Prophylactic Tumor Treating Fields in Management of Patients With Small Cell Lung Cancer
Phase: PHASE2
Conditions: Extensive Stage Lung Small Cell Carcinoma, Limited Stage Lung Small Cell Carcinoma, Stage I Lung Cancer AJCC v8, Stage IA1 Lung Cancer AJCC v8, Stage IA2 Lung Cancer AJCC v8, Stage IA3 Lung Cancer AJCC v8, Stage IB Lung Cancer AJCC v8, Stage II Lung Cancer AJCC v8, Stage IIA Lung Cancer AJCC v8, Stage IIB Lung Cancer AJCC v8, Stage III Lung Cancer AJCC v8, Stage IIIA Lung Cancer AJCC v8, Stage IIIB Lung Cancer AJCC v8, Stage IIIC Lung Cancer AJCC v8, Stage IV Lung Cancer AJCC v8, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8
Sponsor: OHSU Knight Cancer Institute

 
1 
 
 Study Title: Prophylactic Tumor Treating Fields in management of patients with 
Small Cell Lung Cancer 
Protocol Number:  18029 
ClinicalTrials.gov ID: NCT03995667 
Investigational product: Optune 
Version Number:  1.5 
Version Date: 10/27/2020 
Replaces: 08/30/2019 
IND/IDE Status: IND/IDE # G180232 
Principal Investigator: Timur Mitin, MD PhD 
 
Department of Radiation Medicine 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, KPV4  
Portland, OR 97239  
Phone: 503-681-4200 
Fax: 503-681-4202 
Email: mitin@ohsu.edu 
  
Participating 
Investigator(s): 
Jing Zeng, MD 
Department of Radiation Oncology  
University of Washington Medical Center  
1959 NE Pacific Street, Box 356043  
Seattle, Washington 98195-6043  
Phone: 206-598-4100  
Fax: 206-598-6218  
Email: jzeng13@uw.edu 
 
Terence Tai-Weng Sio, MD MS 
Mayo Clinic Arizona 
5779 E. Mayo Blvd. 
Phoenix, AZ 85054 
Phone: 480-342-1267 
Fax: 480-342-3972 
Email: sio.terence@mayo.edu 
 
Joshua Palmer, MD 
Ohio State University Wexner Medical Center 
James Cancer Hospital 
460 W 10th Ave., Columbus, OH 43210 
Phone: 614-293-8415 
Fax: 614-366-8707 
Email: joshua.palmer@osumc.edu 
 
Jerry Jaboin, MD 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, KPV4  

 
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Portland, OR 97239  
Phone: 503 494-8756  
Fax: 503 346-0237 
Email: jaboin@ohsu.edu 
 
Charles R. Thomas, Jr. MD 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, KPV4  
Portland, OR 97239  
Phone: 503 494-8756  
Fax: 503 346-0237 
Email: thomasch@ohsu.edu 
 
Arthur Hung, MD 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, KPV4  
Portland, OR 97239  
Phone: 503 494-8756  
Fax: 503 346-0237 
Email: hunga@ohsu.edu 
 
Nima Nabavizadeh, MD 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, KPV4  
Portland, OR 97239  
Phone: 503 494-8756  
Fax: 503 346-0237 
Email: nabaviza@ohsu.edu 
 
Reid Thompson, MD PhD 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, KPV4  
Portland, OR 97239  
Phone: 503 494-8756  
Fax: 503 346-0237 
Email: thompsre@ohsu.edu 
 
Aaron Grossberg, MD PhD 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, KPV4  
Portland, OR 97239  
Phone: 503 494-8756  
Fax: 503 346-0237 
Email: grossber@ohsu.edu 
 
Blair Murphy, MD 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, KPV4  

 
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Portland, OR 97239  
Phone: 503 494-8756  
Fax: 503 346-0237 
Email: murphbl@ohsu.edu 
  
Wencesley Paez, MD 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, KPV4 
Portland, OR 97239 
Phone: 503 494-8756 
Fax: 503 346-0237 
Email: paezw@ohsu.edu 
 
Ramesh Rengan, MD PhD 
Department of Radiation Oncology  
University of Washington Medical Center  
1959 NE Pacific Street, Box 356043  
Seattle, Washington 98195-6043  
Phone: 206-306-2814 
Fax: 206-417-0347 
Email: rengan@uw.edu 
 
Jason Rockhill, MD PhD 
Department of Radiation Oncology  
University of Washington Medical Center  
1959 NE Pacific Street, Box 356043  
Seattle, Washington 98195-6043  
Phone: 206-598-4100  
Fax: 206-598-6218  
Email: jkrock@uw.edu 
 
Lia Halasz, MD  
Department of Radiation Oncology  
University of Washington Medical Center  
1959 NE Pacific Street, Box 356043  
Seattle, Washington 98195-6043  
Phone: 206-598-4100  
Fax: 206-598-6218  
Email: lhalasz@uw.edu 
 
Yolanda Tseng, MD 
Department of Radiation Oncology  
University of Washington Medical Center  
1959 NE Pacific Street, Box 356043  
Seattle, Washington 98195-6043  
Phone: 206-598-4100  
Fax: 206-598-6218  
Email: ydt2@uw.edu 

 
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Simon Lo, MD   
Department of Radiation Oncology  
University of Washington Medical Center  
1959 NE Pacific Street, Box 356043  
Seattle, Washington 98195-6043  
Phone: 206-598-4100  
Fax: 206-598-6218  
Email: simonslo@uw.edu 
 
Rafael Santana-Davila, MD 
Department of Medicine 
Division of Medical Oncology 
Seattle Cancer Care Alliance 
825 Eastlake Ave E, G4-810 
Seattle, WA 98109-1023 
Phone: 206-606-6680 
Email:  rafaelsd@uw.edu 
 
Jeremy Cetnar, MD 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, KPV4  
Portland, OR 97239  
Phone: 503 494-8756  
Fax: 503 346-0237 
Email: cetnarj@ohsu.edu 
 
Thomas B. Daniels, MD 
Mayo Clinic Arizona 
5779 E. Mayo Blvd. 
Phoenix, AZ 85054 
Phone: 480-342-1267 
Fax: 480-342-3972 
Email: daniels.thomas@mayo.edu 
 
Steven E. Schild, MD 
Mayo Clinic Arizona 
5779 E. Mayo Blvd. 
Phoenix, AZ 85054 
Phone: 480-342-1267 
Fax: 480-342-3972 
Email: sschild@mayo.edu 
 
Helen J. Ross, MD 
Mayo Clinic Arizona 
5779 E. Mayo Blvd. 
Phoenix, AZ 85054 
Phone: 480-342-1267 

 
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Fax: 480-342-3972 
Email: ross.helen@mayo.edu 
 
Panayiotis S. Savvides, MD PhD 
Mayo Clinic Arizona 
5779 E. Mayo Blvd. 
Phoenix, AZ 85054 
Phone: 480-342-1267 
Fax: 480-342-3972 
Email: savvides.panayiotis@mayo.edu 
 
Statistician: 
Yiyi Chen, PhD  
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, KPV4  
Portland, OR 97239  
Portland, OR 97239  
Phone: 503 494-8756 
Fax: 503 346-0237 
Email: chenyiy@ohsu.edu 
 
 
 

 
6 
 
SUMMARY OF CHANGES 
 
# 
Section 
Page(s) 
Change 
Justification 
1. 7 
44, 45 
1. Changing screening to 
up to 12 weeks from 4 
weeks (which in the 
schedule of events 
changed from 28 to 60 
days) kept H&P and 
such to 60 days but used 
the footnote to expand 
the scans to 3 months.   
 
2. Phone Follow up for 
screening was 
unchecked for both LS-
SCLC and ES-SCLC.  
 
3. For CR imaging body 
and Gd-MRI for EOT 
were deleted 
1. kept H&P and such to 60 
days but used the 
footnote to expand the 
scans to 3 months.  
  
2. Not necessary as 
patients will be seen in 
clinic. 
 
3. as to not put excessive 
cost on patient 
/insurance 
2. 4.3 and 
4.3.1 
30,31 
Addition of 4th participating study 
center (Ohio State University) 
and updated calculations for 
subject accrual. 
To assist with target recruitment 
numbers 
3. 12.3 
62 
Change of EDC to Forte EDC 
Improved EDC through KCI 
4.  
 
 
 
5.  
 
 
 
 
 

 
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SYNOPSIS 
 
Study Title Prophylactic Tumor Treating Fields in management of patients with 
Small Cell Lung Cancer 
Protocol # 18029 
Study Center multicenter [U.S. only]   
 
Oregon Health & Science University  
University of Washington (UW Seattle) 
Mayo Clinic (Arizona) 
Ohio State University  
Clinical Phase Phase II 
Investigational 
Component(s)  Medical Device (FDA approved - used for an unapproved indication)  
Interventional 
Study Type Single-arm 
Précis 
 
Small Cell Lung Cancer (SCLC) is a common disease, with a high 
propensity for brain metastases.  Prophylactic cranial irradiation (PCI) is 
a standard therapy for reducing the risk of SCLC brain metastases. 
While PCI is associated with added survival benefit to patients with 
SCLC, the approach is associated with both acute and long-term toxicity.  
As an alternative treatment option, directed electrical fields to the brain 
using the Optune® device is associated with decreasing the risk of tumor 
progression and improvement in overall survival in patients with 
glioblastoma multiforme (GBM).  Applying a similar methodology, this 
pilot study will evaluate the safety and preliminary efficacy of Optune®-
Tumor Treating Fields (TTFields) therapy as a prophylactic approach to 
reducing SCLC brain metastases.  
 
Primary Objective Primary: Observed rate of brain metastases following TTField therapy at 
6 months. 
Secondary Objectives 
1. Rate of brain metastases following TTField therapy at 12 months. 
2. Overall survival of participants with SCLC after using TTField 
therapy. 
3. TTField therapy related side-effects. 
4. Quality of life among participants using TTField therapy. 
5. Observed rate of brain metastases 6-month from the beginning of 
the 4th cycle of chemotherapy to development of brain metastases 
 
Primary Endpoints Incidence of SCLC brain metastases at 6 months from the start of 
TTField therapy 
Secondary Endpoints 
1. Incidence of SCLC brain metastases at 12 months 
2. Overall survival  
3. Incidence of TTfield related adverse events 
4. Quality of life  
5. Incidence of SCLC brain metastases at 6 month from the beginning 
of the 4th cycle of chemotherapy to development of brain 

 
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metastases     
 
 
Number of 
Participants 
A total of 106 participants will be enrolled in this study. Among these, 
target enrollment will include 45 participants with extensive stage 
disease, and 61 participants will have limited stage disease.  
Duration of Therapy Participants will receive TTField therapy for 12 months, or until 
development of brain metastases, whichever comes first.   
Duration of Follow Up Participant followed up will continue until death.  
Inclusion Criteria 
• 
≥ 22 years of age 
• 
Biopsy-proven SCLC 
• 
Clinical Response to standard of care chemo- and/or radiotherapy, 
as defined by no thoracoabdominal tumor progression on CT 
imaging within 12 weeks prior to enrollment.  
• 
No contraindications to treatment with Optune®.  
• 
No other active malignancies, with exception of non-metastatic 
prostate cancer, treated Stage I breast cancer, skin malignancies   
• 
No brain metastases [gadolinium MRI < 12 weeks before 
enrollment].  
• 
No mental conditions that would prevent compliance. 
• 
Life expectancy of at least 3 months. 
• 
ECOG ≤ 2. 
Exclusion Criteria 
• 
Progressive disease.  
• 
Pregnant  
• 
Implanted pacemaker, programmable shunts, defibrillator, deep 
brain stimulator, other implanted electronic devices in the brain, or 
documented clinically significant arrhythmias. 
• 
Evidence of increased intracranial pressure (midline shift > 5mm, 
clinically significant papilledema, vomiting and nausea or reduced 
level of consciousness) 
 
Investigational 
Product(s) 
Optune® is a portable battery powered device that produces alternating 
electrical fields, termed tumor treatment fields (“TTFields”) within the 
human body. These TTFields are applied to the patient by electrically 
insulated surface transducer arrays, which function to disrupt the rapid 
cell division of cancer cells.  
 
Statistical 
Considerations 
Primary Evaluations: 
Incidence of brain metastases 6 months after start of Optune® 
 
Sample Size (statistical assumptions) 
For extensive stage, we need 45 subjects for 80% power to detect a 
50% reduction at a 5% significance level using a test for one proportion, 
assuming the incidence rate is 40% for subjects not receiving Optune®. 
 
For limited stage, we need 61 subjects for 80% power to detect a 50% 
reduction at a 5% significance level, using a test for one proportion, 
assuming the incidence rate is 30% for subjects not receiving Optune®.  

 
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Efficacy Endpoints 
• Presence of brain metastasis at 6 and 12 months 
• Overall Survival 
• Incidence of SCLC brain metastases at 6 month from the beginning of 
the 4th cycle of chemotherapy to development of brain metastases    
Safety Endpoints: 
• Quality of life questionnaire 
• Side effects, particularly cognitive side effects (mental status exam and 
questionnaire) 

 
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SCHEMATIC OF STUDY DESIGN  
 
 
 
Figure 1. Study Overview.  
Participants with small cell lung cancer (SCLC) will be considered for enrollment if no more than 
6 weeks have passed since last standard-of-care chemotherapy or thoracic radiation treatment 
of their primary tumor.  Participants must have demonstrated partial response to treatment and 
show no tumor recurrence within 12 weeks prior to enrollment.  Similarly, participants cannot 
have metastatic brain lesions in the 12 weeks leading up to enrollment.  Participants eligible to 
receive Optune®-generated electrical tumor-treatment field (TTField) therapy will undergo 
continuous treatment for 12 months, or until disease progression, whichever comes first.  This 
study will assess whether Optune® therapy to the brain can be used as a prophylactic approach 
to reducing the formation of brain lesions.  The primary endpoint is the incidence of metastatic 
SCLC brain lesions.  Participants will be clinically evaluated throughout the study for evidence of 
tumor recurrence or metastases, and will also be periodically assessed during the on-treatment 
and off-treatment portions of the study to evaluate treatment effects on quality of life and 
cognitive function.  This study anticipates the accrual of 106 participants over 24-months.  

