Clinical trial NCT01730937: Sorafenib Tosylate With or Without Stereotactic Body Radiation Therapy in Treating Patients With Liver Cancer
Official title: Randomized Phase III Study of Sorafenib Versus Stereotactic Body Radiation Therapy Followed by Sorafenib in Hepatocellular Carcinoma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Adult Primary Hepatocellular Carcinoma
Advanced Adult Primary Liver Cancer
Recurrent Adult Primary Liver Cancer
Lead sponsor: Radiation Therapy Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
name: NRG Oncology
First posted: 2012-11-21
Enrollment: 193
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Overall Survival
timeFrame: 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:
measure: Time to Progression
timeFrame: 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.
measure: Progression-free Survival
timeFrame: 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.
measure: Number of Participants by Highest Grade Adverse Event Reported
timeFrame: 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.
measure: Percentage of Participants With Improvement in the Functional Assessment of Cancer Therapy - Hepatobiliary (FACT-Hep) Total Score 6 Months After the Start of Treatment
timeFrame: Baseline and 6 months
measure: Best Vascular Thrombosis Response up to the Time of Progressive Disease (if Applicable)
timeFrame: 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.
measure: Quality Adjusted Life Years
timeFrame: The EQ-5D-5L is administered at baseline, six months and one year.
Other outcomes:
Locations:
city: Berkeley
country: United States
facility: Alta Bates Summit Medical Center-Herrick Campus
state: California
city: Los Angeles
country: United States
facility: USC / Norris Comprehensive Cancer Center
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center-Mount Zion
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center-Mission Bay
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Bridgeport
country: United States
facility: Saint Vincent's Medical Center
state: Connecticut
city: Miami
country: United States
facility: University of Miami Miller School of Medicine-Sylvester Cancer Center
state: Florida
city: Honolulu
country: United States
facility: Queen's Medical Center
state: Hawaii
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Illinois
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Warrenville
country: United States
facility: Northwestern Medicine Cancer Center Warrenville
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University/Melvin and Bren Simon Cancer Center
state: Indiana
city: Des Moines
country: United States
facility: Iowa Methodist Medical Center
state: Iowa
city: New Orleans
country: United States
facility: Ochsner Medical Center Jefferson
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland/Greenebaum Cancer Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center - Moses Campus
state: New York
city: New York
country: United States
facility: Columbia University/Herbert Irving Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Hershey
country: United States
facility: Penn State Milton S Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania/Abramson Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
city: Burlington
country: United States
facility: University of Vermont Medical Center
state: Vermont
city: Richmond
country: United States
facility: Hunter Holmes McGuire Veterans Administration Medical Center
state: Virginia
city: Seattle
country: United States
facility: ProCure Proton Therapy Center-Seattle
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Milwaukee
country: United States
facility: Froedtert and the Medical College of Wisconsin
state: Wisconsin
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre at Hamilton Health Sciences
state: Ontario
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
city: Toronto
country: Canada
facility: University Health Network-Princess Margaret Hospital
state: Ontario
city: Montreal
country: Canada
facility: CHUM - Hopital Notre-Dame
state: Quebec
city: Montreal
country: Canada
facility: CHUM - Centre Hospitalier de l'Universite de Montreal
state: Quebec
city: Montreal
country: Canada
facility: The Research Institute of the McGill University Health Centre (MUHC)
state: Quebec
city: Chai Wan
country: Hong Kong
facility: Pamela Youde Nethersole Eastern Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
state: Korea
Study officials:
affiliation: Radiation Therapy Oncology Group
name: Laura Dawson
role: PRINCIPAL_INVESTIGATOR
References: