Conditions: Glioblastoma Multiforme Glioblastoma Malignant Glioma GBM
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
Glioblastoma multiforme (GBM) is the most common and deadliest primary malignant neoplasm of the central nervous system in adults. Despite an aggressive multimodality treatment approach including surgery, radiation therapy and chemotherapy, overall survival remains poor. Novocure has shown that when properly tuned, very low intensity, intermediate frequency electric fields (TTFields) stunt the growth of tumor cells. The Optune system (NovoTTFTM Therapy) is a portable battery operated device, which produces TTFields within the human body by means of surface transducer arrays. The TTFields are applied to the patient by means of surface transducer arrays that are electrically insulated, so that resistively coupled electric currents are not delivered to the patient. Optune is currently FDA-approved as a single modality treatment for recurrent GBM when both surgical and radiotherapy options have been exhausted as well as combination with adjuvant temozolomide for newly diagnosed GBM.

This research study is being performed to determine whether or not TTFields combined with pulsed bevacizumab treatment increases overall survival in patients with bevacizumab-refractory GBM compared to historical controls treated with continuous bevacizumab alone or in combination with other chemotherapy.

Detailed description:
Subjects who have evidence of bevacizumab-refractory GBM will be eligible to participate in this research study. Subjects will undergo 12 months of planned continuous treatment with TTFields followed by pulsed bevacizumab treatment when there is evidence of further progression per RANO, with the option of extending treatment up to a total of 24 months in patients who have not progressed and/or have adequate performance status at the 12 month mark. Pulsed bevacizumab dosing is defined by at least one cycle on and at least one cycle off. A cycle is defined as 8 weeks in length. If after one cycle on, there is no evidence of a repeat response; bevacizumab will be continued for one more cycle. If after two cycles on, there is no repeat response; bevacizumab will be continued with or without other standard chemotherapy until death. If after at least one cycle on, there is evidence of repeat response, bevacizumab will be discontinued for at least one cycle or until progression is noted again per RANO, whichever is later, at which time pulsed bevacizumab will be restarted as outlined above. The investigators believe that this approach will produce peaks and troughs in mitotic activities of glioma cells that render glioma cells more sensitive to the antimitotic activity of Optune during peak growth rates, thus lowering disease burden and increasing survival. In addition, the following will be performed: Bevacizumab will be given at 10mg/kg IV every 2 weeks. Physical examination and quality of life (QoL) assessments will be performed bi-monthly. Brain MRI will be performed every 2 months.

Arms:
arm 1: The subjects will undergo 12 months of planned continuous treatment with Optune. The treatment will begin at week 0 and will be continuous throughout the study. Pulsed bevacizumab dosing is defined by at least one cycle on and at least one cycle off. A cycle is defined as 8 weeks in length. If after one cycle on, there is no evidence of a repeat response; bevacizumab will be continued for one more cycle. If after two cycles on, there is no repeat response; bevacizumab will be continued with or without other standard chemotherapy until death. If after at least one cycle on, there is evidence of repeat response, bevacizumab will be discontinued for at least one cycle. In addition, the following will be performed: Bevacizumab will be given, physical examination and quality of life questionnaires will be performed and brain MRI.

Interventions: intervention 1: Bevacizumab intervention 2: Optune intervention 3: Brain MRI intervention 4: Quality of Life Questionnaires
Intervention descriptions: intervention 1: Bevacizumab will be given at 10mg/kg IV every 2 weeks. intervention 2: Optune will be worn continuously for 12 months. Optune is programmed by Novocure to deliver 200 kHz TTFields in two sequential, perpendicular field directions at a maximal intensity of 707mARMS. There will be no adjustments made to the device by investigators or patients/caregivers. intervention 3: Brain MRI will be done at screening and every 8 weeks. intervention 4: The quality of life questionnaires will be performed within 14 days of treatment and every 4 weeks.

Protocol document:
Prot_SAP_000.pdf: 
Version: 04/15/2022 
 
Page 1 of 51 
A Phase 2, Multi-center, Single arm, Historically Controlled Study Testing the 
Combination of TTFields and Pulsed Bevacizumab Treatment in Patients with 
Bevacizumab-refractory Recurrent Glioblastoma 
 
University of Florida 
Department of Neurological Surgery 
PO Box 100265 
Gainesville, FL 32610 
 
Protocol#: 201600074 
Version Date: 04/15/2022 
 
 
Coordinating Center: 
 
University of Florida 
 
Principal Investigator: 
 
David D. Tran, M.D., Ph.D. 
Phone:  (352) 273-9000 
E-mail:  david.tran@neurosurgery.ufl.edu 
 
Washington University PI:  
George Ansstas, M.D. 
 
 
 
 
 
E-mail: gansstas@dom.wustl.edu 
 
 
Sub-Investigators 
 
 
Institution 
 
 
Modality 
Ashley Ghiaseddin, M.D. 
 
University of Florida  
Neuro-Oncology 
 
 
Study Device: 
 
NovoTTF-100A (Optune) 
Study Drug: 
 
Bevacizumab (Avastin®) 
 
 
Clinical Trials.gov #:  
 
NCT02663271 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL: The information contained in this document is regarded as confidential and, except to the 
extent necessary to obtain informed consent, may not be disclosed to another party unless law or regulations 
require such disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them. 


Version: 04/15/2022 
 
Page 2 of 51 
A Phase 2, Multi-center, Single arm, Historically Controlled Study Testing the 
Combination of TTFields and Pulsed Bevacizumab Treatment in Patients with 
Bevacizumab-refractory Recurrent Glioblastoma 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
 
    3/21/2016 
Amendment 1 
12/01/2016 
Amendment 2 
05/23/2017 
Amendment 3 
08/29/2017 
Amendment 4 
10/24/2017 
Amendment 5 
03/09/2018 
Amendment 6 
08/31/2018 
Amendment 7 
11/19/2020 
Amendment 7.1 
04/15/2022 
 
 
 


Version: 04/15/2022 
 
Page 3 of 51 
Summary of Protocol Changes 
Version Date 
Sections Revised 
Purpose 
3/21/2016 
N/A 
-Initial Protocol Release 
12/01/2016 
Title Page 
 
-Individuals updated to reflect current personnel. 
-Version date changed. 
Schema 
-Schema updated for clarity and consistency. 
Table of Contents 
-Updated for pagination. 
4.1, Inclusion Criteria 
-Clarified informed consent as a criterion for inclusion. 
5.0, Registration 
Procedures 
-Clarified timing of protocol intervention in relation to consent 
and registration. 
6.1, Treatment with 
Bevacizumab 
-Specified assessments and defined timeframe and window for 
completion. 
-Included reference to Appendix D, which was added to clarify 
bevacizumab dose modifications in event of adverse events. 
6.2, Treatment with 
TTFields 
-Updated to clarify that compliance with TTFields will be 
monitored by Novocure per usual procedures. 
6.4, Potential Adverse 
Events:  Bevacizumab 
-Included reference to Appendix D, Bevacizumab Dose 
Modifications and Appendix E, Hypertension Management 
which were added to provide clarification for patient 
management. 
7.1.2, Quality of Life 
7.1.3, Response Criteria 
-Clarified timing of assessments for internal consistency. 
8.0, Dose Delays/Dose 
Modifications 
-Updated to include reference to Appendix D, Bevacizumab 
Dose Modifications. 
11.0, Schedule of 
Events 
-Updated for clarity and internal consistency. 
-Updated to clarify procedures (urinalysis/dipstick) and time 
points to monitor for proteinuria and describe modifications in 
bevacizumab dosing based on results.  
16.0, Statistical 
Considerations 
-Updated to reflect the statistical plan for all objectives. 
21.0, Appendix D, 
Bevacizumab 
Modifications 
-New appendix added to clarify recommendations for 
bevacizumab dose modifications in event of adverse events. 
22.0, Appendix E, 
Management of 
Hypertension 
-New appendix added to clarify management of hypertension 
in patients treated with bevacizumab. 


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Page 4 of 51 
 
05/23/2017 
11.0 Schedule of 
Events 
-Schedule of events revised to better reflect the timing of 
assessments (physical exam, pregnancy test, KPS, MMSE) that 
should be associated with screening and registration rather than 
Week 0.  
12.0 Data Submission 
Schedule 
-Data submission time points for KPS and MMSE updated from 
4 to 8 weeks for consistency with schedule of events and to 
reflect treatment standard. 
13.3 Methods for 
Evaluation of 
Measurable Disease 
-Error in verbiage corrected as brain FDG-PET coupled with 
head CT or brain MRI should not be used as the primary or sole 
method of determining response or disease status.  This was an 
unintended error in previous protocol versions. 
9/15/2017 
Table of Contents 
-Updated to reflect change in page numbers. 
4.1  Inclusion Criteria -Revision to allow Bevacizumab refractory patients in the trial 
during any recurrence or progression of disease.  A shift in use 
of  Bevacizumab to later recurrence has become practice.  
Update is needed to capture Bevacizumab refractory patients. 
7.1  Imaging 
-MRI should be obtained every 8 weeks +/- 7 days.  Updated for 
continuity throughout protocol. 
13.1  Antitumor 
effect: Solid Tumors 
-Updated response evaluation to 8 weeks +/- 7 days.  Updated 
for continuity throughout protocol. 
11.0  Schedule of 
Events 
-Study calendar updated to reflect what is included in survival 
follow up. 
13.3.5  Neurological 
Exam and 
Performance Status 
-Updated evaluation every 4 weeks +/- 2 weeks.  Updated for 
continuity throughout protocol. 
Appendix C: RANO 
-Updated RANO measurement form.  
Appendix F: 
Guidance on 
Contraception 
-Appendix F added . 
10/24/2017 
1.0, Protocol 
Synopsis 
-Clarified number of evaluable subjects needed to complete 
study. 


Version: 04/15/2022 
 
Page 5 of 51 
 
 
4.1 Inclusion Criteria 
-Clarified eligibility criterion #1 limiting the number of prior 
progressions on bevacizumab.   
7.1.3  Response 
Criteria 
-Added provision to allow for replacement of subjects who are 
not evaluable.  
03/09/2018 
10.1 Reporting 
Requirements for 
Secondary Sites 
-Reference to events that require reporting added for 
completeness. 
14.0 Data and Safety 
Monitoring 
-Monitoring plan added per DSMB recommendation with onset 
of accrual at secondary site and event reporting clarified. 
15.0 Auditing 
-Requirement for auditing better delineated. 
8/31/2018 
8.0 External 
Palliative Care 
-Section added to allow for subjects to receive treatment with 
bevacizumab locally to decrease travel burden on patients. 
11/19/2020 
Title (throughout) 
 
-Correction of typographical error. 
12.0  Schedule of 
Events 
-MRI timeframe clarified since patients may be scanned prior to 
the Screening Visit, and without this revision the MRI might 
become asynchronous to the protocol treatment timeline. 
 


Version: 04/15/2022 
 
Page 6 of 51 
A Phase 2, Multi-center, Single arm, Historically Controlled Study Testing the Combination 
of TTFields and Pulsed Bevacizumab Treatment in Patients with Bevacizumab-refractory 
Recurrent Glioblastoma 
 
Principal Investigator Signature Page 
 
 
Principal Investigator: 
 
David Tran, M.D., PhD.  
 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
Printed Name of Investigator 
 
 
 
By my signature, I agree to personally supervise the conduct of this study 
and to ensure its conduct in compliance with the protocol, informed 
consent, IRB/HRPO procedures, the Declaration of Helsinki, ICH Good 
Clinical Practices guidelines, and the applicable parts of the United States 
Code of Federal Regulations or local regulations governing the conduct of 
clinical studies. 


