^
11d
New P1 trial
|
ceralasertib (AZD6738)
18d
A multiparametric screen uncovers FDA-approved small molecules that potentiate the nuclear mechano-dysfunctions in ATR-defective cells. (PubMed, Sci Rep)
Candidate hits were also tested in combination with the chemical inhibition of ATR by AZD6738, and their efficacy was further validated in the triple-negative breast cancer cell lines BT549 and HCC1937. We show that those compounds enhancing the abnormal nuclear shape of ATR-defective cells also synergize with AZD6738 to boost the expression of interferon-stimulated genes, highlighting the power of multiparametric screens to identify novel combined therapeutic interventions targeting nuclear mechanics for cancer immunotherapy.
FDA event • Journal • IO biomarker
|
STING (stimulator of interferon response cGAMP interactor 1)
|
ceralasertib (AZD6738)
20d
Olaparib With Ceralasertib in Recurrent Osteosarcoma (clinicaltrials.gov)
P2, N=63, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Dec 2024 --> Jun 2025
Trial completion date • Trial primary completion date
|
Lynparza (olaparib) • ceralasertib (AZD6738)
28d
A First-in-human Study of HRS2398 Tablets in Subjects With Advanced Malignant Tumors (clinicaltrials.gov)
P1, N=28, Completed, Shanghai Hengrui Pharmaceutical Co., Ltd. | Recruiting --> Completed | N=122 --> 28 | Trial primary completion date: May 2023 --> Feb 2024
Trial completion • Enrollment change • Trial primary completion date • Metastases
29d
Combined Therapeutic Strategies Based on the Inhibition of Non-Oncogene Addiction to Improve Tumor Response in EGFR- and KRAS-Mutant Non-Small-Cell Lung Cancer. (PubMed, Cancers (Basel))
The major translational relevance of this study is to exploit new targets for the development of innovative and improved therapeutic strategies with NOA drugs, over combinations including target genes within the oncogene pathway, to overcome resistance to TKI therapies in patients with NSCLC who are oncogene-addicted.
Journal
|
EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation • EGFR mutation • EGFR mutation + KRAS mutation
|
Tagrisso (osimertinib) • Koselugo (selumetinib) • gartisertib (M4344)
1m
Interferon signaling is enhanced by ATR inhibition in glioblastoma cells irradiated with X-rays, protons or carbon ions. (PubMed, Radiother Oncol)
These findings indicate that DNA damage response inhibitors can enhance IFN signaling following X-, proton and carbon ion irradiation, with a strong positive dependency on LET.
Journal
|
STAT1 (Signal Transducer And Activator Of Transcription 1) • IFNB1 (Interferon Beta 1)
|
berzosertib (M6620) • AZD1390
1m
New P3 trial • Checkpoint inhibition • Checkpoint block
|
PD-L1 (Programmed death ligand 1)
|
Imfinzi (durvalumab) • ceralasertib (AZD6738)
1m
Testing the Addition of an Anti-cancer Drug, BAY 1895344, With Radiation Therapy to the Usual Pembrolizumab Treatment for Recurrent Head and Neck Cancer (clinicaltrials.gov)
P1, N=7, Active, not recruiting, National Cancer Institute (NCI) | N=37 --> 7 | Trial completion date: Nov 2024 --> Dec 2025
Enrollment change • Trial completion date • Tumor mutational burden
|
TMB (Tumor Mutational Burden) • CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule)
|
PD-L1 expression
|
PD-L1 IHC 22C3 pharmDx
|
Keytruda (pembrolizumab) • elimusertib (BAY 1895344)
2ms
ATR inhibition potentiates FOLFIRINOX cytotoxic effect in models of pancreatic ductal adenocarcinoma by remodelling the tumour microenvironment. (PubMed, Br J Cancer)
The FOLFIRINOX and VE-822 combination is a promising strategy to improve FOLFIRINOX efficacy and overcome drug resistance in PDAC.
