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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01609790
• Collaborator: NRG Oncology (Other)
• Enrollment: 137
• Locations: 244
• Arms: 2
• Actual Duration (Months): 119.5
• Patients Per Site: 0.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Giant Cell Glioblastoma; Glioblastoma; Gliosarcoma; Oligodendroglioma; Recurrent Brain Neoplasm; Recurrent Glioblastoma	Biological: Bevacizumab; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Other: Placebo Administration; Biological: Trebananib	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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)
2. 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:

1. 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.

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

3. 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).

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

5. 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).

6. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 137 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma
• Actual Study Start Date: Jun 4, 2012
• Actual Primary Completion Date: Oct 2, 2015
• Actual Study Completion Date: May 20, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (bevacizumab and trebananib) Patients receive bevacizumab 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.	Biological: Bevacizumab; Given IV; Other Names: ABP 215 Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF Monoclonal Antibody SIBP04 Anti-VEGF rhuMAb Avastin Bevacizumab awwb Bevacizumab Biosimilar ABP 215 Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Bevacizumab Biosimilar CBT 124 Bevacizumab Biosimilar CT-P16 Bevacizumab Biosimilar FKB238 Bevacizumab Biosimilar GB-222 Bevacizumab Biosimilar HD204 Bevacizumab Biosimilar HLX04 Bevacizumab Biosimilar IBI305 Bevacizumab Biosimilar LY01008 Bevacizumab Biosimilar MIL60 Bevacizumab Biosimilar Mvasi Bevacizumab Biosimilar MYL-1402O Bevacizumab Biosimilar QL 1101 Bevacizumab Biosimilar RPH-001 Bevacizumab Biosimilar SCT501 Bevacizumab Biosimilar Zirabev Bevacizumab-awwb Bevacizumab-bvzr BP102 BP102 Biosimilar HD204 Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer Mvasi MYL-1402O Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF SCT501 SIBP 04 SIBP-04 SIBP04 Zirabev ; Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Biological: Trebananib; Given IV; Other Names: AMG 386 AMG386 Angiopoietin 1/2-Neutralizing Peptibody AMG 386
Active Comparator: Arm II (bevacizumab and placebo) 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.	Biological: Bevacizumab; Given IV; Other Names: ABP 215 Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF Monoclonal Antibody SIBP04 Anti-VEGF rhuMAb Avastin Bevacizumab awwb Bevacizumab Biosimilar ABP 215 Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Bevacizumab Biosimilar CBT 124 Bevacizumab Biosimilar CT-P16 Bevacizumab Biosimilar FKB238 Bevacizumab Biosimilar GB-222 Bevacizumab Biosimilar HD204 Bevacizumab Biosimilar HLX04 Bevacizumab Biosimilar IBI305 Bevacizumab Biosimilar LY01008 Bevacizumab Biosimilar MIL60 Bevacizumab Biosimilar Mvasi Bevacizumab Biosimilar MYL-1402O Bevacizumab Biosimilar QL 1101 Bevacizumab Biosimilar RPH-001 Bevacizumab Biosimilar SCT501 Bevacizumab Biosimilar Zirabev Bevacizumab-awwb Bevacizumab-bvzr BP102 BP102 Biosimilar HD204 Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer Mvasi MYL-1402O Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF SCT501 SIBP 04 SIBP-04 SIBP04 Zirabev ; Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Other: Placebo Administration; Given IV

Outcome Measures

Primary Outcome Measures

1. Number of Patients Experiencing of Dose-limiting Toxicity (Cohort 1) [From start of treatment to 4 weeks.]

   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%.

2. Six-month Progression-free Survival (Cohort 2) [From randomization to six months.]

   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.

Secondary Outcome Measures

1. Incidence of Grade 3+ Treatment-related Toxicity, Measured by CTCAE v. 4 (Cohort 2) [From start of treatment up to 3 years.]

   Adverse events (AEs) are graded by using CTCAE 4.0. Possibly/probably/definitely related to protocol treatment AEs are considered.

2. Overall Survival (Cohort 2) [From randomization up to 3 years.]

   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.

3. Progression-free Survival (Cohort 2) [From randomization up to 3 years.]

   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.

4. Radiographic Response Rate (Cohort 2) [From randomization up to 3 years.]

   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.

5. Percentage of Patients Requiring Dose Reduction/Interruption or Discontinuation in the First 2 and Subsequent Courses (Cohort 1) [From randomization up to 3 years.]

   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)

Other Outcome Measures

1. Tumor Genotype, Expression Profile, and Circulating Angiogenesis Biomarkers (Cohort 2) [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.]

   Biomarker data has not yet been obtained and therefore this outcome measure cannot yet be reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

1. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alaska Breast Care and Surgery LLC	Anchorage	Alaska	United States	99508
2	Alaska Women's Cancer Care	Anchorage	Alaska	United States	99508
3	Anchorage Oncology Centre	Anchorage	Alaska	United States	99508
4	Katmai Oncology Group	Anchorage	Alaska	United States	99508
5	Providence Alaska Medical Center	Anchorage	Alaska	United States	99508
6	Arizona Oncology-Deer Valley Center	Phoenix	Arizona	United States	85027
7	Arizona Oncology Services Foundation	Scottsdale	Arizona	United States	85260
8	Arizona Oncology Associates-West Orange Grove	Tucson	Arizona	United States	85704
9	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California	United States	94704
10	Mills-Peninsula Medical Center	Burlingame	California	United States	94010
11	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California	United States	90027
12	Los Angeles County-USC Medical Center	Los Angeles	California	United States	90033
13	USC / Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
14	Sutter Cancer Research Consortium	Novato	California	United States	94945
15	Saint Joseph Hospital - Orange	Orange	California	United States	92868
16	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California	United States	92868
17	California Pacific Medical Center-Pacific Campus	San Francisco	California	United States	94115
18	Sutter Solano Medical Center/Cancer Center	Vallejo	California	United States	94589
19	Poudre Valley Hospital	Fort Collins	Colorado	United States	80524
20	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut	United States	06105
21	The Hospital of Central Connecticut	New Britain	Connecticut	United States	06050
22	Eastern Connecticut Hematology and Oncology Associates	Norwich	Connecticut	United States	06360
23	William Backus Hospital	Norwich	Connecticut	United States	06360
24	Broward Health Medical Center	Fort Lauderdale	Florida	United States	33316
25	Piedmont Hospital	Atlanta	Georgia	United States	30309
26	Piedmont Fayette Hospital	Fayetteville	Georgia	United States	30214
27	Northeast Georgia Medical Center-Gainesville	Gainesville	Georgia	United States	30501
28	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho	United States	83706
29	Rush - Copley Medical Center	Aurora	Illinois	United States	60504
30	Northwestern University	Chicago	Illinois	United States	60611
31	Rush University Medical Center	Chicago	Illinois	United States	60612
32	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
33	Carle on Vermilion	Danville	Illinois	United States	61832
34	Heartland Cancer Research NCORP	Decatur	Illinois	United States	62526
35	Carle Physician Group-Effingham	Effingham	Illinois	United States	62401
36	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois	United States	60201
37	Illinois CancerCare-Galesburg	Galesburg	Illinois	United States	61401
38	NorthShore University HealthSystem-Glenbrook Hospital	Glenview	Illinois	United States	60026
39	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois	United States	61938
40	Good Samaritan Regional Health Center	Mount Vernon	Illinois	United States	62864
41	Carle Cancer Institute Normal	Normal	Illinois	United States	61761
42	OSF Saint Francis Radiation Oncology at Pekin Cancer Treatment Center	Pekin	Illinois	United States	61554
43	Illinois CancerCare-Peoria	Peoria	Illinois	United States	61615
44	OSF Saint Francis Radiation Oncology at Peoria Cancer Center	Peoria	Illinois	United States	61615
45	Methodist Medical Center of Illinois	Peoria	Illinois	United States	61636
46	OSF Saint Francis Medical Center	Peoria	Illinois	United States	61637
47	Carle Cancer Center	Urbana	Illinois	United States	61801
48	The Carle Foundation Hospital	Urbana	Illinois	United States	61801
49	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois	United States	60555
50	Rush-Copley Healthcare Center	Yorkville	Illinois	United States	60560
51	Menorah Medical Center	Overland Park	Kansas	United States	66209
52	Saint Luke's South Hospital	Overland Park	Kansas	United States	66213
53	Kansas City NCI Community Oncology Research Program	Prairie Village	Kansas	United States	66208
54	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
55	Maine Medical Center- Scarborough Campus	Scarborough	Maine	United States	04074
56	Michigan Cancer Research Consortium NCORP	Ann Arbor	Michigan	United States	48106
57	Saint Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106
58	Beaumont Hospital - Dearborn	Dearborn	Michigan	United States	48124
59	Ascension Saint John Hospital	Detroit	Michigan	United States	48236
60	Green Bay Oncology - Escanaba	Escanaba	Michigan	United States	49829
61	Genesys Hurley Cancer Institute	Flint	Michigan	United States	48503
62	Hurley Medical Center	Flint	Michigan	United States	48503
63	Green Bay Oncology - Iron Mountain	Iron Mountain	Michigan	United States	49801
64	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
65	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
66	Borgess Medical Center	Kalamazoo	Michigan	United States	49048
67	Sparrow Hospital	Lansing	Michigan	United States	48912
68	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan	United States	48154
69	Saint Joseph Mercy Oakland	Pontiac	Michigan	United States	48341
70	Lake Huron Medical Center	Port Huron	Michigan	United States	48060
71	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan	United States	48073
72	Ascension Saint Mary's Hospital	Saginaw	Michigan	United States	48601
73	William Beaumont Hospital - Troy	Troy	Michigan	United States	48085
74	Saint John Macomb-Oakland Hospital	Warren	Michigan	United States	48093
75	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
76	Mercy Hospital	Coon Rapids	Minnesota	United States	55433
77	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
78	Unity Hospital	Fridley	Minnesota	United States	55432
79	Hutchinson Area Health Care	Hutchinson	Minnesota	United States	55350
80	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota	United States	55109
81	Saint John's Hospital - Healtheast	Maplewood	Minnesota	United States	55109
82	Abbott-Northwestern Hospital	Minneapolis	Minnesota	United States	55407
83	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55415
84	Health Partners Inc	Minneapolis	Minnesota	United States	55454
85	North Memorial Medical Health Center	Robbinsdale	Minnesota	United States	55422
86	Metro Minnesota Community Oncology Research Consortium	Saint Louis Park	Minnesota	United States	55416
87	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota	United States	55416
88	Regions Hospital	Saint Paul	Minnesota	United States	55101
89	United Hospital	Saint Paul	Minnesota	United States	55102
90	Saint Francis Regional Medical Center	Shakopee	Minnesota	United States	55379
91	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
92	Rice Memorial Hospital	Willmar	Minnesota	United States	56201
93	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota	United States	55125
94	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
95	Singing River Hospital	Pascagoula	Mississippi	United States	39581
96	Saint Francis Medical Center	Cape Girardeau	Missouri	United States	63703
97	Centerpoint Medical Center LLC	Independence	Missouri	United States	64057
98	Freeman Health System	Joplin	Missouri	United States	64804
99	Mercy Hospital Joplin	Joplin	Missouri	United States	64804
100	Saint Luke's Hospital of Kansas City	Kansas City	Missouri	United States	64111
101	North Kansas City Hospital	Kansas City	Missouri	United States	64116
102	Heartland Hematology and Oncology Associates Incorporated	Kansas City	Missouri	United States	64118
103	Research Medical Center	Kansas City	Missouri	United States	64132
104	Saint Luke's East - Lee's Summit	Lee's Summit	Missouri	United States	64086
105	Liberty Radiation Oncology Center	Liberty	Missouri	United States	64068
106	Mercy Clinic-Rolla-Cancer and Hematology	Rolla	Missouri	United States	65401
107	Heartland Regional Medical Center	Saint Joseph	Missouri	United States	64506
108	Saint Joseph Oncology Inc	Saint Joseph	Missouri	United States	64507
109	Saint Louis Cancer and Breast Institute-South City	Saint Louis	Missouri	United States	63109
110	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
111	Cancer Research for the Ozarks NCORP	Springfield	Missouri	United States	65804
112	Mercy Hospital Springfield	Springfield	Missouri	United States	65804
113	CoxHealth South Hospital	Springfield	Missouri	United States	65807
114	Nebraska Methodist Hospital	Omaha	Nebraska	United States	68114
115	New York Oncology Hematology PC - Albany	Albany	New York	United States	12206
116	New York Oncology Hematology PC - Albany Medical Center	Albany	New York	United States	12208
117	Hematology Oncology Associates of Central New York-Auburn	Auburn	New York	United States	13021
118	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
119	Hematology Oncology Associates of Central New York-East Syracuse	East Syracuse	New York	United States	13057
120	Hematology Oncology Associates of Central New York-Liverpool	Liverpool	New York	United States	13088
121	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York	United States	10016
122	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York	United States	10032
123	Hematology Oncology Associates of Central New York-Rome	Rome	New York	United States	13440