Version: 04/15/2022 
 
Page 7 of 51 
No  
Yes 
No  
No  
Yes 
Yes 
No  
Yes 
Bevacizumab-Refractory 
Recurrent GBM 
(25 Patients) 
Consent, Screening and  
Registration 
NovoTAL Mapping 
Placement of Arrays 
(Planned treatment: 12 months) 
First Radiographic 
Progression 
Bevacizumab 
Re-challenge  
(Continue TTF) 
Hold Bevacizumab 
(1 or more Cycle) 
Continue Bevacizumab 
(1 Cycle) 
Repeat Radiographic 
Response 
Repeat Radiographic 
Response 
Bimonthly Follow Up  
Planned TTF (Optune) 
Monotherapy 
Continue Bevacizumab w/o 
or w/ Other Chemotherapy 
Radiographic Progression 
Hold Bevacizumab 
(1 or more Cycle) 
Radiographic Progression 
Overall Survival 
SCHEMA 


Version: 04/15/2022 
 
Page 8 of 51 
Glossary of Abbreviations 
 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
BBB 
Blood brain barrier 
B-HCG 
Beta human chorionic gonadotropin  
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CNS 
Central nervous system 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DLTs 
Dose Limiting Toxicities 
DSM 
Data and Safety Monitoring  
ECI 
Event of clinical interest 
FDA 
Food and Drug Administration 
FNA 
Fine needle aspiration 
FWA 
Federal wide assurance 
GBM 
Glioblastoma multiforme 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (IRB) 
IB 
Investigator’s brochure 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
INR 
International normalized ratio 
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
IULN 
Institutional upper limit of normal 
IV 
Intravenous (i.v.) 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NSCLC 
Non-small cell lung cancer 


Version: 04/15/2022 
 
Page 9 of 51 
OHRP 
Office of Human Research Protections  
OS 
Overall survival 
PFS 
Progression-free survival 
PI 
Principal investigator 
PK 
Pharmacokinetic 
PT 
Prothrombin time 
PTT 
Partial thromboplastic time 
QASMC 
Quality Assurance and Safety Monitoring Committee 
RANO 
Response Assessment in Neuro-Oncology 
SAE 
Serious adverse event 
SUSAR 
Suspected unexpected serious adverse reaction 
TIL 
Tumor-infiltrating lymphocytes 
TSH 
Thyroid stimulating hormone 
TTFields 
Tumor-treating fields 
UPN 
Unique patient number 
 
 
 


Version: 04/15/2022 
 
Page 10 of 51 
TABLE OF CONTENTS 
 
 PROTOCOL SYNOPSIS .......................................................................................................12 
 BACKGROUND AND RATIONALE ..................................................................................13 
 GLIOBLASTOMA MULTIFORME ............................................................................................. 13 
 BEVACIZUMAB (AVASTIN®) .................................................................................................. 13 
 INTRODUCTION TO ELECTRIC FIELDS .................................................................................... 13 
 NOVOCURE’S TUMOR-TREATING FIELDS (TTFIELDSTM) ....................................................... 14 
 THE OPTUNE SYSTEM ........................................................................................................... 14 
 STUDY RATIONALE ............................................................................................................... 15 
 OBJECTIVES .........................................................................................................................17 
 PRIMARY OBJECTIVES ........................................................................................................... 17 
 SECONDARY OBJECTIVES ...................................................................................................... 17 
 PATIENT SELECTION ........................................................................................................17 
 INCLUSION CRITERIA ............................................................................................................ 17 
 EXCLUSION CRITERIA ........................................................................................................... 18 
 INCLUSION OF WOMEN AND MINORITIES .............................................................................. 18 
 REGISTRATION PROCEDURES .......................................................................................18 
 CONFIRMATION OF PATIENT ELIGIBILITY ............................................................................. 19 
 PATIENT REGISTRATION IN THE UNIVERSITY OF FLORIDA CANCER CENTER DATABASE ...... 19 
 ASSIGNMENT OF UPN ........................................................................................................... 19 
 TREATMENT PLAN .............................................................................................................19 
 TREATMENT WITH BEVACIZUMAB ........................................................................................ 19 
 TREATMENT WITH TTFIELDS ................................................................................................ 20 
6.2.1 Recommendations for Use of Optune .......................................................................... 21 
6.2.2 Skin Care Guidelines ................................................................................................... 21 
 POTENTIAL ADVERSE EVENTS: OPTUNE ............................................................................... 22 
 POTENTIAL ADVERSE EVENTS: BEVACIZUMAB..................................................................... 22 
 STUDY ASSESSMENTS .......................................................................................................22 
 IMAGING ............................................................................................................................... 22 
7.1.1 Lab Work ...................................................................................................................... 23 
7.1.2 Quality of Life .............................................................................................................. 23 
7.1.3 Response Criteria......................................................................................................... 23 
7.1.4 Duration of Therapy .................................................................................................... 23 
7.1.5 Duration of Follow-up ................................................................................................. 24 
 DOSE DELAYS/DOSE MODIFICATIONS ........................................................................24 
 REGULATORY AND REPORTING REQUIREMENTS .................................................24 
 ADVERSE EVENTS (AES) ...................................................................................................... 24 
 SERIOUS ADVERSE EVENTS (SAES) ...................................................................................... 25 


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 UNANTICIPATED PROBLEMS ................................................................................................. 25 
 NONCOMPLIANCE ................................................................................................................. 25 
 SERIOUS NONCOMPLIANCE ................................................................................................... 25 
 PROTOCOL EXCEPTIONS ........................................................................................................ 25 
 REPORTING TO THE IRB AND UFHCC DATA AND SAFETY MONITORING 
BOARD ............................................................................................................................................26 
 
REPORTING REQUIREMENTS FOR SECONDARY SITES ........................................................ 26 
 
REPORTING TO SECONDARY SITES .................................................................................... 26 
 SCHEDULE OF EVENTS .....................................................................................................28 
X3.............................................................................................................................................. 28 
 DATA SUBMISSION SCHEDULE ......................................................................................30 
 MEASUREMENT OF EFFECT ...........................................................................................30 
 
ANTITUMOR EFFECT- SOLID TUMORS ............................................................................... 30 
 
DISEASE PARAMETERS ...................................................................................................... 32 
 
METHODS FOR EVALUATION OF MEASURABLE DISEASE .................................................. 33 
13.3.1 
Evaluation of Target Lesions ................................................................................... 33 
13.3.2 
Evaluation of Non-Target Lesions ........................................................................... 34 
13.3.3 
Evaluation of Best Overall Response ....................................................................... 34 
13.3.4 
Duration of Response ............................................................................................... 35 
13.3.5 
Neurological Exam and Performance Status ........................................................... 35 
13.3.6 
Progression-Free Survival ....................................................................................... 35 
 DATA AND SAFETY MONITORING ................................................................................35 
 AUDITING ..............................................................................................................................36 
 STATISTICAL CONSIDERATIONS ..................................................................................36 
 REFERENCES ........................................................................................................................38 
 APPENDIX A: KARNOFSKY PERFORMANCE SCALE ...............................................41 
 APPENDIX B: MINI-MENTAL STATUS EXAM .............................................................43 
 APPENDIX C:  RANO MEASUREMENT FORM .............................................................46 
 APPENDIX D: BEVACIZUMAB DOSE MODIFICATIONS ...........................................48 
 APPENDIX E: MANAGEMENT OF HYPERTENSION ..................................................50 
23.0 APPENDIX F:  GUIDANCE ON CONTRACEPTION ......................................................51 
 
 
 
 


Version: 04/15/2022 
 
Page 12 of 51 
 PROTOCOL SYNOPSIS 
 
Title 
A Phase 2, Multi-center, Single arm, Historically Controlled Study 
Testing the Combination of TTFields and Pulsed Bevacizumab Treatment 
in Patients with Bevacizumab-refractory Recurrent Glioblastoma 
Study Device & 
Drug 
NovoTTF-100A (Optune); Bevacizumab (Avastin®) 
Study Objectives 
To determine whether or not TTFields combined with pulsed 
bevacizumab treatment increases overall survival in patients with 
bevacizumab-refractory GBM compared to historical controls treated with 
continuous bevacizumab alone or in combination with standard 
chemotherapy. 
Study Design 
Phase 2, single-arm, open-labeled, historically controlled 
Study Hypothesis 
Successive cycles of on/off (or pulsed) bevacizumab dosing will produce 
peaks and troughs, respectively, in mitotic activities of glioma cells that 
render glioma cells more sensitive to the antimitotic activity of TTFields 
during peak growth rates, thus lowering disease burden and increasing 
survival. 
Sample Size 
25 evaluable adult patients with bevacizumab-refractory recurrent primary 
or secondary GBM, WHO Grade IV 
Study population 
Male or female patients with bevacizumab-refractory recurrent GBM 
(WHO grade IV) who are ≥ 22 years of age 
Primary endpoint 
Overall survival 
Secondary 
endpoint 
Rate of repeat response to bevacizumab re-challenge after at least 1 cycle 
Disease assessment 
Per RANO criteria 
Sponsor 
NovoCure Ltd. 
PO Box 15022 
MATAM Center 
Haifa, 31905, Israel 
 
 
 
 


Version: 04/15/2022 
 
Page 13 of 51 
 BACKGROUND AND RATIONALE 
 
 
Glioblastoma Multiforme  
 
Glioblastoma multiforme (GBM) is the most common and deadliest primary malignant 
neoplasm of the central nervous system in adults. Despite aggressive multimodality treatment 
approach including surgery, radiation therapy and chemotherapy, the median overall survival 
(OS) reaches only 14.6 months (1), and increasing to 19.6 months with the addition of 
TTFields in newly diagnosed GBM (ASCO Abstract 2015). Recurrent GBM has an even 
more dismal prognosis with a median overall survival of ~25 weeks (2). 
 
 
 
Bevacizumab (Avastin®) 
 
Bevacizumab (Avastin®, Genentech, Inc., South San Francisco, CA) is an anti-VEGF 
recombinant humanized monoclonal antibody approved in the United States as a single agent 
for recurrent GBM (3, 4). Although radiographic responses are observed on MRI following 
treatment with bevacizumab, to date, no direct comparison between bevacizumab and 
cytotoxic chemotherapy has been conducted, and it remains unclear if bevacizumab improves 
OS in patients with recurrent GBM (3, 4). Once refractory to bevacizumab, patients are 
unlikely to respond to subsequent regimens, whether they contain bevacizumab or not and 
inevitably relapse. Median OS after bevacizumab failure has ranged from approximately 1.1 
to 4.5 months regardless of treatment (5-7). 
 
 
 
Introduction to Electric Fields 
 
In the laboratory setting and in clinical practice, alternating electric fields show a wide range 
of effects on living tissues.  At very low frequencies (under 1 kHz), alternating electric fields 
stimulate excitable tissues through membrane depolarization (8).  The transmission of such 
fields by radiation is insignificant and therefore they are usually applied directly by contact 
electrodes, though some applications have also used insulated electrodes.  Some well-known 
examples of such effects include nerve, muscle, and heart stimulation by alternating electric 
fields (8, 9). In addition, low frequency pulsed electric fields have been claimed to stimulate 
bone growth and accelerate fracture healing (10).  However, as the frequency of the 
alternating electric field increases above 1 kHz, the stimulatory effect diminishes.  Under 
these conditions although a greater fraction of the fields penetrates the cells, due to the 
parallel resistor-capacitor nature of all biological membranes, the stimulatory power greatly 
diminishes as the alternating cell membrane hyper-depolarization cycles are integrated such 
that the net effect is nulled. 
 
At very high frequencies (i.e., above many MHz), while the integration becomes even more 
effective, a completely different biological effect is observed.  At these frequencies tissue 
heating becomes dominant due to dielectric losses.  This effect becomes more intense as field 
intensity or tissue dissipation factor increase (11).  This phenomenon serves as the basis for 
some commonly used medical treatment modalities including diathermy and radio frequency 
tumor ablation, which can be applied through insulated electrodes (12). 


Version: 04/15/2022 
 
Page 14 of 51 
 
Intermediate frequency electric fields (i.e., tens of kHz to MHz) alternate too fast for causing 
nerve-muscle stimulation and involve only minute dielectric losses (heating).  Such fields of 
low to moderate intensities are commonly considered to have no biological effect (11).  
However, a number of non-thermal effects of minor biological consequence have been 
reported even at low field intensities.  These include microscopic particle alignment (i.e., the 
pearl chain effect) and cell rotation (13-15).  With pulsed relatively strong electric fields, > 
103 V/cm and 100 ms pulse length, reversible pore formation appears in the cell membrane, 
a phenomenon usually called electroporation (16, 17). 
 
 
 
Novocure’s Tumor-treating Fields (TTFieldsTM) 
 
Novocure has shown that when properly tuned, very low intensity, intermediate frequency 
electric fields (TTFields) stunt the growth of tumor cells (18).  This inhibitory effect was 
demonstrated in all proliferating cell types tested, whereas non-proliferating cells and tissues 
were unaffected.  Interestingly, different cell types showed specific intensity and frequency 
dependences of TTField inhibition.  It has been shown that two main processes occur at the 
cellular level during exposure to TTFields: arrest of proliferation and dividing cell 
destruction.  The damage caused by TTFields to these replicating cells was dependent on the 
orientation of the division process in relation to the field vectors, indicating that this effect is 
non-thermal.  Indeed, temperature measurements made within culture dishes during 
treatment and on the skin above treated tumors in vivo showed no significant elevation in 
temperature compared to control cultures/mice.  Also, TTFields caused the dividing cells to 
orient in the direction of the applied field in a manner similar to that described in cultured 
human corneal epithelial cells exposed to constant electric fields (19).  At the sub-cellular 
level, it was found that TTFields disrupt the normal polymerization-depolymerization 
process of microtubules during mitosis. Indeed, the described abnormal mitotic 
configurations seen after exposure to TTFields are similar to the morphological 
abnormalities seen in cells treated with agents that interfere directly (20, 21) or indirectly 
(22-25) with microtubule polymerization (e.g., Taxol). 
 
 
The Optune System 
 
The Optune system (NovoTTFTM Therapy) is a portable battery operated device, which 
produces TTFields within the human body by means of surface transducer arrays (26, 27).  
The TTFields are applied to the patient by means of surface transducer arrays that are 
electrically insulated, so that resistively coupled electric currents are not delivered to the 
patient.  The transducer arrays, which incorporate a layer of adhesive hydrogel and a layer 
of hypoallergenic medical tape, are placed on the patient’s shaved head.  The transducer 
arrays must be replaced every three to four days and the scalp re-shaved in order to maintain 
optimal capacitative coupling between the transducer arrays and the patient head.  All the 
treatment parameters are pre-set by Novocure so there are no electrical output adjustments 
available to the patient.  The patient must learn to change and recharge depleted service 
batteries and to connect to an external battery pack overnight. 
 


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Page 15 of 51 
Optune is currently FDA-approved as a single modality treatment for recurrent GBM when 
both surgical and radiotherapy options have been exhausted as well as combination with 
adjuvant temozolomide for newly diagnosed GBM. In the pivotal EF-11 trial in recurrent 
GBM, overall survival (OS) of patients treated with the device was equivalent to those treated 
with standard chemotherapy alone (27). Six-month progression-free survival (6PFS) analysis 
favored the TTFields arm compared to the chemo arm, although not statistically significant. 
Safety and toxicity profile favored the Optune arm compared to the chemotherapy control 
arm. No device-specific grade 3 and 4 toxicities were identified for hematologic, 
gastrointestinal, vascular, renal and respiratory disorders. There was also no increased grade 
3 and 4 central nervous system adverse events. The most common device specific adverse 
event was skin rash due to the transducer arrays. 
 
 
Study Rationale  
 
A post hoc subgroup analysis of the EF-11 study data revealed that patients with 
bevacizumab-refractory GBM achieved median OS of 6.3 months when treated with 
TTFields monotherapy compared to 3.3 months when standard bevacizumab-based 
chemotherapy was continued (HR 0.39, 95% CI 0.19-0.79, p=0.01).  This preliminary data 
suggest that bevacizumab-refractory GBM may be particularly sensitive to the anti-mitotic 
activity of TTFields (28, 29) after bevacizumab withdrawal.  Rapid tumor regrowth and 
radiographic tumor rebound phenomenon has been reported after withdrawal of bevacizumab 
in patients with recurrent high-grade glioma, leading to an accelerated clinical decline (30).  
For this reason, many practitioners are reluctant to discontinue bevacizumab even when 
bevacizumab failure is well documented, and thus this approach represents a potential 
overtreatment.  Molecularly, acquired resistance to bevacizumab in high grade gliomas is 
thought to result from a meschymal transition characterized by an enrichment of slow-
cycling, highly invasive, and treatment-resistant glioma stem-like cells (GSCs) (31, 32). 
After discontinuation of bevacizumab, the microhypoxic stress and pro-GSC environment 
are removed and presumably GSCs exit cell cycle arrest and reactivate rapid proliferation. 
This is during bevacizumab withdrawal that we hypothesis that GBM cells, especially GSCs 
reentering rapid cycling, are most sensitive to the anti-mitotic activities of TTFields.  
Bevacizumab treatment may be resumed temporarily for subsequent radiographic 
progression or worsening symptoms, due to either further disease progression or 
inflammatory responses to TTFields-induced cell death. Once inflammation is controlled, 
bevacizumab is again withdrawn and this cycle can be repeated many times.  We hypothesize 
that successive cycles of on/off (or pulsed) bevacizumab dosing will produce peaks and 
troughs in mitotic activities of GSCs that allows TTFields to work at slowly reducing the 
GSC fraction in tumors, and thus lowering disease infiltration and increasing survival.    
 
We recently conducted a case series study describing the outcomes for 8 patients with 
bevacizumab-refractory GBM, who were treated with TTFields monotherapy first, then with 
concomitant re-challenge with bevacizumab upon subsequent radiographic progression in 5 
of these patients (33). The 8 patients had a median OS of 216 days (7.2 months) from first 
day of treatment with TTFields therapy, which was significantly longer than historical data 
of 1-4 months and consistent with the subgroup analysis of EF-11 data. Of the 5 patients re-
challenged with bevacizumab, median OS from first dose of bevacizumab re-challenge was 


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Page 16 of 51 
172 days (5.7 months), although they all had developed resistance to bevacizumab after 
having received a median time of 236.5 days (7.9 months) of bevacizumab prior to starting 
TTFields. Patients highly adherent to treatment -- who were also those who received pulse 
dose bevacizumab -- had the longest OS. Patient # 4 had an adherence rate of 92.9%; her 
time from first day of TTFields therapy to death was 276 days (9.2 months) and, from first 
dose of bevacizumab re-challenge until death, 150 days (5.0 months).  Patient # 7, with an 
adherence rate of 73.2%, had a time from first day of TTFields to death of 406 days (13.5 
months) and, from first dose of bevacizumab re-challenge until death, of 349 days (11.6 
months) (Fig. 1). 
 
In this case series, we describe 8 patients with recurrent glioblastoma in whom we 
discontinued treatment with bevacizumab successfully - despite the concern of possible rapid 
disease progression upon bevacizumab withdrawal, effectively used TTFields therapy, and 
then re-challenged them with bevacizumab once patients developed symptoms and/or had 
evidence of radiographic progression. This “pulsed dosing” approach to bevacizumab 
administration, combined with TTFields therapy, has not been described in this patient 
population, and although the results from this small study is encouraging this novel approach 
will need to be formally tested in a focused prospective clinical study.  
 
 
 


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 OBJECTIVES 
 
 
Primary Objectives 
 
1. To determine whether or not TTFields combined with pulsed bevacizumab treatment 
increases overall survival in patients with bevacizumab-refractory GBM compared to 
historical controls treated with continuous bevacizumab alone or in combination with 
other chemotherapy. 
 
 
Secondary Objectives 
 
1. To determine whether or not TTFields combined with pulsed bevacizumab treatment re-
sensitizes bevacizumab-refractory GBM to bevacizumab re-challenge. 
 
2. To determine whether or not TTFields combined with pulsed bevacizumab treatment is 
safe in patients with bevacizumab-refractory GBM. 
 
 
  
PATIENT SELECTION 
 
 
Inclusion Criteria 
 
1. Patients must have histologically confirmed GBM, WHO grade IV (GBM variants or 
secondary GBM is allowed) in any recurrence on any therapy, except that only one prior 
tumor progression on bevacizumab is permitted. Prior therapy must include radiation and 
chemotherapy, which includes, but not limited to, temozolomide, PCV, bevacizumab, 
CCNU or BCNU. 
 
2. Unequivocal evidence of tumor progression during prior bevacizumab treatment per 
RANO criteria. 
 
 
3. Patient is a candidate for, and agrees to proceed with additional bevacizumab treatment. 
 
4. Male or female at least 22 years of age or older. 
 
5. Karnofsky Performance Scale (KPS) ≥ 60%. 
 
6. Planned treatment with TTFields therapy.  
 
7. Women of childbearing potential must have a negative serum or urine pregnancy test 
within 14 days of treatment.   
 
8. Participants of childbearing/reproductive potential must use effective contraception as 
outlined in Appendix F. 
 


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9. Participants must be able to understand and willing to comply with protocol requirements 
as assessed by the investigator. 
 
10. Signed informed consent according to institutional guidelines must be obtained prior to 
registration. 
 
 
 
 
Exclusion Criteria 
 
 
1. Inability to undergo brain MRI due to medical or personal reasons. 
 
2. Currently receiving investigational agents that are intended as treatments of recurrent 
GBM. 
 
3. Skull defect such as missing bone or bullet fragments. 
 
4. Uncontrolled intercurrent illness including, but not limited to symptomatic congestive 
heart failure, unstable angina pectoris, heart attack within the previous 12 months, stroke 
(except for TIA) within the previous 6 months, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
 
5. Intracranial hemorrhage except for tumor associated micro hemorrhage. 
 
6. Women who are pregnant or breastfeeding. 
 
7. Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, vagus 
nerve stimulator, and other implanted electronic devices in the brain or the spinal cord. 
 
8. Tumor located entirely in the infratentorium. 
 
9. History of hypersensitivity to hydrogel. 
 
 
 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
 REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to consent and registration with the 
University of Florida. 
 
