A phase I dose-escalation study of INCB028060, an inhibitor of c-MET receptor tyrosine kinase, in patients with advanced solid tumors.
http://meeting.ascopubs.org/cgi/ ... 15_suppl/3091?rss=1
R. C. Donehower, A. Scardina, M. Hill, J. Bowman, R. C. Newton, X. Liu, P. Scherle, Q. Wang, S. Diamond, J. Boer, F. Lee, T. Gau, H. A. Burris, J. C. Bendell, S. F. Jones and J. R. Infante
Background: INCB028060 is a potent and selective inhibitor of c-MET receptor tyrosine kinase (RTK). This first-in-human study aims to determine the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and potential efficacy of INCB028060. Methods: In a standard 3+3 escalation, patients (pts) age =18 years with advanced solid tumors are treated with INCB028060 orally once (QD) or twice daily on a continuous 28-day schedule. C-MET inhibition is evaluated by adding c-MET overexpressing SNU-5 human gastric cancer cells to pts whole blood and then analyzing for inhibition of phospho-c-MET by ELISA. Results: At this time 17 pts have been treated across dose levels of 10, 20, 50, and 70 mg/once daily. Median age is 63 years, median ECOG PS is 0, and the most common tumor types are colorectal (4), NSCLC (3), and prostate/HCC/cholangiocarcinoma (2 each). One pt with breast cancer and diffuse liver metastases treated at 50 mg QD developed grade 3 AST elevation on C1D22, having had grade 2 AST at baseline; the AST continued to rise once treatment was discontinued. The MTD has not been reached and no other grade 3/4 adverse events (AEs) noted. CTC grade 1-2 AEs considered possibly treatment-related have included mild tremor, fatigue, nausea, diarrhea, indigestion, headache, and agitation. The Cmax and AUC values of INCB028060 have been dose-proportional, with a mean half-life of 6.8 hours. For the 70 mg QD cohort, INCB028060 mean plasma concentrations exceeded IC90 for 17 h of the day. At the 70 mg dose level on day 15, the oral CL was 35.2 (+/- 11.5) L/h and renal clearance was negligible. Dose-dependent reductions in phospho-c-MET levels have been detected on day 15 (pre-dose) by whole blood-based PD analysis, with mean inhibition of 41.3%, 45.7%, 67.5% and 69% at 10, 20, 50 and 70 mg/day, respectively. Conclusions: Thus far, toxicity has been manageable with INCB028060. The PK profile is favorable and supports exploration of a BID schedule. Dose-dependent decreases in phospho-c-MET are promising. |
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