On April 17, 2018 Arcus Biosciences, Inc. (NYSE:RCUS), a clinical-stage biopharmaceutical company focused on creating innovative cancer immunotherapies, reported that it will present data today from its Phase 1 trial for AB928, its dual adenosine receptor antagonist, in healthy volunteers in a poster presentation titled "Clinical Pharmacokinetic-Pharmacodynamic Relationship for AB928, a Dual Antagonist of the A2aR and A2bR Adenosine Receptors," at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago, Illinois (Press release, Arcus Biosciences, APR 17, 2018, View Source [SID1234525418]).

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"We are extremely encouraged by the results from our ongoing Phase 1 trial of AB928. The compound has been shown to be safe and well tolerated at all doses evaluated and achieves near complete inhibition of A2aR adenosine receptor activation in blood samples from healthy volunteers," said Terry Rosen, Ph.D., Chief Executive Officer at Arcus. "Importantly, we achieved this level of inhibition under conditions that we believe are representative of the large concentrations of adenosine found in the tumor microenvironment. These results have informed the selection of the starting dose for our clinical trials of AB928 in combination with other anti-cancer agents, and we look forward to starting these trials shortly."

Design of the Phase 1 Trial for AB928 in Healthy Volunteers
The Phase 1 double-blinded, placebo-controlled trial has enrolled 85 healthy volunteers. The trial includes a single-ascending-dose (SAD) portion as well as a multiple-ascending-dose (MAD) portion. In the SAD portion, single doses of 10, 25, 75 and 150 mg and a twice-daily dose of 100 mg have been evaluated. In the MAD portion, doses of 10, 25, 75 and 150 mg QD and 200 mg QD (with food) have been administered to subjects for four consecutive days. In each dosing cohort, 6 subjects received AB928 and 2 subjects received placebo, and dosing in the trial has been completed. Investigators remain blinded regarding subject assignment to the AB928 or placebo arms.
The objective of this trial is to assess the safety, tolerability, pharmacokinetics and pharmacodynamic profile of AB928 and to inform our selection of the starting dose of AB928 for our combination trials in cancer patients.

Summary of the Results Presented
All doses have been safe and well tolerated, and no safety events prevented escalation to higher doses. To assess the pharmacodynamic effects of AB928, blood samples were taken from subjects at different time points following the administration of AB928 or placebo. As of the cut-off date (COD) of March 30, 2018 for the poster presentation, samples from all dosing cohorts, with the exception of the 200 mg QD (with food) MAD cohort, have been evaluated to assess the pharmacodynamic effects of AB928. These samples were treated with NECA (a synthetic analogue of adenosine), which activates A2aR receptors on T cells. The ability of AB928 to block A2aR receptors on T cells was quantified by measuring the levels of pCREB, which is a marker for activation of the A2aR receptor.
When blood samples from the 150 mg MAD cohort were incubated with 5 µM NECA, AB928 achieved complete inhibition of pCREB activation at two hours post-dosing and approximately 90% mean inhibition of pCREB activation at 24 hours post-dosing on day 4. As experiments conducted in vitro by Arcus have demonstrated that NECA is at least 20 times more potent than adenosine at inducing pCREB activation in blood T cells, stimulation with 5 µM NECA should be comparable to stimulation with adenosine concentrations in excess of 100 µM.
The pharmacokinetic profile of AB928 supports once-daily dosing, with a plasma half-life that exceeds 20 hours.
Complete results from this trial, including pharmacodynamic data for the 200 mg BID (with food) dosing cohort, will be released following the unblinding of data in mid-2018.

AB928 Clinical Development Plans
The results from this healthy volunteer trial demonstrate that a safe and well tolerated dose of AB928 can provide near complete inhibition of A2aR receptor activation. Based on these results, Arcus is preparing to initiate clinical trials to evaluate AB928 in combination with three different chemotherapy regimens and in combination with AB122, its PD-1 antibody, in cancer patients. Regulatory submissions to start these trials are underway.
These trials will include a dose-escalation portion to identify the recommended dose of AB928 for each combination regimen. Based on the safety profile of AB928, the initial dose of AB928 for the dose-escalation portion should achieve close to complete inhibition of A2aR receptor activation. Once the recommended dose has been selected, AB928 will be evaluated in 11 expansion cohorts. Each expansion cohort will evaluate the AB928 + chemotherapy combination and/or the AB928 + AB122 combination in one of the following tumor types: non-small cell lung cancer, renal cell carcinoma, gastroesophageal cancer, colorectal cancer, ovarian cancer and triple negative breast cancer. In both the dose escalation portion and expansion cohorts, Arcus will conduct significant biomarker analysis, which will inform patient selection in future trials. Arcus plans to report data from the dose-escalation portion of these trials in the first half of 2019