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

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by Radiation Therapy Oncology Group
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Radiation Therapy Oncology Group
ClinicalTrials.gov Identifier:
NCT01730937
First received: November 15, 2012
Last updated: January 14, 2014
Last verified: January 2014
  Purpose

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.


Condition Intervention Phase
Adult Primary Hepatocellular Carcinoma
Advanced Adult Primary Liver Cancer
Recurrent Adult Primary Liver Cancer
Drug: sorafenib tosylate
Radiation: stereotactic body radiation therapy
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Randomized Phase III Study of Sorafenib Versus Stereotactic Body Radiation Therapy Followed by Sorafenib in Hepatocellular Carcinoma

Resource links provided by NLM:


Further study details as provided by Radiation Therapy Oncology Group:

Primary Outcome Measures:
  • Overall survival (OS) [ Time Frame: From the date of randomization to the date of death or last follow-up. Analysis occurs after 227 deaths have been reported. ] [ Designated as safety issue: No ]
    Will be estimated by the Kaplan-Meier method. The distribution of OS estimates between the 2 arms will be compared using the log rank test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with OS.


Secondary Outcome Measures:
  • TTP [ Time Frame: From the date of randomization to the date of first failure or last follow-up. ] [ Designated as safety issue: No ]
    Will be estimated by the cumulative incidence method. The distribution of TTP estimates between the 2 arms will be compared using Gray's test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with TTP.

  • PFS [ Time Frame: From the date of randomization to the date of first failure or last follow-up. ] [ Designated as safety issue: No ]
    Will be estimated by the Kaplan-Meier method. The distribution of PFS estimates between the 2 arms will be compared using the log rank test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with PFS.

  • Grade 4 or 5 hepatic adverse events, grade 4 or 5 gastrointestinal AEs, grade 4 thrombocytopenia associated with any bleeding or grade 5 thrombocytopenia. All AEs must be definitely or probably related to protocol treatment and use CTCAE version 4.0 [ Time Frame: From the start of treatment to to 90 days. ] [ Designated as safety issue: Yes ]
    A 90% power will be provided to detect an increase in the rate of specified adverse events from 10% to at least 30% with a 1-sided alpha of 0.05, using a Chi-squared test for difference in proportions.

  • Health related quality of life assessments measured by the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) [ Time Frame: Change from baseline to 6 months. ] [ Designated as safety issue: No ]
    Distributions of QOL data collection patterns over all collection points in each treatment arm will be described. Chi-squared tests will be used to test the null hypothesis that the proportion of patients categorized as "improved" will be the same for the 2 treatment arms, versus the alternative hypothesis that the proportion of patients categorized as "improved" is higher for the SBRT+sorafenib arm.

  • Quality adjusted survival defined as the weighted sum of different time in different health states added up to a total quality-adjusted survival time using EuroQol (EQ-5D) [ Time Frame: Combining survival with changed in EQ-5D from start of treatment to 6 and 12 months. ] [ Designated as safety issue: No ]
    To examine trade-offs between the survival time and QOL. They will be combined for each patient into a single measurement: quality-adjusted life years (QALY). If (and only if) the primary endpoint hypothesis is substantiated, a quality-adjusted survival analysis will be conducted. The quality adjusted survival analysis will not be done until after the primary endpoint results are published.


Estimated Enrollment: 368
Study Start Date: April 2013
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1 (sorafenib tosylate)
Patients receive sorafenib tosylate orally PO BID on days 1-28. Treatment repeats every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.
Drug: sorafenib tosylate
Given PO
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
Experimental: Arm 2 (SBRT and sorafenib tosylate)
Patients undergo SBRT every 24-72 hours for a total of 5 fractions over 5 to 15 days. Within 1-5 days post-SBRT, patients receive sorafenib tosylate PO BID on days 1-28. Treatment repeats every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.
Drug: sorafenib tosylate
Given PO
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
Radiation: stereotactic body radiation therapy
Undergo SBRT
Other Names:
  • SBRT
  • stereotactic radiation therapy
  • stereotactic radiotherapy

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.

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

ARM 1: 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 2: Patients undergo SBRT every 24-72 hours for a total of 5 fractions over 5 to 15 days. Within 1-5 days post-SBRT, patients receive sorafenib tosylate PO BID on days 1-28. Treatment repeats every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

Patients are followed weekly during SBRT, monthly during sorafenib tosylate and on the following schedule as a whole from study entry: every 3 months for 3 years, then every 6 months for 2 years and then annually.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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) 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): CT scan chest/abdomen/pelvis with multiphasic liver CT scan within 28 days prior to study entry; if CT contrast is contraindicated, CT chest without contrast and MRI of abdomen 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
  • Prothrombin time/international normalized 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 transjugular intrahepatic portosystemic shunt (TIPS), surgical portosystemic shunt, spontaneous portosystemic shunt or hepatofugal portal vein flow
    • 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) x 2 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; 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 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; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic
  • 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) > 2.0 cm, in sum of maximal diameters (e.g. presence of one 2.4 cm metastatic lymph node or two 1.2 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), as these agents may modulate cytochrome P450 isozymes
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01730937

Locations
United States, Ohio
Ohio State University Medical Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Terence M. Williams    866-627-7616    osu@emergingmed.com   
Principal Investigator: Terence M. Williams         
United States, Texas
M D Anderson Cancer Center Not yet recruiting
Houston, Texas, United States, 77030
Contact: Laura A. Dawson       clinical.trials@uhn.on.ca   
Canada, Ontario
Princess Margaret Hospital Not yet recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: Laura A. Dawson    416-946-2125    laura.dawson@rmp.uhn.on.ca   
Principal Investigator: Laura A. Dawson         
Sponsors and Collaborators
Radiation Therapy Oncology Group
Investigators
Principal Investigator: Laura Dawson Radiation Therapy Oncology Group
  More Information

No publications provided

Responsible Party: Radiation Therapy Oncology Group
ClinicalTrials.gov Identifier: NCT01730937     History of Changes
Other Study ID Numbers: RTOG 1112, NCI-2012-02057, U10CA021661
Study First Received: November 15, 2012
Last Updated: January 14, 2014
Health Authority: United States: Food and Drug Administration
United States: Federal Government

Additional relevant MeSH terms:
Carcinoma
Liver Neoplasms
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Adenocarcinoma
Sorafenib
Niacinamide
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on August 28, 2014