Phase I Trial of BAY 1895344 ATR Inhibitor Combined With Stereotactic Body Radiation Therapy and Pembrolizumab for Recurrent Head and Neck Squamous Cell Carcinoma

This phase I trial evaluates the best dose, possible benefits and/or side effects of combination therapy with elimusertib (BAY 1895344), stereotactic body radiation, and pembrolizumab in treating patients with head and neck squamous cell cancer that has come back (recurrent) and cannot be removed by surgery (unresectable). BAY 1895344 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving BAY 1895344, stereotactic body radiation therapy in combination with pembrolizumab may shrink or stabilize head and neck squamous cell cancer for longer than treatment with radiation and immunotherapy without BAY 1895344.

Start Date06 Jul 2022

Sponsor / Collaborator

National Cancer Institute

NCT05010096 / WithdrawnPhase 1IIT

Strategic Alliance: Phase 1b Trial of the Combination of the ATR Inhibitor BAY1895344 and PI3K Inhibitor Copanlisib in Molecularly Selected Patients With Advanced Solid Tumors (COPABAY)

This phase Ib trial finds out the best dose, possible benefits and/or side effects of BAY1895344 and copanlisib in treating molecularly selected patients with solid tumors that have spread to other places in the body (advanced). BAY1895344 and copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving BAY1895344 and copanlisib together may help control the progression of the disease in patients with advanced solid tumors.

Start Date22 Mar 2022

Sponsor / Collaborator

The University of Texas MD Anderson Cancer Center

NCT05071209 / Active, not recruitingPhase 1/2IIT

A Phase 1/ 2 Study of BAY 1895344 (Elimusertib, NSC#810486) in Pediatric Patients With Relapsed or Refractory Solid Tumors

This phase I/II trial tests the safety, best dose, and whether elimusertib works in treating patients with solid tumors that have come back (relapsed) or does not respond to treatment (refractory). Elimusertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Start Date22 Dec 2021

Sponsor / Collaborator

National Cancer Institute

100 Clinical Results associated with Elimusertib

100 Translational Medicine associated with Elimusertib

100 Patents (Medical) associated with Elimusertib

Literatures (Medical) associated with Elimusertib

01 Dec 2024·BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

SLFN11 and ATR as targets for overcoming cisplatin resistance in ovarian cancer cells

Article

Author: König, Philipp ; Bendas, Gerd ; Eichhorn, Julia Maria ; Suparman, Eloy ; Michaelis, Martin ; Cinatl, Jindrich ; Bückreiß, Nico

The levels and activities of the DNA/RNA helicase schlafen11 (SLFN11) and the serine/threonine-protein kinase ataxia telangiectasia and Rad3-related protein (ATR) may determine cancer cell sensitivity to DNA damaging agents, including platinum drugs. Here, we studied the roles of SLFN11 and ATR in cisplatin resistance of ovarian cancer using cell lines displaying acquired or intrinsic cisplatin resistance. W1CR, the cisplatin-resistant subline of W1 ovarian cancer cells, displayed reduced SLFN11 levels. HDAC inhibition using entinostat returned an epigenetic downregulation of SLFN11 in W1CR cells, caused SLFN11 re-expression and re-sensitized these cells to cisplatin. Moreover, entinostat also sensitized intrinsically resistant EFO21 ovarian cancer cells to cisplatin by upregulating SLFN11. However, SLFN11 was not involved in cisplatin resistance in all other cell models. Thus, SLFN11 expression is not a general cisplatin resistance marker in ovarian cancer. In contrast, inhibition of the DNA damage repair master regulator ATR using sub-toxic concentrations of elimusertib sensitized parental cell lines as well as intrinsically resistant EFO21 cells to cisplatin, and fully reversed acquired cisplatin resistance in cisplatin-adapted sublines W1CR, A2780cis, and Kuramochi^rCDDP²⁰⁰⁰. Mechanisms underlying ATR-mediated cisplatin resistance differed between the cell lines and included CHK1/WEE1 signaling and induction of homologous recombination. In conclusion, SLFN11 and ATR are involved in ovarian cancer cisplatin resistance. Although our data identify ATR as key target for tackling cisplatin resistance in ovarian cancer, future studies are needed to identify biomarkers that indicate, which individual ovarian cancers benefit from SLFN11 re-activation and/or ATR inhibition.

