Clinical trial NCT01135056: Study to Compare Selective Internal Radiation Therapy (SIRT) Versus Sorafenib in Locally Advanced Hepatocellular Carcinoma (HCC)
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)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Hepatocellular Carcinoma
Keywords: Hepatocellular Carcinoma
Randomized
Open-label
Multi-Centre
Phase III
Sorafenib
SIR-Spheres
Lead sponsor: Singapore General Hospital
Sponsor class: OTHER
Collaborators: name: National Cancer Centre, Singapore
name: National Medical Research Council (NMRC), Singapore
name: Singapore Clinical Research Institute
name: Sirtex Medical
First posted: 2010-06-02
Enrollment: 360
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of this study is to assess the efficacy of SIRT as compared with Sorafenib in patients with locally advanced liver cancer in terms of overall survival (OS).

The Study null hypothesis is, there is no difference in overall survival between patients receiving SIRT and those receiving Sorafenib therapy.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Disease must be locally advanced as defined by BCLC (B) intermediate stage or BCLC (C) advanced stage without extra-hepatic disease (only with branch portal vein thrombosis).
* Willing, able and mentally competent to provide written informed consent prior to any testing undertaken for this study protocol, including screening tests and evaluations that are not considered to be part of the subject's routine care.
* Aged 18 years/older (either gender).
* Unequivocal diagnosis of HCC.
* HCC not amenable to surgical resection or immediate liver transplantation, or cannot be optimally treated with local ablative techniques such as RFA, consistent with the practice of the clinical trial centre.
* Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with spiral CT scan or MRI.
* ECOG performance status 0-1.
* Child-Pugh A-B (up to 7 points)
* Adequate haematological, renal and hepatic function as follows:
* Leukocytes ≥ 2,500/μL
* Platelets ≥ 80,000/μL
* Haemoglobin \> 9.5g/dL
* Total bilirubin \< 2.0mg/dL
* INR ≤ 2.0
* ALP ≤ 5 x institutional ULN
* AST and ALT ≤ 5 x institutional ULN
* Albumin ≥ 2.5g/dL
* Creatinine ≤ 2.0mg/dL
* Life expectancy of at least 3 months without any active treatment.
* Suitable for protocol treatment as determined by clinical assessment undertaken by the Investigator.
* Female patients must be either postmenopausal or, if premenopausal, must have a negative pregnancy test and agree to use 2 forms of contraception if sexually active during their study participation.
* Male patients must be surgically sterile, or if sexually active and having a pre-menopausal female partner then must be using an acceptable form of contraception.

Exclusion Criteria:

* Have had more than 2 administrations of hepatic artery directed therapy.
* Subjects who have had hepatic artery directed therapy done \< 4 weeks prior to study entry.
* Have had systemic chemotherapy for HCC except for prior adjuvant or neoadjuvant therapy given more than 6 months from enrolment.
* have had prior treatment with Sorafenib or VEGF inhibitors.
* Prior hepatic radiation therapy for HCC or other malignancy.
* Currently receiving any other investigational agents for the treatment of their cancer.
* Has intractable clinical ascites (in spite of optimal diuretic treatment) or any other clinical signs of liver failure, on physical examination.
* Complete main portal vein thrombosis.
* Any metastatic disease (local-regional lymph nodes measuring less than 2 cm in greatest diameter or lung nodules measuring less than 1 cm are not contraindications as per Investigator discretion).
* Any other concurrent malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for at least 5 years.
* Presence of clinical signs of CNS metastases due to their poor prognosis and because progressive neurologic dysfunction would confound the evaluation of neurologic and other adverse events.
* Uncontrolled inter-current illness including, but not limited to, ongoing or active infection (except viral hepatitis), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Any of the following contraindications to angiography and selective visceral catheterization:
* Bleeding diathesis, not correctable by the standard forms of therapy.
* Severe peripheral vascular disease that would preclude arterial catheterization.
* Portal hypertension with hepato-fugal flow as documented on baseline spiral CT scan.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to SIR-Spheres or Sorafenib.
* Inability or unwillingness to understand or sign a written informed consent document.
* Female subjects who are pregnant or currently breastfeeding.
* Female subjects, unless postmenopausal or surgically sterile, unwillingness to practice effective contraception, as per Investigator discretion during the study. The rhythm method is not to be used as the sole method of contraception.
* Male subjects, unwillingness to practice effective contraception (per Investigator discretion) while taking part in this study, because the effect of the SIR-Spheres treatment on sperm or upon the development of an unborn child are unknown.
* Current enrolment in any other investigational therapeutic drug or device study.