 
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TABLE OF CONTENTS 
SUMMARY OF CHANGES ......................................................................................................... 6 
SYNOPSIS ................................................................................................................................. 7 
SCHEMATIC OF STUDY DESIGN ............................................................................................. 9 
LIST OF TABLES ..................................................................................................................... 16 
LIST OF FIGURES ................................................................................................................... 17 
LIST OF ABBREVIATIONS ...................................................................................................... 18 
1. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...................................... 20 
 
Overview of Small Cell Lung Cancer (SCLC) ............................................................ 20 
1.1.1 Prophylactic Cranial Irradiation ............................................................................. 20 
 
Overview of Optune .................................................................................................. 20 
1.2.1 Mechanism of action ............................................................................................ 20 
1.2.2 Pre-clinical experience ......................................................................................... 20 
1.2.3 Clinical studies of Optune ..................................................................................... 22 
1.2.3.1 
Effect of TTFields therapy on Recurrent GBM Subjects - A Pilot 
Study.................................................................................................... 22 
1.2.3.2 
Effect of TTFields therapy on Newly Diagnosed GBM Subjects - 
A Pilot Study ........................................................................................ 22 
1.2.3.3 
Pivotal Study for Recurrent GBM ......................................................... 23 
1.2.3.4 
TTFields therapy for newly diagnosed GBM ......................................... 23 
1.2.3.5 
Effect of TTFields therapy for non-small cell lung cancer 
(NSCLC) .............................................................................................. 24 
 
Rationale .................................................................................................................. 24 
 
Potential Risks and Benefits ..................................................................................... 25 
1.4.1 Known Potential Risks .......................................................................................... 25 
1.4.2 Known Potential Benefits ..................................................................................... 25 
2. OBJECTIVES ...................................................................................................................... 26 
 
Primary Objectives .................................................................................................... 26 
 
Secondary Objectives ............................................................................................... 26 
3. STUDY DESIGN AND ENDPOINTS .................................................................................... 27 
 
Description of the Study Design ................................................................................ 27 
 
Study Endpoints ........................................................................................................ 27 
3.2.1 Primary Endpoint .................................................................................................. 27 
3.2.2 Secondary Endpoints ........................................................................................... 27 

 
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4. STUDY ENROLLMENT AND WITHDRAWAL ..................................................................... 29 
 
Participant Inclusion Criteria ..................................................................................... 29 
 
Participant Exclusion Criteria .................................................................................... 29 
 
Strategies for Recruitment and Retention ................................................................. 30 
4.3.1 Accrual Estimates ................................................................................................ 30 
4.3.2 Medicare Beneficiaries ......................................................................................... 31 
            4.3.3. Inclusion of Children……………………………………………………………………32 
 
Registration Procedures ........................................................................................... 32 
4.4.1 Participant Registration ........................................................................................ 32 
4.4.1.1 
Local Registration ................................................................................ 33 
4.4.1.2 
Multicenter Registration ....................................................................... 33 
 
Participant Screening and Enrollment ....................................................................... 33 
 
Participant Withdrawal or Discontinuation ................................................................. 33 
4.6.1 Handling Participant Withdrawal and Discontinuation ........................................... 34 
 
Off-Study Criteria ...................................................................................................... 34 
 
Study Discontinuation ............................................................................................... 34 
5. INVESTIGATIONAL PRODUCT .......................................................................................... 36 
 
Optune® .................................................................................................................... 36 
5.1.1 Acquisition ............................................................................................................ 36 
5.1.2 Device Components ............................................................................................. 36 
5.1.2.1 
Optune Electric Field Generator ........................................................... 36 
5.1.2.2 
INE Insulated Transducer Arrays ......................................................... 36 
5.1.2.3 
Additional Components ........................................................................ 37 
5.1.3 Device settings and programming ........................................................................ 37 
5.1.4 Device usage and maintenance ........................................................................... 37 
5.1.4.1 
Battery replacement ............................................................................. 37 
5.1.4.2 
Transducer array placement and replacement ..................................... 38 
5.1.4.3 
Connecting transducer arrays to device ............................................... 38 
5.1.5 Duration of exposure ............................................................................................ 38 
5.1.6 Device Storage and Stability ................................................................................ 38 
5.1.7 Special Consideration for Administration .............................................................. 38 
5.1.7.1 
Topical creams or ointments ................................................................ 38 
5.1.7.2 
Traveling with device ............................................................................ 38 
5.1.7.3 
Troubleshooting Guide ......................................................................... 39 
5.1.8 Accountability ....................................................................................................... 39 
5.1.9 Destruction and Return ........................................................................................ 39 
6. TREATMENT PLAN............................................................................................................. 40 

 
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Dosage and Administration ....................................................................................... 40 
6.1.1 Electric field .......................................................................................................... 40 
6.1.2 Transducer array placement ................................................................................. 40 
 
Treatment Interruptions and Delays .......................................................................... 41 
 
Treatment Period and Maintenance .......................................................................... 41 
 
Concomitant Medication and Supportive Care Guidelines ........................................ 41 
6.4.1 Radionecrosis ...................................................................................................... 41 
6.4.2 Dermatitis ............................................................................................................. 41 
6.4.3 Infection prophylaxis............................................................................................. 42 
6.4.4 Allergic Reaction / Hypersensitivity ....................................................................... 42 
6.4.5 Contraception ....................................................................................................... 42 
6.4.6 Use in Pregnancy ................................................................................................. 43 
 
Precautions associated with use of Optune® device .................................................. 43 
6.5.1 Presence of plates or screws in the participant’s skull bone ................................. 43 
6.5.2 Damage to Optune® device and/or components ................................................... 43 
 
Prohibited Medications, Treatments, and Procedures ............................................... 43 
7. STUDY PROCEDURES/EVALUATIONS AND SCHEDULE ................................................ 44 
 
Study Specific Procedures ........................................................................................ 44 
7.1.1 Medical history ..................................................................................................... 44 
7.1.2 Disease Assessment ............................................................................................ 44 
7.1.3 Medication history ................................................................................................ 44 
7.1.4 Physical examination ............................................................................................ 44 
7.1.4.1 
Vital signs ............................................................................................ 44 
7.1.4.2 
Height and weight ................................................................................ 44 
7.1.4.3 
Performance status .............................................................................. 44 
7.1.5 Adverse event evaluation ..................................................................................... 45 
7.1.6 Assessment of study agent adherence ................................................................. 45 
7.1.7 Magnetic resonance Imaging (MRI) / Computed Tomography (CT) / 
Positron Emission Tomography (PET) ............................................................. 45 
7.1.8 Patient Reported Outcomes ................................................................................. 45 
 
Laboratory Procedures and Evaluations ................................................................... 46 
7.2.1 Hematology .......................................................................................................... 46 
7.2.2 Biochemistry ........................................................................................................ 46 
7.2.3 Pregnancy test ..................................................................................................... 46 
 
Screening Assessments ........................................................................................... 46 
7.3.1 Information to be collected on screening failures .................................................. 47 

 
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Assessments During Treatment ................................................................................ 47 
 
End of Treatment Visit .............................................................................................. 47 
 
Follow-up .................................................................................................................. 47 
 
Unscheduled Visits ................................................................................................... 47 
 
Schedule of Events ................................................................................................... 48 
8. EFFICACY MEASURES ...................................................................................................... 50 
 
Definition of Efficacy Measures ................................................................................. 50 
 
Disease Evaluation ................................................................................................... 50 
 
Efficacy Criteria for Tumor Response ....................................................................... 50 
8.3.1 Evaluation of New Lesions ................................................................................... 50 
 
Evaluation of Survival ............................................................................................... 50 
 
Response Review ..................................................................................................... 50 
9. SAFETY ............................................................................................................................... 51 
 
Specification Of Safety Parameters .......................................................................... 51 
 
Definitions ................................................................................................................. 51 
9.2.1 Adverse Event (AE) .............................................................................................. 52 
9.2.2 Serious Adverse Event (SAE) .............................................................................. 52 
9.2.3 Unanticipated Problems (UP) ............................................................................... 52 
9.2.4 Severity of Event .................................................................................................. 52 
9.2.5 Assessment of Causality Relationship To Optune® Device ................................... 52 
 
Expectedness ........................................................................................................... 53 
 
Adverse Event List(s) ................................................................................................ 53 
9.4.1 Adverse Event List for TTField Therapy with Optune® Device .............................. 53 
 
Adverse Event Assessment and Follow-Up .............................................................. 53 
 
Reporting Procedures ............................................................................................... 54 
9.6.1 OHSU IRB Reporting of Unanticipated Problems and Adverse Events ................ 54 
9.6.2 Central Reporting of Adverse Events for Multicenter Studies ............................... 54 
9.6.3 MedWatch Reporting ............................................................................................ 54 
9.6.4 Manufacturer reporting requirements ................................................................... 55 
9.6.5 Reporting Of Pregnancy ....................................................................................... 55 
 
Study Stopping Rules ............................................................................................... 55 
10. STATISTICAL CONSIDERATIONS .................................................................................. 56 
 Analysis Populations ................................................................................................. 56 
 Description of Statistical Methods ............................................................................. 56 
10.2.1 
Analysis of Primary Endpoint ........................................................................... 56 

 
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10.2.2 
Analysis Of The Secondary Endpoints ............................................................. 56 
 Sample Size, Power, Accrual Rate and Study Duration ............................................ 57 
10.3.1 
Sample size and Power ................................................................................... 57 
 Handling of Missing Data .......................................................................................... 57 
11. CLINICAL MONITORING .................................................................................................. 59 
 OHSU Knight Cancer Institute Data & Safety Monitoring Plan .................................. 59 
 Clinical Data & Safety Monitoring .............................................................................. 59 
 Quality Assurance & Quality Control ......................................................................... 60 
12. DATA HANDLING AND MANAGEMENT RESPONSIBILITIES ........................................ 60 
 Source Data/Documents ........................................................................................... 60 
 Participant & Data Confidentiality .............................................................................. 60 
 Data Collection & Storage: Privacy, Confidentiality & Security .................................. 61 
 Maintenance of Records ........................................................................................... 61 
 Multicenter Guidelines .............................................................................................. 62 
 Publication and Data Sharing Policy ......................................................................... 62 
13. ETHICS/PROTECTION OF HUMAN PARTICIPANTS ...................................................... 63 
 Ethical Standard ....................................................................................................... 63 
 Institutional Review Board......................................................................................... 63 
 Informed Consent ..................................................................................................... 63 
13.3.1 
Consent Procedures and Documentation ........................................................ 63 
 Protocol Review ........................................................................................................ 63 
 Changes to Protocol ................................................................................................. 65 
14. REFERENCES .................................................................................................................. 66 
15. APPENDICES ................................................................................................................... 68 
APPENDIX A: PERFORMANCE STATUS ............................................................................... 69 
 
 
 
 
 

 
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LIST OF TABLES 
 
Table 1. Projected accrual for present study based on Oregon population demographics
 .................................................................................................................................................30 
Table 2. Projected accrual for present study based on Washington population 
demographics .........................................................................................................................31 
Table 3. Projected accrual for present study based on Arizona population………………..31 
Table 4. Projected accrual for present study based on Ohio population……………………32 
Table 3. Method and Timing of QoL Assessments ...............................................................43 
 
 
 

 
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LIST OF FIGURES 
 
Figure 1. Study Overview. ......................................................................................................10 
Figure 2. Optune system components and usage. ...................................................................20 
Figure 3. Alternating current field around quiescent and dividing cells. .....................................21 
Figure 4. Transducer array placement. .................................... Error! Bookmark not defined. 
 
 
 
 

 
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LIST OF ABBREVIATIONS 
 
AC 
Alternating current 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical (Classification System) 
AUC 
Area under the curve 
BUN 
Blood urea nitrogen 
CBC 
Complete blood cell (count) 
CFR 
United States Code of Federal Regulations  
CoC 
National Institutes of Health (NIH) Certificate of Confidentiality 
COWA 
Controlled Oral Word Association 
CR 
Complete response 
CRC 
Clinical Research Coordinator 
CRMS 
Clinical research management system 
CRQA 
Clinical Research Quality & Administration 
CRRC 
Clinical Research Review Committee (OHSU) 
CRF 
Case report form 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTMS 
Clinical Trial Management System 
DFS 
Disease-free survival 
DSMB 
Data and Safety Monitoring Board 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECG, EKG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
eCRIS 
Electronic Clinical Research Information System 
EDC 
Electronic data capture 
FCBP 
Female of childbearing potential 
FDA 
United States Food and Drug Administration 
GBM 
Glioblastoma multiforme 
GCP 
Good Clinical Practice 
HCT 
Hematocrit 
HGB 
Hemoglobin 
HIPPA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HVLT 
Hopkins Verbal Learning Test-Revised 
IB 
Investigator’s brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDE 
Investigational device exemption 
IND 
Investigational new drug application 
IRB 
Institutional Review Board 
IV 
Intravenous 
kHz 
Kilo Hertz 
LDH 
Lactate dehydrogenase 

 
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LFT 
Liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
N/A 
Not applicable 
NCI 
National Cancer Institute 
NCCN 
National Comprehensive Cancer Network 
OHRP 
Office for Human Research Protections 
OHSU 
Oregon Health & Science University 
ORR 
Overall response rate 
PCI 
Prophylactic cranial irradiation 
PD 
Progressive Disease 
PET 
Positron emission tomography 
PI 
Principle Investigator 
PK 
Pharmacokinetics 
PO 
Per os (by mouth, orally) 
PR 
Partial response 
QOL 
Quality of Life 
RBC 
Red blood cell (count) 
RNI 
Reportable new information 
ROS 
Reactive oxygen species 
RT 
Radiation therapy 
SAE 
Serious adverse event 
SCLC 
Small Cell Lung Cancer 
SD 
Stable disease 
SD 
Standard deviation 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SRS 
Stereotactic radio surgery 
TMT 
Trail Making Test 
TMZ 
Temozlomide 
TSMP 
Trial Specific Monitoring Plan 
TTField 
Tumor-treatment field 
UA 
Urinalysis 
ULN 
Upper limit of normal 
UP 
Unanticipated problem 
WBC 
White blood cell (count) 
 

 
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1. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
 
 
OVERVIEW OF SMALL CELL LUNG CANCER (SCLC) 
 
Comprising approximately 14% of all lung cancers, SCLC has an annual incidence of 31,000 
new cases, which are most often attributable to cigarette smoking.  SCLC is characterized as 
having a rapid doubling time and early development of widespread metastases, and without 
treatment, the disease is associated with survival rates of 2 to 4 months.2  SCLC is frequently 
classified as being either a limited-stage or extensive-stage.3  Limited disease (LS-SCLC) is 
defined as the patient having the SCLC involvement restricted to one hemithorax that can be 
encompassed within a tolerable radiation field. Alternatively, extensive disease (ES-SCLC) is 
defined as disease beyond one hemithorax and may include malignant pleural or pericardial 
effusion or hematogenous metastases.   
 
The majority of patients (70%) present with ES-SCLC. Treatment with combination therapies is 
associated with a median survival time of approximately 9 to 10 months from diagnosis, and 
though 20% of these patients have a complete response, 5-year survival is only 2%.4  In 
contrast, LS-SCLC is associated with an 80% complete response rate and an approximate 18 
months survival time.  Multimodal treatment of LS-SCLC, which includes concurrent 
chemotherapy and radiotherapy, can achieve long-term disease-free of 20 to 25%.5,6  
 
PROPHYLACTIC CRANIAL IRRADIATION 
 
Approximately 20% of patients with SCLC have a detectable brain lesion, and the actuarial risk 
of developing brain metastases within 2 years of diagnosis is nearly 80%.5,7,8  Randomized 
studies have shown that prophylactic cranial irradiation (PCI) decreases the risk of developing 
central nervous system metastases by more than 50%.7  The 3-year overall survival of complete 
responders (predominately those with LS-SCLC) that received PCI was 21%, whereas survival 
was only 15% in the control group.7,8  
 
Figure 2. Optune system components and usage.  
A. (1) electric field generator, (2) portable batteries, (3) charger for portable batteries, (4) plug-in 
power supply, (5) connection cable and box, (6) transducer arrays, (7) power cord, (8) shoulder 
bag and strap, (9) portable battery case. B. Model demonstrating wearing of Optune device.  

 
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OVERVIEW OF OPTUNE 
 
Optune® is a portable battery or power supply operated device that produces alternating 
electrical fields, called tumor treatment fields (TTFields) within the human body.  These 
TTFields are applied to the patient by electrically insulated surface transducer arrays, which 
function to disrupt the rapid cell division exhibited by cancer cells.1,9   
 
The Optune system is comprised of two main components: (1) an Electric Field Generator (i.e., 
the Optune device); (2) INE Insulated Transducer Arrays (i.e., the transducer arrays), and 3) 
additional Optune Treatment Kit components that include a power supply, portable battery, 
battery rack, battery charger, connection cable and carrying case.(Figure 2) 
 
Refer to Section 0 for specific details regarding the components of the Optune device.  
 
MECHANISM OF ACTION 
 
TTFields therapy involves the production of alternating electrical fields within the human body 
that disrupt the rapid cell division exhibited by cancer cells with the alternating electrical fields 
applied through the surface of the scalp.   
 
TTFields harness electric fields to arrest the proliferation of tumor cells and to destroy them.1  
The TTField technology takes advantage of the unique characteristics, geometrical shape, and 
rate of dividing cancer cells, which make them susceptible to the effects of the alternating 
electric TTFields.  These special fields alter the tumor cell polarity at an intermediate frequency 
(on the order of 100-300 kHz). The frequency used for a particular treatment is specific to the 
cell type being treated (e.g., 200 kHz for glioblastoma multiforme [GBM]).  TTFields have been 
shown to disrupt mitotic spindle microtubule assembly and to lead to dielectrophoretic 
dislocation of intracellular macromolecules and organelles during cytokinesis.  These processes 
lead to physical disruption of the cell membrane and to programmed cell death.9 
 
PRE-CLINICAL EXPERIENCE 
 
The application of TTFields has very limited effect on non-dividing cells.  In the case of the adult 
brain, most normal adult brain cells have a very slow rate of cellular proliferation and are 
minimally affected by the TTFields.  Preclinical testing in animal models, which compared 
Figure 3. Alternating current field around quiescent and 
dividing cells.  
 
