elimusertib (BAY 1895344)

P1, N=10, Active, not recruiting, National Cancer Institute (NCI) | N=90 --> 10 | Trial completion date: Dec 2024 --> Apr 2025 | Trial primary completion date: Dec 2024 --> Mar 2024

However, combinations of copanlisib/afatinib and copanlisib/elimusertib were significantly more effective in controlling NETc tumor growth. These findings define the genetic landscape of NETc and suggest that a large subset of these highly lethal malignancies might benefit from existing targeted therapies.

P1, N=56, Completed, Bayer | Phase classification: P1b --> P1

As single agent, M1774 suppressed cancer cell viability at nanomolar concentrations, showing greater activity than ceralasertib and berzosertib, but less potency than gartisertib and elimusertib in the small-cell lung cancer H146, H82, and DMS114 cell lines. Low dose of M1774 was found highly synergistic with a broad spectrum of clinical DDAs including TOP1 inhibitors (SN-38/irinotecan, topotecan, exatecan, and exatecan), the TOP2 inhibitor etoposide, cisplatin, the RNA polymerase II inhibitor lurbinectedin, and the PARP inhibitor talazoparib in various models including cancer cell lines, patient-derived organoids, and mouse xenograft models. Furthermore, we demonstrate that M1774 reverses chemoresistance to anticancer DDAs in cancer cells lacking SLFN11 expression, suggesting that SLFN11 can be utilized for patient selection in upcoming clinical trials.

ATR inhibition by Elimusertib in combination with RT may be a promising new treatment strategy in the treatment of TNBC. However, further experiments should be performed to elucidate the underlying molecular mechanisms of the therapeutic efficacy of this combination treatment and its association with DNS repair mechanisms in TNBC, in vitro and in vivo.

P1; Trial primary completion date: Jan 2024 --> Nov 2024

P1, N=96, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Feb 2024 --> Feb 2025

P1; N=37 --> 7 | Trial primary completion date: Apr 2026 --> Jan 2024

We found a subpopulation of glioma sphere-forming cells (GSCs) with substantial synergism with temozolomide (TMZ) using a panel of 3 clinical-grade ataxia-telangiectasia- and Rad3-related kinase inhibitors (ATRis), (elimusertib, berzosertib, and ceralasertib). This research provides a rationale for selectively targeting MGMT-methylated cells using ATRis and TMZ combination. Overall, we believe that MGMT methylation status in GBM could serve as a robust biomarker for patient selection for ATRi combined with TMZ.

Finally, we show that the remarkable response to the 14-d combined ATR/ALK inhibition protocol reflects a robust differentiation response, reprogramming tumor cells to a neuronal/Schwann cell lineage identity. Our results identify an ability of ATR inhibition to promote NB differentiation and underscore the importance of further exploring combined ALK/ATR inhibition in NB, particularly in high-risk patient groups with oncogene-induced replication stress.

P1, N=90, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=64, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting

P1; Suspended --> Active, not recruiting

P1, N=96, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting

P1, N=14, Terminated, Bayer | Active, not recruiting --> Terminated; There was no anticipated benefit of the experimental combination as tested over available standard therapies; therefore Sponsor has decided to terminate the investigation.

P1; Recruiting --> Suspended

P1, N=96, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

These findings demonstrated that BAY 1895344 increased in vitro and in vivo radiosensitivity in HPV-negative HNSCC preclinical models, suggesting therapeutic potential warranting evaluation in clinical trials for patients with locally advanced or recurrent HPV-negative HNSCC.

P1, N=74, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

In several tumour models, elimusertib demonstrated widespread anti-tumour activity stronger than ceralasertib, another ATR inhibitor. This activity is present in both DDR-proficient and DDR-deficient lymphoma models. Furthermore, a combination of ATR and PI3K inhibition by treatment with elimusertib and copanlisib has in vitro and in vivo anti-tumour activity, providing a potential new treatment option for lymphoma patients.

P1, N=14, Active, not recruiting, Bayer | Phase classification: P1b --> P1

BAY 1895344 in combination with either sorafenib or lenvatinib showed mainly synergistic effects in four DTC cell lines...The combinations of BAY 1895344 plus lenvatinib and BAY 1895344 with dabrafenib plus trametinib were more effective than any single therapy in a K1 xenograft model. No appreciable toxicity appeared in animals treated with either a single therapy or a combination treatment. Our findings provide the rationale for the development of clinical trials of BAY 1895344 in the treatment of DTC.

P1b, N=14, Active, not recruiting, Bayer | Recruiting --> Active, not recruiting | N=89 --> 14 | Trial completion date: Mar 2025 --> Nov 2023 | Trial primary completion date: Mar 2025 --> Nov 2023

P2, N=229, Completed, Bayer | Recruiting --> Completed | Trial completion date: Apr 2025 --> Sep 2023

BAY 1895344 in combination with either sorafenib or lenvatinib showed mainly synergistic effects in four DTC cell lines...The combinations of BAY 1895344 plus lenvatinib and BAY 1895344 with dabrafenib plus trametinib were more effective than any single therapy in a K1 xenograft model. No appreciable toxicity appeared in animals treated with either a single therapy or combination treatment. Our findings provide the rationale for the development of clinical trials of BAY 1895344 in the treatment of DTC.

