AZD1390 / AstraZeneca - LARVOL DELTA

DNA damage response inhibitors enhance interferon signaling in an LET-dependent manner after irradiation of glioblastoma cells (ESTRO 2025) - "Material/ Human glioblastoma U-251 and T98G cells were irradiated with X-rays (LET: ~4 keV/mm; 2-30 Gy), protons (LET: 4.8 and 41.9 keV/mm; 2-6 Gy) and carbon ions (LET: 28 and 73 keV/mm; 1-4 Gy), with and without ATR inhibitor (VE-822 at 50-250nM) or ATM inhibitor (AZD1390 at 10nM). These findings indicate that DNA damage response inhibitors can enhance IFN signaling following X-, proton and carbon ion irradiation, with a strong positive dependency on LET. DNA damage response inhibitors may potentially be used in combination with proton or carbon ion therapy to enhance tumor cell radiosensitivity and boost antitumor immune responses."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • STAT1

Enhancing antitumor immunity by targeting cancer associated fibroblasts with radiation and ATM inhibition (ESTRO 2025) - "Cells were treated with radiation (2, 6 or 18 Gy) and inhibitors targeting ATR (VE-822), ATM (AZD1390), CHK1 (LY2606368) and WEE1 (AZD1775). This study demonstrates that combining radiation with ATM inhibition can effectively target CAFs, inducing an IFN-I response. Beyond the well-established radiosensitizing effects of ATM inhibition, our findings reveal a potential novel role for ATM inhibitors in reprogramming NSCLC-CAFs into an immune-activating phenotype. This dual mechanism represents a promising approach to enhance radiotherapy-immunotherapy synergies by reducing the immunosuppressive influences of the tumor microenvironment."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CAFs • CDKN1A • CHEK1 • IFNB1

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

ATM inhibitor AZD1390 sensitizes nasopharyngeal cancer cells to chemotherapy by reversing chemotherapy-induced autophagy (AACR 2025) - "Our findings demonstrated that AZD1390 augments the sensitivity of NPC cell lines to chemotherapy through the reversion of chemotherapy-induced autophagy. Therefore, AZD1390 could potentially serve as a chemosensitizer in NPC treatment."

Head and Neck Cancer • Nasopharyngeal Carcinoma • Oncology • Solid Tumor • ANXA5

Radiosensitization via ATM inhibition in small cell lung cancer leads to increased immunogenicity and tumor infiltration (AACR 2025) - "Evaluation of ATM inhibition (ATMi) in combination with IR increases tumour T cell immunogenicity through a cGAS-STING-mediated mechanism.Methods and Materials: We investigated the combination of ATMi (AZD1390) and IR in SCLC cell-lines SBC5 and SHP77, to determine the synergism of cGAS-STING activation via immunofluorescence... In this study, we demonstrated pharmacological inhibition of ATM enhanced SCLC chemokine expression in a cGAS-STING-dependent manner. We further validated this phenotype in a syngeneic SCLC murine model. Despite this marked improvement in SCLC T cell infiltration no further benefits was observed."

IO biomarker • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • CGAS • CXCL10 • PTPRC • STING

Combined HDAC and ATM inhibition potentiates anticancer effects in glioblastoma preclinical models (AACR 2025) - "Here, we evaluated synergistic effect of combining HDAC and DNA repair enzyme, ataxia telangiectasia mutated (ATM) inhibitors, quisinostat (QST) and AZD1390 to broaden therapeutic window for GBM treatment. In vitro dose-response assays were performed in patient-derived xenograft (PDX)-derived glioma stem cells (GSCs) with both QST and AZD1390 with or without radiation treatment to assess synergy. Our data indicate that QST and AZD1390 act synergistically to radiosensitize GBM cells and increase the therapeutic window for treatment. In vivo experiments are under way to examine efficacy of this combination using orthotopic PDX GBM models. Keywords: glioblastoma, ATM, HDAC, DNA damage repair"

Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • CASP3

ATM Kinase Small Molecule Inhibitors Prevent Radiation-Induced Apoptosis of Mouse Neurons In Vivo. (PubMed, Kinases Phosphatases) - "In fact, multiplex immunostaining showed that a clinical candidate ATMi (AZD1390) protected mouse neurons from apoptosis by 90% at 4 h after radiation. We speculate that the lack of toxicity to neurons is due to a normal ATM-p53 response that, if blocked transiently with an ATMi, is protective. Altogether, in line with previous work using ATM knockout mice, we provide evidence that ATM kinase inhibition using small molecules does not add to neuronal radiation toxicity, and might, in fact, protect them from radiation-induced apoptosis at least in the short term."

