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.

Targeting metabolic vulnerabilities of cancer: Small molecule inhibitors in clinic

“…Keeping this notion in mind, Calithera has developed the arginase inhibitor CB‐1158 (Figure ) with the overall intent of preventing arginine depletion in the local tumor microenvironment. Pre‐clinical data has demonstrated that CB‐1158 reverses the capacity of polymorphonuclear cells and myeloid‐derived suppressor cells to inhibit T‐cell activation and proliferation ex‐vivo by preventing arginine depletion . Moreover, pre‐clinical data has demonstrated that CB‐1158 increases plasma and tumor arginine levels in mouse syngeneic tumor models, resulting in increased pro‐inflammatory markers and activated CD8 T‐cells in the tumor .…”

“…Pre‐clinical data has demonstrated that CB‐1158 reverses the capacity of polymorphonuclear cells and myeloid‐derived suppressor cells to inhibit T‐cell activation and proliferation ex‐vivo by preventing arginine depletion . Moreover, pre‐clinical data has demonstrated that CB‐1158 increases plasma and tumor arginine levels in mouse syngeneic tumor models, resulting in increased pro‐inflammatory markers and activated CD8 T‐cells in the tumor . The pharmacokinetics and pharmacodynamics of CB‐1158 are currently being explored in a Phase 1 study of solid tumors (Table ).…”

“…The pharmacokinetics and pharmacodynamics of CB‐1158 are currently being explored in a Phase 1 study of solid tumors (Table ). To this end, preliminary findings from the Phase 1 study evaluating safety and tolerability of CB‐1158 as a monotherapy and in combination with anti‐PD1 have found that CB‐1158 is well tolerated with no dose‐limiting toxicities or drug‐related grade 3 adverse events . CB‐1158 was found to be rapidly absorbed (T max = 4 hours); doses of 50 and 100 mg resulted in stead‐state plasma trough levels of 1.6 and 4.5 μM which was sufficient to achieve >90% arginase inhibition and increase plasma arginine levels by 2.4‐ and 4‐fold, respectively .…”

Small-Molecule Targets in Immuno-Oncology

“…Parlati and colleagues reported (Steggerda et al, 2016) the biological activities of CB-1158 (Calithera Biosciences), a selective small-molecule inhibitor of both arginase 1 and 2 with a biochemical half maximal inhibitory concentration (IC 50 ) = 0.10-0.3 mM. In murine syngeneic colon and melanoma models, the inhibitor increased plasma and tumor arginine levels, increased pro-inflammatory markers, activated CD8 + T cells in the tumor, and possessed synergistic activity when combined with an anti-PDL-1 mAb, gemcitabine, or adoptive T cell therapy (Steggerda et al, 2016;Papadopoulos et al, 2017). CB-1158 is currently in a phase 1 clinical study to evaluate safety and tolerability as a monotherapy and in combination with anti-PD-1 in patients with solid tumors (Papadopoulos et al, 2017).…”

“…In murine syngeneic colon and melanoma models, the inhibitor increased plasma and tumor arginine levels, increased pro-inflammatory markers, activated CD8 + T cells in the tumor, and possessed synergistic activity when combined with an anti-PDL-1 mAb, gemcitabine, or adoptive T cell therapy (Steggerda et al, 2016;Papadopoulos et al, 2017). CB-1158 is currently in a phase 1 clinical study to evaluate safety and tolerability as a monotherapy and in combination with anti-PD-1 in patients with solid tumors (Papadopoulos et al, 2017). The only reported potent small-molecule arginase 1 inhibitors are analogs of 2(S)-amino-6-boronohexanoic acid, with low nanomolar binding affinity against human arginase I.…”