124	Hematology Oncology Associates of Central New York-Onondaga Hill	Syracuse	New York	United States	13215
125	Mission Hospital	Asheville	North Carolina	United States	28801
126	Mountain Radiation Oncology PA	Asheville	North Carolina	United States	28801
127	AdventHealth Infusion Center Asheville	Asheville	North Carolina	United States	28803
128	Messino Cancer Centers	Asheville	North Carolina	United States	28806
129	AdventHealth Hendersonville	Hendersonville	North Carolina	United States	28792
130	Rutherford Hospital	Rutherfordton	North Carolina	United States	28139
131	Southeast Clinical Oncology Research Consortium NCORP	Winston-Salem	North Carolina	United States	27104
132	Summa Health System - Akron Campus	Akron	Ohio	United States	44304
133	Cleveland Clinic Akron General	Akron	Ohio	United States	44307
134	Summa Health System - Barberton Campus	Barberton	Ohio	United States	44203
135	Strecker Cancer Center-Belpre	Belpre	Ohio	United States	45714
136	Adena Regional Medical Center	Chillicothe	Ohio	United States	45601
137	University of Cincinnati Cancer Center-UC Medical Center	Cincinnati	Ohio	United States	45219
138	Columbus Oncology and Hematology Associates Inc	Columbus	Ohio	United States	43214
139	Riverside Methodist Hospital	Columbus	Ohio	United States	43214
140	Columbus NCI Community Oncology Research Program	Columbus	Ohio	United States	43215
141	Grant Medical Center	Columbus	Ohio	United States	43215
142	The Mark H Zangmeister Center	Columbus	Ohio	United States	43219
143	Mount Carmel Health Center West	Columbus	Ohio	United States	43222
144	Doctors Hospital	Columbus	Ohio	United States	43228
145	Delaware Health Center-Grady Cancer Center	Delaware	Ohio	United States	43015
146	Delaware Radiation Oncology	Delaware	Ohio	United States	43015
147	Grady Memorial Hospital	Delaware	Ohio	United States	43015
148	Fairfield Medical Center	Lancaster	Ohio	United States	43130
149	Lancaster Radiation Oncology	Lancaster	Ohio	United States	43130
150	Marietta Memorial Hospital	Marietta	Ohio	United States	45750
151	Summa Health Medina Medical Center	Medina	Ohio	United States	44256
152	Knox Community Hospital	Mount Vernon	Ohio	United States	43050
153	Licking Memorial Hospital	Newark	Ohio	United States	43055
154	Newark Radiation Oncology	Newark	Ohio	United States	43055
155	Southern Ohio Medical Center	Portsmouth	Ohio	United States	45662
156	University Hospitals Portage Medical Center	Ravenna	Ohio	United States	44266
157	Springfield Regional Medical Center	Springfield	Ohio	United States	45505
158	University of Cincinnati Cancer Center-West Chester	West Chester	Ohio	United States	45069
159	Saint Ann's Hospital	Westerville	Ohio	United States	43081
160	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio	United States	43701
161	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
162	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma	United States	74136
163	Oklahoma Cancer Specialists and Research Institute-Tulsa	Tulsa	Oklahoma	United States	74146
164	Warren Clinic Oncology-Tulsa	Tulsa	Oklahoma	United States	74146
165	Clackamas Radiation Oncology Center	Clackamas	Oregon	United States	97015
166	Willamette Valley Cancer Center	Eugene	Oregon	United States	97401
167	Providence Portland Medical Center	Portland	Oregon	United States	97213
168	Providence Saint Vincent Medical Center	Portland	Oregon	United States	97225
169	UPMC-Heritage Valley Health System Beaver	Beaver	Pennsylvania	United States	15009
170	Saint Luke's University Hospital-Bethlehem Campus	Bethlehem	Pennsylvania	United States	18015
171	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania	United States	19010
172	UPMC Cancer Center at UPMC Horizon	Farrell	Pennsylvania	United States	16121
173	Adams Cancer Center	Gettysburg	Pennsylvania	United States	17325
174	UPMC Cancer Centers - Arnold Palmer Pavilion	Greensburg	Pennsylvania	United States	15601
175	Cherry Tree Cancer Center	Hanover	Pennsylvania	United States	17331
176	UPMC-Johnstown/John P. Murtha Regional Cancer Center	Johnstown	Pennsylvania	United States	15901
177	Lancaster General Hospital	Lancaster	Pennsylvania	United States	17602
178	UPMC Cancer Center at UPMC McKeesport	McKeesport	Pennsylvania	United States	15132
179	UPMC Cancer Center-Natrona Heights	Natrona Heights	Pennsylvania	United States	15065
180	UPMC Jameson	New Castle	Pennsylvania	United States	16105
181	Paoli Memorial Hospital	Paoli	Pennsylvania	United States	19301
182	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
183	UPMC-Presbyterian Hospital	Pittsburgh	Pennsylvania	United States	15213
184	UPMC-Saint Margaret	Pittsburgh	Pennsylvania	United States	15215
185	UPMC-Shadyside Hospital	Pittsburgh	Pennsylvania	United States	15232
186	UPMC Jefferson Regional Radiation Oncology	Pittsburgh	Pennsylvania	United States	15236
187	UPMC-Passavant Hospital	Pittsburgh	Pennsylvania	United States	15237
188	UPMC-Saint Clair Hospital Cancer Center	Pittsburgh	Pennsylvania	United States	15243
189	UPMC Cancer Center at UPMC Northwest	Seneca	Pennsylvania	United States	16346
190	UPMC Uniontown Hospital Radiation Oncology	Uniontown	Pennsylvania	United States	15401
191	UPMC Washington Hospital Radiation Oncology	Washington	Pennsylvania	United States	15301
192	Reading Hospital	West Reading	Pennsylvania	United States	19611
193	Lankenau Medical Center	Wynnewood	Pennsylvania	United States	19096
194	Main Line Health NCORP	Wynnewood	Pennsylvania	United States	19096
195	WellSpan Health-York Hospital	York	Pennsylvania	United States	17403
196	AnMed Health Cancer Center	Anderson	South Carolina	United States	29621
197	Gibbs Cancer Center-Pelham	Greer	South Carolina	United States	29651
198	Spartanburg Medical Center	Spartanburg	South Carolina	United States	29303
199	Rapid City Regional Hospital	Rapid City	South Dakota	United States	57701
200	Texas Oncology-Austin Midtown	Austin	Texas	United States	78705
201	Texas Oncology - Central Austin Cancer Center	Austin	Texas	United States	78731
202	Texas Oncology - South Austin Cancer Center	Austin	Texas	United States	78745
203	Texas Oncology Bedford	Bedford	Texas	United States	76022
204	Texas Oncology at Baylor Charles A Sammons Cancer Center	Dallas	Texas	United States	75246
205	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
206	Texas Oncology - Fort Worth Cancer Center	Fort Worth	Texas	United States	76104
207	Texas Oncology-Grapevine	Grapevine	Texas	United States	76053
208	Texas Oncology-Longview Cancer Center	Longview	Texas	United States	75601
209	Texas Oncology-Seton Williamson	Round Rock	Texas	United States	78665
210	Texas Oncology - Round Rock Cancer Center	Round Rock	Texas	United States	78681
211	Texas Oncology Cancer Center Sugar Land	Sugar Land	Texas	United States	77479
212	Tyler Cancer Center	Tyler	Texas	United States	75702
213	American Fork Hospital / Huntsman Intermountain Cancer Center	American Fork	Utah	United States	84003
214	Sandra L Maxwell Cancer Center	Cedar City	Utah	United States	84720
215	Logan Regional Hospital	Logan	Utah	United States	84321
216	Intermountain Medical Center	Murray	Utah	United States	84107
217	McKay-Dee Hospital Center	Ogden	Utah	United States	84403
218	Utah Valley Regional Medical Center	Provo	Utah	United States	84604
219	Saint George Regional Medical Center	Saint George	Utah	United States	84770
220	Utah Cancer Specialists-Salt Lake City	Salt Lake City	Utah	United States	84106
221	LDS Hospital	Salt Lake City	Utah	United States	84143
222	Cancer Care Northwest - Spokane South	Spokane	Washington	United States	99202
223	Cancer Care Northwest-North Spokane	Spokane	Washington	United States	99218
224	PeaceHealth Southwest Medical Center	Vancouver	Washington	United States	98664
225	Compass Oncology Vancouver	Vancouver	Washington	United States	98684
226	Langlade Hospital and Cancer Center	Antigo	Wisconsin	United States	54409
227	Green Bay Oncology at Saint Vincent Hospital	Green Bay	Wisconsin	United States	54301-3526
228	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin	United States	54301
229	Green Bay Oncology Limited at Saint Mary's Hospital	Green Bay	Wisconsin	United States	54303
230	Saint Vincent Hospital Cancer Center at Saint Mary's	Green Bay	Wisconsin	United States	54303
231	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin	United States	53792
232	Holy Family Memorial Hospital	Manitowoc	Wisconsin	United States	54221
233	Bay Area Medical Center	Marinette	Wisconsin	United States	54143
234	Froedtert Menomonee Falls Hospital	Menomonee Falls	Wisconsin	United States	53051
235	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
236	ProHealth D N Greenwald Center	Mukwonago	Wisconsin	United States	53149
237	Cancer Center of Western Wisconsin	New Richmond	Wisconsin	United States	54017
238	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin	United States	53066
239	Saint Vincent Hospital Cancer Center at Oconto Falls	Oconto Falls	Wisconsin	United States	54154
240	Saint Vincent Hospital Cancer Center at Sturgeon Bay	Sturgeon Bay	Wisconsin	United States	54235-1495
241	Green Bay Oncology - Sturgeon Bay	Sturgeon Bay	Wisconsin	United States	54235
242	ProHealth Waukesha Memorial Hospital	Waukesha	Wisconsin	United States	53188
243	Aspirus Regional Cancer Center	Wausau	Wisconsin	United States	54401
244	Allan Blair Cancer Centre	Regina	Saskatchewan	Canada	S4T 7T1

Sponsors and Collaborators

• National Cancer Institute (NCI)
• NRG Oncology

Investigators

• Principal Investigator: Eudocia Q Lee, NRG Oncology

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01609790
• Other Study ID Numbers: NCI-2012-01969; NCI-2012-01969; S13-00759; CDR0000734205; RTOG-1122; RTOG-1122; RTOG-1122; U10CA180868; U10CA021661
• First Posted: Jun 1, 2012
• Last Update Posted: Jul 21, 2022
• Last Verified: May 1, 2022

• Additional relevant MeSH terms: Glioblastoma; Gliosarcoma; Oligodendroglioma; Brain Neoplasms; Recurrence; Bevacizumab; Antineoplastic Agents, Immunological; Trebananib; Endothelial Growth Factors; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G

Study Results

Participant Flow

Arm/Group Title	Cohort 1: Safety Run-In	Cohort 2: Bevacizumab+Placebo	Cohort 2: Bevacizumab+AMG 386
Arm/Group Description	Bevacizumab every 2 weeks + AMG 386 weekly until disease progression.	Bevacizumab every 2 weeks + placebo weekly until disease progression. Patients who progress will be allowed to cross over and receive treatment with bevacizumab + AMG 386	Bevacizumab every 2 weeks + AMG 386 weekly until disease progression.
Period Title: Overall Study
STARTED	7	65	65
COMPLETED	6	58	57
NOT COMPLETED	1	7	8

Baseline Characteristics

Arm/Group Title	Cohort 1: Safety Run-In	Cohort 2: Bevacizumab+Placebo	Cohort 2: Bevacizumab+AMG 386	Total
Arm/Group Description	Bevacizumab every 2 weeks + AMG 386 weekly until disease progression.	Bevacizumab every 2 weeks + placebo weekly until disease progression. Patients who progress will be allowed to cross over and receive treatment with bevacizumab + AMG 386	Bevacizumab every 2 weeks + AMG 386 weekly until disease progression.	Total of all reporting groups
Overall Participants	6	58	57	121
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56	58	57	58
Sex: Female, Male (Count of Participants)
Female	1 16.7%	22 37.9%	25 43.9%	48 39.7%
Male	5 83.3%	36 62.1%	32 56.1%	73 60.3%

Outcome Measures

1. Primary Outcome

Title	Number of Patients Experiencing of Dose-limiting Toxicity (Cohort 1)
Description	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%.
Time Frame	From start of treatment to 4 weeks.

