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Background BAL0891 is a first-in-class small-molecule mitotic checkpoint inhibitor (MCI) that targets threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1) to disrupt spindle assembly checkpoint (SAC) regulation and induce tumor cell death. BAL0891 demonstrates more potent anti-tumor activity compared to TTK-specific inhibitors, attributed to its prolonged effect on TTK and transient effect on PLK1. In preclinical studies, BAL0891 activated the cGAS/STING pathway and reshaped the tumor immune microenvironment, promoting a ‘cold’ to ‘hot’ transition with increased proinflammatory signals and T cell activation. 1 In a vascularized microphysiological system (MPS) model of triple-negative breast cancer, BAL0891 combined with an immune checkpoint inhibitor significantly enhanced tumor killing versus monotherapy,2 supporting a potential synergistic effect with anti-PD-1 antibody, tislelizumab. In the first-in-human microdose study of TTK-CS-001 in healthy subjects, key BAL0891 pharmacokinetic (PK) parameters were evaluated, with no safety signals observed.Methods This clinical trial, substudy 2, is part of an ongoing multi-cohort, multi-center, open-label phase 1 dose-escalation study of intravenous (IV) BAL0891 as monotherapy and in combination in patients with advanced solid tumors or relapsed/refractory (R/R) acute myeloid leukemia (AML).Primary objectives: 1) To evaluate safety and tolerability in combination with tislelizumab, 2) To estimate the MTD and/or RP2D of BAL0891 and tislelizumab combination treatment and assess pharmacokinetics and pharmacodynamics, and 3) To evaluate tumor response using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and Immune Response Evaluation Criteria in Solid Tumors (iRECIST) criteria. Eligible patients are aged ≥18 years with advanced solid tumors that are refractory to, or intolerant of existing therapy. Patients must have measurable disease, as defined by RECIST 1.1/iRECIST.BAL0891 will be administered on Day 1 and Day 15 every 3 weeks. Tislelizumab will be administered at 200 mg on Day 8 every 3 weeks. Dose escalation will start at BAL0891 40mg and progress until the highest planned dose level is determined to be safe and tolerable, or until the MTD/RP2D is established using the Bayesian logistic regression model- Escalation with overdose control (BLRM-EWOC). Each dose-level cohort will include at least three patients, up to a total of 30 evaluable patients planned for enrollment. Enrollment will begin at the end of 2025 in the United States and South Korea.TTK-CS-101 is now enrolling patients with advanced solid tumors to determine safety and maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of BAL0891 monotherapy and combination with paclitaxel.Trial Registration NCT05768932References Kang, et al. Cancer Res 2025;85(8_Supplement_1):2164. https://doi.org/10.1158/1538-7445.AM2025-2164Wang, et al. Cancer Res 2025;85(8_Supplement_1):2169. https://doi.org/10.1158/1538-7445.AM2025-2169Ethics Approval The study will be conducted in accordance with the Declaration of Helsinki and the International Council for Harmonization Good Clinical Practice guidelines. The study protocol will be reviewed and approved by an Institutional Review Board (IRB), and written informed consent will be obtained from all participants prior to enrollment.