Abstract
BackgroundHepatocellular carcinoma (HCC) is a major cause of cancer-related death. It is a highly vascular tumour with multiple angiogenic factors, most importantly vascular endothelial growth factor (VEGF), involved in HCC progression. Tivozanib is an oral inhibitor of VEGFR-1/2/3 with promising activity against HCC in vivo.MethodsWe conducted a phase 1b/2 study of tivozanib in patients with advanced HCC. The safety, dosing, pharmacokinetics, pharmacodynamics, and preliminary antineoplastic efficacy of tivozanib were evaluated.ResultsTwenty-seven patients received at least one dose of tivozanib. Using a 3+3 design, the recommended phase 2 dose (RP2D) of tivozanib was determined to be 1 mg per os once daily, 21 days on–7 days off. The median progression-free and overall survival were 24 weeks and 9 months, respectively, for patients treated at RP2D. The overall response rate was 21%. Treatment was well tolerated. A significant decrease in soluble plasma VEGFR-2 was noted, assuring adequate target engagement.ConclusionsAlthough this study did not proceed to stage 2, there was an early efficacy signal with a very favourable toxicity profile. A phase 1/2 trial of tivozanib in combination with durvalumab is currently underway.Trial registrationClinicalTrials.gov NCT01835223, registered on 15 April 2013.
Highlights
Hepatocellular carcinoma (HCC) is a major cause of cancer-related death
The 27 patients who were deemed eligible and received at least one dose of tivozanib are included in the safety analysis, the 19 patients who were treated at the recommended phase 2 dose (RP2D) and were evaluable for the primary efficacy endpoint are included in the efficacy analysis
This is to our knowledge the first reported study with tivozanib in patients with advanced HCC
Summary
Hepatocellular carcinoma (HCC) is a major cause of cancer-related death. It is a highly vascular tumour with multiple angiogenic factors, most importantly vascular endothelial growth factor (VEGF), involved in HCC progression. HCC is a highly vascular tumour with multiple angiogenic factors, such as vascular endothelial growth factor (VEGF), plateletderived growth factor (PDGF) and stem cell receptor factor (c-kit), all of which are involved in HCC progression, with VEGF predominating.[4] Elevated VEGF levels correlate with advanced stage and poor prognosis in HCC.[5] Sorafenib, a small-molecule inhibitor of VEGFR-1/2/3, BRAF and PDGFR was the first Food and Drug Administration (FDA)-approved oral angiogenesis inhibitor for previously untreated advanced HCC patients with established overall survival (OS) benefit over placebo in large, randomised phase 3 trials.[6,7] Despite improvement in OS, objective responses are rare (2% or less) and less than half of the patients have meaningful long-term disease control with sorafenib.[7] For almost a decade, sorafenib remained the only systemic treatment option in advanced HCC.
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