M. Marchand (1), L. Claret (1), N. Losic (2), TA Puchalski (3), R. Bruno (1)
(1) Pharsight Consulting Services, Pharsight, a CertaraTM Company, Marseille, France (2) Genmab, Copenhagen, Denmark, (3) Janssen Research & Development, LLC, Spring House, PA, USA
Objectives: Daratumumab is a human CD38 monoclonal antibody with broad-spectrum antitumor activity. The aim of this project was to explore the pharmacokinetics (PK), pharmacodynamic (PD) response and the exposure-response relationship of daratumumab from a Phase I/II study in patients with advanced multiple myeloma (MM). This information was an integral aspect of dose selection.
Methods: Data were available from 25 MM patients with measurable PK who received daratumumab 0.1 to 16 mg/kg weekly by intravenous infusion (data cut 31 July 2012). A population PK model was developed to derive systemic exposure to daratumumab in patients. A simplified tumor growth inhibition (TGI) model [1] was used to estimate response metrics based on time profiles of M-protein and involved free light chain (FLC) after daratumumab administration. Relationship between these TGI metrics and progression free survival (PFS) were assessed.
Results: A 2-compartment population PK model with parallel linear and Michaelis-Menten eliminations best described daratumumab pharmacokinetics, as often described for monoclonal antibodies targeting receptors [2]. Estimated response metrics, i.e. M-protein and involved FLC time to nadir were correlated with daratumumab exposure (p<0.05). Involved FLC and M-protein time to nadir were predictors of PFS (p<0.01).
Conclusions: Daratumumab was shown to inhibit tumor growth and to prolong PFS in an exposure-dependent manner. M-protein and involved FLC TGI responses metrics are biomarkers of response to daratumumab. The PK/PD model together with drug independent clinical endpoint models [3] may be used to optimize dose and schedule for daratumumab and support the Phase II study design.
References:
[1] Claret L., Gupta M., Joshi A., Sarapa N., He J., Powell B., Bruno R., Evaluation of Tumor-Size Response Metrics to Predict Survival and Progression Free Survival in First-Line Metastatic Colorectal Cancer, PAGE 21 (2012) Abstr 2328, J Clin Oncol, accepted for publication.
[2] Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010 Oct;49 (10):633-59.
[3] Bruno R, Jonsson F, Zaki M, Jacques C, Swern A, Richardson P, Rajkumar VS, Claret L. Simulation of clinical outcome for pomalidomide plus low-dose dexamethasone in patients with refractory multiple myeloma based on week 8 M-protein response. Blood (ASH Annual Meeting Abstracts), 118 (21), 1881, 2011.
Reference: PAGE 22 (2013) Abstr 2668 [www.page-meeting.org/?abstract=2668]
Poster: Oncology