01 Dec 2024·BRITISH JOURNAL OF HAEMATOLOGY

Combined MEK1/2 and ATR inhibition promotes myeloma cell death through a STAT3‐dependent mechanism in vitro and in vivo

Article

Author: Kmieciak, Maciej ; Canevarolo, Rafael R. ; Shain, Kenneth H. ; Meads, Mark B. ; Grant, Steven ; Nkwocha, Jewel ; Li, Lin ; Silva, Ariosto S. ; Hu, Xiaoyan ; Alugubelli, Raghunandan R. ; Zhou, Liang ; Sudalagunta, Praneeth R. ; Mann, Hashim

Summary:

Mechanisms underlying potentiation of the anti‐myeloma (MM) activity of ataxia telangiectasia Rad3 (ATR) antagonists by MAPK (Mitogen‐activated protein kinases)‐related extracellular kinase 1/2 (MEK1/2) inhibitors were investigated. 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. Mechanistically, BAY and cobimetinib blocked STAT3 Tyr705 and Ser727 phosphorylation, respectively, and dual dephosphorylation triggered marked STAT3 inactivation and downregulation of STAT3 (Signal transducer and activator of transcription 3) downstream targets (c‐Myc and BCL‐XL). 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. Notably, constitutively active STAT3 c‐MYC or BCL‐XL ectopic expression significantly protected cells from BAY/cobimetinib. In contrast, transfection of cells with a dominant‐negative form of STAT3 (Y705F) sensitized cells to cobimetinib, as did ATR shRNA knockdown. Conversely, MEK1/2 knockdown markedly increased ATRi sensitivity. The BAY/cobimetinib regimen was also active against primary CD138+ MM cells, but not normal CD34+ cells. 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.

01 Nov 2024·JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS

Factors Influencing the Central Nervous System (CNS) Distribution of the Ataxia Telangiectasia Mutated and Rad3-Related Inhibitor Elimusertib (BAY1895344): Implications for the Treatment of CNS Tumors

Article

Author: Sarkaria, Jann N ; Oh, Ju-Hee ; He, Lihong ; Rathi, Sneha ; Hu, Zeng ; Carlson, Brett L ; Zhang, Wenqiu ; Elmquist, William F ; Mladek, Ann C ; Zhang, Wenjuan ; Dragojevic, Sonja ; Bakken, Katrina K ; Burgenske, Danielle M ; Talele, Surabhi ; Connors, Margaret A

Glioblastoma (GBM) is a disease of the whole brain, with infiltrative tumor cells protected by an intact blood-brain barrier (BBB). GBM has a poor prognosis despite aggressive treatment, in part due to the lack of adequate drug permeability at the BBB. Standard of care GBM therapies include radiation and cytotoxic chemotherapy that lead to DNA damage. Subsequent activation of DNA damage response (DDR) pathways can induce resistance. Various DDR inhibitors, targeting the key regulators of these pathways such as ataxia telangiectasia mutated and Rad3-related (ATR), are being explored as radio- and chemosensitizers. Elimusertib, a novel ATR kinase inhibitor, can prevent repair of damaged DNA, increasing efficacy of DNA-damaging cytotoxic therapies. Robust synergy was observed in vitro when elimusertib was combined with the DNA-damaging agent temozolomide; however, we did not observe improvement with this combination in in vivo efficacy studies in GBM orthotopic tumor-bearing mice. This in vitro-in vivo disconnect was explored to understand factors influencing central nervous system (CNS) distribution of elimusertib and reasons for lack of efficacy. We observed that elimusertib is rapidly cleared from systemic circulation in mice and would not maintain adequate exposure in the CNS for efficacious combination therapy with temozolomide. CNS distribution of elimusertib is partially limited by P-glycoprotein efflux at the BBB, and high binding to CNS tissues leads to low levels of pharmacologically active (unbound) drug in the brain. Acknowledging the potential for interspecies differences in pharmacokinetics, these data suggest that clinical translation of elimusertib in combination with temozolomide for treatment of GBM may be limited. SIGNIFICANCE STATEMENT: This study examined the disconnect between the in vitro synergy and in vivo efficacy of elimusertib/temozolomide combination therapy by exploring systemic and central nervous system (CNS) distributional pharmacokinetics. Results indicate that the lack of improvement in in vivo efficacy in glioblastoma (GBM) patient-derived xenograft (PDX) models could be attributed to inadequate exposure of pharmacologically active drug concentrations in the CNS. These observations can guide further exploration of elimusertib for the treatment of GBM or other CNS tumors.

