Conditions: Glioblastoma Multiforme Brain Tumor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 31
Healthy volunteers: no

Brief summary:
The high-grade malignant brain tumors, glioblastoma multiforme (GBM), comprise the majority of all primary brain tumors in adults. This group of tumors also exhibits the most aggressive behavior, resulting in median overall survival of only 9-12 months. Initial therapy consists of either surgical resection, external beam radiation, or both. All patients experience a recurrence after first-line therapy, so improvements in both first-line and salvage therapy are critical to enhancing quality-of-life and prolonging survival. It is unknown if currently used intravenous (IV) therapies even cross the blood brain barrier (BBB). We have shown in a previous phase I trial that a single Superselective Intraarterial Cerebral Infusion (SIACI) of Bevacizumab (up to 15mg/kg) is safe and effective in the treatment of recurrent GBM. Therefore, this phase I/II clinical research trial is an extension of that trial in that we seek to test the hypothesis that repeated dosing of intra-arterial Bevacizumab is safe and effective in the treatment of newly diagnosed malignant glioma. By achieving the aims of this study we will also determine if repeated intra-arterial Bevacizumab improves progression free and overall survival in newly diagnosed patients. We expect that this project will provide important information regarding the utility of repeated SIACI Bevacizumab therapy for malignant glioma, and may alter the way these drugs are delivered to our patients in the near future.

Detailed description:
The experimental aspects of this experimental plan will include:

1. Subjects will first be treated with Mannitol prior to chemotherapy infusion (Mannitol 20%; delivered IA, 12.5 mL over 2 minutes) in order to disrupt the blood brain barrier. This technique has been used in several thousand subjects in previous studies for the IA delivery of chemotherapy for malignant glioma.
2. Subjects will then be treated with repeated intraarterial delivery (SIACI) of Bevacizumab. Each subject will receive one dose of IA Bevacizumab on day 30, followed by chemoradiation. SIACI of Bevacizumab will be repeated every three months for a total of 3 infusions.

Arms:
arm 1: Superselective Intraarterial Cerebral Infusion (SIACI) of Bevacizumab

Interventions: intervention 1: Bevacizumab
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
- 1 - 
Version: 12/26/18 
 
 
 
 
PROTOCOL TITLE: Phase I/II Trial of Repeated Super-Selective Intraarterial Cerebral 
Infusion of Bevacizumab (Avastin) For Treatment of Newly Diagnosed Glioblastoma 
Multiforme 
 
 
IND 108402   
 
 
Version: 12/26/18 
 
PRINCIPAL INVESTIGATOR: 
John A. Boockvar, MD 
130 East 77 Street New York, NY 10075 
3rd Floor, Black Hall Building 
Phone: 212-434-3900 or 212-434-3905 
Fax: 212-434-3899 
 
 
SPONSOR: 
 
John A. Boockvar, MD 
 
 
The Feinstein Institute for Medical Research 
 
 
Northwell Health 
 
 
350 Community Drive 
 
 
Manhasset, NY 11030 
 
 
 
 
 
PERFORMANCE SITES: Lenox Hill Brain Tumor Center 
 
 
 
 
130 East 77th Street 
 
 
 
 
New York, NY 10075 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


- 2 - 
Version: 12/26/18 
  
Principal Investigators: 
John A. Boockvar, MD 
Principal Investigator 
 
 
 
Director, Brain Tumor Center 
 
 
 
 
 
 
Professor of Neurosurgery 
 
 
 
 
 
 
Lenox Hill Hospital 
 
 
 
Feinstein Institute for Medical Research 
 
 
 
 
Co-Investigators: 
David Langer, MD 
 
Co-Investigator 
 
 
 
 
 
 
Director, Neurosurgery 
Director, Moyamoya Center 
Associate Professor of Neurosurgery 
Lenox Hill Hospital 
 
Rafael Ortiz, MD 
 
Co-Investigator 
 
 
 
 
 
 
Director, Neuro-Endovascular Center 
Assistant Professor of Neurology, Radiology, and 
Neurosugery 
Lenox Hill Hospital  
 
 
  
Alexis Demopoulos, MD 
Co-Investigator 
 
 
 
 
 
 
Director, Neuro-oncology 
Brain Tumor Center 
 
 
 
 
 
 
Assistant Professor, Neurology 
Lenox Hill Hospital 
 
 
 
 
 
Sherese Fralin, NP 
 
Co-Investigator 
 
 
 
 
 
 
Lenox Hill Hospital  
 
Tamika Wong, MPH  
Co-Investigator 
 
 
 
 
Lenox Hill Hospital 
 
 
 
Christopher Filippi, MD 
Co-Investigator 
 
 
 
 
 
 
Vice Chairperson, Diagnostic Radiology 
 
 
 
 
 
 
North Shore University Hospital 
 
 
 
Mona Li 
 
 
Research Coordinator, Neurosurgery 
 
 
 
 
 
 
Lenox Hill Hospital  
 
 
 
 
 
 
 
 
 
 
Medical Monitor: 
 
Christina Brennan, MD 
 
 
 
 
 
 
 
 
Clinical Monitor:              Sherese Fralin, MSN, FNP 
 
 
 


- 3 - 
Version: 12/26/18 
Signatures of Approval: 
 
 
 
Principal Investigator: 
 
  
 
 
 
 
Date:  
 
 
 
 
Sponsor: 
 
  
 
 
 
 
Date:  
 
 
 
 
Monitor: 
 
  
 
 
 
 
Date:  
 
 
 
 
 
 
 
 
 
 
 
 
All rights reserved.  No part of this research protocol may be copied, reproduced, referenced, 
stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, 
photocopying, recording, or otherwise, without prior written permission of the Principal 
Investigator. 


- 4 - 
Version: 12/26/18 
IN THE EVENT OF EMERGENCY 
 
Any adverse event experienced by the patient while receiving or within 30 days of receiving 
treatment under this research protocol, even though the event may not appear to be drug-related, 
will be reported according to The Feinstein Institute for Medical Research immediate reporting 
policy.   
 
 
 
 
 
PATIENT ENROLLMENT ON STUDY 
 
Investigators must notify the Clinical Research Coordinator in advance to pre-qualify a patient for 
enrollment.  Once a patient is identified as meeting the study entry criteria, the investigator or 
his/her designee will contact the Principal Investigator or designee (one of the individuals listed 
above) for final approval for patient enrollment. 
 
 


 
- 5 - 
Version: 12/26/18 
1. TABLE OF CONTENTS 
 
 
1. TABLE OF CONTENTS ............................................................................................................. 5 
2. LIST OF TABLES ....................................................................................................................... 6 
       LIST OF APPENDICES .............................................................................................................. 6 
3. STUDY SYNOPSIS ..................................................................................................................... 8 
4. INTRODUCTION ...................................................................................................................... 10 
5. RISK/BENEFIT OF THE STUDY ............................................................................................ 13 
6. OBJECTIVES ............................................................................................................................ 14 
7. PATIENT SELECTION ............................................................................................................. 15 
8. TEST AGENT PREPARATION AND ADMINISTRATION .................................................. 15 
9. EXPERIMENTAL PLAN .......................................................................................................... 16 
10. PATIENT ENTRY AND TIME ON RESEARCH STUDY .................................................... 17 
11. TREATMENT PLAN .............................................................................................................. 18 
12. SUPPORTIVE PRODUCTS/CONCOMITANT  MEDICATIONS ........................................ 19 
14. OVERVIEW OF SCHEDULED PROCEDURES ................................................................... 22 
15. TOXICITY OF INVESTIGATIONAL DRUG ....................................................................... 23 
16. MANAGEMENT OF TOXICITY ........................................................................................... 23 
17. ADVERSE EXPERIENCES .................................................................................................... 25 
18. PRECAUTIONS ...................................................................................................................... 28 
19. REGULATORY CONSIDERATIONS ................................................................................... 28 
20. INVESTIGATOR RESPONSIBILITIES ................................................................................. 30 
21. PROTOCOL DEVIATIONS .................................................................................................... 31 
22. ANALYSIS OF DATA ............................................................................................................ 32 
23. REFERENCES ......................................................................................................................... 32 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
- 6 - 
Version: 12/26/18 
 
2. LIST OF TABLES 
 
TABLE 1 
Overview of Scheduled Procedures ..................................................................................................... 22 
 
TABLE 2     Dosage Modification Criteria and Guidelines for Management of Bevacizumab -Related Toxicities   25 
 
 
 
LIST OF APPENDICES 
 
APPENDIX A  Performance Status Evaluation .......................................................................................................... 35 
 
APPENDIX B  Clinical Symptomatology and Adverse Experience Grading Scale ................................................... 36 
 
APPENDIX C  Clinical Adverse Experiences: Determining Relationship to Test Drug ............................................ 37 
 
APPENDIX D  Risks .................................................................................................................................................. 39 
 
APPENDIX E  Tumor Assessment RANO Response Criteria .................................................................................... 42 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
- 7 - 
Version: 12/26/18 
 
 
PROTOCOL TITLE:  PHASE I/II TRIAL OF REPEATED SUPER-SELECTIVE 
INTRAARTERIAL CEREBRAL INFUSION OF BEVACIZUMAB FOR TREATMENT OF 
NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME  
 
 
Test Materials: 
Mannitol (hexan-1,2,3,4,5,6-hexol (C6H8(OH)6) 
Bevacizumab (Avastin, Genentech Pharmaceuticals)  
 
 
 
 
 
Dosage Levels: 
Mannitol 20% 12.5ml over two minutes for blood brain barrier (BBB) 
disruption 
 
Bevacizumab 15 mg/kg, after BBB disruption, given 1 mL/s   
 
 
 
Route of Administration: 
Repeated Superselective Intraarterial Cerebral Infusion (SIACI)  


 
- 8 - 
Version: 12/26/18 
3. STUDY SYNOPSIS 
 
The current standard of care for newly diagnosed GBM is for patients to undergo tumor resection, 
if possible, followed by oral Temozolomide and radiation (chemoradiation) for 6 weeks. This is 
known as the Stupp protocol. Thereafter they receive maintenance oral Temozolomide 5 days on 
and 23 days off, until their tumor grows more than 25%.  At that point, these patients are deemed 
treatment failures and are given another treatment.  Because of the blood brain barrier (BBB) which 
prevents drugs from penetrating the blood vessel walls well to get into the brain, no one knows for 
sure if these drugs actually get into the brain after ingestion or infusion.   
 
