Sorafenib Tosylate in Treating Patients With Desmoid Tumors or Aggressive Fibromatosis

Desmoid Fibromatosis Clinical Trial

Official title:

A Phase III, Double Blind, Randomized, Placebo-Controlled Trial of Sorafenib in Desmoid Tumors or Aggressive Fibromatosis (DT/DF)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02066181
• Other study ID #: NCI-2014-00264
• Secondary ID: NCI-2014-00264PA
• Status: Completed
• Phase: Phase 3
• Start date: March 21, 2014
• Est. completion date: December 1, 2022

Study information

• Verified date: June 2023
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized phase III trial compares the effects, good and/or bad, of sorafenib tosylate in treating patients with desmoid tumors or aggressive fibromatosis. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the proteins needed for cell growth. [Funding Source - FDA OOPD]

Description:

PRIMARY OBJECTIVES:

I. To compare the progression-free survival (PFS) rates of patients with desmoid tumors (DT)/deep fibromatosis (DF) who receive either sorafenib (sorafenib tosylate) or placebo using a double-blinded randomized phase III study.

SECONDARY OBJECTIVES:

I. To assess toxicity. II. To assess time to surgical intervention. III. To assess tumor response rates and survival.

TERTIARY OBJECTIVES:

I. To evaluate changes in magnetic resonance imaging (MRI) Tesla (T)2 to predict (or correlate) with a biological effect such as tumor growth (by Response Evaluation Criteria in Solid Tumors [RECIST] version [v]1.1), and pain palliation. (Correlative companion study) II. The mechanism of action of sorafenib in DT/DF remains unknown. In patients consenting to undergo the paired tumor biopsies (A091105-ST1), treatment induced changes will be quantified by histology, gene expression profiling, proteomic changes and selected interrogation of key pathways by western blot and reverse transcription-polymerase chain reaction (RT-PCR). (Correlative companion study) III. To collect archival tissue, baseline (tumor, blood) and day 8 (tumor, blood) specimens for basic science research (A091105-ST1). (Correlative companion study) IV. To assess patient-reported adverse events and quality of life (QOL) as measured by the Patient-Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) and the single-item overall Linear Analogue Self-Assessment (LASA) (A091105-HO1). (Correlative companion study) V. To assess pain palliation measured by the "worst pain" item of the Brief Pain Inventory Short Form (A091105-HO1). (Correlative companion study)

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

ARM I: Patients receive sorafenib tosylate orally (PO) once daily (QD) on days 1-28.

ARM II: Patients receive placebo PO QD on days 1-28. Patients may crossover to Arm I upon disease progression.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up annually for up to 3 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 87
• Est. completion date: December 1, 2022
• Est. primary completion date: July 3, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients must have confirmation of DT/DF by local pathologist prior to registration

• Patients may have been treated with locoregional therapies such as major surgery, radiation, radiofrequency ablation, or cryosurgery provided this has been completed at least 4 weeks prior to registration and recovered from therapy related toxicity to less than CTCAE grade 2

• Patients may have been treated with cytotoxic, biologic (antibody), immune or experimental therapy, tyrosine kinase inhibitors, hormone inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs) provided this has been completed at least 4 weeks prior to registration (6 weeks for mitomycin and nitrosoureas) and recovered from any therapy related toxicity to less than CTCAE grade 2

• Patients with prior or current treatment of sorafenib are excluded

• No concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel); low dose aspirin (=< 81 mg/day), low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted; please note that drugs that strongly induce or inhibit cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) or are associated with a risk of torsades are not allowed; chronic concomitant treatment of CYP3A4 inducers is not allowed (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's wort); as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product; the following drugs are strong inhibitors of CYP3A4 and are not allowed during the treatment with sorafenib:

• Boceprevir

• Indinavir

• Nelfinavir

• Lopinavir/ritonavir

• Saquinavir

• Telaprevir

• Ritonavir

• Clarithromycin

• Conivaptan

• Itraconazole

• Ketoconazole

• Mibefradil

• Nefazodone

• Posaconazole

• Voriconazole

• Telithromycin

• Drugs with possible or conditional risk of torsades should be used with caution knowing that sorafenib could prolong the QT interval