News (Medical) associated with Elimusertib

10 Apr 2024

·www.prnewswire.com

Blacksmith Medicines To Highlight Preclinical Oncology Data Demonstrating a Potent and Selective FEN1 Inhibitor Has Synergy with Multiple DDR Drug Classes at AACR Annual Meeting 2024

SAN DIEGO, April 10, 2024 /PRNewswire/ -- Blacksmith Medicines, Inc. (Blacksmith), a leading biopharma dedicated to discovering and developing medicines targeting metalloenzymes, today announced preclinical data on its oncology program targeting flap endonuclease 1 (FEN1), a structure-specific metallonuclease that cleaves 5' DNA flaps during replication and repair, at the American Association for Cancer Research (AACR) Annual Meeting 2024, taking place April 5-10 at the San Diego Convention Center, San Diego CA. "FEN1 has been identified as an important therapeutic metalloenzyme involved in DNA replication and repair but previous drug discovery efforts have been hampered by chemistry limitations resulting in inhibitors lacking potency and selectivity," said Zachary Zimmerman, Ph.D. CEO of Blacksmith. "Using our metalloenzyme fragment-based drug discovery approach, we have identified a highly potent and selective inhibitor of FEN1 having synergies with multiple DDR drug classes that include inhibitors of PARP, PARG, USP1, and ATR." The Blacksmith fragment-based drug discovery platform identified a novel metal-binding pharmacophore that binds to the two magnesium ions in the FEN1 active site. Further elaboration using fragment growth strategies resulted in highly potent and selective inhibitors. The current lead (BSM-1516) is ~65-fold more potent against FEN1 than its related enzyme Exonuclease 1 (Exo1) in biochemical assays (IC50 of 7 nM and 460 nM, respectively), an improvement of more than an order of magnitude in selectivity compared to earlier efforts. FEN1 target engagement in live cells was validated by cellular thermal shift assay (CETSA EC50 of 24 nM). Inhibition of FEN1 led to its increased association with chromatin in S-phase cells and recruitment of PARP1 enzyme. In clonogenic assay, BRCA2-deficient DLD1 cells were ~15-fold more sensitive to FEN1 inhibition than their isogenic BRCA2-wild-type counterparts (EC50 of 350 nM and 5 µM, respectively), confirming the increased susceptibility of HR deficient cancer cells to FEN1 inhibition. Treatment of BRCA2-deficient but not wild-type DLD1 cells with BSM-1516 resulted in cell cycle arrest accompanied by DNA damage signaling and accumulation of chromatin-bound RPA32, a marker of ssDNA. In FEN1-inhibitor-anchored CRISPR screen, it was observed that perturbations in EXO1, USP1, PARP1 and HR pathway genes sensitized cells to FEN1 inhibition. Synergistic relationships of BSM-1516 and its combination potential were further explored in viability studies with a panel of DDR inhibitors (n=25) in BRCA2-proficient and deficient cell lines. Strong synergy was identified with multiple drug classes that included inhibitors of USP1 (KSQ-4279), PARP (Olaparib, Niraparib, Talazoparib, AZD5305), PARG (PDD 00017273) and ATR (AZD6738, VE-822, Elimusertib). In vitro ADME assays and in vivo PK studies showed that BSM-1516 has properties suitable for in vivo testing, either as a single agent or in combination with synergistic DDR inhibitors, an investigation that is currently underway. Poster presentation details