<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03834961</url>
  </required_header>
  <id_info>
    <org_study_id>ADVL1823</org_study_id>
    <secondary_id>NCI-2019-00015</secondary_id>
    <secondary_id>ADVL1823</secondary_id>
    <secondary_id>ADVL1823</secondary_id>
    <secondary_id>U10CA180886</secondary_id>
    <nct_id>NCT03834961</nct_id>
  </id_info>
  <brief_title>Larotrectinib in Treating Patients With Previously Untreated TRK Fusion Solid Tumors and TRK Fusion Relapsed Acute Leukemia</brief_title>
  <official_title>Larotrectinib (LOXO-101, NSC# 788607) for Previously Untreated TRK Fusion Pediatric Solid Tumors and TRK Fusion Relapsed Pediatric Acute Leukemias</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Children's Oncology Group</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Children's Oncology Group</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II trial studies the side effects and how well larotrectinib works in treating&#xD;
      patients with previously untreated TRK fusion solid tumors and TRK fusion acute leukemia that&#xD;
      has come back. Larotrectinib may stop the growth of cancer cells with TRK fusions by blocking&#xD;
      the TRK enzymes needed for cell growth.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVE:&#xD;
&#xD;
      I. To determine the objective response rate (ORR) of children with infantile fibrosarcoma&#xD;
      (IFS) treated with neoadjuvant larotrectinib prior to local control.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To determine event-free survival (EFS), overall survival (OS), and duration of response&#xD;
      (DoR) of children with IFS treated with neoadjuvant larotrectinib prior to local control.&#xD;
&#xD;
      II. To determine the ORR, EFS, OS, and DoR of children with newly diagnosed TRK fusion solid&#xD;
      tumors other than IFS treated with neoadjuvant larotrectinib prior to local control.&#xD;
&#xD;
      III. To describe the toxicity of larotrectinib in children with solid tumors and acute&#xD;
      leukemia.&#xD;
&#xD;
      IV. To determine the percentage of patients with TRK fusion solid tumors with detectable&#xD;
      circulating tumor deoxyribonucleic acid (DNA) at baseline and after 2 weeks, 4 weeks, 24&#xD;
      weeks of treatment, at the time of discontinuation of larotrectinib therapy, and at&#xD;
      progression.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. To determine the EFS, OS, and DoR of children with TRK fusion solid tumors other than IFS&#xD;
      treated with adjuvant larotrectinib following upfront surgery with positive margins after&#xD;
      neoadjuvant larotrectinib.&#xD;
&#xD;
      II. To determine the EFS, OS, and DoR of children with TRK fusion solid tumors who experience&#xD;
      a complete response to larotrectinib and subsequently discontinue larotrectinib therapy.&#xD;
&#xD;
      III. To determine the remission induction rate for patients with recurrent/refractory TRK&#xD;
      fusion leukemia when treated with larotrectinib.&#xD;
&#xD;
      IV. To evaluate the surgical morbidity and extent of resection of initially unresectable&#xD;
      tumors in patients with TRK fusion solid tumors who undergo surgical resection following&#xD;
      neoadjuvant larotrectinib.&#xD;
&#xD;
      V. To evaluate mechanisms of response and resistance to larotrectinib in children with TRK&#xD;
      fusion cancers.&#xD;
&#xD;
      VI. To evaluate the morphologic features of TRK fusion solid tumors at time of initial biopsy&#xD;
      to further define criteria for pathologic diagnosis of these tumors.&#xD;
&#xD;
      VII. To evaluate immunohistochemistry for pan-TRK as a screening method for TRK fusion tumors&#xD;
      and in resection specimens following neoadjuvant treatment with larotrectinib.&#xD;
&#xD;
      VIII. To evaluate the histologic response to larotrectinib in resection specimens following&#xD;
      neoadjuvant treatment.&#xD;
&#xD;
      IX. To evaluate circulating tumor DNA for the detection of the emergence of resistance&#xD;
      mutations and recurrence in patients with TRK fusion solid tumors treated with larotrectinib.&#xD;
&#xD;
      X. To evaluate the ratio of cerebrospinal fluid (CSF) to concurrent plasma concentrations of&#xD;
      larotrectinib in patients with leukemia.&#xD;
&#xD;
      XI. To evaluate the change in neurocognitive/behavioral functioning over time between&#xD;
      baseline and 2 years post-diagnosis of patients treated on this protocol using&#xD;
      parent-reported adaptive functioning (Adaptive Behavior Assessment System [ABAS]-III General&#xD;
      Adaptive Composite), executive function (Behavior Rating Inventory of Executive Function&#xD;
      Scales-Preschool Version [BRIEF-P] or BRIEF-2 Global Executive Composite Score), psychosocial&#xD;
      functioning (Behavior Assessment System for Children [BASC]-3 Internalizing, Externalizing&#xD;
      and Behavioral Symptoms Indices) and quality of life (Pediatric Quality of Life Inventory&#xD;
      [PedsQL] Total score).&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive larotrectinib orally (PO) or by nasogastric (NG) or gastric tube (G-tube)&#xD;
      twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the&#xD;
      absence of disease progression or unacceptable toxicity. Patients whose tumors shrink&#xD;
      sufficiently while taking larotrectinib may undergo surgical resection of their tumor while&#xD;
      on study.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 3, 6, 12, 18, 24, 30, 36,&#xD;
      and 48 months and annually thereafter for up to 5 years from the date of study entry.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 18, 2019</start_date>
