Fulvestrant and Bevacizumab in Treating Patients With Metastatic Breast Cancer

Breast Cancer Clinical Trial

Official title:

Phase II Trial of Fulvestrant and Bevacizumab in Patients With Metastatic Breast Cancer Previously Treated With an Aromatase Inhibitor

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00423917
• Other study ID #: NCCTG-N0539
• Secondary ID: NCI-2009-00649CD
• Status: Completed
• Phase: Phase 2
• Start date: August 2007
• Est. completion date: January 15, 2017

Study information

• Verified date: April 2018
• Source: Alliance for Clinical Trials in Oncology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using fulvestrant may fight breast cancer by blocking the use of estrogen by the tumor cells. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Fulvestrant and bevacizumab may also stop the growth of breast cancer by blocking blood flow to the tumor. Giving fulvestrant together with bevacizumab may be an effective treatment for metastatic breast cancer.

PURPOSE: This phase II trial is studying how well giving fulvestrant together with bevacizumab works in treating patients with metastatic breast cancer.

Description:

OBJECTIVES:

Primary

• Assess the efficacy of fulvestrant and bevacizumab, in terms of 6-month progression-free survival (PFS), in patients with metastatic breast cancer previously treated with an aromatase inhibitor.

Secondary

• Assess the quality of life of patients treated with this regimen.

• Determine the adverse-event profile in these patients.

• Determine the PFS and overall survival of these patients.

• Determine the confirmed response rate, duration of response, time to treatment failure, and time to first cytotoxic agent in patients treated with this regimen.

OUTLINE: This is a multicenter study.

Patients receive fulvestrant intramuscularly on day 1 and bevacizumab IV over 30-90 minutes on days 1 and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, prior to every other course, and at the completion of study treatment.

After completion of study treatment, patients are followed every 3-6 months for 5 years.

PROJECTED ACCRUAL: A total of 51 patients will be accrued for this study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: January 15, 2017
• Est. primary completion date: February 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed breast cancer

• Metastatic disease

• Must have received an aromatase inhibitor (e.g., letrozole, anastrozole, or exemestane) in an adjuvant or metastatic setting

• If tumor is HER2 positive (3+ by immunohistochemistry or amplified by fluorescent in situ hybridization) the patient must have received = 1 prior trastuzumab (Herceptin®)-containing regimen unless there is a contraindication to trastuzumab

• Measurable or nonmeasurable disease, including any of the following :

• Bone metastasis

• Pleural/pericardial effusion

• Ascites

• Inflammatory skin changes

• No microscopic residual disease only

• Enrolled on or refused enrollment on clinical trial NCCTG-N0392

• No evidence of active brain metastasis including leptomeningeal involvement

• CNS metastasis controlled (i.e., at least 2 months of no symptoms or evidence of progression) by prior surgery and/or raditherapy are allowed

• Hormone receptor status:

• Estrogen and/or progesterone receptor-positive tumor

PATIENT CHARACTERISTICS:

• Male or female

• Female patients must be post-menopausal based on any 1 of the following criteria:

• Age = 60 years

• Age = 45 years with last menstrual period = 12 months prior to study entry

• Estradiol and follicle-stimulating hormone levels in postmenopausal range

• History of bilateral oophorectomy

• ECOG performance status 0-2

• Life expectancy > 3 months

• Fertile patients must use effective contraception during and for 30 days after completion of study treatment

• WBC = 3,000 mg/dL

• Hemoglobin > 8 g/dL

• Absolute neutrophil count > 1,000/mm³

• Platelet count = 100,000/mm³

• Bilirubin = 1.5 times upper limit of normal (ULN)

• Alkaline phosphatase = 2.5 times ULN

• AST and ALT = 2.5 times ULN

• Creatinine = 1.5 times ULN

• Urine protein < 1+ OR < 1 g of protein by 24-hour urine collection

• No nephrotic syndrome

• No uncontrolled hypertension (i.e., blood pressure [BP] > 160/90 mm Hg on = 2 occasions at least 5 minutes apart)

