Abstract LB-70: Preliminary results of a Phase I study of AME-133v, an Fc-engineered humanized monoclonal antibody, in low-affinity FcγRIIIa patients with previously-treated follicular lymphoma
Authors: Forero Andres , de Vos Sven , Pohlman Brad , Enas Nathan , Ganjoo Kristen N. , Cronier Damien , Dang Nam H. , Carpenter Susan P. , Smith Mitchell R. , Link Brian K , Wooldridge James E 
Published: May 2019

Abstract
Background: Single-agent rituximab therapy in patients with follicular lymphoma (FL) who have a low-affinity FcγRIIIa (158-FF or VF; F-carriers) is associated with a lower response rate (RR) and time to progression compared to patients with the high affinity genotype (158-VV). Through protein engineering, the humanized monoclonal antibody (mAb) AME-133v was optimized to achieve a 13-20-fold greater affinity for CD20, ~ 6-fold greater potency at mediating ADCC, and ~ 50% lower complement dependent cytotoxicity compared to rituximab in vitro.
Methods: An open-label, multicenter, Phase 1/2 dose-escalation (3+3) study of AME-133v was initiated in patients with relapsed/refractory FL who were confirmed to be FcγRIIIa 158-F-carriers. Eligible patients were treated with four weekly infusions of AME-133v. The objectives of the study are to determine the safety and tolerability, PK profile, objective response rate, and duration of response. The Phase 1 portion is complete and is the subject of this report.
Results: Twenty-three patients were enrolled and 22 (12M/10F; median age 61.5) received AME-133v IV once weekly for 4 doses at 2 (n = 3), 7.5 (n = 3), 30 (n = 4), 100 (n = 6) or 375 mg/m2 (n = 6). All treated patients were confirmed to be FcγRIIIa F-carriers (158-VF =12 and 158-FF =10). Patients treated on the trial received a median of 1 prior treatment regimen (range 0-4); 20/21 patients received prior treatment with rituximab and 18/21 patients had prior chemotherapy. Available safety data (n=20) revealed that 18/20 (90%) patients experienced transient adverse events (AEs) on the day of first infusion that were predominantly CTCAE Grades 1 (17/20, 85%) or 2 (6/20, 30%). One patient had transient Grade 3 bronchospasm responsive to standard care. AEs were reported on the day of subsequent infusions in 6 (30%), 2 (10%), and 4 patients (20%) for the 2nd, 3rd, and 4th infusions, respectively, and all were ≤ Grade 2. Neutropenia (n=1) at the 100 mg/m2 dose level was the only SAE reported by an investigator as related to AME-133v, and this event was the only DLT reported. Thus, the MTD was not established during dose escalation. Lymphocyte subset analysis showed that CD19+ B-cells were selectively decreased during and after treatment with AME-133v. The pharmacokinetic (PK) assessment of AME-133v is ongoing. Response data is available for 16 patients at dose levels 2-100 mg/m2. Investigator-assessed CR or PR (Cheson criteria) at 9 weeks was reported in 4/16 patients (25%) in the 2 (1/3), 30 (1/3), and 100 (2/6) mg/m2 cohorts.
Conclusions: AME-133v is well tolerated at the doses tested, and the MTD was not established. B-cell depletion and clinical responses were observed in the phase 1 study portion. Accrual continues in Phase 2. Further safety, pharmacodynamic, and response data will become available and will be updated in the final abstract.