title: Rationale for optimal obinutuzumab/GA101 dosing regimen in B-cell non-Hodgkin lymphoma.
abstract: Obinutuzumab (GA101) is a type II, glycoengineered anti-CD20 monoclonal antibody for the treatment of hematologic malignancies. Obinutuzumab has mechanisms of action that are distinct from those of rituximab, potentially translating into improved clinical efficacy. We present the pharmacokinetic and clinical data from the phase I/II GAUGUIN and phase I GAUDI studies that were used to identify the obinutuzumab dose and regimen undergoing phase III assessment. In phase I (GAUGUIN and GAUDI), non-Hodgkin lymphoma patients received up to a maximum 9 fixed doses (obinutuzumab 50-2000 mg). In GAUGUIN phase II, patients received obinutuzumab 400/400 mg or 1600/800 mg [first dose day (D)1, D8, cycle (C) 1; second dose D1, C2-C8]. The influence of demographic factors on pharmacokinetics and drug exposure on tumor response and toxicity were analyzed using exploratory graphical analyses. Obinutuzumab serum concentrations with 1600/800 mg were compared with a 1000 mg fixed-dose regimen (D1, D8 and D15, C1; D1, C2-C8) using pharmacokinetic modeling simulations. Factors related to CD20-antigenic mass were more influential on obinutuzumab pharmacokinetics with 400/400 versus 1600/800 mg. Higher serum concentrations were observed with 1600/800 versus 400/400 mg, irrespective of CD20-antigenic mass. Tumor shrinkage was greater with 1600/800 versus 400/400 mg; there was no significant increase in adverse events. Fixed dose 1000 mg with an additional C1 infusion resulted in similar serum concentrations to 1600/800 mg in model-based analyses. The obinutuzumab 1000 mg fixed-dose regimen identified in this exploratory analysis was confirmed in a full covariate analysis of a larger dataset, and is undergoing phase III evaluation. GAUGUIN and GAUDI are registered at www.clinicaltrials.gov (clinicaltrials.gov identifier:00517530 and 00825149, respectively).
authors.affiliation: CHRU Montpellier, UMR-CNRS 5235, Université de Montpellier, France g-cartron@chu-montpellier.fr.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Cartron
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Florence
authors.initials: F
authors.lastname: Hourcade-Potelleret
authors.affiliation: CHRU Lille, Unité GRITA, Université de Lille, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Morschhauser
authors.affiliation: Hospices Civils de Lyon, Université Claude Bernard, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Wenger
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Truppel-Hartmann
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Welwyn, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Carlile
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018951:Antigens, CD20 / Q000235:genetics / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D005260:Female; D015870:Gene Expression; D006801:Humans; D016393:Lymphoma, B-Cell / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000175:diagnosis / Q000209:etiology / Q000473:pathology; D009894:Opportunistic Infections / Q000175:diagnosis / Q000209:etiology / Q000473:pathology; D011239:Prednisolone / Q000627:therapeutic use; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone; C543332:obinutuzumab