An open-label, multicenter, phase Ib/II study of the ATR inhibitor SC0245 in combination with irinotecan in patients with relapsed and refractory extensive stage small cell lung cancer (ES-SCLC).

person Yongfeng Yu Department of Medical Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China info_outline Yongfeng Yu, Dingzhi Huang, Hongming Pan, Chun-lai Li, Sheng Wang, Hai-jun Guo, Rong Su, Li-qin Zhang, Shi-chang Li, Yi-wei Wang, Yong-Jiang Hei, Shun Lu

Authors person Yongfeng Yu Department of Medical Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China info_outline Yongfeng Yu, Dingzhi Huang, Hongming Pan, Chun-lai Li, Sheng Wang, Hai-jun Guo, Rong Su, Li-qin Zhang, Shi-chang Li, Yi-wei Wang, Yong-Jiang Hei, Shun Lu Organizations Department of Medical Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China, Department of Thoracic Oncology, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin, China, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China, Biocity Biopharmaceutics Co., Ltd., Shanghai, China, Department of Medical Oncology, Shanghai Chest Hospital, Shanghai, China Abstract Disclosures Research Funding Biocity Biopharmaceutics Co,.Ltd, Wuxi, China Background: Ataxia telangiectasia and Rad3 related (ATR) is activated in response to replication stress induced by topoisomerase 1 inhibitors (TOP1i) and other DNA damaging agents. SC0245 is a novel potent ATR inhibitor, showing synergistic inhibitory effects when combined with TOP1i in DMS-114 and H446 small cell lung cancer. This is the first report on an ongoing phase Ib/II study of SC0245 in combination with irinotecan (IRI) in patients (pts) with ES-SCLC (ClinicalTrials.gov: NCT05731518). Methods: Multiple escalating doses of SC0245 are being administered orally with a fixed dose of IRI. Pts are being enrolled into five escalating dose cohorts (80 mg once daily (QD), 120 mg QD, 80 mg twice daily (BID), 120 mg BID, 160 mg BID) using a BOIN design. SC0245 is administered daily for 3 days weekly x 3 (e.g, Days 1-3, 8-10 and 15-17) with IRI 80 mg/m 2 on Days 1, 8 and 15. Cycles are repeated every 4 weeks. The primary endpoint is the rate of dose-limiting toxicity (DLT). Tumor assessments are being performed every 8 weeks using RECIST v1.1. Dose expansion in ES-SCLC patients will follow after definition of the recommended phase 2 dose (RP2D). Results: As of the data cut-off-date (December 21, 2023), 15 pts (median age, 65; male, 73.3%) with previously treated solid tumors have been enrolled, with 3, 4, 3 and 5 pts in 80mg QD, 120mg QD, 80mg BID and 120 mg BID dose cohorts, respectively. 12 of 15 pts were DLT evaluable, and one DLT event (Grade 3 febrile neutropenia) occurred in the 80 mg QD dose cohort. Cytopenia, diarrhea, and liver function test elevations, were the main adverse events (AEs) experienced in 73.3%, 46.7% and 40% pts, respectively. Most AEs were grade 1 or 2 in severity and manageable. The only ≥ Grade 3 TRAEs experienced by more than 2 subjects has been leukopenia (3/15, 20.0%). No drug-related deaths occurred. Among the 9 pts who were evaluable for tumor response, one confirmed partial response (PR) was reported in a pt with ES-SCLC (progressed on prior 1 st line of etoposide + carboplatin + serplulimab treatment) treated in the 120mg QD dose cohort, and the response sustained for 32+ weeks; five pts (5/9, 55.6%) had stable disease (SD) as their best response. PK characteristics indicated that SC0245 was rapidly absorbed (median T max, 1.0 to 2.0 h), and drug exposure was proportional to dose for the QD and BID regimens. No drug-drug interactions (DDI) between SC0245 and either IRI or its active metabolite SN38 were observed. Conclusions: SC0245 exhibited favorable safety and PK characteristics when administered in combination with IRI at doses ranging from 80mg QD to 120mg BID and the regimen has demonstrated preliminary antitumor activity in ES-SCLC, supporting further evaluation of the regimen in ES-SCLC and other relevant malignancies. Clinical trial information: NCT05731518.

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