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

Publication ,  Journal Article
Pili, R; Carducci, M; Brown, P; Hurwitz, H
Published in: Invest New Drugs
December 2014

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(2)). 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(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). 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.

Duke Scholars

Published In

Invest New Drugs

DOI

EISSN

1573-0646

Publication Date

December 2014

Volume

32

Issue

6

Start / End Page

1258 / 1268

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor Receptor-2
  • Swine
  • Response Evaluation Criteria in Solid Tumors
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Neoplasms
  • Middle Aged
  • Maximum Tolerated Dose
  • Male
  • Indazoles
 

Citation

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Pili, R., Carducci, M., Brown, P., & Hurwitz, H. (2014). An open-label study to determine the maximum tolerated dose of the multitargeted tyrosine kinase inhibitor CEP-11981 in patients with advanced cancer. Invest New Drugs, 32(6), 1258–1268. https://doi.org/10.1007/s10637-014-0147-9
Pili, Roberto, Michael Carducci, Peter Brown, and Herbert Hurwitz. “An open-label study to determine the maximum tolerated dose of the multitargeted tyrosine kinase inhibitor CEP-11981 in patients with advanced cancer.Invest New Drugs 32, no. 6 (December 2014): 1258–68. https://doi.org/10.1007/s10637-014-0147-9.
Pili, Roberto, et al. “An open-label study to determine the maximum tolerated dose of the multitargeted tyrosine kinase inhibitor CEP-11981 in patients with advanced cancer.Invest New Drugs, vol. 32, no. 6, Dec. 2014, pp. 1258–68. Pubmed, doi:10.1007/s10637-014-0147-9.
Journal cover image

Published In

Invest New Drugs

DOI

EISSN

1573-0646

Publication Date

December 2014

Volume

32

Issue

6

Start / End Page

1258 / 1268

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor Receptor-2
  • Swine
  • Response Evaluation Criteria in Solid Tumors
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Neoplasms
  • Middle Aged
  • Maximum Tolerated Dose
  • Male
  • Indazoles