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    DRUG:

    tuvusertib (M1774)

    i
    Other names: M1774, M 1774, MSC2584415A, VXc-400, VR 1363004, M-1774, MSC 2584415A, VR1363004, VXc 400, MSC-2584415A, VR-1363004, VXc400
    Company:
    EMD Serono
    Drug class:
    ATR inhibitor
    Related drugs:
    21d
    Asia-inclusive drug development leveraging principles of ICH E5 and E17 guidelines: Case studies illustrating quantitative clinical pharmacology as a foundational enabler. (PubMed, Clin Transl Sci)
    Herein, we describe recent case examples of model-informed Asia-inclusive global clinical development in the EMD Serono portfolio, as applied to the ataxia telangiectasia and Rad3-related inhibitors, tuvusertib and berzosertib (oncology), the toll-like receptor 7/8 antagonist, enpatoran (autoimmune diseases), the mesenchymal-epithelial transition factor inhibitor tepotinib (oncology), and the antimetabolite cladribine (neuroimmunological disease). Through these case studies, we illustrate pragmatic approaches to ethnic sensitivity assessments and the application of a model-informed drug development toolkit including population pharmacokinetic/pharmacodynamic modeling and pharmacometric disease progression modeling and simulation to enable early conduct of Asia-inclusive MRCTs. These examples demonstrate the value of a Totality of Evidence approach where every patient's data matter for de-risking ethnic sensitivity to inter-population variations in drug- and disease-related intrinsic and extrinsic factors, enabling inclusive global development strategies and timely evidence generation for characterizing benefit/risk of the proposed dosage in Asian populations.
    Review • Journal
    |
    ATR (Ataxia telangiectasia and Rad3-related protein)
    |
    Tepmetko (tepotinib) • berzosertib (M6620) • cladribine • tuvusertib (M1774)
    1m
    Combined MEK1/2 and ATR inhibition promotes myeloma cell death through a STAT3-dependent mechanism in vitro and in vivo. (PubMed, Br J Haematol)
    Co-administration of the ATR inhibitor (ATRi) BAY1895344 (BAY) and MEK1/2 inhibitors, for example, cobimetinib, synergistically increased cell death in diverse MM cell lines...Similar events occurred in highly bortezomib-resistant (PS-R) cells, in the presence of patient-derived conditioned medium, and with alternative ATR (e.g. M1774) and MEK1/2 (trametinib) inhibitors...Finally, the ATR inhibitor/cobimetinib regimen significantly improved survival in MM xenografts, including bortezomib-resistant models, with minimal toxicity. Collectively, these findings suggest that combined ATR/MEK1/2 inhibition triggers dual STAT3 Tyr705 and Ser727 dephosphorylation, pronounced downregulation of cytoprotective targets and MM cell death, warranting attention as a novel therapeutic strategy in MM.