Journal • BRCA Biomarker
|
BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • ATR (Ataxia telangiectasia and Rad3-related protein)
|
ATM mutation
|
5-fluorouracil • irinotecan • berzosertib (M6620) • leucovorin calcium
2ms
MS201923-0007: ATRi Transition Rollover Study (clinicaltrials.gov)
P1, N=1, Completed, Merck KGaA, Darmstadt, Germany | Active, not recruiting --> Completed
Trial completion
|
berzosertib (M6620)
2ms
DDRiver Solid Tumours 301: Tuvusertib (M1774) in Participants With Metastatic or Locally Advanced Unresectable Solid Tumors (DDRiver Solid Tumors 301) (clinicaltrials.gov)
P1, N=161, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Trial completion date: Jan 2025 --> Jan 2026 | Trial primary completion date: Jan 2025 --> Jan 2026
Trial completion date • Trial primary completion date • Metastases
|
ARID1A (AT-rich interaction domain 1A) • ATRX (ATRX Chromatin Remodeler)
|
ATM mutation • ARID1A mutation
|
Zejula (niraparib) • tuvusertib (M1774)
2ms
PEPN2112: Elimusertib for the Treatment of Relapsed or Refractory Solid Tumors (clinicaltrials.gov)
P1/2, N=31, Active, not recruiting, National Cancer Institute (NCI) | N=23 --> 31 | Trial completion date: Dec 2024 --> Nov 2025 | Trial primary completion date: Dec 2024 --> Sep 2024
Enrollment change • Trial completion date • Trial primary completion date
|
BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • MSH2 (MutS Homolog 2) • CDK12 (Cyclin dependent kinase 12) • WT1 (WT1 Transcription Factor) • ATRX (ATRX Chromatin Remodeler) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A) • FANCA (FA Complementation Group A) • POLD1 (DNA Polymerase Delta 1) • FOXO1 (Forkhead box O1) • XRCC2 (X-Ray Repair Cross Complementing 2) • ATF1 (Activating Transcription Factor 1) • PAX3 (Paired Box 3)
|
elimusertib (BAY 1895344)
2ms
ARTIST: Study of ART0380 in Patients With Biologically Selected Solid Tumors (clinicaltrials.gov)
P2, N=37, Active, not recruiting, Artios Pharma Ltd | Recruiting --> Active, not recruiting | N=60 --> 37 | Trial primary completion date: Mar 2025 --> Nov 2024
Enrollment closed • Enrollment change • Trial primary completion date • Pan tumor • Metastases
|
PD-L1 (Programmed death ligand 1) • PD-1 (Programmed cell death 1)
|
ART0380
2ms
Avelumab and M1774 in ARID1A-mutated Endometrial Cancer (Prior IO) (clinicaltrials.gov)
P2, N=25, Recruiting, Panagiotis Konstantinopoulos, MD, PhD | Not yet recruiting --> Recruiting
Enrollment open • Combination therapy • IO biomarker
|
Bavencio (avelumab) • tuvusertib (M1774)
2ms
Testing the Addition of an Anti-cancer Drug, Berzosertib, to the Usual Treatment (Radiation Therapy) for Chemotherapy-Resistant Triple-Negative and Estrogen and/or Progesterone Receptor Positive, HER2 Negative Breast Cancer (clinicaltrials.gov)
P1, N=42, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025
Trial completion date • Trial primary completion date • Combination therapy
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
|
HER-2 negative
|
berzosertib (M6620)
2ms
Trial completion date • Metastases
|
BRAF (B-raf proto-oncogene)
|
Imfinzi (durvalumab) • ceralasertib (AZD6738)
2ms
New P2 trial
|
Imfinzi (durvalumab) • ceralasertib (AZD6738)
2ms
CORONADO CLL: RP-3500 and Olaparib in DNA Damage Repair Pathway Deficient Relapsed/Refractory Chronic Lymphocytic Leukemia (clinicaltrials.gov)
P1/2, N=5, Terminated, University of Utah | N=39 --> 5 | Trial completion date: Aug 2027 --> Oct 2024 | Recruiting --> Terminated; This study was terminated due to sponsor de-activation of all programs associated with RP-3500 (camonsertib).
Enrollment change • Trial completion date • Trial termination
|
TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • CD20 (Membrane Spanning 4-Domains A1) • SF3B1 (Splicing Factor 3b Subunit 1) • CCND1 (Cyclin D1) • CD5 (CD5 Molecule) • POT1 (Protection of telomeres 1) • FCER2 (Fc Fragment Of IgE Receptor II)
|
TP53 mutation • ATM mutation • Chr t(11;14) • SF3B1 mutation
|
Lynparza (olaparib) • camonsertib (RP-3500)
2ms
ABOYA-119: Study of ATRN-119 in Patients with Advanced Solid Tumors (clinicaltrials.gov)
P1/2, N=132, Recruiting, Aprea Therapeutics | N=45 --> 132
Enrollment change • Metastases
|
ATRN-119
3ms
Chemo-Immunotherapy Followed by Durvalumab and Ceralasertib in Treatment Naïve Patients With Extensive Stage Small Cell Lung Cancer (clinicaltrials.gov)
P2, N=30, Recruiting, Muhammad Furqan | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025
Trial completion date • Trial primary completion date
|
cisplatin • carboplatin • Imfinzi (durvalumab) • etoposide IV • ceralasertib (AZD6738)
3ms
A Translational Study of the ATR Inhibitor Berzosertib as Monotherapy in Four Molecularly Defined Cohorts of Advanced Solid Tumors. (PubMed, Clin Cancer Res)
Across cohorts, only SDH-mutant GIST patients experienced prolonged disease control. Despite evidence of target engagement, patients enrolled to all other cohorts had short PFS, suggesting rapid adaptation to ATR inhibitor monotherapy. Among these patients, those with tumors expressing SLFN11 during berzosertib exposure derived the most clinical benefit.
