1.Phase I study of E7820, an oral inhibitor of integrin alpha-2 expression with antiangiogenic properties, in patients with advanced malignancies.
Mita M1, Kelly KR, Mita A, Ricart AD, Romero O, Tolcher A, Hook L, Okereke C, Krivelevich I, Rossignol DP, Giles FJ, Rowinsky EK, Takimoto C. Clin Cancer Res. 2011 Jan 1;17(1):193-200. doi: 10.1158/1078-0432.CCR-10-0010.
PURPOSE: This phase I study was conducted to characterize the safety profile, pharmacokinetics, pharmacodynamics, dose-limiting toxicity (DLT), and the maximum-tolerated dose of E7820, a novel oral sulfonamide derivative with antiangiogenic properties, when administered to patients with advanced solid malignancies.
2.Enhanced anti-angiogenic effect of E7820 in combination with erlotinib in epidermal growth factor receptor-tyrosine kinase inhibitor-resistant non-small-cell lung cancer xenograft models.
Ito K1, Semba T, Uenaka T, Wakabayashi T, Asada M, Funahashi Y. Cancer Sci. 2014 Aug;105(8):1023-31. doi: 10.1111/cas.12450.
Most non-small-cell lung cancers (NSCLCs) harboring activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to EGFR tyrosine kinase inhibitors (EGFR-TKIs); however, they invariably develop resistance to these drugs. E7820 is an angiogenesis inhibitor that decreases integrin-α2 expression and is currently undergoing clinical trials. We investigated whether E7820 in combination with erlotinib, an EGFR-TKI, could overcome EGFR-TKI-resistance in the NSCLC cell lines A549 (KRAS; G12S), H1975 (EGFR; L858R/T790M), and H1650 (PTEN; loss, EGFR; exon 19 deletion), which are resistant to erlotinib. Immunohistochemical analysis was carried out in xenografted tumors to investigate anti-angiogenesis activity and endothelial cell apoptosis levels by endothelial cell marker CD31 and TUNEL staining, respectively. Treatment with E7820 (50 mg/kg) with erlotinib (60 mg/kg) showed a synergistic antitumor effect in three xenograft models.
3.Application of population pharmacokinetic modeling in early clinical development of the anticancer agent E7820.
Keizer RJ1, Zamacona MK, Jansen M, Critchley D, Wanders J, Beijnen JH, Schellens JH, Huitema AD. Invest New Drugs. 2009 Apr;27(2):140-52. doi: 10.1007/s10637-008-9164-x. Epub 2008 Aug 20.
The aim of this study was to assess the population pharmacokinetics (PopPK) of the novel oral anti-cancer agent E7820. Both a non-linear mixed effects modeling analysis and a non-compartmental analysis (NCA) were performed and results were compared. Data were obtained from a phase I dose escalation study in patients with malignant solid tumors or lymphomas. E7820 was administered daily for 28 days, followed by a washout period of 7 days prior to the start of subsequent cycles. A one compartment model with linear elimination from the central compartment was shown to give adequate fit, while absorption was described using a turnover model. Final population parameter estimates of basic PK parameters obtained with the PopPK method were (RSE): clearance, 6.24 L/h (7.1%), volume of distribution, 66.0 L (8.5%), mean transit time to the absorption compartment, 0.638 h (6.5%). The intake of food prior to dose administration slowed absorption (2.8-fold, RSE 13%) and increased relative bioavailability of E7820 by 36% (RSE 14%), although the effect on C (max) and AUC was not significant.
