M3541 / EMD Serono - LARVOL DELTA

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

MS200770_0001: M3541 in Combination With Radiotherapy in Solid Tumors (clinicaltrials.gov) - P1 | N=15 | Terminated | Sponsor: EMD Serono Research & Development Institute, Inc. | Completed ➔ Terminated; The study was terminated early per sponsor decision to halt further development of M3541 due to pharmaceutical and PK/pharmacodynamics properties that precluded further clinical development.

Trial termination • Oncology • Solid Tumor

Selective inhibition of ATM-dependent double-strand break repair and checkpoint control synergistically enhances the efficacy of ATR inhibitors. (PubMed, Mol Cancer Ther) - "In cancer cells with functional ATM and p53 signaling, selective suppression of ATR catalytic activity by M6620 induced G1 phase arrest to prevent S-phase entry with unrepaired DSBs. The selective ATM inhibitors, M3541 and M4076, suppressed both ATM-dependent cell cycle checkpoints and DSB repair, lowered the p53 protective barrier and extended the life of ATR inhibitor induced DSBs...ATM inhibitor synergistically potentiated the ATR inhibitor efficacy in cancer cells in vitro and increased ATR inhibitor efficacy in vivo at doses that did not show overt toxicities. Further, a combination study in 26 patient-derived xenograft models of triple negative breast cancer with the newer generation ATR inhibitor M4344 and ATM inhibitor M4076 demonstrated substantial improvement in efficacy and survival compared to single-agent M4344, suggesting a novel and potentially broad combination approach to cancer therapy."

Journal • Ataxia • Breast Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Triple Negative Breast Cancer

Selective ATM inhibition augments radiation-induced inflammatory signaling and cancer cell death. (PubMed, Aging (Albany NY)) - "We recently reported two new potent and selective ATM inhibitors, M3541 and M4076, that effectively sensitize cancer cells to radiation and regress human xenografts in clinically relevant animal models. In addition, strong upregulation of PD-L1 expression was observed in the surviving irradiated cancer cells exposed to M3541. Simultaneous activation of the STING pathway and PD-L1 suggested that combination of radiation, ATM inhibitors and PD-L1 targeted therapy may offer a novel approach to radio-immunotherapy of locally advanced tumors."

IO biomarker • Journal • Ataxia • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency

A new class of selective ATM inhibitors as combination partners of DNA double-strand break inducing cancer therapies. (PubMed, Mol Cancer Ther) - "Here, we describe the pharmacological activities of two highly potent and selective ATM inhibitors from a new chemical class, M3541 and M4076. In vitro and in vivo experiments demonstrated strong combination potential with PARP and topoisomerase I inhibitors. M4076 is currently under clinical investigation."

Journal • Ataxia • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency

Phase I trial of ATM inhibitor M3541 in combination with palliative radiotherapy in patients with solid tumors. (PubMed, Invest New Drugs) - P1 | "The MTD and RP2D could not be established as the study closed early due to the absence of a dose-response relationship and non-optimal PK profile. No further clinical development of M3541 was pursued. (Trial registration number ClinicalTrials.gov NCT03225105. Registration date July 21, 2017)."

Combination therapy • Journal • P1 data • Ataxia • Febrile Neutropenia • Hematological Disorders • Immunology • Infectious Disease • Movement Disorders • Nephrology • Neutropenia • Oncology • Primary Immunodeficiency • Solid Tumor

M3541 in Combination With Radiotherapy in Subjects With Solid Tumors (clinicaltrials.gov) - P1; N=15; Completed; Sponsor: EMD Serono Research & Development Institute, Inc.; Active, not recruiting ➔ Completed; Trial completion date: Aug 2020 ➔ Apr 2020

Clinical • Combination therapy • Trial completion • Trial completion date • Oncology • Solid Tumor

Cooperation of the ATM and Fanconi Anemia/BRCA Pathways in Double-Strand Break End Resection. (PubMed, Cell Rep) - "Knockout of genes in the Fanconi anemia (FA)/BRCA pathway results in hypersensitivity to the ATM inhibitor M3541...Knockout of both the FA/BRCA pathway and ATM strongly inhibits end resection and generates toxic levels of NHEJ, thereby elucidating a mechanism of cellular death by synthetic lethality. ATM inhibitors may therefore be useful for the treatment of tumors with a defective FA/BRCA pathway."

Journal • BRCA

M3541 in Combination With Radiotherapy in Subjects With Solid Tumors (clinicaltrials.gov) - P1; N=15; Active, not recruiting; Sponsor: EMD Serono Research & Development Institute, Inc.; Recruiting ➔ Active, not recruiting

Clinical • Combination therapy • Enrollment closed

M3541 in Combination With Radiotherapy in Subjects With Solid Tumors (clinicaltrials.gov) - P1; N=13; Recruiting; Sponsor: EMD Serono Research & Development Institute, Inc.; N=24 ➔ 13; Trial completion date: Dec 2019 ➔ Aug 2020; Trial primary completion date: Jul 2019 ➔ Nov 2019

Clinical • Combination therapy • Enrollment change • Trial completion date • Trial primary completion date