ASP1570 / Astellas - LARVOL DELTA

Enhanced Antitumor Immunity by ASP1570, a Novel Diacylglycerol Kinase Zeta Inhibitor, Offers a Potential Novel Immunotherapy for Treating Cancer. (PubMed, Mol Cancer Ther) - P1/2 | "The antitumor efficacy of ASP1570 was cancelled by CD8+ T-cell depletion, indicating that its antitumor effect depends on CD8+ cytotoxic T-cell activation. Collectively, ASP1570 potentially improves antitumor efficacy in both anti-PD-1-therapy-resistant and anti-PD-1-therapy-responsive tumors by overcoming multiple immunosuppressive signals."

Journal • Oncology • CD8 • CTLA4 • DGKZ • TGFB1 • TIGIT

KEYNOTE-E59: A Study of ASP1570 Alone or in Combination With Pembrolizumab or Standard Therapies in Adults With Solid Tumors (clinicaltrials.gov) - P1/2 | N=310 | Recruiting | Sponsor: Astellas Pharma Global Development, Inc. | Trial completion date: Dec 2027 ➔ May 2028 | Trial primary completion date: Dec 2027 ➔ May 2028

Monotherapy • Trial completion date • Trial primary completion date • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • NTRK

Astellas Presents Scientific Progress in Advanced and Hard-to-Treat Cancers at ESMO 2024 (Astellas Press Release) - "Astellas Pharma Inc...will highlight new data from across its approved and investigational cancer therapies during the 2024 European Society for Medical Oncology (ESMO) Congress being held in Barcelona, Spain on 13-17 September. Eight abstracts across a broad range of cancer types will be presented, reinforcing Astellas' commitment to making a meaningful difference to people living with advanced and hard-to-treat cancers. Six abstracts include data spanning prostate, urothelial, gastric and gastroesophageal junction (GEJ), and pancreatic cancers. Two abstracts feature Phase 1 data presented for the first time from immuno-oncology and targeted protein degradation assets."

Clinical data • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Non Small Cell Lung Cancer • Pancreatic Cancer • Prostate Cancer • Urothelial Cancer

Phase I/II trial of ASP1570, a novel diacylglycerol kinase ζ inhibitor, in patients with advanced solid tumors (ESMO 2024) - P1/2 | "ASP1570 monotherapy had an acceptable safety profile and showed early signs of clinical activity, supporting further evaluation in patients with advanced solid tumors."

Clinical • IO biomarker • Metastases • P1/2 data • Oncology • Solid Tumor • CD8 • PD-1

KEYNOTE-E59: A Study of ASP1570 Taken by Itself or With Pembrolizumab in Adults With Solid Tumors (clinicaltrials.gov) - P1/2 | N=330 | Recruiting | Sponsor: Astellas Pharma Global Development, Inc. | Trial completion date: Apr 2027 ➔ Dec 2027 | Trial primary completion date: Apr 2027 ➔ Dec 2027

Combination therapy • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • NTRK

The diacylglycerol kinase ζ inhibitor ASP1570 augments natural killer cell function. (PubMed, Int Immunopharmacol) - "Accordingly, ASP1570 treatment enhanced IFNγ production and degranulation of immunoreceptor-activated NK cells in vitro and NK cell-mediated tumor clearance in vivo. Thus, ASP1570 enhances both T and NK cell function, which could possibly induce more durable anti-tumor responses for immunotherapy."

Journal • Oncology • CTLA4 • IFNG

Enhanced antitumor immunity by ASP1570 in mouse models: A novel DGKζ inhibitor offers a potential immunotherapy for treating cancer. (AACR-NCI-EORTC 2023) - No abstract available

Preclinical • Oncology

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 (AACR 2023) - "Study periods will consist of screening, treatment with ASP1570 oral dosing in 21-day cycles, end of treatment, follow-up (safety: 45 days after last dose and every 9 weeks thereafter and survival follow-up every 12 weeks), and end of study. The study is actively recruiting and has enrolled 13 participants as of January 2023."

Metastases • P1/2 data • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Manipulation of diacylglycerol and ERK-mediated signaling differentially controls CD8 T cell responses during chronic viral infection. (PubMed, Front Immunol) - "Short-term inhibition of DGKζ with ASP1570, a DGKζ-selective pharmacological inhibitor, augmented CD8+ T cell activation without causing cell death, which reduced virus titers both in the acute and chronic phases of LCMV CL13 infection. The difference seen between DGKζ deficiency and selective ERK enhancement could be potentially explained by the activation of the AKT/mTOR pathway by DGKζ deficiency, since the mTOR inhibitor rapamycin rescued the abrupt cell death seen in virus-specific DGKζ KO CD8+ T cells. Thus, while ERK is downstream of DAG signaling, the two pathways lead to distinct outcomes in the context of chronic CD8+ T cell activation, whereby DAG promotes SLEC differentiation and ERK promotes a memory phenotype."

Journal • CNS Disorders • Infectious Disease • CD8 • DGKZ

A Study of ASP1570 Taken by Itself or With Pembrolizumab in Adults With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=266 | Recruiting | Sponsor: Astellas Pharma Global Development, Inc. | N=168 ➔ 266

Combination therapy • Enrollment change • Metastases • Monotherapy • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • EGFR • NTRK

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 (SITC 2022) - "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."

P1/2 data • Oncology • Solid Tumor • CTLA4

A Study of ASP1570 in Adults With Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=168 | Recruiting | Sponsor: Astellas Pharma Global Development, Inc. | Phase classification: P1 ➔ P1/2 | Trial completion date: Aug 2026 ➔ Apr 2027 | Trial primary completion date: Aug 2026 ➔ Apr 2027

Phase classification • Trial completion date • Trial primary completion date • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • EGFR • NTRK

A Study of ASP1570 in Adults With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=138 | Recruiting | Sponsor: Astellas Pharma Global Development, Inc. | Trial completion date: May 2024 ➔ Jul 2026 | Trial primary completion date: May 2024 ➔ Jul 2026

Trial completion date • Trial primary completion date • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • EGFR

A Study of ASP1570 in Adults With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=138; Recruiting; Sponsor: Astellas Pharma Global Development, Inc.; Not yet recruiting ➔ Recruiting; Trial completion date: Oct 2023 ➔ May 2024; Trial primary completion date: Aug 2023 ➔ May 2024

Clinical • Enrollment open • Trial completion date • Trial primary completion date • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • EGFR