Phase I evaluation of @entity17172 , a @entity7 @entity7 @entity669 kinase inhibitor, in combination with bevacizumab in subjects with advanced solid XXXX .

@entity1 @entity137 @entity390 @entity101 @entity7 @entity5 @entity319 @entity956 @entity158 @entity669 @entity17172
BACKGROUND: Blocking both @entity7 and ligand of the @entity7 @entity7 (R) pathway might be feasible and increase antitumor activity. This phase I study investigated @entity17172 , an oral @entity669 kinase inhibitor targeting @entity319 , combined with bevacizumab, in adults with solid @entity5 . @entity1 AND METHODS: Twenty-six @entity1 were treated in successive cohorts with @entity17172 (twice-daily continuously, 450-900 mg) or bevacizumab (bi-weekly, starting dose 5 mg/kg). Safety, pharmacokinetics, endothelial (progenitor) cell (E(P)C)/growth factor kinetics and efficacy were assessed. RESULTS: Most frequent adverse events were @entity158 , @entity390 , voice changes and fatigue. Five dose-limiting @entity137 (DLTs) occurred: @entity101 (cohort I and II), bowel perforation, lipase increase and @entity956 (cohort III). @entity137 resulted in a bevacizumab dose reduction to 1 mg/kg (cohort III). Due to three DLTs (n = 14), this cohort represented the best-tolerated dose level. Bevacizumab effectively neutralized plasma @entity7 even at 1 mg/kg. Twelve @entity1 had stable disease (clinical benefit 46%). EPC and SDF-1a levels increased during monotherapy @entity17172 . CONCLUSIONS: @entity17172 (450 mg b.i.d.) combined with bevacizumab (1 mg/kg bi-weekly) shows antitumor activity, but accumulating constitutional @entity137 impedes long-term treatment of @entity1 . Therefore, this combination will not be pursued in a phase II setting.
