AZD1390 / AstraZeneca - LARVOL DELTA

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

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

Molecular Characterization of PARP Inhibitor Response Reveals Co-Targeting Strategies in Advanced Prostate Cancer. (PubMed, Cancers (Basel)) - "Tumor cells exposed to longer-term treatment exhibit SLUG-dependent epithelial-mesenchymal transition (EMT) and evidence for altered fatty acid metabolism, both of which may be targeted to enhance PARPi anti-tumor cell effects. This study provides insight into both short and longer-term cellular response to PARPi treatment and provides a foundation for additional efforts to explore effective strategies to maximize the utility of PARP inhibition for managing prostate cancer."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • SNAI2

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

Experience pooling control arms within a complex phase I drug-radiotherapy (RT) platform trial (ESMO-TAT 2024) - P1 | "Table: 77P Treatment within each study arm Study arm 6 week RT period 1 year consolidation period CONCORDE-A Olaparib+RT No treatment RT only CONCORDE-B AZD1390+RT RT only CONCORDE-C Ceralasertib+RT Cerelasertib + durvalumab RT only Durvalumab CONCORDE-E AZD5305+RT Durvalumab RT only Results CONCORDE opened to recruitment in April 2021. Conclusions Pooling RT only patients across arms to estimate DLT rates presents a useful concurrent comparator to put the estimated DLT rate for informing dose escalation into context, and the rate in RT+DDRi patients to help attribute toxicity to the combination of DDRi and thoracic RT. The platform design necessitates fewer comparator patients, compared with multiple standalone comparison design trials."

P1 data • Lung Cancer • Oncology • Solid Tumor

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

An Update on the CONCORDE study: A Phase Ib Platform Study of Novel Agents in Combination With Conventional Radiotherapy in NSCLC (IASLC-WCLC 2023) - P1 | "The primary objective is to assess safety and determine the recommended phase II dose of each DDRi+RT combination. As of 23/03/2023, CONCORDE-A (olaparib), CONCORDE-B (AZD1390) and CONCORDE-C (ceralasertib with consolidation durvalumab) are open to recruitment across 9 centres. The trial continues to recruit and CONCORDE-E (RT+/-AZD5305 with consolidation durvalumab) has been submitted and is due to open in May 2023. One further study arm is planned (CONCORDE-F). 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

Modern era radical radiotherapy toxicity: a preliminary CONCORDE analysis of the calibration arm (ESTRO 2024) - " As of 15/10/2023, 65 patients have been registered in the study from 9 UK centres, of which 49 were randomised in one of 3 arms (CONCORDE-A olaparib, CONCORDE-B AZD1390 and CONCORDE-C ceralasertib with consolidation durvalumab). In this unplanned preliminary analysis, we report low rates of toxicity in patients who receive radical radiotherapy alone in the modern radiotherapy era. Despite small numbers and therefore difficult to draw meaningful conclusions a 7% risk of developing grade 3 pneumonitis is in keeping with figures previously quoted in the literature (3). On reviewing radiotherapy planning statistics, we observe that the patients who experienced more significant pneumonitis had greater GTV volume, lung V20 and mean lung doses."

Gastrointestinal Disorder • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pneumonia • Solid Tumor

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

Inhibition of ATM, ATR and DNA-PK radiosensitises 3D uveal melanoma models to X-rays and proton beam therapy. (PubMed, Front Oncol) - "Here, we investigate the response of 3D spheroid models of UM to both X-rays and PBT in the presence of inhibitors of ATM (AZD1390), ATR (AZD6738) and DNA-PK (AZD7648). We demonstrate that inhibition of these protein kinases significantly suppresses the growth of UM spheroids exposed to both X-rays and PBT, which is primarily driven by delayed and persistent DSBs, leading to the accumulation of chromosomal aberrations. These results highlight the potential of combining ATM, ATR or DNA-PK inhibitors to enhance radiotherapy efficacy, and particularly with targeted PBT, to help improve clinical outcomes in UM."

Journal • Ataxia • Eye Cancer • Immunology • Melanoma • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Uveal Melanoma • ATR

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

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

Single-cell profiling reveals an iron-storage and lysosomal programme in microglia after radiotherapy and ATM inhibition in the adult murine brain (EANO 2026) - "In the adult non-tumour brain, radiotherapy and AZD1390 do not appear to reprogramme microglia into new identities. Rather, they remodel a pre-existing mature landscape and converge on an iron-associated lysosomal stress axis. These data nominate altered metal handling as a plausible component of the normal-brain response to treatment and support a testable hypothesis for tumour-bearing and fractionated models, namely that repeated radiotherapy may reinforce microglial iron stress and thereby influence the wider brain microenvironment."

