CX-1158-101: A first-in-human phase 1 study of CB-1158, a small molecule inhibitor of arginase, as monotherapy and in combination with an anti-PD-1 checkpoint inhibitor in patients (pts) with solid tumors.

Abstract

3005 Background: Arginase is secreted by myeloid-derived suppressor cells (MDSCs) and polymorphonuclear cells (PMNs) in the tumor microenvironment, depleting arginine, an amino acid required for T-cell activation and proliferation. CB-1158 is an oral small molecule inhibitor of arginase. CB-1158 reverses PMN- and MDSC-mediated suppression of T-cells in ex vivo human models, and increases plasma and tumor arginine levels in mouse syngeneic tumor models leading to increased pro-inflammatory markers and activated CD8 T-cells in the tumor. CB-1158 has single agent efficacy in mouse tumor models and synergistically enhances the antitumor efficacy of checkpoint inhibitors. Methods: This is an ongoing phase 1 study to evaluate safety and tolerability of CB-1158 as a monotherapy and in combination with anti-PD-1 in pts with solid tumors. Pharmacokinetics (PK), anti-tumor effects, and biomarkers, including plasma arginine, arginase activity, and effects on immune function in blood and in tumors will be evaluated. CB-1158 was administered BID orally in 28-day cycles. Escalating doses were administered to cohorts for safety evaluation. Additional pts were enrolled at dose levels determined to be safe to support biomarker objectives. Results: Nine pts have been enrolled across two monotherapy dose escalation cohorts (50 and 100 mg) and biomarker cohorts. CB-1158 was rapidly absorbed (Tmax = 4 h) and was cleared with a half-life of 6 h. At doses of 50 and 100 mg, steady-state plasma trough levels were 1.6 and 4.5 µM, sufficient to achieve > 90% arginase inhibition, and plasma arginine levels increased 2.4- and 4-fold, respectively. CB-1158 has been well tolerated with no DLTs or drug-related Grade 3 AEs. Dose escalation is ongoing and updated safety, PK and biomarker data will be presented. Conclusions: CB-1158 is a first-in-class inhibitor of the myeloid-derived immunosuppressive enzyme arginase. CB-1158 has been well tolerated and achieves on-target inhibition resulting in increases in plasma arginine, an amino acid required for T-cell immune responses. Clinical trial information: NCT02903914.