title: 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.affiliation: Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA. emayer@partners.org
authors.forename: Erica L
authors.initials: EL
authors.lastname: Mayer
authors.forename: M E
authors.initials: ME
authors.lastname: Scheulen
authors.forename: J
authors.initials: J
authors.lastname: Beckman
authors.forename: H
authors.initials: H
authors.lastname: Richly
authors.forename: A
authors.initials: A
authors.lastname: Duarte
authors.forename: M M
authors.initials: MM
authors.lastname: Cotreau
authors.forename: A L
authors.initials: AL
authors.lastname: Strahs
authors.forename: S
authors.initials: S
authors.lastname: Agarwal
authors.forename: L
authors.initials: L
authors.lastname: Steelman
authors.forename: E P
authors.initials: EP
authors.lastname: Winer
authors.forename: M N
authors.initials: MN
authors.lastname: Dickler
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C553176:tivozanib; D040281:Vascular Endothelial Growth Factor Receptor-1; D017239:Paclitaxel