• Patients who have recently started or adjusted antihypertensive medications are eligible provided BP is < 140/90 mm Hg on any new regimen for = 3 different observations in = 14 days

• No clinically significant cardiac disease, including any of the following:

• Congestive heart failure

• Symptomatic coronary artery disease

• Unstable angina

• Cardiac arrhythmias not well controlled with medication

• Myocardial infarction within the past 12 months

• No arterial or venous thrombosis within the past 12 months

• No hemoptysis or gastrointestinal hemorrhage within the past 6 months

• No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 4 weeks

• No significant traumatic injury within the past 4 weeks

• No active, unresolved infection

• No history of hypertensive crisis or hypertensive encephalopathy

• No history of bleeding diathesis or uncontrolled coagulopathy

• No history of cerebrovascular accident, hemorrhage, or stroke

• No allergy or hypersensitivity to drug product excipients, murine antibodies, or agents chemically similar to study drugs

• No other malignancy within the past 3 years except for basal cell or squamous cell skin cancer or carcinoma in situ of the cervix

• No other serious medical condition that would preclude study therapy or compliance

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• Prior radiotherapy to a target lesion allowed provided there has been clear progression since radiotherapy was completed

• At least 4 weeks since prior radiotherapy

• Single-dose radiation for palliation or to a nontarget lesion only allowed within the past 4 weeks

• No more than 1 prior chemotherapy regimen for metastatic disease

• No more than 2 prior endocrine (hormonal) therapy regimens in the neoadjuvant, adjuvant, or metastatic setting

• At least 4 weeks since prior major surgery or open biopsy

• At least 4 weeks since prior chemotherapy or immunologic therapy

• At least 2 weeks since prior and no concurrent use of any of the following agents:

• Aspirin (daily low-dose [81 mg] aspirin allowed])

• Thrombolytic agents

• Anticoagulants (low-dose anticoagulation therapy to maintain patency of a vascular access device is allowed)

• No concurrent treatment in another clinical study with investigational procedures or investigational therapies

• No other concurrent anticancer therapy, including chemotherapy, biologic agents, or radiotherapy

• No routine use of granulocyte colony-stimulating factors during course 1

• No concurrent oprelvekin

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Biological:
• bevacizumab

Drug:
• fulvestrant

Locations

Country	Name	City	State
United States	Hickman Cancer Center at Bixby Medical Center	Adrian	Michigan
United States	Morgan Cancer Center at Lehigh Valley Hospital - Cedar Crest	Allentown	Pennsylvania
United States	McFarland Clinic, PC	Ames	Iowa
United States	CCOP - Michigan Cancer Research Consortium	Ann Arbor	Michigan
United States	Saint Joseph Mercy Cancer Center	Ann Arbor	Michigan
United States	Rush-Copley Cancer Care Center	Aurora	Illinois
United States	St. Francis Hospital and Health Centers - Beech Grove Campus	Beech Grove	Indiana
United States	Mary Rutan Hospital	Bellefontaine	Ohio
United States	MeritCare Bemidji	Bemidji	Minnesota
United States	Billings Clinic - Downtown	Billings	Montana
United States	CCOP - Montana Cancer Consortium	Billings	Montana
United States	Hematology-Oncology Centers of the Northern Rockies - Billings	Billings	Montana
United States	Northern Rockies Radiation Oncology Center	Billings	Montana
United States	St. Vincent Healthcare Cancer Care Services	Billings	Montana
United States	Bismarck Cancer Center	Bismarck	North Dakota
United States	Medcenter One Hospital Cancer Care Center	Bismarck	North Dakota
United States	Mid Dakota Clinic, PC	Bismarck	North Dakota
United States	St. Alexius Medical Center Cancer Center	Bismarck	North Dakota
United States	St. Joseph Medical Center	Bloomington	Illinois
United States	Wood County Oncology Center	Bowling Green	Ohio
United States	Bozeman Deaconess Cancer Center	Bozeman	Montana
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	St. James Healthcare Cancer Care	Butte	Montana
United States	Graham Hospital	Canton	Illinois
United States	Memorial Hospital	Carthage	Illinois
United States	Cedar Rapids Oncology Associates	Cedar Rapids	Iowa
United States	Cancer Center of Kansas, PA - Chanute	Chanute	Kansas
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	CCOP - Columbus	Columbus	Ohio
United States	Doctors Hospital at Ohio Health	Columbus	Ohio
United States	Grant Medical Center Cancer Care	Columbus	Ohio
United States	Mount Carmel Health - West Hospital	Columbus	Ohio
United States	Riverside Methodist Hospital Cancer Care	Columbus	Ohio
United States	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota
United States	Geisinger Cancer Institute at Geisinger Health	Danville	Pennsylvania
United States	CCOP - Dayton	Dayton	Ohio
United States	David L. Rike Cancer Center at Miami Valley Hospital	Dayton	Ohio
United States	Good Samaritan Hospital	Dayton	Ohio
United States	Grandview Hospital	Dayton	Ohio
United States	Samaritan North Cancer Care Center	Dayton	Ohio
United States	Veterans Affairs Medical Center - Dayton	Dayton	Ohio
United States	Oakwood Cancer Center at Oakwood Hospital and Medical Center	Dearborn	Michigan
United States	Grady Memorial Hospital	Delaware	Ohio
United States	CCOP - Iowa Oncology Research Association	Des Moines	Iowa
United States	John Stoddard Cancer Center at Iowa Lutheran Hospital	Des Moines	Iowa
United States	John Stoddard Cancer Center at Iowa Methodist Medical Center	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates at John Stoddard Cancer Center	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates at Mercy Cancer Center	Des Moines	Iowa
United States	Mercy Cancer Center at Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Mercy Capitol Hospital	Des Moines	Iowa
United States	Cancer Center of Kansas, PA - Dodge City	Dodge City	Kansas
United States	CCOP - Duluth	Duluth	Minnesota
United States	Duluth Clinic Cancer Center - Duluth	Duluth	Minnesota
United States	Miller - Dwan Medical Center	Duluth	Minnesota
United States	Fairview Southdale Hospital	Edina	Minnesota
United States	St. Anthony's Memorial Hospital	Effingham	Illinois
United States	Cancer Center of Kansas, PA - El Dorado	El Dorado	Kansas
United States	Green Bay Oncology, Limited - Escanaba	Escanaba	Michigan
United States	Eureka Community Hospital	Eureka	Illinois
United States	CCOP - MeritCare Hospital	Fargo	North Dakota
United States	MeritCare Broadway	Fargo	North Dakota
United States	Blanchard Valley Medical Associates	Findlay	Ohio
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Middletown Regional Hospital	Franklin	Ohio
United States	Fredericksburg Oncology, Incorporated	Fredericksburg	Virginia
United States	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota
United States	Galesburg Clinic, PC	Galesburg	Illinois
United States	Galesburg Cottage Hospital	Galesburg	Illinois
