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

Abstract

Abstract 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<0.0001)] and the CCL5 AUC [CCL5: 770,880 ± 516,880; CCL2: 19,195 ± 9,407; CCL3: 5,388 ± 2,454; CCL4: 3,804 ± 1,476 pg/ml·h (P<0.0001)] were elevated in patients compared with other chemokines. The CCL5 baseline and the CCL5 AUC were elevated in patients with sarcoma [24,267 ± 15,108 pg/ml (P=0.0097)] and colon cancer [1,227,720 ± 486,142 pg/ml·h (P=0.0082)], respectively, compared to other types of solid tumors. The CCL5 AUC was shown to be inversely correlated with the CCL2 AUC (P=0.028). The encapsulated CKD-602 AUC was correlated with the CCL5 baseline level (P=0.0121), the CCL2 AUC (P=0.0324), the CCL4 AUC (P<0.0001), and the CCL5 AUC (P=0.0012). The % decrease in MO was correlated with released CKD-602 AUC (P=0.0004) and clearance of encapsulated CKD-602 (P=0.0223). Conclusions: This is the first report that CCL2 and CCL5 are associated with the PK and PD of a pegylated liposomal drug. These results suggest that chemokine production may have a significant impact on the PK and PD of pegylated liposomal formulation of anticancer agents. In addition, the type of solid tumor may influence the interaction. 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