Phase I evaluation of AB928, a novel dual adenosine receptor antagonist, combined with chemotherapy or AB122 (anti-PD-1) in patients (pts) with advanced malignancies

Abstract

Abstract Background High levels of adenosine present in the tumor microenvironment have direct immunosuppressive impact on T-cell function and activation. AB928, a selective, small-molecule dual A2aR/A2bR antagonist, potently blocks the effects of adenosine and, in combination with chemotherapy or anti-PD-1, may have a more profound effect on reactivating anti-tumor immunity. Methods Four phase I, open-label, disease-specific platform studies assessing the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of AB928 in combination with chemotherapy (chemo) or AB122. In dose escalation (3+3 design), AB928 (cohort 1: 75mg, cohort 2: 150mg, cohort 3: 200mg orally once daily) and chemo (pegylated liposomal doxorubicin (PLD), FOLFOX or carboplatin/pemetrexed plus pembrolizumab) or AB122 (240mg IV every 2 weeks) were evaluated in eligible pts with advanced malignancies. The recommended phase II dose of each AB928 combination will advance into tumor-specific dose-expansion cohorts. Adverse events (AEs) were graded according to NCI CTCAE 5.0 and antitumor activity assessed using RECIST v1.1. Results As of 29APR2019, 26 pts have been treated across 4 studies (cohort 1, n=12; cohort 2, n=12; cohort 3, n=2) with time on treatment ranging 9-268 days. In dose escalation, AB928 combination therapy was well tolerated with 1 dose limiting toxicity (Gr 2 rash, <80% dose received, cohort 2, AB928 + PLD), 2 pts with Gr 3 and none with Gr 4-5 AB928-related AEs observed. Preliminary data support linear and dose-proportional AB928PK with similar PD inhibition of pCREB as seen in healthy volunteers. 12 (46%) pts have reached first post-baseline disease assessment; with tumor reduction in 4 (1 partial response, 3 stable disease). Updated data across the studies will be presented at the meeting. Conclusions Early results show a favorable safety profile of AB928 combination therapy and predictable PK/PD correlation. Further evaluation of AB928 + chemotherapy and AB928 + AB122 will continue in cohorts of triple-negative breast, ovarian, colorectal, gastro-esophageal, non-small cell lung, renal cell and castration-resistant prostate cancer. Clinical trial identification NCT03719326, NCT03720678, NCT03846310, NCT03629756. Legal entity responsible for the study Arcus Biosciences, Inc. Funding Arcus Biosciences, Inc. Disclosure J. Powderly: Research grant / Funding (institution): Arcus Biosciences; Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Full / Part-time employment: Genentech; Speaker Bureau / Expert testimony: Merck; Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Carolina BioOncology Institute; Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: BioCytics; Shareholder / Stockholder / Stock options: Iovance; Shareholder / Stockholder / Stock options: BlueBird; Shareholder / Stockholder / Stock options: Juno; Shareholder / Stockholder / Stock options: KitePharma; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): FLX Biosciences; Research grant / Funding (institution): Alkermes; Research grant / Funding (institution): Tempest; Research grant / Funding (institution): Curis; Research grant / Funding (institution): Corvus; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Sequenom. A. Spira: Research grant / Funding (institution): Arcus Biosciences; Honoraria (self), Research grant / Funding (institution): Cytomx; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): BMS; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Arch Oncology; Research grant / Funding (institution): Lam; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Nektar; Shareholder / Stockholder / Stock options: Lilly; Honoraria (self): Ariad; Leadership role: ASCO; Leadership role: US Oncology; Leadership role: Longevity. R. Gutierrez: Research grant / Funding (institution): Arcus Biosciences. D. DiRenzo: Shareholder / Stockholder / Stock options, Full / Part-time employment: Arcus Biosciences. A. Udyavar: Shareholder / Stockholder / Stock options, Full / Part-time employment: Arcus Biosciences. J.J. Karakunnel: Shareholder / Stockholder / Stock options, Full / Part-time employment: Arcus Biosciences; Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. A. Rieger: Shareholder / Stockholder / Stock options, Full / Part-time employment: Arcus Biosciences; Shareholder / Stockholder / Stock options: AstraZeneca. J. Colabella: Shareholder / Stockholder / Stock options, Full / Part-time employment: Arcus Biosciences. D.W. Lai: Shareholder / Stockholder / Stock options, Full / Part-time employment: Arcus Biosciences; Shareholder / Stockholder / Stock options: Primevax. P. de Souza: Research grant / Funding (institution): Arcus Biosciences.