(A) Inside quiescent cells, the field is uniform, and the 
oscillating electric forces result only in "vibration" of ions 
and dipoles (the forces associated with each half cycle 
are denoted white and gray arrows).  
 
(B) In dividing cells, the non-uniform field induces forces 
pushing all dipoles toward the furrow. Note that at 
frequencies of 0.1-1.0 MHz, the cell membrane 
impedance is relatively high, so only a small fraction of 
the currents penetrate the cells as seen from the density 
of lines.  
Adapted from Kirson et al1 

 
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TTFields-treated groups to controls showed that there are no histological differences in the 
major internal organs (including the brain), nor differences in blood characteristics, cardiac 
rhythm, body temperature, or in animal behavior.  Additionally, because the electrical fields 
alternate so rapidly, they have no effect on normal quiescent cells nor do they stimulate nerves 
and muscles.1,9   
 
TTFields have been shown both in vitro and in vivo to effectively inhibit cancer cell replication 
during mitosis without any systemic side effects.  At intensities of approximately 1 V/cm, 
TTFields can be frequency-tuned to effectively inhibit different cancer cell types (i.e., the smaller 
the cell, the higher the frequency needed), due to disruption of microtubule polymerization and 
physical disruption of cell integrity at the cleavage plane during telophase.9 
 
TTFields have been shown to inhibit glioblastoma cells in vitro and in vivo at a frequency of 200 
kHz and an intensity of 0.7 V/cm.1  Extensive safety studies in healthy animals (mice, rats and 
rabbits) and humans have shown that TTFields are not associated with significant systemic 
toxicities. Neither acute, nor chronic systemic toxicities were seen when TTFields were applied 
to the torso or head, at different frequencies (100-200 kHz), different intensities and for different 
periods of time.1,10,11   
 
CLINICAL STUDIES OF OPTUNE 
 
The first-in-human studies of TTFields therapy in a clinical setting evaluated short duration 
therapy to cutaneous metastases in melanoma and advanced breast cancer.12  In this pilot trial, 
TTFields therapy was shown to decrease the growth rate of skin metastases from breast cancer 
and melanoma. Subsequent studies evaluated TTFields therapy in the setting of the most 
common primary malignant brain tumor, GBM, both as a single-treatment agent and in 
combination with chemotherapy. 
 
1.2.1.1 Effect of TTFields therapy on Recurrent GBM Subjects - A Pilot Study 
 
In a European pilot study of patients with recurrent GBM, 10 participants were treated with the 
Optune device.  All patients underwent surgery and radiotherapy for the primary tumor, and 
were treated with multiple four-week treatment courses using continuous, 24-hour a day, 200 
kHz, 0.7 V/cm TTFields.  Patients completed between 1 and 18 treatment courses leading to 
maximal treatment duration of 18 months. Overall, more than seventy four-week treatment 
courses were completed (> 7 courses per patient on average).  The treatment was well 
tolerated with no treatment- related serious adverse events seen in any of the patients.  Patients 
received treatment on average about three quarters of the scheduled time, indicating that 
compliance with treatment was very high.  Mild to moderate contact dermatitis appeared 
beneath the transducer arrays in 8 of the 10 patients during treatment following the first 
treatment course.  The skin irritation improved with use of topical corticosteroids.  Regular 
relocation of the transducer array was necessary in order to allow for continuous treatment. The 
median progression free survival (PFS) of the patients in this study exceeded historical 
controls1 (26.1 weeks versus 9 weeks, respectively).   
 
The PFS at 6 months was 50% compared to 15% in historical controls.13  At the end of the 
study, 8 of the 10 patients had died (at 4 years from study initiation); the remaining 2 patients 
we reported are alive at 5 years follow up and are progression free.  Median OS from diagnosis 
was 14.7 months (compared to 6 months in the historical control). 
 
1.2.1.2 Effect of TTFields therapy on Newly Diagnosed GBM Subjects - A Pilot Study 
 
In a European pilot study of patients with newly diagnosed GBM, 10 participants were treated 

 
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with the Optune® device.  All participants underwent surgery and radiotherapy for the primary 
tumor, and after radiotherapy, the patients then received maintenance temozlomide (TMZ) in 
conjunction with TTField therapy.  TTField therapy was administered in the same manner as in 
the pilot recurrent GBM study described by Wong et al13.  Participants completed between 1 and 
17 treatment courses leading to maximal treatment duration of 16.5 months. Overall, patients 
completed more than 96, four-week treatment courses (> 9.6 courses per patient on average).  
The treatment was well tolerated with no treatment related serious adverse events seen in any 
of the patients.  Participants received scheduled treatment ~80% of the time, again indicating 
that compliance with treatment was very high.  Mild to moderate contact dermatitis was 
experienced by all patients during treatment following the first treatment course, but was 
improved with use of topical corticosteroids.  Regular relocation of the transducer arrays was 
necessary in order to allow for continuous treatment. 
 
Median PFS of the patients in this study exceeded historical controls (14.4 months versus 7.1 
months, respectively). At the end of the study (4 years from initiation), 5 of the 10 patients died, 
and of the remaining 5 patients: 2 were lost to follow up and 3 were reported alive; these 
patients were progression free. Median OS from diagnosis was greater than 40 months 
(compared to 14.6 months in historical controls).14  
 
1.2.1.3 Pivotal Study for Recurrent GBM 
 
In a prospective, randomized, open label, active parallel control trial to compare the 
effectiveness and safety outcomes of recurrent GBM subjects treated with TTField therapy 
(n=120) to those treated with an effective best standard of care chemotherapy (including 
bevacizumab; n=117).10  Participants receiving TTField therapy had comparable overall survival 
to subjects receiving the best available chemotherapy in the United States today (OS = 6.3 vs. 
6.4 months; HR 1.0; p=0.98).  Similar results showing comparability of TTField therapy to BSC 
chemotherapy were seen in all secondary endpoints (e.g., PFS at 6 months = 21.4% for Optune 
vs. 15.2% for chemotherapy). 
 
In this pilot trial, 20 patients in total were treated (10 newly diagnosed glioblastoma; 10 recurrent 
glioblastoma). All patients were treated with multiple 4-week treatment courses using 
continuous TTFields therapy at 200 kHz (optimal frequency for glioblastoma). Patients with 
recurrent glioblastoma received TTFields therapy alone, while patients with newly diagnosed 
glioblastoma received TTFields therapy in combination with TMZ.  The treatment was well 
tolerated with no serious TTFields therapy-related adverse events reported. Mild-to-moderate 
contact dermatitis was the most common adverse event attributed to device use, which 
improved with the use of topical corticosteriods and periodic repositioning of the arrays. Patients 
received TTFields therapy about three quarters of the scheduled time on average. Considering 
the continuous nature of TTFields therapy (i.e., 24 h/day for many months), this figure indicates 
that compliance with treatment was very high, with patients taking very few days off treatment, 
and stopping treatment only for short periods of time for personal needs. Although the number 
of patients in this pilot trial was small, the favorable safety profile and promising efficacy data 
(20% survival at 7-years follow-up) resulted in Novocure embarking on a pivotal trial in recurrent 
glioblastoma. 
 
1.2.1.4 TTFields therapy for newly diagnosed GBM 
 
A large randomized controlled study was designed to assess safety and effectiveness of 
TTFields therapy in 700 patients with newly diagnosed GBM.  Patients were randomized to 
receive TTFields therapy and TMZ (TTFields/TMZ), or TMZ alone. The primary endpoint of PFS 
at final analysis was 7.1 months for those receiving TTFields/TMZ compared to 4.2 months 
among those treated with TMZ alone. This difference of 2.9 months was highly clinically 

 
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significant (log-rank p = 0.001). Overall, those in the combined therapy group had a nearly 31% 
decreased risk of progression compared to patients receiving TMZ alone.  Likewise, the OS was 
almost 30% longer in the TTFields/TMZ arm compared to TMZ alone (19.6 months [95% CI 
16.6-24.1] vs. 15.2 months [95% CI 13.5-18.2], respectively). 
 
1.2.1.5 Effect of TTFields therapy for non-small cell lung cancer (NSCLC) 
 
TTFields therapy for NSCLC has also been evaluated by developing transducer arrays and 
field-generating devices for the torso. In a single-arm pilot study (phase I/II) of 42 patients with 
advanced NSCLC who had tumor progression after at least one prior chemotherapy.11,15  
Participants in this study received pemetrexed together with continuous daily TTFields therapy 
(for a minimum of 12 hrs/day) applied to the chest and upper abdomen until disease 
progression. The primary endpoint was time to “in-field” progression in the lungs and liver (i.e., 
areas where the TTFields therapy was applied).  The median age of patients was 63 years; 76% 
had stage IV disease; 78% had adenocarcinoma and 17% had a performance status of two.  
TTFields was used for an average of 11.2 hrs/day.  The median time to in-field progression was 
28 weeks and the median time to systemic progression was 22 weeks.  The authors reported 
that using this treatment approach, 6 patients (14.6%) had a partial response (PR) and 20 
(48.8%) had stable disease (SD).  Compared to the historical control of 8.3 months reported for 
pemetrexed alone compared to docetaxel16, the median overall survival among participants 
receiving TTFields therapy was 13.8 months.  Likewise, the 1-year survival rate was 57% for 
participants receiving TTFields therapy, compared to the historical control of 30% administered 
pemetrexed alone.16  The authors reported that the combination of chemotherapy and TTFields 
therapy was we well tolerated and, compared to pemetrexed historical control, there was no 
increase in the adverse event rate, or in gastrointestinal or hepatic toxicity.  Except for device-
related mild-to-moderate contact dermatitis in 14 participants, there were no device-related 
cardiac arrhythmias reported and no serious TTFields therapy–related adverse events.  
 
The clinical benefit of TTField therapy for brain metastases from NSCLC is currently being 
investigated in a phase 3, pivotal, open-label study (METIS, NCT02831959).17 In this ongoing 
trial, 270 patients with NSCLC with 1-10 brain metastases are randomized (1:1) to receive 
stereotactic radio surgery (SRS) followed by either TTFields or supportive care alone. The 
primary objectives of this trial is to test the efficacy, safety and neurocognitive outcomes of 
TTFields in this patient population by assessing the time to first cerebral progression. Additional 
study endpoints include assessing the time to neurocognitive failure based on functional tests 
(e.g., HVLT, COWA and TMT). The planned treatment for this study includes continuous 
TTFields therapy at 150 kHz to be applied to the brain within 7 days of SRS. The METIS trial 
has received investigation device exemption from the FDA.  
 
 
RATIONALE 
 
SCLC is a common disease, with a high propensity for brain metastases.  Although the use of 
PCI has for a long time been considered a standard therapy for patients with both LS-SCLC and 
ES-SCLC, recent results from a randomized trial examining PCI vs observation with frequent 
use of brain MRI imaging, revealed no difference in outcomes.18  The findings of this study have 
changed the practice in large academic institutions overnight (personal communication), and 
patients with ES-SCLC are no longer offered PCI as a standard of care in many academic 
centers in the United States.  Large cooperative groups are planning to start a similar 
randomized trial for patients with LS-SCLC.  Overall, this leaves patients with very limited 
treatment options, and given the high risk of brain metastases, the need for novel therapies is 
greatly needed.  
 

 
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TTFields therapy has entered the oncology treatment landscape as an FDA-approved cancer 
treatment for recurrent GBM and is part of the National Comprehensive Cancer Network 
(NCCN) Treatment Guidelines for this disease.  The success of this approach in reducing the 
risk of recurrent GBM has been adopted in the randomized phase 3 METIS trial for patients with 
known brain metastases from NSCLC, which is currently on-going at many US centers.  We 
hypothesize that TTFields can be similarly adapted to prevent the formation of SCLC metastatic 
brain lesions.  TTFields therapy is shown to be safe and lacks the conventional cytotoxic 
systemic side effects.  Thus this alternative interventional could significantly decrease the brain 
metastatic rate as well as lower the need for toxic whole brain irradiation   
 
This study will evaluate the potential for TTFields therapy as a novel approach to reducing the 
rate of in-brain failures in patients with SCLC that have completed standard-of-care chemo- 
radiotherapy.  It is hypothesized that TTFields therapy can be used prophylactically to reduce 
the incidence of brain metastases as compared to historical observational reports, and have no 
effect on the cognitive function of those receiving this treatment modality.  
 
 
POTENTIAL RISKS AND BENEFITS 
 
KNOWN POTENTIAL RISKS  
 
Refer to Section 9.4.1 for a detailed description of any adverse events that have been recorded 
in patients with GBM on clinical trials investigating TTFields therapy, after brain-directed 
therapies (such as surgery, radiation therapy), systemic therapies, and most often with evidence 
of GBM progression.  
 
Results from a randomized study examining TTFields therapy in patients with newly diagnosed 
GBM showed that the only TTFields-related AEs are skin irritation, falls that were observed at a 
slightly higher incidence among patients carrying the Optune® device, headaches related to 
wearing the transducer arrays 24 hours a day, and mild psychiatric symptoms (e.g., anxiety, 
insomnia, confusion) that could be caused by the need to incorporate the device and arrays into 
daily life. 
 
Since TTFields are only applied to the brain, they are unlikely to have an effect on rapidly 
proliferating cells in the rest of the body. 
 
KNOWN POTENTIAL BENEFITS 
 
Given the high rate of brain metastases among patients with SCLC, prophylactic TTFields 
therapy may reduce the risk of brain metastatic lesions and improve overall patient outcomes.  It 
cannot, however, be guaranteed that participants in this study will directly benefit from treatment 
during participation, as the clinical trial is designed to provide information about the safety and 
effectiveness of this investigational approach. 
 

 
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2. OBJECTIVES 
 
 
PRIMARY OBJECTIVES 
 
Observed rate of brain metastases following TTFields therapy at 6 months 
 
 
SECONDARY OBJECTIVES 
 
1. Observed rate of brain metastases following TTFields therapy at 12 months. 
2. Survival of participants with SCLC after using TTFields therapy. 
3. Usage and overall safety characteristics of TTFields therapy. 
4. Quality of life among participants using TTFields therapy. 
5. Observed rate of SCLC brain metastases at 6 month from the beginning of the 4th cycle of 
chemotherapy to development of brain metastases    

 
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3. STUDY DESIGN AND ENDPOINTS 
 
 
DESCRIPTION OF THE STUDY DESIGN 
 
Refer to Section 10, STATISTICAL CONSIDERATIONS for additional information regarding 
statistical methods used in this study. 
 
This is a Phase II pilot study to assess the safety and efficacy of prophylactic TTFields therapy 
in patient with SCLC.  Participants must meet the inclusion criteria, have none of the exclusion 
criteria, and have provided written informed consent before the conduct of any screening tests 
not performed routinely in their treatment. 
 
Participants with either LS-SCLC or ES-SCLC must be no more than 6 weeks from having 
received last dose of chemotherapy for primary tumor (per institutional guidelines), and must 
have at least demonstrated a partial response to treatment, to be considered eligible for TTField 
therapy with the Optune® device.  Participants are encouraged to undergo TTField therapy (200 
kHz) for a minimum of 18 hours per day for a period of 12 months, or until the confirmed 
appearance of metastatic brain lesions, whichever comes first.  Participants that develop 
numerous (>10) supratentorial metastatic lesions before 12 months will discontinue further use 
of TTFields and will receive palliative/supportive care per institutional guidelines (e.g., whole 
brain radiotherapy).  Participants that develop either limited (≤10) supratentorial or any number 
of infratentorial metastases will remain eligible to continue with TTFields therapy for the duration 
of the 12 months after the brain metastatic lesions are addressed according to institutional 
guidelines (e.g. partial brain irradiation stereotactic radiosurgery, stereotactic body radiation 
therapy). Systemic progression will be managed per institutional guidelines (e.g. systemic 
chemotherapy, immunotherapy, radiation therapy, etc.) and patients will remain eligible to 
continue with TTFields therapy for the duration of the 12 months. While on-study, participants 
will be clinically evaluated every 2-3 months per NCCN guidelines and will all be monitored 
remotely by phone calls monthly and will undergo gadolinium (gd)-MRI of the head at 6 months 
to assess occurrence of disease progression (per RECIST v1.1). Participants will be subject to 
periodically answering quality of life (QoL) questionnaires (i.e., baseline, 6 and 12 months after 
initiating treatment).  At the end of study, participants will undergo clinical follow-up 1 and 3 
months after completion of TTField therapy. Subsequent follow-up until death (up to 5 years) will 
be in accordance with standard of care (i.e., every 3 months during years 1 and 2 following last 
chemo-radiotherapy, then every 6 months thereafter).  
 
