Phase 1/2 Trial of ASP1570, a Novel Diacylglycerol Kinase ζ Inhibitor, in Patients With Advanced Solid Tumors
Publication Title
ESMO
Document Type
Abstract
Publication Date
9-2024
Keywords
oregon; chiles
Abstract
Background
Inhibiting diacylglycerol kinase (DGK)ζ has the potential to enhance antitumor immunity. ASP1570, a novel small molecule DGKζ inhibitor, enhanced human T cell activation in vitro and released anergic T cells from their hyporesponsive state. Furthermore, ASP1570 restored T cell functions suppressed by PD-1 and multiple immunosuppressive signals. Here we describe results from ASP1570 first-in-human oral monotherapy in patients with advanced solid tumors.Methods
In this phase 1/2, multicenter, open-label study, patients with locally advanced or metastatic solid tumors who had progressed or were no longer eligible to receive standard therapy were included. During dose escalation, cohorts (n≥3) received escalating doses of ASP1570 10–75 mg orally once or twice daily over a 21-day cycle. The primary endpoint was safety; secondary endpoints were efficacy, pharmacokinetics (PK), and biomarker analysis. Blood and tumor biopsies were used for exploratory biomarker studies.Results
Data cutoff was 31 March 2024. A total of 43 patients (median age 61.0 yrs; 55.8% male) received ≥1 dose of ASP1570 during the dose escalation portion of this study. Dose-dependent increases in inflammatory cytokines and activated peripheral CD8 and NK cells were observed. Limited tumor biopsy data (n=8) showed trends in the tumor microenvironment, aligning with ASP1570’s proposed MOA. PK exposure increased proportionally across examined doses. Treatment-related adverse events (TRAEs) occurred in 35/43 patients (81.4%; grade 3 18.6%; no grade 4 or 5 events). The most common TRAEs were diarrhea (48.8%), nausea (34.9%), and rash (25.6%), with most being grade 1 and reversible with minimal or no medical intervention. Serious TRAEs occurred in 4 patients (9.3%) and 3 patients (7.0%) discontinued treatment due to TRAEs. Dose-limiting toxicities occurred in 4 patients. Among efficacy-evaluable patients, confirmed disease control rate per immune-based RECIST was 50.0% (12/24), including 1 patient with confirmed partial response.Conclusions
ASP1570 monotherapy had an acceptable safety profile and showed early signs of clinical activity, supporting further evaluation in patients with advanced solid tumors.Area of Special Interest
Cancer
Specialty/Research Institute
Oncology
DOI
10.1016/j.annonc.2024.08.1063
Comments
D. Olson1 ∙ A. Dowlati2 ∙ J.J. Luke3 ∙ M. Mckean4 ∙ T. Yoshida5 ∙ D. Park6 ∙ S. Kitano7 ∙ M. Barve8 ∙ Y. Kaneko9 ∙ G. Koelsch10 ∙ S. Soukharev9 ∙ S. Takeshita11 ∙ N. Alsharif9 ∙ N. Hashemi9 ∙ M.R. Patel12