title: Combination antiangiogenic therapy in advanced breast cancer: a phase 1 trial of vandetanib, a VEGFR inhibitor, and metronomic chemotherapy, with correlative platelet proteomics.
abstract: This phase 1 study evaluated the safety and tolerability of antiangiogenic therapy using vandetanib and metronomic cyclophosphamide and methotrexate in metastatic breast cancer. Eligible patients had metastatic breast cancer with 0-4 prior chemotherapy regimens. All received cyclophosphamide 50 mg daily, methotrexate 2.5 mg days 1-2 weekly, and vandetanib daily in 3 dose-escalation cohorts: 100 mg (C1), 200 mg (C2), and 300 mg (C3). The primary endpoint was safety and tolerability; secondary endpoints included response rate and evaluation of platelet-associated proteins. Twenty three patients were treated and evaluable for toxicity. Common mild toxicities included nausea, vomiting, LFTs abnormalities, fatigue, and rash. Three episodes of dose-limiting toxicity occurred in C3. In all cohorts, 1/3 of patients required vandetanib dose reduction, and 22 % ended therapy for toxicity. Of the 20 response-evaluable patients, 10 % demonstrated partial response and 15 % stable disease ≥24 weeks. Proteomic analyses demonstrated changes in platelet content of angiogenesis regulators, including vascular endothelial growth factor and platelet factor 4, with exposure to therapy. This regimen was tolerable at a maximum vandetanib dose of 200 mg; modest clinical activity was observed in this heavily pretreated population. Changes in the platelet proteome may serve as pharmacodynamic markers of angiogenesis inhibition. Metronomic chemotherapy is an attractive partner with biologics and deserves further study in metastatic breast cancer.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, MA 02215, USA. emayer@partners.org
authors.forename: Erica L
authors.initials: EL
authors.lastname: Mayer
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Isakoff
authors.forename: Giannoula
authors.initials: G
authors.lastname: Klement
authors.forename: Sean R
authors.initials: SR
authors.lastname: Downing
authors.forename: Wendy Y
authors.initials: WY
authors.lastname: Chen
authors.forename: Keri
authors.initials: K
authors.lastname: Hannagan
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gelman
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
authors.forename: Harold J
authors.initials: HJ
authors.lastname: Burstein
mesh_terms: D059250:Administration, Metronomic; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D010978:Platelet Factor 4 / Q000378:metabolism; D040901:Proteomics; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors
chemical_list: D054316:Biomarkers, Pharmacological; D010880:Piperidines; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D010978:Platelet Factor 4; D003520:Cyclophosphamide; D040281:Vascular Endothelial Growth Factor Receptor-1; D008727:Methotrexate; C452423:vandetanib