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Clinical Trial
. 2014 Sep;154(1):37-46.
doi: 10.1016/j.clim.2014.06.005. Epub 2014 Jun 11.

A phase I study of PRO131921, a novel anti-CD20 monoclonal antibody in patients with relapsed/refractory CD20+ indolent NHL: correlation between clinical responses and AUC pharmacokinetics

Carla Casulo  1 , Julie M Vose  2 , William Y Ho  3 , Brad Kahl  4 , Mark Brunvand  5 , Andre Goy  6 , Yvette Kasamon  7 , Bruce Cheson  8 , Jonathan W Friedberg  9
Affiliations
Clinical Trial

A phase I study of PRO131921, a novel anti-CD20 monoclonal antibody in patients with relapsed/refractory CD20+ indolent NHL: correlation between clinical responses and AUC pharmacokinetics

Carla Casulo et al. Clin Immunol. 2014 Sep.

Abstract

PRO131921 is a third-generation, humanized anti-CD20 monoclonal antibody with increased antibody-dependent cytotoxicity and complement-dependent cytotoxicity compared to rituximab. In this phase I study, PRO131921 was administered as a single agent to patients with CD20+, relapsed or refractory, indolent non-Hodgkin lymphoma (NHL) who had been treated with a prior rituximab-containing regimen. The primary aim of this study was safety and tolerability of PRO131921. The secondary aim of the study, and focus of this report, was to determine the pharmacokinetics (PK) profile of PRO131921 and establish a correlation between drug exposure and clinical efficacy. Patients were treated with PRO131921 by intravenous infusion weekly for 4 weeks and the dose was escalated based on safety in a 3+3 design. Twenty-four patients were treated with PRO131921 at doses from 25mg/m(2) to 800 mg/m(2). Analysis of PK data demonstrated a correlation between higher normalized drug exposure (normalized AUC) and tumor shrinkage (p = .0035). Also, normalized AUC levels were higher among responders and subjects displaying tumor shrinkage versus subjects progressing or showing no regression (p = 0.030). In conclusion, PRO131921 demonstrated clinical activity in rituximab-relapsed and refractory indolent NHL patients. The observation that higher normalized AUC may be associated with improved clinical responses has potential implications in future trials of monoclonal antibody-based therapies, and emphasizes the importance of early PK studies to optimize antibody efficacy.

Keywords: Area under the curve;; Efficacy; Monoclonal antibody;; Pharmacokinetics;.

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Figures

Figure 1
Figure 1
Change in the sum of the product of the greatest diameters (SPD) assessed at days 78 and 169 of study by cohort. Asterisks indicate disease progression by day 50.
Figure 2
Figure 2
Correlation between dose-normalized AUC and clinical response (P = .03). * Note the CRu response (subject 1026) was reclassified as PR for this figure.
Figure 3
Figure 3
Scatter plot of subject normalized AUC values against Day 78 tumor burden percent change from baseline. * The scatter plot excludes one outlier subject with a normalized AUC of 7.40 and a 38% reduction in Day 78 tumor burden (subject 1024).
Figure 4
Figure 4
Kaplan–Meier progression-free survival among evaluable subjects. 1. Nine subjects experienced progressive disease among 22 evaluable subjects. 2. Median PFS is 11.1 months 3. Progression-free survival is based on radiographic evidence, except in the case of subjects 1017 and 1023 for whom no radiographic assessment was available (early terminations); for these 2 subjects the investigator assessment of progressive disease (PD) was used.
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