ADPORT-601: First-in-human study of adenosine 2A (A2A) and adenosine 2B (A2B) receptor antagonists in patients with select advanced solid tumors.
Authors: Fong Lawrence , Salkeni Mohamad Adham , El-Khoueiry Anthony B. , Grewal Jaspreet Singh , Tester William J , Pachynski Russell Kent , Frigo Daniel , Panaretakis Theocharis , Pastore Desa Rae Electa , Kramer Robert A. , Green George , Fairchild Justin P. , Walters Ian B. , Falchook Gerald Steven , Subudhi Sumit Kumar 
Published: June 2024

e14681

Background: Hypoxic tumors possess high levels of extracellular adenosine within the tumor microenvironment (TME) which suppresses both innate and adaptive immune responses by binding the adenosine receptors A2AR and A2BR. TT-10 (PORT-6) and TT-4 (PORT-7) are potent and selective antagonists of A2AR and A2BR, respectively. Both agents have shown monotherapy activity in both non-immunogenic (4T-1) and immunogenic (CT-26) tumor mouse models. Optimizing inhibition of A2AR and A2BR separately and in combination provides an opportunity to dissect the role of each signaling pathway within the TME. Methods: ADPORT-601 is a multi-center, open-label Phase 1 study, evaluating the safety, efficacy, PK and pharmacodynamics of PORT-6 in participants with mCRPC, RCC, or other selected solid tumors which are refractory to standard therapy. A subsequent arm will similarly test PORT-7 in participants with selected solid tumors. The Phase 1a cohorts utilize a standard 3+3 design. Phase 1b will be initiated once recommended doses have been established and will consist of monotherapy expansion cohorts for each drug, as well as both drugs combined at the optimal doses, and with other immunotherapy agents. A novel IHC-based assay will be implemented to select for patients with high A2AR expression. Metabolomic and gene expression profiling were performed on previously acquired bone biopsy and blood samples, respectively, to characterize the role of adenosine in CRPC. Results: 10 patients with mCRPC (n=6), RCC (n=3) or NSCLC (n=1) have been enrolled at escalating doses. Treatment-related AEs have been G1-2, with fatigue (29%), nausea (29%) and vomiting (14%) being the most reported. No related SAEs or dose limiting toxicities (DLTs) have been observed. Higher adenosine precursor metabolite (e.g., AMP, ADP, ATP, ADPR, inosine) levels were observed in image-guide bone metastatic lesions relative to non-tumor bearing bone controls (P<0.05; n=10/group). A2AR and A2BR mRNA levels were enriched (1.3 and 1.4 log2 fold change, p<0.05, respectively) in the plasma of mCRPC patients compared to those with localized disease. Updated safety, efficacy, PK and adenosine expression data will be reported at the meeting. Conclusions: PORT-6 is well tolerated to date. The TME within mCRPC bone metastases provides a unique target for A2AR and A2BR antagonism. Longitudinal blood and tissue samples, including bone biopsies, are being collected to enable biomarker analyses, allowing for elucidation of the relative contribution of A2AR and A2BR in suppressing anti-tumor immunity. Multi-omic translational analyses of tissue are planned to determine whether potent adenosine receptor antagonism will have an anti-tumor effect and convert the TME from immunosuppressive to proinflammatory. Clinical trial information: NCT04969315 .