Journal • Preclinical • Brain Cancer • CNS Disorders • CNS Tumor • Glioma • Oncology • Solid Tumor

CONCORDE: A Platform Study of Novel Agents in Combination With Radiotherapy in NSCLC (clinicaltrials.gov) - P1 | N=200 | Recruiting | Sponsor: University of Leeds | Trial primary completion date: Apr 2025 ➔ Mar 2026

Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • 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

An update on the CONCORDE study: A phase Ib platform study of DNA damage repair inhibitors (DDRIs) in combination with conventional radiotherapy in NSCLC (ELCC 2025) - P1 | "Recruitment update: Since 17/03/21, 4 arms have opened: A (olaparib, PARPi), B (AZD1390, ATMi), C (ceralasertib, ATRi) and E (saruparib, PARP-1i)...DDRIs have been successfully escalated to dose level 2 (C + E) or 3 (A) with integration of consolidation durvalumab in 2 arms (C + E)...Analysis of patient-reported outcomes and efficacy are ongoing. A multimodality translational program to identify toxicity biomarkers is in development."

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

Ivy 2020-10: AZD1390 in Recurrent and Newly Diagnosed WHO Grade 4 Glioma Patients (clinicaltrials.gov) - P1 | N=97 | Recruiting | Sponsor: Nader Sanai | N=37 ➔ 97 | Trial completion date: Jan 2025 ➔ Sep 2027 | Trial primary completion date: Jul 2024 ➔ Sep 2025

Enrollment change • Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Malignant Glioma • Oncology • Solid Tumor

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 | Not yet recruiting | Sponsor: Children's Oncology Group

New P1 trial • Astrocytoma • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioblastoma • Glioma • Malignant Glioma • Oncology • Pediatrics • Solid Tumor

Targeting the ferroptosis pathway: A novel compound, AZD1390, protects the brain after ischemic stroke. (PubMed, bioRxiv) - "This study identifies ferroptosis as a critical mechanism in ischemic stroke-induced neuronal cell death and highlights ATM inhibition, particularly with AZD1390, as a promising therapeutic candidate for mitigating stroke-associated damage. Targeting ferroptosis may provide a translationally relevant strategy to mitigate neuronal injury and improve clinical outcomes for stroke patients."

Journal • Ataxia • Cardiovascular • Hematological Disorders • Immunology • Ischemic stroke • Movement Disorders • Primary Immunodeficiency • PACERR • PTGS2

AZD1390: Data from P1 trial (NCT03423628) for brain metastases and newly diagnosed glioblastoma in 2026 (AstraZeneca) - Q4 & FY2024 Results

P1 data • Glioblastoma • Oncology

Bragg peak proton irradiation and ATM inhibition for rectal cancer. (ASCO-GI 2025) - "Inhibition of ATM preferentially radiosensitized BP protons compared to x-rays or ENT protons in CRC but not in normal tissue based on weight loss and histopathological evaluation. Differential tumor efficacy and normal tissue toxicity after x-ray, entrance and Bragg Peak Protons +/- ATM inhibitor.Clonogenic survival of pMMR colorectal cancer cell lines after IR (4 Gy) +/- 10nM AZD1390 (ATM inhibitor) of A) HT29, B) CT26, and C) SW480 cell lines. D) γH2AX foci at 24 hours post-IR in HT29."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Rectal Cancer • Solid Tumor

A Study of AZD1390 and Stereotactic Body Radiotherapy (SBRT) for People with Metastatic Solid Tumor Cancer (clinicaltrials.gov) - P1 | N=54 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Recruiting ➔ Active, not recruiting

Enrollment closed • Oncology • Solid Tumor

Interferon signaling is enhanced by ATR inhibition in glioblastoma cells irradiated with X-rays, protons or carbon ions. (PubMed, Radiother Oncol) - "These findings indicate that DNA damage response inhibitors can enhance IFN signaling following X-, proton and carbon ion irradiation, with a strong positive dependency on LET."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • IFNB1 • STAT1

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

AZD1390, an Ataxia Telangiectasia Mutated Inhibitor, Enhances Cisplatin Mediated Apoptosis in Breast Cancer Cells. (PubMed, Exp Cell Res) - "Furthermore, combination of AZD1390 with cisplatin enhances its apoptotic effects in MCF-7 and MDA-MB-231 cells. These findings could aid in developing new treatments for breast cancer that exploit the genomic instability of cancer cells."

