#754 A PHASE 1/2 STUDY OF ASP1570 IN PARTICIPANTS WITH LOCALLY ADVANCED OR METASTATIC SOLID TUMORS WHO HAVE PROGRESSED ON, OR ARE INELIGIBLE FOR, ALL AVAILABLE STANDARD THERAPIES
Publication Title
J Immunother Cancer
Document Type
Abstract
Publication Date
2022
Keywords
california; psjmc
Abstract
Background Cancer immunotherapies target immune checkpoints and have been transformative in the treatment practices of oncology. However, only a subset of all patients in most cancer types effectively respond to these therapies. It has been established that approximately 60% to 70% of patients who receive anti–programmed cell death protein-1 (anti–PD-1) or anti-cytotoxic T-lymphocyte–associated antigen 4 (CTLA4) do not respond to treatment.1 Furthermore, acquired resistance is common, causing some patients who initially responded to the therapy to later experience disease progression. Therefore, there is a significant opportunity for immunotherapy expansion in cancer treatment. Diacylglycerol kinase (DGK) is a large enzyme family of 10 mammalian isoenzymes that catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). In T cells, DGK (such as DGKz) inhibits DAG-mediated signals following T-cell receptor engagement by catalyzing the conversion of DAG to PA.2 Even when PD-1 is blocked by anti–PD-1 antibodies, there may be partial inactivation by DGK. Therefore, DGK inhibitors have the potential to enhance DAG downstream signaling, leading to T-cell activation regardless of the PD-1 signal. ASP1570 is a novel inhibitor against DGKz and has the potential to enhance DAG downstream signaling which can activate T cells regardless of PD-1 signaling and lead to tumor killing. ASP1570 restored T-cell functions suppressed by multiple immunosuppressive signals (PD-1, transforming growth factor beta, prostaglandin E2, and adenosine) and induced tumor growth inhibition in mice models of MC38 (anti-PD1 sensitive) and B16-F1 (tumor-infiltrating lymphocyte poor, anti–PD1 insensitive). Taken together, ASP1570 treatment as a single agent and/or in combination with anti–PD-1 therapy for locally advanced or metastatic solid tumors may result in clinical benefit. Methods This is a phase 1/2, open-label, multicenter, multipledose, dose-escalation/expansion study of ASP1570 in participants with locally advanced or metastatic solid tumors. The study will enroll approximately 168 participants into 2 phases, dose escalation and dose expansion, to assess safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamics (figure 1). The study will consist of the following periods: screening, treatment with ASP1570 daily oral dosing in 21-day cycles, end of treatment, follow-up (safety and survival follow-up), and end of study (figure 2). The study is open for enrollment. Acknowledgements We thank the patients, investigators, and study teams for being involved in this study. Editorial support was provided by OPEN Health and funded by Astellas Pharma, Inc. This study is funded by Astellas Pharma, Inc. Trial Registration NCT05083481
Clinical Institute
Cancer
Specialty/Research Institute
Oncology
Comments
Manish Patel*, 2 David Park, 3 Stefano Tarantolo, 4 Afshin Dowlati, 5 Daniel Olson, 6 Yuichiro Kaneko, 7 Mei Tang, 7 Serguei Soukharev, 6 Masaomi Takizawa, 6 Yohei Okada, 7 Christine Fredericks, 7 Derek Smith, 7 Teresa Flegel, 7 Tsubasa Watanabe, 7 Sue Lee, 8 Jason Luke. 1 Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL, USA; 2 St Jude Crosson Cancer Institute, Fullerton, CA, USA; 3 Midwest Cancer Center, Omaha, NE, USA; 4 University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, OH, USA; 5 University of Chicago Comprehensive Cancer Center, Chicago, IL, USA; 6 Astellas Pharma, Inc., Northbrook, IL, USA; 7 Astellas Pharma Global Development, Inc., Northbrook, IL, USA; 8 UPMC Hillman Cancer Center, Pittsburgh, PA, USA