Background: Bruton tyrosine kinase (BTK) is a clinically validated target with an integral role in the proliferation and survival of neoplastic cells in several B-cell malignancies. Inhibitors of BTK, such as ibrutinib, have revolutionized the treatment landscape for B-cell malignancies. However, long-term use can lead to disease progression and clinical resistance associated with mutations in BTK. ABBV-101 is a reversible BTK degrader. By preclinical kinome profiling, ABBV-101 has demonstrated high selectivity with the potential for best-in-class AE profile. ABBV-101 has also shown potent activity against BTK wildtype and multiple therapy-resistant mutant forms. Degradation eliminates BTK scaffolding and enzymatic functions, which has led to deeper, more durable responses vs covalent and reversible BTKi in animal models (Pan C, et al. ASH 2023). Herein, we describe the first-in-human study of ABBV-101 monotherapy in patients with relapsed/refractory B-cell NHL. Methods: This international phase 1, open-label, multicenter study (NCT05753501) is evaluating the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of ABBV-101. Eligible patients(≥18 years) have measurable disease, received ≥2 prior systemic therapies, and have no available therapies known to provide clinical benefit.Primary objectives are to characterize safety and tolerability of ABBV-101; secondary objectives are to evaluate PK and preliminary efficacy. The study is conducted in 2 parts: dose escalation (part 1) and dose expansion (part 2). Part 1 aims to establish the maximum administered dose and maximum tolerated dose of ABBV-101 guided by a Bayesian optimal interval design; additional patients may be enrolled to a previous dose level to further explore safety, PK, and efficacy. Patients with WHO-defined chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma (including Waldenström macroglobulinemia), and transformed indolent NHL (including Richter’s transformation) are eligible. Part 2 will further characterize the safety and preliminary efficacy of ABBV-101; patients diagnosed with CLL/SLL (up to 3 dose cohorts) and non-germinal center DLBCL (1 cohort) are being enrolled. ABBV-101 is administered orally until disease progression, intolerable toxicity, or other study discontinuation criteria are met. Safety assessments include, but are not limited to, AEs, clinical laboratory parameters, vital signs, and ECG. Response evaluations are performed per disease-specific response criteria at screening and every 8 weeks (1st year), 3 months (2nd year), or 4 months (3rd year onward) until progressive disease. Enrollment is ongoing with active sites in the US and Japan. Clinical trial information: NCT05753501.