    Preclinical • Journal
    |
    MYC (V-myc avian myelocytomatosis viral oncogene homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • BCL2L1 (BCL2-like 1) • STAT3 (Signal Transducer And Activator Of Transcription 3) • CD34 (CD34 molecule) • SDC1 (Syndecan 1)
    |
    Mekinist (trametinib) • Cotellic (cobimetinib) • bortezomib • elimusertib (BAY 1895344) • tuvusertib (M1774)
    2ms
    Study of Avelumab and Tuvusertib in Participants With Advanced Urothelial Cancer That Has Progressed on Prior Anti-PD-(L)1 Therapy (JAVELIN DDRiver Bladder) (clinicaltrials.gov)
    P2, N=0, Withdrawn, EMD Serono Research & Development Institute, Inc. | Not yet recruiting --> Withdrawn | N=70 --> 0
    Enrollment change • Trial withdrawal • Combination therapy • Metastases
    |
    Bavencio (avelumab) • tuvusertib (M1774)
    2ms
    Tuvusertib (M1774) in Combination With Cemiplimab in Participants With Non-Squamous NSCLC (DDRiver NSCLC 322) (clinicaltrials.gov)
    P1/2, N=61, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Recruiting --> Active, not recruiting | N=180 --> 61 | Trial completion date: Sep 2026 --> Mar 2025 | Trial primary completion date: Aug 2026 --> Jun 2024
    Enrollment closed • Enrollment change • Trial completion date • Trial primary completion date • Combination therapy
    |
    Libtayo (cemiplimab-rwlc) • tuvusertib (M1774)
    3ms
    Testing the Combination of Two Anti-cancer Drugs, Peposertib (M3814) and M1774 for Advanced Solid Tumors (clinicaltrials.gov)
    P1, N=66, Recruiting, National Cancer Institute (NCI) | Trial completion date: Aug 2024 --> Aug 2026 | Trial primary completion date: Aug 2024 --> Aug 2026
    Trial completion date • Trial primary completion date • Combination therapy • Metastases
    |
    ATM (ATM serine/threonine kinase) • ARID1A (AT-rich interaction domain 1A) • CCNE1 (Cyclin E1) • PBRM1 (Polybromo 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • ATRX (ATRX Chromatin Remodeler) • ARID1B (AT-Rich Interaction Domain 1B) • ARID2 (AT-Rich Interaction Domain 2) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2) • SS18 (SS18 Subunit Of BAF Chromatin Remodeling Complex)
    |
    peposertib (M3814) • tuvusertib (M1774)
    3ms
    M9466 as Single Agent or in Combination With Tuvusertib in Advanced Solid Tumors (DDRiver 501) (clinicaltrials.gov)
    P1, N=70, Recruiting, EMD Serono Research & Development Institute, Inc. | Not yet recruiting --> Recruiting
    Enrollment open • Combination therapy • Metastases
    |
    tuvusertib (M1774) • M9466
    4ms
    Tuvusertib Combined With Niraparib or Lartesertib in Participants With Epithelial Ovarian Cancer (DDRiver EOC 302) (clinicaltrials.gov)
    P2, N=60, Recruiting, EMD Serono Research & Development Institute, Inc. | Not yet recruiting --> Recruiting
    Enrollment open • Combination therapy
    |
    Zejula (niraparib) • tuvusertib (M1774) • lartesertib (M4076)
    4ms
    Avelumab and M1774 in ARID1A-mutated Endometrial Cancer (Prior IO) (clinicaltrials.gov)
    P2, N=25, Not yet recruiting, Panagiotis Konstantinopoulos, MD, PhD
    New P2 trial • Combination therapy • IO biomarker
    |
    Bavencio (avelumab) • tuvusertib (M1774)
    5ms
    DDRiver Solid Tumours 301: Tuvusertib (M1774) in Participants With Metastatic or Locally Advanced Unresectable Solid Tumors (DDRiver Solid Tumors 301) (clinicaltrials.gov)
    P1, N=204, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Trial completion date: Jul 2024 --> Jan 2025 | Trial primary completion date: May 2024 --> Jan 2025
    Trial completion date • Trial primary completion date • Metastases
    |
    ARID1A (AT-rich interaction domain 1A) • ATRX (ATRX Chromatin Remodeler)
    |
    Zejula (niraparib) • tuvusertib (M1774)
    5ms
    Tuvusertib (M1774) in Combination With Cemiplimab in Participants With Non-Squamous NSCLC (DDRiver NSCLC 322) (clinicaltrials.gov)
    P1/2, N=180, Recruiting, EMD Serono Research & Development Institute, Inc. | Phase classification: P1b/2a --> P1/2
    Phase classification • Combination therapy
    |
    Libtayo (cemiplimab-rwlc) • tuvusertib (M1774)
    6ms
    Tuvusertib Combined With Niraparib or Lartesertib in Participants With Epithelial Ovarian Cancer (DDRiver EOC 302) (clinicaltrials.gov)
    P2, N=60, Not yet recruiting, EMD Serono Research & Development Institute, Inc.
