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

Journal Article

© 2014 The Author(s).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/m<sup>2</sup>). 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/m<sup>2</sup>. The MTD of CEP-11981 was determined to be 97.4 mg/m<sup>2</sup>, with DLTs observed at the 126.6 mg/m<sup>2</sup> 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<sup>2</sup> and 1 patient at 126.6 mg/m<sup>2</sup>), 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<sup>2</sup>. 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.

Full Text

Duke Authors

Cited Authors

  • Pili, R; Carducci, M; Brown, P; Hurwitz, H

Published Date

  • 2014

Published In

Volume / Issue

  • 32 / 6

Start / End Page

  • 1258 - 1268

International Standard Serial Number (ISSN)

  • 0167-6997

Digital Object Identifier (DOI)

  • 10.1007/s10637-014-0147-9