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Ref Type Journal Article
PMID (25152243)
Authors Pili R, Carducci M, Brown P, Hurwitz H
Title An open-label study to determine the maximum tolerated dose of the multitargeted tyrosine kinase inhibitor CEP-11981 in patients with advanced cancer.
Journal Vol Issue Date Pages Journal Short Title
Investigational new drugs 32 6 2014 Dec 1258-68 Invest New Drugs
URL
Abstract Text This phase I study evaluated the pharmacokinetics and pharmacodynamics of CEP-11981, an oral vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, in patients with advanced, relapsed, or refractory solid tumors.Oral CEP-11981 dose escalations followed a modified Fibonacci sequence (from 3.0 to 4.2, 5.9, 11.8, 19.7, 29.6, 41.4, 55.0, 73.0, 97.4, and 126.6 mg/m(2)). The maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), tumor response, and safety were evaluated.CEP-11981 was tolerated at doses between 3.0 and 97.4 mg/m(2). The MTD of CEP-11981 was determined to be 97.4 mg/m(2), with DLTs observed at the 126.6 mg/m(2) dose. The DLTs were grade 4 neutropenia in 1 patient and grade 3 T-wave inversion with chest heaviness and fatigue in 1 patient. All 3 events resolved on stopping CEP-11981. The most frequently reported adverse events of any grade were fatigue, nausea, diarrhea, decreased appetite, abdominal pain, back pain, vomiting, constipation, headache, dizziness, and dyspnea. Treatment-related grade 3/4 neutropenia was observed in the highest-dose cohorts (2 patients at 97.4 mg/m(2) and 1 patient at 126.6 mg/m(2)), indicating some off-target inhibition. VEGF inhibition was greatest in the higher-dose groups. Although no patient experienced complete or partial response, 44% patients achieved stable disease when measured at ≥ 6 weeks, which occurred more frequently in cohorts receiving ≥ 73.0 mg/m(2).In patients with recurrent or refractory solid tumors, disease stabilization was achieved. Despite acceptable tolerability of CEP-11981 at the MTD, further development by the sponsor has ceased.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
CEP-11981 CEP-11981 0 2
Drug Name Trade Name Synonyms Drug Classes Drug Description
CEP-11981 ESK981|CEP11981|CEP 11981 TIE2 Inhibitor 3 VEGFR Inhibitor (Pan) 36 CEP-11981 is a multikinase inhibitor that targets VEGFR1-3 and TIE2, which may inhibit tumor angiogenesis and lead to tumor growth inhibition (PMID: 24982343, PMID: 25152243).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References