title: Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer.
abstract: OBJECTIVE
  To estimate the efficacy and toxicity of AMG 386, an investigational peptide-Fc fusion protein that neutralizes the interaction between the Tie2 receptor and angiopoietin-1/2, plus weekly paclitaxel in patients with recurrent ovarian cancer.
  
  
  METHODS
  Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned 1:1:1 to receive paclitaxel (80 mg/m(2) once weekly [QW], 3 weeks on/1 week off) plus intravenous AMG 386 10 mg/kg QW (arm A), AMG 386 3 mg/kg QW (arm B), or placebo QW (arm C). The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response, CA-125 response, safety, and pharmacokinetics.
  
  
  RESULTS
  One hundred sixty-one patients were randomly assigned. Median PFS was 7.2 months (95% CI, 5.3 to 8.1 months) in arm A, 5.7 months (95% CI, 4.6 to 8.0 months) in arm B, and 4.6 months (95% CI, 1.9 to 6.7 months) in arm C. The hazard ratio for arms A and B combined versus arm C was 0.76 (95% CI, 0.52 to 1.12; P = .165). Further analyses suggested an exploratory dose-response effect for PFS across arms (Tarone's test, P = .037). Objective response rates for arms A, B, and C were 37%, 19%, and 27%, respectively. The incidence of grade ≥ 3 adverse events (AEs) in arms A, B, and C was 65%, 55%, and 64%, respectively. Frequent AEs included hypertension (8%, 6%, and 5% in arms A, B, and C, respectively), peripheral edema (71%, 51%, and 22% in arms A, B, and C, respectively), and hypokalemia (21%, 15%, and 5% in arms A, B, and C, respectively). AMG 386 exhibited linear pharmacokinetic properties at the tested doses.
  
  
  CONCLUSIONS
  AMG 386 combined with weekly paclitaxel was tolerable, with a manageable and distinct toxicity profile. The data suggest evidence of antitumor activity and a dose-response effect, warranting further studies in ovarian cancer.
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Beth.Karlan@cshs.org
authors.forename: Beth Y
authors.initials: BY
authors.lastname: Karlan
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
authors.forename: Gary E
authors.initials: GE
authors.lastname: Richardson
authors.forename: Diane M
authors.initials: DM
authors.lastname: Provencher
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Hansen
authors.forename: Martin
authors.initials: M
authors.lastname: Buck
authors.forename: Setsuko K
authors.initials: SK
authors.lastname: Chambers
authors.forename: Prafull
authors.initials: P
authors.lastname: Ghatage
authors.forename: Charles H
authors.initials: CH
authors.lastname: Pippitt
authors.forename: John V
authors.initials: JV
authors.lastname: Brown
authors.forename: Allan
authors.initials: A
authors.lastname: Covens
authors.forename: Raj V
authors.initials: RV
authors.lastname: Nagarkar
authors.forename: Margaret
authors.initials: M
authors.lastname: Davy
authors.forename: Charles A
authors.initials: CA
authors.lastname: Leath
authors.forename: Hoa
authors.initials: H
authors.lastname: Nguyen
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Stepan
authors.forename: David M
authors.initials: DM
authors.lastname: Weinreich
authors.forename: Marjan
authors.initials: M
authors.lastname: Tassoudji
authors.forename: Yu-Nien
authors.initials: YN
authors.lastname: Sun
authors.forename: Ignace B
authors.initials: IB
authors.lastname: Vergote
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005185:Fallopian Tube Neoplasms / Q000188:drug therapy; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D010534:Peritoneal Neoplasms / Q000188:drug therapy; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects; D016019:Survival Analysis
chemical_list: D011993:Recombinant Fusion Proteins; D017239:Paclitaxel; C551398:trebananib