A first-in-human Phase 1 trial of LY4152199, a B-cell activation factor receptor (BAFF-R) T-cell engager bispecific antibody, in patients with previously treated B-cell malignancies (BAF_FRontier-1 Trial in Progress)

Abstract

Abstract Background: B-cell activating factor receptor (BAFF-R) is essential to B-cell development and survival and is highly expressed across a wide variety of B-cell malignancies. LY4152199 is a fully human BAFF-R×CD3 bispecific antibody using a common light chain on an effector-less IgG1 backbone that engages BAFF-R on the surface of B-cells and CD3 on the surface of T-cells, leading to T-cell mediated elimination of BAFF-R expressing B-cells. Preclinically, LY4152199 demonstrated potent and specific in vitro cytotoxicity and strong dose-dependent in vivo antitumor activity across B-cell tumor models with varying BAFF-R expression levels.1 Study Design and Methods: This is a first-in-human, global, open-label phase 1 trial of LY4152199 in patients (pts) with previously treated B-cell malignancies (NCT07101328). The study will be conducted in 2 parts: phase 1a dose escalation/dose optimization, and phase 1b dose expansion with planned enrollment of up to ~275 pts. Intravenous and subcutaneous administration will be explored in different cohorts. Dose escalation will follow the mTPI-2 method and will enroll pts with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL) and Waldenstrom macroglobulinemia (WM). During dose optimization, pts with de novo or transformed DLBCL will be randomized to at least 2 dose levels to determine the optimal biological dose. Cycle 1 (28 days) will involve accelerated step-up dosing from C1D1 to a target dose on C1D8; in subsequent cycles, the target dose will be administered once every 21 days. The dose limiting toxicity evaluation period will be 28 days. Pts who achieve a complete response will receive 15 cycles of LY4152199 and those with partial response (PR) or stable disease may receive an additional 15 cycles of LY4152199. Dose expansion will enroll the following pts: DLBCL, FL, mantle cell lymphoma (MCL), MZL, WM, chronic lymphocytic leukemia (CLL), SLL, or B-cell acute lymphoblastic leukemia (B-ALL). Pts must be ≥18 years of age with an ECOG performance status of 0-1. Key inclusion criteria include the presence of histologically confirmed relapsed/refractory measurable or assessable disease as defined by the respective diseases, failure or intolerance to at least 1 line of prior therapy, and adequate organ function. Key exclusion criteria include known central nervous system involvement, grade >2 (per CTCAE v5.0) unresolved toxicities from prior therapy, or cytopenias from prior CAR-T or bispecific therapy. In dose escalation, pts with known or suspected peripheral blood involvement by malignant cells with an absolute lymphocyte count of ≥5000 cells/µl are ineligible. Key objectives are to determine the safety, optimal biological dose, PK, and anticancer activity of LY4152199.1Yang W, et al. Blood. 2024,144(1):4511-20