Phase 1/2a Clinical Trial of BI-1206, a Monoclonal Antibody to Fcγriib, in Combination with Rituximab in Subjects with Indolent B-Cell Non-Hodgkin Lymphoma That Has Relapsed or Is Refractory to Rituximab
Authors: Karlsson Ingrid , Gertsson Susanne , Kilany Suzanne , Borggren Marie , Abrisqueta Pau , Carneiro Ana , Cordoba Raul , Hagberg Hans , Jerkeman Mats , Mercadal Santiago , Cohen Jonathon B. , Sancho Juan-Manuel , Teige Ingrid , Mårtensson Linda , Frendéus Björn , McAllister Andres 
Published: November 2021

Abstract
Introduction
BI-1206 is a fully human anti-FcγRIIB antagonistic monoclonal antibody. BI-1206 enhances the activity of anti-CD20 antibodies such as rituximab by blocking the interaction of the anti-CD20 with this inhibitory receptor. This combination may overcome resistance to rituximab and enhance its activity.
Methods
The safety and tolerability profile of BI-1206 in combination with rituximab is currently investigated in the Phase 1/2a clinical trial 17-BI-1206-02. The study population includes subjects with follicular lymphoma (FL), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL) who have relapsed or are refractory to rituximab. Induction therapy consists of four weekly administrations of rituximab and three administrations of BI-1206, both given as i.v. infusions. In the first week of treatment rituximab is administered as single agent. In the following three weeks patients receive BI-1206 followed by rituximab. In Phase 1, a 3+3 study design is used, with escalating doses of BI-1206 and a fixed dose of rituximab (375 mg/m 2), with the aim of selecting the RP2D of BI-1206 for the expansion cohort (Phase 2a).
Patients showing clinical benefit are eligible for continued maintenance therapy with dosing of BI-1206 and rituximab every 8 weeks for up to 7 cycles.
The assessment of the pharmacokinetics (PK) of BI-1206 includes non-compartmental analysis (NCA), and the assessment of the pharmacodynamics (PD) includes B cell depletion, FcγRIIB expression and BI-1206 receptor occupancy (RO).
Results
With a cut-off date of July 20 th, 2021, 16 subjects have received doses of up to 100 mg BI-1206 in combination with rituximab (375 mg/m 2). Nine out of these received all four doses and were evaluated for therapeutic benefit. Three subjects were diagnosed with MCL, 1 with MZL and 12 with FL.
The most frequent adverse advents (AEs) related to BI-1206 have been infusion related reactions (IRRs). These IRRs led to dose limiting toxicities (DLTs) in 4 subjects, 2 experienced G4 platelet drops, and 2 experienced G3 and G4 liver enzyme elevations. No signs of liver damage were observed, and all patients recovered within days of the event, leaving no sequelae. These events have been milder and less frequent after implementation of a novel pre-medication regimen. No DLTs have been observed after implementation of this regimen.
Clinical responses were observed already at the starting dose (30 mg). To date three complete responses (CR) have been observed, one at the 30mg and two at the 70mg dose levels. Two complete responses completed maintenance and one is still on maintenance treatment. The two subjects who developed a CR and finished the study have remained in CR over 1,5 and 2,0 years. Three subjects achieved partial responses (PR), one at 30mg and two at 70mg. One patient on 100 mg is experiencing ongoing stable disease at the cut-off date and is on maintenance treatment. One patient with a blastic form of MCL achieved complete depletion of peripheral tumor cells and achieved a PR.
Increasing doses (30 mg to 70 or 100 mg) of BI-1206 gave rise to a supra-proportional increase in C max as well as an increase in the half-life of BI-1206. A trend of accumulation after consecutive doses was also seen. When comparing the serum-concentrations against the associated RO% of FcγRIIB there was a trend that higher dose levels were close to fully saturating FcgRIIB receptors for up to 72 hours. It is therefore likely that further increases in dose will give rise to complete receptor saturation, which should be maintained for extended periods of time.
Conclusions
Preliminary data of the clinical trial 17-BI-1206-02, where BI-1206 is combined with rituximab is promising. BI-1206 has a good safety profile that induced IRRs that are adequately managed with a novel steroid regimen. At a cut-off date of July 20 th, 2021, 3 CR, 3 PR and one SD have been observed among the 12 evaluable patients who completed the induction treatment. Importantly, the CRs have been very long lasting. This at doses associated only with transient receptor saturation. It may be speculated that doses which enable full RO% for a longer period (e.g., the entire dosing interval), may show additional clinical benefit. Since patients are currently undergoing treatment at higher doses, these data will be updated.

Disclosures
Karlsson: BioInvent International AB: Current Employment. Gertsson: BioInvent International AB: Current Employment. Kilany: BioInvent International AB: Current Employment. Borggren: BioInvent International AB: Current Employment. Abrisqueta: BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Carneiro: Novartis: Membership on an entity's Board of Directors or advisory committees; Pierre-Fabre: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees. Cordoba: Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; ADCTherapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jerkeman: Jansen-Cilag, AbbVie, Gilead, Celgene: Other: part of a research collaboration between Karolinska Institutet and Janssen Pharmaceutica NV for which Karolinska Institutet has received grant support, Research Funding. Mercadal: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Honoraria, Speakers Bureau. Cohen: Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo, BeiGene, Adaptive: Consultancy; Genentech, BMS/Celgene, LAM, BioINvent, LOXO, Astra Zeneca, Novartis, M2Gen, Takeda: Research Funding. Sancho: Takeda: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Teige: BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Mårtensson: BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Frendéus: BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. McAllister: BioInvent International AB: Current Employment, Current equity holder in publicly-traded company.