Abstract CT132: Trial in progress: A phase 1/2 study of ASP1570, a novel inhibitor of DGKζ, in participants with locally advanced or metastatic solid tumors who have progressed on, or are ineligible for, all available standard therapies

• Published in: Cancer research (Chicago, Ill.) Ill.), 2023-04, Vol.83 (8_Supplement), p.CT132-CT132
• Main Authors: Patel, Manish R., Park, David J., Tarantolo, Stefano, Dowlati, Afshin, Olson, Daniel, Kaneko, Yuichiro, Tang, Mei, Soukharev, Serguei, Takizawa, Masaomi, Okada, Yohei, Fredericks, Christine, Flegel, Teresa, Watanabe, Tsubasa, Lee, Sue, Luke, Jason John
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2023-CT132

Background: Checkpoint inhibitors 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 and acquired resistance is common, causing some patients who initially respond to experience disease progression. Thus, there is a significant opportunity for immunotherapy expansion in cancer treatment. Diacylglycerol kinase (DGK) is a large family of mammalian isoenzymes that catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid. Even when PD-1 is blocked by anti-PD-1 antibodies, there may be partial inactivation of T cells by DGK. ASP1570 is a novel inhibitor against DGKζ 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 and induced tumor growth inhibition in mice models of MC38 (anti-PD-1 sensitive) and B16-F1 (tumor-infiltrating lymphocyte [TIL] poor, anti-PD-1 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 provide clinical benefit. Methods: This is a phase 1/2, open-label, multicenter, multiple-dose, 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. Part 1 consists of dose escalation cohorts of 3-12 patients receiving oral administration of ASP1570 in 21-day cycles; 8 total cohorts are planned with doses of 10, 25, 50, 75, 100, 150, and 200 mg administered daily with the final cohort receiving 100 mg administered twice daily. Part 2 consists of ~20 participants per cohort in a two-stage evaluation of safety and efficacy at the recommended phase 2 dose and cohort expansion of an additional ~20 participants each based on expansion criteria. Cohorts are designated for NSCLC and melanoma but may be expanded based on response in other tumor types. Primary endpoints will assess safety and tolerability through dose-limiting toxicities, adverse events, changes in laboratory tests, electrocardiogram results, and vitals. Secondary endpoints will assess efficacy through overall response rate, duration of response, and disease control rate per iRECIST and RECIST v1.1, pharmacokinetics, and influence on TILs. Study periods will consist of s