Journal • Metastases
|
ATM (ATM serine/threonine kinase) • SLFN11 (Schlafen Family Member 11) • ATRX (ATRX Chromatin Remodeler) • CHEK1 (Checkpoint kinase 1)
|
ATM mutation • ATRX mutation
|
berzosertib (M6620)
3ms
ATR inhibition increases reliance on PARP-mediated DNA repair revealing an improved therapeutic strategy for cervical cancer. (PubMed, Gynecol Oncol)
Our findings show that ATRi increased reliance on PARP for metabolic viability, the combination of ATRi and PARPi induced synthetic lethality in cervical cancer in vitro, and reduced tumor burden in vivo.
Journal • PARP Biomarker
|
HRD (Homologous Recombination Deficiency) • RAD51 (RAD51 Homolog A) • PARP1 (Poly(ADP-Ribose) Polymerase 1)
|
Lynparza (olaparib) • ceralasertib (AZD6738)
3ms
Genomic biomarkers predict response to combined ATR inhibition and radiotherapy. (PubMed, Clin Cancer Res)
A recent study reports the novel ATR kinase inhibitor, RP-3500, synergizes with radiation to control Atm-/- tumors in vivo. RP-3500 did not radiosensitize wild-type or Brca-1 deficient tumors, highlighting the need for a genotype-tailored approach.
Journal • BRCA Biomarker
|
BRCA1 (Breast cancer 1, early onset) • BRCA (Breast cancer early onset)
|
camonsertib (RP-3500)
3ms
Trial completion date
|
RAD51 (RAD51 Homolog A)
|
berzosertib (M6620)
3ms
Inhibition of ATM or ATR in combination with hypo-fractionated radiotherapy leads to a different immunophenotype on transcript and protein level in HNSCC. (PubMed, Front Oncol)
The toxic and immunogenic effects of the smKI AZD0156 (ATMi) and VE-822 (ATRi) in combination with a hypo-fractionated scheme of 2x5Gy RT on HPV-negative (HSC4, Cal-33) and HPV-positive (UM-SCC-47, UD-SCC-2) HNSCC cell lines were analyzed as follows: cell death (necrosis, apoptosis; detected by AnxV/PI), expression of immunostimulatory (ICOS-L, OX40-L, TNFSFR9, CD70) and immunosuppressive (PD-L1, PD-L2, HVEM) checkpoint marker using flow cytometry; the release of cytokines using multiplex ELISA and the gene expression of Cal-33 on mRNA level 48 h post-RT. This includes pro-inflammatory signaling induced by RT + ATRi but also anti-inflammatory signals. These findings were confirmed by RNAseq analysis, which further highlighted the immune-suppressive nature of RT + ATMi.
Journal • Combination therapy • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • IL6 (Interleukin 6) • CXCL8 (Chemokine (C-X-C motif) ligand 8) • PD-L2 (Programmed Cell Death 1 Ligand 2) • CD70 (CD70 Molecule) • ICOS (Inducible T Cell Costimulator) • EDIL3 (EGF Like Repeats And Discoidin Domains 3)
|
berzosertib (M6620) • AZD0156
3ms
Combined MEK1/2 and ATR inhibition promotes myeloma cell death through a STAT3-dependent mechanism in vitro and in vivo. (PubMed, Br J Haematol)
Co-administration of the ATR inhibitor (ATRi) BAY1895344 (BAY) and MEK1/2 inhibitors, for example, cobimetinib, synergistically increased cell death in diverse MM cell lines...Similar events occurred in highly bortezomib-resistant (PS-R) cells, in the presence of patient-derived conditioned medium, and with alternative ATR (e.g. M1774) and MEK1/2 (trametinib) inhibitors...Finally, the ATR inhibitor/cobimetinib regimen significantly improved survival in MM xenografts, including bortezomib-resistant models, with minimal toxicity. Collectively, these findings suggest that combined ATR/MEK1/2 inhibition triggers dual STAT3 Tyr705 and Ser727 dephosphorylation, pronounced downregulation of cytoprotective targets and MM cell death, warranting attention as a novel therapeutic strategy in MM.
