peposertib (M3814) / EMD Serono - LARVOL DELTA

Testing the Addition of An Anti-cancer Drug, M3814 (Peposertib), to the Usual Radiation-Based Treatment (Lutetium Lu 177 Dotatate) for Pancreatic Neuroendocrine Tumors (clinicaltrials.gov) - P1 | N=29 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Oct 2025 ➔ Jun 2026 | Trial primary completion date: Oct 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Endocrine Cancer • Gastrointestinal Neuroendocrine Tumor • Neuroendocrine Carcinoma • Neuroendocrine Tumor • Oncology • Solid Tumor

Results of A phase I study of peposertib in combination with MEC in patients with relapsed or refractory Acute Myeloid Leukemia (ASH 2025) - P1 | "MEC, consisting of mitoxantrone, etoposide (ETOP), and cytarabine, is anestablished regimen for the treatment of R/R AML. Overall, combining peposertib with MEC was feasible and did not significantly affect ETOP PK. Despite thehigh risk and heavily pretreated study population, including 78% with prior venetoclax, activity was seenon multiple dose levels, including A2 and A4, which were both expanded and remain RP2D candidatesafter expansion. Additional PK and PD analyses, follow-up, and evaluation of duration of remission,event-free survival, and overall survival, will aid in selecting the final RP2D and informing future studies."

Clinical • Combination therapy • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Infectious Disease • Leukemia • Mucositis • Septic Shock • CYP3A4

Comparative analysis of molecular targeted radiosensitizers in 2D and 3D cancer cell line models. (PubMed, Acta Oncol) - "Integrating multiple culture models enhances the detection of cell line - and drug-specific radiosensitization. Although 2D and 3D cultures produced largely similar results, and 2D assays provide a practical alternative when 3D methods are not feasible, the 3D cultures reveal additional ECM-dependent responses. These results emphasize the utility of physiologically relevant platforms for robust screening and prioritization of candidate radiosensitizers."

Clinical • Journal • Preclinical • Lung Cancer • Oncology • Solid Tumor

Testing the Combination of New Anti-cancer Drug Peposertib With Avelumab and Radiation Therapy for Advanced/Metastatic Solid Tumors and Hepatobiliary Malignancies (clinicaltrials.gov) - P1/2 | N=103 | Suspended | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Suspended

Trial suspension • Tumor mutational burden • Biliary Cancer • Cholangiocarcinoma • Gallbladder Cancer • Oncology • Solid Tumor

Phase I Trial of Peposertib (DNA-PK inhibitor) Plus Radiation in Newly Diagnosed MGMT-Unmethylated Glioblastoma, Updated Clinical, Radiographic, and Biomarker Outcomes (SNO 2025) - P1 | "Updated outcomes remain encouraging and support further development of peposertib. High rate of distant recurrence and positive association between RT-induced changes and PFS suggest that peposertib is active as a radiosensitizer. Further genomic, transcriptomic, and spatial proteomic analyses, are underway and will be presented at the conference."

Biomarker • Clinical • P1 data • Brain Cancer • Glioblastoma • Solid Tumor • H2AX • MGMT

Oncolytic Herpes Simplex Virus Synergizes with DNA-PKcs Inhibitors to Treat Glioblastoma (SNO 2025) - "To validate selectivity and restrict inhibition to GBM cells, we created GSCs with doxycycline-inducible DNA-PKcs shRNA, which significantly reduced sphere formation (Stemness). These findings underscore the vulnerability of human GSCs to DNA-PKcs inhibition in the absence of DNA-damaging agents and its robust synergy with oHSV. Given that both G47Δ and M3814 have been evaluated in clinical trials, this study supports their continued clinical translation and further investigation into combination therapies for GBM."

