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 with grade 3/4 events in >1 patient limited to anemia and lymphopenia. The RP2D demonstrated clinical activity in subjects with relapsed/refractory (R/R) non-Hodgkin lymphoma. The overall 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 5 prior lines of therapy (range 2-10); all DLBCL subjects received prior CAR-T (ASH 2021 Abstract 2494).

Tafasitamab (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 in the US and EU in combination with lenalidomide (LEN) for treating adults with R/R DLBCL who are not eligible for autologous stem cell therapy (ASCT) with an ORR of 55% with a complete response rate of 37%. The addition of 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.

Methods: The XmAb13676-03 trial is a randomized, multicenter, open-label, 2-part study intended to compare the safety and efficacy of plamotamab+TAFA+LEN versus 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 status. Eligible subjects must have documented diagnosis of DLBCL, not otherwise specified, or arising from an indolent lymphoma, 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+.

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. Objective response, overall survival, and duration of response are secondary endpoints. Subjects continue study treatment until progression and are followed for long-term survival.

Summary: The XmAb13676-03 trial has started enrollment and is registered at Clinicaltrials.gov (NCT05328102) and EudraCT (2021-003658-22) and anticipates opening centers in the US, EU, and Asia.

Patel:MEI Pharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Curis, Inc: Research Funding; Abbvie: Consultancy; CRISPR Therapeutics: Research Funding; Loxo Oncology: Consultancy, Research Funding; Aptevo Therapeutics: Research Funding; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Caribou Biosciences: Consultancy; Morphosys: Consultancy; Xencor: Consultancy, Research Funding; Velos Bio: Research Funding; Nurix: Research Funding; Genetech/Roche: Consultancy, Research Funding, Speakers Bureau; Kite pharma: Consultancy, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Research Funding; ADC Therapeutics: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Sunesis Pharmaceuticals: Research Funding; TG Therapeutics: Consultancy, Speakers Bureau; Trillium Therapuetics/Pfizer: Consultancy, Research Funding; Epizyme: Consultancy, Research Funding; Fate Therapeutics: Research Funding. Koh:Sanofi Genzyme: Research Funding. Ayyappan:beigene: Membership on an entity's Board of Directors or advisory committees; Fate therapeutics: Membership on an entity's Board of Directors or advisory committees; Intellisphere: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle genetics: Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Total CME: Speakers Bureau; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; abbvie: Membership on an entity's Board of Directors or advisory committees. Lossos:Adaptive: Honoraria; LRF: Membership on an entity's Board of Directors or advisory committees; NCI: Research Funding. Lee:Xencor: Current Employment, Current equity holder in publicly-traded company. Jin:Xencor: Current Employment, Current equity holder in publicly-traded company. Clynes:Xencor: Current Employment, Current equity holder in publicly-traded company. Kanodia:Xencor: Current Employment, Current equity holder in publicly-traded company. Chiarella:Xencor: Current Employment, Current equity holder in publicly-traded company. Kye:Xencor: Current Employment, Current equity holder in publicly-traded company. Michot:Roche: Other: Nonfinancial support, Research Funding; Sanofi: Research Funding; NH TherAGUuiX: Other: Nonfinancial support; Pfizer: Other: Nonfinancial support, Research Funding; Merck: Other: Nonfinancial support, Research Funding; Janssen Cilag: Research Funding; INCa: Research Funding; MedImmune: Other: Nonfinancial support; GlaxoSmithKline: Other: Nonfinancial support, Research Funding; Boehringer Ingelheim: Other: Nonfinancial support, Research Funding; Bristol Myers Squibb: Other: Nonfinancial support, support for travel to and accomodation at EHA 2022 to present CC-99282-NHL-001 study data;, Research Funding; AstraZeneca: Other: Nonfinancial support, Research Funding.