Abstract B010: Updated data from ABOYA-119: A phase 1/2a trial of ATRN-119, a novel macrocyclic ATR inhibitor, in patients with advanced solid tumors harboring DNA damage repair alterations

Abstract Background: ATR kinase inhibitors disrupt cellular DNA damage repair (DDR) pathways and are emerging as promising targeted therapies for solid tumors. ATRN-119 is a differentiated macrocyclic, highly selective ATR inhibitor demonstrating antitumor activity that correlates with specific DDR, tumor suppressor, or oncogene alterations. Material and Methods: This first-in-human, open-label dose escalation (3+3 design) and dose expansion study of oral ATRN-119 has expanded to seven US sites (NCT04905914). ATRN-119 is being evaluated orally at once-daily (QD) doses from 50 to 1500 mg and twice-daily (BID) doses from 400 to 750 mg in 28-day cycles. Primary objectives include evaluating the safety, identifying the maximum tolerated dose, recommended phase 2 dose, and characterizing the pharmacokinetic (PK) of ATRN-119 and its active metabolite, including food effects. Secondary objectives include evaluating antitumor activity across various solid tumors per RECIST v1.1 (PCWG3 criteria for patients with mCRPC) and serum biomarkers. Key eligibility criteria include advanced solid tumor with ≥ 1 DDR mutation by next-generation-sequencing, failed > 1 standard-of-care therapy, measurable disease (RECIST v1.1; PCWG3), ECOG PS 0 or 1, adequate organ function, and no unresolved therapy-related adverse effects (AE), CNS metastases, or concomitant strong CYP enzyme inhibitor/inducer. Results: As of July 7, 2025, 38 patients have been treated (median age 65 years [range: 42-81]; 53% female; 76.3% White, 18.4% Black, 2.6% American Indian, 2.6% Asian). The most prevalent primary tumor sites were pancreatic (n=8, 21%) and colorectal (n=7, 18%). Gynecologic malignancies comprised 16% of cases (n=6). Breast cancer accounted for 8% (n=3), prostate cancer 5% (n=2), and lung cancer 5% (n=2).The median prior lines of treatments was 4. All patients (100%) experienced at least one adverse event (AE). A total of 12 patients (31.6%) had 18 unique serious AEs (SAEs), with one event of anemia probably related to ATRN-119. The most frequent treatment-related AEs (TRAE) were diarrhea (n=17, 44.7%), nausea (n=12, 31.6%), and fatigue (n=10, 26.3%). Grade 3 TRAEs occurred in six patients: fatigue (n=2, 5.3%), diarrhea (n=2, 5.3%), anemia (SAE; n=1, 2.6%), and elevated bilirubin (n=1, 2.6%). PK analysis demonstrates a dose proportional increase in ATRN-119 exposure through 1100 mg QD, an accumulation ratio of ∼2, and a median half-life of 4.8 hours (IQR 2.7-6.6). Preliminary antitumor activity includes 7 patients achieving stable disease; no objective responses per RECIST v1.1 observed. Conclusion: Continuous oral administration of ATRN-119 demonstrates manageable safety profile and preliminary indications of clinical activity in this ongoing trial. Updated results will be presented at the congress. Citation Format: Amit Mahipal, Reva Schneider, Anthony Tolcher, Shiraj Sen, Patricia LoRusso, Fiona Simpkins, M. Adham Salkeni, Crystal Miller, David Stenehjem, Mike Carleton, Philippe Pultar, David Sommerhalder. Updated data from ABOYA-119: A phase 1/2a trial of ATRN-119, a novel macrocyclic ATR inhibitor, in patients with advanced solid tumors harboring DNA damage repair alterations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B010.