Primary outcomes:
measure: Overall Survival
timeFrame: 2 years
Secondary outcomes:
measure: Progression free survival in the liver
timeFrame: 2 years
measure: Progression free survival overall
timeFrame: 2 years
measure: Tumour Response Rate
timeFrame: 2 years
measure: Toxicity and Safety
timeFrame: Up to 2 years
measure: Health Related Quality of Life (QoL)
timeFrame: Up to 2 years
measure: Liver resection rate
timeFrame: Up to 2 years
measure: Liver Transplantation Rate
timeFrame: Up to 2 years
measure: Time to Disease Progression
timeFrame: Up to 2 years
measure: Disease control rate
timeFrame: 2 years
Other outcomes:
Locations:
city: Jerudong
country: Brunei Darussalam
facility: The Brunei Cancer Centre
state: Brunei
city: Hong Kong
country: China
facility: Queen Mary Hospital
state: Hong Kong
city: Denpasar
country: Indonesia
facility: University of Udayana, Rumah Sakit Sanglah, Indonesia
state: Bali
city: Jakarta
country: Indonesia
facility: Cipto Mangunkusumo Hospital ,University of Indonesia
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University College of Medicine
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul St. Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Kuching
country: Malaysia
facility: Sarawak General Hospital
state: Sarawak
city: Kuala Lumpur
country: Malaysia
facility: University Malaya Medical Center
city: Penang
country: Malaysia
facility: Penang Adventist Hospital
city: Ulaanbaatar
country: Mongolia
facility: National Cancer Center of Mongolia
city: Yangon
country: Myanmar
facility: Yangon GI & Liver Centre
city: Grafton
country: New Zealand
facility: Auckland City Hospital
state: Auckland
city: Manila
country: Philippines
facility: Makati Medical Center
state: Makati City
city: Pasig City
country: Philippines
facility: The Medical City
state: Manila
city: Quezon City
country: Philippines
facility: St. Luke's Medical Center, Philippines
state: Manila
city: Davao
country: Philippines
facility: Davao Doctors Hospital
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Singapore
country: Singapore
facility: National Cancer Center Singapore
city: Singapore
country: Singapore
facility: Khoo Teck Puat Hospital
city: Taipei City
country: Taiwan
facility: National Taiwan University Hospital
state: Taipei
city: Taipei City
country: Taiwan
facility: Taipei Veterans General Hospital
state: Taipei
city: Taoyuan
country: Taiwan
facility: Chang Gung Memorial Hospital
state: Taoyuan Hsien
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Chang Gung Memorial Hospital
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Bangkok
country: Thailand
facility: Chulabhorn Hospital
Study officials:
affiliation: National Cancer Centre, Singapore
name: Pierce KH Chow, MBBS, PhD
role: STUDY_CHAIR
References:
citation: Chow PKH, Gandhi M, Tan SB, Khin MW, Khasbazar A, Ong J, Choo SP, Cheow PC, Chotipanich C, Lim K, Lesmana LA, Manuaba TW, Yoong BK, Raj A, Law CS, Cua IHY, Lobo RR, Teh CSC, Kim YH, Jong YW, Han HS, Bae SH, Yoon HK, Lee RC, Hung CF, Peng CY, Liang PC, Bartlett A, Kok KYY, Thng CH, Low AS, Goh ASW, Tay KH, Lo RHG, Goh BKP, Ng DCE, Lekurwale G, Liew WM, Gebski V, Mak KSW, Soo KC; Asia-Pacific Hepatocellular Carcinoma Trials Group. SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma. J Clin Oncol. 2018 Jul 1;36(19):1913-1921. doi: 10.1200/JCO.2017.76.0892. Epub 2018 Mar 2.
citation: Gandhi M, Choo SP, Thng CH, Tan SB, Low AS, Cheow PC, Goh AS, Tay KH, Lo RH, Goh BK, Wong JS, Ng DC, Soo KC, Liew WM, Chow PK; Asia-Pacific Hepatocellular Carcinoma Trials Group. Single administration of Selective Internal Radiation Therapy versus continuous treatment with sorafeNIB in locally advanced hepatocellular carcinoma (SIRveNIB): study protocol for a phase iii randomized controlled trial. BMC Cancer. 2016 Nov 7;16(1):856. doi: 10.1186/s12885-016-2868-y.