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    DRUG:

    AZD1390

    i
    Other names: AZD1390, AZD 1390, AZD-1390
    Company:
    AstraZeneca
    Drug class:
    ATM kinase inhibitor
    Related drugs:
    3ms
    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.
    Review • Journal • PARP Biomarker
    |
    CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
    |
    AZD1390 • KU-55933 • AZD0156 • M3541 • WSD0628
    4ms
    GBM AGILE: A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma (clinicaltrials.gov)
    P2/3, N=1280, Recruiting, 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
    |
    IDH wild-type
    |
    temozolomide • Stivarga (regorafenib) • lomustine • VT1021 • AZD1390 • Hepacid (pegargiminase) • paxalisib (GDC-0084) • dianhydrogalactitol (VAL-083) • Vyglxia (troriluzole)
    7ms
    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, Children's Oncology Group | Not yet recruiting --> Recruiting | Initiation date: May 2025 --> Feb 2026
    Enrollment open • Trial initiation date
    |
    AZD1390
    8ms
    CONCORDE: A Platform Study of Novel Agents in Combination With Radiotherapy in NSCLC (clinicaltrials.gov)
    P1, N=200, Recruiting, University of Leeds | Trial primary completion date: Apr 2025 --> Mar 2026
    Trial primary completion date
    |
    Lynparza (olaparib) • Imfinzi (durvalumab) • ceralasertib (AZD6738) • AZD1390 • saruparib (AZD5305)
    8ms
    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, Children's Oncology Group
    New P1 trial
    |
    AZD1390
    11ms
    A Study of AZD1390 and Stereotactic Body Radiotherapy (SBRT) for People with Metastatic Solid Tumor Cancer (clinicaltrials.gov)
    P1, N=54, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    AZD1390
    12ms
    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
    |
    STAT1 (Signal Transducer And Activator Of Transcription 1) • IFNB1 (Interferon Beta 1)
    |
    berzosertib (M6620) • AZD1390
    1year
    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, AstraZeneca | N=120 --> 180 | Trial completion date: Apr 2026 --> Sep 2026 | Trial primary completion date: Apr 2026 --> Sep 2026
    Enrollment change • Trial completion date • Trial primary completion date • Combination therapy
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1)
    |
    IDH1 mutation
    |
    AZD1390
    over1year
    ATM inhibition exploits checkpoint defects and ATM-dependent double strand break repair in TP53-mutant glioblastoma. (PubMed, Nat Commun)
    Using this method, we show that patient-derived glioblastoma (GBM) samples with acquired temozolomide (TMZ) resistance display elevated HR and MMEJ activity, suggesting that these pathways contribute to treatment resistance. We further show that a combination of G2/M checkpoint deficiency and reliance upon ATM-dependent DSBR renders TP53 mutant GBMs hypersensitive to TMZ/AZD1390 and radiation/AZD1390 combinations. This report identifies ATM-dependent HR and MMEJ as targetable resistance mechanisms in TP53-mutant GBM and establishes an approach for simultaneously measuring multiple DSBR pathways in treatment selection and oncology research.
    Journal
    |
    TP53 (Tumor protein P53)
    |
    temozolomide • AZD1390
    over1year
    Inhibition of key DNA double strand break repair protein kinases enhances radiosensitivity of head and neck cancer cells to X-ray and proton irradiation. (PubMed, Cell Death Discov)
    Using inhibitors targeting ATM (AZD1390), ATR (AZD6738) and DNA-Pkcs (AZD7648), we observed that this led to significantly decreased clonogenic survival of HNSCC cell lines following both X-ray and proton irradiation. We confirmed that the inhibitors in combination with X-rays and protons led to DSB persistence, and increased micronuclei formation. Cumulatively, our data suggest that targeting DSB repair, particularly via ATM and DNA-Pkcs inhibition, can exacerbate the impact of ionising radiation in sensitising HNSCC cell models.
    Journal
    |
    ATR (Ataxia telangiectasia and Rad3-related protein)
    |
    ceralasertib (AZD6738) • AZD1390 • AZD7648
    over1year
    SADDRIN-1: Sarcomas and DDR-Inhibition; a Combined Modality Study (clinicaltrials.gov)
    P1, N=30, Recruiting, The Netherlands Cancer Institute | N=15 --> 30 | Trial completion date: Mar 2024 --> Jul 2028 | Trial primary completion date: Mar 2024 --> Mar 2026
    Enrollment change • Trial completion date • Trial primary completion date
    |
    Imfinzi (durvalumab) • AZD1390
    over1year
    A Study to Assess the Safety and Tolerability of AZD1390 Given With Radiation Therapy in Patients With Brain Cancer (clinicaltrials.gov)
    P1, N=120, Recruiting, AstraZeneca | Trial completion date: Feb 2025 --> Apr 2026 | Trial primary completion date: Feb 2025 --> Apr 2026
    Trial completion date • Trial primary completion date • Combination therapy
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1)
    |
    IDH1 mutation
    |
    AZD1390