Phase I Study of RO5072759 (GA101) in Patients with Relapsed/Refractory CD20+ Non-Hodgkin Lymphoma (NHL).

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.

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.

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 1^st 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

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.

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