A Phase 1/2, Open-Label, Safety, Tolerability, Pharmacokinetics, and Anti-Tumor Activity Study of Repotrectinib in Pediatric and Young Adult Subjects With Advanced or Metastatic Malignancies Harboring ALK, ROS1, NTRK1-3 Alterations

• Documented genetic ROS1 point mutation, fusion, or amplification or NTRK1-3 fusion as identified by local testing in a Clinical Laboratory Improvement Amendments (CLIA) laboratory in the US or equivalently accredited diagnostic lab outside the United States (US) is required.

• Phase 1: Age \<12 years; Phase 2: Age 12- 25 years

• Prior cytotoxic chemotherapy is allowed.

• Prior immunotherapy is allowed.

• Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer therapy to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 Grade less than or equal to 1.

• All subjects must have measurable disease by RECIST v1.1 or Response Assessment in Neuro-Oncology (RANO) criteria at time of enrollment.

• Subjects with a primary CNS tumor or CNS metastases must be neurologically stable on a stable or decreasing dose of steroids for at least 7 days prior to enrollment.

• Subjects must have a Lansky (\< 16 years) or Karnofsky (≥ 16 years) score of at least 50.

• Life expectancy greater than or equal to 12 weeks, in the investigator's opinion.

⁃ Adequate hematologic, renal and hepatic function.

∙ Phase 2 Inclusion Criteria:

• Cohort Specific Inclusion Criteria:

‣ Cohort 1: Subjects with NTRK fusion gene positive (NTRK+) advanced solid tumors (including primary CNS tumors), that are tropomyosin receptor kinase (TRK) TKI naïve;

⁃ Cohort 2: subjects with NTRK+ advanced solid tumors (including primary CNS tumors), that are TRK TKI pre-treated;

⁃ Cohort 3: subjects with advanced solid tumors with ROS1 gene fusions or other ROS1 aberrations (including amplifications and point mutations) with measurable disease.

• Subjects in Cohorts 1 and 2 must have prospectively confirmed measurable disease by BICR prior to enrollment.