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Ref Type Journal Article
PMID (30819679)
Authors Mahalingam D, Wang JS, Hamilton EP, Sarantopoulos J, Nemunaitis J, Weems G, Carter L, Hu X, Schreeder M, Wilkins HJ
Title Phase 1 Open-Label, Multicenter Study of First-in-Class RORγ Agonist LYC-55716 (Cintirorgon): Safety, Tolerability, and Preliminary Evidence of Antitumor Activity.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 25
Issue 12
Date 2019 06 15
URL
Abstract Text 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 (n = 11), fatigue (n = 7), anemia (n = 4), decreased appetite (n = 4), and nausea (n = 4). Grade 3 AEs were anemia (n = 2), elevated gamma-glutamyl 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).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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
LYC-55716 Cintirorgon|LYC55716 Cintirorgon (LYC-55716) is a retinoic acid-related orphan receptor gamma agonist, which may increase T-cell mediated anti-tumor immune response, potentially leading to inhibition of tumor growth (AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5566, PMID: 30819679).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown lung non-small cell carcinoma not applicable LYC-55716 Case Reports/Case Series Actionable In a Phase I trial, Cintirorgon (LYC-55716) treatment resulted in a partial response in a patient with non-small cell lung cancer who was previously treated with Keytruda (pembrolizumab) and had progressed (PMID: 30819679). 30819679
Unknown unknown Advanced Solid Tumor not applicable LYC-55716 Phase I Actionable In a Phase I trial, Cintirorgon (LYC-55716) treatment resulted in a partial response in 8% (2/25) and stable disease in 44% (11/25) of patients with an advanced solid tumor, with stable disease lasting 2 to 12 months (PMID: 30819679). 30819679
Unknown unknown spindle cell carcinoma not applicable LYC-55716 Case Reports/Case Series Actionable In a Phase I trial, Cintirorgon (LYC-55716) treatment resulted in a partial response in a patient with metastatic spindle cell carcinoma, demonstrating decreased tumor burden (PMID: 30819679). 30819679