Bevacizumab With or Without Trebananib in Treating Patients With Recurrent Brain Tumors

Glioblastoma Clinical Trial

Official title:

Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01609790
• Other study ID #: NCI-2012-01969
• Secondary ID: NCI-2012-01969S1
• Status: Completed
• Phase: Phase 2
• Start date: June 4, 2012
• Est. completion date: May 20, 2022

Study information

• Verified date: May 2022
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This partially randomized phase II trial with a safety run-in component studies the side effects and how well bevacizumab given with or without trebananib works in treating patients with brain tumors that have come back (recurrent). Immunotherapy with monoclonal antibodies, such as bevacizumab, may induce changes in the body's immune system and interfere with the ability of tumor cells to grow and spread. Trebananib may stop the growth of tumor cells by blocking blood flow to the tumor. It is not yet known whether giving bevacizumab together with trebananib is more effective than bevacizumab alone in treating brain tumors.

Description:

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of AMG 386 (trebananib) 15 mg/kg weekly in combination with bevacizumab 10 mg/kg every 2 weeks (Cohort 1). (closed to accrual 10/2/12) II. To assess the efficacy of AMG 386 in combination with bevacizumab 10 mg/kg every 2 weeks compared to bevacizumab monotherapy in bevacizumab-naive patients, as measured by 6-month progression-free survival (PFS6) (Cohort 2).

SECONDARY OBJECTIVES:

I. To further assess the toxicity profile (Cohorts 1 and 2). II. To assess feasibility of AMG 386 15 mg/kg weekly in combination with bevacizumab 10 mg/kg every 2 weeks (Cohort 1 [closed to accrual 10/2/12]), as measured by the percentage of patients requiring dose reduction/interruption or discontinuation in the first 2 and subsequent cycles.

III. To determine the radiographic response rate (RR), median progression-free survival (PFS), and overall survival (OS) in bevacizumab-naive patients (Cohort 2).

IV. To assess the efficacy of AMG 386 15 mg/kg weekly in combination with bevacizumab 10 mg/kg every 2 weeks in patients who have progressed while on bevacizumab, as measured by overall survival (OS) (cross-over from placebo arm of Cohort 2).

V. To correlate outcome to treatment with tumor genotype, expression profile, and circulating angiogenesis biomarkers in tumor specimens (Cohort 2).

VI. To determine the RR, PFS6, and PFS in patients who have progressed while on bevacizumab therapy and receive AMG 386 in combination with bevacizumab (cross-over from placebo arm of Cohort 2).

VII. To determine the serum pharmacokinetics of AMG 386 in patients receiving bevacizumab (Cohort 1 and cross-over from placebo arm of Cohort 2).

OUTLINE: This is a safety study (cohort 1 [closed to accrual 10/2/12]) followed by a randomized study (cohort 2).

Cohort 1: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15 and trebananib IV over 30-60 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/2/12)

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

ARM I: Patients receive bevacizumab and trebananib as in Cohort 1.

ARM II: Patients receive bevacizumab as in Arm I and placebo IV over 30-60 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may cross over to Arm I.

After completion of study treatment, patients are followed up at 30 days, every 2 months for 1 year, every 6 months for 1 year, and then annually thereafter.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 137
• Est. completion date: May 20, 2022
• Est. primary completion date: October 2, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically proven diagnosis of glioblastoma or variants (gliosarcoma, glioblastoma with oligodendroglial features, giant cell glioblastoma); patients will be eligible if the original histology was a lower grade glioma and a subsequent histological diagnosis of glioblastoma or variants is made

• The tumor must be supratentorial; patients with infratentorial disease, spinal cord disease, and/or leptomeningeal disease are excluded

• Patients must have shown unequivocal evidence for tumor progression on the previous treatment regimen (prior to enrollment on this study) by magnetic resonance imaging (MRI) scan of the brain with and without contrast within 14 days prior to registration; the dose of steroids must be stable or decreasing for at least 5 days prior to the scan; patients with tumor progression who then undergo surgical resection prior to enrollment on study may be eligible as long as pathology confirms progressive or recurrent glioblastoma multiforme (GBM) (or variants); for patients who undergo surgical resection, registration on study may not occur any sooner than 28 days from surgery; an MRI scan of the brain with and without contrast is still required within 14 days prior to registration on study but is not required to demonstrate measurable disease or tumor progression after surgery

• Patients unable to undergo MRI because of non-compatible devices can be enrolled, provided computed tomography (CT) scans are obtained and are of sufficient quality; patients without non-compatible devices may not have CT scans performed to meet this requirement

