Clinical Study

A multicentre phase 1b/2 study of tivozanib in patients with advanced inoperable hepatocellular carcinoma



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. Tivozanib is an oral inhibitor of VEGFR-1/2/3 with promising activity against HCC in vivo.


We 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.


Twenty-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.


Although 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 registration NCT01835223, registered on 15 April 2013.

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Fig. 1: Progression-free and overall survival in efficacy population.
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We thank Joshua D. Prey and Sarah A. Schihl for validating the assays for VEGFR-2 and tivozanib, respectively, as well as sample analysis.

Author information

C.F.: Formal analysis, data curation and writing—original draft, review and editing; M.G.: formal analysis, data curation and writing—original draft, review and editing; S.L.: formal analysis, data curation and writing—review and editing; S.K.: formal analysis, data curation and writing—review and editing; B.E.: formal analysis, data curation and writing—review and editing; K.W.: statistical analysis and writing—review and editing; K.A.: statistical analysis and writing—review and editing; J.W.: formal analysis, data curation and writing—review and editing; R.B.: formal analysis, data curation and writing—review and editing; W.B.: formal analysis, data curation and writing—review and editing; R.I.: conceptualisation, formal analysis, funding acquisition, data curation, methodology, project administration and writing—review and editing.

Correspondence to Christos Fountzilas.

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Ethics approval and consent to participate

Subjects were accrued at Roswell Park Comprehensive Cancer Centre, Cleveland Clinic Taussig Cancer Institute and University Hospitals of Cleveland. The RPCI IRB approved the study protocol on 9 November 2012 (Study # I 229112), the University Hospitals of Cleveland IRB on 24 March 2014 (Study # RPCI 1213) and the Cleveland Clinic Taussig Cancer Institute IRB on 5 November 2014 (Study # 14-1373). The study was conducted according to the principles of the Declaration of Helsinki, the International Conference on Harmonisation and the Guidelines for Good Clinical Practice. All patients provided written informed consent. The trial was registered with (NCT01835223).

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Not applicable.

Data availability

Data can be available upon request.

Competing interests

C.F.: AstraZeneca (consultation, fees paid to institute, outside the scope of submitted work).

Funding information

This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Programme from general research support provided by AVEO Pharmaceuticals, Inc. This work was partially supported by grants from the National Cancer Institute (NCI) grant P30CA016056 involving the use of Roswell Park Comprehensive Cancer Centre’s Pathology Network Shared Resource and Bioanalytics, Metabolomics and Pharmacokinetics (BMPK) Shared Resource and the National Centre for Research Resources grant S10OD019977.

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Fountzilas, C., Gupta, M., Lee, S. et al. A multicentre phase 1b/2 study of tivozanib in patients with advanced inoperable hepatocellular carcinoma. Br J Cancer (2020).

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