Phase II Study of Optune Device - TT Field Plus Nivolumab and Ipilimumab for Melanoma With Brain Metastasis
Phase: PHASE2
Conditions: Melanoma With Brain Metastasis
Sponsor: Washington University School of Medicine

Protocol Version: 05/12/20 
 
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Phase II Study of Optune Device - TT Fields plus Nivolumab and Ipilimumab for 
Melanoma with Brain Metastasis 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: 201903162 
Version Date: 05/12/20 
 
Principal Investigator: 
George Ansstas, M.D. 
Phone:  (314) 508-4426 
E-mail:  gansstas@wustl.edu  
 
Sub-Investigators 
 
 
 
Modality 
Ningying Wu, Ph.D.  
 
 
Biostatistics 
Mona Noroozi  
 
 
 
Clinical Research Coordinator 
 
 
Study Drugs:  
 
Nivolumab (Opdivo) 
Ipilimumab (Yervoy) 
 
Study Device: 
 
Optune 
 
ClinicalTrials.gov #: 
NCT03904043 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 
 

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Phase II Study of Optune Device - TT Fields plus Nivolumab and Ipilimumab for 
Melanoma with Brain Metastasis 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
05/02/19 
Amendment #1 Version 
 
 
 
 
 
 
05/11/19 
Amendment #2 Version 
 
 
 
 
 
 
05/12/20 
 
 
 

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Table of Contents 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 5 
1.1 
Melanoma ......................................................................................................................... 5 
1.2 
Nivolumab ........................................................................................................................ 5 
1.3 
Ipilimumab ....................................................................................................................... 6 
1.4 
Optune .............................................................................................................................. 7 
1.5 
Study Rationale ................................................................................................................ 8 
1.6 
Correlative Studies Background....................................................................................... 8 
2.0 
OBJECTIVES ...................................................................................................................... 9 
2.1 
Primary Objective ............................................................................................................ 9 
2.2 
Secondary Objectives ....................................................................................................... 9 
2.3 
Exploratory Objective ...................................................................................................... 9 
3.0 
PATIENT SELECTION ...................................................................................................... 9 
3.1 
Inclusion Criteria .............................................................................................................. 9 
3.2 
Exclusion Criteria ........................................................................................................... 10 
3.3 
Inclusion of Women and Minorities............................................................................... 11 
4.0 
REGISTRATION PROCEDURES ................................................................................... 11 
4.1 
Confirmation of Patient Eligibility ................................................................................. 11 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 11 
4.3 
Assignment of UPN ....................................................................................................... 11 
5.0 
TREATMENT PLAN ........................................................................................................ 12 
5.1 
Study Treatment ............................................................................................................. 12 
5.2 
Toxicity and Response Evaluations ............................................................................... 13 
5.3 
General Concomitant Medication and Supportive Care Guidelines .............................. 13 
5.4 
Women of Childbearing Potential .................................................................................. 14 
5.5 
Duration of Therapy ....................................................................................................... 14 
5.6 
Duration of Follow-up .................................................................................................... 15 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 15 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 15 
7.1 
Definitions ...................................................................................................................... 16 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
17 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University .............................................................................................................. 18 
7.4 
Reporting to Novocure ................................................................................................... 18 
7.5 
Timeframe for Reporting Required Events .................................................................... 18 
8.0 
PHARMACEUTICAL INFORMATION .......................................................................... 18 
8.1 
Nivolumab (Opdivo) ...................................................................................................... 18 
8.2 
Ipilimumab (Yervoy)...................................................................................................... 20 
9.0 
DEVICE INFORMATION ................................................................................................ 22 
9.1 
Optune ............................................................................................................................ 22 
10.0 OPTIONAL CORRELATIVE STUDIES ......................................................................... 26 
11.0 STUDY CALENDAR ....................................................................................................... 27 
12.0 DATA SUBMISSION SCHEDULE ................................................................................. 28 
13.0 MEASUREMENT OF EFFECT........................................................................................ 28 
13.1 RANO............................................................................................................................. 28 

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13.2 RECIST .......................................................................................................................... 32 
14.0 DATA AND SAFETY MONITORING ............................................................................ 37 
15.0 STATISTICAL CONSIDERATIONS............................................................................... 38 
15.1 Study Design .................................................................................................................. 38 
15.2 Primary Endpoint ........................................................................................................... 38 
15.3 Secondary Endpoints ...................................................................................................... 38 
15.4 Accrual ........................................................................................................................... 39 
15.5 Power Analysis ............................................................................................................... 39 
15.6 Data Analysis ................................................................................................................. 39 
15.7 Safety Early Stopping Rule ............................................................................................ 39 
16.0 REFERENCES .................................................................................................................. 41 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 44 
 
 

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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Melanoma  
 
The landscape of treatment for metastatic melanoma continues to rapidly change with the 
continued emergence of effective immunotherapeutic agents. Response to PD-1 inhibitors 
in front-line metastatic melanoma has been demonstrated to be approximately 30-40% and 
can produce both durable remissions and prolong survival. (1,2) T-cell inflamed tumors 
show remarkable sensitivity to this therapeutic class while T-cell poor tumors are generally 
non-responsive. (3) Response to the front-line combination of the CTLA-4 inhibitor 
ipilimumab and the PD-1 inhibitor nivolumab is approximately 60% but with substantial 
toxicity. (4,5) Additionally, the added benefit of the combination over single-agent PD-1 
inhibitors may be limited to those without high PD-L1 expression. (6) Adding ipilimumab 
to PD-1 therapy, therefore, might be capturing additional responders by influencing the 
peri-tumoral milieu such that the cancer becomes more responsive to immune 
manipulation, while avoiding the added toxicity of the combination in patients who were 
poised to respond to anti-PD-1 therapy alone.  
 
In the phase II CheckMate 204 study reported in The New England Journal of Medicine, 
Tawbi et al found that combined nivolumab (Opdivo) and ipilimumab (Yervoy) produced 
a high rate of intracranial clinical benefit in patients with melanoma brain metastases. In 
Checkmate 204, the intracranial clinical benefit rate was 57%, including complete response 
in 26% and partial response in 30%. Median duration of intracranial response was not 
reached at time of analysis (51). 
 
As also reported in the Journal of Clinical Oncology by Kluger et al, pembrolizumab 
(Keytruda) showed activity in brain metastases in patients with melanoma enrolled in a 
phase II study. The study included 23 patients with melanoma with one or more 
asymptomatic untreated 5- to 20-mm brain metastasis not requiring corticosteroid 
treatment. Prior systemic therapy had been received by 70% of patients. Brain metastasis 
response occurred in 6 of the total 23 patients, although 8 patients were not evaluable for 
brain response. Brain and extracerebral responses were concordant, with all responses 
ongoing at 24 months. 
 
1.2 
Nivolumab  
 
PD-1 inhibitors as single agents in the first-line setting have been shown to consistently 
result in response rates of 33-44%. (7-9) Both pembrolizumab and nivolumab have been 
shown superior to ipilimumab in the front-line setting in advanced melanoma. (10,11) As 
such, PD-1 inhibitors have become standard of care in the first-line setting, either alone or 
in combination with ipilimumab. Data for second-line use of any therapy after PD-1 
inhibitors is lacking. While ipilimumab was initially approved based on a study of patients 
who received the drug after failure of prior therapy, no studies of ipilimumab following 
failure on a PD-1 inhibitor have been reported. (12) As such, there are no data that guide 
the appropriate management of patients who have progressed on first-line immune-

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checkpoint therapy with BRAF wild-type mutations. 
 
1.2.1 Pharmacology  
 
Mechanism of Action: Nivolumab is human monoclonal antibody which targets the 
programmed death–1 (PD-1, cluster of differentiation 279 [CD279]) cell surface 
membrane receptor. PD-1 is a negative regulatory receptor expressed by activated 
T and B lymphocytes. Binding of PD-1 to its ligands, programmed death–ligand 1 
(PD-L1) and 2 (PD-L2), results in the down-regulation of lymphocyte activation. 
Nivolumab inhibits the binding of PD-1 to PD-L1 and PD-L2. Inhibition of the 
interaction between PD-1 and its ligands promotes immune responses and antigen-
specific T-cell responses to both foreign antigens as well as self-antigens. 
 
1.2.2 Pharmacokinetics  
 
Distribution: Nivolumab has linear pharmacokinetics after single and multiple 
dosing within the range 0.1 mg/kg to 10 mg/kg. The volume distribution (Vd) is 
8L.  
 
Elimination: Clearance is independent of dose in the range 0.1 mg/kg to 10 mg/kg. 
The total body clearance is 9.5 mL/hr, and the elimination half-life of is 
approximately 26.7 days. Body weight normalized dosing showed approximately 
constant trough concentrations over a wide range of body weights.  
 
1.3 
Ipilimumab 
 
Mechanism of Action: Cytotoxic T-lymphocyte antigen-4 CTLA-4 is a negative regulator 
of T-cell activity. Ipilimumab is a full human monoclonal immunoglobin (lg) antibody that 
binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. 
Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, 
including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition 
of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to 
a general increase in T cell responsiveness, including the anti-tumor immune response. 
 
1.3.1 Pharmacokinetics  
 
Absorption: No formal pharmacokinetic drug interaction studies have been 
conducted with ipilimumab. Ipilimumab is not expected to have pharmacokinetic 
drug-drug interactions, since it is not metabolized by CYP450 or other drug 
metabolizing enzymes.  
 
Distribution: Ipilimumab is confined mainly to the extracellular fluid. Peak 
concentration (Cmax), trough concentration (Cmin), and area under the plasma 
concentration versus time curve (AUC) of ipilimumab increased dose 
proportionally within the dose range examined ipilimumab is confined mainly to 
the extracellular fluid. Peak concentration (Cmax), trough concentration (Cmin), 

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and area under the plasma concentration versus time curve (AUC) of ipilimumab 
increased dose proportionally within the dose range examined. Based on population 
pharmacokinetic analysis, the mean volume of distribution (% coefficient of 
variation) at steady state was 7.47 liters (10%)  
 
Metabolism: Not applicable. Monoclonal antibodies are usually degraded into 
amino acids and small peptides, independently from CYP450 or other drug-
metabolizing enzymes.  
 
Elimination: Clearance increased with body weight, but no dose adjustment is 
required with dosing on a mg/kg basis. Upon repeated dosing every 3 weeks, the 
clearance (CL) of ipilimumab was found to be time-invariant, and systemic 
accumulation was 1.5-fold or less. The mean value (% coefficient of variation) 
generated through population pharmacokinetic analysis for the terminal half-life 
(t1/2) was 15.4 days (34%) and for CL was 16.8 mL/h (38%). 
 
1.4 
Optune  
 
Novocure has shown that when properly tuned, very low intensity, intermediate frequency 
electric fields (TTFields) stunt the growth of tumor cells (13). This inhibitory effect was 
demonstrated in all proliferating cell types tested, whereas non-proliferating cells and 
tissues were unaffected. Interestingly, different cell types showed specific intensity and 
frequency dependences of TTField inhibition. It has been shown that two main processes 
occur at the cellular level during exposure to TTFields: arrest of proliferation and dividing 
cell destruction. The damage caused by TTFields to these replicating cells was dependent 
on the orientation of the division process in relation to the field vectors, indicating that this 
effect is non-thermal. Indeed, temperature measurements made within culture dishes 
during treatment and on the skin above treated tumors in vivo showed no significant 
elevation in temperature compared to control cultures/mice. Also, TTFields caused the 
dividing cells to orient in the direction of the applied field in a manner similar to that 
described in cultured human corneal epithelial cells exposed to constant electric fields (14). 
At the sub-cellular level, it was found that TTFields disrupt the normal polymerization-
depolymerization process of microtubules during mitosis. Indeed, the described abnormal 
mitotic configurations seen after exposure to TTFields are similar to the morphological 
abnormalities seen in cells treated with agents that interfere directly (15,16) or indirectly 
(17-20) with microtubule polymerization (e.g., Taxol).  
 
The OptuneTM system (NovoTTF-200A Therapy) is a portable battery operated device, 
which produces TTFields within the human body by means of surface transducer arrays 
(21, 22). The TTFields are applied to the patient by means of surface transducer arrays that 
are electrically insulated, so that resistively coupled electric currents are not delivered to 
the patient. The transducer arrays, which incorporate a layer of adhesive hydrogel and a 
layer of hypoallergenic medical tape, are placed on the patient’s shaved head. The 
transducer arrays must be replaced every three to four days and the scalp re-shaved in order 
to maintain optimal capacitative coupling between the transducer arrays and the patient 
head. All the treatment parameters are pre-set by Novocure so there are no electrical output 

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adjustments available to the patient. The patient must learn to change and recharge depleted 
service batteries and to connect to an external battery pack overnight.   
 
Optune is currently FDA-approved as a single modality treatment for recurrent GBM when 
both surgical and radiotherapy options have been exhausted as well as combination with 
adjuvant temozolomide for newly diagnosed GBM. In the pivotal EF-11 trial in recurrent 
GBM, overall survival (OS) of patients treated with the device was equivalent to those 
treated with standard chemotherapy alone (22). Six-month progression-free survival 
(6PFS) analysis favored the TTFields arm compared to the chemo arm, although not 
statistically significant. Safety and toxicity profile favored the Optune arm compared to the 
chemotherapy control arm. No device-specific grade 3 and 4 toxicities were identified for 
hematologic, gastrointestinal, vascular, renal and respiratory disorders. There was also no 
increased grade 3 and 4 central nervous system adverse events. The most common device 
specific adverse event was skin rash due to the transducer arrays. 
 
1.5 
Study Rationale 
 
EF-14 trial has shown improvement in survival results in glioblastoma patients when the 
Optune device - TT Fields is added as conjunctive therapy to temozolomide. The 5-year 
survival analysis showed HR (95% CI) of 0.63 (0.53-0.76). Safety has been approved in 
EF-14 trial.  
 
TTFields have also been shown to cause tumor regression in animal models and human 
cancers. Treating mice with a number of injected tumor models, including CT26 colon 
adenocarcinoma, B16/F1 melanoma, Lewis lung carcinoma, and the highly invasive VX2 
carcinoma in rabbits, all demonstrated TTFields-induced tumor regression.  
 
Chen et al. have also applied similar intermediate frequency alternating electric fields to 
B16/F10 melanoma cells, showing similar effects both in vitro and ex vivo. Interestingly, 
they also provide evidence that CD34-positive cell numbers were reduced, indicating an 
effect on the tumor microvasculature in the treated tumors  
 
This phase II study will evaluate the safety of combining TT Fields with immunotherapy 
in melanoma patients with brain metastasis. The data of this study will also inform whether 
this combination will offer advantage in progression free survival (PFS) and overall 
survival. 
 
1.6 
Correlative Studies Background 
 
We plan to collect blood samples to evaluate circulating tumor DNA and correlate with 
imaging. 
 
 

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2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
 
To determine the progression-free survival of treating melanoma with metastasis to the 
brain (intracranial and extracranial) with the combination of Optune and immunotherapy. 
 
2.2 
Secondary Objectives 
 
1. To evaluate the safety of treating melanoma with metastasis to the brain with the 
combination of Optune and immunotherapy by CTCAE version 5.0. 
2. To determine the overall survival of treating melanoma with metastasis to the brain 
with the combination of Optune and immunotherapy. 
 
2.3 
Exploratory Objective 
 
To correlate ctDNA analysis with imaging results. 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Histologically or cytologically confirmed melanoma with metastasis to the brain.  
 
2. Measurable disease defined as lesions that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan or MRI, as ≥ 20 
mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam. 
 
3. Candidate for treatment with immunotherapy. 
 
4. At least 18 years of age. 
 
5. Normal bone marrow and organ function as defined below: 
a. Absolute neutrophil count ≥ 1,500/mcl 
b. Platelets ≥ 100,000/mcl 
c. Total bilirubin ≤ 1.5 x IULN 
d. AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN 
e. Creatinine ≤ IULN OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal 
 
6. Women of childbearing potential and men 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, including at least 5 months (for women of 
childbearing potential) and at least 7 months (for men) after last dose of study drug.  
Should a woman become pregnant or suspect she is pregnant while participating in this 

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study, she must inform her treating physician immediately. 
 
7. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 
3.2 
Exclusion Criteria 
 
1. Received treatment in the metastatic setting. 
 
2. Treated with whole brain radiation. 
 
3. Receiving targeted therapy or on immunosuppressive agents (dexamethasone> 
4mg/day) within 1 week of therapy. 
 
4. A history of other malignancy ≤ 5 years previous with the exception of basal cell or 
squamous cell carcinoma of the skin which were treated with local resection only or 
carcinoma in situ of the cervix. 
 
5. Currently receiving any other investigational agents. 
 
6. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to nivolumab, ipilimumab, or other agents used in the study. 
 
7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac 
arrhythmia. 
 
8. History of pre-existing immunodeficiency disorder or autoimmune condition requiring 
immunosuppressive therapy. This includes inflammatory bowel disease, ulcerative 
colitis, Crohn’s disease, systemic vasculitis, scleroderma, psoriasis, multiple sclerosis, 
hemolytic anemia, immune-mediated thrombocytopenia, rheumatoid arthritis, systemic 
lupus erythematosus, Sjögren’s syndrome, sarcoidosis, or other rheumatologic disease 
or any other medical condition or use of medication which might make it difficult for 
the patient to complete the full course of treatments or to generate an immune response 
to vaccines. 
 
9. Known sensitivity to conductive hydrogels. 
 
10. Skull defects such as missing bone or bullet fragments. 
 
11. Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, vagus 
nerve stimulator, and other implanted electronic devices in the brain or spinal cord. 
 
12. Pregnant and/or breastfeeding.  Women of childbearing potential must have a negative 
pregnancy test within 14 days of study entry. 
 

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13. Known HIV-positivity on combination antiretroviral therapy because of the potential 
for pharmacokinetic interactions with nivolumab and/or ipilimumab.  In addition, these 
patients are at increased risk of lethal infections when treated with marrow-suppressive 
therapy.  Appropriate studies will be undertaken in patients receiving combination 
antiretroviral therapy when indicated. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.   
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
 

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5.0 
TREATMENT PLAN 
 
5.1 
Study Treatment 
 
Participants will receive nivolumab + ipilimumab followed by nivolumab alone as per 
standard of care.  Recommended dosing is as follows: 
 
• 
Ipilimumab at 3 mg/kg IV over 90 minutes on Day 1 of each 21-day cycle for 4 cycles. 
• 
Nivolumab at 1 mg/kg IV over 30 minutes on Day 1 of each 21-day cycle for 4 cycles, 
then at 240 mg IV over 30 minutes on Days 1 and 15 of each 28-day cycle. 
 
During Cycles 1 through 4, ipilimumab should start 30 minutes after the end of nivolumab. 
 
Changes may be made to treatment with nivolumab and ipilimumab at the discretion of the 
treating physician.  Dosing weight is defined as screening weight. 
 
Treatment with Optune will occur as follows: 
Within 2 weeks of the start of ipilimumab (before or after), treatment with Optune will 
begin.  Patients will be instructed on the operation of the Optune device by a representative 
from Novocure.  This training may occur in clinic or at the patient’s home or at another 
mutually agreeable location.  Training will include battery replacement and recharging, 
turning the device on and off, disconnecting and reconnecting the electrodes from the 
device for personal needs, how to handle device error messages, how to handle irritated 
skin, and shaving instructions.  Once the patients are trained in operating the device, they 
will be instructed to continue treatment at home.   
 
All patients will be required to shave their heads to initiate array placement and Optune 
therapy.  Array placement will be performed based on the transducer array map calculated 
during treatment planning.  It is recommended that treatment with the device be continuous 
with breaks allowed for personal needs (e.g., showering, array exchange).  Breaks should 
be no more than 1 hour twice daily.  Use compliance is aimed at a minimum of 60% (14.4 
hours) with the goal of achieving at least 75% (18 hours) of the time per day on average. 
The device log will be downloaded periodically to assess for compliance.  In addition, 
investigators may grant brief breaks in device treatment that last no more than 7 days in 
any 30 day period at the investigator’s discretion. 
 
Optune is programmed by Novocure to deliver 200 kHz TTFields in two sequential, 
perpendicular field directions at a maximal intensity of 707mARMS. There will be no 
adjustments made to the device by investigators or patients/caregivers. 
 
It is recommended that patients replace the transducer arrays 2-3 times per week with the 
help of a caregiver. At each array replacement, it is recommended that the patient’s scalp 
be re-shaved and skin treated according to the guidelines in Section 5.3. 
 

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5.2 
Toxicity and Response Evaluations 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients are 
evaluated from first receiving study treatment until a 100-day follow up after the 
conclusion of treatment or death. 
 
All patients are evaluable for disease response unless they discontinue treatment prior to 
completion of Cycle 2 and have not had any disease assessment. 
 
Patients who discontinue treatment with nivolumab and/or ipilimumab may continue to 
receive treatment with Optune on study.  Patients who discontinue treatment with Optune 
may continue to receive treatment with nivolumab and/or ipilimumab on study. 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
             
Premedication associated with standard drug administration and supportive care (including 
anti-diarrheals, antibiotics, diuretics or other medications) may be given as indicated by 
the current American Society of Clinical Oncology (ASCO) guidelines. Premedication for 
the use of prophylaxis for infusion reactions (e.g., diphenhydramine, acetaminophen, or 
other medications) may be given per institutional standard.  
 
For patients that experience infusion reactions the following prophylactic premedications 
are recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before additional 
nivolumab or ipilimumab administrations.  
 
As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab 
combination, drugs with a predisposition to hepatic toxicity should be used with caution in 
patients treated with nivolumab containing regimen.  
 
5.3.1 Skin Care Guidelines 
 
If the skin beneath the transducer arrays is inflamed, it is recommended that a 
prescription strength steroid ointment (e.g. 3% hydrocortisone or 0.05-0.1% 
Clobetasol) be prescribed to the patient. The patient or caregiver should apply the 
ointment after removing the arrays and cleaning the scalp with baby oil and medical 
alcohol. The ointment should be left on the scalp for at least 30 minutes prior to 
washing the skin with a mild shampoo and applying a new set of arrays. 
 
At each array replacement, it is recommended that the new set of arrays be shifted 
by approximately 2 cm compared to the previous layout so that the array discs are 
placed between the areas of skin irritation. At the next array replacement, the arrays 
should be shifted back to their original location. 
 
If the dermis is breached (ulcers, open sores, punctate lesions, cuts, etc.), it is 
recommended that an antibiotic ointment (e.g. bactroban) be prescribed and used 

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in place of the steroid ointment. 
 
5.3.2 Prohibited Medications 
 
The following medications are prohibited during the study (unless utilized to treat 
a drug related adverse event):  
• 
Immunosuppressive agents  
• 
Immunosuppressive doses of systemic corticosteroids (e.g., prednisone >10 
mg daily or equivalent)  
• 
Any concurrent anti-neoplastic therapy (i.e., chemotherapy, hormonal 
therapy, immunotherapy, extensive, non-palliative radiation therapy, or 
standard or investigational agents for treatment of melanoma)  
 
5.4 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative pregnancy test within 14 days prior to the first day of study treatment.   
 
Female and male patients (along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during participation in the study 
and for  5 months following the last dose of nivolumab (women) and 7 months following 
the last dose of nivolumab (men).  
 
If a patient is suspected to be pregnant, all study treatment should be immediately 
discontinued.  In addition a positive urine test must be confirmed by a serum pregnancy 
test.  If it is confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy or 
within  5 months after the last dose of nivolumab (women) or 7 months after the last dose 
of nivolumab (men), the investigator must be notified in order to facilitate outcome follow-
up. 
 
5.5 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue for up to 
one year or until one of the following criteria applies: 
 
 Documented and confirmed disease progression 
 Death 

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 Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
 General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
 Suspected pregnancy 
 Serious non-compliance with the study protocol 
 Lost to follow-up 
 Patient withdraws consent 
 Investigator removes the patient from study 
 The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
5.6 
Duration of Follow-up 
 
Patients will be followed up at three time points: 30 days from the patient’s discontinuation 
date, again at 100 days after the discontinuation of study treatment for adverse events, and 
finally at 3 years after off-treatment date.  At these time points, the medical record will be 
reviewed to look at progression and survival endpoints.  Patients removed from study for 
unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event. 
 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
Dose modifications for ipilimumab and nivolumab will be made at the discretion of the treating 
investigator following standard of care guidelines. 
 
There are no dose modifications permitted for Optune.  Investigators may grant brief breaks in 
device treatment that last no more than 7 days in any 30-day period at their discretion.  Reasons 
for breaks in treatment longer than 24 hours will be documented. 
 
Patients who discontinue treatment with nivolumab and/or ipilimumab may continue to receive 
treatment with Optune on study.  Patients who discontinue treatment with Optune may continue to 
receive treatment with nivolumab and/or ipilimumab on study. 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outline below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as outlined 
in Section 7.2. 
 

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Novocure requires that all events be reported as outlined in Section 7.4. 
 
7.1 
Definitions 
 
7.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for 
all toxicity reporting.  A copy of the CTCAE version 5.0 can be downloaded from 
the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the 
terms listed that should be used are those provided by the Department of Health 
and Human Services’ Office for Human Research Protections (OHRP).  A copy of 
this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
7.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above 
 
7.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is not 
required or available). 
 
7.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that, had it occurred in a more severe form, might have caused 
death. 

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7.1.5 Unanticipated Problems 
 
Definition: 
 
 unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) 
the characteristics of the subject population being studied; 
 related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
and 
 suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
7.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
 
7.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial 
harm to subjects or others, or that materially compromises the rights or welfare of 
participants. 
 
7.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a singular 
situation. 
 
Pre-approval of all protocol exceptions must be obtained prior to the event. 
 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
 Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 

Protocol Version: 05/12/20 
 
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 Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
 Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event.  The death of a research participant that qualifies 
as a reportable event should be reported within 1 working day of the occurrence of the 
event or notification to the PI of the event. 
 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or 
any BJH or SLCH institution that has been reported to and acknowledged by HRPO as 
reportable.  (Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
a QASMC auditor. 
 
7.4 
Reporting to Novocure 
 
SAEs related to the device should be reported via email to support@novocure.com, or by 
calling 1-855-281-9301 (toll free).  
 
7.5 
Timeframe for Reporting Required Events  
 
Adverse events will be tracked for 100 days after the end of study treatment.  
 
 
8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
Nivolumab (Opdivo) 
 
8.1.1 Nivolumab Description 
 
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody indicated 
for the treatment of patients with: 
 BRAF V600 wild-type unresectable or metastatic melanoma, as a single 
agent 
 BRAF V600 mutation positive unresectable or metastatic melanoma, as a 
single agent 
 Unresectable or metastatic melanoma, in combination with ipilimumab 
 Metastatic non-small cell lung cancer and progression on or after platinum-
based chemotherapy 

Protocol Version: 05/12/20 
 
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 Advanced renal cell carcinoma who have received prior anti-angiogenic 
therapy 
 Classical Hodgkin lymphoma that has relapsed or progressed after 
autologous hematopoietic stem cell transplantation and post-transplantation 
brentuximab vedotin 
 Recurrent or metastatic squamous cell carcinoma of the head and neck with 
disease progression on or after a platinum-based therapy 
 
It is a human monoclonal antibody that blocks the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  Nivolumab is an IgG4 kappa immunoglobulin that has 
a calculated molecular mass of 146 kDa. 
 
8.1.2 Clinical Pharmacology 
 
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T 
cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 
ligands occurs in some tumors and signaling through this pathway can contribute 
to inhibition of active T-cell immune surveillance of tumors. Nivolumab is a human 
immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor 
and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-
mediated inhibition of the immune response, including the anti-tumor immune 
response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in 
decreased tumor growth. 
 
8.1.3 Pharmacokinetics and Drug Metabolism 
 
The pharmacokinetics (PK) of nivolumab was studied in patients over a dose range 
of 0.1 to 20 mg/kg administered as a single dose or as multiple doses of nivolumab 
every 2 or 3 weeks. Nivolumab clearance decreases over time, with a mean 
maximal reduction (% coefficient of variation [CV%]) from baseline values of 
approximately 24.5% (47.6%) resulting in a geometric mean steady state clearance 
(CLss) (CV%) of 8.2 mL/h (53.9%); the decrease in CLss is not considered 
clinically relevant. The geometric mean volume of distribution at steady state (Vss) 
(CV%) is 6.8 L (27.3%), and geometric mean elimination half-life is 25 days 
(77.5%).  Steady-state concentrations of nivolumab were reached by 12 weeks 
when administered at 3 mg/kg every 2 weeks, and systemic accumulation was 
approximately 3-fold. The exposure to nivolumab increased dose proportionally 
over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. 
 
8.1.4 Supplier(s) 
 
Nivolumab will be supplied as a standard of care. 
 
8.1.5 Dosage Form and Preparation 
 
Nivolumab will be provided as a 100 mg/10 mL (10 mg/mL) solution in a single-

Protocol Version: 05/12/20 
 
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use vial. 
 
 Withdraw the required volume of nivolumab and transfer into an 
intravenous container. 
 Dilute nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP, to prepare an infusion with a final concentration 
ranging from 1 mg/mL to 10 mg/mL. 
 Mix diluted solution by gentle inversion. Do not shake. 
 Discard partially used vials or empty vials of nivolumab. 
 
8.1.6 Storage and Stability 
 
The product does not contain a preservative. 
 
After preparation, store the nivolumab infusion either: 
 at room temperature for no more than 8 hours from the time of preparation. 
This includes room temperature storage of the infusion in the IV container 
and time for administration of the infusion or 
 under refrigeration at 2°C to 8°C (36°F-46°F) for no more than 24 hours 
from the time of infusion preparation. 
 
Do not freeze. 
 
8.1.7 Administration 
 
Administer the infusion over 30 minutes through an intravenous line containing a 
sterile, nonpyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer 
to 1.2 micrometer). 
 
Do not coadminister other drugs through the same intravenous line. 
 
Flush the intravenous line at end of infusion. 
 
8.2 
Ipilimumab (Yervoy) 
 
8.2.1 Ipilimumab Description 
 
Ipilimumab is a recombinant, human monoclonal antibody that binds to the 
cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is an IgG1 
kappa immunoglobulin with an approximate molecular weight of 148 kDa. 
Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture. 
 
8.2.2 Clinical Pharmacology 
 
CTLA-4 is a negative regulator of T-cell activity. Ipilimumab is a monoclonal 
antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its 

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ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell 
activation and proliferation, including the activation and proliferation of tumor 
infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-
regulatory cell function, which may contribute to a general increase in T cell 
responsiveness, including the anti-tumor immune response. 
 
8.2.3 Pharmacokinetics and Drug Metabolism 
 
The pharmacokinetics (PK) of ipilimumab was studied in 785 patients with 
unresectable or metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg 
once every 3 weeks for 4 doses. The PK of ipilimumab is linear in the dose range 
of 0.3 to 10 mg/kg. Following administration of ipilimumab every 3 weeks, the 
systemic accumulation was 1.5-fold or less. Steady-state concentrations of 
ipilimumab were reached by the third dose; the mean Cmin at steady state was 19.4 
mcg/mL at 3 mg/kg and 58.1 mcg/mL at 10 mg/kg every 3 weeks. The mean value 
(percent coefficient of variation) based on population PK analysis for the terminal 
half-life (t1/2) was 15.4 days (34%) and for clearance (CL) was 16.8 mL/h (38%). 
 
The effect of renal impairment on the CL of ipilimumab was evaluated in patients 
with mild (GFR <90 and ≥60 mL/min/1.73 m2; n=349), moderate (GFR <60 and 
≥30 mL/min/1.73 m2; n=82), or severe (GFR <30 and ≥15 mL/min/1.73 m2; n=4) 
renal impairment compared to patients with normal renal function (GFR ≥90 
mL/min/1.73 m2; n=350) in population PK analyses. No clinically important 
differences in the CL of ipilimumab were found between patients with renal 
impairment and patients with normal renal function 
 
8.2.4 Supplier 
 
Ipilimumab is supplied as a standard of care.  
 
8.2.5 Dosage Form and Preparation 
 
Ipilimumab (Yervoy) will be provided as a 200 mg/4 mL (50 mg/mL) solution in a 
single-use vial. 
 
 Do not shake product.  
 Inspect parenteral drug products visually for particulate matter and 
discoloration prior to administration. Discard vial if solution is cloudy, there is 
pronounced discoloration (solution may have pale-yellow color), or there is 
foreign particulate matter other than translucent-to-white, amorphous particles.  
 
Preparation of Solution  
 Allow the vials to stand at room temperature for approximately 5 minutes prior 
to preparation of infusion.  
 Withdraw the required volume of ipilimumab and transfer into an intravenous 
bag.  

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 Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, 
USP to prepare a diluted solution with a final concentration ranging from 1 
mg/mL to 2 mg/mL. Mix diluted solution by gentle inversion.  
 Store the diluted solution for no more than 24 hours under refrigeration (2°C to 
8°C, 36°F to 46°F) or at room temperature (20°C to 25°C, 68°F to 77°F).  
 Discard partially used vials or empty vials of ipilimumab. 
 
Administration Instructions  
 Do not mix ipilimumab with, or administer as an infusion with, other medicinal 
products.  
 Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP after each dose.  
 Administer diluted solution over 90 minutes through an intravenous line 
containing a sterile, non-pyrogenic, low-protein-binding in-line filter.  
 
8.2.6 Storage and Stability 
 
Store ipilimumab under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze. 
Protect vials from light. 
 
8.2.7 Administration 
 
Please refer to Section 5.2. 
 
8.2.8 Special Handling Instructions 
 
None. 
 
 
9.0 
DEVICE INFORMATION 
 
9.1 
Optune 
 
9.1.1 Description  
 
In the laboratory setting and in clinical practice, alternating electric fields show a 
wide range of effects on living tissues. At very low frequencies (under 1 kHz), 
alternating electric fields stimulate excitable tissues through membrane 
depolarization (23). The transmission of such fields by radiation is insignificant and 
therefore they are usually applied directly by contact electrodes, though some 
applications have also used insulated electrodes. Some well-known examples of 
such effects include nerve, muscle, and heart stimulation by alternating electric 
fields (23,24). In addition, low frequency pulsed electric fields have been claimed 
to stimulate bone growth and accelerate fracture healing (25). However, as the 
frequency of the alternating electric field increases above 1 kHz, the stimulatory 
effect diminishes. Under these conditions although a greater fraction of the fields 

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penetrates the cells, due to the parallel resistor-capacitor nature of all biological 
membranes, the stimulatory power greatly diminishes as the alternating cell 
membrane hyper-depolarization cycles are integrated such that the net effect is 
nulled. At very high frequencies (i.e., above many MHz), while the integration 
becomes even more effective, a completely different biological effect is observed. 
At these frequencies tissue heating becomes dominant due to dielectric losses. This 
effect becomes more intense as field intensity or tissue dissipation factor increase 
(26). This phenomenon serves as the basis for some commonly used medical 
treatment modalities including diathermy and radio frequency tumor ablation, 
which can be applied through insulated electrodes (27). Intermediate frequency 
electric fields (i.e., tens of kHz to MHz) alternate too fast for causing nerve-muscle 
stimulation and involve only minute dielectric losses (heating). Such fields of low 
to moderate intensities are commonly considered to have no biological effect (26). 
However, a number of non-thermal effects of minor biological consequence have 
been reported even at low field intensities. These include microscopic particle 
alignment (i.e., the pearl chain effect) and cell rotation (28-30). With pulsed 
relatively strong electric fields, > 103 V/cm and 100 ms pulse length, reversible 
pore formation appears in the cell membrane, a phenomenon usually called 
electroporation (31, 32). 
 
9.1.2 Supplier  
 
Novocure has shown that when properly tuned, very low intensity, intermediate 
frequency electric fields (TTFields) stunt the growth of tumor cells (33). This 
inhibitory effect was demonstrated in all proliferating cell types tested, whereas 
non-proliferating cells and tissues were unaffected. Interestingly, different cell 
types showed specific intensity and frequency dependences of TTField inhibition. 
It has been shown that two main processes occur at the cellular level during 
exposure to TTFields: arrest of proliferation and dividing cell destruction. The 
damage caused by TTFields to these replicating cells was dependent on the 
orientation of the division process in relation to the field vectors, indicating that 
this effect is non-thermal. Indeed, temperature measurements made within culture 
dishes during treatment and on the skin above treated tumors in vivo showed no 
significant elevation in temperature compared to control cultures/mice. Also, 
TTFields caused the dividing cells to orient in the direction of the applied field in a 
manner similar to that described in cultured human corneal epithelial cells exposed 
to constant electric fields (34). At the sub-cellular level, it was found that TTFields 
disrupt the normal polymerization-depolymerization process of microtubules 
during mitosis. Indeed, the described abnormal mitotic configurations seen after 
exposure to TTFields are similar to the morphological abnormalities seen in cells 
treated with agents that interfere directly (35, 36) or indirectly (37-40) with 
microtubule polymerization (e.g., Taxol).  
 
Optune is a portable battery operated device, which produces TTFields within the 
human body by means of surface transducer arrays (41, 42). The TTFields are 
applied to the patient by means of surface transducer arrays that are electrically 

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insulated, so that resistively coupled electric currents are not delivered to the 
patient. The transducer arrays, which incorporate a layer of adhesive hydrogel and 
a layer of hypoallergenic medical tape, are placed on the patient’s shaved head. The 
transducer arrays must be replaced every three to four days and the scalp re-shaved 
in order to maintain optimal capacitative coupling between the transducer arrays 
and the patient head. All the treatment parameters are pre-set by Novocure so there 
are no electrical output adjustments available to the patient. The patient must learn 
to change and recharge depleted service batteries and to connect to an external 
battery pack overnight.  
 
Optune is currently FDA-approved as a single modality treatment for recurrent 
GBM when both surgical and radiotherapy options have been exhausted as well as 
combination with adjuvant temozolomide for newly diagnosed GBM. In the pivotal 
EF-11 trial in recurrent GBM, overall survival (OS) of patients treated with the 
device was equivalent to those treated with standard chemotherapy alone (42). Six-
month progression-free survival (6PFS) analysis favored the TTFields arm 
compared to the chemo arm, although not statistically significant. Safety and 
toxicity profile favored the Optune arm compared to the chemotherapy control arm. 
No device-specific grade 3 and 4 toxicities were identified for hematologic, 
gastrointestinal, vascular, renal and respiratory disorders. There was also no 
increased grade 3 and 4 central nervous system adverse events. The most common 
device specific adverse event was skin rash due to the transducer arrays.  In EF 14 
trial, 695 glioblastoma patients randomized 2:1 to TTFields plus maintenance 
temozolomide chemotherapy (n = 466) or temozolomide alone (n = 229). Median 
progression-free survival from randomization was 6.7 months in the TTFields-
temozolomide group and 4.0 months in the temozolomide-alone group (HR, 0.63; 
95% CI, 0.52-0.76; P < .001). Median overall survival was 20.9 months in the 
TTFields-temozolomide group vs 16.0 months in the temozolomide-alone group 
(HR, 0.63; 95% CI, 0.53-0.76; P < .001).  
 
9.1.3 Guidance  
 
A post hoc subgroup analysis of the EF-11 study data revealed that patients with 
bevacizumab-refractory GBM achieved median OS of 6.3 months when treated 
with TTFields monotherapy compared to 3.3 months when standard bevacizumab-
based chemotherapy was continued (HR 0.39, 95% CI 0.19-0.79, p=0.01). This 
preliminary data suggest that bevacizumab-refractory GBM may be particularly 
sensitive to the anti-mitotic activity of TTFields (43,44) after bevacizumab 
withdrawal. Rapid tumor regrowth and radiographic tumor rebound phenomenon 
has been reported after withdrawal of bevacizumab in patients with recurrent high-
grade glioma, leading to an accelerated clinical decline (45). For this reason, many 
practitioners are reluctant to discontinue bevacizumab even when bevacizumab 
failure is well documented, and thus this approach represents a potential 
overtreatment. Molecularly, acquired resistance to bevacizumab in high grade 
gliomas is thought to result from a meschymal transition characterized by an 
enrichment of slow-cycling, highly invasive, and treatment-resistant glioma stem-

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like cells (GSCs) (46, 47). After discontinuation of bevacizumab, the microhypoxic 
stress and pro-GSC environment are removed and presumably GSCs exit cell cycle 
arrest and reactivate rapid proliferation. This is during bevacizumab withdrawal 
that we hypothesis that GBM cells, especially GSCs reentering rapid cycling, are 
most sensitive to the anti-mitotic activities of TTFields. Bevacizumab treatment 
may be resumed temporarily for subsequent radiographic progression or worsening 
symptoms, due to either further disease progression or inflammatory responses to 
TTFields-induced cell death. Once inflammation is controlled, bevacizumab is 
again withdrawn and this cycle can be repeated many times. We hypothesize that 
successive cycles of on/off (or pulsed) bevacizumab dosing will produce peaks and 
troughs in mitotic activities of GSCs that allows TTFields to work at slowly 
reducing the GSC fraction in tumors, and thus lowering disease infiltration and 
increasing survival.  
 
We recently conducted a case series study describing the outcomes for 8 patients 
with bevacizumab-refractory GBM, who were treated with TTFields monotherapy 
first, then with concomitant re-challenge with bevacizumab upon subsequent 
radiographic progression in 5 of these patients (48). The 8 patients had a median 
OS of 216 days (7.2 months) from first day of treatment with TTFields therapy, 
which was significantly longer than historical data of 1-4 months and consistent 
with the subgroup analysis of EF-11 data. Of the 5 patients re-challenged with 
bevacizumab, median OS from first dose of bevacizumab re-challenge was 172 
days (5.7 months), although they all had developed resistance to bevacizumab after 
having received a median time of 236.5 days (7.9 months) of bevacizumab prior to 
starting TTFields. Patients highly adherent to treatment -- who were also those who 
received pulse dose bevacizumab -- had the longest OS. Patient # 4 had an 
adherence rate of 92.9%; her time from first day of TTFields therapy to death was 
276 days (9.2 months) and, from first dose of bevacizumab re-challenge until death, 
150 days (5.0 months). Patient # 7, with an adherence rate of 73.2%, had a time 
from first day of TTFields to death of 406 days (13.5 months) and, from first dose 
of bevacizumab re-challenge until death, of 349 days (11.6 months) (Fig. 1).  
 
In this case series, we describe 8 patients with recurrent glioblastoma in whom we 
discontinued treatment with bevacizumab successfully - despite the concern of 
possible rapid disease progression upon bevacizumab withdrawal, effectively used 
TTFields therapy, and then re-challenged them with bevacizumab once patients 
developed symptoms and/or had evidence of radiographic progression. This 
“pulsed dosing” approach to bevacizumab administration, combined with TTFields 
therapy, has not been described in this patient population, and although the results 
from this small study is encouraging this novel approach will need to be formally 
tested in a focused prospective clinical study. 

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10.0 
OPTIONAL CORRELATIVE STUDIES 
 
Twenty mL of blood will be collected at baseline, Week 3, and Week 12 in a cell-free DNA BCT 
(Streck) tube for patients who consent to this optional collection.  Specimens will be taken to Dr. 
David Chen in the Department of Dermatology or will be frozen and stored. 
 
 
 

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11.0 
STUDY CALENDAR 
 
Screening/baseline evaluations are to be conducted within 2 weeks prior to start of protocol 
therapy.  Scans and x-rays must be done no more than 4 weeks prior to the start of the protocol 
therapy. 
 
 
Screening10 
Baseline10 
Q3W 
x410 
Then Q2W 
x610 
Then Q2W 
x1410 
EOT9, 10 
F/U10 
Informed consent 
X 
 
 
 
 
 
 
Physical exam 
X 
 
X 
X 
X8 
X 
 
CBC 
X 
 
Per SOC 
 
 
CMP 
X 
 
Per SOC 
 
 
TSH w/free T3 
and T4 
 
 
Per SOC 
 
 
Pregnancy test1 
X 
 
 
 
 
 
 
CT C/A/P 
RECIST 
X 
 
 
Q8W for 12 mos, then 
Q12W for 12 mos 
 
 
Brain MRI 
X 
 
 
 
 
Ipilimumab 
 
 
X2 
 
 
 
 
Nivolumab 
 
 
X3 
X3 
X3 
 
 
Optune 
 
 
Daily for 75% of each day7 
 
 
Research blood 
 
X 
X6 
 
 
 
AE assessment 
 
X -------------------------------------------------------------- X4 
Follow-up 
 
 
 
 
 
 
X5 
1. Women of childbearing potential 
2. Ipilimumab is being given as per SOC; recommended dosing is Q3W x4 
3. Nivolumab is being given as per SOC; recommended dosing is Q3W x4, then Q2W for up to 20 doses or until 
progression or intolerable side effect 
4. AEs are collected from baseline through 100 days after last day of treatment 
5. Follow-up consists of 100-day follow-up for AEs and then review of the medical record at 3 years after last day of 
treatment 
6. Blood for research is drawn during treatment at Week 3 and Week 12 
7. Treatment with Optune will start no more than 2 weeks before or after the start of ipilimumab. 
8. Q4W till off treatment. 
9. May take place up to 30 days from last treatment (with immunotherapy or Optune). 
10. (+/- 7 days) 
 
 
 

Protocol Version: 05/12/20 
 
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12.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Prior to starting treatment 
Treatment Form 
Every cycle 
Toxicity Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
Research Blood Form 
Baseline, Week 3, Week 12 
Follow Up Form 
Day 30, Day 100, Year 3 
RANO Form 
Baseline, every 8 weeks for 1 year, every 12 weeks for 1 year 
Progression Form 
Time of progression 
Death Form 
Time of death 
 
 
13.0 
MEASUREMENT OF EFFECT 
 
13.1 
RANO 
 
13.1.1 Antitumor Effect – RANO 
 
Brain MRI will be performed Q8W for 12 months then Q12W for 12 months. 
 
Criteria for response: Response will be evaluated in this study using the updated 
response assessment criteria for high-grade gliomas: Response Assessment in 
Neuro-Oncology (RANO) working group guideline. 
 
Criteria for Response Assessment Incorporating MRI and Clinical Factors 
Response 
Criteria 
Complete response 
 
Requires all of the following: complete disappearance of all enhancing measurable and 
nonmeasurable disease sustained for at least 4 weeks. 
 
No new lesions; stable or improved nonenhancing (T2/FLAIR) lesions. 
 
Patients must be off corticosteroids (or on physiologic replacement doses only) and 
stable or improved clinically. Note: Patients with nonmeasurable disease only cannot 
have a complete response; the best response possible is stable disease.  
Partial response 
Requires all of the following:  
 
≥ 50% decrease compared with baseline in the sum of products of perpendicular 
diameters of all measurable enhancing lesions sustained for at least 4 weeks. 
 
No progression of nonmeasurable disease. 
 
Stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan; the corticosteroid dose at the time of the 
scan evaluation should be no greater than the dose at time of baseline scan. 

Protocol Version: 05/12/20 
 
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Response 
Criteria 
 
Stable or improved clinically. Note: Patients with nonmeasurable disease only cannot 
have a partial response; the best response possible is stable disease.  
Stable disease 
Requires all of the following:  
 
Does not qualify for complete response, partial response, or progression. 
 
Stable nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared with baseline scan. In the event that the corticosteroid dose was increased 
for new symptoms and signs without confirmation of disease progression on 
neuroimaging, and subsequent follow-up imaging shows that this increase in 
corticosteroids was required because of disease progression, the last scan considered to 
show stable disease will be the scan obtained when the corticosteroid dose was 
equivalent to the baseline dose.  
Progression 
Defined by any of the following:  
 
≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions 
compared with the smallest tumor measurement obtained either at baseline (if no 
decrease) or best response, on stable or increasing doses of corticosteroids*. The 
absolute increase in any dimension must be at least 5mm when calculating the 
products. 
 
Significant increase in T2/FLAIR nonenhancing lesion on stable or increasing doses of 
corticosteroids compared with baseline scan or best response after initiation of 
therapy* not caused by comorbid events (e.g. radiation therapy, demyelination, 
ischemic injury, infection, seizures, postoperative changes, or other treatment effects). 
 
Any new measureable lesion. 
 
Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. 
seizures, medication adverse effects, complications of therapy, cerebrovascular events, 
infection, and so on) or changes in corticosteroid dose. 
 
Failure to return for evaluation as a result of death or deteriorating condition; or clear 
progression of nonmeasurable disease.  
 
NOTE. All measurable and nonmeasurable lesions must be assessed using the same techniques as at 
baseline. 
 
Abbreviations: MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery. 
 
Stable doses of corticosteroids include patients not on corticosteroids. 
 
Criteria for progression: Pseudoprogression is a phenomenon where radiographic 
features are consistent with tumor recurrence/progression but is instead related to 
treatment effect. This is a common occurrence in glioblastoma following radiation 
that is generally seen in the first 3-6 months after completing therapy.  
 
 
If follow-up imaging confirms progression, the date of actual progression should 
be back-dated to the date of initial radiographic evidence of progression. 
 
Alternatively, progressive disease can be defined as radiographic evidence of 
progression PLUS significant clinical decline that is felt to be unrelated to a co-
morbid event or concurrent medication.   
  
13.1.2 Disease Parameters 
 
Measurable disease:  Bi-dimensionally measurable lesions with clearly defined 
margins by MRI scan.  All tumor measurements must be recorded in millimeters 
(or decimal fractions of centimeters).   

Protocol Version: 05/12/20 
 
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Non-measurable or evaluable disease:  Uni-dimensionally measurable lesions or 
lesions with margins not clearly defined such as areas of T2/FLAIR signal 
abnormality or poorly defined enhancing abnormality.  
 
Note: For cystic lesions, the only measurable part is any enhancement area around 
the cyst that is clearly defined and bi-dimensionally measurable. The cyst itself 
should not be considered measurable or non-measureable disease. 
 
Target lesions: All measurable lesions that are residual of the lesion treated with 
MLA should be identified as target lesions and recorded and measured.  Target 
lesions should be selected on the basis of their size (lesions with the longest 
diameter), but in addition should be those that lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest 
lesion, which can be measured reproducibly should be selected.  When there are 
too many measurable lesions, choose the largest 3 lesions as target lesions to follow.  
The other measurable lesions should be considered evaluable for the purpose of 
objective status determination. 
 
Non-target lesions:  All non-measurable lesions should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements of these lesions are 
not required, but the presence, absence, or in rare cases unequivocal progression of 
each should be noted throughout follow-up.  
 
13.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler.   
 
 
Clinical lesions:  Clinical lesions will only be considered measurable on brain MRI 
when they are  5 mm diameter as assessed using a ruler. 
 
Histology:  This technique can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases when biopsy or surgical resection 
of a measureable lesion is clinically indicated.  
 
Perfusion/CBV: This advanced brain MRI technique can be used as an adjunct test 
to determine treatment response or disease status.  However, it should not be used 
as the primary or sole method to determine response or disease status.  
 
13.1.3.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions. 
 
Partial Response (PR):  ≥ 50% decrease compared with baseline in the 
sum of products of perpendicular diameters of all target lesions sustained 

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for at least 4 weeks. 
 
Progressive Disease (PD):  At least a 25% increase in the sum of products 
of perpendicular diameters of at least 1 target lesion, taking as reference the 
smallest sum of products of perpendicular diameters on study (this includes 
the baseline sum if that is the smallest on study).  The absolute increase in 
any dimension must be at least 5mm when calculating the products of 
perpendicular diameters. 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
of products of perpendicular diameters while on study. 
 
13.1.3.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions.  
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s). 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions on stable or 
increasing doses of corticosteroids compared with baseline scan or best 
response after initiation of therapy not caused by comorbid events (e.g. 
radiation therapy, demyelination, ischemic injury, infection, seizures, 
postoperative changes, or other treatment effects). Unequivocal progression 
should not normally trump target lesion status.  It must be representative of 
overall disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and 
the progression status should be confirmed at a later time by the review 
panel (or Principal Investigator). 
 
13.1.3.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
Summary of the RANO Response Criteria 
Criterion 
CR 
PR 
SD 
PD 
T1 gadolinium enhancing 
disease 
None 
≥ 50% ↓ 
< 50% ↓ but < 25% ↑ 
≥ 25% ↑* 
T2/FLAIR 
Stable or ↓ 
Stable or ↓ 
Stable or ↓ 
↑* 

Protocol Version: 05/12/20 
 
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Criterion 
CR 
PR 
SD 
PD 
New lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or ↓ 
Stable or ↓ 
NA† 
Clinical status 
Stable or ↑ 
Stable or ↑ 
Stable or ↑ 
↓* 
Requirement for response 
All 
All 
All 
Any* 
Abbreviations: RANO, Response Assessment in Neuro-Oncology; CR, complete response; PR, 
partial response; SD, stable disease; PD, progressive disease; FLAIR, fluid-attenuated inversion 
recovery; NA, not applicable.  
* Progression occurs when this criterion is present.  
† Increase in corticosteroids alone will not be taken into account in determining progression in the 
absence of persistent clinical deterioration.  
 
13.1.3.4 
Duration of Response 
 
Duration of overall response:  The duration of overall response is 
measured from the time measurement criteria are met for CR or PR 
(whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria 
are first met for CR until the first date that progressive disease is objectively 
documented.  
 
Duration of stable disease:  Stable disease is measured from the start of 
the treatment until the criteria for progression are met, taking as reference 
the smallest measurements recorded since the treatment started, including 
the baseline measurements.  
 
13.1.3.5 
Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of 
progression or death, whichever occurs first. 
 
 
13.2 
RECIST 
13.2.1 Antitumor Effect – RECIST 
 
For the purposes of this study, patients should be re-evaluated for response every 
third cycle.  In addition to a baseline scan, confirmatory scans should also be 
obtained not less than 4 weeks following initial documentation of objective 
response. 
 
Response and progression will be evaluated in this study using the new 
international criteria proposed by the revised Response Evaluation Criteria in Solid 
Tumors (RECIST) guideline (version 1.1)17.  Changes in the largest diameter 

Protocol Version: 05/12/20 
 
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(unidimensional measurement) of the tumor lesions and the shortest diameter in the 
case of malignant lymph nodes are used in the RECIST criteria. 
 
13.2.2 Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as 
>20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by 
clinical exam.  All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 
Malignant lymph nodes:  To be considered pathologically enlarged and 
measurable, a lymph node must be >15 mm in short axis when assessed by CT scan 
(CT scan slice thickness recommended to be no greater than 5 mm).  At baseline 
and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 
mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pneumonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum.  The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 

Protocol Version: 05/12/20 
 
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Non-target lesions:  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions 
and should also be recorded at baseline.  Measurements of these lesions are not 
required, but the presence, absence, or in rare cases unequivocal progression of 
each should be noted throughout follow-up.  
 
13.2.3 Methods for Evaluation of Measurable Disease 
 
All baseline evaluations should be performed as closely as possible to the beginning 
of treatment and never more than 4 weeks before the beginning of the treatment.  
CT is the preferred and standard imaging modality. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up.  
 
MRI: Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, 
and temporal resolution; however, there are many image acquisition variables 
involved in MRI, which greatly impact image quality, lesion conspicuity, and 
measurement.  As with CT, the modality used at follow-up should be the same as 
was used at baseline and the lesions should be measured/assessed on the same pulse 
sequence.   
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if it can be documented that the CT performed 
as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV 
and oral contrast), then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement.  If there is concern about radiation exposure 
due to CT, MRI may be used instead of CT in selected instances. 
 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response, stable 
disease or progressive disease. 
 
13.2.4 Response Criteria 
 
13.2.4.1 
Evaluation of Target Lesions 
 

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Complete Response (CR):  Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of one or more new lesions 
is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
 
13.2.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-
pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal 
progression should not normally trump target lesion status.  It must be 
representative of overall disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and 
the progression status should be confirmed at a later time by the review 
panel (or Principal Investigator). 
 
13.2.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started).  The patient's best response assignment will depend on the 

Protocol Version: 05/12/20 
 
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achievement of both measurement and confirmation criteria. 
    
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
                                      For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is not 
advised 
 
 
13.2.4.4 
Duration of Response 
 

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Duration of overall response:  The duration of overall response is 
measured from the time measurement criteria are met for CR or PR 
(whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria 
are first met for CR until the first date that progressive disease is objectively 
documented.  
 
Duration of stable disease:  Stable disease is measured from the start of 
the treatment until the criteria for progression are met, taking as reference 
the smallest measurements recorded since the treatment started, including 
the baseline measurements.  
 
13.2.4.5 
Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of 
progression or death, whichever occurs first. 
 
14.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least five patients have been enrolled) or one 
year after accrual has opened (if fewer than five patients have been enrolled at the six-month mark). 
 
During the phase II, the Principal Investigator will review all patient data at least every six months, 
and provide a semi-annual report to the QASMC. This report will include: 
 HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, 
regulatory coordinator name, and statistician 
 Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date 
of HRPO expiration, date of most recent QA audit, study status, and phase of study 
 History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
 Study-wide target accrual and study-wide actual accrual 
 Protocol activation date 
 Average rate of accrual observed in year 1, year 2, and subsequent years 
 Expected accrual end date 
 Objectives of protocol with supporting data and list the number of participants who have 
met each objective 
 Measures of efficacy 
 Early stopping rules with supporting data and list the number of participants who have met 
the early stopping rules 

Protocol Version: 05/12/20 
 
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 Summary of toxicities 
 Abstract submissions/publications 
 Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
 
15.0 
STATISTICAL CONSIDERATIONS 
 
15.1 
Study Design 
 
This is an open-label, single center, one cohort, non-randomized, phase II study. The aim 
is to evaluate the efficacy and safety of the combination of Optune and immunotherapy in 
melanoma patients with metastasis to the brain.  
 
15.2 
Primary Endpoint 
 
Primary endpoint is intracranial progression-free survival (PFS) at 6 months. The PFS time 
will be calculated as the duration of time from the date of first dose of study treatment to 
the date of earliest intracranial progression or death, whichever occurs first. Patients who 
neither progress nor die by the data cutoff date will be censored at the last follow up. 
Intracranial response and progression will be determined by the investigator using modified 
RANO criteria. 
 
15.3 
Secondary Endpoints 
 
• 
Safety and tolerability will be defined as the number of treatment-related grade 3 or 
greater adverse events (AEs) and discontinuations due to treatment-related AEs. 
Adverse events will be assessed using CTCAE v5.0 criteria. Safety will be monitored 
from the time of initiation of study treatment to 30 days after discontinuation of therapy. 
 
• 
Best intracranial response rate, defined as the percentage of patients with a confirmed 
intracranial complete or partial response, using modified RANO criteria. 
 
• 
Best extracranial response rate, defined as the percentage of patients with a confirmed 
extracranial complete or partial response, using modified RANO criteria. 
 
• 
Extracranial progression-free survival at 6 months, defined as the duration of time from 
the date of first dose of study treatment to the date of earliest extracranial progression 
or death, whichever occurs first. Patients who neither progress nor die by the data cutoff 
date will be censored at the last follow up. Response and progression will be determined 
by the investigator using modified RECIST version 1.1 criteria. 
 

Protocol Version: 05/12/20 
 
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• 
Overall survival (OS) at 6 months, defined as the duration of time from the date of first 
dose of study treatment to death from any cause. Patients who are alive by the data 
cutoff date will be censored at the last follow up. 
 
15.4 
Accrual 
 
In total, 23 patients will be enrolled into the study. Non-random convenience sampling will 
be used. On average, we anticipate that we will enroll 1-2 patients per month. We expect 
to complete enrollment within 24 months.  
 
15.5 
Power Analysis 
 
Previously published study [Long GV Lancet Oncol 2018] suggested a 53% intracranial 6-
month progression-free survival rate for patients without study treatment. For a one sample 
clinical trial, to evaluate 6-month progression free survival, given accrual length is 2 years 
and follow-up length is 6 months, with one-sided significant level of 0.05, assuming the 
proportion of progression free under null hypothesis at 6-month is 53% and the proportion 
of progression free under alternative hypothesis at 6-month is 75%, a sample size of 23 
could yield a power no less than 0.8.  
 
15.6 
Data Analysis 
 
All data will be evaluated as observed, and no imputation method for missing values will 
be used. All data will be presented in a descriptive manner. All analyses will be considered 
as exploratory, even if statistical tests will be used. Descriptive statistics will be used to 
summarize the trial results, i.e., statistics for continuous variables may include means, 
medians, ranges and appropriate measures of variability. Qualitative variables will be 
summarized by counts and percentages. The uncertainty of estimates will be assessed by 
confidence intervals (CI).  
 
PFS and OS will be presented in patient listings and analyzed via the Kaplan-Meier 
method. Median survival and corresponding two-sided 95% CIs will also be computed. 
Survival rates at 6 months with 95% CIs will be estimated using the Kaplan-Meier method. 
Safety data will be summarized by the number and proportions of patients affected in each 
cohort. Further exploratory correlative analyses will be performed via Fisher exact test, t-
test, or nonparametric Wilcoxon–Mann–Whitney test, if needed.  
 
15.7 
Safety Early Stopping Rule 
 
Safety will be reviewed on a continuous basis. Early stopping of this trial is calculated 
based upon the report of treatment-related grade 3 or greater adverse event (AE). A 
Bayesian sequential monitoring design for single-arm clinical trial (Thall, Simon, Estey, 
1995) is used for the calculation of toxicity stopping boundaries, under the assumption that 
AE rate of 55% and or less is acceptable. For a treatment cohort with sample size of 23, 
modeled by a toxicity prior distribution, Beta(0.55, 0.45), assuming the study will stop if 
the estimated posterior probability of the study treatment being more toxic is greater than 

Protocol Version: 05/12/20 
 
Page 40 of 44 
0.8,  the study will be halted if the treatment-related AE occurs in the 4 of the first 5 
patients, or 5 of the first 7, or 6 of the first 8, or 7 of the first 10, or 8 of the first 11, or 9 of 
the first 13, or 10 of the first 15, or 11 of the first 16, or 12 of the first 18, or 13 of the first 
20, or 14 of the first 21, or if the 15th treatment-related grade 3 or above AE is observed 
before the last (23rd) patient has completed the trial. 
 
 
 
 
 
 

Protocol Version: 05/12/20 
 
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16.0 
REFERENCES 
 
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BRAF mutation. N Engl J Med 372:320-330. PMID: 25399552, 2015.  
2. Robert C, Schachter J, Long GV et al. Pembrolizumab versus ipilimumab in advanced 
melanoma. N Engl J Med 372:2521-32. PMID: 25891173, 2015.  
3. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting 
adaptive immune resistance. Nature 515:568-71. PMID: 25428505. PMCID: PMC4246418, 
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4. Postow MA, Chesney J, Pavlick AC et al. Nivolumab and ipilimumab versus ipilimumab in 
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5. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or 
monotherapy in untreated melanoma. N Engl J Med 373:23-34. PMID: 26027431, 2015.  
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monotherapy in untreated melanoma. N Engl J Med 373:23-34. PMID: 26027431, 2015.  
7. Robert C, Long GV, Brady B et al. Nivolumab in previously untreated melanoma without 
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melanoma. N Engl J Med 372:2521-32. PMID: 25891173, 2015.  
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melanoma. N Engl J M 25891173, 2015.  
17. Postow MA, Chesney J, Pavlick AC et al. Nivolumab and ipilimumab versus ipilimumab in 
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21. Huang RR, Jalil J, Economou JS, et al. CTLA4 blockade induces frequent tumor infiltration 
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We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials 
Core which provided protocol development service. The Siteman Cancer Center is supported in 
part by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 
 

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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
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). 
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. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead.