Background: Homologous recombination (HR) is an essential, high-fidelity mechanism to repair DNA double strand breaks (DSBs) in cancer cells. CYT-0851 inhibits HR leading to an accumulation of unrepaired DSBs and tumor cell death. We are reporting the completed Phase 1 dose-escalation results and RP2D selection to support ongoing development of CYT-0851. Methods: Patients (pts) with advanced hematologic and solid tumors were treated with continuous 28-day cycles of increasing doses of CYT-0851 following a 3+3 design. The primary objective was determining the maximum tolerated dose. Secondary objectives included safety, pharmacokinetics, and anti-tumor activity. Results: As of a 15 Nov 2021 data cutoff (DCO), 73 pts with advanced cancers (NHL n = 18; Sarcoma n = 16; Pancreas n = 11; Breast n = 8; HNSCC n = 6; Ovarian n = 4; SCLC n = 4; Other n = 4; Myeloma n = 2) were treated in 12 cohorts (total daily doses: 30 mg to 1200 mg). One pt experienced a dose-limiting toxicity (DLT) of reversible metabolic acidosis at 1200 mg. Two of 3 pts at 800 mg experienced reversible DLT-like events in Cycle 2 of Gr3 dry skin and Gr3 myalgia and polyarthritis, respectively. Three of 10 pts treated at 600 mg experienced DLT-like events in Cycle 1: 1 pt experienced an SAE of Gr3 anorexia with Gr3 stomatitis, vomiting, and dehydration and 2 pts had Gr3 fatigue. No DLTs occurred at 400 mg daily which was selected as the RP2D. 42 pts (57.5%) experienced a CYT-0851-related adverse event (AE), including 12 (16.4%) with a Gr3/4 AE. There were no treatment-related deaths. AE leading to CYT-0851 withdrawal were reported in 2 pts (2.7%) treated with 600 and 800 mg. The most common CYT-0851-related AEs were primarily Gr1/2 and included fatigue (20.5%), hyperuricemia (11%), nausea (11%), alopecia (9.6%), constipation (8.2%) and headache (8.2%). CYT-0851 exposure was approximately dose-proportional across the evaluated doses with an effective half-life of ̃3 days. Exposure at 400 mg daily was consistent with efficacy in preclinical models. 46 pts were evaluable for response at the DCO. 12 pts with NHL were evaluable by Lugano and included 1 CR in FL and 1 PR in DLBCL treated for 393+ and 244 days respectively. 34 pts with solid tumors were evaluable by RECIST v1.1 with 1 PR in a pt with myxofibrosarcoma treated for 313 days and 16 pts with stable disease. Fifteen pts were treated for 100+ days and 5 for 180+ days. Conclusions: CYT-0851 has demonstrated promising and broad clinical activity in a Ph 1 population of pts with advanced cancers. The safety profile is favorable as characterized by events that were infrequent, primarily Gr1/2, and reversible. Six expansion cohorts (DLBCL, Follicular Lymphoma, Myeloma, Pancreatic, Ovarian and Sarcoma) are enrolling to characterize activity at the RP2D. Ph 1 evaluation of CYT-0851 in combination with 3 chemotherapy backbones is also ongoing. Clinical trial information: NCT03997968.