Conditions: Glioblastoma Multiforme Fibrillary Astrocytoma of Brain Glioma of Brainstem Anaplastic Astrocytoma Pilomyxoid Astrocytoma Mixed Oligodendroglioma-Astrocytoma Brain Stem Glioma Diffuse Intrinsic Pontine Glioma
Keywords: GBM AA FA PXA AOA High grade glioma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 13
Healthy volunteers: no

Brief summary:
Central nervous system (CNS) malignancies are the second most common malignancy and the most common solid tumor of childhood, including adolescence. Annually in the United States, approximately 2,200 children are diagnosed with CNS malignancy and rates appear to be increasing. CNS tumors are the leading cause of death from solid tumors in children. Survival duration after diagnosis in children is highly variable depending in part on age at diagnosis, location of tumor, and extent of resection; however, most children with high grade glioma die within 3 years of diagnosis. All patients with high grade glioma 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 previous phase I trials that a single Superselective Intra-arterial Cerebral Infusion (SIACI) of Cetuximab and/or Bevacizumab is safe for the treatment of recurrent glioblastoma multiforme (GBM) in adults, and we are currently evaluating the efficacy of this treatment. Therefore, this phase I/II clinical research trial is an extension of that trial in that we seek to test the hypothesis that intra-arterial Cetuximab and Bevacizumab is safe and effective in the treatment of relapsed/refractory glioma in patients \<22 years of age. We expect that this project will provide important information regarding the utility of SIACI Cetuximab and Bevacizumab therapy for malignant glioma in patients \<22 years of age and may alter the way these drugs are delivered to our patients in the near future.

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

1. Subjects will first be treated with Mannitol prior to chemotherapy infusion (Mannitol 25%; 10 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 of chemotherapy for malignant glioma. We have used this without complication in our patients from our Phase I protocols as well.
2. To treat patients \<22 years of age with recurring or relapsing glioma with a single intraarterial delivery (SIACI) of Cetuximab and Bevacizumab. Our Phase I trials have demonstrated the safety of SIACI delivery of these drugs in adults. This trial will focus on the safety and efficacy in patients \<22 years of age.

Arms:
arm 1: Superselective Intraarterial Cerebral Infusion (SIACI) of Erbitux (200 mg/m\^2) and Bevacizumab (15 mg/kg)

Interventions: intervention 1: SIACI of Erbitux and Bevacizumab
Intervention descriptions: intervention 1: Subjects will receive a single intra-arterial dose of Cetuximab (200 mg/m\^2) and Bevacizumab (15 mg/kg) via Superselective Intraarterial Cerebral Infusion (SIACI).

Protocol document:
Prot_SAP_000.pdf: 
 
 
Protocol and Statistical Analysis Cover Page 
 
Phase I/II Trial Of Super-Selective Intraarterial Infusion Of Erbitux 
(Cetuximab) And Avastin (Bevacizumab) For Treatment Of 
Relapsed/Refractory Intracranial Glioma In Patients Under 22 Years Of 
Age 
 
PI: Dr. Jeffery Greenfield, PhD, MD 
NCT #: 01884740 
WCM Protocol #: 1202012214 
Version Date: August 19, 2021 


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PROTOCOL TITLE:  PHASE I/II TRIAL OF SUPER-SELECTIVE INTRAARTERIAL 
INFUSION OF ERBITUX (CETUXIMAB) AND AVASTIN (BEVACIZUMAB) FOR 
TREATMENT OF RELAPSED/REFRACTORY INTRACRANIAL GLIOMA IN 
PATIENTS UNDER 22 YEARS OF AGE  
 
WMC PROTOCOL NUMBER:  1202012214 
 
 
PRINCIPAL INVESTIGATOR: 
Jeffrey P. Greenfield, MD, PhD 
 
CO-PRINCIPAL INVESTIGATORS: 
Mark M. Souweidane MD 
Y. Pierre Gobin, MD 
Heather McCrea, MD 
 
 
              SPONSOR: Weill Cornell Brain Tumor Center 
The New York Presbyterian Hospital-Weill Medical  
College of Cornell University 
525 East 68th Street 
New York, NY 10021 
Telephone: (212) 746-1996 
Facsimile: (212) 746-7732 
 
 
 
 
PERFORMANCE SITES:  
Weill Cornell Brain Tumor Center 
 
Site PI: Jeffrey Greenfield, MD 
 
The New York Presbyterian Hospital-Weill Medical  
 
College of Cornell University 
525 East 68th Street 
New York, NY 10021 
Telephone: (212) 746-1996 
Facsimile: (212) 746-7732 
 
University of Miami Miller School of Medicine  
Site PI: Heather McCrea, MD, PhD 
1600 NW 10th Ave #1140 
Miami, FL 33136 
Telephone: (305) 585-3627  
 
 
 
 


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PROTOCOL TITLE:  PHASE I/II TRIAL OF SUPER-SELECTIVE INTRAARTERIAL 
INFUSION OF ERBITUX (CETUXIMAB) AND AVASTIN (BEVACIZUMAB) FOR 
TREATMENT OF RELAPSED/REFRACTORY INTRACRANIAL GLIOMA IN 
PATIENTS UNDER 22 YEARS OF AGE 
 
 
CLINICAL INVESTIGATORS: Weill Cornell Brain Tumor Center 
The New York Presbyterian Hospital-Weill Medical College of Cornell University 
 
Principal Investigators: 
 
Jeffrey P. Greenfield, M.D., PhD. 
 Principal Investigator 
 
 
 
 
 
Assistant Professor of Neurological Surgery 
 
 
 
  
Co-Investigators: 
 
 
Mark M. Souweidane, M.D.  
Co-Principal Investigator 
 
 
 
 
 
Professor of Neurological Surgery 
 
 
Y. Pierre Gobin, M.D. 
 
Co-Principal Investigator  
 
 
 
 
 
Professor of Radiology in Neurological Surgery 
 
 
 
 
 
Director, Interventional Neuroradiology 
 
Jared Knopman, M.D. 
 
Co-Investigator 
 
 
 
 
 
Assistant Professor of Neurological Surgery 
 
Apostolos John Tsiouris, M.D. 
Co-Investigator 
 
 
 
 
 
Associate Professor of Radiology 
 
 
 
 
 
Jana Ivanidze, M.D., Ph.D. 
 
Co-Investigator 
 
 
 
 
 
Department of Radiology 
 
 
Yasmin Khakoo, M.D.  
 
Co-Investigator, MSKCC 
 
Kevin DeBraganca, M.D.  
 
Co-Investigator, MSKCC 
 
Heather McCrea, M.D., PhD  
Co-Investigator, U. of Miami Miller School of  
 
 
 
 
Paul Christos, Dr.P.H. 
 
Biostatistician  
 
 
 
 
 
Division of Biostatistics and Epidemiology 
 
 
 
 
 
Department of Public Health 
 
 


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Medical Monitor: 
 
      
Stergios Zacharoulis, M.D. 
 
