Phase 1a/b open-label study of IK-175, an oral AHR inhibitor, alone and in combination with nivolumab in patients with locally advanced or metastatic solid tumors and urothelial carcinoma

TPS3169 Background: Aryl Hydrocarbon Receptor (AHR) is a ligand-activated transcription factor that regulates the activity of multiple innate and adaptive immune cells. Kynurenine, generated from tryptophan by IDO1 and TDO2, is a ligand that binds AHR and leads to a net immunosuppressive tumor microenvironment, making AHR an attractive therapeutic target in multiple cancer types. IK-175 is a selective, small molecule inhibitor of AHR being developed as an oral agent. In preclinical mouse tumor models, IK-175 demonstrates antitumor activity as a single agent or in combination with checkpoint inhibitors. AHR immunohistochemistry (IHC) tumor microarray analysis across 15 different tumor types revealed that bladder cancer has the highest level of AHR protein expression and nuclear localization indicative of ligand-bound and active AHR signaling. Therefore, nuclear AHR in urothelial carcinoma tumors is being investigated for potential predictive clinical benefit with IK-175. Methods: This is a first-in-human, phase 1a/b, open-label, multicenter, dose-escalation and expansion study of IK-175 as a single agent and in combination with nivolumab. The primary objectives are to determine the maximum tolerated dose (MTD) and/or maximum administered dose (MAD), identify the recommended phase 2 dose (RP2D), and evaluate the safety and tolerability of IK-175 alone and in combination with nivolumab. Secondary objectives are to evaluate the pharmacokinetics (PK) of IK-175, evaluate pharmacodynamic (PD) immune effects, and assess preliminary antitumor activity. Key exploratory objectives are to evaluate the PD effects on peripheral immune cells and target gene expression, to assess candidate baseline biomarkers, and correlative analyses of tumor AHR nuclear localization with clinical response. The study is exploring tumor AHR nuclear localization by IHC as a predictive biomarker in patients with urothelial carcinoma. A minimum of 10 patients with a positive AHR nuclear localization test (cutoff for positive AHR is 65% tumor cells positive for 2+/3+ nuclear AHR by a validated IHC assay) will be enrolled in the combination arm. IK-175 is administered daily in 21 or 28 day-cycles as a single agent, and in combination with nivolumab (480 mg q4w on Day 1 of every cycle), in adult patients with advanced solid tumors (dose escalation) and urothelial carcinoma (dose expansion). Key eligibility criteria include patients with histologically confirmed solid tumors (including urothelial carcinoma) who have locally recurrent or metastatic disease that have progressed on or following all standard of care therapies deemed appropriate by the treating physician including prior checkpoint inhibitors. Estimated enrollment is 93 patients; the study began in January 2020 and is ongoing. Clinical trial information: NCT04200963.