Preclinical • Journal
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • BCL2L1 (BCL2-like 1) • STAT3 (Signal Transducer And Activator Of Transcription 3) • CD34 (CD34 molecule) • SDC1 (Syndecan 1)
|
Mekinist (trametinib) • Cotellic (cobimetinib) • bortezomib • elimusertib (BAY 1895344) • tuvusertib (M1774)
3ms
Base-excision repair pathway regulates transcription-replication conflicts in pancreatic ductal adenocarcinoma. (PubMed, Cell Rep)
Co-treatment with ATR inhibitor (VX970) and BER inhibitor (methoxyamine) at clinically relevant doses synergistically enhanced DNA damage and reduced cell proliferation in PDAC cells. The study provides mechanistic insights into the regulation of TRCs in PDAC by the BER pathway, which has biologic and therapeutic implications.
Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
|
berzosertib (M6620) • methoxyamine (TRC102)
3ms
D5330C00004: Ascending Doses of Ceralasertib in Combination With Chemotherapy and/or Novel Anti Cancer Agents (clinicaltrials.gov)
P1/2, N=466, Recruiting, AstraZeneca | Trial completion date: Jul 2026 --> Mar 2025 | Trial primary completion date: Jul 2026 --> Mar 2025
Trial completion date • Trial primary completion date
|
HER-2 (Human epidermal growth factor receptor 2) • ATM (ATM serine/threonine kinase) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D)
|
HER-2 negative • HRD • PALB2 mutation • RAD51C mutation • BRCA mutation • RAD51 mutation
|
Lynparza (olaparib) • carboplatin • Imfinzi (durvalumab) • ceralasertib (AZD6738) • saruparib (AZD5305)
4ms
ATR inhibition activates cancer cell cGAS/STING-interferon signaling and promotes antitumor immunity in small-cell lung cancer. (PubMed, Sci Adv)
This study shows that targeting ATR up-regulates major histocompatibility class I expression in preclinical models and SCLC clinical samples collected from a first-in-class clinical trial of ATR inhibitor, berzosertib, with topotecan in patients with relapsed SCLC. Targeting ATR represents a transformative vulnerability of SCLC and is a complementary strategy to induce STING-interferon signaling-mediated immunogenicity in SCLC.
Journal • PD(L)-1 Biomarker • IO biomarker
|
STING (stimulator of interferon response cGAMP interactor 1)
|
berzosertib (M6620) • topotecan
4ms
Study of Avelumab and Tuvusertib in Participants With Advanced Urothelial Cancer That Has Progressed on Prior Anti-PD-(L)1 Therapy (JAVELIN DDRiver Bladder) (clinicaltrials.gov)
P2, N=0, Withdrawn, EMD Serono Research & Development Institute, Inc. | Not yet recruiting --> Withdrawn | N=70 --> 0
Enrollment change • Trial withdrawal • Combination therapy • Metastases
|
Bavencio (avelumab) • tuvusertib (M1774)
4ms
Tuvusertib (M1774) in Combination With Cemiplimab in Participants With Non-Squamous NSCLC (DDRiver NSCLC 322) (clinicaltrials.gov)
P1/2, N=61, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Recruiting --> Active, not recruiting | N=180 --> 61 | Trial completion date: Sep 2026 --> Mar 2025 | Trial primary completion date: Aug 2026 --> Jun 2024
Enrollment closed • Enrollment change • Trial completion date • Trial primary completion date • Combination therapy
|
Libtayo (cemiplimab-rwlc) • tuvusertib (M1774)
5ms
D5330C00004: Ascending Doses of Ceralasertib in Combination With Chemotherapy and/or Novel Anti Cancer Agents (clinicaltrials.gov)
P1/2, N=466, Recruiting, AstraZeneca | Trial completion date: Dec 2026 --> Jul 2026 | Trial primary completion date: Dec 2026 --> Jul 2026
Trial completion date • Trial primary completion date • Combination therapy • Metastases
|
HER-2 (Human epidermal growth factor receptor 2) • ATM (ATM serine/threonine kinase) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D)
|
Lynparza (olaparib) • carboplatin • Imfinzi (durvalumab) • ceralasertib (AZD6738) • saruparib (AZD5305)
5ms
Study to Evaluate IMP9064 as a Monotherapy or in Combination in Patients With Advanced Solid Tumors (clinicaltrials.gov)
P1, N=61, Recruiting, Impact Therapeutics, Inc. | Phase classification: P1/2 --> P1
