Background: Cisplatin, a well-established backbone of combination therapy of various advanced solid tumors, inhibits DNA synthesis by forming DNA cross-links and adducts. Despite the activity of cisplatin, tumor cells can either be refractory or develop resistance to treatment. Cisplatin has been demonstrated to cause cell cycle G2/M arrest, which may allow for DNA damage response (DDR) and repair. Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad 3-related (ATR) protein kinases are key regulators of DDR, and contribute to maintaining genomic integrity in response to various exogenous and endogenous genotoxic insults like cytotoxic chemotherapy. In fact, cisplatin has been shown to transiently increase ATR expression. Inhibitors of ATR have been studied in combination with cisplatin both in vitro and in vivo, demonstrating enhanced activity. The oral small molecule ATR inhibitor elimusertib, which has been studied as a single agent in a Phase I study, has also demonstrated enhanced activity with cisplatin in vitro in lung cancer and bladder cancer cell lines. We sought to conduct a Phase I study evaluating the combination of elimusertib with cisplatin or with cisplatin and gemcitabine. Methods: In the first cohort, patients with histologically confirmed advanced solid tumors for which cisplatin-based therapy would be considered appropriate, who exhibit adequate organ function, and have received < 300 mg/m² of cisplatin previously are treated with cisplatin on Day (D) 1 and with elimusertib on D2 & 9 of each 21-day cycle. The study follows a phase I queue (IQ) 3+3 dose escalation design, following standard practices for dose-limiting toxicity (DLT) impact on escalation, and when the maximum tolerated dose (MTD) is established with cisplatin alone, this will inform the first dose level of the next cohort, in which patients will be treated with cisplatin on D1, gemcitabine on D1 & 8, and elimusertib on D2 & 9 of each 21-day cycle. An expansion cohort will enroll urothelial carcinoma patients when the second MTD is established. The primary objective of the study is to evaluate the safety and MTD of elimusertib in combination with cisplatin, as well as in combination with cisplatin and gemcitabine. Secondary study objectives include evaluation of pharmacokinetics of elimusertib in these combinations, preliminary efficacy, and evaluating the association between ATM expression and responses to therapy. Currently, 6 patients have been enrolled to the first cohort of the study. Clinical trial information: NCT04491942.