Adult Primary Hepatocellular CarcinomaPhase 3NCT01730937
Sorafenib Tosylate With or Without Stereotactic Body Radiation Therapy in Treating Patients With Liver Cancer
A Phase 3 study testing Sorafenib and stereotactic body radiation therapy in people with Adult Primary Hepatocellular Carcinoma and Advanced Adult Primary Liver Cancer, run by Radiation Therapy Oncology Group at 51 sites in 5 countries.
Trial summary
This randomized phase III trial studies sorafenib tosylate and stereotactic body radiation therapy to see how well they work compared to sorafenib tosylate alone in treating patients with liver cancer. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer
- What is being tested?
- Sorafenib and stereotactic body radiation therapy
- Type of treatment
- Pill or oral medicine, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 193 participants
- Where
- 51 sitesin 5 countries
- Study dates
- Apr 2013to 4 Sep 2025
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients must have a diagnosis of HCC by at least one criterion listed below within 360 days prior to study entry:
- Pathologically (histologically or cytologically) proven diagnosis of HCC,(biopsies are recommended, and are to be submitted for research evaluation if patients consent)
- At least one solid liver lesion or vascular tumor thrombosis (involving portal vein, inferior vena cava (IVC) and/or hepatic vein) > 1 cm with arterial enhancement and delayed washout on multi-phasic computerized tomography (CT) or magnetic resonance imaging (MRI) in the setting of cirrhosis or chronic hepatitis B or C without cirrhosis.
- For patients whose CURRENT disease is vascular only: enhancing vascular thrombosis (involving portal vein, IVC and/or hepatic vein) demonstrating early arterial enhancement and delayed washout on multi-phasic CT or MRI in a patient with known HCC (diagnosed previously <720 days) using the above criteria.
- Measureable hepatic disease and/or presence of vascular tumor thrombosis (involving portal vein, IVC and/or hepatic vein) which may not be measureable as per Response Evaluation Criteria in Solid Tumors (RECIST) on liver CT or MRI, within 28 days of registration
- Appropriate for protocol entry based upon the following minimum diagnostic workup:
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- History/physical examination including examination for encephalopathy, ascites, weight, height, and blood pressure within 14 days prior to study entry
- Assessment by radiation oncologist and medical oncologist or hepatologist who specializes in treatment of HCC within 28 days prior to study entry
- Pre-randomization Scan (REQUIRED for All Patients): Within 28 days prior to study entry, multiphasic liver CT or multiphasic liver MR scan.
- Within 28 days prior to study entry CT chest with CT or MR abdomen and CT or MR pelvis, or positron emission tomography (PET) CT chest/abdomen/pelvis.
- Zubrod performance status 0-2 within 28 days prior to study entry
- All blood work obtained within 14 days prior to study entry with adequate organ marrow function defined as follows:
- Absolute neutrophil count (ANC) >= 1,500 cells/mm^3
- Platelets >= 60,000 cells/mm^3
- Hemoglobin >= 8.0 g/dl (note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 6 times upper limit of normal (ULN)
- Serum creatinine =< 2 x ULN or creatinine clearance >= 60 mL/min
- Barcelona Clinic Liver Cancer (BCLC) stage: intermediate (B) or advanced (C) within 28 days prior to study entry
- Child-Pugh score A within 14 days prior to study entry
- Women of childbearing potential and male participants must agree to practice adequate contraception while on study and for at least 6 months following the last dose of radiation therapy (RT) and for at least 28 days following the last dose of sorafenib (whichever is later)
- Unsuitable for resection or transplant or radiofrequency ablation (RFA)
- Unsuitable for or refractory to transarterial hepatic chemo-embolization (TACE) or drug eluting beads (DEB) for any of the following reasons, as described by Raoul et al (2011):
- Technical contraindications: arteriovenous fistula, including, surgical portosystemic shunt or spontaneous portosystemic shunt
- Severe reduction in portal vein flow: due to tumor portal vein, IVC or atrial invasion or bland portal vein occlusion
- Medical contraindications including congestive heart failure, angina, severe peripheral vascular disease
- Presence of extrahepatic disease
- No response post TACE (or DEB) or progressive HCC despite TACE; prior TACE or DEB is allowed but must be > 28 days from study entry
- Serious toxicity following prior TACE (or DEB); prior TACE or DEB must be > 28 days from study entry
- Other medical comorbidities making TACE (or DEB) unsafe and/or risky (e.g. combination of relative contraindications including age > 80 years, tumor > 10 cm, > 50% replacement of the liver by HCC, extensive multinodular bilobar HCC, biliary drainage)
- Patients treated with prior surgery are eligible for this study if they otherwise meet eligibility criteria
- Patient must be able to provide study-specific informed consent prior to study entry
Who cannot join
- Prior invasive malignancy (except non-melanomatous skin cancer and T1 renal cell carcinoma) unless disease free for a minimum of 2 years (note that carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
- Prior sorafenib use > 60 days and/or grade 3 or 4 sorafenib related toxicity. Note that prior chemotherapy for HCC or a different cancer is allowable
- Prior radiotherapy to the region of the liver that would result in overlap of radiation therapy fields
- Prior selective internal radiotherapy/hepatic arterial yttrium therapy, at any time
- Severe, active co-morbidity, defined as follows:
- Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months PRIOR TO registration
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- Transmural myocardial infarction within the last 6 months prior to study entry
- Unstable ventricular arrhythmia within the last 6 months prior to study entry
- Acute bacterial or fungal infection requiring intravenous antibiotics within 28 days prior to study entry
- Hepatic insufficiency resulting in clinical jaundice, encephalopathy and/or variceal bleed within 28 days prior to study entry
- Bleeding within 28 days prior to study entry due to any cause, requiring transfusion
- Thrombolytic therapy within 28 days prior to study entry. Subcutaneous heparin is permitted.
