CLL - THERAPY, EXCLUDING TRANSPLANTATION: EMERGING THERAPEUTIC AGENTS FOR CLL AND HCL
Phase I Study of RO5072759 (GA101) in Relapsed/Refractory Chronic Lymphocytic Leukemia.
Franck Morschhauser, MD, PhD*,1,
Guillaume Cartron, MD*,2,
Thierry Lamy, MD, PhD*,3,
Noel-Jean Milpied, MD, PhD4,
Catherine Thieblemont, MD, PhD5,
Hervé Tilly, M.D.*,6,
Martin Weisser, MD*,7,
Joe Birkett, Ph.D.*,8 and
Gilles Andre Salles, MD, PhD9
1 Hematology, Centre Hospitalier Universitaire, Lille, France, 2 Haematology-Oncology, UMR-CNRS5235 and CIC BT 509, University Hospital, Montpellier Cedex 5, France, 3 Haematology, CHU Rennes, Rennes, France, 4 Hématologie, CHU de Bordeaux, Bordeaux, France, 5 Hemato-Oncology, Hopital Saint-Louis, APHP - INSERM U 728 - Institut Universitaire d'Hematologie, Paris, France, 6 Hematologie, CENTRE HENRI BECQUEREL, Rouen, France, 7 Roche Diagnostics GmbH, Penzberg, Germany, 8 F.Hoffmann-La Roche, Ltd., Welwyn Garden City, United Kingdom, 9 Hematologie, Centre Hospitalier Lyon-Sud, Pierre-Benite, France
Background: RO5072759 (GA101) is the first humanized and glycoengineeredtype 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 GA101given as a single agent to patients with CD20+ B-CLL for whomno therapy of higher priority was available. A flat, intravenousdose ranging from 400 mg to 2000 mg was given in a safety-driven,dose escalating, 3 x 3 design on days 1, 8 and 22 and subsequentlyevery 3 weeks for a total of 9 infusions. Here, we present thephase I data on 13 B-CLL patients, 33% [9/13 evaluable] withhigh 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-containingtherapy, (8/13). Baseline median hematology parameters includedhemoglobin 12.6 g/dL [9.4 -14.9], WBC 51.8 x 109/L [10-124],platelets 191 x 109/L [48-404], lymphocytes 47.4 x 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 relatedreactions essentially limited to the first infusion. GA101-relatedGrade 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. SAEswere reported in 3 patients (febrile neutropenia, thrombocytopenia,bronchitis, gingivitis, neutropenia and tumor lysis syndrome).Ten patients had infections (17 episodes with only three beingGrade 3). No significant changes to baseline immunoglobulinlevels were observed. Measurement of plasma cytokines duringand immediately after the 1st infusion showed a transient increasein IL6 and IL8 with smaller increases in IL10, IFN- and TNFa.Activation of complement was not observed (C3a, C4a, C5a). Concurrentto cytokine increase was a decrease in T-cell subsets and NKcell counts (peripheral blood) after the first infusion. Atthe end of treatment, CD3 and CD8 counts had recovered whilemedian CD4 and CD16/56 counts remained just below the normalrange, with no clinical sequelae observed. Immunologic monitoringis ongoing.
B-cell (CD19+) depletion was almost complete for all 13 patientsand sustained following the first infusion. Best overall responserate according to IWCLL criteria was 62% (8/13) with 1 CRi,7 PR and 5 SD observed across all FcIIIRA [158F/V polymorphism]genotypes with no clear dose relationship established. Responsesare ongoing with durations ranging from 3.5+ to 8+ months. Endof treatment minimal residual disease (MRD) from 7/11 evaluablepatients was detectable for 6 patients (median reduction of2 log, range 2-4) and negative for one (despite a stable disease,as assessed by CT-scan). GA101 pharmacokinetics were characterizedby one linear and one time-dependent saturable clearance components,consistent with target-mediated disposition, which is also observedwith rituximab. Whilst the plasma concentrations demonstratea dose-dependent increase, there was significant inter and intra-patientvariability. Time-dependent clearance is consistent with a reductionin target-mediated antibody clearance with increasing durationof treatment. With the same doses of GA101, clearance is fasterin B-CLL patients than NHL patients (Salles et al ASH 2008,2009).
Conclusion: These phase I results indicate that GA101 has promising activitywhen given as single agent to heavily pre-treated B-CLL patientsand has a similar safety profile to that observed in NHL patients(Salles et al, ASH 2008, 2009) with an increased incidence oftransient neutropenia in B-CLL. GA101 is currently being exploredas a single agent in phase II in relapsed/refractory B-CLL andindolent/aggressive NHL and in combination with chemotherapyin a phase Ib study.