Phase 1 Open-Label, Multicenter Study of First-in-Class RORγ Agonist LYC-55716 (Cintirorgon): Safety, Tolerability, and Preliminary Evidence of Antitumor Activity

• Published in: Clinical cancer research Vol. 25; no. 12; pp. 3508 - 3516
• Main Authors: Mahalingam, Devalingam, Wang, Judy S, Hamilton, Erika P, Sarantopoulos, John, Nemunaitis, John, Weems, Garry, Carter, Laura, Hu, Xiao, Schreeder, Marshall, Wilkins, H Jeffrey
• Format: Journal Article
• Language: English
• Published: United States 15-06-2019
• Subjects: Adult; Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Benzoxazines - administration & dosage; Benzoxazines - adverse effects; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - metabolism; Neoplasms - drug therapy; Neoplasms - metabolism; Propionates - administration & dosage; Propionates - adverse effects; Receptors, Retinoic Acid - agonists; Retinoic Acid Receptor gamma; Young Adult
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-3185

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 (cintirorgon), a first-in-class, oral, small-molecule RORγ agonist in adults with relapsed/refractory metastatic cancer.
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.
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 (
= 11), fatigue (
= 7), anemia (
= 4), decreased appetite (
= 4), and nausea (
= 4). Grade 3 AEs were anemia (
= 2), elevated gamma-glutamyl transferase (
= 1), and hypophosphatemia (
= 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).
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.