Abstract Number: 7148 Title: "Small molecule inhibitor of FEN1 nuclease utilizing a novel metal binding pharmacophore synergizes with inhibitors of USP1, PARP, PARG and ATR" Session Category: Experimental and Molecular Therapeutics Session Title: Novel Antitumor Agents 6 Session Date and Time: Wednesday April 10, 2024 9:00 AM - 12:30 PM Location: Poster Section 23 Poster Board Number: 10 About FEN1 Flap endonuclease 1 (FEN1) is a structure-specific di-magnesium metallonuclease that cleaves 5' DNA flaps during replication and repair. FEN1 is an attractive target for development of anticancer therapeutics because it is overexpressed in many tumor types and has a large number of synthetic lethality partners including genes in Homologous Recombination (HR) pathway. About metalloenzymes and the Blacksmith platform Metalloenzymes utilize a metal ion cofactor in the enzyme active site to perform essential biological functions. This diverse class of targets has historically been difficult to drug due to small molecule chemistry limitations that have plagued the industry. The Blacksmith metalloenzyme platform has solved this problem by leveraging the following: A large proprietary fragment library of metal-binding pharmacophores (MBPs); A comprehensive database containing a full characterization of the metalloenzyme genome including functions, metal cofactors, and associations to disease; A first-of-its-kind metallo-CRISPR library of custom single guide RNAs; An industry-leading metalloenzyme computational toolkit for docking, modeling and structure-based drug design; and A robust and blocking intellectual property estate covering bioinorganic, medicinal, and computational chemistry approaches for metalloenzyme-targeted medicines. About Blacksmith Medicines At Blacksmith Medicines, we are developing medicines targeting metal-dependent enzymes. Over 30% of known enzymes are metalloenzymes, covering all major enzyme classes: oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases. Metal ions, including magnesium, zinc, iron, manganese and copper, are the essential ingredient in these metalloenzymes. We recognized a large unmet need for new chemical matter and innovative approaches to drug this important class of enzymes. Our purpose-built platform for metalloenzyme-targeted medicines combines, for the first time in industry, a focused library of metal-binding pharmacophores with proprietary computational modeling approaches to rapidly and rationally design small molecule inhibitors that interact with key metal ions in the enzyme's active site. Our comprehensive knowledge of the metal environment and key active site interactions enables Blacksmith to rapidly build potent and selective inhibitors in a stepwise and predictable manner. Blacksmith has executed strategic drug discovery collaborations with Basilea Pharmaceutica International Ltd., Cyteir Therapeutics Inc., Eli Lilly and Company (Lilly), Hoffmann-La Roche Ltd., and Zoetis LLC., and has been awarded non-dilutive Federal funding agreements with CARB-X and NIH/NIAID. Blacksmith investors include Lilly, Evotec A.G., MP Healthcare Partners, MagnaSci Ventures, and Alexandria Venture Investments. For further information, please visit the company's website and LinkedIn Media Contact: Amy Conrad Juniper Point [email protected] 858-366-3243 SOURCE Blacksmith Medicines

