Phase I Study of RO5072759 (GA101) in Patients with Relapsed/Refractory CD20+ Non-Hodgkin Lymphoma (NHL).
Authors: Salles Gilles , Morschhauser Franck , Lamy Thierry , Milpied Noel , Thieblemont Catherine , Tilly Herve , Bieska Gabi , Carlile David , Cartron Guillaume 
Published: October 2019

Abstract
Abstract 1704
Poster Board I-730

Background
RO5072759 (GA101) is the first humanized and glycoengineered type II monoclonal anti-CD20 antibody to enter clinical trials. In vitro data show GA101 exhibits increased antibody-dependent cytotoxicity (ADCC) and strongly enhanced direct cell death compared to rituximab.

Methods
In this first Phase I study, GA101 was administered i.v., as a single agent to patients with CD20+ NHL for whom no therapy of higher priority was available. On days 1, 8 and 22 and subsequently every 3 weeks for a total of 9 infusions, flat doses between 50 mg to 2000 mg were given in a safety-driven, dose escalation, 3 × 3 design. The aim was to determine the safety, tolerability, dose-limiting toxicity (DLT), and the pharmacokinetics of GA101. Preliminary phase I data were reported on the first 12 NHL patients (Salles et al, ASH 2008). Here, we present the definitive results of this phase I on 21 NHL patients. Their median age was 64 yrs (39-83) with the following histologies: follicular (n = 13), mantle cell (n = 4), and diffuse large B-cell, Waldenstrom's macroglobulinemia, small lymphocytic, lymphoplasmocytoid (1 each). Patients had previously received a median of 4 (range 1-7) prior regimens [time from last treatment to study entry 12 months], with 95% of patients exposed to prior rituximab and 10/21 (48%) of patients with prior stem cell transplantation.

Results
GA101 was well tolerated with no DLTs, no dose reductions and no GA101-related Grade 4 toxicities (CTCAE V3.0). Four patients experienced at least one SAE. The most common adverse events were Grade 1 or 2 infusion related reactions essentially limited to the first infusion. Tumor lysis syndrome (Grade 3) was observed in 1 patient. Related Grade 3 hematological toxicities were neutropenia (n = 2; no G-CSF required), anemia (1) and thrombocytopenia (1) and 11/21 patients reported Grade 1-2 infections. No significant change in complement fractions (C3, C3a, C4a, C5, C5a, Bb) was observed. Measurement of plasma cytokines during and immediately after the 1st infusion showed an increase in IL6 and IL8 with a smaller increase in IL10, TNFa and IFN-γ, with recovery by Day 8. Median T-cell (CD3, CD4 and CD8) sub-sets and NK counts were low in all patients prior to therapy. Concurrent to cytokine increase, a further decrease in these lymphocyte sub-sets was observed after the first infusion, recovering thereafter, with median values returning to baseline values by end of treatment. In contrast, B-cell (CD19+) depletion was rapid and sustained in the majority of patients \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(1921\) \end{document}. End of treatment B-cell recovery has been observed in 3 of the responding patients [recovery ranging from 410-532 days after first dose]. No significant changes from baseline immunoglobulin levels were observed. GA101 pharmacokinetics were characterized by two clearance components, one linear component and one time-dependent saturable component consistent with target-mediated disposition, also observed with rituximab. Whilst the plasma concentrations demonstrate a dose-dependent increase, there was significant inter- and intra-patient variability. The time-dependent clearance component is consistent with a reduction in target-mediated antibody clearance with increasing duration of treatment. Responses occurred at all dose levels, and across all FcγIIIRA (158F/V polymorphism) genotypes, with best overall response of 5 CR/CRu, 4 PR (ORR=43%) (all responding patients had histology of fNHL, their median measurable baseline lesions=3295mm2, and 6 patients had prior ASCT), 5 SD, 6 PD & and 1 non-evaluable (premature death unrelated to GA101). Of those 9 responses, 8 responses occurred during the treatment phase. One of the responding patients progressed during the treatment phase and in the follow-up phase one patient with a CR progressed after responding for 5.5 months. Six patients have an ongoing response [4 CR, 2 PR] [response duration ranging from 7.5+ to 17+ months] and in addition, one patient with SD has converted to PR in the follow-up phase [SD for 17 months and PR for 4+ months].

Conclusion
GA101 is a next generation anti-CD20 antibody that has shown promising efficacy in this difficult-to-treat patient population. GA101 is currently being explored as a single agent in phase II in relapsed/refractory indolent/aggressive NHL and B-CLL and in combination with chemotherapy in a phase Ib study.

Disclosures
Salles: Roche: Honoraria. Morschhauser:Roche: Honoraria. Bieska:Roche: Employment. Carlile:Roche: Employment. Cartron:Roche: Honoraria.