  <completion_date type="Anticipated">March 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">March 31, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Objective response rate (ORR) of children with infantile fibrosarcoma (IFS) treated with neoadjuvant larotrectinib prior to local control</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Response rates will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed accounting for the two-stage design.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Event-free survival (EFS) of children with IFS treated with neoadjuvant larotrectinib prior to local control</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Will be computed one year after the last enrollment in a stratum.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS) of children with IFS treated with neoadjuvant larotrectinib prior to local control</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Will be computed one year after the last enrollment in a stratum.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response (DoR) of children with IFS treated with neoadjuvant larotrectinib prior to local control</measure>
    <time_frame>From first observation of either partial response (PR) or complete response (CR) until either the first observation of progressive disease (PD) (event) or last known observation of the patient (censored observation), assessed up to 5 years</time_frame>
    <description>Will be computed one year after the last enrollment in a stratum. Will be defined among patients with a confirmed best response of either PR and CR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ORR of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Response rates will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed accounting for the two-stage design.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EFS of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Will be computed one year after the last enrollment in a stratum.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>OS of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Will be computed one year after the last enrollment in a stratum.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DoR of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control</measure>
    <time_frame>From first observation of either partial response (PR) or complete response (CR) until either the first observation of progressive disease (PD) (event) or last known observation of the patient (censored observation), assessed up to 5 years</time_frame>
    <description>Will be computed one year after the last enrollment in a stratum. Will be defined among patients with a confirmed best response of either PR and CR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade. A patient will be counted only once for a given toxicity for the worst grade of that toxicity reported for that patient. Toxicity information recorded will include the type, severity, time of onset, time of resolution, and the attribution(s) to the study regimen.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of patients with TRK fusion solid tumors with detectable circulating tumor deoxyribonucleic acid (DNA)</measure>
    <time_frame>Baseline up to 5 years</time_frame>
    <description>The percentage of ctDNA and frequency with which patients have detectable ctDNA prior to the start of therapy and at times during therapy when subsequent serial samples are obtained will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit). In cases of treatment resistance, we will also perform exploratory deep sequencing of ctDNA to determine whether this method can detect the emergence of resistance mutations.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">70</enrollment>
  <condition>Central Nervous System Neoplasm</condition>
  <condition>Infantile Fibrosarcoma</condition>
  <condition>Recurrent Acute Leukemia</condition>
  <condition>Refractory Acute Leukemia</condition>
  <condition>Solid Neoplasm</condition>
  <arm_group>
    <arm_group_label>Treatment (larotrectinib)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive larotrectinib PO or by NG or G-tube BID on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity, or complete surgical resection of tumor.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Larotrectinib Sulfate</intervention_name>
    <description>Given PO or via NG or G tube</description>
    <arm_group_label>Treatment (larotrectinib)</arm_group_label>
    <other_name>ARRY 470 Sulfate</other_name>
    <other_name>LOXO 101 Sulfate</other_name>
    <other_name>LOXO-101 Sulfate</other_name>
    <other_name>Vitrakvi</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must be =&lt; 30 years of age at the time of study entry&#xD;
&#xD;
          -  COHORT A: Patients must have a histologic diagnosis of infantile fibrosarcoma with an&#xD;
             NTRK1, NTRK2, or NTRK3 fusion identified in a Clinical Laboratory Improvement&#xD;
             Act/College of American Pathologists (CLIA/CAP) certified laboratory. Fusions may be&#xD;
             identified by fluorescence in situ hybridization (FISH) or molecular techniques&#xD;
             (reverse transcriptase-polymerase chain reaction [RT-PCR] using primers flanking the&#xD;
             fusion junction or next generation sequencing). For fusions identified by FISH, an&#xD;
             ETV6 rearrangement is sufficient for eligibility in Cohort A. Identification of the&#xD;
             upstream TRK fusion partner is not required.&#xD;
&#xD;
          -  COHORT B: Patients must have a histologic diagnosis of any solid tumor other than&#xD;
             infantile fibrosarcoma, including central nervous system (CNS) tumors but excluding&#xD;
             high grade gliomas. An NTRK1, NTRK2, or NTRK3 fusion must be identified in a CLIA/CAP&#xD;