We have recently completed a Phase I clinical trial that has shown that Superselective Intraarterial 
Cerebral Infusion (SIACI) of Bevacizumab is safe up to a dose of 15mg/kg in patients with 
recurrent malignant glioma.  Therefore, this one arm open-label, non-randomized trial is a follow 
up study to that trial and will ask simple questions:  Is it safe to deliver repeated doses of 
Bevacizumab intraarterially using these super selective intraarterial delivery techniques?  Will this 
IA Bevacizumab treatment regimen increase progression free survival (PFS) and overall survival 
(OS)? We expect that this project will provide important information regarding the utility of 
repeated SIACI Bevacizumab therapy for newly diagnosed malignant glioma, and may alter the 
way these drugs are delivered to our patients in the near future.  
 
Current Standard of Care:   
 
 
Day 0 
Maximum surgical debulking with functional preservation  
Day 30 
Start radiation and oral Temozolomide for 6 weeks   
Day 72 
Rest period for one month  
Day 100 
Start oral Temozolomide (5 days on, 23 days off) and repeat each cycle 
 
Experimental portion of this proposal: This trial will have one experimental arm that will test 
adding repeated IA Bevacizumab to the chemoradiation treatment at post-op day 30 and every 3 
months thereafter  
 
Day 0 
Maximum surgical debulking with functional preservation  
Day 30* 
Start single dose of IA Bevacizumab (15mg/kg); followed by radiation and oral 
Temozolomide for 6 weeks (*May be done at 2 weeks for biopsy patients with 
well healed incisions) 
Day 72 
Rest period for one month  
Day 100 
Start oral Temozolomide (5 days on, 23 days off)  and repeat each cycle 
Day 120 
Repeat single dose of IA Bevacizumab (15 mg/kg) 
Day 210 
Repeat single dose of IA Bevacizumab (15 mg/kg) 
 
The experimental aspects of this treatment plan will include: 
1. Subjects will first be treated with Mannitol prior to chemotherapy infusion (Mannitol 20%; 
delivered IA, 12.5 mL over 2 minutes) in order to disrupt the blood brain barrier.  This 
technique has been used in several thousand patients in previous studies for the IA delivery 


 
- 9 - 
Version: 12/26/18 
of chemotherapy for malignant glioma.  We have used this without complication in the 30 
patients from our Phase I protocol as well. 
 
2. Subjects will then be treated with repeated intraarterial delivery (SIACI) of Bevacizumab.  
Each patient will receive one dose of IA Bevacizumab on day 30, followed by 
chemoradiation. SIACI of Bevacizumab will be repeated every three months for a total of 3 
infusions. 
 
Inclusion criteria:  Males or females, 18 years of age, with documented histologic diagnosis 
newly-diagnosed glioblastoma multiforme (GBM). The lesion must be circumscribed to fall within 
an area targetable by IA therapy.  The patient’s KPS  70 and the patient must have a life 
expectancy greater than 12 weeks.   
 
This treatment may be harmful to a fetus in pregnant subjects.  If the subject is a female of 
childbearing age, she will be asked to practice birth control methods while participating in this 
research study and for 3 months following her treatment.  These methods include oral 
contraceptives, contraceptive shots, and barrier methods, such as condom use, sponges, and 
diaphragms.  Fertile males are required to use these barrier methods. 
 
The patient may be responsible for any additional costs associated with enrollment in the trial.  All 
costs of the IA delivery and the cost of the drug will be submitted to the patient’s insurance 
provider.  The Feinstein Institute for Medical Research will not be named as a sponsor of the study 
nor will it cover the cost of the experimental procedure. 
 
Day 0        Day 30 
                Day 72                  Day 100 
                 Day 120 
   
Day 210 
 
 
 
 
 
 
 
Surgery    Single dose of IA        Rest for one       Start Temozolomide, 5       Repeat IA  
    Repeat IA  
                  6 weeks of  
          month              days on, 23 days off;         single dose  
   single dose  
                Temozolomide and  
        repeat each cycle   
                chemoradiation                                      
 
 
Toxicity Monitoring/Assessment: Patients will be treated with a previously tested, dose and 
schedule of Mannitol prior to chemotherapy infusion (Mannitol 20%; 12.5 mL over two minutes) in 
order to disrupt the BBB.  Following BBB disruption, the patient will receive an SIACI with 
Bevacizumab at a dose of 15mg/kg, given 1mL/minute.  Both hematologic and non-hematologic 
dose limiting toxicity will be determined and scored according to the NCI Common Toxicity 
Criteria (version 3.0).  The dose limiting toxicity will be evaluated for 28 days after the SIACI 
chemotherapy infusion.  DLT will be defined as Grade III or worse non-hematologic and 
hematologic toxicity or Grade II or worse CNS hemorrhage.  


 
- 10 - 
Version: 12/26/18 
 
Anti-tumor response: Response will be evaluated after two cycles of chemotherapy (two months), or 
sooner if deemed necessary by the PI, using an MRI with contrast and the Response Assessment in 
Neuro-Oncology (RANO) response criteria (Appendix E).   
 
Study Agents: Mannitol and Bevacizumab are registered agents. 
 
 
 
Safety/Toxicity Monitoring: Hemorrhagic, Dermatologic, gastrointestinal, respiratory and nervous 
system disorders are expected to be the primary toxicity in patients receiving this treatment regimen.  
Patients may at any point during the phase I study receive supportive care, including growth factors, 
blood cell transfusions, as clinically indicated.  
 
 
4. INTRODUCTION  
In patients with GBM, the expression of VEGF is associated with a poor prognosis. Monoclonal 
antibodies to VEGF have inhibited the growth of GBM in vitro and in vivo.  In fact, intravenous 
(IV) Bevacizumab, a VEGF inhibitor, has become the standard of care for recurring relapsing 
GBM.  
Bevacizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that binds to and 
inhibits the activity of VEGF.  It has been show to work synergistically with chemotherapy in 
colorectal, lung, brain and breast carcinomas.   A preliminary report of the combination of 
bevacizumab for patients with malignant gliomas demonstrated an encouraging response rate of 
43% (Bokstein et al. 2008; Buie and Valgus 2008; Chamberlain 2006; de Groot and Yung 2008; 
Desjardins et al. 2008; Kang et al. 2008; Narayana et al. 2008; Poulsen et al. 2008; Sathornsumetee 
and Rich 2007; Vredenburgh et al. 2007; Vredenburgh et al. 2008; Zuniga et al. 2008).  In addition, 
the 6-month overall survival with bevacizumab and irinotecan was improved compared with 
temozolomide (current first line treatment): 77% versus 60% respectively.  Comparison of 
Bevacizumab and CPT-11 shows a 6-month PFS and median PFS in patients with GBM of 43% 
and 24 weeks, compared with previous results of 15% and 9 weeks, respectively (Bao et al. 2006; 
Folkins et al. 2007). The 1-year overall survival with bevacizumab was superior to historical 
controls: 37% versus 21%, respectively.  As a single agent, Bevacizumab achieved a 6-month PFS 
rate of 42.6% as salvage therapy for recurrent gliomas (Beal et al, 2011). Bevacizumab is also 
being studied in conjunction with standard chemo-radiation for newly diagnosed tumors (Arko et 
al, 2010; Leibross et al, 2009).  Two recent trials performed in parallel were done to assess the 
efficacy of IV bevacizumab (Avastin) for newly diagnosed glioblastoma.  One by the RTOG 
(RTOG 0825) in the United States, and one by Roche (AVAGlio), mostly in Europe.  Results were 
presented at the 2013 American Society of Clinical Oncology.  The results showed a significantly 
prolonged progression free survival in both studies and quality of life was preserved in the 
AVAGlio trial but not the RTOG.  Overall survival was not improved, but safety and tolerability 
were acceptable in both studies.  Although the overall survival studies do not support the routine 
use of IV bevacizumab, our trial examining less frequent intra-arterial dose delivery may improve 
both PFS and OS by limiting the resistance or escape from VEGF inhibition that appears after 
prolonged IV bevacizumab chemotherapy. 
 
In conclusion, the use of bevacizumab is strikingly active against recurrent GBM. The standard 
delivery has been IV, but we have had success in our current studies delivering the drug 
intraarterially to patients with recurrent disease, in theory giving them treatment directly to the 


 
- 11 - 
Version: 12/26/18 
tumor, with fewer systemic side effects.  We hypothesize that in patients with newly diagnosed 
GBM, superselective intraarterial cerebral infusion of Bevacizumab, up to a dose of 15 mg/kg, will 
be safe and efficacious and prevent tumor progression in patients. 
 
Clinical Experience with the Individual Chemotherapy Agents 
 
Mannitol:  Intraarterial infusion of Mannitol (20%; delivered IA, 12.5 mL over 2 minutes) in order 
to achieve osmotic disruption of the cerebral circulation has been well described. (Neuwelt et al. 
1999)  Neuwelt et al. performed 3498 BBB disruption procedures of the internal carotid artery 
using the same dose in conjunction with alkylating agent chemotherapy infusions in 405 patients.  
There was no associated risk of intracerebral hemorrhage, seizure or stroke.   We have shown in 
our experience that there was no adverse effect of SIACI of Mannitol. 
 
Bevacizumab:   The current standard of care for recurring relapsing GBM is combination or 
monotherapy IV Bevacizumab chemotherapy.  The currently used intravenous dose of 
Bevacizumab chemotherapy is 10mg/kg IV. In a recent trial of hepatocellular carcinoma, patients 
with locally advanced disease were treated with transcatheter arterial injection of Bevacizumab at a 
dose of 5 mg/kg given via superselective catheter.  There was no toxicity associated with 
intraarterial administration of Bevacizumab.   In our Phase I clinical trial, we found no adverse 
effects of IA therapy with Bevacizumab up to 15mg/kg.   
 
 
Rationale for the dosing schedule: The proposed research trial design utilizes the addition of 
multiple intracranial superselective intraarterial chemotherapy infusions of Bevacizumab at 
diagnosis and combining this treatment with the standard chemoradiation.  
 
Choice of Starting the Dose Used in this Study Regimen:  The standard IV dose of Bevacizumab 
for GBM is 10mg/kg.  The dose for non-small cell lung cancer is 15mg/kg IV.  We have tested the 
Phase I safety SIACI up to15mg/kg. The dose-limiting toxicity of this dose is grade 2 or worse 
CNS hemorrhage or Grade 3 or worse non-hematologic toxicity which would be unexpected given 
the superselective nature of the intraarterial delivery.  
 
