Intra-Arterial TheraSphere Yttrium-90 Glass Microspheres in the Treatment of Patients With Unresectable Hepatocellular Carcinoma: Protocol for the STOP-HCC Phase 3 Randomized Controlled Trial

Nikhil Chauhan, Janet Bukovcan, Eveline Boucher, David Cosgrove, Julien Edeline, Bonnie Hamilton, Laura Kulik, Fayaz Master, Riad Salem, Nikhil Chauhan, Janet Bukovcan, Eveline Boucher, David Cosgrove, Julien Edeline, Bonnie Hamilton, Laura Kulik, Fayaz Master, Riad Salem

Abstract

Background: Globally, hepatocellular carcinoma is the second most common cause of cancer deaths. It remains challenging to intensify cancer treatment without impairing liver function.

Objective: The objective of the TheraSphere in the Treatment of Patients with Unresectable Hepatocellular Carcinoma (STOP-HCC) study is to examine the hypothesis that transarterial radioembolization (TheraSphere yttrium-90 glass microspheres) combined with standard first-line treatment with sorafenib will improve outcomes over treatment with sorafenib alone in unresectable hepatocellular carcinoma. The STOP-HCC study is the largest international, multicenter, prospective study of intra-arterial treatment in combination with sorafenib in unresectable hepatocellular carcinoma. Here we report the study design.

Methods: STOP-HCC is a prospective, phase 3, open-label, randomized controlled study conducted across up to 105 sites in North America, Europe, and Asia. Eligible adults have unresectable hepatocellular carcinoma and a life expectancy of at least 12 weeks, 1 or more unidimensional measurable lesions, Child-Pugh score 7 points or less, and Eastern Cooperative Oncology Group Performance Status score 1 or lower, and are candidates for treatment with sorafenib. Presence of branch portal vein tumor thrombosis is permitted. Patients were randomly assigned in a 1:1 ratio to receive either sorafenib alone or transarterial radioembolization followed by sorafenib within 2 to 6 weeks. The primary outcome is overall survival. Secondary outcomes are time to progression, time to untreatable progression, time to symptomatic progression, tumor response, quality of life, and adverse event occurrence. The study is an adaptive trial, comprising a group-sequential design with 2 interim analyses with 520 patients, and an option to increase the sample size to 700 patients at the second interim analysis. The sample size of 520 patients allows for 417 deaths to give 80% power to detect an increase in median overall survival from 10.7 months for the sorafenib group (based on the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol [SHARP] trial) to 14.2 months for the transarterial radioembolization+sorafenib group (hazard ratio 0.754) with 2-sided alpha of .05. The increased sample size of 700 patients allows for 564 deaths to give 80% power to detect a smaller difference in median overall survival from 10.7 months for the sorafenib group to 13.7 months for the transarterial radioembolization+sorafenib group (hazard ratio 0.781).

Results: Enrollment for the study completed in September 2017. Results of the first and second interim analyses were reviewed by the Independent Data Monitoring Committee. The recommendation of the committee, at both interim analyses, was to continue the study without any changes.

Conclusions: The STOP-HCC study will contribute toward the establishment of the role of combination therapy with transarterial radioembolization and sorafenib in the treatment of unresectable hepatocellular carcinoma with and without branch portal vein tumor thrombosis.

Trial registration: ClinicalTrials.gov NCT01556490; https://ichgcp.net/clinical-trials-registry/NCT01556490 (Archived by WebCite at http://www.webcitation.org/7188iygKs).

Registered report identifier: RR1-10.2196/11234.

Keywords: carcinoma, hepatocellular; clinical trial, phase III; hepatocellular carcinoma; microspheres; randomized controlled trial; research design; sorafenib; yttrium radioisotopes.

Conflict of interest statement

Conflicts of Interest: This study was sponsored by Biocompatibles UK Ltd, a BTG International Group Company. The sponsor was involved in the design of the study. The sponsor funded professional medical writers for the writing of the manuscript. All authors met International Committee of Medical Journal Editors authorship criteria. NC, JB, EB, BH, and FM are employed by BTG International Group Companies; NC and BH own company stock. JE received research grants from and acted as a consultant for BTG. DC was compensated for work on a speakers’ bureau for BTG and advisory board for Bristol-Myers Squibb. LK has been compensated for work on advisory boards for Bristol-Myers Squibb, Bayer, Gilead Sciences, and Eisai and as a nonpromotional speaker for BTG. RS receives research grant funding from and is a consultant to BTG.

©Nikhil Chauhan, Janet Bukovcan, Eveline Boucher, David Cosgrove, Julien Edeline, Bonnie Hamilton, Laura Kulik, Fayaz Master, Riad Salem. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 15.08.2018.

Figures

Figure 1
Figure 1
Clinical trial schema for the TheraSphere in the Treatment of Patients with Unresectable Hepatocellular Carcinoma (STOP-HCC) study. TARE: transarterial radioembolization; TS: TheraSphere microspheres.

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