title: Antitumor activity and safety of tivozanib (AV-951) in a phase II randomized discontinuation trial in patients with renal cell carcinoma.
abstract: OBJECTIVE
  The antitumor activity and safety of tivozanib, which is a potent and selective vascular endothelial growth factor receptor-1, -2, and -3 inhibitor, was assessed in patients with advanced/metastatic renal cell carcinoma (RCC).
  
  
  METHODS
  In this phase II, randomized discontinuation trial, 272 patients received open-label tivozanib 1.5 mg/d (one cycle equaled three treatment weeks followed by a 1-week break) orally for 16 weeks. Thereafter, 78 patients who demonstrated ≥ 25% tumor shrinkage continued to take tivozanib, and 118 patients with less than 25% tumor change were randomly assigned to receive tivozanib or a placebo in a double-blind manner; patients with ≥ 25% tumor growth were discontinued. Primary end points included safety, the objective response rate (ORR) at 16 weeks, and the percentage of randomly assigned patients who remained progression free after 12 weeks of double-blind treatment; secondary end points included progression-free survival (PFS).
  
  
  RESULTS
  Of 272 patients enrolled onto the study, 83% of patients had clear-cell histology, 73% of patients had undergone nephrectomy, and 54% of patients were treatment naive. The ORR after 16 weeks of tivozanib treatment was 18% (95% CI, 14% to 23%). Of the 118 randomized patients, significantly more patients who were randomly assigned to receive double-blind tivozanib remained progression free after 12 weeks versus patients who received the placebo (49% v 21%; P = .001). Throughout the study, the ORR was 24% (95% CI, 19% to 30%), and the median PFS was 11.7 months (95% CI, 8.3 to 14.3 months) in the overall study population. The most common grade 3 and 4 treatment-related adverse event was hypertension (12%).
  
  
  CONCLUSIONS
  Tivozanib was active and well tolerated in patients with advanced RCC. These data support additional development of tivozanib in advanced RCC.
authors.affiliation: Blokhin Oncology Research Center, Russia. nosov@mail.ru
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Nosov
authors.forename: Brooke
authors.initials: B
authors.lastname: Esteves
authors.forename: Oleg N
authors.initials: ON
authors.lastname: Lipatov
authors.forename: Alexei A
authors.initials: AA
authors.lastname: Lyulko
authors.forename: A A
authors.initials: AA
authors.lastname: Anischenko
authors.forename: Raju T
authors.initials: RT
authors.lastname: Chacko
authors.forename: Dinesh C
authors.initials: DC
authors.lastname: Doval
authors.forename: Andrew
authors.initials: A
authors.lastname: Strahs
authors.forename: William J
authors.initials: WJ
authors.lastname: Slichenmyer
authors.forename: Pankaj
authors.initials: P
authors.lastname: Bhargava
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D016001:Confidence Intervals; D018592:Cross-Over Studies; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D009367:Neoplasm Staging; D061214:Patient Safety; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects; D012016:Reference Values; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D010671:Phenylurea Compounds; D011804:Quinolines; C553176:tivozanib