Clinical trial NCT03493932
Conditions: Glioblastoma
Keywords: Glioblastoma Glioma Brain Tumor Immune Therapy Checkpoint Inhibition
Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)
Start date: 2018-09-24; Completion date: 2023-06-27
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

Glioblastoma (GBM) brain tumors almost always return after treatment. When that happens the tumor can never completely be removed by surgery, so most people also receive drugs. Researchers want to see if combining the drugs nivolumab and BMS-986016 may help.

Objectives:

To study how nivolumab affects the brain s immune system in people who have had glioblastoma brain tumors return. To study how nivolumab and BMS-986016 affect brain tumors.

Eligibility:

Adults age 18 and older who have had a return of GBM

Design:

Participants will be screened with:

Medical history

Physical exam

Cheek swab

Heart, blood and urine tests

Chest x-ray

Magnetic resonance imaging (MRI) brain scan. Participants will lie on a table that slides in and out of a cylinder in a strong magnetic field. A contrast agent will be injected in an arm vein.

Participants will stay in the hospital. They will:

Have surgery. A tube will be inserted into the back. Brain tumor and bone marrow samples will be taken. Tubes will be inserted into the brain.

Have a computed tomography brain scan.

Stay in Intensive Care (ICU) 7 days. Fluid from the brain and back will be collected every few hours. In the ICU, participants will get nivolumab by IV for 30 minutes.

Have surgery to remove the tubes.

Have standard surgery to remove as much of the GBM as possible. Bone marrow will be removed.

After leaving the hospital, participants will have visits every 2 weeks to get the study drugs by IV and have physical exams and blood tests.

Participants will have a brain MRI once a month.

...

Detailed description:
Objective

This protocol is being performed to 1) characterize the clinical and 2) immunological response of patients with recurrent glioblastoma to treatment with Nivolumab, together with an anti-Lag-3 antibody, BMS-986016, and to evaluate the safety of brain tumor microdialysis in this patient population.

Study Population

10 patients (total, after replacement for any dropout), 18 years old and older with recurrence of glioblastoma after standard treatment of surgery, chemotherapy, and radiation.

Study Design

Patients will be screened by study neurosurgeons or neuro-oncologists to verify their confirmed or likely diagnosis of a recurrent glioblastoma. Patients will be offered standard of care therapy, including repeat surgery and/or recommendations for chemotherapeutic agents and other trials. If the patients are deemed to be surgical candidates for their potential recurrence, they will be enrolled in the trial. Enrolled patients will then undergo a stereotactic brain biopsy. If a frozen section confirms a diagnosis of recurrent glioblastoma, two microdialysis catheters will be placed in the brain after the biopsy, and a lumbar drain will also be placed. These microdialysis catheters will sample interstitial fluid in and around the brain tumor every 6 hours. We will collect blood and cerebral spinal fluid samples daily for comparison. After two days (Day 3), the patients will be given one dose of Nivolumab, 240mg IV. We will continue to collect samples every six hours from the microdialysis catheters and daily from blood and cerebral spinal fluid for 5 additional days, after which patients will undergo surgical resection of their tumors and removal of the microdialysis catheters and lumbar drain. Nivolumab, at a dose of 240mg IV over 30 minutes every 2 weeks, will be administered after surgery (starting on Day 17(+/- 2 days), two weeks after the first dose on Day 3) followed by BMS 986016, an anti-Lag-3 antibody at a dose of 80mg IV over 60 minutes, until the study neuroradiologist notes tumor progression on MRI or the patient experiences treatment toxicity. While on therapy with Nivolumab and BMS-986016, patients will be seen and examined every 2 weeks +/- two days for signs of toxicity. Patients will be followed for at least three months after the surgical procedure.

Outcome Measures

The primary outcome measures are the proportion of patients who have a measurable increase of interferon gamma levels in the brain tumor tissue after their first dose of Nivolumab as compared to the pre-treatment baseline, the safety of using brain tumor microdialysis to monitor response to immune modulators in patients with recurrent glioblastoma and the safety of the combination of Nivolumab and BMS-986016. Exploratory outcome measures include: 1) To determine the change in interferon gamma production within the tumor microenvironment and in the rest of the body from before and after therapy with the immune checkpoint inhibitor, nivolumab; 2) To evaluate the pathological response of the immune microenvironment of brain tumor tissue to the first dose of Nivolumab; 3) To evaluate the clinical response (progression free survival, overall survival) of recurrent glioblastoma patients to this treatment combination; 4) To describe the difference in survival between responders and non-responders on this treatment combination; 5) To examine the differences in the immune cells and secreted factors of the tumor environment as compared to the immune cells and secreted factors of the cerebral spinal fluid, blood and, potentially, bone marrow in response to this treatment.

Arms: arm 1: Recurrent Glioblastoma patients
Interventions: intervention 1: Nivolumab intervention 2: BMS-986016
Intervention descriptions: intervention 1: OPDIVO is a human programmed death receptor-1 (PD-1) blocking antibody indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. intervention 2: Anti-Lymphocyte Activation Gene-3 antibody undergoing clinical evaluation by Bristol-Myers Squibb

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated Title: Cytokine Microdialysis 
Version Date: 02/25/2023 
 
 
 1
Abbreviated Title: Cytokine Microdialysis 
 
NIH IRB #: 18N0077 
 
Version Date: 02/25/2023 
 
Title: Cytokine microdialysis for real time immune monitoring in glioblastoma patients 
undergoing checkpoint blockade 
 
NIH Principal Investigator: Sadhana Jackson, M.D. 
Surgical Neurology Branch 
National Institute of Neurological Disorders and Stroke 
Building 10, Rm 7D45 
9000 Rockville Pike 
Bethesda, MD 20892 
Phone: 301-496-2921 
E-mail: sadhana.jackson@nih.gov  
Investigational Agents: 
 
Drug Name: 
Nivolumab (BMS-936558) 
IND Number: 
136039 
Sponsor: 
NINDS 
Manufacturer: 
Bristol-Myers Squibb (BMS) 
 
Drug Name: 
Anti-LAG-3 (BMS-986016) 
IND Number: 
136039 
Sponsor: 
NINDS 
Manufacturer: 
Bristol-Myers Squibb (BMS) 
 
Multi-Institutional Protocol Coordinating Center: National Institute of Neurological 
Disorders and Stroke 
 
18N0077 Safety Monitoring Committee Chair (NIHCC): Russell Lonsor, MD 
18N0077 Data and Safety Monitoring Board Chair (Emory University): William 
Theodore, MD 
 
Multi-Institutional Protocol Sites: 
 
Name: 
NIHCC 
Lead 
Investigator: 
Sadhana Jackson, MD 
IRB of Record NIH IRBO 
 


Abbreviated Title: Cytokine Microdialysis 
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Name: 
Emory University Hospital 
Lead 
Investigator: 
Edjah Nduom, MD 
IRB of Record Emory University 
Institutional Review Board 
 
 
 
 


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Précis: 
 
Objective  
 
This protocol is being performed to 1) characterize the clinical and 2) immunological 
response of patients with recurrent glioblastoma to treatment with Nivolumab, together 
with an anti-Lag-3 antibody, BMS-986016, and to evaluate the safety of brain tumor 
microdialysis in this patient population. 
 
Study Population   
 
10 patients (total, after replacement for any dropout), 18 years old and older with 
recurrence of glioblastoma after standard treatment of surgery, chemotherapy, and 
radiation. 
 
Study Design   
 
Patients will be screened by study neurosurgeons or neuro-oncologists to verify their 
confirmed or likely diagnosis of a recurrent glioblastoma. Patients will be offered 
standard of care therapy, including repeat surgery and/or recommendations for 
chemotherapeutic agents and other trials. If the patients are deemed to be surgical 
candidates for their potential recurrence, they will be enrolled in the trial. Enrolled 
patients will then undergo a stereotactic brain biopsy. If a frozen section confirms a 
diagnosis of recurrent glioblastoma, two microdialysis catheters will be placed in the 
brain after the biopsy, and a lumbar drain will also be placed. These microdialysis 
catheters will sample interstitial fluid in and around the brain tumor every 6 hours. We 
will collect blood and cerebral spinal fluid samples daily for comparison. After two days 
(Day 3), the patients will be given one dose of Nivolumab, 240mg IV. We will continue 
to collect samples every six hours from the microdialysis catheters and daily from blood 
and cerebral spinal fluid for 5 additional days, after which patients will undergo surgical 
resection of their tumors and removal of the microdialysis catheters and lumbar drain. 
Nivolumab, at a dose of 240mg IV over 30 minutes every 2 weeks, will be administered 
after surgery (starting on Day 17 (+/- 2 days), two weeks after the first dose on Day 3) 
followed by BMS 986016, an anti-Lag-3 antibody at a dose of 80mg IV over 60 minutes, 
until the study neuroradiologist notes tumor progression on MRI or the patient 
experiences treatment toxicity. While on therapy with Nivolumab and BMS-986016, 
patients will be seen and examined every 2 weeks +/- two days for signs of toxicity. 
Patients will be followed for at least three months after the surgical procedure.  
     
Outcome Measures   
 
The primary outcome measures are the proportion of patients who have a measurable 
increase of interferon gamma levels in the brain tumor tissue after their first dose of 
Nivolumab as compared to the pre-treatment baseline, the safety of using brain tumor 
microdialysis to monitor response to immune modulators in patients with recurrent 


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glioblastoma and the safety of the combination of Nivolumab and BMS-986016. 
Exploratory outcome measures include:  
1) To determine the change in interferon gamma production within the tumor 
microenvironment and in the rest of the body from before and after therapy with the 
immune checkpoint inhibitor, nivolumab; 2) To evaluate the pathological response of the 
immune microenvironment of brain tumor tissue to the first dose of Nivolumab; 3) To 
evaluate the clinical response (progression free survival, overall survival) of recurrent 
glioblastoma patients to this treatment combination; 4) To describe the difference in 
survival between responders and non-responders on this treatment combination; 5) To 
examine the differences in the immune cells and secreted factors of the tumor 
environment as compared to the immune cells and secreted factors of the cerebral spinal 
fluid, blood and, potentially, bone marrow in response to this treatment. 
 
 
 
 


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Table of Contents 
Précis ............................................................................................................................... 3 
List of Abbreviations ............................................................................................................................................ 10 
1.0 Introduction ..................................................................................................................................................... 12 
1.1 Purpose of the Project and Scientific Justification ................................................. 12 
1.2 Standard of care for recurrent glioblastoma patients .............................................. 12 
1.3 Immune therapy – Background ............................................................................... 13 
1.4 Checkpoint inhibition in glioblastoma patients ...................................................... 13 
1.5 
Pharmacology of Nivolumab ............................................................................ 16 
1.6 
Pharmacology of BMS-986016 ........................................................................ 23 
Table 2: Physical and Chemical Properties of BMS-986016 Drug Substance ............................... 24 
1.7 Microdialysis for cytokines..................................................................................... 29 
1.8 Conclusion .............................................................................................................. 30 
2.0 Study Objectives ............................................................................................................................................. 32 
2.1 Primary Goal ........................................................................................................... 32 
2.2 Exploratory Goals ................................................................................................... 32 
3.0 Subjects .............................................................................................................................................................. 32 
3.1 Description of study populations ............................................................................ 32 
3.2 Inclusion Criteria .................................................................................................... 33 
3.3 Exclusion Criteria ................................................................................................... 33 
4.0 Study Design and Methods ......................................................................................................................... 34 
4.1 Study Overview ...................................................................................................... 34 
4.2 Recruitment ............................................................................................................. 35 
4.3 Screening Methods.................................................................................................. 35 
4.4 Study Design ........................................................................................................... 36 
4.5 Study Procedures .................................................................................................... 36 
4.5.1 Summary of Research Procedures (Study Phase 1) ............................................. 36 
4.5.2 Summary of Clinical Care Procedures and follow up (Study Phase 2): .............. 37 
4.5.3 History, Physical Examination, and Neurological Examination (Research and 
Clinical Care) ................................................................................................................ 37 
4.5.4 Pregnancy testing (Research) ............................................................................... 38 
4.5.5 
Blood drawing (Research and Clinical Care) ............................................... 38 
4.5.6 
Electrocardiography (ECG/EKG) ................................................................. 38 
4.5.7 
Echocardiogram ............................................................................................ 38 


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4.5.8 
Chest X-ray (Clinical care) ........................................................................... 38 
4.5.9 
Structural MRI (Magnetic Resonance Imaging) (clinical care and research)39 
4.5.10 
Research surgical procedure (Research) ....................................................... 40 
4.5.10.1 
Lumbar drain placement (Research) ......................................................... 40 
4.5.10.2 
Lumbar puncture (Research) ..................................................................... 40 
4.5.10.3 
Bone Marrow Examination (Research) .................................................... 40 
4.5.10.4 
Stereotactic biopsy (Research) .................................................................. 41 
4.5.10.5 
Microdialyis catheter placement (Research) ............................................. 41 
4.5.11 
Computer-assisted Tomography (CT) Scan (Research) ............................... 42 
4.5.12 
Microdialysis sample retrieval (Research) .................................................... 42 
4.5.13 
CSF Sample retrieval (Research) .................................................................. 42 
4.5.14 
Nivolumab (Research) .................................................................................. 42 
4.5.15 
Anti-LAG-3 antibody, BMS-986016 (Research) ......................................... 43 
4.5.16 
Surgical Treatment and Post-operative care (Clinical Care) ........................ 43 
4.5.17 
Repeat Bone Marrow Examination (Research) ............................................ 44 
4.5.18 
Surgical specimens (Research and Clinical Care) ........................................ 44 
4.5.19 
Follow-up (Research) .................................................................................... 44 
4.5.20 
Other treatments for glioblastoma and concurrent medications (Clinical care)
 
46 
4.6 
Emory University Hospital Site ........................................................................ 46 
4.7 
End of participation ........................................................................................... 47 
5 
Management of Data and Samples .................................................................................................. 47 
5.1 
Sample Storage ................................................................................................. 48 
5.2 
Research Data ................................................................................................... 48 
5.3 
Data and sample sharing plan ........................................................................... 48 
6 
FDA Considerations .............................................................................................................................. 49 
6.1 
IND Status ......................................................................................................... 49 
6.2 
Microdialysis catheter FDA status .................................................................... 49 
7.0 
Risks and Discomforts ......................................................................................................................... 51 
7.1 
History, Physical Examination, and Neurological Examination ...................... 51 
7.2 
Pregnancy testing .............................................................................................. 51 
7.3 
Risks of Blood Drawing.................................................................................... 51 
7.4 
Electrocardiography (ECG/EKG) ..................................................................... 51 
7.5 
Chest X-ray ....................................................................................................... 51 


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7.6 
Echocardiogram ................................................................................................ 51 
7.7 
Risks of Magnetic Resonance Imaging (MRI) ................................................. 51 
7.8 
Risks of anesthesia for the research surgical procedure ................................... 53 
7.9 
Risks of Cerebral Microdialysis catheter placement ........................................ 53 
7.10 
Risks of Lumbar Drain Placement .................................................................... 54 
7.11 
Risks of Lumbar Puncture ................................................................................ 54 
7.12 
Risks of Bone Marrow Examination................................................................. 54 
7.13 
Risks of Computer-assisted Tomography (CT) Scan ....................................... 54 
7.14 
Risks of Microdialysis sample retrieval and prolonged microdialysis catheter 
implantation .................................................................................................................. 54 
7.15 
Risks of CSF sample retrieval and prolonged lumbar drainage ....................... 54 
7.16 
Risks of Nivolumab .......................................................................................... 55 
7.17 
Summary of risks of BMS-986016 monotherapy and combination of BMS-
986016 and nivolumab .................................................................................................. 57 
7.17.1 Summary of Safety ........................................................................................ 57 
7.17.1.2 Potential Risk Associated with Relatlimab Monotherapy or in Combination 
with Nivolumab ........................................................................................................ 58 
7.17.1.2.1 Immune-mediated Adverse Events .......................................................... 58 
7.17.1.2.2 Neurotoxicity ........................................................................................... 59 
7.17.1.2.3 Potential Infusion Reaction and Cytokine Release .................................. 59 
7.17.1.2.4 Opportunistic Infections Due to Immunosuppression ............................. 60 
7.17.1.3 Cardiovascular Events ................................................................................ 60 
7.17.1.4 Other ........................................................................................................... 61 
7.18 
Risks of Surgery for Tumor Resection—Standard Care................................... 61 
8.0 
Subject Safety Monitoring .................................................................................................................. 61 
8.1 Parameters to be monitored .................................................................................... 61 
8.1.1 Study Monitoring Phase 1 – Before surgical resection ........................................ 62 
8.1.2 Study Monitoring Phase 2-Surgical Resection and follow-up period: ................ 64 
8.2 Toxicity Criteria ...................................................................................................... 66 
8.3 Pregnancy ................................................................................................................ 66 
8.4 Overdose ................................................................................................................. 66 
8.5 Other Safety Considerations ................................................................................... 66 
8.6 Criteria for Individual Subject Withdrawal from the Study ................................... 66 
9.0 Outcome Measures ........................................................................................................................................ 68 


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9.1 Primary outcome measure ....................................................................................... 68 
9.2 Exploratory outcome measures ............................................................................... 68 
10.0 Statistical Analysis ...................................................................................................................................... 69 
10.1 Data analysis ......................................................................................................... 69 
10.2 Power analysis ...................................................................................................... 70 
11.0 Human Subjects Protection ..................................................................................................................... 71 
11.1 Subject Selection ................................................................................................... 71 
11.2 Justification for exclusion of participants less than 18 years old.......................... 71 
11.3 Justification for exclusion of other vulnerable subjects ........................................ 71 
11.4 Safeguards for vulnerable populations and sensitive procedures ......................... 72 
12.0 Anticipated Benefit ..................................................................................................................................... 73 
12.1 Overall risk and benefit consideration .................................................................. 73 
13.0 Consent Documents and Process .......................................................................................................... 74 
13.1 Designation of those obtaining consent ................................................................ 74 
13.2 Consent procedures ............................................................................................... 74 
13.3 Consent documents ............................................................................................... 75 
14.0 
Data and Safety Monitoring ............................................................................................................... 75 
14.1 Data and safety monitor ........................................................................................ 75 
14.2 Data and safety monitoring plan ........................................................................... 76 
14.3 Criteria for stopping the study or suspending enrollment or procedures .............. 77 
15.0 Quality Assurance ........................................................................................................................................ 77 
15.1  Quality Assurance Monitor .................................................................................. 78 
15.2  Quality Assurance Plan ........................................................................................ 78 
16.0  
Reporting of Unanticipated Problems, Adverse Events and Protocol Deviations ...... 78 
16.1 FDA Reporting Criteria ........................................................................................ 78 
16.2 Reporting of protocol deviations .......................................................................... 79 
17.0 Alternative Therapies ................................................................................................................................ 80 
18.0 Privacy .............................................................................................................................................................. 80 
19.0 Confidentiality .............................................................................................................................................. 80 
20.0 Conflict of Interest ....................................................................................................................................... 81 
21.0 Technology Transfer .................................................................................................................................. 81 
22.0 Research and Travel Compensation .................................................................................................... 81 
23.0 Definition of Primary and Secondary Data ....................................................................................... 81 


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24.0 References ...................................................................................................................................................... 83 
25.0 Study Calendar .............................................................................................................................................. 86 
26.0 Consent Forms .............................................................................................................................................. 87 
27.0 Eligibility Checklist ..................................................................................................................................... 87 
Appendix A: Bristol-Myers Squibb Adverse Event Reporting: ........................................................... 90 
APPENDIX C: INVESTIGATOR BROCHURE FOR RELATLIMAB (BMS-986016) ........................... 94 
Appendix D: Serious Adverse Reactions in Patients Treated with Relatlimab in Combination 
with Nivolumab ...................................................................................................................................................... 95 
APPENDIX E: KARNOFSKY PERFORMANCE STATUS ............................................................................. 97 
APPENDIX F: SOCIAL MEDIA LANGUAGE ................................................................................................... 97 
 
 
 


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List of Abbreviations  
AE 
 
Adverse Events 
ALT 
 
Alanine Transaminase 
ANOVA 
Analysis of Variance 
AST 
 
Aspartate Transaminase 
AT 
 
Aminotransferase 
BMS  
Bristol-Myers Squibb 
CD3,4, 8 
Cluster of Differentiation 3, 4, 8, etc 
CL 
 
Confidence Limits 
CNS 
 
Central nervous system 
CRFs  
Case Report Forms 
CSF 
 
Cerebral Spinal Fluid 
CT 
 
Computer-assisted Tomography 
CTLA-4 
Cytotoxic T-Lymphocyte Associated protein 4 
DILI  
Drug Induced Liver Injury 
DoH 
 
Declaration of Helinski 
DPA  
Durable Power of Attorney 
DSMB  
Data and Safety Monitoring Board 
DTI 
 
Diffusion Tensor Imaging 
FDA  
Food and Drug Administration 
FOXP3 
Forkhead box P3 
FWA  
Federalwide Assurance 
GDS  
Genomic Data Sharing 
ICU 
 
Intensive Care Unit 
IFNg  
Interferon Gamma 
IL2 
 
Interleukin-2 
IMM  
Independent Medical Monitor 
IND 
 
Investigational New Drug 
IRB 
 
Institutional Review Board 
IV 
 
Intravenous 
LAG3  
lymphocyte activation gene 3 
MRI 
 
magnetic resonance imaging 
NCI 
 
National Cancer Institute 
NINDS 
National Institute of Neurological Disorders and Stroke 
NOB  
Neuro-Oncology Branch 
NPCU  
Neuroscience Patient Care Unit 
PD-1  
Programmed Death 1 
PD-L1  
Programmed Death Ligand 1 
PI 
 
Principle Investigator  
PRPL  
Patient Recruitment Public Liaison 
QA 
 
Quality Assurance 
RANO  
Response Assessment in Neuro-Oncology 
SAE 
 
Serious Adverse Event 
SMC  
Safety Monitoring Committee 
SNB 
 
Surgical Neurology Branch 
TGFB-2 
Transforming Growth Factor Beta-2 


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TNF   
Tumor Necrosis Factor 
ULN  
Upper Limit of Normal 
 


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1.0 Introduction 
  
1.1 Purpose of the Project and Scientific Justification 
This protocol is a pilot study being performed to 1) determine the response of the brain’s 
immune system to treatment with Nivolumab in patients that have a recurrence of the 
glioblastoma 2) Determine the safety of the use of Nivolumab together with an anti-Lag-
3 antibody, BMS-986016 , in recurrent glioblastoma patients 3) determine the difference 
in response between the brain and the peripheral immune system to this drug 4) evaluate 
the response of recurrent glioblastoma patients to this combination treatment 5) 
determine whether immune factors will predict whether a patient will respond to this 
immune treatment 6) examine the differences in the immune cells and secreted factors of 
the tumor environment as compared to the immune cells and secreted factors of the 
cerebral spinal fluid, blood and, potentially, bone marrow 7) evaluate the safety of using 
brain tumor microdialysis to monitor response to immune modulators in patients with 
recurrent glioblastoma. 
 
1.2 Standard of care for recurrent glioblastoma patients 
Glioblastoma is the most common primary malignancy of the brain, and the prognosis 
with conventional therapy is poor, with a median survival of only 14.6 months after 
standard chemotherapy and radiation[1]. After the recent failure of bevacizumab to show 
consistent efficacy in trials while treating recurrent glioblastoma, there is no established 
standard of care for these patients[2]. The Joint Tumor Section of the American 
Association of Neurological Surgeons and Congress of Neurological Surgeons has 
attempted to compile guidelines for the treatment of recurrent or progressive 
glioblastoma. Per their guidelines, there is Level II evidence to support cytoreductive 
surgery in such patients as planned in this trial[3]. There is only Level III evidence to 
support radiotherapy in selected patients for local control when the target tumor is 
amenable for additional radiotherapy[4]. As such, at the time of recurrence, clinical trials 
often represent the best treatment option for a recurrent glioblastoma patient. For 
chemotherapeutic agents, there is level II evidence for the use of temozolomide when the 
patient did not receive temozolomide at initial diagnosis[5]. This is increasingly rare, as 
temozolomide has been established as standard of care for newly diagnosed glioblastoma 
patients. The committee has also supported the use of use of BCNU-impregnated wafers 
as a surgical adjunct in selected patients who undergo surgical resection with Level II 
evidence. These wafers, implanted into the resection cavity of glioblastoma patients, were 
approved by the FDA after a study showed that median survival was 31 weeks after 
implantation, but the placebo arm received no therapy other than placebo wafers[6]. 
Furthermore, the drug was approved prior to the establishment of temozolomide as 
standard of care, and further studies have shown significant side effects from the use of 
these wafers, without significant increases in survival, and as such, they are not currently 
widely used[7]. Bevacizumab has also been approved by the FDA for treatment of 
recurrent glioblastoma patients. However, recently, a large European trial showed that 
this treatment does not appear to be effective in increasing overall survival in recurrent 
glioma patients, and as such, there no longer is consensus that this is the best treatment 
for patients at recurrence[2]. Given the lack of high quality evidence for any treatment for 


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recurrent glioblastoma patients, there is not any strong recommendation for one 
established therapy for recurrent glioblastoma patients. The committee presented a 
recommendation that clinical trials be considered for recurrent glioblastoma patients, 
after individual patient characteristics have been taken into account.  
 
1.3 Immune therapy – Background 
The immune system constantly samples and interrogates the cells of the body to detect 
abnormal proteins associated with neoplastic transformation, which mark the neoplastic 
cells for destruction. When it is working well, immune surveillance keeps neoplastic 
processes at bay, whereas impaired immune function can enhance the risk of tumor 
development. For this reason, immune therapy has been attractive for treating cancerous 
processes, going back to Coley’s toxin[8], a mixture of killed bacteria employed in 1893 
as a vaccine to exploit a previously observed relationship between infection and cancer 
regression. Despite the initial enthusiasm and theoretical promise, immune therapy for 
cancer has largely been pushed to the wayside by chemotherapy and radiation until 
recently. 
 
Many years of study into the microenvironment of malignant tumors has shown that 
many of these lesions produce immunosuppressive factors that keep the immune system 
in check and unable to detect the tumor, allowing these lesions to continue to proliferate 
unchecked[9]. This occurs even though many of these lesions evoke an inflammatory 
influx of immune cells[10]. To enhance immune responses to malignant tumors, 
investigators have recently developed monoclonal antibodies that target and inactivate 
immunosuppressive pathways.  
 
Programmed Death 1 (PD-1) is a T cell surface immunosuppressive receptor; it is 
activated by Programmed Death Ligand 1 and 2 (PD-L1 and PD-L2)[11]. PD-L1 is 
upregulated in the tumor microenvironment of many tumors, and engagement of this 
ligand with its receptor, PD-1, reduces the cellular immune response within the tumor 
microenvironment[11]. Previously, immune therapy employing autologous killer T-cells 
stimulated with interleukin 2 (IL2) resulted in tumor regression in some patients 
undergoing this very taxing therapy of metastatic melanoma[12]. More recently, targeting 
of the immunosuppressive checkpoint, PD-1, has provided initial evidence that immune 
therapy could be applied more broadly to other cancers. Nivolumab, a monoclonal 
antibody targeting PD-1 was found to be efficacious and approved[13] for advanced 
melanoma, as was Pembrolizumab, another PD-1 inhibitor[14]. Lymphocyte Activation 
Gene 3 (LAG-3) is another checkpoint present on activated T cells (Figure 1) [15]. LAG-
3 and PD-1 are co-expressed on the surface of tumor infiltrating T-cells in ovarian cancer 
patients, and denote poorly functional CD8+ T effector cells[16]. The efficacy of single 
agent checkpoint inhibition may be limited by compensatory upregulation of other 
checkpoints, and this may be overcome by using combinations of checkpoint 
inhibitors[17].  
 