             certified laboratory. Fusions may be identified by FISH or molecular techniques&#xD;
             (RT-PCR using primers flanking the fusion junction or next generation sequencing). For&#xD;
             fusions identified by FISH, there must be an identified rearrangement in NTRK1, NTRK2,&#xD;
             or NTRK3 (e.g., an ETV6 rearrangement is not sufficient for eligibility) unless the&#xD;
             patient has a diagnosis of congenital mesoblastic nephroma in which case an ETV6&#xD;
             rearrangement is sufficient for eligibility. Identification of the upstream TRK fusion&#xD;
             partner is not required.&#xD;
&#xD;
          -  COHORT C: Patients must have a histologic diagnosis of relapsed or refractory acute&#xD;
             leukemia with an NTRK1, NTRK2, or NTRK3 fusion identified in a CLIA/CAP certified&#xD;
             laboratory. Fusions may be identified by FISH or molecular techniques (RT-PCR using&#xD;
             primers flanking the fusion junction or next generation sequencing). For fusions&#xD;
             identified by FISH, there must be an identified rearrangement in NTRK1, NTRK2, or&#xD;
             NTRK3 (e.g., an ETV6 rearrangement is not sufficient for eligibility). Identification&#xD;
             of the upstream TRK fusion partner is not required.&#xD;
&#xD;
          -  SOLID TUMORS (COHORTS A AND B): Patients must have measurable disease. Patients must&#xD;
             have disease that cannot be completely resected without a predicted functional,&#xD;
             neurologic, or significant cosmetic deficit in the opinion of the investigator.&#xD;
&#xD;
          -  LEUKEMIA (COHORT C): Patients must have &gt;= 5% blasts in the bone marrow.&#xD;
             Extramedullary disease is permitted.&#xD;
&#xD;
          -  Patients must have a Lansky or Karnofsky performance status score of &gt;= 50,&#xD;
             corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1 or 2. Use&#xD;
             Karnofsky for patients &gt; 16 years of age and Lansky for patients =&lt; 16 years of age.&#xD;
             NOTE: Neurologic deficits in patients with CNS tumors must have been stable for at&#xD;
             least 7 days prior to study enrollment. Patients who are unable to walk because of&#xD;
             paralysis, but who are up in a wheelchair, will be considered ambulatory for the&#xD;
             purpose of assessing the performance score.&#xD;
&#xD;
          -  COHORTS A AND B: No prior anti-cancer therapy, including radiotherapy, other than&#xD;
             surgical resection is permitted.&#xD;
&#xD;
               -  Patients who experience recurrence after surgery alone and no other anti-cancer&#xD;
                  therapy will be eligible.&#xD;
&#xD;
               -  If not eligible due to prior anticancer therapy, patients may be eligible for the&#xD;
                  larotrectinib arm of Pediatric MATCH (APEC1621A) or treatment with commercial&#xD;
                  larotrectinib off study.&#xD;
&#xD;
          -  COHORT C: Patients with relapsed leukemia (Cohort C) must have fully recovered from&#xD;
             the acute toxic effects of all prior anti-cancer therapy and must meet the following&#xD;
             minimum duration from prior anti-cancer directed therapy prior to enrollment. If after&#xD;
             the required timeframe, the numerical eligibility criteria are met, e.g. blood count&#xD;
             criteria, the patient is considered to have recovered adequately.&#xD;
&#xD;
               -  Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive.&#xD;
                  The duration of this interval must be discussed with the study chair and the&#xD;
                  study-assigned research coordinator prior to enrollment.&#xD;
&#xD;
                    -  A waiting period prior to enrollment is not required for patients receiving&#xD;
                       standard cytotoxic maintenance chemotherapy (i.e., corticosteroid,&#xD;
                       vincristine, thioguanine [6MP], and/or methotrexate).&#xD;
&#xD;
                    -  A waiting period is not required for patients receiving a single dose of&#xD;
                       intrathecal methotrexate, hydrocortisone, and/or cytarabine within 7 days&#xD;
                       prior to enrollment.&#xD;
&#xD;
                    -  &gt;= 14 days must have elapsed after the completion of other cytotoxic&#xD;
                       therapy, with the exception of hydroxyurea, for patients not receiving&#xD;
                       standard maintenance therapy. Additionally, patients must have fully&#xD;
                       recovered from all acute toxic effects of prior therapy.&#xD;
&#xD;
                         -  Note: Cytoreduction with hydroxyurea must be discontinued &gt;= 24 hours&#xD;
                            prior to the start of protocol therapy.&#xD;
&#xD;
               -  Anti-cancer agents not known to be myelosuppressive (e.g., not associated with&#xD;
                  reduced platelet or absolute neutrophil [ANC] counts): &gt;= 7 days after the last&#xD;
                  dose of agent. The duration of this interval must be discussed with the study&#xD;
                  chair and the study-assigned research coordinator prior to enrollment.&#xD;
&#xD;
               -  Anti-cancer agents that are antibodies: &gt;= 21 days must have elapsed from&#xD;
                  infusion of last dose of antibody, and toxicity related to prior antibody therapy&#xD;
                  must be recovered to grade =&lt; 1. There is an exception for blinatumomab&#xD;
                  infusions, for which patients must have been off for at least 3 days and all drug&#xD;
                  related toxicity must have resolved to grade 2 or lower as outlined in the&#xD;