 
 
 
 
Pediatric Hematology/Oncology 
NewYork-Presbyterian Hospital 
Telephone: (212) 305-9770 
 
Clinical Monitor: 
 
 
Alexa Gura, NP 
 
 
 
 
 
Pediatric Neurological Surgery 
 
 
 
 
 
The New York Presbyterian Hospital-Weill Medical 
 
 
 
 
 
Telephone: (866) 426 7787  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 New York 
Presbyterian Hospital-Weill Medical College of Cornell University. 


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IN THE EVENT OF EMERGENCY 
 
Any death, serious* adverse experience, or unexpected (and severe) adverse experience 
undergone 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, must be promptly 
reported (within 24 hours) by telephone or telefax to the Sponsor or designee.  Reports should be 
made to: 
 
 
Clinical Research Coordinator  
 
The New York Presbyterian Hospital-Weill Medical  
 
College of Cornell University 
525 East 68th Street 
New York, NY 10021 
Telephone: 
(212) 746-2438 
Facsimile:   
(212) 746-7732 
 
 
Contact at (212) 746-1996 may be made after business hours, weekends, and on holidays.  Leave 
a message and a return call will be placed. 
 
 
 
*A serious adverse experience is one which constitutes a definite hazard or handicap to the patient, including, but not limited 
to an event which: 
- 
is fatal 
- 
is life-threatening 
- 
requires or prolongs hospitalization 
- 
is persistently or significantly disabling/incapacitating 
- 
is a congenital anomaly/birth defect 
- 
 necessitates either surgical or medical intervention to prevent the following outcomes: allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
 
 
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. 
.  
 
 
 
 
 
 
 


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LIST OF TABLES 
 
TABLE 1 Scheduled Study Procedures Flow Chart ................................................................... 24 
 
 
 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
LIST OF TABLES ......................................................................................................................... 5 
LIST OF APPENDICES ................................................................................................................ 5 
SCIENTIFIC BACKGROUND ...................................................................................................... 10 
RATIONALE FOR THIS STUDY ................................................................................................. 13 
I 
OBJECTIVES ............................................................................................................ 14 
II 
PATIENT SELECTION ............................................................................................ 15 
Test Drug Preparation and Administration .......................................................................... 16 
Supplies of CEA-CIDETM .................................................................................................... 16 
Preparation of Radiolabeled CEA-CIDETM ...................................................................... 16 
Dose Interruption or Discontinuation ..................................................................................... 17 
III 
EXPERIMENTAL PLAN ....................................................................................... 17 
A. 
Control Methods ....................................................................................................... 17 
Duration of this Trial ............................................................................................................... 18 
D. 
Patient Entry and Time on Study ........................................................................... 19 
Enrollment Process ................................................................................................................. 19 
Assignment of Patient Identification ...................................................................................... 20 
Inpatient / Outpatient Requirements....................................................................................... 20 
End of Study and Follow-up Evaluation Schedule ................................................................ 20 
Disease / Tumor Assessment ...................................................................................................... 23 
1. 
Serious Adverse Events .............................................................................................. 28 
Documenting Adverse Events .................................................................................................... 28 
D. Reporting SAEs, Unexpected Adverse Events, and Patient Deaths ...................................... 28 
Time-frame for Reporting ...................................................................................................... 28 
Information to be Provided by the Investigator ..................................................................... 29 
VIII 
PRECAUTIONS ....................................................................................................... 30 
Precautions  Regarding Procreation ........................................................................................... 30 
B. 
Additional Precautions ............................................................................................... 30 
IX 
REGULATORY CONSIDERATIONS .................................................................. 30 
Conditions for Modifying or Terminating the Study ................................................................. 31 
1. 
Modifications ............................................................................................................. 31 
2. 
Termination ................................................................................................................ 31 
C. 
Informed Consent ....................................................................................................... 31 
X 
INVESTIGATOR RESPONSIBILITIES .............................................................. 33 
A. 
Medical Supervision ................................................................................................... 33 
B. 
Confidentiality ............................................................................................................ 33 
Record Retention ........................................................................................................................ 33 
Drug Dispensing Log ................................................................................................................. 33 
Patient Exclusion Log ................................................................................................................ 33 
Recording and Processing of Data ............................................................................................. 33 
Record Retention ........................................................................................................................ 33 
Laboratory Reports ..................................................................................................................... 33 
Monitoring .................................................................................................................................. 34 
XI 
PROTOCOL DEVIATIONS ................................................................................... 34 
APPENDIX B .................................................................................................................................... 35 
Performance Status Evaluation .......................................................................................... 35 
APPENDIX E .................................................................................................................................... 36 


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Clinical Symptomatology and Adverse Event Grading Scale .......................................... 36 
Clinical Adverse Events:  Determining Relationship to Test Drug ................................. 37 
  


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PROTOCOL TITLE:  PHASE I/II TRIAL OF SUPER-SELECTIVE INTRAARTERIAL 
INFUSION OF ERBITUX (CETUXIMAB) AND AVASTIN (BEVACIZUMAB) FOR 
TREATMENT OF RELAPSED/REFRACTORY INTRACRANIAL GLIOMA IN 
PATIENTS UNDER 22 YEARS OF AGE 
 
 
Test Materials: 
Mannitol (hexan-1,2,3,4,5,6-hexol (C6H8(OH)6) 
Cetuximab (Erbitux, Genentech Pharmaceuticals)  
Bevacizumab (Avastin, Genentech Pharmaceuticals)  
 
 
 
 
Dosage Levels: 
Mannitol 25% 3-10ml/s for 30s (total dose, 90-300ml) for blood brain 
barrier (BBB) disruption 
 
Cetuximab intra-arterial 200mg/m2  
 
Bevacizumab intra-arterial 15mg/kg  
 
 
Route of Administration: 
Intracranial Superselective Intra-arterial  


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STUDY SYNOPSIS 
 
This is an open-label, non-randomized, single-arm, Phase I and II research study of intracranial 
superselective intra-arterial Erbitux (Cetuximab) and Avastin (Bevacizumab) for treatment of 
relapsed/refractory or unresectable glial neoplasms of the brain in children and young adults under 
the age of 22.  
 
Overview and Background: Central nervous system (CNS) malignancies are the second most 
common malignancy and the most common solid tumor of childhood, including adolescence.  
Annually in the United States, approximately 2,200 children are diagnosed with CNS malignancy 
and rates appear to be increasing.  CNS tumors are the leading cause of death from solid tumors in 
children.  Over 90% of CNS tumors are located in the brain, and approximately 25% of CNS tumors 
are supratentorial.  Of CNS malignancies in those under 20, 52% are astrocytomas of various 
grades, 21% PNETs, 15% other gliomas, and 9% ependymomas, though the frequency of these 
tumors varies further depending on age within this population.  Pilocytic (WHO grade I) 
astrocytomas can have relatively good prognosis with 5 year survival as high as 95% after gross 
total resection, but higher grade gliomas, anaplastic astrocytoma (AA) (WHO grade III) and 
glioblastoma multiforme (GBM) (WHO Grade IV), have 5 year survivals of approximately 50% 
and 19.5% respectively.  Ependymomas and primitive neuroectodermal tumors (PNETs) have 
similarly poor prognosis with 5 years survival of 56.9% and 56.8%.  Overall, for all grades of 
malignant brain tumor, 5 year survival is 64.6% for those 0-14 and 66% for those 0-20.  In addition 
to the poor prognosis from patient’s tumors, the effect of adjuvant therapy, especially radiation, on 
the developing brain can pose a major obstacle in the treatment of pediatric patients and lead to 
developmental, endocrinologic, behavioral, and cognitive problems in the children who do survive 
their initial tumor.    
 
