First-in-Human, Phase 1/2 Trial to Assess the Safety and Clinical Activity of Subcutaneous GEN3013 (DuoBody®-CD3×CD20) in B-Cell Non-Hodgkin Lymphomas

Introduction: CD20-specific monoclonal antibodies (mAbs) have demonstrated efficacy in the treatment of B-cell non-Hodgkin lymphomas (B-NHL); however, a significant proportion of patients (pts) present with refractory disease or will experience relapse. GEN3013 (DuoBody®-CD3×CD20) is the first subcutaneously administered IgG1 bispecific antibody (bsAb) that targets the T-cell surface antigen CD3 and the B-cell surface antigen CD20, triggering T-cell-mediated killing of B cells. In vitro, GEN3013 efficiently activates and induces cytotoxic activity of CD4+ and CD8+ T cells in the presence of B cells (Hiemstra et al. Blood 2018), and results in long-lasting depletion of B cells in cynomolgus monkeys. Subcutaneous (SC) GEN3013 in cynomolgus monkeys resulted in lower plasma cytokine levels, and similar bioavailability and B-cell depletion, compared with intravenous administration. GEN3013 has higher potency in vitro than most other CD3×CD20 bsAbs in clinical development (Hiemstra et al. HemaSphere 2019). SC GEN3013 in pts with B-NHL is being evaluated in a first-in-human, Phase 1/2 trial (NCT03625037), which comprises a dose-escalation part and a dose-expansion part. Here we report preliminary dose-escalation data. Methods: Pts with CD20+ B-NHL with relapsed, progressive, or refractory disease following anti-CD20 mAb treatment, and ECOG PS 0-2 were included. During dose escalation, pts received SC GEN3013 flat dose in 28-day cycles (q1w: cycle 1-2; q2w: cycle 3-6; q4w thereafter) until disease progression or unacceptable toxicity. Risk of cytokine release syndrome (CRS) was mitigated with the use of a priming dose and premedication with corticosteroids, antihistamines, and antipyretics. Primary endpoints were adverse events (AEs) and dose-limiting toxicities (DLTs). Secondary endpoints included pharmacokinetics (PK), immunogenicity (anti-drug antibodies [ADA]), pharmacodynamics (PD) (cytokine measures; laboratory parameters), and anti-tumor activity (tumor size reduction; objective and best response). Results: At data cut-off (June 28, 2019), 18 pts were enrolled into the dose-escalation part of the trial, with safety data available for pts receiving doses starting at 4 µg. Most pts had diffuse large B-cell lymphoma (DLBCL; n=14) and were heavily pre-treated; 10 pts had received ≥3 prior lines of therapy (overall median [range]: 3 [1-11]). The median age was 58.5 years (range: 21-80), and 13 pts were male. At a median follow-up of 1.9 months, pts received a me