A Phase I dose-escalation study of the VEGFR inhibitor tivozanib hydrochloride with weekly paclitaxel in metastatic breast cancer.

Abstract

Tivozanib is a potent selective tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. This Phase Ib study investigated the safety/tolerability, pharmacokinetics (PK), and activity of tivozanib with weekly paclitaxel in metastatic breast cancer (MBC). MBC patients with no prior VEGFR TKI treatment received daily oral tivozanib (3 weeks on, 1 week off) with weekly paclitaxel 90 mg/m(2). Standard 3 + 3 dose escalation was used; tivozanib cohorts (C) included C1 0.5 mg, C2 1.0 mg, and C3 1.5 mg. Assessments included Response Evaluation Criteria in Solid Tumors response, PK, and vascular function. Eighteen patients enrolled. Toxicities in >20 % of patients included fatigue, alopecia, nausea, diarrhea, peripheral sensory neuropathy, and hypertension. Grade 3/4 toxicities in >15 % of patients included fatigue and neutropenia. Maximum tolerated dose was tivozanib 1.5 mg with paclitaxel 90 mg/m(2). Four patients withdrew because of toxicity and one due to progressive disease. Thirteen patients were evaluable for response: four (30.8 %) had confirmed partial response; four had stable disease ≥6 months (30.8 %). PK data suggest no influence of paclitaxel on tivozanib concentrations. Tivozanib plus weekly paclitaxel was tolerable at all dose levels, supporting their combination at full dose. Activity in this small population was encouraging.

• Authors: Erica L Mayer, M E Scheulen, J Beckman, H Richly, A Duarte, M M Cotreau, A L Strahs, S Agarwal, L Steelman, E P Winer, M N Dickler
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 140 Issue 2 Pg. 331-9 (Jul 2013) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 23868188 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Phenylurea Compounds
• Protein Kinase Inhibitors
• Quinolines
• tivozanib
• Vascular Endothelial Growth Factor Receptor-1
• Paclitaxel

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Breast Neoplasms (drug therapy, genetics, pathology)
• Dose-Response Relationship, Drug
• Drug-Related Side Effects and Adverse Reactions (classification, pathology)
• Female
• Humans
• Middle Aged
• Neoplasm Metastasis (drug therapy, genetics, pathology)
• Paclitaxel (administration & dosage)
• Phenylurea Compounds (administration & dosage, adverse effects, pharmacokinetics)
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Quinolines (administration & dosage, adverse effects, pharmacokinetics)
• Vascular Endothelial Growth Factor Receptor-1 (antagonists & inhibitors, metabolism)