164TiP Phase I study of LOXO-101, a selective TRK inhibitor, in pediatric patients with cancer

Abstract

Background 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-101isthefirstsmall-moleculeselectiveinhibitorofTRKA,-B,and-Cinclinical 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. Trialdesign: Wehaveinitiatedanopen-label, multi-centerPhaseIdoseescalation/dose expansionstudywithLOXO-101inpediatricpatientswithsolidtumorsandprimary CNS tumors (NCT02637687). Patients with advanced cancer between the ages of 1 and 21yearsareeligible,aswellaspatientsasyoungas1-monthofagewithaprimary diagnosis ofIFSorCMNandadocumentedNTRKfusion. Twice-dailyoraldosingof LOXO-101 capsulesisadministeredon acontinuous28-dayschedule. LOXO-101is available in an oral liquid formulation for patients unable to swallow capsules. PK- directedintra-subjectdoseescalationispermitted,withtargetexposuresequivalentto 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 andinitialevidenceoftheefficacyofLOXO-101indifferenttumortypes.Eligibilityfor 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 indentification: NCT02637687 Legal entity responsible for the study: Loxo Oncology, Inc. Funding: Loxo Oncology, Inc. Disclosure: S. Smith, M. Reynolds, S. Cruickshank: Consultant fees paid by Loxo Oncology, Inc. L. Donahue: Employee and stockholder of Loxo Oncology, Inc. M.C. Cox: Employee and stock hold of Loxo Oncology, Inc. All other authors have declared no conflicts of interest.