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

• Published in: Breast cancer research and treatment Vol. 140; no. 2; pp. 331 - 339
• Main Authors: Mayer, Erica L., Scheulen, M. E., Beckman, J., Richly, H., Duarte, A., Cotreau, M. M., Strahs, A. L., Agarwal, S., Steelman, L., Winer, E. P., Dickler, M. N.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.07.2013; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Angiogenesis; Antimitotic agents; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Biological and medical sciences; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer; Cancer research; Cancer therapies; Care and treatment; Clinical Trial; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions - classification; Drug-Related Side Effects and Adverse Reactions - pathology; Female; Gynecology. Andrology. Obstetrics; Humans; Inhibitor drugs; Kinases; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Metastasis; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Metastasis - drug therapy; Neoplasm Metastasis - genetics; Neoplasm Metastasis - pathology; Oncology; Oncology, Experimental; Paclitaxel - administration & dosage; Phenylurea Compounds - administration & dosage; Phenylurea Compounds - adverse effects; Phenylurea Compounds - pharmacokinetics; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Quinolines - administration & dosage; Quinolines - adverse effects; Quinolines - pharmacokinetics; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-1 - metabolism; United States > US; Metastatic breast cancer; VEGFR inhibitor; Tivozanib; Paclitaxel; Antineoplastic agent; Breast disease; Dose escalation; Administration schedule; Breast cancer; Malignant tumor; Metastasis; Vascular endothelium growth factor receptor; Mammary gland diseases; Increasing dose; Hydrochlorides; Taxane derivatives; Ureas; Advanced stage; Inhibitor; Antimitotic; Cancer
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-013-2632-9

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.