http://cancerres.aacrjournals.or ... etingAbstracts/2079
Abstract 2079: Antitumoral activity of INC280 against adult glioblastoma brain tumors xenografts.
Stephen T. Keir1, Martin A. Roskoski1, Sabrina Wagner2, Ralph Tiedt2, Darell D. Bigner1, and Henry S. Friedman1
1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC;
2Novartis Pharma AG, Switzerland.
INTRODUCTION: INC280 is an oral, highly selective c-Met receptor tyrosine kinase inhibitor. The hepatocyte growth factor (HGF)-c-Met pathway is one of the most frequently dysregulated pathways in human cancers. Aberrant HGF-c-Met signaling has been documented in a wide range of human malignancies. The c-Met pathway can be activated by abnormal HGF and c-Met expression levels, c-Met activating mutations and gene amplifications. At this time, INC280 is in development for the treatment of solid tumors with activation of the c-Met pathway. As a part of this study, we looked at the antitumoral activity of INC280 in adult glioblastoma (GBM) brain tumor xenografts with elevated levels of Met or HGF expression.
METHODS: Met expression and copy number was determined by ELISA and qPCR, HGF mRNA by RT-qPCR. Adult GBM tumor xenografts were grown subcutaneously in athymic BALB/c mice. After tumor size reached 200-500 mm3 subcutaneously, groups of 10 mice were randomly treated with either drug vehicle/control or INC280 (10mg/kg BID) PO for 30 days. Tumor responses for subcutaneous xenografts were assessed by tumor growth delay and regression.
RESULTS: Based on activation of the c-Met pathway, the following two xenograft lines were selected for treatment with INC280: D-09-0337 MG and D-09-0477 MG. As a single agent, INC280 demonstrated statistically significant (p<0.001) growth delays of 40.23 and 30.13 days in D-09-0337 MG and D-09-0477 MG, respectively. In addition, when treated with INC280, tumors implanted with D-09-0337 MG (10 out of 10) or D-09-0477 MG (4 out of 10) regressed.
CONCLUSION: Our results demonstrate the therapeutic efficacy of the inhibition of a c-Met receptor tyrosine kinase in adult brain tumor xenografts with activation of the c-Met pathway. These results warrant further exploration of INC280 in clinical trials for the treatment of adult brain tumor patients with dysregulated proto-oncogene c-Met and its ligand HGF.
Study Efficacy and Safety of INC280 in Patients With Advanced Hepatocellular Carcinoma.
香港有肝癌临床组，2期，但目前没有招募病人。 http://clinicaltrials.gov/show/NCT01737827
The protocol consists of two independent parts (Dose-Determining Part and Dose Expansion Part). Approximately 6 patients will be treated with INC280 300 mg twice a day in the Dose-Determining Part. Approximately 50 patients will be treated with INC280 in the Dose Expansion Part. The dose for the Expansion Part can be lower, equal or higher than in the Dose-Determining Part will be determined after the Dose Determining Part at the dose decision analysis.
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