Outcome Measure Data

Analysis Population Description

All eligible patients who started study treatment

Arm/Group Title	Safety Run-In
Arm/Group Description	Bevacizumab every 2 weeks + AMG 386 weekly until disease progression.
Measure Participants	6
Number [participants]	0 0%

2. Primary Outcome

Title	Six-month Progression-free Survival (Cohort 2)
Description	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.
Time Frame	From randomization to six months.

Outcome Measure Data

Analysis Population Description

Randomized patients evaluable for 6 months progression-free survival (PFS).

Arm/Group Title	Cohort 2: Bevacizumab+Placebo	Cohort 2: Bevacizumab+AMG 386
Arm/Group Description	Bevacizumab every 2 weeks + placebo weekly until disease progression. Patients who progress will be allowed to cross over and receive treatment with bevacizumab + AMG 386	Bevacizumab every 2 weeks + AMG 386 weekly until disease progression.
Measure Participants	56	53
Number (95% Confidence Interval) [percentage of participants]	41.1 685%	22.6 39%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Safety Run-In, Cohort 2: Bevacizumab+AMG 386
	Comments	Assuming a 36% 6-month (6m) rate in the placebo arm [from the March 2009 Food and Drug Administration (FDA) briefing], a 55% rate in the AMG 386 arm, and an exponential distribution corresponds to median PFS of 4.1 and 7 months, respectively, with a hazard ratio of 0.59 (AMG 386 arm vs. placebo arm). A total of 114 patients (57 per arm) will yield 85% power to detect an absolute 19% difference of 6m PFS rate at a 1-sided alpha level of 0.15 based on a 2-sample proportion test.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.98
	Comments
	Method	Z-test
	Comments	One-sided test, significance level 0.15

3. Secondary Outcome

Title	Incidence of Grade 3+ Treatment-related Toxicity, Measured by CTCAE v. 4 (Cohort 2)
Description	Adverse events (AEs) are graded by using CTCAE 4.0. Possibly/probably/definitely related to protocol treatment AEs are considered.
Time Frame	From start of treatment up to 3 years.

Outcome Measure Data

Analysis Population Description

Randomized and eligible patients who started protocol treatment.

Arm/Group Title	Cohort 2: Bevacizumab+Placebo	Cohort 2: Bevacizumab+AMG 386
Arm/Group Description	Bevacizumab every 2 weeks + placebo weekly until disease progression. Patients who progress will be allowed to cross over and receive treatment with bevacizumab + AMG 386	Bevacizumab every 2 weeks + AMG 386 weekly until disease progression.
Measure Participants	57	57
Number [participants]	21 350%	20 34.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Safety Run-In, Cohort 2: Bevacizumab+AMG 386
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.85
	Comments
	Method	Chi-squared
	Comments

4. Secondary Outcome

Title	Overall Survival (Cohort 2)
Description	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.
Time Frame	From randomization up to 3 years.

Outcome Measure Data

Analysis Population Description

All randomized and eligible patients.

Arm/Group Title	Cohort 2: Bevacizumab+Placebo	Cohort 2: Bevacizumab+AMG 386
Arm/Group Description	Bevacizumab every 2 weeks + placebo weekly until disease progression. Patients who progress will be allowed to cross over and receive treatment with bevacizumab + AMG 386	Bevacizumab every 2 weeks + AMG 386 weekly until disease progression.
Measure Participants	58	57
Median (95% Confidence Interval) [Months]	11.5	7.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Safety Run-In, Cohort 2: Bevacizumab+AMG 386
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.09
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.46
	Confidence Interval	(2-Sided) 95%; 0.95 to 2.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Progression-free Survival (Cohort 2)
Description	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.
Time Frame	From randomization up to 3 years.

Outcome Measure Data

Analysis Population Description

All randomized and eligible patients.

Arm/Group Title	Cohort 2: Bevacizumab+Placebo	Cohort 2: Bevacizumab+AMG 386
Arm/Group Description	Bevacizumab every 2 weeks + placebo weekly until disease progression. Patients who progress will be allowed to cross over and receive treatment with bevacizumab + AMG 386	Bevacizumab every 2 weeks + AMG 386 weekly until disease progression.
Measure Participants	58	57
Number (95% Confidence Interval) [percentage of participants]	4.8 80%	4.2 7.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Safety Run-In, Cohort 2: Bevacizumab+AMG 386
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.51
	Confidence Interval	(2-Sided) 95%; 1.02 to 2.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Radiographic Response Rate (Cohort 2)
Description	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.
Time Frame	From randomization up to 3 years.

Outcome Measure Data

Analysis Population Description

All randomized and eligible patients.

Arm/Group Title	Cohort 2: Bevacizumab+Placebo	Cohort 2: Bevacizumab+AMG 386
Arm/Group Description	Bevacizumab every 2 weeks + placebo weekly until disease progression. Patients who progress will be allowed to cross over and receive treatment with bevacizumab + AMG 386	Bevacizumab every 2 weeks + AMG 386 weekly until disease progression.
Measure Participants	58	57
Number (95% Confidence Interval) [percentage of participants]	5.9 98.3%	4.2 7.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Safety Run-In, Cohort 2: Bevacizumab+AMG 386
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7
	Comments
	Method	Chi-squared
	Comments

7. Secondary Outcome

Title	Percentage of Patients Requiring Dose Reduction/Interruption or Discontinuation in the First 2 and Subsequent Courses (Cohort 1)
Description	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)
Time Frame	From randomization up to 3 years.

Outcome Measure Data

Analysis Population Description

Eligible patients

Arm/Group Title	Safety Run-In
Arm/Group Description	Bevacizumab every 2 weeks + AMG 386 weekly until disease progression.
Measure Participants	6
In first 2 cycles	6 100%
In first 6 cycles	3 50%
In first 12 cycles	5 83.3%

