Abstract P042: Phase I/II first-in-human study of TT-10 (A2AB inhibitor) as a single agent in subjects with advanced selected solid tumors
Authors: Kumar Sushant , Mookhtiar Kasim , Pastore Desa Rae , Schwartz Brian , Reddy Vijay 
Published: December 2021

Abstract
Immunotherapy has emerged as a potent tool for cancer treatment by activating the immune system to recognize and attack cancer cells. Immune checkpoint blockage has shown notable clinical success in several malignancies such as advanced non-small cell lung cancer, melanoma, advanced kidney cancer and several other indications, as demonstrated with the approval of CTLA-4 and PD-1/PD-L1 checkpoint inhibitors. However, the efficacy of checkpoint inhibitors to date is limited to only a subset of patients, even within the same cancer type. Thus, the continued focus in the cancer immunotherapy field is to identify new immunosuppressive pathways that allow cancer cells to evade immune surveillance. One emerging pathway of interest is the purinergic pathway, in which adenosine is recognized as a key metabolic checkpoint, and high levels of extracellular adenosine have been evidenced to mediate profound tumor resistance. In this first-in-human Phase I/II study, we explore selective inhibition of the adenosine A2A receptor (A2AR) with TT-10, an oral immune-oncology agent, as a treatment option for subjects with select solid tumors. TT-10 is being evaluated as a single agent, in an open-label, non-randomized, multicenter, dose-escalation (phase 1) and dose-expansion (phase 2) study in subjects with renal cell cancer (RCC), castrate resistant prostate cancer (CRPC) and non-small cell lung cancer (NSCLC) (NCT# NCT04969315). Phase 1 (Cohort A) will explore ascending doses of TT-10, taken orally (10, 20, 50, 100, 200 mg, BID), utilizing a 3+3 design in 28-day cycles to identify the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (R2PD). Enrollment will be open to all three indications. Phase 2 will begin once RP2D is determined and will enroll up to 60 subjects, with approximately 15 subjects per cohort (B.) RCC, (C.) CRPC, (D.) NSCLC (E.) Exploratory Tumor Biopsy). The primary objectives of this study are to evaluate the safety, tolerability, and MTD or the RP2D of TT-10 monotherapy. Secondary objectives are to obtain a preliminary estimate of efficacy, evaluate PK and anti-tumor activity of TT-10 monotherapy, with exploratory objectives inclusive of identification of candidate biomarkers and biomarkers that might predict response, as well as, exploring if adenosine signature and/or receptor expression in tumor tissue at baseline might predict response. Subjects must have locally advanced, recurrent or metastatic neoplastic disease that is not curable by currently available, failure to respond to standard therapy or for whom no appropriate therapies are available, and have a life expectancy of ≥ 3 months to be eligible for the trail. Select subjects that would like to participate in Cohort E.) Exploratory Tumor Biopsy must have an accessible tumor for pre and post dose biopsies. Enrollment of phase 1 is expected to start October 2021.
Citation Format: Sushant Kumar, Kasim Mookhtiar, Desa Rae Pastore, Brian Schwartz, Vijay Reddy. Phase I/II first-in-human study of TT-10 (A2AB inhibitor) as a single agent in subjects with advanced selected solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P042.