- Known bleeding or clotting disorder
- Uncontrolled psychotic disorder
- Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic
- Maximal diameter of any one hepatocellular carcinoma > 15 cm
- Total sum of maximum diameters of each definite parenchymal hepatocellular carcinoma within the liver or maximum diameter of a single conglomerate HCC > 20 cm
- More than 5 discrete intrahepatic parenchymal foci of HCC
- Direct tumor extension into the stomach, duodenum, small bowel or large bowel
- Measureable common or main branch biliary duct involvement with HCC
- Extrahepatic metastases or malignant nodes (that enhance with typical features of HCC) > 3.0 cm, in sum of maximal diameters (e.g. presence of one 3.4 cm metastatic lymph node or two 2 cm lung lesions); note that benign non-enhancing periportal lymphadenopathy is not unusual in the presence of hepatitis and is permitted, even if the sum of enlarged nodes is > 2.0 cm
- Prior liver transplant
- HIV positive with CD4 (T-cell count) count < (350) cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ (350) cells/microliter, and no known detectable viral load, at the time of study entry. Note also that HIV testing is not required for eligibility for this protocol
Trial locations and contacts
51 sites in 5 countries.
51 sites in 5 countries
United States41 sites
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, 48109
University of Colorado Hospital
Aurora, Colorado, 80045
University of Maryland/Greenebaum Cancer Center
Baltimore, Maryland, 21201
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, 21287
Alta Bates Summit Medical Center-Herrick Campus
Berkeley, California, 94704
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, 02114
Boston Medical Center
Boston, Massachusetts, 02118
Saint Vincent's Medical Center
Bridgeport, Connecticut, 06606
University of Vermont Medical Center
Burlington, Vermont, 05401
Northwestern University
Chicago, Illinois, 60611
University of Illinois
Chicago, Illinois, 60612
Case Western Reserve University
Cleveland, Ohio, 44106
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
Decatur Memorial Hospital
Decatur, Illinois, 62526
Iowa Methodist Medical Center
Des Moines, Iowa, 50309
Penn State Milton S Hershey Medical Center
Hershey, Pennsylvania, 17033-0850
Queen's Medical Center
Honolulu, Hawaii, 96813
M D Anderson Cancer Center
Houston, Texas, 77030
Indiana University/Melvin and Bren Simon Cancer Center
Indianapolis, Indiana, 46202
University of Mississippi Medical Center
Jackson, Mississippi, 39216
USC / Norris Comprehensive Cancer Center
Los Angeles, California, 90033
Loyola University Medical Center
Maywood, Illinois, 60153
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, 33136
Froedtert and the Medical College of Wisconsin
Milwaukee, Wisconsin, 53226
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, 08903
Ochsner Medical Center Jefferson
New Orleans, Louisiana, 70121
Columbia University/Herbert Irving Cancer Center
New York, New York, 10032
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
University of Pennsylvania/Abramson Cancer Center
Philadelphia, Pennsylvania, 19104
Providence Portland Medical Center
Portland, Oregon, 97213
Hunter Holmes McGuire Veterans Administration Medical Center
Richmond, Virginia, 23249
University of Rochester
Rochester, New York, 14642
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, 84112
UCSF Medical Center-Mount Zion
San Francisco, California, 94115
UCSF Medical Center-Mission Bay
San Francisco, California, 94158
ProCure Proton Therapy Center-Seattle
Seattle, Washington, 98133
University of Washington Medical Center
Seattle, Washington, 98195
Washington University School of Medicine
St Louis, Missouri, 63110
Stony Brook University Medical Center
Stony Brook, New York, 11794
Montefiore Medical Center - Moses Campus
The Bronx, New York, 10467
Northwestern Medicine Cancer Center Warrenville
Warrenville, Illinois, 60555
Canada7 sites
Tom Baker Cancer Centre
Calgary, Alberta, T2N 4N2
Juravinski Cancer Centre at Hamilton Health Sciences
Hamilton, Ontario, L8V 5C2
London Regional Cancer Program
London, Ontario, N6A 4L6
CHUM - Hopital Notre-Dame
Montreal, Quebec, H2L 4M1
CHUM - Centre Hospitalier de l'Universite de Montreal
Montreal, Quebec, H2X 3E4
The Research Institute of the McGill University Health Centre (MUHC)
Montreal, Quebec, H3H 2R9
University Health Network-Princess Margaret Hospital
Toronto, Ontario, M5G 2M9
About this study
Official title: Randomized Phase III Study of Sorafenib Versus Stereotactic Body Radiation Therapy Followed by Sorafenib in Hepatocellular Carcinoma
This randomized phase III trial studies sorafenib tosylate and stereotactic body radiation therapy to see how well they work compared to sorafenib tosylate alone in treating patients with liver cancer. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Stereotactic body radiation therapy may be able to send the radiation dose directly to the tumor and cause less damage to normal tissue. Giving sorafenib tosylate together with stereotactic body radiation therapy may kill more tumor cells.
