title: Randomised, phase II, placebo-controlled, trial of fulvestrant plus vandetanib in postmenopausal women with bone only or bone predominant, hormone-receptor-positive metastatic breast cancer (MBC): the OCOG ZAMBONEY study.
abstract: Biomarkers of bone turnover, including urine N-telopeptide (uNTx), have been used as surrogate measures of response to bone-targeted therapies. Vascular endothelial growth factor (VEGF) levels correlate with extent of bone metastases. We assessed whether vandetanib, an inhibitor of VEGF, epidermal growth factor receptor and RET signalling, improved uNTx response when added to fulvestrant (F) in breast cancer patients with bone metastases. Postmenopausal patients with bone predominant, hormone-receptor-positive metastatic breast cancer were randomised to F (500 mg IM days 1, 15, 29, then monthly) with either vandetanib (100 mg PO OD) (FV) or placebo (FP). The primary objective was uNTx response. Secondary objectives included PFS, OS, RECIST response, pain scores and toxicity. Sixty-one patients were allocated to FV and 68 to FP. Out of 127 analyzable patients, an uNTx response occurred in 66 % for FV and 54 % for FP (p = 0.21). No difference was detected between groups for PFS; HR = 0.95 (95 % CI 0.65-1.38) or OS HR = 0.69 (95 % CI 0.37-1.31). For the 62 patients with measurable disease, clinical benefit rates were 41 and 43 %, respectively (p = 0.47). Serious adverse events were similar, 3.3 % for FV versus 5.9 % for FP. Elevated baseline uNTx (>65 nM BCE/mmol Cr) was prognostic for PFS, HR = 1.55 (95 % CI 1.04-2.30) and for OS, HR = 2.32 (95 % CI 1.25-4.33). The addition of vandetanib to fulvestrant did not improve biomarker response, PFS or OS in patients with bone metastases. Baseline bone turnover was prognostic for PFS and OS.
authors.affiliation: Division of Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa Hospital Research Institute and University of Ottawa, Box 912, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada, mclemons@toh.on.ca.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Clemons
authors.forename: Brandy
authors.initials: B
authors.lastname: Cochrane
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Pond
authors.forename: Nadia
authors.initials: N
authors.lastname: Califaretti
authors.forename: Stephen K L
authors.initials: SK
authors.lastname: Chia
authors.forename: Rebecca Alexandra
authors.initials: RA
authors.lastname: Dent
authors.forename: Xinni
authors.initials: X
authors.lastname: Song
authors.forename: Andre
authors.initials: A
authors.lastname: Robidoux
authors.forename: Sameer
authors.initials: S
authors.lastname: Parpia
authors.forename: David
authors.initials: D
authors.lastname: Warr
authors.forename: Daniel
authors.initials: D
authors.lastname: Rayson
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Pritchard
authors.forename: Mark N
authors.initials: MN
authors.lastname: Levine
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D024042:Collagen Type I / Q000652:urine; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D008875:Middle Aged; D010455:Peptides / Q000652:urine; D010880:Piperidines / Q000008:administration & dosage; D017698:Postmenopause; D011799:Quinazolines / Q000008:administration & dosage; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D024042:Collagen Type I; D010455:Peptides; D010880:Piperidines; D011799:Quinazolines; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C052929:collagen type I trimeric cross-linked peptide; D000077267:Fulvestrant; D004958:Estradiol; C452423:vandetanib