AZD1390 / AstraZeneca - LARVOL DELTA

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

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

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

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

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

ATM inhibition increases the anti-tumor efficacy of radium-223 (Ra-223) against prostate cancer bone metastasis in preclinical models. (PubMed, JBMR Plus) - "Radiosensitization with either the ATMi AZD0156 or AZD1390 prior to 300 kBq/kg Ra-223 treatment further reduced bone metastasis by 94.1% and 88.7%, respectively, whereas combining AZD1390 with 50 kBq/kg synergistically reduced tumor size and the number of mice with tumors in bone by 50% compared with Ra-223 alone. Instead, this treatment combination increased subsets of anti-tumor immune cells. Taken together, our data suggest that ATMi may be an effective radiosensitizer for increasing efficacy of Ra-223 in prostate cancer bone metastases, reducing Ra-223-induced adverse effects on bone."

Journal • Preclinical • Genito-urinary Cancer • Oncology • Osteosarcoma • Prostate Cancer • Solid Tumor

ATM inhibitors in cancer radiotherapy: Mechanisms, clinical development, and future directions. (PubMed, Eur J Med Chem) - "Inhibitors such as KU-55933, KU-60019, and AZD1390 have shown the potential to sensitize cancer cells to radiotherapy by impairing DNA repair, thereby enhancing treatment efficacy...Currently, none have gained approval from the FDA or EMA, but six candidates, AZD1390, AZD0156, ZN-B-2262, SYH2051, WSD0628 and M3541 are in clinical trials, often as adjuncts to radiotherapy or in combination with PARP inhibitors. Their safety and effectiveness, however, are still under investigation. This review synthesizes ATM's dual roles and the therapeutic promise of targeting ATM in cancer radiotherapy."

Journal • Review • Ataxia • Brain Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • CDKN1A • CHEK1 • CHEK2

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