Phase 1 open-label, multicenter study of first-in-class RORγ agonist LYC-55716 (Cintirorgon): Safety, tolerability, and preliminary evidence of antitumor activity

Devalingam Mahalingam, Judy S. Wang, Erika P. Hamilton, John Sarantopoulos, John Nemunaitis, Garry Weems, Laura Carter, Xiao Hu, Marshall Schreeder, H. Jeffrey Wilkins

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Purpose: Transcription factor retinoic acid receptor-related orphan receptor γ (RORγ) regulates type 17 effector T-cell differentiation and function and is key to immune cell regulation. Synthetic RORγ agonists modulate immune cell gene expression to increase effector T-cell activity and decrease immune suppression. A phase 1 study evaluated the safety and tolerability of LYC-55716 (cintiRORγon), a first-in-class, oral, small-molecule RORγ agonist in adults with relapsed/ refractory metastatic cancer. Patients and Methods: Patients received 28-day treatment cycles of oral LYC-55716; dose and dosing regimen were determined according to pharmacokinetic profile and safety. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective tumor response rate. Results: No dose-limiting toxicities occurred among the 32 enrolled patients who received LYC-55716 150 mg BID to 450 mg BID. Treatment-related adverse events (AE) were primarily grade 1-2 and included diarrhea (n = 11), fatigue (n=7), anemia (n=4), decreased appetite (n=4), and nausea (n = 4). Grade 3 AEs were anemia (n = 2), elevated gammaglutamyl transferase (n = 1), and hypophosphatemia (n = 1). Pharmacokinetic concentrations achieved levels expected for target gene regulation. Pharmacodynamic results indicated RORγ pathway engagement. Two patients (NSCLC and sarcomatoid breast cancer) had confirmed partial responses; 11 had disease stabilization for 2 to 12 months (6 received >4 months of treatment). Conclusions: These data support the safety and tolerability of LYC-55716 and selection of 450 mg BID dose for a phase 2a study assessing LYC-55716 clinical activity, safety, and biomarkers in patients with NSCLC, head and neck, gastroesophageal, renal cell, urothelial, and ovarian cancers.

Original languageEnglish (US)
Pages (from-to)3508-3516
Number of pages9
JournalClinical Cancer Research
Volume25
Issue number12
DOIs
StatePublished - Jun 15 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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