CLL-118 A Phase 1 Study With the Novel B-Cell Lymphoma 2 Inhibitor BGB-11417 as Monotherapy or in Combination With Zanubrutinib in Patients With B-Cell Malignancies: Preliminary Data

Jacob D. Soumerai, Stephen Opat, Chan Y. Cheah, Masa Lasica, Emma Verner, Peter J. Browett, Henry Chan, Eva González Barca, James Hilger, Yiqian Fang, David Simpson, Constantine S. Tam

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)S267-S268
JournalClinical Lymphoma, Myeloma and Leukemia
Volume22
DOIs
Publication statusPublished - Oct 2022

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