A phase I trial of vatalanib (PTK/ZK) in combination with bevacizumab in patients with refractory and/or advanced malignancies

Clin Adv Hematol Oncol. 2011 Nov;9(11):845-52.

Abstract

Background: Vatalanib is an orally active, small molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR). Bevacizumab is also an angiogenesis inhibitor, but it possesses a different mechanism of action. This phase I study was conducted to determine the dose-limiting toxicity, maximum-tolerated doses, and recommended phase II doses of the combination of vatalanib and bevacizumab.

Patients and methods: Treatment cycles were 4 weeks in length. Patients received oral vatalanib once or twice daily continuously. Bevacizumab was administered intravenously starting on day 15 of cycle 1, and dosing was repeated at 2-week intervals in patients with at least stable disease for 4 cycles. After 4 cycles, only patients with a partial or complete response continued treatment with the combination of vatalanib and bevacizumab. Patients with stable disease were allowed to continue single-agent vatalanib from cycle 5 until disease progression or intolerable toxicity.

Results: A total of 27 patients received 93 cycles of treatment. Dose escalation was difficult due to enhanced toxicities (primarily proteinuria and hypertension) with the regimen that required numerous dose modifications. Interruption of vatalanib and bevacizumab dosing due to proteinuria occurred in 4 patients enrolled at dose level 3, with 1 of these patients developing grade 3 nephrotic range proteinuria. As a result, further dose escalation with the combination regimen was abandoned.

Conclusions: Further development of bevacizumab and oral VEGF tyrosine kinase inhibitor combination regimens is questionable due to the additive toxicities that occur; future investigations should proceed with caution.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Angiogenesis Inhibitors / administration & dosage
  • Angiogenesis Inhibitors / pharmacokinetics
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bevacizumab
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Phthalazines / administration & dosage
  • Phthalazines / pharmacokinetics
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacokinetics
  • Pyridines / administration & dosage
  • Pyridines / pharmacokinetics
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
  • Young Adult

Substances

  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal, Humanized
  • Phthalazines
  • Protein Kinase Inhibitors
  • Pyridines
  • Bevacizumab
  • vatalanib
  • Receptors, Vascular Endothelial Growth Factor