Oral TRK Inhibitor LOXO-101 (Larotrectinib) for Treatment of Advanced Pediatric Solid or Primary Central Nervous System Tumors

This is a multicenter, open label, Phase 1 / 2 study in pediatric patients with advanced solid or primary CNS tumors. LOXO‑101 (larotrectinib) will be administered orally (PO) twice daily (BID), with the dose adjusted by body surface area (BSA).

Inclusion Criteria

• Pediatric patients ≥ 1 year old on Cycle 1 Day 1 (C1D1)
• Phase 1 only: Between 1 and 21 years of age at C1D1 with a locally advanced or metastatic solid tumor or primary CNS tumor that has relapsed, progressed or was nonresponsive to available therapies and for which no standard or available systemic curative therapy, or ≥1 month old with a diagnosis malignancy and with a documented NTRK fusion that has progressed or was nonresponsive to available therapies, and for which no standard or available curative therapy exists or patients with locally advanced infantile fibrosarcoma who would require, in the opinion of the Investigator, disfiguring surgery or limb amputation to achieve a complete surgical resection
• Phase 2 only: Ages >/= 1 month of age at C1D1 with a locally advanced or metastatic infantile fibrosarcoma, Patients with locally advanced infantile fibrosarcoma who would require, in the opinion of the Investigator, disfiguring surgery or limb amputation to achieve a complete surgical resection enrollment or ages 1 month through 21 years of age at C1D1 with a locally advanced or metastatic solid tumor or primary CNS tumor that has relapsed, progressed or was nonresponsive to available therapies and for which no standard or available systemic curative therapy with a documented NTRK gene fusion (identified through molecular assays as routinely performed at CLIA or other similarly-certified laboratories) or (including Expansion Phase) potential patients older than 21 years of age with a tumor diagnosis with histology typical of a pediatric patient and an NTRK fusion may be considered for enrollment following discussion between the local site Investigator and the Sponsor's Medical Monitor.
• Karnofsky (those 16 years old or older) or Lansky (those younger than 16 years) performance score of at least 50
• Adequate hematologic function: Absolute neutrophil count (ANC) ≥ 1.0 109/L, platelet count ≥ 100.0 109/L and hemoglobin ≥ 8.0 g/dL (patients with bone marrow involvement will not be evaluable for hematologic DLT and can enroll with ANC ≥ 0.75 109/L, platelet count ≥ 50.0 109/L and hemoglobin ≥ 8.0 g/dL)
• Adequate hepatic function: Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 upper limit of normal (ULN) for age (patients with documented Gilbert's Disease may be enrolled with Sponsor approval).
• Adequate renal function: Estimated glomerular filtration rate ≥ 30 mL/minute using the Cockroft-Gault formula or: a serum creatinine based on age/gender as outlined in the protocol

Exclusion Criteria

• Investigational agent, anticancer therapy, or major surgery within 14 days (2 weeks) prior to C1D1
• Clinically significant active cardiovascular disease or history of prolonged QT interval corrected for heart rate (QTc)
• Current treatment with a strong cytochrome P450 (CYP) 3A4 inhibitor or inducer (EIAEDs and dexamethasone for CNS tumors or metastases, on a stable dose, are allowed)
• Phase 2 Only: Prior progression while receiving approved or investigational tyrosine kinase inhibitors targeting TRK, including entrectinib, crizotinib and lestaurtanib. Patients who received a TRK inhibitor for less than 28 days of treatment and discontinued because of intolerance remain eligible.

This is a multicenter, open label, Phase 1/2 study in pediatric patients with advanced solid or primary CNS tumors. LOXO‑101 (larotrectinib) will be administered orally (PO) twice daily (BID), with the dose adjusted by body surface area (BSA). Dose Escalation Phase will proceed through the planned 4 dose levels, or until the MTD is reached, or until the Sponsor determines that a suitable dose has been achieved based on PK exposure.. Expansion Cohorts may be enrolled to better characterize safety and efficacy in patients with specific abnormalities in the NTRK genes or proteins.

Lead Organization
Loxo Oncology, Inc.