Study to Compare Selective Internal Radiation Therapy (SIRT) Versus Sorafenib in Locally Advanced Hepatocellular Carcinoma (HCC)
The primary objective of this study is to determine a difference, if any, in overall survival between SIRT and Sorafenib.
The Study null hypothesis is, there is no difference in overall survival between patients receiving SIRT and those receiving Sorafenib therapy.
Drug: Sorafenib tosylate
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase III Multi-Centre Open-Label Randomized Controlled Trial of Selective Internal Radiation Therapy (SIRT) Versus Sorafenib in Locally Advanced Hepatocellular Carcinoma (SIRveNIB)|
- Overall Survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]Overall Survival is defined as the time from the date of randomisation to the date of death due to any cause. All patients will be followed up until death to compare the overall survival between the two treatments. 2 years is an estimated time frame.
- Progression free survival in the liver [ Time Frame: 2 years ] [ Designated as safety issue: No ]Progression-free survival in the liver is defined as the time interval between randomisation and the date of tumour progression in the liver or death, whichever is earlier. Tumour progression in the liver will be determined from serial CT scans. Diagnosis of tumour progression of disease should be made using the RECIST guideline version 1.1. 2 years is an estimated time frame.
- Progression free survival at any site [ Time Frame: 2 years ] [ Designated as safety issue: No ]
Progression-free survival at any site is defined as the time interval between randomisation and the date of tumour progression at any site in the body or death, whichever is earlier. Tumour progression at any site in the body will be measured by any definitive imaging technique including CT scan, MRI study or other nuclear medicine scan. The Investigator should clearly indicate the site of tumour progression (hepatic or extra-hepatic) at the time of recurrence.
2 years is an estimated time frame.
- Tumour Response Rate (Liver +/- any sites) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
Tumour response and progression will be evaluated in this study using the new response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) [European Journal of Cancer (45): 228 - 247, 2009] (http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf).
2 years is an estimated time frame
- Toxicity and Safety [ Time Frame: up to 2 years ] [ Designated as safety issue: Yes ]Toxicity will be assessed using the National Cancer Institute Common Terminology Criteria (NCI-CTC) version 4.02. Patients for both treatment arms will be followed-up for safety and toxicity from the time of study entry (randomisation day) until 30 days post study conclusion or until commencement of the next alternative therapy, which ever is earlier.
- Quality of Life (QoL) [ Time Frame: up to 2 years ] [ Designated as safety issue: No ]Quality of life (QoL) will be measured by using the EQ-5D questionnaire. QoL for patients will be measured until their first disease progression up to 2 years (estimated) which ever is earlier.
- Liver resection rate [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]Patients will be assessed for suitability for liver resection every 12 weekly until their study conclusion up to 2 years which ever is earlier.
- Liver Transplantation Rate [ Time Frame: up to 2 years ] [ Designated as safety issue: No ]Patients will be assessed for suitability for liver transplantation every 12 weekly until their study conclusion up to 2 years which ever is earlier.
- Time to Disease Progression [ Time Frame: up to 2 years ] [ Designated as safety issue: No ]Time to Disease Progression (TTP) is defined as a measure of time after a disease is diagnosed (or treated) until the disease starts to get worse. Disease Progression will be measured by RECIST guideline version 1.1. TTP will be measured every 12 weekly up to 2 years (estimated).
|Study Start Date:||July 2010|
|Estimated Study Completion Date:||July 2015|
|Estimated Primary Completion Date:||July 2015 (Final data collection date for primary outcome measure)|
Active Comparator: Sorafenib, Multikinase Inhibitor, Tablet
Sorafenib is a multikinase inhibitor that decreases tumor cell proliferation.
Sorafenib was shown to inhibit multiple intracellular (c-CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT- 3, RET, VEGFR-1, VEGFR- 2, VEGFR- 3, and PDGFR- ß). Several of these kinases are thought to be involved in tumor cell signaling, angiogenesis and apoptosis. Sorafenib inhibited tumor growth of the human hepatocellular carcinoma and renal cell carcinoma, and several other human tumor xenografts in immunocompromised mice. A reduction in tumor angiogenesis and increases in tumor apoptosis was seen in models of human hepatocellular and renal cell carcinoma. Additionally a reduction in tumor cell signaling was seen in a model of human hepatocellular carcinoma.
Drug: Sorafenib tosylate
Oral Tablet, 400mg B.i.d, until progression or unacceptable toxicity develops
Other Name: Nexavar
Active Comparator: SIR-Spheres, Microspheres, Device
SIR-Spheres consist of biocompatible resin microspheres containing yttrium-90, with a size between 20 and 60 microns in diameter. Yttrium-90 is a high-energy pure beta-emitting isotope with no primary gamma emission. The half life of yttrium-90 is 64.1 hours. In clinical use which requires the isotope to decay to infinity, 94% of the radiation is delivered in 11 days leaving only background radiation with no therapeutic value.
SIR-Spheres is implanted into hepatic tumours by delivery via either the common hepatic artery or the right or left hepatic artery using a catheter or implanted port . Once SIR-Spheres is implanted into the liver, it is not metabolised or excreted and it stays permanently in the liver.
One time treatment. Dose administered based on tumour volume. Each vial is 3.0GBq.
Other Name: Yttrium-90 Microspheres
Hepatocellular carcinoma (HCC) is the 5th most common cancer worldwide but unfortunately between 70 - 80% of all HCC are in the Asia-Pacific because of the prevalence of chronic viral hepatitis in the region. The increase in the prevalence of chronic hepatitis C in the Western world however predicts that HCC will similarly be an important cause of death there in the next 20 years.
Only 15-20% of HCC are today potentially curable by surgery at the time of diagnosis. Another 10-15% of patients may benefit from potentially curative locally ablative therapy such as radio-frequency ablation. Prognosis in the majority of patients has been dismal as conventional systemic therapies have been largely inefficacious. The first successfully trialed systemic targeted therapy, sorafenib (2007) prolonged survival by a modest average of 3 months in patients with good underlying liver function.
While the liver is radio-sensitive, external beam radiation causes significant radio-toxicity. To overcome this, selective internal radiation therapy (SIRT) was developed to deliver a radiation source directly to liver cancer via the arterial route. Sir-sphere is radioactive yttrium on a 90 micro-meter diameter resin carrier and is an established therapy in colorectal metastasis. Sir-sphere has been reported to cause significantly tumour regression in HCC.
This study will evaluate the efficacy of SIRT using SIR-Spheres yttrium-90 microspheres compared to sorafenib in the treatment of patients with locally advanced primary HCC.
|Contact: Pierce KH Chow, MBBS, PhD||+65 6321 firstname.lastname@example.org|
|Contact: Sophie Elizabeth Moss||+65 6508 email@example.com|
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|Study Chair:||Pierce KH Chow, MBBS, PhD||Singapore General Hospital|