PB2102: PHASE 2 RANDOMIZED, OPEN-LABEL, MULTICENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF PLAMOTAMAB COMBINED WITH TAFASITAMAB (TAFA) + LENALIDOMIDE (LEN) VS TAFA+LEN IN RELAPSED OR REFRACTORY DLBCL

Background: Plamotamab (XmAb13676) is a humanized bispecific antibody that binds both CD20 and CD3 and thereby recruits cytotoxic T cells to kill CD20-expressing malignant cells. In a Phase 1 trial in B-cell malignancies, plamotamab was generally well tolerated, with no Grade ≥ 3 cytokine release syndrome events at the recommended Phase 2 dose (RP2D) regimen, and other safety events being generally mild or moderate in severity. The RP2D demonstrated clinical activity in subjects with relapsed/refractory (R/R) non-Hodgkin lymphoma. The objective response rate (ORR) in follicular lymphoma (FL) was 100% (4/4), with a complete response rate of 50% (2/4). The ORR in diffuse large B-cell lymphoma (DLBCL) was 40% (2/5). Subjects were heavily pretreated with a median of 4 prior lines of therapy (range 2-8) for FL and a median of 5 lines of therapy for DLBCL (range 4-10); all DLBCL subjects received prior CAR-T (ASH 2021 Abstract 2494). TAFA is a humanized CD19-directed cytolytic monoclonal antibody that contains an IgG1/2 hybrid Fc domain with 2 amino acid substitutions to modify the Fc-mediated functions of the antibody and mediates B-cell lysis through apoptosis and immune effector mechanisms. TAFA is indicated for use in the US and EU in combination with LEN for treating adults with R/R DLBCL who are not eligible for autologous stem cell therapy (ASCT). Addition of the CD3xCD20 plamotamab to the TAFA+LEN doublet offers the potential for improved efficacy through recruitment of distinct T cell and Fc-mediated cytotoxic mechanisms while also overcoming tumor resistance that might otherwise arise from single antigenic loss of either CD19 or CD20. These characteristics support a study of the combination of plamotamab, TAFA, and LEN. Aims: This trials-in-progress abstract details eligibility criteria and trial design of the Phase 2 XmAb13676-03 trial. Methods: This randomized, multicenter, open-label, 2-part study is intended to compare the safety and efficacy of plamotamab+TAFA+LEN vs TAFA+LEN in adult subjects with DLBCL who have relapsed or are refractory to ≥ 1 prior line of therapy and are ineligible for or refuse ASCT. Prior therapy must include multiagent chemoimmunotherapy that includes an anti-CD20 mAb. The trial consists of 2 parts, performed sequentially; Part 1 is a 2-cohort safety run-in that serves to identify the optimal dose of plamotamab (20 or 50 mg) to be administered with TAFA+LEN (shown in figure). Part 2 randomizes 200 subjects in a 1:1 ratio to the 2 treatment arms (with dosing regimen selected from Part 1), stratified by international prognostic index risk score, number of lines of prior therapy, and primary refractory (y/n). Eligible subjects must have documented diagnosis of DLBCL, not otherwise specified, CD20+ and CD19+ lymphoma, and relapsed or primary refractory disease. Exclusion criteria include central nervous system (CNS) lymphoma or secondary CNS involvement. Subjects with prior CAR-T are eligible if current biopsy is CD19+. Results: The primary objectives are safety and efficacy. The primary endpoint in Part 1 is safety and the primary endpoint in Part 2 is progression-free survival with disease assessed at regular intervals. Response, overall survival, and duration of response are secondary endpoints. Subjects continue study treatment until progression and are followed for long-term survival. Image:Summary/Conclusion: The XmAb13676-03 trial is registered at EudraCT (2021-003658-22) and anticipates enrolling in centers in the US, EU, and Asia.