• History/physical examination within 14 days prior to registration

• Karnofsky performance scale >= 70 within 14 days prior to registration

• Patients who have received prior treatment with interstitial brachytherapy, stereotactic radiosurgery, or implanted chemotherapy sources, such as wafers of polifeprosan 20 with carmustine, must have confirmation of progressive disease within 14 days prior to registration based upon nuclear imaging, magnetic resonance (MR) spectroscopy, perfusion imaging, or histopathology

• Leukocytes > 3,000/mm^3 (within 14 days prior to registration)

• Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (within 14 days prior to registration)

• Hemoglobin >= 10.0 g/dL (note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 10.0 g/dL is acceptable) (within 14 days prior to registration)

• Platelets >= 100,000 cells/mm^3 (within 14 days prior to registration)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 X institutional upper limit of normal (within 14 days prior to registration)

• Bilirubin =< 2.0 mg/dL (within 14 days prior to registration)

• Creatinine within normal upper institutional limits or creatinine clearance > 60 mL/min/1.73 m^2 (per 24 hour urine collection or calculated according to the Cockcroft-Gault formula) for subjects with creatinine levels above the institutional normal (within 14 days prior to registration)

• Patients with creatinine levels below normal institutional limits are eligible

• Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 (within 14 days prior to registration)

• Urinary protein =< 30 mg/dL in urinalysis or =< 1+ on dipstick (within 14 days prior to registration)

• Generally well-controlled blood pressure with systolic blood pressure =< 140 mm Hg AND diastolic blood pressure =< 90 mm Hg within 5 days prior to registration; the use of anti-hypertensive medications to control hypertension is permitted

• Women of childbearing potential must have a negative serum beta-human chorionic gonadotropin (HCG) pregnancy test within 14 days prior to registration

• Women of childbearing potential and male patients who are sexually active must practice adequate contraception during therapy and for 180 days (6 months) afterwards

• Patient must provide study specific informed consent prior to study entry

Exclusion Criteria:

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)

• Prior systemic cytotoxic chemotherapy within (i.e., =<) 28 days (42 days for nitrosoureas or mitomycin C) prior to registration, or patients who have not returned to baseline or =< Common Terminology Criteria for Adverse Events (CTCAE) version 4 (v. 4) grade 2 from adverse events (excluding alopecia) due to agents administered more than 28 days prior to registration

• Patients who received non-cytotoxic drug therapy must be off treatment for at least 14 days prior to registration; prior treatment with anti-vascular endothelial growth factor (VEGF) targeted agents; AMG 386 therapy; or other molecules that inhibit angiopoietins or TEK tyrosine kinase, endothelial (Tie2) receptor including, but not limited to, XL-820, XL-184 (cabozantinib-s-malate), and CVX-060/PF-4856884 is not allowed regardless of time frame

• Patients who have not yet completed at least 21 days (30 days for prior monoclonal antibody therapy) since ending other investigational device or drug trials, or who are currently receiving other investigational treatments

• Treatment within 30 days prior to enrollment with strong immune modulators, including but not limited to systemic cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, methotrexate, azathioprine, rapamycin, thalidomide, lenalidomide, and targeted immune modulators such as abatacept (CTLA-4-Ig), adalimumab, alefacept, anakinra, belatacept (LEA29Y), efalizumab, etanercept, infliximab, or rituximab

• Prior radiotherapy within 90 days (3 months) prior to registration unless there is either: a) histopathologic confirmation of recurrent tumor; or b) new enhancement on MRI outside of the radiation treatment field

• Major surgical procedure (including craniotomy and open brain biopsy) or significant traumatic injury within 28 days prior to registration or those patients who receive a non-central nervous system (CNS) minor surgical procedures (e.g. core biopsy or fine needle aspiration) within 3 days prior to registration; there is no waiting period for central line placement; there is a 7-day window for recovery prior to registration for patients who underwent stereotactic biopsy of the brain

• Prior therapy with anti-VEGF targeted agents (e.g. bevacizumab, cediranib, vandetanib, aflibercept, sunitinib, sorafenib, etc.); prior therapy with thalidomide and lenalidomide is allowed as long as treatment has not occurred within 30 days prior to enrollment

• More than 2 relapses

• Therapeutic anticoagulation with warfarin < 7 days prior to registration; (therapeutic or prophylactic therapy with aspirin, a low-molecular weight heparin, or a Factor Xa inhibitor is acceptable)