AACR

10 Apr 2023

·www.bayer.com

Bayer to present latest research across its advancing oncology portfolio at AACR 2023 Annual Meeting

Abstracts: ND04, 5047, CT276, 2116, 4035, 433, CT126, 1964, 925, CT228, 311, 5043, CT082 Berlin, April 11, 2023 – Bayer will present latest research across its oncology portfolio at the American Association for Cancer Research (AACR) 2023 Annual Meeting , taking place from April 14-19 in Orlando (FL), USA. Bayer is advancing its oncology R&D efforts in three scientific areas that have the potential to address unmet needs in cancer patients: next-generation Immuno-Oncology, Targeted Radionuclide Therapies and Precision Molecular Oncology. Data from all three areas of scientific focus will be showcased during this year’s meeting. Bayer is progressing novel research around its prostate cancer treatment darolutamide. The presentation highlights the synergistic anti-cancer effects of a PSMA (prostate-specific membrane antigen)-actinium-225 conjugate in combination with darolutamide in preclinical prostate cancer models. Darolutamide, which is jointly developed by Bayer and Orion Corporation, is an oral androgen receptor inhibitor indicated for the treatment of men with non-metastatic castration-resistant prostate cancer (nmCRPC), who are at high risk of developing metastatic disease and for the treatment of men with metastatic hormone-sensitive prostate cancer (mHSPC). Bayer will present the first clinical Phase 1 results on aryl hydrocarbon receptor (AhR) inhibitor BAY 2416964, the company’s most advanced Immuno-Oncology program. A focus of the presentation will be on the target engagement results and pharmacokinetics from its ongoing monotherapy dose-escalation study to explore a potential optimal dose and schedule to effectively inhibit AhR. These results, along with a mathematical model-informed approach have supported the currently ongoing dose expansion for BAY 2416964. In the New Drugs on the Horizon session at AACR, Bayer will present preclinical data on its novel selective diacylglycerol kinase (DGK) zeta inhibitor BAY 2965501, which is under Phase 1 clinical evaluation. The enzyme DGKzeta is a lipid kinase that can down-modulate T-cell activation by catalyzing the conversion of diacylglycerol to phosphatidic acid, thus acting as a ligand-independent, intracellular immune checkpoint. An inhibition of DGKzeta has been demonstrated to enhance T-cell priming against suboptimal tumor antigens and has the potential to overcome multiple immune-suppressive mechanisms in the tumor microenvironment. Based on these data, a first-in-human trial with BAY 2965501 in patients with advanced solid tumors was initiated and is currently enrolling patients. Both small molecule inhibitors in Immuno-Oncology are being jointly developed in a strategic research alliance with the German Cancer Research Center (DKFZ) in Heidelberg, Germany. From its focus area Precision Molecular Oncology, Bayer will show new preclinical data on its mutEGFR/HER2 inhibitor, which was developed in collaboration with the Broad Institute of MIT and Harvard in Cambridge (MA), USA. BAY 2927088 is a reversible small molecule inhibitor that is currently being evaluated in a first-in-human, Phase 1 clinical trial in non-small cell lung cancer (NSCLC) patients with mutations in epidermal growth factor receptors (EGFR & HER2) including exon20 insertions and point mutations. For the first time, Bayer will present the design of the clinical trial and the preclinical activity profile of the inhibitor in human epidermal growth factor receptor 2 ( HER2) mutant NSCLC. Bayer will also report new data looking at larotrectinib, a highly selective and central nervous system (CNS)-active tropomyosin receptor kinase (TRK) inhibitor, approved for the treatment of patients with TRK fusion solid tumors, exploring the concordance between tissue and circulating tumor DNA (ctDNA) testing for neurotrophic tyrosine receptor kinase (NTRK) gene fusions from samples in larotrectinib clinical trials. Additional research to be presented from Bayer’s Targeted Alpha Therapy program evaluates the antitumor efficacy and potential benefit of the combination of radium-223 with 177Lu-PSMA-617 in a preclinical model of bone metastatic prostate cancer. The combination of radium-223 and 177Lu PSMA imaging and therapy (I&T) is currently being investigated in patients with metastatic castration-resistant prostate cancer (mCRPC) in a phase 1/2 trial (AlphaBet, NCT05383079). Key presentations on Bayer research to be presented at AACR 2023 are listed below: Oral presentation: BAY 2965501: A highly selective DGKzeta inhibitor for cancer immuno-therapy with first-in-class potential Abstract ND04, Session DDT001 – New Drugs on the Horizon: Part 1 Sunday, April 16, 2:05 PM – 2:20 PM (EDT), Tangerine Ballroom 2 (WF2) - Convention Center Poster presentations: PSMA-targeted actinium-225 conjugate (225Ac-pelgifatamab) potentiates the antitumor efficacy of darolutamide in hormone-dependent and -independent prostate cancer models Abstract #5047 / 14, Session PO.ET08.02 - Theranostics and Radionuclides/Pharmacologic Approaches Tuesday, April 18, 1:30 PM - 5:00 PM (EDT), Section 19, Convention Center Preliminary analysis of pharmacokinetic (PK) and target engagement biomarkers from a first-in-human Phase I study of immunomodulatory aryl hydrocarbon