Sorafenib Tosylate With or Without Stereotactic Body Radiation Therapy in Treating Patients With Liver Cancer

NCT ID: NCT01730937

Last Updated: 2025-10-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 193 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-04-30
• Study Completion Date: 2025-09-04

Brief 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. 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.

Detailed Description

PRIMARY OBJECTIVES:

I. To determine if stereotactic body radiation therapy (SBRT) improves overall survival in hepatocellular carcinoma (HCC) patients treated with sorafenib (sorafenib tosylate).

SECONDARY OBJECTIVES:

I. 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.

V. 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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Sorafenib Alone

400 mg sorafenib twice a day for 28-day cycle. Continue up to 5 years in the absence of disease progression or unacceptable toxicity.

Group Type: ACTIVE_COMPARATOR

Sorafenib

Intervention Type: DRUG

By mouth (PO)

SBRT followed by Sorafenib

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.

Group Type: EXPERIMENTAL

Sorafenib

Intervention Type: DRUG

By mouth (PO)

stereotactic body radiation therapy

Intervention Type: RADIATION

Intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and proton therapy are allowed.

Interventions

Sorafenib

By mouth (PO)

Intervention Type: DRUG

stereotactic body radiation therapy

Intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and proton therapy are allowed.

Intervention Type: RADIATION

Other Intervention Names

BAY 43-9006; BAY 43-9006 Tosylate Salt; BAY 54-9085; Nexavar; SFN; Sorafenib Tosylate; SBRT; stereotactic radiation therapy; stereotactic radiotherapy; stereotactic ablative body radiation therapy,; stereotactic ablative radiotherapy; SABR

Eligibility Criteria

Inclusion Criteria

• 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:

• 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

Exclusion Criteria

• 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
• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

NRG Oncology

OTHER

Sponsor Role: collaborator

Radiation Therapy Oncology Group

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Laura Dawson

Role: PRINCIPAL_INVESTIGATOR

Radiation Therapy Oncology Group

Locations

Alta Bates Summit Medical Center-Herrick Campus

Berkeley, California, United States

USC / Norris Comprehensive Cancer Center

Los Angeles, California, United States

UCSF Medical Center-Mount Zion

San Francisco, California, United States

UCSF Medical Center-Mission Bay

San Francisco, California, United States

University of Colorado Hospital

Aurora, Colorado, United States

Saint Vincent's Medical Center

Bridgeport, Connecticut, United States

University of Miami Miller School of Medicine-Sylvester Cancer Center

Miami, Florida, United States

Queen's Medical Center

Honolulu, Hawaii, United States

Northwestern University

Chicago, Illinois, United States

University of Illinois

Chicago, Illinois, United States

Decatur Memorial Hospital

Decatur, Illinois, United States

Loyola University Medical Center

Maywood, Illinois, United States

Northwestern Medicine Cancer Center Warrenville

Warrenville, Illinois, United States

Indiana University/Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, United States

Iowa Methodist Medical Center

Des Moines, Iowa, United States

Ochsner Medical Center Jefferson

New Orleans, Louisiana, United States

University of Maryland/Greenebaum Cancer Center

Baltimore, Maryland, United States

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, United States

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, United States

Boston Medical Center

Boston, Massachusetts, United States

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, United States

University of Mississippi Medical Center

Jackson, Mississippi, United States

Washington University School of Medicine

St Louis, Missouri, United States

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, United States

Columbia University/Herbert Irving Cancer Center

New York, New York, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

University of Rochester

Rochester, New York, United States

Stony Brook University Medical Center

Stony Brook, New York, United States

Montefiore Medical Center - Moses Campus

The Bronx, New York, United States

Case Western Reserve University

Cleveland, Ohio, United States

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States

Providence Portland Medical Center

Portland, Oregon, United States

Penn State Milton S Hershey Medical Center

Hershey, Pennsylvania, United States

University of Pennsylvania/Abramson Cancer Center

Philadelphia, Pennsylvania, United States

M D Anderson Cancer Center

Houston, Texas, United States

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, United States

University of Vermont Medical Center

Burlington, Vermont, United States

Hunter Holmes McGuire Veterans Administration Medical Center

Richmond, Virginia, United States

ProCure Proton Therapy Center-Seattle

Seattle, Washington, United States

University of Washington Medical Center

Seattle, Washington, United States

Froedtert and the Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Peter MacCallum Cancer Centre

Melbourne, Victoria, Australia

Tom Baker Cancer Centre

Calgary, Alberta, Canada

Juravinski Cancer Centre at Hamilton Health Sciences

Hamilton, Ontario, Canada

London Regional Cancer Program

London, Ontario, Canada

University Health Network-Princess Margaret Hospital

Toronto, Ontario, Canada

CHUM - Hopital Notre-Dame

Montreal, Quebec, Canada

CHUM - Centre Hospitalier de l'Universite de Montreal

Montreal, Quebec, Canada

The Research Institute of the McGill University Health Centre (MUHC)

Montreal, Quebec, Canada

Pamela Youde Nethersole Eastern Hospital

Chai Wan, , Hong Kong

Samsung Medical Center

Seoul, Korea, South Korea

Countries

United States; Australia; Canada; Hong Kong; South Korea

References

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.

Reference Type: DERIVED

PMID: 39699905 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

NCI-2012-02057

Identifier Type: REGISTRY

Identifier Source: secondary_id

U10CA021661

Identifier Type: NIH

Identifier Source: secondary_id

View Link

RTOG-1112

Identifier Type: -

Identifier Source: org_study_id