Bevacizumab With or Without Anti-Endoglin Monoclonal Antibody TRC105 in Treating Patients With Recurrent Glioblastoma Multiforme

Adult Glioblastoma Clinical Trial

Official title:

Phase I/Comparative Randomized Phase II Trial of TRC105 Plus Bevacizumab Versus Bevacizumab in Bevacizumab-Naive Patients With Recurrent Glioblastoma Multiforme

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01648348
• Other study ID #: NCI-2012-01989
• Secondary ID: NCI-2012-01989CD
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: November 2012
• Est. completion date: April 15, 2017

Study information

• Verified date: April 2018
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This partially randomized phase I/II trial studies the side effects and the best dose of anti-endoglin monoclonal antibody TRC105 when given together with bevacizumab and to see how well they work in treating patients with glioblastoma multiforme that has come back. Monoclonal antibodies, such as anti-endoglin monoclonal antibody TRC105 and bevacizumab, may find tumor cells and help kill them. Giving anti-endoglin monoclonal antibody TRC105 together with bevacizumab may be an effective treatment for glioblastoma multiforme.

Description:

PRIMARY OBJECTIVES:

I. To establish a maximum tolerated dose (MTD) of TRC105 (anti-endoglin monoclonal antibody TRC105) combined with bevacizumab in this patient population. (Phase I) II. To assess the safety and adverse events of TRC105 in combination with bevacizumab in this patient population. (Phase II) III. To determine the efficacy of TRC105 in combination with bevacizumab in recurrent glioblastoma as measured by progression-free survival and compare it with the efficacy of bevacizumab alone in this patient population. (Phase II)

SECONDARY OBJECTIVES:

I. To assess the proportion of patients, who are progression free at 6 months, treated with TRC105 in combination with bevacizumab as compared to bevacizumab alone. (Phase II) II. To assess the overall survival of patients treated with TRC105 in combination with bevacizumab compared to bevacizumab alone. (Phase II) III. To compare the impact of the treatment on the patients quality of life (QOL) using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire (QLQ)-C15-Palliative Care (PAL) and QLQ-brain neoplasm (BN)20 Patient Questionnaires. (Phase II) IV. To estimate patient recommendations for study participation to others using the Was It Worth It (WIWI) Questionnaire. (Phase II)

TERTIARY OBJECTIVES:

I. To evaluate the pharmacokinetics of TRC105. (Phase I) II. To evaluate the immunogenicity of TRC105. (Phase I) III. To determine the relationship between tumor biomarkers, circulating biomarkers of vascular response and vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) single-nucleotide polymorphisms (SNPs) in predicting efficacy and/or toxicity of treatment. (Phase II) IV. To assess the utility of magnetic resonance imaging (MRI) imaging including apparent diffusion coefficient (ADC) as a predictor of response and survival. (Phase II) V. To assess the utility of dynamic contrast enhanced (DCE) MRI as a predictor of response to bevacizumab with or without TRC105. (Phase II)

OUTLINE: This is a phase I dose-escalation study of anti-endoglin monoclonal antibody TRC105, followed by a randomized phase II study.

Phase I (closed to accrual 1/14/14): Patients receive bevacizumab intravenously (IV) over 30-90 minutes on day 1 and anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 and 11 of course 1 and days 1 and 8 of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Phase II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive bevacizumab IV over 30-90 minutes on day 1 and anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 and 11 of course 1 and days 1 and 8 of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 3 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 116
• Est. completion date: April 15, 2017
• Est. primary completion date: May 11, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histological confirmation of grade 3 or 4 glioma, including astrocytoma, oligodendroglioma, and mixed gliomas, as determined by pre-registration central pathology review (Phase I)

• Histological confirmation of glioblastoma multiforme (grade 4 astrocytoma) as determined by pre-registration central pathology review; note: gliosarcomas and other grade 4 astrocytoma variants (e.g., giant cell) are eligible; glioblastoma (GBM) with oligodendroglial features are NOT PERMITTED in this study if they are 1p19q co-deleted; sites submitting GBM with oligodendroglial features will be asked to provide results of 1p/19q co-deletion status (Phase II)

