title: A phase II, randomized, placebo-controlled study of vismodegib as maintenance therapy in patients with ovarian cancer in second or third complete remission.
abstract: OBJECTIVE
  Hedgehog pathway inhibition has been suggested as a potential maintenance treatment approach in ovarian cancer through disruption of tumor-stromal interactions. Vismodegib is an orally available Hedgehog pathway inhibitor with clinical activity in advanced basal cell carcinoma and medulloblastoma. This phase II, randomized, double-blind, placebo-controlled trial was designed to provide a preliminary estimate of efficacy in patients with ovarian cancer in second or third complete remission (CR).
  
  
  METHODS
  Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in second or third CR were randomized 1:1 to vismodegib (GDC-0449; 150 mg daily) or placebo three to 14 weeks after completing chemotherapy. Treatment continued until radiographic progression or toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS).
  
  
  RESULTS
  One hundred four patients were randomized to vismodegib (n = 52) or placebo (n = 52); median PFS was 7.5 months and 5.8 months, respectively [HR 0.79; 95% confidence interval (CI), 0.46-1.35]. The HR was 0.66 (95% CI, 0.36-1.20) for second CR patients (n = 84) and 1.79 (95% CI, 0.50-6.48) for third CR patients (n = 20). The most common adverse events in the vismodegib arm were dysgeusia/ageusia, muscle spasms, and alopecia. Grade 3/4 adverse events occurred in 12 patients (23.1%) with vismodegib and six (11.5%) with placebo. Hedgehog expression was detected in 13.5% of archival tissues.
  
  
  CONCLUSIONS
  In this study, the sought magnitude of increase in PFS was not achieved for vismodegib maintenance versus placebo in patients with ovarian cancer in second or third CR. The frequency of Hedgehog ligand expression was lower than expected.
authors.affiliation: Royal Marsden Hospital, Sutton, Surrey, United Kingdom. stan.kaye@rmh.nhs.uk
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Kaye
authors.forename: Louis
authors.initials: L
authors.lastname: Fehrenbacher
authors.forename: Robert
authors.initials: R
authors.lastname: Holloway
authors.forename: Amnon
authors.initials: A
authors.lastname: Amit
authors.forename: Beth
authors.initials: B
authors.lastname: Karlan
authors.forename: Brian
authors.initials: B
authors.lastname: Slomovitz
authors.forename: Paul
authors.initials: P
authors.lastname: Sabbatini
authors.forename: Ling
authors.initials: L
authors.lastname: Fu
authors.forename: Robert L
authors.initials: RL
authors.lastname: Yauch
authors.forename: Ilsung
authors.initials: I
authors.lastname: Chang
authors.forename: Josina C
authors.initials: JC
authors.lastname: Reddy
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D006801:Humans; D060046:Maintenance Chemotherapy; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012074:Remission Induction; D016896:Treatment Outcome
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D015415:Biomarkers; C538724:HhAntag691; D011725:Pyridines