title: Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF) has a crucial role in angiogenesis, and is a valid target in metastatic breast cancer. Motesanib is an investigational oral inhibitor of VEGF receptors. We aimed to determine whether treatment with motesanib plus paclitaxel is better than placebo plus paclitaxel in patients with HER2-negative locally recurrent or metastatic breast cancer.
  
  
  METHODS
  Between Dec 1, 2006, and July 4, 2008, patients with untreated HER2-negative metastatic breast cancer were randomly assigned (using a randomisation list created by personnel not associated with the study) in a 1:1:1 ratio to paclitaxel (90 mg/m(2) on days 1, 8, and 15 every 3 weeks) plus either masked motesanib 125 mg orally once per day (n=91), masked placebo orally once per day (n=94), or open-label bevacizumab 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle (n=97), after stratification according to adjuvant or neoadjuvant chemotherapy (taxane-containing regimens vs other regimens vs none), number of metastatic sites (<3 vs ≥3), and hormone receptor status (positive vs negative). Placebo was provided as a replica of motesanib 25 mg tablets. The primary endpoint was objective response rate (ORR) based on the population as assigned to treatment. This trial is registered with ClinicalTrials.gov, number NCT00356681.
  
  
  RESULTS
  ORRs for the motesanib group and the placebo group did not differ significantly (49%vs 41%; absolute difference 8% [95% CI -6 to 22]; p=0.31). The ORR in the bevacizumab group (52%) was similar to that in the motesanib group. The most common grade 3 or higher adverse events included diarrhoea (18 of 92 patients in the motesanib group, none of 89 patients in the placebo group, and four of 96 patients in the bevacizumab group), fatigue (11, eight, and six), hypertension (11, one, and seven), and peripheral sensory neuropathy (ten, seven, and 19). More patients in the motesanib group had serious adverse events than did those in the placebo or bevacizumab groups (34, 26, and 21 patients, respectively); the most common of these in the motesanib group were gastrointestinal in nature.
  
  
  CONCLUSIONS
  Data from this trial do not support the further investigation of motesanib at this dose and schedule in this population.
  
  
  BACKGROUND
  Amgen.
authors.affiliation: Grupo Español de Investigación en Cáncer de Mama, Madrid, Spain. mmartin@geicam.org
authors.forename: Miguel
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authors.lastname: Martin
authors.forename: Henri
authors.initials: H
authors.lastname: Roche
authors.forename: Tamas
authors.initials: T
authors.lastname: Pinter
authors.forename: John
authors.initials: J
authors.lastname: Crown
authors.forename: M John
authors.initials: MJ
authors.lastname: Kennedy
authors.forename: Louise
authors.initials: L
authors.lastname: Provencher
authors.forename: Frank
authors.initials: F
authors.lastname: Priou
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Eiermann
authors.forename: Encarna
authors.initials: E
authors.lastname: Adrover
authors.forename: Istvan
authors.initials: I
authors.lastname: Lang
authors.forename: Manuel
authors.initials: M
authors.lastname: Ramos
authors.forename: Jean
authors.initials: J
authors.lastname: Latreille
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Jagiełło-Gruszfeld
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Pienkowski
authors.forename: Emilio
authors.initials: E
authors.lastname: Alba
authors.forename: Raymond
authors.initials: R
authors.lastname: Snyder
authors.forename: Sachin
authors.initials: S
authors.lastname: Almel
authors.forename: Janusz
authors.initials: J
authors.lastname: Rolski
authors.forename: Montserrat
authors.initials: M
authors.lastname: Munoz
authors.forename: Rebecca
authors.initials: R
authors.lastname: Moroose
authors.forename: Sara
authors.initials: S
authors.lastname: Hurvitz
authors.forename: Ana
authors.initials: A
authors.lastname: Baños
authors.forename: Henry
authors.initials: H
authors.lastname: Adewoye
authors.forename: Yong-Jiang
authors.initials: YJ
authors.lastname: Hei
authors.forename: Mary-Ann
authors.initials: MA
authors.lastname: Lindsay
authors.forename: Matthieu
authors.initials: M
authors.lastname: Rupin
authors.forename: David
authors.initials: D
authors.lastname: Cabaribere
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Lemmerick
authors.forename: John R
authors.initials: JR
authors.lastname: Mackey
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009841:Oligonucleotides; D017239:Paclitaxel / Q000008:administration & dosage / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D007211:Indoles; D009536:Niacinamide; D009841:Oligonucleotides; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C519562:imetelstat