• Chronic daily NSAID use as treatment for controlling desmoid tumors is not allowed, and should be stopped >= 3 days prior to registration; NSAIDS are allowed when used for desmoid tumor-related pain or for symptoms that are unrelated to desmoid disease (eg. headache, arthritis)

• Patients must have measurable disease

• Patients have to meet one of the following criteria to be eligible:

• Disease determined unresectable or entailing unacceptably morbid surgery based on 1 or more of the following characteristics:

• Multifocal disease

• Disease in which there is involvement or inadequate plane from:

neurovascular bundle, bone, skin, or viscera

• Large size in relationship to location OR multi-compartment involvement

• Progression by radiographic imaging (10% increase in size by RECIST v1.1 within 6 months of registration)

• Patients with symptomatic disease which meets the following criteria Brief Pain Inventory (BPI) score greater than or equal to 3 AND one of the following:

• Inability to control pain with NSAIDs and considering addition of narcotics OR

• > 30% increase in current use of narcotics OR

• Addition of a new opioid narcotic

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2

• Patients who are pregnant or nursing are not eligible

• No patients with a history of cardiac disease: congestive heart failure > class II New York Heart Association (NYHA); active coronary artery disease (CAD) (myocardial infarction or unstable angina within 6 months prior to study entry)

• No patients with inadequately controlled hypertension (defined as a blood pressure of >= 150 mmHg systolic and/or >= 90 mmHg diastolic), or any prior history of hypertensive crisis or hypertensive encephalopathy

• No patients with clinically significant gastrointestinal (GI) bleeding or bleeding diathesis within 30 days prior to registration

• Absolute neutrophil count >= 1,500/mm^3

• Hemoglobin >= 8 g/dl

• Platelets >= 75,000/mm^3

• Total bilirubin =< 1.5 x upper limits of normal (ULN)

• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST])/serum glutamate pyruvate transaminase (SGPT) (aspartate aminotransferase [ALT]) =< 1.5 x ULN

• Calculated creatinine clearance >= 50 mL/min using the Cockcroft-Gault equation

Related Conditions & MeSH terms

• Desmoid Fibromatosis
• Fibroma

Intervention

Other:
• Laboratory Biomarker Analysis
Optional correlative studies
• Placebo Administration
Given PO
• Quality-of-Life Assessment
Optional ancillary studies

