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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Randomized Phase III Study of Sorafenib Versus Stereotactic Body Radiation Therapy Followed by Sorafenib in Hepatocellular Carcinoma

Conditions
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Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer

Intervention / Treatment
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* Drug: Sorafenib
* Radiation: stereotactic body radiation therapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sorafenib Alone<br>400 mg sorafenib twice a day for 28-day cycle. Continue up to 5 years in the absence of disease progression or unacceptable toxicity. | Drug: Sorafenib<br>* By mouth (PO)<br>* Other names: Sorafenib Tosylate;|
| Experimental: SBRT followed by Sorafenib<br>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. | Drug: Sorafenib<br>* By mouth (PO)<br>* Other names: Sorafenib Tosylate;Radiation: stereotactic body radiation therapy<br>* Intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and proton therapy are allowed.<br>* Other names: SABR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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 | 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. | The EQ-5D-5L is administered at baseline, six months and one year. |