ceralasertib (AZD6738)

P2, N=114, Active, not recruiting, Assistance Publique Hopitaux De Marseille | Recruiting --> Active, not recruiting | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Oct 2023 --> Oct 2024

P2, N=74, Active, not recruiting, Seoul National University Hospital | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=26, Recruiting, Seoul National University Hospital | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

Notably, 9b-induced ATM degradation synergistically enhanced the efficacy of ATR inhibitor AZD6738 both in vitro and in vivo. This work establishes the synthetic lethality-inducing properties of ATR inhibitors in the ATM-deficient context, thereby providing new avenues to innovative therapies for colorectal cancer.

In addition, ATR inhibition plays a significant role in the activation of the immune system by increasing the tumor mutational burden and neoantigen load as well as by triggering the accumulation of cytosolic DNA and subsequently inducing the cGAS-STING pathway and the type I IFN response. Taken together, we review stimulating data showing that ATR kinase inhibition can alter the DDR network, the immune system, and their interplay and, therefore, potentially provide a novel strategy to improve the efficacy of antitumor therapy, using ATR inhibitors as monotherapy or in combination with genotoxic drugs and/or immunomodulators.

P1, N=52, Recruiting, Massachusetts General Hospital | Trial primary completion date: May 2022 --> May 2024

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.

P2, N=50, Suspended, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

Responses to ceralasertib monotherapy were limited in ATM-altered tumors, despite reaching target plasma levels. Alternative pt selection and combination treatment strategies are being explored.

P1, N=200, Recruiting, University of Leeds | Trial completion date: May 2027 --> Mar 2028 | Trial primary completion date: Mar 2023 --> Apr 2025

The Ataxia telangiectasia and Rad3-related (ATR) inhibitor ceralasertib in combination with the PD-L1 antibody durvalumab demonstrated encouraging clinical benefit in melanoma and lung cancer patients who progressed on immunotherapy. IFNI also promotes anti-proliferative effects of ceralasertib on tumor cells. Here, we report that broad immunomodulatory changes following intermittent ATR inhibition underpins the clinical therapeutic benefit and indicates its wider impact on antitumor immunity.

P2, N=30, Recruiting, Muhammad Furqan | Trial primary completion date: Dec 2023 --> Mar 2024

A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)-ceralasertib (ATR kinase inhibitor), durvalumab-olaparib (PARP inhibitor), durvalumab-danvatirsen (STAT3 antisense oligonucleotide) or durvalumab-oleclumab (anti-CD73 monoclonal antibody). Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumor immunity. Durvalumab-ceralasertib is under further investigation in immunotherapy-refractory NSCLC.ClinicalTrials.gov identifier: NCT03334617.

P2, N=39, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

Proteasome-mediated ATR degradation by ZS-7 lasted approximately 12 h after washout in the LoVo cell lines. Notably, ZS-7 demonstrated reasonable PK profiles and, as a single agent or in combination with cisplatin, showed improved antitumor activity and safety profiles compared with the parent inhibitor AZD6738 in a xenograft mouse model of LoVo human colorectal cancer cells upon intraperitoneal (i.p.) administration.

P1, N=11, Active, not recruiting, Acerta Pharma BV | Trial completion date: Jun 2023 --> Jun 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.

This work shows that ATRi prevents T1D by specifically inducing cell death in self-antigen activated, highly proliferative diabetogenic T cells through the induction of DNA damage, resulting in the inhibition of IFNγ production and proliferation. These findings support the consideration of repurposing ATRi for T1D prevention.

P2, N=42, Completed, Se-Hoon Lee | Active, not recruiting --> Completed | Trial primary completion date: May 2023 --> Oct 2023

The five AML cell lines demonstrated sensitivity to monotherapy with GSK-368, AZD-1390, or AZD-6738 (EC50 value ranges from 5.461 to 7.349 nM, 5.821 to 10.120 nM, and 7.618 to 10.100 nM, respectively). DNMT1, ATM, and ATR possess potential as therapeutic targets for AML. Both individual targeting and combination targeting of these molecules have been confirmed as promising therapeutic approaches for AML.

Antitumor activity of olaparib alone or combined with an ATR inhibitor (ATRi, ceralasertib) or CHK1 inhibitor (CHK1i, MK-8776) was evaluated in OC cell lines sensitive (PEO1, PEO4) and resistant (PEO1-OR) to olaparib. Overall, the addition of ATRi or CHK1i to olaparib effectively overcomes resistance to PARPi exerting anti-proliferative effect in BRCA2 olaparib-resistant OC cells and alters expression of DDR-related proteins. These new molecular insights into cellular response to olaparib combined with ATR/CHK1 inhibitors might help improve targeted therapies for olaparib-resistant OC.

