A Study to Test the Effect of the Drug Larotrectinib in Adults and Children With NTRK-fusion Positive Solid Tumors

Inclusion Criteria:

   - Locally-advanced or metastatic malignancy with an NTRK1, NTRK2, or NTRK3 gene fusion,
   identified through molecular assays as routinely performed at CLIA or other
   similarly-certified laboratories. Subjects who have an NTRK gene fusion identified in
   a lab where CLIA or equivalent certification cannot be confirmed by the Sponsor at the
   time of consent may have been enrolled in Cohort 9 as per protocol versions 1.0 - 8.0.
   From protocol version 9.0: CLIA or similar certification of the lab performing the
   fusion assay is required. However, patients may be included after discussion with the
   sponsor if the lab performing the fusion assay is not CLIA or similar certified.

   - Subjects who have received prior standard therapy appropriate for their tumor type and
   stage of disease, or who have no satisfactory alternative treatments and in the
   opinion of the Investigator, would be unlikely to tolerate or derive clinically
   meaningful benefit from appropriate standard of care therapy.

   - Subjects must have at least one measurable lesion as defined by RECIST v1.1
   (Eisenhauer et al. 2009). Subjects with solid tumors without RECIST v1.1 measurable
   disease (e.g., evaluable disease only) had been eligible for enrollment to Cohort 8 as
   per protocol versions 1.0 - 8.0, regardless of tumor type. Subjects with primary CNS
   tumors should meet the following criteria:

      1. Have received prior treatment including radiation and/or chemotherapy, with
      radiation completed > 12 weeks prior to C1D1 of therapy, as recommended or
      appropriate for that CNS tumor type.

      2. Have ≥ 1 site of bi-dimensionally measurable disease (confirmed by magnetic
      resonance imaging [MRI] and evaluable by RANO criteria), with the size of at
      least one of the measurable lesions ≥ 1 cm in each dimension and noted on more
      than one imaging slice.

      3. Imaging study performed within 28 days before enrollment. If on steroid therapy,
      the dose must be stable for at least 7 days immediately before and during the
      imaging study.

      4. Must be neurologically stable based on stable neurologic exam for 7 days prior to
      enrollment.

      For subjects eligible for enrollment to bone health cohort, inclusion criterion 3
      is modified as the following:

      5. Subjects must have at least one lesion at baseline (measurable or non-measurable
      as defined by RECIST v1.1 or RANO criteria, as appropriate to tumor type).

      6. Subjects with primary CNS tumors must be neurologically stable based on stable
      neurologic exam for 7 days prior to enrollment.

   - At least 18 years of age

   - Performance Status: Eastern Cooperative Oncology Group (ECOG) score ≤ 3. If enrolled
   with primary CNS tumor to be assessed by RANO, Karnofsky Performance Score (KPS) ≥
   50%.

   - Tumor tissue before treatment (mandatory). If neither fresh tissue can be obtained nor
   archival tissue is available patients might be enrolled after consultation with the
   sponsor.

   - Adequate organ function as defined by the following criteria:

      1. Serum AST and serum ALT < 2.5 x upper limit of normal (ULN), or AST and ALT < 5 x
      ULN if liver function abnormalities are due to underlying malignancy

      2. Total bilirubin < 2.5 x ULN, except in the setting of biliary obstruction.
      Subjects with a known history of Gilberts Disease and an isolated elevation of
      indirect bilirubin are eligible

      3. Serum creatinine < 2.0 x ULN OR an estimated glomerular filtration rate ≥ 30
      mL/minute using the Cockcroft-Gault formula: (140- age) x body weight (kg) x 0.85
      (if female)/serum creatinine (mg/dL) x 72 with either result acceptable for
      enrollment.

   - Ability to comply (or for guardian to ensure compliance) with outpatient treatment,
   laboratory monitoring, and required clinic visits for the duration of study
   participation.

   - Willingness of men and women of reproductive potential to use double effective birth
   control methods, defined as one used by the subject and another by his/her partner,
   for the duration of treatment and for 1 month following study completion.

   - For subjects eligible for enrollment to bone health cohort only: life expectancy of at
   least 6 months, based on investigator assessment.

Exclusion Criteria:

   - Investigational agent or anticancer therapy within 2 weeks prior to the planned start
   of larotrectinib or 5 half-lives, whichever is shorter, and without recovery of acute
   and/or clinically significant toxicities from that therapy.

   - Prior progression while receiving approved or investigational tyrosine kinase
   inhibitors targeting TRK. Subjects who received less than 28 days of treatment and
   discontinued because of intolerance or toxicity are eligible.

   - Symptomatic or unstable brain metastases. (Note: Subjects with asymptomatic brain
   metastases are eligible to participate in the study.) Subjects with primary CNS tumors
   are eligible.

   - Uncontrolled concurrent malignancy that would limit assessment of efficacy of
   larotrectinib. Allowed conditions may include, but are not limited to in situ cancers
   of cervix, breast, or skin, superficial bladder cancer, limited-stage prostate cancer,
   and basal or squamous cancers of the skin.

   - Active uncontrolled systemic bacterial, viral, or fungal infection CTCAE grade ≥ 2;
   unstable cardiovascular disease, or other systemic disease that would limit compliance
   with study procedures. Unstable cardiovascular disease is defined as:

      1. In adults, persistently uncontrolled hypertension defined as systolic blood
      pressure (BP) > 150 mmHg and/or diastolic BP > 100 mmHg despite antihypertensive
      therapy.

      2. Myocardial infarction within 3 months of screening.

      3. Stroke within 3 months of screening.

   - Inability to discontinue treatment with a strong CYP3A4 inhibitor or inducer

   - Currently recovering from AEs/ ADRs due to previous treatments (excluding alopecia).
   Inclusion is only advised once the AE/ADR resolves or recovers to baseline or at least
   to CTCAE grade 1.

   - Known or suspected hypersensitivity against the active substance or any of the
   ingredients of the IMP.

   - Known history of HIV infection. All patients must be screened for HIV up to 28 days
   prior to study drug start using a blood test for HIV according to local regulations.

   - HBV or HCV infection. All patients must be screened for HBV and HCV up to 28 days
   prior to study drug start using the routine hepatitis virus laboratorial panel.
   Patients positive for HBsAg or HBcAb will be eligible if they are negative for HBVDNA.
   Patients positive for anti-HCV antibody will be eligible if they are negative for
   HCV-RNA.