United States	InterCommunity Cancer Center of Western Illinois	Galesburg	Illinois
United States	Great Falls Clinic - Main Facility	Great Falls	Montana
United States	Green Bay Oncology, Limited at St. Mary's Hospital	Green Bay	Wisconsin
United States	Green Bay Oncology, Limited at St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin
United States	St. Mary's Hospital Medical Center - Green Bay	Green Bay	Wisconsin
United States	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin
United States	Van Elslander Cancer Center at St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan
United States	Mason District Hospital	Havana	Illinois
United States	Geisinger Hazleton Cancer Center	Hazleton	Pennsylvania
United States	St. Peter's Hospital	Helena	Montana
United States	Memorial Cancer Institute at Memorial Regional Hospital	Hollywood	Florida
United States	Hopedale Medical Complex	Hopedale	Illinois
United States	Hutchinson Area Health Care	Hutchinson	Minnesota
United States	Dickinson County Healthcare System	Iron Mountain	Michigan
United States	Foote Memorial Hospital	Jackson	Michigan
United States	Mayo Clinic - Jacksonville	Jacksonville	Florida
United States	Joliet Oncology-Hematology Associates, Limited - West	Joliet	Illinois
United States	Glacier Oncology, PLLC	Kalispell	Montana
United States	Kalispell Medical Oncology at KRMC	Kalispell	Montana
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	Charles F. Kettering Memorial Hospital	Kettering	Ohio
United States	Cancer Center of Kansas, PA - Kingman	Kingman	Kansas
United States	Haematology-Oncology Associates of Ohio and Michigan, PC	Lambertville	Michigan
United States	Fairfield Medical Center	Lancaster	Ohio
United States	Sparrow Regional Cancer Center	Lansing	Michigan
United States	Southwest Medical Center	Liberal	Kansas
United States	Lima Memorial Hospital	Lima	Ohio
United States	Meeker County Memorial Hospital	Litchfield	Minnesota
United States	St. Mary Mercy Hospital	Livonia	Michigan
United States	McDonough District Hospital	Macomb	Illinois
United States	HealthEast Cancer Care at St. John's Hospital	Maplewood	Minnesota
United States	Minnesota Oncology Hematology, PA - Maplewood	Maplewood	Minnesota
United States	Strecker Cancer Center at Marietta Memorial Hospital	Marietta	Ohio
United States	Bay Area Cancer Care Center at Bay Area Medical Center	Marinette	Wisconsin
United States	Mercy Cancer Center at Mercy Medical Center - North Iowa	Mason City	Iowa
United States	Northwest Ohio Oncology Center	Maumee	Ohio
United States	St. Luke's Hospital	Maumee	Ohio
United States	Saint Anthony Memorial Health Centers	Michigan City	Indiana
United States	Hennepin County Medical Center - Minneapolis	Minneapolis	Minnesota
United States	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota
United States	Community Medical Center	Missoula	Montana
United States	Guardian Oncology and Center for Wellness	Missoula	Montana
United States	Montana Cancer Center at St. Patrick Hospital and Health Sciences Center	Missoula	Montana
United States	Montana Cancer Specialists at Montana Cancer Center	Missoula	Montana
United States	Trinity Cancer Center at Trinity Medical Center - 7th Street Campus	Moline	Illinois
United States	Community Cancer Center of Monroe	Monroe	Michigan
United States	Mercy Memorial Hospital - Monroe	Monroe	Michigan
United States	Licking Memorial Cancer Care Program at Licking Memorial Hospital	Newark	Ohio
United States	Cancer Center of Kansas, PA - Newton	Newton	Kansas
United States	BroMenn Regional Medical Center	Normal	Illinois
United States	Community Cancer Center	Normal	Illinois
United States	Green Bay Oncology, Limited - Oconto Falls	Oconto Falls	Wisconsin
United States	Alegant Health Cancer Center at Bergan Mercy Medical Center	Omaha	Nebraska
United States	CCOP - Missouri Valley Cancer Consortium	Omaha	Nebraska
United States	Creighton University Medical Center	Omaha	Nebraska
United States	Immanuel Medical Center	Omaha	Nebraska
United States	St. Charles Mercy Hospital	Oregon	Ohio
United States	Toledo Clinic - Oregon	Oregon	Ohio
United States	Community Hospital of Ottawa	Ottawa	Illinois
United States	Oncology Hematology Associates of Central Illinois, PC - Ottawa	Ottawa	Illinois
United States	Cancer Center of Kansas, PA - Parsons	Parsons	Kansas
United States	Cancer Treatment Center at Pekin Hospital	Pekin	Illinois
United States	CCOP - Illinois Oncology Research Association	Peoria	Illinois
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	Oncology Hematology Associates of Central Illinois, PC - Peoria	Peoria	Illinois
