A randomised phase II study of TSU-68 in patients with hepatocellular carcinoma treated by transarterial chemoembolisation

doi:10.1016/j.ejca.2013.05.011

European Journal of Cancer

Volume 49, Issue 13, September 2013, Pages 2832-2840

https://doi.org/10.1016/j.ejca.2013.05.011 Get rights and content

Abstract

Background

TSU-68 is an antitumour drug that acts by inhibiting angiogenesis. We evaluated the efficacy and safety of TSU-68 in combination with transarterial chemoembolisation (TACE) in patients with intermediate-stage hepatocellular carcinoma (HCC).

Patients and Methods

In this multicenter, open-label phase II study, we randomised patients with HCC who had been treated with a single session of TACE to receive either 200 mg TSU-68 twice daily or no medication. The primary end-point was progression-free survival (PFS).

Results

A total of 103 patients were enrolled. Median PFS was 157.0 days (95% confidence interval [CI], 124.0–230.0 days) in the TSU-68 group and 122.0 days (95% CI, 73.0–170.0 days) in the control group. The hazard ratio was 0.699 (95% CI, 0.450–1.088). Fatigue, elevated aspartate aminotransferase (AST), elevated alkaline phosphatase, oedema and anorexia were more frequent in the TSU-68 group than in the control group. The most frequent grade 3/4 adverse events were AST elevation (46% of patients in the TSU-68 group and 12% of controls) and alanine aminotransferase elevation (26% of patients in the TSU-68 group and 8% of controls). Two deaths, grade 5 hepatic failure and melena were noted in the TSU-68 group.

Conclusion

This exploratory study shows a trend towards prolonged PFS with TSU-68 treatment after a single session of TACE, but this observation was not statistically significant. The two deaths were related to the study treatment. These results suggest that further examination of the study design is necessary to determine whether TSU-68 has any clinical benefits when combined with TACE.

Introduction

Hepatocellular carcinoma (HCC) is the fifth-most common cancer, and its incidence is still increasing worldwide.¹ It is reported to be the third leading cause of cancer death, with about 560,000 cases diagnosed per year, more than 80% of which occur in developing countries. Infection with hepatitis B virus (HBV) accounts for 55% of global HCC and 80% of cases in the Asia Pacific and sub-Saharan African regions.² Infection with Hepatitis C virus (HCV) is the chief cause of HCC in industrialised countries.3, 4

Current treatments for HCC include hepatic resection, liver transplantation, radio frequency ablation (RFA), transarterial chemoembolisation (TACE) and chemotherapy. Other than sorafenib, there are no standard chemotherapy treatments for advanced-stage HCC;5, 6 accordingly, there is an urgent need to improve treatments and prevent recurrence or progression.

TACE is the most widely used standard treatment for unresectable HCC.7, 8, 9 However, the curative effect of TACE is limited, and most patients suffer intrahepatic recurrence. Numerous reports have indicated that angiogenesis is closely associated with tumour growth after TACE; therefore treatments that combine antiangiogenic agents with TACE are anticipated to contribute to improved treatment of HCC.

TSU-68 is a receptor tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet-derived growth factor receptor-β (PDGFR-β).10, 11, 12, 13, 14 In phase I/II study, TSU-68 showed favourable efficacy and a high safety profile in HCC patients who had been heavily pretreated,¹⁵ including those with Child–Pugh B cirrhosis.

We conducted a randomised phase II trial to assess the efficacy and safety of TSU-68 after TACE.