                  inclusion/exclusion criteria.&#xD;
&#xD;
               -  Corticosteroids: If used to modify immune adverse events related to prior&#xD;
                  therapy, &gt;= 14 days must have elapsed since last dose of corticosteroid. A&#xD;
                  waiting period prior to enrollment is not required for patients receiving&#xD;
                  corticosteroid for leukemia therapy/cytoreduction.&#xD;
&#xD;
               -  Hematopoietic growth factors: &gt;= 14 days after the last dose of a long-acting&#xD;
                  growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor. For&#xD;
                  agents that have known adverse events occurring beyond 7 days after&#xD;
                  administration, this period must be extended beyond the time during which adverse&#xD;
                  events are known to occur. The duration of this interval must be discussed with&#xD;
                  the study chair and the study-assigned research coordinator.&#xD;
&#xD;
               -  Interleukins, interferons and cytokines (other than hematopoietic growth&#xD;
                  factors): &gt;= 21 days after the completion of interleukins, interferon or&#xD;
                  cytokines (other than hematopoietic growth factors ).&#xD;
&#xD;
               -  Stem cell infusions (with or without total body irradiation [TBI]):&#xD;
&#xD;
                    -  Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem&#xD;
                       cell infusion including donor lymphocyte infusion (DLI) or boost infusion:&#xD;
                       &gt;= 84 days after infusion and no evidence of graft versus host disease&#xD;
                       (GVHD).&#xD;
&#xD;
                    -  Autologous stem cell infusion including boost infusion: &gt;= 42 days.&#xD;
&#xD;
               -  Cellular therapy: &gt;= 42 days after the completion of any type of cellular therapy&#xD;
                  (e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.)&#xD;
&#xD;
               -  Radiation therapy (XRT)/external beam irradiation including protons: &gt;= 14 days&#xD;
                  after local XRT; &gt;= 150 days after TBI, craniospinal XRT or if radiation to &gt;=&#xD;
                  50% of the pelvis; &gt;= 42 days if other substantial BM radiation.&#xD;
&#xD;
               -  Radiopharmaceutical therapy (e.g., radiolabeled antibody): &gt;= 42 days after&#xD;
                  systemically administered radiopharmaceutical therapy.&#xD;
&#xD;
               -  Patients must not have received prior exposure to TRK inhibitors (including&#xD;
                  larotrectinib, LOXO-195, entrectinib, lorlatinib, crizotinib, or lestaurtinib).&#xD;
&#xD;
          -  For patients with solid tumors without known bone marrow involvement: Peripheral&#xD;
             absolute neutrophil count (ANC) &gt;= 1000/mm^3 (within 7 days prior to enrollment).&#xD;
&#xD;
          -  For patients with solid tumors without known bone marrow involvement: Platelet count&#xD;
             &gt;= 100,000/mm^3 (transfusion independent, defined as not receiving platelet&#xD;
             transfusions for at least 7 days prior to enrollment).&#xD;
&#xD;
          -  For patients with solid tumors without known bone marrow involvement: Hemoglobin &gt;=&#xD;
             8.0 g/dL at baseline (within 7 days prior to enrollment) (may receive red blood cell&#xD;
             [RBC] transfusions).&#xD;
&#xD;
          -  Patients with solid tumors with known bone marrow metastatic disease will be eligible&#xD;
             for study provided they meet the blood counts above (may receive transfusions provided&#xD;
             they are not known to be refractory to red cell or platelet transfusions). These&#xD;
             patients will not be evaluable for hematologic toxicity.&#xD;
&#xD;
          -  For patients with leukemia: Platelet count &gt;= 20,000/mm^3 (within 7 days prior to&#xD;
             enrollment) (may receive platelet transfusions; must not be known to be refractory to&#xD;
             red cell or platelet transfusion).&#xD;
&#xD;
          -  For patients with leukemia: Hemoglobin &gt;= 8.0 g/dL at baseline (within 7 days prior to&#xD;
             enrollment) (may receive RBC transfusions; must not be known to be refractory to red&#xD;
             cell or platelet transfusion).&#xD;
&#xD;
          -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) &gt;= 70&#xD;
             mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows (within 7 days&#xD;
             prior to enrollment):&#xD;
&#xD;
               -  1 month to &lt; 6 months (male 0.4 mg/dL, female 0.4 mg/dL)&#xD;
&#xD;
               -  6 months to &lt; 1 year (male 0.5 mg/dL, female 0.5 mg/dL)&#xD;
&#xD;
               -  1 to &lt; 2 years (male 0.6 mg/dL, female 0.6 mg/dL)&#xD;
&#xD;
               -  2 to &lt; 6 years (male 0.8 mg/dL, female 0.8 mg/dL)&#xD;
&#xD;
               -  6 to &lt; 10 years (male 1 mg/dL, female 1 mg/dL)&#xD;
&#xD;
               -  10 to &lt; 13 years (male 1.2 mg/dL, female 1.2 mg/dL)&#xD;
&#xD;
               -  13 to &lt; 16 years (male 1.5 mg/dL, female 1.4 mg/dL)&#xD;
&#xD;
               -  &gt;= 16 years (male 1.7 mg/dL, female 1.4 mg/dL)&#xD;
&#xD;
                    -  For patients &lt; 1 month of age, serum creatinine levels must be &lt; 1.5 x the&#xD;
                       treating institution's creatinine upper limit of normal (ULN) for patients &lt;&#xD;
                       1 month of age or the creatinine clearance or radioisotope GFR must be &gt;= 70&#xD;
                       mL/min/1.73 m^2.&#xD;
&#xD;
          -  Patients with solid tumors: Bilirubin (sum of conjugated + unconjugated) =&lt; 1.5 x&#xD;
             upper limit of normal (ULN) for age (within 7 days prior to enrollment). After&#xD;