Phase classification • Combination therapy • Metastases
|
senaparib (IMP4297) • IMP9064
5ms
Testing the Combination of Two Anti-cancer Drugs, Peposertib (M3814) and M1774 for Advanced Solid Tumors (clinicaltrials.gov)
P1, N=66, Recruiting, National Cancer Institute (NCI) | Trial completion date: Aug 2024 --> Aug 2026 | Trial primary completion date: Aug 2024 --> Aug 2026
Trial completion date • Trial primary completion date • Combination therapy • Metastases
|
ATM (ATM serine/threonine kinase) • ARID1A (AT-rich interaction domain 1A) • CCNE1 (Cyclin E1) • PBRM1 (Polybromo 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • ATRX (ATRX Chromatin Remodeler) • ARID1B (AT-Rich Interaction Domain 1B) • ARID2 (AT-Rich Interaction Domain 2) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2) • SS18 (SS18 Subunit Of BAF Chromatin Remodeling Complex)
|
peposertib (M3814) • tuvusertib (M1774)
5ms
M9466 as Single Agent or in Combination With Tuvusertib in Advanced Solid Tumors (DDRiver 501) (clinicaltrials.gov)
P1, N=70, Recruiting, EMD Serono Research & Development Institute, Inc. | Not yet recruiting --> Recruiting
Enrollment open • Combination therapy • Metastases
|
tuvusertib (M1774) • M9466
5ms
A Study of AZD6738 and Acalabrutinib in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) (clinicaltrials.gov)
P1, N=11, Active, not recruiting, Acerta Pharma BV | Trial completion date: Jun 2024 --> Aug 2026
Trial completion date • Combination therapy
|
Calquence (acalabrutinib) • ceralasertib (AZD6738)
5ms
Sculpting the tumour microenvironment by combining radiotherapy and ATR inhibition for curative-intent adjuvant immunotherapy. (PubMed, Nat Commun)
We also observe increased richness in the TCR repertoire and emergence of numerous and large TCR clonotypes that cluster based on antigen specificity in response to NKG2A/PD-L1/ATRi/RT. Collectively, our data point towards potential combination approaches for the treatment of HNSCC.
Journal
|
CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • CD40LG (CD40 ligand) • KLRC1 (Killer Cell Lectin Like Receptor C1)
5ms
ATTACC: Study of RP-3500 (Camonsertib) With Niraparib or Olaparib in Advanced Solid Tumors (clinicaltrials.gov)
P1/2, N=196, Active, not recruiting, Repare Therapeutics | Recruiting --> Active, not recruiting | Phase classification: P1b/2 --> P1/2
Enrollment closed • Phase classification • Metastases
|
Lynparza (olaparib) • Zejula (niraparib) • camonsertib (RP-3500)
5ms
Trial primary completion date • Metastases
|
EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase)
|
Imfinzi (durvalumab) • docetaxel • ceralasertib (AZD6738)
5ms
Genotype-Directed Synthetic Cytotoxicity of ATR Inhibition with Radiotherapy. (PubMed, Clin Cancer Res)
We investigated the synergistic potential of the ATR inhibitor (ATRi) RP-3500 and RT in two Atm-null and isogenic murine models, both in vitro and in vivo...Lastly, early results from our clinical trial showed complete responses in patients. Genotype-directed radiosensitization with ATRi and RT can unleash significant therapeutic benefit and could represent a novel approach to develop more effective combinatorial synthetic cytotoxic RT-based treatments.
Journal • BRCA Biomarker
|
BRCA1 (Breast cancer 1, early onset) • ATM (ATM serine/threonine kinase)
|
camonsertib (RP-3500)
6ms
An Open-Label Phase 1 Study of Ceralasertib in Japanese Patients With Advanced Solid Malignancies (clinicaltrials.gov)
P1, N=12, Completed, AstraZeneca | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Mar 2024
Trial completion • Trial completion date • Metastases
|
ceralasertib (AZD6738)
6ms
Tuvusertib Combined With Niraparib or Lartesertib in Participants With Epithelial Ovarian Cancer (DDRiver EOC 302) (clinicaltrials.gov)
P2, N=60, Recruiting, EMD Serono Research & Development Institute, Inc. | Not yet recruiting --> Recruiting
Enrollment open • Combination therapy
|
Zejula (niraparib) • tuvusertib (M1774) • lartesertib (M4076)