receptor (AhR) inhibitor BAY2416964 Abstract #CT276 / 16, Session PO.CT01.04 - Phase I Clinical Trials 2 Tuesday, April 18, 1:30 PM - 5:00 PM (EDT), Section 47, Convention Center Phosphorylated extracellular signal-regulated kinase (pERK) activation in T effector cells as a target engagement biomarker for the DGKζ inhibitor BAY 2965501 in clinical trials Abstract #2116 / 19, Session PO.CL01.11 - Biomarkers for Elucidation of Tumor Biology and Metastasis Monday, April 17, 9:00 AM – 12:30 PM (EDT), Section 38, Convention Center Preclinical activity of BAY 2927088 in HER2 mutant non-small cell lung cancer Abstract #4035 / 9, Session PO.ET09.08 - Tyrosine Kinase and Phosphatase Inhibitors 2 Tuesday, April 18, 9:00 AM - 12:30 PM (EDT), Section 21, Convention Center Mechanisms of resistance to BAY 2927088, the first reversible inhibitor targeting EGFR exon 20 insertion mutations in non-small cell lung cancer Abstract #433 / 28, Session PO.ET03.02 - Drug Resistance in Molecular Targeted Therapies 2 Sunday, April 16, 1:30 PM - 5:00 PM (EDT), Section 15, Convention Center An open-label, first-in-human study of BAY2927088 in patients with advanced non-small cell lung cancer (NSCLC) harboring an EGFR and/or HER2 mutation Abstract #CT126 / 14, Session PO.CTP01.02 - Phase I Clinical Trials in Progress Monday, April 17, 1:30 PM - 5:00 PM (EDT), Section 46, Convention Center Racial and ethnic trends in next-generation sequencing (NGS) utilization among adult patients with selected advanced tumor types: a large commercial database analysis Abstract #1964 / 5, Session PO.PR01.02 - Cancer Disparities Research Monday, April 17, 9:00 AM - 12:30 PM (EDT), Section 28, Convention Center NTRK gene fusion in adults and pediatrics with solid tumors: a record linkage study of expression frequency and patient characteristics using the Auria Biobank in Finland Abstract #925 / 8, Session PO.CL11.01 - Analyses Using Clinical and Genomic Databases Sunday, April 16, 1:30 PM – 5:00 PM (EDT), Section 38, Convention Center Concordance between tissue and circulating tumor DNA (ctDNA) testing for neurotrophic tyrosine receptor kinase (NTRK) gene fusions in larotrectinib (laro) clinical trials Abstract #CT228 / 18, Session PO.CT02.02 - Phase II Clinical Trials 2 Tuesday, April 18, 9:00 AM - 12:30 PM (EDT), Section 47, Convention Center Optimization of treatment schedule for the combination therapy of ATR inhibitor elimusertib and PARP inhibitor niraparib in preclinical tumor models Abstract #311 / 13, Session: Targeting Replication Stress and the Immune Microenvironment Sunday, April 16, 1:30 PM - 5:00 PM (EDT), Section 11, Convention Center Radium-223 demonstrates increased antitumor activity in combination with 177Lu-PSMA-617 in the intratibial LNCaP xenograft model of bone metastatic prostate cancer Abstract #5043 / 10, Session PO.ET08.02 - Theranostics and Radionuclides/Pharmacologic Approaches Tuesday, April 18, 1:30 PM - 5:00 PM (EDT), Section 19, Convention Center Next-generation sequencing (NGS) and cytokine assessment from a Phase III study of copanlisib in combination with rituximab in patients with indolent non-Hodgkin lymphoma (iNHL) – associations with survival endpoints Abstract #CT082 / 10, Session PO.CT03.01 - Phase III and Pediatric Clinical Trials Monday, April 17, 9:00 AM - 12:30 PM (EDT), Section 47, Convention Center About Oncology at Bayer Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The company has the passion and determination to develop innovative medicines that help improve and extend the lives of people living with cancer. The oncology franchise at Bayer includes six marketed products across various indications and several compounds in different stages of clinical development. Bayer focuses its research activities on first-in-class innovations across the following scientific platforms: Precision Molecular Oncology, Targeted Alpha Therapies, and Immuno-Oncology. Across the areas of focus, we have several prostate cancer treatments on the market or in development, with the goal of extending survival while limiting side effects of treatment throughout the different stages of the disease. Another key focus at Bayer is on innovative precision oncology treatments, with an approved TRK inhibitor exclusively designed to treat tumors that have an NTRK gene fusion, the oncogenic driver of tumor growth and spread. The company’s approach to research prioritizes targets and pathways with the potential to impact the way that cancer is treated. About Bayer Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. Its products and services are designed to help people and the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating a positive impact with its businesses. At the same time, the Group aims to increase its earning power and create value through innovation and growth. The Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2022, the Group employed around 101,000 people and had sales of 50.7 billion euros. R&D expenses before special items amounted to 6.2 billion euros. For more information, go to www.bayer.com . Find more information at https://pharma.bayer.com Follow us on Facebook: http://www.facebook.com/bayer Follow us on Twitter: @BayerPharma Forward-Looking Statements This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at www.bayer.com . The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

