AZD1390 / AstraZeneca - LARVOL DELTA

Combination activity of T-DXd and dato-DXd with DNA damage response inhibitors (ESMO-TAT 2026) - "We profiled the activity of two TOP1i-charged ADCs (T-DXd, Dato-DXd), in combination with DDRi, targeted against ATM (AZD1390), ATR (ceralasertib), PARP (olaparib, saruparib) or WEE1 (adavosertib), using preclinical cancer models. Combinations of TOP1i-ADCs with selected DDR inhibitors and optimized dosing schedules, enhance therapeutic response and reduce toxicity, guiding ongoing and future clinical investigations."

Oncology • PARP1 • TOP1

ATM inhibition with AZD1390 and conventional radiotherapy in non-small cell lung cancer: interim report from the CONCORDE phase Ib trial (NCT04550104) (ESTRO 2025) - P1 | "Oesophagitis duration was prolonged (median 67 days, range 8-181), and 7 participants required morphine (50%). AZD1390 was escalated to dose level 3 (40mg once-daily on RT days). Based on the observed oesophageal toxicity, the independent Safety Review Committee decided to close Arm B early. Analysis of patient-reported outcomes, efficacy outcomes and oesophagus-derived cfDNA are ongoing."

P1 data • Ataxia • Brain Cancer • CNS Tumor • Gastrointestinal Disorder • Glioblastoma • Immunology • Lung Cancer • Movement Disorders • Non Small Cell Lung Cancer • Oncology • Primary Immunodeficiency • Solid Tumor • Squamous Cell Carcinoma

Modeling pharmacokinetics and efficacy of the ATM inhibitor WSD0628 in GBM and melanoma metastasis PDX models (AACR 2026) - "The integration of highly potent radiosensitizers, such as the ATM inhibitors AZD1390 or WSD0628, could reverse resistance and significantly improve local control of these tumors. Taken together, we have developed a model to predict efficacious dosing of a brain tumor based on the free drug hypothesis, which allows integration of multiple aspects of in vitro modeling with measured drug levels in animal models to predict total plasma levels associated with robust sensitizing effects. Assuming similar tissue to plasma partitioning in human GBM, this model could be directly applied to interpret the ongoing Phase 1 PK analysis of WSD0628 in recurrent GBM."

Clinical • PK/PD data • Brain Cancer • Glioblastoma • Melanoma • Oncology • Solid Tumor

Small cell lung cancer humanized mouse models identifies unique T cell infiltration immune phenotypes in response to combination immune-radiation therapies. (AACR 2026) - "We further characterized SCLC hu-mice for their ability to model therapeutic sensitivity, focusing on a novel triplet regimen, AZD1390 (ATM inhibitor) with radiotherapy (RT) and durvalumab (aPDL1), to investigate how DNA damage repair inhibition plus RT can reshape the immune microenvironment and sensitize SCLC subtypes to aPDL1. Immunodeficient mice were intravenously injected with human PBMCs and subcutaneously engrafted with a panel of human SCLC cell-lines corresponding to all subtypes. Our preclinical observations demonstrate PBMC hu-mice as a viable platform to model intrinsic immune-tumor characteristics of engrafted human SCLC cell-lines. Combinatory radiation therapy enhanced anti-PDL1 efficacy in select models. Future studies will aim to identify response-defining features of treated models to improve patient selection in clinical trials."

IO biomarker • Preclinical • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ASCL1 • CD8 • CGAS • CXCL10 • ENTPD1 • IFNG • ITGAE • NEUROD1 • POU2F3 • STING

Particle therapy, ATM and PD-1 inhibition for pMMR rectal cancer (AACR 2026) - "The ATM inhibitor AZD1390 was delivered via oral gavage at 20 mg/kg, PO 1 hour prior to radiation... DaRT and BP protons ATMi prime pMMR colorectal cancer to PD1i, and all elements are clinically translatable."

IO biomarker • pMMR • Colorectal Cancer • Oncology • Rectal Cancer • Solid Tumor • PTPRC

Synergistic inhibition of PARP and ATM leads to unresolved DNA damage and cohesin-mediated collapse in pediatric osteosarcoma (AACR 2026) - "To explore rational combinations with PARPi in OS, we performed a genome-scale CRISPR-Cas9 screen in the presence of the PARPi olaparib in two OS cell lines...Next, we tested a small molecule ATM inhibitor (ATMi), AZD1390, combined with multiple PARPi, using a novel drug synergy platform in a panel of OS including low-passage patient-derived cell lines, observing profound synergy across OS models compared to non-OS cell lines using ATP-based assays and live cell imaging...Bortezomib therapy rescued dual-treated cells from WAPL depletion and partially rescued apoptosis in dual treated cells, confirming proteasomal degradation in this context...In vivo work has confirmed an increase in survival in mice bearing OS tumors treated with the combination compared to control. We are repeating these experiments to confirm the clinical relevance for OS patients using synergistic low doses to achieve efficacy without toxicity."