• Intratumoral hemorrhage or peritumoral hemorrhage, demonstrated by MRI or CT scan, CTCAE, v. 4 grade 2 or greater or evidence of significant hemorrhage (regardless of CTCAE, v. 4 grade) defined as > 1 cm diameter of blood (including postoperative hemorrhage)

• Gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE, v. 4 grade 3 or greater within 30 days prior to study entry

• Severe, active co-morbidity, defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalization within 180 days (6 months) prior to registration

• Transmural myocardial infarction within 180 days (6 months) prior to registration

• History of stroke, cerebral vascular accident (CVA), or transient ischemic attack within 180 days (6 months) prior to registration

• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration

• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration

• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

• Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol

• Known coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhages in the past

• History of non-healing wounds or ulcers, or bone fractures within 90 days (3 months) prior to registration

• History of venous or arterial thromboembolism within 12 months prior to registration

• Prior allergic reaction to the study drugs involved in this study

Related Conditions & MeSH terms

• Brain Neoplasms
• Giant Cell Glioblastoma
• Glioblastoma
• Gliosarcoma
• Oligodendroglioma
• Recurrence
• Recurrent Brain Neoplasm
• Recurrent Glioblastoma

Intervention

Biological:
• Bevacizumab
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies
• Pharmacological Study
Correlative studies
• Placebo Administration
Given IV

Biological:
• Trebananib
Given IV

Locations

Country	Name	City	State
Canada	Allan Blair Cancer Centre	Regina	Saskatchewan
United States	Cleveland Clinic Akron General	Akron	Ohio
United States	Summa Health System - Akron Campus	Akron	Ohio
United States	New York Oncology Hematology PC - Albany	Albany	New York
United States	New York Oncology Hematology PC - Albany Medical Center	Albany	New York
United States	American Fork Hospital / Huntsman Intermountain Cancer Center	American Fork	Utah
United States	Alaska Breast Care and Surgery LLC	Anchorage	Alaska
United States	Alaska Women's Cancer Care	Anchorage	Alaska
United States	Anchorage Oncology Centre	Anchorage	Alaska
United States	Katmai Oncology Group	Anchorage	Alaska
United States	Providence Alaska Medical Center	Anchorage	Alaska
United States	AnMed Health Cancer Center	Anderson	South Carolina
United States	Michigan Cancer Research Consortium NCORP	Ann Arbor	Michigan
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	Langlade Hospital and Cancer Center	Antigo	Wisconsin
United States	AdventHealth Infusion Center Asheville	Asheville	North Carolina
United States	Messino Cancer Centers	Asheville	North Carolina
United States	Mission Hospital	Asheville	North Carolina
United States	Mountain Radiation Oncology PA	Asheville	North Carolina
United States	Piedmont Hospital	Atlanta	Georgia
United States	Hematology Oncology Associates of Central New York-Auburn	Auburn	New York
United States	Rush - Copley Medical Center	Aurora	Illinois
United States	Texas Oncology - Central Austin Cancer Center	Austin	Texas
United States	Texas Oncology - South Austin Cancer Center	Austin	Texas
United States	Texas Oncology-Austin Midtown	Austin	Texas
United States	Summa Health System - Barberton Campus	Barberton	Ohio
United States	UPMC-Heritage Valley Health System Beaver	Beaver	Pennsylvania
United States	Texas Oncology Bedford	Bedford	Texas
United States	Strecker Cancer Center-Belpre	Belpre	Ohio
United States	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California
United States	Saint Luke's University Hospital-Bethlehem Campus	Bethlehem	Pennsylvania
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania
United States	Mills-Peninsula Medical Center	Burlingame	California
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Sandra L Maxwell Cancer Center	Cedar City	Utah
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	University of Cincinnati Cancer Center-UC Medical Center	Cincinnati	Ohio
United States	Clackamas Radiation Oncology Center	Clackamas	Oregon
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	Mercy Hospital	Coon Rapids	Minnesota
United States	Texas Oncology at Baylor Charles A Sammons Cancer Center	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Carle on Vermilion	Danville	Illinois
United States	Beaumont Hospital - Dearborn	Dearborn	Michigan
United States	Heartland Cancer Research NCORP	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	Ascension Saint John Hospital	Detroit	Michigan
United States	Hematology Oncology Associates of Central New York-East Syracuse	East Syracuse	New York
United States	Fairview Southdale Hospital	Edina	Minnesota
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Green Bay Oncology - Escanaba	Escanaba	Michigan
United States	Willamette Valley Cancer Center	Eugene	Oregon
United States	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois
United States	UPMC Cancer Center at UPMC Horizon	Farrell	Pennsylvania
United States	Piedmont Fayette Hospital	Fayetteville	Georgia
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Poudre Valley Hospital	Fort Collins	Colorado
United States	Broward Health Medical Center	Fort Lauderdale	Florida
United States	Texas Oncology - Fort Worth Cancer Center	Fort Worth	Texas
United States	Unity Hospital	Fridley	Minnesota
United States	Northeast Georgia Medical Center-Gainesville	Gainesville	Georgia
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Adams Cancer Center	Gettysburg	Pennsylvania
United States	NorthShore University HealthSystem-Glenbrook Hospital	Glenview	Illinois
United States	Texas Oncology-Grapevine	Grapevine	Texas
United States	Green Bay Oncology at Saint Vincent Hospital	Green Bay	Wisconsin
United States	Green Bay Oncology Limited at Saint Mary's Hospital	Green Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center at Saint Mary's	Green Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin
United States	UPMC Cancer Centers - Arnold Palmer Pavilion	Greensburg	Pennsylvania
United States	Gibbs Cancer Center-Pelham	Greer	South Carolina
United States	Cherry Tree Cancer Center	Hanover	Pennsylvania
United States	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut
United States	AdventHealth Hendersonville	Hendersonville	North Carolina
United States	Hutchinson Area Health Care	Hutchinson	Minnesota
United States	Centerpoint Medical Center LLC	Independence	Missouri
United States	Green Bay Oncology - Iron Mountain	Iron Mountain	Michigan
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	UPMC-Johnstown/John P. Murtha Regional Cancer Center	Johnstown	Pennsylvania
United States	Freeman Health System	Joplin	Missouri
United States	Mercy Hospital Joplin	Joplin	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	Heartland Hematology and Oncology Associates Incorporated	Kansas City	Missouri
United States	North Kansas City Hospital	Kansas City	Missouri
United States	Research Medical Center	Kansas City	Missouri
United States	Saint Luke's Hospital of Kansas City	Kansas City	Missouri
United States	Fairfield Medical Center	Lancaster	Ohio
United States	Lancaster General Hospital	Lancaster	Pennsylvania
United States	Lancaster Radiation Oncology	Lancaster	Ohio
United States	Sparrow Hospital	Lansing	Michigan
United States	Saint Luke's East - Lee's Summit	Lee's Summit	Missouri
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Liberty Radiation Oncology Center	Liberty	Missouri
United States	Hematology Oncology Associates of Central New York-Liverpool	Liverpool	New York
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Logan Regional Hospital	Logan	Utah
United States	Texas Oncology-Longview Cancer Center	Longview	Texas
United States	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California
United States	Los Angeles County-USC Medical Center	Los Angeles	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Holy Family Memorial Hospital	Manitowoc	Wisconsin
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	Bay Area Medical Center	Marinette	Wisconsin
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	UPMC Cancer Center at UPMC McKeesport	McKeesport	Pennsylvania
