Background: Cell growth regulation and proliferation is dependent on cyclins and CDKs. Cyclin E1 (CCNE1) is a cell cycle regulator that activates CDK2. A broad range of aggressive cancers overexpress cyclin E and/or harbor CCNE1 gene amplifications. Inhibition or loss of CDK2 impairs the growth of CCNE1-amplified cell lines and cyclin E overexpression represents one of several CDK4/6 inhibitor resistance mechanisms, including in hormone receptor–positive/human epidermal growth factor receptor-2–negative (HR+/HER2−) breast cancer, making CDK2 inhibition a promising novel therapeutic approach. BLU-222 is an investigational, oral, potent, and selective CDK2 inhibitor in early clinical development with best-in-class potential. Methods: VELA (NCT05252416) is an international, open-label, phase 1/2 study evaluating the safety, PK, pharmacodynamics, and efficacy of BLU-222. In monotherapy dose-escalation, adult patients (pts) enrolled regardless of CCNE1 status, but CCNE1 amplification or progression after a CDK4/6 inhibitor were of specific interest. Pts with ECOG PS 0–2 and confirmed nonresectable tumors who had progressed following standard of care for advanced relapsed/recurrent disease were enrolled. BLU-222 was administered BID in continuous 28-day cycles, with dose escalation employing a Bayesian Optimal Interval design to identify the maximum tolerated dose. Blood samples were collected for PK and circulating biomarker analysis. Results: By Jan 29, 2023, 27 pts were enrolled in 6 escalating BID dose cohorts and included in the safety population. Median age was 64 y (range, 29–85); 85% were female. The most frequent cancer types were breast (44%, 12/27), endometrial (15%, 4/27), ovarian (11%, 3/27), and prostate (11%, 3/27). No pts discontinued treatment due to AEs. The most common (≥15%) AEs (all-cause AE; treatment-related AE) were nausea (33%; 26%), vomiting (22%; 11%), anemia (22%; 19%), diarrhea (22%; 22%), and fatigue (18%; 15%). Transient visual AEs (including blurred vision, photophobia, vision change) were seen in 5 pts (19%). These visual symptoms were mild except in 1 pt with Grade (Gr) 3 blurred vision/photophobia; all had fully resolved by/after the data cut-off. There were 2 dose limiting toxicities reported at the 2 highest dose levels: nausea (Gr 3; n=1) and blurred vision/photophobia (Gr 3; n=1). Translational pharmacodynamic data has shown early evidence of pathway modulation. One partial response was seen in a pt with HR+/HER2− metastatic breast cancer previously treated with 5 lines of therapy, including palbociclib, abemaciclib, and capecitabine. Conclusions: As of the cutoff date, BLU-222 monotherapy was generally well tolerated in pts at the BID doses tested. Dose escalation is ongoing to determine the recommended phase 2 dose. Preliminary evidence of cell cycle pathway modulation and clinical activity have been observed. Clinical trial information: NCT05252416.