Clinical • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • ANXA5 • CASP3 • CASP7 • HRD

Testing the Addition of an Anti-Cancer Drug, AZD1390, During Radiation Therapy for Newly Diagnosed High Grade Glioma, Diffuse Midline Glioma, or Diffuse Intrinsic Pontine Glioma (clinicaltrials.gov) - P1 | N=54 | Recruiting | Sponsor: Children's Oncology Group | Initiation date: Feb 2026 ➔ Jun 2025

Trial initiation date • Astrocytoma • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioblastoma • Glioma • High Grade Glioma • Oncology • Pediatrics • Solid Tumor

Ivy 2020-10: AZD1390 in Recurrent and Newly Diagnosed WHO Grade 4 Glioma Patients (clinicaltrials.gov) - P1 | N=97 | Active, not recruiting | Sponsor: Nader Sanai | Recruiting ➔ Active, not recruiting | Trial completion date: Sep 2027 ➔ Dec 2026 | Trial primary completion date: Sep 2025 ➔ Jun 2026

Enrollment closed • Trial completion date • Trial primary completion date • Brain Cancer • Glioblastoma • Glioma • High Grade Glioma • Oncology • Solid Tumor

An Update on the CONCORDE study: A Phase Ib Platform Study of DNA Damage Repair Inhibitors (DDRis) in Combination With Conventional Radiotherapy in NSCLC (BTOG 2025) - P1 | "In 2 study arms, participants also receive consolidation durvalumab ±DDRi for up to 12 months...The primary objective is to assess safety and to determine the recommended phase II dose of each DDRi. Since 17/03/21, 4 arms have opened: A (olaparib, PARPi), B (AZD1390, ATMi), C (ceralasertib, ATRi) and E (saruparib, PARP-1i)... CONCORDE continues to recruit patients to three study arms (A,C,E). The platform demonstrated excellent capability in identifying excess toxicity in DDRi-RT combinations, leading to Arm–B closure. Analysis of patient-reported outcomes and efficacy are ongoing."

Combination therapy • P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • PARP1

CONCORDE: a phase Ib platform study of novel agents in combination with conventional radiotherapy in NSCLC (BTOG 2023) - "The primary objective is to assess safety and determine the recommended phase II dose of each DDRi+RT combination. As of 06/01/2023, CONCORDE-A (olaparib) and CONCORDE-B (AZD1390) are open to recruitment across 9 centres. The trial continues to recruit and CONCORDE-C (RT±ceralasertib with consolidation durvalumab±ceralasertib) has been approved and is due to open in January 2023. Two further study arms are planned. A parallel multimodality translational program to identify biomarkers of treatment response, toxicity and the impact on the immune system are in development."

Combination therapy • P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma

Olaparib, AZD1390, ceralasertib, saruparib and consolidation durvalumab (CONCORDE) phase Ib platform study of novel DNA damage response inhibitor (DDRi) agents in combination with radiotherapy in non-small cell lung cancer (NSCLC). (ASCO 2024) - "A parallel multimodality translational program to identify biomarkers of treatment response, toxicity and the impact on the immune system are in development. Biomarkers of interest include plasma toxicity markers, immune cell profiling, radiomics and ctDNA."

Combination therapy • P1 data • Infectious Disease • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

ATM Inhibition Enhances Knock-in Efficiency by Suppressing AAV-Induced Activation of Apoptotic Pathways. (PubMed, Commun Biol) - "In cells receiving circular plasmid donors, ATM inhibition with AZD1390 markedly reduced the knock-in and EJ-TI efficiencies, consistent with its canonical role in DSB repair. In contrast, with linear AAV donors, ATM inhibition enhanced the knock-in efficiency by suppressing the overactivation of the ATM-p53-caspase 3 apoptotic pathway and partially suppressing classical non-homologous end-joining. These findings highlight the critical influence of donor DNA configuration on DNA damage response signaling and provide a strategy for optimizing genome editing efficiency by selectively modulating the ATM pathways, an approach that may have significant implications for gene therapy, cell engineering, and other applications."

Journal • Ataxia • Gene Therapies • Immunology • Movement Disorders • Primary Immunodeficiency • ATR • CASP3

SADDRIN-1: Sarcomas and DDR-Inhibition; a Combined Modality Study (clinicaltrials.gov) - P1 | N=12 | Terminated | Sponsor: The Netherlands Cancer Institute | N=30 ➔ 12 | Trial completion date: Jul 2028 ➔ Dec 2025 | Recruiting ➔ Terminated; Endpoint has been reached.

