Background: Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key component of the caspase recruitment domain-containing protein 11 (CARD 11)-B-cell lymphoma/leukemia 10 (BCL 10)-MALT1 signalosome complex, which activates nuclear factor-kappaB (NF-κB) signaling in response to B-cell–receptor or T-cell–receptor stimulation. Activation of NF-κB signaling promotes survival and proliferation of B-cell lymphoma and T-cell lymphoma. ONO-7018 is an oral, potent, and selective MALT1 inhibitor that has demonstrated preclinical efficacy in several lymphoma models (Morishita D, et al. Blood. 2020). Therefore, ONO-7018 has therapeutic potential for non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). This study aims to determine the maximum tolerated dose (MTD) and to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of ONO-7018 as monotherapy in patients with relapsed or refractory NHL or CLL. Methods: This Phase I, first-in-human, open-label, multicenter study will be done in two parts, a dose-escalation phase (part 1) and a dose-expansion phase (part 2). An estimated 54 eligible patients will be enrolled. Patients must be adults with relapsed/refractory NHL or CLL with measurable disease; all acute toxic effects of prior antitumor therapy should be grade ≤1; have Eastern Cooperative Oncology Group performance status 0 to 2; and have adequate bone marrow, renal, and hepatic function. Exclusion criteria include history of other lymphoid malignancy, central nervous system involvement, active autoimmune disease, systemic and active infection, serious or uncontrolled medical disorder, and patient inability to swallow tablets. ONO-7018 will be administered orally. In part 1, patients will be assigned to a dose level cohort (≤4 dose levels: DL1-DL4) using a 3+3 dose-escalation design. In part 2, patients will be given the recommended dose level from part 1, following safety review. The primary endpoints include dose-limiting toxicity, MTD, and treatment-emergent adverse events. Secondary endpoints include pharmacokinetics, objective response rate, duration of response, progression-free survival, and overall survival. The study began February 13, 2023, and is currently recruiting; part 1 is ongoing. Clinical trial information: NCT05515406.