United States	Summa Health Medina Medical Center	Medina	Ohio
United States	Froedtert Menomonee Falls Hospital	Menomonee Falls	Wisconsin
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	Knox Community Hospital	Mount Vernon	Ohio
United States	ProHealth D N Greenwald Center	Mukwonago	Wisconsin
United States	Intermountain Medical Center	Murray	Utah
United States	UPMC Cancer Center-Natrona Heights	Natrona Heights	Pennsylvania
United States	The Hospital of Central Connecticut	New Britain	Connecticut
United States	UPMC Jameson	New Castle	Pennsylvania
United States	Cancer Center of Western Wisconsin	New Richmond	Wisconsin
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Licking Memorial Hospital	Newark	Ohio
United States	Newark Radiation Oncology	Newark	Ohio
United States	Carle Cancer Institute Normal	Normal	Illinois
United States	Eastern Connecticut Hematology and Oncology Associates	Norwich	Connecticut
United States	William Backus Hospital	Norwich	Connecticut
United States	Sutter Cancer Research Consortium	Novato	California
United States	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin
United States	Saint Vincent Hospital Cancer Center at Oconto Falls	Oconto Falls	Wisconsin
United States	McKay-Dee Hospital Center	Ogden	Utah
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	Saint Joseph Hospital - Orange	Orange	California
United States	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California
United States	Menorah Medical Center	Overland Park	Kansas
United States	Saint Luke's South Hospital	Overland Park	Kansas
United States	Paoli Memorial Hospital	Paoli	Pennsylvania
United States	Singing River Hospital	Pascagoula	Mississippi
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	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Arizona Oncology-Deer Valley Center	Phoenix	Arizona
United States	UPMC Jefferson Regional Radiation Oncology	Pittsburgh	Pennsylvania
United States	UPMC-Passavant Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Presbyterian Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Saint Clair Hospital Cancer Center	Pittsburgh	Pennsylvania
United States	UPMC-Saint Margaret	Pittsburgh	Pennsylvania
United States	UPMC-Shadyside Hospital	Pittsburgh	Pennsylvania
United States	Saint Joseph Mercy Oakland	Pontiac	Michigan
United States	Lake Huron Medical Center	Port Huron	Michigan
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Southern Ohio Medical Center	Portsmouth	Ohio
United States	Kansas City NCI Community Oncology Research Program	Prairie Village	Kansas
United States	Utah Valley Regional Medical Center	Provo	Utah
United States	Rapid City Regional Hospital	Rapid City	South Dakota
United States	University Hospitals Portage Medical Center	Ravenna	Ohio
United States	North Memorial Medical Health Center	Robbinsdale	Minnesota
United States	Mercy Clinic-Rolla-Cancer and Hematology	Rolla	Missouri
United States	Hematology Oncology Associates of Central New York-Rome	Rome	New York
United States	Texas Oncology - Round Rock Cancer Center	Round Rock	Texas
United States	Texas Oncology-Seton Williamson	Round Rock	Texas
United States	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan
United States	Rutherford Hospital	Rutherfordton	North Carolina
United States	Ascension Saint Mary's Hospital	Saginaw	Michigan
United States	Saint George Regional Medical Center	Saint George	Utah
United States	Heartland Regional Medical Center	Saint Joseph	Missouri
United States	Saint Joseph Oncology Inc	Saint Joseph	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	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	LDS Hospital	Salt Lake City	Utah
United States	Utah Cancer Specialists-Salt Lake City	Salt Lake City	Utah
United States	California Pacific Medical Center-Pacific Campus	San Francisco	California
United States	Maine Medical Center- Scarborough Campus	Scarborough	Maine
United States	Arizona Oncology Services Foundation	Scottsdale	Arizona
United States	UPMC Cancer Center at UPMC Northwest	Seneca	Pennsylvania
United States	Saint Francis Regional Medical Center	Shakopee	Minnesota
United States	Spartanburg Medical Center	Spartanburg	South Carolina
United States	Cancer Care Northwest - Spokane South	Spokane	Washington
United States	Cancer Care Northwest-North Spokane	Spokane	Washington
United States	Cancer Research for the Ozarks NCORP	Springfield	Missouri
United States	CoxHealth South Hospital	Springfield	Missouri
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Springfield Regional Medical Center	Springfield	Ohio
United States	Green Bay Oncology - Sturgeon Bay	Sturgeon Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center at Sturgeon Bay	Sturgeon Bay	Wisconsin
United States	Texas Oncology Cancer Center Sugar Land	Sugar Land	Texas
United States	Hematology Oncology Associates of Central New York-Onondaga Hill	Syracuse	New York
United States	William Beaumont Hospital - Troy	Troy	Michigan
United States	Arizona Oncology Associates-West Orange Grove	Tucson	Arizona
United States	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma
United States	Oklahoma Cancer Specialists and Research Institute-Tulsa	Tulsa	Oklahoma
United States	Warren Clinic Oncology-Tulsa	Tulsa	Oklahoma
United States	Tyler Cancer Center	Tyler	Texas
United States	UPMC Uniontown Hospital Radiation Oncology	Uniontown	Pennsylvania
United States	Carle Cancer Center	Urbana	Illinois
United States	The Carle Foundation Hospital	Urbana	Illinois
United States	Sutter Solano Medical Center/Cancer Center	Vallejo	California
United States	Compass Oncology Vancouver	Vancouver	Washington
United States	PeaceHealth Southwest Medical Center	Vancouver	Washington
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	UPMC Washington Hospital Radiation Oncology	Washington	Pennsylvania
United States	ProHealth Waukesha Memorial Hospital	Waukesha	Wisconsin
United States	Aspirus Regional Cancer Center	Wausau	Wisconsin
United States	University of Cincinnati Cancer Center-West Chester	West Chester	Ohio
United States	Reading Hospital	West Reading	Pennsylvania
United States	Saint Ann's Hospital	Westerville	Ohio
United States	Rice Memorial Hospital	Willmar	Minnesota
United States	Southeast Clinical Oncology Research Consortium NCORP	Winston-Salem	North Carolina
United States	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota
United States	Lankenau Medical Center	Wynnewood	Pennsylvania
United States	Main Line Health NCORP	Wynnewood	Pennsylvania
United States	WellSpan Health-York Hospital	York	Pennsylvania
United States	Rush-Copley Healthcare Center	Yorkville	Illinois
United States	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)	NRG Oncology