Enrollment change • Trial completion date • Trial termination • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Safety and preliminary efficacy of AZD1390 + radiation therapy (RT) for glioblastoma (GBM) (AACR 2024) - P1 | "The standard of care backbone for newly diagnosed GBM is intensity-modulated RT (IMRT) with concomitant and adjuvant temozolomide. Concurrent AZD1390 and IMRT administration is tolerated with a manageable safety profile, including at doses shown to achieve clear target engagement in the Phase 0 study. Preliminary efficacy is encouraging in Arm A. These data suggest the potential for AZD1390 to act as a radiosensitizer for the treatment of GBM. Clinical investigation is ongoing."

Clinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • MGMT

Safety and Preliminary Efficacy of AZD1390 + Radiation Therapy for Glioblastoma (ASTRO 2024) - P1 | "The standard of care backbone for newly diagnosed GBM is intensity-modulated radiation therapy (IMRT) with concomitant and adjuvant temozolomide. Concurrent AZD1390 and IMRT administration is tolerated with a manageable safety profile, at doses shown to achieve clear target engagement in the Phase 0 study. Preliminary efficacy is encouraging in Arm A. These data suggest the potential for AZD1390 to act as a radiosensitizer for the treatment of GBM. Clinical investigation is ongoing."

Clinical • Ataxia • Brain Cancer • CNS Tumor • Fatigue • Glioblastoma • Immunology • Movement Disorders • Oncology • Pain • Primary Immunodeficiency • Solid Tumor

DNA Damage Sensing and TP53 Function as Modulators of Sensitivity to Calicheamicin-Based Antibody-Drug Conjugates for Acute Leukemia. (PubMed, Cancers (Basel)) - "These results support further evaluation of combination therapies with corresponding small-molecule inhibitors (currently pursued for therapy of other cancers) toward clinical testing as novel strategies to increase the efficacy of CLM-based ADCs such as GO and InO."

Journal • Hematological Malignancies • Leukemia • Oncology • TP53

Role of DNA damage sensing and TP53 function as modulators of sensitivity to calicheamicin-based antibody-drug conjugates (ADCs) for acute leukemia (ASH 2025) - "Better survival of some patients with the CD33 ADC, gemtuzumab ozogamicin (GO), and the CD22 ADC, inotuzumab ozogamicin (InO), validate these efforts, but these ADCs are ineffective in many others...CLM-induced cytotoxicity was assessed in vitro in the presence/absence of a Mouse Double Minute 2 homolog (MDM2) inhibitor (idasanutlin), Ataxia-Telangiectasia Mutated (ATM) inhibitor (AZD1390, lartesertib), Ataxia Telangiectasia and Rad3-related (ATR) inhibitor (ceralasertib), Checkpoint Kinase 1 and Checkpoint Kinase 1 (Chk1/Chk2) inhibitors (prexasertib, BML-277), and poly(ADP-ribose) polymerase (PARP) inhibitor (veliparib)... Our studies identify ATM, MDM2, and TP53 as key modulators of CLM-induced cytotoxicity in acute leukemia cells. These results support further evaluation of combination therapies with corresponding small molecule inhibitors (currently pursued in patients with other cancers) toward possible clinical testing as novel strategies to increase the efficacy..."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Ataxia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Immunology • Leukemia • Movement Disorders • Primary Immunodeficiency • CD22 • CD33 • CDKN1A • FBXW7 • TP53

ATM/DNA-PK Inhibitor XRD-0394 Enhances Radiation-Induced Pro-Inflammatory Responses in Glioma Models (SNO 2025) - "We previously evaluated the radiosensitizing effect of the ATM inhibitor AZD1390 in both p53-mutant and wild-type DMGs and observed enhanced sensitivity in p53-mutant models (Mangoli et al., in press). In conclusion, a dual inhibitor of ATM and DNA-PK enhances radiation-induced cytotoxicity and pro-inflammatory signaling in GBM and DMG models. Ongoing studies will further define the therapeutic potential of this combination strategy."

IO biomarker • Ataxia • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • High Grade Glioma • Immunology • Inflammation • Movement Disorders • Primary Immunodeficiency • Solid Tumor • CCR4 • STING

IDENTIFICATION OF A DNA REPAIR INHIBITOR FOR THE COMBINATION WITH LURBINECTEDIN AND RADIOTHERAPY IN SARCOMA CELL LINES (CTOS 2025) - "Objective: Improved multimodal treatment could optimize therapeutic outcomes for sarcoma patients. Our preclinical data suggest that the combination of LU with RT has no sensitizing effect compared to LU treatment alone in sarcoma cell lines. However, combining LU and IR with DNA repair inhibitors such as the ATRi VE-822 is a promising way to improve sarcoma treatment."