             approval of the study chair or designee, infants with a higher total bilirubin due to&#xD;
             physiologic or breast milk jaundice are eligible if the conjugated (direct) bilirubin&#xD;
             is =&lt; 2 mg/dL.&#xD;
&#xD;
          -  Patients with solid tumors: Serum glutamate pyruvate transaminase (SGPT) (alanine&#xD;
             aminotransferase [ALT]) =&lt; 135 U/L (within 7 days prior to enrollment). For the&#xD;
             purpose of this study, the ULN for SGPT is 45 U/L.&#xD;
&#xD;
          -  Patients with solid tumors: Serum albumin &gt;= 2 g/dL (within 7 days prior to&#xD;
             enrollment).&#xD;
&#xD;
          -  Patients with leukemias: Conjugated (direct) bilirubin =&lt; 1.5 x upper limit of normal&#xD;
             (ULN) for age (within 7 days prior to enrollment).&#xD;
&#xD;
          -  Patients with leukemias: SGPT (ALT) =&lt; 225 U/L (within 7 days prior to enrollment).&#xD;
             For the purpose of this study, the ULN for SGPT is 45 U/L.&#xD;
&#xD;
          -  Patients with leukemias: Serum albumin &gt;= 2 g/dL (within 7 days prior to enrollment).&#xD;
&#xD;
          -  Patients with seizure disorder may be enrolled if on a stable antiepileptic regimen&#xD;
             for &gt;= 14 days and well controlled.&#xD;
&#xD;
          -  Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE]&#xD;
             version [v] 5) except tendon reflex decreased resulting from prior therapy must be =&lt;&#xD;
             grade 2.&#xD;
&#xD;
          -  All patients and/or their parents or legal guardians must sign a written informed&#xD;
             consent.&#xD;
&#xD;
          -  All institutional, Food and Drug Administration (FDA), and National Cancer Institute&#xD;
             (NCI) requirements for human studies must be met.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant or breast-feeding women will not be entered on this study due to risks of&#xD;
             fetal and teratogenic adverse events as seen in animal/human studies, OR because there&#xD;
             is yet no available information regarding human fetal or teratogenic toxicities.&#xD;
             Pregnancy tests must be obtained in girls who are post-menarchal. Female patients of&#xD;
             reproductive potential may not participate unless they have agreed to use a highly&#xD;
             effective contraceptive method for the duration of study therapy and for at least one&#xD;
             month after the final dose of larotrectinib. Males of reproductive potential with a&#xD;
             non-pregnant female partner of child-bearing potential must use a highly effective&#xD;
             contraception for the duration of the study and for at least one month after the final&#xD;
             dose of larotrectinib. Because of the unknown risk of larotrectinib in nursing&#xD;
             infants, nursing women should discontinue breastfeeding during treatment with&#xD;
             larotrectinib and for 3 days following the final dose.&#xD;
&#xD;
          -  Patients with solid tumors, including CNS tumors, requiring corticosteroids who have&#xD;
             not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to&#xD;
             enrollment are not eligible. Patients with leukemia may receive systemic&#xD;
             corticosteroids for cytoreduction up to 24 hours prior to the start of protocol&#xD;
             therapy. If used to modify immune adverse events related to prior therapy, &gt;= 14 days&#xD;
             must have elapsed since last dose of corticosteroid.&#xD;
&#xD;
          -  Patients who are currently receiving another investigational drug are not eligible.&#xD;
&#xD;
          -  Patients who are currently receiving other anti-cancer agents are not eligible [except&#xD;
             leukemia patients receiving corticosteroids or hydroxyurea, which may be continued&#xD;
             until 24 hours prior to start of protocol therapy]. Patients with leukemia should&#xD;
             receive a single dose of intrathecal cytarabine, hydrocortisone, and/or methotrexate&#xD;
             within 7 days prior to Day 1 of Cycle 1 at the time of the baseline lumbar puncture.&#xD;
&#xD;
          -  Patients who are receiving cyclosporine, tacrolimus or other agents to prevent&#xD;
             graft-versus-host disease post bone marrow transplant are not eligible for this trial.&#xD;
&#xD;
          -  Patients currently receiving a strong CYP3A4 inducer or inhibitor are not eligible.&#xD;
             Strong inducers or inhibitors of CYP3A4 should be avoided from 14 days prior to&#xD;
             enrollment to the end of the study. Note: CYP3A4 inducing anti-epileptic drugs and&#xD;
             dexamethasone for CNS tumors or metastases, on a stable dose, are allowed.&#xD;
&#xD;
          -  Patients with malabsorption syndrome or other conditions that significantly limit&#xD;
             enteral absorption are not eligible.&#xD;
&#xD;
          -  Patients who are unable to swallow capsules or liquid and do not have gastric access&#xD;
             via a nasogastric or gastrostomy tube are not eligible.&#xD;
&#xD;
          -  Patients who have an uncontrolled infection are not eligible.&#xD;
&#xD;
          -  Patients who have received prior solid organ transplantation are not eligible.&#xD;
&#xD;
          -  Patients who in the opinion of the investigator may not be able to comply with the&#xD;
             safety monitoring requirements of the study are not eligible.&#xD;
&#xD;
          -  Patients with high grade gliomas (HGG) are not eligible.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>30 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Theodore W Laetsch</last_name>
    <role>Principal Investigator</role>
