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Transcription profiling of human tumours at baseline and after 21 days of treatment with sorafenib and dacarbazine

ABSTRACT: Background New approaches are needed to improve prognostic accuracy for treatment response and to explore the complexities of drug effects on human tumours. We developed a strategy of global genomic investigation of sequential tumor biopsies at baseline and 21 days post-treatment, and applied this approach in a phase I study of sorafenib plus dacarbazine in patients with solid tumours. Methods 23 patients received 21-day cycles of oral sorafenib, 400 mg twice daily and dacarbazine, 1000 mg/m2 by 1-h intravenous infusion on day 1. Efficacy was assessed using response evaluation criteria in solid tumours. Differential gene expression was assessed through genomic microarray analysis of biopsy tissue from the same tumour at baseline and on day 21. Seven parameters characterizing vascularisation using dynamic enhanced-contrast ultrasonography (DCE-US) were assessed. Changes from baseline in the two parameters were characterized for patients with and without a clinical response to treatment at 3 months.Findings 23 patients were evaluable for efficacy and 17 for gene expression and DCE-US analyses. One patient had a partial response; 14 had stable disease. Genomic analyses identified a 247-gene signature that distinguished progressors from nonprogressors at 3 months. Expression of four genes was significantly associated with progression at 3 months. Functional parameters of DCE-US representing blood volume at baseline, day 8, and day 21 correlated with 3-month disease progression status.Interpretation This novel approach of sequential investigations in a phase I trial was feasible, detecting early changes in gene expression and tumour vascularity that may be predictive of clinical outcome.

ORGANISM(S): Homo sapiens

SUBMITTER: Lazar V

PROVIDER: S-ECPF-TABM-760 | biostudies-other | 2014 Apr

REPOSITORIES: biostudies-other

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Project description:What is already known about this subjectSorafenib is a multikinase inhibitor with activity against B-raf, C-raf, VEGFR2, PDGFR? and FGFR1. Sorafenib is clinically approved for the treatment of renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). The pharmacokinetics (PK) of sorafenib are highly variable between subjects. Sorafenib exposure increases less than dose proportionally (likely due to limited solubility). Sorafenib undergoes enterohepatic recycling (EHC).What this study addsThis is the first study to characterize the PK of sorafenib using a model based on sorafenib's known disposition characteristics such as delayed/solubility-limited GI absorption and EHC. The parameterization of the EHC model used a square wave function to describe the gall bladder emptying. This study evaluated the effect of baseline bodyweight, BSA, age, gender, liver function parameters, kidney function parameters and genotype with respect to CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5 on sorafenib PK. No clinically important covariates were identified. This model can be used to simulate and explore alternative dosing regimens and to develop exposure-response relationships for sorafenib.AimsTo characterize the pharmacokinetics (PK) of sorafenib in patients with solid tumours and to evaluate the possible effects of demographic, clinical and pharmacogenetic (CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5) covariates on the disposition of sorafenib.MethodsPK were assessed in 111 patients enrolled in five phase I and II clinical trials, where sorafenib 200 or 400 mg was administered twice daily as a single agent or in combination therapy. All patients were genotyped for polymorphisms in metabolic enzymes for sorafenib. Population PK analysis was performed by using nonlinear mixed effects modelling (NONMEM). The final model was validated using visual predictive checks and nonparametric bootstrap analysis.ResultsA one compartment model with four transit absorption compartments and enterohepatic circulation (EHC) adequately described sorafenib disposition. Baseline bodyweight was a statistically significant covariate for distributional volume, accounting for 4% of inter-individual variability (IIV). PK model parameter estimates (range) for an 80 kg patient were clearance 8.13 l h(-1) (3.6-22.3 l h(-1) ), volume 213 l (50-1000 l), mean absorption transit time 1.98 h (0.5-13 h), fraction undergoing EHC 50% and average time to gall bladder emptying 6.13 h.ConclusionsOverall, population PK analysis was consistent with known biopharmaceutical/PK characteristics of oral sorafenib. No clinically important PK covariates were identified.

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Transcription profiling of human tumours at baseline and after 21 days of treatment with sorafenib and dacarbazine

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