 
STUDY ENDPOINTS 
 
PRIMARY ENDPOINT 
 
Objective 
Endpoint 
Start  
End  
Observed rate of brain metastases 
following TTFields therapy at 6 
months 
Incidence of SCLC brain 
metastases at 6 mo  
Start of TTFields 
[baseline] 
6 mo 
 
SECONDARY ENDPOINTS 
 
Objective 
Endpoint 
Start  
End  

 
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Observed rate of brain 
metastases following 
TTFields therapy at 12 
months 
Incidence of any SCLC brain 
metastases at 12 mo  
Start of TTFields 
[baseline] 
12 mo 
Overall survival of 
participants with SCLC 
after using TTFields 
therapy. 
Overall survival 
Start of TTFields 
[baseline] 
 Death 
or last 
follow-up 
at 60 
months. 
 
TTFields therapy 
related side effects. 
1. Incidence of TTFields related 
AEs  
Start of TTFields 
[baseline] 
12 mo 
2. Incidence of cognitive AEs using 
Mini Mental State Exam 
(MMSE) 
6, 12 mo 
12 mo 
Quality of life among 
participants using 
TTFields therapy. 
EORTC QLQ-C30 questionnaire at 
6 and 12 mo 
Start of TTFields 
[baseline] 
6, 12 mo 
Observed rate of SCLC 
brain metastases at 6 
month from the beginning 
of the 4th cycle of 
chemotherapy to 
development of brain 
metastases    
Incidence of SCLC brain metastases 
at 6 month from the beginning of the 
4th cycle of chemotherapy to 
development of brain metastases    
Start of the 
4th cycle of 
chemotherapy 
[baseline] 
6 mo 
 
 

 
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4. STUDY ENROLLMENT AND WITHDRAWAL 
 
 
PARTICIPANT INCLUSION CRITERIA 
 
To be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. Ability to understand and the willingness to sign a written informed consent document. 
2. Age ≥ 22 years at time of informed consent.  Both men and women and members of all 
races and ethnic groups will be included. 
3. Pathologically confirmed LS-SCLC or ES-SCLC. 
a. LSCLC – Stage I-III (Tany, Nany, M0) that can be safely treated with radiation doses. 
Excludes T3-4 due to multiple nodules that are too extensive of have tumor/nodal 
volume that is too large to be encompassed in a tolerable radiation plan.19 
b. ESCLC – Stage IV (Tany, Nany, M1), or T3-4 due to multiple nodules that are too 
extensive of have tumor/nodal volume that is too large to be encompassed in a tolerable 
radiation plan.19 
4. Must be no more than 6 weeks from having received last dose of chemo- and/or 
radiotherapy for primary tumor to anticipated start of TTField therapy. 
5. Partial response to standard of care (chemo- and/or radiotherapy) as judged by treating 
physicians with no evidence of recurrence as observed by thoracoabdominal CT within 12 
weeks of enrollment. 
6. No brain metastases as observed by gd-MRI within 12 weeks of enrollment.  
7. No previous or currently active second malignancy, with exception of non-metastatic 
prostate cancer, treated Stage I breast cancer, skin malignancies.  
8. Life expectancy of at ≥3 months. 
9. ECOG performance status ≤ 2 (Karnofsky ≥ 60; Refer to Appendix A).  
10. Participants must be willing and able to fully comply with the minimum required 18 hours/day 
of TTField therapy.  
11. Women of child-bearing potential must agree to use adequate contraception (hormonal or 
barrier method of birth control; abstinence) prior to study entry and for the duration of study 
participation. 
 
 
PARTICIPANT EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
 
1. Malignant disease, other than that being treated in this study, with exception of non-
metastatic prostate cancer, treated Stage I breast cancer, skin malignancies. 
2. Implanted pacemaker, defibrillator or deep brain stimulator, or documented clinically 
significant arrhythmias. 
3. Active implanted medical device (e.g. deep brain stimulators, spinal cord stimulators, vagus 
nerve stimulators, pacemakers, defibrillators, and programmable shunts). 
a. External medical devices (e.g., insulin pumps) are permitted.  
4. Skull defect (e.g. missing bone with no replacement). 
5. Shunt. 
6. Bullet fragments 
7. Evidence of increased intracranial pressure (midline shift > 5mm, clinically significant 
papilledema, vomiting and nausea or reduced level of consciousness). 
8. Sensitivity to conductive hydrogels. 

 
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9. Pregnant or lactating women. 
10. Underlying serious skin condition on the scalp, which in the opinion of the investigator, 
would prevent or interfere with TTField therapy. 
11. Any condition that, in the opinion of the investigator, would interfere with evaluation of study 
treatment or interpretation of participant safety or study results. 
 
 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Participants for this study will primarily be recruited from Hematology/Oncology or Radiation 
Oncology practices within either OHSU, UW Seattle, Mayo Clinic Arizona or Ohio State 
Univeristy. Participants may be identified and referred to this study by their primary treating 
physician from within OHSU, UW Seattle, Mayo Clinic Arizona, Ohio State University or from the 
outside community. Participants may also initiate contact with the investigator through 
information of this study posted on the clinicaltrials.gov website. This pilot study aims to enroll 
106 participants, approximately half from each investigational study site. Total time to accrual 
will be approximately 24 months.  
 
ACCRUAL ESTIMATES 
 
A total of 106 participants anticipated to be equally enrolled from the four participating study 
sites, OHSU, UW Seattle, Mayo Clinic Arizona, and Ohio State University.  Among these 106 
participants, we expect to enroll 45 patients with extensive stage disease and 61 patients with 
limited stage disease.  We will continue enrolling patients from the four sites until the targeted 
sample size has been reached within each disease category (i.e. we will stop enroll patients 
with extensive stage disease if the number has reached 45, but will continue to enroll subjects 
with limited stage disease until we have 61 patients in the sub-category, and vice versa.) . 
 
No OHSU Knight Cancer Institute study will focus on any particular gender, racial or ethnic 
subset. No participant will be excluded from the study on the basis of gender, racial or ethnic 
origin. Male, female and minority volunteers will be recruited for this study from the general 
population and approximately 50% men and 50% women will be studied. Gender-
nonconforming and gender-fluid individuals as members of the general population will also be 
recruited. 
 
The projected gender, racial, and ethnic composition of the study will represent that of the states 
of Oregon (Table 1), Washington (Table 2), Arizona (Table 3), and Ohio (Table 4). 
 
4.3.2    Medicare Coverage Related to Investigational Device Exemption (IDE) Studies 
 
In this study Medicare beneficiaries will be given access to potentially useful therapies 
available in the clinical trial context. Enrollment of Medicare beneficiaries in clinical trials will 
allow collection of sufficient evidence to demonstrate or not demonstrate a new therapy’s 
effectiveness for use in the Medicare population based on age, disability, or other eligibility 
status. The Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA) 
allowed Medicare payment of the routine costs of care furnished to Medicare beneficiaries in 
certain categories of Investigational Device Exemption (IDE) studies. Covering the costs in 
these IDE studies removes a financial barrier that could otherwise discourage medicare 
beneficiaries from participating. CMS finalized changes to the IDE regulations (42 CFR § 405 
Subpart B), effective January 1, 2015. CMS added criteria for coverage of IDE studies and 
changed from local Medicare Administrative Contractor (MAC) review and approval of IDE 
studies to a centralized review and approval of IDE studies. 

 
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An approval for a Category A (Experimental) IDE study will allow coverage of routine care items 
and services furnished in the study, but not of the Category A device, which is statutorily 
excluded from coverage. 
 
 
Table 1. Projected accrual for present study based on Oregon population demographics 
 
Females 
Males 
Totals 
N 
% OR pop. 
N 
% OR pop. 
N 
% OR pop. 
Ethnic category  
 
 
 
 
 
 
Hispanic or Latino 
2 
6.6 
3 
6.5 
5 
13.1 
Not Hispanic or Latino 
12 
43.8 
10 
37.9 
22 
86.9 
Ethnic category participant totals* 14 
 
13 
 
27 
100* 
Racial category 
  
 
 
American Indian or Alaskan Native 
0-1 
0.9 
0-1 
0.9 
1 
1.8 
Asian 
1 
2.4 
1 
2.3 
2 
4.7 
Black or African American 
0-1 
1.1 
0-1 
1.0 
1 
2.2 
Native Hawaiian or other Pacific Islander 
0 
0.2 
0 
0.2 
0 
0.4 
White 
10 
43.9 
9 
43.2 
21 
87.1 
Two or more races 
1 
1.9 
1 
1.9 
2 
3.8 
Racial category participant totals* 14 
50.4 
13 
49.6 
27 
100 
Source: Adapted from U.S. Census Bureau, 2017.  
N, projected participant accrual based on percentage of OR population demographic (% OR pop.).  
*Totals may not equal 100 due to rounding. 
 
Table 2. Projected accrual for present study based on Washington population demographics 
 
Females 
Males 
Totals 
N 
% WA pop. 
N 
% WA pop. 
N 
% WA pop. 
Ethnic category  
 
 
 
 
 
 
Hispanic or Latino 
3-4 
6.4 
3-4 
6.4 
7 
12.7 
Not Hispanic or Latino 
10 
43.7 
9 
43.7 
20 
87.6 
Ethnic category participant totals* 14 
 
13 
 
27 
100* 
Racial category 
  
 
 
American Indian or Alaskan Native 
1 
1.0 
1 
1 
1 
1.9 
Asian 
2-3 
4.5 
2-3 
4.5 
5 
8.9 
Black or African American 
1 
2.1 
1 
2.1 
2 
4.2 
Native Hawaiian or other Pacific Islander 
0 
0.4 
0 
0.4 
0 
0.8 
White 
9 
39.8 
9 
39.8 
18 
79.5 
Two or more races 
1 
2.4 
1 
2.3 
2 
4.6 
Racial category participant totals* 14 
50.0 
13 
50.0 
27 
100 
Source: Adapted from U.S. Census Bureau, 2017.  
N, projected participant accrual based on percentage of WA population demographic (% WA pop.).  
*Totals may not equal 100 due to rounding. 
 
Table 3. Projected accrual for present study based on Arizona population demographics 
 
Females 
Males 
Totals 
N 
% AZ pop. 
N 
% AZ pop. 
N 
% AZ pop. 
Ethnic category  
 
 
 
 
 
 
Hispanic or Latino 
3 
15.5 
3 
15.5 
6 
31.1 

 
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Not Hispanic or Latino 
10 
43.7 
10 
43.7 
20 
54.1 
Ethnic category participant totals* 13 
 
13 
 
26 
100* 
Racial category 
  
 
 
American Indian or Alaskan Native 
1 
2.5 
1 
2.5 
1 
5.3 
Asian 
2-3 
1.6 
2-3 
1.6 
5 
3.2 
Black or African American 
1 
2.1 
1 
2.1 
2 
5.2 
Native Hawaiian or other Pacific Islander 
0 
0. 
0 
0.4 
0 
0.3 
White 
8 
41.3 
8 
41.3 
16 
82.6 
Two or more races 
1 
1.4 
1 
1.4 
2 
2.9 
Racial category participant totals* 13 
50.0 
13 
50.0 
26 
100 
Source: Adapted from U.S. Census Bureau, 2017.  
N, projected participant accrual based on percentage of AZ population demographic (% AZ pop.).  
*Totals may not equal 100 due to rounding. 
 
Table 4. Projected accrual for present study based on Ohio population demographics 
 
Females 
Males 
Totals 
N 
% OH pop. 
N 
% OH pop. 
N 
% OH pop. 
Ethnic category  
 
 
 
 
 
 
Hispanic or Latino 
3 
6.0 
3 
6.0 
6 
14.0 
Not Hispanic or Latino 
10 
44.7 
10 
44.7 
20 
78.4 
Ethnic category participant totals* 13 
 
13 
 
26 
100* 
Racial category 
  
 
 
American Indian or Alaskan Native 
1 
1.0 
1 
1 
1 
0.3 
Asian 
1-2 
1.2 
1-2 
1 
1 
2.5 
Black or African American 
2-3 
6.5 
2-3 
6.5 
4 
13.1 
Native Hawaiian or other Pacific Islander 
0 
0.05 
0 
0.05 
0 
0.1 
White 
8 
40.5 
8 
40.5 
20 
81.1 
Two or more races 
1 
1.2 
1 
1.2 
2 
2.4 
Racial category participant totals* 13 
51.0 
13 
49.0 
26 
100 
Source: Adapted from U.S. Census Bureau, 2017.  
N, projected participant accrual based on percentage of OH population demographic (% OH pop.).  
*Totals may not equal 100 due to rounding. 
 
 
4.3.3    INCLUSION OF CHILDREN 
 
This protocol does not include children (<18-years-old) as the number of children with SCLC is 
limited. 
 
 
REGISTRATION PROCEDURES 
 
In order to participate in this study signed informed consent will be obtained from the participant. 
The Institutional Review Board (IRB) approved informed consent must be signed and dated by 
each participant prior to undergoing any study procedures or before any prohibited medications 
are withheld from the participant in order to participate in this study.  
 
PARTICIPANT REGISTRATION 
 

 
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4.4.1.1 Local Registration 
 
This is a single-arm phase II trial, and there is no randomization for treatment.  
 
Participants will be required to give written informed consent to participate in the study before 
any screening tests or evaluations are conducted that are not part of standard care. 
 
Registration from all consented participants must be entered into the OHSU electronic Clinical 
Research Management System (CRMS, e.g., eCRIS). At a minimum, registration of OHSU 
participants will include: Signed copies of the most recently IRB-approved, informed consent 
form and HIPAA authorization 
 
4.4.1.2 Multicenter Registration 
 
The OHSU coordinating center study team manages the participant registration process. 
Investigators at participating sites identify eligible participants and send source documents that 
support eligibility to OHSU for review and verification before the participating site may enroll and 
treat the participant. The OHSU coordinating center team verifies completeness of documents, 
enters registration information into the Knight CRMS, and assigns a study number/identifier.  
The coordinating center sends an email to the participating site indicating whether or not the 
participant is eligible and assigns a participant number/identifier.   
 
Registration will include a minimum of the following: 
• 
De-identified source documentation of eligibility 
• 
Signed copies of the most recently IRB-approved, informed consent form and HIPAA 
authorization. 
 
Each site is expected to maintain a screening log of all participants who are approached for the 
study.  The log documents an explanation for exclusion due to screen failure.  This log should 
be submitted to the coordinating center on a regular basis. Participating sites are required to 
retain, in a confidential manner, sufficient information on each participant so that the participant 
may be contacted should the need arise. 
 
 
PARTICIPANT SCREENING AND ENROLLMENT 
 
In order to participate in this study, signed informed consent must be obtained from the 
participant or the participant's legally acceptable representative.  The current Institutional 
Review Board (IRB) approved informed consent must be signed and dated by each participant 
prior to undergoing any study procedures or before any prohibited medications are withheld 
from the participant in order to participate in this study.  
 
Screening will begin once the participant has provided written informed consent to participate in 
the study and ends on Day 1 of the study.  All screening and baseline evaluations will be 
performed during the screening phase (i.e., up to 10 days before initiating TTField therapy).  
Day 1 of the clinical trial will be when participants start TTField therapy. Total accrual of all 
participants is anticipated to take a total of 24 months. 
 
 
PARTICIPANT WITHDRAWAL OR DISCONTINUATION 
 
Participants are free to withdraw consent and discontinue participation in the study at any time 
and without prejudice to further treatment.  If a participant no longer wants to receive 
investigational product, but is willing to come for follow-up appointments, the participant’s 

 
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request should be honored, if possible.  The following are examples demonstrating why a 
participant’s treatment might be discontinued: 
• 
Toxicity precludes further study treatment.  
• 
There is a need for any treatment not allowed by the protocol.  
• 
The participant fails to meet the criteria for study treatment.  
• 
Disease recurrence or progression.  
o TTFields therapy has been established to control supratentorial primary glioblastoma.  
TTfields may control supratentorial disease better than infratentorial disease.  
Participants that develop supratentorial metastatic lesions will be removed from the 
study.  Participants that develop infratentorial metastases, or systemic metastases, will 
be able to continue with treatment for the duration of the 12 months treatment period. 
• 
Investigator’s discretion.  
 