• Evidence of tumor progression by MRI or computed tomography (CT) scan following radiation therapy or following the most recent anti-tumor therapy; note: patients who have had surgical treatment at recurrence are eligible if they had a resection with measurable or non-measurable residual disease on postoperative imaging or if there is imaging evidence of disease progression as compared to the first postoperative scan

• Measurable or evaluable disease by gadolinium MRI or contrast CT scan; note: patients who have had a gross total resection (GTR) are eligible on the basis of evaluable disease

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2

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

• Platelet count >= 100,000/mm^3

• White blood cells (WBC) >= 3,000/mL

• Hemoglobin >= 10.0 g/dL; note: this level may be reached by transfusion

• Total bilirubin =< institutional upper limit of normal (ULN)

• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2 x ULN

• Creatinine =< ULN

• Life expectancy >= 12 weeks

• Negative serum pregnancy test done =< 7 days prior to registration, for women of childbearing potential only

• Urine protein creatinine (UPC) ratio < 1; note: urine protein must be screened by urine analysis for UPC ratio; for UPC ratio >= 1.0, 24-hour urine protein must be obtained and the level should be < 1,000 mg for registration

• Fixed or decreasing dose of corticosteroids (or no corticosteroids) >= 7 days prior to registration

• Calculated glomerular filtration rate (GFR) must be >= 60 ml/min; GFR will be calculated as needed per institutional guidelines

• Any number of prior chemotherapy regimens for recurrent disease (Phase I); =< 1 chemotherapy or other non-antiangiogenic regimen for recurrent disease (Phase II)

• Last dose of bevacizumab >= 2 weeks prior to registration (Phase I); note: for the phase II study only, prior exposure to bevacizumab is not allowed

• Surgery >= 4 weeks prior to registration

• Completion of radiation therapy >= 12 weeks prior to registration and prior chemotherapy >= 4 weeks prior to registration (>= 6 weeks from nitrosourea-containing regimens)

• Small molecular cell cycle inhibitors >= 2 weeks from registration

• Ability to provide informed written consent

• Ability to complete questionnaire(s) by themselves or with assistance

• Willing to return to enrolling institution for follow-up

• Willing to discontinue use of medications that inhibit platelet function >= 10 days prior to registration; aspirin at doses greater than 325 mg/day must be discontinued >= 10 days prior to registration and avoided through the study; note: nonsteroidal anti-inflammatory drug (NSAID) medications are recommended in place of aspirin; if NSAIDs or aspirin are used, histamine (H)-2 blockers and proton pump inhibitor (PPI) medications are recommended

• Willing to provide mandatory blood and tissue samples for correlative research purposes (Phase I and II)

Exclusion Criteria:

• Any of the following:

• Pregnant women

• Nursing women

• Men or women of childbearing potential who are unwilling to employ adequate contraception throughout the duration of the study and for at least 6 months after treatment has ended

• Prior hypersensitivity to bevacizumab or toxicity requiring discontinuation of bevacizumab (Phase I)

• Any prior exposure to any VEGF or VEGF inhibitor including, but not limited to, bevacizumab, cediranib, vandetanib, sunitinib, pazopanib, aflibercept, or sorafenib (Phase II)

• Prior hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies (Phase I and II)

• Prior hypersensitivity to triptan derivatives (Phase I and II)

• Other active malignancy =< 3 years prior to registration; exceptions: non-melanotic skin cancer or carcinoma-in-situ of the cervix; note: if there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy) for their cancer

• Uncontrolled infection

• Immunocompromised patients or patients known to be human immunodeficiency virus (HIV) positive and currently receiving combination antiretroviral therapy; patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial

• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and adverse events of the prescribed regimens

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements

• History of hypertensive crisis or hypertensive encephalopathy

• Clinically significant cardiovascular disease defined as follows:

• Inadequately controlled hypertension (i.e., systolic blood pressure [SBP] > 160 mm Hg and/or diastolic blood pressure [DBP] > 90 mm Hg despite antihypertensive therapy)

• History of cerebrovascular accident (CVA) within 6 months

• Myocardial infarction or unstable angina within 6 months

• New York Heart Association classification II, III, or IV cardiovascular disease

• Serious and inadequately controlled cardiac arrhythmia

• Significant vascular disease (i.e., aortic aneurysm, history of aortic dissection)

• Clinically significant peripheral vascular disease

• Evidence or history of bleeding diathesis (greater than normal risk of bleeding, i.e., hereditary hemorrhagic telangiectasia type I or HHT-1) or coagulopathy in the absence of therapeutic anti-coagulation or any hemorrhage/bleeding event > grade 3 within 4 weeks prior to registration; note: patients with full-dose anticoagulants are eligible provided the patient has been on a stable dose for at least 2 weeks of low molecular weight heparin; therapeutic Coumadin and aspirin doses > 325 mg daily are not allowed

• Receiving any other investigational agent that would be considered as a treatment for the primary neoplasm

• Prior treatment with TRC105

• Serious or non-healing wound, active ulcer, or untreated bone fracture

• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess =< 6 months prior to registration

• History of invasive procedures defined as follows:

• Major surgical procedure, open biopsy, or significant traumatic injury =< 28 days prior to registration

• Anticipation of need for major surgical procedures during the study

• Core biopsy =< 7 days prior to registration

• History of significant vascular disease (i.e., aortic aneurysm requiring surgical repair, or recent peripheral arterial thrombosis) within 6 months prior to registration

Related Conditions & MeSH terms

• Adult Anaplastic Astrocytoma
• Adult Anaplastic Oligodendroglioma
• Adult Giant Cell Glioblastoma
• Adult Glioblastoma
• Adult Gliosarcoma
• Adult Mixed Glioma
• Astrocytoma
• Brain Neoplasms
• Glioblastoma
• Glioma
• Gliosarcoma
• Oligodendroglioma
• Recurrent Adult Brain Neoplasm

Intervention

Biological:
• Anti-Endoglin Chimeric Monoclonal Antibody TRC105
Given IV
• Bevacizumab
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies
• Pharmacological Study
Correlative studies
• Quality-of-Life Assessment
Ancillary studies

Locations

Country	Name	City	State
United States	Bixby Medical Center	Adrian	Michigan
United States	Hickman Cancer Center	Adrian	Michigan
United States	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania
United States	Mary Greeley Medical Center	Ames	Iowa
United States	McFarland Clinic PC-William R Bliss Cancer Center	Ames	Iowa
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	Hematology Oncology Associates of Central New York-Auburn	Auburn	New York
United States	University Medical Center Brackenridge	Austin	Texas
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Bronson Battle Creek	Battle Creek	Michigan
United States	Strecker Cancer Center-Belpre	Belpre	Ohio
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	Constantinou, Costas L MD (UIA Investigator)	Bettendorf	Iowa
United States	Billings Clinic Cancer Center	Billings	Montana
United States	Montana Cancer Consortium NCORP	Billings	Montana
United States	Saint Vincent Healthcare	Billings	Montana
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Saint Joseph Medical Center	Bloomington	Illinois
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Parkland Health Center-Bonne Terre	Bonne Terre	Missouri
United States	McFarland Clinic PC-Boone	Boone	Iowa
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Toledo Clinic Cancer Centers-Bowling Green	Bowling Green	Ohio
United States	Bozeman Deaconess Hospital	Bozeman	Montana
United States	Lafayette Family Cancer Center-EMMC	Brewer	Maine
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Saint James Community Hospital and Cancer Treatment Center	Butte	Montana
United States	Cooper Hospital University Medical Center	Camden	New Jersey
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Southeast Cancer Center	Cape Girardeau	Missouri
United States	Memorial Hospital of Carbondale	Carbondale	Illinois
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	Rocky Mountain Oncology	Casper	Wyoming
United States	Mercy Hospital	Cedar Rapids	Iowa
United States	Oncology Associates at Mercy Medical Center	Cedar Rapids	Iowa
United States	Centralia Oncology Clinic	Centralia	Illinois
United States	Cancer Center of Kansas - Chanute	Chanute	Kansas
United States	Massachusetts General Hospital	Charlestown	Massachusetts
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	Northwestern University	Chicago	Illinois
United States	Adena Regional Medical Center	Chillicothe	Ohio
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	Big Horn Basin Cancer Center	Cody	Wyoming
United States	Billings Clinic-Cody	Cody	Wyoming
United States	Kootenai Medical Center	Coeur d'Alene	Idaho
United States	Columbus NCI Community Oncology Research Program	Columbus	Ohio
United States	Columbus Oncology and Hematology Associates Inc	Columbus	Ohio
United States	Doctors Hospital	Columbus	Ohio
United States	Grant Medical Center	Columbus	Ohio
United States	Mount Carmel Health Center West	Columbus	Ohio
United States	Riverside Methodist Hospital	Columbus	Ohio
United States	The Mark H Zangmeister Center	Columbus	Ohio
United States	New Hampshire Oncology Hematology PA-Concord	Concord	New Hampshire
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	Baptist Health Corbin	Corbin	Kentucky
United States	Oncology Hematology Care Inc-Crestview	Crestview Hills	Kentucky
United States	Michiana Hematology Oncology PC-Crown Point	Crown Point	Indiana
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Good Samaritan Hospital - Dayton	Dayton	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Samaritan North Health Center	Dayton	Ohio
United States	Beaumont Hospital-Dearborn	Dearborn	Michigan
United States	Cancer Care Center of Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Delaware Health Center-Grady Cancer Center	Delaware	Ohio
United States	Delaware Radiation Oncology	Delaware	Ohio
United States	Grady Memorial Hospital	Delaware	Ohio
United States	Saint John Hospital and Medical Center	Detroit	Michigan
United States	Cancer Center of Kansas - Dodge City	Dodge City	Kansas
United States	Essentia Health Cancer Center	Duluth	Minnesota
United States	Essentia Health Saint Mary's Medical Center	Duluth	Minnesota
United States	Miller-Dwan Hospital	Duluth	Minnesota
United States	Saint Luke's Hospital of Duluth	Duluth	Minnesota
United States	Greenville Health System Cancer Institute-Easley	Easley	South Carolina
United States	Hematology Oncology Associates of Central New York-East Syracuse	East Syracuse	New York
United States	Fairview-Southdale Hospital	Edina	Minnesota
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Cancer Center of Kansas - El Dorado	El Dorado	Kansas
United States	Hardin Memorial Hospital	Elizabethtown	Kentucky
