A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas.

Background: 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. Patients and methods: 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. Results: 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. Conclusion: 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. Clinical Trial Number: NCT01782313.