No further participant contact should be made if the participant withdraws consent for 
participation in the study. Information about the reason(s) for discontinuation and collection of 
any new or ongoing adverse events (AEs) should be collected at the time the participant 
withdraws consent.  
 
For all other reasons for discontinuation from the study treatment phase, the participant should 
return to the clinic for the end of treatment (EOT) visit according to Section 7.   
 
HANDLING PARTICIPANT WITHDRAWAL AND DISCONTINUATION 
 
Participants that withdraw or discontinue from this study will not be replaced.  
 
 
OFF-STUDY CRITERIA 
 
Criteria that can take a participant off-study include: 
• 
Participant requests to be withdrawn from study without further follow-up, 
• 
Completed study follow-up period, 
• 
Death, 
• 
Screen failure 
 
 
STUDY DISCONTINUATION 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to Novocure, IRB, and other 
regulatory authorities as needed.  If the study is prematurely terminated or suspended, the 
Investigator will promptly inform the IRB and will provide the reason(s) for the termination or 
suspension.  Reasons for terminating the study may include the following: 
• 
Incidence or severity of adverse events, in this or other studies, indicates a potential 
health hazard to participants. 
• 
Demonstration of efficacy that would warrant stopping. 
• 
Data that are not sufficiently complete and/or evaluable. 
• 
Investigator(s) do not adhere to the study protocol, or applicable regulatory guidelines in 
conducting the study.  
• 
Participant enrollment is unsatisfactory.  
• 
Submission of knowingly false information from the study site to Novocure, or local or 
other regulatory authorities. 
• 
Upon instruction by local or other regulatory, or oversight authority.    

 
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Study may resume once concerns about safety, protocol compliance, data quality are 
addressed and satisfy the Sponsor, IRB and/or FDA. 

 
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5. INVESTIGATIONAL PRODUCT 
 
A list of the adverse events and potential risks associated with the investigational or other 
agents administered in this study can be found in Section 9.4. 
 
 
OPTUNE® 
 
The second generation Optune® device weighs 2.7 lbs and the treatment kit is comprised of the 
following components: an Electric Field Generator, INE Insulated Transducer Arrays (i.e., the 
transducer arrays), and additional device components that include a power supply, portable 
battery, battery rack, battery charger, connection cable and carrying case (Figure 2).   
 
The investigator, or other qualified designee, will provide participants, as well caregiver or family 
member (if needed), with training and instruction on how to operate the Optune® device for 
continuous at-home treatment.  Along with providing training and instruction, participants issued 
an Optune® device will be provided a patient information and operation manual.   
 
Please refer to patient information and operation manual for instructions on using device.  
 
ACQUISITION 
 
The Optune® device and components of the treatment kit will be supplied by manufacture 
(Novocure, Inc) to the individual participant.  Transducer arrays will be shipped as per 
company’s policy.   
 
For investigator and study team: The manufacturer will contact each participant after eligibility is 
confirmed and the individual is enrolled on the study.  A nurse coordinator, or other designated 
healthcare provider, from Novocure Inc. will meet with each participant to discuss the 
application of device, skin care, in the same way patients with GBM are started on the device. 
 
For participants: Participants are required to make arrangements with Novocure Inc. 
representative for this study to arrange for replacement of device parts and transducer arrays.  
 
DEVICE COMPONENTS 
 
5.1.1.1 Optune Electric Field Generator 
 
The Optune Electric Field Generator is a portable, battery or power supply operated device.  
The outputs are connected to two pairs of insulated transducer array sets operated sequentially.  
The intensity of the field, the frequency of the waves, and the temperature of the transducer 
arrays are pre-set, and are controlled by two microcontrollers that run Novocure's software.  The 
output parameters of the Electric Field Generator are either pre-programmed or set by the 
service technician through a “service only” USB-type connector.  The device status and 
monitored parameters are continuously stored in an internal log memory and can be transferred 
by an isolated serial connection to a PC.  In addition, the front panel includes visual indicators 
for power ON, Treatment ON, alarms and low battery.  
 
5.1.1.2 INE Insulated Transducer Arrays 
 
Two sets of INE Insulated Transducer Arrays are connected to the Electric Field Generator. 
Each set includes a pair of arrays, with 9 serially interconnected single transducers in each 

 
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array. Each transducer array includes 8 thermistors. A single, sterile, 'ready to use’ INE 
Insulated Transducer Array unit incorporates the following: one INE transducer array; 
conductive gel layer; mid-pads; medical tape; and overlapping liner. The transducer arrays are 
made from high dielectric constant insulated ceramic discs soldered to a flexible circuit board. 
The flexible printed circuit incorporates the components required for delivering the current for 
each ceramic plate and for measuring the temperature of the thermistors. At the set parameters, 
the electrodes do not cause significant heating due to dielectric losses of the insulation or 
induced fields in the target tissue. As an additional safety feature, the temperature of the 
transducer arrays is monitored by a temperature sensor. If temperature rises beyond 41°C, the 
device automatically shuts off. 
 
5.1.1.3 Additional Components 
 
In addition, the following components are also included in the Optune Treatment Kit: power 
supply, portable battery, battery rack, battery charger, connection cable and carrying case 
Optune can be powered by a mains-connected power supply of 24V± 2 V. The power supply 
connects to the power connector on the front panel of the device. Alternatively, Optune can also 
be powered by battery using a portable, external 33 V ± 2 V (when fully charged) rechargeable 
battery. Several batteries placed in a battery rack can be recharged at the same time using a 
dedicated battery charger, when not connected to the device. The connection between the 
battery and the device is through a dedicated connector on the device's front panel. The 
transducer arrays are connected to the device by a spiral extension cable. Patients carry the 
device and the battery in a specialized over-the-shoulder bag, which allows them to receive 
continuous treatment without changing their daily routine. 
 
DEVICE SETTINGS AND PROGRAMMING  
 
TTField therapy will be administered at a set frequency of 200 kHz.  These treatment 
parameters are preset by the manufacturer such that there are no electrical output adjustments 
available to the participant.  
 
DEVICE USAGE AND MAINTENANCE 
 
The investigator, or other qualified healthcare provider from either participating site or Novocure 
Inc., will provide participants with training and instruction on how to operate the Optune® device 
for continuous at-home treatment.  
 
Please refer to patient information and operation manual for instructions on using device.  
 
5.1.1.4 Battery replacement  
 
Participants will be trained to change and recharge depleted device batteries and to connect to 
the external power supply.  Use of the external power supply does not have a time limit and can 
be used with either U.S. (120V AC) or European (230V AC) outlets.  
 
For battery use: the Optune® device uses a single battery at a time.  All other supplied batteries 
should remain in the battery charger.  Each battery lasts 2 to 3 hours, and a yellow low Battery 
indicator light will turn on; indicating that the battery requires replacement.  The treatment will 
continue to run while the yellow low battery indicator is illuminated until the audible alarm 
sounds and the red error light illuminates. Once this happens the treatment will stop and the 
device must be turned off and the battery replaced. 

 
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5.1.1.5 Transducer array placement and replacement 
 
The investigator other designated healthcare provider will provide detail instructions regarding 
the placement/replacement and positioning of the transducer arrays on the participants head.   
 
Placement of the transducers arrays to the head requires that the entire scalp be shaved using 
an electric razor (ensuring that there is no remaining stubble). The shaved scalp should be 
wiped with 70% isopropyl alcohol prior to placement of transducer arrays.  The two black 
transducer arrays are to be placed in the front and back of the head and the two white arrays 
are placed on the sides.  Removing liner covering gel on the transducer arrays, place each 
transducer array on head and press the entire edge of transducer array tape to the scalp.  
 
Transducer arrays need to be replaced 1 to 2 times per week (every 4 days at most).  The 
Optune® device’s alarm will beep with increased frequency if not properly functioning, and this is 
a likely indicator that hair growth is preventing the transducer arrays from making good contact 
with the scalp.  The old transducer arrays should be removed and the scalp needs to be re-
shaved in order to maintain optimal contact.  To ensure consistency, the new transducer arrays 
should be replace in the same general location as before, but a shift the transducer arrays less 
than an inch is permitted. 
 
5.1.1.6 Connecting transducer arrays to device 
 
Each of the 4 transducer array connectors with black and white connection ends must be 
connected to the matching sockets on the connection cable.  That is, the 2 connectors with the 
black connection ends are to be plugged into the two black sockets and the 2 white connection 
ends are to be plugged into the white sockets.  Press firmly to be sure the connectors are 
pushed in all the way.  
 
DURATION OF EXPOSURE  
 
Participants are required to have a minimum 18 hours per day of TTField therapy.  Participant 
will be able to carry the device in an over-the-shoulder bag or backpack so that they can receive 
continuous treatment.  
 
DEVICE STORAGE AND STABILITY 
 
Storage conditions for the device and additional parts has an allowable temperature range of     
-5°C to 40°C (23°F to 104°F), and a relative humidity range of 15-75%.  Storage conditions for 
the transducer arrays has an allowable temperature range of 5°C to 27°C (41°F to 81°F), and 
relative humidity range of 35-50%.  
 
SPECIAL CONSIDERATION FOR ADMINISTRATION 
 
5.1.1.7 Topical creams or ointments  
Allow for 15 minutes after the application of a cream or ointment to the scalp before replacing 
transducer arrays.  After 15 minutes, the scalp should be wiped again with 70% isopropyl 
alcohol and the transducer arrays applied to the scalp once dry. 
 
5.1.1.8 Traveling with device 
 

 
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Optune's portable batteries contain lithium ion material and are restricted from being checked as 
luggage for passenger aircraft travel.  They can be carried in the passenger cabin.  The Optune 
device and transducer arrays will activate metal detectors.  
 
5.1.1.9 Troubleshooting Guide  
 
Participants should carry a copy of the Troubleshooting guide (Section 26 of the Patient 
information and operation manual).  This guide is necessary to ensure the Optune® device is 
properly functioning and prevent any unwanted break in treatment. Participants that continue to 
experience problems with the device should contact the Principle Investigator or designated 
member of the study team to resolve these issues.  
 
ACCOUNTABILITY 
 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful 
record of the inventory and disposition of each study device.   
 
Responsibility for device accountability at the study site rests with the Investigator; however, the 
Investigator may assign some of these accountability duties to an appropriate designee. 
Inventory and accountability records must be maintained and readily available for inspection by 
the study monitor and are open to inspection at any time by any applicable regulatory authorities 
or other oversight bodies. 
 
The Investigator or designee will collect and retain all used and unused components of the 
Optune® device treatment kit until full accounting has been completed. The Investigator or 
designee must maintain records that document: 
• Device delivery to the study site. 
• The inventory at the site. 
• Device use by each participant. 
• Return of device and components of treatment kit to the Investigator or designee. 
• Destruction or return of device and components of treatment kit for final disposal. 
 
These records should include dates, quantities, serial numbers (if available), and the unique 
code numbers (if available) assigned to the device and components of the treatment kit and 
study participants. 
 
The investigational product must be used only in accordance with this protocol. The Investigator 
will also maintain records adequately documenting that the participants were provided with the 
correct investigational device specified. 
 
Completed accountability records will be archived by the site. At the completion of the study, the 
Investigator or designee will oversee shipment of any remaining study drug back to Novocure, 
Inc. for destruction according to institutional standard operating procedures.   
 
DEVICE RETURN 
 
Participants are required to return used transducer arrays to the investigational site for 
subsequent return to manufacturer.  Upon participant withdrawal from the study or upon 
completion of treatment, participants are required to return the Optune® device and any used or 
unused components of the treatment kit to the investigational site for return to manufacturer.  

 
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6. TREATMENT PLAN 
 
 
DOSAGE AND ADMINISTRATION 
 
In this study, a treatment cycle is defined as 4 weeks (or 1 month).  Using the Optune® device, 
participants will receive multiple 1-month treatment courses, in which TTField therapy will be 
administered to the participants’ head continuously (18-24 hours per day) for the entire duration 
of the 12 month study, or until disease progression, whichever comes first.   
 
Treatment will be administered on an out-patient basis.  Reported adverse events and potential 
risks are described in Section 9.  No investigational or commercial agents or therapies other 
than those described in this protocol may be administered with the intent to treat the 
participant's malignancy. 
 
ELECTRIC FIELD 
 
Participants receiving TTField therapy will have 4 transducer arrays placed on their scalp and 
connected to the portable Optune® device which will be set to generate 200 kHz electric field in 
2 perpendicular directions that are operated sequentially. The field intensity will be set at >0.7 
V/cm at the center of the brain.  These device settings are preset by the manufacturer.  
Participants will receive detailed written instructions and practical training by the Principle 
Investigator or designated member of the study team on how to operate the device for 
continuous at-home treatment.   
 
TRANSDUCER ARRAY PLACEMENT 
 
TTFields are applied to the shaved scalp via two pairs of orthogonally positioned transducer 
arrays.  Since no brain metastatic lesions are present (or clinically observable) at time of 
enrollment, there is no need to precisely position arrays around a tumor as is the case in 
treating GBM.20,21  Instead to create the 2 perpendicular field directions, each pair of transducer 
arrays will be centered on the participants head such that one pair is placed on the left and right 
side of the head, and the second pair placed anteriorly and posteriorly.  Transducer arrays 
should be replaced every 2 to 3 days, with a slight relocation of the new arrays ~2 cm from prior 
location (Figure 4).  
 
Figure 4: Transducer array 
layouts found to deliver a 
uniform field distribution to the 
entire brain. Each layout 
comprises two pairs of arrays. 
One layout comprises the pairs 
of arrays shown in schematics 
A and B. The second layout 
comprises the pairs of arrays 
shown in schematics C and D. 

 
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TREATMENT INTERRUPTIONS AND DELAYS  
 
Although uninterrupted treatments are preferred, participants are allowed 2 daily breaks in 
treatment not to exceed 1 ± 2 hours each for personal needs (e.g. bathing).  Additionally, 
participants are allowed to suspend TTField treatment for 2 ± 1 days at the end of each 4 week 
treatment cycle.   
 
TTField therapy may be delayed for up to 8 weeks (i.e., two treatment cycles) for any reason, 
but should be clearly documented in the case report form (CRF).  If TTField therapy is not 
restarted after a delay of two treatment cycles, then the participant will be removed from the 
study. 
 
 
TREATMENT PERIOD AND MAINTENANCE 
 
Participants will receive TTField therapy on continuous basis (i.e., 18-24 hours a day, 7 days a 
week) for a period of 12 months.  Participants that develop supratentorial metastatic lesions 
(>10) before 12 months will discontinue further use of TTFields and will be provided 
supportive/palliative treatments and supportive care (e.g., management of radionecrosis) 
consistent with institutional standard of care (e.g., whole brain radiation therapy). Participants 
that develop either limited (≤10) supratentorial or any number of infratentorial mestastases will 
remain eligible to continue with TTFields therapy for the duration of the 12 months after the 
brain metastatic lesioins are addressed according to the institutional guidelines (e.g. partial 
brain irradiation, stereotactic radiosurgery, stereotactic body radiation therapy). These 
participants will be clinically monitored per institutional guidelines.  Participants that develop 
systemic progression, which can be treated per institutional standard of care (e.g. systemic 
chemotherapy, immunotherapy, radiation therapy, etc.), may remain eligible to continue with 
TTField therapy for the duration of the 12 months treatment period.  Information regarding 
systemic therapy must be recorded in CRF.   
 
After 12 months study period, participants will not be able to stay on the TTField therapy, and 
will be clinically monitored per institutional guidelines.  
 
 
CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES 
 
In keeping with the community standards of medical care, all treatments considered necessary 
for a participant’s welfare may be administered at the discretion of the investigator.  All 
concomitant medication will be recorded on the CRF including all prescription, over-the-counter 
(OTC), herbal supplements, and IV medications and fluids.  If changes occur during the trial 
period, documentation of drug dosage, frequency, route, and date may also be included on the 
CRF. 
 
