Abstract LB-228: Pharmacokinetics of Tremelimumab, a fully human anti-CTLA-4 monoclonal antibody, in subjects with unresectable malignant mesothelioma
Authors: Calabro' Luana , Narwal Rajesh , Robbins Paul B. , Pietro Alessandra D. , Cutaia Ornella , Fonsatti Ester , Annesi Diego , Fazio Carolina , Ibrahim Ramy , Maio Michele 
Published: May 2015

Abstract
Purpose: Tremelimumab is a fully human IgG2 monoclonal antibody specific for cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4/CD152). Tremelimumab blocks the interaction of CTLA-4 with its ligands B7.1 and B7.2, and enhances human T-cell activation, as demonstrated by increased interleukin-2 production in in-vitro/in-vivo studies. The primary objectives of this analysis were to assess the preliminary population pharmacokinetics (PK) of tremelimumab in mesothelioma and identify the impact of potential patient/disease characteristics on PK variability.
Methods: Tremelimumab serum concentration-time data were collected from a second-line, single-arm phase-2 study (NCT01649024/NCT01655888) designed to evaluate clinical activity along with safety and tolerability of multiple IV doses of tremelimumab in patients with malignant mesothelioma. Two dosing regimens were tested: 15 mg/kg every 90 days (Q90D) up to 4 doses in a 12 month period until progressive disease or unacceptable toxicity and, 10 mg/kg every 4 weeks (Q4W) for 6 months followed by 10 mg/kg every 12 weeks (Q12W) until progressive disease or unacceptable toxicity. A total of 40 subjects provided evaluable PK data at various prespecified time points following both dosing regimens. Tremelimumab serum concentrations were determined using a validated enzyme-linked immunosorbent assay (ELISA) with a lower limit of quantitation (LLOQ) of 0.156 µg/mL. PK analysis was performed using a non-linear mixed effects modeling approach with NONMEM 7.2 software.
Results: Tremelimumab PK exposure in mesothelioma subjects was similar to previous melanoma studies following 15 mg/kg Q90D. Following the 15 mg/kg Q90D, PK exposure was below the target trough level of ∼30 µg/mL for about half of the dosing interval with almost all subjects below the LLOQ at the end of the 90-day dosing interval. Following more frequent dosing of 10 mg/kg Q4W, PK exposure was increased and maintained at or above the target level in the majority of subjects over the entire dosing interval. Tremelimumab PK was best described using a 2-compartment linear model with first order elimination. Following IV dosing, the typical clearance (CL) and central volume of distribution (Vc) were 0.2 L/day and 3.5 L, respectively. The between-subject variability for CL and Vc were 22% and 7%, respectively. The estimated typical PK parameters were similar to other monoclonal antibodies without target mediated elimination. The baseline body weight and Eastern Cooperative Oncology Group (ECOG) performance status were identified as significant covariates for CL, whereas only baseline body weight was significant covariate for volume of distribution.
Conclusions: A 2-compartment population PK model adequately described tremelimumab PK in subjects with mesothelioma. PK parameter estimates were similar in both mesothelioma and melanoma populations. Tremelimumab 10 mg/kg Q4W yielded higher exposure than 15 mg/kg Q90D with a majority of subjects maintaining concentrations above the target trough level of ∼30 µg/mL over the dosing interval. Preliminary covariate screening identified body weight and ECOG as influential factors for PK parameters. These correlations will be further validated using data from larger clinical trials.
Citation Format: Luana Calabro', Rajesh Narwal, Paul B. Robbins, Alessandra Di Pietro, Ornella Cutaia, Ester Fonsatti, Diego Annesi, Carolina Fazio, Ramy Ibrahim, Michele Maio. Pharmacokinetics of Tremelimumab, a fully human anti-CTLA-4 monoclonal antibody, in subjects with unresectable malignant mesothelioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-228. doi:10.1158/1538-7445.AM2014-LB-228