    New P2 trial • Combination therapy
    |
    Zejula (niraparib) • tuvusertib (M1774) • lartesertib (M4076)
    6ms
    Testing the Combination of Two Anticancer Drugs M1774 (Tuvusertib) and Avelumab to Evaluate Their Safety and Effectiveness in Treating Merkel Cell Skin Cancer, MATRiX Trial (clinicaltrials.gov)
    P2, N=50, Recruiting, National Cancer Institute (NCI) | Initiation date: Sep 2024 --> May 2024
    Trial initiation date • Metastases
    |
    Bavencio (avelumab) • tuvusertib (M1774)
    6ms
    Study of Avelumab and Tuvusertib in Participants With Advanced Urothelial Cancer That Has Progressed on Prior Anti-PD-(L)1 Therapy (JAVELIN DDRiver Bladder) (clinicaltrials.gov)
    P2, N=70, Not yet recruiting, EMD Serono Research & Development Institute, Inc.
    New P2 trial
    |
    Bavencio (avelumab) • tuvusertib (M1774)
    6ms
    M9466 as Single Agent or in Combination With Tuvusertib in Advanced Solid Tumors (DDRiver 501) (clinicaltrials.gov)
    P1, N=70, Not yet recruiting, EMD Serono Research & Development Institute, Inc.
    New P1 trial • Combination therapy • Metastases
    |
    tuvusertib (M1774) • M9466
    7ms
    M1774 Human Mass Balance Study (DDRIVER Solid Tumors 303) (clinicaltrials.gov)
    P1, N=6, Recruiting, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Not yet recruiting --> Recruiting
    Enrollment open • Metastases
    |
    tuvusertib (M1774)
    8ms
    POP-ART: A Study on Tuvusertib (Oral ATR Inhibitor) in Combination With PLX038 (Topo1 Inhibitor) in Patients With Advanced Solid Tumors (clinicaltrials.gov)
    P1, N=92, Not yet recruiting, Institut Curie
    New P1 trial • Combination therapy • Metastases
    |
    PLX038 • tuvusertib (M1774)
    8ms
    DDRiver Solid Tumours 301: Tuvusertib (M1774) in Participants With Metastatic or Locally Advanced Unresectable Solid Tumors (DDRiver Solid Tumors 301) (clinicaltrials.gov)
    P1, N=204, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Recruiting --> Active, not recruiting
    Enrollment closed • Metastases
    |
    ARID1A (AT-rich interaction domain 1A) • ATRX (ATRX Chromatin Remodeler)
    |
    ATM mutation • ARID1A mutation
    |
    Zejula (niraparib) • tuvusertib (M1774)
    8ms
    M1774 Human Mass Balance Study (DDRIVER Solid Tumors 303) (clinicaltrials.gov)
    P1, N=6, Not yet recruiting, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
    New P1 trial • Metastases
    |
    tuvusertib (M1774)
    8ms
    Study of M1774 in Combination With DNA Damage Response Inhibitor or Immune Checkpoint Inhibitor (DDRiver Solid Tumors 320) (clinicaltrials.gov)
    P1, N=72, Recruiting, EMD Serono Research & Development Institute, Inc. | Trial completion date: Dec 2023 --> May 2026 | Trial primary completion date: Dec 2023 --> Mar 2026
    Trial completion date • Trial primary completion date • Combination therapy • Checkpoint inhibition • IO biomarker • Metastases
    |
    Bavencio (avelumab) • tuvusertib (M1774) • lartesertib (M4076)
    8ms
    The novel ATR inhibitor M1774 induces replication protein overexpression and broad synergy with DNA-targeted anticancer drugs. (PubMed, Mol Cancer Ther)
    As single agent, M1774 suppressed cancer cell viability at nanomolar concentrations, showing greater activity than ceralasertib and berzosertib, but less potency than gartisertib and elimusertib in the small-cell lung cancer H146, H82, and DMS114 cell lines. Low dose of M1774 was found highly synergistic with a broad spectrum of clinical DDAs including TOP1 inhibitors (SN-38/irinotecan, topotecan, exatecan, and exatecan), the TOP2 inhibitor etoposide, cisplatin, the RNA polymerase II inhibitor lurbinectedin, and the PARP inhibitor talazoparib in various models including cancer cell lines, patient-derived organoids, and mouse xenograft models. Furthermore, we demonstrate that M1774 reverses chemoresistance to anticancer DDAs in cancer cells lacking SLFN11 expression, suggesting that SLFN11 can be utilized for patient selection in upcoming clinical trials.
