Abstract 3776: Antitumor response to inotuzumab ozogamicin (INO) in patients with refractory or relapsed indolent B-cell non-Hodgkin's lymphomas (NHL): Pharmacokinetic-pharmacodynamic (PK-PD) modeling and interim results from a phase II study
Authors: Luu Kenneth , Vandendries Erik , Volkert Angela , Ogura Michinori , Goy Andre , Boni Joseph 
Published: August 2012

Abstract
Background: INO (CMC-544) is a novel antibody-drug conjugate composed of a CD22-directed IgG4 antibody linked to calicheamicin, a potent cytotoxin. In this phase II study, INO was administered 1.8 mg/m2 intravenously once every 28 days for a planned 4 to 8 cycles to patients with indolent B-cell NHL who were refractory to rituximab. Objective: The aim of this analysis was to evaluate the antitumor activity of INO by performing PK-PD modeling of the INO concentrations and tumor size (as determined from the sum of products of diameters). Methods: Analysis was performed with a set of 28 patients with indolent NHL (24 follicular, 2 small lymphocytic lymphoma, 2 marginal zone) having evaluable data at the interim stage of the study. Population PK-PD modeling was conducted using NONMEM v. 7.1.2. Longitudinal tumor size data included measurements from the pre-screen time, during INO therapy, and up to 15 months of follow up. The PK of total calicheamicin was described by a linear 2-compartment model. Tumor size (T) was described by an exponential net growth (kgr) model with an inhibitory drug effect (slope) on kgr and drug concentration (Cp), such that dT/dt = kgr(1-slope x Cp)T. Results: Of the 28 subjects evaluated, 18 exhibited tumor shrinkage (maximum reduction from baseline with a range of 12%-100% and a median of 68%), among which 10 were progression free/without tumor regrowth in the range of 10-18 months post first dose. Tumor shrinkage was seen as early as 54 days post treatment initiation, with peak tumor shrinkage as early as Day 103. The population estimates of clearance (CL), central (V1), peripheral (V2) volumes of distribution, and intercompartmental clearance (Q) were 2.69 (±0.41) L/day/m2, 30.4 (±1.79) L/m2, 90.9 (±19.8) L/m2 and 5.50 (±1.29) L/day/m2, respectively. The population parameter estimates of the PD model were 9.41 x 10−4 (±5.33 x 10−4) day−1 for kgr and 0.396 (±0.178) ng/mL−1 for the slope. Simulations from the model using 1,000 virtual subjects (1.8 mg/m2 every 28 days for a total of 4 cycles) showed that the median 10% tumor shrinkage can be seen as early as 35 days, with peak suppression occurring as early as 161 days. In addition, the duration of response was sustained beyond 1 year post treatment, and the tumor size does not return to baseline for up to 2 years after the first treatment. Conclusions: Antitumor response to INO in this study was characterized by a markedly long duration of response. PK-PD modeling improved the quantitative understanding of the time course of tumor size relative to inotuzumab treatment. The model, with updated data from the ongoing study, has utility in optimizing the dose and treatment regimen for subsequent follow-up studies in indolent lymphoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3776. doi:1538-7445.AM2012-3776