title: A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas.
abstract: Soft tissue sarcomas (STSs) overexpress vascular endothelial growth factors (VEGF) and VEGF-receptors (VEGFR) activation have been associated with tumor aggressiveness. Tivozanib is a potent small molecule tyrosine kinase inhibitor against VEGFR1-3, with activity against PDGFRα/β and cKIT. The primary endpoint of this study was progression free survival (PFS) rate at 16 weeks. Secondary end points were overall survival (OS), response rate, safety and correlative studies.
  
  
  
  A Simon two-stage phase II trial was performed using tivozanib given orally at 1.5 mg daily, 3 week on 1 week off on a 28 day cycle until disease progression or intolerable toxicity.
  
  
  
  Fifty-eight patients were enrolled and treated with tivozanib. Leiomyosarcoma was the most common STS histological type in our cohort (47%) and 27 patients (46%) had received at least 3 lines of therapy prior to study entry. Up to 24 patients (41%) had prior VEGF targeted therapies. Partial response and stable disease were observed in 2 (3.6%) and 30 (54.5%) patients. The 16 week PFS rate was 36.4% [95% confidence interval (CI) 23.7-49.1] and a median PFS of 3.5 months (95% CI 1.8-3). Median OS observed was 12.2 months (95% CI 8.1-16.8). The most frequent all grade toxicities were fatigue (48.3%), hypertension (43.1%), nausea (31%) and diarrhea (27.6%). The most common grade three toxicity was hypertension (22.4%). Correlative studies demonstrate no correlation between the expression of VEGFR 1, 2 or 3, PDGFRα/β or FGF, and activity of tivozanib.
  
  
  
  Tivozanib was well tolerated and showed antitumor activity with a promising median PFS and PFS rate at 4 months in a heavily pretreated population of metastatic STSs. Our results support further studies to assess the clinical efficacy of tivozanib in STS.
  
  
  
  NCT01782313.
authors: Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, USA.
authors: M
authors: M
authors: Agulnik
authors: Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, USA.
authors: R L B
authors: RLB
authors: Costa
authors: Division of Hematology/Oncology, University of Iowa Hospitals and Clinics, Iowa City, USA.
authors: M
authors: M
authors: Milhem
authors: Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, USA.
authors: A W
authors: AW
authors: Rademaker
authors: Division of Hematology/Oncology, Washington University in St. Louis, St Louis, USA.
authors: B C
authors: BC
authors: Prunder
authors: Division of Hematology/Oncology, Washington University in St. Louis, St Louis, USA.
authors: D
authors: D
authors: Daniels
authors: Division of Hematology/Oncology, Washington University in St. Louis, St Louis, USA.
authors: B T
authors: BT
authors: Rhodes
authors: Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, USA.
authors: C
authors: C
authors: Humphreys
authors: Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, USA.
authors: S
authors: S
authors: Abbinanti
authors: Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, USA.
authors: L
authors: L
authors: Nye
authors: Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, USA.
authors: R
authors: R
authors: Cehic
authors: Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, USA.
authors: A
authors: A
authors: Polish
authors: Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, USA.
authors: C
authors: C
authors: Vintilescu
authors: Division of Hematology/Oncology, University of Wisconsin, Madison, USA.
authors: T
authors: T
authors: McFarland
authors: Division of Hematology/Oncology, University of Minnesota, Minneapolis, USA.
authors: K
authors: K
authors: Skubitz
authors: Division of Hematology/Oncology, Mayo Clinic, Rochester, USA.
authors: S
authors: S
authors: Robinson
authors: Division of Hematology/Oncology, Mayo Clinic, Rochester, USA.
authors: S
authors: S
authors: Okuno
authors: Division of Hematology/Oncology, Washington University in St. Louis, St Louis, USA.
authors: B A
authors: BA
authors: Van Tine
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D012509:Sarcoma / Q000188:drug therapy* / Q000401:mortality; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000401:mortality; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011804:Quinolines; C553176:tivozanib; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: phase II; sarcoma; tivozanib; tyrosine kinase inhibitor