ceralasertib (AZD6738)

P2, N=21, Not yet recruiting, Mario Negri Institute for Pharmacological Research

P2, N=104, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P2, N=30, Recruiting, Muhammad Furqan | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

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.

P1/2, N=466, Recruiting, AstraZeneca | Trial completion date: Jul 2026 --> Mar 2025 | Trial primary completion date: Jul 2026 --> Mar 2025

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

Collectively, these results show that the novel PARP1 selective inhibitor AZD5305 yields a potent antitumor response in PDX models with HRD and delays PARPi resistance alone or in combination with carboplatin or ceralasertib, which supports its use in the clinic as a new therapeutic option.

P1, N=11, Active, not recruiting, Acerta Pharma BV | Trial completion date: Jun 2024 --> Aug 2026

P2, N=132, Recruiting, OHSU Knight Cancer Institute | Trial primary completion date: Dec 2024 --> Dec 2025

P3, N=594, Active, not recruiting, AstraZeneca | Trial primary completion date: May 2025 --> Aug 2025

P1, N=12, Completed, AstraZeneca | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Mar 2024

Overall, our study demonstrates that ceralasertib and RT combined preferentially sensitises PTEN-depleted NSCLC models in vitro and in vivo, with no impact on early inflammatory response indicative of RP. These findings provide a rationale for evaluating ATR inhibition in combination with RT in NSCLC patients with PTEN mutations.

P2, N=50, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting

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

In BALTIC, all combination regimens demonstrated tolerable safety profiles, but antitumor activity was limited in refractory/resistant ES-SCLC. Among patients treated with durvalumab plus tremelimumab, an association of on-treatment reduction in ctDNA with longer OS suggests the potential use of ctDNA as a surrogate of treatment response, warranting further investigation.

P2, N=174, Recruiting, Institute of Cancer Research, United Kingdom | N=40 --> 174 | Trial completion date: Mar 2023 --> Apr 2026 | Trial primary completion date: Mar 2023 --> Apr 2026

P2, N=63, Recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Jun 2024 --> Dec 2024

In addition, ICT10336 exhibited a superior and efficient multicellular penetration ability in 3D tumor models, and selectively eradicated cells at the hypoxic core compared to AZD6738. In summary, the preclinical data demonstrate a new strategy of tumor-targeted delivery of ATR inhibitors with significant potential of enhancing the therapeutic index.

P2, N=86, Active, not recruiting, University of Pennsylvania | Recruiting --> Active, not recruiting

P2, N=194, Active, not recruiting, AstraZeneca | Trial completion date: Apr 2024 --> Jun 2025

P2, N=54, Active, not recruiting, AstraZeneca | Trial completion date: Feb 2024 --> Feb 2025

Using inhibitors targeting ATM (AZD1390), ATR (AZD6738) and DNA-Pkcs (AZD7648), we observed that this led to significantly decreased clonogenic survival of HNSCC cell lines following both X-ray and proton irradiation. We confirmed that the inhibitors in combination with X-rays and protons led to DSB persistence, and increased micronuclei formation. Cumulatively, our data suggest that targeting DSB repair, particularly via ATM and DNA-Pkcs inhibition, can exacerbate the impact of ionising radiation in sensitising HNSCC cell models.

P1, N=51, Recruiting, National Cancer Institute (NCI) | N=15 --> 51

P3, N=563, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting | Trial completion date: May 2025 --> Aug 2025

P2, N=30, Recruiting, Muhammad Furqan | Trial completion date: May 2024 --> Sep 2024

P2, N=423, Active, not recruiting, University of Birmingham | Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Sep 2023 --> Sep 2024

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

C+O was well tolerated and active in pts with platinum sensitive HGSOC warranting further evaluation. Efficacy was seen regardless of the presence of tumor genomic instability.

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.