1.4 Checkpoint inhibition in glioblastoma patients 
 


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One immunosuppressive factor, Transforming Growth Factor Beta-2 (TGFB-2) was first 
identified in lysates of glioblastoma tissues, and since then, many immunosuppressive 
factors have been identified within the glioblastoma microenvironment[9, 18, 19]. While 
there was once a concept of immune privilege in the brain, meaning that the immune 
system lacked effective immune surveillance due to the blood brain barrier and absence 
of clearly identified lymphatic channels, subsequent studies have shown this to be 
false[20, 21]. The brain has numerous cells engaged in constant immune surveillance, 
and there is widespread belief that these checkpoint inhibitors, Nivolumab and 
Ipilimumab, could target immunosuppression in the glioblastoma microenvironment, just 
as they have done in other systemic tumors. Preclinical models have supported this 
argument, with murine anti-CTLA-4 antibodies showing a significant treatment effect 
and numerous long-term survivors in an aggressive immune-competent murine glioma 
model system[22]. Anti PD-1 and PD-L1 antibodies were shown to be similarly 
effective[23, 24].  
The successes of these therapeutics are not guaranteed in the human brain for numerous 
reasons. The murine immune system and the human immune system are very different, 
with different cytokine profiles and dynamics for cell infiltration and inflammation. 
There has been a suggestion in some cancers that PD-L1 expression on the native tumor 
is correlated with response to checkpoint inhibitor therapy[25], but unlike common 
glioma cell lines used in preclinical models, the expression of PD-L1 in the glioma 
microenvironment is heterogeneous and may not be as robust as once reported[26]. 
Beyond this, even in the successful trials of these inhibitors, these treatments seem to 
only be effective in a small subset of patients, and these treatments can cause widespread 
systemic inflammation, causing several side effects, many of them severe[27]. Systemic 
immunophenotyping in checkpoint inhibitor trials in other cancers has thus far yielded 
data of limited value in the glioblastoma population[28]. No clear predictors of response 
to these checkpoint inhibitors in systemic cancers have been identified. Furthermore, 
while we know that immune cells can infiltrate the glioblastoma microenvironment, we 
do not know whether systemic immune stimulation from checkpoint inhibitors will 
translate to a response in the immune cells that traffic to glioblastoma microenvironment. 
To understand the role systemic checkpoint inhibitors could play in glioblastoma therapy, 
research needs to be conducted to quickly and accurately determine if systemically-
administered checkpoint inhibitors reach the brain tumor, immediately impact the tumor 
microenvironment, and evoke a therapeutic anti-tumor immune effect.  This research 
could provide data that would predict if checkpoint inhibitor immunotherapy could be 
developed as a standard therapy for glioblastoma or whether we need to focus our 
resources elsewhere. Such due diligence of early evaluation of the therapeutic potential of 
a new glioblastoma therapy is particularly important in light of the recent failed trials for 
rindopepimut, a vaccine targeted at the epidermal growth factor variant III, in newly 
diagnosed patients (data not yet published), which showed great initial promise in a Phase 
II study[29]. A recent presentation at the American Association of Neurological Surgeons 
(AANS) 2016 Annual Meeting demonstrated that treatment of patients with recurrent 
glioblastoma with ipilimumab, or the combination of ipilimumab and nivolumab, resulted 
in nearly equivalent overall survival of two cohorts of 10 patients. Significantly more side 
effects were seen in the ipilimumab and nivolumab arm compared to the nivolumab-alone 
arm. A more recent presentation of the results of the Checkmate 143 trial at the 2017 


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World Federation of Neuro-Oncology Societies meeting demonstrated that Nivolumab 
did not show efficacy as a single agent in recurrent glioblastoma patients as compared to 
bevacizumab. While the treatment as a single agent may have been effective in certain 
patient subsets, preclinical data suggests that a combination of anti-PD-1 and BMS-
986016  may be more efficacious in cancer models (unpublished BMS data, Table 1, 
Appendix C), and this approach is currently undergoing Phase I testing in glioblastoma 
(NCT02658981). As such, we believe that this drug combination has the potential to 
confer additional benefit to our patients, improving the risk/benefit ratio of the study. 
Both drugs are being provided for this study by the manufacturer, Bristol-Myers Squibb, 
at no cost. 
 
Figure 1. Model for Augmented T-cell Activity Mediated by Inhibition of LAG-3 
and PD-1 (BMS-986016 Investigator Brochure, Appendix C) 
 


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Table 1: Number of Tumor-free Mice at End of Study by Treatment Group: MC38 Tumor 
Model Studies (BMS-986016 Investigator Brochure, Appendix C) 
 
1.5 Pharmacology of Nivolumab 
1.5.1 Introduction 
 
 
Nivolumab (also referred to as Opdivo, BMS-936558, MDX1106, or ONO-4538) is a 
human monoclonal antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) 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. 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. 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 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. 
 
Nivolumab has been shown to bind specifically to the human PD-1 receptor and not to 
related members of the CD28 family. Nivolumab inhibits the interaction of PD-1 with its 
ligands, PD-L1 and PD-L2, resulting in enhanced T-cell proliferation and interferon-
gamma (IFN-γ) release in vitro. Nivolumab binds with high affinity to activated human 
T-cells expressing cell surface PD-1 and to cynomolgus monkey PD-1. In a mixed 


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lymphocyte reaction (MLR), nivolumab promoted a reproducible concentration-
dependent enhancement of IFN-release. 
 
1.5.2  Non-clinical Studies 
 
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, nivolumab 
was well tolerated at doses up to 50 mg/kg, administered weekly for 5 weeks, and at 
doses up to 50 mg/kg, administered twice weekly for 27 doses.  While nivolumab alone 
was well tolerated in cynomolgus monkeys, combination studies have highlighted the 
potential for enhanced toxicity when combined with other immunostimulatory agents. 
 
In addition, an enhanced pre- and postnatal development (ePPND) study in pregnant 
cynomolgus monkeys with nivolumab was conducted. Administration of nivolumab at up 
to 50 mg/kg 2QW was well tolerated by pregnant monkeys; however, nivolumab was 
determined to be a selective developmental toxicant when administered from the period 
of organogenesis to parturition at 10 mg/kg (area under the concentration-time curve 
[AUC] from time zero to 168 hours [AUC(0-168 h)] 117,000g•h/mL). Specifically, 
increased developmental mortality  (including late gestational fetal losses and extreme 
prematurity  with  associated  neonatal mortality) was noted in the  absence  of  overt  
maternal  toxicity.  There  were  no nivolumab-related  changes  in surviving  infants  
tested  throughout  the  6-month  postnatal period. Although the cause of these pregnancy 
failures was undetermined, nivolumab-related effects on pregnancy maintenance  are 
consistent with the established role of PD-L1 in maintaining fetomaternal tolerance in 
mice. 
 
1.5.3  Effects in Humans 
 
The pharmacokinetics (PK), clinical activity, and safety of nivolumab have been assessed 
in subjects with non-small cell lung cancer (NSCLC), melanoma, clear-cell renal cell 
carcinoma (RCC), classical Hodgkin Lymphoma (cHL), urothelial carcinoma (UC), 
squamous cell carcinoma of the head and neck (SCCHN), in addition to other tumor 
types. The Investigator Brochure (IB) references the most recent US Prescribing 
Information (USPI) and EU Summary of Product Characteristics (SmPC) as the basis for 
the current state of knowledge on nivolumab for use treating cancer in humans.  
 
Nivolumab monotherapy is approved in multiple regions, including the US and EU, for 
unresectable or metastatic melanoma, previously treated metastatic NSCLC, previously 
treated advanced RCC, previously treated relapsed or refractory cHL, and previously 
treated advanced or metastatic UC; it is also approved for the treatment of previously 
treated recurrent or metastatic SCCHN in the US. In addition, nivolumab has been 
approved for use in combination with ipilimumab for unresectable melanoma in multiple 
countries, including the US and EU. 
Nivolumab is being investigated both as monotherapy and in combination with 
chemotherapy, targeted therapies, and other immunotherapies for the treatment of several 
types of cancer. Single- dose nivolumab monotherapy is also being investigated for the 
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focus primarily on data from clinical studies that are relevant to ongoing clinical 
investigations not in the approved USPI and SmPC (small cell lung cancer [SCLC]), 
gastric cancer, hepatocellular carcinoma [HCC], colorectal cancer [CRC], glioblastoma 
[nivolumab monotherapy], and Merkel cell carcinoma [MCC]; SCLC, gastric and 
esophageal cancers, NSCLC, RCC, and CRC [nivolumab combination therapy]; and Ono  
 
1.5.4 Nivolumab Drug Description, Prep and Storage Conditions 
 
Nivolumab, also referred to as BMS-936558-01 or BMS-936558, is a soluble protein 
consisting of 4 polypeptide chains, which include 2 identical heavy chains and 2 identical 
light chains. The physical and chemical properties of nivolumab are provided in Table 
3.1-1 of the Nivolumab Investigator’s brochure (included below). 
 
Drug Preparation 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) and 40 mg/4 mL (10 mg/mL) 
Vials of nivolumab injection must be stored at 2°C to 8°C (36°F to 46°F) and protected 
from light and freezing. 
 
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-
micron pore size, low-protein binding (polyethersulfone membrane) in-line filter at the 
protocol-specified doses and infusion times. It is not to be administered as an IV push or 
bolus injection. When the dose is based on patient weight (ie, mg/kg), nivolumab 
injection can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride 
Injection, USP or 5% Dextrose Injection, USP to protein concentrations as low as 0.35 
mg/mL. When the dose is fixed (eg, 240 mg, 360 mg, or 480 mg flat dose), nivolumab 
injection can be infused undiluted or diluted so as not to exceed a total infusion volume 
of 120 mL. 
 
During drug product preparation and handling, vigorous mixing or shaking is to be 
avoided. Instructions for dilution and infusion of nivolumab injection may be provided in 
the clinical protocol, pharmacy binder, pharmacy manual, or pharmacy reference sheet. 
Care must be taken to assure sterility of the prepared solution as the product does not 
contain any antimicrobial preservative or bacteriostatic agent. Nivolumab infusions are 
compatible with polyvinyl chloride (PVC) or polyolefin containers and infusion sets, and 
glass bottles. 
 
Storage conditions 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) and 40 mg/4 mL (10 mg/mL) 


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Vials of nivolumab injection must be stored at 2°C to 8°C (36°F to 46°F) and protected from light 
and freezing. 
 
Undiluted Nivolumab Injection and Diluted Nivolumab Injection in the IV Container 
The administration of nivolumab infusion must be completed within 24 hours of preparation. If 
not used immediately, the infusion solution may be stored under refrigeration conditions (2°C to 
8°C, 36°F to 46°F) for up to 24 hours, and a maximum of 8 hours of the total 24 hours can be at 
room temperature (20°C to 25°C, 68°F to 77°F) and room light. The maximum of 8 hours under 
room temperature and room light conditions includes the product administration period. 
 
First Nivolumab dose preparation and administration 
Nivolumab will be administered first. As with all injectable drugs, care should be taken 
when handling and preparing Nivolumab.  Whenever possible, Nivolumab infusions 
should be prepared in a laminar flow hood, glovebox, or safety cabinet using standard 
procedures for the safe handling of intravenous agents applying aseptic techniques. 
Gloves are required. If nivolumab solution comes in contact with the skin or mucosa, 
immediately and thoroughly wash with soap and water. 
Visually inspect drug product solution for particulate matter and discoloration prior to 
administration. Nivolumab is a clear to opalescent, colorless to pale yellow solution. 
Discard the vial if the solution is cloudy, discolored, or contains extraneous particulate 
matter other than a few translucent-to-white, proteinaceous particles. Do not shake the 
vial. 
Preparation 
To prepare 240mg dose: 
1.  Withdraw the required volume of Nivolumab and transfer into a 50 mL 0.9% Sodium 
Chloride, USP or 5 % Dextrose for Injection, USP bag. Infusion final volume for flat 
dosing should not exceed 120 mL in total volume.  
2. Mix diluted solution by gentle inversion, do not shake. 
3. Discard partially used vials or empty vials of Nivolumab. 
Storage of Infusion 
The product does not contain a preservative. After preparation, store the 
Nivolumab infusion either: 
• at room temperature for no more than 8 hours from the time of 
preparation. This includes room temperature storage of the 
infusion in the IV container and time for administration of the 
infusion  
or 
• under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 
24 hours from the time of infusion preparation. 
Do not freeze. 


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Administration 
Administer the infusion over 30 minutes through an intravenous line containing a sterile, 
non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 
micrometer). Do not coadminister other drugs through the same intravenous line. Flush 
the intravenous line at end of infusion with appropriate amount of diluent (e.g. 15-
20 ml) to ensure that the total dose is administered. Total infusion and flush time 
should equal to 30 minutes.  
Nivolumab should not be infused concomitantly in the same intravenous line with other 
agents. No physical or biochemical compatibility studies have been conducted to evaluate 
the co-administration of Nivolumab with other agents. 
 
First Nivolumab dose infusion monitoring 
Monitoring for an infusion reaction and cytokine release on day 3 of the protocol will 
consist of clinical observation with q15 minute vital signs, including temperature, during 
and for the first hour after infusion. Specifically, we will be checking the patients for 
fever, chills, shakes, itching, rash, hypertension or hypotension or difficulty breathing 
during the administration or immediately afterwards (within the following 2 hours). The 
patients will be treated according to I-O AE Algorithms from Appendices B and C; 
Investigator Brochures for Nivolumab (BMS-936558) and Relatlimab (BMS-986016). 
Generally, Grade 1 infusion reactions will be observed. Grade 2 or 3 infusion reactions 
will prompt interruption of the patient’s infusion until the observed symptom returns to 
the level of a Grade 1 reaction. Patients will be given 25mg of Benadryl IV and 650 mg 
of Tylenol PO for any grade 2 or 3 reaction. The Benadryl can be repeated once for 
symptom resolution until the reaction returns to a level of Grade 1. If a patient has a 
Grade 2 or 3 reaction, subsequent infusions will be preceded by 25mg of Benadryl IV and 
650mg of Tylenol PO 30 minutes prior to dosing. Grade 4 reactions will cause 
discontinuation of the therapy. Please see section 1.6.5 for monitoring of combined 
infusions, below. 
 
1.5.5  Clinical Pharmacokinetics 
 
The Pharmacokinetics (PK) of nivolumab was studied in subjects with cancer over a dose 
range of 0.1 to 20 mg/kg administered as a single dose or as multiple doses of nivolumab 
every 2 or 3 weeks. Nivolumab clearance (CL) decreases over time, with a mean 
maximal reduction (% coefficient of variation [CV%]) from baseline values of 
approximately 24.5% (47.6%) resulting in a geometric mean steady state clearance 
(CLss) (CV%) of 8.2 mL/h (53.9%); the decrease in CLss is not considered clinically 
relevant. The geometric mean volume of distribution at steady state (Vss) was 6.8 L 
(27.3%), and geometric mean elimination half-life (t1/2) was 25 days (77.5%). Steady-
state concentrations of nivolumab were reached by 12 weeks when administered at 3 
mg/kg Q2W, and systemic accumulation was approximately 3.7-fold. The exposure to 
nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg 
administered every 2 weeks. Additionally, nivolumab has a low potential for drug-drug 
interactions. The clearance of nivolumab increased with increasing body weight. The 


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PPK analysis suggested that the following factors had no clinically important effect on 
the CL of nivolumab: age (29 to 87 years), gender, race, baseline LDH, PD-L1 status, 
solid tumor type, baseline tumor size, and hepatic impairment.  
 
Although ECOG status, baseline glomerular filtration rate (GFR), albumin, and body 
weight had an effect on nivolumab CL, the effect was not clinically meaningful. PPK 
analysis suggest that nivolumab CL in subjects with cHL was approximately 32% lower 
relative to subjects with NSCLC; however, the lower CL in cHL subjects was not 
considered to be clinically relevant as nivolumab exposure was not a significant predictor 
for safety risks for these patients. When nivolumab is administered in combination with 
ipilimumab, the CL of nivolumab was increased by 29%, whereas there was no effect on 
the clearance of ipilimumab. 
 
PPK and exposure response analyses have been performed to support use of nivolumab 
240 mg Q2W, 360 mg Q3W, and 480 mg Q4W dosing regimens in subjects with cancer 
in addition to the 3 mg/kg Q2W regimen. A flat dose of nivolumab 240 mg Q2W was 
selected since it is identical to a dose of 3 mg/kg for subjects weighing 80 kg, the 
observed median body weight in nivolumab- treated cancer patients, while the nivolumab 
360 mg Q3W and 480 mg Q4W regimens allow flexibility of dosing with less frequent 
visits and in combination with other agents using alternative dosing schedules to Q2W. 
Using a PPK model, the overall distributions of nivolumab exposures (Cavgss, Cminss, 
Cmaxss, and Cmin1) are comparable after treatment with either nivolumab 3 mg/kg or 
240 mg Q2W. Following nivolumab 360 mg Q3W and 480 mg Q4W, Cavgss are 
expected to be similar to those following nivolumab 3 mg/kg or 240 mg Q2W, while 
Cminss are predicted to be 6% and ~16% lower, respectively, and are not considered to 
be clinically relevant. Following nivolumab 360 mg Q3W and 480 mg Q4W, Cmaxss are 
predicted to be approximately ~23% and ~43% greater, respectively, relative to that 
following nivolumab 3 mg/kg Q2W dosing. However, the range of nivolumab exposures 
(median and 90% prediction intervals) following administration of 240 mg flat Q2W, 360 
mg Q3W, and 480 mg Q4W regimens across the 35 to 160 kg weight range are predicted 
to be maintained well below the corresponding exposures observed with the well 
tolerated 10 mg/kg nivolumab Q2W dosing regimen 
 
The PK of single-dose nivolumab monotherapy in subjects with sepsis is under 
evaluation; however, no data are currently available. 
 
Administration of nivolumab using a 30-minute infusion time has been evaluated in 
subjects with cancer. Previous clinical studies of nivolumab monotherapy for the 
treatment of cancer have used a 60-minute infusion duration wherein nivolumab has been 
safely administered up to 10 mg/kg over long treatment periods. Infusion reactions 
including high-grade hypersensitivity reactions have been uncommon across the 
nivolumab clinical program. In CA209010, a dose association was observed for infusion 
site reactions and hypersensitivity reactions (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg and 
18.5% at 10 mg/kg). All the events were Grade 1-2 and were manageable. An infusion 
duration of 30 minutes for 3 mg/kg nivolumab (30% of the dose provided at 10 mg/kg) is 
not expected to present any safety concerns compared to the prior experience at 10 mg/kg 


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nivolumab dose infused over a 60-minute duration. The safety of nivolumab 3 mg/kg 
administered as a 30-min infusion was assessed in CA209153 in patients (n=322) with 
previously treated advanced NSCLC. Overall, there were no clinically meaningful 
differences in the frequency of hypersensitivity/infusion-related reactions (of any cause 
or treatment-related) in cancer patients administered nivolumab over a 30-min infusion 
compared with that reported for patients with the 60-min infusion. Thus, it was shown 
that nivolumab can be safely infused over 30 min in subjects with cancer. 
 
 
1.5.6 Clinical Efficacy 
 
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy and 
in combination with ipilimumab in several tumor types, including NSCLC, melanoma, 
RCC, cHL, SCLC, gastric cancer, urothelial cancer, HCC, and CRC. In confirmatory 
trials, nivolumab as monotherapy demonstrated a statistically significant improvement in 
OS as compared with the current standard of care in subjects with advanced or metastatic 
NSCLC, unresectable or metastatic melanoma, advanced RCC, or SCCHN. Nivolumab in 
combination with ipilimumab improved PFS and ORR over ipilimumab alone in subjects 
with unresectable or metastatic melanoma. 
 
1.5.7  Clinical Safety 
 
The overall safety experience with nivolumab is based on experience in approximately 
23,507 subjects as either monotherapy or in combination with other therapeutics. In 
general, for monotherapy, the safety profile is similar across tumor types. The only 
exception is pulmonary inflammation AEs, which may be numerically greater in subjects 
with NSCLC, possibly because in some cases, it can be difficult to distinguish between 
nivolumab-related and unrelated causes of pulmonary symptoms and radiographic 
changes. The most frequently reported treatment-related AE is fatigue, which is almost 
always of low grade. 
 
Most related AEs are thought to be due to the effects of inflammatory cells on specific 
tissues. A variety of preferred terms (PTs) have been used to describe similar kinds of 
organ-related AEs, with the result being that AE frequency tables organized by PTs can 
lead to underestimation of the frequency of similar kinds of organ-related AEs. To 
address this issue, select AE categories were created. Select AE categories group together 
the most common and impactful PTs by organ category. These categories include the 
following: pulmonary, GI, hepatic, skin, endocrine, hypersensitivity/infusion reaction, 
and renal AEs. The frequency of select AE categories is provided in the sub-sections for 
individual indications in the investigator’s brochure. It is also useful to consider the 
management of nivolumab-related AEs by organ category as the diagnostic work-up 
often requires excluding other potential diagnoses and, when appropriate, instituting 
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1.6 Pharmacology of BMS-986016 
1.6.1  Introduction 
 
BMS-986016 is a human lymphocyte activation gene 3 (LAG-3)-specific antibody that is  
isolated after immunization of transgenic mice expressing human immunoglobulin (Ig) 
genes. BMS-986016 has been given the generic name of relatlimab. It is expressed as an 
IgG4 isotype antibody and includes a stabilizing hinge mutation (S228P). BMS-986016 
binds to LAG-3 with high affinity and inhibits the negative regulatory function of LAG-3 
in vitro. Binding of BMS-986016 to LAG-3 prevents binding of this receptor to cells 
bearing its ligand, major histocompatibility complex (MHC) Class II, the peptide antigen 
presentation molecule recognized by CD4+ T cells. By blocking the normal 
downregulatory pathway, BMS-986016 enhances the anti-tumor immune response and, 
thus, has the potential to inhibit the growth of multiple malignancies when administered as 
a single agent or in combination with other therapeutic immuno-oncology (IO) monoclonal 
antibodies. 
 
1.6.2  Nonclinical Characterization 
 
BMS-986016 binds to human (half maximal effective concentration [EC50] = 0.11 nM) 
and cynomolgus monkey (EC50 = 29.11 nM) LAG-3 but does not bind to mouse LAG-3. 
Using surrogate antibodies recognizing mouse LAG-3 (C9B7W and 19C7), anti-tumor 
activity has  been demonstrated in 3 murine syngeneic in vivo tumor models (Sa1N 
fibrosarcoma, MC38 colon adenocarcinoma, and A20 B-cell lymphoma). Both tumor 
inhibition and the number of tumor-free mice were increased by BMS-986016 
monotherapy, while the combination of BMS-986016 with a blocking anti-programmed 
cell death protein 1 (PD-1) antibody provided enhanced anti-tumor activity higher than the 
activity of either agent alone and higher than the activity of anti-cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) antibody in some subjects. 
 
In a repeat-dose study in monkeys, following weekly intravenous (IV) doses of BMS-
986016 monotherapy (30 and 100 mg/kg) or dosed in combination with nivolumab (100 
mg/kg of BMS-986016 and 50 mg/kg of nivolumab [an anti-PD-1 antibody]) for 4 weeks, 
the total serum clearance (CLT) of BMS-986016 was 0.12 mL/h/kg, and the elimination 
half-life (T-HALF) was 414 hours (estimated  by  population  pharmacokinetic  [PK]  
analysis  of  pooled  data  from  all 3 groups). There was no apparent PK drug-drug 
interaction between BMS-986016 and nivolumab. 
Based on the  BMS-986016  NOAEL  determined  from  the  GLP-compliant  toxicity  
study  (100 mg/kg/week IV), the maximum  IV  dose  provides  a  safety  multiple  of  
approximately  10 times for both the maximum observed concentration (Cmax) and 
AUC(0-336h) after the first 800-mg dose. Overall, the nonclinical toxicology assessment 
of BMS-986016 has demonstrated an acceptable profile, supporting its continued clinical 
use in humans. 
 
1.6.3 Effects in Humans 
 


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As of the clinical cutoff date of 29-Jun-2016, 89 subjects have been treated with BMS-
986016 in 2 ongoing studies assessing PK, clinical activity, and safety. The current Phase 
1 clinical program is evaluating advanced solid tumors (special focus in non-small cell lung 
cancer [NSCLC], renal cell carcinoma, and malignant melanoma) in Study CA224-020 and 
relapsed-refractory hematological malignancies (Hodgkin and non-Hodgkin lymphomas) 
in Study CA224-022. BMS-986016 is being investigated both as monotherapy and in 
combination with nivolumab. As of 29-Jun-2016, BMS-986016 monotherapy has been 
administered to 60 subjects, as follows: 8 subjects at 20 mg, 13 subjects at 80 mg, 24 
subjects at 240 mg, and 15 subjects at 800 mg, all receiving a flat dose on a biweekly (q2w) 
regimen. Twenty-two of these subjects were from Study CA224-020, and 38 subjects were 
from Study CA224-022. As of 29-Jun-2016, combination therapy with BMS-986016 and 
nivolumab has been administered to 29 subjects, as follows: 7 subjects at 20 mg BMS-
986016/80 mg nivolumab and 9 subjects at 20 mg BMS-986016/240 mg nivolumab,  9 
subjects  at  80 mg  BMS-986016/240  mg nivolumab,  and 4 subjects at 240 mg BMS-
986016/240 mg nivolumab, with all regimens at a flat dose q2w. Safety information 
presented in this Investigator Brochure (IB) focuses primarily on information obtained 
from Phase 1 studies at 4 ascending doses of BMS-986016 monotherapy (flat doses of 20, 
80, 240, and 800 mg) from Studies CA224-020 and CA224-022 and 4 ascending doses of 
BMS-986016  and  nivolumab   combination   therapy   (flat   doses   of   20 mg   BMS-
986016/80 nivolumab, 20 mg  BMS-986016/240 mg  nivolumab,  80 mg  BMS-
986016/240 mg  nivolumab,  and  240  mg  BMS-986016/240 mg  nivolumab)  from   Study 
CA224-020. 
 
1.6.4 BMS-986016 Drug Description, Prep and Storage Conditions 
 
BMS-986016, also referred to as BMS-986016-01 or anti-LAG-3, was selected for 
dosage form development. BMS-986016 is a soluble protein consisting of 4 polypeptide 
chains that include 2 identical heavy chains and 2 identical light chains and is a human 
IgG4 monoclonal antibody directed against human LAG-3. BMS-986016 is produced 
from cell culture using a Chinese Hamster Ovary (CHO) cell line. The physical and 
chemical properties of BMS-986016 drug substance are summarized in the table below. 
Table 2: Physical and Chemical Properties of BMS-986016 Drug Substance 
BMS Number 
BMS-986016-01 
Other Names 
Anti-LAG-3; BMS-986016 
Molecular Weight 
147,179 Daltons 
Appearance 
Clear to opalescent, colorless to pale 
yellow liquid, may 
contain particles 
Solution pH 
5.0 to 6.0 
 


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BMS-986016 Injections 
BMS-986016 injections are to be administered as an IV infusion through a 0.2/0.22-µm 
pore size, low-protein-binding polyethersulfone membrane in-line filter at the protocol-
specified doses. It is not to be administered as an IV push or bolus injection. BMS-
986016 injection can be diluted with 0.9% sodium  chloride  injection  (normal  saline)  
to  protein  concentrations  no  lower  than 0.33 mg/mL. Detailed instructions for drug 
product dilution and administration are provided in the pharmacy manual for the clinical 
study. 
  
Care must be taken to assure sterility of the prepared solution, as the product does not 
contain any anti-microbial preservative or bacteriostatic agent. No incompatibilities 
between BMS-986016 injection (without the pentetic acid) and polyolefin bags or non-
di(2-ethylhexyl)phthalate (DEHP) infusion set have been observed. No incompatibilities 
between BMS-986016 (with the pentetic acid) and polyolefin, polyvinyl chloride (PVC) 
bags, or non-DEHP infusion set have been observed. 
  
Recommended Storage Conditions 
The drug products should be stored at 2°C to 8°C (36°F to 46°F) with protection from 
light. Donot freeze the drug product. The administration of BMS-986016 infusions and 
the co-administration of BMS-986016 and nivolumab must be completed within 24 hours 
of preparation. If not used immediately, the infusion solution may be stored in a 
refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours and a maximum of 4 hours of 
the total 24 hours can be at room temperature (20°C to 25°C; 68°F to 77°F) and exposed 
to room light. The maximum 4-hour period under room temperature and room light 
conditions includes the product administration period. 
 