United States	OSF St. Francis Medical Center	Peoria	Illinois
United States	Proctor Hospital	Peoria	Illinois
United States	Illinois Valley Community Hospital	Peru	Illinois
United States	St. Joseph Mercy Oakland	Pontiac	Michigan
United States	Mercy Regional Cancer Center at Mercy Hospital	Port Huron	Michigan
United States	Cancer Center of Kansas, PA - Pratt	Pratt	Kansas
United States	Perry Memorial Hospital	Princeton	Illinois
United States	Reid Hospital & Health Care Services	Richmond	Indiana
United States	Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center	Robbinsdale	Minnesota
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	Seton Cancer Institute at Saint Mary's - Saginaw	Saginaw	Michigan
United States	CentraCare Clinic - River Campus	Saint Cloud	Minnesota
United States	Coborn Cancer Center	Saint Cloud	Minnesota
United States	Arch Medical Services, Incorporated at Center for Cancer Care and Research	Saint Louis	Missouri
United States	Missouri Baptist Cancer Center	Saint Louis	Missouri
United States	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota
United States	Park Nicollet Cancer Center	Saint Louis Park	Minnesota
United States	HealthEast Cancer Care at St. Joseph's Hospital	Saint Paul	Minnesota
United States	Regions Hospital Cancer Care Center	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Cancer Center of Kansas, PA - Salina	Salina	Kansas
United States	Firelands Regional Medical Center	Sandusky	Ohio
United States	North Coast Cancer Care, Incorporated	Sandusky	Ohio
United States	Mayo Clinic Scottsdale	Scottsdale	Arizona
United States	St. Francis Cancer Center at St. Francis Medical Center	Shakopee	Minnesota
United States	Welch Cancer Center at Sheridan Memorial Hospital	Sheridan	Wyoming
United States	Mercy Medical Center - Sioux City	Sioux City	Iowa
United States	Siouxland Hematology-Oncology Associates, LLP	Sioux City	Iowa
United States	St. Luke's Regional Medical Center	Sioux City	Iowa
United States	Avera Cancer Institute	Sioux Falls	South Dakota
United States	Medical X-Ray Center, PC	Sioux Falls	South Dakota
United States	Sanford Cancer Center at Sanford USD Medical Center	Sioux Falls	South Dakota
United States	St. Margaret's Hospital	Spring Valley	Illinois
United States	Valley Cancer Center	Spring Valley	Illinois
United States	Community Hospital of Springfield and Clark County	Springfield	Ohio
United States	Mercy Medical Center	Springfield	Ohio
United States	Geisinger Medical Group - Scenery Park	State College	Pennsylvania
United States	Green Bay Oncology, Limited - Sturgeon Bay	Sturgeon Bay	Wisconsin
United States	Flower Hospital Cancer Center	Sylvania	Ohio
United States	Mercy Hospital of Tiffin	Tiffin	Ohio
United States	CCOP - Toledo Community Hospital	Toledo	Ohio
United States	St. Vincent Mercy Medical Center	Toledo	Ohio
United States	Toledo Clinic, Incorporated - Main Clinic	Toledo	Ohio
United States	Toledo Hospital	Toledo	Ohio
United States	UVMC Cancer Care Center at Upper Valley Medical Center	Troy	Ohio
United States	Natalie Warren Bryant Cancer Center at St. Francis Hospital	Tulsa	Oklahoma
United States	Carle Cancer Center at Carle Foundation Hospital	Urbana	Illinois
United States	CCOP - Carle Cancer Center	Urbana	Illinois
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	St. John Macomb Hospital	Warren	Michigan
United States	Fulton County Health Center	Wauseon	Ohio
United States	Cancer Center of Kansas, PA - Wellington	Wellington	Kansas
United States	Mount Carmel St. Ann's Cancer Center	Westerville	Ohio
United States	Associates in Womens Health, PA - North Review	Wichita	Kansas
United States	Cancer Center of Kansas, PA - Medical Arts Tower	Wichita	Kansas
United States	Cancer Center of Kansas, PA - Wichita	Wichita	Kansas
United States	CCOP - Wichita	Wichita	Kansas
United States	Via Christi Cancer Center at Via Christi Regional Medical Center	Wichita	Kansas
United States	Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center	Wilkes-Barre	Pennsylvania
United States	Mercy Hospital at Wilkes-Barre	Wilkes-Barre	Pennsylvania
United States	Clinton Memorial Hospital	Wilmington	Ohio
United States	Cancer Center of Kansas, PA - Winfield	Winfield	Kansas
United States	HealthEast Cancer Care at Woodwinds Health Campus	Woodbury	Minnesota
United States	Minnesota Oncology Hematology, PA - Woodbury	Woodbury	Minnesota
United States	Ruth G. McMillan Cancer Center at Greene Memorial Hospital	Xenia	Ohio
United States	Genesis - Good Samaritan Hospital	Zanesville	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
Alliance for Clinical Trials in Oncology	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

