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Phase 1 Safety Of ICOS Agonist Antibody JTX-2011 Alone And With Nivolumab (nivo) In Advanced Solid Tumors; Predicted Vs Observed Pharmacokinetics (PK) In ICONIC.

Howard A. Burris, Margaret K. Callahan, Anthony W. Tolcher, Shivaani Kummar, Gerald Steven Falchook, Russell Kent Pachynski, Scott S. Tykodi, Geoffrey Thomas Gibney, Tanguy Y. Seiwert, Justin F. Gainor, Patricia LoRusso, James Hilbert, Josh F Apgar, Fei Hua, John M Burke, Manny Lazaro, Myles Clancy, Baoyu Ding, Elizabeth G. Trehu, Timothy Anthony Yap

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3033 Background: JTX-2011 is an agonist monoclonal antibody that targets ICOS, Inducible CO-Stimulator of T cells. A dual mechanism of action is intended to activate antigen-specific CD4 T effector cells and selectively deplete intratumoral T regulatory cells. JTX-2011 is equally potent across human, rodent, and non-human primate species. Methods: A quantitative systems pharmacology (QSP) model describing target binding by JTX-2011 and target mediated drug disposition in blood, tumor and non-tumor tissues was based on preclinical potency and non-linear PK data across species. The model was translated to predict PK and target engagement (TE) in humans to facilitate dose selection. The QSP model predicts > 95% TE for 21 days at the top planned dose. We present safety and actual/predicted PK from a Phase 1 study of JTX-2011 alone (Part A) and safety in combination with nivo (Part B). Results: 25 subjects have been dosed, 19 in 4 cohorts of JTX-2011 alone at .003, .01, .03, and .1 mg/kg IV q 21 days, and 6 in 2 cohorts of JTX-2011 .01 mg/kg and .03 mg/kg IV plus nivo 240 mg IV q21 days. Safety data from ≥ 1 cycle is available for 12 subjects in Part A (7 ≥ 3 cycles), and 3 in Part B (all ≥ 3 cycles). PK data is available for cycle 1 of Part A. Mean age (±SD) is 60 (±10.6). Mean prior systemic therapies is > 5 (range 1-11). Tumor types include endometrial, triple negative breast, melanoma, lung, pancreatic and colorectal cancers. No dose limiting toxicities have been reported. 3 Grade 3 adverse events (AEs) were reported in 2 Part A subjects: anemia and hypoxia (unrelated SAE) at .003 mg/kg and JTX-2011 related diarrhea at .1 mg/kg. Grade 1-2 AEs in ≥2 subjects are chills, pyrexia, neck pain, dizziness, and nausea. 5 subjects had JTX-2011 related Grade 1-2 infusion reactions up to 6 hours post infusion. Non-linear exposure increase was observed. While PK at lower doses is consistent with model predictions, AUC and t1/2at 0.03 and 0.1 mg/kg doses are higher than predicted, suggesting higher than predicted TE. Conclusions: JTX-2011 has been well tolerated up to 0.1 mg/kg and with nivo at .01 mg/kg IV q 21 days. Greater than linear exposure increase was observed and TE may be higher than QSP model prediction. Clinical trial information: NCT02904226.