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Ref Type abstract
PMID
Authors Susanna Ulahannan; Jason T. Henry; Kathleen N. Moore; Gerald S. Falchook; Meredith S. Pelster; Elisa Fontana; Bryony Harrop; Nicola Little; Helen Millward; Amelia Fielding; Sara Busacca; Emre Karakoc; Suraj Menon; Sarah V. Holt; Niall Martin; Graeme C. Smith; Desiree Headley; Ian C. Smith; Bert H. O'Neil; Babar Bashir
Title Abstract CT267: First results of ART0380 (an ATR kinase inhibitor) with low dose irinotecan in advanced or metastatic solid tumors
Journal Vol Issue Date Pages Journal Short Title
Cancer Research 85 Supplement_2 April 15, 2025
URL https://aacrjournals.org/cancerres/article/85/8_Supplement_2/CT267/761473/Abstract-CT267-First-results-of-ART0380-an-ATR
Abstract Text Background: Replication stress (RS) is a critical cancer vulnerability. ART0380 is an inhibitor of Ataxia-Telangiectasia and Rad3-related (ATR), the primary orchestrator of the cellular response to RS. This is the first clinical report of a development approach wherein tumor cells experience a triple combination of biological insults: induced RS by irinotecan, endogenous RS via ataxia-telangiectasia mutated (ATM) loss, and prevention of rescue from RS by ATR inhibition (NCT04657068). Methods: Patients (pts) with advanced cancers who had no satisfactory alternative treatment option received escalating doses of ART0380 (25mg to 400mg) on days 1-3 and 8-10 in combination with low dose irinotecan (60mg/m2 or 85mg/m2) on days 1 and 8 of a 21-day cycle. Pts in dose expansion were selected based on ATM protein expression. Key objectives included safety, tolerability, and preliminary efficacy. Results: At the data cut-off (01Nov24), 87 patients were dosed with ART0380 + irinotecan. The recommended phase 2 dose (RP2D) was established as 200mg ART0380 on days 1-3 and 8-10 and 60mg/m2 irinotecan on days 1 and 8 of a 21-day cycle. At the RP2D (N=58), the median prior lines of therapy was 3 (range 1-7) with 59% of pts receiving prior irinotecan. The most common treatment related adverse events were neutropenia (53%), anemia (41%), fatigue (33%) and diarrhea (31%). Grade≥3 related diarrhea, nausea and vomiting each occurred in 1 pt. By intent-to-treat (ITT) analysis, the confirmed objective response rate (ORR) was higher in pts with ATM protein loss by immunohistochemistry compared to those with tumors that expressed ATM protein (see Table 1). Further analyses with longer follow-up will be available for conference presentation. Conclusions: ART0380 and low dose irinotecan is well tolerated and suitable for long-term dosing. Clinically meaningful activity has been demonstrated and further refined via biomarker selection (45% confirmed RECIST response rate in patients with ATM negative cancers).

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