High-grade malignant brain tumors, glioblastoma multiforme (GBM) and anaplastic astrocytoma 
(AA) exhibit the most aggressive behavior, resulting in median overall adult survival durations of 
only 9-12 months for GBM, and 3-4 years for AA, from initial diagnosis, despite multimodal 
treatment approaches.  Survival duration after diagnosis in children is highly variable depending in 
part on age at diagnosis, location of tumor, and extent of resection; however, most children with 
high grade glioma die within 3 years of diagnosis.  Infants often have more aggressive disease while 
juvenile GBM may more closely mirror the adult course.  Initial therapy consists of surgical 
resection for most pediatric brain tumors, with the exception of diffuse pontine glioma whose 
location frequently precludes surgical intervention aside from biopsy.  The timing and combinations 
of adjuvant or concomitant chemotherapy and radiation in the initial treatment of pediatric low and 
high-grade gliomas is much less well defined than in adult glioma therapy and significant variations 
exists between major pediatric cancer centers. Many children with fully or partially resectable high 
grade tumors experience a recurrence after first-line therapy, therefore improvements in both first-
line and salvage therapy are critical to enhancing quality-of-life and prolonging survival.   
 
Besides other chemotherapeutic drugs Erbitux (Cetuximab) is currently used to treat recurring GBM 
after failure of standard radiation and chemotherapy with temozolomide. Because of the blood brain 
barrier (BBB) where IV drugs do not penetrate the blood vessel walls well to get into the brain, no 
one knows for sure if these IV drugs actually get into the brain after infusion.  We have recently 
completed a Phase I clinical trial that has shown that SIACI of Cetuximab is safe and effective in 
adult patients at 200 mg/kg with recurrent malignant glioma.  Avastin(Bevacizumab) has been 
shown to be active in a range of tumors including GBM and anaplastic astrocytoma.(Bokstein et al. 


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2008; Kang et al. 2008; Narayana et al. 2008; Vredenburgh et al. 2008; Zuniga et al. 2008).  We 
have recently completed a Phase I clinical trial demonstrating the safety of SIACI of avastin at 15 
mg/kg in adults. Therefore, this phase I and II clinical research trial will test the hypothesis that 
Bevacizumab and Cetuximab can be safely and effectively used by direct intracranial superselective 
intra-arterial infusion in patients <22 years of age with relapsed/refractory intracranial glioma.  
 
Therefore the experimental aspects of this treatment plan will include: 
1. Subjects will first be treated with Mannitol prior to chemotherapy infusion (Mannitol 25%; 
3-10 mL/s for 30seconds) in order to disrupt the blood brain barrier.  This technique has 
been used in several thousand patients in previous studies for the IA delivery of 
chemotherapy for malignant glioma.  We have used this without complication in our Phase I 
protocols as well. 
2. To treat patients with intra-arterial delivery (SIACI) of Erbitux and Avastin for patients with 
recurring or relapsing glioma.   
3. With the implementation of Protocol Version December 6, 2019, the dosing of 
Bevacizumab and Cetuximab changed from a single dosing, to monthly dosing. Dosing will 
continue until patients demonstrate radiographic progression. 
 
Inclusion criteria: Males or females, <22 years of age, with documented histologic diagnosis of 
relapsed or refractory glioblastoma multiforme (GBM), anaplastic astrocytoma (AA), fibrillary 
astrocytomas (FA), pilomyxoid astrocytoma, PXA, oligodendroglioma, or anaplastic mixed 
oligoastrocytoma  (AOA) or patients with radiographic pontine glioma.  
 
Anti-tumor response: Response will be evaluated after one cycle of chemotherapy via an MRI with 
the injection of contrast performed on post procedure day 0, 1 month post procedure, and every 
month thereafter.   
 
Study Agents: Mannitol, Erbitux, and Avastin are registered agents. 
 
 
 
Safety/Toxicity Monitoring: Patients will be treated with a previously tested, dose and schedule of 
Mannitol prior to chemotherapy infusion (Mannitol 25%; 3-10 mL/s for 30 seconds) in order to 
disrupt the blood brain barrier.  Following blood brain barrier disruption the patient will receive an 
intracranial superselective intra-arterial catheterization and infusion with Erbitux (Cetuximab) at a 
dose of 200mg/m2 over 30 minutes and Avastin (Bevacizumab) at a dose of 15mg/kg over 30 
minutes.  Both hematologic and non-hematologic adverse events will be determined and scored 
according to the NCI Common Toxicity Criteria (version 4.0).  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/II study 
receive supportive care, including growth factors, blood cell transfusions, as clinically indicated.   
 
INTRODUCTION  
Each year approximately 2200 children less than age 20 are diagnosed with malignant central 
nervous system tumors.  These brain tumors are typically treated by surgery, radiation therapy and 
chemotherapy, either individually or in combination.  Present therapies are inadequate, as evidenced 


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by the low 5-year survival rate for brain cancer patients, 66% for all types of pediatric CNS tumors 
and significantly lower for more aggressive tumor types.  Glioma is the most common form of 
primary brain cancer, afflicting approximately 7,000 patients in the United States each year.  Over 
50% of pediatric CNS tumors are gliomas.  High grade astrocytomas are relatively uncommon 
(<10% of CNS tumors); however these tumors have devastating consequences with most affected 
children surviving less than 3 years from diagnosis despite surgical and adjuvant intervention.  
These highly malignant cancers remain a significant unmet clinical need in oncology.  GBM (the 
highest grade of glioma) often has a high expression of EFGR (Epidermal Growth Factor Receptor). 
The importance of EGFR is well established in adult glioblastoma.  Pediatric glioblastoma was 
previously thought to have lower expression levels, but recent evidence suggests that expression 
may play an important role in pediatric tumors as well.  In contrast, normal human brain does not 
express EGFR, making this an exciting target in the treatment of brain tumors.  Several methods of 
inhibiting this receptor have been tested, including monoclonal antibodies, vaccines, and tyrosine 
kinase inhibitors.  GBM also has a high expression of vascular endothelial growth factor (VEGF), a 
protein that is produced by both tumor cells and stromal cells, including inflammatory cells.(Buie 
and Valgus 2008; Chamberlain 2006; de Groot and Yung 2008; Poulsen et al. 2008; 
Sathornsumetee and Rich 2007; Vredenburgh et al. 2007) In human GBM specimens, the 
expression of VEGF is associated with a poor prognosis.(Desjardins et al. 2008; Zuniga et al. 2008) 
Conversely, in a xenograft model, antibodies to VEGF have inhibited the growth of GBM.(Buie and 
Valgus 2008; Kang et al. 2008; Vredenburgh et al. 2008) Avastin and Irinotecan intravenous 
chemotherapy has become the standard of care for recurring relapsing GBM (de Groot and Yung 
2008).  Intra-arterial delivery of chemotherapy with Avastin has become widely used in other solid 
tumors including Hepatocellular and Pancreatic Carcinoma.   
 