    Journal • PARP Biomarker
    |
    SLFN11 (Schlafen Family Member 11) • PLK1 (Polo Like Kinase 1) • CHEK1 (Checkpoint kinase 1) • CCNB1 (Cyclin B1) • CDC45 (Cell Division Cycle 45)
    |
    SLFN11 expression
    |
    cisplatin • Talzenna (talazoparib) • etoposide IV • irinotecan • berzosertib (M6620) • ceralasertib (AZD6738) • topotecan • elimusertib (BAY 1895344) • Zepzelca (lurbinectedin) • tuvusertib (M1774) • gartisertib (M4344)
    9ms
    First-in-Human Study of the Ataxia Telangiectasia and Rad3-related (ATR) Inhibitor Tuvusertib (M1774) as Monotherapy in Patients with Solid Tumors. (PubMed, Clin Cancer Res)
    Tuvusertib demonstrated manageable safety and exposure-related target engagement. Further clinical evaluation of tuvusertib is ongoing.
    P1 data • Journal • BRCA Biomarker • PARP Biomarker
    |
    ARID1A (AT-rich interaction domain 1A) • ATRX (ATRX Chromatin Remodeler) • BRCA (Breast cancer early onset) • DAXX (Death-domain associated protein)
    |
    ARID1A mutation • BRCA wild-type
    |
    tuvusertib (M1774)
    9ms
    NRG-GY031: Testing Different Amounts of the Combination of Drugs M1774 and ZEN-3694 for the Treatment of Recurrent Ovarian and Endometrial Cancer (clinicaltrials.gov)
    P1, N=60, Recruiting, National Cancer Institute (NCI) | Initiation date: May 2024 --> Dec 2023
    Trial initiation date
    |
    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MSI (Microsatellite instability) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • ARID1A (AT-rich interaction domain 1A) • MUC16 (Mucin 16, Cell Surface Associated) • HEXIM1 (HEXIM P-TEFb Complex Subunit 1)
    |
    MSI-H/dMMR
    |
    ZEN-3694 • tuvusertib (M1774)
    10ms
    Testing the Combination of Two Anticancer Drugs M1774 (Tuvusertib) and Avelumab to Evaluate Their Safety and Effectiveness in Treating Merkel Cell Skin Cancer, MATRiX Trial (clinicaltrials.gov)
    P2, N=50, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Trial completion date: Jun 2025 --> Jan 2028 | Initiation date: Dec 2023 --> Sep 2024 | Trial primary completion date: Jun 2025 --> Jan 2028
    Enrollment open • Trial completion date • Trial initiation date • Trial primary completion date • Metastases
    |
    Bavencio (avelumab) • tuvusertib (M1774)
    11ms
    Testing Different Amounts of the Combination of Drugs M1774 and ZEN-3694 for the Treatment of Recurrent Ovarian and Endometrial Cancer (clinicaltrials.gov)
    P1, N=60, Recruiting, National Cancer Institute (NCI) | Phase classification: P1b --> P1
    Phase classification
    |
    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MSI (Microsatellite instability) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • ARID1A (AT-rich interaction domain 1A) • MUC16 (Mucin 16, Cell Surface Associated) • HEXIM1 (HEXIM P-TEFb Complex Subunit 1)
    |
    MSI-H/dMMR
    |
    ZEN-3694 • tuvusertib (M1774)
    12ms
    Testing the Effect of M1774 on Hard-to-Treat Refractory SPOP-mutant Prostate Cancer (clinicaltrials.gov)
    P2, N=20, Recruiting, National Cancer Institute (NCI) | Initiation date: Apr 2024 --> Oct 2023
    Trial initiation date
    |
    SPOP (Speckle Type BTB/POZ Protein) • RAC1 (Rac Family Small GTPase 1) • FDFT1 (Farnesyl-Diphosphate Farnesyltransferase 1) • MVD (Mevalonate Diphosphate Decarboxylase)
    |
    SPOP mutation
    |
    tuvusertib (M1774)
