AZD1390 / AstraZeneca - LARVOL DELTA

GBM AGILE: A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma (clinicaltrials.gov) - P2/3 | N=1280 | Recruiting | Sponsor: Global Coalition for Adaptive Research | Trial completion date: Jun 2028 ➔ Jun 2030 | Trial primary completion date: Jun 2026 ➔ Jun 2028

Trial completion date • Trial primary completion date • Brain Cancer • Glioblastoma • Hematological Disorders • Oncology • Solid Tumor

AZD1390: Data from P1 trial (NCT03423628) for brain metastases and newly diagnosed glioblastoma in H1 2026 (AstraZeneca) - H1 & Q2 2025 Results

P1 data • Glioblastoma • Oncology

DNA Damage Response Regulation Alleviates Neuroinflammation in a Mouse Model of α-Synucleinopathy. (PubMed, Biomolecules) - "In this study, we evaluated the therapeutic potential of AZD1390, a highly selective and brain-penetrant ATM inhibitor, in reducing neuroinflammation and improving behavioral outcomes in a mouse model of α-synucleinopathy...Overall, these results suggest that targeting the DDR via ATM inhibition reduces genotoxic stress, suppresses neuroinflammation, and improves behavioral outcomes in a mouse model of α-synucleinopathy. These findings underscore the therapeutic potential of DDR modulation in PD and related synucleinopathy."

Journal • Preclinical • Ataxia • CNS Disorders • Immunology • Inflammation • Movement Disorders • Parkinson's Disease • Primary Immunodeficiency • CDKN1A

Achieving human brain exposure with the oral ataxia-telangiectasia mutated kinase inhibitor AZD1390, a substrate of aldehyde oxidase. (PubMed, Drug Metab Dispos) - "This case example demonstrates that despite the lack of relevant translational pharmacokinetics information from animals, via careful human in vitro benchmarking, certain AO substrates with suitable properties can be progressed and generate acceptable oral clinical pharmacokinetics. AZD1390 is a successful case example of prosecuting an AO substrate in the clinic after many documented failures."

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

Combinatorial assessment of DXd-based antibody drug conjugates with DNA damage response inhibitors in ovarian and endometrial cancers (EACR 2025) - "Our findings indicate that combining Dato-DXd and T-DXd with specific DDR inhibitors potentially enhances anti-tumour activity in ovarian and endometrial cancer models, which offers potential pathways for clinical translation. These combinations, particularly those involving ATM and ATR inhibitors, support the need for further investigation in clinical settings."

Endometrial Cancer • Oncology • Ovarian Cancer • Solid Tumor • HER-2 • TACSTD2

Preclinical Evaluation of T-DXd and AZD1390 in HER2-Low, Triple-Negative Breast Cancer Models (EACR 2025) - "T-DXd plus AZD1390 shows significant synergy in growth reduction of cancer cells in 2D and 3D culture conditions, even at low nanomolar concentrations. This combination shows promising results to enhance target therapies for TNBC patients."

Preclinical • Ataxia • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Triple Negative Breast Cancer • CASP3 • CASP7 • HER-2 • TOP1

Restoring RAI Sensitivity via ATM Inhibition and Genotoxic Stress (SNMMI 2025) - "In vitro and in vivo models evaluated the synergistic effects of combining ATM inhibitors (AZD1390) with RAI therapy... Single-cell analysis revealed a progressive increase in ATM expression during thyroid cancer progression, with the highest levels observed in anaplastic thyroid carcinoma (ATC) and RAI-R PTC. Immunohistochemistry confirmed elevated ATM expression in RAI-R patient samples compared to RAI-sensitive counterparts. Mechanistically, RAI-induced DNA damage primarily resulted in AP site accumulation rather than double-strand breaks (DSBs)."

Ataxia • Endocrine Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma

Global Coalition for Adaptive Research Announces Initiation of AZD1390 in GBM AGILE Trial (GlobeNewswire) - "The Global Coalition for Adaptive Research (GCAR) today announced the activation of AstraZeneca's AZD1390 in GBM AGILE...the world's first global adaptive platform trial for glioblastoma. The AZD1390 arm will be evaluated for the treatment of adult patients with newly diagnosed glioblastoma."

Trial status • Glioblastoma

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 | Not yet recruiting ➔ Recruiting | Initiation date: May 2025 ➔ Feb 2026

Enrollment open • Trial initiation date • Astrocytoma • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioblastoma • Glioma • Malignant Glioma • Oncology • Pediatrics • Solid Tumor

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