Brain Cancer • Glioblastoma • Herpes Simplex • Solid Tumor

Phase I Trial of Peposertib (DNA-PK inhibitor) Plus Radiation in Newly Diagnosed MGMT-Unmethylated Glioblastoma, Updated Clinical, Radiographic, and Biomarker Outcomes (SNO 2025) - P1 | "Updated outcomes remain encouraging and support further development of peposertib. High rate of distant recurrence and positive association between RT-induced changes and PFS suggest that peposertib is active as a radiosensitizer. Further genomic, transcriptomic, and spatial proteomic analyses, are underway and will be presented at the conference."

Biomarker • Clinical • P1 data • Brain Cancer • Glioblastoma • Solid Tumor • H2AX • MGMT

Combined DNA-PK and PARP Inhibition as a Therapeutic Strategy in BRCA-Mutated Prostate Cancer: An in Vitro Pilot Study. (PubMed, Technol Cancer Res Treat) - "Scramble LNCaP, BRCA1 KO, and BRCA2 KO cells were treated with the PARPi talazoparib, the DNA-PK inhibitor nedisertib and their combination. Therapeutically targeting NHEJ presents a promising approach in treating BRCA-mutated PCa. Further in vivo investigations are required to assess the tolerability of this drug combination."

Journal • Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ANXA5 • BRCA • BRCA1 • BRCA2

Phase I Trial of Peposertib (DNA-PK inhibitor) Plus Radiation in Newly Diagnosed MGMT-Unmethylated Glioblastoma, Updated Clinical, Radiographic, and Biomarker Outcomes (WFNOS 2025) - P1 | "Updated outcomes remain encouraging and support further development of peposertib. High rate of distant recurrence and positive association between RT-induced changes and PFS suggest that peposertib is active as a radiosensitizer. Further genomic, transcriptomic, and spatial proteomic analyses, are underway and will be presented at the conference."

Biomarker • Clinical • P1 data • Brain Cancer • Glioblastoma • Glioma • Solid Tumor • H2AX • MGMT

Phase I Trial of Peposertib (DNA-PK inhibitor) Plus Radiation in Newly Diagnosed MGMT-Unmethylated Glioblastoma, Updated Clinical, Radiographic, and Biomarker Outcomes (WFNOS 2025) - P1 | "Updated outcomes remain encouraging and support further development of peposertib. High rate of distant recurrence and positive association between RT-induced changes and PFS suggest that peposertib is active as a radiosensitizer. Further genomic, transcriptomic, and spatial proteomic analyses, are underway and will be presented at the conference."

Biomarker • Clinical • P1 data • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • H2AX • MGMT

Oncolytic Herpes Simplex Virus Synergizes with DNA-PKcs Inhibitors to Treat Glioblastoma (WFNOS 2025) - "To validate selectivity and restrict inhibition to GBM cells, we created GSCs with doxycycline-inducible DNA-PKcs shRNA, which significantly reduced sphere formation (Stemness). These findings underscore the vulnerability of human GSCs to DNA-PKcs inhibition in the absence of DNA-damaging agents and its robust synergy with oHSV. Given that both G47Δ and M3814 have been evaluated in clinical trials, this study supports their continued clinical translation and further investigation into combination therapies for GBM."

Brain Cancer • Glioblastoma • Herpes Simplex • Solid Tumor

Optimizing CRISPR/Cas-Mediated CD-19 CAR knock-in efficiency, cell viability and cell expansion in human primary T cells using a cGMP-compliant electroporation platform (ESGCT 2024) - "Complexing Ribonucleoproteins (RNPs) with anionic polymer PGA (Poly-L-Glutamic acid) or treating T cells post-EP with Homology-Directed Repair (HDR) enhancing small molecules such as, M3814, Trichostatin A (TSA) and a commercial HDR enhancer further increased the GFP knock-in efficiency by 3-5-fold, depending on the small molecule used. As with GFP KI, addition of PGA in RNP or HDR enhancing drug post-EP further enhanced the CD-19 CAR KI efficiency by 2-3-fold. In summary, we present data on KO/KI optimization, cell viability, cell expansion, cell phenotyping and potency assay post electroporation and clearly demonstrate that using MaxCyte’s GMP-compliant electroporation platform and GenScript’s reagents can engineer T cells from multiple donors with high efficiency that can be used for the treatment of diseases including cancer."

RAB11A

Peposertib and Radiation Therapy, Followed by Temozolomide for the Treatment of Patients With Newly Diagnosed MGMT Unmethylated Glioblastoma or Gliosarcoma (clinicaltrials.gov) - P1 | N=29 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Oct 2025 ➔ Dec 2027 | Trial primary completion date: Oct 2025 ➔ Dec 2027

Trial completion date • Trial primary completion date • Brain Cancer • Glioblastoma • Gliosarcoma • Oncology • Sarcoma • Solid Tumor • MGMT

Inhibition of DNA Damage Response Factor DNA-PKcs-mediated H2AX Phosphorylation Enhances Selinexor-induced Anti-multiple Myeloma Effects (IMS 2025) - "DNA-PKcs-mediated H2AX phosphorylation promotes DNA damage repair and survival of myeloma cells in response to XPO1 inhibitor Selinexor. DNA-PKcs inhibition increases Selinexor-induced DNA damage and enhances MM sensitivity to Selinexor. The combination of DNA-PKcs inhibitor Nedisertib with Selinexor demonstrates strong synergistic anti-MM effects both in vitro and in vivo."

IO biomarker • Hematological Malignancies • Multiple Myeloma • XPO1

NRG-HN008: Testing the Addition of M3814 (Peposertib) to Radiation Therapy for Patients With Advanced Head and Neck Cancer Who Cannot Take Cisplatin (clinicaltrials.gov) - P1 | N=42 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Sep 2025 ➔ Dec 2025 | Trial primary completion date: Sep 2025 ➔ Dec 2025

Trial completion date • Trial primary completion date • Head and Neck Cancer • Hypopharyngeal Cancer • Laryngeal Cancer • Oncology • Oral Cancer • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD4

DNA-PKcs inhibition as a therapeutic approach for differentiated thyroid cancer. (PubMed, Endocr Relat Cancer) - "M3814 in combination with lenvatinib demonstrated synergism in vitro, and this combination was more effective than any single therapy in an FTC-133 xenograft model. These results reveal that M3814 has significant potential in treating DTC, singly or in drug combination."

Journal • Gene Therapies • Oncology • Solid Tumor • Thyroid Gland Carcinoma

Enhanced Antitumor Efficacy of DNA Damage Response Inhibitors Combined with 225Ac-DOTA-girentuximab (SNMMI 2025) - "Lartesertib and peposertib exhibited IC50 values of 3.543 µM and 0.7712 µM, respectively, in SK-RC-52 cells. The IC50 value for 225Ac-DOTA-girentxuimab in SK-RC-52 cells was 0.1505 kBq/mL. Synergy mapping analysis revealed an additive effect between 225Ac-DOTA-girentuximab and lartesertib."

Clinical • Ataxia • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • CA9

Improving Solubility by Crystallographic Disorder: Enabling Peposertib First-in-Human Trials. (PubMed, Eur J Pharm Sci) - "It allowed fast entry into first-in-human clinical trials with the objective of transitioning to a bio-enabling formulation, which necessitates a more time-consuming development process. To the best of our knowledge, this is the first time a crystallographically disordered phase has not only been discovered but also thoroughly investigated, and consequently utilized to accelerate entry into clinical development."

Journal • P1 data • Infectious Disease • Oncology • Solid Tumor

Targeting synthetic lethality between non-homologous end joining and radiation in very-high-risk medulloblastoma. (PubMed, Cell Rep Med) - "Both genetic and pharmacological perturbation of DNA-PK enhance radiosensitivity in TP53-deficient SHH medulloblastoma, leading to cell death. In vivo treatment of both somatic and germline TP53-mutant SHH medulloblastoma models with peposertib, a small-molecule inhibitor of DNA-PK, significantly improves survival when combined with radiotherapy, strongly supporting further clinical investigation."

Journal • Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • SHH • TP53

Targeting the Non-Homologous End-Joining Pathway Sensitizes MDM2-Amplified Liposarcoma to Doxorubicin-Induced Senescence in a p53-dependent Manner (EACR 2025) - "We used an unbiased approach to identify therapeutic strategies sensitizing to these current DDLPS therapies.Material and Three parallel genome-wide CRISPR-Cas9 knockout screens were conducted in DDLPS cells to sensitize to palbociclib (CDK4 inhibitor), nutlin-3a (MDM2 inhibitor) or doxorubicin...Following validation of both pathways, we focused on mechanistic characterization of doxorubicin sensitization by genetic perturbation of TDP2 or pharmacological inhibition of PRKDC using peposertib... These findings provide a rationale for targeting the NHEJ pathway to enhance the efficacy of doxorubicin in an MDM2-amplified cancer, highlighting a potential therapeutic strategy that exploits p53-dependent cell cycle arrest and senescence for improved treatment outcomes. Furthermore, we provide, to our knowledge, the first evidence of maintained p53 activity in untreated MDM2 amplified DDLPS."

Liposarcoma • Oncology • Sarcoma • Solid Tumor • CCNE1 • CDK2 • CKS1B • E2F3 • MDM2 • PRKDC • XRCC4

Targeting Artemis Sensitizes B Cells to Topoisomerase 2 Poisons by Disrupting DNA-PKcs-Dependent Repair. (PubMed, Res Sq) - "Inhibition of the Artemis activator, DNA-PKcs, with peposertib (M3814) sensitizes B cells to Top2 poisons while ATM or ATR inhibition does not...Clinical data demonstrates that high Artemis expression correlates with poor survival in several cancers, and we demonstrate that Artemis function is critical for survival following combination drug treatment. These insights can be leveraged to unlock new avenues for the treatment of aggressive cancers by enhancing the cytotoxicity of agents through blockade of DNA break repair."

Journal • Oncology • TOP2A

THE DNA-PK INHIBITOR, M3814 (PEPOSERTIB), IS CYTOTOXIC TO CHRONIC LYMPHOCYTIC LEUKEMIA CELLS EX VIVO AND SYNERGISTIC WITH VENETOCLAX (EHA 2025) - "We previously found that M3814 is synergistic with chemotherapy, but not ibrutinib, in CLL cells, even in those with p53 dysfunction (Kost, S. et al 2023, Blood Cancer J). These novel results indicate that DNA-PK inhibition by M3814 enhances the activity of VEN in CLL cells ex vivo and may overcome VEN resistance. As both VEN and M3814 are being evaluated clinically, these findings have potential for the treatment of leukemia."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • BCL2 • CD40LG • IGH

A Study Combining the Peposertib (M3814) Pill With Standard Chemotherapy in Patients With Ovarian Cancer With an Expansion in High Grade Serous Ovarian Cancer and Low Grade Serous Ovarian Cancer (clinicaltrials.gov) - P1 | N=54 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2025 ➔ Jun 2026 | Trial primary completion date: Jun 2025 ➔ Jun 2026

Platinum resistant • Platinum sensitive • Trial completion date • Trial primary completion date • Carcinosarcoma • Fallopian Tube Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Peritoneal Cancer • Sarcoma • Solid Tumor • Urothelial Cancer

Testing the Addition of an Anti-cancer Drug, M3814, to the Usual Treatment (Mitoxantrone, Etoposide, and Cytarabine) for Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=48 | Suspended | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2025 ➔ Jun 2026 | Trial primary completion date: Jun 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD4 • PML • RARA

ETCTN 10563: Testing Low-Dose Common Chemotherapy (Liposomal Doxorubicin) in Combination With an Anti-Cancer Drug, Peposertib, in Advanced Sarcoma (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: May 2025 ➔ May 2026 | Trial primary completion date: May 2025 ➔ May 2026

Trial completion date • Trial primary completion date • Leiomyosarcoma • Liposarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Synovial Sarcoma • Undifferentiated Pleomorphic Sarcoma