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Tumor Genotype, Expression Profile, and Circulating Angiogenesis Biomarkers (Cohort 2)	Biomarker data has not yet been obtained and therefore this outcome measure cannot yet be reported.	From randomization to date of death or last followup. Statistical analysis occurs when tumor genotype, expression profile and circulating angiogenesis biomarkers have been determined from the tissue specimens.
Primary	Number of Patients Experiencing of Dose-limiting Toxicity (Cohort 1)	Dose-limiting toxicity (DLT), defined as a clinically significant adverse event or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications and meets any of the criteria below. Any DLT must be a toxicity possibly related to protocol treatment during first 4 weeks: grade 4 hematologic toxicity, grade 3/4 thrombocytopenia, or grade 3/4 non-hematologic toxicity; Gastrointestinal fistula, bowel perforation, intracranial hemorrhage, wound dehiscence, or reversible posterior leukoencephalopathy of any grade; Delay of treatment > 28 days. If 2+ of patients experience a DLT among 6 eligible patients, this drug combination will be considered unsafe and a lower dose of AMG will be explored; otherwise conclude that this drug combination is safe. The probability of claiming safe dose is no more than 16% when the true DLT rate is >45%, and the probability of claiming safe dose is at least 78% when the true DLT rate is <= 15%.	From start of treatment to 4 weeks.
Primary	Six-month Progression-free Survival (Cohort 2)	As determined by central review of MRI exams, assessed using RANO criteria for progression that is defined by any of the following: > 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared to the smallest tumor measurement obtained either at baseline (if no decrease) or best response, on stable or increasing doses of corticosteroids; Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids compared to baseline scan or best response following initiation of therapy, not due to co-morbid events; Any new lesion; Clear clinical deterioration not attributable to other causes apart from the tumor or changes in corticosteroid dose; Failure to return for evaluation due to death or deteriorating condition; Clear progression of non-measurable disease.	From randomization to six months.
Secondary	Incidence of Grade 3+ Treatment-related Toxicity, Measured by CTCAE v. 4 (Cohort 2)	Adverse events (AEs) are graded by using CTCAE 4.0. Possibly/probably/definitely related to protocol treatment AEs are considered.	From start of treatment up to 3 years.
Secondary	Overall Survival (Cohort 2)	Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. This analysis was planned to occur when all patients had been potentially followed for at least 6 months.	From randomization up to 3 years.
Secondary	Progression-free Survival (Cohort 2)	Progression-free survival time is measured from randomization to the date of first progression or death or, otherwise, the last follow-up date on which the patient was reported alive. This analysis was planned to occur when all patients had been potentially followed for at least 6 months.	From randomization up to 3 years.
Secondary	Radiographic Response Rate (Cohort 2)	Proportion of patients with best overall response of complete response (CR) or partial response (PR) recorded from the start of the treatment until disease progression/recurrence. Response determined by site-reported radiology review of MRI exams using Response Assessment in Neuro-Oncology Criteria (RANO) criteria. CR: Complete disappearance of all enhancing measurable disease (MD) + non-measurable disease (NMD) sustained >= 4 wks; No new lesions; Stable or improved non-enhancing (T2/FLAIR) lesions; Off corticosteroids (or on physiologic replacement doses only); Stable/improved clinically. PR: >= 50% decrease vs. baseline of sum of products of perpendicular diameters of all measurable enhancing lesions sustained >= 4 wks; No progression of NMD; No new lesions; Stable/improved non-enhancing (T2/FLAIR) lesions on <= dose of corticosteroids vs. baseline scan; Corticosteroid dose at evaluation scan <= baseline scan dose; Stable or improved clinically. NMD only cannot be a CR or PR.	From randomization up to 3 years.
Secondary	Percentage of Patients Requiring Dose Reduction/Interruption or Discontinuation in the First 2 and Subsequent Courses (Cohort 1)	Feasibility of trebananib weekly in combination with bevacizumab every 2 weeks, measured by the percentage of patients requiring dose reduction/interruption or discontinuation in the first 2 and subsequent courses (Cohort 1)	From randomization up to 3 years.