    <affiliation>Children's Oncology Group</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Children's Hospital of Alabama</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35233</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Arkansas Children's Hospital</name>
      <address>
        <city>Little Rock</city>
        <state>Arkansas</state>
        <zip>72202-3591</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kaiser Permanente Downey Medical Center</name>
      <address>
        <city>Downey</city>
        <state>California</state>
        <zip>90242</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital Los Angeles</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90027</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kaiser Permanente-Oakland</name>
      <address>
        <city>Oakland</city>
        <state>California</state>
        <zip>94611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Orange County</name>
      <address>
        <city>Orange</city>
        <state>California</state>
        <zip>92868</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UCSF Medical Center-Mission Bay</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94158</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital Colorado</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center</name>
      <address>
        <city>Denver</city>
        <state>Colorado</state>
        <zip>80218</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Yale University</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06520</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Alfred I duPont Hospital for Children</name>
      <address>
        <city>Wilmington</city>
        <state>Delaware</state>
        <zip>19803</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MedStar Georgetown University Hospital</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20007</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's National Medical Center</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Broward Health Medical Center</name>
      <address>
        <city>Fort Lauderdale</city>
        <state>Florida</state>
        <zip>33316</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Golisano Children's Hospital of Southwest Florida</name>
      <address>
        <city>Fort Myers</city>
        <state>Florida</state>
        <zip>33908</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Florida Health Science Center - Gainesville</name>
      <address>
        <city>Gainesville</city>
        <state>Florida</state>
        <zip>32610</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nemours Children's Clinic-Jacksonville</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32207</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Jackson Memorial Hospital-Holtz Children's Hospital</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Miami Miller School of Medicine-Sylvester Cancer Center</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nicklaus Children's Hospital</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33155</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nemours Children's Hospital</name>
      <address>
        <city>Orlando</city>
        <state>Florida</state>
        <zip>32827</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Joseph's Hospital/Children's Hospital-Tampa</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33607</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Healthcare of Atlanta - Egleston</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kapiolani Medical Center for Women and Children</name>
      <address>
        <city>Honolulu</city>
        <state>Hawaii</state>
        <zip>96826</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Luke's Cancer Institute - Boise</name>
      <address>
        <city>Boise</city>
        <state>Idaho</state>
        <zip>83712</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Jude Midwest Affiliate</name>
      <address>
        <city>Peoria</city>
        <state>Illinois</state>
        <zip>61637</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Riley Hospital for Children</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Iowa/Holden Comprehensive Cancer Center</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>52242</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Norton Children's Hospital</name>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <zip>40202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ochsner Medical Center Jefferson</name>
      <address>
        <city>New Orleans</city>
        <state>Louisiana</state>
        <zip>70121</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sinai Hospital of Baltimore</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana-Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>C S Mott Children's Hospital</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Helen DeVos Children's Hospital at Spectrum Health</name>
      <address>
        <city>Grand Rapids</city>
        <state>Michigan</state>
        <zip>49503</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bronson Methodist Hospital</name>
      <address>
        <city>Kalamazoo</city>
        <state>Michigan</state>
        <zip>49007</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Minnesota/Masonic Cancer Center</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55455</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic in Rochester</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Mississippi Medical Center</name>
      <address>
        <city>Jackson</city>
        <state>Mississippi</state>
        <zip>39216</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Mercy Hospitals and Clinics</name>