Drug:
• Sorafenib Tosylate
Given PO

Locations

Country	Name	City	State
Canada	University Health Network-Princess Margaret Hospital	Toronto	Ontario
United States	Pali Momi Medical Center	'Aiea	Hawaii
United States	Queen's Cancer Center - Pearlridge	'Aiea	Hawaii
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	PCR Oncology	Arroyo Grande	California
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Central Care Cancer Center - Bolivar	Bolivar	Missouri
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Cox Cancer Center Branson	Branson	Missouri
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Miami Valley Hospital South	Centerville	Ohio
United States	Christiana Care Health System-Concord Health Center	Chadds Ford	Pennsylvania
United States	Northwestern University	Chicago	Illinois
United States	Oncology Hematology Care Inc-Anderson	Cincinnati	Ohio
United States	Oncology Hematology Care Inc-Blue Ash	Cincinnati	Ohio
United States	Oncology Hematology Care Inc-Eden Park	Cincinnati	Ohio
United States	Oncology Hematology Care Inc-Kenwood	Cincinnati	Ohio
United States	Oncology Hematology Care Inc-Mercy West	Cincinnati	Ohio
United States	John B Amos Cancer Center	Columbus	Georgia
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	Oncology Hematology Care Inc-Crestview	Crestview Hills	Kentucky
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Dayton NCI Community Oncology Research Program	Dayton	Ohio
United States	Good Samaritan Hospital - Dayton	Dayton	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Miami Valley Hospital North	Dayton	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	Fairview Southdale Hospital	Edina	Minnesota
United States	Oncology Hematology Care Inc-Healthplex	Fairfield	Ohio
United States	Blanchard Valley Hospital	Findlay	Ohio
United States	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio
United States	Unity Hospital	Fridley	Minnesota
United States	Wayne Hospital	Greenville	Ohio
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Cancer and Blood Specialists-Henderson	Henderson	Nevada
United States	Comprehensive Cancer Centers of Nevada - Henderson	Henderson	Nevada
United States	Comprehensive Cancer Centers of Nevada-Southeast Henderson	Henderson	Nevada
United States	GenesisCare USA - Henderson	Henderson	Nevada
United States	Las Vegas Cancer Center-Henderson	Henderson	Nevada
United States	Hawaii Cancer Care Inc - Waterfront Plaza	Honolulu	Hawaii
United States	Hawaii Cancer Care Inc-Liliha	Honolulu	Hawaii
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	Kuakini Medical Center	Honolulu	Hawaii
United States	Queen's Cancer Center - Kuakini	Honolulu	Hawaii
United States	Queen's Medical Center	Honolulu	Hawaii
United States	Straub Clinic and Hospital	Honolulu	Hawaii
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	M D Anderson Cancer Center	Houston	Texas
United States	Hutchinson Area Health Care	Hutchinson	Minnesota
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	Freeman Health System	Joplin	Missouri
United States	Mercy Hospital Joplin	Joplin	Missouri
United States	Kettering Medical Center	Kettering	Ohio
United States	Cancer and Blood Specialists-Shadow	Las Vegas	Nevada
United States	Cancer and Blood Specialists-Tenaya	Las Vegas	Nevada
United States	Cancer Therapy and Integrative Medicine	Las Vegas	Nevada
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	Comprehensive Cancer Centers of Nevada - Central Valley	Las Vegas	Nevada
United States	Comprehensive Cancer Centers of Nevada - Northwest	Las Vegas	Nevada
United States	Comprehensive Cancer Centers of Nevada-Summerlin	Las Vegas	Nevada
United States	GenesisCare USA - Fort Apache	Las Vegas	Nevada
United States	GenesisCare USA - Las Vegas	Las Vegas	Nevada
United States	GenesisCare USA - Vegas Tenaya	Las Vegas	Nevada
United States	HealthCare Partners Medical Group Oncology/Hematology-Centennial Hills	Las Vegas	Nevada
United States	HealthCare Partners Medical Group Oncology/Hematology-Maryland Parkway	Las Vegas	Nevada
United States	HealthCare Partners Medical Group Oncology/Hematology-San Martin	Las Vegas	Nevada
United States	HealthCare Partners Medical Group Oncology/Hematology-Tenaya	Las Vegas	Nevada
United States	Las Vegas Cancer Center-Medical Center	Las Vegas	Nevada
United States	Nevada Cancer Research Foundation NCORP	Las Vegas	Nevada
United States	OptumCare Cancer Care at Fort Apache	Las Vegas	Nevada
United States	Radiation Oncology Centers of Nevada Central	Las Vegas	Nevada
United States	Radiation Oncology Centers of Nevada Southeast	Las Vegas	Nevada
United States	Summerlin Hospital Medical Center	Las Vegas	Nevada
United States	Beebe Medical Center	Lewes	Delaware
United States	Wilcox Memorial Hospital and Kauai Medical Clinic	Lihue	Hawaii