Tan WW, Dueck AC, Flynn P, Steen P, Anderson D, Rowland K, Northfelt D, Perez EA. N0539 phase II trial of fulvestrant and bevacizumab in patients with metastatic breast cancer previously treated with an aromatase inhibitor: a North Central Cancer Treatmen — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Six-month Progression-free Survival (PFS) Rate at 6 Months	The primary endpoint of this trial is the 6-month progression-free survival rate. A patient is considered to be a 6-month progression-free survivor if the patient is on study treatment 6 months from registration without a documentation of disease progression. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Additionally, if some patients are lost to follow-up not having been observed for at least 6 months, an estimate and 95% confidence interval for the 6-month progression-free survival rate incorporating censoring will be computed using the method of Kaplan-Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.	at 6 months
Secondary	Progression Free Survival	Time to disease progression is defined as the time from registration to the earliest date of documentation of disease progression. If a patient dies without a documentation of disease progression the patient will be considered to have had disease progression at the time of their death. If the patient is declared to be a major treatment violation, the patient will be censored on the date the treatment violation was declared to have occurred. In the case of a patient starting treatment and then never returning for any evaluations, the patient will be censored for progression 1 day post-registration. The distribution of time to progression will be estimated using the method of Kaplan-Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.	Up to 5 years
Secondary	Overall Survival	Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier (1958).	Up to 5 years
Secondary	Quality of Life, as Measured by the Largest Mean Change in LASA Overall QOL and Physical Well-being Items	Quality of life (QOL) assessment will be a secondary exploratory component of this trial. QOL of patients was measure using the 6-item Linear Analogue Self-Assessment (LASA).The LASA consists of six single-item numeric analog scales measuring overall QOL; mental, physical, emotional, and spiritual well-being; and level of activity each on a scale of 0 ('As bad as it can be') to 10 ('As good as it can be') during the past week. Items were transformed to a 0 (worst QOL or well-being) to 100 (best QOL or well-being) scale for statistical analysis. Mean change from baseline of the largest mean change in overall QOL and physical well-being are reported below.	Up to 5 years
Secondary	Objective Response Rate as Measured by RECIST Criteria in Patients With Measurable Disease	A confirmed response is defined to be either a CR or PR noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. The confirmed response rate will be estimated by the number of confirmed responses in evaluable patients with measurable disease divided by the total number of evaluable patients with measurable disease. The appropriate confidence interval will be calculated. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.	Up to 5 years
Secondary	Time to First Cytotoxic Agent	Time to first dose of a cytotoxic agent is defined to be the time from the date of registration to the date at which a patient recieves the first dose of a cytotoxic agent. The distribution of time to first dose of a cytotoxic agent will be estimated using the method of Kaplan-Meier (1958).	Up to 5 years
Secondary	Duration of Response/Time to Disease Progression in Patients With Measurable Disease	Duration of response is defined for all evaluable patients with measurable disease who have achieved a confirmed response as the date at which the patient's earliest best objective status is first noted to be either a CR or PR to the earliest date progression is documented. If a patient dies subsequent to the confirmed response without a documentation of disease progression, the patient will be considered to have had disease progression at the time of their death. In the case of a patient failing to return for evaluations before a documentation of disease progression, the patient will be censored for progression on the date of last evaluation. The distribution of duration of response will be estimated using the method of Kaplan-Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.	Up to 5 years