Abstract 754: The effect of CC chemokine ligand-2 (CCL2/MCP-1) and CC chemokine ligand-5 (CCL5/RANTES) on the pharmacokinetics (PK) and the pharmacodynamics (PD) of pegylated liposomal CKD602 (S-CKD602) in patients with advanced solid tumors

Introduction: S-CKD602, pegylated liposomal formulation of CKD-602, a camptothecin analog, is cleared by the mononuclear phagocyte system (MPS). A phase I study of S-CKD602 reported high interpatient variability in the PK of encapsulated and released CKD-602. In addition, there was a bi-directional interaction between S-CKD602 and monocytes (MO), primary cells of MPS. The exact mechanisms underlying these interactions are unknown. Chemokine ligands play essential roles in migration and activation of MO. These factors may have important effects on nanoparticle PK and PD but have not been evaluated. Thus, we assessed the relationship of chemokines on the PK and PD of S-CKD602 in patients with refractory solid tumor. Methods: S-CKD602 was given IV over 1 h q 3 weeks. The doses ranged from 0.10 to 2.5 mg/m2. PK studies of encapsulated and released CKD-602 in plasma were performed on cycle 1. Blood was collected prior to dose, at the end of the infusion, and from 3 h to 336 h post infusion. The % decrease in MO at their nadir was calculated. The concentrations of CCL2, CCL3, CCL4, and CCL5 in plasma at baseline, 48 h and 96 h post infusion were determined using the Bio-Plex system and analyzed using Bio-Plex software. Quartile distribution was assessed and used for Spearman's correlation coefficient to determine the association between chemokine baseline level and area under the concentration versus time curve (AUC) of chemokines with S-CKD602 PK and PD. The Kruskal-Wallis test was used for comparison among chemokines and cancer types. Results: The CCL5 baseline concentration [CCL5: 10,457 ± 11,549; CCL2: 182.44 ± 104.70; CCL3: 53.00 ± 19.60; CCL4: 42.88 ± 18.64 pg/ml (P 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 754. doi:1538-7445.AM2012-754