Sorafenib Tosylate with or without Stereotactic Body Radiation Therapy in Treating Patients with Liver Cancer

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Basic Trial Information

PhaseTypeStatusAgeTrial IDs
Phase IIITreatmentActive18 and overRTOG-1112
NCI-2012-02057, NCT01730937

Trial Description

Summary

This randomized phase III trial studies sorafenib tosylate and stereotactic radiosurgery (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 radiosurgery, also known as stereotactic body radiation therapy, uses focused, high-dose radiation to help shrink tumors. It is not yet known whether giving sorafenib tosylate together with stereotactic radiosurgery is more effective than sorafenib tosylate alone in treating liver cancer.

Further Study Information

PRIMARY OBJECTIVES:

I. To determine if stereotactic body radiation therapy (SBRT) (stereotactic radiosurgery) 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.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive sorafenib tosylate orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo stereotactic radiosurgery every 24-72 hours for a total of 5 fractions over 5 to 15 days. Within 1-5 days post-stereotactic radiosurgery, patients receive sorafenib tosylate as in Arm I. Treatment repeats every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3, 6, and 12 months.

Eligibility Criteria

Inclusion Criteria:

Patients must have an HCC diagnosis (initial, recurrent, progressive and/or refractory to other therapies) by at least one criterion listed below =< 360 days prior to study entry

Pathologically (histologically or cytologically) proven diagnosis of HCC

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)

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): CT scan chest/abdomen/pelvis with multiphasic liver CT or multiphasic liver magnetic resonance (MR) scan within 28 days prior to study entry; MRI of abdomen with contrast and pelvis is permitted

Zubrod performance status 0-2 within 28 days prior to study entry

Absolute neutrophil count (ANC) >= 1,500 cells/mm^3

Platelets >= 70,000 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)

Total bilirubin < 2 mg/dL

Internationalized normal ratio (INR) < 1.7

Albumin >= 28 g/L

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 6 times upper limit of normal (ULN)

Serum creatinine =< 1.5 x ULN or creatinine clearance >= 60 mL/min

Barcelona Clinic Liver Cancer (BCLC) stage: intermediate (B) or advanced (C) within 14 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) 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; note that prior chemotherapy for HCC or a different cancer is allowable

Prior radiotherapy to the region of the liver that would result in excessive doses to normal tissues due to 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 before 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 60 days prior to study entry

Bleeding within 60 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

Any one hepatocellular carcinoma > 15 cm

Total maximal sum of hepatocellular carcinomas or 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

Use of regular phenytoin, carbamazepine, hypericum perforatum (also known as St. John's wort) or rifampin

Use of combination anti-retroviral therapy for human immunodeficiency virus (HIV)

Prior liver transplant

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

NRG Oncology

  • National Cancer Institute
Laura Ann Dawson, Principal Investigator

Trial Sites

U.S.A.