8. Other Pre-specified Outcome

Title	Tumor Genotype, Expression Profile, and Circulating Angiogenesis Biomarkers (Cohort 2)
Description	Biomarker data has not yet been obtained and therefore this outcome measure cannot yet be reported.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Adverse Event Reporting Description	Randomized and eligible patients who started protocol treatment are included in the adverse event tables. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Arm/Group Title	Cohort 1: Safety Run-In		Cohort 2: Bevacizumab+Placebo		Cohort 2: Bevacizumab+AMG 386
Arm/Group Description	Bevacizumab every 2 weeks + AMG 386 weekly until disease progression.		Bevacizumab every 2 weeks + placebo weekly until disease progression. Patients who progress will be allowed to cross over and receive treatment with bevacizumab + AMG 386		Bevacizumab every 2 weeks + AMG 386 weekly until disease progression.
All Cause Mortality
	Cohort 1: Safety Run-In		Cohort 2: Bevacizumab+Placebo		Cohort 2: Bevacizumab+AMG 386
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Cohort 1: Safety Run-In		Cohort 2: Bevacizumab+Placebo		Cohort 2: Bevacizumab+AMG 386
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/6 (83.3%)		22/57 (38.6%)		20/57 (35.1%)
Cardiac disorders
Ventricular fibrillation	0/6 (0%)		0/57 (0%)		1/57 (1.8%)
Endocrine disorders
Hyperthyroidism	0/6 (0%)		0/57 (0%)		1/57 (1.8%)
Gastrointestinal disorders
Retroperitoneal hemorrhage	0/6 (0%)		0/57 (0%)		1/57 (1.8%)
General disorders
Edema limbs	0/6 (0%)		1/57 (1.8%)		1/57 (1.8%)
Flu like symptoms	0/6 (0%)		1/57 (1.8%)		0/57 (0%)
Gait disturbance	0/6 (0%)		3/57 (5.3%)		0/57 (0%)
Non-cardiac chest pain	0/6 (0%)		0/57 (0%)		1/57 (1.8%)
Infections and infestations
Infections and infestations - Other	0/6 (0%)		0/57 (0%)		1/57 (1.8%)
Lung infection	0/6 (0%)		1/57 (1.8%)		0/57 (0%)
Meningitis	0/6 (0%)		1/57 (1.8%)		0/57 (0%)
Sepsis	0/6 (0%)		1/57 (1.8%)		0/57 (0%)
Skin infection	1/6 (16.7%)		1/57 (1.8%)		1/57 (1.8%)
Urinary tract infection	2/6 (33.3%)		1/57 (1.8%)		1/57 (1.8%)
Wound infection	0/6 (0%)		0/57 (0%)		1/57 (1.8%)
Injury, poisoning and procedural complications
Fall	0/6 (0%)		1/57 (1.8%)		1/57 (1.8%)
Hip fracture	1/6 (16.7%)		0/57 (0%)		0/57 (0%)
Spinal fracture	0/6 (0%)		1/57 (1.8%)		0/57 (0%)
Wound dehiscence	0/6 (0%)		1/57 (1.8%)		0/57 (0%)
Investigations
Aspartate aminotransferase increased	1/6 (16.7%)		0/57 (0%)		0/57 (0%)
Lymphocyte count decreased	0/6 (0%)		0/57 (0%)		1/57 (1.8%)
Platelet count decreased	0/6 (0%)		0/57 (0%)		1/57 (1.8%)
Metabolism and nutrition disorders
Hyperglycemia	1/6 (16.7%)		1/57 (1.8%)		1/57 (1.8%)
Hyponatremia	0/6 (0%)		3/57 (5.3%)		0/57 (0%)
Metabolism and nutrition disorders - Other	0/6 (0%)		1/57 (1.8%)		0/57 (0%)
Musculoskeletal and connective tissue disorders
Arthritis	0/6 (0%)		1/57 (1.8%)		0/57 (0%)
Generalized muscle weakness	0/6 (0%)		2/57 (3.5%)		1/57 (1.8%)
Muscle weakness lower limb	0/6 (0%)		1/57 (1.8%)		2/57 (3.5%)
Muscle weakness upper limb	0/6 (0%)		1/57 (1.8%)		0/57 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other	1/6 (16.7%)		2/57 (3.5%)		3/57 (5.3%)
Nervous system disorders
Aphonia	0/6 (0%)		1/57 (1.8%)		0/57 (0%)
Ataxia	0/6 (0%)		0/57 (0%)		1/57 (1.8%)
Cerebrospinal fluid leakage	0/6 (0%)		1/57 (1.8%)		0/57 (0%)
Cognitive disturbance	0/6 (0%)		2/57 (3.5%)		1/57 (1.8%)
Depressed level of consciousness	0/6 (0%)		1/57 (1.8%)		0/57 (0%)
Dizziness	0/6 (0%)		0/57 (0%)		1/57 (1.8%)
Dysphasia	0/6 (0%)		2/57 (3.5%)		0/57 (0%)
Encephalopathy	0/6 (0%)		2/57 (3.5%)		0/57 (0%)
Headache	0/6 (0%)		1/57 (1.8%)		1/57 (1.8%)
Intracranial hemorrhage	0/6 (0%)		1/57 (1.8%)		1/57 (1.8%)
Memory impairment	0/6 (0%)		1/57 (1.8%)		0/57 (0%)
Nervous system disorders - Other	0/6 (0%)		0/57 (0%)		2/57 (3.5%)
Seizure	2/6 (33.3%)		4/57 (7%)		4/57 (7%)
Stroke	0/6 (0%)		2/57 (3.5%)		1/57 (1.8%)
Transient ischemic attacks	0/6 (0%)		1/57 (1.8%)		0/57 (0%)
Psychiatric disorders
Confusion	0/6 (0%)		2/57 (3.5%)		3/57 (5.3%)
Delirium	0/6 (0%)		1/57 (1.8%)		1/57 (1.8%)
Renal and urinary disorders
Acute kidney injury	0/6 (0%)		1/57 (1.8%)		0/57 (0%)
