RET is a receptor tyrosine kinase with critical roles in normal physiology. Fusions of the RET kinase with a partner protein have been identified in ∼2% of nonsmall cell lung cancers (NSCLC) and a subset of papillary thyroid cancers and other tumors. RET mutations occur in the majority of medullary thyroid cancers (MTC). Although multikinase inhibitors with anti-RET activity are in the clinic, their activity is limited by incomplete RET inhibition in patients, toxicity from off-target effects (e.g.VEGFR2) and poor pharmacokinetics (PK). LOXO-292 is a potent and specific inhibitor of RET, including fusions, activating mutations and potential acquired resistance mutations, with minimal inhibition of off targets, including > 100-fold selectivity for VEGFR2.
This is an open label, multi-center, dose escalation and expansion Phase 1 study in adult patients with advanced solid tumors. Major eligibility criteria for dose escalation include prior cancer treatment (prior treatment with anti-RET TKIs allowed) and normal hematopoietic and major organ function. During dose escalation, when a dose level is achieved that is safe and consistent with RET target engagement, enrollment will be limited to patients with RET-fusion NSCLC, MTC and other tumors with RET alterations or increased RET activity, as identified in tumor or blood by prior molecular assays performed locally. Once the Maximum Tolerated Dose (MTD) or recommended dose for further study is identified, patients will be enrolled to one of five dose expansion cohorts, depending on tumor type (i.e. NSCLC, MTC, other cancer), prior TKI therapy and type of RET alteration. The starting dose of LOXO-292 is 20 mg orally once per day, and dose escalation is proceeding using a 3 + 3 design. The primary endpoint is establishment of the MTD/recommended dose for further study. Key secondary endpoints include: safety and tolerability, PK parameters and preliminary assessment of anti-tumor activity. Patients undergo safety, clinical and PK assessments and radiographic evaluation for their disease at regular intervals.
Clinical trial identification
Treatment of patients has begun. The study has been submitted to the NIH (https://clinicaltrials.gov) and the ClinicalTrials.gov Identifier is pending and will be provided as soon as available.
Legal entity responsible for the study
S. Smith, T. Eary, S. Cruickshank, M. Nguyen, S. Rothenberg: Ownership interest in Loxo Oncology. All other authors have declared no conflicts of interest.