1004P - Phase I/II trial of ASP1570, a novel diacylglycerol kinase ζ inhibitor, in patients with advanced solid tumors

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.

Clinical trial identification

NCT05083481.

Editorial acknowledgement

Medical writing support was provided by Shawna Matthews, PhD, CMPP, of Oxford PharmaGenesis Inc.

Legal entity responsible for the study

Astellas Pharma Inc.

Funding

Astellas Pharma Inc.

Disclosure

D. Olson: Financial Interests, Personal, Advisory Board: Novartis, Alphasights, GLG Consulting, Iovance, Obsidian Therapeutics; Financial Interests, Institutional, Local PI: Takeda, Astellas, Inhibrix; Financial Interests, Institutional, Coordinating PI: Immunocore; Non-Financial Interests, Principal Investigator: CTRL Therapeutics. A. Dowlati: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Merck, Ipsen, Amgen, Seattle Genetics, AbbVie, Bristol Myers Squibb. J.J. Luke: Financial Interests, Personal, Stocks/Shares: Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI; Financial Interests, Personal, Advisory Board: AbbVie, Immutep, Evaxion; Financial Interests, Personal, Speaker, Consultant, Advisor: Eisai, EMD Serono, Day One. M. Mckean: Financial Interests, Institutional, Other, Consulting: Pfizer, Castle Biosciences, IQVIA, Merck, Moderna; Financial Interests, Institutional, Research Grant: Acentage Pharma Group, Bicycle Therapeutics, Dragonfly Therapeutics, Epizyme, Exelixis, Genentech, GSK, Ideaya Biosciences, Ikena Oncology, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Moderna, NBE Therapeutics, Novartis, Oncorus, Plexxicon, Prelude Therapeutics, Regeneron, Sapience Therapeutics, Seattle Genetics, Tizona Therpeutics, Tmunity Therapeutics, TopAlliance Biosciences, Aadi Biosciences, Alpine Immune Sciences, Arcs Biosciences, Arvinas, ASCO, Astellas, Bayer, BioMed Valley Discoveries, BioNTech, C4 Therapeutics, EMD Serono, Erasca, Foghorn Therapeutics, G1 Therapeutics, Gilead Sciences, ImmVira Pharma, Kechow Pharma, Kezar Life Sciences, Kinnate BioPharma, MedImmune, Mereo BioPharma, Metabomed, Nektar, OncoC4, PACT Pharma, Pfizer, Poseida, Pyramid Biosciences, Scholar Rock, Synthrox, Takeda Pharmaceuticals, Teneobio, Tempest Therapeutics, Xilio, Aulos Bioscienc, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, InconVir, Jazz Pharmaceutical, Krystal Biotech, NucMito Pharmaceuticals, OnKure, Remix Therapeutics. T. Yoshida: Financial Interests, Personal, Advisory Board: Pfizer, MSD, Amgen; Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai pharmaceutical, Pfizer, Takeda, Lilly, Ono Pharmaceutical, Novartis, Daiichi Sankyo, MSD, BMS; Financial Interests, Institutional, Local PI: AstraZeneca, Novartis, Amgen, Daiichi Sankyo, BMS, MSD, Ono Pharmaceutical, BluePrint, Chugai pharmaceutical, AbbVie. S. Kitano: Financial Interests, Personal, Advisory Board, Scientific Advisor: ImmuniT Research, United Immunity, Sumitomo Pharma; Financial Interests, Personal, Advisory Board, Scientific advisor: Rakuten Medical; Financial Interests, Personal, Other, lecture fee: AstraZeneca; Financial Interests, Personal, Other, Lecture fee: Pfizer, Taiho, Novartis, MSD, Eisai, Bristol Myers Squibb, GSK, Chugai, Takeda, Janssen, Merck KgaA; Financial Interests, Personal, Other, Scientific adviser, Lecture fee: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: PMDA (Pharmaceuticals and Medical Devices Agency); Financial Interests, Personal and Institutional, Local PI, Clinical Trial, Research Grant: Daiichi Sankyo; Financial Interests, Personal and Institutional, Local PI, Clinical Trial: AstraZeneca, Pfizer, MSD, Eisai, Incyte, Takeda, Eli Lilly Japan K.K., Loxo Oncology, AbbVie; Financial Interests, Personal and Institutional, Local PI, Clinical trial, Research Grant: Nippon Boehringer Ingelheim; Financial Interests, Personal and Institutional, Local PI, Clinical trial: Astellas; Financial Interests, Personal and Institutional, Coordinating PI, Clinical trial, Research Grant: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal and Institutional, Local PI, Clinical trial: GSK; Financial Interests, Personal and Institutional, Local PI, Clinical Trial, Research Grant: Chugai; Financial Interests, Personal and Institutional, Research Grant: Takara Bio Inc. M. Barve: Financial Interests, Personal, Speaker, Consultant, Advisor: TEMPUS Labs, I-Mab; Financial Interests, Personal, Stocks/Shares: Texas Oncology. Y. Kaneko: Financial Interests, Personal, Other: Fortrea. G. Koelsch: Financial Interests, Personal, Full or part-time Employment: Astellas Pharma Global Development, Inc. S. Soukharev, S. Takeshita, N. Alsharif, N. Hashemi: Financial Interests, Personal, Full or part-time Employment: Astellas. M.R. Patel: Financial Interests, Personal, Advisory Board, Financial interest: Daiichi, Janssen, Accutar, Olema, Mitsubishi, Kura, Nurix; Financial Interests, Personal, Advisory Board, Financial Interest: ION; Financial Interests, Institutional, Local PI, institution received research funding: Daiichi. All other authors have declared no conflicts of interest.