CD20-Tcb (RG6026), a Novel "2:1" Format T-Cell-Engaging Bispecific Antibody, Induces Complete Remissions in Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma: Preliminary Results from a Phase I First in Human Trial
Authors: Hutchings Martin , Iacoboni Gloria , Morschhauser Franck , Offner Fritz , Sureda Anna , Salles Gilles Andre , Carlo-Stella Carmelo , Martinez Lopez Joaquin , Thomas Denise , Morcos Peter N , Quackenbush Betsy , Ferlini Cristiano , Bacac Marina , Broeske Ann-Marie E. , Dimier Natalie , Moore Tom , Weisser Martin , Dickinson Michael 
Published: October 2019

Abstract
Despite advancements in outcomes with the introduction of anti-CD20 monoclonal antibody therapy, a substantial proportion of B-cell Non-Hodgkin's Lymphoma (B-NHL) patients do not sustain a durable response to standard of care treatment. T-cell bispecific antibodies (TCBs) represent a new class of disease-targeting agents shown to activate T-cells to kill cancer cells, offering this exciting mechanism of action with 'off the shelf' availability. CD20-TCB (RG6026) is a novel T-cell-engaging bispecific antibody whose "2:1" format possesses two CD20 binders in addition to a CD3 binder, enabling increased tumor antigen avidity, rapid T-cell activation, and enhanced tumor cell killing. NP30179 is a multicenter phase I dose escalation trial investigating the safety, tolerability, pharmacokinetics (PK), biomarker responses, and antitumor activity (assessed by overall response rate [ORR] and complete response rate [CR] per Lugano 2014 criteria) of single agent CD20-TCB. Patients receive escalating doses of CD20-TCB as intravenous infusions with dose escalation guided by a model implementing the Bayesian continuous reassessment method with overdose control. In order to reduce the potential risk of cytokine release syndrome (CRS) induced by CD20-TCB mediated systemic T-cell activation, a single dose of 1000 mg obinutuzumab (G) pretreatment (Gpt) is administered seven days prior to start of CD20-TCB and has preclinically been shown to debulk peripheral B cells and reduce systemic cytokine release (Bacac et al. Clin Canc Res 2018).
As of July 29th 2018 a total of 64 patients (pts) with aggressive r/r B-NHL (DLBCL/PMBCL/trFL/Richter´s transformation (n=47)) and indolent r/r B-NHL (FL(n=17)) received CD20-TCB doses ranging from 5 µg to 1800 µg in a Q2W schedule. Median age was 64 years (range 28-82), 61% were male, median prior lines of therapy was 3 (range 1-10). A single DLT (myocardial infarction) was observed at 220 µg and until the maximum tested dose CD20-TCB was well tolerated. The most reported AEs were pyrexia (n=14, all Gr 1 and 2), neutropenia (all grades n=17, Gr 3 and 4 n=14) and cytokine release syndrome (CRS, n=14, all Grade 1-2 according to the criteria by Lee et al. Blood 2014). Two patients received tocilizumab for CRS management all CRS events were manageable and resolved, without leading to dose reduction or study withdrawal. No CNS toxicity was reported so far in this study. Fifty-five pts had at least one post-baseline response assessment and were eligible for efficacy analysis. Responses were observed from 15 µg onwards, and complete responses (CR) occurred from 300 µg onwards following two cycles of treatment. At doses of 300 µg or above (n=29) the ORR and CR rate by investigator assessment was 38% and 24%, respectively (FL: 3/5 pts and 2/5 pts respectively, aggressive B-NHL: 8/24 pts and 5/24 pts respectively). All CRs are sustained thus far with a median follow up 96 days (range 26-152). Responses were seen across various NHL subtypes and across prognostic factors such as prior lines of therapy, refractoriness to the most recent line of therapy, tumor burden, and IPI or FLIPI. CD20-TCB exposure and receptor occupancy increased dose-dependently across the investigated dose range; dose-escalation is continuing to optimize these factors. No anti-drug-antibodies have occurred.
CD20-TCB is a novel 2:1 format T-cell-engaging bispecific antibody which already at suboptimal doses displays promising clinical activity in heavily-pretreated B-NHL. In addition, Gpt has shown clinical proof of principle as an approach to efficiently mitigate CRS. An update on safety and efficacy as well as biomarker data will be presented.

Disclosures
Hutchings: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Iacoboni:Celgene: Other: Travel funding; Roche: Honoraria. Morschhauser:Janssen: Other: Scientific Lectures; BMS: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sureda:Takeda: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria; Merck: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Sanofi: Honoraria. Salles:Janssen: Honoraria; Merck: Honoraria; Gilead Sciences: Honoraria; Epizyme: Honoraria; Amgen: Honoraria; Acerta: Honoraria; Abbvie: Honoraria; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Morphosys: Honoraria; Pfizer: Honoraria; Servier: Honoraria; Takeda: Honoraria. Carlo-Stella:Rhizen Pharmaceuticals: Research Funding; Boehringer Ingelheim: Consultancy; Sanofi: Consultancy; MSD: Other: Advisory Board; Genenta Science: Other: Advisory Board; BMS: Other: Advisory Board; Amgen: Other: Advisory Board; Janssen: Other: Advisory Board; AstraZeneca: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board. Martinez Lopez:Celgene: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; Jansen: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Thomas:Roche: Employment, Equity Ownership. Morcos:Roche: Employment, Equity Ownership. Quackenbush:Roche: Employment. Ferlini:Roche: Employment. Bacac:F. Hoffmann-La Roche Ltd.: Employment, Other: stock, Patents & Royalties. Broeske:Roche: Employment, Equity Ownership. Dimier:Roche: Employment, Equity Ownership. Moore:Roche: Employment. Weisser:Roche: Employment, Equity Ownership, Patents & Royalties. Dickinson:GSK: Consultancy.