All concomitant medications received within 30 days before starting TTField therapy and 30 
days after completing TTField therapy should be recorded.  Concomitant medications 
administered after 30 days after the last TTField treatment should be recorded for SAEs as 
defined in Section 9. 
 
Supportive measures for optimal medical care are to be given throughout the study as indicated 
by the treating physician’s assessment of the participant’s medical need and institutional and 

 
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general medical guidelines for the care of participants undergoing treatment of SCLC. In 
general, medications required to treat AEs, manage cancer symptoms, concurrent diseases and 
supportive care agents, such as pain medications, anti-emetics and anti-diarrheals are allowed.   
 
Participants may use a wig or hat to cover the transducer arrays for cosmetic reasons.  
 
If patient develops radionecrosis after stereotactic radiosurgery (SRS) for disease progression 
in the brain with a single brain metastatic lesion, patient will be managed by the treating team 
per standard of care for SRS-related radionecrosis.  Radionecrosis will be managed clinically by 
oral corticosteroids (dexamethasone).  If the symptoms do not respond to steroids after 
appropriate duration and corticosteroid dose administration, subjects will be treated with 
administration of bevacizumab (10 mg/kg every two weeks for 4 doses), followed by a period of 
observation with surveillance MRI every six to eight weeks.  If radionecrosis is not controlled 
medically, patient will be considered for surgical resection, delayed by 4 weeks after the last 
administration of bevacizumab.      
 
 
DERMATITIS 
 
Dermatitis is often observed at sites on the scalp where the transducer arrays are located, 
should be managed with topical corticosteroids (e.g., clobetasol 0.5% [twice daily for ≤2 
weeks])22 and/or per institutional guidelines. The transducer arrays can also be slightly moved, 
but no more than 2 cm (0.75 inch) from original location.   
 
INFECTION PROPHYLAXIS 
 
Use of topical antibiotics (e.g., bacitracin, triple antibiotic ointment [polymixin B, neomycin, and 
bacitracin)]) may be administered per institutional guidelines to the scalp prior to replacing 
transducer arrays.   
 
ALLERGIC REACTION / HYPERSENSITIVITY 
 
The transducer arrays utilize a conductive hydrogel, which may cause allergic reactions.  In the 
event of severe allergic reactions such as shock and respiratory failure, TTField therapy should 
be immediately discontinued, the transducer arrays removed from the scalp, and the scalp 
washed to remove residual conductive hydrogel.  Appropriate supportive therapy should be 
administered per institutional guidelines, which may include (but not limited to): epinephrine, IV 
fluids, corticosteroids, vasopressors, oxygen, bronchodilators, antihistamines, or 
acetaminophen.  
 
Participants with Grade 2 skin symptoms may be premedicated with Diphenhydramine, 50 mg 
po (or equivalent dose of antihistamine), as well as acetaminophen, 500-1000 mg po (or 
equivalent dose of antipyretic). 
 
CONTRACEPTION 
 
Participants of child bearing potential should start using birth control from time of enrollment 
(Day -60 to -10) and throughout the study period up to 30 days after the completing TTField 
therapy.  
 
The following are considered adequate barrier methods of contraception: diaphragm, condom, 
copper intrauterine device, sponge, or spermicide. Appropriate hormonal contraceptives will 

 
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include any registered and marketed contraceptive agent that contains an estrogen and/or a 
progestational agent (including subcutaneous, intrauterine, or intramuscular agents). 
 
Participants should be informed that receiving TTField therapy may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in this 
study participants must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in Section 9.6. If there is any 
question that a participant will not reliably comply with the requirements for contraception, that 
individual should not be entered into the study. 
 
USE IN PREGNANCY 
 
If a participant inadvertently becomes pregnant while receiving TTField therapy, the participant 
will immediately be removed from the study.  The site will contact the participant at least 
monthly and document the participant’s status until the pregnancy has been completed or 
terminated. The investigative site will report the outcome of the pregnancy to the manufacturer 
without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn).  The site investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the manufacturer.  
 
 
PRECAUTIONS ASSOCIATED WITH USE OF OPTUNE® DEVICE 
 
PRESENCE OF PLATES OR SCREWS IN THE PARTICIPANT’S SKULL BONE  
 
The ceramic discs of the transducer array must not be placed directly on any existing plates or 
screws in the participant’s skull bone.  
 
DAMAGE TO OPTUNE® DEVICE AND/OR COMPONENTS 
 
Participants are not to use the Optune® device or any component if any parts look damaged 
(torn wires, loose connectors, loose sockets, cracks or breaks in the plastic case). Likewise, the 
Optune® device and transducer arrays are not be used if they are wet.  
 
 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
 
Participants can receive anti-cancer systemic chemotherapy, biological therapy, 
immunotherapy, or radiation therapy while receiving TTField therapy per standard of care or the 
clinical discretion of the investigator. Participants that have disease progression requiring 
clinical intervention with one or more of the aforementioned treatments can remain on the study 
as long as there is no widespread supratentorial disease progression (>10 lesions). Participants 
may receive other medications that the investigator deems to be medically necessary. 
 
Participant exclusion criteria (Section 4.2) describes other medications prohibited in this trial. 

 
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7. STUDY PROCEDURES/EVALUATIONS AND SCHEDULE  
 
 
STUDY SPECIFIC PROCEDURES 
 
MEDICAL HISTORY  
 
A medical history will be obtained by the investigator or qualified designee. In addition to 
collecting information on demographics, the medical history will include all active conditions, and 
any condition diagnosed within the prior 10 years that are considered to be clinically significant 
by the Investigator. Details regarding the participant’s urothelial cancer will be recorded 
separately and not listed as medical history. 
 
DISEASE ASSESSMENT 
 
The investigator or qualified designee will obtain prior and current details regarding the 
participant’s SCLC. 
 
MEDICATION HISTORY  
 
A complete medication history will be acquired concurrent with medical history. Any AEs 
occurring prior to TTField therapy will be captured in the CRF.  
 
PHYSICAL EXAMINATION  
 
Physical exams must be performed by a medically qualified individual such as a licensed 
physician, Physician’s Assistant or advanced Registered Nurse Practitioner as local law permits. 
The physical exam at baseline should include a complete physical exam per institutional 
standards. All other physical exams after baseline will include an evaluation of any AEs, or any 
previously reported symptoms, or prior physical examination findings. 
 
A physical examination may include evaluating: weight, general appearance, head, ears, eyes, 
nose, throat, neck, skin, cardiovascular system, respiratory system, gastrointestinal system, and 
nervous system. A complete head and neck exam may include mirror and fiber-optic 
endoscopic examination. 
 
As part of screening/baseline visit, physical examination is to be conducted within 14 days prior 
to start of treatment. All physical examinations will also include: 
 
7.1.1.1 Vital signs  
Vitals to be collected (BP, HR, temperature). As part of screening/baseline visit, vitals should be 
obtained within 14 days prior to start of treatment. Vitals will also be obtained during treatment.  
 
Significant findings that were present prior to the signature of the informed consent must be 
included in the Medical History CRF page. Significant new findings that begin or worsen after 
informed consent must be recorded on the Adverse Event CRF page.  
 
7.1.1.2 Height and weight  
 
Height is only required as part of screening.  
 
7.1.1.3 Performance status  
 

 
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Performance status will be determined for all participants at screening and at select times during 
treatment as per assessment schedule in Section 7.8. Refer to Appendix A for performance 
criteria. 
 
ADVERSE EVENT EVALUATION  
 
Toxicities and adverse experiences will be assessed at each visit using the NCI CTCAE 5.03. 
Safety will be monitored by assessing physical examination, vital signs, body height and weight, 
performance status, and pregnancy, as well as collecting of AEs at every visit. 
 
Adverse events will be monitored from the time the participant signs the Consent Form. 
Participants will be instructed to report all AEs during the study and will be assessed for the 
occurrence of AEs throughout the study, including and up to 3 months following completion of 
TTFields therapy.  All AEs (serious and non-serious) must be recorded on the source 
documents and CRFs regardless of the assumption of a causal relationship with the study drug.  
 
For details on AE collection and reporting, refer to Section 9.  
 
ASSESSMENT OF STUDY AGENT ADHERENCE 
 
Participants will be responsible for self-administering TTField therapy using the Optune® device.  
Participants will receive instruction on how to operate Optune® device and place transducer 
arrays on the scalp from the investigator or other qualified, designated member of the research 
team.   
 
MAGNETIC RESONANCE IMAGING (MRI) / COMPUTED TOMOGRAPHY (CT) / POSITRON 
EMISSION TOMOGRAPHY (PET) 
 
Tumor imaging for patients with SCLC may be performed by computed tomography (CT), or 
fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT, or magnetic resonance 
imaging (MRI) per institutional guidelines.  Real-time determination of measurable disease by a 
radiologist will be used to determine participant eligibility.   
 
A thoracoabdominal CT scan is required within 12 weeks prior to enrollment in this trial.  
Subsequent thoracoabdominal CT imaging should be performed according to standard of care 
(Section 7.8); or upon the discretion of the investigators if clinically indicated.   
 
A gd-MRI of the head is required within 12 weeks prior to enrollment to assess presence of 
metastatic brain lesions.  On-study, Gd-MRI will occur per standard of care, with imaging taking 
place every 3 months for the first 24 months, after which participants will have Gd-MRI every 6 
months.18  The brain MRI protocol specifies 1.5 Tesla magnetic resonance imaging and includes 
axial images of 3 mm slice thickness with T1-post gadolinium, T2 and T2 flair sequences. All 
MRI images will be centrally reviewed by expert neuroradiologist at OHSU. 
 
All subsequent imaging assessment should be performed according to Schedule of Events 
(Section 7.8).  
 
PATIENT REPORTED OUTCOMES 
 
QoL care metrics will be assessed according to Schedule of Events (Section 7.8). Study 
participants will be asked to complete 2 questionnaires, each of which will be conducted prior to 

 
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TTField therapy (i.e., baseline), and again at 6 and 12 from starting TTField therapy (Table 3). 
The purpose of completing the questionnaires is to obtain a rich description of patients’ 
experiences of QoL and various symptoms. It will take <45 minutes to complete the 
questionnaires. The validated questionnaires were selected based on our clinical knowledge 
and experience with this patient population.  
 
Table 3. Method and Timing of QoL Assessments 
 
Measurement 
Baseline 
6 months 
12 months (i.e. EOT 
QoL 
EORTC QLQ-C30 
X 
X 
X 
MMSE 
Mini Mental State Exam 
X 
X 
X 
 
 
LABORATORY PROCEDURES AND EVALUATIONS 
 
Except for on-study pregnancy testing, all laboratory evaluations will be performed as part of 
standard of care.  Any additional on-study hematological and biochemical assessments will only 
be performed per physician’s discretion, if clinically indicated.  
 
HEMATOLOGY 
 
Hemoglobin, hematocrit, white blood cells (WBC) with differential count, platelet count will be 
collected as needed 
 
BIOCHEMISTRY  
 
Serum chemistry (performed as needed) to include complete metabolic profile (albumin, alkaline 
phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium), and phosphorus. 
 
PREGNANCY TEST  
A serum or urine pregnancy test is required during screening for all persons of childbearing 
potential. The pregnancy test is required within 72 hours prior to starting TTField therapy and 
results must be available prior to administration of TTField therapy. If the urine pregnancy test is 
positive, a serum pregnancy test must be performed per institutional standards.  
 
 
SCREENING ASSESSMENTS 
 
Toxicities which occur prior to the start of treatment will not be subject to analysis. Consent must 
be obtained before initiation of any clinical screening procedure that is performed solely for the 
purpose of determining eligibility for this research study. Evaluations performed as part of 
routine care before informed consent can be utilized as screening evaluations if done within the 
defined time period.  
 
Participants will undergo screening evaluations to determine study eligibility. All qualifying 
screening and eligibility assessments must be performed within 60 days prior to study 
registration. Laboratory baseline evaluations are to be conducted within 14 days prior to study 
registration. Radiologic imaging must be done within 12 weeks of study registration. For 
participants for whom there are 14 days or fewer between registration and the start of treatment, 
the day 1 laboratory data may be omitted. Refer to schedule of events (Section 7.8) for 
additional details. 
 

 
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INFORMATION TO BE COLLECTED ON SCREENING FAILURES 
  
A participant who signed an informed consent form but failed to be started on treatment for any 
reason will be considered a screen failure. Those found not to be eligible after signing the main 
study consent will be considered screening failures, and data will be handled in the same 
manner. The demographic information, informed consent, and inclusion/exclusion pages must 
also be completed for screen failures. No other data will be entered into the clinical database for 
individuals who are screen failures. 
 
 
ASSESSMENTS DURING TREATMENT 
 
Refer to the schedule of events (Section 7.8) for timing and details of specific procedures to be 
conducted.  Except for head MRI scans that is scheduled every three months for the 1st year 
while participants are on-treatment, all other imaging will be in accordance with standard-of-care 
guidelines.  Clinical evaluations are scheduled to occur every two months for ES-SCLC patients, 
and every three months for LS-SCLC patients while participants are on-treatment. Follow-up 
phone calls will occur every other month for months patients are not seen for clinical evaluation 
at the clinic. Follow-up and clinical evaluations will resume to standard-of-care after completion 
of the treatment period.  Imaging can be done within ± 1 week.  All other studies can be 
obtained ± 3 days of the stated time point. 
 
 
END OF TREATMENT VISIT 
 
The end of treatment (EOT) visit should be conducted 10 ± 10 days following completion of 
TTField therapy.  All AEs that occur prior to the EOT visit should be recorded.  Participants with 
an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the 
beginning of a new anti-cancer therapy, whichever occurs first.  Imaging (CT and/or MRI as 
appropriate) will be used to assess disease staging.   
 
 
FOLLOW-UP 
 
Aside from clinical follow-up at 1 and 3 months after completion of TTField therapy, all 
subsequent follow-up, including imaging studies, clinical evaluations, and any laboratory 
procedures will be consistent with institutional standard of care oncology follow-up visit.  Starting 
from the last chemo-radiotherapy treatment for the primary tumor, these standard of care 
oncology follow-up visits should occur every 3 to 4 months during years 1 and 2, and then every 
6 months thereafter. All participants will be followed (via medical record, or by other means such 
as a phone call) for survival status following TTField therapy discontinuation at 6, 12, 24, 36, 
and 60 months. 
 
 
UNSCHEDULED VISITS 
 
Unscheduled study visits may occur at any time if medically warranted. Any assessments 
performed (e.g., imaging, laboratory or clinical assessments) at those visits should be recorded 
in the eCRF. 
 