United States	Nebraska Cancer Research Center	Lincoln	Nebraska
United States	Nebraska Hematology and Oncology	Lincoln	Nebraska
United States	Southeast Nebraska Cancer Center - 68th Street Place	Lincoln	Nebraska
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota
United States	Saint John's Hospital - Healtheast	Maplewood	Minnesota
United States	Sovah Health Martinsville	Martinsville	Virginia
United States	Loyola University Medical Center	Maywood	Illinois
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Health Partners Inc	Minneapolis	Minnesota
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Good Samaritan Regional Health Center	Mount Vernon	Illinois
United States	Yale University	New Haven	Connecticut
United States	Cancer Center of Western Wisconsin	New Richmond	Wisconsin
United States	New Ulm Medical Center	New Ulm	Minnesota
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Christiana Care Health System-Christiana Hospital	Newark	Delaware
United States	Christiana Gynecologic Oncology LLC	Newark	Delaware
United States	Delaware Clinical and Laboratory Physicians PA	Newark	Delaware
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Faith Regional Health Services Carson Cancer Center	Norfolk	Nebraska
United States	Great Plains Health Callahan Cancer Center	North Platte	Nebraska
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Alegent Health Bergan Mercy Medical Center	Omaha	Nebraska
United States	Alegent Health Immanuel Medical Center	Omaha	Nebraska
United States	Alegent Health Lakeside Hospital	Omaha	Nebraska
United States	Creighton University Medical Center	Omaha	Nebraska
United States	Missouri Valley Cancer Consortium	Omaha	Nebraska
United States	Nebraska Cancer Specialists - Omaha	Omaha	Nebraska
United States	Oncology Hematology West PC	Omaha	Nebraska
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Beebe Health Campus	Rehoboth Beach	Delaware
United States	Saint Mary's Regional Medical Center	Reno	Nevada
United States	Reid Health	Richmond	Indiana
United States	North Memorial Medical Health Center	Robbinsdale	Minnesota
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	Delbert Day Cancer Institute at PCRMC	Rolla	Missouri
United States	Mercy Clinic-Rolla-Cancer and Hematology	Rolla	Missouri
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Saint Louis Cancer and Breast Institute-South City	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Metro Minnesota Community Oncology Research Consortium	Saint Louis Park	Minnesota
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	Lewis Cancer and Research Pavilion at Saint Joseph's/Candler	Savannah	Georgia
United States	Low Country Cancer Care	Savannah	Georgia
United States	Regional West Medical Center Cancer Center	Scottsbluff	Nebraska
United States	TidalHealth Nanticoke / Allen Cancer Center	Seaford	Delaware
United States	Saint Francis Regional Medical Center	Shakopee	Minnesota
United States	Siouxland Regional Cancer Center	Sioux City	Iowa
United States	CoxHealth South Hospital	Springfield	Missouri
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Springfield Regional Cancer Center	Springfield	Ohio
United States	Springfield Regional Medical Center	Springfield	Ohio
United States	Lakeview Hospital	Stillwater	Minnesota
United States	Upper Valley Medical Center	Troy	Ohio
United States	Oklahoma Cancer Specialists and Research Institute-Tulsa	Tulsa	Oklahoma
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	MedStar Washington Hospital Center	Washington	District of Columbia
United States	Sibley Memorial Hospital	Washington	District of Columbia
United States	Rice Memorial Hospital	Willmar	Minnesota
United States	Christiana Care Health System-Wilmington Hospital	Wilmington	Delaware
United States	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota
United States	Wright-Patterson Medical Center	Wright-Patterson Air Force Base	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Percent Change in Tumor Size by Response Evaluation Criteria in Solid Tumors Version 1.1 (Correlative Companion Study-Imaging Study)	Best response (ordinal variable) and percent T2 signal change (continuous) will be correlated by Spearman?s rho.	Baseline up to 3 years
Other	Percent Changes in MRI T2 Signal (Correlative Companion Study-Imaging Study)	Percent T2 signal change (continuous) will be correlated by Spearman?s rho. The percent changes in MRI T2 signal from Week 8 to subsequent imaging will be compared between groups with > 30% pain palliation using t-test or a nonparametric alternative (e.g., Wilcoxon rank-sum test).	Baseline up to 3 years
