An open-label study to determine the maximum tolerated dose of the multitargeted tyrosine kinase inhibitor CEP-11981 in patients with advanced cancer

Roberto Pili, Michael Carducci, Peter Brown, Herbert Hurwitz

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Background 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. Methods 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/m2). The maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), tumor response, and safety were evaluated. Results CEP-11981 was tolerated at doses between 3.0 and 97.4 mg/m2. The MTD of CEP-11981 was determined to be 97.4 mg/m2, with DLTs observed at the 126.6 mg/m2 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/m2 and 1 patient at 126.6 mg/m2), 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/m2. Conclusions 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.

Original languageEnglish (US)
Pages (from-to)1258-1268
Number of pages11
JournalInvestigational New Drugs
Volume32
Issue number6
DOIs
StatePublished - Dec 1 2014
Externally publishedYes

Keywords

  • Dose-finding study
  • Multitargeted inhibition
  • Safety profile
  • Tie-2
  • Tyrosine kinase inhibitor
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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