A phase I study of irinotecan combined with BAY1895344 (ATR inhibitor) in advanced solid tumors: Results of ETCTN 10402 dose escalation.

Thatcher Ross Heumann Vanderbilt-Ingram Cancer Center, Nashville, TN info_outline Thatcher Ross Heumann, Shannon Stockton, Michael Cecchini, Raid Aljumaily, Cathy Shyr, Jennifer Whisenant, Jason S. Starr, Farshid Dayyani, Joaquina Celebre Baranda, Nikolaos Trikalinos, S. Percy Ivy, Patricia LoRusso, Satya Das, Steven Gore, Jan Hendrik Beumer, Jordan Berlin

Authors Thatcher Ross Heumann Vanderbilt-Ingram Cancer Center, Nashville, TN info_outline Thatcher Ross Heumann, Shannon Stockton, Michael Cecchini, Raid Aljumaily, Cathy Shyr, Jennifer Whisenant, Jason S. Starr, Farshid Dayyani, Joaquina Celebre Baranda, Nikolaos Trikalinos, S. Percy Ivy, Patricia LoRusso, Satya Das, Steven Gore, Jan Hendrik Beumer, Jordan Berlin Organizations Vanderbilt-Ingram Cancer Center, Nashville, TN, Yale University Cancer Center, New Haven, CT, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, Vanderbilt University Medical Center, Department of Biomedical Informatics, Nashville, TN, Department of Hematology-Oncology, Mayo Clinic Florida, Jacksonville, FL, University of California, Irvine Chao Family Comprehensive Cancer Center, Orange, CA, University of Kansas Cancer Center, Fairway, KS, Washington University School of Medicine in St. Louis, Siteman Cancer Center, St. Louis, MO, National Cancer Institute-Cancer Therapy Evaluation Program, Bethesda, MD, Cullgen, Inc., San Diego, CA, Division of Cancer Treatment and Diagnosis National Cancer Institute, Bethesda, MD, UPMC Hillman Cancer Center, Pittsburgh, PA Abstract Disclosures Research Funding NCI Cancer Therapy Evaluation Program Bayer Background: ATR protein kinase is activated by replication stress and recruited to stalled forks or single strand DNA defects in various cancers. The topoisomerase-I (Top1) inhibitor irinotecan induces DNA damage. The ATR inhibitor BAY1895344 (elimusertib) has demonstrated cytotoxic potential in SCLC and GI cancer xenografts when combined with Top1 inhibitors . Methods: This phase Ia trial assessed elimusertib in combination with irinotecan in adult patients with refractory advanced solid tumors for whom irinotecan can be considered standard care. Patients with previous irinotecan exposure were excluded. Two dosing schedules were used: 1) Biweekly - irinotecan IV (starting at 150 mg/m 2 ) D1 + elimusertib (starting dose 20 mg PO BID) D1,D2 (cycle=14 days); 2) Weekly - irinotecan (starting at 50 mg/m 2 ) IV on D1,8,15 with elimusertib (starting at 20 mg PO daily) on D2,D3,D9,D10 and D16,D17 (cycle=21 days). Dose escalation utilized a 3+3 design. Primary objectives were to assess safety and tolerability and estimate the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives included estimating pharmacokinetic (PK) profiles and assessing anti-tumor activity. Results: A total of 21 patients were enrolled in dose escalation (N=9 [Biweekly] and N=12 [Weekly], median age 58 and 2 lines of prior therapy. For the Biweekly cohort: 3/3 patients enrolled at dose level (DL) 1 experienced hematologic dose-limiting toxicity (DLT); 6 patients received DL-1 without any DLTs. The weekly regimen escalation comprised of 12 patients: 6 enrolled in DL1 with 2/6 having hematologic DLT and 5/6 unable to complete ≥75% of cycle 1 dosing; 6 enrolled in DL-1 with no DLTs observed. Notable grade 3+ treatment-related adverse events and summary best response are summarized (Table 1). The majority of evaluable patients in both schedules had initial disease control (56% [biweekly] and 67% [weekly]). One confirmed partial response was seen in the biweekly RP2D. Median progression-free survival was 2.1 mo [biweekly] and 2.5 mo [weekly]. PK results will be presented at time of meeting. Conclusions: Both RP2D and MTD of elimusertib in combination with irinotecan were reached for both dosing schedules: irinotecan 150 mg/m 2 IV D1 + elimusertib 10 mg BID PO D1,D2 (biweekly) and irinotecan 25 mg/m 2 IV on D1 + elimusertib (20 mg PO daily) on D2,D3 (weekly). Dose escalation was notably limited by myelotoxicity. Due to sponsor decision, the study was halted prior to planned expansion but the concept of ATR + topo I combination remains scientifically relevant. Clinical trial information: NCT04514497. Irinotecan Biweekly Irinotecan Weekly Select Grade 3+ TRAEs N=9 N=12 Neutropenia 5 (55.6%) 7 (58.3%) Febrile Neutropenia 1 (11%) 1 (8.3%) Thrombocytopenia 2 (22.2%) 1 (8.3%) Sepsis 0 1 (8.3%) Best Response N=9 N=9 Partial Response 1 (11.1%) [DOR 4.1 mo] 0 Stable Disease 4 (44.4%) 6 (67%) Progression 4 (44.4%) 3 (33%)

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