Abstract
Abstract 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. It has a more potent anti-tumor activity as compared to TTK-specific inhibitors due to its combined prolonged effect on TTK and transient effect on PLK1. In preclinical studies, BAL0891 demonstrated potent anti-tumor activity as a monotherapy and in combination with paclitaxel and carboplatin. In the first-in-human microdose study of TTK-CS-001 in healthy subjects, key BAL0891 pharmacokinetic (PK) parameters were investigated (i.e., clearance, half-life, exposure), and no safety signals were detected. Trial design: This clinical trial is a multiple-cohort, open-label phase 1 study with 3 dose-escalation substudies, investigating intravenous (IV) BAL0891 as monotherapy, and in combination with carboplatin or paclitaxel, in patients with advanced solid tumors. Primary objectives: 1) To evaluate safety/tolerability 2) To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of BAL0891 monotherapy and in combination with carboplatin/paclitaxel. Eligibility: Patients ages ≥18 years with advanced/metastatic solid tumors that are refractory to, or intolerant of existing therapy may participate in this study. Patients enrolled in dose level ≥4 of Substudy 1 and all patients in Substudies 2 and 3 must have measurable disease. Substudy 1: Monotherapy BAL0891: IV doses of BAL0891 on Days 1 (D1) and 8 (D8) every 3 weeks (Q3W). A Bayesian logistic regression model (BLRM) will guide dose escalations, with 8 nominal DLs of 5/10/20/40/80/160/320/480 mg. Substudy 2: Phase 1 BAL0891 D1, D8 + carboplatin AUC5-6 D1 Q3W. Substudy 3: Phase 1 BAL0891 D1, D15 + paclitaxel 70-80 mg/m2 D1, D8, D15 Q4W. Substudies 2 and 3 may begin once the maximum tolerated dose (MTD) of BAL0891 monotherapy has been established or at the first signs of expected target toxicity and/or efficacy with monotherapy. Enrollment began in February 2023 and is ongoing in the United States and South Korea. Clinical trial information; NCT05768932 Citation Format: Shivaani Kummar, Minal Barve, Eric Feldman, Seunghyun Ma, Jaime Merchan, Seock-Ah Im, Sun Young Rha. Trial in progress: Phase 1 study of BAL0891 as monotherapy and in combination with chemotherapy in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C024.
