Neurotrophin ligands and their receptors TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3) are important for growth regulation, differentiation and survival of neurons. Translocations involving the NTRK1/2/3 kinase domain, mutations involving the TRK ligand-binding site, amplifications of NTRK, TRK splice variants, and autocrine/paracrine signaling have been described in diverse tumor types and may contribute to tumorigenesis. A broad range of pediatric malignancies have been found to harbor NTRK fusions, including infantile fibrosarcoma (IFS), congenital mesoblastic nephroma (CMN), secretory breast cancer, pediatric papillary thyroid cancer, pediatric gliomas and Ph-like acute lymphoblastic leukemia. Additionally, TRK protein over-expression is common in neuroblastoma. LOXO-101 is the first small-molecule selective inhibitor of TRKA, -B, and -C in clinical development and has demonstrated tumor inhibition in preclinical models and clinically meaningful responses in patients with TRK fusion cancers in an adult phase 1 trial.
We have initiated an open-label, multi-center Phase I dose escalation/dose expansion study with LOXO-101 in pediatric patients with solid tumors and primary CNS tumors (NCT02637687). Patients with advanced cancer between the ages of 1 and 21 years are eligible, as well as patients as young as 1-month of age with a primary diagnosis of IFS or CMN and a documented NTRK fusion. Twice-daily oral dosing of LOXO-101 capsules is administered on a continuous 28-day schedule. LOXO-101 is available in an oral liquid formulation for patients unable to swallow capsules. PK-directed intra-subject dose escalation is permitted, with target exposures equivalent to the recommended Phase 2 dose in adults of 100 mg BID. Dose escalation utilizes a Rolling 6 design. The objective of the study is to determine the maximum tolerated dose and initial evidence of the efficacy of LOXO-101 in different tumor types. Eligibility for the dose expansion cohorts will require patient tumor samples to have documented alterations of an NTRK gene or TRK protein. Molecular abnormalities will be characterized through the analysis of archival tissue. Enrollment began in December 2015 and is ongoing.
Clinical trial identification
Legal entity responsible for the study
Loxo Oncology, Inc.
Loxo Oncology, Inc.
S. Smith, M. Reynolds, S. Cruickshank: Paid consultant for Loxo Oncology. L. Donahue, M.C. Cox: Employee and stock holder of Loxo Oncology. All other authors have declared no conflicts of interest.