United States	Elkhart Clinic	Elkhart	Indiana
United States	Elkhart General Hospital	Elkhart	Indiana
United States	Michiana Hematology Oncology PC-Elkhart	Elkhart	Indiana
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois
United States	Oncology Hematology Care Inc-Healthplex	Fairfield	Ohio
United States	Blanchard Valley Hospital	Findlay	Ohio
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	McFarland Clinic PC-Trinity Cancer Center	Fort Dodge	Iowa
United States	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas
United States	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio
United States	Fredericksburg Oncology Inc	Fredericksburg	Virginia
United States	Unity Hospital	Fridley	Minnesota
United States	Saint Jude Medical Center	Fullerton	California
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Western Illinois Cancer Treatment Center	Galesburg	Illinois
United States	NorthShore University HealthSystem-Glenbrook Hospital	Glenview	Illinois
United States	Wayne Memorial Hospital	Goldsboro	North Carolina
United States	Altru Cancer Center	Grand Forks	North Dakota
United States	Mercy Health Saint Mary's	Grand Rapids	Michigan
United States	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan
United States	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana
United States	Greenville Health System Cancer Institute-Andrews	Greenville	South Carolina
United States	Greenville Health System Cancer Institute-Butternut	Greenville	South Carolina
United States	Greenville Health System Cancer Institute-Eastside	Greenville	South Carolina
United States	Greenville Health System Cancer Institute-Faris	Greenville	South Carolina
United States	Greenville Memorial Hospital	Greenville	South Carolina
United States	Wayne Hospital	Greenville	Ohio
United States	Greenwich Hospital	Greenwich	Connecticut
United States	Greenville Health System Cancer Institute-Greer	Greer	South Carolina
United States	PinnacleHealth Cancer Center-Community Campus	Harrisburg	Pennsylvania
United States	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut
United States	Saint Peter's Community Hospital	Helena	Montana
United States	Hematology Oncology Associates of Illinois-Highland Park	Highland Park	Illinois
United States	NorthShore University HealthSystem-Highland Park Hospital	Highland Park	Illinois
United States	New Hampshire Oncology Hematology PA-Hooksett	Hooksett	New Hampshire
United States	Hutchinson Area Health Care	Hutchinson	Minnesota
United States	Cancer Center of Kansas-Independence	Independence	Kansas
United States	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	Allegiance Health	Jackson	Michigan
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	McFarland Clinic PC-Jefferson	Jefferson	Iowa
United States	Capital Region Medical Center-Goldschmidt Cancer Center	Jefferson City	Missouri
United States	Borgess Medical Center	Kalamazoo	Michigan
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	Presence Saint Mary's Hospital	Kankakee	Illinois
United States	Kettering Medical Center	Kettering	Ohio
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	Cancer Center of Kansas-Kingman	Kingman	Kansas
United States	Kinston Medical Specialists PA	Kinston	North Carolina
United States	Community Howard Regional Health	Kokomo	Indiana
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	IU Health La Porte Hospital	La Porte	Indiana
United States	LRGHealthcare-Lakes Region General Hospital	Laconia	New Hampshire
United States	Fairfield Medical Center	Lancaster	Ohio
United States	Sparrow Hospital	Lansing	Michigan
United States	Lawrence Memorial Hospital	Lawrence	Kansas
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	Beebe Medical Center	Lewes	Delaware
United States	Baptist Health Lexington	Lexington	Kentucky
United States	Cancer Center of Kansas-Liberal	Liberal	Kansas
United States	NorthShore Hematology Oncology-Libertyville	Libertyville	Illinois
United States	Lima Memorial Hospital	Lima	Ohio
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Saint Mary Mercy Hospital	Livonia	Michigan
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	Baptist Health Madisonville/Merle Mahr Cancer Center	Madisonville	Kentucky
United States	Cancer Center of Kansas-Manhattan	Manhattan	Kansas
United States	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota
United States	Saint John's Hospital - Healtheast	Maplewood	Minnesota
United States	Marietta Memorial Hospital	Marietta	Ohio
United States	OneHealth Marion General Hospital	Marion	Ohio
United States	McFarland Clinic PC-Marshalltown	Marshalltown	Iowa
United States	Toledo Clinic Cancer Centers-Maumee	Maumee	Ohio