    12ms
    Testing the Combination of Two Anti-cancer Drugs, Peposertib (M3814) and M1774 for Advanced Solid Tumors (clinicaltrials.gov)
    P1, N=66, Recruiting, National Cancer Institute (NCI) | Phase classification: P1b --> P1 | Initiation date: Nov 2023 --> Feb 2024
    Phase classification • Trial initiation date
    |
    ATM (ATM serine/threonine kinase) • ARID1A (AT-rich interaction domain 1A) • CCNE1 (Cyclin E1) • PBRM1 (Polybromo 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • ATRX (ATRX Chromatin Remodeler) • ARID1B (AT-Rich Interaction Domain 1B) • ARID2 (AT-Rich Interaction Domain 2) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2) • SS18 (SS18 Subunit Of BAF Chromatin Remodeling Complex)
    |
    ATM mutation • ARID1A mutation • CCNE1 amplification • PBRM1 mutation • CCNE1 mutation
    |
    peposertib (M3814) • tuvusertib (M1774)
    1year
    M1774 in Combination With Cemiplimab in Participants With Non-Squamous NSCLC (DDRiver NSCLC 322) (clinicaltrials.gov)
    P1b/2a, N=180, Recruiting, EMD Serono Research & Development Institute, Inc. | Not yet recruiting --> Recruiting
    Enrollment open • Combination therapy
    |
    Libtayo (cemiplimab-rwlc) • tuvusertib (M1774)
    1year
    Testing the Combination of Two Anti-cancer Drugs, Peposertib (M3814) and M1774 for Advanced Solid Tumors (clinicaltrials.gov)
    P1b, N=66, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting | Initiation date: May 2023 --> Nov 2023
    Enrollment open • Trial initiation date • Combination therapy • Metastases
    |
    ATM (ATM serine/threonine kinase) • ARID1A (AT-rich interaction domain 1A) • CCNE1 (Cyclin E1) • PBRM1 (Polybromo 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • ATRX (ATRX Chromatin Remodeler) • ARID1B (AT-Rich Interaction Domain 1B) • ARID2 (AT-Rich Interaction Domain 2) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2) • SS18 (SS18 Subunit Of BAF Chromatin Remodeling Complex)
    |
    ATM mutation • ARID1A mutation • CCNE1 amplification • PBRM1 mutation • CCNE1 mutation
    |
    peposertib (M3814) • tuvusertib (M1774)
    1year
    NRG-GY031: Testing Different Amounts of the Combination of Drugs M1774 and ZEN-3694 for the Treatment of Recurrent Ovarian and Endometrial Cancer (clinicaltrials.gov)
    P1b, N=60, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Initiation date: Aug 2023 --> May 2024
    Enrollment open • Trial initiation date
    |
    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MSI (Microsatellite instability) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • ARID1A (AT-rich interaction domain 1A) • MUC16 (Mucin 16, Cell Surface Associated) • HEXIM1 (HEXIM P-TEFb Complex Subunit 1)
    |
    MSI-H/dMMR
    |
    ZEN-3694 • tuvusertib (M1774)
    over1year
    Testing the Effect of M1774 on Hard-to-Treat Refractory SPOP-mutant Prostate Cancer (clinicaltrials.gov)
    P2, N=20, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Initiation date: Aug 2023 --> Apr 2024
    Enrollment open • Trial initiation date
    |
    SPOP (Speckle Type BTB/POZ Protein)
    |
    SPOP mutation
    |
    tuvusertib (M1774)
    over1year
    MATRIX: I/II Phase Study Evaluating M1774 in Combination With Fulvestrant in HR+ and HER2- Advanced Breast Cancers (clinicaltrials.gov)
    P1/2, N=57, Not yet recruiting, Institut Paoli-Calmettes