 
48 
 
 
SCHEDULE OF EVENTS  
 
Visit Days 
(± 5 Days) 
Screening 
Treatment Period (weeks)‡ 
EOT 
Follow-Up† 
Days 
-60 to -1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
1 mo 
+3 mo 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
MedicationsA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical ExamB 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LS-SCLC 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X* 
X 
ES-SCLC 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Phone Follow-upC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LS-SCLC 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X* 
 
ES-SCLC 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
CT imaging body 
XD 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Gd-MRI 
XD 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Device training 
XE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology F 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Biochemistry F 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Pregnancy testG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEH 
 
X--------------------------------------------------------------------------------X 
X 
X 
QoLI 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Survival status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
XI 
‡TTField therapy will be applied at a fixed frequency of 200 kHz. Treatment should be continuous, with an allowable 2 hr per day maximum break 
from treatment. Eligible participants must be no more than 6 weeks from last dose of chemo-radiotherapy of primary tumor with at least partial 
response to treatment.  
†Aside from clinical follow-up at 1 and 3 months after completion of TTField therapy, all subsequent follow-up, including imaging studies and 

 
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laboratory evaluations will be consistent with standard of care oncology follow-up visit. Starting from the last chemo-radiotherapy treatment for the 
primary tumor [i.e., off-study], these standard of care oncology follow-up visits will occur every 3 months during years 1 and 2, and then every 6 
months thereafter [up to 5 years]). 
*  1 month follow-up visit could be an in-person visit or a phone call visit. 
A For prior medications – record all medications taken within 30 days of Cycle 1. For concomitant medications – enter new medications started 
during the trial through the EOT visit. Record all medications taken for SAEs as defined in Section 7.8  
B All physical exams will include assessing weight, vital signs, and ECOG performance status. Height will be measured at screening visit only. 
CPhone calls will be done to follow-up on patient status in between in clinic evaluations.  
DInitial imaging at screening must be within 12weeks prior to the first dose of TTField therapy. Scans performed as part of routine clinical 
management are acceptable for use as the screening scan if they are of diagnostic quality and performed within 12 weeks prior to the first dose of 
trial treatment. Measureable disease based on RECIST 1.1 must be confirmed by investigator and/or radiologist before enrollment. 
EThe investigator, or other qualified designee, will provide participants, as well caregiver or family member (if needed), with training and instruction 
on how to operate the Optune® device for continuous at-home treatment. 
F Any additional on-study hematological and biochemical assessments will only be performed per physician’s discretion, if clinically indicated. 
G For persons of reproductive potential, a urine pregnancy test should be performed within 72 hours prior start of trial treatment. Persons will asked 
pregnancy status thereafter at the beginning of every treatment cycle. If persons are unsure, then a urine pregnancy test will be performed within 72 
hours prior to the next trial cycle. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test performed by the local study 
site laboratory will be required. Pregnancy tests (serum and/or urine tests) should be repeated, if required, per institutional guidelines. 
H AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.03. All AEs, whether gradable by CTCAE or not, will also be 
evaluated for seriousness. Record all AEs occurring within 30 days after the last trial treatment. Report all SAEs (related and unrelated to trial 
treatment) occurring up until 90 days after the last dose of trial treatment, or the start of new anti-cancer treatment, whichever comes first. 
Afterwards, report only SAEs that are related to trial treatment. 
I QoL assessments will be administered before start of treatment (baseline), at 28 weeks, and again at end of treatment (12 months). 
I All participants will be followed for survival status following TTField therapy discontinuation at 6, 12, 24, 36, and 60 months. 
 
 
 

 
50 
 
8. EFFICACY MEASURES 
 
Response and progression will be evaluated in this study using the international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1)23.   
 
 
DEFINITION OF EFFICACY MEASURES 
 
Evaluable for toxicity: All participants who initiated TTFields therapy (regardless of duration) will 
be considered evaluable for safety.  
 
Evaluable for objective response: Only those participants who have received at least one cycle 
of TTField therapy (i.e., 4 weeks) will be considered evaluable for response.  
 
 
DISEASE EVALUATION 
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. Use of MRI is also acceptable.   
 
 
EFFICACY CRITERIA FOR TUMOR RESPONSE 
 
EVALUATION OF NEW LESIONS 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in scanning 
technique, imaging modality, or findings thought to represent something other than tumor. 
However, a lesion identified on a follow-up scan in an anatomical location that was not scanned 
at baseline is considered new and will indicate progressive disease (PD).  If a new lesion is 
equivocal (because of small size etc.), follow-up evaluation will clarify if it truly represents new 
disease and if PD is confirmed, progression should be declared using the date of the initial scan 
on which the lesion was discovered. 
 
 
EVALUATION OF SURVIVAL 
 
Overall Survival: 
Overall Survival (OS) is defined as the time from start of TTField therapy 
(Day 1) to death due to any cause, or last follow-up at 60 months. 
 
 
RESPONSE REVIEW 
 
Response assessment will be determined by the investigator. 
 

 
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9. SAFETY 
 
 
SPECIFICATION OF SAFETY PARAMETERS 
 
The Investigator is responsible for monitoring the safety of participants who have enrolled in the 
study.  Safety assessments will be based on medical review of adverse events and the results 
of safety evaluations at specified time points as described in Section 7.8, Schedule of Events.  
Any clinically significant adverse events persisting at the end of treatment visit will be followed 
by the Investigator until resolution/stabilization or death, whichever comes first. 
 
 
DEFINITIONS 
 
ADVERSE EVENT (AE) 
 
An adverse event is defined as any undesirable physical, psychological or behavioral effect 
experienced by a participant during their participation in an investigational study, in conjunction 
with the use of the investigational product, whether or not considered intervention-related (21 
CFR 312.32 (a)). In general, this includes signs or symptoms experienced by the participant 
from the time of signing the informed consent to completion of the study.   
 
AEs may include, but are not limited to: 
• 
Subjective or objective symptoms spontaneously offered by the participant and/or 
observed by the Investigator or medical staff.  
• 
Clinically significant laboratory abnormalities.  
• 
A significant worsening of the participant’s condition from study entry.  
• 
Disease signs and symptoms and/or laboratory abnormalities existing prior to the use of 
the study treatment that resolve but then recur after treatment.  
• 
Disease signs and symptoms and/or laboratory abnormalities existing prior to the use of 
the study treatment which increase in frequency, intensity, or a change in quality after 
treatment.  
 
SERIOUS ADVERSE EVENT (SAE) 
 
An AE or suspected adverse reaction is considered "serious" if, in the view of either the 
Investigator, it results in any of the following outcomes: 
  
• 
Death,  
• 
A life-threatening adverse event,  
• 
In-patient hospitalization or prolongation of existing hospitalization,  
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or 
• 
A congenital anomaly/birth defect.  
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and/or participant may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include: 
 
• 
Allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
• 
Blood dyscrasias or convulsions that do not result in in-patient hospitalization, or 

 
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• 
The development of drug dependency or drug abuse.  
 
UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers UPs involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all 
of the following criteria: 
 
1. 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 participant 
population being studied; 
2. 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 
3. Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than previously known or recognized. 
4. This definition could include an unanticipated adverse device effect, any serious adverse 
effect on health or safety or any life-threatening problem or death caused by, or associated 
with, a device, if that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious problem associated 
with a device that relates to the rights, safety, or welfare of participants (21 CFR 812.3(s)). 
 
This study will use the OHRP definition of UP. 
 
SEVERITY OF EVENT 
 
The Investigator will grade the severity of each AE using, when applicable, the current version 
of the CTCAE v5.0. In the event of an AE for which no grading scale exists, the Investigator will 
classify the AE as defined below:  
 
• Mild (grade 1) – An event that is usually transient in nature and generally not interfering with 
normal activities 
• Moderate (grade 2) – An event that is sufficiently discomforting to interfere with normal 
activities 
• Severe (grade 3) – An event that is incapacitating with inability to work or do usual activity, 
or inability to work or perform normal daily activity 
• Life-threatening/debilitating (grade 4) – An event that puts the participant at immediate or 
potential risk of death, requires hospitalization, or which drastically impacts a participant’s 
well-being 
• Fatal (grade 5) 
 
ASSESSMENT OF CAUSALITY RELATIONSHIP TO OPTUNE® DEVICE  
 
For all collected AEs, the clinician who examines and evaluates the participant will determine 
the AE’s causality based on temporal relationship and his/her clinical judgment. The degree of 
certainty about causality will be graded using the categories below. 
 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 

 
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• Possible – The AE may be related to the study treatment.  
• Unlikely – The AE is doubtfully related to the study treatment. 
• Unrelated –The AE is clearly NOT related to the study treatment. 
 
Per 21 CFR 803.3, Medical Device Reporting: the definition of caused or contributed means that 
a death or serious injury was or may have been attributed to a medical device, or that a medical 
device was or may have been a factor in a death or serious injury, including events occurring as 
a result of:  
 
1. Failure 
2. Malfunction,  
3. Improper or inadequate design 
4. Manufacture 
5. Labeling, or  
6. User error. 
 
 
EXPECTEDNESS 
 
The Principle Investigator will be responsible for determining whether an AE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the study agent. 
 
 
ADVERSE EVENT LIST(S)  
 
ADVERSE EVENT LIST FOR TTFIELD THERAPY WITH OPTUNE® DEVICE 
 
Detailed information about the risks and expected AEs associated with using the Optune® may 
be found in the current edition of the manufacturer’s Patient Information and Operation Manual.  
The most frequent adverse reactions associated with use of Optune® device is dermatitis. 
 
 
ADVERSE EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an UP, AE or SAE may come to the attention of study personnel during study 
visits and interviews of a study participant presenting for medical care, or upon review by a 
study monitor. All AEs including local and systemic reactions not meeting the criteria for SAEs 
will be captured on the appropriate CRF. Information to be collected includes event description, 
time of onset, clinician’s assessment of severity, seriousness, expectedness, relationship to 
study product (assessed only by those with the training and authority to make a diagnosis), and 
date of resolution/stabilization of the event. All AEs occurring while on study must be 
documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 

 
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At each study visit, the Investigator will inquire about the occurrence of AE/SAEs since the last 
visit. Events will be followed for outcome information until resolution or stabilization.  
 
The Investigator will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for AEs) or 30 days (for SAEs) after the last day of study 
participation or until the participant receives alternative therapy for his/her SCLC, whichever 
occurs first. Any SAE that occurs after treatment with alternative therapy will be reported only if 
the Investigator or current treating physician has assessed the SAE as related to the study 
treatment. Adverse events will be evaluated using the current version of the CTCAE v5.0. 
  
 
REPORTING PROCEDURES 
 
OHSU IRB REPORTING OF UNANTICIPATED PROBLEMS AND ADVERSE EVENTS 
 
Unanticipated Problems and AEs will be reported to OHSU IRB according to the policies, 
procedures and guidelines posted on the OHSU IRB web site. 
 
Events that must be reported by the Investigator to the IRB are detailed in the OHSU IRB 
Investigator Guidance: Prompt Reporting Requirements (HRP-801). At a minimum, events 
requiring reporting to the IRB include: 
• 
Any new or increased risk related to the research, including AEs or IDE safety reports 
that require a change to the protocol or consent,  
• 
New FDA black box warning,  
• 
Publications identifying new risks,  
• 
Data Safety Monitoring Board/Committee letters recommending changes or discussing 
new risks 
• 
Unanticipated adverse device effect 
• 
Unauthorized disclosure of confidential participant information 
 
CENTRAL REPORTING OF ADVERSE EVENTS FOR MULTICENTER STUDIES  
 
A participating site must report an SAE to the institution’s local IRB for action as required, as 
well as to the OHSU coordinating center study team by phone, fax, or email within 24 hours of 
learning of the event (or as instructed in the protocol, if different).  The participating center will 
send the coordinating center materials regarding the SAE. 
 
The OHSU coordinating center study team will review and submit SAEs to the FDA, OHSU IRB, 
and any other required contacts as required by the Knight Data Safety Monitoring Plan (DSMP). 
The PI at the Coordinating Center is responsible for distributing IND and/or IDE Action Letters or 
Safety Reports, as applicable, to participating institutions for review and submission to their 
institution’s local IRB. 
 
MEDWATCH REPORTING  
 
The Investigator is required to report AEs to the FDA through the MedWatch reporting program, 
even if the trial involves a commercially available agent or device.  AEs to be reported include 
any UPs (i.e., not listed in the package insert) and any SAEs with a suspected association to the 
investigational product. 

 
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AEs that occur during clinical studies are to be reported to FDA as specified in the Form FDA 
3500, the MedWatch Voluntary Reporting form (available here), or completed online. A copy of 
Form FDA 3500 and supporting materials will be kept on file in the study regulatory binder.  
 
MANUFACTURER REPORTING REQUIREMENTS 
 
In the event that a participant experiences an episode of seizure while on study, the investigator 
or treating physician must report the event to Novocure Inc., and describe the causality 
relationship of the event to the Optune® Device (refer to Section 9.2.5).  
 
REPORTING OF PREGNANCY 
 
To ensure participant safety, each pregnancy in a participant on study treatment must be 
reported within 24 hours of learning of its occurrence. The pregnancy should be followed to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and the 
presence or absence of any birth defects, congenital abnormalities, or any pregnancy- or 
childbirth-related and/or newborn complications. 
 
The pregnancy should be recorded on the CRF and reported by the Investigator to Novocure, 
Inc., as well as any regulatory authority, as needed.  Pregnancy follow-up should be reported 
using the same form. Any SAE experienced during pregnancy must be reported.  
 
 
STUDY STOPPING RULES 
 
The overall study will be paused, and appropriate authorities (e.g., IRB, Knight Data and Safety 
Monitoring Committee) notified if the following events occur: 
• 
Life-threatening grade 4 toxicity attributable to protocol therapy that is unmanageable, or 
unexpected. 
• 
Death suspected to be related to Optune® device. 
 

 
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10. STATISTICAL CONSIDERATIONS 
 
Refer to Section 3.1, Description of the Study Design for a detailed description of the study 
design and endpoints. 
 
 
ANALYSIS POPULATIONS  
 
This is a phase II multi-center single-arm pilot study to evaluate the incidence of metastatic 
brain lesions in participants with SCLC that receive TTField therapy.  All participants that 
initiated TTField therapy will be considered evaluable for efficacy analysis.  All participants who 
initiated TTFields therapy (regardless of duration) will be considered evaluable for safety.  The 
anticipated enrollment is 106 participants, of which 45 participants will have ESCLC and 61 
participants will have LSCLC.  
 
 
DESCRIPTION OF STATISTICAL METHODS 
 
ANALYSIS OF PRIMARY ENDPOINT 
 
The primary endpoint is the incidence of SCLC brain metastases following 6 months of TTField 
therapy. Descriptive statistical analysis will be conducted for all participants, overall and by 
disease group (extensive stage and limited stage). The incidence rate of SCLC brain 
metastases at 6 month will be reported with 95% confidence interval, overall and by disease 
group (extensive stage vs. limited stage), by type (infratentorial vs. supratentorial). One sample 
test of proportion will be used to determine if the incidence rate is significantly reduced 
compared to historical controls for each disease group (assumed to be 40% and 30% for 
extensive stage and limited stage, respectively). Logistic regression model will be conducted to 
identify if there is any center difference (Oregon, Washington, Arizona, vs Ohio) after controlling 
for other covariates (for example, the compliance of patients in using the device) of that may 
influence the incidence of SCLC brain metastases.  Expecting the models for extensive stage 
and limited stage could be quite different, we will start with fitting two separate logistic 
regression models for each disease group. In addition to the above listed variables, patient 
characteristics, tumor characteristics will also be included as covariates to start the model 
building. Specifically, for each disease group, we will fit univariable logistic regression model for 
all potential covariates. Variables with p-value < 0.25 in the univariable logistic regression model 
will be included to build multivariable logistic regression model. Purposeful selection method 
combined with Akaike Information Criteria (AIC) will be used for final model determination for 
each disease group. If it turned out that the two final models have similar covariates and effect 
size, we will also develop a pooled logistic regression model using all subjects. The pooled 
logistic regression model will force the disease group as a covariate to the model, and all other 
variables included in the model will be carefully evaluated for confounding effect and for 
potential interaction with disease group.  
 
ANALYSIS OF THE SECONDARY ENDPOINTS 
 
For incidence of SCLC brain metastases following 12 months of TTField therapy, we will use 
exactly the same approach as described in Section 10.2.1.  
 
The distribution of overall survival will be graphically described using Kaplan-Meier plot, for all 
subjects together, and for each disease group (extensive stage and limited stage). If estimable, 
the median survival time will be reported with 95% confidence interval. The analysis is just for 
description. No hypothesis testing is planned for this endpoint. However, we will fit two cox 

 
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proportional hazard regression model to identify risk factors that may impact the OS. Covariates 
evaluated in the univariable analysis in Section 10.2.1 will also be evaluated in the cox 
proportional hazard regression model. OS at 6, 12, 24, 36 and 60 months after completion of 
TTField therapy will be reported.  
 
We will estimate TTField therapy-related toxicity and along with an exact confidence interval 
using the safety set. A summary table of observed AEs will also be reported by disease group 
(extensive stage and limited stage). 
 
The Quality of life scores will be recorded over time (See Section 7.8 for details) using the 
EORTC QLQ-C30 questionnaire.  Summary of QoLs and its change over time will be presented 
graphically using box plot and spaghetti plot, in addition to a summary table of QoL over time. 
No hypothesis testing is planned for QoL.   
 
Incidence of cognitive AEs will be assessed by measuring changes in MMSE scores over time. 
Descriptive statistical analysis will be conducted on the endpoint. (See Section 7.8 for details on 
time points for measurement)  
To evaluate how the time of last cycle of chemotherapy or chemoradiation therapy impact our 
observed indidence of SCLC brain metastases, we will also conduct a parellel analysis using 
SCLC brain metastases rate at 6-month from the beginning of the 4th cycle of chemotherapy to 
development of brain metastases as a secondary endpoint. We will use exactly the same 
approach as described in Section 10.2.1.  
 
