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TPS272 Background: The tumor microenvironment contains high levels of immunosuppressive adenosine, which binds to and activates the A2a and A2b receptors (R) on immune cells, resulting in an ineffective anti-tumor immune response. Extracellular adenosine is primarily produced by the enzyme CD73. In prostate cancer (PC), the activity of prostatic acid phosphatase produces additional adenosine. AB928 is the first clinical-stage small molecule dual antagonist of both A2aR and A2bR, which is highly potent, pharmacodynamically active, and has been well tolerated in dose escalation studies as a single agent or in combination with chemo/immunotherapy. Targeting the adenosine pathway in combination with standard of care regimens may have a more profound effect on activating and inducing sustained anti-tumor immunity. Methods: This Phase 1b/2, open-label, multi-cohort platform study will evaluate the efficacy and safety of AB928 combination therapy in participants with metastatic castrate resistant PC (mCRPC). Each cohort will independently assess AB928 plus AB122 (anti-PD-1 antibody) in combination with standard of care (SOC; enzalutamide, docetaxel) or AB928 plus AB680 (CD73 inhibitor) with or without AB122. Cohort eligibility is informed by prior treatment history. In Ph1b, up to 15 participants will receive investigational products at the single-agent recommended dose with SOC per label guidance. Provided safety and activity stopping criteria are not met, further accrual will proceed in Ph2 and, depending on treatment cohort, may involve randomization to enzalutamide or docetaxel; crossover to experimental therapy will be allowed following progression on control treatment. Investigator-assessed antitumor response (radiologic, prostate specific antigen) will follow PCWG3 criteria. Conclusions: This Ph1b/2 study is the first to target the adenosine axis using a dual A2aR/A2bR antagonist (AB928) together with a small molecule CD73 inhibitor (AB680), anti-PD-1 antibody (AB122), and SOC for mCRPC. Study enrollment is proceeding in the United States; results will be shared in upcoming scientific conferences.

Adenosine suppresses antitumor immune responses via A2a and A2b receptors expressed on intratumoral immune cells. This effect is mediated by increased cyclic adenosine 5′-monophosphate (AMP) levels and phosphorylation of cyclic AMP response element binding protein (CREB). We conducted a phase 1, placebo-controlled, single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study to assess the safety, tolerability, pharmacokinetics (PK), including food effect (FE), and pharmacodynamics (PD) of oral AB928, a novel dual A2aR/A2bR antagonist, in healthy volunteers. AB928 doses between 10 and 200 mg once daily and 100 mg twice daily were evaluated. The study enrolled 85 subjects (randomized 3:1, AB928:placebo), 40 each in the SAD and MAD cohorts, and 5 in the FE cohort. AB928 was well tolerated up to the highest dose tested and did not affect any physiologic parameters potentially sensitive to adenosine inhibition. No safety concern was identified. The PK profile of AB928 was linear and dose-proportional, and a clear PK/PD correlation was demonstrated. Significant inhibition of adenosine receptor-mediated phosphorylated CREB was observed at peak plasma concentrations in all dose cohorts and at trough plasma concentrations in the higher-dose cohorts. AB928 plasma levels ≥1 μM were associated with ≥90% adenosine receptor inhibition. In the postprandial state, the rate of AB928 absorption decreased but the extent of absorption was unchanged. Together, these data support further clinical development of oral AB928 in cancer patients.

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: 75 mg, cohort 2: 150 mg, cohort 3: 200 mg orally once daily) and chemo (pegylated liposomal doxorubicin (PLD), FOLFOX or carboplatin/pemetrexed plus pembrolizumab) or AB122 (240 mg 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, 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.