United States	Toledo Radiation Oncology at Northwest Ohio Onocolgy Center	Maumee	Ohio
United States	Cancer Center of Kansas - McPherson	McPherson	Kansas
United States	Community Memorial Hospital	Menomonee Falls	Wisconsin
United States	Mount Sinai Medical Center	Miami Beach	Florida
United States	Froedtert and the 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	Memorial Regional Cancer Center Day Road	Mishawaka	Indiana
United States	Michiana Hematology Oncology PC-Mishawaka	Mishawaka	Indiana
United States	Saint Joseph Regional Medical Center-Mishawaka	Mishawaka	Indiana
United States	Community Medical Hospital	Missoula	Montana
United States	Saint Patrick Hospital - Community Hospital	Missoula	Montana
United States	Garneau, Stewart C MD (UIA Investigator)	Moline	Illinois
United States	Spector, David MD (UIA Investigator)	Moline	Illinois
United States	Trinity Medical Center	Moline	Illinois
United States	Mercy Memorial Hospital	Monroe	Michigan
United States	Toledo Clinic Cancer Centers-Monroe	Monroe	Michigan
United States	Knox Community Hospital	Mount Vernon	Ohio
United States	ProHealth D N Greenwald Center	Mukwonago	Wisconsin
United States	Mercy Health Mercy Campus	Muskegon	Michigan
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	Mount Sinai Hospital	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	Licking Memorial Hospital	Newark	Ohio
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Newark Radiation Oncology	Newark	Ohio
United States	Regional Hematology and Oncology PA	Newark	Delaware
United States	Cancer Center of Kansas - Newton	Newton	Kansas
United States	Illinois Cancer Specialists-Niles	Niles	Illinois
United States	Lakeland Community Hospital	Niles	Michigan
United States	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Saint Joseph Hospital - Orange	Orange	California
United States	Saint Charles Hospital	Oregon	Ohio
United States	Toledo Clinic Cancer Centers-Oregon	Oregon	Ohio
United States	Florida Hospital Orlando	Orlando	Florida
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	Radiation Oncology of Northern Illinois	Ottawa	Illinois
United States	Baptist Health Paducah	Paducah	Kentucky
United States	Cancer Center of Kansas - Parsons	Parsons	Kansas
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	OSF Saint Francis Radiation Oncology at Pekin Cancer Treatment Center	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	OSF Saint Francis Radiation Oncology at Peoria Cancer Center	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Valley Radiation Oncology	Peru	Illinois
United States	Michiana Hematology Oncology PC-Plymouth	Plymouth	Indiana
United States	Saint Joseph Mercy Oakland	Pontiac	Michigan
United States	Lake Huron Medical Center	Port Huron	Michigan
United States	Southern Ohio Medical Center	Portsmouth	Ohio
United States	Kootenai Cancer Center	Post Falls	Idaho
United States	Cancer Center of Kansas - Pratt	Pratt	Kansas
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Rapid City Regional Hospital	Rapid City	South Dakota
United States	Spectrum Health Reed City Hospital	Reed City	Michigan
United States	Beebe Health Campus	Rehoboth Beach	Delaware
United States	Reid Health	Richmond	Indiana
United States	North Memorial Medical Health Center	Robbinsdale	Minnesota
United States	Mayo Clinic	Rochester	Minnesota
United States	Saint Mary's of Michigan	Saginaw	Michigan
United States	Coborn Cancer Center at Saint Cloud Hospital	Saint Cloud	Minnesota
United States	Saint Cloud Hospital	Saint Cloud	Minnesota
United States	Lakeland Hospital	Saint Joseph	Michigan
United States	Marie Yeager Cancer Center	Saint Joseph	Michigan
United States	Missouri Baptist Medical Center	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	Sainte Genevieve County Memorial Hospital	Sainte Genevieve	Missouri
United States	Cancer Center of Kansas - Salina	Salina	Kansas
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	Sharp Memorial Hospital	San Diego	California
United States	UCSF Medical Center-Mount Zion	San Francisco	California
United States	UCSF Medical Center-Parnassus	San Francisco	California
United States	Kootenai Cancer Clinic	Sandpoint	Idaho
United States	Maine Center for Cancer Medicine-Scarborough	Scarborough	Maine
United States	Nanticoke Memorial Hospital	Seaford	Delaware
United States	Greenville Health System Cancer Institute-Seneca	Seneca	South Carolina
United States	Saint Francis Regional Medical Center	Shakopee	Minnesota
United States	Welch Cancer Center	Sheridan	Wyoming
United States	Mercy Medical Center-Sioux City	Sioux City	Iowa
United States	Saint Luke's Regional Medical Center	Sioux City	Iowa