The DNA-damaging drugs, topotecan, trabectedin, and temozolomide were combined with varied inhibitors of DNA damage response enzymes including PARP (olaparib or talazoparib), ATM (ataxia telangiectasia mutated; AZD-1390), ATR (ataxia telangiectasia and Rad3-related protein; berzosertib or elimusertib), and DNA-PK (DNA-dependent protein kinase; nedisertib or VX-984). The potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways was assessed in multicellular tumor spheroids. Although most combinations demonstrated additive cytotoxicity, synergistic cytotoxicity was observed for several drug combinations.

Our findings suggest that Elimusertib suppresses the ATR-based Chk1 pathway in TNBC cells. Therefore, ATR inhibition by Elimusertib could be a potential therapeutic strategy especially in tumor protein p53 (p53) mutant TNBC patients.

P1, N=64, Recruiting, National Cancer Institute (NCI) | N=36 --> 64 | Trial completion date: Jul 2023 --> Jul 2024 | Trial primary completion date: Jul 2023 --> Jul 2024

P2, N=239, Recruiting, Bayer | Trial completion date: Apr 2024 --> Apr 2025

Based on in vitro efficiency, central nervous system (CNS) penetrance ability and feasible translational potential, two combinations using a DNA alkylating or topoisomerase inhibitors in combination with an ataxia telangiectasia mutated and rad3 (ATR) inhibitor (topotecan/elimusertib and melphalan/elimusertib respectively) were validated in vitro and in vivo. Importantly, IA administration of melphalan combined with elimusertib led to a significant increase in survival in a CPC genetic mouse model. In conclusion, this study is, to the best of our knowledge, the first that identifies multiple promising combinatorial therapeutics for CPC and emphasizes the potential of IA delivery for the treatment of CPC.

P1/2, N=23, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting

Background: HER3, a member of the ERBB family of receptor tyrosine kinases that activates multiple oncogenic signaling pathways, is overexpressed in 50-70% of breast cancers (BC). The combination of HER3-DXd plus ATR inhibitors has therapeutic potential for overcoming tamoxifen resistance in HER3+/ER+ BC.

P1/2, N=23, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

Our data demonstrate that DS-8201 and DNA damage repair inhibitors together have synergistic anticancer effects in NCI-N87 xenograft models, effects that may reflect upregulation of γ-H2AX protein in tumor tissues. Collectively, our results indicate that the combination of DS-8201, BAY1895344, and AZD2281 exerts significant synergistic antitumor activity, suggesting that DNA damage-repair inhibitors in combination with HER2-targeted ADCs is a potential approach for treating HER2-positive malignancies, offering a promising strategy for future clinical applications.

P1, N=74, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023

Elimusertib is preclinically active in vitro and in vivo against primary CS cell lines and xenografts, respectively. CS models harboring HRD or with pure/mixed endometrioid histology demonstrated higher sensitivity to ATR inhibition. Clinical trials with elimusertib in CS patients are warranted.

BAY1895344 demonstrates promising in vivo activity against biologically aggressive PDX models of uLMS harboring ATRX mutations, with no significant toxicity. Clinical trials of BAY1895344 in uLMS patients are warranted.

To validate the combination antitumor effect of SG and selected kinase target inhibitors, sulforhodamine B staining proliferation assays, cell cycle analysis, and caspase 3/7 activity assays were performed in Trop-2+ TNBC and HR+ BC cell lines, including cell lines resistant to tamoxifen and double-resistant to tamoxifen and CDK4/6 inhibitor (palbociclib or abemaciclib)...We identified 69 kinase targets in TNBC cell line BT-20 and 44 kinase targets in HR+ BC cell line T47D (tamoxifen/abemaciclib double-resistant) by the sensitivity index analysis (>0.15) of RNAi screening results, and further pathway analysis revealed DNA damage response (DDR), (drug: BAY1895344), PI3k/Akt/mTOR (drug: copanlisib), and MAPK (drug: trametinib) as potential target canonical pathways whose targeting enhanced the cytotoxic effect of SG in both TNBC and HR+ BC...Among inhibitors of these targets, DDR pathway inhibitor BAY1895344 had the most robust synergy with SG, compared to two other target inhibitors, against Trop-2+ TNBC and HR+ BC cell lines. These in vitro data warrant future in vivo validation studies of the synergistic antitumor effect of SG and BAY1895344 in metastatic HER2– breast cancer.

P2, N=239, Active, not recruiting, Bayer | Recruiting --> Active, not recruiting

Elimusertib demonstrated clinical benefit in heavily pretreated gynecologic cancers with DDR defects, including platinum-resistant ovarian cancer with previous PARPi treatment. A Phase I study of elimusertib plus niraparib is ongoing (NCT04267939).

BAY1895344 demonstrates promising in vivo activity against a PDX model of uLMS that harbors ATRX mutations, with no significant toxicity. Phase I trials of BAY1895344 are currently ongoing, and its clinical use in uLMS warrants further investigation.