Cetuximab (Erbitux, IMC-C225) is a recombinant human (IgG1)/mouse (Fv regions) chimeric 
monoclonal antibody which binds specifically to the epidermal growth factor receptors (EGFR) and 
competitively inhibits the binding of EGFR and other ligands. Cetuximab-binding also results in 
internalization of the antibody-receptor complex, which causes a down-regulation of EGFR 
expression on the cell surface. Consequently, signal transduction through this pathway is blocked, 
which inhibits tumor growth and ultimately leads to cell death. Studies have suggested that 
cetuximab also decreases angiogenesis, mediates antibody-dependent cell-mediated cytoxicity, and 
positively increases the activity with radiotherapy and chemotherapy. Data from a recent stratified 
phase II trial, in which cetuximab was administered intravenously to 55 patients with recurrent 
high-grade gliomas, 28 who were EGFR Positive and 27 who were EGFR Negative. The primary 
end point for this study was the response rate in both study arms separately. 5.5% had a partial 
response and 29.6% had stable disease. We recently showed in our Phase I trial that intra-arterial 
Cetuximab is safe for the treatment of recurrent GBM patients >18 years of age.  
 
Bevacizumab(Avastin) is a humanized immunoglobulin (Ig) G1 monoclonal antibody that binds to 
and inhibits the activity of VEGF.  Bevacizumab is synergistic with chemotherapy in colorectal, 
lung, brain and breast carcinomas. As a single agent, Bevacizumab prolonged the time to 
progression for patients with metastatic renal cell carcinoma compared with that for patients 
receiving placebo (Vredenburgh et al. 2007). Monoclonal antibodies to VEGF have inhibited the 
growth of GBM in vitro and in vivo (Sathornsumetee and Rich 2007).  In fact, Avastin and 
Irinotecan intravenous chemotherapy has become the standard of care for recurring relapsing GBM 
in adult patients.  A preliminary report of the combination of bevacizumab and irinotecan for 
patients with malignant gliomas demonstrated an encouraging response rate of 43%.(Vredenburgh 
et al. 2007) In addition, the 6-month overall survival with bevacizumab and irinotecan was 


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improved compared with temozolomide: 77% versus 60% respectively. Comparison of Avastin and 
CPT-11 show a 6-month Progression Free Survival (PFS) and median PFS in patients with GBM of 
43% and 24 weeks, compared with previous results of 15% and 9 weeks, respectively, in patients 
with GBM.(Vredenburgh et al. 2007) The 1-year overall survival with bevacizumab and Irinotecan 
was superior to historical controls: 37% versus 21%, respectively. We recently showed in our Phase 
I trial that intra-arterial delivery of Avastin is safe for the treatment of recurrent GBM in patients 
>18 years of age.  This study is a follow up study to assess the effects of intra-arterial Cetuximab 
and Avastin in patients <22 years of age. 
 
Clinical Experience with the Individual Chemotherapy Agents 
 
Mannitol:  Intraarterial infusion of Mannitol (25%; 3-10ml/s for 30seconds) in order to achieve 
osmotic disruption of the cerebral circulation has been well described. 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. 
 
Erbitux:  The currently used intravenous dose of Erbitux chemotherapy is 400mg/m2 IV.  In our 
recently completed Phase I clinical trial an intra-arterial dose of 200 mg/m2 was safe for the 
treatment of GBM and no adverse effects were detected in the treated patients. 
 
Avastin: The currently used intravenous dose of Avastin chemotherapy is 10mg/kg IV.  In our 
recently completed Phase I clinical trial an intra-arterial dose of 15 mg/m2 was safe for the treatment 
of GBM and no adverse effects were detected in the treated patients. 
 
Rationale for the dosing schedule: The proposed research trial design utilizes the addition of 
intracranial superselective intraarterial chemotherapy infusion of Cetuximab and Avastin. With the 
implementation of protocol version 6 December 2019, infusion frequency was changed from a 
single, one time dosing to monthly dosing due to favorable early results for this trial. 12 patients 
were treated on the initial one time dosing schedule – of that, 4 patients exhibited subjective 
symptom improvement that allowed 2 of them to return to school. At a 1 month timepoint used to 
determine response, 5 had responses (2 had stable disease, 2 had a PR, and 1 had a CR). Response 
was determined by comparison of linear and volumetric criteria as demonstrated by Shah et al 2005. 
Thus, it is the belief that increasing to monthly dosing will improve patient responses. 
 
Choice of Starting the Dose Used in this Study Regimen:  In our Phase I trials, we have 
determined that Erbitux and Avastin are safely delivered intraarterialy at doses of 200 mg/m2 and 15 
mg/kg respectively in patients >18 years of age.  Since these doses are body surface area and weight 
based, we will use the same dosages in this study for patients <22 years of age.  Three patients will 
receive these doses to confirm safety in patients <22 years of age and additional patients will then 
be treated with these dosages to assess efficacy.   
 
Cerebral Angiography: The basic concept of cerebral angiography involves the navigation of a 
catheter up through the vasculature to the aortic arch.  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 


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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 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 and 
then the internal carotid artery.  The vertebral arteries are also selectively cannulated and images of 
the posterior cerebral circulation are obtained. 
 
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 the vessel supplying 
the territory containing the brain tumor.  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 Cetuximab/Avastin 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.  
 
RISK/BENEFIT OF THE STUDY  
 
Data generated from clinical trials using IV Erbitux and Avastin indicate both safety and efficacy of 
these drugs.  Available preclinical and clinical data demonstrate the safety and activity of intra-
arterial Erbitux and Avastin in other solid cancer models.  Our data in adults also indicates safety of 
IA Erbitux and Avastin.  We will be able to follow prospectively patients who receive IA Erbitux 


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and Avastin to better understand the safety and ultimate efficacy of this regimen in patients <22 
years of age with recurrent/refractory glioma.     
 
Intravenous Erbitux use is most likely to result in the following toxicities: skin toxicity, 
thrombocytopenia, confusion, lymphopenia, infusion related allergic reaction, intratumoral 
hemorrhage, diarrhea and fatigue. We have not reported any toxicities with superselective intra-
arterial Erbitux infusion.  
 