  
Cerebral Angiography 
The basic concept of cerebral angiography involves the navigation of a catheter up through the 
vasculature to the aortic arch.  A typical four vessel angiogram studies the major vessels that supply 
the cerebral circulation either originate from the arch directly or from major tributaries that arise 
from the arch.  These vessels include the Inominate Artery and Subclavian Arteries.  Angiography 
begins with arterial access.  By convention this usually involves the puncture and cannulation of 
the right femoral artery using the Seldinger technique.  Local anesthetic is applied to the femoral 
skin and a single wall puncture needle is used to access the artery.  Once the artery is entered then a 
wire is passed through the puncture needle into the artery and the needle is exchanged for an 
introducer sheath.  The original wire is then removed.  The introducer sheath is connected to a 
continuous heparinized saline flush.  This introducer sheath then becomes the portal of entry for the 
diagnostic catheter.  Under direct visualization of fluoroscopy, the diagnostic angiography catheter 
is then passed through the introducer sheath up the femoral artery, iliac artery and into the 
descending aorta with the use of a guide wire.  This guide wire is later used to access the cerebral 


 
- 12 - 
Version: 12/26/18 
vasculature.  The catheter and wire are then advanced together from the descending aorta to the 
thoracic aorta and into the aortic arch.  Once in the arch the catheter wire combination are used to 
cannulate the Inominate artery.  The Inominate artery gives rise to the right Common Carotid artery 
and the right Subclavian artery.  The right vertebral artery usually has its origin from the proximal 
right Subclavian artery.  The guide wire is advanced into the right Common Carotid artery and 
diagnostic catheter is then advanced over it.  The wire is then removed and an angiographic image 
is obtained of the carotid bifurcation.  The wire is then re-introduced and either the external or 
internal carotid artery is then accessed.  For the intracranial circulation, a roadmap, an image 
generated by injecting contrast and allowing software to subtract out bone, is generated and the 
guide wire is advanced into the internal carotid artery.  With the catheter in the internal carotid 
artery, a cerebral angiogram is performed over the cranium in AP and Lateral views.  The same 
procedure is repeated on the left side of the cerebral circulation, with the catheter first being placed 
in the internal carotid artery.  The vertebral arteries are also selectively cannulated and images of 
the posterior cerebral circulation are obtained.  Decisions regarding which vessels to study will be 
determined by the angiographers and will be limited to the vessels felt to be supplying the tumor.  
 
 
Super-selective Angiography 
Most endovascular interventions begin with super-selective catheterization of a specific vessel.  
Prior to this the patient is given a Heparin bolus to obtain an automated coagulation time of 
approximately three times baseline (Usually 50 units/kg).  Next, the diagnostic catheter is 
exchanged for a guiding catheter.  A guiding catheter is stiffer and will provide more support to a 
micro catheter necessary for super selective catheterization. A new roadmap image is generated and 
now the micro catheter is introduced with a micro-guide wire.  The specific vessel leading to the 
specific pathology is identified and the micro-guide wire is advanced into this vessel.  The micro-
catheter is then subsequently advanced over this micro-guide wire and the guide wire is removed.  
A super-selective angiogram is then performed by injecting contrast through the micro catheter to 
confirm that it is in the desired vessel, in this case meaning the vessel supplying the territory 
containing the brain tumor (see Figure 1).  Even more super selective catheterization can be 
performed in order to localize the lesion more specifically. Once the desired catheter position has 
been achieved, the infusion of Mannitol and Bevacizumab will be performed over the specified 
time course.  On the completion of the infusion, the micro catheter is removed and an angiogram is 
performed from the guiding catheter to check the cerebral circulation before the catheter and 
introducer sheath are removed.  The guiding catheter is removed and homeostasis is achieved at the 
femoral artery with either manual compression or the use of an arterial closure device.  
 
 
Figure 1.  
Superselective Intracranial Angiography.  Fig. 1. Patient Response to IA Mannitol and 
Bevacizumab: MRI images of patient 1 who underwent SIACI of unlabeled Avastin for recurrent 
GBM.  A.  Sagittal post contrast MRI showing tumor recurrence (yellow arrow).  B.  
Superselective Microcatheter delivery (yellow arrow) in relation to the craniotomy site with visible 
miniplates.  C.  Contrast injection into the superselective catheter (yellow arrow) supplying the 
tumor.  D. Sagittal, coronal and axial post contrast images prior to a single dose of Intraarterial 
Avastin (2mg/kg).  E. The same images of the tumor 3-weeks after a single superselective 
intraarterial intracerebral injection (SIACI) showing diminished enhancement of gadolinium in the 
tumor suggesting tumor response.   


 
- 13 - 
Version: 12/26/18 
 
 
 
 
 
5. RISK/BENEFIT OF THE STUDY  
 
Data generated from clinical trials using IV Bevacizumab indicate both safety and efficacy of this 
drug.  Available preclinical and clinical data demonstrate the safety and activity of intraarterial 
Bevacizumab in other solid cancer models.  We will be able to follow prospectively patients who 
receive IA Bevacizumab and with standard chemoradiation to better understand the safety and 
ultimate efficacy of this regimen in patients with newly diagnosed glioblastoma.     
 
Intraarterial Bevacizumab use is most likely to result in the following toxicities: CNS hemorrhage 
(3%) thromboemboloic event (11%), proteinuria (6%), and fatigue (11%).  We have not reported any 
toxicities with superselective intraarterial Avastin infusion.[11]   
    
This treatment would likely be harmful to a gestating embryo or fetus, if pregnancy were to occur.  
Women of childbearing potential and fertile men will be informed as to the potential risk of 


 
- 14 - 
Version: 12/26/18 
procreation while participating in this research trial and will be advised that they must use effective 
contraception during the treatment period.  A pregnancy test will be performed on each 
premenopausal female of childbearing potential immediately prior to entry into the research study.  
 
There may be unknown or unanticipated discomforts or risks in addition to those specified above.  
CNS hemorrhage may lead to death.  Because some of these procedures are relatively new and are 
attempts to advance medical knowledge, however, every precaution will be taken to assure the 
patients’ personal safety and to minimize discomfort.  In addition, risks of carotid and cerebral 
angiography apply to these patients.  These include but are not limited to infection, bleeding, stroke, 
death, vessel injury, groin hematoma and retroperitoneal hematoma.  Recent data indicates that the 
risk of cerebral angiography is less than 1%.  
 
Individual patients may benefit by having a decreased risk of recurrence of brain tumor.  They may 
also live longer. Alternatively, there may be no benefit to the patient’s participation in this research 
study.  Society will benefit if an effective first-line therapy is identified for an illness which attacks 
mainly middle-aged, productive individuals.   
 
 
6. OBJECTIVES 
 
6.1  
Primary study endpoint:   
The primary endpoint will be the 6-month composite overall response rate (CORR).  We 
will determine this composite overall response rate (CORR) through the Response 
Assessment in Neuro-Oncology (RANO) criteria at 6 months (Appendix E), which accounts 
for treatment response as a composite of MRI changes, clinical response and changes in 
steroid use. We will define “evaluable” patients as patients who met eligibility 
requirements, have initiated therapy, and were not removed from the study for non-
compliance or patient withdrawal within the first 6 months. 
 
6.2  
 Primary objective: 
In addition to the 6 month CORR, we will assess the 6-month progression-free survival 
(PFS) and overall survival (OS) by Kaplan-Meier survival analysis, assuming adequate 
follow-up time.  PFS will be measured from the date of the first dose of SIACI 
Bevacizumab to the date of progression.  OS will be measured from the date of the first 
dose of SIACI Bevacizumab to the date of death.  A two-year follow-up time is expected to 
determine the safety of repeated superselective intracranial intraarterial infusions of 
Bevacizumab at a dose of 15 mg/kg IA.   
 
 
6.3 
 Secondary objectives: 
The safety of repeated SIACI of mannitol and Bevacizumab at 15mg/kg, coupled with 
chemoradiotherapy will be assessed.  The descriptive frequency of subjects experiencing 
toxicities will also be tabulated.  Toxicities will be assessed and graded according to the 
NCI Common Toxicity Criteria, version 3.0.   
 
 


 
- 15 - 
Version: 12/26/18 
7. PATIENT SELECTION 
 
 
7.1   Criteria for Inclusion: 
 
 Male or female patients of 18 years of age. 
 
 Patients with  documented histologic diagnosis of glioblastoma multiforme (newly 
diagnosed) 
 
 Patients must have at least one confirmed and evaluable tumor site.  
*A confirmed tumor site is one which is biopsy-proven.  NOTE: Radiographic 
procedures (e.g., Gd-enhanced MRI or CT scans) documenting existing lesions must 
have been performed within three weeks of treatment on this research study. 
 
 Patients must have a Karnofsky performance status 70% (or the equivalent ECOG 
level of 0-2) (see Appendix A; Performance Status Evaluation) and an expected 
survival of  three months. 
 
 Patients must agree to use a medically effective method of contraception during and for 
a period of three months after the treatment period.  A pregnancy test will be performed 
on each premenopausal female of childbearing potential immediately prior to entry into 
the research study.   
 
 
7.2   Criteria for Exclusion: 
 Previous treatment with Bevacizumab. 
 
 Women who are pregnant or lactating.   
 
 Women of childbearing potential and fertile men who decline to use effective 
contraception during and for a period of three months after the treatment period. 
 
 Patients with significant intercurrent medical or psychiatric conditions that would 
place them at increased risk or affect their ability to receive or comply with 
treatment or post-treatment clinical monitoring.   
 
 
8. TEST AGENT PREPARATION AND ADMINISTRATION 
 
8.1          Supplies of research study agent 
 
 
    Bevacizumab (Pharmacy) 
 
 
 
 
 
 
         8.2        Preparation of the research study agent 
 


 
- 16 - 
Version: 12/26/18 
           1. Bevacizumab 
 
Chemical name:  Bevacizumab 
Storage: Store vials at 2 degrees to 8 degrees C.   
Stability:  Protect from light, do not freeze or shake.    Do not mix with dextrose-
containing solutions.  Diluted solutions are stable for up to 8 hours under 
refrigeration 
 
                        Half life: 20 days (range: 11-50 days) 
Excretion: 2.75-5ml/kg/day 
 
8.3        Doses of Research Study Agent:  
 
Bevacizumab: The dose for IA  Bevacizumab will be 15mg/kg  
 
 
8.4        Route of Administration  
 
 Bevacizumab will be given intracerebrally by superselective intraarterial infusion 
(SIACI).    
 
8.5 Dosing Procedure 
 
The doses and schedule of treatment for all of the drugs to be used in the research 
study are given above. This is an outpatient regimen, in which the drug is administered 
IA.  Tumor response will be assessed after every 2 months with new MRI, which is 
standard of care for patients with GBM, or sooner at the PI’s discretion. 
 
1. Dose Interruption or Discontinuation: 
If an unacceptable toxicity is experienced during any portion of a patient’s 
infusion, the investigator will follow the procedures outlined (see Section VII.B; 
Management of Toxicity; Dose Interruption or Discontinuation). 
 
 
9. EXPERIMENTAL PLAN 
 
9.1 
Control Methods 
 
There may be multiple research study sites, but no activation of additional sites may 
occur until there is IRB approval at those sites and either institutional agreements 
are obtained between The Feinstein Institute for Medical Research and these sites or 
until site-specific agreements with the drug suppliers are executed. 
 
This is an open-label research trial, non-randomized phase I/II clinical research trial.   
 
 
 


 
- 17 - 
Version: 12/26/18 
9.2 
Duration of this Research Trial 
 
To complete the trial approximately 23 patients will be required.  The Feinstein 
Institute for Medical Research will be employed for this research study.  Overall, it is 
anticipated that accrual to complete the study will be 12-18 months.   
  
            9.3     Statistical Considerations: Trial Design/Sample Size 
 
For the current standard of care treatment with the Stupp protocol, we estimate that 
the probability of a Composite Overall Response Rate response (CORR) at 6 months 
is 60%. Therefore we estimate that a 6-month CORR of at least 85% with 
intraarterial bevacizumab would be clinically meaningful and worthy of further 
study.  
 
A Simon two-stage “optimal” design (Simon, 1989) will be used whereby 9 patients 
would be treated in the first stage. If, amongst these 9 patients, there are 6 or fewer 
responders, then the study will be terminated. Conversely, if there are 7 or more 
responders amongst these initial 9 patients, then the study will enroll 14 additional 
patients for a total of 23 patients. If 18 or more out of the 23 patients respond, then 
the new treatment will be considered effective and a candidate for further larger 
clinical trials.  
 
This design corresponds to testing the null hypothesis that the true objective 
response rate is 60% or less versus the alternative hypothesis that the true response 
rate is 85% or greater, with alpha = 0.05 and power = 0.80. 
 
 
 
9.4      Accrual Rate 
 
The planned sample size is 23 subjects. Assuming that 10% of patients are 
unevaluable or ineligible, we anticipate that a total of 25 patients will be enrolled in 
the study.  Accrual is expected at a rate of 2-3 subjects per month. 
 
 
10. PATIENT ENTRY AND TIME ON RESEARCH STUDY 
 
10.1 
 Enrollment Process 
 
Once a patient is identified as meeting the research study eligibility criteria, the patient 
will be asked to make an appointment with the PI to discuss treatment options.  
 
The clinical coordinator and PI will maintain a Patient Log in order to ensure 
compliance with the entry criteria.  In order to complete this log and confirm patient 
eligibility, the following will be documented: 
 
· 
Patient initials, sex, age, Karnofsky Performance Status. 


 
- 18 - 
Version: 12/26/18 
· 
Underlying diagnosis. 
· 
Copies of operative and pathology reports. 
· 
Copies of relevant lab reports.  
· 
Copies of imaging reports documenting the location and extent of disease. The 
Sponsor may request copies of films. 
· 
Confirmation of compliance with all inclusion/exclusion criteria. 
 
10.2 
     Assignment of Patient Identification 
 
Patients meeting the research study entry criteria will be assigned patient 
identification code as they enter the research study. Patient identification numbers 
will be assigned in chronological order.   
 
Information regarding patient identification, as well as the amount of medication 
given to the subject, will be recorded in a research binder, as well as in the CRFs. 
 
10.3 
    Inpatient / Outpatient Requirements 
 
Patients will be treated on an outpatient basis.  
 
Patients will be followed routinely by their private physician and oncologist as 
necessary, but must be evaluated by the investigative site one month after the IA 
procedure, and as clinically indicated. 
 
10.4         End of Research study 
 
All patients will be monitored for tumor response (by MRI scanning) and toxicity 
(by physical examination and blood tests) for the duration of bevacizumab 
therapy.   
      
10.5 
   Follow-up Monitoring for Response and Safety   
 
Patients in the phase I/II study, will be closely monitored for dermatologic and 
respiratory toxicity.  The primary observation period after IA therapy will be 28 
days.  After the 28 day period, the patient will continue the oral Temozolomide 
regimen.  Thereafter, toxicities will be monitored by history, physical examination 
and blood tests, as outlined in Table 1 below.  Tumor response assessment by MRI 
will be performed after every 2 cycles of treatment with Temozolomide using the 
RANO Response Criteria, sooner if deemed necessary by the PI.   
 
11. TREATMENT PLAN 
 
Superselective intraarterial Dose of Bevacizumab will be given at a dose of 15mg/kg 
IA after recovery from surgical resection, usually 4 weeks after craniotomy and tumor 
resection, and 2 weeks after biopsy, then every 90 days until three doses have been 
given. The patient will start chemoradiation concurrently. 
 


 
- 19 - 
Version: 12/26/18 
12. SUPPORTIVE PRODUCTS/CONCOMITANT MEDICATIONS 
 
All medications and all concomitant therapy administration during the research study 
with the reasons for therapy use will be recorded in the data collection form. Surgery 
will also be recorded.  For all subsequent visits, all concomitant therapy, which is 
continuing or has been added, discontinued or had a dosage change since the 
previous visit will be recorded. All patients should be maintained on the same 
medications throughout the research study period, as medically feasible. 
 
1. 
Antiemetic medications: The specific post-treatment antiemetic therapy will be left to 
the investigators discretion, but the use of dexamethasone or any other steroids as 
antiemetics should avoided. Dose and frequency of usage for antiemetic therapy 
administered to treat patients receiving the research study drug will be recorded in the 
data collection form. For all subsequent visits, all concomitant therapy, which is 
continuing or has been added, discontinued or had dosage changed since the previous 
visit must be recorded. 
 
2. 
Platelets: Platelet transfusions should be given to all patients if platelets are below 
25,000/mm3, and/or at the investigators discretion if any signs of bleeding occur. 
 
3. 
Use of growth factors:  The use of growth factors is permitted at the clinician’s 
discretion. 
 
4. 
Corticosteroids: A reasonable dose of corticosteroid (e.g., dexamethasone) will be 
determined on clinical grounds for each patient if needed to alleviate increased 
intracranial pressure.   An effort will be made to keep the patient on this steroid dose 
until the next scan is obtained. Changing steroid doses may complicate the 
interpretation of tumor response.  Corticosteroid doses can be tapered as clinically 
indicated if the patient appears to be responding to therapy, as judged by serial scans, 
and neurological examination.  Patients on steroids will receive prophylaxis for PCP 
pneumonia with Bactrim, unless they have a history of allergy to sulfa drugs. 
 
 
13. PARAMETERS TO BE MEASURED 
 
All patients enrolled in this will be evaluated according to the procedures described 
in Sections A, B and C below.  All screening studies are to be performed 4 weeks 
prior to research study entry and, as noted below, some tests will be repeated within 
two weeks prior to initiation of treatment.  Patients will be assessed for the presence 
of measurable disease and tumor response by MRI of the brain with and without 
contrast.  A tumor response assessment (RANO Response Criteria) will be performed 
within 2 weeks of completion of every 2nd cycle of treatment of maintenance 
Temozolomide, sooner if deemed necessary by the PI. Stable disease or better is 
required for patients to remain on research study. 
 
             


 
- 20 - 
Version: 12/26/18 
13.1  Safety Assessments 
 
  
All evaluations should be performed on or about the indicated research study day.  
 
1. Assessment of Patient Eligibility and Signing of Informed Consent 
 
· 
Screening/Baseline: All patients must meet all inclusion criteria and not have 
any exclusion criteria to be eligible for the research study.  All patients must 
sign an informed consent prior to enrollment, and prior to submitting to any 
research protocol-related procedure, unless such testing was performed as part 
of the routine clinical diagnosis or management of the patient. 
 
2. Medical History (complete history at screening, including primary and secondary 
diagnoses; updates at the indicated times thereafter) 
 
3. Disease Confirmation  
 
· 
Screening/Baseline: This needs to include a pathology report as well as reports 
from imaging studies (particularly MRI scans) to confirm that there is at least 
one measurable target or index lesion. If there is only one target lesion, it will 
be required that it show progression or be documented by biopsy.  When 
possible, biopsy tissue will be sent to neuropathology for evaluation of tumor 
mutations such as VEGF over expression.     
 
4. Performance Status Evaluation, Karnofsky or ECOG (see Appendix A) 
 
· 
Screening/Baseline 
· 
Prior to the start of research protocol treatment (within 1-2 weeks) 
· 
Monthly (i.e., after every cycle) assessments will be made.   
· 
Every 6 months thereafter for ongoing stable disease or better. 
· 
For patients who need to go off research study, a final determination will be 
done.  
 
5. Vital Signs (to include: body temperature, pulse rate, blood pressure, and 
respiration rate) 
 
· 
Screening/Baseline 
· 
In conjunction with the Physical Examination 
· 
As clinically indicated 
 
6. Physical Examination (complete at screening, including height and weight; 
thereafter complete excluding height) 
 
· 
Screening/Baseline: This will be performed within 1-2 weeks of initiation of 
treatment.  It will be repeated every cycle and then every 3 months thereafter 
as specified in Table 1.   
 


 
- 21 - 
Version: 12/26/18 
7. Hematology (to include CBC with differential and platelet count) 
 
· 
Baseline PT and PTT levels as well as complete CBC within 1-2 weeks of 
initiation of treatment. 
· 
Thereafter, at the time of the monitoring Physical Examinations. 
· 
As clinically indicated. 
· 
Upon early departure from the research study  
 
8. Serum Chemistries (to include: Na, K, Cl, Ca, bicarbonate, BUN, creatinine, 
glucose, bilirubin, AST, ALT, alkaline phosphatase, LDH, albumin, total protein)  
 
· 
Screening/Baseline: this must be within 2 weeks of enrollment on research 
study. 
· 
Thereafter, at the time of the monitoring Physical Examinations, if deemed 
necessary by the PI.  (see Table 1).   
· 
As clinically indicated 
· 
Upon early departure from the research study 
  
9. Pregnancy Test  (urine or serum; in pre-menopausal, non-sterilized females) 
 
· 
Screening/Baseline (negative result must be documented on CRF)  
· 
As clinically indicated 
 
10. Respiratory ( Chest x-ray) 
 Screening/Baseline (within 4 weeks prior to procedure) 
 As clinically indicated 
 
 
 
 
13.2 
Disease/Tumor Assessment  
  
1. 
MRI (contrast-enhanced) for Lesion Measurements (i.e., brain) and a response 
assessment through RANO criteria 
 
 Screening/Baseline (within 3 weeks prior to research study entry). 
 
 Response will be assessed after every other cycle of the research protocol or sooner if 
deemed necessary by the PI, with a contrast-enhanced MRI and response assessment 
through RANO criteria.  
 
Contrast-enhanced MRI will be considered the standard method for evaluating tumor 
involvement.  The location and dimensions of “target” (or “index”) lesions, as well as 
other measurable lesions, will be documented on the patient’s CRF.  Lesion 
dimensions will also be recorded.  MRI imaging must, whenever possible, use the 
same “cuts” for all follow-up imaging studies to assure accuracy of the data collected.  
For all objective responses the duration of the response will be determined, from the 


 
- 22 - 
Version: 12/26/18 
day the initial response is observed (using baseline images for comparison) to the time 
that progression is observed.  
 
 
 
14. OVERVIEW OF SCHEDULED PROCEDURES 
 
Table 1: 
 
Protocol Activity 
Screening and 
Enrollment 
Prior to IA 
Procedure 
IA Procedure 
(Day 301, 120, 
and 210 post 
surgery) 
1 Month After 
Procedure 
Every 2 
Months 
Informed consent 
X 
 
 
 
 
Confirm 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Physical/Neurological 
Exam 
X 
 
 
X 
 
Vital signs 
X 
 
 
X 
 
KPS  
X 
 
 
X 
 
Hematology  
 
X2 
 
X 
 
Blood chemistry 
 
X2 
 
X 
 
Pregnancy test 
 
X2 
 
 
 
IA Administration of 
Mannitol and 
Bevacizumab 
 
 
X 
 
 
ECG 
 
X3 
 
 
 
Brain MRI  
 
X2 
 
 
X 
Chest X-Ray 
 
X3 
 
 
 
CT Scan  
 
X4 
 
 
 
 
Bodily Fluid 
Amount 
Frequency 
Total 
 
Blood 
4 tbsp 
12 
48tbsp 
 
Urine 
15-20 mL 
Once, then as 
needed 
20 mL or 
more 
 
Other_______
__ 
 
 
 
 
 
 
                                                 
1 May be done at 2 weeks for biopsy subjects with well healed incisions 
2 Within 2 weeks of IA procedure 
3 Within 4 weeks of IA procedure 
4 If clinically needed 


 
- 23 - 
Version: 12/26/18 
15. TOXICITY OF INVESTIGATIONAL DRUG 
 
To date, at least 10,000 cancer patients have received bevacizumab at a dose ranging from 3mg/kg 
up to 20mg/kg IV every two weeks in previous clinical trials.  Bevacizumab is used in Colorectal, 
breast, head and neck, brain, prostate, and renal cancer 
Adverse events associated with IV bevacizumab administration reported in two recent clinical trials 
include hypertension, pain, headache, dizziness, alopecia, nausea/vomiting, stomatitis, fatigue, and 
thromboembolism.   We do not anticipate any problems with intraarterial thrombosis at the catheter 
insertion site with bevacizumab and have not seen that to date in our patients.  We are also aware of 
the sensitivity to endotoxin when it is delivered intrathecally, particularly at the highest product 
dose levels.  Therefore, we will be alert to any Adverse Events that might be attributable to 
endotoxin exposure at the highest bevacizumab product dose levels.   
 
16. MANAGEMENT OF TOXICITY 
 
Careful assessment of toxicity experienced by the patient will be carried out throughout the course 
of this research study.  Grades of toxicity (Modified NCI Common Toxicity Criteria 3.0) will be 
utilized as the criteria to determine appropriate management of the patient with respect to research 
study status. 
 
All clinical adverse experiences, whether observed by the investigator, or observed or experienced 
by the patient, will be reported.  Any significant change from baseline in a laboratory parameter will 
be reported to the Sponsor and will be documented.  All treatment-emergent clinical and laboratory 
adverse events must be carefully evaluated for severity (see Appendix B; mild, moderate, severe, 
life-threatening), duration, and relationship to research protocol treatment (see Appendix C; 
unrelated, remote, possible, probable, related).  Such information will be documented on the 
appropriate page of the patient’s CRF. 
 
The investigator, co-investigator, or designated health professional must be present at the time of 
scheduled patient visits for follow-up monitoring and should also to evaluate whether compliance 
with the research protocol is being maintained.  If, at any point during the research study, significant 
changes occur in either the patient’s clinical status or laboratory parameters, such changes will be 
followed until the parameter either returns to baseline or is adequately explained. 
 
Clinical experience, thus far, indicates that adverse experiences (AEs) related to the use of 
bevacizumab are mostly cardiovascular (hypertension), and GI (acute nausea and vomiting).  Other 
AEs that may occur but are less common in association with the administration of this agent is: 
neurotoxicity (including headache), diarrhea, anorexia and fatigue.  These AEs are generally mild to 
moderate, reversible and/or manageable with symptomatic treatment, dose delays or reductions.   In 
our experience with IA Bevacizumab, we have not seen any significant AE’s related to the route of 
administration 
 
16.1  Dose Modification  
Toxicity grading is based on NCI-CTCAE, v 3.0.  


 
- 24 - 
Version: 12/26/18 
Table 2 
Dosage Modification Criteria and Guidelines for Management  
of Bevacizumab -Related Toxicities 
NCI-CTCAE (v 3.0) Grade 
Bevacizumab Dose Modification 
Guideline for Management 
Diarrhea 
Grade 1 
None 
Consider Loperamide (4 mg at first 
onset, followed by 2 mg q 2–4 
hours until free of diarrhea for 12 
hours) 
Grade 2 
None 
(Interrupt Bevacizumab if diarrhea 
persists over 48–72 hours despite 
optimal medical management) 
Loperamide (4 mg at first onset, 
followed by 2 mg q 2–4 hours until 
diarrhea free for 12 hours) 
Grade  3 
Interrupt bevacizumab.  
Bevacizumab should not be started. 
Interrupt bevacizumab until 
resolution to Grade 1, and restart 
at next reduced dose 
Grade 4 
Discontinue study treatment. 
 
Pulmonary Events  
All Grades 
Temporarily interrupt bevacizumab 
pending the diagnostic evaluation.  
If the pulmonary adverse event is 
assessed as related to Bevacizumab, 
discontinue the patient from study 
treatment. 
Unexplained dyspnea, either new 
or progressive, should be 
aggressively evaluated.   
Rash 
Tolerable rash 
None 
Any of the following:  minocycline 
a, topical tetracycline, topical 
clindamycin, topical silver 
sulfadiazine, diphenhydramine, 
oral prednisone (short course) at 
discretion of investigator 
Intolerable rash 
Consider interruption reduction if 
unresponsive to symptomatic 
management.  Re-escalation is 
allowed. 
Manage as described above 
Grade 4 
Discontinue study treatment. 
Manage as described above 
a Recommended dose:  200 mg po bid (loading dose) followed by 100 mg po bid for  
7–10 days. 
 
 
16.2 Dose Interruption: Any sign of acute allergic reaction to bevacizumab, depending upon the 
severity, may necessitate temporary interruption or permanent discontinuation of the 
offending agent. 
 
16.3  Removing Patients From Study 
 
Every effort will be made to keep the patient on research study; however, in the event 
that a patient is withdrawn from the research study, the investigator should document 
the reasons for withdrawal as thoroughly as possible.  This evaluation should include 


 
- 25 - 
Version: 12/26/18 
final observations, as required by the research protocol at the time of the patient’s 
withdrawal.  The reason(s) for early termination must be clearly documented on the 
appropriate page of the patient’s case report form (CRF).  A CRF must be completed 
for any patient who receives ANY amount of treatment on this research study.  
 
 
1. Criteria for Early Termination of Treatment under this Research Protocol: Patients meeting 
any of the following criteria will have participation in the research study discontinued: 
 
a. Significant deviation from the research protocol or eligibility criteria.  Such patients 
will be considered protocol violations and will be removed from research study. 
 
b. Patients who develop an intercurrent illness, which, in the opinion of the investigator, 
would prevent their safe completion of treatment or required research study-related 
evaluations. 
 
c. Patients who are non-compliant with the research study or follow-up procedures. 
 
d. Patients who withdraw consent and elect to terminate their participation in the 
research study. 
 
e. The occurrence of a grade 3 or greater coagulopathy. 
 
f. Progression of disease as documented by MRI scan after the 2nd cycle of the treatment 
regimen of this research protocol.  
 
g. Termination of the research study by the Sponsor. 
 
h. Any other reason, which, in the opinion of the investigator, would justify removing 
the patient from the research study.  In such a case, the investigator’s reason for a 
patient’s removal must be recorded on the patient’s CRF. 
 
2.   Replacements: Should a patient withdraw or need to be withdrawn from the research study  
prior to the second cycle of treatment, a replacement subject will be sought using the stipulated 
research protocol entry criteria.  Patients who have received 2 cycles of treatment and have 
completed toxicity and tumor response assessments, but have shown disease progression, will be 
not be eligible to receive additional treatment under this research protocol, but will be considered 
evaluable and will not be replaced by additional patients. 
 
 
17. ADVERSE EXPERIENCES 
 
17.1 Definition: An adverse experience (AE) is any undesirable, noxious, or pathological 
change, compared to pre-existing conditions, that occurs to a subject during a clinical research 
study or the follow-up period, whether or not it is considered to be related to the test drug.  
Adverse experiences include: 
 
· 
Suspected adverse drug reactions. 


 
- 26 - 
Version: 12/26/18 
· 
Reactions from drug overdose, abuse, withdrawal, sensitivity, or toxicity. 
· 
Significant changes or abnormalities, when compared to baseline, in structure 
(sign), function (symptom), clinical laboratory results, or physiological testing.  
This includes any worsening of a pre-existing condition temporally associated 
with the use of research study medication. 
· 
Other medical events, regardless of their relationship to the test drug, such as 
injury, surgery, accidents, extensions of symptomatology, or apparently unrelated 
illnesses. 
 
17.2    Evaluation: The investigator will determine the seriousness, intensity, and causality of 
an adverse experience associated with the use of the test medication (i.e., experiences 
where there is a reasonable possibility that the experience may have been caused by the 
test medication) based on the following definitions: 
 
 
 
 
1. Serious Adverse Experiences (notify Sponsor if adverse experience is both 
serious and unexpected within 24 hours [see below]; document on CRF) 
 
THE DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) IS ANY OF 
THE FOLLOWING: 
 
 ANY DEATH THAT OCCURS WHILE THE PATIENT IS ENROLLED 
IN THE STUDY INCLUDING THE FOLLOW-UP PERIOD OR WITHIN 
30 DAYS OF COMPLETING THE STUDY. 
 IMMEDIATELY LIFE-THREATENING ADVERSE EVENT. 
 REQUIRES INPATIENT HOSPITALIZATION. 
 PROLONGATION OF AN EXISTING HOSPITALIZATION. 
 CONGENITAL ANOMALY/BIRTH DEFECT 
 MEDICALLY IMPORTANT EVENT*  
 DISABILITY/INCAPACITY (PERSISTENT OR SIGNIFICANT) 
  
*Medically important events that may not result in death, be live-threatening or require 
hospitalization, may be considered a serious adverse experience when, based upon 
appropriate medical judgment, the experience may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in the definition. 
 
2. Unexpected Adverse Experience  
An unexpected adverse experience is any adverse drug experience, the 
specificity or severity of which is not consistent with those noted in the current 
research protocol and/or Investigator’s Brochure.  This refers to any adverse drug 
experience that has not been previously observed, (e.g.,not included in the 
Investigator’s Brochure), rather than from the perspective of such an experience 
not being anticipated from the pharmacologic properties of the product.  
 
3. Non-serious Adverse Experiences  
 


 
- 27 - 
Version: 12/26/18 
All other adverse experiences, not fulfilling the previous definitions, are classified 
as non-serious. 
 
17.3    Documenting Adverse Experiences: All adverse experiences (including SAEs) are 
to be accurately recorded on the Adverse Experience page of the patient’s CRF.  Each 
experience will be graded on a four-point scale (see Appendix B; mild, moderate, 
severe, life-threatening) as to severity.  The date of onset as well as the duration of 
the experience will be recorded.  In addition, the method used to treat the adverse 
experience and the outcome of the adverse experience will also be noted.  The 
investigator will attempt to assess the relationship of the experience (unrelated, 
remote, possible, probable, related) to the test drug. 
 
           17.4      Reporting SAEs, Unexpected Adverse Experiences, and Patient Deaths 
 
1. All  SAE’s will be reported according the Northwell Health policy.  
 
 
      
 
       
  
2. Information to be Provided by the Investigator 
 
Initial Information: At the time of the initial contact(s), the investigator must 
transmit information to the Sponsor or designee for completion of a Safety Report.  
The Sponsor or designee will require that all of the following information about 
the patient and the adverse experience: 
 
· 
Patient identification code, sex, age or date of birth 
· 
Height, weight or body surface area (where required for dose calculation) 
· 
Underlying diagnosis and extent of disease 
· 
Dose and frequency of test medications administered 
· 
Dates of test medication administration 
· 
Description of event, including date of onset and duration 
· 
Date of death (if applicable) 
· 
Intervention(s) required 
· 
Concomitant therapy (including regimen(s) and indication) 
· 
Pertinent laboratory data/diagnostic test (including dates) 
· 
Pertinent medical history 
· 
Test medication status (dose interrupted, discontinued) 
· 
Did event abate after interruption of test medication administration (if 
applicable)? 
· 
Did event recur after test medication was reintroduced (if applicable)? 
 
 
In addition to the above information, the Sponsor will require the 
investigator’s assessment of the following: 
 
· 
Severity of the adverse experience 
· 
Relationship of the adverse experience to research study treatment 
· 
Outcome of the adverse experience 


 
- 28 - 
Version: 12/26/18 
 
 
 
 
 
E. Follow-up Information on an SAE: Appropriate diagnostic tests should be performed and 
therapeutic measures, if indicated, should be instituted.  Appropriate consultation and follow-
up evaluations should be carried out until the event has resolved or is otherwise explained.  
Follow-up data concerning the SAE (e.g., diagnostic test reports, physician's summaries, etc.) 
must also be submitted to the Sponsor, as they become available, preferably by telefax. 
 
            Review of an SAE: The PI will review each serious and unexpected adverse experience report 
and further evaluate the relationship of this adverse experience to test medications and to the 
patient’s underlying disease.  Based on this assessment, a decision will be made concerning 
the need for further action.  The primary consideration governing further action is whether 
new findings affect the safety of other patients participating in the clinical research study.  If 
the discovery of a new adverse experience related to test medication raises concern over the 
safety of its continued administration to patients, the PI will take immediate steps to notify 
the IRB and all investigators participating in clinical studies of the test drugs used in this 
research protocol 
 
 
Further action required may include any of the following:   
 
· 
Modification of the research protocol. 
· 
Discontinuation or suspension of the research study. 
· 
Alteration of the informed consent process by modification of the existing 
consent form and informing current research study participants of new 
findings. 
· 
Modification of previously identified expected adverse experiences lists to 
include adverse experiences newly identified as test medication-related. 
18. PRECAUTIONS 
 
18.1Precautions Regarding Procreation: Women of childbearing potential and fertile men 
will be informed as to the potential risk of procreation while participating in this research 
trial and will be advised that they must use effective contraception during the treatment 
period.  A pregnancy test will be performed on each premenopausal, female of 
childbearing potential immediately prior to entry into the research study.  A negative 
pregnancy test must be documented on the CRF prior to administration of the test 
material. 
 
18.2. Additional Precautions: Information regarding precautions and adverse experiences 
associated with this test medication can be found in the Scientific Background section 
of this document and in the package inserts for the individual research study 
medications. 
 
 
19. REGULATORY CONSIDERATIONS 
 
19.1   Conditions for Modifying or Terminating the Research Study 
 


 
- 29 - 
Version: 12/26/18 
1. Modifications 
 
In the event that modifications in the experimental design, dosages, parameters, 
patient selection, etc., are indicated or required, such changes will only be 
instituted following consultation between the Sponsor and investigator and will 
be accomplished through formal amendments to this research protocol and 
approval by the appropriate review committees, except where necessary to 
eliminate apparent hazards to patients. 
 
A modification to the research protocol will not be made without the express 
written approval of the Sponsor.  Any amendment prepared by the Sponsor will 
be implemented according to the Sponsor’s standard operation procedures and 
will be reported to the appropriate IRB(s), and made a formal component of the 
research protocol document. 
 
2. Termination 
 
Should the Sponsor and/or the investigator(s) discover conditions, during the 
course of the research study, that indicate it should be discontinued, an appropriate 
procedure for termination will be instituted.  The principal investigator is 
responsible for assuring continuing review and approval of the clinical research 
study.  The investigator must also promptly report all changes in the research 
activity and all unanticipated problems involving risk to the patients or others to 
his/her IRB.  If the research study remains in progress for more than one year, the 
investigator must obtain annual renewal and re-approval from the IRB.  
Documentation of renewal must be submitted to the Sponsor. 
 
19.2   Informed Consent 
 
A copy of the IRB-approved consent form document to be utilized during this research 
study will be maintained by the PI. 
 
Prior to entry into this research study, the purpose and nature of the research study 
and possible adverse effects must be explained to each patient in the presence of a 
witness.  It is the responsibility of the investigator to obtain written informed consent 
from each patient.  A copy of the signed informed consent document should then be 
given to the patient.  The original executed version must remain in the patient’s file 
and must be available for verification by a representative of the Sponsor. 


 
- 30 - 
Version: 12/26/18 
The study will rely on the Karnofsky Performance Scale and the discussion with the 
research team to assess the subject’s capacity to consent themselves into the study. 
This discussion will only be performed by clinicians experienced in determining 
capacity. In addition, the study will utilize a research review questionnaire in the 
consent form to assist in making this determination. Individuals that are deemed to 
have the ability to consent themselves will also be required to designate a research 
proxy to act on their behalf if it is determined that they later lose the capacity to make 
decisions about participation. In situations that a subject is deemed cognitively 
impaired, they may be enrolled into the study using a legally authorized representative 
or research proxy. The subject will then be asked to provide assent, as appropriate. 
 
19.3   Documents to be Submitted Prior to Study Initiation 
 
 
 
The following documents must be submitted prior to research study initiation: 
 
· 
Curriculum vitae of the principal investigator and each sub-investigator.  
Physician CVs should include medical license numbers. 
 
· 
Written, signed notification of IRB approval of the research protocol (copy). 
 
· 
Written, signed notification of the approval of the informed consent document to 
be utilized during the research study (copy). 
 
· 
The stamped/signed by IRB informed consent document to be utilized during the 
research study (copy). 
 
· 
Signed and dated Investigator Agreement; agreement appears as final page of the 
research protocol (original). 
 
 
20. INVESTIGATOR RESPONSIBILITIES  
 
20.1   Medical Supervision: Medical supervision for the conduct of this research protocol is the 
responsibility of the Principal Investigator.  The Principal Investigator may delegate certain day-
to-day activities to a sub-investigator, but retains overall responsibility for ensuring that the 
research study is conducted properly and in accordance with the design and intent herein.  The 
Principal Investigator is responsible for ensuring that drugs and devices are available for treating 
possible medical emergencies.  The Principal Investigator is responsible for ensuring that the 
research study is conducted according to sound medical practices. 
 
20.2    Confidentiality: The PI affirms that all research study results and information furnished by 
acquired by the Sponsor during the course of the research study will be maintained in strict 
confidence.  Such information, as well as data generated from this research study, may need to 
be communicated to the PI’s or sub-investigators’ review committees, under an appropriate 
understanding of confidentiality.  
 
20.3   Patient Exclusion Log: A record listing all patients considered for entry into the research 


 
- 31 - 
Version: 12/26/18 
study and subsequently excluded must be maintained by the PI and his department.  Patients 
excluded from the research study will have the reason for exclusion recorded on the Patient 
Exclusion Log. 
 
20.4   Recording and Processing of Data: Individual CRFs must be completed in black ink.  All 
data must be carefully completed to permit meaningful interpretation.  CRFs are designed for 
computer processing and analysis.  Corrections to entered data may be made by drawing a single 
line through the information to be corrected.  All such corrections must be initialed and dated.  
No correction fluid or obscuring tape may be utilized.  A completed CRF is required for every 
patient who received any amount of test medication.  CRFs must be signed by either the PI or 
his designee. 
  
20.5   Record Retention: Records from the research study must be retained by co-investigators until 
they can be retrieved by the PI or designee once the data from individual research study patients 
has been collected and CRFs completed.  
 
20.6  Laboratory Reports: Prior to initiation of this research study, the investigator must supply the 
PI or designee with the normal laboratory values for the laboratories to be utilized.  The 
corresponding laboratory certification number must also be noted.  Laboratory safety evaluations 
must be performed at the intervals specified.  If unexplained laboratory abnormalities occur, 
corroborative tests will be performed until the laboratory parameter has returned to normal 
and/or adequate explanation of the abnormality has been provided.  Copies of any additional 
records pertinent to the research study (e.g. laboratory data, radiological reports, patient chart 
summaries, autopsy reports) must be made available to the PI, if requested, with due precaution 
taken to ensure patient confidentiality. 
 
20.7  Monitoring: This research study will be monitored by representatives of the PI throughout its 
duration.  Monitoring will be in the form of personal visits with the investigator and his/her staff 
as well as any appropriate communications by telephone, telefax, or mail.  Every effort will be 
made to maintain the anonymity and confidentiality of patients during this clinical research 
study. In addition to the study’s stopping rules and routine medical assessments that are 
performed at each study visit, the Director of Clinical Research, Cardiovascular Division, 
Northwell Health, Christina Brennan, MD, will be serving as the study’s medical monitor. Dr. 
Brennan has vast clinical trial experience and extensive endovascular experience. She has the 
knowledge and expertise required to review the incoming data to determine if aspects of the 
study need to be changed or stopped. In addition, any unanticipated problems will be reported to 
the IRB and regulatory agencies as per their specific reporting requirements. Data will be 
reviewed after each dose limiting toxicity and any unanticipated adverse events.  In addition, the 
IND monitoring will be conducted by Alexis Demopolous, MD and Sherese Fralin, MSN, FNP 
in adherence to FDA regulations. 
 
 
21. PROTOCOL DEVIATIONS 
 
Departures from either the research protocol entry criteria or the experimental plan, as 
outlined herein, must be reported the principal investigator and the Office of the IRB as per 
their reporting requirements. Anticipated deviations should be submitted to the Principal 


 
- 32 - 
Version: 12/26/18 
Investigator and the IRB prior to its initiation so that a protocol exception may be granted. 
The investigator must contact the PI or designee to discuss the associated circumstances. The 
PI will decide as to the subject’s continued research protocol eligibility status. All research 
protocol deviations and the reasons for such deviations must be noted on the appropriate page 
of the subject’s CRF. 
 
22. ANALYSIS OF DATA 
Data Review During this Research study: All research study data are to be reviewed at regular 
meetings of the principal participants to monitor the progress of the project. 
 
 
23. REFERENCES 
1. 
Bokstein, F., S. Shpigel, and D.T. Blumenthal, Treatment with bevacizumab and 
irinotecan for recurrent high-grade glial tumors. Cancer, 2008. 112(10): p. 2267-73. 
2. 
Buie, L.W. and J. Valgus, Bevacizumab: a treatment option for recurrent glioblastoma 
multiforme. Ann Pharmacother, 2008. 42(10): p. 1486-90. 
3. 
Chamberlain, M.C., MRI in patients with high-grade gliomas treated with bevacizumab 
and chemotherapy. Neurology, 2006. 67(11): p. 2089; author reply 2089. 
4. 
de Groot, J.F. and W.K. Yung, Bevacizumab and irinotecan in the treatment of 
recurrent malignant gliomas. Cancer J, 2008. 14(5): p. 279-85. 
5. 
Desjardins, A., et al., Bevacizumab plus irinotecan in recurrent WHO grade 3 malignant 
gliomas. Clin Cancer Res, 2008. 14(21): p. 7068-73. 
6. 
Kang, T.Y., et al., Irinotecan and bevacizumab in progressive primary brain tumors, an 
evaluation of efficacy and safety. J Neurooncol, 2008. 89(1): p. 113-8. 
7. 
Narayana, A., et al., Feasibility of using bevacizumab with radiation therapy and 
temozolomide in newly diagnosed high-grade glioma. Int J Radiat Oncol Biol Phys, 
2008. 72(2): p. 383-9. 
8. 
Poulsen, H.S., et al., Bevacizumab plus irinotecan in the treatment patients with 
progressive recurrent malignant brain tumours. Acta Oncol, 2008: p. 1-7. 
9. 
Sathornsumetee, S. and J.N. Rich, Antiangiogenic therapy in malignant glioma: 
promise and challenge. Curr Pharm Des, 2007. 13(35): p. 3545-58. 
10. 
Vredenburgh, J.J., et al., Phase II trial of bevacizumab and irinotecan in recurrent 
malignant glioma. Clin Cancer Res, 2007. 13(4): p. 1253-9. 
11. 
Vredenburgh, J.J., et al., Experience with irinotecan for the treatment of malignant 
glioma. Neuro Oncol, 2008. 
12. 
Zuniga, R.M., et al., Efficacy, safety and patterns of response and recurrence in patients 
with recurrent high-grade gliomas treated with bevacizumab plus irinotecan. J 
Neurooncol, 2008. 
13. 
Folkins, C., et al., Anticancer therapies combining antiangiogenic and tumor cell 
cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. 
Cancer Res, 2007. 67(8): p. 3560-4. 
14. 
Bao, S., et al., Stem cell-like glioma cells promote tumor angiogenesis through vascular 
endothelial growth factor. Cancer Res, 2006. 66(16): p. 7843-8. 
15. 
Neuwelt, E.A., et al., Cerebrovascular Biology and the various neural barriers: 
challenges and future directions. Neurosurgery, 1999. 44(3): p. 604-8; discussion 608-9. 
16.  
Wong, E.T., et al., Bevacizumab for recurrent glioblastoma multiforme: a meta-analysis. 
J Natl Compr Canc Netw, 2011. 9(4): p. 403-7.  


 
- 33 - 
Version: 12/26/18 
17. 
Arko, L, et al., Experimental approaches for the tretament of malignant gliomas. 
Pharmacology and Therapeutics, 2010. 128: 1-36. 
18. 
Beal, Kathryn, et al., Antiangiogenic agents i the treatment of recurrent or newly 
diagnosed glioblastoma: Analysis of single-agent asnd combined modality approaches. 
Radiation Oncology 2011. 6:2. 
19. 
Liebross, R.H., et al., A feasibility trial of concurrent radiation, temozolomide, and 
bevacizumab followed by temozolomide and bevacizumab for resectable and unresectable 
glioblastoma multiforme of the brain. Int J Radiat Onc Biol Phys 75 (3, Supplement), 
S125.  
20. 
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ. 
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl 
J Med. Mar 10 2005;352(10):987-96 
21.  
Simon R. Optimal Two-Stage Design for Phase II Clinical Trials. Controlled Clinical 
Trials. 1989; 10:1-10  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. 
 
Superselective Intracranial Angiography.  The patient was a 30 year male with seizures.  MRI 
showed a contrast enhancing lesion in the left mesial temporal lobe (Figure 1A and B).  
Angiography showed a vascular lesion supplied by the anterior choroidal artery (Figure 1C).  
Superselective catheter angiography (yellow arrows Figure 1D and 1E) allowed selective delivery 
of contrast only in the distribution of the anterior choroidal artery.   


 
- 34 - 
Version: 12/26/18 
 
 
 


 
- 35 - 
Version: 12/26/18 
 
APPENDIX A 
 
 
Performance Status Evaluation 
 
 
Percent 
 
Karnofsky Performance Status 
Description 
 
Level 
 
ECOG* 
 
100 
 
Normal; no complaints, no evidence of 
disease 
 
0 
 
Normal Activity 
 
90 
 
Able to carry on normal activity; minor 
signs or symptoms of disease 
 
80 
 
Normal activity with effort; some signs 
or symptoms of disease 
 
1 
 
Symptoms but ambulatory 
 
70 
 
Cares for self; unable to carry on normal 
activity or do active work 
 
60 
 
Requires occasional assistance but is able 
to care for most needs 
 
2 
 
In bed < 50% of time 
 
50 
 
Requires considerable assistance and 
frequent medical care 
 
40 
 
Disabled; requires special care and 
assistance 
 
3 
 
In bed > 50 % of time 
 
30 
 
Severely disabled; hospitalization is 
indicated although death is not imminent 
 
20 
 
Very sick; hospitalization is necessary 
 
4 
 
100% bedridden 
 
10 
 
Moribund; fatal processes progressing 
rapidly 
 
Abstracted from: 
Karnofsky DA, et al., Cancer. 1948; 
1:634-656 
 
*ECOG 
Eastern Cooperative Oncology 
Group 
 


 
- 36 - 
Version: 12/26/18 
APPENDIX B 
 
Clinical Symptomatology and Adverse Experience Grading Scale 
 
 
 Mild:  Awareness of symptom, but, easily tolerated.  Usually transient requiring no special 
treatment; does not interfere with usual status or activities 
 
 Moderate: May be ameliorated by simple therapeutic measures; may interfere with usual 
activities 
 
 Severe: Incapacitating; unable to perform usual activities 
 
 
 
 Life-threatening:  Requires immediate intervention; need for emergency treatment 
 
 


 
- 37 - 
Version: 12/26/18 
APPENDIX C 
Clinical Adverse Experiences:  Determining Relationship to Test Drug 
 
 
Unrelated 
 
This category applies to those adverse experiences which, after careful medical 
consideration, are clearly felt to be due to extraneous causes (disease, environment, etc.) 
that are unrelated to the administration of test drug. 
 
 
Remote (must have first two) 
 
This category applies to those adverse experiences which, after careful medical 
consideration, are felt unlikely to be related to the administration of the test drug.  The 
relationship of an adverse experience to the test drug can be considered remote if: 
 
 It does not follow a reasonable temporal sequence from administration of 
the drug. 
 
 It could readily have been a result of the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to 
the patient. 
 It does not follow a known response pattern to the suspected drug. 
 
 It does not reappear or worsen when the drug is re-administered. 
 
 
Possible (must have first two) 
 
This category applies to those adverse experienceswhich, after careful medical 
consideration, are felt unlikely to be related to the administration of the test drug, but the 
possibility cannot be ruled out with certainty.  The relationship of an adverse experience to 
the test drug can be considered possible if: 
 
 It follows a reasonable temporal sequence from administration of the drug. 
 
 It could readily have been a result of the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to 
the patient. 
 It follows a known response pattern to the suspected drug. 
 
Probable (must have first three) 
 
This category applies to those adverse experiences which, after careful medical 
consideration, are felt with a high degree of certainty to be related to the administration of 


 
- 38 - 
Version: 12/26/18 
the test.  The relationship of an adverse experience to the test drug can be considered 
probable if: 
 
 It follows a reasonable temporal sequence from administration of the drug.  
 
 It could not be reasonably explained by the known characteristics of the 
patient’s clinical state, environmental or toxic factors, or other modes of 
therapy administered to the patient. 
 
 It disappears or decreases upon cessation of drug or reduction in dose*. 
 
 It follows a known response pattern to the suspected drug. 
 
 
Related (must have first three) 
 
This category applies to those adverse experiences, which, after careful medical 
consideration, are felt to be related to the administration of the test.  The relationship of 
an adverse experience to the test drug can be considered related if: 
 
 It follows a reasonable temporal sequence from administration of the drug 
or drug levels have been established in body fluids or tissues. 
 
 It could not be reasonably explained by the known characteristics of the 
patient’s clinical state, environmental or toxic factors, or other modes of 
therapy administered to the patient. 
 
 It disappears or decreases upon cessation of drug or reduction on dose and 
appears upon re-challenge*. 
 
 It follows a known response pattern to the suspected drug. 
 
 
*There are exceptions when an adverse experience does not disappear upon 
discontinuation of the drug, yet drug relatedness clearly exists; e.g., 1) tardive dyskinesia, 
2) fixed drug eruptions. 
 
 
 
 
 
 
 
 
 
 
 


 
- 39 - 
Version: 12/26/18 
APPENDIX D 
Risks 
 
General Anesthesia 
Any operation using anesthesia includes a risk of an adverse reaction to anesthetic 
agents.  The risks of anesthesia are the same for any surgical procedure for which anesthesia 
is used.  After receiving a general anesthetic side effects may include the following. 
 The most common side effects are nausea and vomiting, from 3 to 5% (1% means one 
in one hundred).   
 Other side effects include dry throat, sore throat, sore jaw, sore muscles and perhaps 
some short-term memory loss or confusion.  The vast majority of patients recover 
from these side effects in a day or so.   
 There is a risk of unexpected and unusual reactions to the anesthesia that can lead to 
heart problems such as a myocardial infarction (heart attack) or lung problems such 
as respiratory failure (breathing failure).   
 All procedures involving anesthesia carry the risk of death. 
 
Angiography 
The super selective delivery of Bevacizumab to the tumor first involves “catheter 
angiography” via groin.  Angiography involves the placement of a catheter in the groin via 
femoral artery.  The catheters are then threaded up to the arteries in the brain.  Risks 
associated with the angiography procedure are very small but include: 
 Pain at the groin site, groin hematoma (<1%)  
 Stroke in the brain (<0.05%) 
 Allergic reaction and damaging of blood vessels that may lead to bleeding 
  
Therapy with Mannitol 
Treatment with Mannitol has been used extensively to break down the blood brain barrier or 
wall between blood vessels and the brain tissue.  The risks associated with this therapy 
include: 
 Increased risk of a hemorrhage of blood into either the brain tumor or into adjacent 
normal brain tissue.  This is called a hemorrhagic stroke and has a risk of about 1%. 
 The resulting blood clot in the brain is called a “hematoma” and can itself cause 
weakness on one side of the body, speech problems, memory loss, understanding 
difficulties.  A large hematoma in the brain can also require surgery to remove the 
hematoma and relieve pressure from the brain (this risk is less than 0.05%).   
 If a subject suffers from increased intracerebral pressure, intra-arterial infusion with 
Mannitol, may increase or decrease that pressure.   
 
Other risks related to Mannitol include: 
 Pulmonary congestion, fluid imbalance, acidosis, thirst/dryness of mouth, urinary 
retention, edema, headache, blurred vision, convulsions, nausea, vomiting, rhinitis, 
arm pain, skin necrosis, thrombophlebitis, chills, dizziness, urticaria, dehydration, 
hypotension, tachycardia, fever and angina-like chest pains 
 
 


 
- 40 - 
Version: 12/26/18 
Intra-arterial therapy with Bevacizumab 
 
Bevacizumab is a drug that targets the protein on the tumor called VEGF.  Intravenous 
treatment with this drug has been shown to cause some adverse side effects.  We hope by 
delivering this drug “selectively” to the tumor, we may minimize the body’s exposure to the 
drug, however, the safety of this method is unknown and is the purpose of this study. 
 The subject’s body will be exposed to some of the Bevacizumab as it “re-circulates” in 
the blood stream. Therefore, although the method of delivery of Bevacizumab is 
different, subjects may experience some of the systemic risks of Bevacizumab, which are 
most likely rash and diarrhea. These symptoms can often be managed with medications 
and rarely cause the need to stop the therapy with Bevacizumab.   
 In clinical trials, additional serious side effects in subjects receiving Bevacizumab 
included gastrointestinal complaints and even perforation of the stomach or intestine.    
 Bevacizumab has been shown to slow wound healing in other clinical trials and has been 
shown to cause bleeding in the lungs.  Blood clots in the lungs have also been reported 
which may cause subjects to have trouble breathing.   
 Elevation of blood pressure may occur and congestive heart failure may occur. 
 The most common adverse events seen in subjects receiving Bevacizumab across all 
studies were weakness, pain, abdominal pain, headache, hypertension, diarrhea, nausea, 
vomiting, loss of appetite, mouth sores, constipation, upper respiratory infection, 
nosebleeds, difficulty breathing, skin irritation, and proteinuria (a possible sign of kidney 
malfunction).  
 Additional risks associated with bevacizumab include: bleeding of the brain and spinal 
cord, bleeding of the vagina, rectal bleeding, alteration of taste, dry skin, scaling skin, 
excessive tearing of the eyes, and back pain. 
 Reduction in the dose or interruption of Bevacizumab will be considered if changes in 
liver function are severe. There may be additional risks as a result of the super selective 
method of drug delivery; the risks are unknown. 
 
Blood-Drawing   
There are no major risks of having blood drawn.  It can be uncomfortable and can sometimes 
cause a bruise.  In rare cases, it can cause fainting.  Only trained staff will draw blood.   
 
Magnetic Resonance Imaging (MRI) Studies 
The magnetic resonance imaging (MRI) machine is a powerful magnet.  This magnet may 
cause any metal in the body to move. Otherwise, there are no known risks of MRI.   
 Some people with claustrophobia (fear of closed spaces) may find the MRI scanner 
too confining.  In that case, subjects can ask to be removed from the scanner and this 
will be done immediately.   
 The MRI scanner makes a loud beeping sound.  Subjects may be asked to wear 
protective earplugs during scanning.   
 The dye that is injected for the scan is well tolerated.   
 Subjects may feel dizzy, queasy or get a headache with it or notice a cold feeling near 
the injection site.   
 There is a rare chance of having an allergic reaction to the dye that very rarely can be 
serious and life threatening. 
 


 
- 41 - 
Version: 12/26/18 
 
 
Chest x-rays 
In this study, subjects will be exposed to radiation during the chest X-ray.  While we cannot 
be sure any dose of radiation is completely safe, the amount subjects will be exposed to in 
this study is not known to cause health problems.  
 
CT scans  
 In this study, subjects will be exposed to radiation during the CT scan.  Although the amount 
subjects will be exposed to is higher than that of a usual x-ray, the risk of harmful effects 
from a single exam is very small. 
 
Collection of Sensitive Information  
Some of the questions we will ask subjects are personal.  They may feel embarrassed or 
stressed. Subjects may ask to see the questions before deciding whether or not to take part in 
this study. 
 
Unknown Side Effects 
As with any drug, there might be side effects that are unknown at this time. Subjects will be 
closely watched for side effects.  Subjects should report any unusual events to the study staff.  
 
Risks to Women of Childbearing Potential and Pregnant Women  
We do not know the effects of Bevacizumab on fertility or a fetus.  For this reason, if 
subjects believe they are pregnant or have a chance of becoming pregnant, they should not 
take part in this study.  A blood pregnancy test will be performed prior to the start of study 
procedures.  If subjects are pregnant, they will not be allowed to be in the study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
- 42 - 
Version: 12/26/18 
 
 
APPENDIX D 
Tumor Assessment-RANO Response Criteria 
 
 
Complete Response (CR)  
 
disappearance of all enhancing measureable and 
non-measureable disease sustained for at least 4 
weeks 
 
no new lesions 
 
stable or improved non-enhancing (T2/FLAIR) lesions 
 
off corticosteroids or on stable physiologic doses only 
 
stable or improved clinically 
Partial Response (PR)  
 
≥ 50% decrease compared with baseline in the sum of 
products of perpendicular diameters of all 
measureable enhancing lesions sustained for at least 
4 weeks  
 
no progression of non-measurable disease 
 
no new lesions 
 
stable or improved non-enhancing (T2/FLAIR) lesions 
 
same or reduced corticosteroid dose compared with 
baseline  
 
stable or improved clinically 
Stable Disease (SD)  
 
does not qualify for complete response, partial 
response or progression 
 
stable non-enhancing (T2/FLAIR) lesions on same or 
lower corticosteroid dose compared to baseline scan. 
 
stable clinically 
 Progressive Disease 
(PD) 
 
≥25% increase of enhancing lesions on stable or 
increasing doses of corticosteroids 
 
significant increase in T2/FLAIR non-enhancing lesion 
on stable or increasing doses of corticosteroids 
compared with baseline scan or best response after 
initiation of therapy not caused by co-morbid events  
 
any new lesion 
 
clear clinical deterioration not attributable to other 
causes apart from the tumor or changes in 
corticosteroid dose 
 
clear progression of non-measurable disease 
 
 


 
 
 
                                                                                           Page 43 of  43 
 
INVESTIGATOR STATEMENT 
 
 
 
I have read Research protocol entitled: 
 
PROTOCOL TITLE:  PHASE I/II TRIAL OF REPEATED SUPER-SELECTIVE 
INTRAARTERIAL CEREBRAL INFUSION OF BEVACIZUMAB FOR TREATMENT 
OF NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME  
 
and as the responsible investigator, I agree to conduct this research study as outlined herein.   
 
 
 
 
 
_________________________________________ 
Principal Investigator (please print) 
 
 
_________________________________________                                       _______________ 
 
Principal Investigator (signature) 
 
 
 
Date 
 
 
_________________________________________ 
Investigator Address 
 
 
_________________________________________ 
Investigator Telephone Number 
 
 
 
Signature on this page assures the Sponsor that, to the best of the investigator’s knowledge, the affiliated 
IRB operates in accordance with the U.S. Code of Federal Regulations, and that the investigator 
understands, and agrees to abide by, all regulatory obligations while conducting this clinical investigation.  
 
 
 
 
 
Once signed, the original of this form should be detached from the research protocol 
and returned to the Sponsor (please retain a copy for your files).