Abstract 4854
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, <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 AB928 PK 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.
Editorial acknowledgement
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.
Resources from the same session
5650 - Tissue-based activation of mucosal-associated invariant T (MAIT) cells in combination ipilimumab and nivolumab checkpoint inhibitor (CI) colitis.
Presenter: Sarah Sasson
Session: Poster Display session 3
Resources:
Abstract
5944 - Significance of severe immune-related adverse effects (irAE) on patients with advanced tumors treated with immune checkpoint inhibitors being admitted for secondary toxicity: Clinical relevance and next steps
Presenter: Leyre Zubiri
Session: Poster Display session 3
Resources:
Abstract
5989 - Implementation of a dedicated immuno-oncology toxicity service reduces the acute impact of immune-related adverse events
Presenter: Anna Olsson-Brown
Session: Poster Display session 3
Resources:
Abstract
3267 - Cardiotoxic and pro-inflammatory effects induced by the association of immune checkpoint inhibitor Pembrolizumab and Trastuzumab in preclinical models
Presenter: Nicola Maurea
Session: Poster Display session 3
Resources:
Abstract
3417 - Interstitial lung disease associated with immune-checkpoint inhibitors in malignant diseases
Presenter: Akira Yamagata
Session: Poster Display session 3
Resources:
Abstract
2071 - A Phase 1 Study of Intraperitoneal MCY-M11 Anti-Mesothelin CAR for Women with Platinum Resistant High Grade Serous Adenocarcinoma of the Ovary, Primary Peritoneum, or Fallopian Tube, or Subjects with Peritoneal Mesothelioma with Recurrence after Prior Chemotherapy
Presenter: Christina Annunziata
Session: Poster Display session 3
Resources:
Abstract
4935 - Trial in progress: First-in-human study of a novel anti-NY-ESO-1–anti-CD3, TCR-based bispecific (IMCnyeso) as monotherapy in NY-ESO-1/LAGE-1A-positive advanced solid tumors (IMCnyeso-101)
Presenter: Juanita Lopez
Session: Poster Display session 3
Resources:
Abstract
5613 - Nimotuzumab-Cisplatin-Radiation versus Cisplatin-Radiation in HPV negative oropharyngeal cancer
Presenter: Kumar Prabhash
Session: Poster Display session 3
Resources:
Abstract
2576 - Interim analysis of a single arm phase 2 study of adjuvant nivolumab after salvage resection in head and neck squamous cell carcinoma patients previously treated with definitive therapy.
Presenter: Trisha Wise-draper
Session: Poster Display session 3
Resources:
Abstract
4758 - A Phase I Study of the CDK4/6 Inhibitor, Palbociclib in combination with Cetuximab and Intensity Modulated Radiation Therapy (IMRT) for Locally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN); A Result of Dose Escalation Cohort
Presenter: Nuttapong Ngamphaiboon
Session: Poster Display session 3
Resources:
Abstract