Context: B-cell lymphoma 2 (BCL2) is aberrantly expressed in many hematologic malignancies and promotes tumorigenesis. BGB-11417-101 (NCT04277637) is an ongoing, first-in-human, phase 1/1b dose-escalation/expansion study evaluating the safety, tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose of oral BGB-11417, a potent, highly selective BCL2 inhibitor, alone or in combination with zanubrutinib, a BTK inhibitor, in patients with relapsed/refractory (R/R) B-cell malignancies. Design: BGB-11417 (40, 80, 160, 320, or 640 mg once daily [QD]) with weekly or daily ramp-up to target dose was given as monotherapy or combined with zanubrutinib (320 mg QD or 160 mg twice daily) 8-12 weeks before BGB-11417. Dose-limiting toxicity was evaluated by Bayesian logistic regression. Adverse events (AEs) were reported per CTCAE v5.0. Results: As of December 17, 2021, 58 patients received BGB-11417 (monotherapy=32; combination=26). Of patients receiving monotherapy, 26 with non-Hodgkin lymphoma (NHL; 17 diffuse large B-cell lymphoma, 6 follicular lymphoma, and 3 marginal zone lymphoma) received ≤640 mg and six with CLL/SLL received ≤160 mg; for those receiving combination treatment, 19 with R/R CLL/SLL received BGB-11417 ≤160 mg and seven with R/R MCL received ≤80 mg. MTD has not been reached. Median follow-up was 3.9 months (range=0.1–20.4). Two grade ≥3 AEs (neutropenia=1, autoimmune hemolytic anemia=1) occurred in combination cohorts. Twenty patients discontinued treatment (disease progression=17; AE=1; other=2). One high-risk patient with CLL (monotherapy) had laboratory tumor lysis syndrome (<2%) that resolved without intervention. Early data show that most patients had a reduction in the sum of products of perpendicular diameters; two patients with NHL (monotherapy) had responses (complete response=1). Patients with CLL/SLL had notable reductions in absolute lymphocyte counts at doses ≥1 mg; two responses (≥ partial response) occurred with monotherapy and 12 with combination treatment (≥ partial response + lymphocytosis). Conclusions: Preliminary findings suggest that BGB-11417 has promising efficacy and is tolerable at ≤640 mg as monotherapy and ≤160 mg combined with zanubrutinib. Dose escalation continues as MTD has not been reached. Enrollment is ongoing; data for Waldenström macroglobulinemia and treatment-naïve CLL/SLL are forthcoming.