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 genefusion, identified through molecular assays as routinely performed at CLIA or othersimilarly-certified laboratories. Subjects who have an NTRK gene fusion identifiedin a lab where CLIA or equivalent certification cannot be confirmed by the Sponsorat 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 labperforming the fusion assay is required. However, patients may be included afterdiscussion with the sponsor if the lab performing the fusion assay is not CLIA orsimilar certified.

• Subjects who have received prior standard therapy appropriate for their tumor typeand stage of disease, or who have no satisfactory alternative treatments and in theopinion of the Investigator, would be unlikely to tolerate or derive clinicallymeaningful 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 measurabledisease (e.g., evaluable disease only) had been eligible for enrollment to Cohort 8as per protocol versions 1.0 - 8.0, regardless of tumor type. Subjects with primaryCNS tumors should meet the following criteria:

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

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

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

4. Must be neurologically stable based on stable neurologic exam for 7 days priorto 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 ornon-measurable as defined by RECIST v1.1 or RANO criteria, as appropriate totumor type).

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

• At least 18 years of age

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

• Tumor tissue before treatment (mandatory). If neither fresh tissue can be obtainednor archival tissue is available patients might be enrolled after consultation withthe 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 < 5x 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 ofindirect bilirubin are eligible

3. Serum creatinine < 2.0 x ULN OR an estimated glomerular filtration rate ≥ 30mL/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 acceptablefor enrollment.

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

• Willingness of men and women of reproductive potential to use double effective birthcontrol 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 ofat least 6 months, based on investigator assessment.

Exclusion Criteria:

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

• Prior progression while receiving approved or investigational tyrosine kinaseinhibitors targeting TRK. Subjects who received less than 28 days of treatment anddiscontinued because of intolerance or toxicity are eligible.

• Symptomatic or unstable brain metastases. (Note: Subjects with asymptomatic brainmetastases are eligible to participate in the study.) Subjects with primary CNStumors are eligible.

• Uncontrolled concurrent malignancy that would limit assessment of efficacy oflarotrectinib. Allowed conditions may include, but are not limited to in situcancers of cervix, breast, or skin, superficial bladder cancer, limited-stageprostate 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 limitcompliance with study procedures. Unstable cardiovascular disease is defined as:

1. In adults, persistently uncontrolled hypertension defined as systolic bloodpressure (BP) > 150 mmHg and/or diastolic BP > 100 mmHg despiteantihypertensive 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 atleast to CTCAE grade 1.

• Known or suspected hypersensitivity against the active substance or any of theingredients of the IMP.

• Known history of HIV infection. All patients must be screened for HIV up to 28 daysprior 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 daysprior to study drug start using the routine hepatitis virus laboratorial panel.Patients positive for HBsAg or HBcAb will be eligible if they are negative forHBVDNA. Patients positive for anti-HCV antibody will be eligible if they arenegative for HCV-RNA.