Abstract 4147: CCX559, an orally administered small molecule PD-L1 inhibitor for the treatment of solid tumors

Abstract

Abstract Background: The small molecule CCX559 is a novel, highly potent inhibitor of human PD-L1 being developed as an oral treatment for cancer patients. We have previously demonstrated that CCX559 has nanomolar potency and high selectivity for PD-L1; that it enhances primary T cell activation and has anti-tumor efficacy, including the ability to induce complete responses, using in vivo models1. Results: Safety pharmacology studies in preclinical animal species demonstrated pharmacokinetics and an acceptable safety profile for CCX559, which supported the initiation of human trials in patients with advanced tumors. Prior findings from toxicology studies were consistent with immune modulation, including consumptive coagulopathy, increased white blood cell counts, and changes in IL-6 plasma levels. A Phase 1, first in patient, multicenter, open-label, dose-escalation study was initiated, with a starting dose of once-daily (QD) oral dosing at 30 mg. The primary objectives are safety/tolerability, as well pharmacokinetic (PK) assessments aimed at determining a future phase 2 dose. Secondary objectives include pharmacodynamic (PD) assessments of immune cell activation in patient peripheral blood samples, as well as anti-tumor effects. For PK, intensive blood sampling is done on day 1 and day 21 of the first cycle of dosing; additional samples are collected on select days throughout the 21-day treatment cycles. PD analyses are done on selected blood draws as well. The first patient dosed (30 mg QD) showed that the drug was well tolerated with no adverse events reported. Preliminary PK results from this patient revealed CCX559 exposure levels consistent with preclinical predictions. Moreover, PD samples showed elevations in T cell proliferation and activation within the first 15 days, when compared to the predose sample. In conclusion, the preclinical data support clinical development of CCX559. CCX559 shows encouraging initial PK and PD results, and patient enrollment is ongoing in the trial (ACTRN12621001342808).