Larotrectinib For Previously Untreated NTRK-fusion Positive Pediatric Solid Tumors and NTRK-fusion Positive Relapsed Pediatric Acute Leukemias

Larotrectinib is a highly selective oral small molecule inhibitor of the TRK family of tyrosine kinases (TRKA, TRKB, and TRKC) which are encoded by the NTRK genes (NTRK1, NTRK2, and NTRK3). Fusions of these genes (TRK fusions) occur across a wide range of pediatric and adult malignancies, and are nearly pathognomonic for infantile fibrosarcoma. Preclinical studies have shown that larotrectinib is active in cancer cell lines harboring TRK fusions, while having no activity in cell lines without these fusions. Ongoing clinical trials of larotrectinib in children and adults have shown a 75% centrally confirmed objective response rate in patients with relapsed or refractory TRK fusion cancers across a wide range of tumor types, including a 93% objective response rate in children with TRK fusion cancers on a Phase 1 trial. This study also established a pediatric recommended phase 2 dose. Given the remarkable activity seen in the relapsed/refractory setting, this open label two-stage phase 2 trial will enroll newly diagnosed patients with any TRK fusion solid tumor. The primary cohort will be patients with infantile fibrosarcoma, and patients with other TRK fusion solid tumors will be analyzed in a separate cohort. This study will also include an exploratory cohort for patients with relapsed or refractory TRK fusion acute leukemias, and the results of this cohort will be reported descriptively. Larotrectinib will be administered orally twice daily on a continuous dosing schedule of 28-day cycles at a dose of 100 mg/m2/dose with a maximum of 100 mg/dose. Patients with localized tumors who achieve sufficient tumor shrinkage to allow complete resection and those who achieve a complete response will discontinue larotrectinib at protocol specified timepoints and continue to be followed for recurrence. Patients who do not meet these criteria will receive 26 cycles (approximately 2 years) of therapy and then be followed for recurrence. The primary endpoint will be the objective response rate in patients with infantile fibrosarcoma. We will also evaluate event-free survival (EFS), duration of response (DOR), and overall survival (OS). These endpoints will be separately evaluated in patients with all other TRK fusion solid tumors combined. A Simon two-stage design that incorporates the best overall response within 6 months will be utilized.