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Clinical Trial
. 2016 Feb;101(2):226-34.
doi: 10.3324/haematol.2015.133421. Epub 2015 Dec 11.

Rationale for optimal obinutuzumab/GA101 dosing regimen in B-cell non-Hodgkin lymphoma

Guillaume Cartron  1 , Florence Hourcade-Potelleret  2 , Franck Morschhauser  3 , Gilles Salles  4 , Michael Wenger  5 , Anna Truppel-Hartmann  2 , David J Carlile  6
Affiliations
Clinical Trial

Rationale for optimal obinutuzumab/GA101 dosing regimen in B-cell non-Hodgkin lymphoma

Guillaume Cartron et al. Haematologica. 2016 Feb.

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).

Trial registration: ClinicalTrials.gov NCT00517530 NCT00825149.

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Figures

Figure 1.
Figure 1.
Mean obinutuzumab concentrations. Mean obinutuzumab concentrations (± standard error of mean) observed in (A) phase I and (B) phase II of GAUGUIN.
Figure 2.
Figure 2.
Serum concentrations of obinutuzumab and tumor sizes. (A) Inter-individual serum concentrations of obinutuzumab by tumor burden and dose group in patients with iNHL participating in phase II of GAUGUIN. (B) Inter-individual change in tumor size by dose group in patients with iNHL.
Figure 3.
Figure 3.
Time-course of obinutuzumab serum concentrations stratified by clinical parameters and dose group in patients with non-Hodgkin lymphoma participating in phase II of GAUGUIN.
Figure 4.
Figure 4.
Time course of obinutuzumab serum concentrations in the 1600/800 mg dose group stratified by disease type.
Figure 5.
Figure 5.
Change in tumor size by mean plasma concentration of obinutuzumab during the first six weeks of treatment in phase I and II of the GAUGUIN study.
Figure 6.
Figure 6.
Predicted serum concentrations of obinutuzumab 1000/1000 mg (blue line) versus 1600/800 mg (red line).
See this image and copyright information in PMC

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