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	0/6 (0%)		1/57 (1.8%)		0/57 (0%)
Pleural effusion	0/6 (0%)		1/57 (1.8%)		0/57 (0%)
Respiratory failure	0/6 (0%)		0/57 (0%)		1/57 (1.8%)
Vascular disorders
Hypertension	0/6 (0%)		1/57 (1.8%)		3/57 (5.3%)
Thromboembolic event	0/6 (0%)		1/57 (1.8%)		2/57 (3.5%)
Other (Not Including Serious) Adverse Events
	Cohort 1: Safety Run-In		Cohort 2: Bevacizumab+Placebo		Cohort 2: Bevacizumab+AMG 386
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		57/57 (100%)		54/57 (94.7%)
Blood and lymphatic system disorders
Anemia	3/6 (50%)		14/57 (24.6%)		9/57 (15.8%)
Cardiac disorders
Sinus tachycardia	1/6 (16.7%)		1/57 (1.8%)		0/57 (0%)
Ear and labyrinth disorders
Hearing impaired	1/6 (16.7%)		0/57 (0%)		2/57 (3.5%)
Endocrine disorders
Cushingoid	1/6 (16.7%)		0/57 (0%)		2/57 (3.5%)
Eye disorders
Blurred vision	0/6 (0%)		4/57 (7%)		7/57 (12.3%)
Dry eye	1/6 (16.7%)		1/57 (1.8%)		1/57 (1.8%)
Eye disorders - Other	0/6 (0%)		5/57 (8.8%)		9/57 (15.8%)
Gastrointestinal disorders
Abdominal pain	0/6 (0%)		4/57 (7%)		5/57 (8.8%)
Constipation	3/6 (50%)		15/57 (26.3%)		6/57 (10.5%)
Diarrhea	2/6 (33.3%)		13/57 (22.8%)		8/57 (14%)
Dry mouth	0/6 (0%)		3/57 (5.3%)		1/57 (1.8%)
Dyspepsia	0/6 (0%)		6/57 (10.5%)		3/57 (5.3%)
Dysphagia	1/6 (16.7%)		1/57 (1.8%)		3/57 (5.3%)
Fecal incontinence	1/6 (16.7%)		2/57 (3.5%)		0/57 (0%)
Gastrointestinal disorders - Other	1/6 (16.7%)		3/57 (5.3%)		1/57 (1.8%)
Mucositis oral	1/6 (16.7%)		4/57 (7%)		4/57 (7%)
Nausea	2/6 (33.3%)		14/57 (24.6%)		8/57 (14%)
Vomiting	2/6 (33.3%)		11/57 (19.3%)		2/57 (3.5%)
General disorders
Chills	0/6 (0%)		3/57 (5.3%)		0/57 (0%)
Edema face	0/6 (0%)		1/57 (1.8%)		4/57 (7%)
Edema limbs	2/6 (33.3%)		12/57 (21.1%)		12/57 (21.1%)
Fatigue	4/6 (66.7%)		38/57 (66.7%)		37/57 (64.9%)
Fever	1/6 (16.7%)		6/57 (10.5%)		0/57 (0%)
Gait disturbance	1/6 (16.7%)		13/57 (22.8%)		7/57 (12.3%)
General disorders and administration site conditions - Other	0/6 (0%)		4/57 (7%)		2/57 (3.5%)
Injection site reaction	1/6 (16.7%)		1/57 (1.8%)		1/57 (1.8%)
Localized edema	0/6 (0%)		4/57 (7%)		1/57 (1.8%)
Malaise	1/6 (16.7%)		1/57 (1.8%)		0/57 (0%)
Non-cardiac chest pain	1/6 (16.7%)		2/57 (3.5%)		2/57 (3.5%)
Pain	2/6 (33.3%)		8/57 (14%)		8/57 (14%)
Infections and infestations
Esophageal infection	1/6 (16.7%)		0/57 (0%)		0/57 (0%)
Soft tissue infection	1/6 (16.7%)		0/57 (0%)		0/57 (0%)
Upper respiratory infection	0/6 (0%)		3/57 (5.3%)		3/57 (5.3%)
Urinary tract infection	1/6 (16.7%)		1/57 (1.8%)		4/57 (7%)
Vaginal infection	1/6 (16.7%)		0/57 (0%)		0/57 (0%)
Injury, poisoning and procedural complications
Bruising	0/6 (0%)		4/57 (7%)		4/57 (7%)
Fall	2/6 (33.3%)		5/57 (8.8%)		9/57 (15.8%)
Fracture	1/6 (16.7%)		1/57 (1.8%)		1/57 (1.8%)
Investigations
Activated partial thromboplastin time prolonged	0/6 (0%)		2/57 (3.5%)		3/57 (5.3%)
Alanine aminotransferase increased	3/6 (50%)		15/57 (26.3%)		9/57 (15.8%)
Alkaline phosphatase increased	2/6 (33.3%)		5/57 (8.8%)		4/57 (7%)
Aspartate aminotransferase increased	0/6 (0%)		9/57 (15.8%)		6/57 (10.5%)
Blood bilirubin increased	0/6 (0%)		3/57 (5.3%)		3/57 (5.3%)
CPK increased	1/6 (16.7%)		0/57 (0%)		0/57 (0%)
Creatinine increased	1/6 (16.7%)		1/57 (1.8%)		2/57 (3.5%)
Investigations - Other	1/6 (16.7%)		3/57 (5.3%)		3/57 (5.3%)
Lymphocyte count decreased	2/6 (33.3%)		17/57 (29.8%)		15/57 (26.3%)
Neutrophil count decreased	0/6 (0%)		6/57 (10.5%)		4/57 (7%)
Platelet count decreased	1/6 (16.7%)		10/57 (17.5%)		10/57 (17.5%)
Weight gain	1/6 (16.7%)		0/57 (0%)		3/57 (5.3%)
Weight loss	2/6 (33.3%)		6/57 (10.5%)		2/57 (3.5%)
White blood cell decreased	1/6 (16.7%)		11/57 (19.3%)		10/57 (17.5%)
Metabolism and nutrition disorders
Anorexia	2/6 (33.3%)		10/57 (17.5%)		5/57 (8.8%)
Dehydration	1/6 (16.7%)		2/57 (3.5%)		3/57 (5.3%)
Hyperglycemia	2/6 (33.3%)		22/57 (38.6%)		16/57 (28.1%)
Hyperkalemia	0/6 (0%)		4/57 (7%)		2/57 (3.5%)
Hypermagnesemia	0/6 (0%)		3/57 (5.3%)		5/57 (8.8%)
Hypernatremia	1/6 (16.7%)		1/57 (1.8%)		2/57 (3.5%)
Hypoalbuminemia	2/6 (33.3%)		5/57 (8.8%)		5/57 (8.8%)
Hypocalcemia	2/6 (33.3%)		3/57 (5.3%)		5/57 (8.8%)
Hypoglycemia	1/6 (16.7%)		2/57 (3.5%)		2/57 (3.5%)
Hypokalemia	1/6 (16.7%)		8/57 (14%)		5/57 (8.8%)
Hypomagnesemia	1/6 (16.7%)		6/57 (10.5%)		4/57 (7%)
Hyponatremia	2/6 (33.3%)		9/57 (15.8%)		7/57 (12.3%)
Hypophosphatemia	1/6 (16.7%)		8/57 (14%)		5/57 (8.8%)
Metabolism and nutrition disorders - Other	0/6 (0%)		5/57 (8.8%)		1/57 (1.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/6 (33.3%)		11/57 (19.3%)		5/57 (8.8%)
Arthritis	1/6 (16.7%)		0/57 (0%)		2/57 (3.5%)
Back pain	2/6 (33.3%)		7/57 (12.3%)		2/57 (3.5%)
Bone pain	1/6 (16.7%)		2/57 (3.5%)		0/57 (0%)
Flank pain	1/6 (16.7%)		0/57 (0%)		0/57 (0%)
Generalized muscle weakness	3/6 (50%)		9/57 (15.8%)		10/57 (17.5%)
Muscle weakness left-sided	1/6 (16.7%)		12/57 (21.1%)		6/57 (10.5%)
Muscle weakness lower limb	1/6 (16.7%)		5/57 (8.8%)		8/57 (14%)
Muscle weakness right-sided	0/6 (0%)		3/57 (5.3%)		4/57 (7%)
Muscle weakness upper limb	1/6 (16.7%)		2/57 (3.5%)		1/57 (1.8%)
Musculoskeletal and connective tissue disorder - Other	0/6 (0%)		2/57 (3.5%)		3/57 (5.3%)
Myalgia	1/6 (16.7%)		3/57 (5.3%)		3/57 (5.3%)
Neck pain	1/6 (16.7%)		2/57 (3.5%)		1/57 (1.8%)
Pain in extremity	2/6 (33.3%)		9/57 (15.8%)		9/57 (15.8%)
Nervous system disorders
Amnesia	1/6 (16.7%)		1/57 (1.8%)		2/57 (3.5%)
Ataxia	2/6 (33.3%)		5/57 (8.8%)		4/57 (7%)
Cognitive disturbance	0/6 (0%)		8/57 (14%)		2/57 (3.5%)
Concentration impairment	1/6 (16.7%)		0/57 (0%)		2/57 (3.5%)
Depressed level of consciousness	1/6 (16.7%)		2/57 (3.5%)		0/57 (0%)
Dizziness	2/6 (33.3%)		11/57 (19.3%)		11/57 (19.3%)
Dysarthria	0/6 (0%)		6/57 (10.5%)		6/57 (10.5%)
Dysgeusia	1/6 (16.7%)		0/57 (0%)		1/57 (1.8%)
Dysphasia	1/6 (16.7%)		10/57 (17.5%)		7/57 (12.3%)
Facial muscle weakness	2/6 (33.3%)		0/57 (0%)		0/57 (0%)
Facial nerve disorder	1/6 (16.7%)		0/57 (0%)		0/57 (0%)
Headache	2/6 (33.3%)		32/57 (56.1%)		19/57 (33.3%)
Lethargy	1/6 (16.7%)		1/57 (1.8%)		1/57 (1.8%)
Memory impairment	1/6 (16.7%)		11/57 (19.3%)		10/57 (17.5%)
Nervous system disorders - Other	1/6 (16.7%)		9/57 (15.8%)		7/57 (12.3%)
Paresthesia	1/6 (16.7%)		7/57 (12.3%)		8/57 (14%)
Peripheral sensory neuropathy	2/6 (33.3%)		5/57 (8.8%)		5/57 (8.8%)
Seizure	1/6 (16.7%)		11/57 (19.3%)		5/57 (8.8%)
Somnolence	1/6 (16.7%)		0/57 (0%)		1/57 (1.8%)
Tremor	0/6 (0%)		5/57 (8.8%)		3/57 (5.3%)
Psychiatric disorders
Agitation	1/6 (16.7%)		1/57 (1.8%)		2/57 (3.5%)
Anxiety	0/6 (0%)		9/57 (15.8%)		4/57 (7%)
Confusion	3/6 (50%)		7/57 (12.3%)		6/57 (10.5%)
Depression	1/6 (16.7%)		9/57 (15.8%)		9/57 (15.8%)
Insomnia	3/6 (50%)		9/57 (15.8%)		11/57 (19.3%)
Renal and urinary disorders
Hematuria	2/6 (33.3%)		5/57 (8.8%)		5/57 (8.8%)
Proteinuria	1/6 (16.7%)		9/57 (15.8%)		7/57 (12.3%)
Urinary frequency	2/6 (33.3%)		3/57 (5.3%)		4/57 (7%)
Urinary incontinence	3/6 (50%)		5/57 (8.8%)		4/57 (7%)
Urinary retention	1/6 (16.7%)		0/57 (0%)		0/57 (0%)
Urinary urgency	1/6 (16.7%)		1/57 (1.8%)		0/57 (0%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/6 (16.7%)		2/57 (3.5%)		1/57 (1.8%)
Cough	2/6 (33.3%)		12/57 (21.1%)		8/57 (14%)
Dyspnea	1/6 (16.7%)		7/57 (12.3%)		3/57 (5.3%)
Epistaxis	0/6 (0%)		7/57 (12.3%)		3/57 (5.3%)
Hoarseness	0/6 (0%)		6/57 (10.5%)		4/57 (7%)
Laryngeal inflammation	1/6 (16.7%)		1/57 (1.8%)		0/57 (0%)
Nasal congestion	0/6 (0%)		4/57 (7%)		0/57 (0%)
Postnasal drip	2/6 (33.3%)		1/57 (1.8%)		1/57 (1.8%)
Productive cough	2/6 (33.3%)		2/57 (3.5%)		1/57 (1.8%)
Sore throat	1/6 (16.7%)		4/57 (7%)		4/57 (7%)
Skin and subcutaneous tissue disorders
Alopecia	2/6 (33.3%)		3/57 (5.3%)		3/57 (5.3%)
Dry skin	0/6 (0%)		1/57 (1.8%)		6/57 (10.5%)
Periorbital edema	1/6 (16.7%)		0/57 (0%)		1/57 (1.8%)
Pruritus	2/6 (33.3%)		1/57 (1.8%)		4/57 (7%)
Purpura	0/6 (0%)		3/57 (5.3%)		1/57 (1.8%)
Rash acneiform	0/6 (0%)		4/57 (7%)		4/57 (7%)
Rash maculo-papular	1/6 (16.7%)		5/57 (8.8%)		2/57 (3.5%)
Skin and subcutaneous tissue disorders - Other	0/6 (0%)		5/57 (8.8%)		3/57 (5.3%)
Vascular disorders
Hematoma	2/6 (33.3%)		1/57 (1.8%)		1/57 (1.8%)
Hypertension	3/6 (50%)		24/57 (42.1%)		25/57 (43.9%)
Thromboembolic event	1/6 (16.7%)		2/57 (3.5%)		7/57 (12.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.