Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

4822 - Final results of the Phase 1 study in healthy volunteers of AB928, a dual antagonist of the A2aR and A2bR adenosine receptors being studied as an activator of anti-tumor immune response.

Date

20 Oct 2018

Session

Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

Presenters

Lisa Seitz

Citation

Annals of Oncology (2018) 29 (suppl_8): viii649-viii669. 10.1093/annonc/mdy303

Authors

L.C. Seitz1, D. Ashok1, M. Leleti2, J. Powers2, B. Rosen2, D. Miles2, E. Sharif2, L. Jin3, A. Park1, S. Young1, A. Rieger4, U. Schindler5, J. Karakunnel4, M. Walters5

Author affiliations

  • 1 Quantitative Biology, Arcus Biosciences, Inc., 94545 - Hayward/US
  • 2 Chemistry, Arcus Biosciences, Inc., 94545 - Hayward/US
  • 3 Pharmacokinetics And Drug Metabolism, Arcus Biosciences, Inc., 94545 - Hayward/US
  • 4 Clinical Development, Arcus Biosciences, Inc., 94545 - Hayward/US
  • 5 Biology, Arcus Biosciences, Inc., 94545 - Hayward/US
More

Resources

Abstract 4822

Background

Adenosine suppresses anti-tumor immune responses via A2aR and A2bR receptors on intra-tumoral immune cells. This effect is mediated by increased cAMP levels and phosphorylation of the transcription factor CREB. A placebo-controlled study in healthy volunteers was conducted to assess the safety, tolerability and PK/PD (pCREB levels in blood T cells) profile of AB928, in order to select AB928 doses for the ongoing studies in cancer patients.

Methods

This placebo-controlled double-blind study had single ascending dose (SAD) and multiple ascending dose (MAD) arms. AB928 doses between 10 and 200 mg qd and 100 mg bid were evaluated. Whole blood from AB928 and placebo-treated subjects was stimulated ex vivo with the adenosine agonist NECA. Flow cytometry was used to assess levels of pCREB. AB928 plasma concentrations were determined using LC-MS-MS.

Results

The study enrolled 85 participants (randomized 3:1, active:placebo), 40 each in the SAD and MAD arms, plus 5 in a food-effect assessment cohort. The effects of 1, 5 and 10 mM NECA were assessed in whole-blood samples obtained at various time points post-dose. The PD response at each timepoint was correlated with the associated AB928 plasma levels. In all dose groups, significant inhibition at peak plasma concentrations was observed. Significant inhibition was also observed 24 hours post-dose in the higher dose groups. Final unblinded safety and PK/PD results from this study will be presented.

Conclusions

AB928 was well tolerated in this study. No stopping rules were met and dose escalation continued until maximal PD effects were observed. There was no evidence of the physiological effects associated with other adenosine receptor antagonists tested in humans. The MTD was not reached in this study. Significant inhibition of A2aR-mediated CREB phosphorylation in blood T cells was observed in all dose groups at peak plasma concentrations, as well as at trough in the higher dose groups. The resulting PK/PD correlations were used to guide dose selection in several ongoing oncology studies, the outlines of which will be described in this presentation.

Clinical trial identification

EudraCT: 2017-002943-14.

Legal entity responsible for the study

Arcus Biosciences, Inc.

Funding

Arcus Biosciences, Inc.

Editorial Acknowledgement

Disclosure

L.C. Seitz, D. Ashok, M. Leleti, J. Powers, B. Rosen, D. Miles, E. Sharif, L. Jin, A. Park, S. Young, A. Rieger, U. Schindler, J. Karakunnel, M. Walters: Employee and stock owner: Arcus.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.