Section snippets

Eligibility criteria

Eligible patients were (1) diagnosed with HCC by histology/cytology or by radiography; (2) showed no indications for, or no response to, resection or locoregional therapies such as RFA; (3) were ⩾20 years of age; (4) had Eastern Cooperative Oncology Group performance status (ECOG PS) of ⩽2; (5) had HCC ⩽80 mm; (6) had target lesions that were all of the hypervascular and nodular type with a minimum size of 10 mm; (7) did not have any vascular invasion; (8) had no extrahepatic spread; (9) had

Patient characteristics

A total of 103 patients were enroled from 15th September 2006 to 14th November 2007. As shown in Fig. 1A and B, 52 patients were randomised into the TSU-68 group and 51 patients were randomised into the control group. The 52 patients in the TSU-68 group received treatment with the investigational drug and 50 were classified as FAS. Two patients in this group were excluded because they did not meet the eligibility criteria. The 51 patients in the control group were all eligible and were

Discussion

TACE is the standard treatment for unresectable HCC and is performed repeatedly for local recurrence and new intrahepatic lesions. However, there have been few studies that have reported the antitumour effects of TACE based on mRECIST or the improvement of TACE treatment by chemotherapeutic or molecular target agents.²¹

TSU-68 was initially thought to have a typical and high tolerability profile. During treatment, grade 3 or higher adverse events rarely occurred, with the exception of

Clinical trials

This study is registered with JAPIC Clinical Trial Information, number JapicCTI-101087.

Funding

This study was supported by Taiho Pharmaceutical Co., Ltd. (Study No. 10032080).

Conflict of interest statement

None declared.

Acknowledgements

We are grateful to Drs. Yutaka Ariyoshi, Tomohide Tamura and Yuh Sakata for their extramural review. This trial was supported by Taiho Pharmaceutical Co., Ltd.

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Multiple systemic agents have recently been approved in the first- and second-line setting for hepatocellular carcinoma (HCC), increasing the therapeutic options for patients and treating physicians. The randomised controlled trials that led to these approvals were predominantly conducted in a population comprised of patients with advanced HCC. However, these trials also included a subset of patients who had progressed after locoregional therapies (LRTs), mostly transarterial chemoembolisation. With a greater number of systemic agents available, the role of LRTs has become a topic of debate, specifically regarding when to transition to systemic therapy in unresectable HCC and the potential opportunities for combining locoregional and systemic therapies. Trials of immuno-oncology agents (notably T cell checkpoint inhibitors) are ongoing in the advanced disease setting and these agents also present opportunities for combination therapies, both with other systemic agents and with LRTs in earlier stage disease. This article will review strategies to guide patient selection for LRT as well as the development of locoregional-systemic combinations based on scientific rationale and the challenges of clinical trial design in this setting.
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Orantinib has shown preliminary efficacy and a good safety profile in advanced hepatocellular carcinoma.23,24 A phase 2 study showed that orantinib combined with a single TACE seemed to prolong progression-free survival, but this observation was not statistically significant, and overall survival did not improve.25 The adverse event profile of orantinib is different to other molecularly targeted agents; hand–foot syndrome and hypertension, which are frequently observed with sorafenib and brivanib, are rarely recorded with orantinib.
Orantinib is an oral multi-kinase inhibitor. This study was done to evaluate the efficacy of orantinib combined with conventional transcatheter arterial chemoembolisation (cTACE) in patients with unresectable hepatocellular carcinoma.
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A randomised phase II study of TSU-68 in patients with hepatocellular carcinoma treated by transarterial chemoembolisation

Abstract

Background

Patients and Methods

Results

Conclusion

Introduction

Section snippets

Eligibility criteria

Patient characteristics

Discussion

Clinical trials

Funding

Conflict of interest statement

Acknowledgements

Ann Hepatol

Lancet Oncol

Lancet

Hepatology

J Hepatol

Hepatol Res

Cancer Treat Rev

Lancet Oncol

Eur J Cancer

Eur J Cancer

Am J Gastroenterol

Global cancer statistics, 2002

CA Cancer J Clin

And hepatocellular carcinoma

Ann Hepatol

Viral hepatitis and liver cancer: the case of hepatitis C

Oncogene

Sorafenib in advanced hepatocellular carcinoma

N Engl J Med

Management of hepatocellular carcinoma

Hepatology

SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors

Cancer Res