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

Overcoming Olaparib Resistance in BRCA-Mutated Triple-Negative Breast Cancer: Synergistic Potential of DNA Repair Pathway Inhibitors (SABCS 2024) - "Two PARP inhibitors (olaparib and talazoparib) are FDA-approved for patients with metastatic gBRCA mutated breast cancer...Based on target identification, we selected inhibitors of ATR (elimusertib, gartisertib), ATM (AZD1390), PLK4 (CFI-400945), CDK12 (SR-4835), PI3KCA (copanlisib), and AKT (capivasertib) for proliferation assays... Our preclinical study identified DNA repair pathways as potential targets to enhance the efficacy of olaparib in both parent and olaparib-refractory gBRCA mutated TNBC cell lines. Future in vivo studies, including patient-derived xenografts and additional mechanistic analyses to further understand dual DNA targeting synergy, are warranted to validate this therapeutic approach for TNBC with gBRCA mutation."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • CDK12 • DRD • HER-2 • PIK3CG • PIK3R3 • PLK4

A Study to Assess the Safety and Tolerability of AZD1390 Given With Radiation Therapy in Patients With Brain Cancer (clinicaltrials.gov) - P1 | N=180 | Recruiting | Sponsor: AstraZeneca | N=120 ➔ 180 | Trial completion date: Apr 2026 ➔ Sep 2026 | Trial primary completion date: Apr 2026 ➔ Sep 2026

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • IDH1

Global Coalition for Adaptive Research Announces Evaluation of AZD1390 in GBM AGILE Trial (PRNewswire) - "The Global Coalition for Adaptive Research (GCAR) today announced that they have executed an agreement with AstraZeneca for the evaluation of AstraZeneca's compound, AZD1390, in GBM AGILE...the world's first global adaptive platform trial for glioblastoma. The AZD1390 arm will be evaluated for the treatment of newly diagnosed glioblastoma, with recruitment of patients expected to begin by Q2 2025."

Commercial • Trial status • Glioblastoma • Oncology

Safety and preliminary efficacy of AZD1390 + radiation therapy for glioblastoma (SNO 2024) - P1 | "BACKGROUND: Glioblastoma is an aggressive cancer; intensity-modulated radiation therapy (IMRT) with concomitant and adjuvant temozolomide is the first-line standard of care. Concurrent AZD1390 and IMRT demonstrated manageable safety at doses with known target engagement. Preliminary efficacy is encouraging (Arm A). AZD1390 can potentially act as a radiosensitizer for glioblastoma treatment."

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

A phase 0/1b study of AZD1390 plus radiotherapy in newly diagnosed, MGMT-unmethylated and recurrent glioblastoma patients. (SNO 2024) - P1 | "AZD1390 is well-tolerated in both newly-diagnosed and recurrent GBM patients, achieving pharmacologically relevant concentrations in Gd-nonenhancing tumor tissue, and suppressing radiation-induced increase in pRAD50 levels. These data are the first to demonstrate AZD1390-mediated PD and PK responses in nGBM and rGBM patients. Clinical outcomes data are maturing and will be reported."

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

The association between alterations in the ataxia telangiectasia mutated (ATM) gene and response to immune checkpoint inhibitors (SITC 2024) - "If confirmed/validated in larger datasets it would highlight the importance of the distinction between ATM and other DDR alterations. It also would support considering the novel combination of ICIs and an ATM inhibitor such as AZD1390 in patients with ATM alterations."

Checkpoint inhibition • IO biomarker • Tumor mutational burden • Colon Cancer • Non-melanoma Skin Cancer • Oncology • Solid Tumor • ATM • BRCA1 • BRCA2 • CHEK1 • CHEK2 • FANCF • KRAS • MLH1 • MSH2 • PARP1 • RAD51