Phase 1Phase 3Phase 2Immunotherapy

100 Deals associated with Elimusertib

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Alveolar Rhabdomyosarcoma	Phase 2	US	National Cancer Institute	22 Dec 2021
Alveolar Rhabdomyosarcoma	Phase 2	CA	National Cancer Institute	22 Dec 2021
Recurrent Ewing Sarcoma	Phase 2	US	National Cancer Institute	22 Dec 2021
Recurrent Ewing Sarcoma	Phase 2	CA	National Cancer Institute	22 Dec 2021
Recurrent Lymphoma	Phase 2	US	National Cancer Institute	22 Dec 2021
Recurrent Lymphoma	Phase 2	CA	National Cancer Institute	22 Dec 2021
Refractory Ewing Sarcoma	Phase 2	US	National Cancer Institute	22 Dec 2021
Refractory Ewing Sarcoma	Phase 2	CA	National Cancer Institute	22 Dec 2021
Refractory Lymphoma	Phase 2	US	National Cancer Institute	22 Dec 2021
Refractory Lymphoma	Phase 2	CA	National Cancer Institute	22 Dec 2021

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04514497 (ETCTN 10402, ASCO2024) Manual	Phase 1	Advanced Malignant Solid Neoplasm	21	Irinotecan 150 mg/m2 IV D1 + Elimusertib 10 mg BID PO D1,D2 (biweekly)	zvidumjiec(yztrysjxrx) = For the Biweekly cohort: 3/3 patients enrolled at dose level (DL) 1 experienced hematologic dose-limiting toxicity (DLT); 6 patients received DL-1 without any DLTs. The weekly regimen escalation comprised of 12 patients: 6 enrolled in DL1 with 2/6 having hematologic DLT and 5/6 unable to complete ≥75% of cycle 1 dosing; 6 enrolled in DL-1 with no DLTs observed. bzvaybxfpg (nvbierkbyd )	Positive	24 May 2024
NCT04514497 (ETCTN 10402, ASCO2024) Manual	Phase 1	Advanced Malignant Solid Neoplasm	21	Irinotecan 25 mg/m2 IV on D1 + Elimusertib 20 mg PO daily on D2,D3 (weekly)		Positive	24 May 2024
NCT04514497 (ETCTN 10402, ASCO2024)	Phase 1	Unresectable Malignant Solid Neoplasm \| Metastatic Lung Cancer \| Pancreatic adenocarcinoma metastatic ... Top1 inhibitor View more	8	Topotecan 1 mg/m2IV	svnhjvpext(hcckxiveea) = one of patient experiencing respiratory failure and cardiac arrest in setting of pancytopenia related to study drug oyohehxuup (texsdlpauh ) View more	Negative	24 May 2024
NCT05071209 (ASCO 12023 \| ASCO 22023) Manual	Phase 1	Solid tumor	8	Elimusertib	yfrnwbopfq(nfnijjcgaj) = At 24 mg/m2/dose, no DLTs were observed. xfhcpgrcwx (ddswybkvbp ) View more	Positive	26 May 2023
NCT03188965 (EP294/#883, IGCS2022)	Phase 1	Female Genital Neoplasms \| DNA Damage BRCA1 \| BRCA2 \| ATM mutations	45	Elimusertib 40 mg	tcckujgtnn(zcyuixeany) = observed in 69%/20% of patients hwlnnesijx (pheyydaznw ) View more	Positive	04 Dec 2022
SGO2022	Phase 1	Uterine Leiomyosarcoma	-	BAY1895344	jotzncklok(ifvsglweui) = aporcooehe esunfkuljm (yccoqkbysx )	Positive	01 Aug 2022
SGO2022	Phase 1	Uterine Leiomyosarcoma	-	Control vehicle	jotzncklok(ifvsglweui) = fcbndcuboe esunfkuljm (yccoqkbysx )	Positive	01 Aug 2022

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