Preclinical • Fibrosarcoma • Liposarcoma • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • Synovial Sarcoma • ANXA5

ATM/DNA-PK Inhibitor XRD-0394 Enhances Radiation-Induced Pro-Inflammatory Responses in Glioma Models (WFNOS 2025) - "We previously evaluated the radiosensitizing effect of the ATM inhibitor AZD1390 in both p53-mutant and wild-type DMGs and observed enhanced sensitivity in p53-mutant models (Mangoli et al., in press). In conclusion, a dual inhibitor of ATM and DNA-PK enhances radiation-induced cytotoxicity and pro-inflammatory signaling in GBM and DMG models. Ongoing studies will further define the therapeutic potential of this combination strategy."

IO biomarker • Ataxia • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • Immunology • Inflammation • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • CCR4 • STING

YL0712-3, a Novel ATR/ATM Inhibitor, Demonstrates Anti-Tumor Activity in TP53 Mutant DLBCL through Synthetic Lethality and Degradation of Mutant p53 (ASH 2024) - "The in vitro activity of YL0712-3 was assessed across various TP53 mutant and wild-type DLBCL cell lines, with ATR inhibitor Elimusertib and ATM inhibitor AZD1390 as positive controls. Conclusion : The ATR/ATM inhibitor YL0712-3 effectively targets TP53 mutant DLBCL cells by inhibiting the ATM/Chk2 and ATR/Chk1 pathways and inducing proteasome-mediated degradation of mutant p53 protein. YL0712-3 exhibits promising anti-tumor activity in both in vitro and in vivo models, especially when combined with R-CHOP, presenting a potential therapeutic strategy for TP53 mutant DLBCL."

Synthetic lethality • Ataxia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Immunology • Lymphoma • Movement Disorders • Non-Hodgkin’s Lymphoma • Oncology • Primary Immunodeficiency • Targeted Protein Degradation • CHEK2

ATM/DNA-PK Inhibitor XRD-0394 Enhances Radiation-Induced Pro-Inflammatory Responses in Glioma Models (WFNOS 2025) - "We previously evaluated the radiosensitizing effect of the ATM inhibitor AZD1390 in both p53-mutant and wild-type DMGs and observed enhanced sensitivity in p53-mutant models (Mangoli et al., in press). In conclusion, a dual inhibitor of ATM and DNA-PK enhances radiation-induced cytotoxicity and pro-inflammatory signaling in GBM and DMG models. Ongoing studies will further define the therapeutic potential of this combination strategy."

IO biomarker • Ataxia • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • High Grade Glioma • Immunology • Inflammation • Movement Disorders • Primary Immunodeficiency • Solid Tumor • CCR4 • STING

AZD1390: Data from P1 trial (NCT03423628) for brain metastases and newly diagnosed glioblastoma in H2 2026 (AstraZeneca) - Q3 2025 Results

P1 data • Glioblastoma • Oncology

Inhibition of ATM and xCT Enhances Radiation Sensitivity and Suppresses Tumor Growth in Glioblastoma (ASTRO 2025) - "Irradiation was specifically administered to brain with 2 Gy per day for five consecutive days, with or without ATM inhibitors (AZD0156, AZD1390, 1 mg/kg) and the xCT inhibitor sulfasalazine (100 mg/kg). Our study demonstrated that the simultaneous inhibition of ATM and xCT significantly enhanced the radiosensitivity of GBM both in vitro and in vivo. Furthermore, GBM tumor growth was markedly suppressed with this approach. These findings suggest that radiotherapy combined with ATM and xCT inhibition may serve as a promising strategy for overcoming radioresistance in GBM and improving therapeutic outcomes."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Quantitative Imaging of ATM: PET and Autoradiography Studies Using [11C]AZD1390. (PubMed, ACS Chem Neurosci) - "The binding parameters [Kd (0.23 nM), Ki (0.58 nM), and Bmax (267.0 fmol/mg tissue)] demonstrate the high affinity of [11C]AZD1390 and imply that ATM is present at levels (Bmax) sufficient for reliable quantification in the brain. While AZD1390 may not be ideal for accurately measuring ATM concentrations due to saturable efflux or other dose nonlinearity mechanisms, these findings support the overall feasibility of quantifying ATM in vivo using PET imaging."

Journal • Ataxia • Brain Cancer • Glioblastoma • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor