A Phase II Trial of Bevacizumab in Patients With Recurrent Solid Tumor Brain Metastases Who Have Failed Whole Brain Radiation Therapy
Phase: PHASE2
Conditions: Metastatic Cancer, Unspecified Adult Solid Tumor, Protocol Specific
Sponsor: Northwestern University

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A Phase II Trial of Bevacizumab in Patients with Recurrent Solid Tumor 
Brain Metastases Who Have Failed Whole Brain Radiation Therapy
PRINCIPAL INVESTIGATOR:
Priya Kumthekar, MD
Northwestern University
710 North Lake Shore Drive
Abbott Hall, Room 1123
Chicago, IL 60611
Phone: 312-503-1818
Fax: 312-908-5073
p-kumthekar@northwestern.edu
SUB-INVESTIGATORS:
Jeffrey Raizer, MD
jraizer@nmff.org
 
Kristin Swanson, PhD
kristin.swanson@northwestern.edu
PARTICIPATING SITES:
Andrew Lassman, MD
Columbia University
The Neurological Institute of New York
710 West 168th Street
New York, NY 10032-3784
Phone: 212-342-0571
abl7@columbia.edu 
Sean Grimm, MD
Northwestern Medicine Cancer Center
4405 Weaver Pkwy.
Warrenville, IL 60555
Phone: 630.352.5450
Sean.Grimm@CadenceHealth.org
BIOSTATISTICIAN:
Alfred Rademaker, PhD
rademaker@northwestern.edu 
STUDY INTERVENTION
Bevacizumab
FUNDING SOURCE:
Genentech
IND STATUS:
EXEMPTION # 117883
VERSION DATE:
February 6, 2019
LEAD SITE/COORDINATING SITE:
Northwestern University
Robert H. Lurie Comprehensive Cancer Center
Clinical Research Office
676 N. St. Clair Street, Suite 1200
Chicago, IL 60611
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STUDY SUMMARY
Title
A Phase II Trial of Bevacizumab in Patients with Recurrent Solid Tumor Brain 
Metastases Who Have Failed Whole Brain Radiation Therapy
Short Title
Bevacizumab in Recurrent Solid Tumor Brain Metastases
Protocol Date
February 6, 2019
Study 
Duration
12-18 months
Study Centers
Northwestern University (PI: P. Kumthekar); Columbia University (PI: A. 
Lassman); Northwestern Medicine Cancer Center (Cadence Health Cancer Center) 
(PI: Sean Grimm)
Objectives
Primary
Determine the radiographic response in patient’s brain metastases treated with 
bevacizumab. 
Secondary  
1)
Estimate progression free survival rate at 6 months. 
2)
Determine the time to progression based on MRI or CT scans.
3)
Determine the time to response based on radiographic imaging.
4)
Determine the duration of response based on radiographic imaging.
5)
Determine the overall survival.
6)
Collect safety data.
7)
Assess changes in quality of life using the FACT-Br while on treatment.
Accrual Goal
27
Diagnosis and 
Main Inclusion 
Criteria

Patients must have recurrent, measurable brain metastases from a solid 
tumor after whole brain radiation therapy (WBRT).

Patients must have failed prior WBRT.

Patients must have completed WBRT >12 weeks prior to enrollment to limit 
cases of pseudoprogression; however if new lesions are noted < 12 weeks 
but > 4 weeks prior to enrollment, those patients are eligible.

Patients may be on other systemic chemotherapies if progressive CNS 
disease occurs while on these treatments.  New systemic chemotherapies 
should not be started unless required to treat systemic disease but should not 
start until at least 1 follow up imaging study has been performed. 

Patients with leptomeningeal metastases are not eligible for therapy.

No limitations on prior CNS directed therapies

Patients must be age > 18 years with a KPS of > 60 

Patients must be > 4 weeks from any surgery. 

Patients may not have known hypersensitivity to any component of 
bevacizumab. 
Treatment 
Summary
Patients will receive bevacizumab at a dose of 10 mg/kg intravenously every two 
weeks until CNS disease progression or death from systemic disease.
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Analysis 
Summary
The primary endpoint will be objective radiographic tumor response.  Secondary 
endpoints will include PFS at 6 months, time to progression, time to response, 
duration of response, OS, and safety. 
Note: As of December 31, 2018, patients will no longer be followed and follow 
up information will not be collected.
A Simon two-stage optimal phase II clinical trial design will be used. If 0 responses 
are observed in the first 9 patients, it will be concluded that the true response rate 
was 5% or less and no further patients will be enrolled. If 1 or more responses are 
observed in the first 9 patients, 15 additional patients will be enrolled to a total of 24 
evaluable patients. If 3 or more responses are observed, there would be evidence 
that the regimen used was active (true response rate is at least 25%). This design 
will declare the regimen as active when the true response rate is 25% with 90% 
probability (power = 0.90) at the 1-sided 0.10 alpha level. To account for dropouts, 
we will plan for 27 patients total to be able to have 24 evaluable patients.
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TABLE OF CONTENTS
Study Summary .............................................................................................................................2
Table of Contents...........................................................................................................................4
Schema............................................................................................................................................5
1
Introduction - Background & Rationale..............................................................................6
2
Objectives & endpoints........................................................................................................14
3
Selection of Subjects.............................................................................................................15
4
Patient Registration..............................................................................................................18
5
Treatment Plan.....................................................................................................................19
6
Endpoint Assessment ...........................................................................................................24
7
Study Parameters .................................................................................................................29
8
Drug Formulation and Procurement..................................................................................31
9
Statistical Considerations ....................................................................................................34
10
Adverse Events..................................................................................................................35
11
Data Collection & Submission.........................................................................................47
12
Pathology Requirements ..................................................................................................48
13
Administrative, Ethical & Regulatory Considerations .................................................48
14
Appendix............................................................................................................................55
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SCHEMA
This is a phase II trial for patients with brain metastases (BM) who progress after whole brain radiation 
therapy (WBRT). Patients will receive bevacizumab at a dose of 10 mg/kg IV every 2 weeks until CNS 
disease progression or death from systemic disease.   
Progressive BM after WBRT
Bevacizumab 10 mg/kg q 2 weeks 
(1 cycle = 28 days/4 weeks)
Continue until progression or death from 
systemic disease
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1
INTRODUCTION - BACKGROUND & RATIONALE 
1.1
Metastatic Disease - Overview & Current Treatment Options
Metastatic brain tumors are by far the most common intracranial malignancy totaling 
about 170,000 per year and developing in about 40% of all cancer patients1-4. Metastases 
out number primary brain tumors by about 4:1. The most common primary malignancies 
of brain metastases include lung cancer (compromises about 50%), breast cancer (15%), 
melanoma (9%), and unknown primary (about 11%)5.  Metastatic disease can cause 
neurologic issues ranging from headache to seizures, motor and sensory impairment, and 
other focal neurologic deficits. In general , prognosis is poor with a median survival time 
of 1 month for untreated patients, and approximately 4 months for treated patients2,  with 
only 10% being alive at one year after diagnosis6.    
When determining treatment for patients with brain metastases, histology, number of 
lesions, and resectability of lesions are taken into account. Because over 70% of patients 
present with multiple metastases at diagnosis5, focal treatments such as surgical resection 
and radiosurgery are ineffective. For these patients, whole brain radiation therapy 
(WBRT) should be performed, although some practitioners use radiosurgery for patients 
with ≤ 3 lesions and withhold WBRT. Typically WBRT is given in 10 fractions of 3 Gy 
over 2 weeks for a total dose of 30 Gy, but other schedules have been used, such as 15 
fractions of 2.5 Gy over 3 weeks for a total dose of 37.5 Gy.  The Radiation Therapy 
Oncology Group (RTOG) has evaluated these and various other radiation fractionation 
schedules, however median survival seems independent of the dose schedule3.  
For patients with brain metastases from systemic cancers who fail WBRT, median 
survival is 4-6 months. Patients with the limited or no extracranial disease, KPS > 70, and 
age < 65 have survivals over 10 months. Using the updated GPA, survival is 2.8 to 11.1 
months depending on score and histology7. This group of patients is increasing with 
improvements in systemic therapy; leading to a group of patients whose demise is from 
CNS involvement. 
Systemic chemotherapy has been shown to have activity in the treatment of brain and 
leptomeningeal metastases8, 9, but no one drug has proven to be overly effective.   
Lassman et al. treated 31 patients with CNS metastasis with HD MTX and found a 
median overall survival (OS) of approximately 5 months with a 28% response and stable 
disease rate10. Temozolomide has been shown to have median survivals of approximately 
5 months in patients who have failed WBRT11-13. In a trial of HER2 positive breast cancer 
patients with BM, 22 patients treated lapatinib and capecitabine or topotecan, had a 
partial response (PR) rate of 22% and a stable disease (SD) rate of 40%; median time on 
trial was approximately 4 months14. Topotecan has been used in both breast and lung 
cancer patients with BM with survivals of 6.25 and 7.25 months15, 16. Finally patients with 
solid tumors who had BM entered in to various phase I trials had a survival of 7.5 
months17.
1.2
Bevacizumab
Bevacizumab is recombinant humanized monoclonal IgG1 antibody that selectively binds 
to and neutralizes the biologic activity of human vascular endothelial growth factor 
(VEGF). Bevacizumab inhibits the binding of VEGF to its receptors, Flt-1 and KDR, on 
the surface of endothelial cells. Neutralization of the biologic activity of VEGF can result 
in the reduction of tumor vascularization and subsequent reduction in tumor growth. It is 
currently FDA approved for recurrent glioblastoma multiforme (GBM), lung cancer and 
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renal cell cancer18.  Bevacizumab has shown activity in recurrent malignant GBM 19 
leading to accelerated FDA approval. 
1.2.1
Clinical Data
Bevacizumab has been studied in a multitude of phase I, II, and III clinical trials 
in more than 5000 patients and in multiple tumor types. In addition, data are 
available from 3,863 patients enrolled in two post market studies in metastatic 
colorectal cancer (CRC). Approximately 130,000 patients have been exposed to 
bevacizumab as a marketed product or in clinical trials. The following discussion 
summarizes some of the efficacy results pertinent to this particular trial. Please 
refer to the bevacizumab Investigator Brochure for descriptions of all completed 
phase I, II, and III trials reported to date.
In a large phase III study (AVF2107g) in patients with metastatic CRC, the 
addition of bevacizumab, to irinotecan/5-fluorouracil/leucovorin (IFL) 
chemotherapy resulted in a clinically and statistically significant increase in 
duration of survival, with a hazard ratio of death of 0.67 (median survival 15.6 
vs. 20.3 months; p < 0.001). Similar increases were seen in PFS (6.2 vs. 10.6 
months; p < 0.001), overall response rate (35% vs. 45%; p < 0.01) and duration 
of response (7.1 vs. 10.4 months; p < 0.01) for the combination arm versus the 
chemotherapy only arm (bevacizumab Investigator Brochure, October 2005).
Based on the survival advantage demonstrated in study AVF2107g, bevacizumab 
was designated for priority review and was approved on 26 February 2004 in the 
United States for first-line treatment in combination with IV 5-FUbased 
chemotherapy for subjects with metastatic colorectal cancer. Additional data 
from phase III trials in metastatic CRC (E3200), non-small cell lung cancer 
(NSCLC; E4599), and metastatic breast cancer (E2100) have also demonstrated 
clinical benefit from bevacizumab when added to chemotherapy.  
In Study E3200, the addition of bevacizumab to FOLFOX chemotherapy resulted 
in improved OS compared with FOLFOX alone (13.0 vs. 10.8 months, 
respectively, HR  0.75; p  0.01) in a population of previously treated CRC 
patients. There was also improved OS in first-line NSCLC patients (E4599) 
treated with carboplatin/paclitaxel  bevacizumab compared with chemotherapy 
alone (12.3 vs. 10.3 months, respectively; HR  0.80; p = 0.003). The results 
from this trial were the basis for FDA approval of bevacizumab for use in 
combination with carboplatin  paclitaxel as first-line treatment of patients with 
unresectable, locally advanced, recurrent or metastatic, non-squamous NSCLC in 
October 2006.  Finally, patients with untreated metastatic breast cancer (E2100) 
who received bevacizumab in combination with weekly paclitaxel had a marked 
improvement in PFS compared with chemotherapy alone (13.3 vs. 6.7 months, 
respectively; HR  0.48; p  0.0001) (see the Bevacizumab Investigator Brochure 
for additional details).
1.2.2
Safety Profile
In the initial phase I and II clinical trials, four potential bevacizumab-associated 
safety signals were identified: hypertension, proteinuria, thromboembolic events, 
and hemorrhage.  Additional completed phase II and phase III studies of 
bevacizumab as well as spontaneous reports have further defined the safety 
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profile of this agent. Bevacizumab-associated adverse events identified in phase 
III trials include congestive heart failure (CHF) primarily in metastatic breast 
cancer, gastrointestinal perforations, wound healing complications, and arterial 
thromboembolic events (ATE). These and other safety signals are described in 
further detail as follows and in the bevacizumab Investigator Brochure.
1.2.2.1 Hypertension
An increased incidence of hypertension has been observed in patients 
treated with bevacizumab. Grade 4 and 5 hypertensive events are rare. 
Clinical sequelae of hypertension are rare but have included hypertensive 
crisis, hypertensive encephalopathy, and reversible posterior 
leukoencephalopathy syndrome (RPLS) 20, 21. There is no information on 
the effect of bevacizumab in patients with uncontrolled hypertension at 
the time of initiating bevacizumab therapy. Therefore, caution should be 
exercised before initiating bevacizumab therapy in these patients. 
Monitoring of blood pressure is recommended during bevacizumab 
therapy.  Optimal control of blood pressure according to standard public 
health guidelines is recommended for patients on treatment with or 
without bevacizumab.  
Temporary interruption of bevacizumab therapy is recommended in 
patients with hypertension requiring medical therapy until adequate 
control is achieved. If hypertension cannot be controlled with medical 
therapy, bevacizumab therapy should be permanently discontinued.  
Bevacizumab should be permanently discontinued in patients who 
develop hypertensive crisis or hypertensive encephalopathy.
1.2.2.2 Proteinuria  
An increased incidence of proteinuria has been observed in patients 
treated with bevacizumab compared with control arm patients. In the 
bevacizumab-containing treatment arms of clinical trials (across all 
indications), the incidence of proteinuria (reported as an adverse event) 
was up to 38% (metastatic CRC Study AVF2192g). The severity of 
proteinuria has ranged from asymptomatic and transient events detected 
on routine dipstick urinalysis to nephrotic syndrome; the majority of 
proteinuria events have been grade 1. Grade 3 proteinuria was reported in 
up to 3% of bevacizumab-treated patients, and Grade 4 in up to 1.4% of 
bevacizumab-treated patients. The proteinuria seen in bevacizumab 
clinical trials was not associated with renal impairment and rarely 
required permanent discontinuation of bevacizumab therapy.  
Bevacizumab should be discontinued in patients who develop Grade 4 
proteinuria (nephrotic syndrome). Patients with a history of hypertension 
may be at increased risk for the development of proteinuria when treated 
with bevacizumab. There is evidence from the dose-finding, phase II 
trials (AVF0780g, AVF0809s, and AVF0757g) suggesting that Grade 1 
proteinuria may be related to bevacizumab dose.
1.2.2.3 Thromboembolic Events 
Both venous and arterial thromboembolic (TE) events, ranging in 
severity from catheter-associated phlebitis to fatal, have been reported in 
patients treated with bevacizumab in the colorectal cancer trials and, to a 
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lesser extent, in patients treated with bevacizumab in NSCLC and breast 
cancer trials. 
1.2.2.3.1
Venous thromboembolism (including deep venous 
thrombosis, pulmonary embolism, and 
thrombophlebitis) 
In the phase III pivotal trial in metastatic CRC, there was 
a slightly higher rate of venous TE events in patients 
treated with bevacizumab plus chemotherapy compared 
with chemotherapy alone (19% vs. 16%). 
In Study AVF2107g, a phase III, pivotal trial in 
metastatic CRC, VTE events, including deep venous 
thrombosis, pulmonary embolism, and thrombophlebitis, 
occurred in 15.2% of patients receiving chemotherapy 
alone and 16.6% of patients receiving 
chemotherapy  bevacizumab. The incidence of Grade 
 3 venous VTE events in one NSCLC trial (E4599) was 
higher in the bevacizumab-containing arm compared to 
the chemotherapy control arm (5.6% vs. 3.2%).  One 
event (0.2%) was fatal in the bevacizumab-containing 
arm; not fatal events were reported in the 
carboplatin/paclitaxel arm (see bevacizumab Investigator 
Brochure). In metastatic CRC clinical trials, the 
incidence of VTE events was similar in patients 
receiving chemotherapy  bevacizumab and those 
receiving the control chemotherapy alone. 
In clinical trials across all indications the overall 
incidence of VTE events was 2.8%17.3% in the 
bevacizumab-containing arms compared with 
3.2%15.6% in the chemotherapy control arms. The use 
of bevacizumab with chemotherapy does not 
substantially increase the risk of VTE event compared 
with chemotherapy alone.  However, patients with 
metastatic CRC who receive bevacizumab and 
experienced a VTE event may be at higher risk for 
recurrence of VTE event.
1.2.2.3.2
Arterial thromboembotic events  
An increased incidence of ATE events was observed in 
patients treated with bevacizumab compared with those 
receiving control treatment. ATE events include 
cerebrovascular accidents, myocardial infarction, 
transient ischemic attacks (TIAs), and other ATE events.  
In a pooled analysis of data from five randomized phase 
II and III trials (mCRC [AVF2107g, AVF2192g, 
AVF0780g]; locally advanced or metastatic NSCLC 
[AVF0757g]; metastatic breast cancer [AVF2119g]), the 
incidence rate of ATE events was 3.8% (37 of 963) in 
patients who received chemotherapy  bevacizumab 
compared with 1.7% (13 of 782) in patients treated with 
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chemotherapy alone. ATE events led to a fatal outcome 
in 0.8% (8 of 963) of patients treated with 
chemotherapy  bevacizumab and 0.5% (4 of 782) of 
patients treated with chemotherapy alone.  
Cerebrovascular accidents (including TIAs) occurred in 
2.3% of patients treated with chemotherapy 
 bevacizumab and 0.5% of patients treated with 
chemotherapy alone. Myocardial infarction occurred in 
1.4% of patients treated with chemotherapy 
 bevacizumab compared with 0.7% of patients treated 
with chemotherapy alone (see the bevacizumab 
Investigator Brochure for additional details).
Aspirin is a standard therapy for primary and secondary 
prophylaxis of ATE events in patients at high risk of 
such events, and the use of aspirin ≤ 325 mg daily was 
allowed in the 5 randomized studies discussed above. 
Use of aspirin was assessed routinely as a baseline or 
concomitant medication in these trials, though safety 
analyses specifically regarding aspirin use were not 
preplanned. Due to the relatively small numbers of 
aspirin users and ATE events, retrospective analyses of 
the ability of aspirin to affect the risk of such events 
were inconclusive. However, similarly retrospective 
analyses suggested that the use of up to 325 mg of 
aspirin daily does not increase the risk of grade 1-2 or 
grade 3-4 bleeding events, and similar data with respect 
to metastatic colorectal cancer patients were presented at 
ASCO 200522. Further analyses of the effects of 
concomitant use of bevacizumab and aspirin in 
colorectal and other tumor types are ongoing.
1.2.2.4 Gastrointestinal perforation 
Patients with metastatic carcinoma may be at increased risk for 
the development of gastrointestinal perforation and fistula when 
treated with bevacizumab and chemotherapy. Bevacizumab 
should be permanently discontinued in patients who develop 
gastrointestinal perforation. A causal association of intra-
abdominal inflammatory processes and gastrointestinal 
perforation to bevacizumab treatment has not been established. 
Nevertheless, caution should be exercised when treating patients 
with intra-abdominal inflammatory processes with bevacizumab. 
Gastrointestinal perforation has been reported in other trials in 
non-colorectal cancer populations (e.g., ovarian, renal cell, 
pancreas, breast, and NSCLC) and may be higher in incidence in 
some tumor types.
1.2.2.5 Fistula  
Bevacizumab use has been associated with serious cases of 
fistulae including events resulting in death. Fistulae in the GI 
tract are common (1%–10% incidence) in patients with 
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metastatic CRC, but uncommon (0.1%1%) or rare (0.01%–
0.1%) in other indications. In addition, fistulae that involve areas 
of the body other than the GI tract (e.g., tracheoesophageal, 
bronchopleural, urogenital, biliary) have been reported 
uncommonly (0.1%–1%) in patients receiving bevacizumab in 
clinical studies and postmarketing reports. Events were reported 
at various timepoints during treatment, ranging from 1 week to 
 1 year following initiation of bevacizumab, with most events 
occurring within the first 6 months of therapy. Permanently 
discontinue bevacizumab in patients with tracheoesophageal 
fistulae or any Grade 4 fistula. Limited information is available 
on the continued use of bevacizumab in patients with other 
fistulae.  In cases of internal fistula not arising in the GI tract, 
discontinuation of bevacizumab should be considered.
1.2.2.6 Wound healing complications 
Wound healing complications such as wound dehiscence have 
been reported in patients receiving bevacizumab. In an analysis 
of pooled data from two trials in metastatic colorectal cancer, 
patients undergoing surgery 28-60 days before study treatment 
with 5-FU/LV plus bevacizumab did not appear to have an 
increased risk of wound healing complications compared to 
those treated with chemotherapy alone23. Surgery in patients 
currently receiving bevacizumab is not recommended. No 
definitive data are available to define a safe interval after 
bevacizumab exposure with respect to wound healing risk in 
patients receiving elective surgery; however, the estimated half-
life of bevacizumab is 21 days. Bevacizumab should be 
discontinued in patients with severe wound healing 
complications. If patients receiving treatment with bevacizumab 
require elective major surgery, it is recommended that 
bevacizumab be held for 4–8 weeks prior to the surgical 
procedure. Patients undergoing a major surgical procedure 
should not begin or restart bevacizumab until 4 weeks after that 
procedure (in the case of high-risk procedures such as liver 
resection, thoracotomy, or neurosurgery, it is recommended that 
chemotherapy be restarted no earlier than 6 weeks and 
bevacizumab no earlier than 8 weeks after surgery).
1.2.2.7 Hemorrhage
Overall, grade 3 and 4 bleeding events were observed in 4.0% of 
1132 patients treated with bevacizumab in a pooled database 
from eight phase I, II, and III clinical trials in multiple tumor 
types (bevacizumab Investigator Brochure, October 2005). The 
hemorrhagic events that have been observed in bevacizumab 
clinical studies were predominantly tumor-associated 
hemorrhage (see below) and minor mucocutaneous hemorrhage. 
1.2.2.7.1 Tumor-Associated Hemorrhage  
Major or massive pulmonary hemorrhage or hemoptysis 
has been observed primarily in patients with NSCLC.  
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Life-threatening and fatal hemoptysis was identified as a 
bevacizumab-related adverse event in NSCLC trials.  
These events occurred suddenly and presented as major 
or massive hemoptysis. Among the possible risk factors 
evaluated (including squamous cell histology, treatment 
with anti-rheumatic/anti-inflammatory drugs, treatment 
with anticoagulants, prior radiotherapy, bevacizumab 
therapy, previous medical history of atherosclerosis, 
central tumor location, and cavitation of tumors during 
therapy), the only variables that showed statistically 
significant correlations with bleeding were bevacizumab 
therapy and squamous cell histology.
Of patients experiencing pulmonary hemorrhages 
requiring medical intervention, many had cavitation 
and/or necrosis of the tumor, either preexisting or 
developing during bevacizumab therapy. Patients 
developing lung cavitation on treatment should be 
assessed by the treating physician for risk-benefit.
In Study E4599, in which squamous cell carcinoma was 
excluded, the rate of any type of Grade  3 hemorrhage 
was 1.0% in the control arm (carboplatin and paclitaxel) 
versus 4.1% in the carboplatin and paclitaxel 
 bevacizumab arm (Sandler et al. 2006).  
GI hemorrhages, including rectal bleeding and melena 
have been reported in patients with CRC, and have been 
assessed as tumor-associated hemorrhages. Tumor-
associated hemorrhages were also seen rarely in other 
tumor types and locations, including a case of CNS 
bleeding in a patient with hepatoma with occult CNS 
metastases and a patient who developed continuous 
oozing of blood from a thigh sarcoma with necrosis.
1.2.2.7.2 Mucocutaneus Hemorrage  
Across all bevacizumab clinical trials, mucocutaneous 
hemorrhage has been seen in 20%-40% of patients 
treated with bevacizumab. These were most commonly 
Grade 1 epistaxis that lasted less than 5 minutes, 
resolved without medical intervention and did not 
require any changes in bevacizumab treatment regimen. 
There have also been less common events of minor 
mucocutaneous hemorrhage in other locations, such as 
gingival bleeding and vaginal bleeding. 
1.2.2.8 Reversible Posterior Leukoencephalopathy Syndrome  
There have been rare reports of bevacizumab-treated patients 
developing signs and symptoms that are consistent with RPLS, a 
rare neurologic disorder that can present with the following signs 
and symptoms (among others):  seizures, headache, altered 
mental status, visual disturbance, or cortical blindness, with or 
without associated hypertension. Brain imaging is mandatory to 
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confirm the diagnosis of RPLS. In patients who develop RPLS, 
treatment of specific symptoms, including control of 
hypertension, is recommended along with discontinuation of 
bevacizumab. The safety of reinitiating bevacizumab therapy in 
patients previously experiencing RPLS is not known20, 21. 
Adequate brain imaging using MRI must be performed as a 
follow-up measurement for patients with PRES. 
1.2.2.9 Congestive heart failure 
In clinical trials CHF was observed in all cancer indications 
studied to date, but predominantly in patients with metastatic 
breast cancer. In the phase III clinical trial of metastatic breast 
cancer (AVF2119g), 7 (3%) bevacizumab-treated patients 
experienced CHF, compared with two (1%) control arm patients.  
These events varied in severity from asymptomatic declines in 
left ventricular ejection fraction (LVEF) to symptomatic CHF 
requiring hospitalization and treatment. All the patients treated 
with bevacizumab were previously treated with anthracyclines 
(doxorubicin cumulative dose of 240360 mg/m2). Many of 
these patients also had prior radiotherapy to the left chest wall.  
Most of these patients showed improved symptoms and/or left 
ventricular function following appropriate medical therapy24. In 
a randomized, phase III trial of patients with previously 
untreated metastatic breast cancer (E2100), the incidence of 
LVEF decrease (defined as Grade 3 or 4) in the 
paclitaxel  bevacizumab arm was 0.3% versus 0% for the 
paclitaxel alone arm. No information is available on patients 
with preexisting CHF of New York Heart Association (NYHA) 
Class IIIV at the time of initiating bevacizumab therapy, as 
these patients were excluded from clinical trials. Prior 
anthracyclines exposure and/or prior radiotherapy to the chest 
wall may be possible risk factors for the development of CHF.  
Caution should be exercised before initiating bevacizumab 
therapy in patients with these risk factors. A phase II trial in 
patients with refractory acute myelogenous leukemia reported 
5 cases of cardiac dysfunction (CHF or LVEF decrease to 
 40%) among 48 patients treated with sequential cytarabine, 
mitoxantrone, and bevacizumab. All but 1 of these patients had 
significant prior exposure to anthracyclines as well25. 
Two additional studies investigated concurrent administration of 
anthracyclines and bevacizumab. In 21 patients with 
inflammatory breast cancer treated with neoadjuvant docetaxel, 
doxorubicin, and bevacizumab, no patients developed clinically 
apparent CHF; however, patients had asymptomatic decreases in 
LVEF to  40%26. In a small phase II study in patients with soft 
tissue sarcoma, 2 of the 17 patients treated with bevacizumab 
and high-dose doxorubicin (75 mg/m2) developed CHF 
(one Grade 3 event after a cumulative doxorubicin dose of 
591 mg/m2, one Grade 4 event after a cumulative doxorubicin 
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dose of 420 mg/m2); an additional 4 patients had asymptomatic 
decreases in LVEF (D’Adamo et al. 2004).Other studies in 
patients with various tumor types and either a history of 
anthracycline exposure or concomitant use with bevacizumab are 
ongoing. Patients receiving concomitant anthracyclines or with 
prior exposure to anthracyclines should have a baseline MUGA 
scans or echocardiograms (ECHOs) with a normal LVEF.
1.2.2.10 Neutropenia
Increased rates of severe neutropenia, febrile neutropenia, or 
infection with severe neutropenia (including some fatalities) 
have been observed in patients treated with some myelotoxic 
chemotherapy regimens plus bevacizumab in comparison to 
chemotherapy alone27.
1.3
Rationale for the Current Study
Many patients who have controlled systemic disease often have progressive or recurrent 
BM. For these patients no standard option for treatment exists. Repeat WBRT may be an 
option but is best suited for those who had a durable initial response. For some patients, 
radiosurgery might be used for 1-3 lesions and then chemotherapy can be considered. 
Limited data exist for patients who have repeat WBRT. In this clinical setting, survival is 
estimated at about 4 months28, 29.  For patients who receive chemotherapy survival is 
about 6 months30, 31 with variable responses to treatment and time to tumor progression. 
Data is limited in patients who fail WBRT.  
Bevacizumab administration has proven to be safe without an increased incidence of 
CNS bleeding in malignant glioma32. A more recent review has shown that specifically in 
patients with BM treated with bevacizumab, the bleed rate is comparable to those not 
receiving bevacizumab33. One additional report of 6 patients noted safety and activity of 
bevacizumab in patients with BM from NSCLC34.  It is rational and appears safe to 
consider treating patients with progressive or recurrent BM post-WBRT with 
bevacizumab as options are limited with no standard agent used for salvage therapy. 
We propose to conduct a phase II trial of patients with brain metastases who have failed 
WBRT. Patients will receive bevacizumab at a dose of 10 mg/kg IV every 2 weeks until 
CNS disease progression or death from systemic disease. This will be a dual-center, 
open-label trial following a Simon two-stage optimum design. If 0 responses are 
observed in the first 9 patients, it will be concluded that the true response rate was less 
that 5% and no further patients will be enrolled. If 1 or more responses are observed in 
the first 9 patients, a total of 24 evaluable patients will be required. We will plan for 27 
patients total to be able to have 24 evaluable patients.
2
OBJECTIVES & ENDPOINTS
2.1
Primary Objective
The primary objective of this study will be to determine the radiographic response rate in 
patients with solid tumor brain metastases treated with bevacizumab after failing WBRT.
2.2
Secondary Objectives
Secondary objectives will include the following:
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2.2.1
Estimate the PFS rate at 6 months 
2.2.2
Determine the time to progression based on MRI or CT scans.
2.2.3
Determine the time to response based on radiographic imaging.
2.2.4
Determine the duration of response based on radiographic imaging.
2.2.5
Determine overall survival.
2.2.6
Collect additional safety data.
2.2.7
Assess changes in quality of life using the FACT-Br while on treatment.
2.3
Primary Endpoint
The primary endpoint will be objective radiographic tumor response. Response will be 
assessed prior to every odd-numbered cycle.
2.4
Secondary Endpoints
Secondary endpoints will include:
2.4.1
PFS assessed at 6 months.
2.4.2
Time to progression of disease based on MRI or CT scans performed prior to 
every odd-numbered cycle.
2.4.3
Time to response based on radiographic imaging performed prior to every odd-
numbered cycle.
2.4.4
Duration of the response based on radiographic imaging performed prior to every 
odd-numbered cycle.
2.4.5
OS rate. 
2.4.6
Safety as measured by adverse events assessed prior to every cycle.
2.4.7
Quality of life will be assessed at baseline and prior to every odd-numbered cycle 
during treatment using the FACT-Br tool. 
3
SELECTION OF SUBJECTS
The target population for this phase II trial is patients with BM from solid tumor malignancies 
who have failed WBRT. Males and females ≥ 18 years of age will be recruited with no preference 
to gender. No exclusion to this study will be based on race.  Minorities will actively be recruited 
to participate. The eligibility criteria listed below are interpreted literally and will not be waived.
Patients will be recruited in the Neuro-Oncology clinics of Northwestern University, 
Northwestern Medicine Cancer Center/Cadence Health Cancer Center and Columbia University. 
This will be a multi-center trial with the Robert H. Lurie Comprehensive Cancer Center of 
Northwestern University serving as the lead site. Patients may be referred to the Principal 
Investigator (PI), Dr. Priya Kumthekar, MD, at 312-503-1818, or to the local PIs at Columbia 
University or Northwestern Medicine Cancer Center/Cadence Health Cancer Center. Enrollment 
will be on a first-come-first-serve basis. A total accrual of 27 patients is planned for this study. It 
is estimated that approximately 1-2 patients may be enrolled per month. It is anticipated that this 
trial will take place over approximately 12-18 months in which time we expect to undergo 
accrual, evaluation and follow-up.
3.1
Inclusion Criteria
3.1.1
Patients must have a histologically or cytologically confirmed non-CNS primary 
solid malignancy at the time of initial diagnosis. NOTE: Brain lesions are not 
required to have pathologic confirmation. In addition, a copy of the pathology 
report for the primary tumor is sufficient for registration purposes.
3.1.2
Patients must have radiographically-confirmed recurrent brain metastases from a 
solid tumor after WBRT.
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3.1.3
Patients must have measurable disease in the brain, defined as at least 1 lesion 
measuring ≥ 5 mm unidimensionally on imaging.
3.1.4
Patients must have been on a stable dose of corticosteroids ≥ 5 days prior to 
obtaining their baseline Gd-MRI of brain.
3.1.5
Patients must have completed WBRT >12 weeks prior to enrollment to limit 
cases of pseudoprogression; however if new lesions are noted < 12 weeks but > 4 
weeks prior to enrollment, those patients are eligible.
3.1.6
Patients who underwent radiosurgery to treat a progressive lesion must have 
confirmation of tumor by tissue, MRS, MR perfusion or PET and the lesion must 
be measurable. NOTE: Radiosurgery may be done to a lesion that will not be 
used for response evaluation and should be done > 2 weeks prior to enrollment.
3.1.7
Patients may be on other systemic chemotherapies if progressive CNS disease 
occurs while on these treatments. NOTE:  New systemic chemotherapies should 
not be started unless required to treat systemic disease and should not start until 
at least 1 follow up imaging study has been performed. 
3.1.8
Patients may have received any number of prior CNS directed therapies – there 
are no limitations.
3.1.9
Patients must be age ≥ 18 years.
3.1.10 Patients must have a life expectancy of ≥ 12 weeks.
3.1.11 Patients must have a Karnofsky Performance Score (KPS) of ≥ 60.
3.1.12 Patients must exhibit adequate bone marrow, liver, and renal function, within 14 
days prior to registration, defined as:
WBC
≥ 3,000/µl
ANC
≥ 1,500/mm3
Platelets
≥ 100,000/mm3
Hemoglobin
≥ 10 gm/dl (may be reached by transfusion)
SGOT and bilirubin
< 2 x ULN (or < 5 x ULN if liver is involved)
Creatinine
< 1.5 x ULN
3.1.13 Patients of both sexes must agree to the use of barrier contraceptives throughout 
the duration of treatment on this trial and for 3 months after discontinuing 
treatment. NOTE:  Hormonal contraceptives are not acceptable as a sole method 
of contraception. 
3.1.14 Patients must be > 4 weeks from any major surgery. 
3.1.15 Patients NOT on warfarin must have a PT/INR < 1.4 within 14 days prior to 
registration.
Patients on full-dose anticoagulants (e.g., warfarin or LMW heparin) must meet 
BOTH of the following criteria within 14 days prior to registration:

No active bleeding or pathological condition that carries a high risk of 
bleeding (e.g., tumor involving major vessels or known varices).

In-range INR (between 2 and 3) on a stable dose of oral anticoagulant or 
on a stable dose of LMW heparin. 
3.1.16 Female patients of child-bearing potential must have a negative pregnancy test 
within 14 days prior to registration.
3.1.17 Patients must be willing and able to comply with study and/or follow-up 
procedures.
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3.1.18 Patients must sign an informed consent prior to registration and before 
undergoing any study-specific procedures indicating that they are aware of the 
investigational nature of this study.
3.2
Exclusion Criteria
3.2.1
Patients with a diagnosis of intrathoracic lung carcinoma of squamous cell 
histology are not eligible for participation.
3.2.2
Female patients who are pregnant or breast feeding, or adults of reproductive 
potential who are not using barrier birth control methods, are not eligible for 
participation.
3.2.3
Patients must not have baseline proteinuria within 14 days prior to registration as 
demonstrated by either:

Urine protein: creatinine (UPC) ratio < 1.0 at screening, 
OR

Urine dipstick for proteinuria ≤ 2+.  
NOTE:  Patients discovered to have ≥ 2+ proteinuria on dipstick 
urinalysis at baseline should undergo a 24 hour urine collection 
and must demonstrate ≤ 1g of protein in 24 hours to be eligible.
3.2.4
Patients must not have experienced any major surgical procedure, open biopsy, 
or significant traumatic injury within 28 days prior to registration, or be 
anticipated to need a major surgical procedure during the course of the study. 
NOTE:  The exception is craniotomy. Patients with brain tumors who have 
undergone craniotomy or intracranial biopsy must be cleared by their neuro-
surgeon to participate at the time of registration.
3.2.5
Patients must not have experienced a core biopsy or other minor surgical 
procedure within 7 days prior to registration. NOTE:  This excludes placement of 
a vascular access device up to 2 days prior to registration. 
3.2.6
Patients with a history of abdominal fistula, gastrointestinal perforation, or intra-
abdominal abscess within the previous 6 months are not eligible for participation.
3.2.7
Patients with a serious, non-healing wound, ulcer, or bone fracture are not 
eligible for participation due to the effects on vasculature by bevacizumab which 
may impair healing.
3.2.8
Patients known to be HIV or Hepatitis B and/or C positive are not eligible for 
participation. NOTE:  HIV and hepatitis testing is not required for study 
participation.
3.2.9
Patients with a history of any other cancer (except for non-melanoma skin cancer 
or carcinoma in-situ of the cervix), are not eligible for participation unless they 
are in complete remission and have been off of all therapy for that disease for a 
minimum of 3 years.
3.2.10 Patients receiving or participating on any other experimental agents/clinical trials 
are not eligible for participation.
3.2.11 Patients with a known hypersensitivity to any component of bevacizumab are not 
eligible for participation.
3.2.12 Patients with any significant medical illnesses or infection that, in the 
investigator’s opinion, cannot be adequately controlled with appropriate therapy 
or would compromise the patient’s ability to tolerate this therapy are not eligible 
for participation.
3.2.13 Patients with leptomeningeal disease are not eligible for participation.
3.2.14 Patients who have received previous treatment with bevacizumab for CNS 
disease are not eligible for participation.
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3.2.15 Patients with inadequately controlled hypertension (defined as systolic blood 
pressure >150 and/or diastolic blood pressure > 100 mmHg) are not eligible for 
participation.
4
PATIENT REGISTRATION 
Patients may not begin protocol treatment prior to registration. All patient registrations will be 
centralized through the Clinical Research Office (CRO) at the lead site, Northwestern University. 
Patients from both sites will be registered on a first-come-first serve basis.  Please contact the 
Quality Assurance Monitor (QAM) at croqualityassurance@northwestern.edu with questions.  
Study-specific training will be provided prior to site activation.
4.1
Access to the Registration Program
Eligible patients will be registered to the study via the Northwestern Oncology Trial 
Information System (NOTIS) using the web-based application, which can be found 
through the CRO’s website at:  https://www.cancertrials.northwestern.edu.   Please note 
that a password is required to use this program.  If needed, one will be provided during 
the study activation period, prior to training on the NOTIS system.
4.2
Registering a Patient
4.2.1
For potential patients, study teams are asked to inform the QAM of the date and 
time that the patient will need to be registered 
(croqualityassurance@northwestern.edu).  
4.2.2
BEFORE a patient can be treated on study, please complete and submit the 
following items to confirm eligibility and receive a subject identification number: 

Patient’s signed and dated informed consent form.

Copy of the pathology report (to confirm diagnosis).

Eligibility eCRF (complete in NOTIS)

Eligibility checklist (signed and dated by the treating physician – upload 
in NOTIS)
4.2.3
Go to NOTIS to register the patient and complete the Eligibility electronic case 
report form (eCRF). Please refer to the CRO’s website for instructional videos on 
registering a patient. Study-specific training will also be provided prior to study 
activation.
4.2.4
The QAM will review the registration, register the patient, assign an 
identification number, and send a confirmation of registration to involved 
personnel. Registration will then be complete and the patient may begin study 
treatment.
4.3
Beginning Study Treatment
Once eligibility is confirmed, the patient will be registered to the study and a subject I.D. 
number will be assigned by the QAM. An email will be sent to confirm approval of the 
Eligibility eCRF.  Registration will then be complete and patient may begin study 
treatment.
5
TREATMENT PLAN
5.1
Treatment Administration
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Patients will receive bevacizumab at a dose of 10 mg/kg IV every 2 weeks per local 
institutional guidelines. One cycle of treatment will be defined as 28 days (or 
approximately 4 weeks). Treatment will continue until CNS disease progression or death 
from systemic disease. The dose will remain stable unless there is a > 10% increase in 
weight from baseline. The initial dose will be delivered over a period of 90 +/-15 
minutes.  
If the first infusion is tolerated without infusion-associated adverse events (fevers or 
chills), the second infusion may be delivered over a period of 60 +/-10 minutes. If the 60 
minute infusion is well tolerated, all subsequent infusions may be delivered over a period 
of 30 +/-10 minutes. The infusion should be slowed to 50% or less or interrupted for 
subjects who experience any infusion-associated symptoms. When the subject’s 
symptoms have completely resolved, the infusion may be continued at no more than 50% 
of the rate prior to the reaction and increased in 50% increments every 30 minutes if well 
tolerated. Infusions may be restarted at the full rate during the next cycle. 
If a subject experiences an infusion-associated adverse event, he or she may be pre-
medicated for the next study drug infusion per treating investigator’s discretion; however, 
the infusion time may not be decreased for the subsequent infusion. If done, pre-
medication should be according to local institutional practice for infusions. If the next 
infusion is well tolerated with premedication, the subsequent infusion time may then be 
decreased by 30+/-10 minutes as long as the subject continues to be pre-medicated. If a 
subject experiences an infusion-associated adverse event with the 60-minute infusion, all 
subsequent doses should be given over 90 +/-15 minutes. Similarly if a subject 
experiences an infusion-associated adverse event with the 30-minute infusion, all 
subsequent doses should be given over 60 +/-10 minutes.
Prior to administration of bevacizumab, all patients with have their urine dipped for protein. If a result of 2+ is seen, 
urine will be sent for random urine and protein for a UPC ratio. If the UPC is >1.0, a 24 hour urine protein will be 
required to confirm the result is < 1 g protein. Patients must also have a blood pressure of ≤ 160/90 in order to 
receive treatment. 
5.2
Dose Modifications & Toxicity Management
5.2.1
Dose Delays/Interruptions
There will be no reductions to the bevacizumab dose.  If adverse events occur 
that require holding bevacizumab, the dose will remain the same once treatment 
resumes. Adverse events requiring delays or permanent discontinuation of 
bevacizumab are listed in Table 1 below. Regardless of the reason for holding 
study drug treatment, the maximum allowable length of treatment interruption is 
4 weeks; the only exception to this is for a surgical procedure in a patient who is 
benefiting from treatment.
5.2.2
Toxicity Management Guidelines
Any toxicity associated or possibly associated with bevacizumab treatment 
should be managed according to standard medical practice and should be based 
on the NCI’s Common Toxicity Criteria for Adverse Events version 4.0 (CTCAE 
v. 4.0).  Discontinuation of bevacizumab will have no immediate therapeutic 
effect.  Bevacizumab has a terminal half-life of 21 days; therefore, its 
discontinuation results in slow elimination over several months.  There is no 
available antidote for bevacizumab.  
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Subjects should be assessed clinically for toxicity prior to, during, and after each 
infusion.  If unmanageable toxicity occurs because of bevacizumab at any time 
during the study, treatment with bevacizumab should be discontinued. 
Infusion of bevacizumab should be interrupted for subjects who develop dyspnea 
or clinically significant hypotension. Subjects who experience a grade 3 or 4 
allergic reaction/hypersensitivity, adult respiratory distress syndrome, or 
bronchospasm (regardless of grade) will be discontinued from bevacizumab 
treatment.
All AEs – including all out of range laboratory values – should be recorded as on 
the appropriate eCRF as outlined in Section 10.  Abnormal laboratory tests and 
other objective measures that meet the criteria for an SAE or result in 
discontinuation of the trial drug should be reported as outlined in Section 10. All 
patients who have grade 3 or 4 laboratory values at the time of withdrawal must 
be followed up until the lab values have returned to grade 1 or 2 or until 30 days 
after the date of withdrawal (whichever comes first), unless these values are not 
likely to improve because of the underlying disease.  
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Table1: Bevacizumab Dose Management Due to Adverse Events
Hypertension
Grade/Event
Action to be Taken
Grade 1 or 2
None
Grade 3
If not controlled to ≤ 150/100 mmHg with medication, discontinue bevacizumab.
Grade 4
(including hypertensive 
encephalopathy)
Discontinue bevacizumab.
Hemorrhage
Grade/Event
Action to be Taken
Grade 1 or 2
non-pulmonary &
non-CNS events
None
Grade 3
non-pulmonary &
non-CNS events
Subjects who are also receiving full-dose anticoagulation will be discontinued from bevacizumab.  
All other subjects will have bevacizumab held until all of the following criteria  are met:

The bleeding has resolved and hemoglobin is stable.

There is no bleeding diathesis that would increase the risk of therapy.

There is no anatomic or pathologic condition that significantly increases the risk of hemorrhage 
recurrence.
Subjects who experience a repeat grade 3 hemorrhagic event will be discontinued from receiving 
bevacizumab.
Grade 4
non-pulmonary or
non-CNS events
Discontinue bevacuzimab.
Grade 1
pulmonary event
Subjects who are also receiving full-dose anticoagulation will be discontinued from bevacizumab.  
All other subjects will have bevacizumab held until all of the following criteria  are met:

The bleeding has resolved and hemoglobin is stable.

There is no bleeding diathesis that would increase the risk of therapy.

There is no anatomic or pathologic condition that significantly increases the risk of hemorrhage 
recurrence.

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Grade ≥ 2
pulmonary event
Discontinue bevacizumab.
Any Grade CNS bleeding
Discontinue bevacizumab.
Venous Thrombosis
Grade/Event
Action to be Taken
Grade 1 or 2
None
Grade 3 (1st occurrence)
Hold bevacizumab. If the planned duration of full-dose anticoagulation is < 2 weeks, bevacizumab 
should be held until the full-dose anticoagulation period is over.  If the planned duration of full-dose 
anticoagulation is > 2 weeks, bevacizumab may be resumed during the period of full-dose 
anticoagulation if all of the following criteria  are met:

The subject must have an in-range INR (usually between 2 and 3) if on warfarin.

LMWH, warfarin, or other anticoagulant dosing must be stable prior to restarting bevacizumab 
treatment.

The subject must not have had a grade 3 or 4 hemorrhagic event while on anticoagulation.
Grade 3 (recurrent) or Grade 4 (any 
occurrence)
Discontinue bevacizumab.
Arterial Thromboembolic Event
New onset, worsening, or unstable angina, myocardial infarction, transient ischemic attack, cerebrovascular accident, and any other arterial 
thromboembolic event
Any grade
Discontinue bevacizumab.
Congestive Heart Failure (Left ventricular systolic dysfunction
Grade/Event
Action to be Taken
Grade 1 or 2
None
Grade ≥ 3
Discontinue bevacizumab.
Proteinuria
Grade/Event
Action to be Taken
Grade 1
None
Grade 2
Hold bevacizumab for ≥ 2 g/24hrs, and resume when proteinuria is < 2 g/24hrs.                                          
For 2+ dipstick: may administer bevacizumab and obtain 24 hr urine prior to next dose.
For 3+ dipstick: obtain 24 hr urine prior to bevacizumab administration.
Grade 3
Hold bevacizumab treatment until proteinuria is < 2 g/24hrs, as measured by 24 hr urine collection.
Grade 4
(nephrotic syndrome)
Discontinue bevacizumab.

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GI Perforation
Any grade
Discontinue bevacizumab.
Fistula
Grade/Event
Action to be Taken
TE fistula – any grade
Discontinue bevacizumab.
Grade 4 fistula
Discontinue bevacizumab.
Bowel Obstruction
Grade/Event
Action to be Taken
Grade 1
Continue patient on bevacizumab for partial obstruction NOT requiring medical intervention.
Grade 2
Hold bevacizumab for partial obstruction requiring medical intervention.  Patient may restart upon 
complete resolution.
Grade ≥ 3
Hold bevacizumab for complete obstruction. If surgery is necessary, patient may restart bevacizumab 
after full recovery from surgery, and at investigator’s discretion.
Wound Dehiscence
Any grade (requiring medical or 
surgical therapy)
Discontinue bevacizumab.
Reversible Posterior Leukoencephalopathy
Any grade (confirmed by MRI)
Discontinue bevacizumab.
Hematologic
Grade 4 febrile neutropenia and/or 
Grade 4 thrombocytopenia 
(regardless of attribution)
Hold bevacizumab until recovery to ≤ grade 1 or baseline.
Hypersensitivity/Allergic Reactions
Any grade (related to bevacizumab)
Discontinue bevacizumab.
Other Unspecified Bevacizumab-Related Adverse Events
Grade/Event
Action to be Taken
Grade 1 or 2
None
Grade 3
Hold bevacizumab until recovery to ≤ grade 1.
Grade 4
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5.3
Supportive Care Guidelines
Supportive care includes any prescription medications, transfusions, or over-the-counter 
preparations used by a patient. All supportive care therapies must be recorded on the 
appropriate eCRF. Throughout the study, investigators may prescribe any concomitant 
medication or treatment deemed necessary to provide adequate supportive care, except 
for those listed below in 5.3.2. 
5.3.1
Permitted Supportive Care & Concomitant Therapies

Preventative measures such as prophylactic cytokine are permitted.

Transfusion of blood products and hematopoietic growth factors are allowed 
per local institutional guidelines.

Febrile neutropenia may be managed according to local institutional 
Infectious Disease guidelines. Measures may include appropriate laboratory 
testing (such as blood and urine cultures) and the institution of broad-
spectrum antibiotics. If a source for the fever is not identified or the fever 
resolves when the neutrophil count recovers, antibiotics may be discontinued 
and the patient observed.

The use of antiemetics will be left to the treating investigators’ discretion.

Therapies considered necessary for the well-being of the patient may be 
given at the discretion of the investigator, such as analgesics, chronic 
treatments for concomitant medical conditions, or agents required for life-
threatening medical problems.

Non-protocol systemic anti-cancer therapies may be started if needed due to 
progressive systemic disease as long as patients have stable or improved 
metastatic brain metastases.
5.3.2
Concomitant Therapies Not Permitted
Patients should not schedule any elective surgeries (excluding placement of 
vascular access device) during the study treatment period or until 28 days after 
their last administration of study treatment. If a patient undergoes any unexpected 
surgery during the course of the study, the patient must discontinue all study 
treatment immediately, and the PI should be notified as soon as possible. A 
patient may be allowed to resume study treatment after the surgical case is 
reviewed by the PI and study team to determine the appropriateness of resuming 
study treatment.
5.4
Duration of Therapy
Patients will remain on treatment as long as there is no evidence of disease progression or 
development of unacceptable toxicity. In addition, the patient and/or treating investigator 
may choose to discontinue treatment if it is felt to be in the best interest of the patient or 
if the patient is no longer able to comply with study requirements.
5.5
Duration of Follow Up
Follow-up for survival and documentation of subsequent anti-cancer treatments will 
occur at the time of routine clinic visits which occur approximately every 8-12 weeks.  
Survival follow-up will continue until disease progression or death.
Note: As of December 31, 2018, patients will no longer be followed and follow 
up information will not be collected.
6
ENDPOINT ASSESSMENT
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Response will be assessed based on RANO Criteria35: For patients with residual tumor post-
operatively or measurable tumor after failing a prior therapy. 
6.1
Response Criteria
* Progression occurs when this criterion is present.
**Increase in corticosteroids alone will not be taken into account in determining 
progression in the absence of persistent clinical deterioration.
NB: Note up to 5 largest lesions will be measured, the remaining will be evaluable.
6.2
Definitions
6.2.1
Measurable disease
At least 1 unidimensionally measurable lesion ≥ 5 mm with clearly defined 
margins by CT or MRI scan. 
6.2.2
Evaluable disease
Unidimensionally measurable lesions, masses with margins not clearly defined. 
6.2.3
Non-evaluable disease
Not applicable for response evaluation.
6.2.4
Objective status (to be recorded at each evaluation)
If there are too many measurable lesions to measure at each evaluation, choose 
the largest two to be followed before a patient is entered on study.  The 
remaining lesions will be considered evaluable for the purpose of objective status 
determination.  Unless progression is observed, objective status can only be 
determined when ALL measurable and evaluable sites and lesions are assessed.
6.2.5
Complete response (CR)
Requires ALL of the following: 
6.2.5.1 Complete disappearance of all enhancing measurable and nonmeasurable 
disease sustained for at least 4 weeks
6.2.5.2 No new lesions
6.2.5.3 Stable or improved nonenhancing (T2/FLAIR) lesions
6.2.5.4 Patients must be off corticosteroids (or on physiologic replacement doses 
only) and stable or improved clinically. 
Note: Patients with nonmeasurable disease only cannot have a complete 
response; the best response possible is stable disease.
Criterion
CR
PR
SD
PD#
T1 gadolinium enhancing 
disease 
None      
> 50% 2 ↓
< 50% ↓ but  
< 25% ↑
> 25%↑
T2/FLAIR
Stable or ↓ 
Stable or ↓ 
Stable or ↓ 
↑*
New Lesion
None  
None  
None  
Present
Corticosteroids
None
Stable or ↓ 
Stable or ↓ 
NA**
Clinical Status
Stable or ↑ 
Stable or ↑ 
Stable or ↑ 
↓*
Requirement for Response
All
All
All
Any*
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6.2.6
Partial response (PR)
Requires ALL of the following: 

A 50% decrease compared with baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at 
least 4 weeks.

No progression of nonmeasurable disease and no new lesions.

Stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose 
of corticosteroids compared with baseline scan and stable or improved 
clinically. 
Note: Patients with nonmeasurable disease only cannot have a partial response; 
the best response possible is stable disease. 
6.2.7
Stable disease (SD)
Requires ALL of the following: 

Does not qualify for CR, PR, or PD.

Stable nonenhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan. 
In the event that the corticosteroid dose was increased for new symptoms 
and signs without conﬁrmation of disease progression on neuroimaging, 
and subsequent follow-up imaging shows that this increase in 
corticosteroids was required because of disease progression, the last scan 
considered to show stable disease will be the scan obtained when the 
corticosteroid dose was equivalent to the baseline dose.
6.2.8
Progressive disease (PD) 
Deﬁned by ANY of the following:

A 25% increase in sum of the products of perpendicular diameters of 
enhancing lesions compared with baseline, on stable or increasing doses 
of corticosteroids

Signiﬁcant increase in T2/FLAIR nonenhancing lesion on stable or 
increasing doses of corticosteroids compared with baseline scan after 
initiation of therapy not caused by comorbid events (e.g., radiation 
therapy, demyelination, ischemic injury, infection, seizures, 
postoperative changes, or other treatment effects).

Any new lesion(s).

Clear clinical deterioration not attributable to other causes apart from the 
tumor (e.g., seizures, medication adverse effects, complications of 
therapy, cerebrovascular events, infection, etc) or changes in 
corticosteroid dose.

Failure to return for evaluation as a result of death or deteriorating 
condition.

Clear progression of nonmeasurable disease.
6.2.9
Unknown
Progression has not been documented and one or more measurable or evaluable 
sites have not been assessed.
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6.2.10 Best response
This will be calculated from the sequence of objective statuses.  For patients with 
all disease sites assessed every evaluation period, the best response will be 
defined as the best objective status as measured according to the definitions 
above. If the response does not persist at the next regular scheduled MRI, the 
response will still be recorded based on the prior scan, but will be designated as a 
non-sustained response. If the response is sustained (is still present on the 
subsequent MRI), it will be recorded as a sustained response, lasting until the 
time of tumor progression. Best response is unknown if the patient does not 
qualify for a best response or increasing disease and if all objective status 
determinations before progression are unknown.
6.3
Assessment of Secondary Endpoints
6.3.1
Progression-free survival (PFS)
PFS will be defined as the time from the first study treatment to the first 
occurrence of progression or death up to 6 months.
6.3.2
Time to progression
Time to progression will be defined as the time from the date of first treatment to 
the date of first observation of progressive disease, non-reversible neurologic 
progression or increasing steroid requirements (applies to SD only), death due to 
any cause, or early discontinuation of treatment. This will be assessed based on 
MRI or CT scans.
6.3.3
Duration of response
The duration of overall response is measured from the time measurement criteria 
are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment 
started). Duration of stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started. 
6.3.4
Overall survival (OS)
Overall survival will be calculated from date of first dose of bevacizumab to the 
date of death.  
Note: As of December 31, 2018, patients will no longer be followed and 
follow up information will not be collected.
6.3.5
Evaluation of toxicity/safety data
All patients will be evaluable for toxicity from the time of their first treatment 
with bevacizumab. Adverse events will be assessed prior to the start of every 
cycle.
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7
STUDY PARAMETERS
Screening
Treatment 10
Treatment 
Discontinuation
Cycle 1
Subsequent cycles
Assessment or Procedure
Baseline 8
D1 12
D15 12
D1 12
D15 12
Prior to every 
odd cycle
Informed consent
X
Review of eligibility
X
Medical history
X
X
Physical examination 1
X
X
X
Vital signs 2 
X
X
X
X
X
X
12-lead ECG 3
X
Karnofsky performance 
score
X
X
X
Intra-cranial tumor 
assessment (Gd-MRI or 
CT) 4
X
X
X
CT C/A/P 9
X
X
FACT-Br 11
X
X
CBC and platelets
X
X
Complete chemistry panel
X
X
Urinalysis or dipstick 13
X
X
X
X
X
Pregnancy test 5
X
PT,  INR and aPTT 14
X
Review of concomitant 
medications
X
X
X
X
X
Adverse events
X
X
X
X
X
Study treatment
Bevacizumab administration 6, 12
Follow-up 7
X

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1.
Physical exam including neurologic exam. Baseline exam should include height and weight; height does not need to be re-recorded at 
subsequent exams.
2.
Vital signs should include temperature, pulse, respiratory rate, and blood pressure. Blood pressure should be ≤ 160/90 on the day of 
treatment in order to receive the next bevacizumab dose.
3.
ECG is required only at screening and then as clinically indicated thereafter.
4.
Ideally Gd-MRI of brain or CT if MRI contra-indicated.
5.
Urine or serum pregnancy test for female patients of child-bearing potential.
6.
Patients will receive bevacizumab at a dose of 10 mg/kg IV every 2 weeks per local institutional guidelines (1 cycle = 28 days). Treatment 
will continue until CNS disease progression or death from systemic disease.
7.
Follow-up for survival and documentation of subsequent anti-cancer treatments. Patients will be seen at the time of routine clinic visits 
which occur approximately every 8-12 weeks.  Survival follow-up will continue until disease progression or death.  Note: As of 
December 31, 2018, patients will no longer be followed and follow up information will not be collected.
8.
Baseline assessments should be completed within 14 days prior to registration unless otherwise noted.
9.
Baseline CT of chest/abdomen/pelvis should be within 28 days prior to registration.
10. One cycle of treatment = 28 days (or approximately 4 weeks).
11. The FACT-Br will be administered to patients prior to every odd-numbered cycles before the scheduled MRI/CT is performed
12. A window of ±3 days is allowed for completion of tests, assessments, and treatment. 
13. If urine dipstick shows > 2+ protein, results of UPC and CBC must be obtained prior to receiving the next bevacizumab dose.
14. PT/INR and aPTT should be repeated as clinical indicated thereafter.

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8
DRUG FORMULATION AND PROCUREMENT
8.1
Bevacizumab
8.1.1
Other names
Avastin®, rhuMAb VEGF, RO4876646
8.1.2
Classification/type of agent
Bevacizumab is a vascular endothelial growth factor-specific angiogenesis 
inhibitor. The structure consists of human IgG1 framework regions and antigen-
binding complementary-determining regions from a murine monoclonal antibody
8.1.3
Mode of action
Bevacizumab is a recombinant humanized immunoglobulin G (IgG1) 
monoclonal antibody that binds VEGF, a secreted factor that regulates 
angiogenesis. Bevacizumab prevents the interaction of VEGF with its receptors 
and neutralizes the biological activity of VEGF. Many human tumors have been 
shown to have increased VEGF gene expression, when compared to normal 
surrounding tissues. Bevacizumab has been shown to inhibit in vivo growth of a 
variety of human tumors, providing proof of preclinical efficacy and the role of 
VEGF in oncogenesis. For further details and molecule characterization, please 
refer to the bevacizumab Investigator Brochure.
8.1.4
Storage and stability
Upon receipt of the study drug, vials are to be refrigerated at 2C–8C (36F–
46F) and should remain refrigerated until just prior to use. DO NOT FREEZE.  
DO NOT SHAKE.   Vials should be protected from light. Opened vials must be 
used within 8 hours.  VIALS ARE FOR SINGLE USE ONLY. Vials used for 
1 subject may not be used for any other subject. Once study drug has been added 
to a bag of sterile saline, the solution must be administered within 8 hours.
8.1.5
Dose specifics
Patients will receive bevacizumab at a dose of 10 mg/kg every 2 weeks (1 cycle 
= 28 days/4 weeks). It is not necessary to correct dosing based on ideal weight.
8.1.6
Preparation
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile 
liquid concentrate for solution for intravenous (IV) infusion. Bevacizumab may 
be supplied in 5-cc (100-mg) and 20-cc (400-mg) glass vials containing 4 mL 
and 16 mL of bevacizumab, respectively (all at 25 mg/mL). Vials contain 
bevacizumab with phosphate, trehalose, polysorbate 20, and Sterile Water for 
Injection (SWFI), USP. Vials contain no preservative and are suitable for single 
use only. Bevacizumab should be diluted in a total volume of 100 mL of 0.9 
Sodium Chloride Injection, USP.  
8.1.7
Protocol administration
Administration will be as continuous IV infusion per local institutional practice. 
Anaphylaxis precautions should be observed during study drug administration. 
Please refer to Section 5.1 for further details.  
8.1.8
Incompatibilities
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Bevacizumab is incompatible with dextrose and should not be administered or 
mixed with dextrose solutions.
8.1.9
Availability
Bevacizumab will be provided to patients by the study sponsor, Northwestern 
University, with support from Genentech. The contact information for 
bevacizumab supply is as follows:  
Avastin IST Clinical Trials Associate
650-225-5250 (fax)
avastinistdrug-d@gene.com 
Drug will be shipped from Genentech directly to each study site.  
8.1.10 Side effects
Major side effects reported include: hypertension, proteinuria (ranging from 
asymptomatic and transient events detected on routine dipstick urinalysis to 
nephrotic syndrome), thromboembolic events-venous and arterial 
thromboembolic (TE) events (ranging in severity from catheter-associated 
phlebitis to fatal), gastrointestinal perforation, wound-healing complications, 
hemorrhage, and congestive heart failure. For additional information regarding 
adverse events and the safety experience with bevacizumab, please refer to the 
bevacizumab Investigator Brochure. The frequency of bevacizumab-related side 
effects is summarized below.
Likely (occurring in more than 20% of patients)
hypertension
anorexia
dysgeusia
generalized pain
constipation
weakness
headache
diarrhea
proteinuria (possible kidney damage
dizziness
stomatitis
respiratory infection
alopecia
GI bleeding
epistaxis
abdominal pain
dyspepsia
dyspnea
vomiting
neutropenia & subsequent infection 
(including pneumonia)
Common (occurring in 3-20% of patients)      
hypotension
hypokalemia
dehydration
fatigue (possible 
weakness)
hyponatremia
urinary urgency/frequency
nerve damage (possible 
numbness, tingling, 
and/or burning)
flatus
vaginal bleeding
confusion (possible 
headache, confusion, 
seizures, and/or coma)
weight loss
fever/infection/neutropenia
abnormal gait
nausea
hemorrhage
dry skin
dry mouth
hyperbilirubinemia
desquamation
gastritis
muscle and/or bone pain
skin discoloration
decreased intestinal 
function (possible 
vomiting, swelling, 
hyperlacrimation
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and/or pain)
nail disorder
tumor hemorrhage
dysphonia
syncope
tumor pain
pleuritis
chills
shivering
build-up in the lung tissues
palpitations
bradycardia
infusion reactions
leukemia
hematuria
anemia
Bevacizumab may commonly cause thrombosis to the brain, heart, lungs, or other 
organs, which may cause stroke and/or myocardial infarction.
Bevacizumab may commonly cause perforation to the stomach, small intestine or 
large intestine, which can cause leakage of the contents of these organs and lead 
to infection.
Rare but serious (occurring in fewer than 3% of patients) 
heart failure
peritoneal abscess
pulmonary hemorrhage
myocardial infarction
intestinal necrosis
pulmonary hypertension
angina
intestinal obstruction
wound dehiscence
severe hypertension
portal vein obstruction
sudden, rapid loss of a 
skin graft or other 
grafted tissue
cerebral hemorrhage, 
causing stroke
eye infection
wound healing problems
subarachnoid 
hemorrhage
blurry vision
allergic reaction
bleeding gums
kidney damage
homonymous 
hemianopsia
liver damage
nasal fistula
confusion
alexia
hymoptysis
sudden decrease in 
blood supply to the 
brain resulting in 
decreased brain function
spinal compression 
fracture
pericardial and pleural 
effusion worsening
Bevacizumab may rarely cause brain damage (encephalopathy), including 
reversible posterior leukoencephalopathy syndrome (RPLS), a medical condition 
related to leakiness of blood vessels in the brain, which can cause confusion, 
blindness or vision changes, seizure, changes in brain scans, and/or other 
symptoms.  Leukoencephalopathy may occur up to 18 months after the last dose 
of study drug. 
Bevacizumab may rarely cause fistulas between areas of the body which may 
result in death.
8.1.11 Other side effects

Rarely (in about 1-2% of patients), bevacizumab may cause bleeding in 
the brain in patients who have received bevacizumab for the treatment of 
primary brain tumors.

In most patients, blood pressure can be controlled with routine 
medications taken by mouth while bevacizumab is continued. However, 
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uncontrolled high blood pressure and high blood pressure resulting in 
disturbance of organ function may occur.

Bevacizumab may also block VEGF. VEGF is important for the 
formation of new blood vessels at sites of low blood flow. Low blood 
flow exists in conditions such as coronary artery disease and 
cerebrovascular disease (abnormality of the brain resulting from blood 
vessel problems). Prolonged blockage of VEGF with bevacizumab could 
worsen any pre-existing heart or cerebrovascular disease.

The impact of bevacizumab on future fertility is currently unknown.  
However, it is possible that treatment with bevacizumab may affect 
fertility and decrease the likelihood of becoming pregnant in the future.
9
STATISTICAL CONSIDERATIONS 
9.1
Study Design
A Simon two-stage optimum phase II clinical trial design will be used in this study. If 
zero responses are observed in the first 9 patients, it could be concluded that the true 
response rate was 5% or less and no further patients would be enrolled. If one or more 
responses are observed in the first stage, a total of 24 evaluable patients would be 
required. If three or more responses are observed, there would be evidence that the 
regimen used was active (true response rate is at least 25%). The primary endpoint will 
be objective radiographic tumor response.  Secondary endpoints include progression-free 
survival at 6 months, time to progression, time to response, duration of response, overall 
survival, and safety.
9.2
Sample Size & Power Calculations
A Simon two-stage optimal phase II clinical trial design will be used. If 0 responses are 
observed in the first 9 patients, it will be concluded that the true response rate was 5% or 
less and no further patients will be enrolled. If 1 or more responses are observed in the 
first 9 patients, 15 additional patients will be enrolled to a total of 24. If 3 or more 
responses are observed, there would be evidence that the regimen used was active (true 
response rate is at least 25%). This design will declare the regimen as active when the 
true response rate is 25% with 90% probability (power=.90) at the 1-sided 0.10 alpha 
level. To account for dropouts, we will plan for 27 patients total to have 24 evaluable 
patients.
9.3
Planned Analyses
The primary outcome, radiographic response rate, will be estimated using the Atkinson 
and Brown confidence limits (new reference).   To estimate time to progression, 
progression-free survival and overall survival, Kaplan-Meier curves will be calculated.  
PFS6 will be determined from the progression-free survival curve.   Time to response in 
responders will be estimated using a Kaplan-Meier curve.  Duration of response in 
responders will be estimated as the time from response to progression, and will be 
summarized using descriptive statistics such as median and range.  Safety data will be 
summarized using frequencies and percentages, and adverse events will be characterized 
by type, frequency, timing of occurrence and attribution.  Changes in FACT-BR while on 
treatment will be analyzed using a longitudinal linear model that estimates the mean level 
at specific times, or a population averaged mean FACT-BR as a function of time.
10 ADVERSE EVENTS
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This trial will be conducted in accordance with the Data Safety Monitoring Plan (DSMP) of the 
Robert H. Lurie Comprehensive Cancer Center (Lurie Cancer Center) of Northwestern University 
(see Appendices for link).  The level of risk attributed to this study requires High Intensity 
Monitoring, as outlined in the DSMP. In addition, the study will abide by all safety reporting 
regulations, as set forth in the Code of Federal Regulations.
10.1
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during a trial (see Section 7 and the study calendar for time 
points). In addition, certain adverse events must be reported in an expedited manner to 
allow for optimal monitoring and patient safety and care. 
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be followed until: 
•
the adverse event resolves or the symptoms or signs that constitute the 
adverse event return to baseline; 
•
any abnormal laboratory values have returned to baseline; 
•
there is a satisfactory explanation other than the study drug for the changes 
observed; or
•
death.
The study period during which all AEs and serious adverse events (SAEs) must be 
reported begins after informed consent is obtained and initiation of study treatment any 
study procedures and ends 30 days following the last administration of study treatment or 
study discontinuation/termination, whichever is earlier. After this period, investigators 
should only report SAEs that are attributed to prior study treatment.
10.2
Definitions & Descriptions
10.2.1 Adverse Event
An AE is any untoward medical occurrence in a patient receiving study treatment 
and which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporarily associated with the use of 
an experimental intervention, whether or not related to the intervention.
Recording of AEs should be done in a concise manner using standard, acceptable 
medical terms. In general, AEs are not procedures or measurements, but should 
reflect the reason for the procedure or the diagnosis based on the abnormal 
measurement. Preexisting conditions that worsen in severity or frequency during 
the study should also be recorded (a preexisting condition that does not worsen is 
not an AE). Further, a procedure or surgery is not an AE; rather, the event 
leading to the procedure or surgery is considered an AE.
If a specific medical diagnosis has been made, that diagnosis or syndrome should 
be recorded as the AE whenever possible.  However, a complete description of 
the signs, symptoms and investigations which led to the diagnosis should be 
provided. For example, if clinically significant elevations of liver function tests 
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are known to be secondary to hepatitis, “hepatitis” and not “elevated liver 
function tests” should be recorded. If the cause is not known, the abnormal test or 
finding should be recorded as an AE, using appropriate medical terminology (e/g/ 
thrombocytopenia, peripheral edema, QT prolongation).
This includes the following:

AEs not previously observed in the subject that emerge during the 
protocol-specified AE reporting period, including signs or symptoms 
associated with solid tumor brain metastases that were not present prior 
to the AE reporting period.

Complications that occur as a result of protocol-mandated interventions.

If applicable, AEs that occur prior to assignment of study treatment 
associated with medication washout, no treatment run-in, or other 
protocol-mandated interventions.

Preexisting medical conditions (other than the condition being studied) 
judged by the investigator to have worsened in severity or frequency or 
changed in character during the protocol-specified AE reporting period.
10.2.2 Severity of AEs
All adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03 available at 
http://ctep.cancer.gov/reporting/ctc.html.
If no CTCAE grading is available, the severity of an AE is graded as follows:
•
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities.
•
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities.
•
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status.
•
Life-threatening (grade 4): the patient was at risk of death at the time of the 
event.
•
Fatal (grade 5): the event caused death.
10.2.3 Causality of AEs
Expected AEs are those adverse events that are listed or characterized in the 
current Investigator Brochure (IB). Unexpected AEs are those not listed in the 
current IB or not identified. This includes adverse events for which the 
specificity or severity is not consistent with the description in the IB. For 
example, under this definition, hepatic necrosis would be unexpected if the IB 
only referred to elevated hepatic enzymes or hepatitis.
The relationship of an AE to the study drug(s) should be defined as 
unrelated, unlikely, possibly, probably, or definitely related.  
10.2.3.1
Related
A causal relationship is clinically/biologically highly plausibly, 
there is a plausible time sequence between onset of the AE and 
administration of the study drug, there is a reasonable response 
on withdrawal, the AE cannot be reasonably explained by any 
other known factor and the event re-appears upon rechallenge.
10.2.3.2
Probable
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A causal relationship is clinically/biologically highly plausible 
and there is a plausible time sequence between onset of the AE 
and administration of the study drug and there is a reasonable 
response on withdrawal.
10.2.3.3
Possible
A causal relationship is clinically/biologically plausible and 
there is a plausible time sequence between onset of the AE and 
administration of the study drug.
10.2.3.4
Unlikely
A causal relationship is improbable and another documented 
cause of the AE is most plausible.
10.2.3.5
Unrelated
A causal relationship can be definitively excluded and another 
documented cause of the AE is most plausible.
10.2.4 Serious Adverse Event (SAE)
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 30 days after the last administration of study drug, must be 
reported upon discovery or occurrence.
An SAE is any untoward medical occurrence that at any dose results in one of the 
following outcomes:

Results in death.
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself.

Is life-threatening.
The patient was at risk of death at the time of the event; it does not refer 
to an event that hypothetically might have caused death if it were more 
severe.

Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly/birth defect.

Is an important medical event.
Any event that does not meet the above criteria, but that in the judgment 
of the investigator jeopardizes the patient, may be considered for 
reporting as a serious adverse event. The event may require medical or 
surgical intervention to prevent one of the outcomes listed in the 
definition of “Serious Adverse Event“. 
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency.
10.2.5 Exceptions to AE & SAE Definitions
Generally speaking, any adverse event that results in hospitalization or prolonged 
hospitalization should be documented and reported as an SAE, as described 
above.  Likewise, any condition responsible for surgery should be documented as 
an AE if the condition meets the criteria for an AE.  However, for the purposes of 
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this study, neither the condition, hospitalization, prolonged hospitalization, nor 
surgery are reported as AEs or SAEs under the following circumstances:

Hospitalization or prolonged hospitalization is for a diagnostic or 
elective surgical procedure for a preexisting condition.  Surgery should 
not be reported as an outcome of an adverse event if the purpose of the 
surgery was elective or diagnostic and the outcome was uneventful.

Hospitalization or prolonged hospitalization is required to allow efficacy 
measurement for the study.

Hospitalization or prolonged hospitalization is required for study-
directed therapy of the target disease of the study, unless it is a 
worsening or increase in frequency of hospital admissions as judged by 
the principal investigator.

Hospitalization or prolonged hospitalization is due to social reasons (i.e. 
awaiting transport home).
10.2.6 Unanticipated Problems Involving Risk to Subject or Others (UPIRSO)
In order for an adverse event to be reported to the Northwestern University 
IRB, it must qualify as a UPIRSO.  In order to qualify as a UPIRSO, the 
event must meet ALL three of the following criteria:  

Is unanticipated in terms of nature, severity, or frequency

Places the research subject or others at a different or greater risk of harm

Is deemed to be at least possibly related to participation in the study.   
10.3
Procedures for Eliciting & Recording AEs
10.3.1 Eliciting AEs
A consistent methodology for eliciting AEs at all subject evaluation timepoints 
should be adopted. Examples of non-directive questions include:

“How have you felt since your last clinical visit?”

“Have you had any new or changed health problems since you were 
last here?”
All AEs and SAEs whether volunteered by the subject, discovered by study 
personnel during questioning, or detected through physical examination, 
laboratory test, or other means will be reported appropriately. Each reported AE 
or SAE will be described by its duration (i.e., start and end dates), regulatory 
seriousness criteria if applicable, suspected relationship to bevacizumab (see 
following guidance), and actions taken.
To ensure consistency of AE and SAE causality assessments, investigators 
should apply the following general guideline:
Yes
There is a plausible temporal relationship between the onset of the AE and 
administration of bevacizumab, and the AE cannot be readily explained by the 
subject’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
AE follows a known pattern of response to bevacizumab; and/or the AE abates or 
resolves upon discontinuation of bevacizumab or dose reduction and, if 
applicable, reappears upon re-challenge.
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No
Evidence exists that the AE has an etiology other than bevacizumab (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal relationship to 
bevacizumab administration (e.g., cancer diagnosed 2 days after first dose of 
study drug).
Expected adverse events are those adverse events that are listed or characterized 
in the Package Insert or current Investigator Brochure (IB). 
Unexpected adverse events are those not listed in the package insert or current IB 
or not identified. This includes adverse events for which the specificity or 
severity is not consistent with the description in the package insert or IB For 
example, under this definition, hepatic necrosis would be unexpected if the 
package insert or IB only referred to elevated hepatic enzymes or hepatitis.
10.3.2 Recording AEs
Investigators should use correct medical terminology/concepts when reporting 
AEs or SAEs. Avoid colloquialisms and abbreviations.
10.3.2.1 Diagnosis vs. Signs & Symptoms
If known at the time of reporting, a diagnosis should be reported rather 
than individual signs and symptoms (e.g., record only liver failure or 
hepatitis rather than jaundice, asterixis, and elevated transaminases). 
However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of 
reporting, it is ok to report the information that is currently available. If a 
diagnosis is subsequently established, it should be reported as follow-up 
information.
10.3.2.2Deaths
All deaths that occur during the protocol-specified AE reporting period, 
regardless of attribution, will be reported to the appropriate parties (see 
10.4). When recording a death, the event or condition that caused or 
contributed to the fatal outcome should be reported as the single medical 
concept. If the cause of death is unknown and cannot be ascertained at 
the time of reporting, report “Unexplained Death.”
10.3.2.3Preexisting Medical Conditions
A preexisting medical condition is one that is present at the start of the 
study. Such conditions should be reported as medical and surgical 
history. A preexisting medical condition should be re-assessed 
throughout the trial and reported as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When 
reporting such events, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”).
10.3.2.4Hospitalizations for Medical or Surgical Procedures
Any AE that results in hospitalization or prolonged hospitalization 
should be documented and reported as an SAE. If a subject is 
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hospitalized to undergo a medical or surgical procedure as a result of an 
AE, the event responsible for the procedure, not the procedure itself, 
should be reported as the SAE. For example, if a subject is hospitalized 
to undergo coronary bypass surgery, record the heart condition that 
necessitated the bypass as the SAE. Please refer to Section 10.2.5 for 
certain exceptions under which hospitalization or prolongation of 
hospitalization does not require reporting.
10.3.2.5Pregnancy
If a female subject becomes pregnant while receiving investigational 
therapy or within 90 days after the last dose of study drug, a report 
should be completed and expeditiously submitted to the appropriate 
parties, including Genentech, Inc. Follow-up to obtain the outcome of the 
pregnancy should also occur. Abortion, whether accidental, therapeutic, 
or spontaneous, should always be classified as serious, and expeditiously 
reported as an SAE. Similarly, any congenital anomaly/birth defect in a 
child born to a female subject exposed to bevacizumab should be 
reported as an SAE.
10.3.2.6Post-Study AEs
The investigator should expeditiously report any SAE occurring after a 
subject has completed or discontinued study participation if attributed to 
prior bevacizumab exposure. If the investigator should become aware of 
the development of cancer or a congenital anomaly in a subsequently 
conceived offspring of a female subject who participated in the study, 
this should be reported as an SAE.
10.3.2.7Reconciliation
The study Sponsor (Northwestern University) agrees to conduct 
reconciliation for the product. Genentech and the Sponsor will agree to 
the reconciliation periodicity and format, but agree at minimum to 
exchange monthly line listings of cases received by the other party. If 
discrepancies are identified, the Sponsor and Genentech will cooperate in 
resolving the discrepancies. The responsible individuals for each party 
shall handle the matter on a case-by-case basis until satisfactory 
resolution.
10.3.2.8AEs of Special Interest (AESIs)
AESIs are defined as a potential safety problem, identified as a result of 
safety monitoring of the product. The bevacizumab (Avastin) AESIs are: 

Hypertension ≥ grade 3

Proteinuria ≥ grade 3

GI perforation, abscesses and fistulae (any grade)

Wound healing complications ≥ grade 3

Haemorrhage ≥ grade 3 (any grade CNS bleeding; ≥ grade 2 
haemoptysis

Arterial thromboembolic events (any grade)

Venous thromboembolic events ≥ grade 3

PRES (any grade)

CHF ≥ grade 3
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
Non-GI fistula or abscess ≥ grade 2
10.3.2.9Other Non-serious AESIs
Required to be reported  no more than 24 hours after learning of the 
event:

Cases of an elevated ALT or AST in combination with either an elevated 
bilirubin or clinical jaundice

Suspected transmission of an infectious agent by the study drug
10.4
Adverse Event Reporting
All SAEs and AESIs, regardless of attribution, occurring during the study or within 30 
days of the last administration of bevacizumab must be reported upon discovery or 
occurrence. Additional expedited or routine reporting to other entities may be required, 
depending on the nature of the SAE.
The NU CRO SAE Form is the preferred format for reporting. 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description (section 5) of the form:

Protocol description (and number)

The patient’s identification number

Description of the event, severity, treatment, and outcome if known

Supportive laboratory results and diagnostics

Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication

The hospital discharge summary (if available/applicable)
Follow-up information may be added to a previously submitted report by any of the 
following methods:

Adding to the original NU CRO SAE Form and submitting it as follow-up. 

Adding supplemental summary information and submitting it as follow-up with 
the original NU CRO SAE Form.

Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. DOB, initial, patient number), protocol description and number, 
brief AE description, and notation that additional or follow-up information is 
being submitted (The patient identifiers are important so that the new information 
is added to the correct initial report).
10.4.1 Routine Reporting
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF. Routine AEs will be reviewed by the Data Monitoring Committee (DMC) 
according to the study’s phase and risk level, as outlined in the DSMP. 
10.4.2 Determining if Expedited Reporting is Required
This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) must 
also be reported accordingly.
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1)
Identify the type of adverse event using the NCI CTCAE v 4.03.
2)
Grade the adverse event using the NCI CTCAE v 4.03.
3)
Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows:

Definite: AE is clearly related to the study treatment.

Probable: AE is likely related to the study treatment.

Possible: AE may be related to the study treatment.

Unlikely: AE not likely to be related to the study treatment.

Unrelated: AE is clearly NOT related to the study treatment.
4)
Determine the prior experience of the adverse event.
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in:

the current protocol

the drug package insert

the current Investigator’s Brochure
10.4.3 Expedited Reporting of SAEs/Other Events
10.4.3.1 Reporting to the Northwestern University QAM/DMC
All SAEs must be reported to the assigned QAM within 24 hours of 
becoming aware of the event. Completion of the NU CRO SAE Form, 
provided as a separate document, is required.
The completed form should assess whether or not the event qualifies as a 
UPIRSO. The report should also include:

Protocol description and number(s)

The patient’s identification number

A description of the event, severity, treatment, and outcome (if 
known)

Supportive laboratory results and diagnostics

The hospital discharge summary (if available/applicable)
All SAEs will be reported to, and reviewed by, the DMC at their next 
meeting.
10.4.3.2 Reporting to the Northwestern University IRB
The following information pertains to the responsibilities of the lead site 
(Northwestern University). Additional participating sites should follow 
their local IRB guidelines for reporting to their local IRBs.

Any death of an NU subject that is unanticipated in nature and at 
least possibly related to study participation will be promptly reported 
to the NU IRB within 24 hours of notification. 

Any death of an NU subject that is actively on study treatment 
(regardless of whether or not the event is possibly related to study 
treatment)
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
Any death of a non-NU subject that is unanticipated and at least 
possibly related and any other UPIRSOs will be reported to the NU 
IRB within 5 working days of notification.

All other deaths of NU subjects not previously reported, other non-
NU subject deaths that were unanticipated and unrelated, and any 
other SAEs that were not previously reported as UPIRSOs will be 
reported to the NU IRB at the time of annual continuing review.
10.4.3.3 Reporting to the FDA
The FDA will be notified within 7 calendar days of any SAE that is 
associated with study treatment, is unexpected, and is fatal or life-
threatening.  Such reports should also be faxed to Genentech within 7 
calendar days of first learning of the event.
The FDA will be notified within 15 calendar days of any SAE that is 
associated with the study treatment, unexpected, and serious but not fatal 
or life-threatening. This includes any previous SAEs that were not 
initially deemed reportable, but are later determined to meet the criteria 
for reporting (i.e. by the DMC).
All other SAEs will be reported on an annual basis as part of the annual 
FDA report.  All IND annual reports submitted to the FDA by the 
Sponsor-Investigator should be copied to Genentech. Copies of such 
reports should be faxed to Genentech Drug Safety:
Fax: (650) 238-6067
Written IND safety reports with Analysis of Similar Events are to be 
submitted to the FDA, Genentech, and all participating investigators 
within 15 calendar days of first learning of the event. The FDA prefers 
these reports on a MedWatch 3500 form, but alternative formats are 
acceptable (e.g., summary letter).
10.4.3.4 Reporting to Genentech
Investigators must report all SAEs to Genentech within the timelines 
described below. The completed NU CRO SAE Form should be faxed or 
emailed immediately upon completion to Genentech Drug Safety at:
Fax: (650) 238-6067
Email: us_drug.safety@gene.com
Occasionally Genentech may contact the reporter for additional 
information, clarification, or current status of the patient for whom the 
AE was reported. For questions regarding SAE reporting, you may 
contact the Genentech Drug Safety representative or the MSL assigned to 
the study. Relevant follow-up information should be submitted to 
Genentech Drug Safety as soon as it becomes available and/or upon 
request.
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SAEs, pregnancy reports and AEs of special interest (AESIs), where the 
patient has been exposed to bevacizumab, will be sent on a the NU CRO 
SAE Form to the fax/email listed above. Transmission of these reports 
(initial and follow-up) will be either electronically or by fax and within 
the timelines specified below:

Serious AE reports that are related to bevacizumab shall be 
transmitted to Roche within fifteen (15) calendar days of the 
awareness date.

Serious AE reports that are unrelated to the Product shall be 
transmitted to Roche within thirty (30) calendar days of the awareness 
date.

Pregnancy reports: While such reports are not serious AEs or ADRs 
per se, as defined herein, any reports of pregnancy, where the fetus 
may have been exposed to the Product, shall be transmitted to Roche 
within thirty (30) calendar days of the awareness date. Pregnancies 
will be followed up until the outcome of the pregnancy is known, 
whenever possible, based upon due diligence taken to obtain the 
follow-up information.

AESIs requiring expedited reporting shall be forwarded to Roche 
within fifteen (15) calendar days of the awareness date. Others shall 
be sent within thirty (30) calendar days.
All non-serious AEs originating from the study will be forwarded in a 
quarterly report to Roche.
Special situation reports
In addition to all AEs, pregnancy reports and AESIs, the following 
Special Situations Reports should be collected and transmitted to Roche 
even in the absence of an Adverse Event within 30 calendar days:

Data related to the Product usage during pregnancy or breastfeeding

Data related to overdose, abuse, off-label use, misuse, 
inadvertent/erroneous administration, medication error or 
occupational exposure, with or without association with an AE/SAE 
unless otherwise specified in the protocol

Data related to a suspected transmission of an infectious agent via a 
medicinal product (STIAMP)

Lack of therapeutic efficacy
In addition, reasonable attempts should made to obtain and submit the 
age or age group of the patient, in order to be able to identify potential 
safety signals specific to a particular population
10.4.3.4Study Close-Out
Any study report submitted to the FDA by the Sponsor-Investigator 
should be copied to Genentech. This includes all IND annual reports and 
the Clinical Study Report (final study report). Additionally, any literature 
articles that are a result of the study should be sent to Genentech. Copies 
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of such reports should be mailed to the assigned Clinical Operations 
contact for the study:
Avastin (bevacizumab) Protocols
avastin-gsur@gene.com 
650-745-0978 (fax)
11 DATA COLLECTION & SUBMISSION
Study-specific instructions regarding the entry and submission of data using eCRFs through 
NOTIS will be provided at the time of training prior to study activation. In addition, instructional 
videos on data entry using NOTIS and eCRFs are available on the CRO’s website at: 
https://www.cancertrials.northwestern.edu/working-with-the-cro.  The Internal and Affiliate Data 
Compliance Policies of the Lurie Cancer Center’s DMC regarding will be strictly enforced.
11.1
Study Chart
In addition to the regular hospital chart, a separate patient folder will be kept which 
includes:

The patient's signed, dated informed consent document.

A pathology report confirming study disease.
11.2
Patient Registration (please refer to Section 4.0)
Please refer to Section 4.0 for more extensive instructions.  BEFORE a patient can be 
treated on study, please complete and submit the following items through NOTIS to 
confirm patient eligibility and receive a subject registration number:

Eligibility eCRF.

Signed and dated informed consent document.

Pathology Report or other documentation of disease as required by the protocol.
11.3
Data Submission Guidelines
Once a subject is confirmed and enrolled to the study, eCRFs should be submitted to the 
QAM through NOTIS according to the detailed data submission guidelines (provided in a 
separate document in NOTIS). Specific timeframes will be defined according to the study 
parameters table (Section 7.0), but in general, on-study data should be submitted no later 
than 5 business days after the date of subject registration.  Generally, for all phase II 
patients, data are due at the end of each cycle. Accrual on a trial may be suspended if data 
is not submitted within 90 days after the data’s due date (as it is defined by the protocol).
12 PATHOLOGY REQUIREMENTS
All patients who were not operated on at Northwestern Memorial Hospital or Columbia 
University or Northwestern Medicine Cancer Center/Cadence Health Cancer Center will be asked 
to submit their pathology for review at whichever site they intend to enroll. One to two 
representative H&E stained slides from a pre-registration biopsy-demonstrating lesion along with 
a copy of the pathology report will be requested for this review. NOTE:  A copy of the pathology 
report is sufficient for registration purposes.
13 ADMINISTRATIVE, ETHICAL & REGULATORY CONSIDERATIONS
13.1
Conduct
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This study will be conducted in accordance with the Declaration of Helsinki, Good 
Clinical Practices (GCP) guidelines. and all applicable government regulations and 
Institutional research policies and procedures.  The Principal Investigator or qualified 
designees are responsible for reporting all amendments, safety updates, and protocol 
violations.  This study will be monitored in accordance with the Data Safety Monitoring 
Plan of the Lurie Cancer Center of Northwestern University and will abide by its policies 
and practices.  
13.2
Amendments
The Principal Investigator will formally initiate all amendments to the protocol and/or 
informed consent.  All amendment s will be subject to the review and approval of the 
appropriate local, institutional, and governmental regulatory bodies.   Amendments will 
be distributed by the lead institution (Northwestern) to all affiliate sites upon approval by 
the Northwestern University IRB.  
13.3
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol.
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki.
The investigator is responsible for ensuring that no patient participates in any study-
related examination or activity before that patient has given informed consent.  The 
informed consent will be provided both through the written informed consent document 
and through verbal review of all information contained therein.  Information provided in 
this way is to include potential benefits, aims of the study, potential harms or side effects 
and methods of the study.  The patient will be given opportunity to ask questions about 
any aspect of the information and will be given time to review the information on their 
own.  The patient may, after having been provided with this detailed written and verbal 
information, provide written consent.  The patient will then be provided a copy of the 
executed informed consent for their reference.  The patient is free to withdraw consent at 
any time and for any reason.  The only consequence of consent withdrawal is that the 
patient is no longer able to participate in the study.  
13.4
Protected Health Information (PHI)
In accordance with the Health Information Portability and Accountability Act (HIPAA), 
patients who have provided written informed consent must also sign a subject 
authorization to release medical information to the study Sponsor and allow a regulatory 
authority, or Institutional Review Board access to subject’s medical information relevant 
to the study.  This authorization may be combined with the informed consent form in 
accordance with local institutional practice.
13.5
Instructions for Participating Sites
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Research Office at Northwestern University:
•
Signed and completed Letter of Invitation to participate in the study.
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•
Signed copy of Northwestern University’s Data Monitoring Committee policy 
pertaining to data submission.
•
Draft informed consent form should for review/approval prior to submission to the 
local IRB
•
A copy of the official IRB approval letter for the protocol and informed consent. 
•
CVs and medical licensure for the local PI and any sub-investigators who will be 
involved in the study at the site.
•
Form FDA 1572 appropriately filled out and signed with appropriate documentation.
Additional activities may be required prior to site activation (i.e. contract execution, 
study-specific training). Full requirements will be outlined in a memo upon receipt of the 
signed Letter of Invitation.
13.6
Data Management and Monitoring/Auditing
This study will be conducted in compliance with the Data Safety Monitoring Plan 
(DSMP) of the Robert H. Lurie Comprehensive Cancer Center of Northwestern 
University. The level of risk attributed to this study requires High Risk Monitoring, as 
outlined in the DSMP. The assigned QAM, with oversight from the Data Monitoring 
Committee, will monitor this study in accordance with the study phase and risk level. 
Please refer to NOTIS for additional data submission instructions.
13.7
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol. 
13.7.1 Emergency Modifications
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval. 
For any such emergency modification implemented, an IRB modification form 
must be completed within 5 business days of making the change, and the QAM 
must be notified within 24 hours of such change. 
13.7.2 Other Protocol Deviations
All other deviations from the protocol must be reported to the assigned QAM 
using the appropriate form.
A protocol deviation is any unplanned variance from an IRB approved protocol 
that: 
•
Is generally noted or recognized after it occurs.
•
Has no substantive effect on the risks to research participants.
•
Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected.
•
Did not result from willful or knowing misconduct on the part of the 
investigator(s). 
A protocol deviation may be considered an instance of Promptly Reportable 
Non-Compliance (PRNC) if it:
•
Has harmed or increased the risk of harm to one or more research 
participants.
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•
Has damaged the scientific integrity of the data collected for the study.
•
Results from willful or knowing misconduct on the part of the 
investigator(s).
•
Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies.
13.8
Investigator Obligations
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The PI is responsible for personally overseeing the treatment of all study 
patients. The PI must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study 
completion.
The Principal Investigator at each institution or site will be responsible for assuring that 
all the required data will be collected, entered onto the appropriate eCRFs, and submitted 
within the study-specific timeframes. Periodically, monitoring visits may be conducted 
and the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. The study may also be subject to routine audits by the 
Audit Committee, as outlined in the DSMP.
13.9
Publication Policy
All potential publications and/or data for potential publications (e.g. manuscripts, abstracts, posters, 
clinicaltrials.gov releases) must be approved in accordance with the policies and processes set forth in the Lurie 
Cancer Center DSMP. For trials that require high intensity monitoring, the assigned QAM will prepare a preliminary 
data summary (to be approved by the DMC) no later than 3 months after the study reaches its primary completion 
date (the date that the final subject is examined or receives an intervention for the purposes of final data collection 
for the primary endpoint). If the investigator’s wish to obtain DMC-approved data prior to this point (or prior to the 
point dictated by study design), the PI must send a written request for data to the QAM which includes justification. 
If the request is approved, data will be provided no later than 4 weeks after this request approval. The data will be 
presented to the DMC at their next available meeting, and a final, DMC-approved dataset will be released along 
with any DMC decisions regarding publication. The investigators are expected to use only DMC-approved data in 
future publications. The investigators should submit a copy of the manuscript to the biostatistician to confirm that 
the DMC-approved data are used appropriately.  Once the biostatistician gives final approval, the manuscript may be 
submitted to external publishers.
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research : an official journal of the American Association for Cancer Research 2011;17:4110-
4118.
18.
Cohen MH SY, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab 
(Avastin) as treatment of recurrent glioblastomamultiforme. Oncologist 2009;14:1131-1138.
19.
Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with 
irinotecan in recurrent glioblastoma. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 2009;27:4733-4740.
20.
Glusker P, Recht L, Lane B. Reversible posterior leukoencephalopathy syndrome and 
bevacizumab. The New England journal of medicine 2006;354:980-982; discussion 980-982.
21.
Ozcan C, Wong SJ, Hari P. Reversible posterior leukoencephalopathy syndrome and 
bevacizumab. The New England journal of medicine 2006;354:980-982; discussion 980-982.
22.
Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients 
with platinum-resistant ovarian cancer or peritoneal serous cancer. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology 2007;25:5180-5186.
23.
Scappaticci FA, Fehrenbacher L, Cartwright T, et al. Surgical wound healing 
complications in metastatic colorectal cancer patients treated with bevacizumab. Journal of 
surgical oncology 2005;91:173-180.
24.
Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine 
compared with bevacizumab plus capecitabine in patients with previously treated metastatic 
breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 2005;23:792-799.
25.
Karp JE, Gojo I, Pili R, et al. Targeting vascular endothelial growth factor for relapsed 
and refractory adult acute myelogenous leukemias: therapy with sequential 1-beta-d-
arabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clinical cancer research : an official 
journal of the American Association for Cancer Research 2004;10:3577-3585.
26.
Wedam SB, Low JA, Yang SX, et al. Antiangiogenic and antitumor effects of 
bevacizumab in patients with inflammatory and locally advanced breast cancer. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 2006;24:769-
777.
27.
Sanborn RE, Sandler AB. The safety of bevacizumab. Expert opinion on drug safety 
2006;5:289-301.
28.
Sadikov E BA, Yi QL, Wells W, Dawson L, Millar BA, Laperriere N. Value of Whole 
Brain Re-irradiation for Brain Metastases-single center experience. Clin Oncol (R Coll Radiol) 
2007;19:532-538.
29.
Wong WW SS, Sawyer TE, Shaw EG. Analysis of Outcome in Patients reirradiated for 
Brain Metastases. Int J Radiat Oncol Biol Phys 1996;34:585-590.
30.
Abrey LE OJ, Raizer JJ, Mack M, Rodavitch A, Boutros DY, Malkin MG. A phase II 
trial of temozolomide for patients with recurrent or progressive brain metastases. J Neurooncol 
2001;53:259-265.
31.
Iwamoto FM OA, Raizer JJ, Nolan CP, Hormigo A, Lassman AB, Gavrilovic IT, Abrey 
LE. A phase II trial of vinorelbine and intensive temozolomide for patients with recurrent or 
progressive brain metastases. J Neurooncol 2008;81:85-90.
32.
Nghiemphu PL GR, Pope WB, Lai A, Cloughesy TF. Safety of anticoagulation use and 
bevacizumab in patients with glioma. Neuro Oncol 2008;10:355-360.
33.
Besse B LS, Compton P, Huang J, Augustus S, Rohr U. Bevacizumab safety in patients 
with central nervous system metastases. Clin Caner Res 2010;16:269-278.
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De Braganca KC JY, Azzoli CG, Kris MG, Pietanza MC, Nolan CP, Omuro AM, 
Holodny AI, Lassman AB. Efficacy and safety of bevacizumab in active brain metastases from 
non-small cell lung cancer. J Neurooncol 2010;100:443-447.
35.
Quant EC WP. Response Assessment in Neuro-Oncology. Curr Oncol Rep 2011;13:50-
56.Atkinson EN & Brown BW.  Confidence limits for probability of response in multistage 
Phase II clinical trials. Biometrics 1985;41:741-744.
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14 APPENDIX
14.1
Appendix I – Karnofsky Performance Status and Neurological Function
Patient's performance status and Neurologic Functions will be graded according to the following scales:
Karnofsky Performance Status
KPS 100
Normal; no complaints; no evidence of disease
KPS   90
Able to carry on normal activity; minor signs or symptoms of disease
KPS   80
Normal activity with effort; some sign or symptoms of disease
KPS   70
Cares for self; unable to carry on normal activity or do active work
KPS   60
Requires occasional assistance, but is able to care for most personal needs
KPS   50
Requires considerable assistance and frequent medical care
KPS   40
Disabled; requires special care and assistance
KPS   30
Severely disabled; hospitalization is indicated, although death no imminent
KPS   20
Very sick; hospitalization necessary; active support treatment is necessary
KPS   10
Moribund; fatal processes progressing rapidly
KPS     0
Dead
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14.2
Appendix II – New York Heart Association (NYHA) Guidelines
The Stages of Heart Failure – NYHA Classification
In order to determine the best course of of therapy, physicians often assess the stage of heart failure 
according to the New York Heart Association (NYHA) functional classification system. This system 
relates symptoms to everyday activities and the patient's quality of life.
Class
Patient Symptoms
Class I (Mild)
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, or dyspnea (shortness of breath).
Class II (Mild)
Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnea.
Class III (Moderate)
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation, or dyspnea.
Class IV (Severe)
Unable to carry out any physical activity without discomfort. Symptoms of 
cardiac insufficiency at rest. If any physical activity is undertaken, 
discomfort is increased.
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14.3
Appendix III – Procedures for Obtaining a Urine Protein
1)
Obtain at least 4 ml of a random urine sample (does not have to be a 24 hour urine) 
2)
Determine protein concentration (mg/dL) 
3)
Determine creatinine concentration (mg/dL) 
4)
Divide #2 by #3 above: urine protein / creatinine ratio = protein concentration (mg /dL) / creatinine 
concentration (mg /dL)
The UPC directly correlates with the amount of protein excreted in the urine per 24 hrs (i.e. a UPC of 1 
should be equivalent to 1g protein in a 24hr urine collection)
                                           
Protein and creatinine concentrations should be available on standard reports of urinalyses, not dipsticks. 
If protein and creatinine concentrations are not routinely reported at an Institution, their measurements 
and reports may need to be requested.
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14.4
Appendix IV – SAFETY REPORTING FAX COVER SHEET
SAFETY REPORTING FAX COVER SHEET
Genentech Supported Research
FAX No: (650) 238-6067
Genentech Study Number
Principal Investigator
Site Name
Reporter name
Reporter Telephone #
Reporter Fax #
Initial Report Date
[DD] / [MON] / [YY]
Follow-up Report Date
[DD] / [MON] / [YY]
Subject Initials
(Enter a dash if patient has no middle 
name)
[ ] - [ ] - [ ]
SAE or Safety Reporting questions, contact Genentech Safety: (888) 835-2555
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET
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14.5
Appendix V – Protocol History of Changes
Initial Version Approved by Scientific Review Committee – January 10, 2013
Updated Version Prior to IRB Submission – April 30, 2013
Approved by Scientific Review Committee:  April 30, 2013
Section(s) Affected
Prior Version
Updates
Rationale
Title Page
n/a
Adds NU Sub-Investigators:
Kristin Swanson, PhD
Carly Bridge, ND
Administrative 
Title Page
IND status listed as 
“TBD”.
Updates IND status to 
“Exemption # 117883
Administrative 
updated based on 
receipt of FDA 
exemption 
notification.
Synopsis, 9.0 
(Statistical 
Considerations).
n/a
Revises wording of the 
sample size and power 
calculation (does not change 
actual numbers).
Clarifications 
requested by 
Genetech.
Appendices
n/a
Adds Appendix V – 
Protocol History of Changes
Administrative
Updated Version During Initial IRB Review – May 23, 2013
Approved by Scientific Review Committee – May 23, 2013
Section(s) Affected
Prior Version
Updates
Rationale
Synopsis, 9.0 
(Statistical 
Considerations)
Accrual for the 
second stage of 
enrollment 
incorrectly listed 
as an additional 17 
patients.
Corrects this to an 
additional 15 patients.
This corrects an 
error that was 
noted in the 
previous version. 
This change does 
not affect the 
overall (total) 
accrual for the 
study.
Updated Version #2 During Initial IRB Review – May 30, 2013
Approved by Scientific Review Committee – June 5, 2013
Section(s) Affected
Prior Version
Updates
Rationale
Throughout
n/a
Correction of minor 
grammatical and/or 
typographical errors.
Administration
Section 1.2.2.8 
(Reversible Posterior 
n/a
Adds that adequate brain 
imaging with MRI should 
Added for 
clarity.
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Leukoencephalopathy 
Syndrome)
be performed for any 
patients developing RPLS.
Section 3.2 
(Exclusion Criteria)
n/a
Adds language clarifying 
the eligibility of patients 
with brain tumors who have 
had a recent craniotomy or 
cranial biopsy, as well as 
patients who have had 
placement of a vascular 
access device prior to 
registration.
Added for 
clarity.
Section 5.2.2 – Table 
1 (Bevacizumab Dose 
Management Due to 
Adverse Events)
1. Allowed 
treatment to be 
held for Grade 
1 CNS bleed & 
then restarted 
under certain 
conditions.
2. n/a
3. Allowed 
treatment to be 
held for Grade 
4 thrombosis & 
then restarted 
under certain 
conditions.
4. Allowed 
treatment to be 
held for Grade 
3 congestive 
heart failure & 
then restarted 
under certain 
conditions.
5. n/a
1. Changed to 
“Discontinue 
bevacizumab” for any 
grade CNS bleed.
2. Adds that for recurrent 
Grade 3 thrombosis, 
bevacizumab should be 
discontinued.
3. Changed to 
“Discontinue 
bevacizumab” for any 
Grade 4 thrombosis.
4. Changed to 
“Discontinue 
bevacizumab” for any ≥ 
Grade 3 CHF.
5. Adds instructions for 
grade 4 febrile 
neutropenia and/or grade 
4 thrombocytopenia 
(regardless of 
relationship to 
bevacizumab); adds 
All changes 
made at the 
request of the 
drug supplier 
(Genentech).
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instructions for 
hypersensitivity/allergic 
reactions.
Section 7.0 (Study 
Parameters)
1. Medical history 
to be 
performed at 
treatment 
discontinuation
.
2. Chemistry 
panel only 
performed at 
baseline.
3. Adverse events 
assessment & 
review 
concomitant 
medications 
only done on 
day 1 of each 
cycle.
4. n/a
1. Removes this test (not 
necessary).
2. Adds a chemistry panel 
to every cycle (day 1).
3. Adds AE assessment 
and conmeds review to 
day 15 of every cycle.
4. Adds a footnote stating 
that PT/PTT should be 
repeated after baseline 
only as clinically 
indicated.
Safety – all 
changes made at 
the request of the 
drug supplier 
(Genentech).
Section 10.3.2 
(Recording AEs)
n/a
Adds a section on non-
serious adverse events of 
special interest (AESIs) that 
should be reported to 
Genentech within stated 
timeframes.
Change made at 
the request of the 
drug supplier 
(Genentech).
Amendment 1 – April 3, 2014
Approved by Scientific Review Committee – May 7, 2014
Section(s) Affected
Prior Version
Amendment 1 Changes
Rationale
Cover-page
Carly Bridge, ND 
listed as a sub-
investigator.
Removes Dr. Bridge as a 
sub-investigator.
Administrative – 
she is no longer 
at NU.
3.1 (Inclusion 
Criteria), 6.2 
(Definitions)
Defined 
measureable 
disease as being ≥ 
1 cm (10 mm).
Changes the definition of 
measurable disease to ≥ 5 
mm.
The previous 
requirement was 
too restrictive for 
the population 
being studied.
5.2.2 (Toxicity 
Management 
Guidelines)
Previously stated 
that only certain 
out-of-range lab 
Clarifies that ALL out-of-
range lab values must be 
reported (along with any 
Updated to be 
consistent with 
what was 
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values needed to 
be reported as AEs.
other AE) on the appropriate 
eCRF as outlined in Section 
10 of the protocol.
required in 
Section 10.
Amendment 2 – April 15, 2015
Approved by Scientific Review Committee – April 15, 2015
Section(s) Affected
Prior Version
Amendment 2 Changes
Rationale
7.0 (Study 
Parameters)
Footnote 12: A 
window of +/- 3 
days is allowed for 
completion of tests 
and assessments.
A window of +/- 3 days is 
allowed for completion of 
tests, assessments, and 
treatment.
Allows for a 
window of +/- 3 
days for 
treatment
Amendment 3 – January 8, 2016
Section(s) Affected
Prior Version
Amendment 3 Changes
Rationale
Cover-page
NA
Added Northwestern 
Medicine Cancer Center, 
Warrenville, IL as a new 
participating site. 
New 
participating has 
been added.
Synopsis
NA
Added Northwestern 
Medicine Cancer Center 
under study centers
To update the 
external site that 
has been added.
Section 3.0 Selection 
of Subjects
NA
Added Northwestern 
Medicine Cancer Center 
(Cadence Health Cancer 
Center) to the list of sites 
where patients will be 
recruited from.
To complete the 
list of 
participating 
sites.
Section 12.0 
Pathology 
Requirements
NA
Added Northwestern 
Medicine Cancer Center 
(Cadence Health Cancer 
Center) to the list of sites.
To complete the 
list of 
participating 
sites.
Amendment 4 – March 17, 2017
Approved by Scientific Review Committee - 3/22/2017
Section(s) Affected
Prior Version
Amendment 2 Changes
Rationale
Statistician
Biostatistician
Aligns with new 
NU IIT template
n/a
Study Intervention: 
Bevacizumab
Aligns with new 
NU IIT template
Title page
n/a
Added Version Date
Aligns with new 
NU IIT template
Study Summary
Title “Synopsis”
Title: “Study Summary”
Aligns with new 
NU IIT template
Section 3.1.3 
(Inclusion Criteria)
n/a
Clarified that lesion 
measurement must be 
Per PI.  For 
clarification, 
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≥5mm 
unidimensionally
definition of 
measurable 
disease stated 
“bidimensional” 
lesion 
measurement ≥ 
5mm, however 
this study is 
using modified 
RANO criteria 
that requires only 
unidimensional 
lesion 
measurement 
≥5mm.
Section 3.1.12 
Inclusion Criteria
List of organ and bone 
marrow function 
requirements for 
eligibility
Converted list of organ 
and bone marrow 
function requirements 
into a table
To adhere to NU 
protocol template
Section 4.0 (Patient 
Registration)
Listed QAM phone 
number (312-69-1355) 
and business hours
Removes phone number 
and business hours
Adds QAM email 
address
The QAM email 
provides faster 
access to QA as 
it is a group 
email.  Business 
hours are not 
listed because 
QA email inbox 
is monitored 
outside of regular 
business hours.
Section 4.2 
(Registering a 
Patient)
n/a
Adds additional 
instructions for 
registration procedures 
including using NOTIS 
to provide an eligibility 
checklist and eCRF
Aligns with new 
NU IIT Template
Section 5.5 Duration 
of Follow Up
n/a
Addition of description 
of duration of follow up
Clarification of 
length of time 
patients will be 
followed for 
survival.
Section 6.2.1 
(Measurable Disease 
Definition)
“At least 1 
bidimensionally 
measurable lesion ≥ 5 
mm with clearly 
defined margins by CT 
“At least 1 
unidimensionally 
measurable lesion ≥ 5 
mm with clearly defined 
margins by CT or MRI 
Per PI.  For 
clarification, 
definition of 
measurable 
disease stated 
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or MRI scan.”
scan.”
“bidimensional” 
measurable 
lesion ≥ 5mm, 
however this 
study is using 
modified RANO 
criteria that 
requires only 
unidimensional 
measurable 
lesion ≥5mm.
Section 7.0 Study 
Parameters

Footnote #5 – n/a
Footnote #6: Follow 
up will occur 
approximately every 8 
weeks.

Footnote #5: length of 
cycle (1 cycle = 28 
days)

Footnote #6: follow up 
will occur 
approximately every 
8-12 weeks.
Duration of follow 
up added

Clarification 
of length of 
cycle

To extend the 
window of 
when patients 
schedule their 
follow up 
visits.  Allow 
for fewer 
deviations.
Clarification 
of duration of 
follow up
n/a
Adds a reference to 
safety reporting abiding 
by the Code of Federal 
Regulations
Administrative
Description of AE 
monitoring
Clarifies monitoring of 
AEs with standard NU 
IIT template language
To adhere to NU 
IIT template
Section 10.0 
(Adverse Event 
Monitoring and 
Reporting)
Section 10.1 Adverse 
Event Monitoring
n/a
Included AE language 
from the NU IIT 
template 
To adhere to NU 
IIT template
Section 10.2.1 
Adverse Event
n/a
Further define adverse 
event
To adhere to NU 
IIT template
Section 10.2.2 
(Severity of AEs)
Stated that AE’s 
should follow CTCAE 
v4.0
Changes CTCAE 
version to 4.03
Adds language for 
general severity grading 
if no CTCAE grading is 
available
Administrative
Added for 
reference
Section 10.2.4 
Serious Adverse 
Event
Description of SAEs
Further clarifies SAEs 
using language from the 
NU IIT Template
To adhere to NU 
IIT template
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Section 10.2.6 
Unanticipated 
Problems Involving 
Risk to Subject or 
Others (UPIRSO)
Description of 
UPIRSO
Further clarifies 
UPIRSOs using 
language from the NU 
IIT Template
To adhere to NU 
IIT template
10.3.1 Eliciting AEs
n/a
Addition of language 
from Genentech AE 
template regarding 
eliciting AEs from 
patients
Per Genentech, 
further 
explanation on 
eliciting AEs was 
necessary.
Section 10.4 
(Reporting of SAEs),
Referred to the 
MedWatch 3500A 
form for reporting 
SAE’s
n/a
UPIRSO’s had to be 
reported within 10 
calendar days to the 
IRB
Listed Reporting 
requirements to the 
FDA
Deletes MedWatch 
3500A and adds 
reference to the NU 
CRO SAE form. Also 
adds the patient 
identification number 
and discharge summary 
as required reporting 
information
Adds 10.4.2.2 - death of 
an NU patient on study 
treatment must be 
reported to the IRB
Changes UPIRSO 
reporting requirement to 
5 days
Removes language for 
FDA reporting 
requirements
Administrative - 
the NU CRO 
SAE Form and 
added 
requirements 
align with CRO 
policies
Added to align 
with CRO 
policies
Changed to align  
with CRO 
policies
The study is 
IND-exempt and 
does not require 
FDA reporting
n/a
Addition of reporting 
instruction from NU IIT 
Template
To adhere to the 
NU IIT template
Included inaccurate fax 
number for reporting 
SAE’s to Genentech
650-225-5288 and no 
email
Updates contact 
information to include 
email address and new 
fax number:
us_drug.safety@gene.co
m
650-238-6067
Administrative 
update from 
sponsor
n/a
Addition of AE/SAE 
reporting instructions 
for Genentech
Per Genentech, 
added from the 
Genentech 
template
Section 10.4.3 
Expedited Reporting 
of SAEs/Other Events
Section 10.4.3.4 
Reporting to 
Genentech
n/a
Addition of “Special 
Situation Reports” 
instructions
Per Genentech, 
added from the 
Genentech 
template
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Section 10.4.3.5 
Study Close-Out
Directions for 
contacting Genentech 
for study close out
Updated language 
explaining study close-
out communications 
with Genentech
Per Genentech, 
added from the 
Genentech 
template
Section 11.3 (Data 
Submission 
Guidelines)
Included Data 
Submission Guidelines 
in the protocol
Removes Data 
Submission Guidelines 
from the protocol.
Refers to a separate 
document in NOTIS for 
data submission 
guidelines
Administrative –
guidelines will 
no longer be 
included in NU 
protocols. In 
effect, changes to 
the guidelines 
will not require a 
protocol 
amendment
Section 13.3 (IRB 
Approval and 
Consent)
Listed requirements for 
patients to give 
consent prior to study 
participation
Adds the requirement 
for the consent to be 
IRB-approved and to 
follow GCP
Administrative – 
language added 
to align with 
CRO policies
Sections 13.5 
(Instructions for 
Participating Sites), 
13.6 (Data 
Management and 
Monitoring/Auditing)
, 13.7 (Adherence to 
the Protocol),
13.8 (Investigator 
Obligations),
13.9 (Publication 
Policy)
n/a
Adds listed sections 
from the NU IIT 
template
Additional 
administrative 
language added 
to align with 
CRO policies
Amendment 5 – February 6, 2019
Approved by Scientific Review Committee:
Section(s) Affected
Prior Version
Amendment 5 Changes
Rationale
Study Summary; 
Section 5.5 (Duration 
of Follow-Up); 
Section 6.3.4 (Overall 
Survival); Section 7 
(Study Parameters)
Patients followed until 
death
As of December 31, 
2018, patients will no 
longer be followed and 
follow up information 
will not be collected
Study PIs are 
already working 
on publication 
and not going to 
collect any more 
data.
Section 6.2.8 
(Progressive Disease)
A 25% increase in 
sum of the products 
of perpendicular 
diameters of 
enhancing lesions 
compared with the 
smallest tumor 
A 25% increase in 
sum of the products 
of perpendicular 
diameters of 
enhancing lesions 
compared with 
baseline, on stable or 
Update the 
definitions of 
response to 
match the data 
that has been 
obtained
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measurement 
obtained either at 
baseline (if no 
decrease) or best 
response, on stable 
or increasing doses 
of corticosteroids
Signiﬁcant increase 
in T2/FLAIR 
nonenhancing lesion 
on stable or 
increasing doses of 
corticosteroids 
compared with 
baseline scan or 
best response after 
initiation of therapy 
not caused by 
comorbid events 
(e.g., radiation 
therapy, 
demyelination, 
ischemic injury, 
infection, seizures, 
postoperative 
changes, or other 
treatment effects).
increasing doses of 
corticosteroids
Signiﬁcant increase 
in T2/FLAIR 
nonenhancing lesion 
on stable or 
increasing doses of 
corticosteroids 
compared with 
baseline scan after 
initiation of therapy 
not caused by 
comorbid events 
(e.g., radiation 
therapy, 
demyelination, 
ischemic injury, 
infection, seizures, 
postoperative 
changes, or other 
treatment effects).
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