1.6.5 Handling and Dose Preparation for Nivolumab/BMS-986016 Administration 
 
Nivolumab Handling and Dose Preparation 
 
Nivolumab will be administered first. As with all injectable drugs, care should be taken 
when handling and preparing Nivolumab.  Whenever possible, Nivolumab infusions 
should be prepared in a laminar flow hood, glovebox, or safety cabinet using standard 
procedures for the safe handling of intravenous agents applying aseptic techniques. 
Gloves are required. If nivolumab solution comes in contact with the skin or mucosa, 
immediately and thoroughly wash with soap and water. 
Dose Preparation and Administration 
Visually inspect drug product solution for particulate matter and discoloration prior to 
administration. Nivolumab is a clear to opalescent, colorless to pale yellow solution. 
Discard the vial if the solution is cloudy, discolored, or contains extraneous particulate 
matter other than a few translucent-to-white, proteinaceous particles. Do not shake the 
vial. 
Preparation 


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To prepare 240mg dose: 
1.  Withdraw the required volume of Nivolumab and transfer into a 50 mL 0.9% Sodium 
Chloride, USP or 5 % Dextrose for Injection, USP bag. Infusion final volume for flat 
dosing should not exceed 120 mL in total volume.  
2. Mix diluted solution by gentle inversion, do not shake. 
3. Discard partially used vials or empty vials of Nivolumab. 
Storage of Infusion 
The product does not contain a preservative. After preparation, store the 
Nivolumab infusion either: 
• at room temperature for no more than 8 hours from the time of 
preparation. This includes room temperature storage of the 
infusion in the IV container and time for administration of the 
infusion  
or 
• under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 
24 hours from the time of infusion preparation. 
Do not freeze. 
Administration 
Administer the infusion over 30 minutes through an intravenous line containing a sterile, 
non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 
micrometer). Do not coadminister other drugs through the same intravenous line. Flush 
the intravenous line at end of infusion with appropriate amount of diluent (e.g. 15-
20 ml) to ensure that the total dose is administered. Total infusion and flush time 
should equal to 30 minutes.  
Following completion of the nivolumab infusion, BMS 986016 should be administered. 
Preferably, the infusion of BMS 986016 should begin within 15 to 30 minutes after the 
end of the Nivolumab infusion.  
Nivolumab should not be infused concomitantly in the same intravenous line with other 
agents. No physical or biochemical compatibility studies have been conducted to evaluate 
the co-administration of Nivolumab with other agents. 
 
1.6.6 BMS-986016 handling and Dose Preparation following Nivolumab 
administration 
As above, BMS-986016 infusion will be timed for 15-30 minutes after the completion of 
Nivolumab dosing. As with all injectable drugs, care should be taken when handling and 
preparing BMS-986016.  Whenever possible, BMS-986016 infusions should be prepared 
in a laminar flow hood, glovebox, or safety cabinet using standard procedures for the safe 
handling of intravenous agents applying aseptic techniques. Gloves are required. If 


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BMS-986016 solution comes in contact with the skin or mucosa, immediately and 
thoroughly wash with soap and water. 
Dose Preparation and Administration 
Visually inspect drug product solution for particulate matter and discoloration prior to 
administration. BMS-986016 is a clear to slightly opalescent, colorless to pale yellow 
solution. Discard the vial if the solution is cloudy, discolored, or contains extraneous 
particulate matter other than a few translucent-to-white, proteinaceous particles. Do not 
shake the vial. 
Preparation 
• Withdraw the required volume of BMS-986016 and transfer into an 
intravenous container. BMS-986016  80 mg dose  (8 ml BMS-986016 10 
mg/ml solution) may be mixed with 52 ml NS to a total volume = 60 ml 
which can be infused over 60 minutes at 1 ml/min followed by flush. 
Note: No incompatibilities between BMS-986016 injection and polyolefin 
or Non-DEHP IV components have been observed. 
• Mix diluted solution by gentle inversion. Do not shake.  
• Discard partially used vials or empty vials of BMS-986016 
Storage of Infusion 
The product does not contain a preservative. After preparation, store the 
BMS-986016 infusion either:  
 
• at room temperature for no more than 4 hours from the time of 
preparation. This includes room temperature storage of the 
infusion in the IV container and time for administration of the 
infusion  
or 
  
• under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 
24 hours from the time of infusion preparation. Do not freeze. 
 
Note: the time needed for room temperature storage of the infusion 
in the IV container and time for administration of the infusion (up 
to 4 hours) must be subtracted from this 24 hour period. For 
example, a 1-hour infusion and 1-hour room temperature handling 
and storage will result in no more than 22 hours allowed under 
refrigeration storage.  
 
 
Administration 
Administer the infusion over 60 minutes through an intravenous line containing a sterile, 
non-pyrogenic, polyethersulfone low protein binding in-line filter (pore size of 0.2/0.22 


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micrometer). Do not co-administer other drugs through the same intravenous line. Flush 
the intravenous line at end of infusion with 0.9% Sodium Chloride Injection, USP 
(15-20 ml) to ensure that the total dose is administered. Total infusion and flush 
time should equal to 60 minutes.  
NOTE: When dosing sequentially with Nivolumab, the BMS-986016 infusion should 
begin within 15 to 30 minutes after the end of the Nivolumab infusion. 
 
1.6.7 Infusion monitoring for combination of Nivolumab and BMS-986016 
Monitoring for an infusion reaction and cytokine release on Day 17 (+/- 2 days) of the 
protocol will consist of clinical observation in the day hospital ward or 7SW of the NIH 
Clinical Center. The total infusion monitoring time will be expected to last 4-5 hours for 
most patients. First, the patient will receive Nivolumab as an IV infusion over 30 
minutes. Patients with a prior Grade 2 or 3 infusion reaction will have pretreatment with 
25mg of Benadryl IV together with 650mg of Tylenol PO. During both infusions, 
patients will have q15 minute vital signs, including temperature, pulse, blood pressure 
and pulse oximetry. BMS-986016 infusion will begin 15-30 minutes after completion of 
the Nivolumab infusion. BMS-986016 will then be given as an IV infusion over 60 
minutes with ongoing monitoring. The patients will also be monitored for two hours after 
completion of the BMS-986016 in the day hospital or 7SW. Specifically, we will be 
checking the patients for fever, chills, shakes, itching, rash, hypertension or hypotension 
or difficulty breathing during the administration or immediately afterwards (within the 
following 2 hours). The patients will be treated according to I-O AE Algorithms from 
Appendices B and C; Investigator Brochures for Nivolumab (BMS-936558) and 
Relatlimab (BMS-986016). Generally, Grade 1 infusion reactions will be observed. 
Grade 2 or 3 infusion reactions will prompt interruption of the patient’s infusion until the 
observed symptom returns to the level of a Grade 1 reaction. Patients will be given 25mg 
of Benadryl IV and 650 mg of Tylenol PO for any grade 2 or 3 reaction. The Benadryl 
can be repeated once for symptom resolution until the reaction returns to a level of Grade 
1. If a patient has a Grade 2 or 3 reaction, subsequent infusions will be preceded by 25mg 
of Benadryl IV and 650mg of Tylenol PO 30 minutes prior to dosing. Grade 4 reactions 
will cause discontinuation of the therapy. Patients will be instructed to inform the clinical 
team of any symptoms including, but not limited to, fever, chills, itching, shortness of 
breath, stomach discomfort, diarrhea, new neurological symptoms, seizures, changes in 
urinary function, chest pain, palpitations, rashes or any other significant concern in 
between drug doses. 
 
1.6.8 Clinical Pharmacokinetics 
 
An interim determination of BMS-986016 multiple dose PK was carried out using all 
available serum concentration data from Studies CA224020 and CA224022. 
Noncompartmental analysis was performed using concentration-time data after the first 
dose (Cycle 1) and ninth dose (Cycle 3). In general, the maximum observed 
concentration (Cmax) and area under the concentration versus time curve over the dosing 
interval (AUC[TAU]) values over the first dosing interval increased approximately 
proportional to the increment in the BMS-986016 dose. BMS-986016 accumulation from 


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the first to ninth doses of a Q2W regimen was around 2- to 3-fold for AUC(TAU) and 
1.2- to 
1.8-fold for Cmax. BMS-986016 effective half-life was estimated to be approximately 20 
days. The PK of BMS-986016 or nivolumab were not altered when given in combination. 
 
BMS-986016 population PK was best described by a 2 compartment model with parallel 
linear and non-linear CL. The linear portion represents the non-specific clearance (CL), 
and non-linear component represents target-mediated CL. The linear CL was 0.18 L/day, 
and the volume of distribution in the central compartment was 4.5 L. The maximum rate 
of non-linear elimination (Vmax) was 2.5 mg/day, and the concentration that achieved 
50% of Vmax (Km) was 5.7 µg/mL. 
 
Currently available data suggest that BMS-986016 monotherapy exhibits a low level of 
immunogenicity, with 6 out of 42 subjects having at least 1 post-baseline positive ADA 
samples. There are limited data available in combination cohort to make inference on 
immunogenicity rate. 
 
1.6.9 Clinical Safety 
 
As of the clinical cutoff date of 15-Jul-2020, treatment with BMS-986016 in combination 
with nivolumab has been administered to 1332 subjects. Treatment-related AEs were 
reported in 890 (66.8%) subjects, with the most commonly reported (≥ 5% of subjects) 
being fatigue (15.5%), pruritus (7.4%), diarrhea (8.6%), asthenia (7.4%), rash (7.1%), 
arthralgia (7.5%), hypothyroidism (7.2%) and increased lipase (6.5%). Most drug-related 
AEs were Grade 1-2. Grade 3-4 drug-related AEs were reported in 199 (14.9%) subjects, 
and 2 (0.2%) subjects reported Grade 5 events (dyspnoea and pulmonary fibrosis). The 
types of treatment-related AEs, as well as the rates of treatment-related AEs, appeared 
comparable to historical nivolumab monotherapy rates. All treatment-related AEs, except 
for 1 Grade 4 myocarditis (240 mg relatlimab/240 mg nivolumab Q2W), as well as 1 
Grade 4 potential drug-induced liver injury, 1 Grade 5 dyspnea, and 1 Grade 3 
pneumonitis (all at a dose level of 80 mg relatlimab/240 mg nivolumab Q2W), were 
reversible and manageable by withholding study treatment administration, providing 
standard medical care, and/or following immune-related AE algorithms. Safety results to 
date indicate that sequential, coadministration, and the FDC of relatlimab + nivolumab 
have similar safety profiles. 
 
1.7 Microdialysis for cytokines 
Microdialysis has been well established for 25 years as a safe, reliable way of measuring 
the in vivo concentrations of various molecules in the microenvironment of various 
human tissues, including the brain[30]. The probes, which can be implanted directly into 
the brain through minimally invasive openings into the skull, are catheters which contain 
small semi-permeable membranes at their tips that allow the diffusion of small molecules 
in and out of the probe[31]. By slowly infusing isotonic fluids in and out of the system, 
the levels of various solutes within the brain can be determined without the need for 
multiple biopsies of the area of interest. Initial work in the brain focused mostly on 


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neurotransmitters and on changes in their levels in specific areas of the brain in response 
to various stimuli. The technique of placement of these probes within the brain has been 
performed safely for years [32]. Due to research on the inflammatory response to trauma, 
there is a well-established body of literature on the practice of recovery of cytokines from 
the brain by dialysis, and this has recently been safely applied to brain tumor patients[33]. 
In this study, interferon gamma levels were undetectable after the inflammatory response 
to surgery had died down. These soluble factors can give a real-time accounting of the 
inflammatory response to an insult in the brain, giving a level of detail about reactions to 
immune stimuli that would be completely unattainable by other methods.  
 
For our study, we propose the use of microdialysis to determine if checkpoint inhibitors 
have their desired effect in the tumor microenvironment. Presently, an anti-tumor 
immune response is suspected when serial MRI imaging over several months documents 
initial increase in tumor enhancement, signifying an inflammatory response to therapy, 
followed by reduced volume of enhancing tumor indicating tumor regression. 
Interpretation of anti-tumor response by MRI is complex because the MRI appearance of 
an inflammatory response to immunotherapy can appear similar to that of tumor 
recurrence or growth. Instead of waiting months to determine if an immune response to 
the tumor has occurred, we intend to use microdialysis of cytokines as a real-time test to 
measure immune response to a checkpoint inhibitor shortly after its administration, 
providing an answer within days of the first dose. Recent study in mice has shown that 
PD-1 blockade leads to an upregulation of interferon gamma production in circulating T 
lymphocytes responding to an infection[34], and this agrees with previous research that 
shows that interferon gamma is upregulated when PD-L1 is blocked in vitro[35]. Further, 
in recurrent glioblastoma patients, there is evidence that regulatory T cells in the systemic 
circulation of these patients release increasing amounts of IFNg (interferon gamma) in 
response to nivolumab[36]. Of note, other markers of cytotoxic activity, such as 
Granzyme A and Perforin 1, are much larger proteins than IFNg, and as such reliable 
recovery of this proteins by microdialysis is unlikely. As such, our hypothesis is that 
checkpoint blockade with Nivolumab will lead to an upregulation of the inflammatory 
cytokine interferon gamma in the tumor microenvironment as measured by cerebral 
microdialysis. After the intensive inpatient monitoring period, patients will be placed on 
combined therapy of BMS-986016  and Nivolumab in combination. In this way, we will 
be able to continue to follow immune cell populations in the blood of patients, so that we 
can determine if the systemic effects of checkpoint blockade differ between patients on 
Nivolumab versus patients on the combination of Nivolumab and BMS-986016  
treatment. 
 
 
1.8 Conclusion 
This protocol seeks to enroll patients with recurrent glioblastoma for treatment with 
nivolumab and for immune monitoring with cerebral microdialysis. Currently, there is 
not an established standard of care for these recurrent glioblastoma patients, and so they 
will not be forgoing any proven therapeutic options. The study is designed primarily to 
discover whether interferon gamma will be produced within the brain in response to 


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systemic checkpoint inhibitor therapy. Patients will undergo a surgical procedure that 
includes brain tumor needle biopsy to confirm the diagnosis of recurrent glioblastoma. If 
the diagnosis of recurrent glioblastoma is confirmed by frozen section, they will proceed 
with the remainder of the protocol. If this diagnosis cannot be definitively confirmed on 
frozen section, the patient will not proceed with the placement of microdialysis catheters 
or lumbar drain. If the patient does have frozen section evidence of recurrent 
glioblastoma, 2 microdialysis catheters will be implanted, one into the tumor, and one 
into the surrounding brain. A lumbar intrathecal catheter will also be inserted to serial 
sample cerebral spinal fluid (CSF). A bone marrow examination may be performed to 
evaluate the baseline status of the patients’ hematopoietic tissue. To allow the 
inflammatory response to catheter implantation to subside, we will wait two days after 
surgery before administering the PD-1 inhibitor, Nivolumab. We will then take samples 
every 6 hours from the microdialysis catheters, and daily samples from blood and 
cerebral spinal fluid. At the end of five days, we will remove the dialysis catheters and 
lumbar intrathecal catheter and resect the recurrent glioblastoma tumors. A repeat bone 
marrow examination may be performed to evaluate if Nivolumab causes any changes in 
the patients’ hematopoietic tissue. Following tumor resection, the patient will receive 
Nivolumab and an anti-LAG-3 antibody, BMS-986016 , until tumor progression or until 
the patient experiences an immune mediated toxicity that prevents further treatment, as 
defined in Appendix A. We will analyze the cerebral spinal fluid, microdialysis fluid and 
blood for immune markers by proteomic analysis. We will measure changes in immune 
markers in the various compartments (brain tumor, brain, blood, CSF and potentially 
bone marrow) between before and after their first dose of nivolumab and determine the 
relative immune effects of Nivolumab in these compartments. Recent data in melanoma 
patients suggests that after a month of treatment, changes in histological markers of 
immune response such as cluster of differentiation 8 (CD8), CD4, CD3, PD-1, PD-L1 
and lymphocyte activation gene 3 (LAG3) may be predictive of response to PD-1 
inhibitors[37]. As such, if we are unable to establish interferon gamma as a suitable 
marker of immune response, we will evaluate pathological response as our primary 
outcome measure. 
 
The relationship between markers of inflammation in the interstitial fluid, cerebral spinal 
fluid and serum have been investigated by the neuroimmunology community for years, 
but there are many answers left to be unlocked. This protocol aims to gather a truly 
unprecedented collection of data which could be used to better understand the unique 
immune environment of the brain as compared to the rest of the body. Potential gains 
could be a better understanding of how cerebral spinal fluid samples reflect changes in 
the immune microenvironment of the brain – is there a reliable relationship between 
cytokine levels in the interstitial fluid and cerebral spinal fluid, or are they completely 
different and unrelated? Are there other proteins that are better predictors of the nature of 
the immune populations in the brain? Are there serum markers that better predict 
intracranial inflammation than CSF markers do? Such findings could be applied to other 
neuroinflammatory disorders, such as multiple sclerosis or cryptococcal meningitis. The 
technique of microdialysis for cytokines, using proteomic analysis of the dialysates, 
which has not been done, could be applied to other disorders as well. For all of these 
reasons, while we feel that this protocol may provide critical information in the treatment 


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of brain tumors, we also feel that the study has the potential to create generalizable 
knowledge that will have a high impact in the scientific community. The National 
Institutes of Health Clinical Center is the only institution that is perfectly positioned to 
perform a trial such as this with the potential to truly revolutionize how we view 
inflammation in the brain.  
2.0 Study Objectives  
 
2.1 Primary Goal 
To determine the proportion of patients who have a measurable increase of interferon 
gamma levels in the brain tumor tissue after their first dose of Nivolumab as compared to 
the pre-treatment baseline as measured by cerebral microdialysis, to evaluate the safety of 
using brain tumor microdialysis to monitor response to immune modulators in patients 
with recurrent glioblastoma and to evaluate the safety of the combination of Nivolumab 
and BMS-986016 antibody treatment. 
 
 
2.2 Exploratory Goals 
1) To determine the change in interferon gamma production within the tumor 
microenvironment and in the rest of the body from before and after therapy with the 
immune checkpoint inhibitor, nivolumab;  
2) To evaluate the pathological response of the immune microenvironment of brain tumor 
tissue to the first dose of Nivolumab;  
3) To evaluate the clinical response (progression free survival, overall survival) of 
recurrent glioblastoma patients to treatment with BMS-986016 and Nivolumab;  
4) To describe the difference in survival between responders and non-responders;  
5) To examine the differences in the immune cells and secreted factors of the tumor 
environment as compared to the immune cells and secreted factors of the cerebral spinal 
fluid, blood and potentially bone marrow in response to this treatment;  
 
3.0 Subjects 
 
3.1 Description of study populations 
• The study population will consist of patients, 18 or older, with first recurrence of 
their previously treated glioblastoma. 
• Accrual ceiling will be 25 
• Target number of completed patients will be 10 
• Withdrawals who do not complete the initial study procedures, specifically, 
microdialysis monitoring period and resection portion of the study, will be 
replaced up to the accrual ceiling of 25 patients 


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• NIH employees may participate. NIH employees who are 
subordinates/relatives/co-workers of the investigators can be considered for 
inclusion in the trial on a case by case basis 
 
3.2 Inclusion Criteria 
To be eligible for entry into the study, a candidate must meet all the following criteria: 
 
1. 
Be 18years of age or older. 
2. 
Have recurrent glioblastoma that is amenable to surgical resection.  
3. 
Agree to undergo brain surgery. 
4. 
Are eligible for 03-N-0164 “Evaluation and Treatment of Neurosurgical 
Disorders” protocol 
5. 
Willing and able to appoint a durable power of attorney. 
6. 
Are willing to use an effective method of contraception during the clinical study 
as defined on the consent and for 24 weeks (for women) or 33 weeks (for men) after the 
last dose of the study drug. 
 
3.3 Exclusion Criteria 
 
Candidates will be excluded if they: 
 
1. Have a bleeding disorder that cannot be corrected before invasive testing or 
surgery, or other medical conditions that would make surgery unsafe, such as lung 
or cardiac disease that would render them unable to tolerate the risk of general 
anesthesia, or severe immunodeficiency. 
2. Has a known additional malignancy that is progressing or requires active 
treatment within 3 years of registration. Exceptions include basal cell carcinoma 
of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has 
undergone potentially curative therapy.  
3. Are pregnant or breastfeeding 
4. Cannot have an MRI scan. 
5. Are claustrophobic 
6. Are not able to lie on their back for up to 60 minutes 
7. Have primary CNS lymphoma.  
8. Has received systemic immunosuppressive treatments, aside from systemic 
corticosteroids (such as methotrexate, chloroquine, azathioprine, etc) within six 
months of registration. 
9. Has active autoimmune disease that has required systemic treatment in the past 2 
years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment 
10. Have a significant cardiac history, such as 2 or more MIs OR 2 or more coronary 
revascularization procedures. 


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11. Have abnormal findings on ECG such as prolonged QT interval, T-wave 
abnormalities or arrhythmia. Abnormal findings on ECG will prompt an 
evaluation by a cardiologist prior to enrollment in the study 
12. Are currently undergoing treatment with another therapeutic agent for 
glioblastoma 
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-
CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody 
(including ipilimumab or any other antibody or drug specifically targeting T-cell 
co-stimulation or checkpoint pathways). 
14. Have an ejection fraction <50% on screening echocardiogram 
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies) at the time of enrollment. 
16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 
RNA [qualitative] is detected) at the time of enrollment. 
17. Have an active infection that requires systemic antibacterial, antiviral or 
antifungal therapy < 7 days prior to initiation of study drug therapy  
18. Have a history of transfer of autologous or allogeneic T cells  
19. Have a history of solid organ or tissue transplants 
20. Have cardiac Troponin T or I > 2x the institutional upper limit of normal at 
screening 
21. At the time of enrollment, lack of consent capacity due to cognitive impairment 
that would make them incapable of understanding the explanation of the 
procedures in this study. Cognitive capacity to consent will be determined at the 
time of enrollment. Patients with mental disorders or those patients who are 
cognitively impaired yet still retain consent capacity will not be excluded.  
22. Cannot speak English or Spanish fluently 
23. Patients that require dexamethasone > 4 mg/ day or equivalent of steroids 
 
4.0 Study Design and Methods 
 
4.1 Study Overview 
The NINDS neurology and neurosurgery staff, in collaboration with the Neuro-Oncology 
Branch (NOB) in the National Cancer Institute, will evaluate patients with recurrent 
glioblastoma for this study. Those patients for whom standard of care would involve 
surgical resection of their radiographic recurrence will be eligible for the trial. Enrolled 
patients will undergo MRI before undergoing surgery. Stereotactic biopsy will be 
performed to confirm the recurrence. If the frozen section from the biopsy does not 
confirm recurrent tumor, the patient will not undergo further study procedures and will be 
replaced. If the diagnosis of recurrent tumor is confirmed, microdialysis catheters will be 
placed in the tumor and in the peritumoral area. A lumbar drain will also be placed at the 
time of surgery, and the patient will be admitted to the intensive care unit. Samples will 
be collected from the microdialysis catheters every 6 hours. Collection of cerebral spinal 
fluid and blood samples will be done daily. Two days after surgery, Nivolumab will be 
administered. Samples will be collected daily from blood and cerebral spinal fluid and 


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every 6 hours from microdialysis catheters until 5 days after Nivolumab administration. 
The patients will then have their tumors resected, and extracted tumor tissue will be 
processed for immune cell infiltration. Patients will then receive outpatient treatment with 
nivolumab and BMS-986016 every two weeks (+/- 2 days) and outpatient clinical 
monitoring with MRI every four weeks until tumor recurrence. 
 
Relationship to other protocols: 
 
Patients being followed by the NOB may also be enrolled in their natural history 
protocol. All patients at the NIH Clinical Center site will be enrolled in the 03-N-0164: 
Evaluation and Treatment of Neurosurgical Disorders protocol for tissue banking related 
to surgical resection. 
 
4.2 Recruitment  
Subjects at the NIH Clinical Center site will be referred by the Neuro-Oncology Branch, 
self-referred through the Patient Recruitment Public Liaison (PRPL) office, recruited 
from patients already participating in 03-N-0164, or referred through community 
physicians. Advertisements will be pre-approved by the IRB. Subjects who are interested 
in participating in this study will send medical records for review to determine whether 
they meet the criteria for enrollment. There will be no direct solicitation or recruitment of 
NIH employees. 
 
The direct link to the study information on clinicaltrials.gov 
(https://clinicaltrials.gov/ct2/show/NCT03493932) and/or the direct link to study 
information on the NINDS  “Clinical Trials in the Spotlight” public web page [the link to 
the direct study information on Spotlight will go here once approved by the IRB]  will be 
posted periodically on the official NINDS Twitter and Facebook accounts. The NINDS 
“Clinical Trials in the Spotlight” public web page for the trial will contain the same 
language as the IRB approved flyer. IRB approved ads and/or flyers (Appendix F) may 
also be posted on the official NINDS Twitter and Facebook Accounts. 
 
Flyers may be posted electronically on websites such as NIH or NCI websites, advocacy 
support group websites such as the American Brain Tumor Association or National Brain 
Tumor Alliance, publications’ websites including the Washington Post.  
 
During prescreening, physician investigators on this study will review medical records to 
determine if patients likely have recurrent glioblastoma. If a potential subject does not 
meet the inclusion criteria for the study, or if they choose not to enroll, their records will 
be destroyed or returned at the person’s request. Expected accrual rate is 1-2 patients per 
month. 
 
4.3 Screening Methods 
After a patient has signed consent for this protocol, screening will occur, during which 
patients will have a history and physical exam that may identify unsuspected exclusion 
criteria. The patient will undergo blood tests, including a troponin, an EKG, a chest X-ray 


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and an echocardiogram. Study investigators will again review records to attempt to 
identify exclusion criteria. Screening will also include a blood or urine pregnancy test for 
women of childbearing age, as pregnant women cannot be enrolled in the protocol. After 
screening has completed, the patient will be fully enrolled in the trial. 
 
4.4 Study Design 
This protocol is an open label, non-blinded single armed pilot study of the use of 
nivolumab and BMS-986016 in recurrent glioblastoma patients.  
 
4.5 Study Procedures 
 
4.5.1 Summary of Research Procedures (Study Phase 1) 
Patients will receive pre-operative structural MRI and pre-operative blood work. Pre-
operative imaging and blood work will occur between the time of enrollment and the 
surgical procedure. Clinical care considerations and the availability of the operating room 
schedule will determine the timing and acuity of these tests, and these tests will occur 
between several days to 2 weeks before surgery.  
 
At the time of surgery, adults will be admitted to the Neuroscience Patient Care Unit 
(NPCU). The patient will be asked to sign a standard surgical consent form that covers 
the tumor biopsy, microdialysis probe placement, and lumbar drain placement. These 
surgical procedures will be considered the beginning of  Phase 1 of the trial for safety 
monitoring purposes. For the research surgical procedure, on study day 1, the stereotactic 
biopsy will be performed using frameless stereotaxy. A frozen section will be sent from 
the biopsy tissue. If the biopsy confirms recurrent tumor, the patient will continue with 
study procedures. If the biopsy is not consistent with recurrent tumor, the patient will not 
undergo further study procedures and will be replaced. The burrholes for the 
microdialysis catheters will be placed using stereotactic guidance in a similar fashion to 
the biopsy procedure. Lumbar drain placement will also be performed in this same 
surgical procedure. While the patient is under anesthesia, a hematology fellow may 
perform a bone marrow examination. Following biopsy and microdialysis catheter 
implantation, subjects will stay in the ICU for 24 hours, and then be moved to a private 
inpatient room with a one-on-one sitter until the time of resection, 7 days after the initial 
biopsy. The first dose of Nivolumab will be given at 48 hours after the biopsy on study 
day 3. The lumbar drain catheters will remain clamped in between CSF sampling to allow 
the patients to be mobile during their inpatient stay. A stereotactic CT scan will be 
performed after the biopsy and microdialysis catheter placement to verify accurate 
placement and assess for procedural complications. Phase 1 will end at the start of 
surgical resection of the tumor, and clinical care will then commence as outlined below. 
Primary outcome measures will be assessed at the conclusion of enrollment, as all 
samples will be sent for cytokine testing at that time. All patients will come for a safety 
monitoring visit 2 weeks after their second surgery (+/-1 week) for safety evaluation. All 
patients will continue with routine examinations and Nivolumab and BMS-986016 


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therapy every 2 weeks, starting on study Day 17 (+/- 2 days) until recurrence or a dose 
limiting toxicity is experienced with appropriate imaging. 
 
4.5.2 Summary of Clinical Care Procedures and follow up (Study Phase 2): 
For safety monitoring purposes, Phase 2 will commence at the beginning of surgical 
resection of the tumor, as part of the patient’s clinical care. Surgical resection performed 
per standard of care procedure. Apart from surgery, as noted in the introduction, there is 
no current established standard of care treatment for recurrent glioblastoma patients. 
While oncologists have the option of using BCNU impregnated carmustine wafers or 
Bevacizumab, these treatments have been shown to have questionable benefit in 
glioblastoma patients. In short, a craniotomy will be planned and performed depending 
on the location of the recurrent tumor and the previous incisions. A maximal safe 
resection of the recurrent tumor will be performed utilizing stereotaxis, functional 
monitoring, and intra-operative imaging as needed. After the surgical tumor resection and 
removal of the dialysis catheters and lumbar drain, the patient will be admitted to the ICU 
until stable, and then they will be transferred to the Patient Care unit for routine post-
operative care. The decision to transfer patients from the ICU to the NPCU and decision 
regarding discharge from the hospital following surgery will depend on clinical care 
considerations only and are dependent on the individual patient. Patients will receive 
post-operative structural MRI, and may receive a CT as clinically indicated. Upon 
discharge from the hospital, a summary letter will be sent to the patient’s physician of 
record, describing the care rendered. All patients will be seen in the Outpatient 
Neuroscience Clinic 2 weeks (+/- 1 week) after their surgery and will undergo history, 
physical and neurological examination at that time. This visit is for post-operative care 
and is separate from the scheduled Day 17 (+/-2) visit.  
 
