of patients with TRK fusion solid tumors with detectable
 circulating tumor deoxyribonucleic acid (DNA) at baseline and after 2 weeks, 4 weeks, 24
 weeks of treatment, at the time of discontinuation of larotrectinib therapy, and at
 progression.

 EXPLORATORY OBJECTIVES:

 I. To determine the EFS, OS, and DoR of children with TRK fusion solid tumors other than IFS
 treated with adjuvant larotrectinib following upfront surgery with positive margins after
 neoadjuvant larotrectinib.

 II. To determine the EFS, OS, and DoR of children with TRK fusion solid tumors who experience
 a complete response to larotrectinib and subsequently discontinue larotrectinib therapy.

 III. To determine the remission induction rate for patients with recurrent/refractory TRK
 fusion leukemia when treated with larotrectinib.

 IV. To evaluate the surgical morbidity and extent of resection of initially unresectable
 tumors in patients with TRK fusion solid tumors who undergo surgical resection following
 neoadjuvant larotrectinib.

 V. To evaluate mechanisms of response and resistance to larotrectinib in children with TRK
 fusion cancers.

 VI. To evaluate the morphologic features of TRK fusion solid tumors at time of initial biopsy
 to further define criteria for pathologic diagnosis of these tumors.

 VII. To evaluate immunohistochemistry for pan-TRK as a screening method for TRK fusion tumors
 and in resection specimens following neoadjuvant treatment with larotrectinib.

 VIII. To evaluate the histologic response to larotrectinib in resection specimens following
 neoadjuvant treatment.

 IX. To evaluate circulating tumor DNA for the detection of the emergence of resistance
 mutations and recurrence in patients with TRK fusion solid tumors treated with larotrectinib.

 X. To evaluate the ratio of cerebrospinal fluid (CSF) to concurrent plasma concentrations of
 larotrectinib in patients with leukemia.

 XI. To evaluate the change in neurocognitive/behavioral functioning over time between
 baseline and 2 years post-diagnosis of patients treated on this protocol using
 parent-reported adaptive functioning (Adaptive Behavior Assessment System [ABAS]-III General
 Adaptive Composite), executive function (Behavior Rating Inventory of Executive Function
 Scales-Preschool Version [BRIEF-P] or BRIEF-2 Global Executive Composite Score), psychosocial
 functioning (Behavior Assessment System for Children [BASC]-3 Internalizing, Externalizing
 and Behavioral Symptoms Indices) and quality of life (Pediatric Quality of Life Inventory
 [PedsQL] Total score).

 OUTLINE:

 Patients receive larotrectinib orally (PO) or by nasogastric (NG) or gastric tube (G-tube)
 twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the
 absence of disease progression or unacceptable toxicity. Patients whose tumors shrink
 sufficiently while taking larotrectinib may undergo surgical resection of their tumor while
 on study.

 After completion of study treatment, patients are followed up at 3, 6, 12, 18, 24, 30, 36,
 and 48 months and annually thereafter for up to 5 years from the date of study entry.
Inclusion Criteria:

 -  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 (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.

 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.

 -  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.