Intravenous Avastin use is most likely to result in the following toxicities: CNS hemorrhage (3%) 
thromboemboloic (11%), proteinuria (6%), and fatigue (11%).  There have been to date no detailed 
(observed or documented) toxicities reported with superselective intra-arterial Avastin 
infusion.(Vredenburgh et al. 2008)   
 
This treatment could be harmful to a gestating embryo or fetus, if pregnancy were to occur.  
Females of childbearing potential and fertile males should 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 should be performed on each 
postpubertal 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 should 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 therapy is identified for an illness, which attacks children 
and which is almost uniformly fatal in a short time frame. 
 
 
I. 
OBJECTIVES/ENDPOINTS 
 
1. PRIMARY ENDPOINTS  
 
• The safety of intra-arterial delivery of previously determined doses of intra-arterial 
Avastin and Cetuximab in pediatric patients is a primary endpoint of the study (see 
statistics below).  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 4.0.  Exact 95% confidence intervals around the 
toxicity proportions will be calculated to assess the precision of the obtained 
estimates. We will assess if patients are stable disease at 3 months post initial 
injection. 
. 
• Composite overall response rate at 6 months:  The composite overall response rate 
(CORR) at 6 months will be examined.  The overall response proportion along with 


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a 95% confidence interval will be estimated via binomial proportions.  We will 
define “evaluable” patients as patients who met eligibility requirements and have 
initiated therapy. 
 
• Increased progression-free survival (PFS) and overall survival (OS) will be assessed 
by Kaplan-Meier survival analysis, assuming adequate follow-up time.  PFS will be 
measured from the date of the first dose of SIACI Cetuximab/Avastin to the date of 
progression.  OS will be measured from the date of diagnosis to the date of death.  
Subjects will be followed for one year after their last dose of study treatment, or 
until death.  
 
2. SECONDARY ENDPOINTS 
 
• Assessment of symptom improvement  
 
 
II. 
PATIENT SELECTION 
 
A. Criteria for Inclusion: 
 
• 
Male or female patients, <22 years of age, with a documented histologic diagnosis of 
relapsed or refractory glioblastoma multiforme (GBM), anaplastic astrocytoma (AA), 
fibrillary astrocytomas (FA), pilomyxoid astrocytoma (PXA), oligodendroglioma, or 
anaplastic mixed oligoastrocytoma  (AOA), or radiologically diagnosed brainstem 
glioma 
 
• 
Patients must have at least one confirmed and evaluable tumor site.∗  
*A confirmed tumor site is one in which is biopsy-proven with the exception of 
brainstem glioma which will be eligible with radiographic diagnosis.  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 or Lansky performance status ≥60%.  Karnofsky is 
used for patients ≥16 years and Lansky for those <16. (see Appendix A; Performance 
Status Evaluation) and an expected survival ≥ three months. 
 
• 
No chemotherapy for three weeks prior to treatment under this research protocol and 
no external beam radiation for eight weeks prior to treatment under this research 
protocol. 
 
• 
Patients must have adequate hematologic reserve with absolute neutrophils≥1000/mm3 
and platelets ≥100,000/ mm3.   
 
• 
Pre-enrollment chemistry parameters must show: bilirubin<1.5X the institutional 
upper limit of normal (IUNL); AST or ALT<2.5X IUNL and creatinine<1.5X IUNL. 
 


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• 
Pre-enrollment coagulation parameters (PT and PTT) must be ≤1.5X the IUNL. 
 
• 
Concomitant Medications: 
 
• 
Growth factor(s): Must not have received within 1 week of entry onto this study. 
 
• 
Steroids: Systemic corticosteroid therapy is permissible in patients with CNS 
tumors for treatment of increased intracranial pressure or symptomatic tumor 
edema. Patients with CNS tumors who are receiving dexamethasone must be on 
a stable or decreasing dose for at least 1 week prior to study entry. 
 
• 
Patients of reproductive age 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.   
 
• 
Patients or their parents/guardians must be able to understand and give written 
informed consent.  Informed consent must be obtained at the time of patient screening. 
 
• 
Because of known concerns with Avastin and wound healing, craniotomy patients are 
eligible for the treatment if they have had a craniotomy greater than two weeks prior to 
IA therapy.  Craniotomy or major procedure after SIACI Avastin therapy should wait 
4 weeks.  Minor surgeries may be performed after two weeks. 
B. Criteria for Exclusion 
 
• Females who are pregnant or lactating.   
 
• Females 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 and for a period of three months after the 
treatment period.  If they do not agree, they will be ineligible for the study.  
 
• Patients with significant concurrent 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.    
 
 
III. TEST AGENT PREPARATION AND ADMINISTRATION 
A.  
Supplies of research study agents  
 
 
    Erbitux (Pharmacy) 
 
 
Avastin (Pharmacy)  
 
 
 
 
B.     Preparation of the research study agents 
           1. Erbitux 
Chemical name:  Cetuximab 


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Storage: Store vials at 2 degrees to 8 degrees C.   
Stability:  Protect from light, do not freeze or shake.   
 
                            Half life: 4.75 days  
 Excretion: 2.75-5ml/kg/day 
 
 
 
2. Avastin 
Chemical name:  Bevacizumab 
Storage: Store vials at 2 degrees to 8 degrees C.   
Stability:  Protect from light, do not freeze or shake.   
 
                            Half life: 20 days (range:  11-50days) 
 Excretion: 2.75-5ml/kg/day 
 
C.  Doses of Research study Drugs:  
Erbitux®: The dose for IA Erbitux will be 200mg/m2. 
Avastin®: The dose for IA Avastin will be 15 mg/kg. 
 
D.  Route of Administration  
 Erbitux® and Avastin® will be given intracerebrally by superselective intraarterial 
infusion    
 
E.  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 via IA delivery. Treatment will be administered monthly. Tumor 
response will be assessed with baseline MRI on post procedure day 1, MRI one and 
three month post procedure.  
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). 
 
IV. 
EXPERIMENTAL PLAN 
 
A. 
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 New York Presbyterian Hospital-Weill Medical College of 
Cornell University 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.   
 


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B. 
Duration of this Research Trial 
 
To complete the trial approximately 40 patients will be required.  The New York 
Presbyterian Hospital-Weill Medical College of Cornell University and the 
University of Miami will be employed for this research study.  Overall, it is 
anticipated that accrual to complete the study will be 6 years.   
 
 
C. 
Trial Design/Sample Size and Statistical Considerations:  
 
The primary endpoint will be the 6 month composite overall response rate (CORR).  
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.  
 
Sample size: 
 
Intra-arterial Cetuximab and Bevacizumab (single arm study):  
 
The 6-month CORR for patients treated with Cetuximab has been estimated to be 
20%; therefore, the target 6-month CORR for the intra-arterial Cetuximab and 
Bevacizumab arm will be ≥18%.  Sample size recommendations for the phase II 
design are determined according to Simon’s two-stage optimum design.  We project 
a CORR at 6 months of 5%, below which the regimen will be unacceptable, and a 
CORR at 6 months of 18%, above which the regimen will be considered worthy of 
further exploration.  The null hypothesis that the 6-month CORR is less than or equal 
to 5% will be tested against the alternative hypothesis that the 6-month CORR is 
greater than or equal to 18%. 
 
The sample size computations were performed assuming a 5% level of significance 
and 80% power.  Patients will be continuously accrued throughout the study up to a 
maximum of 44 patients.  If 1 or fewer patients out of the first 17 evaluable patients 
respond after 6 months of follow-up, the study will be terminated and the regimen 
will be declared to have a negative result.  If 2 or more patients out of the first 17 
evaluable patients respond after 6 months of follow-up, ongoing accrual will proceed 
to the target sample size of 44 patients (i.e., if all 44 patients have not been accrued 
at this point).  The treatment will be declared effective and worthy of further testing 
if 5 or more patients respond after 6 months of follow-up among the 44 patients 
entered in the study.  This two-stage design yields a ≥0.80 probability of a positive 
result if the true 6-month CORR is ≥18%.  It yields a ≥0.95 probability of a negative 
result if the true 6-month CORR is ≤5%.  A 95% confidence interval constructed 
around the expected 6-month CORR of 18% can be estimated to be within ± 11.4% 
of the observed CORR. 
 
Numbers of observed patients with CORR after  
6 months of follow-up required to accept or reject H0 at each stage.   
Under this design, H0 will not be rejected at Stage 1. 
 


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N 
Accept H0 
Reject H0 
Stage 1 
17 
≤ 1 
--- 
Stage 2  
44 
≤ 4 
≥ 5 
 
 
Analysis Plan for Endpoints: 
 
Primary Endpoints: 
 
The primary endpoint in both treatment arms is the 6-month CORR.  A ninety-five 
percent confidence interval will be estimated for the 6-month CORR via binomial 
proportions.   
 
Secondary Clinical Endpoints: 
 
Secondary endpoints include median PFS and OS in both treatment arms.  Median 
PFS and OS, including survival curves, will be estimated using Kaplan-Meier 
methodology.  Greenwood’s formula will be used to calculate 95% confidence 
intervals for the Kaplan-Meier estimates. 
 
The frequency of subjects experiencing toxicities will be tabulated.  Toxicities will 
be assessed and graded according to CTCAE v. 4.0 terminology.  Exact 95% 
confidence intervals around the toxicity proportions will be calculated to assess the 
precision of the obtained estimates. 
 
All p-values will be two-sided with statistical significance evaluated at the 0.05 alpha 
level.  Ninety-five percent confidence intervals will be calculated to assess the 
precision of the obtained estimates.  All analyses will be performed in SAS Version 
9.2 (SAS Institute, Inc., Cary, North Carolina) and STATA Version 12.0 (StataCorp, 
College Station, Texas). 
 
 
Sample Size/Accrual Rate 
 
The planned sample size is 47 patients (3 for initial safety and 44 for determination 
of efficacy).  Assuming that 10% of patients are unevaluable/ineligible at the 
efficacy phase, we anticipate that a total of 50 patients will be enrolled in the 
efficacy phase of the study.  Total sample size will therefore be 53 patients (3 for 
initial safety and 50 for efficacy phase).  Accrual is expected at a rate of 2-3 subjects 
per month. 
 
 
D. 
Patient Entry and Time on Research Study 
 
1. Enrollment Process 
 


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Patients will be centrally registered with Weill Cornell Medicine, Joint Clinical 
Trials Office, Cancer Clinical Trials Operations. To register a patient, the following 
documents must be email to the Joint Clinical Trials Office’s central regulatory 
mailbox - CancerCTRegistrar@med.cornell.edu.  
• WCMC Patient Registration Form 
• First and last page of the fully executed informed consent form, plus 
additional pages if with subject’s markings 
• Fully executed HIPAA research authorization form (if separate from 
the consent document) 
• Eligibility checklist signed and dated by investigator and second study 
team member 
• Documentation of any eligibility waivers granted 
 
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.  Research study center 
designations will be assigned to other centers, who are selected to participate in 
this research trial. 
 
Information regarding patient identification, as well as the number of vials of test 
medication utilized for the patient and the dose administered to the patient, will 
be recorded on the Drug Dispensing Log (to be provided by the Sponsor), as well 
as in the CRFs. 
 
3. Inpatient / Outpatient Requirements 
 
Patients will be treated on an outpatient basis.  
 
Patients may be followed routinely by their private physician when necessary. 
Follow up procedures which are standard of care and do not involve study 
treatment, may be conducted at external sites if this is more feasible for the 
subject. In this case,  relevant medical records will be requested by WCM for 
data collection. 
 
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 study therapy.   
 
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 start treatment as recommended by 
patient’s neurooncologist.  Thereafter, toxicities will be monitored by history, 


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physical examination and blood tests, chest xray as outlined in Table 1 below.  
Tumor response assessment by MRI will be performed on post procedure day 1, 
at 1 month and 3 months post procedure.  
 
E.  Treatment Plan  
 
Superselective intra-arterial Dose of Erbitux® and Avastin® will be given at a dose of 
200mg/m2 IA and 15 mg/kg respectively, on a monthly basis.     
 
 
 
 
F. 
Supportive products/concomitant medications: 
 
All medications within four weeks prior to administration of research study drug, 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 must 
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. 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. Platelets may be given if counts are >25,000/mm3, at the investigators 
discretion if any signs of bleeding occur. 
 
3. 
Use of hematopoietic growth factors:  The use of hematopoietic 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.   
 
V. 
PARAMETERS TO BE MEASURED 
 
All patients enrolled in this will be evaluated according to the procedures described 
in Sections A and B and below.  All screening studies are to be performed ≤4 weeks 


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prior to research study entry and, as noted below, some tests will be repeated 1-4 
days prior to initiation of treatment.  Patients will be assessed for the presence of 
measurable disease and tumor response by MRI scan.  An MRI will be performed on 
post procedure day 1, at one and three month post procedure. 
 
             
A. 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 or 
their parent/guardian 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 with the exception of radiographically diagnosed brainstem glioma.  
Biopsy tissue will be sent to neuropathology for evaluation of tumor 
mutations such as VEGF over expression. 
 