      <address>
        <city>Kansas City</city>
        <state>Missouri</state>
        <zip>64108</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cardinal Glennon Children's Medical Center</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mercy Hospital Saint Louis</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63141</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital and Medical Center of Omaha</name>
      <address>
        <city>Omaha</city>
        <state>Nebraska</state>
        <zip>68114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Nebraska Medical Center</name>
      <address>
        <city>Omaha</city>
        <state>Nebraska</state>
        <zip>68198</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center</name>
      <address>
        <city>Lebanon</city>
        <state>New Hampshire</state>
        <zip>03756</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hackensack University Medical Center</name>
      <address>
        <city>Hackensack</city>
        <state>New Jersey</state>
        <zip>07601</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Morristown Medical Center</name>
      <address>
        <city>Morristown</city>
        <state>New Jersey</state>
        <zip>07960</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Montefiore Medical Center - Moses Campus</name>
      <address>
        <city>Bronx</city>
        <state>New York</state>
        <zip>10467</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mission Hospital</name>
      <address>
        <city>Asheville</city>
        <state>North Carolina</state>
        <zip>28801</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Carolinas Medical Center/Levine Cancer Institute</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>28203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novant Health Presbyterian Medical Center</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>28204</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital Medical Center of Akron</name>
      <address>
        <city>Akron</city>
        <state>Ohio</state>
        <zip>44308</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cincinnati Children's Hospital Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cleveland Clinic Foundation</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nationwide Children's Hospital</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dayton Children's Hospital</name>
      <address>
        <city>Dayton</city>
        <state>Ohio</state>
        <zip>45404</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Oklahoma Health Sciences Center</name>
      <address>
        <city>Oklahoma City</city>
        <state>Oklahoma</state>
        <zip>73104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oregon Health and Science University</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lehigh Valley Hospital-Cedar Crest</name>
      <address>
        <city>Allentown</city>
        <state>Pennsylvania</state>
        <zip>18103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Philadelphia</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Christopher's Hospital for Children</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19134</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Pittsburgh of UPMC</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15224</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rhode Island Hospital</name>
      <address>
        <city>Providence</city>
        <state>Rhode Island</state>
        <zip>02903</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>BI-LO Charities Children's Cancer Center</name>
      <address>
        <city>Greenville</city>
        <state>South Carolina</state>
        <zip>29605</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Jude Children's Research Hospital</name>
      <address>
        <city>Memphis</city>
        <state>Tennessee</state>
        <zip>38105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dell Children's Medical Center of Central Texas</name>
      <address>
        <city>Austin</city>
        <state>Texas</state>
        <zip>78723</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical City Dallas Hospital</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75230</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UT Southwestern/Simmons Cancer Center-Dallas</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Texas Health Science Center at San Antonio</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Primary Children's Hospital</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84113</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of The King's Daughters</name>
      <address>
        <city>Norfolk</city>
        <state>Virginia</state>
        <zip>23507</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seattle Children's Hospital</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Providence Sacred Heart Medical Center and Children's Hospital</name>
      <address>
        <city>Spokane</city>
        <state>Washington</state>
        <zip>99204</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mary Bridge Children's Hospital and Health Center</name>
      <address>
        <city>Tacoma</city>
        <state>Washington</state>
        <zip>98405</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Wisconsin Carbone Cancer Center</name>
      <address>
        <city>Madison</city>
        <state>Wisconsin</state>
        <zip>53792</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Marshfield Medical Center-Marshfield</name>
      <address>
        <city>Marshfield</city>
        <state>Wisconsin</state>
        <zip>54449</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Wisconsin</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>IWK Health Centre</name>