2604 Background: AB928, a selective, small-molecule A2aR/A2bR antagonist, potently blocks the immunosuppressive effects of high adenosine concentrations in the tumor microenvironment. Preclinically, combining adenosine receptor inhibition with either chemotherapy or anti-PD-1 resulted in greater tumor control, suggesting AB928 may have additive activity when paired with either of these agents in cancer pts. Methods: Three dose-escalation (3+3 design) studies are assessing the safety, pharmacokinetics (PK), pharmacodynamics, and clinical activity of increasing doses of AB928 (75, 150, 200 mg orally once daily) in combination with: standard pegylated liposomal doxorubicin in triple-negative breast cancer (TNBC) and ovarian cancer (OC); standard mFOLFOX6 in gastroesophageal cancer (GEC) and colorectal cancer (CRC); and AB122 (240 mg every 2 weeks) in various advanced tumors. Following identification of the recommended phase 2 dose of AB928 in combination with chemotherapy or AB122 in dose escalation, the following tumor cohorts may be expanded (15-40 pts/cohort) to further test the combinations: TNBC and OC, GEC and CRC, and renal cell carcinoma. Results: As of 01Feb2019, 9 pts were treated across the 3 studies, and time on treatment ranged from 1-182 days (table). Overall, AB928 combination therapy was well tolerated. Two pts underwent post-baseline disease assessment; both had stable disease. Preliminary data indicate that AB928 PK and adenosine receptor coverage in cancer pts are similar to what was previously assessed in healthy volunteers. AB122 PK and PD-1 coverage are equally unaffected by AB928 co-administration. Updated data, including biomarker data, will be presented at the meeting. Conclusions: Early results showed a favorable safety profile of AB928 combination therapy. All 3 studies are actively recruiting pts. Clinical trial information: NCT03719326; NCT03720678; NCT03629756. [Table: see text]

INTRODUCTION: CD73 converts extracellular adenosine monophosphate (AMP), derived from adenosine triphosphate, into adenosine (ADO). ADO suppresses immune responses, including those of T cells, natural killer (NK) cells and dendritic cells, via A2aR and A2bR receptors. Activation of these receptors results in increased intracellular levels of cyclic AMP (cAMP) and phosphorylation of the cAMP response element-binding protein (CREB). Monitoring the degree of pCREB induced by activation of the Aa2R and A2bR receptors in peripheral blood allows for a specific measurement of target engagement by AB928. In mice, the pCREB assay, coupled with changes in immune cell infiltrate and tumor growth rates, allows for a fuller understanding of the drug's PK/PD relationship. METHODS: Mouse and human whole blood was stimulated with the adenosine agonist NECA (5'-N-Ethylcarboxamidoadenosine) following in vitro spike in or in vivo dosing with AB928. Multi-color phospho-flow cytometry was used to assess levels of pCREB on immune cells. AB928 levels in plasma samples were determined using LC-MS-MS after protein precipitation. RESULTS: A2aR mRNA was the most prevalent adenosine receptor in CD4+ and CD8+ T cells. NK cells also express primarily A2aR, although A2bR was also detected. Dendritic cells and CD14+ monocytes expressed both A2aR and A2bR. NECA stimulation of mouse whole blood resulted in a significant increase in the levels of pCREB within CD8+ T cells with an EC50 of 100 nM, while in human whole blood the EC50 was higher at 700 nM. AB928 (100 nM) exhibited comparable shifts in the NECA dose response between human and murine whole blood, 15 and 16-fold, respectively. Due to the high level of adenosine in the tumor microenvironment, doses of AB928 associated with plasma levels that significantly inhibited 5 μM NECA in the whole-blood pCREB assay were selected for mouse efficacy studies. At these doses, significant reductions in tumor growth were noted. In human whole blood, approximately 90 nM AB928 was required to inhibit 50% of the 5 μM NECA-induced pCREB signal. Inhibition was observed on both CD4+ and CD8+ T cells. NECA-induced pCREB elevations were observed in CD14+ cells less frequently than T cells; however, when the signal was observed, AB928 inhibited it. The human pCREB assay is being utilized to monitor the PD responses in an ongoing clinical trial. Preliminary PK/PD results from this study will be presented. CONCLUSIONS: Systemic extent of receptor (A2aR and A2bR) occupancy by the novel dual antagonist AB928 can be assessed in humans and mice based on the extent of receptor-mediated CREB phosphorylation in blood lymphocytes. AB928 retains much of its inherent potency when competing against high concentrations of adenosine under physiologically relevant conditions (i.e., whole blood). Citation Format: Lisa Seitz, Devika Ashok, Manmohan R. Leleti, Jay P. Powers, Brandon Rosen, Dillon Miles, Lixia Jin, Adam Park, Tim Park, Steve Young, Ferdie Soriano, Aimee Rieger, Ulrike Schindler, Joyson Karakunnel, Matt J. Walters. Pharmacokinetic-pharmacodynamic relationship for AB928, a dual antagonist of the A2aR and A2bR adenosine receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3769.