Preclinical • Brain Cancer • Glioblastoma • 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 | Active, not recruiting | Sponsor: Children's Oncology Group | Recruiting ➔ Active, not recruiting

Enrollment closed • Astrocytoma • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioblastoma • Glioma • High Grade Glioma • Oncology • Pediatrics • Solid Tumor

SCLC humanized mice identify T cell infiltration phenotypes in response to combination immune-radiation therapies. (PubMed, iScience) - "We evaluated peripheral blood mononuclear cell (PBMC) humanized mice (hu-mice) as a platform to capture subtype-specific tumor-immune interactions and therapeutic sensitivity to the triplet regimen: AZD1390 (ATM inhibitor), radiotherapy (RT), and durvalumab (aPDL1). Responding xenografts showed enrichment of CD39+CD103+ tumor-reactive T cells with reduced terminal exhaustion (TCF1-TOX+). Overall, PBMC hu-mice may effectively recapitulate SCLC immune contextures and guide development of combinatorial strategies to overcome aPDL1 resistance."

IO biomarker • Journal • Preclinical • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ASCL1 • CCL5 • CD8 • CXCL10 • ENTPD1 • ITGAE • NEUROD1 • POU2F3

A Study to Assess the Safety and Tolerability of AZD1390 Given With Radiation Therapy in Patients With Brain Cancer (clinicaltrials.gov) - P1 | N=159 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

Enrollment closed • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

H3K27M enhances basal ATM signaling but is not required for radiosensitization of diffuse midline glioma via ATM inhibition with AZD1390. (PubMed, Mol Cancer Ther) - "Finally, AZD1390 sensitized orthotopic H3K27M mutant tumors to radiotherapy in both immune deficient and syngeneic immune competent hosts with minimal adverse effects. Taken together, these data provide a direct mechanistic link between the H3K27M mutation and ATM expression and support the recently initiated clinical investigation of AZD1390 with radiotherapy in newly diagnosed pHGG."

Journal • Ataxia • Brain Cancer • Diffuse Midline Glioma • Glioma • High Grade Glioma • Immunology • Movement Disorders • Oncology • Pediatrics • Primary Immunodeficiency • Solid Tumor

Ex vivo TruCulture/L blood culture tubes enable sensitive, longitudinal pharmacodynamic assessment of AZD1390 in patient PBMCs when tumour biopsies are not feasible (EACR 2026) - "Building on prior assay development that demonstrated robust ex vivo DDR activation and measurable inhibition with DDR agents, we translated an innovative, clinically amenable blood tube culture system to support pharmacodynamic (PD) assessment for the ATM inhibitor AZD1390.Material and We developed bespoke TruCulture/L tubes® that permit immediate ex vivo stimulation of whole blood with or without bleomycin to activate ATM pathway signaling. Ex vivo stimulation using TruCulture®/L blood culture tubes provides a practical, clinically amenable approach to overcome low baseline levels of PD biomarkers in PBMCs. The workflow enables longitudinal detection of target engagement–related PD effects when tumour biopsies are impractical and can be readily adapted to settings where biomarkers require controlled exogenous activation to achieve reliable measurement."

Biopsy • PK/PD data • Preclinical • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • RAD50

Human ADME Study of [14C]-AZD1390 (clinicaltrials.gov) - P1 | N=8 | Not yet recruiting | Sponsor: AstraZeneca

New P1 trial • Oncology • Solid Tumor

Radiosensitisation of Head and Neck Cancer Cells to Protons of Increasing LET Through Targeting DNA Double Strand Break Repair. (PubMed, Cells) - "We demonstrate that inhibitors against ATR (AZD6738), and particularly ATM (AZD1390) and DNA-Pkcs (AZD7648), could significantly decrease clonogenic survival of HNSCC cell lines following PBT at both low and relatively high LET (~2 keV/µm and ~8 keV/µm, respectively). We confirmed that the inhibitors in combination with PBT led to DSB persistence through neutral comet assays and monitoring γH2AX/53BP1 foci. We also show that this strategy can enhance the sensitivity of patient-derived organoids of HNSCC to PBT of both low and high LET, highlighting this as a strategy which should be exploited further."

Journal • Ataxia • Head and Neck Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ATR • TP53BP1

GCAR-7213: Trial Designed To Evaluate Multiple Regimens In Newly Diagnosed and Recurrent Glioblastoma (GBM) (clinicaltrialsregister.eu) - P2/3 | N=120 | Active, not recruiting | Sponsor: Global Coalition For Adaptive Research Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

AZD1390: Data from P1 trial (NCT03423628) for brain metastases and newly diagnosed glioblastoma in H2 2026 (AstraZeneca) - Q1 2026 Results

P1 data • Glioblastoma • Oncology

Inhibition of ATM reverses radioiodine resistance in differentiated thyroid cancer via genotoxic stress amplification. (PubMed, J Transl Med) - "ATM promotes RAI resistance by enabling repair of AP sites and enforcing cell cycle arrest. Its inhibition converts sublethal lesions into cytotoxic damage and restores RAI sensitivity, highlighting ATM as a promising therapeutic target in RAI-refractory DTC. Further studies are required to evaluate long-term safety and durability of therapeutic response."

Journal • Ataxia • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland 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