Read the detailed description
PRIMARY OBJECTIVES:
- To determine if stereotactic body radiation therapy (SBRT) improves overall survival in hepatocellular carcinoma (HCC) patients treated with sorafenib (sorafenib tosylate).
SECONDARY OBJECTIVES:
- To determine the difference in time to progression (TTP) and progression-free survival (PFS) in HCC patients treated with sorafenib compared to SBRT followed by sorafenib.
II. To measure differences in toxicity in HCC patients treated with sorafenib versus SBRT followed by sorafenib.
III. To measure vascular thrombosis response post sorafenib versus SBRT followed by sorafenib.
IV. To measure differences in health related quality of life (QOL) and quality-adjusted survival in HCC patients treated with sorafenib compared to SBRT followed by sorafenib.
- Collection of biospecimens for future correlative studies to investigate differences in potential biomarkers in patients treated with sorafenib versus SBRT followed by sorafenib.
- Conditions
- Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer
- Being tested
- Sorafenib, stereotactic body radiation therapy
- Medical subject headings
- Carcinoma, Hepatocellular
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SorafenibDrug
Also called BAY 43-9006, BAY 43-9006 Tosylate Salt, BAY 54-9085, Nexavar
By mouth (PO)
stereotactic body radiation therapyRadiation
Also called SBRT, stereotactic radiation therapy, stereotactic radiotherapy, stereotactic ablative body radiation therapy,
Intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and proton therapy are allowed.
| Study group | Role | What they receive |
|---|---|---|
| Sorafenib Alone | Active comparator | 400 mg sorafenib twice a day for 28-day cycle. Continue up to 5 years in the absence of disease progression or unacceptable toxicity. Receives: Drug: Sorafenib |
| SBRT followed by Sorafenib | Experimental | 27.5 Gy to 50 Gy stereotactic body radiation therapy (SBRT) in 5 fractions 24-72 hours apart over 5-15 days followed within 1-5 days by one cycle of 200 mg sorafenib twice a day. Starting with second cycle, if tolerable, increase to 400 mg sorafenib twice a day. Continue up to 5 years in the absence of disease progression or unacceptable toxicity. Receives: Drug: Sorafenib; Radiation: stereotactic body radiation therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall Survival
An event for overall survival (OS) is death due to any cause. Survival time is defined as time from randomization to the date of death or last known follow-up (censored). Rates are estimated by the Kaplan-Meier method. Analysis was to occur after 153 deaths were reported.
Measured: From randomization to last follow-up: weekly during SBRT, post-SBRT/pre-sorafenib, monthly during sorafenib, and overall, from study entry: every 3 months for 2 years, then every 6 months. Maximum follow-up at time of analysis was 7.6 years.
Secondary outcomes (6)
Time to Progression
Progression (failure) is defined as any of the following events: new tumor thrombosis, progression of hepatocellular carcinoma (HCC) within liver excluding tumor thrombosis status, progression of distant metastases that were present at study entry, new HCC within the liver including tumor thrombosis, and vascular thrombosis events=progression-new enhancing tumor thrombosis/progression-Increase in the volume of enhancing portion of thrombosis. Time to progression was measured from the date of randomization to the date of first failure, death (competing risk), or last follow-up (censored). Progression rates are estimated by the cumulative incidence method. The protocol specifies only that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided as a summary of the distributions.