Other	Time to Pain Progression Measured by the ?Worst Pain? Item of the Brief Pain Inventory Short Form (Correlative Companion Study- A091105-H01 QOL Study)	Defined as a >= 30% increase compared with baseline in the worst pain intensity score (BPI-SF ?worst pain? item) or either a >= 30% increase in the average daily use of any type of opioid narcotic or the addition of a new opioid narcotic compared with baseline. Estimated for each arm using Kaplan-Meier estimates and will be compared between arms using a log- rank test. Descriptive statistics will include means, standard deviations, medians, and ranges for each continuous or ordinal scale/subscale/item by group at each time point.	Date of randomization to the earliest date that pain progression is observed, assessed up to 12 weeks
Other	Time to Pain Palliation Measured by the ?Worst Pain? Item of the Brief Pain Inventory Short Form (Correlative Companion Study-A091105-H01 QOL Study)	Defined at each time point as >= 30% decrease from baseline in the worst pain intensity score (BPI-SF ?worst pain? item), with neither a concomitant >= 30% increase in average daily use of any opioid narcotic, nor addition of any new opioid narcotic, relative to baseline. Estimated for each arm using Kaplan-Meier estimates and will be compared between arms using a log- rank test. Descriptive statistics will include means, standard deviations, medians, and ranges for each continuous or ordinal scale/subscale/item by group at each time point.	Date of randomization to the earliest date that confirmed pain palliation is observed, assessed up to 12 weeks
Other	Duration of Pain Palliation Measured by the ?Worst Pain? Item of the Brief Pain Inventory Short Form (Correlative Companion Study- A091105-H01 QOL Study)	Defined for all patients who experience confirmed pain palliation. Descriptive statistics will include means, standard deviations, medians, and ranges for each continuous or ordinal scale/subscale/item by group at each time point. Descriptive graphical techniques will include mean plots by group for each continuous or ordinal scale/subscale/item. Relative frequencies of responses for each ordinal item will also be generated at each time point by group.	Time from the earliest date that confirmed pain palliation is observed to the earliest date that pain progression is observed, assessed up to 12 weeks
Other	Rate of Pain Palliation Measured by the ?Worst Pain? Item of the Brief Pain Inventory Short Form (Correlative Companion Study-A091105-H01 QOL Study)	Rate of pain palliation at week 8 confirmed as week 12 will be compared between arms using a two-sided alpha=0.05 chi-squared tests at the time of the final analysis. Descriptive statistics will include means, standard deviations, medians, and ranges for each continuous or ordinal scale/subscale/item by group at each time point. Descriptive graphical techniques will include mean plots by group for each continuous or ordinal scale/subscale/item. Relative frequencies of responses for each ordinal item will also be generated at each time point by group.	Baseline up to 12 weeks
Other	Cadherin-associated Protein, Beta 1 (CTNNB1) Genotype (Correlative Companion Study-A091105-ST1 Study)	Associations among the possible predictors of response to sorafenib and CTNNBI mutations will be examined using Fisher?s exact test, Kruskal-Wallis test, or Spearman?s correlation coefficient as appropriate. Strata will be compared by using the log-rank test. Multivariate models will be constructed by introducing all variables aforementioned simultaneously into the model and then eliminating variables using the backward selection method. P values will be two-tailed and considered significant at alpha 0.05.	Up to 3 years
Other	False Discovery Rate (Correlative Companion Study- A091105-ST1 Study)	Permutation testing of the same selection will be performed 1000 times and the sample group labels switched around in each permutation. A two-sided t-test will be used to identify differentially expressed genes on log transformed data and those with a twofold change. False discovery rate will be assessed by permutation testing (n = 1000) of the sample group labels. Enrichment will be assessed by one-sided Fisher?s exact test with estimated false discovery rate.	Up to day 8
Other	Treatment-specific Gene Expression Signature (Correlative Companion Study- A091105-ST1 Study)	The analysis will identify over- and under-expressed genes in pre-treatment and day 8 biopsies as compared to all control samples.	Up to day 8
Other	Changes in Immunohistochemistry Score of Vascular Endothelial Growth Factor (Correlative Companion Study- A091105-ST1 Study)	Compared by paired t-test. Quantitative changes will be correlated with disease status at 1 year by Fishers exact test.	Baseline up to day 8
