lartesertib (M4076) / EMD Serono 
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  • ||||||||||  Rencarex (girentuximab) / Heidelberg Pharma, Esteve, Merck (MSD)
    Preclinical Evaluation of DNA Damage Response Inhibitors and 225Ac-DOTA-girentuximab Combination Therapy (Hall F) -  Sep 27, 2024 - Abstract #EANM2024EANM_1366;    
    The synergistic effect was evident with 225Ac-DOTA-girentuximab + peposertib, whereas 225Ac-DOTA-girentuximab + lartesertib exhibited an additive effect. Analysis of DDR biomarkers indicated elevated levels of DNA-PK phosphorylation, with phosphorylated ATM showing a comparatively lesser increase.
  • ||||||||||  M4076 / EMD Serono
    A first-in-human phase I study of the ATM inhibitor M4076 in patients with advanced solid tumors (DDRiver Solid Tumors 410): Part 1A results (Section 45; Poster Board #3) -  Mar 14, 2023 - Abstract #AACR2023AACR_5994;    
    P1
    Future investigations on M4076 as combination therapy are planned.Table 1: Safety overviewDose(Safety set)Patients with TRAEs(Grade ?3)DLT analysis set(Patients with ?80% of the planned dose or DLT per investigator)DLTDLT AE terms100 mg(n = 2)Non = 2NoNA200 mg(n = 7)n = 1 (decreased lymphocyte count, maculo?papular rash)n = 5Yes(n = 1)Grade 3 maculo-papular rash (TRAE, required drug withdrawal; resolved)300 mg(n = 9)n = 3 (anemia, spontaneous bacterial peritonitis)n = 7Yes(n = 1)Grade 1 maculo-papular rash; Grade 2 fever (TRAEs, required treatment discontinuation; resolved)400 mg(n = 4)n = 2 (nausea, maculo?papular rash, hypersensitivity)n = 4Yes(n = 2)Grade 3 maculo-papular rash (TRAEs, required dose reduction/interruption and/or concomitant medication; resolved)MedDRA version 23.0, NCI?CTCAE version 5.0. Data cutoff: 2 Nov 2022AE, adverse event; DLT, dose-limiting toxicity; NA, not applicable; TRAE, treatment-related AE
  • ||||||||||  M4076 / EMD Serono, M3541 / EMD Serono
    Journal, PD(L)-1 Biomarker, IO biomarker:  Selective ATM inhibition augments radiation-induced inflammatory signaling and cancer cell death. (Pubmed Central) -  Jan 20, 2023   
    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.
  • ||||||||||  lartesertib (M4076) / EMD Serono
    Enrollment closed, Metastases:  First-in-human Study of M4076 in Advanced Solid Tumors (DDRiver Solid Tumors 410) (clinicaltrials.gov) -  Jan 12, 2023   
    P1,  N=30, Active, not recruiting, 
    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. Recruiting --> Active, not recruiting
  • ||||||||||  lartesertib (M4076) / EMD Serono
    Trial completion date, Trial primary completion date, Metastases:  First-in-human Study of M4076 in Advanced Solid Tumors (DDRiver Solid Tumors 410) (clinicaltrials.gov) -  Aug 26, 2022   
    P1,  N=30, Recruiting, 
    Recruiting --> Active, not recruiting Trial completion date: Aug 2022 --> May 2023 | Trial primary completion date: Aug 2022 --> May 2023
  • ||||||||||  M4076 / Merck (MSD)
    Journal:  Atropisomerism - a neglected way to escape out of solubility flatlands. (Pubmed Central) -  Mar 17, 2022   
    Additionally, selecting one enantiomer also leads to improved solubility of the drug compared to its racemic compound. While this effect is well known for enantiomers and racemic compounds where chirality is introduced via a chiral central atom, here we describe the first case where improved solubility is realized by selecting an axially chiral atropisomer.
  • ||||||||||  M4076 / Merck (MSD), KU-55933 / AstraZeneca
    Journal:  Molecular basis of human ATM kinase inhibition. (Pubmed Central) -  Nov 24, 2021   
    We determined the structure of the kinase domain bound to ATPγS and to the ATM inhibitors KU-55933 and M4076 at 2.8 Å, 2.8 Å and 3.0 Å resolution, respectively. The mode of action and selectivity of the ATM inhibitors can be explained by structural comparison and provide a framework for structure-based drug design.
  • ||||||||||  lartesertib (M4076) / EMD Serono
    Enrollment open, Metastases:  First-in-human Study of M4076 in Advanced Solid Tumors (DDRiver Solid Tumors 410) (clinicaltrials.gov) -  Jun 7, 2021   
    P1,  N=30, Recruiting, 
    The mode of action and selectivity of the ATM inhibitors can be explained by structural comparison and provide a framework for structure-based drug design. Not yet recruiting --> Recruiting