Abstract CT132: Safety and dose selection for LYC-55716, a first-in-class RORγ agonist to treat solid tumors: Phase I results from an open-label, multicenter Phase I/IIa trial
Authors: Mahalingam Devalingam , Wang Judy S. , Hamilton Erika P. , Weems Garry , Schreeder Marshall , Wilkins H. Jeffrey 
Published: August 2018

Abstract
Background: LYC-55716, a first-in-class, oral, small-molecule agonist of the retinoic acid receptor-related orphan receptor γ (RORγ), is under development as a novel immuno-oncology agent for solid tumors. Preclinical data show that LYC-55716 modulates gene expression to reprogram immune cells for improved anti-tumor effector function as well as decreased immunosuppressive mechanisms, resulting in slower tumor growth and enhanced survival. An ongoing, open-label, Phase I/IIa trial is evaluating the safety and tolerability of the investigational agent LYC-55716 in patients with advanced solid tumors.
Methods: The Phase I portion of the trial (NCT02929862) enrolled adults with locally advanced or metastatic solid tumors (no specific exclusions) who had progressed on standard therapy. Patients received 28-day treatment cycles of LYC-55716 in which dose and dosing regimen were determined according to PK profile and safety. Primary endpoints were safety (monitoring of adverse events [AEs], physical examination, lab results) and incidence of dose-limiting (Grade 3-4) toxicities during the first treatment cycle. Secondary endpoints included pharmacokinetics (PK) and response assessment. Pharmacodynamic markers of RORγ activation were also evaluated.
Results: Data to date: Thirty-two patients were enrolled (23-79 y; 63% female); 27 completed ≥1 (28-day) treatment cycle. Treatment-related AEs occurring in ≥3 patients included diarrhea (n=7 [22%]); fatigue (n=5 [16%]); and anemia, poor appetite, and dry mouth (n=3 [9%] each). No dose-limiting toxicities were observed during Phase 1. The majority of treatment-related AEs were Grade 1-2; Grade 3 treatment-related AEs were reported only for anemia, elevated gamma-glutamine transferase, and hypophosphatemia; no Grade 4 treatment-related AEs occurred. None of the 5 deaths or 14 serious AEs (in 11 patients) were considered treatment-related, and no subjects withdrew due to AEs. LYC-55716 demonstrated an estimated elimination half-life of ~12 h. Twice daily dosing resulted in minimum plasma concentrations that were consistently higher than QD dosing and the highest BID dose resulted in a median minimum plasma concentration that exceeded by ~24-fold the 50% effective concentration that preclinical studies had indicated was required for target gene regulation. Pharmacodynamic data indicated target engagement, consistent with PK evidence of exposure levels in the predicted efficacious range. Updated data, including details of Phase II dose selection and response assessment, will be presented.
Conclusion: Phase I data support the safety of LYC-55716 and selection of a BID dosing regimen for the ongoing Phase 2a phase of the trial in patients with non-small cell lung, head and neck, gastroesophageal, renal cell, urothelial, and ovarian cancers.
Citation Format: Devalingam Mahalingam, Judy S. Wang, Erika P. Hamilton, Garry Weems, Marshall Schreeder, H. Jeffrey Wilkins. Safety and dose selection for LYC-55716, a first-in-class RORγ agonist to treat solid tumors: Phase I results from an open-label, multicenter Phase I/IIa trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT132.