 
 
SAMPLE SIZE, POWER, ACCRUAL RATE AND STUDY DURATION 
 
SAMPLE SIZE AND POWER 
 
A total of 106 participants with SCLC will be accrued into this study of which 45 and 61 
participants will be characterized as having either ESCLC or LSCLC disease, respectively.  For 
ESCLC, we need 45 subjects for 80% power to detect a 50% reduction at a 5% significance 
level using a two-sided exact test for one proportion, assuming the incidence rate is 40% for 
subjects not receiving Optune®. PASS 15 “Test for one proportion” procedure was used for 
sample size computation. We will use two-sided exact test for one proportion to test the 
incidence rate against the null hypothesis of 40%. P < 0.05 will be considered statistically 
significant.  
 
For participants with LSCLC, we need 61 subjects for 80% power to detect a 50% reduction at a 
5% significance level, using a two-sided exact test for one proportion, assuming the incidence 
rate is 30% for subjects not receiving Optune®.PASS 15 “Test for one proportion” procedure 
was used for sample size computation. We will use two-sided exact test for one proportion to 
test the incidence rate against the null hypothesis of 30%. P < 0.05 will be considered 
statistically significant.  
 
 
HANDLING OF MISSING DATA 
 
Every attempt will be made to obtain data at the defined time points as described in the primary 
and secondary endpoints.  For time points that have no data, we will evaluate whether or not the 
other time points can be used to fulfill the primary and secondary data.  If the data are not 
sufficient to analyze specific endpoints, the participant’s data may be excluded entirely or 

 
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partially, depending on the specific endpoints in question and in consultation with the 
biostatistician.  No missing data will be imputed. Whenever possible, all available data will be 
included in the analysis.  A sample size for each analysis will be clearly stated along with the 
reason for exclusion, if any participant is excluded from the analysis due to missing data. 
 

 
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11. CLINICAL MONITORING 
 
 
OHSU KNIGHT CANCER INSTITUTE DATA & SAFETY MONITORING PLAN 
 
This study is under the oversight of the Knight Cancer Institute’s DSMC as described in the 
Knight institutional DSMP.  The Knight DSMP outlines the elements required to ensure the 
safety of clinical trial participants, the accuracy and integrity of the data and the appropriate 
modification of cancer-related clinical trials for which significant benefits or risks have been 
discovered or when the clinical trial cannot be successfully concluded.  The Knight DSMP also 
describes the methods and procedures for ensuring adequate oversight of cancer-related 
research at OHSU. 
 
As described in the Knight DSMP, regardless of a trial’s risk level and any specific Knight 
oversight in place, the Investigator is singularly responsible for overseeing every aspect of the 
design, conduct, and final analysis of his/her investigation. 
 
The Knight DSMC will review and monitor study progress, toxicity, safety and other data from 
this study. Information that raises any questions about participant safety or protocol 
performance will be addressed by the Investigator, statistician and study team.  Should any 
major concerns arise, the Knight DSMC may recommend corrective action and determine 
whether or not to suspend the study. 
 
The Knight DSMC will review each protocol every 6 months, but may occur more often, if 
required, to review toxicity and accrual data (please refer to Knight DSMP for additional details 
on audit frequency).  The Knight DSMC will review accrual, toxicity, response and reporting 
information.  Information to be provided to the DSMC may include: participant accrual; treatment 
regimen information; AEs and SAEs reported by category; summary of any deaths on study; 
audit results; and a summary provided by the study team.  Other information (e.g. scans, 
laboratory values) will be provided upon request.  
 
 
CLINICAL DATA & SAFETY MONITORING 
 
The OHSU Investigator is ultimately, singularly responsible for overseeing every aspect of the 
investigation, including design, governing conduct at all participating sites, and final analysis of 
study data.  
 
In the absence of a formal monitoring plan, the Investigator may work with his/her study team to 
conduct and document internal monitoring of the study to verify protection of human 
participants, quality of data, and/or ongoing compliance with the protocol and applicable 
regulatory requirements. 
 
If at any time Investigator noncompliance is discovered at OHSU, the Investigator shall promptly 
either secure compliance or end the study with participating site. 
 
Independent audits will be conducted by the Knight DSMC to verify that the rights and well-
being of human participants are protected, that the reported trial data are accurate, that the 
conduct of the trial is in compliance with the protocol and applicable regulatory requirements, 
and that evidence of ongoing investigator oversight is present. 
 

 
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QUALITY ASSURANCE & QUALITY CONTROL 
 
The investigational site will provide direct access to all trial related source data/documents, and 
reports for the purpose of monitoring by the monitor and/or sponsor, and auditing by the Knight 
DSMC and/or regulatory authorities.  
 
Quality assurance (QA) auditing activities will occur as detailed in the Knight DSMP.  All 
discrepancies, queries, deviations, observations, and findings will be compiled into a final audit 
report along with a Corrective and Preventative Action Plan. 
 
The Sponsor-investigator, or study monitor, will verify that the clinical trial is conducted and data 
are generated, documented (recorded), and reported in compliance with the protocol, GCP, and 
the applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)). 
 

 
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12. DATA HANDLING AND MANAGEMENT RESPONSIBILITIES 
 
SOURCE DATA/DOCUMENTS 
 
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported.  All source documents should be completed in a neat, legible 
manner to ensure accurate interpretation of data.  The Investigator will maintain adequate case 
histories of study participants, including accurate CRFs and source documentation. 
 
 
PARTICIPANT & DATA CONFIDENTIALITY 
 
The information obtained during the conduct of this clinical study is confidential, and unless 
otherwise noted, disclosure to third parties is prohibited.  Information contained within this study 
will be maintained in accordance with applicable laws protecting participant privacy, including 
the provisions of the Health Insurance Portability and Accountability Act (HIPAA). 
 
Participant confidentiality is strictly held in trust by the participating Investigator(s) and study 
team. This confidentiality is extended to cover testing of biological samples and genetic tests in 
addition to the clinical information relating to participants.  Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence.  No 
information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the sponsor. 
 
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB 
or manufacturer supplying study product may inspect all documents and records required to be 
maintained by the Investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study.  The clinical study site will 
permit access to such records.  
 
Upon enrollment, participants will be assigned a code that will be used instead of their name, 
medical record number or other personally identifying information.  Electronic files for data 
analysis will contain only the participant code. Codes will not contain any part of the 18 HIPAA 
identifiers (e.g., initials, DOB, MRN).  The key associating the codes and the participants’ 
personally identifying information will be restricted to the Investigator and study staff.  The key 
will be kept secure on a restricted OHSU network drive a in a limited access folder. 
 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study.  At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by local IRB and institutional regulations.  Study 
participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored within the Knight Cancer Institute per OHSU’s Information 
Security Directives.  Individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by 
clinical sites and by Knight Cancer Institute research staff will be secured and password 
protected per OHSU’s Information Security Directives. At the end of the study, all study 
databases will be de-identified and archived within the Knight Cancer Institute. 
 
 
DATA COLLECTION & STORAGE: PRIVACY, CONFIDENTIALITY & SECURITY  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 

 
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the site Investigator. The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. Standard institutional practices will be followed as 
described in the OHSU’s Information Security Directives to maintain the confidentiality and 
security of data collected in this study. Study staff will be trained with regard to these 
procedures. 
 
Loss of participant confidentiality is a risk of participation. Efforts will be made to keep study 
participant identities confidential except as required by law. Participants’ samples will be 
identified by code only. Specifically, each consenting participant will be assigned a unique 
coded identifier consisting of numbers. This identifier will be associated with the participant 
throughout the duration of their participation in the trial. The coded identifier will also be used to 
identify any participant specific samples. 
 
Basic accrual tracking information (demographic, consent, visit information) will be captured in 
OHSU’s electronic clinical information research system (eCRIS), hosted on OHSU secure 
servers and managed by OHSU’s information technology group at their data center in downtown 
Portland, Oregon. Any additional printed documents containing participant identifiers, such as 
those from the medical record to confirm eligibility, will be filed in binders and kept in a locked, 
secure location. 
 
Study outcome data will be captured in electronic case report forms (eCRFs) using the 
electronic data capture (EDC) system, Forte. The Forte EDC is a web-hosted application is an 
approved EDC system that has been reviewed by OHSU Security.To further preserve 
confidentiality, PHI in the EDC system will be limited to just birth date and visit dates.  The web-
accessible EDC system is password protected and encrypted with role-based security, and 
administered by designated informatics staff within OHSU or Knight Cancer Institute.  All users 
of the database are assigned a unique ID, username, and password and must complete training 
appropriate to their role before they are authorized to enter, access, and store data in the 
database.  
 
Data from correlative studies will be entered into the EDC system by study personnel at OHSU. 
All other electronic data extracts will be stored only on OHSU encrypted computers and 
restricted drives, limited only to study investigators and staff with authorization to access the 
data. Quality assurance will be conducted as outlined in Section 11.3, Quality Assurance & 
Quality Control. 
 
 
MAINTENANCE OF RECORDS 
 
Records and documents pertaining to the conduct of this study, source documents, consent 
forms, laboratory test results and medication inventory records, must be retained by the 
Investigator for a period of 2 years following the date a marketing application is approved for the 
drug for the indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indicate, until 2 years after the investigation is discontinued 
and FDA is notified.  It is the responsibility of the sponsor to inform the Investigator when these 
documents no longer need to be retained. 
 
If the Investigator relocates or for any reason withdraws from the study, the study records must 
be transferred to an agreed upon designee, such as another institution or another investigator at 
OHSU. Records must be maintained according to institutional or FDA requirements.  

 
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MULTICENTER GUIDELINES  
 
OHSU Coordinating Center will manage trial data in the following ways:  
1. Confirm that all sites have received and are using the most recent version of the protocol. 
The protocol must not be rewritten or modified by anyone other than the OHSU Investigator. 
Documentation of the version that was sent to the site must be kept in the regulatory 
binders.  
2. Confirm that the protocol and informed consent form have local IRB approval at each site 
prior to registration of the first participant. Documentation of IRB approval from other sites 
for continuing review must be submitted and kept in the binder.  
3. Provide centralized participant registration in the clinical research management system. 
4. Ensure collection and review of applicable source documents and case reports by the 
OHSU Investigator to ensure protocol compliance. 
5. Maintain documentation for all SAE reports and submit regular summaries of all AEs, SAEs 
and UPs from all sites to the Knight DSMC per DSMC requirements. 
6. Ensure that relevant IRB correspondence and study status changes are communicated to all 
participating sites within 5 business days. Any changes that affect participant safety of study 
enrollments will be communicated immediately. 
7. Submit documentation to the FDA such as protocol amendments, annual reports, and safety 
reports for unexpected, fatal or life-threatening events that are associated with the use of the 
investigational product. 
8. Participating sites must submit regulatory documents including, but not limited to the 
following:  
9. Current CV (signed and dated) for each Investigator. 
10. Current medical license number for physician investigators. 
11. Current signed FDA Form 1572.  
12. Certificate of completion of institution-required human participant training course, the NIH 
online training in the protection of human research participants or other appropriate training. 
13. Documentation of institutional Conflict of Interest. 
14. IRB approved site-specific ICF (must be reviewed and approved by OHSU Investigator and 
study team prior to submission to the local IRB). 
15. All IRB approved documents and approval memorandums. 
16. Delegation log. 
17. DSMP. 
18. Completed CRFs (data entry) within 10 business days of study visit. 
 
 
PUBLICATION AND DATA SHARING POLICY 
 
This study will comply with the NIH Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final 
peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication. The investigators will work to expedite the analysis of 
data for release of results on all pre-specified outcomes in a timely and reasonable fashion at 
the completion of the study. If the results show negative outcomes and/or the study is 
terminated, the expedient release of such information and reporting will be of priority. 
 
This study will adhere to the requirements set forth by the ICMJE and FDAAA that requires all 
clinical trials to be registered in a public trials registry (e.g., ClinicalTrials.gov) prior to participant 
enrollment.  

 
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13. ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
 
 
ETHICAL STANDARD 
 
The Investigator will ensure that this study is conducted in full conformity with Regulations for 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
21 CFR Part 56, 21 CFR 312 (for IND studies), 21 CFR 812 (for IDE studies), and/or the ICH 
E6. 
 
 
INSTITUTIONAL REVIEW BOARD 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether previously consented participants need to be re-consented. 
 
 
INFORMED CONSENT 
 
Written informed consent will be obtained from all participants, or the legally authorized 
representative of the participant, participating in this trial, as stated in the Informed Consent 
section of 21 CFR Part 50.. Documentation of the consent process and a copy of the signed 
consent shall be maintained in the participant’s medical record.  
 
CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreement to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of participation will be provided to the participants and their families 
as appropriate. Consent forms will be IRB-approved and the participant will be asked to read 
and review the document. The Investigator will explain the research study to the participant and 
answer any questions that may arise. All participants will receive a verbal explanation in terms 
suited to their comprehension of the purposes, procedures, and potential risks/benefits of the 
study, alternatives to participation, and of their rights as research participants. Participants will 
have the opportunity to carefully review the written consent form and ask questions prior to 
signing. The participants should have the opportunity to discuss the study with their surrogates 
or think about it prior to agreeing to participate. The participant will sign the informed consent 
document prior to any procedures being done specifically for the study. The participants may 
withdraw consent at any time throughout the course of the trial. A copy of the informed consent 
document will be given to the participants for their records. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will 
not be adversely affected if they decline to participate in this study. 
 
 
PROTOCOL REVIEW 
 
The protocol and informed consent form for this study must be reviewed and approved in writing 
by the OHSU Knight Cancer Institute’s Clinical Research Review Committee (CRRC) and the 
appropriate IRB prior to any participant being consented on this study.   
 

 
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CHANGES TO PROTOCOL  
 
Any modification of this protocol must be documented in the form of a protocol revision or 
amendment submitted by the Investigator and approved by the CRRC and IRB, before the 
revision or amendment may be implemented.  The only circumstance in which the amendment 
may be initiated without regulatory approval is for a change necessary to eliminate an apparent 
and immediate hazard to the participant.  In that event, the Investigator must notify the IRB (and 
sponsor/FDA if under an IND/IDE) within 5 business days after the implementation.  
 
An Investigator who holds an IND or IDE application must also notify the FDA of changes to the 
protocol per 21 CFR 312 or 21 CFR 812, respectively.  

 
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14. REFERENCES 
 
1. 
Kirson, E.D., 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). 
2. 
Howlader, N., et al. SEER Cancer Statistics Review, 1975-2014, National Cancer 
Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2014/, based on November 
2016 SEER data submission, posted to the SEER web site, April 2017. SEER Cancer 
Statistics Review (CSR) 1975-2014 (2017). 
3. 
Micke, P., et al. Staging small cell lung cancer: Veterans Administration Lung Study 
Group versus International Association for the Study of Lung Cancer—what limits limited 
disease? Lung Cancer 37, 271-276 (2002). 
4. 
Lee, C.B., Morris, D.E., Fried, D.B. & Socinski, M.A. Current and evolving treatment 
options for limited stage small cell lung cancer. Current Opinion in Oncology 18, 162-172 
(2006). 
5. 
Murray, N. & Turrisi, A.T. A Review of First-Line Treatment for Small-cell Lung Cancer. 
Journal of Thoracic Oncology 1, 270-278 (2006). 
6. 
Takada, M., et al. Phase III study of concurrent versus sequential thoracic radiotherapy 
in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: 
results of the Japan Clinical Oncology Group Study 9104. Journal of Clinical Oncology 
20, 3054-3060 (2002). 
7. 
Aupérin, A., et al. Prophylactic cranial irradiation for patients with small-cell lung cancer 
in complete remission. New England Journal of Medicine 341, 476-484 (1999). 
8. 
Slotman , B., et al. Prophylactic Cranial Irradiation in Extensive Small-Cell Lung Cancer. 
New England Journal of Medicine 357, 664-672 (2007). 
9. 
Kirson, E.D., et al. Disruption of Cancer Cell Replication by Alternating Electric Fields. 
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15. APPENDICES 

 
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APPENDIX A: PERFORMANCE STATUS 
 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but 
unable to carry out any work 
activities.  Up and about more than 
50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead.