Abstract 884 Background: RO5072759 (GA101) is the first humanized and glycoengineered type II monoclonal anti-CD20 antibody to enter clinical trials. In vitro, GA101 exhibits increased antibody-dependent cytotoxicity (ADCC) and strongly enhanced direct cell death compared to rituximab. Methods: A Phase I study was initiated to determine the safety, tolerability, dose-limiting toxicity (DLT), and pharmacokinetics of GA101 given as a single agent to patients with CD20+ B-CLL for whom no therapy of higher priority was available. A flat, intravenous dose ranging from 400 mg to 2000 mg was given in a safety-driven, dose escalating, 3 × 3 design on days 1, 8 and 22 and subsequently every 3 weeks for a total of 9 infusions. Here, we present the phase I data on 13 B-CLL patients, 33% [9/13 evaluable] with high risk cytogenetics (17p or 11q) and 70% [7/10 evaluable] displaying unmutated IgVH status, who received a median of 3 [1-8] prior regimens, including fludarabine (13/13) and rituximab-containing therapy, (8/13). Baseline median hematology parameters included hemoglobin 12.6 g/dL [9.4 -14.9], WBC 51.8 × 109/L [10-124], platelets 191 × 109/L [48-404], lymphocytes 47.4 × 109/L [7.0-119.3]. Results: GA101 was well tolerated with no DLTs and no dose reductions. The most common adverse events were Grade 1 or 2 infusion related reactions essentially limited to the first infusion. GA101-related Grade 3/4 hematological toxicities included transient neutropenia (n=9), febrile neutropenia (n=1) and transient thrombocytopenia (n=1). Neutropenia recovered spontaneously or with G-CSF. SAEs were reported in 3 patients (febrile neutropenia, thrombocytopenia, bronchitis, gingivitis, neutropenia and tumor lysis syndrome). Ten patients had infections (17 episodes with only three being Grade 3). No significant changes to baseline immunoglobulin levels were observed. Measurement of plasma cytokines during and immediately after the 1st infusion showed a transient increase in IL6 and IL8 with smaller increases in IL10, IFN-γ and TNFa. Activation of complement was not observed (C3a, C4a, C5a). Concurrent to cytokine increase was a decrease in T-cell subsets and NK cell counts (peripheral blood) after the first infusion. At the end of treatment, CD3 and CD8 counts had recovered while median CD4 and CD16/56 counts remained just below the normal range, with no clinical sequelae observed. Immunologic monitoring is ongoing. B-cell (CD19+) depletion was almost complete for all 13 patients and sustained following the first infusion. Best overall response rate according to IWCLL criteria was 62% (8/13) with 1 CRi, 7 PR and 5 SD observed across all FcγIIIRA [158F/V polymorphism] genotypes with no clear dose relationship established. Responses are ongoing with durations ranging from 3.5+ to 8+ months. End of treatment minimal residual disease (MRD) from 7/11 evaluable patients was detectable for 6 patients (median reduction of 2 log, range 2-4) and negative for one (despite a stable disease, as assessed by CT-scan). GA101 pharmacokinetics were characterized by one linear and one time-dependent saturable clearance components, consistent with target-mediated disposition, which is also observed with rituximab. Whilst the plasma concentrations demonstrate a dose-dependent increase, there was significant inter and intra-patient variability. Time-dependent clearance is consistent with a reduction in target-mediated antibody clearance with increasing duration of treatment. With the same doses of GA101, clearance is faster in B-CLL patients than NHL patients (Salles et al ASH 2008, 2009). Conclusion: These phase I results indicate that GA101 has promising activity when given as single agent to heavily pre-treated B-CLL patients and has a similar safety profile to that observed in NHL patients (Salles et al, ASH 2008, 2009) with an increased incidence of transient neutropenia in B-CLL. GA101 is currently being explored as a single agent in phase II in relapsed/refractory B-CLL and indolent/aggressive NHL and in combination with chemotherapy in a phase Ib study. Disclosures: Morschhauser:Roche Products Limited : Honoraria. Cartron:Roche Products Limited : Consultancy, Honoraria. Milpied:Roche Products Limited : Honoraria. Weisser:Roche Diagnostics : Employment. Birkett:Roche Products Limited : Employment. Salles:Roche Products Limited : Honoraria.