4. Performance Status Evaluation, Karnofsky or Lansky (see Appendix A) 
· 
Screening/Baseline: Prior to the start of research protocol treatment (within 
1-4 days) 
· 
Cycle 1 Day 2Day 1 of each subsequent cycle 
· 
End of Treatment Visit 
 
5. Vital Signs (to include: body temperature, pulse rate, blood pressure, and respiration rate) 
· 
Screening/Baseline 
· 
Day 1 of each cycle 
· 
Cycle 1 Day 2 
· 
End of Treatment Visit 
 
6. Physical Examination (complete at screening, including height and weight; thereafter 
complete excluding height) 
· 
Screening/Baseline: This will be performed within 1-4 days of initiation of 
treatment.   
· 
Day 1 of Each Cycle 
· 
Cycle 1 Day 2 


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· 
End of Treatment Visit 
 
7. Hematology (to include CBC with differential and platelet count) 
· 
Screening/Baseline: This will be performed within 1-4 days of initiation of 
treatment. 
· 
Cycle 1 Day 1 (post initial treatment) 
· 
Day 1 of each cycle  
· 
End of Treatment Visit 
 
8. Serum Chemistries (to include: Na, K, Cl, bicarbonate, BUN, creatinine, glucose, bilirubin, 
AST, ALT, alkaline phosphatase, LDH, creatinine, Ca, Mg, phosphorus, albumin, total 
protein, uric acid)  
· 
Screening/Baseline: This must be within 2 weeks of enrollment on research 
study. 
· 
Day 1 of Each Cycle 
· 
Cycle 1 Day 2 
· 
End of Treatment Visit 
  
9. PT and PTT  
· 
Screening/Baseline: This will be performed within 1-4 days of initiation of 
treatment. 
· 
Day 1 of Each Cycle 
· 
Cycle 1 Day 2 
· 
End of Treatment Visit 
 
10. Urinalysis 
· 
Screening/Baseline: This will be performed within 1-4 days of initiation of 
treatment. 
· 
Thereafter, as clinically indicated. 
 
11. Pregnancy Test  (urine or serum; in postpubertal females) 
· 
Screening/Baseline (negative result must be documented on CRF)  
· 
As clinically indicated 
 
12. Imaging and Tumor Assessment  
- 
MRI Head and Tumor Assessment using RANO criteria to be obtained 
- 
Screening/Baseline: This will be performed within 1-4 days of initiation of 
treatment. 
- 
Day 1 of Each Cycle 
- 
Cycle 1 Day 2 
 
13. Survival Follow Up 
· 
After discontinuing treatment, phone calls will be made for survival follow 
up every 6 months until death or up to one year whichever comes first. 
 
B. 
Disease/Tumor Assessment  
  
1. MRI (contrast-enhanced) for Lesion Measurements (i.e., brain)  


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 Screening/Baseline (within 3 weeks prior to research study entry). 
 
 Response will be assessed with a contrast-enhanced MRI on post procedure day one 
after intra-arterial treatment, at one month post procedure, and then repeated every 
month thereafter until disease progression.  
 
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 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 day the initial 
response is observed (using baseline images for comparison) to the time that 
progression is observed. If disease progression is documented at any time after 
treatment, no further imaging will be required.   
 
The criteria for progression is based on the Response Assessment in Neuro-
Oncology (RANO). The criteria for imaging response is based on volumetric 
segmentation of enhancing and T2 FLAIR positive tumor (Shah et al 2005). 
 
Imaging which is conducted at an external institution will be re-read by a radiologist 
at Weill Cornell Medicine. 
 
VI. OVERVIEW OF SCHEDULED PROCEDURES 
 
 
Baseline 
(within 4 days of 
C1D1) 
 
Cycle 1 Day 
1 (Tx Day) 
Cycle 1 Day 2 
(Post Tx)a 
Cycle X Day 
1 
 
Cycle X Day 
2)a 
End Of 
Treatment 
Visit  
Follow-Up 
Tests & 
Observations  
 
 
 
 
 
 
 
History 
X 
 
 
 
 
 
 
Physical Exam 
and Vital Signs 
X 
X 
X 
X 
 
X 
 
Performance 
Status 
X 
 
X 
X 
 
X 
 
Tumor 
Measurement 
X 
 
X 
X 
 
 
 
Toxicity 
Evaluation 
X 
X 
X 
X 
 
 
 
Documentation of 
dexamethasone 
dose 
X 
 
X 
 
 
 
 
Laboratory  
 
 
 
 
 
 
 
CBC, diff, 
platelets 
X 
 
X 
X 
X 
X 
 
PT, PTT 
X 
 
 
X 
X 
X 
 


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Chemistries 
(including 
electrolytes) 
X 
 
X 
X 
X 
X 
 
Urinalysis 
X 
As clinically indicated 
 
 
Pregnancy Test 
(urine or serum, in 
postpubertal 
females) 
X 
As clinically indicated 
 
 
Imaging 
 
 
 
 
 
 
 
MRI Head 
X 
 
X 
Xd 
 
 
 
Survival Follow-
Up 
 
 
 
 
 
 
 
Phone Call 
 
 
 
 
 
 
Xc 
Treatment  
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
a Occur approximately 24 hours post-op.  
b To occur once every 30  
c phone calls for survival follow up are required every 6 months until death or 1 year whichever occurs first. 
d to occur within 3 days  of treatment, and to be resulted prior to treatment  
 
 
 
 
 
 
 
 
VII. TOXICITY OF INVESTIGATIONAL DRUG 
 
All screening studies are to be performed ≤4 weeks prior to research study entry (imaging study 
must be completed within three weeks of study procedure) and, as noted below, some tests will be 
repeated 1-4 days 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 (MRI) will be performed on post procedure day one, at one month post 
procedure, and every month thereafter. 
 
To date, at least 5,000 cancer patients have received Erbitux. Erbitux is approved by the Food and 
Drug Administration to treat squamous cell carcinoma of the head and neck and colorectal cancer. 
We have treated patients with SIACI Mannitol/Erbitux for the treatment of malignant brain tumors 
and did not observed any dose limiting toxicity from the drug up to a dose of 200 mg/m2. 
Hemorrhagic, Dermatologic, gastrointestinal, respiratory and nervous system disorders may occur 
as primary toxicity in patients receiving this treatment regimen.  
 
To date, at least 10,000 cancer patients have received Avastin at a dose ranging from 3mg/kg up to 
20mg/kg IV every two weeks in previous clinical trials.  Avastin is used in Colorectal, head and 
neck, brain, prostate, and renal cancer.  We have treated patients with SIACI Mannitol/Avastin for 
the treatment of malignant brain tumors and did not observed any dose limiting toxicity from the 


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drug up to a dose of 200 mg/m2. Adverse events associated with IV Avastin administration reported 
in two recent clinical trials include hypertension, pain, headache, dizziness, alopecia, 
nausea/vomiting, stomatitis, fatigue and thromboembolism.    
 
VIII. 
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 4.0) will be 
utilized as the criteria to determine appropriate management of the patient. 
 
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, subinvestigator, 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 Erbitux 
and Avastin 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 Cetuximab and Bevacizumab, we have not seen any significant AE’s related 
to the route of administration. 
 
A)  Dose Modification: Set doses of Erbitux or Avastin will be delivered to patients as determined 
by safe dosages in the Phase I adult trials conducted to date.  Dose modification is not 
planned. 
 
B) Dose Interruption: Any sign of acute allergic reaction to Erbitux or Avastin will, depending    
upon the severity, necessitate temporary interruption or permanent discontinuation of the  
offending agent during infusion. 
 
C) 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 and 
notify the PI.  This evaluation should include final observations, as required by the research 
protocol at the time of the patient’s withdrawal.  The reason(s) for early termination must be 


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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.  
 