The following steps must be taken before registering patients to this study: 


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1. Confirmation of patient eligibility by University of Florida 
2. Registration of patient in OnCore, the University of Florida Cancer Center’s Clinical 
Trial Management System 
3. Assignment of unique patient number (UPN) 
 
Once the patient has been entered in OnCore, the study coordinator will forward verification of 
enrollment and the UPN via email. 
 
 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below and scanning and 
emailing it to the University of Florida research coordinator at least one business day prior to 
registering patient: 
 
1. Your name and contact information (telephone/fax numbers and email address) 
2. Your site PI’s name, the registering MD’s name, and your institution name 
3. Patient’s race, sex, and DOB 
4. Three letters (or two letters and a dash) for the patient’s initials 
5. Currently approved protocol version date 
6. Copy of signed consent form (patient name may be blacked out) 
7. Planned date of enrollment 
8. Completed eligibility checklist, signed and dated by a member of the study team 
9. Copy of appropriate source documentation confirming patient eligibility 
 
 
Patient Registration in the University of Florida Cancer Center Database 
 
Registrations may be submitted Monday through Friday between 8am and 5pm EST. Urgent 
late afternoon or early morning enrollments should be planned in advance and coordinated 
with the University of Florida research coordinator. Registration will be confirmed by the 
research coordinator or his/her delegate by email within one business day. Verification of 
eligibility and registration should be kept in the patient chart. 
 
All patients at all sites must be registered through OnCore at the University of Florida. 
 
 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  Patients 
will also be identified by first, middle, and last initials.  If the patient has no middle initial, a 
dash will be used on the case report forms (CRFs).  All data will be recorded with this 
identification number on the appropriate CRFs. 
 
 TREATMENT PLAN 
 
 
Treatment with Bevacizumab 
 


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Patients with unequivocal evidence of bevacizumab-refractory GBM per RANO criteria will 
be eligible. Patients will undergo 12 months of planned continuous treatment with TTFields 
followed by pulsed bevacizumab treatment when there is evidence of further progression per 
RANO, with the option of extending treatment up to a total of 24 months in patients who have 
not progressed and/or have adequate performance status at the 12 month mark.  Pulsed 
bevacizumab dosing is defined by at least one cycle on and at least one cycle off.  A cycle is 
defined as 8 weeks in length (Fig. 2).  If after one cycle on, there is no evidence of a repeat 
response bevacizumab will be continued for one more cycle.  If after two cycles on, there is 
no repeat response bevacizumab will be continued with or without other standard 
chemotherapy until death.  If after at least one cycle on, there is evidence of repeat response, 
bevacizumab will be discontinued for at least one cycle or until progression is noted again per 
RANO, whichever is later, at which time pulsed bevacizumab will be restarted as above.  
Bevacizumab will be given at 10mg/kg IV every 2 weeks. Physical examination, KPS and 
MMSE will be performed within 28 days (+/- 7) of starting treatment with TTFields and every 
8 (+/- 2) weeks thereafter.  Brain MRI will be performed at screening and every 8 weeks (+/- 
7) days thereafter.   
 
Dose modifications for bevacizumab will be in accordance with guidelines in Appendix D. 
 
Patients may be infused locally at the discretion of the enrolling investigator. 
 
 
Treatment with TTFields 
 
Patients will undergo 12 months of planned treatment with TTFields.  Therapy will be given 
as per standard of care (see Section 6.2.1 for recommended use of the TTFields). 3D mapping 
and placement maps of recurrent tumors will be completed by the principal investigator. 
Placement of transducer arrays will be provided by Novocure. Scalp shaving, array 
placement and all device support services (including patients’ and families’ education of 
device operation, downloading and processing of technical and compliance data, and 
troubleshooting device malfunction) will be provided by device support specialists employed 
by Novocure. The minimum treatment compliance required for this study is wearing the 
system for an average of no less than 60% of the time over each 4-week period with the goal 
of achieving 75% or more of the time over each 4-week period.  Compliance with TTFields 
will be monitored by Novocure per usual procedures.   If a patient’s compliance drops below 
60% over any given 4-week period, the patient will be trained on the importance of 
compliance and any barriers to compliance will be addressed.   If a patient’s compliance is 
below 60% for 2 consecutive 4-week periods, the patient will be removed from study. At the 
discretion of treating investigators, patients can have an additional treatment break during 


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each 4 week period of no more than 3 consecutive days as needed for personal reasons as 
long as the overall compliance for any 4 week period does not drop below 60% because of 
the additional break. 
 
6.2.1 Recommendations for Use of Optune 
 
All patients will be required to shave their heads to initiate array placement and 
TTField therapy.  Array placement will be performed based on the transducer array 
map calculated during treatment planning.  It is recommended that treatment with the 
device be continuous with breaks allowed for personal needs (e.g., showering, array 
exchange).  Breaks should be no more than 1 hour twice daily.   Use compliance is 
aimed at a minimum of 60% (14.4 hours) with the goal of achieving at least 75% (18 
hours) of the time per day on average.  In addition, investigators may grant brief 
breaks in device treatment that last no more than 3 days in any 30 day period at the 
investigator’s discretion.   
 
Optune is programmed by Novocure to deliver 200 kHz TTFields in two sequential, 
perpendicular field directions at a maximal intensity of 707mARMS.  There will be 
no adjustments made to the device by investigators or patients/caregivers. 
 
It is recommended that patients replace the transducer arrays 2-3 times per week with 
the help of a caregiver.  At each array replacement, it is recommended that the 
patient’s scalp be re-shaved and skin treated according to the guidelines in section 
6.2.2. 
 
There will be no dose adjustments to the device for adverse events.  Reasons for 
breaks in treatment for longer than 24 hours will be documented. 
 
6.2.2 Skin Care Guidelines 
 
If the skin beneath the transducer arrays is inflamed, it is recommended that a 
prescription strength steroid ointment (e.g. 3% hydrocortisone or 0.05-0.1% 
Clobetasol) be prescribed to the patient.  The patient or caregiver should apply the 
ointment after removing the arrays and cleaning the scalp with baby oil and medical 
alcohol.  The ointment should be left on the scalp for at least 30 minutes prior to 
washing the skin with a mild shampoo and applying a new set of arrays. 
 
At each array replacement, it is recommended that the new set of arrays be shifted by 
approximately 2 cm compared to the previous layout so that the array discs are placed 
between the areas of skin irritation.  At the next array replacement, the arrays should 
be shifted back to their original location. 
 
If the dermis is breached (ulcers, open sores, punctate lesions, cuts, etc.), it is 
recommended that an antibiotic ointment (e.g. bactroban) be prescribed and used in 
place of the steroid ointment. 
 


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Potential Adverse Events: Optune 
 
Treatment with Optune is not expected to cause any serious side effects.  However, it is 
possible that treatment may cause any of the following: 
 
• Local warmth and tingling “electric” sensation beneath the transducer array 
• Allergic reaction to the adhesive or the gel 
• Skin irritation or skin breakdown 
• Infection at the sites of transducer array contact with the skin 
• Transducer array overheating leading to pain and/or local skin burns 
• Headache 
• Fatigue 
 
Treatment with Optune is FDA approved and standard of care.   
 
 
Potential Adverse Events: Bevacizumab 
 
See Appendix D for bevacizumab dose modifications. 
 
In initial Phase I and Phase II clinical trials, the following four potential bevacizumab-
associated safety signals were identified: 
 
• Hypertension  (See Appendix E for guidelines on hypertension management)  
• proteinuria  
• thromboembolic events 
• hemorrhage   
 
Additional completed Phase II and Phase III studies of bevacizumab as well as spontaneous 
reports have further defined the safety profile of this agent. Bevacizumab-associated adverse 
events identified in phase III trials include: 
 
• congestive heart failure (CHF) primarily in metastatic breast cancer 
• gastrointestinal perforations  
• wound healing complications   
• arterial thromboembolic events (ATE)  
• visceral arterial ischemia  
• disseminated intravascular coagulation resulting in death was reported in a single case 
recently 
 
 STUDY ASSESSMENTS 
 
 
Imaging 
 
Patients will undergo standard brain MRI scans without then with gadolinium contrast every 
8 weeks (+/- 7) days) while on study as per routine care.  Information from these scans will be 


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recorded in the study database.  If a patient develops symptoms that are potentially indicative 
of disease progression, scans may be done sooner than every 8 weeks as per standard practice. 
 
7.1.1 Lab Work 
 
No additional lab work is required during study treatment. Labs are to be 
performed as clinically indicated during bevacizumab treatment as per standard 
practice. 
 
7.1.2 Quality of Life 
 
Quality of life will be assessed every 8 weeks (+/- 2 weeks) by way of the MMSE 
(Appendix B) and assessment of Karnofsky Performance Scale (Appendix A), as 
performed as a part of routine standard-of-care assessments. 
 
7.1.3 Response Criteria 
 
All patients are evaluable for response and for assessment of QoL after completing 
at least 8 weeks of treatment with the Optune device with compliance rate > 60% 
in at least one 4-week period.  Subjects failing to meet these criteria will be 
replaced. 
 
7.1.4 Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to 
the patient’s health and/or the patient no longer wishes to continue protocol 
therapy, the protocol therapy should be discontinued and the reason(s) for 
discontinuation documented in the case report forms. 
 
In the absence of treatment delays due to adverse events, subjects will be removed 
from the study for the following reasons:  
 
• GI perforation 
• Documented and confirmed disease progression after bevacizumab re-challenge 
• Death 
• Adverse event(s) that in the judgment of the investigator may cause severe or 
permanent harm or which rule out continuation of study treatment  
• General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
• Pregnancy 
• Less than 60% compliance with the TTFields Therapy for 2 consecutive 4-week 
periods 
• Other serious noncompliance with the study protocol, e.g. missed appointments 
without valid reason 
• Lost to follow-up 
• Patient withdraws consent 


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• Investigator removes the patient from study 
• The Coordinating or participating site decides to close the study 
 
7.1.5 Duration of Follow-up 
 
Patients will have one follow-up visit 30 days (+/- 7 days) after stopping treatment.  
Patients will then be followed every 8 weeks (+/- 2 weeks) for up to 2 years for 
survival. Survival information can be obtained by telephone or from clinic notes.   
 
 
 EXTERNAL PALLIATIVE CARE 
 
Subjects enrolled in this trial may receive bevacizumab at an institution (e.g. local hospital, clinic, 
infusion center or other appropriate administration site) not selected as a research site for this 
study, if a trial investigator determines that it would be in the subject’s best interest to receive 
treatment in a local setting.  The trial investigators will retain responsibility for overseeing 
protocol-related activities, ensuring the study interventions are administered in accordance with the 
IRB-approved protocol and ensuring any applicable protocol-related data, including but not limited 
to, safety data and adverse events are reported to trial investigators.   
 
 DOSE DELAYS/DOSE MODIFICATIONS 
 
The standard dose for bevacizumab is 10mg/kg IV every 2 weeks. If adverse events occur during 
the bevacizumab cycle, the standard dose can be adjusted at the principal investigator’s 
discretion and per accepted standard practice, for example, decrease dose (7.5 mg/kg every 2 
weeks), or maintain standard dose but increase the time frame between doses (10mg/kg every 
three weeks), or hold for toxicities as outlined in Appendix D, Bevacizumab Dose 
Modifications.  There will be no “dose” adjustments to the device for adverse events.  Reasons 
for breaks in treatment for longer than 24 hours will be documented. 
 
 
 REGULATORY AND REPORTING REQUIREMENTS 
 
 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any abnormal 
sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.  A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human 
Services’ Office for Human Research Protections (OHRP).  A copy of this guidance can be 
found on OHRP’s website: 


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http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
 Serious Adverse Events (SAEs) 
 
Definition: any adverse event that results in any of the following:  
 
• Death 
• A life-threatening adverse event 
• Inpatient hospitalization or prolonging existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
 
Note:  The term “life-threatening” refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe.  
 
 Unanticipated Problems 
 
Definition: 
 
• unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied; 
• related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
• suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that govern 
human- subject’s research or failure to follow the determinations of the IRB.  Noncompliance 
may occur due to lack of knowledge or due to deliberate choice to ignore regulations, institutional 
policies, or determinations of the IRB. 
 
 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks that result in substantial harm to 
subjects or others, or that materially compromises the rights or welfare of participants. 
 
 Protocol Exceptions 
 


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Definition: A planned deviation from the approved protocol that are under the research 
team’s control. Exceptions apply only to a single participant or a singular situation. 
 
Local IRB approval of all protocol exceptions must be obtained prior to the event. For all 
sites, the UF PI will issue approval of the exception, but it must be submitted to the local 
IRB with documentation of local approval forwarded to UF. UF IRB approval is not required 
for protocol exceptions occurring at secondary sites.   
 
   Reporting to the IRB and UFHCC Data and Safety Monitoring Board 
 
Each PI is required to promptly notify their IRB of the following events:  
 
• Any unanticipated problems involving risks to participants or others 
• Non-compliance with federal regulations or the requirements of the IRB 
• Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study.  
 
These events must be reported to the institution’s IRB of record within 10 working days (or 
in accordance with local IRB policies) of the occurrence of the event or notification to the PI 
of the event. The death of a research participant that qualifies as a reportable event should be 
reported within 1 working day of the occurrence (or in accordance with the local IRB 
policies) of the event or notification to the PI of the event.  
 
 Reporting Requirements for Secondary Sites 
 
The research team at each secondary site is required to promptly notify the UF PI and research 
coordinator of all reportable events (as described above 9.2 to 9.6) within 1 working day of 
the occurrence of the event or notification of the secondary site’s PI of the event. This 
notification may take a place via email if there is not yet enough information for a formal 
written report (using either an FDA MedWatch form if required or an institutional SAE 
reporting form).  A formal written report must be sent to the UF PI and research coordinator 
within 4 calendar days (for fatal or life-threatening adverse experiences) or 11 calendar days 
(for serious, unexpected adverse experiences). 
 
Each secondary site is responsible for reporting events to their local IRB in accordance with 
institutional guidelines.  
 
 Reporting to Secondary Sites 
 
The University of Florida PI (or designee) will notify the research team at each secondary site, 
of all reportable events that have occurred at other sites (as described above) within 10 
working days of the occurrence of the event or notification of the PI of the event. This includes 
events that take place both at the University of Florida and at other secondary sites, if 
applicable.  
 
 


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  SCHEDULE OF EVENTS  
 
 
Screening and 
Registration 
Week 0 
Week 8 
On-Treatment 
Management 
30-day 
Post-Tx 
Follow-up 
Survival 
Follow-up 
Informed consent1 
X 
 
 
 
 
 
Medical history2 
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
 
 
Physical examination 
X3 
 
X3 
X3 
 
 
Pregnancy test 
X4 
 
 
 
 
 
Urine Dipstick/Urinalysis 
 
 
X11 
X11 
 
 
Pulsed bevacizumab5 
 
 
X8 
X8 
 
 
MRI 
X6 
 
X6 
X6 
 
 
Optune 
 
X7 
X7 
X7 
 
 
Karnofsky Performance Scale 
X3 
 
X3 
X3 
 
 
MMSE 
X3 
 
X3 
X3 
 
 
AE Monitoring 
X 
X 
X 
X 
X 
 
Post treatment follow-up 
 
 
 
 
X9 
 
Survival contact 
 
 
 
 
 
X10 
1. No study-specific procedures are to be performed prior to obtaining informed consent.  However, assessments performed according to SOC prior to consent 
may be used to fulfill the screening requirement, if completed within the window for screening. Study treatment should start within 14 (+/-3) days after 
informed consent is obtained. 
2. Medical history may be performed at any time prior to registration. 
3. Physical exam, KPS and MMSE will be performed within 28(+/-7) days of Optune treatment and every 8 (+/- 2) weeks thereafter. 
4. Urine or serum pregnancy test is required for women of child-bearing potential only within 14 (+/- 3) days of treatment. 
5. Bevacizumab infusions will be given at 10mg/kg as per SOC. 
6. Patients will undergo SOC brain MRI scans with RANO response evaluation at screening, and then every 8 weeks (+/- 7 days) from Week 0 (Optune treatment 
start) 
7. Optune treatment will begin at week 0 [14 (+/- 3) days from day of consent] and will be continuous throughout the study.   
8. Pulsed bevacizumab dosing will begin at the time of progression. If repeat response is determined after 1 cycle, bevacizumab will be discontinued for at least 
1 cycle; however if after one cycle, there is no evidence of a repeat response (progression continues) bevacizumab will be given for another cycle.  If progression 
continues after the second cycle, the patient will be withdrawn from the study and will continue SOC treatment until death.  
9. Patients will undergo a 30-day post treatment follow-up visit after treatment discontinuation or study withdrawal.  Post treatment follow-up can take place via 
telephone if the patient is no longer being seen in clinic.  


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10. All patients will have their survival status documented every 8 weeks (+/- 1 month) for up to two years.  Survival follow up is defined as: alive status or date 
of death.  Survival information can be obtained via telephone or from clinic notes.  
11. Urinalysis or urine dipstick will be performed prior to each dose of bevacizumab as per standard of care.  Monitor proteinuria by urine dipstick for development 
or worsening proteinuria with serial analyses during therapy.  Patients with 2+ or greater urine dipstick reading should undergo further assessment with 24h 
urine collection.  Suspend administration for > 2g/24hrs and resume when < 2g/24 hrs.  Discontinue in patients with nephrotic syndrome. 
 


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 DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
following schedule: 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Registration Form 
Eligibility Form 
On-Study Form 
Prior to starting treatment 
Treatment Summary Form for TTFields Every 4 weeks  until completion of treatment  
Treatment Summary Form for 
Bevacizumab  
Every 2 weeks while patient is on the cycle 
MRI Form 
Baseline and every 2 months thereafter until 
completion of treatment 
KPS Form 
MMSE 
Every 8 weeks until completion of treatment  
Survival Information 
Every 8 weeks after withdrawal or 30-day  post 
treatment follow-up 
Adverse Events Form 
As per Section 9.0 
 
Participating site(s) must respond to queries generated by the University of Florida within 28 days 
of request. The University of Florida may institute corrective action measures for any site with 
delinquent or poor quality data. 
 
 
 MEASUREMENT OF EFFECT 
 
 Antitumor Effect- Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks 
+/- 7 days.  In addition to a baseline scan, confirmatory scans should also be obtained 8 
weeks +/- 7 days following initial documentation of objective response. If a patient develops 
symptoms that are potentially indicative of disease progression, scans may be done sooner 
than every 8 weeks as per standard practice. 
 
Response and progression will be evaluated in this study using the updated response 
assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology 
(RANO) working group guideline (34). 
 
 


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Criteria for Determining First Progression Depending on Time from Initial 
Chemoradiotherapy 
 
First Progression 
Definition 
Progressive disease 
< 12 weeks after 
completion of 
chemoradiotherapy 
Progression can only be defined using diagnostic imaging if there is new 
enhancement outside of the radiation field (beyond the high-dose region or 
80% isodose line) or if there is unequivocal evidence of viable tumor on 
histopathologic sampling (e.g., solid tumor areas [i.e., > 70% tumor cell 
nuclei in areas], high or progressive increase in MIB-1 or Ki67proliferation 
index compared with prior biopsy, or evidence for histologic progression or 
increased anaplasia in tumor). Note: Given the difficulty of differentiating 
true progression from pseudoprogression, clinical decline alone, in the 
Absence of radiographic or histologic confirmation of progression, will not 
be sufficient for definition of progressive disease in the first 12 weeks after 
completion of concurrent chemoradiotherapy.  
Progressive disease 
≥ 12 weeks after 
chemoradiotherapy 
completion 
1. New contrast-enhancing lesion outside of radiation field on decreasing, 
stable, or increasing doses of corticosteroids. 
2. Increase by ≥ 25% in the sum of the products of perpendicular diameters 
between the first postradiotherapy scan, or a subsequent scan with 
smaller tumor size, and the scan at 12 weeks or later on stable or 
increasing doses of corticosteroids.  
3. Clinical deterioration not attributable to concurrent medication or 
comorbid conditions is sufficient to declare progression on current 
treatment but not for entry onto a clinical trial for recurrence.  
4. For patients receiving antiangiogenic therapy, significant increase in 
T2/FLAIR non-enhancing lesion may also be considered progressive 
disease. The increased T2/FLAIR must have occurred with the patient 
on stable or increasing doses of corticosteroids compared with baseline 
scan or best response after initiation of therapy and not be a result of 
comorbid events (e.g., effects of radiation therapy, demyelination, 
ischemic injury, infection, seizures, postoperative changes, or other 
treatment effects).  
 
 
 


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Criteria for Response Assessment Incorporating MRI and Clinical Factors 
(Adapted from JCO 2010) 
Response 
Criteria 
Complete 
response 
Requires all of the following:  
• 
Complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 
4 weeks. 
• 
No new lesions; stable or improved non-enhancing (T2/FLAIR) lesions. 
• 
Patients must be off corticosteroids (or on physiologic replacement doses only) and stable or improved 
clinically. Note: Patients with non-measurable disease only cannot have a complete response; the best 
response possible is stable disease.  
Partial 
response 
Requires all of the following:  
• 
≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all 
measurable enhancing lesions sustained for at least 4 weeks. 
• 
No progression of non-measurable disease. 
• 
No new measureable lesion.  
• 
Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared with baseline scan; the corticosteroid dose at the time of the scan evaluation should be no 
greater than the dose at time of baseline scan. 
• 
Stable or improved clinically. Note: Patients with non-measurable disease only cannot have a partial 
response; the best response possible is stable disease.  
Stable 
disease 
Requires all of the following:  
• 
Does not qualify for complete response, partial response, or progression. 
• 
Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with 
baseline scan. In the event that the corticosteroid dose was increased for new symptoms and signs without 
confirmation of disease progression on neuroimaging, and subsequent follow-up imaging shows that this 
increase in corticosteroids was required because of disease progression, the last scan considered to show 
stable disease will be the scan obtained when the corticosteroid dose was equivalent to the baseline dose. 
Progression 
Defined by any of the following:  
• 
≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions (with the absolute 
increase of at least 1 dimension of at least 5 mm) compared with the smallest tumor measurement 
obtained either at baseline (if no decrease) or best response, on stable or increasing doses of 
corticosteroids*. 
• 
Significant increase in T2/FLAIR nonenhancing lesion on stable or increasing doses of corticosteroids 
compared with baseline scan or best response after initiation of therapy* not caused by comorbid events 
(e.g. radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or 
other treatment effects). 
• 
Any new measureable lesion (at least 10mm in at least 2 perpendicular dimensions).  
• 
Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. seizures, medication 
adverse effects, complications of therapy, cerebrovascular events, infection, and so on) or changes in 
corticosteroid dose. 
• 
Failure to return for evaluation as a result of death or deteriorating condition; or clear progression of 
nonmeasurable disease.  
NOTE. All measurable and nonmeasurable lesions must be assessed using the same techniques as at baseline. 
Abbreviations: MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery. 
* Stable doses of corticosteroids include patients not on corticosteroids.  
   Disease Parameters 
 


Version: 04/15/2022 
 
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Measurable disease:  Bi-dimensionally measurable lesions with clearly defined margins by 
MRI scan. All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Non-measurable or evaluable disease: Uni-dimensionally measurable lesions or lesions 
with margins not clearly defined such as areas of T2/FLAIR signal abnormality or poorly 
defined enhancing abnormality. 
 
Note: For cystic lesions, the only measurable part is any enhancement area around the cyst 
that is clearly defined and bi-dimensionally measurable. The cyst itself should not be 
considered measurable or non-measureable disease. 
 
Target lesions: Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), but in addition should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement in which circumstance the next largest lesion, which can 
be measured reproducibly should be selected. When there are too many measurable lesions, 
choose the largest 3 lesions as target lesions to follow. The other measurable lesions should 
be considered evaluable for the purpose of objective status determination. 
 
Non-target lesions:  All non-measurable lesions should be identified as non-target lesions 
and should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler.  All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 2 weeks before the beginning of the treatment. 
 
Clinical lesions:  Clinical lesions will only be considered measurable on brain MRI when 
they are ≥ 5 mm diameter as assessed using a ruler. 
 
Histology: This technique can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases when biopsy or surgical resection of a measureable 
lesion is clinically indicated.  
 
Perfusion/CBV: This advanced brain MRI technique can be used as an adjunct test to 
determine treatment response or disease status.  However, it should not be used as the 
primary or sole method to determine response or disease status.  
Brain FDG-PET coupled with head CT or brain MRI: This advanced metabolic imaging 
technique can be used as an adjunct test to determine response or disease status. However it 
should not be used as the primary or sole method of determining response or disease status. 
 
14.3.1 Evaluation of Target Lesions 


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Complete Response (CR):  Disappearance of all target lesions. 
 
Partial Response (PR): ≥ 50% decrease compared with baseline in the sum of 
products of perpendicular diameters of all target lesions sustained for at least 4 weeks. 
 
Progressive Disease (PD): At least a 25% increase in the sum of products of 
perpendicular diameters of at least 1target lesion, taking as reference the smallest 
sum of products of perpendicular diameters on study (this includes the baseline sum 
if that is the smallest on study).  
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of products of 
perpendicular diameters while on study. 
 
14.3.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s). 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions on stable or increasing doses 
of corticosteroids compared with baseline scan or best response after initiation of 
therapy* not caused by comorbid events (e.g. radiation therapy, demyelination, 
ischemic injury, infection, seizures, postoperative changes, or other treatment 
effects). Unequivocal progression should not normally trump target lesion status.  It 
must be representative of overall disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
14.3.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
Summary of the RANO Response Criteria 
 
Criterion 
CR 
PR 
SD 
PD 
T1 gadolinium enhancing disease 
None 
≥ 50% ↓ 
< 50% ↓ but < 25% ↑ ≥ 25% ↑* 


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Page 35 of 51 
Criterion 
CR 
PR 
SD 
PD 
T2/FLAIR 
Stable or ↓ Stable or ↓ Stable or ↓ 
↑* 
New measureable lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or ↓ Stable or ↓ 
NA† 
Clinical status 
Stable or ↑ Stable or ↑ Stable or ↑ 
↓* 
Requirement for response 
All 
All 
All 
Any* 
Abbreviations: RANO, Response Assessment in Neuro-Oncology; CR, complete response; PR, partial response; SD, 
stable disease; PD, progressive disease; FLAIR, fluid-attenuated inversion recovery; NA, not applicable.  
* Progression occurs when this criterion is present.  
† Increase in corticosteroids alone will not be taken into account in determining progression in the absence of 
persistent clinical deterioration.  
 
14.3.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) until 
the first date that recurrent or progressive disease is objectively documented (taking 
as reference for progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
14.3.5 Neurological Exam and Performance Status 
 
Patients will be graded using the Karnofsky Performance Status scale and their 
neurological function evaluated as improved, stable or deteriorated in addition to 
objective measurement of tumor size. These parameters will be used to determine the 
overall response assessment and will be collected every 4 weeks (+/- 2 weeks). 
 
14.3.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression 
or death, whichever occurs first. 
 
 
 DATA AND SAFETY MONITORING 
 
 


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Page 36 of 51 
The study principal investigator and clinical research coordinator will monitor for serious toxicities 
on an ongoing basis. Once the principal investigator or clinical research coordinator becomes aware 
of an adverse event, the AE will be reported to the IRB and DSMB, if applicable, according to 
institutional guidelines. 
 
Adverse events meeting the definition of an SAE must be reported to the Coordinating Center 
within 1 working day of the investigator’s discovery by e-mail and entered into OnCore within 72 
hours.  These events will be assessed by the Protocol Chair and reported to the IRB and DSMB per 
institutional requirements, FDA as applicable and other participating investigators as outlined in 
the protocol. 
 
Data and safety monitoring will be performed by the UF Health Cancer Center (UFHCC) Data 
Integrity and Safety Committee (DISC).  The UFHCC SRMC conducts initial review of IITs and 
determines the level of risk which corresponds with DISC review requirements.  Given the risk level 
assigned to this protocol, this trial will undergo review by the DISC annually to review study and 
toxicity data.  The UFHCC DISC will also conduct monitoring and audit activities as outlined in the 
DISC Charter.  Any study subject enrolled on the trial, regardless of enrollment site, may be subject 
to DISC monitoring or audit.  Audit activities are done to verify data accuracy, assess protocol 
compliance and adherence to GCP and ensure timely and complete reporting of safety data.  Consent 
documents, treatment records and regulatory documents, among others, may be reviewed.  Once 
notified of an impending audit, the UF coordinator will notify secondary sites of the audit date and 
date by which applicable source documentation must be provided to the Coordinating Center 
(usually within 72 hours from the site notification).  The results of DISC activities will be provided 
to the PI, IRB and secondary sites. 
 
The Coordinating Center will periodically review data entry in OnCore and notify sites of missing, 
incomplete or inconsistent data as applicable. 
 
 
  AUDITING 
 
The University of Florida is the Coordinating Center and will also be responsible for auditing this 
study as described above.  Any reports of local audits performed at secondary sites should be 
provided to the Coordinating Center.   
 
 
 STATISTICAL CONSIDERATIONS 
 
Statistical Considerations for the Primary Objective of the Proposed Trial 
 
For primary endpoint OS, Kaplan-Meier Curve will be generated. Median survival and its 95% 
confidence interval (CI) will be calculated if applicable. One-sample log-rank test will be used to 
compare OS between study intervention vs. historical control. 
Statistical details of the clinical trial design and assumptions/results of a power analysis of the 
proposed trial sample size follow: 
 


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Page 37 of 51 
Accrual and follow-up: 
Patient accrual rate: 2 patients per month 
Accrual period: 12 months (10 to 18 months considered) 
Follow-up after the end of accrual: 6 months  
 
Historical control group (EF-11): N=21 
In the pivotal EF-11 trial in recurrent GBM, a post hoc subgroup analysis of the data revealed that 
patients with bevacizumab-refractory GBM achieved median OS of 6.3 months when treated with 
TTFields monotherapy compared to 3.3 months when standard bevacizumab-based chemotherapy 
was continued (HR 0.39, 95% CI 0.19-0.79, p=0.01).  The length of follow-up was 24 months and 
the median survival time was 3.3 months. 
 
Testing scenario  
The Wald test statistic will be used to test the following null (H0) and alternative (H1) hypotheses: 
H0:  HR >= 1   (log (HR) >= 0) 
H1:  HR <   1   (log (HR) <   0) 
(The HR is the ratio of the experimental group hazard rate to the control group hazard rate) 
1-tailed alpha-level:  0.05 
Power level:  80%, 90%, 95% 
 
Assumptions: 
Survival times in both the historical control group and the experimental group are assumed to follow 
Weibull distributions(35). Given the observed historical control group median survival time and the 
trajectory of the survival curve from the Novocure EF11 post-hoc analysis, the  Weibull shape 
parameter k appears to fall somewhere between 1.5 and 2.5: 
 
k=1.5 (accelerating hazard function, probability of dying in the next instant increases over time) 
 
k=2.5 (hazard function accelerating more rapidly, probability of dying in the next instant increases 
more rapidly over time). 
 
For Weibull-distributed survival times, the hazard ratio (experimental vs control) is equal to the ratio 
of the control group median survival time (m1) to the experimental group median survival time (m2), 
raised to the power of the shape parameter k: HR = (m1/m2)k 
 
This is why the minimum detectable m2 for fixed m1 and fixed detectable HR decreases as the shape 
parameter k increases (a more rapidly accelerating hazard function will result in more observable 
deaths in a fixed period of time). 
 
Largest hazard ratio (HR) < 1 (or smallest median survival time > 3.3 months) that can be detected 
at 80%, 90%, or 95% power and a 1-tailed significance level of 0.05, by sample size (N=20 to 36, 
or 10 to 18 months of accrual at 2 patients per month) and shape parameter k=1.50, 2.50: 
 
Weibull Shape Parameter k = 1.5 
 
80% Power 
90% Power 
95% Power 


Version: 04/15/2022 
 
Page 38 of 51 
Sample 
Size 
N Months 
Accrual 
HR  
LD50 
HR  
LD50 
HR  
LD50 
20 
10 
0.43   
5.8     
0.37   
6.4     
0.32   
7.1 
22 
11 
0.45   
5.7     
0.38   
6.3     
0.33   
6.9 
24 
12 
0.46   
5.6     
0.39   
6.2     
0.35   
6.6 
26 
13 
0.47   
5.5     
0.40   
6.1     
0.36   
6.5 
28 
14 
0.47   
5.5     
0.41   
6.0     
0.37   
6.4 
30 
15 
0.48   
5.4     
0.42   
5.9     
0.37   
6.4 
32 
16 
0.48   
5.4     
0.42   
5.9     
0.38   
6.3 
34 
17 
0.49   
5.3     
0.43   
5.8     
0.39   
6.2 
36 
18 
0.49   
5.3     
0.43   
5.8     
0.39   
6.2 
 
 
Table 5: Weibull Shape Parameter k = 2.5 
 
80% Power 
90% Power 
95% Power 
Sample 
Size 
N Months 
Accrual 
HR  
LD50 
HR  
LD50 
HR  
LD50 
20 
10 
0.45   
4.5 
0.39   
4.8     
0.35   
5.0 
22 
11 
0.46   
4.5 
0.40   
4.8     
0.36   
5.0 
24 
12 
0.47   
4.5 
0.41   
4.7     
0.36   
5.0 
26 
13 
0.47   
4.5 
0.42   
4.7     
0.37   
4.9 
28 
14 
0.48   
4.4 
0.42   
4.7     
0.38   
4.9 
30 
15 
0.49   
4.4 
0.43   
4.6     
0.38   
4.9 
32 
16 
0.49   
4.4 
0.43   
4.6     
0.39   
4.8 
34 
17 
0.49   
4.4 
0.44   
4.6     
0.39   
4.8 
36 
18 
0.50   
4.4 
0.44   
4.6     
0.40   
4.8 
 
Statistical Considerations for the Secondary Objectives of the Proposed Trial 
 
To address our secondary objectives, we will generate point estimates with 95% confidence 
intervals (CI) for the proportion of patients demonstrating repeat response after one cycle of 
Bevacizumab, after two cycles, and after greater than two cycles.  We will also use proportion 
point estimates with 95% CI's to characterize the rates of various adverse events observed during 
the course of the trial.  Although we will have no historical data to serve as a basis for comparison 
of repeat response rates associated with pulsed Bevacizumab treatment, we will contrast our 
observed adverse event rates with those that have been established for standard treatment with 
Bevacizumab. 
 
                     
 
 
  
 REFERENCES 
 


Version: 04/15/2022 
 
Page 39 of 51 
1. 
R. Stupp et al., Effects of radiotherapy with concomitant and adjuvant temozolomide versus 
radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year 
analysis of the EORTC-NCIC trial. The Lancet Oncology 10, 459-466 (2009). 
2. 
E. T. Wong et al., Outcomes and prognostic factors in recurrent glioma patients enrolled 
onto phase II clinical trials. J Clin Oncol 17, 2572-2578 (1999). 
3. 
H. S. Friedman et al., Bevacizumab Alone and in Combination With Irinotecan in Recurrent 
Glioblastoma. Journal of Clinical Oncology 27, 4733-4740 (2009). 
4. 
J. J. Vredenburgh et al., Bevacizumab Plus Irinotecan in Recurrent Glioblastoma 
Multiforme. Journal of Clinical Oncology 25, 4722-4729 (2007). 
5. 
F. M. Iwamoto et al., Patterns of relapse and prognosis after bevacizumab failure in recurrent 
glioblastoma. Neurology 73, 1200-1206 (2009). 
6. 
A. A. Kanner, E. T. Wong, J. L. Villano, Z. Ram, E. F. Investigators, Post Hoc analyses of 
intention-to-treat population in phase III comparison of NovoTTF-100A system versus best 
physician's choice chemotherapy. Semin Oncol 41 Suppl 6, S25-34 (2014). 
7. 
E. C. Quant et al., Role of a second chemotherapy in recurrent malignant glioma patients 
who progress on bevacizumab. Neuro Oncol 11, 550-555 (2009). 
8. 
C. Polk, Ed., Therapeutic Applications of Low-Frequency Sinusoidal and Pulsed Electric 
and Magnetic Fields, (CRC Press, Inc, Connecticut, 1995), pp. 1404-1416. 
9. 
Y. Palti, Stimulation of internal organs by means of externally applied electrodes. Journal of 
applied physiology 21, 1619-1623 (1966). 
10. 
C. A. Bassett, The development and application of pulsed electromagnetic fields (PEMFs) 
for ununited fractures and arthrodeses. Clinics in plastic surgery 12, 259-277 (1985). 
11. 
E. L. Elson, Ed., Biologic Effects of Radiofrequency and Microwave Fields: In Vivo and In 
Vitro Experimental Results, (CRC Press Inc, Connecticut, 1995), pp. 1424-1430. 
12. 
C. K. Chou, Ed., Radiofrequency Hyperthermia in Cancer Therapy, (CRC Press Inc, 
Connecticut, 1995), pp. 1424-1430. 
13. 
S. Takashima, H. P. Schwan, Alignment of microscopic particles in electric fields and its 
biological implications. Biophysical journal 47, 513-518 (1985). 
14. 
U. Zimmermann, J. Vienken, G. Pilwat, Rotation of cells in an alternating electric field: the 
occurrence of a resonance frequency. Zeitschrift fur Naturforschung. Section C: Biosciences 
36, 173-177 (1981). 


Version: 04/15/2022 
 
Page 40 of 51 
15. 
C. Holzapfel, J. Vienken, U. Zimmermann, Rotation of cells in an alternating electric field: 
theory and experimental proof. The Journal of membrane biology 67, 13-26 (1982). 
16. 
P. Pawlowski, I. Szutowicz, P. Marszalek, M. Fikus, Bioelectrorheological model of the cell. 
5. Electrodestruction of cellular membrane in alternating electric field. Biophysical journal 
65, 541-549 (1993). 
17. 
P. Pawlowski, M. Fikus, Bioelectrorheological model of the cell. 4. Analysis of the extensil 
deformation of cellular membrane in alternating electric field. Biophysical journal 65, 535-
540 (1993). 
18. 
E. D. Kirson et al., Disruption of cancer cell replication by alternating electric fields. Cancer 
research 64, 3288-3295 (2004). 
19. 
M. Zhao, J. V. Forrester, C. D. McCaig, A small, physiological electric field orients cell 
division. Proceedings of the National Academy of Sciences of the United States of America 
96, 4942-4946 (1999). 
20. 
M. A. Jordan, D. Thrower, L. Wilson, Effects of vinblastine, podophyllotoxin and 
nocodazole on mitotic spindles. Implications for the role of microtubule dynamics in mitosis. 
Journal of cell science 102 ( Pt 3), 401-416 (1992). 
21. 
E. K. Rowinsky, R. C. Donehower, Paclitaxel (taxol). The New England journal of medicine 
332, 1004-1014 (1995). 
22. 
C. E. Walczak, E. C. Gan, A. Desai, T. J. Mitchison, S. L. Kline-Smith, The microtubule-
destabilizing kinesin XKCM1 is required for chromosome positioning during spindle 
assembly. Current biology : CB 12, 1885-1889 (2002). 
23. 
S. L. Kline-Smith, C. E. Walczak, The microtubule-destabilizing kinesin XKCM1 regulates 
microtubule dynamic instability in cells. Molecular biology of the cell 13, 2718-2731 (2002). 
24. 
T. M. Kapoor, T. U. Mayer, M. L. Coughlin, T. J. Mitchison, Probing spindle assembly 
mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, Eg5. The 
Journal of cell biology 150, 975-988 (2000). 
25. 
H. Maiato et al., MAST/Orbit has a role in microtubule-kinetochore attachment and is 
essential for chromosome alignment and maintenance of spindle bipolarity. The Journal of 
cell biology 157, 749-760 (2002). 


Version: 04/15/2022 
 
Page 41 of 51 
26. 
E. D. Kirson et al., Alternating electric fields arrest cell proliferation in animal tumor models 
and human brain tumors. Proceedings of the National Academy of Sciences of the United 
States of America 104, 10152-10157 (2007). 
27. 
R. Stupp et al., NovoTTF-100A versus physician's choice chemotherapy in recurrent 
glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer 48, 
2192-2202 (2012). 
28. 
E. Fonkem, E. T. Wong, NovoTTF-100A: a new treatment modality for recurrent 
glioblastoma. Expert Rev Neurother 12, 895-899 (2012). 
29. 
E. T. Wong et al., Response assessment of NovoTTF-100A versus best physician's choice 
chemotherapy in recurrent glioblastoma. Cancer Med 3, 592-602 (2014). 
30. 
R. M. Zuniga et al., Rebound tumour progression after the cessation of bevacizumab therapy 
in patients with recurrent high-grade glioma. J Neurooncol 99, 237-242 (2010). 
31. 
Y. Piao et al., Acquired Resistance to Anti-VEGF Therapy in Glioblastoma Is Associated 
with a Mesenchymal Transition. Clinical Cancer Research 19, 4392-4403 (2013). 
32. 
Y. Piao et al., Glioblastoma resistance to anti-VEGF therapy is associated with myeloid cell 
infiltration, stem cell accumulation, and a mesenchymal phenotype. Neuro-Oncology,  
(2012). 
33. 
G. Ansstas, D. D. Tran, Treatment with Tumor Treating Fields Therapy and Pulse Dose 
Bevacizumab in Patients with Bevacizumab-Refractory Recurrent Glioblastoma: A Case 
Series. Case Reports in Neurology DOI: 10.1159/000442196,  (2015). 
34. 
P. Y. Wen et al., Updated response assessment criteria for high-grade gliomas: response 
assessment in neuro-oncology working group. J Clin Oncol 28, 1963-1972 (2010). 
35. 
J. Wu, X. Xiong, Group Sequential Design for Randomized Phase III Trials under the 
Weibull Model. J Biopharm Stat,  (2014). 
 
 
 
 
 APPENDIX A: Karnofsky Performance Scale 
 


Version: 04/15/2022 
 
Page 42 of 51 
Able to carry on normal activity and to work; no 
special care needed. 
100 Normal no complaints; no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
80 
Normal activity with effort; some 
signs or symptoms of disease.  
Unable to work; able to live at home and care for most 
personal needs; varying amount of assistance needed. 
70 
Cares for self; unable to carry on 
normal activity or to do active work. 
60 
Requires occasional assistance, but 
is able to care for most of his 
personal needs. 
50 
Requires considerable assistance 
and frequent medical care.  
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely 
disabled; 
hospital 
admission is indicated although 
death not imminent. 
20 
Very 
sick; 
hospital 
admission 
necessary; 
active 
supportive 
treatment necessary. 
10 
Moribund; 
fatal 
processes 
progressing rapidly. 
0 
Dead 
 
 


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Page 43 of 51 
 APPENDIX B: Mini-Mental Status Exam 
 
Do you have any trouble with your memory? 
May I ask you some questions about your memory? 
 
 
RESPONSE 
SCORE 
ORIENTATION TO TIME 
What is the … 
year? 
 
0 
1 
 
season? 
 
0 
1 
month of the year? 
 
0 
1 
day of the week? 
 
0 
1 
date? 
 
0 
1 
 
ORIENTATION TO PLACE 
Where are we now?  
What is the … 
state (province)? 
 
0 
1 
county (or city/town)? 
 
0 
1 
City/town (or part of 
city/neighborhood)? 
 
0 
1 
Building (name or type)? 
 
0 
1 
Floor of the building 
(room number or 
address)? 
 
0 
1 
 
REGISTRATION 
Listen carefully.  I am going to say three words.  You say them back after I stop.  Ready? 
Here they are … APPLE [pause], PENNY [pause], TABLE [pause].  Now repeat those words 
back to me. 
 
APPLE 
 
0 
1 
PENNY 
 
0 
1 
TABLE 
 
0 
1 
Now keep those words in mind.  I am going to ask you to say them again in a few minutes. 
 
ATTENTION AND CALCULATION [Serial 7s] 
Now I’d like you to subtract 7 from 100.  Then keep subtracting 7 from each answer until I tell 
you to stop. 
What is 100 take away 7? 
 
0 
1 
If needed, say: Keep going 
 
0 
1 
If needed, say: Keep going 
 
0 
1 
If needed, say: Keep going 
 
0 
1 
If needed, say: Keep going 
 
0 
1 
 


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Page 44 of 51 
 
RESPONSE 
SCORE 
Spell WORLD forward, then backward 
 
D=1 
L=1 R=1 
O=1 
W=1  
 
RECALL 
What were those three words I asked you to 
remember? 
 
 
APPLE 
 
0 
1 
PENNY 
 
0 
1 
TABLE 
 
0 
1 
 
NAMING 
What is this? 
[Point to a pencil or pen.]  
0 
1 
What is this? 
[Point to a watch.] 
 
0 
1 
 
REPETITION 
Now I am going to ask you to repeat what I say.  Ready?  “NO IFS, ANDS, OR BUTS.”  Now 
you say that. 
 
NO IFS, ANDS, OR BUTS. 
 
0 
1 
 
COMPREHENSION 
Listen carefully because I am going to ask you to do something. 
Take this paper in your right hand [pause], fold it in half [pause], and put it on the floor (or 
table). 
 
TAKE IN RIGHT 
HAND 
 
0 
1 
FOLD IN HALF 
 
0 
1 
PUT ON FLOOR 
 
0 
1 
 
READING 
Please read this and do what it says. [Show examinee the words on the stimulus form.] 
 
CLOSE YOUR EYES 
 
0 
1 
 
WRITING 
Please write a sentence. 
 
0 
1 
 


Version: 04/15/2022 
 
Page 45 of 51 
DRAWING 
Please copy this 
design. 
0 
1 
 
 
Total Score 
=  
 
Assessment of level of consciousness 
 
Alert 
Drowsy 
Stuporous 
Comatose / Unresponsive 
 
 
 
 
 
 
 
 
 
 


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Page 46 of 51 
 APPENDIX C:  RANO Measurement Form 
 
Study ID: 
Pulsed Bevacizumab 
Name: 
 
DOB: 
Subject ID: 
Baseline Scan Date: 
TARGETLesion(s)* 
Lesion 
Location/Id
entifier 
Series No. 
Image No. 
Measureme
nt 1 (cm) 
Measureme
nt 2 (cm) 
Product(cm2) 
T1 
 
 
 
 
 
0.00 
T2 
 
 
 
 
 
0.00 
T3 
 
 
 
 
 
0.00 
T4 
 
 
 
 
 
0.00 
T5 
 
 
 
 
 
0.00 
                                                                                                              Sum of Products of Diameters (SPD) 
0.00 
*Measurable lesions must be contrast enhancing, have 2 perpendicular diameters >10mm & no cavity or cyst in 
measurement. Select a minimum of 2 & a maximum of 5 lesions. Largets lesions that are suitable for reproducible 
measurements are preferred. 
 
NON-
TARGETLesion(s)^ 
Lesion 
Location/Id
entifier 
Series No. 
Image No. 
Measureme
nt 1 (cm) 
Measureme
nt 2 (cm) 
Enhancing or Non-enhancing? 
NT1 
 
 
 
 
 
 
NT2 
 
 
 
 
 
 
NT3 
 
 
 
 
 
 
NT4 
 
 
 
 
 
 
NT5 
 
 
 
 
 
 
^Non-measurable lesions include lesions that are too small (<10 x 10mm), lesions that do not enhance, and lesions with a poorly defined 
margin. Non-target lesions can also include measurable lesions not included in the 5 target lesions. 
Dexamethasone Dose: 
________ 
mg 
Frequency: 
BID_____________ 
Indication:  
Clinical status 
             
Intracranial EdemaPhysiologic ReplacementOther (Specify) _____________________Clear deterioration due to tumorClear deterioration due to non-tumor 
causesOthers (specify) ______________________Stable ClinicallyImproved Clinically 
 
 
 
 
Study ID: 
Pulsed Bevacizumab 
 
Name: 
 
DOB: 
Subject ID: 
 
Subsequent Scan Date: 
 
TARGETLesion(s)* 
Lesion 
Location/Id
entifier 
Series No. 
Image No. 
Measureme
nt 1 (cm) 
Measureme
nt 2 (cm) 
Product(cm
2) 
SPD from 
Baseline 
or Best 
Response 
 
% 
Change 
of SPD 
T1 
 
 
 
 
 
0.00 
T2 
 
 
 
 
 
0.00 
T3 
 
 
 
 
 
0.00 
T4 
 
 
 
 
 
0.00 
T5 
 
 
 
 
 
0.00 
                                                                                                              Sum of Products of Diameters (SPD) 
0.00 
 
#DIV/0 
*Measurable lesions must be contrast enhancing, have 2 perpendicular diameters >10mm & no cavity or cyst in 
measurement. Select a minimum of 2 & a maximum of 5 lesions. Largets lesions that are suitable for reproducible 
measurements are preferred. 
 
 


Version: 04/15/2022 
 
Page 47 of 51 
NON-
TARGETLesion(s)^ 
Lesion 
Location/Id
entifier 
Series No. 
Image No. 
Measureme
nt 1 (cm) 
Measureme
nt 2 (cm) 
Enhancing 
or Non-
enhancing? 
 
NT1 
 
 
 
 
 
 
L3 
 
 
 
 
 
 
L4 
 
 
 
 
 
 
L5 
 
 
 
 
 
 
^Non-measurable lesions include lesions that are too small (<10 x 10mm), lesions that do not enhance, and lesions 
with a poorly defined margin. Non-target lesions can also include measurable lesions not included in the 5 target 
lesions. 
Dexamethasone Dose: 
________ 
mg 
Frequency: 
BID_____________ 
Indication:  
Clinical status 
Intracranial EdemaPhysiologic ReplacementOther (Specify) _____________________Clear deterioration due to tumorClear deterioration due to non-tumor 
causesOthers (specify) ______________________Stable ClinicallyImproved Clinically 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version: 04/15/2022 
 
Page 48 of 51 
 
 APPENDIX D: BEVACIZUMAB DOSE MODIFICATIONS 
 
Cardiovascular 
Hypertension 
See Section below for management. 
Congestive heart 
failure Grade 3 
Hold until grade ≤1 or baseline level. Then resume 
treatment. If second recurrence, discontinue. 
Grade 4 
Discontinue  
Dermatolog
y/ Skin 
Wound complication, 
non- infectious, Any 
grade
Discontinue  
Gastrointestinal Fistula or leak – Any grade Discontinue  
Obstruction, 
Grade 1 
Grade 2 
 
Continue patient on study for partial 
obstruction NOT requiring medical intervention 
Hold until resolution. Then resume treatment. 
Grade 3-4 
Hold until resolution. If surgery is necessary, patient 
may restart after full recovery from surgery, and at 
investigator’s discretion. 
Perforation, Any grade 
Discontinue 
Hemorrhage 
– non CNS, 
non 
pulmonary 
Grade 3 
Discontinue for subjects who are also receiving full-
dose anticoagulation  
All other subjects hold until the bleeding has 
resolved and hemoglobin is stable and there is no 
structural or pathologic condition that would 
increase bleeding recurrence.
 
Discontinue for any recurrent Grade 3 hemorrhagic 
event
Grade 4 
Discontinue and go to event monitoring. 
Hemorrhage 
– CNS or 
pulmonary 
Grade 1 
Discontinue for subjects who are also receiving full-
dose anticoagulation. 
All other subjects hold until All other subjects hold 
until the bleeding has resolved and hemoglobin is 
stable and there is no structural or pathologic 
condition that would increase bleeding recurrence. 
Grade > 2 
Discontinue 


Version: 04/15/2022 
 
Page 49 of 51 
Renal and 
Urinary 
Disorders 
Proteinuria, Grade 2 (2+ 
proteinuria; urinary protein 
1.0-3.4g/24h) 
 
Proteinuria 
Grade 3 (≥3.5 g/24 hr) 
Check 24h urine if not already done.  Suspend 
administration for > 2g/24hrs and resume when < 
2g/24 hrs. 
 
 
Hold until proteinuria improves to ≤ 2g/24h.. Then 
resume treatment
Grade 4 
(nephrotic syndrome) 
Discontinue  
Neurology 
CNS cerebrovascular 
ischemia 
Any grade 
Discontinue 
Leukoencephalopathy 
syndrome (radiographic 
findings) 
Any grade 
Hold pending workup and management, including 
control of blood pressure. 
Discontinue if Reversible Posterior 
Leukoencephalopathy Syndrome (RPLS) is 
diagnosed.  
Vascular 
Thrombus/embolism Grade 
3 or 4  
Hold and start full dose anticoagulation for at least 2 
weeks. Bevacizumab can be restarted and 
anticoagulation is decreased in half (only for DVT); 
No reduction in anti-coagulation for PE, if the 
subject is asymptomatic after at least 2 weeks on full 
dose anti-coagulation and has not had a grade 3 or 4 
hemorrhagic event while on full dose 
Peripheral arterial ischemia 
Any grade 
Discontinue  
Visceral arterial ischemia 
Any grade 
Discontinue  
All other non- 
hematologic 
adverse 
events 
(excluding 
alopecia) 
Grade 3-4 
(excludes nausea/vomiting 
that has not been 
pre-medicated) 
Hold and address symptomatic relief per standard 
practice. Resume bevacizumab when symptoms 
decrease to grade <=2. If symptoms do not resolve to 
grde <=2 by 4 weeks, discontinue bevacizumab.  
 
 
 
 
 
 
 
 
 
 


Version: 04/15/2022 
 
Page 50 of 51 
 APPENDIX E: MANAGEMENT OF HYPERTENSION  
 
Grade 
(CTCAE v3.0) 
Antihypertensive 
Therapy 
Blood 
Pressure 
Bevacizumab Dose 
Grade 1 
None 
Routine 
No change 
Grade 2 
(asymptomatic) 
Initiate monotherapy 
(e.g. ACE inhibitors or 
calcium-channel blocker) 
Increase frequency 
and monitor per 
local standard until 
stabilized. 
No change 
Grade 2 
(symptomatic/ 
persistent) 
OR 
diastolic BP 
>110 mm Hg 
OR 
Grade 3 
     Add or increase dose 
of  agent(s): e.g. beta-
blockers,  diuretics, 
calcium channel blockers 
Increase frequency 
and monitor per 
local standard and/or 
refer to HTN 
specialist for expert 
management until 
stabilized. 
Hold bevacizumab until 
symptoms resolve and 
diastolic BP ≤110 
mm/Hg and resume 
treatment at 25% dose 
reduction, but no less 
than 5mg/kg IV every 2 
weeks.  If HTN is not 
controlled to <= grade 
2 in > 3 weeks, 
discontinue 
bevacizumab. 
Grade 4 
Urgent Treatment per local 
standard 
Per local standard 
Discontinue bevazimuab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Page 51 of 51 
23.0 APPENDIX F:  GUIDANCE ON CONTRACEPTION 
 
For the purposes of the proposed study, “highly effective” contraceptive methods are defined as 
those, alone or in combination, that result in a low failure rate (i.e., less than 1 percent per year) 
when used consistently and correctly, and include the following: 
 
• Surgical sterilization at least 6 months before Study Drug administration 
• Implants 
• Levonorgestrel (LNG) and Copper T IUDs 
• Sexual abstinence 
 
Subjects who prefer methods which evidence a higher (6-9%) failure rate with typical use will be 
required to employ at least two methods of contraception concurrently.  These methods include the 
following: 
 
• Injectable hormone depos 
• Oral contraceptive pill 
• Hormone patch 
• Vaginal ring 
 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are NOT acceptable methods of contraception. 
 
http://www.cdc.gov/reproductivehealth/unintendedpregnancy/pdf/contraceptive_methods_508.pdf 
for a list of contraceptive methods and effectiveness.