    New P1/2 trial • Combination therapy • Metastases
    |
    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • RB1 (RB Transcriptional Corepressor 1) • ARID1A (AT-rich interaction domain 1A) • CDK12 (Cyclin dependent kinase 12) • ATRX (ATRX Chromatin Remodeler) • BRCA (Breast cancer early onset) • CHEK2 (Checkpoint kinase 2) • FANCA (FA Complementation Group A) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • RAD54L (DNA Repair And Recombination Protein RAD54) • FANCL (FA Complementation Group L) • PPP2R2A (Protein Phosphatase 2, Regulatory Subunit B, Alpha) • ERCC4 (ERCC Excision Repair 4, Endonuclease Catalytic Subunit) • FANCD2 (FA Complementation Group D2) • XRCC1 (X-Ray Repair Cross Complementing 1)
    |
    BRCA2 mutation • HR positive • HER-2 negative • ATM mutation • ARID1A mutation • PALB2 mutation
    |
    fulvestrant • tuvusertib (M1774)
    over1year
    DDRiver Solid Tumours 301: M1774 in Participants With Metastatic or Locally Advanced Unresectable Solid Tumors (DDRiver Solid Tumors 301) (clinicaltrials.gov)
    P1, N=204, Recruiting, EMD Serono Research & Development Institute, Inc. | N=130 --> 204
    Enrollment change • Metastases
    |
    ARID1A (AT-rich interaction domain 1A) • ATRX (ATRX Chromatin Remodeler)
    |
    ATM mutation • ARID1A mutation
    |
    Zejula (niraparib) • tuvusertib (M1774)
    over1year
    Testing Different Amounts of the Combination of Drugs M1774 and ZEN-3694 for the Treatment of Recurrent Ovarian and Endometrial Cancer (clinicaltrials.gov)
    P1b, N=60, Not yet recruiting, National Cancer Institute (NCI)
    New P1 trial
    |
    MSI (Microsatellite instability) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • ARID1A (AT-rich interaction domain 1A)
    |
    MSI-H/dMMR • MYC expression
    |
    ZEN-3694 • tuvusertib (M1774)
    over1year
    Testing the Combination of Two Anticancer Drugs M1774 (Tuvusertib) and Avelumab to Evaluate Their Safety and Effectiveness in Treating Merkel Cell Skin Cancer, MATRiX Trial (clinicaltrials.gov)
    P2, N=50, Not yet recruiting, National Cancer Institute (NCI)
    New P2 trial • Metastases
    |
    Bavencio (avelumab) • tuvusertib (M1774)
    over1year
    Testing the Combination of the Anti-Cancer Drugs Temozolomide and M1774 to Evaluate Their Safety and Effectiveness (clinicaltrials.gov)
    P1/2, N=58, Recruiting, National Cancer Institute (NCI) | Initiation date: Jun 2023 --> Sep 2023
    Trial initiation date • Tumor mutational burden
    |
    temozolomide • tuvusertib (M1774)
    over1year
    Testing the Combination of the Anti-Cancer Drugs Temozolomide and M1774 to Evaluate Their Safety and Effectiveness (clinicaltrials.gov)
    P1/2, N=58, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | N=42 --> 58
    Enrollment open • Enrollment change • Tumor mutational burden
    |
    temozolomide • tuvusertib (M1774)
    over1year
    Testing the Combination of Two Anti-cancer Drugs, Peposertib (M3814) and M1774 for Advanced Solid Tumors (clinicaltrials.gov)
    P1b, N=66, Suspended, National Cancer Institute (NCI) | Not yet recruiting --> Suspended
    Trial suspension • Combination therapy • Metastases
    |
    ATM (ATM serine/threonine kinase) • ARID1A (AT-rich interaction domain 1A) • CCNE1 (Cyclin E1) • PBRM1 (Polybromo 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • ATRX (ATRX Chromatin Remodeler) • ARID1B (AT-Rich Interaction Domain 1B) • ARID2 (AT-Rich Interaction Domain 2) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2) • SS18 (SS18 Subunit Of BAF Chromatin Remodeling Complex)
    |
    ATM mutation • ARID1A mutation • CCNE1 amplification • PBRM1 mutation • CCNE1 mutation
    |
    peposertib (M3814) • tuvusertib (M1774)
    over1year
    DDRiver Solid Tumours 301: M1774 in Participants With Metastatic or Locally Advanced Unresectable Solid Tumors (DDRiver Solid Tumors 301) (clinicaltrials.gov)
    P1, N=130, Recruiting, EMD Serono Research & Development Institute, Inc. | Trial completion date: Dec 2023 --> Apr 2024 | Trial primary completion date: Mar 2023 --> Mar 2024
    Trial completion date • Trial primary completion date • Metastases
    |
    ARID1A (AT-rich interaction domain 1A) • ATRX (ATRX Chromatin Remodeler)
    |
    ATM mutation • ARID1A mutation
    |
    Zejula (niraparib) • tuvusertib (M1774)
    over1year
    Testing the Effect of M1774 on Hard-to-Treat Refractory SPOP-mutant Prostate Cancer (clinicaltrials.gov)
    P2, N=20, Not yet recruiting, National Cancer Institute (NCI)
    New P2 trial
    |
    SPOP (Speckle Type BTB/POZ Protein)
    |
    SPOP mutation
    |
    tuvusertib (M1774)
    over1year
    Combination of M1774 and niraparib can overcome ATR and PARP inhibitor resistance in BRCA1 mutated ovarian cancer models (AACR 2023)
    Collectively, these results indicate that the combination of M1774 and niraparib can overcome PARP inhibitor resistance and ATR inhibitor resistance in BRCA1-mutant ovarian cancer PDX models and demonstrate the utility of organoid cultures for discerning mechanisms of resistance and strategies to restore drug sensitivity. Combined M1774-mediated ATR inhibition and PARP inhibition may be a promising therapeutic strategy for the treatment of ovarian cancer.
    Preclinical • BRCA Biomarker • PARP Biomarker
    |
    BRCA1 (Breast cancer 1, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
    |
    BRCA1 mutation • BRCA mutation
    |
    Zejula (niraparib) • tuvusertib (M1774)
    almost2years
    Testing the Combination of Two Anti-cancer Drugs, Peposertib (M3814) and M1774 for Advanced Solid Tumors (clinicaltrials.gov)
    P1b, N=66, Not yet recruiting, National Cancer Institute (NCI)
    New P1 trial • Combination therapy • Metastases
    |
    ATM (ATM serine/threonine kinase) • ARID1A (AT-rich interaction domain 1A) • CCNE1 (Cyclin E1) • PBRM1 (Polybromo 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • ATRX (ATRX Chromatin Remodeler) • ARID1B (AT-Rich Interaction Domain 1B) • ARID2 (AT-Rich Interaction Domain 2) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2) • SS18 (SS18 Subunit Of BAF Chromatin Remodeling Complex)
    |
    ATM mutation • ARID1A mutation • CCNE1 amplification • PBRM1 mutation • CCNE1 mutation
    |
    peposertib (M3814) • tuvusertib (M1774)
    3years
    M1774 in Participants With Metastatic or Locally Advanced Unresectable Solid Tumors (DDRiver Solid Tumors 301) (clinicaltrials.gov)
    P1, N=130, Recruiting, EMD Serono Research & Development Institute, Inc. | Trial primary completion date: Sep 2021 --> Mar 2023
    Clinical • Trial primary completion date
    |
    ATRX (ATRX Chromatin Remodeler)
    |
    ATM mutation
    |
    Zejula (niraparib) • tuvusertib (M1774)