Abstract CT026: Evidence of immune activation in the first-in-human Phase Ia dose escalation study of the adenosine 2a receptor antagonist, AZD4635, in patients with advanced solid tumors
Authors: Bendell Johanna , Bauer Todd , Patel Manish , Falchook Gerald , Karlix Janet L. , Lim Emerson , Mugundu Ganesh , Mitchell Patrick D. , Pouliot Gayle P. , Moorthy Ganesh , Linghu Bolan , McGrath Lara , Harrop Bryony , Shao Wenlin , Drake Charles G. , Sachsenmeier Kris , Merchant Melinda S. 
Published: August 2019

Extracellular adenosine signals through the Adenosine 2a Receptor (A2aR) leading to immunosuppression, in part though decreased antigen presentation and decreased effector T cells. AZD4635 inhibits A2aR signaling and leads to improved immune activation and anti-tumor activity in preclinical models. This multicenter Phase I clinical trial (NCT02740985) assessed the safety, PK, pharmacodynamic, and preliminary clinical activity of AZD4635 as monotherapy (125mg BID, 75mg QD, 100mg QD) and in combination (75 or 100mg QD) with durvalumab @ 1.5g IV q4 wk in subjects with refractory solid tumors. Peripheral blood was analyzed for pharmacokinetics. Isolated blood mononuclear cells and tumor biopsies were analyzed by Nanostring technology and TCR sequencing. Thirty-eight adult subjects with advanced malignancies were treated with AZD4635 monotherapy (n=15) or in combination with durvalumab (n=23). All subjects had at least 1 prior regimen (median 3). The maximum tolerated dose (MTD) of AZD4635 was identified as 100 mg PO daily both as monotherapy and with durvalumab. The mean plasma concentration of AZD4635 at the MTD was above the in vitro IC50 for A2aR inhibition over the dosing interval. Most common adverse events (&gt;15%) attributed to the investigational treatment included Grade 1-2 nausea, fatigue, vomiting, and dizziness. Two dose limiting toxicities (DLT; Gr3 Nausea and Gr2 abdominal pain) were noted at 125mg BID dose and one DLT (Gr2 nausea + Gr2 fatigue requiring dose reduction in week 2) occurred in a subject dosed with 75 mg QD in combination with durvalumab. Three confirmed responses were observed in 8 RECIST evaluable subjects with metastatic castration resistant metastatic prostate cancer (mCRPC) treated with monotherapy AZD4635 (1 PR) or combination with durvalumab (1CR + 1PR). In addition, a durable PSA decrease &gt;99% was observed on AZD4635 monotherapy in 1 of 4 RECIST non-evaluable mCRPC subjects. As of the data cut off (4Oct18), these subjects had 11-16 months of treatment. Other tumor types in subjects with SD for &gt; 6 months of therapy included head & neck, bladder, GI cancers and sarcoma. Biomarker data from blood and tumor samples revealed increased gene expression consistent with dendritic cell activation, antigen presentation and cytotoxic T cell activation. TCR analysis showed changes in T cell repertoire following AZD4635 therapy. AZD4635, an oral antagonist of A2aR, was well tolerated at 100mg daily in patients with refractory solid tumors as both monotherapy and in combination with durvalumab. As in preclinical studies, evaluation of gene expression revealed post-treatment increases in antigen presentation as well as evidence of both innate and adaptive immune activity. Durable responses were seen in patients with mCRPC, Further evaluation is ongoing in both immune checkpoint naïve and refractory patients.

Citation Format: Johanna Bendell, Todd Bauer, Manish Patel, Gerald Falchook, Janet L. Karlix, Emerson Lim, Ganesh Mugundu, Patrick D. Mitchell, Gayle P. Pouliot, Ganesh Moorthy, Bolan Linghu, Lara McGrath, Bryony Harrop, Wenlin Shao, Charles G. Drake, Kris Sachsenmeier, Melinda S. Merchant. Evidence of immune activation in the first-in-human Phase Ia dose escalation study of the adenosine 2a receptor antagonist, AZD4635, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT026.