Patients will be taken off study if their disease progresses, or if they have a grade 4 or higher 
adverse event.  
 
 
D) Replacements: Should a patient withdraw or need to be withdrawn from the research study, a  
replacement subject will be sought using the stipulated research protocol entry criteria.  
Patients who 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. 
 
IX. 
ADVERSE EXPERIENCES 
 
A. Adverse Experience 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. 
• 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. 
 
B. Evaluating Adverse Experiences: The investigator will determine the seriousness, intensity, 
and causality of an adverse event based on the grading definitions found in the CTCAE 
version 4.0 or higher. 
 
 
 
The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for 
each referenced AE. Should a subject experience any AE not listed in the CTCAE, the 
following grading system should be used to assess severity: 
 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special treatment, 
and not interfering with the subject’s daily activities 
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the subject, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures 


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Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to be in 
imminent danger of death 
Grade 5 (Death related to AE) – experiences which result in subject death 
 
 
 
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 WHICH OCCURS WHILE THE SUBJECT IS ACTIVELY ENROLLED IN 
THE STUDY OR WITHIN 30 DAYS OF COMPLETING THE STUDY TREATMENT: 
 
• DEATH  
• 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. 
 
C. 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 D; 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(s) (see Appendix E; Clinical Adverse Experiences: Determining Relationship to Test 
Drug).    
 
D. Reporting SAEs, Unexpected Adverse Experiences, and Patient Deaths 
 
1. Time-frame for Reporting: Any death or serious and unexpected adverse 
experience of any patient during treatment or within 30 days of completing treatment 
under this research protocol must be promptly reported (within 24 hours) by 
telephone or telefax to the Sponsor or designee. 
 
2. Procedure for Reporting All Serious Adverse Events For A Non-IND Study: 
 
 
      


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 To report a SAE:   
 
• 
Notify Drug Safety Surveillance (DSS) within 2 working days of the event. 
(DEATHS, REGARDLESS OF CAUSE, OR IMMEDIATELY LIFE 
THREATENING EVENTS POSSIBLY RELATED TO STUDY DRUG 
MUST BE REPORTED WITHIN 24 HOURS.)  
                                 
• We will notify our IRB of the event promptly per IRB requirements. 
 
We will also notify the above if the following occurs: 
 
• PREGNANCY (IN PATIENT OR PARTNER) - we acknowledge that these 
are not serious unless a serious outcome is seen (e.g., miscarriage, congenital 
anomaly) 
• OVERDOSE - we acknowledge that these are not serious unless a serious 
outcome occurs 
 
3. 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 
 


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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. 
 
F. 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. 
 
 
X. 
PRECAUTIONS 
 
A. 
Precautions Regarding Procreation: Females 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 postpubertal, 
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. 
 
B. 
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. 
 
 
XI. 
REGULATORY CONSIDERATIONS 
 


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A. Conditions for Modifying or Terminating the Research Study 
 
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 reapproval from the 
IRB.  Documentation of renewal must be submitted to the Sponsor. 
 
B. Informed Consent 
 
A copy of the IRB-approved consent form document to be utilized during this 
research study must be submitted to the Sponsor for review prior to research study 
initiation. 
 
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. 
 
C. Documents to be Submitted to the Sponsor Prior to Research study Initiation 
 
 
 
The following documents must be submitted to the Sponsor prior to research study 
initiation: 
 


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• 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). 
 
 
XII.  
MONITORING PLAN  
 
A. Institutional Review Board: Weill Cornell Medicine (WCM) requires that all 
research approved by the WCM IRB include an appropriate plan for the monitoring 
of data to ensure the safety of human subjects. Research supported by Federal 
agencies will be monitored according to all regulations and guidelines of the relevant 
Federal agency.  
 
B. Data and Safety Monitoring Board: The WCM DSMB will review the IRB approved 
protocol, informed consent documents, and data safety monitoring plan (DSMP) 
prior to study initiation. During the course of the study, the DSMB will perform a 
review of cumulative data annually to evaluate safety, efficacy, study conduct, and 
scientific validity and integrity of the trial. The WCM DSMB will also review all 
SAEs occurring on the study using the same reporting policy as the WCM IRB 
(http://researchintegrity.weill.cornell.edu/institutional_review_board/irb_adv.html). 
The WCM DSMB may also convene as need if stopping criteria are met or other 
safety issues arise that the Principal Investigator and/or IRB would like the WCM 
DSMB to address. The study Principal Investigator is responsible for submitting all 
written DSMB recommendations to the IRB upon receipt.  
 
C. Efficacy: Additionally, if no subjects out of the first 13 subjects respond after 6 
months of follow-up, the study will be terminated for lack of treatment efficacy. 
 
D. After Amendment dated 30 March 2020 – the study will be terminated for the 
following reasons: 
i.If no subjects out of the first 10 subjects respond within the first 6 
months of therapy, the study will be terminated for lack of treatment 
efficacy 
ii. If the there are more than 2 grade IV (or higher) toxicities seen in the 
same subject (out of the first 10 subjects), the study will be 
terminated for excessive toxicity 
 


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XIII. 
INVESTIGATOR RESPONSIBILITIES  
 
A. 
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 subinvestigator, 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. 
 
B. 
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 subinvestigators’ 
review committees, under an appropriate understanding of confidentiality.  
 
C. 
Record Retention- Records from the Drug Dispensing Log: Research study center 
personnel will maintain adequate records of the receipt and disposition of all test 
medications used in the research study.  Records should include dates, quantities 
received, quantities dispensed, and the identification code of the patient who 
received the test medications.  The investigator agrees to administer the research 
study medications only to patients under his/her personal supervision.   
 
D. 
Patient Exclusion Log: A record listing all patients considered for entry into the 
research study and subsequently excluded must be maintained by the PI.  Patients 
excluded form the research study will have the reason for exclusion recorded on the 
Patient Exclusion Log, which will be provided by the Sponsor. 
 
E. 
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. 
 
F. 
Record Retention: Records from the research study must be retained by 
subinvestigators until they can be retrieved by the PI or designee once the data from 
individual research study patients has been collected and CRFs completed.  
 
G. 
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 


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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. 
 
H. 
Monitoring: This research study will be monitored by representatives of the PI and 
Sponsor (The New York Presbyterian Hospital-Weill Medical College of Cornell 
University) 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.  
 
 
XIV. 
PROTOCOL DEVIATIONS 
 
Departures from either the research protocol entry criteria or the experimental plan, 
as outlined herein, will be determined as allowable on a case-by-case basis.  The 
investigator must contact the PI or designee as soon as possible to discuss the 
associated circumstances. The PI will then decide as to the patient’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 patient’s CRF. 
 
 
XV. 
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.   
 


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APPENDIX A 
 
 
Performance Status Evaluation 
 
 
 


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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 
 
 


 
 
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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 readministered. 
 
 
Possible (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, 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 


 
 
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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 rechallenge*. 
 
• 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.