lartesertib (M4076) / EMD Serono - LARVOL DELTA

Molecular Characterization of PARP Inhibitor Response Reveals Co-Targeting Strategies in Advanced Prostate Cancer. (PubMed, Cancers (Basel)) - "Tumor cells exposed to longer-term treatment exhibit SLUG-dependent epithelial-mesenchymal transition (EMT) and evidence for altered fatty acid metabolism, both of which may be targeted to enhance PARPi anti-tumor cell effects. This study provides insight into both short and longer-term cellular response to PARPi treatment and provides a foundation for additional efforts to explore effective strategies to maximize the utility of PARP inhibition for managing prostate cancer."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • SNAI2

Tuvusertib Combined With Niraparib or Lartesertib in Participants With Epithelial Ovarian Cancer (DDRiver EOC 302) (clinicaltrials.gov) - P2 | N=63 | Completed | Sponsor: EMD Serono Research & Development Institute, Inc. | Active, not recruiting ➔ Completed

Trial completion • Breast Cancer • Epithelial Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • BRCA2 • HRD

MS201924_0020: Study of Tuvusertib (M1774) in Combination With DNA Damage Response Inhibitor or Immune Checkpoint Inhibitor (DDRiver Solid Tumors 320) (clinicaltrials.gov) - P1 | N=120 | Completed | Sponsor: EMD Serono Research & Development Institute, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Jan 2027 ➔ Jul 2026 | Trial primary completion date: Jan 2027 ➔ Jul 2026

Checkpoint inhibition • dMMR • IO biomarker • Trial completion • Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Endometrial Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor • Triple Negative Breast Cancer • ARID1A • ATM

Tuvusertib Combined With Niraparib or Lartesertib in Participants With Epithelial Ovarian Cancer (DDRiver EOC 302) (clinicaltrials.gov) - P2 | N=63 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Trial primary completion date: Sep 2025 ➔ Jun 2026

Trial primary completion date • Breast Cancer • Epithelial Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • BRCA2 • HRD

Study of Tuvusertib (M1774) in Combination With DNA Damage Response Inhibitor or Immune Checkpoint Inhibitor (DDRiver Solid Tumors 320) (clinicaltrials.gov) - P1 | N=120 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Trial completion date: Apr 2026 ➔ Jan 2027 | Trial primary completion date: Apr 2026 ➔ Jan 2027

Checkpoint inhibition • IO biomarker • Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Endometrial Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor • Triple Negative Breast Cancer • ARID1A • ATM

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

Tuvusertib Combined With Niraparib or Lartesertib in Participants With Epithelial Ovarian Cancer (DDRiver EOC 302) (clinicaltrials.gov) - P2 | N=63 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Trial completion date: Jan 2028 ➔ Jun 2026 | Trial primary completion date: Jan 2028 ➔ Sep 2025

Trial completion date • Trial primary completion date • Breast Cancer • Epithelial Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • BRCA2 • HRD

DNA Damage Sensing and TP53 Function as Modulators of Sensitivity to Calicheamicin-Based Antibody-Drug Conjugates for Acute Leukemia. (PubMed, Cancers (Basel)) - "These results support further evaluation of combination therapies with corresponding small-molecule inhibitors (currently pursued for therapy of other cancers) toward clinical testing as novel strategies to increase the efficacy of CLM-based ADCs such as GO and InO."

Journal • Hematological Malignancies • Leukemia • Oncology • TP53

Role of DNA damage sensing and TP53 function as modulators of sensitivity to calicheamicin-based antibody-drug conjugates (ADCs) for acute leukemia (ASH 2025) - "Better survival of some patients with the CD33 ADC, gemtuzumab ozogamicin (GO), and the CD22 ADC, inotuzumab ozogamicin (InO), validate these efforts, but these ADCs are ineffective in many others...CLM-induced cytotoxicity was assessed in vitro in the presence/absence of a Mouse Double Minute 2 homolog (MDM2) inhibitor (idasanutlin), Ataxia-Telangiectasia Mutated (ATM) inhibitor (AZD1390, lartesertib), Ataxia Telangiectasia and Rad3-related (ATR) inhibitor (ceralasertib), Checkpoint Kinase 1 and Checkpoint Kinase 1 (Chk1/Chk2) inhibitors (prexasertib, BML-277), and poly(ADP-ribose) polymerase (PARP) inhibitor (veliparib)... Our studies identify ATM, MDM2, and TP53 as key modulators of CLM-induced cytotoxicity in acute leukemia cells. These results support further evaluation of combination therapies with corresponding small molecule inhibitors (currently pursued in patients with other cancers) toward possible clinical testing as novel strategies to increase the efficacy..."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Ataxia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Immunology • Leukemia • Movement Disorders • Primary Immunodeficiency • CD22 • CD33 • CDKN1A • FBXW7 • TP53

Study of Tuvusertib (M1774) in Combination With DNA Damage Response Inhibitor or Immune Checkpoint Inhibitor (DDRiver Solid Tumors 320) (clinicaltrials.gov) - P1 | N=120 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Recruiting ➔ Active, not recruiting

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

Tuvusertib Combined With Niraparib or Lartesertib in Participants With Epithelial Ovarian Cancer (DDRiver EOC 302) (clinicaltrials.gov) - P2 | N=63 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Recruiting ➔ Active, not recruiting | N=130 ➔ 63

Enrollment change • Enrollment closed • Epithelial Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor

A First-in-Human Study of ATM Inhibitor Lartesertib as Monotherapy in Patients with Advanced Solid Tumors. (PubMed, Clin Cancer Res) - P1 | "Lartesertib achieved target exposure and engagement without significant hematological toxicity. Further clinical evaluation of lartesertib in combination therapy is ongoing."

Journal • Monotherapy • P1 data • Ataxia • Hematological Disorders • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor

Tuvusertib Combined With Niraparib or Lartesertib in Participants With Epithelial Ovarian Cancer (DDRiver EOC 302) (clinicaltrials.gov) - P2 | N=130 | Recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | N=60 ➔ 130

Enrollment change • Epithelial Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor

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

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

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

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