California
Los Angeles

USC / Norris Comprehensive Cancer Center

Anthony El-Khoueiry
Ph: 323-865-0451

Anthony El-Khoueiry
Principal Investigator

San Francisco

UCSF Medical Center-Mount Zion

Albert J. Chang
Ph: 877-827-3222

Albert J. Chang
Principal Investigator

Colorado
Aurora

University of Colorado Cancer Center - Anschutz Cancer Pavilion

Tracey Elizabeth Schefter
Ph: 720-848-0650

Tracey Elizabeth Schefter
Principal Investigator

Connecticut
Bridgeport

Saint Vincent's Medical Center

Christopher Michael Iannuzzi
Ph: 203-576-6329
Email: twhite@stvincents.org

Christopher Michael Iannuzzi
Principal Investigator

Florida
Miami

University of Miami Miller School of Medicine-Sylvester Cancer Center

Raphael L. Yechieli
Ph: 866-574-5124
Email: Sylvester@emergingmed.com

Raphael L. Yechieli
Principal Investigator

Illinois
Chicago

Northwestern University

John Patrick Hayes
Ph: 312-695-1301
Email: cancer@northwestern.edu

John Patrick Hayes
Principal Investigator

University of Illinois

Neeta Kiran Venepalli
Ph: 312-355-3046

Neeta Kiran Venepalli
Principal Investigator

Decatur

Decatur Memorial Hospital

James Lloyd Wade
Ph: 217-876-4740
Email: kcheek@dmhhs.org

James Lloyd Wade
Principal Investigator

Warrenville

Northwestern Medicine Cancer Center Warrenville

Lisa A. McGee
Ph: 630-315-1918
Email: Claudine.Gamster@CadenceHealth.org

Lisa A. McGee
Principal Investigator

Indiana
Indianapolis

Indiana University/Melvin and Bren Simon Cancer Center

Mark Peter Langer
Ph: 317-274-2552

Mark Peter Langer
Principal Investigator

Iowa
Des Moines

Iowa Methodist Medical Center

Robert J. Behrens
Ph: 515-282-2921

Robert J. Behrens
Principal Investigator

Maryland
Baltimore

Johns Hopkins University/Sidney Kimmel Cancer Center

Joseph Michael Herman
Ph: 410-955-8804
Email: jhcccro@jhmi.edu

Joseph Michael Herman
Principal Investigator

Massachusetts
Boston

Boston Medical Center

Lisa A. Kachnic
Ph: 800-811-8480

Lisa A. Kachnic
Principal Investigator

Massachusetts General Hospital Cancer Center

Andrew Xiuxuan Zhu
Ph: 877-726-5130

Andrew Xiuxuan Zhu
Principal Investigator

New York
Bronx

Montefiore Medical Center - Moses Campus

Nitin Ohri
Ph: 718-904-2730
Email: aecc@aecom.yu.edu

Nitin Ohri
Principal Investigator

New York

Columbia University/Herbert Irving Cancer Center

Abby B. Siegel
Ph: 212-305-8615

Abby B. Siegel
Principal Investigator

Rochester

University of Rochester

Yuhchyau Chen
Ph: 585-275-5830

Yuhchyau Chen
Principal Investigator

Stony Brook

Stony Brook University Medical Center

Alexander M. Stessin
Ph: 800-862-2215

Alexander M. Stessin
Principal Investigator

Ohio
Columbus

Ohio State University Comprehensive Cancer Center

Terence Marques Williams
Ph: 800-293-5066
Email: Jamesline@osumc.edu

Terence Marques Williams
Principal Investigator

Texas
Houston

M D Anderson Cancer Center

Sunil Krishnan
Ph: 713-792-3245

Sunil Krishnan
Principal Investigator

Vermont
Burlington

University of Vermont Medical Center

Christopher J. Anker
Ph: 802-656-4101

Christopher J. Anker
Principal Investigator

Wisconsin
Milwaukee

Froedtert and the Medical College of Wisconsin

Beth A. Erickson
Ph: 414-805-4380

Beth A. Erickson
Principal Investigator

Canada

Ontario
Hamilton

Juravinski Cancer Centre at Hamilton Health Sciences

Anand Swaminath
Ph: 905-387-9495

Anand Swaminath
Principal Investigator

London

London Regional Cancer Program

Michael I. Lock
Ph: 519-685-8600

Michael I. Lock
Principal Investigator

Toronto

University Health Network-Princess Margaret Hospital

Laura Ann Dawson
Ph: 416-946-4501
Email: clinical.trials@uhn.on.ca

Laura Ann Dawson
Principal Investigator

Quebec
Montreal

CHUM - Hopital Notre-Dame

Helene Castel
Ph: 514-890-8000ext12725
Email: info.cr.chum@ssss.gouv.qc.ca

Helene Castel
Principal Investigator

Hong Kong

Chai Wan

Pamela Youde Nethersole Eastern Hospital

Ada Lai Yau Law
Ph: 011 852 2595 7920

Ada Lai Yau Law
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifier NCT01730937

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.