Other	Changes in Immunohistochemistry Score of Platelet-derived Growth Factor Receptor (Correlative Companion Study- A091105-ST1 Study)	Compared by paired t-test. Quantitative changes will be correlated with disease status at 1 year by Fishers exact test.	Baseline up to day 8
Other	Changes in Immunohistochemistry Score of Beta-catenin Cytoplasm/Nuclear Ratio (Correlative Companion Study- A091105-ST1 Study)	Compared by paired t-test. Quantitative changes will be correlated with disease status at 1 year by Fishers exact test.	Baseline up to day 8
Primary	Progression-free Survival(PFS) Rate	PFS is defined as the time from randomization to the first occurrence of progression or death due to any cause. If no event exists, the PFS will be censored at the last disease assessment. Data following cross over will be analyzed and summarized separately from the data from the main course of treatment for these patients in an exploratory and hypothesis generating manner. Intention to treat principles will be used. Patient disease status was evaluated using RECSIT v1.1. Patients ending treatment for symptomatic deterioration without radiographic evidence of PD, were classified as having PD. Otherwise, patients not yet showing disease progression were classified as having no progression at the most recent disease assessment and in the following cases: crossing over to receive sorafenib, date of first non-protocol directed anti-cancer therapy, lost to follow-up, withdrawal of consent, and changing imaging methods from that which was used at study entry.	Time from randomization to the first occurrence of progression or death due to any cause, assessed up to 3 years
Secondary	Incidence of Adverse Events, Using the Patient Reported Outcomes-Common Terminology Criteria in Adverse Events Version 4.0	INCLUDED IN THE ADVERSE EVENTS PORTION OF THE RESULTS SECTION. Frequency tables, summary statistics, and categorical analysis will be used to compare the distributions of toxicity for patients treated with sorafenib tosylate vs placebo. Data for patients who have crossed over or having received surgical or radiotherapy intervention will be summarized independently from their primary course of study treatment in an exploratory and hypothesis generating manner.	Up to 3 years
Secondary	Time to Surgical Intervention During Treatment	A log rank test will be used to compare the distributions of time to surgical intervention between the two arms using a 2-sided test and alpha=0.05 level of significance. Kaplan-Meier methodology will be used to estimate various time points and 95% confidence intervals will be calculated for these estimates. Surgery will be classified by outcome (eg, complete-macroscopic, complete-microscopic, or partial), type, location (eg, limb), thereafter analyzed by categorical analysis and descriptive statistics. Non-parametric methods will be used, as appropriate. Too few patients had surgery during treatment to perform analysis.	Time between randomization to the patient undergoing therapeutic surgical resection for this disease, assessed up to 3 years
Secondary	Overall Survival	Kaplan-Meier methodology and log rank tests will be used to compare overall survival between the groups at various time points (eg, 1 year rate, 2 year rate, etc) and 95% confidence intervals will be calculated for these estimates. Data following crossover will be analyzed and summarized separately from the main course of treatment for these patients in an exploratory and hypothesis generating manner.	Time between the date of randomization to until death, assessed up to 3 years
Secondary	Best Objective Status Between the Two Treatment Arms According to Response Evaluation Criteria in Solid Tumors Version 1.1	Compared between the two treatment arms and using the Cochran-Mantel-Haenszel test. Complete Response (CR): All of the following must be true: a. Disappearance of all target lesions. b. Each target lymph node must have reduction in short axis to <1.0 cm. Partial Response (PR): At least a 30% decrease in PBSD (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the BSD. Patients on Arm II (placebo) who crossover are censored for Best Objective Status at the time of crossover.	Up to 3 years
Secondary	Duration of Response	Kaplan Meier methodology will be used to estimate the distribution of duration of response and the log-rank test will be used to test for a difference in duration of response between the two arms. Patients on Arm II (placebo) who crossover are censored for Duration of Response at the time of crossover.	Time between first tumor response and progression, assessed up to 3 years

External Links

•   Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive.