Conditions: Recurrent Glioblastoma
Keywords: recurrent glioblastoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 5
Healthy volunteers: no

Brief summary:
Phase I/II trial in which participants with recurrent glioblastoma will receive a combination of tumor treating fields(portable device), nivolumab with or without ipilimumab.

Detailed description:
Phase I/II trial in which participants with recurrent glioblastoma will receive a combination of tumor treating fields(portable device), nivolumab with or without ipilimumab.

The NovoTTF200A (OptuneTM) device is worn continuously for a goal of 75% or more of the time, ranging from at least 18 hours daily uninterrupted or 22 hours daily with 2-3 days off monthly. Therapy is planned for approximately 24 months.

Infusions with nivolumab will start within 1 week of study start. Ipilimumab will either start with the second nivolumab infusion or at after tumor progression. Nivolumab is infused intravenously at 240 mg once every 2 weeks with or without ipilimumab for a maximum of 24 months. Ipilimumab is dosed at 1 mg/kg once every 6 weeks for a maximum of 4 doses (24 weeks). Infusions will continue until maximum doses are completed or there is confirmed tumor progression, intolerable adverse effects or withdrawal of consent.

Arms:
arm 1: Nivolumab 240 mg IV every 2 weeks for maximum of 24 months. TTF (Optune) for max of 24 months arm 2: Nivolumab 3 mg/kg IV with ipilimumab then 240 mg every 2 weeks for maximum of 24 months.

Ipilimumab 1 mg/kg IV every 6 weeks maximum of 4 times. NovoTTF200A (Optune) TTF for maximum 24 months

Interventions: intervention 1: Nivolumab 240 mg IV intervention 2: Nivolumab 3 mg/kg intervention 3: Ipilimumab 1 mg/kg intervention 4: NovoTTF200A (Optune)
Intervention descriptions: intervention 1: Nivolumab IV 240mg IV every 2 weeks for maximum of 24 months. intervention 2: Nivolumab IV 3mg/kg every 2 weeks for maximum of 24 months. intervention 3: Ipilimumab IV 1 mg/kg every 6 weeks for maximum of 4 doses. intervention 4: A device to be worn continuously for a goal of 75% of the time, ranging from 18 hours daily nonstop or 22 hours daily with 2-3 days off monthly.

Protocol document:
Prot_SAP_001.pdf: 
Protocol # 2017-ODI-002 
 
 
 
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Protocol Title: 
A phase I/II trial of combination Tumor Treating Fields, Nivolumab plus/minus Ipilimumab for recurrent 
glioblastoma 
 
 
Protocol Version: 2.0 
Date: 17-Jul-2019 
Protocol Number: 2017-ODI-002 
BMS Protocol Number: CA209-9Y8 
 
Principal Investigator: 
Yazmin Odia, MD MS – Lead Physician of Medical Neuro-Oncology 
Miami Cancer Institute (MCI), Baptist Health South Florida (BHSF) 
8900 North Kendall Drive, 3N528 
Miami, FL 33176 
Cell: 646-634-9655 
Office: 786-527-8082 
Email: YazminO@BaptistHealth.net 
 
Co-Investigators: 
Fabio M. Iwamoto, MD – Columbia University Medical Center / New York Presbyterian 
Siddhartha A. Venkatappa, MD – Medical Oncology, MCI, BHSF 
 
Collaborators: 
Muni Rubens, PhD – Biostatistician, MCI, BHSF 
Zuanel Diaz, PhD – Protocol Support Laboratory, MCI, BHSF 
 
Sponsor: 
Miami Cancer Institute at Baptist Health, Inc. 
8900 N. Kendall Drive 
Miami, FL 33176 
 
Study Funding and Investigational Agent provided by: 
Bristol-Myers Squibb (BMS), Inc. 
Bristol-Myers Squibb Corporate Headquarters 
345 Park Avenue 
New York, NY 10154 
 
Novocure, Inc. 
1500 Broadway, 17th Floor 
New York, NY 10036 
 
Agent(s): 
Tumor Treating Fields (TTFields) via NovoTTF200A (OptuneTM) Device 
Nivolumab (OpdivoTM) 
Ipilimumab (YervoyTM) 
 
FDA IND Number: 138164 
 
 
NCT03430791


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TABLE OF CONTENTS 
1. OBJECTIVES ......................................................................................................................... 4 
1.1 
Study Design .................................................................................................................................. 4 
1.2 
Primary Objectives ....................................................................................................................... 5 
1.3 
Secondary Objectives ................................................................................................................... 5 
2. BACKGROUND ..................................................................................................................... 5 
2.1 
Glioblastoma Overview ................................................................................................................ 5 
2.2 
Tumor Treating Fields (TTFields) Therapy using NovoTTF-200A (OptuneTM) Device ........ 6 
2.3 
Rationale for Immunotherapy in Glioblastoma ......................................................................... 7 
2.4 
Nivolumab ..................................................................................................................................... 8 
2.5 
Ipilimumab .................................................................................................................................. 11 
2.6 
Rationale for Combination of TTFields and Immunotherapy ............................................... 12 
2.7 
Correlative Studies Background ............................................................................................... 15 
3. PARTICIPANT SELECTION ............................................................................................ 16 
3.1 
Eligibility Criteria....................................................................................................................... 16 
3.2 
Exclusion Criteria ....................................................................................................................... 17 
3.3 
Inclusion of Women and Minorities .......................................................................................... 18 
4. REGISTRATION PROCEDURES ..................................................................................... 18 
5. TREATMENT PLAN ........................................................................................................... 18 
5.1 
Study Design ................................................................................................................................ 18 
5.2 
Pre-Treatment Criteria .............................................................................................................. 19 
5.3 
Treatment and Evaluation Cycles ............................................................................................. 20 
5.4 
End of Treatment Visit ............................................................................................................... 20 
5.5 
General Concomitant Medication and Supportive Care Guidelines ..................................... 21 
5.6 
Contraception.............................................................................................................................. 24 
5.8 
Criteria for Taking a Participant off Protocol Therapy ......................................................... 25 
5.9 
Duration of Follow Up ................................................................................................................ 26 
5.10 
Criteria for Taking a Participant Off Study .......................................................................... 26 
6. DOSING DELAYS/DOSE MODIFICATIONS ................................................................. 27 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ........................... 29 
7.1 
Reporting of Serious Adverse Events ....................................................................................... 29 
7.2 
Definition of Serious Adverse Events ........................................................................................ 32 
7.3 
Expected Toxicities ..................................................................................................................... 35 
7.4 
Adverse Event Characteristics .................................................................................................. 35 
8. PHARMACEUTICAL INFORMATION ........................................................................... 35 
8.1 
Product Supply, Administration and Inventory ...................................................................... 35 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................ 36 
9.1 
Biomarker Analyses ................................................................................................................... 36 
10. STUDY CALENDAR ........................................................................................................... 36 
11. MEASUREMENT OF EFFECT ......................................................................................... 38 
11.1 
Definitions ................................................................................................................................. 38 
11.2 
Disease Parameters .................................................................................................................. 38 
11.3 
Response/Progression Categories ........................................................................................... 39 
11.4 
Methods for Evaluation of Disease ......................................................................................... 40 


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11.5 
Evaluation of Best Response .................................................................................................... 40 
12. DATA REPORTING / REGULATORY REQUIREMENTS .......................................... 40 
12.1 
Data Reporting ......................................................................................................................... 41 
12.2 
Data Collection ......................................................................................................................... 41 
12.3 
Regulatory Requirements ........................................................................................................ 41 
13. STATISTICAL CONSIDERATIONS ................................................................................ 43 
13.1 
Study Design and Sample Size ................................................................................................ 43 
13.2 
Definitions ................................................................................................................................. 43 
13.3 
Enrollment and Study Duration ............................................................................................. 44 
13.4 
Statistical Analyses ................................................................................................................... 44 
13.5 
Interim Monitoring .................................................................................................................. 45 
14. KEY REFERENCES ............................................................................................................ 46 
APPENDIX A .............................................................................................................................. 47 
Karnofsky Performance Status (KPS) Criteria ................................................................................. 47 
APPENDIX B .............................................................................................................................. 48 
Neurologic Assessment In Neuro-Oncology (NANO) Scale .............................................................. 48 
APPENDIX C .............................................................................................................................. 50 
Functional Assessment of Cancer Therapy-Brain 4.0 (FACT-Br) ................................................... 50 
APPENDIX D .............................................................................................................................. 53 
TTFields Compliance Reports Generated by NovoTTF200A (OptuneTM) ...................................... 53 
APPENDIX E .............................................................................................................................. 54 
Toxicity Management Algorithms for Nivolumab ............................................................................. 54 
APPENDIX F .............................................................................................................................. 59 
Toxicity Management Algorithms for Ipilimumab ........................................................................... 59 
  
 
 
 


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1. OBJECTIVES 
 
1.1 
Study Design 
This is an open-label, phase II trial with two parallel arms, two-stage design and appropriate 
stopping rules for poor efficacy. Arm A will enroll patients without prior PD1/PDL1 checkpoint 
inhibitor, while Arm B will enroll patients with prior PD1/PDL1 checkpoint inhibitor. We expect 
to enroll at least 30 (15 in each Arm) and a maximum of 60 (30 in each Arm) evaluable subjects. 
All subjects will receive TTFields therapy plus nivolumab infusions for a maximum of 24 
months, plus/minus concurrent ipilimumab for a maximum of 4 doses (see study schema below). 
The NovoTTF200A (OptuneTM) device is worn continuously for ≥75% of the time, ranging 18 
hours/day uninterrupted to 22 hours/day with 2-3 days off monthly. TTFields therapy begins once 
approved by insurance and an in-home initiation arranged. The goal is to start within 1 month of 
trial enrollment. Treatment is planned for ~24 months. 
Infusions will start within 1 week of study enrollment. Nivolumab will be dosed every 2 weeks 
IV 240 mg as monotherapy and 3 mg/kg with ipilimumab. Nivolumab therapy will not exceed 24 
months. Ipilimumab starts with the second infusion of nivolumab for Arm B (prior PD1/PDL1 
checkpoint inhibitor) or after progression on nivolumab monotherapy for Arm A (no prior 
PD1/PDL1 checkpoint inhibitor). Ipilimumab infusions will be dosed as 1 mg/kg once every 6 
weeks for a maximum of 4 doses (24 weeks). Infusions will continue until a maximum of 24 
months or when there is confirmed tumor progression, intolerable adverse effects or withdrawal 
of consent. 


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All patients will undergo clinical evaluation prior to each infusion every 2 weeks until the 
maximum 24 months of therapy, thereafter every 8 weeks during the maintenance phase. 
Neuroimaging studies (contrast-enhanced brain MRI or CT for patients unable to undergo MRI) 
and quality of life FACT-BR questionnaires will be administered at baseline then every 6 weeks 
during the treatment phase or every 8 weeks during the maintenance phase until off study.  
 
All subjects will remain on study until death, progressive disease, unacceptable toxicity or 
withdrawal of consent. If the participant undergoes another surgery for presumed tumor 
progression but pathological findings are consistent with pseudoprogression (inflammation and 
necrosis rather than active tumor), the participant will deemed to not have had tumor progression 
and may continue treatment with nivolumab after review with the principal investigator. 
 
1.2 
Primary Objectives 
 
To evaluate the anti-tumor activity of combining TTFields therapy via the NovoTTF200A 
(OptuneTM) device, nivolumab, plus/minus ipilimumab therapy as assessed by objective response 
rate (ORR) by modified immunotherapy iRANO criteria from study enrollment among patients 
with bevacizumab-naïve, recurrent glioblastoma. 
 
1.3 
Secondary Objectives 
 
• 
Estimate objective response rate (ORR) by standard RANO criteria  
• 
Estimate progression free survival (PFS)  
• 
Estimate overall survival (OS) 
• 
Assess safety 
• 
Assess rates of compliance above the 75% goal for TTFields therapy via the NovoTTF200A 
(OptuneTM) 
• 
Assess rates and reasons of discontinuation of any component of therapy 
• 
Exploratory analysis of tumor and serum biomarkers in relation to clinical outcome (ORR, 
PFS and OS) 
• 
Quality of life assessment based on the Functional Assessment of Cancer Therapy-Brain 
(FACT-Br) 
• 
Multivariable analyses of prognostic factors, including age, functional status, MGMT 
hypermethylation status 
 
2. BACKGROUND  
 
2.1 
Glioblastoma Overview 
 
In 2014, 23,300 patients were newly diagnosed with a central nervous system (CNS) cancer, 
while 14,000 deaths were attributed to CNS malignancy (Siegel et al., 2014). Glioblastoma is the 
most common and lethal primary CNS malignancy and comprises 15% of all brain cancers (Patel 
et al., 2014). The 3- and 5-year survival rate for glioblastoma remain at ~10-15% and ~1-5%, 
respectively (Stupp et al., 2009). Glioblastoma remains a significant unmet clinical need with 
dismal survival and limited effective treatment options. There is an urgent and unmet need for 
innovative, safe, and effective therapy combinations for glioblastoma.  


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2.2 
Tumor Treating Fields (TTFields) Therapy using NovoTTF-200A (OptuneTM) Device 
 
Refer to the Investigator’s Brochure (IB) for detailed preclinical and clinical data. 
 
2.2.1 Background 
NovoTTF-200A (OptuneTM) is a portable battery operated device that produces TTFields within 
the human body by means of surface electrodes. The TTFields are applied to the patient by means 
of surface electrodes that are electrically insulated, so that resistively coupled electric currents are 
not delivered to the patient. 
 
The electrodes are placed on the patient’s shaved head over a layer of adhesive hydrogel and held 
in place with hypoallergenic medical tape. The electrodes must be replaced every 3-4 days and 
the scalp re-shaved in order to maintain optimal capacitative coupling between the electrodes 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 device batteries and to connect to an external plug in power supply. 
 
These alternating electrical fields physically interfere with cell division by causing misalignment 
of microtubule subunits in the mitotic spindle during the metaphase to anaphase transition and by 
dielectrophoretic movement of intracellular macromolecules and organelles during telophase. 
This causes failure of cytokinetic furrow formation and resultant mitotic blebbing, leading to the 
disruption of chromosome segregation and eventual cell death (Kirson et al., 2007; Kirson et al., 
2004). The exact pathways by which spindle disruption and physical aggregation of 
macromolecules lead to cell death are unknown. TTFields therapy has been tested in several pilot 
clinical studies including small single arms study as monotherapy for recurrent glioblastoma and 
for newly diagnosed glioblastoma. More recently, 2 large phase III trials have been completed. 
TTFields therapy has been approved for recurrent glioblastoma since 2011.  
 
2.2.2 Clinical Data 
• 
EF-11 Phase III trial comparing NovoTTF-100A monotherapy to physician’s choice 
chemotherapy in recurrent glioblastoma  
This randomized trial compared standard chemotherapy per local practice (active 


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treatment control group) with NovoTTF-200A in a prospective, multicenter phase III trial. 
This international clinical study enrolled 237 patients with recurrent glioblastoma or with 
glioblastoma that hadn’t responded to traditional therapy. Patients in the study were randomly 
assigned to receive either the NovoTTF-200A System or chemotherapy treatment. The study 
showed comparable overall survival rates between patients treated with the NovoTTF-200A 
System and those who underwent chemotherapy (Stupp et al., 2012). 
This new minimally invasive and chemotherapy-free local treatment modality 
demonstrated a statistically non-significant increased response rate (14 versus 
9.6%, p = 0.19), an improved PFS6 rate (21% versus 15%, p = 0.13), and a trend towards 
reduction of the risk of death (hazard ratio 0.86, 95% CI 0.66–1.12, p = 0.27), as well as 
sustained improvement in quality of life. In addition, there was improvement in the cognitive 
and emotional functions in the NovoTTF-200A arm compared to chemotherapy.  Mild to 
moderate (grade 1 and 2) contact dermatitis on the scalp beneath the transducer arrays 
occurred in 16% of NovoTTF-100 patients. This condition was easily treated with topical 
corticosteroids, resolved completely after treatment and did not require substantial treatment 
breaks. However, they did not experience the significant side effects associated with 
chemotherapy, including nausea, anemia, fatigue and serious infections. In 2011, the FDA 
based its approval of the NovoTTF-200A System for recurrent glioblastoma on results from 
this study. 
 
• 
EF-14 Phase III prospective multicenter trial of NovoTTF-200A with temozolomide 
compared to temozolomide alone in patients with newly diagnosed glioblastoma 
This is a prospective randomized open-label phase III study of NovoTTF-200A 
concomitant with temozolomide versus temozolomide alone after standard radiation and 
temozolomide for newly diagnosed glioblastoma. The trial was designed to randomize 700 
patients in a 2:1 ratio and the primary endpoint was progression-free survival but study was 
also powered for overall survival.  
A pre-specified interim analysis was performed on the first 315 patients randomized (210 
on the temozolomide and NovoTTF-200A, 105 on temozolomide only). The median PFS was 
3.9 months in the temozolomide group and 7.1 months in the NovoTTF-200A concomitant 
with temozolomide (p=0.0013). The 1-year survival was 68.3% in the temozolomide alone 
arm and 74.5% in the NovoTTF-200A concomitant with temozolomide arm. The median 
survival times were 15.6 months and 20.5 months (p=0.0042), respectively. In addition, there 
was no concern raised by the review of the safety data on these patients and no new 
significant toxicity was described in the NovoTT-200A group. These interim analyses led the 
independent DSMC to suspend enrollment in the trial and permit patients randomized to 
temozolomide alone to receive NovoTTF-200A.(Stupp et al., 2015) The results of this trial 
led to FDA approval of NovoTTF-200A for newly diagnosed glioblastoma patients.  
 
2.2.3 Safety Profile 
Mild to moderate (grade 1 and 2) contact dermatitis on the scalp beneath the transducer arrays 
occurred in 16% of NovoTTF-100 patients in the EF-11 trial, and 44% of patients in the EF-14 
trial. This condition was easily treated with topical corticosteroids, resolved completely after 
treatment, was stopped and did not require substantial treatment breaks. The risk of headaches, 
seizures or cerebral edema does not seem to be increased in patients on NovoTTF-200A. 
 
2.3 
Rationale for Immunotherapy in Glioblastoma 
Modified from Sampson J, et al. ASCO 2015: Preliminary Safety and Activity of Nivolumab and its 
Combination with Ipilimumab in Recurrent Glioblastoma: CHECKMATE-143 (NCT02017717) 
 


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Immunologic factors have been clinically associated with gliomas. A reduced risk of gliomas and 
longer survival is associated with elevated immunoglobulin (Ig) E levels compared to normal 
(Schwartzbaum J, et al. J NCI 2012; Turner MC. Cancer Immunol Immunother 2012; Lin Y, et 
al. Chin Med J (Engl) 2011; Schlehofer B, et al. Allergy 2011). Programmed death-1 (PD-1) and 
cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are immune checkpoint receptors that 
regulate immunity. Binding of PD-1 with its 
ligands, PD-L1 and PD-L2, downregulates the T 
cell immune function (Yao Y, et al. Neuro Oncol 
2009). PD-1 is expressed on tumor-infiltrating 
lymphocytes whereas PD-L1 is expressed on 
tumor cells and microglia in most glioblastomas 
(Yao Y, et al. Neuro Oncol 2009). Diffuse 
fibrillary expression of PD-L1 is evident in both 
newly diagnosed and recurrent glioblastoma 
(Figure A; Berghoff AS, et al. J Clin Oncol 2014; 
Berghoff AS, et al. Neuro Oncol 2015). PD-L1 
expression correlates with malignancy grade of 
gliomas (Yao Y, et al. Neuro Oncol 2009). CTLA-
4 signaling attenuates the immune response by 
increasing the T-cell activation threshold and 
potentially increasing activity of suppressor T cells 
(Riley JL, June CH. Blood 2005). 
 
In a murine model of glioblastoma, antibodies that inhibit PD-1 can prolong survival. Preclinical 
studies in mice showed that combined PD-1/CTLA-4 blockade was more effective than either 
agent alone at increasing tumor infiltration of T-effector cells and decreasing T-regulatory cell 
numbers (Curran MA, et al. 
Proc Natl Acad Sci USA 
2010). Nivolumab is a fully 
human, IgG4 monoclonal 
antibody that targets the PD-
1 immune checkpoint 
pathway and prevents 
binding of PD-1 with PD-L1 
and PD-L2. Ipilimumab is a 
fully humanized IgG1 
monoclonal antibody that 
binds to CTLA-4. Figure 
depicts the mechanisms of 
action (modified from Pillai RN, et al. AACR 2017: CHECKMATE-817 (NCT02869789)). 
Patients with melanoma brain metastases had objective responses to ipilimumab, suggesting 
efficacy in the central nervous system (Margolin K, et al. Lancet Oncol. 2012). Combination 
immunotherapy with nivolumab and ipilimumab may improve outcomes for patients with 
recurrent glioblastoma, while early phase studies reveal tolerable toxicity profile comparable to 
other tumor types. 
 
2.4 
Nivolumab 
 
Refer to the Investigator’s Brochure (IB) for detailed background information. 
 


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2.4.1 Background  
An intact immune surveillance is important in controlling outgrowth of neoplastic transformation.  
Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes (TILs) in 
cancer tissue and favorable prognosis in various malignancies.  In particular, the presence of 
CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to 
correlate with improved prognosis and long-term survival in many solid tumors. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member that is 
related to CD28 and CTLA-4 and that negatively regulates antigen receptor signaling upon 
binding to its ligands (PD-L1 and/or PD-L2).  The murine PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for 
ligand binding and a cytoplasmic tail, which is responsible for the binding of signaling molecules.  
The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 
to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector 
molecules, such as CD3ζ, PKCθ and ZAP70, which are involved in the CD3 T-cell signaling 
cascade.  The mechanism by which PD-1 down modulates T-cell responses is similar to, but 
distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins.  
PD-1 is expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-
cells, T regulatory and Natural Killer cells.  PD-1 is also expressed during thymic development 
on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.  
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or induced in a variety of 
cell types, including non-hematopoietic tissues and various tumors.  Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region 
and containing short cytoplasmic regions with no known signaling motifs.  Binding of either PD-
1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is 
expressed at low levels on various non-hematopoietic tissues, particularly vascular endothelium. 
PD-L2 protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue 
or chronic inflammatory environments.  PD-L2 is thought to control immune T-cell activation in 
lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral 
tissues.  Although healthy organs express little (if any) PD-L1, a variety of cancers express 
abundant levels of this T-cell inhibitor.  PD-1 may also regulate tumor-specific T-cell expansion 
in subjects with melanoma (MEL).  This suggests that the PD-1/PD-L1 pathway is critical tumor 
immune evasion and, thus, an attractive therapeutic target. 
 
Nivolumab (also referred to as BMS-936558, MDX1106, or ONO-4538) is a human monoclonal 
antibody (HuMAb) that targets the programmed death-1 (PD-1) cluster of differentiation 279 
(CD279) cell surface membrane receptor. PD-1 is a negative regulatory molecule expressed by 
activated T and B lymphocytes.1 Binding of PD-1 to its ligands, programmed death–ligands 1 
(PD-L1) and 2 (PD-L2), results in the down-regulation of lymphocyte activation. 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. Nivolumab is expressed in Chinese 
hamster ovary (CHO) cells and is produced using standard mammalian cell cultivation and 
chromatographic purification technologies. The clinical study product is a sterile solution for 
parenteral administration.  
 
 


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OpdivoTM (nivolumab) is approved for the treatment of several types of cancer in multiple regions 
including the United States (US, Dec-2014), the European Union (EU, Jun-2015), and Japan (Jul-
2014).  
 
Nivolumab has been approved as monotherapy for: 
• 
Metastatic melanoma 
• 
Metastatic non-small cell lung cancer (NSCLC) progressing on or after platinum-based 
chemotherapy 
• 
Advanced renal cell carcinoma after anti-angiogenic therapy 
• 
Classical Hodgkin lymphoma relapsed or progressed after autologous hematopoietic stem cell 
transplantation (HSCT) and brentuximab vedotin, or 3 or more lines of systemic therapy that 
includes autologous HSCT, 
• 
Recurrent or metastatic squamous cell carcinoma of the head and neck progressing on or after 
a platinum-based therapy 
• 
Locally advanced or metastatic urothelial carcinoma progressing on or within 12 months of 
platinum-based chemotherapy 
 
OpdivoTM (nivolumab) has also been approved as in combination with ipilimumab for metastatic 
melanoma. Nivolumab is also being investigated in various other types of cancer as monotherapy 
or in combination with other therapies, and as single-dose monotherapy for the treatment of 
sepsis.  
 
2.4.2 Preclinical and Clinical Data 
Refer to the Investigator’s Brochure (IB) for Preclinical and Clinical details. 
 
2.4.3 Clinical Activity in Subjects with Glioblastoma  
Cohort 2 of CheckMate 143 (CA209143) was a randomized phase 3, open-label study comparing 
nivolumab monotherapy with bevacizumab for recurrent glioblastoma. Toxicity profile was 
comparable to other cancers. Nivolumab did not meet the primary endpoint of superior OS when 
compared with bevacizumab (HR = 1.04; P = 0.76, see Figure below).   


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Objective response rate (ORR) with nivolumab was lower than bevacizumab (7.8% vs. 23.1%), 
while stable disease was noted in 21.6% and 46.8%, respectively. There was a longer time to best 
response (3.0 vs. 1.5 months) as well as prolonged response duration (11.1 vs. 5.3 months) with 
nivolumab compared to bevacizumab. As a single agent, nivolumab revealed minimal and 
delayed but durable response in recurrent glioblastoma 
 
2.4.4 Pharmacokinetic Studies 
Refer to the Investigator’s Brochure (IB) for Pharmacokinetic data. 
 
2.4.5 Safety Profile 
Refer to the Investigator’s Brochure (IB) for Pharmacokinetic data. 
 
Most common adverse reactions (≥20%) in patients treated with nivolumab as monotherapy, 
included fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, 
constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia. 
In combination with ipilimumab, the most common reactions were fatigue, rash, diarrhea, nausea, 
pyrexia, vomiting, and dyspnea. 
 
Nivolumab should be withheld for moderate and permanently discontinued for any of the 
following serious or life-threatening adverse reactions: pneumonitis, colitis, hepatitis 
(transaminase or total bilirubin elevation), nephritis and renal dysfunction, hypophysitis, adrenal 
insufficiency, encephalitis, or infusion reactions. 
 
Patients with prior allogeneic HSCT should be monitored for signs of hyperacute, grade 3-4 acute 
GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-
mediated adverse reactions. Transplant-related mortality has occurred. Nivolumab can cause fetal 
harm. 
 
2.5 
Ipilimumab 
 
Refer to the Investigator’s Brochure (IB) for detailed background information. 
 
2.5.1 Background  
Ipilimumab (also known as BMS-734016, MDX010, MDX-CTLA4) is a fully human monoclonal 
immunoglobulin (Ig) G1κ specific for human cytotoxic T-lymphocyte antigen 4 (CTLA-4, cluster 
of differentiation [CD] 152) expressed on a subset of activated T cells. CTLA-4 is a negative 
regulator of T-cell activity.  
Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, 
CD80/CD86. Blockade of CTLA-4 augments 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 (Treg) function, which contribute to an increase in T-cell 
responsiveness, including the anti-tumor response.  
 
YervoyTM (ipilimumab) 3 mg/kg is approved for use in advanced melanoma in over 47 countries, 
including the United States (US, 25-Mar-2011), the European Union (EU, 13-Jul-2011), and 
Australia (Jul-2011). YervoyTM (ipilimumab) 10 mg/kg is approved as adjuvant treatment of 
unresectable or metastatic melanoma in the US. 
 
2.5.2 Preclinical and Clinical Data 
Refer to the Investigator’s Brochure (IB) for Preclinical and Clinical details. 


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Ipilimumab is being investigated in various non-melanoma cancers as monotherapy or in 
combination with other therapies, including multiple phase I/II studies in patients with 
glioblastoma. 
 
2.5.3 Pharmacokinetic Studies 
Refer to the Investigator’s Brochure (IB) for Pharmacokinetic data. 
 
2.5.4 Safety Profile 
Refer to the Investigator’s Brochure (IB) for Toxicity data. 
 
Blockade of CTLA-4 by ipilimumab leads to T-cell activation, inflammatory adverse events, 
primarily involving the skin (dermatitis/pruritus), GI tract (diarrhea/colitis), liver (hepatitis), 
endocrine glands (e.g., hypophysitis and adrenal or thyroid abnormalities), and other less frequent 
organs (e.g., uveitis/episcleritis). Most occur from treatment onset, but few occur weeks to 
months after discontinuation. Most are reversible with dose modifications, interruptions or 
discontinuation. In rare cases, these inflammatory toxicities prove fatal. 
 
Patients should be assessed for signs and symptoms of enterocolitis, dermatitis, neuropathy, and 
endocrinopathy. Comprehensive metabolic panels (including liver function, adrenocorticotropic 
hormone [ACTH] level, and thyroid function tests) should be evaluated at baseline and before 
each dose of ipilimumab. It is advised to rule-out alternative etiologies for any suspected 
inflammatory toxicity. In general, for severe inflammatory or life-threatening adverse effects, 
ipilimumab should be permanently discontinued and systematic high-dose corticosteroid initiated. 
For moderate immune-mediated toxicities, ipilimumab should be held or delayed, and moderate-
dose corticosteroids considered.  
 
Based on limited clinical experience, corticosteroids do not seem to limit anti-tumor response, 
e.g. disease control was maintained in subjects with objective responses who received 
corticosteroid administration for concomitant serious inflammatory AEs. 
 
2.6 
Rationale for Combination of TTFields and Immunotherapy 
 
The possible synergism between TTFields and Immunotherapy in preclinical studies and a 
retrospective glioma cohort warrants study in clinical trials 
 
2.6.1 Preclinical Data 
TTFields therapy exhibits treatment duration-dependent intrinsic cytotoxic property toward 
cancer cells (Stupp et al, Eur J Cancer 2012; Stupp et al, JAMA 2016). The cellular response to 
TTFields application is characterized by exposure of calreticulin on the cell surface, release of 
HMGB1, and secretion of ATP—all of which are hallmark features of immunogenic cell death 
that can potentially generate a systemic anticancer immune response (Gilad et al, Poster: AAI 
2016). Immunotherapy shows promise for various tumor histologies in multiple clinical trials. 
Combining TTFields with anti-PD-1 may achieve tumor control by further enhancing antitumor 
immunity (Figure 1: Gilad et al, Poster: AAI 2016). 


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2.6.2 Clinical Data 
Tumor-treating fields (TTFields) are approved for use in patients with glioblastomas at recurrence 
(2011) or adjuvant setting (2016) due to overall survival benefit in various trials. In the EF11 
study for recurrent glioblastoma, TTFields monotherapy showed a response rate of 14% 
compared to <5% response for any salvage therapy as per physician preference, including CCNU, 
bevacizumab, etc. (Stupp et al, Eur J Cancer 2012). The phase III (EF-14) trial for newly 
diagnosed glioblastoma also revealed an increase in median survival from 19.8 to 24.5 months for 
patients treated with adjuvant TTFields and temozolomide versus temozolomide alone. 
 
Given preliminary preclinical data demonstrating synergy between TTFields and checkpoint 
immunotherapy, the rates and outcomes of combination TTFields and immunotherapy were 
analyzed in a retrospective gliomas cohort (Odia et al, Posters: SNO 2016 and AACR 2017; 
Schulte et al, SNO 2017).  
 
Since 12/2012, 52 patients with newly diagnosed or recurrent gliomas were treated with TTFields 
therapy at Columbia University. Of 52 treated patients, 21 (40%) were women and 3 (6%), 5 
(10%) and 43 (84%) had WHO grade II, III and IV gliomas, respectively. Median age at 
diagnosis was 58 (23-84) years.  TTFields therapy was used at recurrence in 42 (81%), with a 
range of 0-4 prior recurrences. Prior therapies included bevacizumab (21, 20%), resection [gross 
total in 28 (54%)], radiation [mainly 60 Gy in 30 fractions, 44 (85%)] and temozolomide (100%). 
Median duration of TTFields therapy was 2.4 (0.1-20.3) months. Eleven (21%) patients met the 
TTFields compliance goal of 75%. Concurrent systemic therapy was used in 40 (77%), including 
TTFields in Combination With Anti-PD-1 Are Therapeutically Effective in Vivo 
For in vivo experiments, 10-12-week-old male C57Bl/6 mice were injected directly into 
the lungs with Lewis lung carcinoma (LLC-1; 3x103 cells) (Figure 1A). Application of 
TTFields to the mouse lungs was initiated 6 days afterwards and maintained for 7 days. 
Mice received an I.P. injection of anti-PD-1 (αPD-1; RMP1-14; 250 μg) or Rat IgG2a 
(2A3; 250 μg) (Bioxcell), as indicated in the scheme. The combined treatment of 
TTFields and anti-PD-1 led to a significant decrease in tumor volume as compared to 
control mice and to mice treated with anti-PD-1 alone (Figure 1B).  
Modified from Gilad et al, AAI 2016. 


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temozolomide (16, 31%), nitrosourea (4, 8%), bevacizumab (19, 37%), or checkpoint 
immunotherapy (28, 54%). Nivolumab was the predominant immunotherapy used and dosed 240 
mg every 2 weeks. Only 2 (4%) experienced skin toxicity requiring TTFields therapy 
interruption. 
 
Progression free (PFS) and overall (OS) survival among all patients was 3.6 and 21.5 months, 
respectively. Median PFS was significantly increased among glioblastoma patients treated with 
concurrent immunotherapy (4.6 vs. 3.5 months, p=0.04). There was a trend toward increased 
overall survival after TTFields therapy with addition of immunotherapy (8.3 vs. 6.5 months, 
p=0.32).   
 
Objective response rate (ORR: defined as complete response, partial response or stable disease 
for 6 months) based on RANO was increased in patients treated with concurrent immunotherapy 
versus all other antineoplastic therapy (26% vs. 13%).  This is greater than the 14% reported in 
the phase II EF-11 trial of NovoTTF100A monotherapy (Stupp et al, Eur J Cancer 2012) or  the 
<5-10% objective response seen for early phase trials of checkpoint inhibitor monotherapy, 
including nivolumab, for recurrent glioblastoma (Preusser et al, Nat Rev Neurol 2015). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TTFields therapy improves survival for patients with glioblastomas. Immunotherapy also shows 
promise in various neoplasms. The possible synergism between these modalities in preclinical 
studies and the retrospective glioma series warrants further study as proposed. 
 
2.6.3 Rationale for dose schedule 
A phase I trial of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 doses 
followed by maintenance nivolumab 3 mg/kg every 2 weeks revealed tolerable immune-related 
Example of Radiographic 
Response 
A patient with recurrent 
glioblastoma experienced 
clinical improvement and 
marked partial response on 
combination 
NovoTTF200A (OptuneTM) 
and nivolumab. Pre-
treatment post-gadolinium 
T1 (A) and T2 (B) 
compared to post-treatment 
post-gadolinium T1 (C) 
and T2 (D) are shown. 


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toxicity profiles among patients with recurrent glioblastoma and comparable to other tumor types 
(Sampson J, et al. ASCO 2015: CHECKMATE-143 (NCT02017717) glioblastoma arm). The 
most common causes of discontinuation were AEs: diarrhea, alanine aminotransferase (ALT) 
increased, aspartate aminotransferase (AST) increased, lipase increased, diabetic ketoacidosis, 
hypocalcemia, hypomagnesemia, hyperthyroidism, cholecystitis, and sepsis. 
 
Another multi-cohort phase 3b/4 trial assessed the efficacy of nivolumab IV 240 mg every 2 
weeks plus a maximum of 4 doses of ipilimumab IV 1 mg/kg every 6 weeks followed by 
maintenance nivolumab for a maximum of 24 months in patients with stage IIIb to IV non-small 
cell lung cancer (NSCLC), newly diagnosed or recurrent after platinum-based therapy (Pillai RN, 
et al. AACR 2017: CHECKMATE-817 (NCT02869789)). The study revealed a tolerable toxicity 
profile comparable to monotherapy profiles, with discontinuation rates of 12% for any grade or 
grade 3-4 treatment related toxicities. Objective response rates (ORR) were improved for the 
combination of nivolumab and ipilimumab compared to nivolumab monotherapy. Efficacy 
measures were comparable to more intense dosing regimens. 
 
CheckMate 012 was a multi-cohort phase 1 trial of nivolumab as monotherapy or in combination 
with other agents in 
chemotherapy-naïve 
patients with NSCLC 
The combination of 
nivolumab (3 mg/kg) 
every 2 weeks (Q2W) 
plus ipilimumab (1 
mg/kg) every 12 or 6 
weeks (Q12W or 
Q6W) showed 
promising efficacy. 
Nivolumab in 
combination with 
ipilimumab was well 
tolerated and treatment-related adverse events (TRAEs) were consistent with the known safety 
profiles of the individual agents. The discontinuation rates attributable to TRAEs in the 
nivolumab plus ipilimumab cohorts were similar to nivolumab monotherapy (12% for any grade 
and 12% for grade 3/4). No treatment-related deaths occurred at the time of analysis. 
 
The combination of nivolumab (3 mg/kg) every 2 weeks plus ipilimumab (1 mg/kg) every 6 
weeks as the proposed has been well-tolerated, while nivolumab is approved and proven safe as 
monotherapy when dosed as 240 mg every 2 weeks. Hence, this study utilizes distinct dosing 
schedules for nivolumab when dosed as monotherapy versus in combination with ipilimumab 
based on approved and proven safe dosing. 
 
 
2.7 
Correlative Studies Background 
 
Archival tumor tissue will be collected to evaluate molecular predictors of outcome such as 
MGMT promoter methylation, PDL-1 tumor expression, and tumor mutational load as per 
available funding. 
 
 


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3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
1. Male or female patients with age ≥18 years. 
 
2. Histologically confirmed World Health Organization Grade IV glioblastoma with 
supratentorial distribution. 
 
3. Unequivocal evidence of progressive disease on contrast-enhanced brain CT or MRI as 
defined by RANO criteria, or documented recurrent glioblastoma on biopsy.  
 
4. Measurable disease based on RANO criteria. 
 
5. Prior therapies including radiation and temozolomide.  
 
6. Any number of recurrences are allowed. Resection of recurrent glioblastoma is not 
considered a prior treatment. 
 
7. From the projected start of study treatment, the following periods must have elapsed: 4 weeks 
from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for 
temozolomide and 6 weeks from nitrosoureas), or 4 weeks from any other antibodies or any 
other antineoplastic therapies.  
 
8. Must be at least 12 weeks from radiotherapy or progression outside of the high-dose radiation 
target volume or unequivocal evidence of progressive tumor on biopsy. 
 
9. All adverse events Grade > 1 related to prior therapies (chemotherapy, radiotherapy, and/or 
surgery) must be resolved, except for alopecia. 
 
10. Karnofsky Performance Status (KPS) ≥ 60 (see Appendix A). 
 
11. Adequate organ and marrow function as defined below, all screening labs should be 
performed within 14 days of treatment initiation: 
• 
absolute neutrophil count  
≥ 1,000/mcL 
• 
platelets 
≥ 100,000/mcL 
• 
hemoglobin  
> 8.0 mg/dL 
• 
total bilirubin  
≤ 2.0 x upper limit of normal 
• 
AST (SGOT)/ALT (SGPT)  
≤2.5 × upper limit of normal  
• 
creatinine or creatinine clearance  
≥60 mL/min/1.73 m2 for creatinine >ULN 
 
12. Corticosteroid dose must be stable or decreasing for at least 5 days prior to enrollment.  
 
13. Nivolumab and ipilimumab are potentially teratogenic or abortifacient. Women of 
childbearing potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to entry and for the duration of study. Should a 
woman become pregnant or suspect she is pregnant while she or her partner is participating in 
this study, she should inform her treating physician immediately. Male subjects should agree 
to use adequate method of contraception starting with the first dose through 7 months after 
the last dose of therapy. 
 


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14. Brain CT or MRI within 14 days prior to start of study drug.  
 
15. Archival tissue for evaluation of correlative objectives (if available).  
 
16. Ability to understand and the willingness to provide written informed consent. 
 
3.2 
Exclusion Criteria 
1. Infratentorial disease 
 
2. Bevacizumab within 2 months of enrollment. Prior use of ipilimumab or other CTLA-4 
inhibitor or prior TTFields. 
 
3. Tumors with known IDH1 (isocitrate dehydrogenase 1) or IDH2 mutations as determined by 
immunohistochemistry for the IDH1 R132H variant or by direct sequencing. IDH1/2-mutant 
gliomas have a prolonged overall survival rate compared to IDH1/2-wildtype gliomas 
(Parsons et al., 2008; Yan et al., 2009), indicating distinct natural history.  
 
4. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to nivolumab or ipilimumab or their excipients. 
 
5. Current or planned participation in a study of an investigational agent or using an 
investigational device. 
 
6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
7. Active or life-threatening infection requiring intravenous or >2 weeks of systemic therapy.  
 
8. Prior stereotactic radiotherapy, convection enhanced delivery (CED) or brachytherapy 
requires a biopsy to confirm radiographic progression is consistent with progressive tumor 
and not treatment-related necrosis unless the recurrent lesion is outside of any prior high-dose 
radiation target volume or distant from the prior CED or brachytherapy site. 
 
9. There is an unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with these agents, so breastfeeding must be discontinued by 
enrollment on study. 
 
10. Uncontrolled HIV or AIDS is not allowed. Patients with known history of HIV but with 
undetectable viral load on antiretroviral therapy are allowed.  
 
11. CHF, or MI or hemorrhagic/ischemic stroke in the last 3 months  
 
12. Active illicit drug use or diagnosis of alcoholism 
 
13. Known additional malignancy that is progressing or requires active treatment within 3 years 
of start of study drug. Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin, in situ cervical cancer or other in situ malignancy that has undergone 
potentially curative therapy and/or with >90% probability of survival beyond 5 years.  
 
14. Any surgery (not including minor diagnostic procedures such as lymph node biopsy) within 2 
weeks of start of treatment. Incomplete recovery from any side effects of previous procedures 


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is also exclusionary. 
15. Any significant autoimmune disorders expected to impact multiple or internal organs, 
excluding mild eczema or autoimmune thyroiditis treated with thyroidectomy and requiring 
systemic immunosuppressive or immunomodulatory therapy. 
 
16. Any implanted programmable cranial device, including reprogrammable ventriculoperitoneal 
shunt (VPS) or cochlear implants, that precludes use of TTFields (Optune) therapy. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4. REGISTRATION PROCEDURES 
 
Each institution will register eligible participants per local registration procedures. The investigator is 
responsible for enrolling only those patients who have met all eligibility criteria.  
 
 
5. TREATMENT PLAN  
 
5.1 
Study Design 
 
This is an open-label Phase II trial with two parallel arms, two-stage design with appropriate 
stopping rules for poor efficacy. Arm A will enroll patients without prior history of any 
PD1/PDL1 checkpoint inhibitor, while Arm B will enroll patients with prior PD1/PDL1 
checkpoint inhibitor. We expect to enroll at least 30 (15 in each Arm) and a maximum of 60 (30 
in each Arm) evaluable subjects on this study. The study schema is depicted below. 
NovoTTF200A (Optune) is a device to be worn continuously for a goal of ≥75% of the time, 
ranging from 18 hours daily nonstop or 22 hours daily with 2-3 days off monthly. Patients will be 
encouraged to meet compliance goals via timely feedback and troubleshooting concerns. 
TTFields therapy begins once approved by insurance and an in-home initiation visit scheduled. 
The goal is to start within 1 month of starting immunotherapy infusions. Treatment is planned for 
~24 months. 
 
Infusions will start within 14 days of sreening/baseline visits. Nivolumab will be dosed every 2 
weeks IV 240 mg as monotherapy and 3 mg/kg with ipilimumab. Nivolumab will not exceed 48 
doses (24 months). Ipilimumab starts with the second infusion of nivolumab for Arm B (prior 
immunotherapy) or after progression on single agent nivolumab for Arm A (no prior 
immunotherapy). Ipilimumab infusions will be dosed as 1 mg/kg once every 6 weeks for a 
maximum of 4 doses (24 weeks).  
 
Infusions will continue until maximum duration of ipilimumab and nivolumab therapy or when 
there is confirmed tumor progression, death, intolerable adverse effects or withdrawal. After the 
maximum of 24 months of therapy, clinical, radiographic and quality of life assessments are 
performed every 8 weeks until or when there is confirmed tumor progression, death, or 
withdrawal. One treatment cycle is defined as 6 weeks for the initial 24 months, thereafter every 8 
weeks will define observation cycles. 
 
 


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Reported adverse events and potential risks are described in Section 7. Dose modifications are 
described in Section 6. No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the participant's malignancy. 
 
5.2 
Pre-Treatment Criteria 
 
All patients must sign an informed consent prior to any study-specific procedure.  
For screening, patients will have the following tests done at the treating institution or in a local 
lab within 14 days of treatment initiation: 
Hematology Panel 
ANC 
Platelet count 
Hematocrit 
Hemoglobin 
RBC  
WBC with differential 
 
 
 
 
 
 
Blood Chemistry Panel 
AST (SGOT) 
ALT (SGPT) 
Creatinine and BUN 
Total/direct bilirubin 
Alkaline phosphatase 
Calcium 
Magnesium 
Phosphate 
Potassium 
Sodium 
Random glucose 
Total protein and Albumin 
Others 
Pregnancy test (blood) 
Urine analysis  
PT, PTT, INR 
TSH and free T4 
LDH 
ACTH 
 
 
 
 
 
 


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Hematologic lab values should be re-evaluated on cycle 1 day 1 and need to meet eligibility 
parameters to start treatment. 
 
Patients will undergo complete history, including concomitant medications, physical examination, 
measurement of vital signs (pulse, sitting or supine blood pressure, respiratory rate, temperature) 
and weight, and clinical assessment of Karnofsky performance status (KPS). 
Patients must have had a contrast-enhanced brain MRI or CT scan within 14 days of starting 
study drug. Measurable disease is required for enrollment. 
 
5.3 
Treatment and Evaluation/ Observation Cycles  
 
Blood draws are also performed within 2 days of each infusion. Screening/ Baseline lab results 
may be used for C1D1 if performed within 14 days of initial treatment. Hematology and blood 
chemistry panel results must be reviewed by an investigator prior to each infusion. After the 
maximum of 24 months of therapy, blood draws will only be performed with every clinical and 
radiographic assessment every 8 weeks.  
 
Prior to each infusion every 2-3 weeks and beyond the initial 24 months every 8 weeks, patients 
will undergo physical examination, neurological exam, and KPS assessment. Response 
assessment by MRI or CT and FACT-BR quality of life questionnaires will be performed every 6 
weeks for the initial 24 months of therapy and thereafter every 8 weeks. Targeted questioning will 
collect adverse events and concomitant medications.   
 
To confirm objective response (OR), partial or complete response (see section 11.1 for 
definitions) by tumor measurements must be confirmed by repeat assessments performed ≥4 
weeks after the criteria for response are first met. Progression should also be confirmed by repeat 
scans ≥4 weeks after progression first suspected on MRI or CT. 
 
If the participant undergoes another surgery for presumed tumor progression, but pathological 
findings are consistent with pseudoprogression, the participant will be deemed to not have had 
tumor progression and may continue treatment with nivolumab after principal investigator 
review.  
 
5.4 
End of Treatment Visit 
 
For patients who come off study for toxicity or withdrawal of consent, tumor imaging is at the 
judgment of the investigator, suggested every 8-12 weeks in the appropriate setting after 
termination of the study therapy. 
 
If patients come off treatment for progression of disease (Arm B only), intolerance, or 
withdrawal, they will be seen for assessments of efficacy and safety.  
 
Patients will have repeat safety labs, a clinical examination, weight and KPS assessments, and 
concurrent medications within 30 days of the last infusion.  
 
If tumor assessments are not done within 4 weeks, these will be obtained within the next 2 weeks 
after the End of Treatment Visit. After the end of treatment, each subject will be followed for 30 
days for adverse event monitoring and 100 days for serious adverse event reporting. Participants 
removed from protocol therapy for unacceptable adverse events (Section 7) will be followed until 
resolution or stabilization of the adverse event. 
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follow-up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up. Subjects will be followed for survival every 
2-3 months for a minimum of 1 year, or indefinitely until death or loss to follow-up.  
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
 
Any medication taken by a subject during the course of the study and the reason for its use will be 
documented in the clinical source documentation. 
 
5.5.1 Supportive Care Guidelines 
 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below. Where appropriate, these guidelines include 
the use of oral or intravenous treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids. Note 
that several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. For each disorder, attempts should be made to rule out other causes 
such as metastatic disease or bacterial or viral infection, which might require additional 
supportive care. The treatment guidelines are intended if the events are suspected as related to 
nivolumab or ipilimumab. 
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. If after the evaluation, the event is deemed 
unrelated to immunotherapy, the investigator does not need to follow the treatment guidance (as 
outlined below). Refer to Section 6 for dose modification.  
 
Pneumonitis:  
• 
For Grade 2 events, treat with systemic corticosteroids.  
• 
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
• 
When symptoms improve to Grade 1 or less, taper steroid over 4 or more weeks. 
• 
Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
 
Infusion Reactions:  
• 
Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion. 
 
Diarrhea/Colitis:  
Carefully monitor for signs and symptoms of enterocolitis (e.g. diarrhea, abdominal pain, blood or 
mucus in stool, with or without fever) and of bowel perforation (e.g. peritoneal signs and ileus).   
• 
Advised all to drink liberal quantities of clear fluids.  If oral fluid intake is insufficient, IV 
fluid and electrolytes supplementation is advised.  For Grade 2 or higher diarrhea, consider 
GI consultation and endoscopy to confirm or rule out colitis. 
• 
For Grade 2 events, administer oral corticosteroids.  
• 
For Grade 3 or 4 events, treat with IV followed by high dose oral steroids.   
When symptoms improve to Grade 1 or less, taper steroid over 4 or more weeks. 
 
Hypophysitis: 


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• 
For Grade 2 events, treat with corticosteroids. 
• 
For Grade 3-4, treat initially with IV followed by oral corticosteroids.  
• 
When symptoms improve to Grade 1 or less, taper steroid over 4 or more weeks.  
• 
Replace hormones as warranted as the steroid dose is tapered 
 
Type 1 diabetes mellitus [if new onset, Grade ≥3 Hyperglycemia, associated with ketosis 
(ketonuria) or metabolic acidosis (DKA)] 
• 
Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 
3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 
• 
Evaluate serum glucose, metabolic panel, glycosylated hemoglobin, and C-peptide as 
well as urine ketones. 
 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid 
function (at the start of treatment, periodically during treatment, and as indicated based on clinical 
evaluation) and for clinical signs and symptoms of thyroid disorders. 
• 
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) preferred. 
 
In hypothyroidism, thyroid hormone replacement therapy with levothyroxine or 
liothyroinine as per standard of care. 
• 
Grade 3-4 hyperthyroidism  
 
Treat initially with IV followed by oral corticosteroids. When symptoms improve to 
Grade 1 or less, taper steroid over 4 or more weeks.  
 
Replace hormones as warranted as the steroid dose is tapered 
 
Hepatic: 
• 
For Grade 2 events, monitor liver function tests more frequently (consider weekly) until 
returned to baseline. Treat with IV or oral corticosteroids 
• 
For Grade 3-4 events, treat with intravenous corticosteroids for 24-48 hours. 
• 
When symptoms improve to Grade 1 or less, taper steroid over 4 or more weeks. 
 
Immune-mediated myocarditis  
• 
For suspected immune-mediated myocarditis, ensure adequate evaluation to exclude 
other etiologies, and administer corticosteroids as appropriate. 
• 
Permanently discontinue the related immunotherapy for confirmed immune-mediated 
myocarditis. 
 
Renal Failure or Nephritis: 
• 
For Grade 2 events, treat with oral corticosteroids. 
• 
For Grade 3-4 events, treat with IV or oral corticosteroids. 
• 
When symptoms improve to Grade 1 or less, taper steroid over 4 or more weeks. 
 
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)  
• 
For signs or symptoms of SJS or TEN, withhold immunotherapy and refer the patient for 
specialized care for assessment and treatment.  
• 
 If SJS or TEN is confirmed, permanently discontinue the related immunotherapy.  
 
Refer to Appendices E and F for Toxicity Management Algorithms for Nivolumab and Ipilimumab, 
respectively. 
 


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TREATMENT GUIDELINES FOR INFUSION REACTIONS 
NCI CTCAE Grade 
Treatment 
Premedication for Next Dose 
Grade 1 
Mild reaction; infusion 
interruption and 
intervention not 
indicated 
Increase monitoring of vital signs as 
medically indicated until medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion 
interruption but responds
promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hours 
Stop Infusion and monitor 
Additional therapy options: 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDS 
• 
Acetaminophen 
• 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until medically 
stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of 
stopping infusion, the infusion may be 
restarted at 50% of the original rate 
(e.g., from 100 mL/hr to 50 mL/hr).  
Otherwise dosing held until symptoms 
resolve and premedication required for 
the next scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication 
should discontinue therapy. 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion with: 
• 
Diphenhydramine 50 mg 
PO (or equivalent dose of 
antihistamine) 
• 
Acetaminophen 500-1000 
mg PO (or equivalent 
antipyretic 
Grades 3 or 4 
Grade 3: Prolonged (i.e., 
not rapidly responsive to 
medication and/or brief 
interruption); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
Stop Infusion. 
Additional medical options: 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDS 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen 
• 
Pressors 
• 
Corticosteroids 
• 
Epinephrine 
Increase monitoring of vital signs as 
medically indicated until medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Permanently discontinue related 
immunotherapy 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of drug administration. 
 


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5.5.2 Diet/Activity/Other Considerations 
 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
 
5.6 
Contraception 
 
Nivolumab and ipilimumab have adverse effects on a fetus in utero and may have transient 
adverse effects on the composition of sperm.   
 
Male subjects are considered to be of non-reproductive potential if they have azoospermia 
(whether due to having had a vasectomy or due to an underlying condition).   
 
Female subjects are considered of non-reproductive potential if any below apply:  
1. Congenital or acquired condition that prevents childbearing 
2. Postmenopausal (12 or more months with no menses without an alternative medical cause; in 
women < 45 years of age a high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not using 
hormonal contraception or hormonal replacement therapy. In the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient. 
3. Status post hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, 6 or more weeks prior to start of treatment. 
 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 5 months for female and 
7 months for male subjects after the last dose of study drug by any of the following methods:   
1. Abstinence from heterosexual activity 
** Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle and if 
considered acceptable by local regulatory agencies and ERCs/IRBs.  Periodic abstinence 
(e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are 
not acceptable methods of contraception.  
2. Acceptable contraception during heterosexual activity by subject or partner 
• 
Single method (one of the following is acceptable): 
 
intrauterine device (IUD) 
 
vasectomy of a female subject’s male partner  
 
contraceptive rod implanted into the skin 
• 
Combination method (requires use of two of the following): 
 
diaphragm with spermicide (NOT in conjunction with cervical cap/spermicide) 
 
cervical cap with spermicide (nulliparous women only) 
 
contraceptive sponge (nulliparous women only)  
 
male condom or female condom (cannot be used together) 
 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection  
 
** If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region. 
 


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In order to participate in the study subjects of childbearing potential must adhere to the 
contraception requirement (described above) from the day of study medication initiation (or 14 
days prior to the initiation of study medication for oral contraception) throughout the study period 
up to 5 months for female and 7 months for male subjects after the last dose of trial therapy.  If 
there is any question that a subject of childbearing potential will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study. Subjects should 
be informed that taking the study medication might involve unknown risks to the fetus (unborn 
baby) if pregnancy were to occur during the study.   
 
5.6.1 Pregnancy 
 
If a subject inadvertently becomes pregnant while on treatment, the subject will immediately be 
removed from the study.  The site will contact the subject at least monthly and document the 
subject’s status until the pregnancy has been completed or terminated.  The outcome of the 
pregnancy will be reported to BMS within 2 working days if the outcome is a serious adverse 
experience (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn).   
 
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn.   If a male subject impregnates his 
female partner the study personnel at the site must be informed immediately and the pregnancy 
reported to BMS. 
 
5.6.2 Nursing Women 
 
It is unknown whether nivolumab or ipilimumab are excreted in human milk.  Since many drugs 
are excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
 
5.7 
Subject Withdrawal/Discontinuation Criteria 
 
Subjects may withdraw consent at any time for any reason or withdrawn from the trial at the 
discretion of the investigator for any untoward effect.  A subject may also be withdrawn by the 
investigator or the Sponsor if enrollment is inappropriate, the trial plan is violated, or for 
administrative and/or other safety reasons.   
 
5.8 
Criteria for Taking a Participant off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. Treatment will be discontinued for clinical or radiographic progression of disease, 
intolerance despite dose modification (defined as NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 Grade 3 or 4 that does not return to Grade 1 or 2 after 
interruption or reduction of dose for 4 weeks), or patient withdrawal. A patient who experiences a 
dose-limiting toxicity (DLT) can remain on study at a reduced dose, if deemed by the physician 
to be safe and beneficial for the patient to continue. 
 
In the absence of treatment delays due to adverse events, treatment may continue until one of the 
following criteria applies: 
• 
Global deterioration of health-related symptoms (clinical progression), 
• 
Confirmed radiographic disease progression, 


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• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Treatment interruption for more than 4 consecutive weeks due to intolerance despite 
appropriate dose modification, 
• 
Participant decides to withdraw from the study, or 
• 
General or specific changes in the participant's condition render the participant unacceptable 
for further treatment in the opinion of the treating investigator, 
• 
Protocol non-compliance, 
• 
Pregnancy, 
• 
Lost to follow-up, or 
• 
Study termination by Investigator, Institution or IRB. 
 
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient. In any circumstance, every effort should be made to document patient outcome, if 
possible. The Investigator should inquire about the reason for withdrawal, request that all unused 
investigational product(s) be returned, request the patient to return for a final visit, if applicable, 
and advise follow-up with the patient regarding any unresolved adverse events. 
 
If the patient withdraws from the trial and also withdraws consent for disclosure of future 
information, then no further evaluations should be performed and no additional data should be 
collected. The Investigator may retain and continue to use any data collected before such 
withdrawal of consent.  
 
If the participant undergoes another surgery for presumed tumor progression but pathological 
findings are consistent with pseudoprogression (inflammation and necrosis rather than active 
tumor), the participant will deemed to not have had tumor progression and may continue 
treatment with nivolumab after review with the principal investigator. 
 
5.9 
Duration of Follow Up 
 
After documented progression each subject will be followed by telephone or medical record 
review for survival until they meet criteria for removal from study as per below. 
 
5.10 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following apply: lost to follow-up, 
withdrawal of consent, or death. The reason for taking a participant off study, and date the 
participant was removed, must be documented in the case report form (CRF). 
 
Severe adverse events, availability of new adverse toxicology in animals, and financial 
difficulties due to withdrawal of funds may result in stopping the trial. The investigator or IRB 
may take such actions. If the trial is terminated for safety reasons, subjects will be notified 
immediately and assured that appropriate treatment and follow-up will be available. If an 
investigator terminates the trial, the investigator will inform the subjects and IRB about the 
reason for such action. Similar notifications will be sent by the IRB if it takes such an action. 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the clinical source documentation. 
 


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6. DOSING DELAYS/DOSE MODIFICATIONS 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications for 
nivolumab and ipilimumab.  
 
Patients with Grade 3-4 scalp skin toxicity from NovoTTF200A (OptuneTM) application, should hold 
TTFields therapy until resolved to Grade <2, then resume at same compliance goal of 75% or above. 
Interval maximal topical or systemic therapy advised. Repositioning of arrays is advised for any 
Grade <2 along with maximal medical therapy. 
 
Adverse events (both non-serious and serious) associated with nivolumab and/or ipilimumab 
exposure may represent an immunologic etiology.  These adverse events may occur shortly after the 
first dose or several months after the last dose of treatment. Immunotherapy must be withheld for 
drug-related toxicities and severe or life threatening toxicities. See Section 5.5.1 for supportive care 
guidelines, including use of corticosteroids. 
 
Criteria for disrupting treatment, dose modification, or discontinuation for adverse events that are 
attributable to nivolumab or ipilimumab are listed below. After dose modifications are per the clinical 
judgment of the investigator and agreement of the subject, the treatment will be resumed according to 
the table below. Dose modification may not be required for adverse events that are clinically 
manageable.  
 
Dose Modification Guidelines for Drug-Related Adverse Events 
 
 


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If a patient experiences other adverse events, or several adverse events and there are conflicting 
recommendations based on Grade, the investigator will use the lowest reduced the dose. Dose 
modifications will be made based on an adverse event that occurs during any time during a cycle.  
 
Participants who experience an adverse event that requires a treatment delay or dose reduction should 
be monitored with appropriate laboratory testing or other clinical evaluation at least weekly until 
resolution; if the adverse event does not resolve within 12 weeks, the Investigator will determine the 
best course of action. 


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For holds for reasons other than treatment related toxicities, if the participant does not meet criteria to 
resume treatment within 6 weeks of the event precipitating the hold, the study agent(s) may be 
restarted, as long as there has been no significant evidence of disease progression (e.g., by clinical 
findings, symptoms, tumor markers) during the treatment interruption. 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor. The reason for interruption should be 
documented in the patient's study record. 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
An Adverse Event (AE) is defined as any untoward medical occurrence in any subject given a 
pharmaceutical or biomedical product and irrespective of a causal relationship with this treatment. An 
adverse event can therefore be any unfavorable and unintended sign (Example an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-specified 
procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or 
intensity) of a preexisting condition that is temporally associated with the use of any nivolumab or 
ipilimumab infusion or TTFields therapy is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in frequency or 
severity from expected levels are not to be considered adverse events. Examples of this may include, 
but are not limited to onset of menses or menopause occurring at a physiologically appropriate time. 
 
Adverse events may occur during the course of the clinical trial or within the follow-up period 
specified by the protocol, from overdose (whether accidental or intentional), from abuse and from 
withdrawal. Adverse events may also occur in screened subjects during any pre-allocation baseline 
period as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
 
Progression of the cancer under study is not considered an adverse event. 
 
All adverse events will be recorded starting from the date of screening and at each examination 
through 100 days following cessation of treatment. Serious Adverse Events will be followed through 
100 days following cessation of treatment. Both Adverse Events and Serious Adverse Events will not 
be collected for subjects until they have signed the informed consent form and undergone protocol-
specified procedures or intervention. If the subject requires a blood draw, fresh tumor biopsy etc., the 
subject is first required to provide consent to the main study and AEs will be captured according to 
guidelines for standard AE reporting.  
 
AE monitoring and reporting is a routine part of every clinical trial. All Adverse Events regardless of 
seriousness or relationship to the Investigational Product will be recorded in the Case Report Forms. 
Serious Adverse Events should be reported per the requirements described in Section 7.1. 
 
7.1 
Reporting of Serious Adverse Events  
 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose or during 
any use trial therapies as defined in section 7.2. Progression of the cancer under study is not 
considered an adverse event. 


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All Serious Adverse Events (SAEs) that occur following the subject’s written consent to 
participate in the study through 100 days of discontinuation of dosing for Nivoulmab/Ipilumumab 
must be reported to BMS Worldwide Safety, whether related or not related to study drugs. All 
Serious Adverse Events (SAEs) that occur following the subject’s written consent to participate 
in the study through 100 days of discontinuation of NovoTTF200A (OptuneTM) and/or last dose 
of any infusion, whether related or not related to study device or agents will be collected and 
reported. If applicable, SAEs must be collected that relate to any later protocol-specified 
procedure (e.g., a follow-up skin biopsy). 
 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug or device, are collected, including those thought to be associated with 
protocol-specified procedures. The investigator should report any SAE occurring after these 
aforementioned time periods, which is believed to be related to study drug or protocol-specified 
procedure. 
 
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form. 
 
If the BMS safety address is not included in the protocol document (e.g., multicenter studies 
where events are reported centrally), the procedure for safety reporting must be 
reviewed/approved by the BMS Protocol Manager. Procedures for such reporting must be 
reviewed and approved by BMS prior to study activation. 
 
An appropriate SAE form (e.g. ex-US = CIOMS form or USA = Medwatch form) should be used 
to report SAEs to BMS. The BMS protocol ID number must be included on the form submitted 
by the Sponsor/Investigator.  
 
BMS Contact: 
Worldwide.Safety@bms.com and aepbusinessprocess@bms.com 
Novocure Contact: 
Support@novocure.com 
CIOMS Form: 
http://www.cioms.ch/index.php/cioms-form-i 
MedWatch Form: 
https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/For
ms/UCM048334.pdf 
 
The Sponsor will reconcile the clinical database SAE cases (case level only) transmitted to BMS 
Global Pharmacovigilance (Worldwide.Safety@bms.com). Frequency of reconciliation should be 
every 3 months and prior to the database lock or final data summary. BMS GPV&E will email, 
upon request from the Investigator, the GPV&E reconciliation report. Requests for reconciliation 
should be sent to aepbusinessprocess@bms.com. The data elements listed on the GPV&E 
reconciliation report will be used for case identification purposes. If the Investigator determines a 
case was not transmitted to BMS GPV&E, the case should be sent immediately to BMS. 
 
In accordance with local regulations, BMS will notify investigators of all reported SAEs that are 
suspected (related to the investigational product) and unexpected (i.e., not previously described in 
the IB). An event meeting these criteria is termed a Suspected, Unexpected Serious Adverse 
Reaction (SUSAR). Investigator notification of events will be in the form of a SUSAR Report.  
 
o Other important findings which may be reported by BMS as an Expedited Safety Report (ESR) 
include: increased frequency of a clinically significant expected SAE, an SAE considered 


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associated with study procedures that could modify the conduct of the study, lack of efficacy 
that poses significant hazard to study subjects, clinically significant safety finding from a 
nonclinical (eg, animal) study, important safety recommendations from a study data monitoring 
committee, or sponsor decision to end or temporarily halt a clinical study for safety reasons. 
 
o Upon receiving an ESR from BMS, the investigator must review and retain the ESR with the 
IB. Where required by local regulations or when there is a central IRB/IEC for the study, the 
sponsor will submit the ESR to the appropriate IRB/IEC. The investigator and IRB/IEC will 
determine if the informed consent requires revision. The investigator should also comply with 
the IRB/IEC procedures for reporting any other safety information.  
 
o In addition to the Sponsor Investigator’s responsibility to report events to their local HA, 
suspected serious adverse reactions (whether expected or unexpected) shall be reported by 
BMS to the relevant competent health authorities in all concerned countries according to local 
regulations (either as expedited and/or in aggregate reports). 
 
o Canada Phase IV AE reporting requirement: 
 
The Division 8 of the Food and Drug Regulations in Canada require that any cases of 
Unusual Failure in Efficacy occurring in Canada be reported to the Canadian Health 
Authorities in an expedited manner. 
 
Canadian sites will record single cases of Unusual Failure in Efficacy as an Adverse 
Event. This reporting requirement is specific for Canadian sites only.  
 This AE is required to be reported to BMS within 24 hours by the Investigator/site staff 
becoming aware of the report 
 For transmission purposes, report this AE using the paper SAE form. 
 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS and 
Novocure within 24 hours. For BMS, SAEs must be recorded on either CIOMS or MedWatch 
form and pregnancies must be reported on a Pregnancy Surveillance Form or can be submitted on 
the aforementioned SAE form to BMS. 
• 
SAE Email Address:  Worldwide.Safety@BMS.com 
• 
SAE Facsimile Number:  +1 609-818-3804 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.)  
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to BMS (or designee) 
using the same procedure used for transmitting the initial SAE report.  
 
All SAEs should be followed to resolution or stabilization. 
 
Bristol-Myers Squibb, Inc., Novocure, Inc., and Miami Cancer Institute will submit all required SAE 
Reports and Annual Progress Reports to the FDA as required by FDA or other local regulators.   
Investigators must report to Bristol-Myers Squibb, Inc. and Novocure, Inc. any serious adverse 
event (SAE) that occurs after the initial dose of study treatment, during treatment, or within 30 
days of the last treatment on the local institutional SAE form. An FDA Form 3500A (MedWatch) 
or the local institutional SAE form may be used. 
 
Investigators must report SAEs to the local IRB following local IRB reporting requirements.  


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7.2 
Definition of Serious Adverse Events  
 
SERIOUS ADVERSE EVENTS 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose or during 
any use trial therapies that: 
• 
Results in death, 
• 
Is life threatening, (defined as an event in which the participant was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe) 
• 
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below) 
• 
Results in persistent or significant disability/incapacity, 
• 
Results in or prolongs an existing inpatient hospitalization, 
• 
Is a congenital anomaly/birth defect, 
• 
Is a new cancer (that is not a condition of the study), 
• 
Is associated with an overdose, 
• 
Is another important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon appropriate 
medical and scientific judgment, may jeopardize the subject or may require intervention [e.g., 
medical, surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result 
in hospitalization.)  
• 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the 
study drug is an SAE.   
 
Although pregnancy, overdose, potential drug-induced liver injury (DILI), and cancer are not 
always serious by regulatory definition, these events must be handled as SAEs. 
 
Any component of a study endpoint that is related to study therapy should be reported as an SAE 
(e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported). 
 
NOTE regarding hospitalizations: The PI determines if information regarding hospitalizations 
are considered SAEs and should be included in the protocol. This is supplemental information 
that is included in BMS sponsored trials) 
 
The following hospitalizations are not considered SAEs in BMS clinical studies:  
− 
Visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event) 
− 
Elective surgery, planned prior to signing consent 
− 
Admissions as per protocol for a planned medical/surgical procedure 
− 
Routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy). 
− 
Medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study. Appropriate documentation is required in these cases. 
− 
Admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason). 
− 
Admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols). 


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Progression of the cancer under study is not considered an adverse event. 
 
ADVERSE EVENTS 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug and 
that does not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of investigational product, whether or not considered 
related to the investigational product. 
 
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The casual relationship can be one of the following: 
Definite: The AE is clearly related to the study treatment. 
Probable: The AE is likely related to the study treatment. 
Possible: The AE may be related to the study treatment. 
Unlikely: The AE is doubtfully related to the study treatment. 
Unrelated: The AE is clearly NOT related to the study treatment. 
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship.  
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.) 
 
NONSERIOUS ADVERSE EVENT 
• 
Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim or final 
study reports as specified in the agreement or, if a regulatory requirement [eg, IND US trial] as 
part of an annual reporting requirement.  
• 
Non-serious AE information should also be collected from the start of a placebo lead-in 
period or other observational period intended to establish a baseline status for the subjects.  
A non-serious adverse event is an AE not classified as serious.  
 
Non-serious Adverse Event Collection and Reporting 
The collection of non-serious AE information should begin at initiation of study drug. All non-
serious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 30 days following the last dose of 
study treatment.  
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for non-serious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as appropriate.  
 
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported to BMS as such. 
The following laboratory abnormalities should be documented and reported appropriately: 
• 
any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
any laboratory abnormality that required the participant to have study drug discontinued or 
interrupted 
• 
any laboratory abnormality that required the subject to receive specific corrective therapy.  
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (e.g., anemia versus low hemoglobin value). 
Potential Drug Induced Liver Injury (DILI)  


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Specific criteria for identifying potential DILI have not been identified for this protocol. Standard 
medical practice in identifying and monitoring hepatic issues should be followed. 
Wherever possible, timely confirmation of initial liver related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs. 
 
Potential drug induced liver injury is defined as:  
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
AND 
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
 
Wherever possible, timely confirmation of initial liver related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs. 
 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 5 half-lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for 
participant).  
 
The investigator must immediately notify Worldwide.Safety@bms.com of this event via either 
the CIOMS, MedWatch or appropriate Pregnancy Surveillance Form in accordance with SAE 
reporting procedures.  
 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant. Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable, offspring information must be reported on the CIOMS, 
MedWatch or appropriate Pregnancy Surveillance Form.  A BMS Pregnancy Surveillance Form 
may be provided upon request. 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. In 
order for Sponsor or designee to collect any pregnancy surveillance information from the female 
partner, the female partner must sign an informed consent form for disclosure of this information. 
  
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE. 
 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, X-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a non-serious or serious AE, 


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as appropriate, and reported accordingly. 
 
7.3 
Expected Toxicities 
 
Refer to the Investigator’s Brochure (IB) for detailed toxicity information. Refer to sections 2.2.3, 
2.4.5 and 2.5.4 for summaries for OptuneTM (NovoTTF200A), OpdivoTM (nivolumab), and 
YervoyTM (ipilimumab), respectively. 
 
7.4 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:   
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 
can be downloaded from the CTEP web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Attribution of the AE: 
Definite: The AE is clearly related to the study treatment. 
Probable: The AE is likely related to the study treatment. 
Possible: The AE may be related to the study treatment. 
Unlikely: The AE is doubtfully related to the study treatment. 
Unrelated: The AE is clearly NOT related to the study treatment. 
 
 
8. PHARMACEUTICAL INFORMATION 
Refer to the Investigator’s Brochure (IB) and Lab Manual for detailed information. 
 
8.1 
Product Supply, Administration and Inventory 
8.1.1 Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
 
8.1.2 Availability 
Bristol-Myers Squibb (BMS), Inc. will provide nivolumab (OpdivoTM) and ipilimumab 
(YervoyTM). BMS will provide Nivolumab in 100 mg vials, 10mg/mL. BMS will provide 
Ipilimumab in 200 mg vials, 5 mg/mL. 
Novocure, Inc. will provide the NovoTTF200A (OptuneTM) device once insurance approved and 
as per standard practice. 
 
8.1.3 Administration 
Refer to the Investigator’s Brochure (IB) and Lab Manual for detailed information regarding drug 
and device administration. 
 
The infusions of nivolumab and ipilimumab will each be infused over 30 minutes in the same 
way as in the CHECKMATE-142 (NCT02060188) study.  On days that nivolumab and 
ipilimumab are both administered, the nivolumab is given first in sequence. 
8.1.4 Accountability 
The investigator, or a responsible party designated by the investigator, should maintain a careful 


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record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form. (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage). 
 
8.1.5 Destruction and Return 
Unused supplies of nivolumab or ipilimumab will be destroyed on-site according to local 
practices within 60 days of completion of the study, after accountability has been completed. 
 
Unused arrays and all NovoTTF200A (OptuneTM) device components will be returned to 
Novocure, Inc. at the end of TTFields therapy while on or after trial as per standard practice. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Biomarker Analyses 
 
Correlative assays will be performed on archival tissue to measure biomarkers of therapeutic 
response, including MGMT, PD1/PDL1 expression, mutational load, etc., as funding permits. 
Collection and processing procedures as well as supplies needed are detailed in the Laboratory 
Manual associated with this protocol.  
 
Archival tumor assessments of immune regulation will be performed on tissue obtained from 
participants. If available, a minimum of one (1) formalin-fixed paraffin-embedded (FFPE) 
archival tumor tissue block (preferred) or a minimum of 4 FFPE unstained sections from most 
recent pre-registration biopsy/surgery are to be submitted within 60 days of registration. 
Please refer to the study Laboratory Manual for shipping instructions. 
 
 
10. STUDY CALENDAR 
 
Study visits and procedures have ±2 day scheduling window, except for Screening visit and neuroimaging 
(contrast-enhanced CT or MRI) that have a ±7 day window. A treatment cycle is defined as 6 weeks with 
3 treatments of Nivolumab and 1 treatment of Ipilimumab (Arm B only).Schedule of Assessments 
Footnotes:  
* For Cortisol, TSH/free T4, and ACTH, baseline lab results suffice to clear for C1D1 and any cycle X W1, 
W3, W5 results suffice to clear for next infusion on W3, W5, and cycle X+1 W1, respectively. 
1. Abbreviated Physical Exam on Day 1 of each Treatment Cycle 
2. Neurological assessments will use the NANO scale 
3. Vital signs: Vital signs: systolic and diastolic blood pressure, respiration, pulse, oral temperature prior to each 
infusion 
4. Determine if significant weight loss or gain (±10%) prior to every infusion 
5. Hematologic lab values should be re-evaluated on cycle 1 day 1 and need to meet eligibility parameters to start 
treatment 
6. Pregnancy tests (minimum sensitivity 25 IU/L or equivalent units of HCG) are required for women with 
childbearing potential, defined as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., menses at any 
time in the preceding 24 consecutive months). 
7. Every 2-3 months, via telephone, for all subjects for a minimum of 1 year, or indefinitely until death or loss to 
follow-up 
8. Obtain archival tumor tissue (if available) at enrollment, in accordance with the Laboratory Manual.. 


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Study Visits/ Windows
Screening/ Baseline
Observation
End of Treatment
Follow-Up
C__W1
C__W3, W5
After max therapy or 
toxicity discontinuation 
Every 6 weeks (±7 days)
(±2 days)
Every 8 weeks (±7 
days) 
Informed Consent
x
.
Medical/Rx History
x
x
x
x
x
Physical exam1, Neurologic 
Exam2, KPS
x
x
x
x
x
Vital signs3, Weight4
x
x
x
x
x
Height
x
Hematology5
x
Full Serum Chemistry
x
AM Cortisol Testing*
x
x
x
TSH, free T4*
x
x
x
x
ACTH*
x
x
x
x
PT, PTT, INR*
x
Urinalysis
x
Pregnancy Test6
x
FACT-BR Questionnaire 
x
x
x
x
NovoTTF200A (OptuneTM)7
x
x
Nivolumab
x
x
Ipilimumab (Arm B Only)
x
MRI or CT Scan
x
AE/ SAE
Con-meds
x
x
x
x
x
Disease Status and Survival8
x
Archival Tumor Tissue9
x
Screening/ Baseline: within 24 hours of start of treatment
Treatment Cycles: every 6 weeks while on immunotherapy
Schedule of Assessments
Treatment Cycles
AEs are recorded from the date of initiation of therapy and at each examination until 30 days after last dose of 
Nivolumab. SAEs will be followed through 100 days after last dose of Nivolumab.
Screening/ Baseline: Within 14 days of Treatment
Treatment Cycles: Every 6 weeks (within 7 days prior to treatment)
Observation : Every 8 weeks Every 8 weeks (±7 days)
Screening/ Baseline: within 14 days prior to first infusion
Treatment Cycles: within 2 days prior to each infusion
Observation : every 8 weeks with each clinical and/or CT/MRI assessment
Procedures
Within 14 days of 
Treatment
30 (±3 days) after last 
dose
Every 2-3 months


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11. MEASUREMENT OF EFFECT 
 
After signing informed consent patients will undergo screening procedures including baseline 
radiologic imaging by contrast-enhanced CT or MRI within 14 days prior to starting therapy. 
Patients who remain on study will have tumor assessments performed every 6 weeks while on a 
maximum of 24 months of therapy, thereafter every 8 weeks while off therapy (Observation period). 
In addition to reassessment scans, confirmatory scans should also be obtained at ≥4 weeks following 
initial documentation of objective response. To be assigned a status of PR or CR changes in tumor 
measurements must be confirmed by repeat assessments that should be performed at ≥4 weeks after 
the criteria for response are first met. 
 
Response will be assessed by the modified immune Revised Assessment in Neuro-Oncology 
(iRANO) response criteria.  
 
11.1 
Definitions 
 
Evaluable for Objective Response 
Only those patients with measurable disease present at baseline will be enrolled on study.  
 
Only patients who received at least one cycle (6 weeks) of therapy and response assessment with 
brain MRI or CT at least 6 weeks from the first dose will be considered evaluable for overall 
survival or disease progression. Patients who discontinue therapy for reasons other than 
progression prior to response assessment will not be evaluable for survival and will be replaced. 
 
Only patients with measurable disease present at baseline, completing at least one cycle (6 weeks) 
of therapy, and disease re-evaluated radiographically will be considered evaluable for partial or 
complete response.  
 
Any patient who initiates treatment and is later found to be ineligible for study (e.g., protocol 
violation) will be withdrawn from study but will be followed for disease progression, toxicity and 
survival. The experience of such patients will be characterized separately from that of evaluable 
patients. Reasons for exclusion of enrolled patients from the analysis set for efficacy, or for 
safety, will be characterized. 
 
Evaluable Non-Target Disease Response   
Patients with lesions present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle (6 weeks) of therapy, and have had their 
disease re-evaluated will be considered evaluable for non-target disease. The response assessment 
is based on the presence, absence, or unequivocal progression.  
 
All patients who have received at least one dose infusion of nivolumab and/or initiate TTFields 
therapy are evaluable for safety and toxicity. 
 
Disease Parameters 
For the purposes of this study, patients will be evaluated for response approximately every 6 
weeks of therapy starting from the first dose for the initial 24 months, thereafter approximately 
every 8 weeks. In addition to baseline scans, confirmatory scans will be obtained at ≥4 weeks 
following initial documentation of objective response or disease progression. 
 
11.2 
Disease Parameters 
 


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Measurable Disease 
Bi-dimensionally, contrast-enhancing, measurable lesions with clearly defined margins by CT or 
MRI scan, with a minimal diameter of 1 cm, and visible on 2 axial slices (≥5 mm apart with 0 
mm skip). Measurement of tumor around a cyst or surgical cavity, if necessary, requires a 
minimum thickness of 3 mm. If there are too many measurable lesions to measure at each 
evaluation, the investigator must choose the largest two to be followed before a participant is 
entered on study. The remaining lesions will be considered non-measureable for the purpose of 
objective response determination. Unless progression is observed, objective response can only be 
determined when all measurable and non-measurable lesions are assessed.  
 
Non-Measurable Evaluable Disease 
Unidimensionally measurable lesions, masses with margins not clearly defined, lesions with 
maximal diameter <1cm.  
 
11.3 
Response/Progression Categories 
The RANO Response Criteria will be used in this study as summarized below.  
 
11.3.1 Complete response (CR).  
All of the following criteria must be met: 
a. Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 8 weeks. In the absence of a confirming scan at least 4 weeks 
later, this scan will be considered only stable disease.  
b. No new lesions.  
c. All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline.  
d. Participants must be on no steroids or on physiologic replacement doses only.  
e. Stable or improved clinically, for clinical signs and symptoms present at baseline and 
recorded to be disease related. 
f. Stable or improved non-enhancing (T2/FLAIR) lesions.  
Non-measurable disease cannot have a complete response. 
 
11.3.2 Partial response (PR) 
All of the following criteria must be met: 
a. Greater than or equal to 50% decrease compared to baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at least 8 
weeks. In the absence of a confirming scan at least 4 weeks later, this scan will be 
considered only stable disease.  
b. No progression of non-measurable disease.  
c. No new lesions.  
d. All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline.  
e. The steroid dose at the time of the scan evaluation should be no greater than the dose 
at time of baseline scan.  
f. Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan.  
g. Stable or improved, for clinical signs and symptoms present at baseline and recorded 
to be disease related clinically.  
Non-measurable disease cannot have a partial response.  
11.3.3 Progressive disease (PD) 
Any of the following criterions must be met: 
a. >25% increase in sum of the products of perpendicular diameters of enhancing 


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lesions (over best response or baseline if no decrease) on stable or increasing doses of 
corticosteroids and sustained for at least 8 weeks. In the absence of a confirming scan 
at least 4 weeks later, this scan will be considered only stable disease. 
b. Any new enhancing measurable lesion.  
c. Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. 
seizures, medication side effects, complications of therapy, cerebrovascular events, 
infection, etc.). The definition of clinical deterioration is left to the discretion of the 
investigator, but it is recommended that a decline in the Karnofsky Performance 
Score (KPS) from 100 or 90 to 70 or less, a decline in KPS of at least 20 from 80 or 
less, or a decline in KPS from any baseline to 50 or less, for at least 7 days, be 
considered neurologic deterioration, unless attributable to co-morbid events or 
changes in corticosteroid dose.  
d. Failure to return for evaluation due to death or deteriorating condition.  
 
11.3.4 Stable disease (SD) 
All of the following criteria must be met: 
a. Does not qualify for CR, PR, or progression.  
b. All measurable and non-measurable sites must be assessed using the same techniques 
as baseline.  
c. Stable clinically. 
 
11.3.5 Unknown response status 
Progressive disease has not been documented and one or more measurable or non-
measurable lesions have not been assessed.  
 
11.4 
Methods for Evaluation of Disease 
 
All measurements must be performed and recorded in metric notation using ruler, calipers, or 
digital measurement tools. All baseline measurement should be performed as close to initiation of 
treatment and never >4 weeks before the treatment. 
 
The same method and technique of measurement should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam.  
 
11.5 
Evaluation of Best Response 
 
The best overall response is the best response recorded from the treatment start until disease 
progression (using as reference for progressive disease the smallest measurements recorded since 
the treatment started). If a response recorded at one scheduled MRI does not persist at the next 
regular scheduled MRI, the response will still be recorded based on the prior scan, but will be 
designated as a non-sustained response. If the response is sustained, i.e. still present on the 
subsequent MRI at least four weeks later, it will be recorded as a sustained response, lasting until 
the time of tumor progression. Participants without measurable disease may only achieve SD or 
PD as their best “response.” 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Lists, guidelines, and instructions for reporting adverse events are listed in Section 7. 
 


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12.1 
Data Reporting 
Investigative sites are responsible for completing and submitting data and/or data forms 
according to the user requirements.  
 
12.2 
Data Collection 
 
12.2.1 Data Collection Forms 
The Miami Cancer Institute (MCI) Clinical Trial Office (CTO) will be responsible for all 
data management.  
 
Case Report Forms will be generated by the CTO. Case Report Forms will be completed 
in a timely manner by the respective site. The trial will use a web-based Electronic Data 
Capture (EDC) system for all data collection. Case Report Form completion may be 
formally delegated to other study personnel listed in the delegation of authority (DOA) 
form and signed by the PI or co-investigator. 
The following steps will ensure accurate, consistent, complete and reliable data: 
1. The Investigator/Institution will conduct an initiation meeting at the study site prior 
to the start of the study. The study protocol, procedures and CRFs will be reviewed in 
detail and the study personnel will be trained to carry out the procedures defined in 
the protocol. 
2. The Investigator will maintain a Study Site Binder for storing study related 
regulatory and study site documentation: study logs and forms. 
3. All written study documentation entries must be made in blue or black ink. The 
investigator must review all entries for completeness and accuracy. When changes or 
corrections are made on any study documentation, the person making the change 
must draw a single line through the error, then initial and date the correction. 
4. Periodic monitoring by the MCI CTO data management team will verify the accuracy 
of data entered on each CRF against the raw data from source documents at the site. 
Items needing correction/clarification will be identified and brought to the attention 
of the study site personnel and Principal Investigator, and corrections will be made as 
appropriate. 
5. Once the Investigator/Institution performs a final review of the CRF, study database 
will be validated using appropriate validation processes. 
 
12.2.2 Registration and Eligibility  
The investigator will confirm patient eligibility. The investigator is responsible for 
enrolling only those patients who meet protocol eligibility criteria. 
 
12.2.3 Data Safety and Monitoring Board (DSMB) 
Miami Cancer Institute DSMB will provide trial oversight per the Data Safety 
Monitoring Plan (DSMP). 
 
12.3 
Regulatory Requirements 
 
12.3.1 Patient Consent Form 
Informed consent must be obtained before protocol-specified procedures or interventions 
are carried out. The investigator will explain the nature of the study and will inform the 
subject that participation is voluntary and that they can withdraw at any time. A copy of 
the signed consent form will be given to every participant and the original will be 
maintained with the subject’s records. 


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The consent form must be approved by the IRB. Consent forms are written to be 
understood by prospective subjects. The Informed Consent should be translated and 
certified into the local language of the respondent, as deemed necessary. Informed 
consent will be documented by the use of a written consent form approved by the IRB 
and signed and dated by the subject and by the person who conducted the informed 
consent discussion. The signature confirms the consent is based on information that has 
been understood. Each signed informed consent form must be kept on file by the 
investigator for possible inspection by Regulatory Authorities. The subject should receive 
a copy of the signed and dated written informed consent form and any other written 
information provided to the subjects, and should receive copies of any signed and dated 
consent form updates and any amendments to the written information provided to 
subjects. 
 
12.3.2 Site Monitoring 
To ensure compliance with current federal regulations and the ICH guidelines, data 
generated by this study must be available for inspection upon request by representatives 
of the FDA, national and local health authorities, and duly authorized representative of 
any entity providing support for this trial. Routine monitoring or audit activities for this 
study should be conducted by appropriately authorized personnel as warranted. The 
general scope of such visits would be to inspect study data (regulatory requirements), 
source documentation and CRF completion in accordance with current FDA Good 
Clinical Practices (GCP), the ICH guidelines and the respective local and national 
government regulations and guidelines. 
 
12.3.3 Institutional Review Board Approval 
This protocol, the informed consent document, relevant supporting information and all 
types of patient recruitment and advertisement information must be submitted to the local 
IRB for review and must be approved before the study is initiated. An amendment to 
remove a life-threatening situation can by implemented by the Investigator prior to 
obtaining IRB approval by the site. In such situations, the IRB must be notified 
immediately and the amendment forwarded to the IRB for their consideration. 
 
The investigator is responsible for keeping the local IRB informed of the progress with 
study renewal at least once a year. The investigator must also keep the local IRB 
informed of any significant adverse events, per local institutional guidelines. 
 
12.3.4 Records Retention  
FDA regulations (21 CFR 312.62) require clinical investigators to retain all study-related 
documentation, including source document and CRFs for: 
• 
Two years after the FDA approved the marketing application, or 
• 
Two years after the FDA disapproves the application for the indication being studied, or 
• 
Two years after the FDA is notified of the discontinuation of the trial, and that an 
application will not be submitted. 
 
For all studies, including studies with FDA-IND exemption, the Investigator/ Institution 
will take measures to prevent accidental or premature destruction of study documents. 
For such studies conducted under IND exemption, records will be retained for a 
minimum of seven (7) years past official study termination. Sponsored trials should be 
contacted upon the study team becoming aware of the relocation of study documents or 
prior to destroying any study documents. 


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13. STATISTICAL CONSIDERATIONS 
 
13.1 
 Study Design and Sample Size 
 
We propose an open label, two parallel arm, two-stage, phase II trial to determine the efficacy, 
in terms of objective response rate (ORR), of combination therapy with tumor treating fields 
(TTFields) therapy, nivolumab with or without ipilimumab in adult patients with bevacizumab-
naïve, recurrent glioblastoma. Best objective response rate (ORR) is defined as the proportion of 
evaluable patients who achieve complete (CR) or partial response (PR) according to modified 
immunotherapy iRANO criteria. Secondary objectives include safety, ORR by standard RANO 
criteria, overall survival (OS), progression-free survival (PFS), clinical benefit (defined as ORR 
plus stable disease >12 weeks), compliance rates of TTFields therapy at or above goal of 75%, 
and exploratory correlations between response or survival and compliance rates, serum and/or 
tumor tissue biomarkers. Primary analyses are performed for each arm, but secondarily assessed 
for the entire cohort as well. 
 
The EF-11 study showed a response rate of 14% among patients with recurrent glioblastomas 
treated with TTFields alone compared to physician’s choice medical therapy (Stupp et al, Eur J 
Cancer 2012). Thus, the null H0 is set at 14% and H1 (target ORR) set at 35% for each arm. 
Power is set at 85% with a 1-sided alpha of 0.05.  
 
If no response is seen after 15 eligible patients are accrued in either arm, that arm will close for 
futility. Based on a MiniMax design, if >2 responses are seen on the first 15 patients in either 
arm, then 15 more patients will be accrued in the arm. If ≥7 responses are seen among the 30 
patients in either arm, this regimen deserves further investigation. Sample size will be 30 
maximum per cohort/arm for a total of 30 to 60 subjects enrolled on study. 
 
13.2 
Definitions 
 
Evaluable: All study-eligible patients who receive at least one infusion of nivolumab will be 
considered evaluable for safety and toxicity. To be evaluable for efficacy, patients must be study 
eligible, receive at least one cycle (6 weeks) of immunotherapy and complete initial disease 
assessment at ≥ 6 weeks after starting therapy.  
 
Exclusions: Any patient who is enrolled on study, but does not receive any component of study 
treatment, will be excluded from all efficacy analyses. Any patient who initiates treatment and is 
later found to be ineligible for study (e.g., protocol violation) will be withdrawn from study but 
will be followed for disease progression, toxicity and survival. The experience of such patients 
will be characterized separately from that of evaluable patients. Reasons for exclusion of 
enrolled patients from the analysis set for efficacy, or for safety, will be characterized. 
 
Overall response rate (ORR): Overall response rate is the proportion of patients whose best 
overall response per modified iRANO criteria or standard RANO criteria is complete (CR) or 
partial (PR) after at least 6 weeks from start of therapy. iRANO additionally requires best overall 
response of CR or PR to be sustained, that is, confirmed by a second assessment at ≥ 4 weeks 
later. Patients who clinically progress before the initial radiographic assessment after 1 cycle (6 
weeks) will be considered nonresponders. 
 
Progression-free survival (PFS): PFS will be measured from the start date of treatment until 


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documented evidence of disease progression, clinical progression or death from any cause, after 
at least 8 weeks from start of therapy. Radiographic progression should be confirmed by a 
second assessment at ≥4 weeks later. For patients who remain alive without progression, follow 
up time will be censored at the date of last assessment. 
 
Overall survival (OS): Survival will be measured from the start date of treatment to the date of 
death from any cause or last contact (censored observations).  
 
13.3 
Enrollment and Study Duration 
 
We expect to enroll at an average rate of two patients per month and complete accrual within 
two years. Patients will be followed for a minimum of one additional year. Thus study duration 
is expected to be approximately three years. 
 
13.4 
Statistical Analyses 
 
Baseline characteristics will be summarized using descriptive statistics: count, percentage, range, 
median, mean, and standard deviation as appropriate. Data include demographics (age, sex, 
race/ethnicity), performance status, laboratory parameters and prior therapy.  
 
Treatment duration will be summarized by the number of immunotherapy cycles (6 weeks each). 
Frequency and reason for dose modifications and discontinuation of any therapy will be detailed.  
 
We will report the objective response rate with corresponding two-side 90% confidence interval 
(CI) using the exact binomial method (Armitage et al, 2002). We will also report the objective 
response rate, the median and range for time to response, and duration of CR or PR. Time to 
progression will be summarized by the median and range for patients whose best response is SD 
as well as for all patients who develop progressive disease. 
 
The Kaplan-Meier method will be used to estimate progression-free and overall survival. Point 
estimates for the proportion of progression-free and surviving patients will be given for selected 
times, specifically 6 and 12 months, along with corresponding 95% confidence intervals using the 
log-log transformed method and Greenwood’s variance. To the extent possible with 30-60 study 
patients, we will investigate the relationship between tissue and serum biomarkers and overall 
response using logistic regression. Similarly, biomarker associations with progression free and 
overall survival will be explored using the log rank test and Cox regression. 
 
Safety will be assessed by tabulating toxicities according to type, grade, duration, and attribution 
to study treatment in accordance with NCI Common Terminology Criteria for Adverse Events 
(CTCAE version 4.0). We will also report the distribution of worst grade toxicity in study 
patients.  
 
TTFields compliance data is collect during monthly in-home visits by Novocure representative in 
order to assess NovoTTF200A (OptuneTM) function and address patient concerns. The 
compliance rates are an average (mean ± stdev) over the 28-31 days of the month and provided in 
graphical and numerical form. Appendix D shows sample compliance reports with weighted 
average (mean ± stdev) per month. These data are provided as part of standard of care and 
included in the patient medical record. The weighted average will be compared to ORR, OS and 
PFS using the appropriate logistic or Cox regression models. 
 
Quality of life will be assessed using the NRG/RTOG tool Functional Assessment of Cancer 


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Therapy-Brain (FACT-Br). FACT-Br is a validated tool measuring general quality of life (QOL) 
that assesses symptoms or problems associated with CNS tumors across 5 scales (Cella DF, 1993; 
Weitzner MA, 1995). FACT-Br yields data about total QOL, as well as dimensions of disease 
specific physical, social/family, emotional, and functional well-being. The FACT-Br is written at 
the 4th grade reading level. Patients can complete it in 5-10 minutes. The self-report of quality of 
life can be completed by the patient or with the assistance of the examiner and does not require 
pre-certification. 
 
Analysis of QOL will focus on the 33-item FACT-G score and the 20-item brain subscale, FACT-
BR. Scores will be calculated in accordance with FACIT scoring guidelines (www.facit.org). 
Descriptive summaries of FACT-G and FACT-BR at baseline and at each planned follow-up will 
include median and range, means and standard deviations as well as graphical depiction. To the 
extent that a clinically meaningful difference can be established, we will also categorize changes 
from baseline as indicating improvement, worsening, or no change and summarize these by 
counts and percentages. 
 
13.5 
Interim Monitoring 
 
The study team will continuously monitor study accruals, toxicities and clinical outcome. Early 
stopping for futility will be considered after 15 patients have been enrolled and treated in each 
arm. Using a Minimax design, the chance of early stoppage under the null is calculated at 65%. 
The median time to response for nivolumab is 2 months. Once subject 15 is enrolled for each 
arm, we will wait a minimum of 8 (median time to response) and maximum of 12 weeks (2 MRI 
cycles) to assess response if an objective response by iRANO has not been noted in the already 
accrued patients. 
 
 
 


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14. KEY REFERENCES 
Kirson, E.D., Dbaly, V., Tovarys, F., Vymazal, J., Soustiel, J.F., Itzhaki, A., Mordechovich, D., 
Steinberg-Shapira, S., Gurvich, Z., Schneiderman, R., et al. (2007). Alternating electric fields arrest 
cell proliferation in animal tumor models and human brain tumors. Proceedings of the National 
Academy of Sciences of the United States of America 104, 10152-10157. 
Kirson, E.D., Gurvich, Z., Schneiderman, R., Dekel, E., Itzhaki, A., Wasserman, Y., 
Schatzberger, R., and Palti, Y. (2004). Disruption of cancer cell replication by alternating electric 
fields. Cancer research 64, 3288-3295. 
Parsons, D.W., Jones, S., Zhang, X., Lin, J.C., Leary, R.J., Angenendt, P., Mankoo, P., Carter, H., 
Siu, I.M., Gallia, G.L., et al. (2008). An integrated genomic analysis of human glioblastoma 
multiforme. Science 321, 1807-1812. 
Patel, M.A., Kim, J.E., Ruzevick, J., Li, G., and Lim, M. (2014). The future of glioblastoma 
therapy: synergism of standard of care and immunotherapy. Cancers 6, 1953-1985. 
Siegel, R., Ma, J., Zou, Z., and Jemal, A. (2014). Cancer statistics, 2014. CA: a cancer journal for 
clinicians 64, 9-29. 
Stupp, R., Hegi, M.E., Mason, W.P., van den Bent, M.J., Taphoorn, M.J., Janzer, R.C., Ludwin, 
S.K., Allgeier, A., Fisher, B., Belanger, K., et al. (2009). Effects of radiotherapy with concomitant 
and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised 
phase III study: 5-year analysis of the EORTC-NCIC trial. The Lancet Oncology 10, 459-466. 
Stupp, R., Taillibert, S., Kanner, A.A., Kesari, S., Steinberg, D.M., Toms, S.A., Taylor, L.P., 
Lieberman, F., Silvani, A., Fink, K.L., et al. (2015). Maintenance Therapy With Tumor-Treating 
Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. 
JAMA 314, 2535-2543. 
Stupp, R., Wong, E.T., Kanner, A.A., Steinberg, D., Engelhard, H., Heidecke, V., Kirson, E.D., 
Taillibert, S., Liebermann, F., Dbaly, V., et al. (2012). NovoTTF-100A versus physician's choice 
chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. 
European journal of cancer 48, 2192-2202. 
Yan, H., Parsons, D.W., Jin, G., McLendon, R., Rasheed, B.A., Yuan, W., Kos, I., Batinic-
Haberle, I., Jones, S., Riggins, G.J., et al. (2009). IDH1 and IDH2 mutations in gliomas. The New 
England journal of medicine 360, 765-773. 
 
 


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APPENDIX A 
 
Karnofsky Performance Status (KPS) Criteria 
 
 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his/her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated. Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead. 


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APPENDIX B 
 
Neurologic Assessment In Neuro-Oncology (NANO) Scale 
 
Scoring assessment is based on direct observation and testing performed during clinical evaluation 
and is not based on historical information or reported symptoms. Please check 1 answer per 
domain. Please check “Not assessed” if testing for that domain is not done. Please check “Not 
evaluable” if a given domain cannot be scored accurately due to pre-existing conditions, co-morbid 
events and/or concurrent medications. 
 
Study #, Participant # and Initials:   ______________      ____________/____________ 
Date Assessment Performed (day/month/year):   ______________________________________ 
Study time point (i.e. cycle 1, day 1, etc.):  ___________________________________________ 
Assessment performed by (please print name):  _______________________________________ 
 
Domains                                                                           
  
Key Considerations 
Gait 
0 
   Normal 
1 
   Abnormal but walks without assistance 
2 
   Abnormal and requires assistance  
(companion, cane, walker, etc.) 
3 
   Unable to walk 
   
   Not assessed 
   
   Not evaluable 
 
Strength 
0 
   Normal 
1 
   Movement present but decreased 
 against resistance 
2 
   Movement present but none against resistance 
3 
   No movement 
   
   Not assessed 
   
   Not evaluable 
 
Ataxia (upper extremity) 
0 
   Able to finger to nose touch without difficulty 
1 
   Able to finger to nose touch but difficult 
2 
   Unable to finger to nose touch 
   
   Not assessed 
   
   Not evaluable 
 
Sensation 
0 
   Normal 
1 
   Decreased but aware of sensory modality 
2 
   Unaware of sensory modality 
   
   Not assessed 
   
   Not evaluable 
 
Study #, Participant # and Initials:   ______________      ____________/____________ 
Date Assessment Performed (day/month/year):   ______________________________________ 
Study time point (i.e. cycle 1, day 1, etc.):  ___________________________________________ 
Visual Fields 
• 
Walking is ideally assessed by at least 10 steps 
• 
Test each limb separately 
• 
Recommend assess proximal (above knee or 
elbow) and distal (below knee or elbow) major 
muscle groups 
• 
Score should reflect worst performing area 
• 
Patients with baseline level 3 function in one 
major muscle group/limb can be scored based on 
assessment of other major muscle groups/limb 
• 
Non-evaluable if strength is compromised  
• 
Trunk/lower extremities assessed by gait domain  
• 
Particularly important for patients with 
brainstem and cerebellar tumors  
• 
Score based on best response of at least 3 
attempts 
• 
Recommend evaluating major body areas 
separately (face, limbs and trunk)  
• 
Score should reflect worst performing area 
• 
Sensory modality includes but not limited to light 
touch, pinprick, temperature and proprioception 
• 
Patients with baseline level 2 function in one 
major body area can be scored based on 
assessment of other major body areas 


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0 
   Normal 
1 
   Inconsistent or equivocal partial 
           hemianopsia (≥quadrantopsia) 
2 
   Consistent or unequivocal partial  
           hemianopsia (≥quadrantopsia) 
3 
   Complete hemianopsia 
   
   Not assessed 
   
   Not evaluable 
 
Facial Strength 
0 
   Normal 
1 
   Mild/moderate weakness 
2 
   Severe facial weakness 
   
   Not assessed 
   
   Not evaluable 
 
Language 
0 
   Normal 
1 
   Abnormal but easily conveys meaning  
to examiner 
2 
   Abnormal and difficulty conveying  
meaning to examiner 
3 
   Abnormal. If verbal, unable to convey  
          meaning to examiner. OR non-verbal  
          (mute/global aphasia) 
   
   Not assessed 
   
   Not evaluable 
 
Level of Consciousness 
0 
   Normal 
1 
   Drowsy (easily arousable) 
2 
   Somnolent (difficult to arouse) 
3 
   Unarousable/coma  
   
   Not assessed 
   
   Not evaluable 
 
Behavior 
0 
   Normal 
1 
   Mild/moderate alteration 
2 
   Severe alteration 
   
   Not assessed 
   
   Not evaluable 
 
 
• 
Patients who require corrective lenses should be 
evaluated while wearing corrective lenses  
• 
Each eye should be evaluated and score should 
reflect the worst performing eye  
• 
Particularly important for brainstem tumors 
• 
Weakness includes nasolabial fold flattening, 
asymmetric smile and difficulty elevating 
• 
Assess based on spoken speech. Non-verbal cues 
or writing should not be included. 
• 
Level 1: Includes word finding difficulty; few 
paraphrasic errors/neologisms/word 
substitutions;  but able to form sentences 
(full/broken) 
• 
Level 2: Includes inability to form sentences (<4 
words per phrase/sentence); limited word 
output; fluent but “empty” speech. 
• 
None  
• 
Particularly important for frontal lobe tumors 
• 
Alteration includes but is not limited to apathy, 
disinhibition and confusion 
• 
Consider subclinical seizures for significant 
alteration 


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APPENDIX C 
Functional Assessment of Cancer Therapy-Brain 4.0 (FACT-Br)  
 


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Refer to: www.facit.org 
 
 


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APPENDIX D 
TTFields Compliance Reports Generated by NovoTTF200A (OptuneTM) 
Panels show example graphs of compliance: Top = Low compliance; Middle = Compliance near 
goal; Bottom = Compliance above goal of 75%. The report also includes the number of days 
included, which allows calculation of weighted averages across the duration of TTFields therapy. 
 


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APPENDIX E 
Toxicity Management Algorithms for Nivolumab 
(Appendix 3 of Investigator Brochure BMS-936558/MDX1106/ONO-4538) 
 
 
 


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APPENDIX F 
Toxicity Management Algorithms for Ipilimumab 
(Appendix 3 of Investigator Brochure BMS-734016/MDX-010) 
 
 


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