lartesertib (M4076) / EMD Serono - LARVOL DELTA

Study of Tuvusertib (M1774) in Combination With DNA Damage Response Inhibitor or Immune Checkpoint Inhibitor (DDRiver Solid Tumors 320) (clinicaltrials.gov) - P1 | N=123 | Recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | N=72 ➔ 123

Checkpoint inhibition • dMMR • Enrollment change • IO biomarker • Colorectal Cancer • Endometrial Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor • Triple Negative Breast Cancer

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

DDRiver EOC 302: A Randomised Phase 2 Study Of Tuvusertib With Niraparib Or Lartesertib In Patients With Epithelial Ovarian Cancer That Has Progressed On Prior PARP Inhibitor Therapy (ESGO 2025) - P1, P2 | "The study is currently open and enrolling patients in the USA, UK, Australia, Switzerland, and the EU. Results N/A - TiP abstractConclusion N/A - TiP abstract"

Clinical • P2 data • Epithelial Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor

Discovery of a Novel and Potent Dual-Targeting Inhibitor of ATM and HDAC2 Through Structure-Based Virtual Screening for the Treatment of Testicular Cancer. (PubMed, Drug Des Devel Ther) - "In vivo experiments exhibited that AMH-4 was more effective than lartesertib and vorinostat in inhibiting the growth of NTERA-2 cL.D1 xenograft tumors with low toxicity. Overall, these results suggest that AMH-4 is an effective and low toxicity candidate for the treatment of testicular germ cell tumors."

Journal • Ataxia • Genito-urinary Cancer • Germ Cell Tumors • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Testicular Cancer • HDAC2

Preclinical Evaluation of DNA Damage Response Inhibitors and 225Ac-DOTA-girentuximab Combination Therapy (EANM 2024) - "The combination of 225Ac-DOTA-girentuximab and DDRi proved to be more effective than either monotherapy alone. 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."

Combination therapy • IO biomarker • Preclinical • Ataxia • Immunology • Kidney Cancer • Movement Disorders • Oncology • Primary Immunodeficiency • Renal Cell Carcinoma • Solid Tumor • CA9

Tuvusertib Combined With Niraparib or Lartesertib in Participants With Epithelial Ovarian Cancer (DDRiver EOC 302) (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Oncology • Ovarian Cancer • Solid Tumor

Pharmacodynamic (PD) and immunophenotyping analyses of ATR inhibitor (ATRi) tuvusertib + ATM inhibitor (ATMi) lartesertib in a phase Ib study in patients with advanced unresectable solid tumors. (ASCO 2024) - P1 | " PD analysis comprised γ-H2AX in serial blood samples, stimulated ex vivowith 4-NQO, bleomycin, or controls... Tuvusertib and lartesertib combination PD outcomes were in line with respective monotherapy observations. 3,4 The combination did not cause any consistent change in the levels of immune cell subsets at all dose levels tested, except a mild, transient decrease in monocytes and NK cells, in line with the tuvusertib monotherapy observations. 1."

Clinical • Metastases • P1 data • PK/PD data • Ataxia • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • ATM • PTPRC

Tuvusertib Combined With Niraparib or Lartesertib in Participants With Epithelial Ovarian Cancer (DDRiver EOC 302) (clinicaltrials.gov) - P2 | N=60 | Not yet recruiting | Sponsor: EMD Serono Research & Development Institute, Inc.

Combination therapy • New P2 trial • Oncology • Ovarian Cancer • Solid Tumor

In vitro evaluation of myelosuppressive effects of ATRi tuvusertib and ATMi lartesertib (M4076), alone and in combination (AACR 2024) - "The phenotypic and functional changes induced by tuvusertib and lartesertib on in vitro cultures of erythroid, myeloid, and megakaryocytic cells are consistent with clinical observations in monotherapy studies, suggesting these models may be used to better understand and predict the hematological effects of monotherapies and combinations in the clinic. In vitro washout experiments may help support the concept of intermittent clinical regimens and warrant further investigation.1. Martorana, et al."

Preclinical • Oncology • CD33 • CD34 • GYPA • ITGA2B • TFRC

Phase Ib trial of ATR inhibitor (ATRi) tuvusertib + ATM inhibitor (ATMi) lartesertib (M4076) in patients (pts) with advanced solid tumors (AACR 2024) - P1 | "Multiple tolerated combination doses were identified. Tuvusertib 180 mg QD + lartesertib 150 mg QD 2 w on/2 w off was selected for investigation in expansion cohorts in pts with prostate and endometrial cancer."

Clinical • Metastases • P1 data • Endometrial Cancer • Genito-urinary Cancer • Melanoma • Oncology • Prostate Cancer • Solid Tumor • ATM • PTPRC

Combined inhibition of ATR and ATM with tuvusertib and lartesertib (M4076) impacts the tumor microenvironment (AACR 2024) - "Turchick A, Zimmermann A, et al. Mol Cancer Ther 2023; 22(7):859-872."

Biomarker • IO biomarker • Tumor microenvironment • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD8 • PD-L1

Study of M1774 in Combination With DNA Damage Response Inhibitor or Immune Checkpoint Inhibitor (DDRiver Solid Tumors 320) (clinicaltrials.gov) - P1 | N=72 | Recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Trial completion date: Dec 2023 ➔ May 2026 | Trial primary completion date: Dec 2023 ➔ Mar 2026

Checkpoint inhibition • Combination therapy • IO biomarker • Metastases • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

First-in-human Study of M4076 in Advanced Solid Tumors (DDRiver Solid Tumors 410) (clinicaltrials.gov) - P1 | N=30 | Completed | Sponsor: EMD Serono Research & Development Institute, Inc. | Active, not recruiting ➔ Completed

Trial completion • Oncology • Solid Tumor • CHEK2

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

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 (AACR 2023) - P1 | "PD evaluation was based on the modulation of γ-H2AX (a direct ATM target) in ex vivo bleomycin stimulated CD45+ lymphocytes, by flow cytometry. 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..."

Clinical • Metastases • P1 data • Oncology • Solid Tumor • PTPRC

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

First-in-human Study of M4076 in Advanced Solid Tumors (DDRiver Solid Tumors 410) (clinicaltrials.gov) - P1 | N=30 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Oncology • Solid Tumor • CHEK2

First-in-human Study of M4076 in Advanced Solid Tumors (DDRiver Solid Tumors 410) (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Trial completion date: Aug 2022 ➔ May 2023 | Trial primary completion date: Aug 2022 ➔ May 2023

Trial completion date • Trial primary completion date • Oncology • Solid Tumor • CHEK2

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

Atropisomerism - a neglected way to escape out of solubility flatlands. (PubMed, J Pharm Sci) - "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."

Journal • Ataxia • Immunology • Movement Disorders • Primary Immunodeficiency

Molecular basis of human ATM kinase inhibition. (PubMed, Nat Struct Mol Biol) - "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."

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

First-in-human Study of M4076 in Advanced Solid Tumors (DDRiver Solid Tumors 410) (clinicaltrials.gov) - P1; N=30; Recruiting; Sponsor: EMD Serono Research & Development Institute, Inc.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Oncology • Solid Tumor • CHEK2

First-in-human Study of M4076 in Advanced Solid Tumors (DDRiver Solid Tumors 410) (clinicaltrials.gov) - P1; N=30; Not yet recruiting; Sponsor: EMD Serono Research & Development Institute, Inc.

Clinical • New P1 trial • Oncology • Solid Tumor • CHEK2