4.5.3 History, Physical Examination, and Neurological Examination (Research and 
Clinical Care) 
A credentialed doctor, physician assistant or nurse practitioner who is capable of making 
an independent determination of the patient’s suitability for this trial will take a medical 
history and perform a physical examination. This clinician will have to be knowledgeable 
about the study as a whole, particularly the risks of the study interventions and eligibility 
criteria. This physical examination is for purposes of clinical care only and does not 
replace any examination the patient may receive from his/her own physicians. For 
patients who have been referred to the Surgical Neurology Branch as a surgical 
candidate, this history and physical will be deemed sufficient as part of the evaluation for 
participation in the trial. If the patient in question is a patient currently being followed by 
the Surgical Neurology Branch, such that they have not been specifically referred to the 
Surgical Neurology Branch for surgical resection prior to being identified as a trial 
participant, the patient’s records will be sent to an outside independent neurosurgeon to 
determine suitability of the patient for repeat surgical resection. The history and physical 
will be repeated at each visit for Nivolumab and BMS-986016  infusion and monitoring, 
every two weeks (+/- 2 days). 
 


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4.5.4 Pregnancy testing (Research) 
Pregnant women may not be enrolled in this protocol, and pregnancy will be determined 
through serum or urine testing during screening. Subsequent pregnancy testing will be 
performed prior to each scheduled MRI (monthly, during follow-up). Women of 
childbearing age will have to agree to use an effective method of contraception for the 
duration of their participation in the protocol and for 24 weeks post last treatment of 
Nivolumab. Men will have to agree to use an effective method of contraception for the 
duration of their participation in the protocol and for 33 weeks post last treatment of 
Nivolumab. For the purposes of this study, effective methods of contraception will be 
considered to be: hormonal contraception (birth control pills, injected hormones or 
vaginal ring); intrauterine device; barrier methods (condom or diaphragm) used with 
spermicide; surgical sterilization (hysterectomy, tubal ligation, or vasectomy). 
 
4.5.5 Blood drawing (Research and Clinical Care) 
Blood will be drawn through a needle in the patient’s arm. For adults, blood tests will be 
drawn prior to MRI to evaluate kidney function (if required per MRI contrast 
requirements) and before surgery to evaluate serum chemistry, including markers of liver 
functioning, hematology and coagulation. Up to 35ml of blood will be withdrawn for 
research purposes at the time of study enrollment. Up to 35ml of blood will also be drawn 
daily during the immune monitoring period for research including pharmacokinetic 
analysis after checkpoint inhibition to determine the expression of inflammatory markers 
and cell content of the blood at these time points. On Day 3, additional samples of up to 
10 ml of blood (total on Day 3 up to 45ml) will be drawn. Up to 5ml of blood will be 
withdrawn before, and  6 hours +/- 2 hours after the completion of the nivolumab dose 
for pharmacokinetic analysis. Up to 35ml of blood will also be drawn at every 2 week 
(+/- 2 days) visit for Nivolumab infusion. We will not exceed 550ml in any 8-week 
period, consistent with existing IRB limits. 
 
4.5.6 Electrocardiography (ECG/EKG) 
We will perform an ECG during the initial enrollment into the trial and at each 2-week 
(+/- 2 days) follow-up appointment to detect signs of cardiomyopathy. Prolonged QT 
interval, arrhythmia, T-wave abnormalities or any other concerning ECG findings will 
prompt a consultation to cardiology to rule out pre-existing cardiac pathology prior to 
dosing of the study drugs.  
 
4.5.7 Echocardiogram 
The echocardiogram uses sound waves to look at the patient’s heart. A standard 
echocardiogram will be performed at the initial enrollment into the trial. 
 
4.5.8 Chest X-ray (Clinical care) 
All patients will have a chest x-ray as part of their routine clinical evaluation prior to 
enrollment in the trial. The chest x-ray is being performed as routine clinical care as all 


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patients who undergo neurosurgery at the NIH Clinical Center are required to have a 
chest x-ray by anesthesia.  
 
4.5.9 Structural MRI (Magnetic Resonance Imaging) (clinical care and research) 
MRI evaluation is standard of care for patients with brain tumors.  During the initial 
evaluation, patients may have imaging from an outside institution that can provide 
diagnostic information.  However, prior to surgery, patients under this protocol will need 
to have a recent structural (no older than two weeks prior to biopsy/microdialysis 
placment) MRI obtained. This MRI is for standard clinical care. After the standard of 
care surgical resection, another MRI will be performed. This MRI is also for standard 
clinical care.  MRI will also be repeated every 4 weeks during the treatment period with 
Nivolumab and BMS 986016 or earlier as indicated due to change in symptom burden. 
These MRIs are for research purposes. MRI uses a strong magnetic field and radio waves 
to take pictures of the brain. The MRI scanner is a metal cylinder surrounded by a strong 
magnetic field.  During the MRI, the patient will lie on a table that can slide in and out of 
the cylinder.  The patient will be in the scanner about 60 minutes. The patient may be 
asked to lie still for up to 15 minutes at a time. While in the scanner, the patient will hear 
loud knocking noises, and will be fitted with earplugs or earmuffs to muffle the sound. 
The patient will be able to communicate with the MRI staff at all times during the scan, 
and may ask to be moved out of the machine at any time.   
 
MRI scans may include intravenous administration of an FDA-approved, macrocyclic, 
gadolinium-based MRI contrast agent. Unless otherwise specified in the protocol, 
contrast agents will be used at FDA-approved doses. NIH Clinical Center Radiology and 
Imaging Sciences guidelines for gadolinium administration will be followed. Under 
certain circumstances, participants in this study may receive a linear chelate. Examples of 
situations in which this may occur include the following: (1) prior sensitivity to all 
macrocyclic agents; (2) participation in a longitudinal study in which a linear chelate was 
previously given, there is a clear advantage to maintaining the same gadolinium protocol, 
and T1 signal change in the basal ganglia or dentate nuclei was not observed; or (3) after 
consultation with, and approval by, a radiologist credentialed at the NIH Clinical Center. 
A list of the instances in which a linear chelate was administered, along with the 
justification for its administration, will be provided to the IRB at the time of continuing 
review. 
 
To assess white matter tracts, DTI will be performed in all patients. Data are acquired 
with a single-shot spin-echo echo-planar imaging sequence that utilizes standard 
acquisition and reconstruction methods. The data are acquired with isotropic voxels 
dimensions of ~2 mm, full k-space coverage, minimal TE based on the b-value, minimal 
TR based on required imaging time to cover the whole brain, and acceleration from 
parallel imaging. A custom set of diffusion directions and weightings are acquired with 
maximal b-value= 1100 s/mm2. The total scan time for the DTI acquisition is 
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4.5.10 Research surgical procedure (Research) 
Following preoperative evaluation, patients will be admitted (Study Day 0) and the study 
will begin with a stereotactic biopsy of the patient’s recurrent lesion and the insertion of 
two small microdialysis catheters into the brain. For safety monitoring purposes, this will 
be the beginning of Phase 1 of the study. One microdialysis catheter will be placed in the 
tumor and one into the peritumoral area. On the day of surgery, general anesthesia will be 
administered in the operating suite.  
 
4.5.10.1 
Lumbar drain placement (Research) 
A lumbar drain will be placed in each patient in the standard fashion. The patient will be 
placed on their left or right side, depending on what makes the most sense for the 
subsequent craniotomy. The patient’s knees will be pulled towards their chest. The touhy 
needle supplied with the lumbar drain catheter will be inserted with the bevel parallel to 
the ligaments at a cranial/caudal level most consistent with L4/5, using the patient’s 
posterior superior iliac crests as landmarks. The needle will be guided towards the 
umbilicus until it is in the intrathecal space, and the bevel will be turned cranially. The 
lumbar drain will then be inserted through the needle into the intrathecal space. The 
needle will then be removed, CSF flow will be confirmed, and the catheter will be 
attached, sterilely, to the CSF drainage bag and clamped. In the event that the lumbar 
drain fails during the microdialysis monitoring period, the lumbar drain will be removed. 
The patient will be offered the option of replacement of the lumbar drain on the floor or 
fluoroscopy suite (as medically indicated), or lumbar puncture, below. Placement of the 
lumbar drain on the floor would be performed as above.  
 
4.5.10.2 
Lumbar puncture (Research) 
In the event that the lumbar drain fails and the patient opts against replacement of the 
lumbar drain on the floor, a lumbar puncture will be performed in the operating room on 
Day 8 for research purposes. This will be performed under general anesthesia. For the 
lumbar puncture, the patient will lie on their side, curled up with their knees at their 
chest, or sitting upright. Their lower back will be cleaned. A needle will be inserted 
through the numbed skin and into the space between the bones in their back. Up to 15 ml 
of cerebrospinal fluid (CSF) will be removed for research purposes, beyond what CSF is 
lost during usual performance of the procedure. After the fluid is collected, the patient 
will continue with surgical resection as indicated.  
 
4.5.10.3 
Bone Marrow Examination (Research) 
For the bone marrow examination, aspirate and core biopsy may be collected according 
to conventional clinical technique from the hip of the patient.  If the procedure is 
performed, it will be done by a clinical provider credentialed to perform this procedure, 
and is typically performed at the end of the research surgical procedure while the patient 
is under anesthesia. The decision to perform this examination is at the discretion of the 
primary investigator.  
 


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4.5.10.4 
Stereotactic biopsy (Research) 
Patients will undergo placement of a surgical head frame and will be registered into our 
neuronavigation system. A plan will be made on the neuronavigation for the location of 
the biopsy and the targets for placement of the microdialysis catheters.  The biopsy and 
catheter sites as planned above will be prepped and draped in the usual sterile fashion. 
First, at the biopsy site, a small stab incision will be made, and the pneumatic drill will be 
used to make a small burr hole in the skull in the trajectory of the needle biopsy. The dura 
will be incised, the pial surface of the brain will be coagulated, and we will then open the 
pia. The needle will then be passed along the trajectory to the target using the 
neuronavigation system. Adequate biopsies will be taken to confirm the diagnosis of 
recurrence. This confirmation will be done by frozen section. There will be at least 4 
samples taken, but there may be as many as 20, from different sites, if the diagnosis is 
hard to confirm. If a diagnosis of recurrent glioblastoma cannot be confirmed by the 
frozen section, the patient will not proceed with the rest of the study procedures. Once 
adequate tissue has been removed, the needle will be removed. 
 
4.5.10.5 
Microdialyis catheter placement (Research) 
After the brain biopsy is performed confirming recurrent glioblastoma, the 
neuronavigation system will be utilized to plan a needle trajectory from two skull burr 
holes to the dialysis probe targets. The MD 71 catheter we will implant has one inlet and 
one outlet tube which is designed for sampling only. The surgeon’s discretion will be 
used to pick solid, contrast-enhancing portions of the lesion that appear to best represent 
the most pathological portion of the tumor for microdialysis catheter placement. The 
surgeon’s discretion will also be used to pick a second site that does not appear to be 
contrast-enhancing tumor for the peritumoral catheter. A stab incision on the scalp will be 
made at the site of each planned burr hole, one planned to go into the contrast-enhancing 
tumor, and one into the peri-tumoral area, at least 10mm away from the contrast 
enhancing margin of the tumor, using neuronavigation system guidance as above. This 
will be done using the surgeon’s discretion. We will assess the peritumoral catheter target 
using the following criteria: 
1) A lack of contrast-enhancement as noted on the neuronavigation system 
2) The closest adequate area to the tumor site, as assessed by the surgeon 
3) Adequate brain tissue surrounding the placement site to allow the catheter to sit in 
the tissue undisturbed, as assessed by the surgeon 
4) A safe path to the insertion site, as assessed by the surgeon 
Once the dura and pial surface are pierced, as above, the catheter will be passed along the 
established trajectory into the brain tissue. A guide needle may be used to place the 
microdialysis catheter. The part of the catheter outside the skull will be tunneled under 
the skin to a second stab incision, where it will exit the scalp. The ends of the tubing 
connected to the cannulas will be sterilely sealed and secured.  The scalp wound will be 
closed, and the head frame removed while anesthetized.  Patients will be awakened from 
anesthesia and returned to the Intensive Care Unit for immediate postoperative care. The 
dialysis machines will be attached to each catheter in the ICU. 
 


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4.5.11 Computer-assisted Tomography (CT) Scan (Research) 
This research study involves exposure to radiation from a CT scan of the head following 
biopsy/microdialysis catheter placement surgery to evaluate for the development of a 
blood clot and accurate placement of the microdialysis catheters.  
 
4.5.12 Microdialysis sample retrieval (Research) 
Upon arrival in the intensive care unit, the MD 71 High Cut off brain microdialysis 
catheters will be connected to a portable syringe pump to perfuse artificial CSF 
(Perfusion Fluid CNS, ref. no. P000151, CMA, Solna, Sweden) with 3.5% human serum 
albumin at a rate of 0.3 µl/min for approximately 7 days.  The inlet tubing of the catheter 
will be connected to a CMA 107 Microdialysis Pump (ref. no. P000127, a, Solna 
Sweden).  From the immediate post-operative period until 24 hours post-microdialysis 
implantation, the patients will be monitored in the ICU and then moved to an inpatient 
floor with a one-on-one sitter until study day 8 due to the presence of the microdialysis 
catheters. Microdialysis samples will be removed from the microdialysis system every 6 
hours +/- 2 hours using the collection system of the microdialysis system. In the event 
that the microdialysis catheter must be removed prior to the completion of the 
microdialysis monitoring period for reasons, including, but not limited to, microdialysis 
catheter failure, complication requiring early removal of microdialysis catheters, etc, the 
catheter will be removed on the unit and the patient will continue with into Phase 2 of the 
trial with surgical resection as indicated.  
 
4.5.13 CSF Sample retrieval (Research) 
CSF will be taken daily while the subject is in the ICU and during the patient’s inpatient 
stay. The lumbar drain will remain clamped until the time of sampling. At that time, the 
first 5ml will be drained off to allow the clearance of debris and sediment, and then up to 
15ml of CSF will be collected for studies and stored at -80 degrees C. On Day 3, 
additional samples of up to 10ml of CSF will be drawn (total for Day 3 up to 25ml of 
CSF). Up to 5ml will be withdrawn before, and 6 hours +/- 2 hours after the completion 
of the nivolumab dose for pharmacokinetic analysis. In the event that the lumbar drain 
fails and is not replaced, CSF collection will cease until the lumbar puncture performed 
in the operating room on Day 8. Up to 15ml will be withdrawn in the operating room 
during the lumbar puncture. 
 
4.5.14 Nivolumab (Research) 
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody. Nivolumab 
monotherapy is approved in multiple countries, including the US and EU, for 
unresectable or metastatic melanoma, previously treated metastatic NSCLC, and 
previously treated advanced RCC; it is also approved for the treatment of cHL in the US. 
The FDA has recently approved Nivolumab for the treatment of patients with recurrent or 
metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease 
progression on or after platinum-based therapy; and it was also approved for treatment of 
patients with locally advanced or metastatic urothelial carcinoma who have disease 
progression during or following platinum-containing chemotherapy or have disease 


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progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-
containing chemotherapy. In addition, nivolumab has been approved for use in 
combination with ipilimumab for unresectable melanoma in multiple countries, including 
the US and EU. Nivolumab is being investigated both as monotherapy and in 
combination with chemotherapy, targeted therapies, and other immunotherapies. This 
drug will be provided as part of a drug-only sponsorship from Bristol-Myers Squibb. It 
will be given on study day 3 at a dose of 240mg given intravenously over 30 minutes. It 
will be given subsequently as an intravenous infusion over 30 minutes at a dosage of 
240mg every 2 weeks together with BMS 986016, starting on Day 17 (+/- 2 days), as 
outlined in Section 1.6.4, above. It is produced by Bristol-Myers Squibb, New York, NY. 
The Investigator Brochure is listed as Appendix B. Please see section 4.5.19 for 
definition of duration of therapy.  
 
4.5.15 Anti-LAG-3 antibody, BMS-986016 (Research) 
BMS-986016 is a Lymphocyte Activation Gene-3 (LAG-3) blocking antibody which is 
undergoing study both as monotherapy and as combination therapy with Nivolumab for 
the treatment of advanced cancers. This drug will be provided as part of a drug only 
sponsorship from Bristol-Myers Squibb. It will be given beginning on study Day 17 (+/- 
2 days). It will be given as an intravenous infusion over 60 minutes at a dosage of 80mg 
every 2 weeks (+/- 2 days). It is produced by Bristol-Myers Squibb, New York, NY. The 
Investigator Brochure is listed as Appendix C. The patients will have BMS-986016 
infusions every 2 weeks (+/- 2 days) with the Nivolumab until progression. Please see 
section 4.5.19, below, for discussion of duration of therapy.   
 
4.5.16 Surgical Treatment and Post-operative care (Clinical Care) 
After the conclusion of microdialysis monitoring, patients will undergo resection of their 
brain tumor as per protocol 03-N-0164. The beginning of this surgery will be noted as the 
start of Phase 2 of the study for safety monitoring purposes. The type of surgery that will 
be performed will be decided upon by the neurosurgeon and will be discussed with the 
patient before surgery.   
When deemed necessary, as per standard clinical practice, a surgical procedure will be 
performed with intraoperative motor, sensory and speech mapping. The decision to 
perform a surgical procedure in an awake vs anesthetized manner will be determined 
based on standard clinical practice. Generally, awake surgery is employed in the case of 
language mapping, and in some cases for motor mapping, whereas intraoperative 
monitoring with anesthesia may be used for motor mapping. This surgery will be done in 
accordance with standard of care. The patients will receive a post-operative MRI, and 
will be watched in the Intensive Care Unit, as would be our typical practice, until the 
patient is stable for transfer to the Neurosurgical floor at the discretion of the treating 
physicians. When the patient is stable for discharge from the hospital, they will be 
discharged home or to a suitable rehabilitation facility, as indicated. 
 


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4.5.17 Repeat Bone Marrow Examination (Research) 
For the bone marrow examination, aspirate and core biopsy may be collected according 
to conventional clinical technique from the hip of the patient.  If the procedure is 
performed, it will be done by a clinical provider credentialed to perform this procedure, 
and typically is performed at the end of the research surgical procedure while the patient 
is under anesthesia. 
 
4.5.18 Surgical specimens (Research and Clinical Care) 
A portion of the brain tissue specimen will remain after the neuropathologist removes the 
amount that is required to make a pathologic diagnosis at both biopsy and resection. This 
remaining tissue will be used for research purposes, consistent with NIH guidelines under 
protocol 03-N-0164. Tissue obtained through this protocol will be evaluated for 
molecular, cellular, and genetic markers of tumor tissue and normal tissue. Specimens 
will be evaluated for inflammatory markers including cytokines, interleukins, TNF-a, T 
cells, microglia, and reactive astrocytes. Remaining tissue will be frozen and stored for 
use in brain research studies in the future either at NIH or at other institutions. We will 
obtain consent from patients to use their specimens in future studies and at other 
collaborating institutions. 
 
Brain specimens stored in the tissue bank of the Surgical Neurology Branch, NINDS, will 
remain frozen until they are used. A biologist in the Surgical Neurology Branch will track 
brain specimens.   
 
The banked and processed research specimens are coded and stored without personal 
identifiers. The specimens and data from this research will remain stored after completion 
of the protocol. Because research specimen testing does not affect the care of the patient, 
the patient will not be notified of the results of his/her research tests, nor will the results 
appear in the medical record or be given to the referring physician. 
 
4.5.19 Follow-up (Research) 
Upon discharge from the hospital, a summary letter will be sent to the patient’s physician 
of record, describing the care rendered. Dosing of study medications will commence on 
Day 17 (+/- 2 days). Safety monitoring for infusions is discussed in section 8.2, below. 
Additionally, all patients will be seen in the Outpatient Neuroscience Clinic 2 weeks (+/- 
1 week) after their surgery. This visit requirement is separate from the Day 17 (+/- 2 
days) study visit. If appropriate, this post-operative care visit will be conducted in the day 
hospital, during the Day 17 (+/- 2 days) study visit. It may also occur on 7SW, if the 
patient remains admitted in the hospital, post-operatively. The patients will continue to 
receive Nivolumab, as above, at a dose of 240mg IV every two weeks and BMS-986016 
antibody at a dose of 80mg IV every two weeks until progression. The first dose of both 
study medications will begin on study Day 17 (+/-2 days). Details of the infusion can be 
found in section 1.6.4. Between study visits, no specific precautions are needed. Patients 
will be reminded to call us with any clinical concerns regarding potential adverse events, 
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insufficiency, skin lesions, hypophisitis, respiratory concerns, cardiovascular 
compromise, renal insufficiency or liver failure. Detailed safety monitoring procedures 
are outlined in section 8, below. Section 8.6 contains the list of toxicities which will 
prompt automatic discontinuation of the study drugs. Additionally, we will follow the I-O 
treatment algorithm for Nivolumab in Appendix B, below. Steroids will be used for 
symptomatic management as needed, per the discretion of the treating physician. Steroid 
use will not be a criterion for removal from the study. 
 
Prior to documenting removal from protocol therapy, effort must be made to have all 
subjects complete a safety visit approximately 30 days following the last dose of study 
therapy.  
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or until one of the following criteria 
from section 8.6, below, occurs. 
 
Subjects initially meeting radiologic criteria for disease progression may continue 
receiving study medication until confirmation of progression. Progression will be defined 
by Response Assessment in Neuro-Oncology Criteria (RANO) criteria, as it has been 
adopted for immunotherapy trials[38]. The initial radiological suspicion of progression 
will be raised when: 
- ≥ 25% ↑ sum of biperpendicular diameters of enhancing disease (new lesions will be 
added to the sum of the diameter of enhancing disease during the treatment period and 
will not automatically be assumed to be progression). 
 
This continuation of therapy can continue for a total of 12 weeks with MRIs performed 
every 4 weeks, as per protocol. iRANO criteria has suggested that this treatment 
extension only be implemented during the first 6 months of therapy, however there is not 
yet enough data about treatment of recurrent glioblastoma patients with checkpoint 
inhibition to be sure of the time course of pseudoprogression. As such, this additional 
observation period will be implemented at any time while patients are on study 
medications. Patients will only be eligible to continue therapy in the face of MRI 
evidence of potential progression if the patient is believed to be demonstrating clinical 
benefit as deemed by the investigator, the patient is tolerating the study medications and 
the patient has not significantly declined, neurologically. Of note, if the patient’s decline 
reverses with corticosteroids or surgical sampling of the patient’s mass demonstrates 
treatment effect only, the patient may continue on therapy or resume therapy.  
 
Subjects with confirmed radiologic progression (approximately 12 weeks after initially 
assessed progression) will discontinue study medication and enter the survival follow up 
phase of the study. If progression is confirmed, then the date of disease progression will 
be the first date the subject met the criteria for progression.  
 
To determine clinical progression, subjects with neurological decline will receive a 
clinical MRI to evaluate for progression by imaging (standard of care). 
 


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During Phase 2, in any patient with significant neurologic decline where disease 
progression cannot be differentiated from pseudoprogression, and/or in n those cases in 
which radiologic progression cannot be differentiated from pseudoprogression and it is 
the investigator’s opinion that a surgical biopsy or resection to obtain tumor tissue for 
histopathology is in the subject’s best interests, a surgical resection may be performed 
following consultation with the medical monitor and outside consultant neurosurgeon. If 
tumor pathology confirms progression, then the subject will be discontinued from study 
medication per protocol discontinuation criteria and the date of progression will be the 
day that it was first suspected. If the patient’s decline reverses with corticosteroids and/or 
tumor pathology reveals treatment-related changes and does not confirm disease 
progression, we will discuss resumption of therapy with our Safety Monitoring 
Committee (for patients enrolled at NIH) and the Data and Safety Monitoring Board (for 
patients enrolled at the Emory Site). The subject will then continue all on-treatment 
tumor assessments as per the treatment schedule.  
 
4.5.20 Other treatments for glioblastoma and concurrent medications (Clinical 
care) 
There is no accepted standard of care treatment that patients will be forgoing during the 
study period. Steroid use will be permitted for symptomatic management while the patient 
remains on study, if indicated, at the discretion of the treating physicians in accordance 
with the I-O AE Algorithms from Appendices B and C; Investigator Brochures for 
Nivolumab (BMS-936558) and Relatlimab (BMS-986016). Any concerns regarding 
treatment of Nivolumab or BMS-986016 side effects will be referred to the SMC (for 
patients enrolled at NIH) and DSMB (for patients enrolled at the Emory Site).. Patients 
will not receive any other experimental or off-label treatment while on the study. As all 
patients will have undergone standard of care radiation at the time of admission to the 
study, and additional radiation is not a standard treatment for recurrent glioblastoma, no 
additional radiation will be given to patients while on the study. Patients will be evaluated 
for additional radiation or other treatments at the time of progression. If the patient is lost 
to follow-up prior to documented progression or death, patient will be censored as of the 
date of the last adequate evaluation (MRI and exam). If patient dies prior to 
documentation of progression, progression will be defined as the date of death, if patient 
has been attending regularly scheduled follow-ups.  
 
4.6 
Emory University Hospital Site 
For all patients enrolled at Emory University Hospital, all procedures and follow-up will 
be as above, but they will be carried out in the equivalent units at Emory University 
Hospital.  The activities performed at Emory University Hospital will fall under the 
oversight of the Emory University IRB.  


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4.7 
End of participation 
Active participation in this protocol and treatment with BMS-986016 and nivolumab will 
end upon:  
• clinical progression (neurological decline followed by confirmation of 
progression by imaging or pathological diagnosis) or 
• confirmed radiological progression and investigator determination that the patient 
is no longer benefiting from treatment with the study treatment or  
• meeting any other “Criteria for individual subject withdrawal” as listed in section 
8.6 
After this point, participants will be considered on survival follow-up until death. For 
subjects removed for clinical or radiological progression as described above, we will 
perform a follow-up assessment at the next scheduled imaging visit and no less than 4 
weeks after the prior assessment of disease progression.  
 
Survival Follow-up Phase  
 
Participants who have discontinued study medication will enter the survival follow-up 
phase of the study after their final follow-up assessment.  Participants enrolled at the NIH 
Clinical Center site will continue to be enrolled in protocol 03-N-0164 and data on 
subject progress will be shared with this protocol (NIH medical/research records).  For 
those who decide to pursue care elsewhere and not through protocol 03-N-0164, we will 
perform phone calls approximately monthly to check on the status of the individual until 
death. We will attempt to gather Karnofsky Performance Status Rating, ongoing 
treatment information, follow-up any potential side effects from this study treatment, and 
vital status (alive/deceased). 
 
During this phase, patients may transfer their care to an outside physician, or they may 
choose to enroll in further studies at the NIH Clinical Center under the care of the 
investigators of this protocol.  If they chose to pursue their treatment outside of the NIH, 
all the medical care records will be transferred to the outside physician, with the subject’s 
permission. Further consultation at the NIH under another NIH protocol will be possible 
by referral. 
 
All other procedures in this protocol will be used for clinical care purposes. However, 
data acquired through all procedures will also be used for research purposes to investigate 
the relation between checkpoint inhibition and inflammatory markers in the brain, 
cerebral spinal fluid, blood and potential bone marrow. These additional research 
components are designed to provide new knowledge regarding the mechanism of action 
and effectiveness of such therapies in brain tumor patients.  
 
5 
Management of Data and Samples 
 


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5.1 Sample Storage 
All collected research samples, including surgical tumor specimens, CSF, microdialysate, 
and blood will be coded and stored in secured freezers on the NIH campus.  All patients 
enrolled in this protocol will be assigned a sequential code and all biological samples 
collected for this patient will be labeled with the patient’s code, date of collection, type of 
sample, sample number, and barcode which will be linked back to relevant sample 
information in the study laboratory notebooks and Labmatrix. The study samples may be 
shared with collaborators that have a research interest in the coded samples. Only the 
study investigators will have access to the code key. 
 
Loss or destruction of samples that impacts the care or safety of human subjects will be 
immediately reported to the IRB. Loss or destruction of samples that would not impact 
the care or safety of human subjects but would impact the acquisition of knowledge, will 
reported to the IRB within 7 days of each occurrence.   
 
Samples collected from patients enrolled at the Emory University site will be transferred 
to the NIH laboratory prior to primary analysis in accordance with technology transfer 
and/or Sponsor’s trial agreement documents. 
 
5.2 
Research Data 
Research data will be coded for storage and analysis. The codes will be maintained by the 
Principal Investigator and the study coordinator. Research data include data from 
structural imaging, neurological examination, tissue analysis of surgical specimens and 
analysis of fluids taken for analysis. All investigators will have access to the coded data. 
Electronic data will be stored on a secure server and paper data will be stored in locked 
filing cabinets in the investigators’ offices. Research data will not be used for any type of 
treatment and will not be placed in the patient’s chart.   
 
Data regarding clinical outcomes will be coded and stored electronically on a secure 
server and in paper format in locked filing cabinets in the investigators’ offices. 
 
Data collected from patients enrolled at the Emory University site will be transferred to 
the NIH prior to primary analysis in accordance with technology transfer and/or 
Sponsor’s trial agreement documents. 
 
5.3 Data and sample sharing plan 
Samples and data may be shared with other NIH protocols, other investigators, or 
databases/repositories, under the following guidelines:  
 
Identified data and samples may be shared with investigators on our branch protocol 03-
N-0164 as participants in this protocol are also enrolled in 03-N-0164.  
 


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Data and samples may be shared with collaborating laboratories at NIH or outside of NIH 
and/or submitted to NIH-designated repositories and databases. Coded data and samples 
will also be shared with Bristol-Myers Squibb. 
 
Samples and data will be stripped of identifiers and may be coded (“de-identified”) or 
unlinked from an identifying code (“anonymized”). When coded data is shared, the key 
to the code will not be provided to collaborators, but will remain at NIH.  Data and 
samples may be shared with investigators and institutions with an FWA or operating 
under the Declaration of Helsinki (DoH) and reported at the time of continuing review.  
Sharing with investigators without an FWA or not operating under the DoH will be 
submitted for prospective IRB approval.  Submissions to NIH-sponsored or supported 
databases and repositories will be reported at the time of Continuing Review.  
Submission to non-NIH sponsored or supported databases and repositories will be 
submitted for prospective IRB approval.  
 
Required approvals from the collaborating institution will be obtained and materials will 
be shipped in accordance with NIH and federal regulations.    
As no large scale genomic data will be acquired during the course of this protocol, this 
protocol is not subject to the NIH Genomic Data Sharing (GDS) policy.  
Under the Human Data Sharing (HDS) policy, de-identified non-genomic study data will 
be shared with the NINDS data repository (data.ninds.nih.gov). Furthermore, applicable 
(e.g., generated via CRIS) identified data will be shared via BTRIS following standard 
Clinical Center operating procedures including BTRIS data access policies. Data to be 
shared include baseline characteristics as well as key study outcome variables in a 
tabulated format, after adequate data cleaning, processing, and quality control. Data 
sharing will be performed at the time of publication and/or thereafter. 
Research data will also be shared with Bristol-Myers Squibb as a result of their drug-only 
sponsorship of this trial. Data shared with Bristol-Myers Squibb will be coded, as defined 
above. 
Research data that will be shared with Emory University will comply with technology 
transfer and/or Sponsor’s trial agreement documents. 
6 FDA Considerations 
 
6.1 
IND Status 
We have an approved IND to pursue this study, IND# 136039 
  
6.2 
Microdialysis catheter FDA status 
The tubing of the catheters will be connected to a portable syringe pump to perfuse 
artificial CSF (Perfusion Fluid CNS, ref. no. P000151, CMA, Solna, Sweden) with 3.5% 


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human serum albumin at a rate of 0.3 µl/min for 7 days.  The inlet tubing of the catheter 
will be connected to a CMA 107 Microdialysis Pump (ref. no. P000127, CMA, Solna 
Sweden). The catheters used will be the 71 High Cut off brain microdialysis catheter (ref. 
no. 8010320). This is materially very similar to the 70 brain microdialysis catheter (ref. 
no. P000049, CMA, Solna Sweden) which has been cleared for FDA use, and is currently 
being used by one of the co-investigators, Sadhana Jackson, in a trial at Johns Hopkins 
University, placed directly into the tumors, with no morbidity reported as of yet. The only 
difference between the FDA approved CMA 70 catheter and the MD 71 catheter are that 
the semi-permeable membrane has pores that are 100vkD in size in the MD 71 catheter, 
while they are 20 kD in size on the CMA 70 catheters. Otherwise, they are made of the 
same material, are inserted in the same way, and are the same size, so the risk of 
placement should be identical. Two recurrent glioblastoma patients have had the CMA 70 
catheter inserted by the study PI in the setting of an NCI trial in recent weeks with no 
morbidity. Badie et al.[33] recently used these catheters under IRB approval without an 
IDE in 10 brain tumor patients undergoing resection for intracranial tumors, and no 
morbidity was experienced by the patients in the study.  
 
The CMA 107 pump is materially very similar to the CMA 106 pump (Ref P000003, 
CMA, Solna Sweden) which has been FDA approved for use with the aforementioned 
MD 71 catheter. This pump was used by Badie et al. under IRB approval without an IDE 
[33]. The difference between the FDA approved CMA 106 pump and the CMA 107 
pump is that the CMA 107 pump has variable flow rates. That said, we will be using the 
flow rate, 0.3 µl/min, that is used by the FDA approved CMA 106 pump. The outlet of 
the catheter will be attached to 106 Syringe (Ref 8010191, CMA, Solna Sweden) in 
accordance with its FDA approval. The CMA 107 pump is materially very similar to the 
CMA 106 pump (Ref P000003, CMA, Solna Sweden) which has been FDA approved for 
use with the aforementioned MD 71 catheter. This catheter was used by Badie et al. 
under IRB approval without an IDE [33].  
 
The Perfusion Fluid CNS is FDA approved for use with the MDialysis CMA 106 pump 
and CMA 70 catheter. Perfusion Fluid CNS with 3.5% human serum albumin has been 
shown to be superior to Perfusion Fluid CNS alone with regards to fluid recovery and 
accuracy of cytokine sampling in the brain[39]. Our own in vitro laboratory testing 
confirmed this finding, with higher recovery of cytokines and more consistent results 
(unpublished data). This fluid has also been safely used in numerous studies of cerebral 
microdialysis for cytokines using the CMA 71 catheter without any reported 
morbidity[40, 41].  
 
Given the determination by CDRH that our investigation is considered a significant risk 
device study, we will ensure the following: 
 
a) 
The 71 High Cutoff Microdialysis Catheter (71 MD Catheter) will be 
labeled appropriately with “CAUTION—Investigational device. Limited by 
Federal (or United States) law to investigational use.”  
 


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The device status was reviewed by the FDA as part of our IND submission for the use of 
Nivolumab and BMS-986016 in this patient population, and the use of the catheter was 
approved. 
7.0 
Risks and Discomforts 
Risks and discomforts of the surgical procedures will be discussed with the subject on an 
individual basis, as is the case in the clinical practice of medicine and surgery. 
 
7.1 
History, Physical Examination, and Neurological Examination   
There is a minimal risk from history, physical, and neurological examination.   
     
7.2 
Pregnancy testing 
There is a minimal risk from pregnancy testing. 
 
7.3 
Risks of Blood Drawing 
During this study, no more research blood will be drawn beyond 4 cups over the duration 
of the study. The blood tests are for clinical care and research purposes. The patient may 
experience some discomfort at the site of needle entry, and there is a risk of a "black-and-
blue" mark. There is a remote risk of fainting or local infection. 
 
7.4 
Electrocardiography (ECG/EKG) 
There is minimal medical risk or discomfort from the ECG. 
 
7.5 
Chest X-ray 
There is minimal medical risk or discomfort from a chest x-ray. The chest x-ray is being 
performed as routine clinical care as all patients who undergo neurosurgery at the NIH 
Clinical Center are required to have a chest x-ray by anesthesia. 
 
7.6 
Echocardiogram 
There is minimal medical risk or discomfort from the echocardiogram. 
 
7.7 
Risks of Magnetic Resonance Imaging (MRI) 
People are at risk for injury from the MRI magnet if they have pacemakers or other 
implanted electrical devices, brain stimulators, some types of dental implants, aneurysm 
clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins 
and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery 
pump, or shrapnel fragments. Welders and metal workers are also at risk for injury 
because of possible small metal fragments in the eye of which they may be unaware. 
Subjects will be screened for these conditions before having any scan, and if they have 
any, they will not receive an MRI scan. If subjects have a question about any metal 
objects being present in their body, they should inform the staff. In addition, all magnetic 


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objects (for example, watches, coins, jewelry, and credit cards) must be removed before 
entering the MRI scan room. 
 
It is not known if MRI is completely safe for a developing fetus. Therefore, all women 
who are able to get pregnant will have a pregnancy test done no more than 24 hours 
before each MRI scan. The scan will not be done if the pregnancy test is positive.  
 
People with fear of confined spaces may become anxious during an MRI. Those with 
back problems may have back pain or discomfort from lying in the scanner. The noise 
from the scanner is loud enough to damage hearing, especially in people who already 
have hearing loss. Everyone having a research MRI scan will be fitted with hearing 
protection. If the hearing protection comes loose during the scan, the subjects will let 
MRI staff know right away. Subjects will notify staff of any hearing or ear problems. 
Subjects will be asked to complete an MRI screening form for each MRI scan. There are 
no known long-term risks of MRI scans. 
 
Symptoms from the contrast infusion are usually mild and may include feeling hot, 
burning, or 
coldness in the arm during the injection, a metallic taste, headache, allergic reactions and 
nausea. In an extremely small number of individuals, more severe symptoms have been 
reported including shortness of breath, wheezing, hives, and lowering of blood pressure. 
Unless specifically allowed by the protocol, participants will not receive gadolinium-
based contrast agents for research purposes if they have previously had an allergic 
reaction to them. Individuals with a history of anaphylaxis to other agents or chronic 
asthma requiring treatment will not receive gadolinium under this protocol unless they 
have previously received gadolinium and tolerated it well. Participants will be asked 
about such allergic reactions and history of asthma before a contrast agent is 
administered.  
 
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis,” which has resulted in a very small number of deaths. If 
subjects are 60 years old or greater or have diabetes, kidney disease or liver disease, 
blood work to assess kidney function will be performed within 4 weeks before any MRI 
scan with gadolinium contrast. Participants may not receive gadolinium for a research 
MRI scan if kidney function is not normal. There is no evidence for the potential of 
gadolinium-related toxicity in people with normal kidney function. This protocol follows 
NIH Clinical Center guidelines for kidney-function screening related to gadolinium 
administration. 
 
Most of the gadolinium contrast is eliminated in the urine. However, recent studies have 
found very small amounts of residual gadolinium in the body, including the brain, by 
imaging and at autopsy. Macrocyclic gadolinium-containing contrast agents are 
substantially less likely to leave gadolinium behind than linear agents. The use of 
macrocyclic vs. linear agents in this study is delineated in the procedures section above. 
There is presently no evidence that the retained gadolinium is associated with any adverse 
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7.8 
Risks of anesthesia for the research surgical procedure 
The duration of anesthesia for the research surgical procedure is expected to be 
approximately 120 minutes.  The risks of anesthesia depend on the subject’s age 
and concurrent medical conditions.  More common side effects are temporary 
drowsiness, nausea, and vomiting following recovery from anesthesia. Rare side 
effects include aspiration, extreme changes in body temperature, hypertension or 
hypotension, changes in heart rate or rhythm, hypoxia, and allergic reactions to 
the anesthetic drugs.  Some of these side effects may be life-threatening or lead to 
life-threatening conditions such as myocardial infarction or stroke.  An 
anesthesiologist will evaluate subjects for potential anesthesia risks prior to the 
procedure.  To reduce the risk of aspiration, subjects will not be allowed to eat or 
drink for 8 hours before the procedure, and until adequate recovery from 
anesthesia after the procedure.  Some subjects may also have an endotracheal tube 
inserted to reduce this risk and facilitate mechanical ventilation.  Intubation is 
associated with a small risk of laryngospasm, bronchospasm, hypertension, 
damage to teeth and lips, swelling of the larynx, sore throat, and hoarseness due to 
injury or irritation of the larynx. 
 
7.9 
Risks of Cerebral Microdialysis catheter placement 
Risks of microdialysis will be discussed with the patients, but the research literature 
indicates that this does not present more than minimal additional theoretical risk. 
Immediat theoretical risk of the surgery for placmeent would include brain hemorrahge. 
A recent study by Badie et al., with microdialysis catheters being implanted in the 
peritumoral area in brain tumor patients after resection, reported no morbidity from 
microdialysis catheter placement or sample collection[33]. A study of the use of the 
CMA 70 catheter, materially very similar to the MD 71 catheter to be used in this study, 
in 174 patients revealed no incidents of hemorrhage or infection attributable to the 
microdialysis catheters. A study of microdialysis in recurrent glioblastoma patients prior 
to resection of their lesion also showed that in the 8 patients that had catheters implanted, 
there were no observed complications[42]. A recent article used the MD 71 catheter that 
we plan to use in this study to investigate the cytokine changes in glioblastoma tissue and 
surrounding brain to radiotherapy [43]. In this study, 11 patients had biopsies, and then 
microdialysis catheters were placed directly into the tumor, and another catheter was 
placed 10mm away from the contrast-enhancing tissue. No morbidity was noted from 
placement of these catheters.  In another study, 7 patients with malignant glioma or 
lymphoma had resections of their tumor, and then two MD 71 catheters placed – one at 
the tumor resection margin, and one 20mm away from the resection cavity[44]. No 
morbidity from placement of these catheters was noted in this study. The stereotactic 
biopsy is being done as a part of the microdialysis implantation surgery, and it carries a 
risk of symptomatic hemorrhage of 1%[45]. Stereotactic biopsy with a frameless 
neuronavigation system carries a risk of about 1% of inaccurate biopsy [46]. If an 
inaccurate biopsy is performed, and a diagnosis cannot be made, the patient may have to 
undergo a repeat stereotactic biopsy. 
 


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7.10 
Risks of Lumbar Drain Placement 
Lumbar drain placement during surgery presents minimal risk to the patients. Risks 
would include headache, cerebral spinal fluid leak, infection, epidural hematoma, and 
retained lumbar drain catheter. Lumbar drain placement in the ICU or inpatient unit 
carries the same risks, but additionally carries the risk of back pain during placement.  
 
7.11 
Risks of Lumbar Puncture 
The risks of lumbar puncture under anesthesia include headache, epidural hematoma and 
cerebral spinal fluid leak. 
 
7.12 
Risks of Bone Marrow Examination 
Although rare, there is a potential for bleeding at the site and local infection. Bleeding 
can be stopped by applying local pressure, and infection can be treated with antibiotics. 
In the long term minimal scarring may occur but in most cases the biopsy site is 
indistinguishable within a few months.  
 
7.13 
Risks of Computer-assisted Tomography (CT) Scan 
A CT scan of the head requires that the patient lie still for a short time while images are 
formed. During the CT scan, the patient will be exposed to an effective dose of 0.27 rem. 
The chest X-ray requires that the patient sit still, briefly, while images are formed. During 
the chest X-ray, the patient will be exposed to an effective dose of 0.01 rem. This is 
below the Radiation Safety Committee guidelines of 5 rem per year. This exposure is less 
than a human typically is exposed to during the year, but could result in a theoretical 
small increase in the patient’s cancer risk. 
 
7.14 
Risks of Microdialysis sample retrieval and prolonged microdialysis catheter 
implantation 
There is minimal risk to microdialysis sample retrieval. Microdialysis catheters have been 
used in clinical patient care for periods of time up to 10 days without increased risk of 
infection[47]. Another recently completed study with the CMA 70 catheter was also just 
performed in recurrent glioblastoma patients[48]. In this study, 12 patients received either 
a biopsy or a surgical resection, and then microdialysis catheters were placed into the 
wall of the resection cavity or tumor tissue, if there was residual tissue. Levels of 5-FU, 
the expected metabolite of the initial drug, 5-FC, were measured by microdialysis for a 
minimum of 8 days, and these measurements continued up to 11 days. No infections (or 
any other morbidity) were reported in this trial. Given the evidence, we do not believe 
that there is an increased risk of infection for microdialysis sampling for 7 days. 
 
7.15 
Risks of CSF sample retrieval and prolonged lumbar drainage 
There is minimal risk to cerebral spinal fluid retrieval from the lumbar drain. Prolonged 
use of a lumbar drain in a neurointensive care unit has a risk of infection, with infection 
rates reported at between 4.2 and 5.7%[49, 50] 
 


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7.16 
Risks of Nivolumab  
In clinical trials using nivolumab for other indications, the most common adverse events 
(graded using the Common Terminology Criteria for Adverse Events v3.0), regardless of 
causality, were fatigue, decreased appetite, diarrhea, nausea, cough, dyspnea, constipation, 
vomiting, rash, pyrexia, and headache. Common treatment-related adverse events included 
fatigue, rash, diarrhea, pruritus, decreased appetite, and nausea. Serious adverse effects 
were rare and included Grade 3 or 4 pneumonitis, sarcoiditis and elevated alanine 
aminotransferase levels. In approving Nivolumab for the treatment of metastatic non-small 
cell lung cancer, the FDA reviewed the Checkmate 057 trial[51]. Of the 582 patients 
randomized in the CM057 study, 287 received Nivolumab. The most common adverse 
events, occurring in some grade in at least 10% of patients were: 30% of patients had cough 
(0.3% grade 3-4), 29% had decreased appetite (1.7% grade 3-4), 23% had constipation 
(0.7% grade 3-4), 11% had pruritus (none grade 3-4). The most common laboratory 
abnormalities were hyponatremia in 35% (6% grade 3-4) of patients, increased alkaline 
phosphatase in 27% of patients (2.8% grade 3-4), increased alanine aminotransferase in 
23% (2.4% grades 3-4), increased creatinine in 18% (0% grade 3-4), increased thyroid-
stimulating hormone in 17%.  
 
Following FDA approval of Nivolumab, reported serious adverse events also include 
increase risk of transplant-related complications including rejection of solid organ or tissue 
transplants and onset of graft versus host disease with unknown frequency.   
 
Detailed monitoring for these adverse effects are outlined in section 8, below. While 
patients are at home, they will be instructed to contact us for any suspected adverse events, 
whether suspected to be related to the medication or not for further guidance and treatment. 
Generally, for any reported new symptom or adverse event, non-immune events (such as 
disease progression) will be ruled out. Once these are ruled out, and the adverse event is 
deemed to be related to Nivolumab or BMS-986016, the side effects will be generally 
managed with administration of high-dose (2–4 mg/kg prednisolone equivalent) 
corticosteroids followed by a tapered dose and interruption of nivolumab therapy. Mild 
adverse events will be treated with a short course of steroids, followed by interruption of 
their Nivolumab dose. For non-serious (Grade 1-2) events, that are successfully treated, the 
patients will be considered for re-entry into the Nivolumab treatment portion of the trial. 
For Grade 3 events, treatment will generally be continued until the patient returns to 
baseline, and the patient’s steroids will then be tapered to off over 4-6 weeks. A detailed 
treatment algorithm for potential immune-related side effects is present in appendics B and 
C; Investigator Brochures. A list of adverse events which will prompt automatic 
discontinuation of Nivolumab and BMS-986016 are noted in section 8.6, below. Table 3 
is provided as a reference for the adverse events from Nivolumab monotherapy in 
glioblastoma patients, even though the combination treatment for ipilimumab is also 
reported. 
 
 


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Table 3: Summary of Safety of Nivolumab Alone and in Combination with Ipilimumab in 
subjects with Recurrent Glioblastoma 


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Table 3 (Continued): Summary of Safety of Nivolumab Alone and in Combination with 
Ipilimumab in subjects with Recurrent Glioblastoma 
 
 
7.17 
Summary of risks of BMS-986016 monotherapy and combination of BMS-
986016 and nivolumab 
7.17.1 Summary of Safety 
This section summarizes the potential risks of treatment with relatlimab alone and in 
combination with nivolumab, and the specific tests, observations, and precautions that are 
required in clinical studies. As of the clinical cutoff date of 15-Jul-2020, across 3 safety 
studies (Studies CA224020, CA224022, and CA224034), relatlimab monotherapy has 
been administered to 66 subjects across multiple doses: 20 mg (8 subjects), 80 mg (13 
subjects), 240 mg (27 subjects) and 800 mg (18 subjects) relatlimab, flat dose, Q2W. The 
safety profile of relatlimab monotherapy appears manageable with no MTD reached. The 
MAD was 800 mg Q2W. There were 4 drug related SAEs in monotherapy: Grade 3 
pneumonitis, Grade 2 pneumonitis, and Grade 3 allergic reaction in monotherapy in 
Study CA224020 at a dose of 800 mg relatlimab Q2W; and a Grade 3 aseptic meningitis 
in monotherapy in Study CA224022 at a dose of 800 mg relatlimab Q2W. There was no 


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apparent relationship in the incidence, severity, or causality of AEs to relatlimab at these 
dose levels. All AEs were reversible or manageable (in the setting of immune-mediated 
endocrine events) by withholding drug administration and following treatment algorithms 
specified in the protocols where applicable. There were 6 Grade 1 to Grade 2 infusion-
related reactions with relatlimab monotherapy (1 in Study CA224020 and 5 in Study 
CA224022), which were manageable and reversible with recommended treatment 
guidelines in the protocol. A total of 29 subjects died due to malignant neoplasm 
progression following relatlimab monotherapy (19 subjects in Study CA224020, 9 
subjects in Study CA224022, and 1 in Study CA224034).  There were 4 drug-related 
SAEs in monotherapy: Grade 3 pneumonitis, Grade 2 pneumonitis, and Grade 3 allergic 
reaction in monotherapy in Study CA224020 at a dose of 800 mg relatlimab Q2W; and 
Grade 3 aseptic meningitis in monotherapy in Study CA224022 at a dose of 800 mg 
relatlimab Q2W. There was no apparent relationship in the incidence, severity, or 
causality of AEs to relatlimab at these dose levels. A total of 29 subjects died due to 
malignant neoplasm progression following relatlimab monotherapy (19 in Study 
CA224020, 9 in Study CA224022, and 1 in Study CA224034). As of the clinical cutoff 
date of 15-Jul-2020, treatment with relatlimab in combination with nivolumab has been 
administered to 1431 subjects in Studies CA224020 (1332 subjects), CA224022 (68 
subjects), and CA224034 (31 subjects). The safety profile of relatlimab combined with 
nivolumab is manageable with currently no MTD reached, as combination dose 
evaluation remains ongoing. 
Across Studies CA224020, CA224022, and CA224034 for both monotherapy and 
combination therapy, drug-related AEs were reported in 1036 subjects. The most frequent 
drug-related AEs included fatigue, decreased appetite, pruritus, diarrhea, rash, rash 
maculo-papular, anemia, asthenia, hypothyroidism, and hyperthyroidism. The types of 
drug-related AEs, as well as the rates of drug-related AEs, appeared comparable to 
historical nivolumab monotherapy rates. All drug-related AEs, except for 1 Grade 4 
myocarditis (240 mg relatlimab/240 mg nivolumab Q2W), as well as 1 Grade 4 potential 
drug-induced liver injury, 1 Grade 5 dyspnea, and 1 Grade 3 pneumonitis (all at a dose 
level of 80 mg relatlimab/240 mg nivolumab Q2W), were reversible or manageable by 
withholding study drug administration, providing standard medical care, and/or following 
immune-related AE algorithms.  
A list of all SARs reported for relatlimab monotherapy and relatlimab + nivolumab 
combination therapy is present in Investigator Brochure Appendix 1. 
7.17.1.2 Potential Risk Associated with Relatlimab Monotherapy or in Combination 
with Nivolumab 
7.17.1.2.1 Immune-mediated Adverse Events 
Monotherapy with relatlimab is investigational and the type and grade of potential effects 
of inflammatory cells on specific tissues induced by the drug are unknown. The 
inflammatory effects could include well-characterized events documented for other T 
cell-directed antibodies including pneumonitis, colitis, hepatitis, nephritis, 
endocrinopathy, and neurologic and skin AEs. Unanticipated events may also occur. In 
combination with nivolumab, the frequency, severity, and reversibility of immune-
mediated adverse events (IMAEs) appears comparable to those of nivolumab 


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monotherapy. Recommended IMAE management algorithms are included in the 
nivolumab (BMS-936558, anti-PD-1 antibody) IB and every relatlimab clinical study 
protocol. Nivolumab management guidelines should be reviewed. The guidance applies 
to all IO agents and regimens. A general principle is that differential diagnoses should be 
diligently evaluated according to standard medical practice. Non-inflammatory etiologies 
should be considered and appropriately treated. Corticosteroids are a primary therapy for 
IO drug-related AEs. The oral equivalent of the recommended IV doses may be 
considered for ambulatory patients with low-grade toxicity. The lower bioavailability of 
oral corticosteroids should be taken into account when switching to the equivalent dose 
of oral corticosteroids. In addition, refer to any specific management guidance included 
in the study drug protocol. 
7.17.1.2.2 Neurotoxicity 
Given the toxicology studies showing choroid plexus inflammation in the setting of 
combination therapy, diligence regarding clinical monitoring of all subjects for signs and 
symptoms of neurologic toxicities was emphasized and should be maintained. In the 
early-phase studies, subjects with active neurological disease, as well as those with a 
confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to 
informed consent, have been excluded. As of the clinical data cutoff date of 15-Jul-2020, 
the observed drug-related AEs with potential for neurotoxic etiology have occurred at 
rates and with severity comparable to what would be expected with nivolumab 
monotherapy. The current relatlimab safety experience includes 10 (1 with monotherapy 
and 9 in combination with nivolumab) cases of aseptic meningitis (which is a rare IMAE 
with nivolumab monotherapy), neurotoxicity remains a specific IMAE of interest when 
combining relatlimab and nivolumab. The aseptic meningitis cases all presented with new 
or worsening headache with diagnosis made based upon increased immune cells found on 
CSF analysis in the absence of identifiable infectious etiology. Most cases responded to 
steroid therapy, 1 case responded without steroid therapy, and 1 case recurred during the 
steroid taper (responded to repeated high dose steroid treatment with taper). Two cases of 
encephalitis, Grade 3, have occurred with relatlimab in combination with nivolummab. 
No cases of myasthenia, demyelination or Guillain-Barre Syndrome have occurred. 
Refer to the specific treatment protocol for individual study-specific eligibility criteria; 
required procedures and instructions regarding neurotoxicity evaluation and monitoring 
as guidance may evolve with the increasing clinical and safety experience with 
combination of relatlimab and nivolumab. 
7.17.1.2.3 Potential Infusion Reaction and Cytokine Release 
Clinical studies of novel therapeutics have highlighted the risk of cytokine release as a 
consequence of treatment with some immune-modulatory mAbs. Nonclinical data, 
however, have demonstrated that relatlimab monotherapy or combination therapy with 
nivolumab does not induce cytokine release when presented to human PBMCs, regardless 
of concentration, donor, or incubation time. Consistent with the lack of cytokine release, 
there was no evidence that relatlimab induced T, B, or NK-cell activation, as measured 
by surface expression of CD25 and CD69. Thus, the risk of cytokine release after 
relatlimab administration as a monotherapy or as a combination therapy with nivolumab 
was assessed to be low based on these data and the minimal effector function mediated 


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by IgG4 (cross-linking through Fc receptors). Based on preliminary data as of 15-Jul- 
2020, infusion reactions of low grade (Grade 1 to 2) have been reported in 72 subjects 
treated across all 3 studies, 5 subjects with relatlimab monotherapy and 67 subjects with 
combination therapy. Infusion reactions were manageable and reversible following 
recommended treatment guidelines in the protocol. No cytokine release syndrome has 
been reported with doses up to 800 mg relatlimab monotherapy Q2W or with 
combination therapy up to 480 mg relatlimab/480 mg nivolumab Q4W. Nevertheless, 
relatlimab does have factors/attributes influencing risk, as described in the European 
Medicines Agency Committee for Medicinal Products for Human Use Guideline on 
strategies to identify and mitigate risks for FIH clinical studies, with investigational 
medicinal products (10-Jul-2007). Therefore, in addition to conventional safety 
assessments, the FIH study monitoring plan included the following precautions: 
1) Monitor for infusion reactions during and after administration of relatlimab. 
2) Monitor for any potential signs of cytokine release syndrome after the 
administration of relatlimab. 
3) Use a staggered dosing (sentinel subject) approach in the first dose cohorts 
evaluated in dose escalation to allow for thorough safety evaluation of the first 
dose prior to administration to subsequent subjects. 
Refer to the specific treatment protocol for individual study-specific guidance regarding 
infusion reactions. 
7.17.1.2.4 Opportunistic Infections Due to Immunosuppression 
Some subjects may require prolonged treatment with high-dose corticosteroids or 
alternative immunosuppressants for the treatment of immune-related AEs induced by 
relatlimab monotherapy or in combination with nivolumab. Subjects may develop 
opportunistic infections after receiving prolonged treatment with immunosuppressant 
agents, and these cases may require additional laboratory tests and invasive procedures 
for proper management. Prophylactic antibiotics and antifungal agents may also be 
indicated when prolonged treatment with corticosteroids has been planned. 
7.17.1.3 Cardiovascular Events 
Myocarditis has been observed with nivolumab monotherapy treatment (see nivolumab 
IB version 19, Appendix 1). No cases of myocarditis have been reported with 
monotherapy relatlimab treatment. However, 15 cases (1.1% of all grade myocarditis, 
autoimmune myocarditis, or immune mediated myocarditis have been reported for 
relatlimab in combination with nivolumab. These include 5 Grade 1, 3 Grade 2, 5 Grade 
3, and 2 Grade 4 cases.  
 