      <address>
        <city>Halifax</city>
        <state>Nova Scotia</state>
        <zip>B3K 6R8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Universitaire Sainte-Justine</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H3T 1C5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>January 22, 2019</study_first_submitted>
  <study_first_submitted_qc>February 6, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 8, 2019</study_first_posted>
  <last_update_submitted>August 31, 2023</last_update_submitted>
  <last_update_submitted_qc>August 31, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 5, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Larotrectinib</keyword>
  <keyword>TRK fusion</keyword>
  <keyword>NTRK fusion</keyword>
  <keyword>Infantile fibrosarcoma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Nervous System Neoplasms</mesh_term>
    <mesh_term>Central Nervous System Neoplasms</mesh_term>
    <mesh_term>Fibrosarcoma</mesh_term>
    <mesh_term>Acute Disease</mesh_term>
  </condition_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>October 13, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/61/NCT03834961/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03834961
org study id: ADVL1823
secondary id: NCI-2019-00015
secondary id: ADVL1823
secondary id: ADVL1823
secondary id: U10CA180886
nct id: NCT03834961
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Objective response rate (ORR) of children with infantile fibrosarcoma (IFS) treated with neoadjuvant larotrectinib prior to local control
time frame: Up to 5 years
description: Response rates will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed accounting for the two-stage design.
measure: Event-free survival (EFS) of children with IFS treated with neoadjuvant larotrectinib prior to local control
time frame: Up to 5 years
description: Will be computed one year after the last enrollment in a stratum.
measure: Overall survival (OS) of children with IFS treated with neoadjuvant larotrectinib prior to local control
time frame: Up to 5 years
description: Will be computed one year after the last enrollment in a stratum.
measure: Duration of response (DoR) of children with IFS treated with neoadjuvant larotrectinib prior to local control
time frame: From first observation of either partial response (PR) or complete response (CR) until either the first observation of progressive disease (PD) (event) or last known observation of the patient (censored observation), assessed up to 5 years
description: Will be computed one year after the last enrollment in a stratum. Will be defined among patients with a confirmed best response of either PR and CR.
measure: ORR of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control
time frame: Up to 5 years
description: Response rates will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed accounting for the two-stage design.
measure: EFS of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control
time frame: Up to 5 years
description: Will be computed one year after the last enrollment in a stratum.
measure: OS of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control
time frame: Up to 5 years
description: Will be computed one year after the last enrollment in a stratum.
measure: DoR of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control
time frame: From first observation of either partial response (PR) or complete response (CR) until either the first observation of progressive disease (PD) (event) or last known observation of the patient (censored observation), assessed up to 5 years
description: Will be computed one year after the last enrollment in a stratum. Will be defined among patients with a confirmed best response of either PR and CR.
measure: Incidence of adverse events
time frame: Up to 5 years
description: Per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade. A patient will be counted only once for a given toxicity for the worst grade of that toxicity reported for that patient. Toxicity information recorded will include the type, severity, time of onset, time of resolution, and the attribution(s) to the study regimen.
measure: Percentage of patients with TRK fusion solid tumors with detectable circulating tumor deoxyribonucleic acid (DNA)
time frame: Baseline up to 5 years
description: The percentage of ctDNA and frequency with which patients have detectable ctDNA prior to the start of therapy and at times during therapy when subsequent serial samples are obtained will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit). In cases of treatment resistance, we will also perform exploratory deep sequencing of ctDNA to determine whether this method can detect the emergence of resistance mutations.
arm group label: Treatment (larotrectinib)
arm group type: Experimental
description: Patients receive larotrectinib PO or by NG or G-tube BID on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity, or complete surgical resection of tumor.
intervention type: Drug
intervention name: Larotrectinib Sulfate
description: Given PO or via NG or G tube
arm group label: Treatment (larotrectinib)
other name: ARRY 470 Sulfate
other name: LOXO 101 Sulfate
other name: LOXO-101 Sulfate
other name: Vitrakvi
criteria: 
gender: All
minimum age: N/A
maximum age: 30 Years
healthy volunteers: No
last name: Theodore W Laetsch
role: Principal Investigator
affiliation: Children's Oncology Group
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country: Canada
country: United States
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Neoplasms
mesh term: Nervous System Neoplasms
mesh term: Central Nervous System Neoplasms
mesh term: Fibrosarcoma
mesh term: Acute Disease
provided document: 