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• W4282946769 abstract "Abstract Inhibition of ataxia telangiectasia and Rad-3 related (ATR) kinase offers therapeutic promise for DNA damage response deficient tumors. In addition, ATR inhibitors may offer even broader clinical utility when combined with PARPi’s, chemo, immune or radiation therapy. Flat-fixed dosing of ATR inhibitors alone or in combination has provided clinical benefit but is associated with on target, dose limiting haematological toxicity. Strategies to refine dose selection of this class of medicine may further optimize clinical benefit. The aim of our ongoing investigation is to determine if the dose selection for clinical development of the novel ATR inhibitor ART0380 (IACS-030380) may be optimized based on the degree of PD engagement in both tumor and normal tissue from patients. To do this, we have utilized in vitro and in vivo cancer models to help us understand the dynamic and temporal response to several biomarkers of ATR inhibition and DNA damage. Once established in vitro, we selected key markers, such as γH2AX and pKAP1, to explore in vivo using doses predicted to be biologically effective in man and have shown that these are modulated following exposure to ART0380. To enable the serial assessment of PD engagement in both tumor and normal tissue, we have developed an assay in the phase 1 study of ART0380 (NCT04657068) to measure γH2AX levels in circulating tumor cells (CTC’s) and normal cells (PBMC’s). A significant advantage of this approach is that samples are taken from the same blood draw and at several timepoints following exposure to ART0380. So far, our studies have shown that in patients, who have experienced drug exposures predicted to be biologically effective, γH2AX levels in CTC’s increase by up to 20% respectively from baseline while γH2AX in PBMC’s remains unaffected. This observation may highlight that target engagement has taken place for ART0380 in the tumor without an effect in normal tissue, a phenomena perhaps explained by the pharmacokinetic profile of ART0380. The clinical study is ongoing and we continue to monitor individual patient responses, toxicity, and correlate with PD engagement in tumor and normal tissue circulating biopsies. In addition, we are now expanding our analysis into a multiplexed assay where we will measure pKAP1 as well as γH2AX to build a more detailed assessment of PD activity in patients. Updated data will be presented. Citation Format: Manish Patel, Kathleen N. Moore, Desiree Piscitello, Jayesh Majithiya, Marina Roy Luzarraga, Helen Millward, Sarah V. Holt, Melissa Johnson. A pharmacodynamic platform using liquid biopsy to support dose selection for the ATR inhibitor ART0380 (IACS-030380) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB520." @default.
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• W4282946769 date "2022-06-15" @default.
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• W4282946769 title "Abstract LB520: A pharmacodynamic platform using liquid biopsy to support dose selection for the ATR inhibitor ART0380 (IACS-030380)" @default.
• W4282946769 doi "https://doi.org/10.1158/1538-7445.am2022-lb520" @default.
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