United States	Siouxland Regional Cancer Center	Sioux City	Iowa
United States	Hematology Oncology Associates of Illinois - Skokie	Skokie	Illinois
United States	Memorial Hospital of South Bend	South Bend	Indiana
United States	Michiana Hematology Oncology PC-South Bend	South Bend	Indiana
United States	Northern Indiana Cancer Research Consortium	South Bend	Indiana
United States	South Bend Clinic	South Bend	Indiana
United States	Greenville Health System Cancer Institute-Spartanburg	Spartanburg	South Carolina
United States	Central Illinois Hematology Oncology Center	Springfield	Illinois
United States	Memorial Medical Center	Springfield	Illinois
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Springfield Clinic	Springfield	Illinois
United States	Springfield Regional Medical Center	Springfield	Ohio
United States	Stamford Hospital/Bennett Cancer Center	Stamford	Connecticut
United States	Lakeview Hospital	Stillwater	Minnesota
United States	Missouri Baptist Sullivan Hospital	Sullivan	Missouri
United States	Missouri Baptist Outpatient Center-Sunset Hills	Sunset Hills	Missouri
United States	Cancer Care Specialists of Illinois-Swansea	Swansea	Illinois
United States	Flower Hospital	Sylvania	Ohio
United States	Hematology Oncology Associates of Central New York-Onondaga Hill	Syracuse	New York
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Mercy Hospital of Tiffin	Tiffin	Ohio
United States	Mercy Saint Anne Hospital	Toledo	Ohio
United States	Saint Vincent Mercy Medical Center	Toledo	Ohio
United States	Toledo Clinic Cancer Centers-Toledo	Toledo	Ohio
United States	Toledo Community Hospital Oncology Program CCOP	Toledo	Ohio
United States	University of Toledo	Toledo	Ohio
United States	Munson Medical Center	Traverse City	Michigan
United States	Upper Valley Medical Center	Troy	Ohio
United States	Oklahoma Cancer Specialists and Research Institute-Tulsa	Tulsa	Oklahoma
United States	MD Anderson Cancer Center at Cooper-Voorhees	Voorhees	New Jersey
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	Saint John Macomb-Oakland Hospital	Warren	Michigan
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	ProHealth Waukesha Memorial Hospital	Waukesha	Wisconsin
United States	Fulton County Health Center	Wauseon	Ohio
United States	Cancer Center of Kansas - Wellington	Wellington	Kansas
United States	Reading Hospital	West Reading	Pennsylvania
United States	Saint Ann's Hospital	Westerville	Ohio
United States	Michiana Hematology Oncology PC-Westville	Westville	Indiana
United States	Associates In Womens Health	Wichita	Kansas
United States	Cancer Center of Kansas - Wichita	Wichita	Kansas
United States	Cancer Center of Kansas-Wichita Medical Arts Tower	Wichita	Kansas
United States	Via Christi Regional Medical Center	Wichita	Kansas
United States	Wichita NCI Community Oncology Research Program	Wichita	Kansas
United States	Rice Memorial Hospital	Willmar	Minnesota
United States	Christiana Care Health System-Wilmington Hospital	Wilmington	Delaware
United States	Cancer Center of Kansas - Winfield	Winfield	Kansas
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota
United States	Ann Arbor Hematology -Oncology Associates	Ypsilanti	Michigan
United States	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in DCE-MRI Utility	Associations between the change of DCE-MRI and PFS6 will be assessed using two-sample t-test.	Baseline to up to 2 years
Other	Change in MRI ADC Utility	MRI ADC histogram metrics such as overall ADC, mean ADC of lower curve, percentage of ADC in lower curve, and skewness at baseline and change from baseline to the first follow-up MRI will be analyzed for association with progression free and overall survival. Kaplan-Meier survival curves, logrank and Cox regression tests will be used to estimate and compare the equality of the overall survival and progression-time distributions of patient subsets defined by the ADC histogram metrics.	Baseline to up to 2 years
Other	Changes in Tumor and Circulating Biomarkers	Binary endpoints and categorical endpoints will be compared using Chi-Squared or Fisher's Exact tests between treatment groups. Continuous endpoints will be analyzed using change-from-baseline measures and compared using t-tests between treatment groups and time-points. Cox proportional hazards regression will be used to determine if there are differences in PFS and OS between the treatment groups after correcting for each biomarker in conjunction with standard clinical variables.	Baseline to up to 2 years