P2, N=72, Completed, AstraZeneca | Active, not recruiting --> Completed

P2, N=54, Active, not recruiting, AstraZeneca | Phase classification: P2a --> P2

Responses were observed in patients without germline or somatic BRCA1/2 mutations, including patients with mutations in other homologous recombination repair genes and tumours with functional homologous recombination deficiency by RAD51 foci. Conclusion The response rate to olaparib and ceralasertib did not meet pre-specified criteria for activity in the overall evaluable population, but responses were observed in patients who would not be expected to respond to Olaparib monotherapy.

Materials and methodsIn the customized shRNA library screen, 2009 shRNAs developed to target 671 genes were pool-cloned into a retroviral vector allowing doxycycline-inducible expression to generate a plasmid shRNA library (Antonova et al...We validated, genetically and pharmacologically, DNMT1 and ATR using several AML1/ETO-positive (SKNO-1, Kasumi-1) and AML1/ETO-negative cell lines (OCI-AML3, HL60) with median IC50 for decitabine 74 nM (range 44-219), azacytidine 146 nM (range 14-267), berzosertib 219 nM (range 16-460) and ceralasertib 85 nM (range 42-328)...Some of these epigenetic regulators, such as DNMT1 and ATR, are susceptible to pharmacological inhibition by small molecules showing promising preclinical and clinical efficacy, and confirmation studies (Baeten et al. , ASH meeting 2022) appear warranted.

Promising drugs inhibiting kinases like Wee1 (Adavosertib), Wee1+Myt1 (PD166285), ATR (AZD6738) and Chk1 (UCN-01) have been developed, but clinical data has shown variable efficacy for them with poorly understood mechanisms of resistance. Elevated Myt1 levels also conferred resistance to inhibitors of ATR or Chk1 inhibitor. Our data supports that Myt1 overexpression is a common mechanism by which cancer cells can acquire resistance to a variety of drugs entering the clinic that aim to induce mitotic catastrophe by abrogating the G2/M checkpoint.

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.

P2, N=86, Recruiting, University of Pennsylvania | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=74, Active, not recruiting, Seoul National University Hospital | Recruiting --> Active, not recruiting | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Jun 2023 --> Dec 2023

P2, N=104, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

Ceralasertib monotherapy was tolerated at 160 mg BD intermittent and associated with anti-tumor activity.

'Clearance' of ctDNA to become undetectable at C2D1 identified sporadic TNBC patients who benefited from olaparib and ceralasertib. Although 'clearance' of ctDNA was associated with good outcome on olaparib plus ceralasertib, median CDR was not predictive of treatment benefit. This contrasts the results of ctDNA dynamic assessment of cohort A-D, where median CDR was highly predictive of treatment benefit.

When used sequentially with LBS-007, hydroxyurea provided a robust response yielding GI50's between 1 and 3 nM for LBS-007, effectively blocking DNA replication origins (LBS-007) and inducing fork stalls (HU)...Most impressively, the combination of LBS-007 and venetoclax was exponentially enhanced when used in conjunction with ceralasertib (4.8 pM)...Our results identify a unique and potentially efficacious strategy to treat one of the most difficult to treat subtypes of AML. These findings will provide the rationale for potential clinical trials using CDC7 inhibition in p53 mutated or R/R AML.

P1/2, N=466, Recruiting, AstraZeneca | Trial completion date: Feb 2026 --> Jun 2026 | Trial primary completion date: Feb 2026 --> Jun 2026

P1, N=87, Active, not recruiting, Royal Marsden NHS Foundation Trust | Unknown status --> Active, not recruiting | Trial completion date: Dec 2020 --> Dec 2023 | Trial primary completion date: Sep 2020 --> Dec 2023

P2, N=273, Active, not recruiting, AstraZeneca | Trial completion date: Sep 2023 --> Sep 2024

We show that metronomic dosing of ovarian cancer cells with AZD6738 results in resistance to ATR/ Chk1 inhibitors, that loss of CDC25A expression represents a mechanism of resistance to ATRi treatment in ovarian cancer cells and identify several circulating biomarker candidates of CDC25A low, AZD6738-resistant ovarian cancer cells.

P2, N=180, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

Cerala, a selective and potent ATR inhibitor, in combination with olaparib, has demonstrated activity in pts with homologous recombination deficiency-positive, PARPi-resistant OC (CAPRI; NCT03462342). Secondary objectives include assessment of antitumour activity, pharmacokinetics and pharmacodynamic biomarkers. Recruitment started in April 2023 and sites across North America, Europe and Asia Pacific will enrol up to 150 pts in total.

However, enhancement of AST-3424 cytotoxicity by G2 arrest inhibitors, including adavosertib, AZD7762 and ceralasertib was only observed in HT29 but not in H460 cells. Conclusions DNA repair plays an essential role in AST-3424-mediated in vitro biological activities and in vivo anti-tumor activity. The preclinical data presented in this study support a new approach for cancer treatment.

These data provide further preliminary support for the efficacy signals seen with the ceralasertib/durvalumab combination in ICB pre-treated NSCLC. The outcome data in prospectively stratified RAS mutant patients which has not been reported before looks particularly promising. Determining the immunological and molecular basis of response or resistance to the ceralasertib/durvalumab combination is a translational priority.