Measured: From randomization to last follow-up: weekly during SBRT, post-SBRT/pre-sorafenib, monthly during sorafenib, and overall, from study entry: every 3 months for 2 years, then every 6 months. Maximum follow-up at time of analysis was 7.6 years.
Progression-free Survival
Failure for progression-free survival (PFS) include death, new tumor thrombosis, progression of hepatocellular carcinoma (HCC) within liver excluding tumor thrombosis status, progression of distant Mets that were present at study entry, new HCC within liver including tumor thrombosis, and vascular thrombosis events =progression-new enhancing tumor thrombosis/progression-Increase in the volume of enhancing portion of thrombosis. PFS time is defined as the time from randomization to the date of first failure, date of death, or last known follow-up (censored). PFS rates are estimated by the Kaplan-Meier method. The protocol specifies only that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided as a summary of the distributions.
Measured: From randomization to last follow-up: weekly during SBRT, post-SBRT/pre-sorafenib, monthly during sorafenib, and overall, from study entry: every 3 months for 2 years, then every 6 months. Maximum follow-up at time of analysis was 7.6 years.
Number of Participants by Highest Grade Adverse Event Reported
Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Measured: From randomization to last follow-up: weekly during SBRT, post-SBRT/pre-sorafenib, monthly during sorafenib, and overall, from study entry: every 3 months for 2 years, then every 6 months. Maximum follow-up at time of analysis was 7.6 years.
Percentage of Participants With Improvement in the Functional Assessment of Cancer Therapy - Hepatobiliary (FACT-Hep) Total Score 6 Months After the Start of Treatment
The FACT-Hep total score measures quality of life in patients with hepatobiliary cancer. Possible scores range from 0 to 180, with higher scores indicating a better outcome. Improvement in FACT-Hep total score is defined as an increase from the baseline to 6-month score of at least 5 points.
Measured: Baseline and 6 months
Best Vascular Thrombosis Response up to the Time of Progressive Disease (if Applicable)
Complete response: Complete resolution of thrombosis, with recanalization of vessel.
Partial response (PR):
- Partial recanalization (if prior complete blockage)
- Unequivocal reduction in the maximal girth
- Unequivocal reduction in the volume, or elimination, of arterial enhancing portion
Progressive disease (PD): any unequivocal, unambiguous
- New enhancing tumor thrombosis
- Increase in the volume of enhancing portion
- Unequivocal progression of thrombosis (non-measurable disease), the increase in overall tumor burden (enhancing thrombosis) must be comparable to the increase required for the Response Evaluation Criteria in Solid Tumor 1.1 definition of PD of measurable disease (e.g. ≥ 73% increase in volume, which is similar to 20% increase in diameter, and at least a 5 mm absolute increase).
Stable disease:
- No/small changes that do not meet the above criteria for PR or PD
- Increase in the volume of non-enhancing thrombosis
- New bland non-enhancing thrombosis
Measured: From randomization to last follow-up. Imaging occurs every 3 months for two years then every six months. Maximum follow-up at time of analysis was 7.6 years.
Quality Adjusted Life Years
Quality adjusted life years is calculated as the weighted sum of the number of years spent in different health states. The weight value is a utility score between 0 (worst health state) and 1 (best health state) derived from the EQ-5D-5L questionnaire, designed to describe and value health based on mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
Measured: The EQ-5D-5L is administered at baseline, six months and one year.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Nov 2012 (estimated)
- Study startApr 2013
- Primary completion1 Jul 2022
- Study completion4 Sep 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Adult Primary Hepatocellular CarcinomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 193 participants (actual)
Sponsor and investigators
- Lead sponsor
- Radiation Therapy Oncology Group
- Sponsor type
- Research network
- Collaborators
- National Cancer Institute (NCI), NRG Oncology
- Responsible party
- Sponsor
- Investigators
- Laura Dawson, Principal investigator, Radiation Therapy Oncology Group
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01730937
- Sponsor's protocol ID
- RTOG-1112
- Other IDs
- NCI-2012-02057, U10CA021661
- Status last verified
- Sep 2025
- First submitted
- 15 Nov 2012
- Last updated
- 28 Jan 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Dawson LA, Winter KA, Knox JJ, Zhu AX, Krishnan S, Guha C, Kachnic LA, Gillin MT, Hong TS, Craig TD, Williams TM, Hosni A, Chen E, Noonan AM, Koay EJ, Sinha R, Lock MI, Ohri N, Dorth JA, Delouya G, Swaminath A, Moughan J, Crane CH. Stereotactic Body Radiotherapy vs Sorafenib Alone in Hepatocellular Carcinoma: The NRG Oncology/RTOG 1112 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2025 Feb 1;11(2):136-144. doi: 10.1001/jamaoncol.2024.5403.
PubMed 39699905