Primary	Maximum Tolerated Dose (MTD) (Phase I) as Measured by the Number of Participants With Dose Limiting Toxicities	MTD for this study will be defined as the highest safely tolerated dose level where at most 1 out of 6 patients experience dose-limiting toxicity (DLT) with the next higher dose having at least 2 patients out of a maximum of 6 patients experience DLT. A total of 6 patients treated at the MTD will be sufficient to identify common toxicities at the MTD. The number of DLT's will be reported here.	28 days
Primary	Progression-free Survival (PFS) (Phase II)	Progression Free Survival time is defined as the time from study randomization to documentation of disease progression. Patients who die without documentation of progression will be considered to have had tumor progression at the time of death. Patients who fail to return for evaluation after beginning therapy will be censored for progression on the last day of therapy or date last known to be alive, whichever is later. Patients who are still alive and have not progressed will be censored for progression at the time of the last tumor assessment. The time-to-progression distribution will be estimated using the Kaplan-Meier method.	The time from study randomization to documentation of disease progression, assessed up to 2 years
Secondary	Overall Toxicity Rate for Grade 3 or Higher Adverse Events Considered at Least Possibly Related to Treatment (Phase II)	The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns within patient groups. The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment will be compared using a Fisher's Exact test between the 2 treatment groups.	Up to 2 years
Secondary	Overall Survival (Phase II)	Survival time is defined to be the length of time from start of study therapy to death due to any cause. All patients meeting the eligibility criteria that have signed a consent form and begun treatment will be considered evaluable for estimation of the survival distribution. The distribution of overall survival for both groups of the study will be estimated using the Kaplan-Meier method, and be compared using log-rank tests.	The time from start of study therapy to death due to any cause, assessed up to 2 years
Secondary	Progression Free Survival at 6 Months (PFS6) (Phase II) as Measured by the Percentage of Participants With Progression Free Survival at 6 Months	PFS6 is defined as the time from start of study therapy to the date of first observation of disease progression or death due to any cause (whichever comes first). The medians and confidence intervals given are the Kaplan-Meier estimates.	The time from study randomization to documentation of disease progression, assessed at 6 months
Secondary	Quality of Life (QOL) as Assessed by the EORTC QLQ-C15-PAL Questionnaire [Item 15: Global Health Status/Quality of Life] (Phase II)	Quality of Life (QOL) as assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C15-PAL questionnaire, as measured by the change from baseline to the end of cycle 2 (4 weeks) in the EORTC QLQ-C15-PAL item 15, Global health status/quality of life, score. The assessment was scored using EORTC's scoring algorithms. The score range is from 0-100 (0 corresponding to worst outcome; 100 corresponding to best outcome). Range of the change in scores from baseline to cycle 2 (4 weeks) is (-100,100). The mean change in score and 95% confidence interval of the change from baseline to the end of cycle 2 (4 weeks) are reported below.	Baseline and 4 weeks
Secondary	QOL Assessed by EORTC-QLQ-BN20 Patient Questionnaire [Items 1-20] (Phase II)	QOL assessed by EORTC-QLQ-BN20 Patient Questionnaire (Brain cancer module), as measured by the change from baseline to the end of cycle 2 (4 weeks) in the EORTC QLQ-BN20 Items 1-20 are used to score the following 11 symptom scales: Future uncertainty (Items 1-3,5), Visual disorder (Items 6-8), Motor dysfunction (Items 10,15, 19), Communication deficit (Items 11-13), Headaches (Item 4), Seizures (Item 9), Drowsiness (Item 14), Itchy Skin (Item 17), Hair Loss (Item 16), Weakness of legs (Item 18), and Bladder control (Item 20). The assessment was scored using EORTC's scoring algorithms. The score range for each of the 11 symptom scales is from 0-100 (0 corresponding to not severe;100 corresponding to most severe). Range of changes in scores from baseline to cycle 2 (4 weeks) is (-100,100). The mean change in score and 95% confidence interval of each symptom scale are reported below.	Baseline and 4 weeks
Secondary	QOL Assessed by WIWI Questionnaire (Phase II)	Quality of life (QOL) assessed by Was it worth it? (WIWI) questionnaire, as measured by the percentage of patients answering yes to the question "Was it worthwhile for you to participate in this research study?"	Up to 4 weeks