Given the clinical significance of myocarditis and the known nonclinical mouse double 
LAG-3/PD-1 knockout myocarditis phenotype, increased cardiac surveillance during the 
first 2 months of therapy with troponin measurements (at baseline and prior to study drug 
administration) was instituted, as well as excluding subjects with a history of myocarditis. 
Thus, all subjects treated in the expansion cohorts in Studies CA224020, CA224022, and 
CA224034 have had troponin surveillance as well as ECG monitoring. In this setting, 
there have been 12 cases of symptomatic myocarditis (5 Grade 2, 5 Grade 3, and 2 Grade 
4) and 5 reported cases of asymptomatic troponin increases without evidence of cardiac 


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dysfunction but with imaging (cardiac-specific MRI or PET) abnormalities consistent 
with myocardial inflammation (Grade 1 myocarditis per Common Terminology Criteria 
for Adverse Events, version 4). In all of the symptomatic cases, there was ejection 
fraction improvement with immunosuppression and discontinuation of study therapy. In 
the Grade 1 myocarditis cases, study drug was held and precautionary steroid treatment 
was given without any of the subjects developing evidence of cardiac dysfunction. 
Subjects experiencing myocarditis may be considered for re-challenge with study 
medication pending follow-up cardiac evaluations and assessment of cancer disease 
status. 
Refer to the specific study protocol for individual study specific eligibility criteria, 
required procedures, and instructions regarding cardiac toxicity monitoring and 
evaluation, as guidance may evolve with the increasing clinical and safety experience 
with the combination of relatlimab and nivolumab. All troponin elevations or suspected 
cardiac toxicity should result in immediate repeat testing and cardiac evaluation.  
Please note that myocarditis AE management algorithm applicable to studies under 
version CTCAE v4.0, and relatlimab myocarditis algorithm applicable to studies under 
CTCTAE v5.0 are included in Appendices B and C; Investigator Brochures for 
Nivolumab (BMS-936558) and Relatlimab (BMS-986016). 
7.17.1.4 Other 
Risks from the PK, PD, and clinical safety phlebotomy procedures are standard and 
include discomfort at the phlebotomy site, bleeding, bruising, and, rarely, infection and 
fainting. Risks from tumor biopsy include removal of tissue that can elicit pain, pressure, 
or discomfort in the area where the tissue was taken. Pain and discomfort can last for 
several hours and up to several days after the biopsy procedure. Subjects may experience 
bleeding, redness, swelling, bruising, and infection in the area where the tissue was taken 
or may feel faint or dizzy. 
 
7.18 
Risks of Surgery for Tumor Resection—Standard Care 
Standard of care neurosurgical techniques will be used for removing the tumor and risks 
of surgery are standard for intracranial surgery, including aphasia, hemiparesis, and 
sensory loss.  The risk of neurological deficit depends on the proximity of the tumor to 
language, motor, and somatosensory cortex.  
8.0 
Subject Safety Monitoring 
 
8.1 Parameters to be monitored 
There will be ongoing extensive patient education before and after surgery to ensure that 
the patient reports all adverse events at the time they occur.  All personnel involved in 
this study are provided with training and written guidelines concerning the definitions of 
adverse events (AE) and serious adverse events (SAE) and their responsibilities if they 
believe they have identified an AE/SAE, including reporting any SAE within 24 hours 
and the completion of the AE/SAE Form.   
 


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8.1.1 Study Monitoring Phase 1 – Before surgical resection  
Once the patient has been enrolled into the trial, they will be considered to be in Phase 1 
of the trial which precedes the surgical resection of the tumor. This period will include 
the research surgical procedure, the monitoring period in the intensive care unit and 
inpatient unit and the first dose of Nivolumab. All patients will be monitored for adverse 
events graded as per the National Cancer Institute Common Terminology Criteria for 
Adverse Events.  
 
Of note, there is a possibility, though remote, that a frozen section could indicate 
recurrent tumor, but that the final pathology may only demonstrate treatment effects with 
no viable tumor. If that is the case, the patient’s microdialysis catheters and lumbar drain 
can be removed in the  inpatient unit without returning to the operating room. The patient 
would then be withdrawn from the study as per 8.6, below, and would be replaced. 
Microdialysis catheter removal in the inpatient unit has been performed in the setting of 
research studies quite commonly. The microdialysis catheters in a recently completed 
study of regadenoson as a blood-brain barrier opening agent in glioblastoma at the NIH 
were removed in the intensive care unit with no morbidity. 
 
Additionally, as noted in 8.6, below, a patient who experiences a grade 3 or 4 toxicity 
during Phase 1 of the trial which precludes the completion of the inpatient monitoring 
period will be withdrawn from the trial. At that time, the patient’s microdialysis catheters 
and lumbar drain would be removed in the inpatient unit. Surgical resection would 
proceed as per standard of care if still clinically indicated. Otherwise, further standard of 
care treatment will be offered. The patient can also return to the care of their physicians 
outside of the NIH. 
 
In addition to our standard post-operative care for our patients, we will be specifically 
assessing our patients for the following adverse events that are likely to be related to the 
research surgical procedure – intracerebral hemorrhage, meningitis and wound infection. 
Any grade of adverse events, as defined by CTCAE version 5.0, which occur within the 
first 3 patients will trigger an evaluation by the Safety Monitoring Committee to approve 
the enrollment of the next patient. Any adverse event Grade 2 or higher or any delay in 
planned surgery in any patient at any point during the pilot trial due to an adverse event 
related to the experimental procedures in Phase 1 will also trigger an evaluation by the 
Safety Monitoring Committee (for patients enrolled at NIH) and the Data and Safety 
Monitoring Board (for patients enrolled at the Emory Site) to approve the enrollment of 
the next patient. 
 
Infusion reaction: Monitoring for an infusion reaction will begin on day 3 of the protocol 
within the patient’s inpatient stay. This monitoring will consist of clinical observation, 
with q15 minute vital signs, during the infusion and for the first two hours after infusion. 
Specifically, we will be checking the patients for fever, chills, shaking, itching, rash, 
hypertension or hypotension or difficulty breathing during the administration of 
Nivolumab or immediately afterwards (within the subsequent 2 hours).  
 


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For infusion reactions, the patients will be treated according to I-O AE Algorithms from 
Appendices B and C; Investigator Brochures for Nivolumab (BMS-936558) and 
Relatlimab (BMS-986016). Generally, Grade 1 infusion reactions will be observed. 
Grade 2 or 3 infusion reactions will prompt interruption of the patient’s infusion until the 
observed symptom returns to the level of a Grade 1 reaction. Patients will be given 25mg 
of Benadryl IV and 650 mg of Tylenol PO for any grade 2 or 3 infusion reaction. The 
Benadryl can be repeated once for symptom resolution until the reaction returns to a level 
of Grade 1. If a patient has a Grade 2 or 3 reaction, subsequent infusions will be preceded 
by 25mg of Benadryl IV and 650mg of Tylenol PO 30 minutes prior to dosing. Grade 4 
reactions will cause discontinuation of the therapy.  
 
Additionally, the following safety monitoring procedures will be undertaken during 
Phase 1 of the trial: 
 
-The patient will undergo an immediate post-operative neurological examination within 4 
hours of the completion of the case to rule out any neurological morbidity after the 
research biopsy and microdialysis catheter placement; 
-The patient’s dressing will be examined on a daily basis for signs of infection including 
increased tenderness, foul odor, discharge or discoloration of the dressing. 
-A CT scan will be performed in the immediate post-operative period within 8 hours of 
the completion of the case to ensure lack of hemorrhage at site of catheter implantation;  
-In the intensive care unit, the patient will undergo monitoring in the ICU for 24 hours 
after microdialysis catheterization, and then an inpatient stay with a one-on-one sitter (7 
days) after biopsy 
-The patient will have q2hr neurological checks for the first 24 hours after surgery 
-During the remainder of the patient’s time while admitted, they will have q4hr 
neurological checks while awake; 
-If any significant neurological changes are found on the neurological checks, the patient 
will be sent for a STAT head CT to rule out late onset of hemorrhage; 
-Patient will have q4hr temperature checks while admitted 
-Patient will be watched for signs and symptoms of adrenal insufficiency while admitted 
during nursing checks and daily physical exams 
-Patients will have skin examinations and will be asked for signs and symptoms of 
immune-mediated rash while admitted 
-CSF will be collected from the lumbar drain for safety monitoring on Mondays and 
Thursdays while the patient is in the inpatient unit, as long as the lumbar drain remains in 
place. We will send a cell count, protein, glucose, gram stain and culture from each 
sample 
-Patients will undergo a CBC with differential daily while in the inpatient unit to watch 
for signs of infection. 
-Patients will be monitored with metabolic panels daily during the microdialysis 
monitoring period 
-Patients will undergo liver function testing on day 3 prior to study drug administration.  
-Patients will undergo CPK testing on day 3 prior to study drug administration. 
Lab values that would preclude dosing of Nivolumab include: 
-Creatinine > Upper limit of normal and > 1.5x baseline 


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-AST > 3.0 times upper limit of normal 
-ALT > 3.0 times upper limit of normal 
-Total bilirubin > 1.5 times upper limit of normal 
-WBC > 2.0 times upper limit of normal 
-CPK > 2.0 times upper limit of normal 
-Patients will be followed with QAC and QHS accuchecks for glycemic control while 
admitted 
-If the flow through either of a patient’s microdialysis catheters stops, this catheter will 
be removed in the inpatient unit. 
 
8.1.2 Study Monitoring Phase 2-Surgical Resection and follow-up period: 
Once the patient goes into surgery for tumor resection, they will be considered to be in 
Phase 2 of the trial. The patient’s post-resection care until Day 17 (+/- 2 days) will be 
carried out largely in accordance with standard of care. The patient will stay in the ICU 
for at least 24 hours after the surgical resection. The patient will receive a post-operative 
MRI to ensure adequate resection and lack of surgical complications that would be 
evident on MRI. Once the patient is deemed stable to transfer from the ICU, they will 
then be monitored in the NPCU for 2-5 days, on average, before being discharged to 
home.  
 
While being monitored as an inpatient, patients will be specifically evaluated by the 
medical and nursing staff for symptoms and signs of 1) focal neurologic dysfunction, 
such as weakness, sensory loss, and aphasia; 2) general neurologic dysfunction, such as 
somnolence; 3) increased intracranial pressure; and 4) infection of the wound, brain, or 
meninges.  
 
During the study follow-up period, from discharge from the hospital through the 
discontinuation of study medications, monitoring will be carried out in accordance with 
the prescriber information for Nivolumab. Additional precautions will be taken due to the 
addition of BMS-986016 to the dosing regimen. 
 
Pre-infusion monitoring will include a rigorous evaluation prior to each dose of study 
medications. Prior to the first dose, patients will undergo an echocardiogram, free T3 and 
T4 and baseline ACTH and AM cortisol. Prior to each dose, lab tests will include: 
-complete blood count with differential  
-liver function tests with AST, ALT and Tbili,  
-metabolic panel with creatinine, 
-CRP  
-TSH 
-CPK (prior to the first dose of nivolumab) 
-troponin (prior to the first five doses of BMS-986016),  
-EKG (prior to the first five doses of BMS 986016) 
 
Prior to each dose, patients will also undergo: 


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-History and physical examination with detailed neurological examination, skin 
examination and evaluation for signs of adrenal insufficiency and evaluation for 
respiratory compromise; 
-Vital signs 
-MRI (at every other treatment visit, starting on Day 17 (+/- 2 days)); 
 
Lab values that would preclude dosing of Nivolumab and BMS-986016 include: 
-Creatinine > Upper limit of normal and > 1.5x baseline 
-AST > 3.0 times upper limit of normal 
-ALT > 3.0 times upper limit of normal 
-Total bilirubin > 1.5 times upper limit of normal 
-WBC > 2.0 times upper limit of normal 
-CPK > 2.0 times upper limit of normal 
 
Prolonged QT interval, arrhythmia, T-wave abnormalities or any other concerning ECG 
findings will prompt a consultation to cardiology to rule out pre-existing or newly 
developed cardiac pathology prior to dosing of the study drugs. 
 
Monitoring for an infusion reaction and cytokine release on Day 17 (+/- 2 days) of the 
protocol will consist of clinical observation in the day hospital ward or 7SW (if the 
patient remains admitted to the hospital) of the NIH Clinical Center. The total infusion 
monitoring time will be expected to last 4-5 hours for most patients. First, the patient will 
receive Nivolumab as an IV infusion over 30 minutes. Patients with a prior Grade 2 or 3 
infusion reaction will have pretreatment with 25mg of Benadryl IV together with 650mg 
of Tylenol PO. During both infusions, patients will have q15 minute vital signs, including 
temperature, pulse, blood pressure and pulse oximetry. BMS-986016 infusion will begin 
15-30 minutes after completion of the Nivolumab infusion. BMS-986016 will then be 
given as an IV infusion over 60 minutes with ongoing monitoring. The patients will also 
be monitored for two hours after completion of the BMS-986016 in the day hospital or 
7SW. Specifically, we will be checking the patients for fever, chills, shakes, itching, rash, 
hypertension or hypotension or difficulty breathing during the administration or 
immediately afterwards (within the following 2 hours). The patients will be treated 
according to I-O AE Algorithms from Appendices B and C; Investigator Brochures for 
Nivolumab (BMS-936558) and Relatlimab (BMS-986016).  Generally, Grade 1 infusion 
reactions will be observed. Grade 2 or 3 infusion reactions will prompt interruption of the 
patient’s infusion until the observed symptom returns to the level of a Grade 1 reaction. 
Patients will be given 25mg of Benadryl IV and 650 mg of Tylenol PO for any grade 2 or 
3 reaction. The Benadryl can be repeated once for symptom resolution until the reaction 
returns to a level of Grade 1. If a patient has a Grade 2 or 3 reaction, subsequent infusions 
will be preceded by 25mg of Benadryl IV and 650mg of Tylenol PO 30 minutes prior to 
dosing. Grade 4 reactions will cause discontinuation of the therapy. Patients will be 
instructed to inform the clinical team of any symptoms including, but not limited to, 
fever, chills, itching, shortness of breath, stomach discomfort, diarrhea, new neurological 
symptoms, seizures, changes in urinary function, chest pain, palpitations, rashes or any 
other significant concern in between drug doses. 
 


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Additionally, we will follow the I-O AE Algorithms from Appendices B and C; 
Investigator Brochures for Nivolumab (BMS-936558) and Relatlimab (BMS-986016). 
Additionally lab tests will be ordered as clinically indicated. 
Adverse effects will be monitored systematically throughout the study with formal 
assessments at each evaluation visit.  In addition, subjects will be encouraged to contact 
the investigators by telephone any time there is any concern about side effects.  If 
necessary, an unscheduled clinical visit with the investigator will be arranged.  Patients 
will have access to clinicians day and night for the duration of the study.  The Principal 
Investigator, in collaboration with the Safety Monitoring Committee (for patients 
enrolled at NIH) and the Data and Safety Monitoring Board (for patients enrolled at the 
Emory Site), will be responsible for monitoring data collected to ensure the safety of 
subjects.   
 
Monitoring for safety of individual subjects during participation in study procedures will 
be performed by the medical staff and the research nurses.   
 
8.2 Toxicity Criteria 
Toxicities and adverse events will be recorded and categorized according to severity, 
relationship to procedure, and relationship to the study procedure or study drugs.  Level 
of toxicity is based on the NCI CTCAE criteria. 
 
8.3 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 (eg, 
dose tapering if necessary for participant). The patient will continue to be followed until 
the outcome of the pregnancy can be determined, and will then continue with routine 
surveillance imaging as per the protocol. 
8.4 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. 
8.5 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 nonserious or 
serious AE, as appropriate, and reported accordingly.  
8.6 Criteria for Individual Subject Withdrawal from the Study 
Subjects may withdraw from the study at any time for the following reasons:  
1. Subject's prerogative:  The subject desires to discontinue participation in this 
study. 


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2. Investigator's prerogative:  The subject is unwilling or unable to comply with the 
protocol. 
 
Subjects must discontinue study drugs for the following reasons: 
1. The biopsy indicates that the patient does not have a true pathological recurrence 
of their tumor 
2. The patient experiences a grade 3 or 4 toxicity during Phase 1 of the trial which 
precludes the completion of the inpatient monitoring period 
3. The patient experiences a toxicity consistent with the Nivolumab prescribing 
information that requires discontinuation of Nivolumab. Such toxicities will be 
deemed sufficient to discontinue both Nivolumab and BMS-986016. Specifically, 
these toxicities are: 
a. Immune-mediated pneumonitis: Grade 3 or 4 immune-mediated 
pneumonitis will prompt automatic discontinuation of study drugs 
b. Immune-mediated colitis: Grade 4 immune-mediated colitis will prompt 
automatic discontinuation of study drugs 
c. Immune-mediated hepatitis: Grade 3 or 4 immune-mediated hepatitis will 
prompt automatic discontinuation of study drugs 
d. Immune-mediated endocrinopathies: Grade 4 immune-mediated 
hypophysitis; Grade 3 or 4 immune-mediated adrenal insufficiency; and 
Grade 4 hyperglycemia will prompt automatic discontinuation of study 
drugs. Additionally, thyroid function will be followed, and thyroid 
hormone replacement will be given as needed 
e. Immune-mediated nephritis and renal dysfunction: Grade 4 serum 
creatinine elevation will prompt automatic discontinuation of study drugs 
f. Immune-mediated skin adverse reactions: Grade 4 rash will prompt 
automatic discontinuation of study drugs 
g. Immune-mediated encephalitis: Grade 4 encephalitis will prompt 
automatic discontinuation of study drugs 
h. Infusion reactions: Grade 3 or 4 infusion reactions will prompt automatic 
discontinuation of study drugs 
i. In addition to the above, due to the report of myocarditis in one patient on 
the combination of BMS-986016 and Nivolumab, Grade 4 myocarditis 
will prompt automatic discontinuation of study drugs 
4. Clinical progression  
5. Confirmed radiological progression and investigator determination that the patient 
is no longer benefiting from treatment with the study treatment 
 
If study drug is discontinued, the patient will enter the survival follow-up phase of the 
study.  
 
Additionally, if a patient is removed from the study for clinical or radiological 
progression of disease, we will perform a follow-up assessment at the next scheduled 
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9.0 Outcome Measures 
 
9.1 Primary outcome measure  
The primary outcome measures are:  
 
1. 
The proportion of patients that have a rise in interferon gamma levels within 
the tumor microenvironment of 4 pg/ml or higher before the first dose of 
Nivolumab as compared to the 5th day after treatment with Nivolumab. 
2. 
The safety of the use of microdialysis catheters for immune monitoring in 
recurrent glioblastoma patients 
3. 
The safety of the combination of nivolumab and BMS-986016 in recurrent 
glioblastoma patients 
 
9.2 Exploratory outcome measures 
Exploratory outcome measures and include:   
1. The change in interferon gamma expression from before, during and after 
Nivolumab treatment in the brain microenvironment, cerebral spinal fluid and the 
blood.  
2. The difference between the IHC staining for CD3, CD4, CD8, CD20, CD45RO, 
CD57, CD68, FOXP3, Granzyme B, LAG3, PD-1, CD14, CD33, CD163, and 
CD206 before and after Nivolumab therapy. These markers will be evaluated as 
density of cells, defined as the number of positive cells per mm2. PD-L1 
expression will be evaluated in tumor cells using H-score, which includes the 
percentage of positive cells showing membrane staining pattern (0–100) 
multiplied by the intensity of the staining (0 to 3+), with a total score ranging 
from 0 to 300. The final score for each marker will be expressed as the average 
score of the areas analyzed within the tumor region (tumor center). 
3. Progression free survival and overall survival of recurrent glioblastoma patients 
after treatment. Progression free survival is defined as the time length from the 
first dose of study drug with recurrence to progression as defined by iRANO 
criteria, and the overall survival is defined as the time length from the first dose of 
study drug to death. If a lesion is 25% larger but there remains a question as to 
disease progression or pseudoprogression due to treatment, the patient can remain 
on treatment until this can be defined. If true progression occurred earlier, the 
earlier date will be used for censorship. If patient is lost to follow-up prior to 
documented progression or death, patient will be censored as of the date of the last 
adequate evaluation (MRI and exam). If patient dies prior to documentation of 
progression, progression will be defined as the date of death, if patient has been 
attending regularly scheduled follow-ups.  
4. The difference in progression free survival and overall survival between patients 
who have an interferon gamma response versus those that do not have one. 


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5. The difference in the immune cells and secreted factors of the tumor environment 
as compared to the immune cells and secreted factors of the cerebral spinal fluid, 
blood and potential bone marrow in response to this treatment 
10.0 Statistical Analysis 
 
10.1 Data analysis 
Primary goals 
1) To determine the proportion of patients who have an increase of interferon 
gamma production within the tumor microenvironment from before and after 
therapy with the immune checkpoint inhibitor, nivolumab.  
The change will be dichotomized as increase vs. no increase with the threshold of 
4pg/ml. The proportion of the patients with increase will be evaluated by exact 
binomial test.  
 
2) To evaluate the safety of using brain tumor microdialysis to monitor response to 
immune modulators in patients with recurrent glioblastoma. 
Descriptive statistics, such as frequency and percentage, will be used to evaluate 
the safety of these procedures. 
 
3) To evaluate the safety of the combination of Nivolumab and BMS-986-016 in the 
treatment of recurrent glioblastoma patients. 
Descriptive statistics, such as frequency and percentage, will be used to evaluate 
the safety of these treatments. 
 
Exploratory Goals  
1) To determine the change in interferon gamma production within the tumor 
microenvironment and in the rest of the body from before and after therapy with the 
immune checkpoint inhibitor, nivolumab.  
A one-sample t-test or Wilcoxon signed rank test will be performed to evaluate the 
change (continuous) over time (between pre- and post-treatment) in the outcome 
measures 
2) To evaluate the pathological response of the immune microenvironment of brain tumor 
tissue to the first dose of Nivolumab 
A one-sample t-test or Wilcoxon signed rank test will be performed to evaluate the 
change between pre- and post-treatment for each marker evaluated.  
3) To evaluate the clinical response (progression free survival, overall survival) of 
recurrent glioblastoma patients to this treatment  
The Kaplan-Meier method will be used to estimate the survival function and generate 
survival curves. The study is not powered to detect significant differences in survival 
between the patients in this cohort and historical controls. 
4) To describe the difference in survival between responders and non-responders 
Descriptive statistics will be used. The study is not powered to detect significant 
differences in survival between the patients in this cohort and historical controls. 


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5) To examine the differences in the immune cells and secreted factors of the tumor 
environment as compared to the immune cells and secreted factors of the cerebral spinal 
fluid, blood and potential bone marrow in response to this treatment  
Repeated measures ANOVA or Friedman test will be performed to evaluate the change 
(continuous) over time (between pre- and post-treatment) and between brain 
compartments (or between brain and the peripheral immune system, or between the two 
different micro dialysis catheters). 
 
10.2 Power analysis 
The power analysis was performed using the primary outcome, which is defined as 
increase vs. no increase based on the difference in expression of interferon gamma 
between baseline and the 5th day after nivolumab treatment with the threshold of 4pg/ml. 
The hypothesis is that the proportion of the patients with increase is greater than 0.2 . The 
expected proportion is 0.7.  The following table shows the estimated power based on 10 
subjects for different null and observed proportions using the two-sided exact binomial 
test. 
 
 
Table 6 - The estimated power of 10 subjects for different null and observed proportions 
Null 
Hypothesis  
Expected 
Proportion 
Actual 
Alpha 
Estimated 
Power 
0.1 
0.9 
0.0128 
>.999 
0.8 
0.0128 
>.999 
0.7 
0.0128 
0.989 
  
0.6 
0.0128 
0.945  
0.2 
0.9 
0.00637 
0.998 
0.8 
0.00637 
0.967 
  
0.7 
0.00637 
0.85 
0.3 
0.9 
0.01059 
0.987 
  
0.8 
0.01059 
0.879 
0.4 
0.9 
0.01834 
0.930  
 
Table 6 indicates that a sample size of 10 subjects: (a) will have 85 power to reject the 
null hypothesis: p<=0.2 when >=7 subjects are found to have increased interferon gamma 
in five days after the treatment and (b) will have 93.0% power to reject the null 
hypothesis: p<=0.4 when >=9 subjects are found to have increased interferon gamma. 


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Table 7 - 95% confidence limits (CL) for proportions with a sample size of 10 subjects.  
Observed 
95% CL 
proportion 
  
  
1 
0.6915 
1 
0.9 
0.555 
0.9975  
0.8 
0.4439 
0.9748 
0.7 
0.3475 
0.9333 (a) 
0.6 
0.2624 
0.8784 
0.5 
0.1871 
0.8129 
0.4 
0.1216 
0.7376 
0.3 
0.0667 
0.6525 
 
Table 7 presents the 95% confidence limits for the observed binomial proportion 0.3 to 
1.0 based on a sample size of 10 subjects.  For a sample size of 10 subjects, if 7 subjects 
are observed with increased interferon gamma in five days, the interval of (0.35, 0.93) 
will have 95% probability to include the true proportion (a). 
11.0 Human Subjects Protection 
 
11.1 Subject Selection 
Enrollment will be equitable among those individuals who meet the inclusion criteria and 
will not be based on race, ethnicity, or gender.   
 
Patients who are considered for this protocol are those with recurrent glioblastoma who 
are surgical candidates. The patient population for this study is restricted to patients with 
recurrent glioblastoma, as experimental therapy is warranted in the care of these patients 
and surgical resection is indicated for these patients. 
 
11.2 Justification for exclusion of participants less than 18 years old  
Participants under the age of 18 years are excluded because glioblastoma is rarely seen in 
the younger population. An adult’s immune system is also different so the effects of 
immune modulators in children and young adults may also be different than in adults.   
 
11.3 Justification for exclusion of other vulnerable subjects  
Subjects who lack consent capacity due to cognitive impairment, or patients with mental 
disorders or with cognitive impairment that renders them unable to give consent will be 
excluded because they will be unlikely to be able to safely participate in ongoing 
microdialysis monitoring in the intensive care unit.  
 
Subjects who do not speak English or Spanish will be excluded from the protocol, as 
there is a need for close communication between the investigators and subjects, given the 
nature of the interventions in this trial. 
 


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Pregnant and breastfeeding women are excluded as we do not know if Nivolumab can 
harm a developing fetus or breastfeeding infant. 
 
11.4 Safeguards for vulnerable populations and sensitive procedures  
Adults who participate in the protocol are required to sign a durable power of attorney 
because of the possibility that they may become unable to make decisions about research 
participation and medical care during the course of participation.  
 
If a patient loses consent capacity after enrollment but before completion of the 
monitoring period in the inpatient unit and the subsequent tumor resection, they will 
proceed through the trial, granted that the patient opts to sign assent and their durable 
power of attorney believes that they would want to proceed. If a patient loses capacity 
after enrollment but before completion of the monitoring period in the inpatient unit and 
refuses to sign the assent or the durable power of attorney determines that the patient 
would not want to continue with the trial, they are removed from the trial and replaced.  
Those who lose capacity after enrollment and after completion of the monitoring period 
and subsequent tumor resection will be given the opportunity to continue in the study. In 
this latter case, a memorandum will be generated that includes a justification for their 
continued involvement in the protocol, and their DPA will be referred to for further 
decision-making while at the National Institutes of Health.  
 
