Phase I evaluation of telatinib, a VEGF receptor tyrosine kinase inhibitor, in combination with bevacizumab in subjects with advanced solid tumors.

Abstract

BACKGROUND:

Blocking both receptor and ligand of the vascular endothelial growth factor (receptor) VEGF(R) pathway might be feasible and increase antitumor activity. This phase I study investigated telatinib, an oral tyrosine kinase inhibitor targeting VEGFR-2, combined with bevacizumab, in adults with solid tumors.

PATIENTS AND METHODS:

Twenty-six patients were treated in successive cohorts with telatinib (twice-daily continuously, 450-900 mg) or bevacizumab (bi-weekly, starting dose 5 mg/kg). Safety, pharmacokinetics, endothelial (progenitor) cell (E(P)C)/growth factor kinetics and efficacy were assessed.

RESULTS:

Most frequent adverse events were pain, nausea, voice changes and fatigue. Five dose-limiting toxicities (DLTs) occurred: hypertension (cohort I and II), bowel perforation, lipase increase and atrial flutter (cohort III). Cumulative toxicity resulted in a bevacizumab dose reduction to 1 mg/kg (cohort III). Due to three DLTs (n = 14), this cohort represented the best-tolerated dose level. Bevacizumab effectively neutralized plasma VEGF even at 1 mg/kg. Twelve patients had stable disease (clinical benefit 46%). EPC and SDF-1α levels increased during monotherapy telatinib.

CONCLUSIONS:

Telatinib (450 mg b.i.d.) combined with bevacizumab (1 mg/kg bi-weekly) shows antitumor activity, but accumulating constitutional toxicity impedes long-term treatment of patients. Therefore, this combination will not be pursued in a phase II setting.

• Authors: M H G Langenberg, P O Witteveen, J Roodhart, M P Lolkema, H M W Verheul, M Mergui-Roelvink, E Brendel, J Krätzschmar, B Loembé, A Nol-Boekel, O Christensen, J H M Schellens, E E Voest
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 22 Issue 11 Pg. 2508-2515 (Nov 2011) ISSN: 1569-8041 [Electronic] England
• PMID: 21378200 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Protein Kinase Inhibitors
• Pyridazines
• Pyridines
• telatinib
• Bevacizumab
• FLT1 protein, human
• Protein-Tyrosine Kinases
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Adult
• Aged
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects, pharmacokinetics)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, pharmacokinetics)
• Bevacizumab
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (drug therapy, metabolism)
• Protein Kinase Inhibitors (administration & dosage, adverse effects)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyridazines (administration & dosage, adverse effects, pharmacokinetics)
• Pyridines (administration & dosage, adverse effects, pharmacokinetics)
• Vascular Endothelial Growth Factor Receptor-1 (antagonists & inhibitors)
• Young Adult