407TiP - Phase 1 study of LOXO-101, a selective TRK inhibitor, in pediatric patients with cancer

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Clinical Research
Basic Scientific Principles
Presenter Theodore Laetsch
Citation Annals of Oncology (2016) 27 (6): 114-135. 10.1093/annonc/mdw368
Authors T.W. Laetsch1, R. Nagasubramanian2, S.G. Dubois3, L. Mascarenhas4, D. Hawkins5, N. Shukla6, B. Turpin7, S. Smith8, M. Reynolds8, S. Cruickshank8, L. Donahue9, M.C. Cox8, A. Pappo10
  • 1Department Of Pediatrics, University of Texas Southwestern Medical Center at Dallas, 75235 - Dallas/US
  • 2Pediatric Hematology/oncology, Nemours Children's Hospital, Orlando/US
  • 3Dana-farber/boston Children’s Cancer And Blood Disorders Center, Boston Children's Hospital, Boston/US
  • 4Department Of Oncology, Childrens Hospital Los Angeles University of Southern California, Los Angeles/US
  • 5Department Of Hematology/oncology, Seattle Children's Hospital, Seattle/US
  • 6Department Of Pediatrics, Memorial Sloan Kettering Cancer Center, New York/US
  • 7Department Of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati/US
  • 8Clinical Development, Loxo Oncology, Inc, 94107 - South San Francisco/US
  • 9Clinical Operations, Loxo Oncology, Inc, 06901 - Stamford/US
  • 10Solid Tumor Division, St Jude Children's Research Hospital, Memphis/US



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.

Trial design

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.