The decision process discussed with the DPA will include a summary of risks of the 
research and likelihood of benefit (if any) for adults unable to consent. The procedure 
utilized for obtaining the surrogate consent (assent) will be documented, including the 
procedures for allowing dissent.  
 
The Ability to Consent Assessment Team (ACAT) will be used to provide additional 
safeguards and protections for vulnerable subjects.  If there are any questions about 
capacity to consent, the Ability to Consent Assessment Team (ACAT) may be consulted. 
The ACAT may also be consulted, at the discretion of the PI on an ad hoc basis if the 
subject’s mentation changes over the course of the study. 
  
Safeguards for females of childbearing potential:  Pregnant women may not be enrolled 
in this trial. Pregnancy testing will be performed during the initial screening portion of 
the trial, and every month, prior to MRI scanning, subsequently; and contraception is 
required during the duration of the trial. Contraception is also required for the 24 weeks 
after the last exposure to the study drug for those patients of childbearing potential. 
Subjects who are capable of fathering children will need to use effective contraception 
until 33 weeks after the last exposure to the study drug. 
 
Safeguards for pediatric patients:  Pediatric patients will not be enrolled in this trial. 
 
Safeguards for NIH employees: Protections for employees and staff participating in this 
study include 1) assuring that the participation or refusal to participate will have no 
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2) giving employees and staff who are interested in participating the “NIH Information 
Sheet on Employee Research Participation” prior to obtaining consent, and 3) assuring 
that there will be no direct solicitation of employees or staff.  4) Independent consent 
monitoring will be provided by the NIH HSPU. 5) The PI will train study staff regarding 
obtaining and handling potentially sensitive and private information about co-workers 
through staff discussions and written branch/section procedures.  No compensation will 
be provided for this protocol.  
 
Sensitive information will be collected from employees participating in the study, 
including pregnancy status, full medical history, family medical history, psychiatric 
history, substance abuse history and other components of a full medical history. Surgical 
treatment will require the employee to be disrobed in front of other clinical center staff. 
These sensitive procedures will be disclosed to employees at the time of enrollment. 
Sensitive information that is made part of the medical record will be accessible to the 
NIH staff that are involved in the medical care of the patient. Whenever possible, only 
coded data will be made available to those research staff involved in data processing, and 
protected health information will only be shared as needed to match patient data to other 
clinical data for processing. 
 
Safeguards for subjects who do not speak English: Subjects who speak Spanish as their 
primary language will be given the option of reading and signing the Spanish consent for 
this protocol. A Spanish interpreter will be used to maximize communication between the 
investigators and participants during the consent process and to help the investigators 
answer participant questions. An interpreter will be used for all procedures for those 
subjects who do not understand English fluently. If a Spanish interpreter is not available, 
Spanish-speaking staff or the interpreter phone line will be used. An interpreter will also 
be available throughout the duration of the study and at any follow-up appointments for 
all patients.  
 
Sensitive procedures: No sensitive procedures (deception, placebo, medication 
withdrawal, etc.) will be used. 
12.0 Anticipated Benefit 
Subjects will receive Nivolumab and BMS 986016, agents that may have activity for the 
treatment of brain tumors, though this is not yet proven. This may present the possibility 
of direct benefit if the therapy slows the progression of the tumor, but any benefit may be 
short-lived. Increased knowledge of the immune activity of this treatment will not 
directly medically benefit the patient, but may guide further treatment for future 
glioblastoma patients.  
 
12.1 Overall risk and benefit consideration 
The risks are reasonable in relation to anticipated benefit 


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13.0 Consent Documents and Process 
 
13.1 Designation of those obtaining consent 
Study investigators designated as able to obtain consent on Study Personnel Page, will 
obtain informed consent. Only advanced medical practitioners that are credentialed at the 
level of a nurse practitioner, physician’s assistant or physician will be permitted to obtain 
consent. All study investigators obtaining informed consent have completed the NINDS 
HSPU ‘Elements of Successful Informed Consent’ training.  
 
13.2 Consent procedures  
Cognitive capacity to consent will be determined at the time of enrollment by the treating 
advanced medical practitioner. At the time of enrollment, a lack of consent capacity due 
to cognitive impairment is a state that would make them incapable of understanding the 
explanation of the procedures in this study, and the patient would be excluded from 
enrollment. If there is any question of the ability of the patient to consent, the ACAT will 
be consulted. All participants will receive a verbal explanation in terms suited to their 
comprehension of the purposes, procedures and potential risks of the study and of their 
rights as research participants. Participants will have the opportunity to carefully review 
the written consent form and ask questions regarding this study prior to signing. 
 
Adults must be able to provide consent upon study entry.  
 
The risks and benefits of the proposed study will be explained to the subject. This 
discussion will include the discussion of the procedures that are research only as opposed 
to the standard of care. We will also discuss the potential treatments available in the 
community and other clinical trials available at the National Institutes of Health such as 
additional radiation, alternative chemotherapeutic agents or surgical treatment without 
additional therapy. A copy of the informed consent document will be given to the patient. 
The consent documents contain all required elements and are attached separately. Copies 
of the consent documents will be maintained in the research records. The original consent 
will be placed in the patient’s medical record. Adults must appoint a durable power of 
attorney (DPA) upon study entry. If there is any question of the ability of the DPA to 
consent, the ACAT will be consulted. The DPA will only be invoked if medically 
necessary due to a new lack of decision-making capacity that occurs during the trial as a 
result of medical treatment or progression of disease. 
 
It is possible that as a result of the research or standard of care neurosurgical procedures 
that the patient could lose consent capacity over the course of the study. A patient could 
also become incapacitated as a result of progression of their lesion during the continued 
Nivolumab treatment in the follow-up period. If a patient loses consent capacity after 
enrollment but before completion of the monitoring period in the inpatient unit and the 
subsequent tumor resection, they will proceed through the trial, granted that the patient 
opts to sign assent and their durable power of attorney believes that they would want to 
proceed. If a patient loses capacity after enrollment but before completion of the 
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of attorney determines that the patient would not want to continue with the trial, they are 
removed from the trial and replaced.  Those who lose capacity after enrollment and after 
completion of the monitoring period and subsequent tumor resection will be given the 
opportunity to continue in the study. In this latter case, a memorandum will be generated 
that includes a justification for their continued involvement in the protocol, and their 
DPA will be referred to for further decision-making while at the National Institutes of 
Health.  
 
We will present any patients who lose consent capacity with an assent form to continue 
with their participation in the study. The patient’s DPA or other appropriate 
representative would be taken through the consent process at this time. A copy of the 
assent form is attached. Written assent will be obtained from those without consent 
capacity. Any dissent from the patient will be respected.  
Subjects who speak Spanish as their primary language will be given the option of 
reading and signing the Spanish consent for this protocol. A Spanish interpreter will be 
used to maximize communication between the investigators and participants during the 
consent process and to help the investigators answer participant questions. An interpreter 
will be used for all procedures for those subjects who do not understand English 
fluently. If a Spanish interpreter is not available, Spanish-speaking staff or the 
interpreter phone line will be used. An interpreter will also be available throughout the 
duration of the study and at any follow-up appointments for all patients.  
 
13.3 Consent documents 
The consent form contains all required elements. The following consent documents are 
submitted with this protocol – subject consent (English and Spanish) and assent (English 
and Spanish). 
14.0 
Data and Safety Monitoring 
14.1 Data and safety monitor 
This protocol will utilize a Safety Monitoring Committee (SMC) (for patients enrolled at 
NIH) and the Data and Safety Monitoring Board (for patients enrolled at the Emory Site), 
and an Independent Medical Monitor (IMM) to review AEs and safety reports.  The 
Safety Monitoring Committee (for patients enrolled at NIH) will be composed of: 
• Russell Lonser, MD: Chairman of Neurosurgery, OSUMC, Former Chief of 
Surgical Neurology Branch, NINDS; considerable experience in invasive 
neurosurgical trials at the NIH Clinical Center and elsewhere including first in 
human studies, surgical practice focuses on neurosurgical oncology 
• Richard Sherry, MD: Staff Clinician, Surgery Branch, National Cancer Institute, 
National Institutes of Health; extensive experience as a surgeon in the design and 
conduct of clinical trials of immunotherapies in cancer patients. 
• Kilian Salerno, MD: Staff Clinician, Radiation Oncology Branch, National 
Cancer Institute, National Institutes of Health: experienced clinician in the 
treatment of primary and recurrent glioblastoma patients with radiation therapy. 


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• A backup SMC member will be provided by the IND Sponsor, if required.  The 
backup SMC member will have experience with immunotherapy or treatment of 
primary and recurrent glioblastoma patients. 
 
The DSMB members and Chairperson were appointed by NINDS Clinical Trials Unit 
(CTU) and approved by the CD and IRB. The members reflect the disciplines and 
medical specialties necessary to interpret the data from the study and ensure participant 
safety.  The membership of the DSMB are outlined in the DSMB Charter. 
 
Dr. Lauren Reoma, MD, NINDS Staff Clinician, will serve as the IMM for this trial. A 
backup IMM will be supplied by the IND sponsor, if required.  The backup IMM will be 
an NINDS clinician with knowledge of FDA regulation and immune therapy. 
 
14.2 Data and safety monitoring plan 
Study investigators will evaluate the safety of study subjects throughout the conduct of 
the study and respond to adverse events (AEs) in a timely manner.  The IMM will be sent 
once weekly written patient status reports during the inpatient admission of any study 
patient for the study procedures (Week 0 through Week 2), or more frequently if needed. 
The IMM may also be consulted in person and as needed to discuss clinical issues. In 
person consultations with the IMM will be documented. 
 
The DSMB serves as the Sponsor’s medical monitor and will make final determinations 
of relatedness and expectedness on behalf of the Sponsor (NINDS). The DSMB is 
charged with reviewing all safety and efficacy data at a twice-yearly meeting. This 
meeting may take place in person, as a teleconference, or via email. The DSMB may be 
consulted in person and as needed to discuss clinical issues. The DSMB will operate 
under the rules of an approved charter that will be reviewed during the first DSMB 
meeting.  
 
All SAEs, or Grade 3 or higher AEs that are at least possibly related to the research will 
be forwarded to the DSMB as soon as possible but no later than 7 days after the PI learns 
of the event, and advice will be sought on whether or not any changes in the research plan 
are warranted. 
 
The Safety Monitoring Committee (SMC) (for patients enrolled at NIH) and the Data and 
Safety Monitoring Board (for patients enrolled at the Emory Site) will meet at intervals 
specified by the needs of the trial, via conference call, email, or web-meeting by a 
password protected phone line/secured email/web meeting.  The SMC will meet at the 
following intervals: 
• Prior to enrolling the first subject to confirm the monitoring plan 
• After each subject completes day 24 +/- 2 days  
• At least semiannually while the study is open to enrollment or has participants in 
active follow-up  
 


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Additional meetings may be scheduled when necessary for adequate monitoring. Reports 
containing cumulative safety data and a summary of study progress will be provided to 
the SMC and DSMB at the semiannual meetings.  Participant specific safety reports will 
be provided to the SMC and DSMB after each subject completes day 24 +/- 2 days. For 
the first 3 patients, the SMC and DSMB will review the available data at day 24 +/- 2 
days prior to approving the dosing of the next subject.  After that, the SMC will review 
the data from day 24 +/- 2 days within 4 weeks after completion of the visit, however 
further patients may initiate dosing before the SMC and DSMB review. SMC and DSMB 
meeting minutes will be documented and reported to the Principal Investigator, and to the 
IRB, through the PI, and NINDS Clinical Director.  Data review will be coded, and no 
interim analysis is planned.  
After each meetings, the DSMB chair will provide a report to the PI and NINDS Clinical 
Trials Unit (CTU) and Office of the Clinical Director (OCD). 
 
All SAEs, or Grade 3 or higher AEs that are at least possibly related to the trial will be 
forwarded to the SMC (for patients enrolled at NIH) and the DSMB (for patients enrolled 
at the Emory Site) and the IMM as soon as possible but no later than 7 days after the PI 
learns of the event, and advice will be sought on whether or not any changes in the 
research plan are warranted. 
 
This multi-institutional study will be monitored in accordance with the Sponsor’s Data 
Safety Monitoring Charter. 
 
14.3 Criteria for stopping the study or suspending enrollment or procedures 
If, in the judgment of the PI, IMM, the SMC or DSMB, a specific study procedure is 
yielding frequent unexpected or adverse outcomes, that procedure will be suspended until 
a review can be undertaken in consultation with the IRB. Specifically, for the first 3 
patients, if any grade toxicity that is related to the study procedure occurs during Phase 1 
of the trial, the Safety Monitoring Committee will be convened to discuss study 
procedures and to see if any changes need to be made. Any adverse event Grade 2 or 
higher or any delay in planned surgery due to an adverse event related to the 
experimental procedures in Phase 1 at any point of the trial will also trigger an evaluation 
by the Safety Monitoring Committee to approve the enrollment of the next patient. This 
meeting will need to occur within 2 weeks of the adverse event. Enrollment will be halted 
until this meeting is convened.  
 
After the first 3 patients, the study will be automatically paused and further enrollment 
will be halted for any Grade 3 or higher SAE in Phase 1 of the trial. Enrollment will be 
halted until this meeting is convened and the IRB has reviewed and approved the findings 
of the committee. Depending on the results of this meeting, the procedure in question 
may be dropped from the protocol via an amendment, or specific language may be added 
to the protocol and consent forms to reflect the changing risk level. 
15.0 Quality Assurance 
 


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15.1  Quality Assurance Monitor    
The Principal Investigator will ensure that:  
• 
the protocol is being correctly followed  
• 
changes to the protocol have been approved by the IRB  
• 
accurate, complete, and current records are being maintained and are secure  
• 
subject withdrawal or study failure is noted in the records and  
• 
informed consent has been correctly documented 
 
15.2  Quality Assurance Plan 
A Contract Research Organization (CRO) will monitor this protocol.  On-site monitoring 
will be carried out by the CRO.  An initial visit will be conducted by the CRO, following 
final approval of the protocol by the IRB and FDA.  During the initial visit, the study 
team and the monitor will determine the frequency of monitoring visits.  The PI/sponsor 
via the CRO, will be responsible for providing adequate oversight of the investigation to 
ensure adequate protection of the rights, welfare, and safety of human subjects and the 
quality and integrity of the resulting data.   
 
This multi-institutional study will be monitored in accordance with the Sponsor’s QA 
Monitoring Plan. 
16.0  Reporting of Unanticipated Problems, Adverse Events and Protocol 
Deviations 
 
Reportable events will be tracked and reported in compliance with Policy 801. 
 
16.1 FDA Reporting Criteria 
The protocol’s IMM will act as IND Sponsor’s (NINDS) Medical Monitor.  
 
Additionally, we will follow the reporting requirements as outlined in 21CFR312.32. The 
sponsor will notify the FDA of any unexpected fatal or life-threatening suspected adverse 
reactions as soon as possible but no later than 7 calendar days from initial receipt of such 
information using the MedWatch Form 3500a. 
 
The Sponsor is also responsible for reporting any of the following to the FDA and to all 
investigators no later than 15 calendar days after determining that the information qualifies 
for reporting using the MedWatch Form 3500a: suspected adverse reaction that is both 
serious and unexpected; any findings from clinical, epidemiological, or pooled analysis 
of multiple studies or any findings from animal or in vitro testing that suggest a 
significant risk in humans exposed to the drug; or clinically significant increase in the 
rate of a serious suspected adverse reaction over that listed in the protocol or either 
investigator brochure. If FDA requests any additional data or information, the sponsor must 
submit it to the FDA as soon as possible, but no later than 15 calendars days after receiving 
the request. 


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16.2 Reporting of protocol deviations 
For safety monitoring, during the microdialysis monitoring period and during subsequent 
protocol visits, safety checks performed within +/- 5 minutes of stated guidelines will not 
be considered protocol violations. More than two missed safety checks during infusion 
monitoring during the microdialysis monitoring period in Phase 1 of the study or during 
any individual subsequent infusion during Phase 2 of the study will be considered a 
protocol deviation.  
 
Patients who miss one or more doses of study drug due to treatment of inflammatory side 
effects will not be censored if these side effects are mild and/or treatable (Grade 1 or 2). 
Such patients will continue on the study drug when this is safe. This will not be 
considered a study deviation. Patients who miss one visit will be counseled that further 
missed follow-up will cause for them to be removed from the Nivolumab and BMS-
986016 treatment portion of the trial. Patients that miss two or more consecutive 
treatments with Nivolumab and BMS-986016 will be censored at the time that they are 
lost to follow-up. These would be reported as study deviations. We do not expect 
omissions such as these to affect the primary study outcomes, as these are focusing on the 
effects of the treatment in the immediate post-surgical period. Based on our experience 
working with the Neuro-oncology Branch in this patient population, we do not expect to 
lose many patients in this treatment period.   
 
In the event that circumstances beyond our control preclude the travel of one or more of 
the study participants to the NIH Clinical Center for a visit, or otherwise would put their 
health at greater risk (i.e. epidemic or pandemic), we will endeavor to establish 
capabilities for remote visits. Specifically, for safety visits, the study team will arrange 
for local laboratory studies to be done, which include comprehensive metabolic panel 
(with creatinine), GGT, TSH, CPK, CRP, Liver function tests (including Tbili, AST and 
ALT), CBC with diff, MRI Brain with/without contrast, and conduct a telehealth visit 
with the patient. This telehealth visit will adhere to HHS guidance 
(https://www.hhs.gov/hipaa/for-professionals/special-topics/emergency-
preparedness/notification-enforcement-discretion-telehealth/index.html) and can use all 
telehealth modalities under the good faith provision during a pandemic/epidemic as 
allowed by HHS for care of study participants. Unscheduled visits, due to safety, may 
also be conducted remotely through telehealth and/or offsite laboratory and radiologic 
studies and/or in conjunction with a local physician with the supervision of the study PI. 
The laboratory studies will be performed through LabCorp or with the local physician, 
and results will be sent to the study team for safety monitoring and oversight.  Radiology 
studies will be arranged through a local, non-study physician, or directly by the study 
team, at a site close to the participants home area if travel to the NIH is not possible. If a 
patient is scheduled for an infusion, the study team will engage with a local physician to 
oversee the infusion and study visit at the outside non-research site under the direction of 
the study PI. The outside physician would be provided the protocol and all instructions 
for safety monitoring of the infusion, according to protocol, with oversight and 
instruction from the study PI.  As per FDA guidance, The study team will attempt to 


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collect research blood at these visits to be sent to the NIH Clinical Center when possible, 
to address study outcome measures. During a pandemic affecting patient travel, serial 
missed research collections will not be considered major study deviations and will be 
reported to the IRB at the time of continuing review. 
 
Additional reporting requirements to BMS are listed in Appendix A. 
17.0 Alternative Therapies  
Other treatments available for recurrent glioblastoma include continuing medical therapy 
(standard radiation and chemotherapy for brain tumors) and surgery to remove recurrent 
tumor.  Furthermore, subjects do not have to participate in this study to receive surgery. 
They may prefer to receive evaluation and surgical treatment under the care of their own 
physicians at an outside facility. 
18.0 Privacy 
All research activities will be conducted in as private a setting as possible. 
19.0 Confidentiality 
Data collected through this protocol is collected for clinical purposes by clinicians and 
for research purposes. Medical records with identifiers will be maintained in locked 
storage in the Surgical Neurology Branch office or at Emory University Hospital. All 
research data will be de-identified and stored with code numbers as a reference. 
Electronic records and data will be maintained in computer files which are password-
protected and housed on the NINDS network or the Emory University network. Access to 
all files will be restricted to the Principal Investigator, study coordinators, and the 
research team. Data collected through patient participation in protocol 03-N-0164 will be 
shared with this protocol. All team members have completed the OHSRP training. 
 
All collected research samples, including surgical tumor specimens, CSF, microdialysate, 
and blood will be coded and stored in secured freezers on the NIH campus or at Emory 
University Hospital.  All patients enrolled in this protocol will be assigned a sequential 
code and all biological samples collected for this patient will be labeled with the patient’s 
code, date of collection, type of sample, sample number, and barcode which will be 
linked back to relevant sample information in the study laboratory notebooks and 
Labmatrix.. All study data will be kept on password-protected computers on the NIH 
campus or at Emory University Hospital.  Only study investigators will have access to the 
stored data and samples, except as noted in the data and sample sharing procedures, 
above. The study investigators will have access to the code key. 
 
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20.0 Conflict of Interest 
NIH guidelines on conflict of interest have been distributed to all investigators. Bristol-
Myers Squibb, the maker of Nivolumab and BMS-986-016, is providing a drug-only 
sponsorship for this study. No investigator has a conflict of interest for this study, and no 
payment or any other benefit, financial or otherwise, will be received by any investigator 
or the NIH in relation to this trial. 
21.0 Technology Transfer 
We are currently negotiating a Clinical Trials Agreement for the performance of this 
study with the drug sponsorship of Bristol-Myers Squibb. A CRADA is not needed, as no 
funding will be sent directly to the NIH. Coded data will be shared with Bristol-Myers 
Squibb as a result of this agreement. 
 
Data and samples may also be shared with collaborating laboratories at NIH or outside of 
NIH and/or submitted to NIH-designated repositories and databases if consent for sharing 
was obtained.  Required approvals from the collaborating institution will be obtained and 
materials will be shipped in accordance with NIH and federal regulations.    
22.0 Research and Travel Compensation  
The subject will not receive financial compensation for participating in this research 
study.  Enrolled subjects at the NIH will be reimbursed for domestic travel, lodging, and 
meals according to the NINDS travel policy.  Domestic guardian travel and meals will be 
provided if medically required. Enrolled subjects at Emory University Hospital will not 
receive reimbursement for travel. 
23.0 Definition of Primary and Secondary Data 
Primary data are data that are collected specifically for the purposes of the research. 
Non-interventional research designs based on use of primary data from patients and/or 
healthcare providers include but are not limited to: 
• prospective research (eg, active data collection with active ascertainment of AEs by 
clinical encounter such as patient interview) and surveys directed proactively to either 
patients and/or healthcare providers to capture 
• information on treatment AEs for a BMS product 
 
Secondary data are data that were originally collected for other purposes (such as patient 
charts, administrative claims, insurance database, etc). 
Such research includes but is not limited to: 
• database studies, eg, insurance claims database analyses 
• existing surveys, eg, NHANES 
• medical chart review studies. 


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24.0 References 
 
1. 
Stupp, R., et al., Radiotherapy plus concomitant and adjuvant temozolomide for 
glioblastoma. N Engl J Med, 2005. 352(10): p. 987-96. 
2. 
Taal, W., et al., Single-agent bevacizumab or lomustine versus a combination of 
bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB 
trial): a randomised controlled phase 2 trial. Lancet Oncol, 2014. 15(9): p. 943-
53. 
3. 
Ryken, T.C., et al., The role of cytoreductive surgery in the management of 
progressive glioblastoma : a systematic review and evidence-based clinical 
practice guideline. J Neurooncol, 2014. 118(3): p. 479-88. 
4. 
Ryu, S., et al., The role of radiotherapy in the management of progressive 
glioblastoma : a systematic review and evidence-based clinical practice 
guideline. J Neurooncol, 2014. 118(3): p. 489-99. 
5. 
Olson, J.J., et al., The role of cytotoxic chemotherapy in the management of 
progressive glioblastoma : a systematic review and evidence-based clinical 
practice guideline. J Neurooncol, 2014. 118(3): p. 501-55. 
6. 
Brem, H., et al., Placebo-controlled trial of safety and efficacy of intraoperative 
controlled delivery by biodegradable polymers of chemotherapy for recurrent 
gliomas. The Polymer-brain Tumor Treatment Group. Lancet, 1995. 345(8956): 
p. 1008-12. 
7. 
Nagpal, S., The role of BCNU polymer wafers (Gliadel) in the treatment of 
malignant glioma. Neurosurg Clin N Am, 2012. 23(2): p. 289-95, ix. 
8. 
McCarthy, E.F., The toxins of William B. Coley and the treatment of bone and 
soft-tissue sarcomas. Iowa Orthop J, 2006. 26: p. 154-8. 
9. 
Nduom, E.K., M. Weller, and A.B. Heimberger, Immunosuppressive mechanisms 
in glioblastoma. Neuro Oncol, 2015. 17 Suppl 7: p. vii9-vii14. 
10. 
Heimberger, A.B., et al., Incidence and prognostic impact of FoxP3+ regulatory 
T cells in human gliomas. Clin Cancer Res, 2008. 14(16): p. 5166-72. 
11. 
Curran, M.A., et al., PD-1 and CTLA-4 combination blockade expands infiltrating 
T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. 
Proc Natl Acad Sci U S A, 2010. 107(9): p. 4275-80. 
12. 
Rosenberg, S.A., et al., Observations on the systemic administration of 
autologous lymphokine-activated killer cells and recombinant interleukin-2 to 
patients with metastatic cancer. N Engl J Med, 1985. 313(23): p. 1485-92. 
13. 
Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 
antibody in cancer. N Engl J Med, 2012. 366(26): p. 2443-54. 
14. 
Ribas, A., et al., Pembrolizumab versus investigator-choice chemotherapy for 
ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, 
phase 2 trial. Lancet Oncol, 2015. 16(8): p. 908-18. 
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Workman, C.J., et al., Lymphocyte activation gene-3 (CD223) regulates the size 
of the expanding T cell population following antigen activation in vivo. J 
Immunol, 2004. 172(9): p. 5450-5. 
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Matsuzaki, J., et al., Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are 
negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl 
Acad Sci U S A, 2010. 107(17): p. 7875-80. 


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17. 
Huang, R.Y., et al., Compensatory upregulation of PD-1, LAG-3, and CTLA-4 
limits the efficacy of single-agent checkpoint blockade in metastatic ovarian 
cancer. Oncoimmunology, 2017. 6(1): p. e1249561. 
18. 
Wrann, M., et al., T cell suppressor factor from human glioblastoma cells is a 
12.5-kd protein closely related to transforming growth factor-beta. EMBO J, 
1987. 6(6): p. 1633-6. 
19. 
Fontana, A., et al., Glioblastoma cells release interleukin 1 and factors inhibiting 
interleukin 2-mediated effects. J Immunol, 1984. 132(4): p. 1837-44. 
20. 
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and class II histocompatibility antigens and the presence of scattered T 
lymphocytes in rat central nervous system. Proc Natl Acad Sci U S A, 1987. 
84(7): p. 2082-6. 
21. 
Harling-Berg, C.J., T.J. Park, and P.M. Knopf, Role of the cervical lymphatics in 
the Th2-type hierarchy of CNS immune regulation. J Neuroimmunol, 1999. 
101(2): p. 111-27. 
22. 
Fecci, P.E., et al., Systemic CTLA-4 blockade ameliorates glioma-induced 
changes to the CD4+ T cell compartment without affecting regulatory T-cell 
function. Clin Cancer Res, 2007. 13(7): p. 2158-67. 
23. 
Wainwright, D.A., et al., Durable therapeutic efficacy utilizing combinatorial 
blockade against IDO, CTLA-4 and PD-L1 in mice with brain tumors. Clin 
Cancer Res, 2014. 
24. 
Zeng, J., et al., Anti-PD-1 blockade and stereotactic radiation produce long-term 
survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys, 2013. 
86(2): p. 343-9. 
25. 
Borghaei, H., et al., Nivolumab versus Docetaxel in Advanced Nonsquamous Non-
Small-Cell Lung Cancer. N Engl J Med, 2015. 373(17): p. 1627-39. 
26. 
Nduom, E.K., et al., PD-L1 expression and prognostic impact in glioblastoma. 
Neuro Oncol, 2015. 
27. 
Wolchok, J.D., et al., Nivolumab plus ipilimumab in advanced melanoma. N Engl 
J Med, 2013. 369(2): p. 122-33. 
28. 
Tarhini, A.A., et al., Baseline circulating IL-17 predicts toxicity while TGF-beta1 
and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of 
melanoma. J Immunother Cancer, 2015. 3: p. 39. 
29. 
Schuster, J., et al., A phase II, multicenter trial of rindopepimut (CDX-110) in 
newly diagnosed glioblastoma: the ACT III study. Neuro Oncol, 2015. 17(6): p. 
854-61. 
30. 
Meyerson, B.A., et al., Microdialysis in the human brain: extracellular 
measurements in the thalamus of parkinsonian patients. Life Sci, 1990. 46(4): p. 
301-8. 
31. 
Azeredo, F.J., T. Dalla Costa, and H. Derendorf, Role of microdialysis in 
pharmacokinetics and pharmacodynamics: current status and future directions. 
Clin Pharmacokinet, 2014. 53(3): p. 205-12. 
32. 
Glenn, T.C., et al., Energy dysfunction as a predictor of outcome after moderate 
or severe head injury: indices of oxygen, glucose, and lactate metabolism. J Cereb 
Blood Flow Metab, 2003. 23(10): p. 1239-50. 


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33. 
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changes in intracerebral cytokine levels after craniotomy and in response to 
treatment with a targeted anti-cancer agent. J Neurooncol, 2014. 118(1): p. 169-
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negative feedback controls T cell effector function in inflamed tissues. Immunity, 
2014. 40(2): p. 235-47. 
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a potential mechanism of immune paralysis. Cancer Res, 2003. 63(21): p. 7462-7. 
36. 
Lowther, D.E., et al., PD-1 marks dysfunctional regulatory T cells in malignant 
gliomas. JCI Insight, 2016. 1(5). 
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Chen, P.L., et al., Analysis of Immune Signatures in Longitudinal Tumor Samples 
Yields Insight into Biomarkers of Response and Mechanisms of Resistance to 
Immune Checkpoint Blockade. Cancer Discov, 2016. 6(8): p. 827-37. 
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report of the RANO working group. Lancet Oncol, 2015. 16(15): p. e534-42. 
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temporal profiles and evidence for cerebral parenchymal production. J Cereb 
Blood Flow Metab, 2011. 31(2): p. 658-70. 
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response to human traumatic brain injury. PLoS One, 2012. 7(6): p. e39677. 
41. 
Helmy, A., et al., Recombinant human interleukin-1 receptor antagonist promotes 
M1 microglia biased cytokines and chemokines following human traumatic brain 
injury. J Cereb Blood Flow Metab, 2016. 36(8): p. 1434-48. 
42. 
Blakeley, J.O., et al., Effect of blood brain barrier permeability in recurrent high 
grade gliomas on the intratumoral pharmacokinetics of methotrexate: a 
microdialysis study. J Neurooncol, 2009. 91(1): p. 51-8. 
43. 
Tabatabaei, P., et al., Radiotherapy induces an immediate inflammatory reaction 
in malignant glioma: a clinical microdialysis study. J Neurooncol, 2017. 131(1): 
p. 83-92. 
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Marcus, H.J., et al., In vivo assessment of high-grade glioma biochemistry using 
microdialysis: a study of energy-related molecules, growth factors and cytokines. 
J Neurooncol, 2010. 97(1): p. 11-23. 
45. 
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after stereotactic brain biopsy. J Neurosurg, 2001. 94(4): p. 545-51. 
46. 
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biopsy without intraoperative neuropathological examination. J Neurosurg, 2010. 
113(2): p. 170-8. 
47. 
Thelin, E.P., et al., Microdialysis Monitoring of CSF Parameters in Severe 
Traumatic Brain Injury Patients: A Novel Approach. Front Neurol, 2014. 5: p. 
159. 
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retrospective cohort study. J Neurol Neurosurg Psychiatry, 1999. 67(4): p. 468-
73. 
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Liang, H., et al., Risk Factors for Infections Related to Lumbar Drainage in 
Spontaneous Subarachnoid Hemorrhage. Neurocrit Care, 2016. 25(2): p. 243-9. 
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25.0 Study Calendar 
 
 
 
 
 
Before 
Surgery 
 
Day 
 
1 
 
Qday 
 
Day 1 1
- 
Day 8 
 
Day  
 
3 
 
Q6h 
Day 1  
- 
  Day 8 
 
Day 
 
8 
 
Day  
 
17 
(+/- 2 
Days) 
 
Day 31 and 
every 
2 wk. 
until 
Progression 
(+/- 2 Days) 
Survival 
Follow-
up 
(approx.. 
monthly 
until 
death) 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics and Medical 
history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
(neuro exam, skin exam, vitals, 
weight, Karnofsky Status)* 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
CT Head 
 
X 
 
 
 
 
 
 
 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
Comprehensive metabolic 
panel (with creatinine)+ GGT 
 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
TSH 
X 
 
 
X 
 
 
X 
X 
 
CPK 
 
 
 
X 
 
 
X 
X 
 
CRP 
 
 
 
X 
 
 
X 
X 
 
Free T3 and T4 
X 
 
 
 
 
 
X 
 
 
Liver function tests (including 
Tbili, AST and ALT) 
X 
 
 
X 
 
 
X 
X 
 
CBC with differential 
X 
X 
X 
X 
 
X 
X 
X 
 
Monitoring for infusion reaction 
and cytokine release syndrome 
 
 
 
X 
 
 
X 
 
 
QAC and QHS accuchecks 
 
 
X 
X 
 
 
 
 
 
ACTH and Cortisol** 
X 
 
 
 
 
 
X 
X 
 
MRI Brain with/without contrast 
X 
 
 
 
 
X 
X 
X*** 
 
Biopsy/microdialysis catheter 
placement 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Nivolumab administered 
 
 
 
X 
 
 
X 
X 
 
BMS-986016 antibody 
administered 
 
 
 
 
 
 
X 
X 
 
Research blood sample taken  
X 
X 
X 
X 
 
X 
X 
X 
 


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PK Blood sample taken 
 
 
 
X 
 
 
 
 
 
EKG and Troponin level**** 
X 
 
 
 
 
 
X 
X 
 
Echocardiogram 
X 
 
 
 
 
 
X 
 
 
CSF sample taken***** 
 
X 
X 
X 
 
X 
 
 
 
PK CSF sample taken 
 
 
 
X 
 
 
 
 
 
Microdialysis sample taken 
 
 
 
X 
X 
X 
 
 
 
Surgical resection/ 
Microdialysis catheter removal 
 
 
 
 
 
X 
 
 
 
Bone marrow 
examination****** 
 
X 
 
 
 
X 
 
 
 
Adverse event evaluation 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
 
Telephone/Medical Record 
follow-up 
 
 
 
 
 
 
 
 
 
X 
*Neurological exams will be conducted q2h for the first 24 hours after the research 
surgical procedure, then q4h while awake for the remainder of the microdialysis 
monitoring period 
**Baseline ACTH and AM Cortisol levels will be obtained, and then further testing will 
be at the discretion of the treating physicians as clinically indicated 
***MRI will be performed every other site visit in follow-up starting at day 17 (every 4 
weeks) 
****EKG and Troponin level will be taken before each of the first 5 doses of study drugs 
*****In addition to daily research samples, CSF will be collected qMonday and 
Thursday for cell count, protein, glucose, gram stain and culture during inpatient stay as 
long as the lumbar drain remains in place 
******Bone marrow examination is performed at the discretion of the PI 
 
26.0 Consent Forms 
 
Adult subject 
Adult assent 
27.0 Eligibility Checklist 
 
Inclusion Criteria 
Note that if any box is marked “NO”, the subject is not eligible for 
enrollment. 
 (Yes/No) 
1. 18 years of age or older. 
 
2. Have recurrent glioblastoma that is amenable to surgical 
resection.  
 
3. Agree to undergo brain surgery. 
 


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4. Are eligible for 03-N-0164 “Evaluation and Treatment of 
Neurosurgical Disorders” protocol 
 
 
5. Willing and able to appoint a durable power of attorney. 
 
6. Are willing to use an effective method of contraception during 
the clinical study as defined on the consent during the duration 
of the study and for 24 weeks (for women) or 33 weeks (for 
men) after the last dose of the study drug. 
 
 
Exclusion Criteria 
Note that if any box is marked “YES”, the subject is not eligible for 
enrollment. 
 (Yes/No) 
1. Have a bleeding disorder that cannot be corrected before 
invasive testing or surgery, or other medical conditions that 
would make surgery unsafe, such as lung or cardiac disease that 
would render them unable to tolerate the risk of general 
anesthesia, or severe immunodeficiency. 
 
2. Has a known additional malignancy that is progressing or 
requires active treatment within 3 years of registration. 
Exceptions include basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin, or in situ cervical cancer that has 
undergone potentially curative therapy.  
 
3. Are pregnant or breastfeeding 
 
4. Cannot have an MRI scan. 
 
5. Are claustrophobic 
 
6. Are not able to lie on their back for up to 60 minutes 
 
7. Have primary CNS lymphoma.   
 
8. Has received systemic immunosuppressive treatments, aside 
from systemic corticosteroids (such as methotrexate, 
chloroquine, azathioprine, etc) within six months of registration. 
 
9. Has active autoimmune disease that has required systemic 
treatment in the past 2 years (i.e. with use of disease modifying 
agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg., thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic 
treatment. 
 
10. Have a significant cardiac history, such as 2 or more MIs OR 2 
or more coronary revascularization procedures. 
 


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11. Have abnormal findings on ECG such as prolonged QT interval, 
T-wave abnormalities or arrhythmia. Abnormal findings on ECG 
will prompt an evaluation by a cardiologist prior to enrollment in 
the study 
 
12. Are currently undergoing treatment with another therapeutic 
agent. 
 
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-
PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated 
antigen-4 (CTLA-4) antibody (including ipilimumab or any 
other antibody or drug specifically targeting T-cell co-
stimulation or checkpoint pathways). 
 
14. Have an ejection fraction <50% on screening echocardiogram 
 
15. Has a known history of Human Immunodeficiency Virus (HIV) 
(HIV 1/2 antibodies) at the time of enrollment. 
 
16. Has known active Hepatitis B (e.g., HBsAg reactive) or 
Hepatitis C (e.g., HCV RNA [qualitative] is detected) at the time 
of enrollment. 
 
17. Have an active infection that requires systemic antibacterial, 
antiviral or antifungal therapy < 7 days prior to initiation of 
study drug therapy 
 
18. Have a history of transfer of autologous or allogeneic T cells  
 
19. Have a history of solid organ or tissue transplants 
 
20. Have cardiac Troponin T or I > 2x the institutional upper limit of 
normal at screening 
 
21. At the time of enrollment, lack consent capacity due to cognitive 
impairment that would make them incapable of understanding 
the explanation of the procedures in this study. Cognitive 
capacity to consent will be determined at the time of enrollment. 
Patients with mental disorders or those patients who are 
cognitively impaired yet 
 
22. Cannot speak English or Spanish fluently 
 
23. Patients that require dexamethasone > 4 mg/ day or equivalent of 
steroids 
 
 
 
 


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Appendix A: Bristol-Myers Squibb Adverse Event Reporting: 
 
Adverse Event Reporting 
 
Adverse Events that are routinely collected according to GCP shall be submitted to BMS 
every three (3) months by the last working day of the third month.  
The Adverse Event information required to be sent to BMS is noted in an attached 
‘Bristol-Myers Squibb Early Asset Investigator Sponsored Research (ISR) Import Plan’ 
which describes the method of collection and submission to BMS via the mailbox: 
MG-RD-GPVE-PHARMACOVIGILANCE@bms.com 
When the file is submitted to BMS, it must be noted  the file contains all Non Serious 
Adverse Events: only adverse events not previously submitted to BMS within the 3 
months. 
 
SERIOUS ADVERSE EVENTS 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
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 is a congenital anomaly/birth defect is an 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 [eg, 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 (eg, 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 considered related to study therapy should be 
reported as an SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, 
anaphylaxis must be reported). 
 
NOTE: (PI determines if this 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:  
a 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) 


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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) 
 
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: 
Related: There is a reasonable causal relationship between study drug administration and 
the AE. 
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.  
 
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 
Nonserious Adverse Events are to be provided to BMS in aggregate via interim or final 
study reports as specified in the agreement or, if a regulatory requirement [e.g. IND US 
trial] as part of an annual reporting requirement.  
Nonserious 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 nonserious adverse event is an AE not classified as serious.  
 
Following the subject’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, are collected, including those thought to be associated 
with protocol-specified procedures. The investigator should report any SAE occurring 


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after these time periods that is believed to be related to study drug or protocol-specified 
procedure.  The duration of SAE collection should be extended to: 
100 days for nivolumab 
 
Worldwide.Safety@bms.comaepbusinessprocess@bms.com 
SAEs, whether related or not related to study drug, and pregnancies must be reported to 
BMS within 24 hours. SAEs must be recorded on BMS or an approved form; pregnancies 
must be reported on a Pregnancy Surveillance Form. 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  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. 
 
For studies conducted under an Investigator IND in the US, any event that is both serious 
and unexpected must be reported to the Food and Drug Administration (FDA) as soon as 
possible and no later than 7 days (for a death or life-threatening event) or 15 days (for all 
other SAEs) after the investigator’s or institution’s initial receipt of the information. BMS 
will be provided with a simultaneous copy of all adverse events filed with the FDA.  
 
SAEs should be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/. 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
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 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.  
 


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It is expected that wherever possible, the clinical rather than laboratory term would be 
used by the reporting investigator (eg, anemia versus low hemoglobin value). 
 
Potential Drug Induced Liver Injury (DILI) 
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:  
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase), 
AND 
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. 
 
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 (eg, 
dose tapering if necessary for participant).  
 
The investigator must immediately notify Worldwide.Safety@bms.com of this event via 
the 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 
Pregnancy Surveillance Form [provided upon request from BMS] 
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 


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these procedures are required by the protocol, should also be recorded as a nonserious or 
serious AE, as appropriate, and reported accordingly.  
APPENDIX B: INVESTIGATOR BROCHURE FOR NIVOLUMAB (BMS-936558) 
 
APPENDIX C: INVESTIGATOR BROCHURE FOR RELATLIMAB (BMS-
986016) 
 


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Appendix D: Serious Adverse Reactions in Patients Treated with Relatlimab in 
Combination with Nivolumab 
 
 


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APPENDIX E: KARNOFSKY PERFORMANCE STATUS 
 
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 their personal needs. 
50 – Requires considerable assistance and frequent medical care. 
40 – Disabled; requires special care and assistance. 
30 – Severely disabled; hospital admission is indicated although death not imminent. 
20 – Very sick; hospital admission necessary; active supportive treatment necessary. 
10 – Moribund; fatal processes progressing rapidly. 
0 – Dead 
APPENDIX F: SOCIAL MEDIA LANGUAGE 
 
The below language will be used with social media posts.  
 
Facebook posts: 
         
The National Institute of Neurological Disorders and Stroke is seeking people from 
across the nation with recurrent glioblastoma to participate in a research study. Domestic 
travel costs will be reimbursed. This study will evaluate the safety and effects of 2 
experimental drugs, nivolumab and relatlimab. The study will look at their effect on the 
immune response in the brain and on the brain tumor. We will also evaluate the safety of 
experimental microdialysis catheters. These are thin tubes placed in the brain temporarily 
to monitor brain immune function. For more information, visit: 
https://clinicaltrials.gov/ct2/show/NCT03493932 
         


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Researchers at the National Institute of Neurological Disorders and Stroke are seeking 
participants from across the nation for a new research study for people with recurrent 
glioblastoma. Domestic travel costs will be reimbursed. For more information on this 
research visit https://clinicaltrials.gov/ct2/show/NCT03493932 or email 
SNBrecruiting@nih.gov <mailto:SNBrecruiting@nih.gov>  #BTSM #endbraincancer 
         
 
Tweets: 
         
Malignant brain tumors often recur after treatment. This @NIH research study looks at 
the safety and effect of 2 experimental drugs on brain immune response in recurrent 
glioblastoma patients: https://clinicaltrials.gov/ct2/show/NCT03493932. Domestic travel 
costs will be reimbursed for participants  
         
NINDS researchers are studying the safety and effects of 2 experimental drugs on brain 
immune response in those with recurrent glioblastoma. The NIH will reimburse your 
domestic travel costs. Learn more about this research here: 
https://clinicaltrials.gov/ct2/show/NCT03493932 #BTSM #endbraincancer 
 
Learn about a NINDS research study to evaluate the safety and effects of 2 experimental 
drugs on brain immune response in those with recurrent #braintumors. If you live far 
from the NIH, your domestic travel costs will be reimbursed: 
https://clinicaltrials.gov/ct2/show/NCT03493932 #BTSM #endbraincancer 
         
The @NIH brain tumor team is seeking participants for a new research study for people 
with recurrent glioblastoma: https://clinicaltrials.gov/ct2/show/NCT03493932 We 
welcome participants from across the US. The NIH will reimburse your domestic travel 
costs for screening and study participation #BTSM 
 
The @NIH brain tumor team is actively recruiting people from across the nation with 
recurrent glioblastoma for a research study at the @NIHClinicalCntr: 
https://clinicaltrials.gov/ct2/show/NCT03493932 The NIH will reimburse your domestic 
travel costs to Bethesda, MD.  #endbraincancer #BTSM 
 
 

ICF_001.pdf: 
PI: Edjah Nduom, MD                                               Page 1 of 20                                               Version Date: 11/30/2020
Protocol #: 18-N-0077                                                                                                                          IRB Form 06162020
 
You Are Being Asked to Be in a Research Study
Concise presentation of key concepts
You are being asked to be in a research study. A research study is designed to answer 
a scientific question. If you agree to be in the study you will be one of 5 people who are 
being studied, at Emory. 
Why is this study being done? 
This study is being done to answer the question: is the study drug, nivolumab, effective 
on the brain’s immune system in people who have had a return of glioblastoma brain 
tumors? You are being asked to be in this research study because you have 
glioblastoma brain tumor. 
Do you have to be in the study? 
It is your decision to be part of this research study. You do not have to be in it. Your 
choice will not affect your access to medical care for your condition. Before you make 
your decision, you should take time to learn about the study.
What do I have to do if I choose to participate in this study?
If you are eligible and want to be part of the study, you will participate for until/unless 
your tumor comes back.  The researchers will ask you to do the following: review 
medical history, physical examination, blood tests, urinalysis, electrocardiogram (ECG), 
chest x-ray, MRI scan, and hospitalization due to surgery.  Some of these procedures 
will be paid for by the study.   
How is this study going to help you? 
If you are in the study, you will be helping the researchers answer the study question.
 
What are the risks or discomforts I should know about before making a 
decision?  
The study will take time. The drug that is being tested may not work any better than 
regular care, and may even cause harm. All studies have some risks.  Some risks are 
relatively small, like being bored or losing time.  Some are more serious – for this 
study, these include risks of the drug, some of which include, lymph node 
inflammation, diabetes, blockage of bile ducts, irregular heart beat, fluid in the lungs, 
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loss of privacy, and breach of confidentiality.  A full list of expected risks, their 
frequency and severity are in the “What are the possible risks and discomforts?” 
section of this document.
Alternatives to Joining This Study
The alternative to being in this study is to receive medical or surgical treatment for your 
GBM at Emory or elsewhere. Medical care for GBM that has regrown may include 
radiation, chemotherapy and/or surgery. 
Costs
The study will pay for some of the items and procedures in this study. It will not pay for 
your regular medical care. More information is below in the Costs section of the 
consent form. 
What Should I Do Next?
Read this form, or have it read to you.  Make sure the study doctor or study staff 
explains the study to you. Ask questions (e.g., about exact time commitment, about 
unfamiliar words, more details on specific procedures, etc.) Make sure you understand 
which parts of these are research and which are standard care that you would have 
even if you did not join the study.  Take time to consider this, and talk about it with your 
family and friends.
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Protocol #: 18-N-0077                                                                                                                          IRB Form 06162020
Emory University
Consent to be a Research Subject / HIPAA Authorization 
Title:  18-N-0077: Cytokine microdialysis for real time immune monitoring in glioblastoma patients 
undergoing checkpoint blockade
IRB #:  STUDY00001398
Principal Investigator:  Edjah Nduom, MD
Sponsor:  National Institute of Neurological Disorders and Stroke (NINDS)
Study-Supporter:  Bristol-Myers Squibb
Introduction
You are being asked to be in a medical research study. This form is designed to tell you everything 
you need to think about before you decide if you want to be a part of the study.  It is entirely your 
choice.  If you decide to take part, you can change your mind later on and withdraw from the 
research study. The decision to join or not join the research study will not cause you to lose any 
medical benefits.  If you decide not to take part in this study, your doctor will continue to treat you.
Before making your decision:

Please carefully read this form or have it read to you

Please listen to the study doctor or study staff explain the study to you 

Please ask questions about anything that is not clear
You can take a copy of this consent form, to keep. Feel free to take your time thinking about whether 
you would like to participate. You may wish to discuss your decision with family or friends. Do not sign 
this consent form unless you have had a chance to ask questions and get answers that make sense 
to you.  By signing this form you will not give up any legal rights.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
law. This Web site will not include information that can identify you. At most the Web site will include 
a summary of the results. You can search this Web site at any time.
What is the purpose of this study?
The purpose of this study is to look at the effects of a drug, nivolumab, on the brain’s immune system 
in people who have had a return of glioblastoma brain tumors. We will also look at the effects of 
nivolumab and an experimental drug, BMS-986016, on the brain tumor.
Background
Glioblastoma (GBM) brain tumors almost always return after treatment with surgery, radiation or 
drugs. When a GBM tumor returns, people usually have more surgery to remove as much of the 
tumor as possible. The tumor can never completely be removed by surgery, so most people also 
receive drugs, like chemotherapy. Many types of cancer are use drugs that help the body’s own 
immune system attack tumors. Nivolumab is an immunotherapy drug that is used to treat some types 
of cancer such as lung cancer or melanoma. Recent studies in GBM suggest that nivolumab alone 
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does not treat returned GBM. Therefore, in this study, we will combine nivolumab with an 
experimental drug called BMS-986016. BMS-986016 also works on the immune system. We will see 
if BMS-986016 is safe to combine with nivolumab. We will see how the 2 drugs together affect 
returned GBM tumors.
We will also study the effects of nivolumab on the brain’s immune system and on genes involved in 
the immune system. We will use small tubes, called microdialysis catheters, put into the brain to 
collect brain fluids and molecules. We will look at immune cells and genes before and after the first 
dose of nivolumab. The microdialysis catheters we will use are not FDA approved and are also 
experimental. These tubes are very similar to microdialysis catheters used in people who have had 
brain injuries.
What will I be asked to do?
Study Overview
This study requires an initial visit lasting 1-2 days to see if you are eligible to participate. If you are 
eligible, you will be hospitalized for 2 weeks. During the hospitalization you will have 2 surgeries. 
During the first surgery we will take a sample of the tumor and place the microdialysis tubes, as 
described below. The second surgery, one week later, will be to remove the tubes and as much of the 
tumor as possible. After leaving the hospital, you will have outpatient visits lasting about 5 hours 
every other week until there are signs that the tumor has returned.
The first surgery is for research purposes only. During the first surgery, we will take a tissue sample 
of your tumor. We will place two experimental tubes into the brain. One tube will go into the tumor. 
One tube will go into the brain around the tumor. We will do 2 other procedures during the first 
surgery. We will place a third small tube into your back, between the bones of the spine and into the 
fluid-filled sac surrounding the spinal cord. We will use that tube to collect spinal fluid over the next 
week. All of the surgery procedures will be done while you are under general anesthesia.
After surgery, you will be monitored in the intensive care unit. Two days after the surgery, you will 
receive a single dose of nivolumab. Cerebrospinal fluid (CSF) samples will be taken periodically 
throughout the next week from the tubes in the brain and your back. We will also draw blood samples.
Seven days after your first surgery, you will have the second surgery. During the second surgery, we 
will remove as much of your tumor as safely possible. We will remove the tubes in your brain and 
back. All of these procedures will be done while you are under general anesthesia.
Sixteen days after the surgery, you will start getting nivolumab and BMS-986016 every 2 weeks. We 
will check your tumor with MRI scans every 4 weeks to see if it is changing in size. We will also ask 
you about any side effects you notice from the study drugs and you will have blood tests to monitor 
for side effects. We may have to stop the drugs if you have serious side effects.
Initial visit to see if you are eligible to participate
We will review your brain MRI scans to see if your GBM has returned and its location. You may need 
to have another MRI scan of the brain at Emory. You will have a history and physical exam. You will 
have blood tests including blood cell counts, clotting and blood chemistries. You will have a chest x-
ray and urinalysis. You will have an electrocardiogram (ECG) and echocardiogram. All participants 
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who can physically become pregnant will have a pregnancy test. You will not be able to be in the 
study if you are pregnant. These are the tests you will have to see if you are eligible to participate:
History and Physical examination
We will review your medical records and ask you about your medical history. You will have a physical 
exam. Please note that this physical exam is for research purposes only. It does not replace any 
exam you may receive from your own physicians.
Electrocardiography (ECG)
The ECG records the electrical activity of the heart. For the ECG, we will place small metal disc or 
sticky pad electrodes on your chest. You will be asked to lie still for a few minutes while the ECG is 
recorded.
The echocardiogram uses sound waves to look at the heart. For the echocardiogram, a gel will be 
placed on your chest. A probe, like a small microphone, will be moved over your chest to look at your 
heart.
Magnetic Resonance Imaging (MRI)
Magnetic resonance imaging (MRI) uses a strong magnetic field and radio waves to take pictures of 
your brain. The MRI scanner is a metal cylinder surrounded by a strong magnetic field. You will lie on 
a table that can slide in and out of the cylinder. You will be in the scanner about 60 minutes. You may 
be asked to lie still for up to 15 minutes at a time. While in the scanner you will hear loud knocking 
noises, and you will be fitted with earplugs or earmuffs to muffle the sound. You will be able to 
communicate with the MRI staff at all times during your scan, and you may ask to be moved out of 
the machine at anytime.
During part of the MRI, you will receive gadolinium, a contrast agent, through an intravenous (IV) 
catheter. A needle will be used to guide a thin plastic tube (catheter) into one of your arm veins. The 
needle will be removed, leaving only the catheter in the vein. The catheter will be taped to the skin to 
hold it in place.
Blood Drawing
Blood will be drawn through a needle in your arm. We will draw no more than 1 cup of blood at any 
one time. We will take no more than 2 and a half cups of blood from you in any 8 week period during 
the study.
Prior to Surgery
If you are eligible and agree to participate, you will be scheduled for hospitalization and surgery. You 
will have to stop taking some drugs before surgery. You will need to stop any of these drugs at least 7 
days before surgery:

Aspirin (such as Excedrin)

Nonsteroidal anti-inflammatory medications, like ibuprofen (Advil, Motrin), celecoxib 
(Celebrex), and diclofenac (Cambria, Voltaren) and others

Vitamin E or supplements with vitamin E
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Other supplements or drugs may have to be held as well. Please let us know about all medicines and 
supplements you are taking.
Hospitalization and Surgery
You will be admitted to the hospital, usually 1-2 days before surgery.
First Surgery:
The first study surgery is for research purposes only. On the day of the first surgery, you will be taken 
to the operating room. You will get general anesthesia. We will place a tube into your back (called a 
“lumbar drain”) so that we can collect spinal fluid for a week after surgery. We will then take a biopsy 
of your brain tumor. The sample will be used to make sure your tumor has come back. Some of the 
sample may be saved for research use. Next, we will place 2 microdialysis tubes into the brain. One 
tube will be placed in the tumor. Another tube will be placed near the tumor. The tubes will be placed 
through small holes in your scalp and skull.
After the surgery, you will be taken to the intensive care unit for monitoring.
A few hours after surgery, you will have a computed tomography (CT) scan of the brain. The CT scan 
will let us check for bleeding from the surgery and to make sure that the microdialysis tubes are in the 
right places. CT scanning uses x-rays to obtain an image of the brain. The CT scanner is shaped like 
a metal cylinder. You will lie on a table that slides in and out of the scanner. You will be in the scanner 
for about 15 minutes. You may be asked to lie still for up to 10 minutes at a time. You will be able to 
communicate with the CT staff at all times, and you may ask to be moved out of the machine at any 
time. 
Monitoring in the Intensive Care Unit (ICU) and Inpatient Unit
When people have surgery for a GBM, they usually stay in the ICU for one night after surgery. In this 
study, you will need to stay in the ICU for 24 hours after the first surgery, and then be transferred to 
an inpatient room. We will collect fluid from the catheters in your brain every 6 hours and from the 
catheter in your back once a day. You will be able to walk around between fluid collection but you 
cannot leave the floor. You will also have blood drawn every day for research purposes. Your lumbar 
drain could fall out or stop working. If these happen, we will offer to place a new lumbar drain. You 
can also opt for a lumbar puncture during the second surgery instead.
First Dose of Nivolumab
Two days after surgery, during your 1 week stay in the ICU and inpatient floor, you will get a single 
dose of nivolumab through an IV. The nivolumab infusion will take 30 minutes. After getting 
nivolumab, we will watch you closely over the next 3 hours for side effects. We will check your vital 
signs (blood pressure, breathing, temperature and pulse) frequently. We will ask you how you are 
feeling. We will collect additional fluid from the catheters in your back (2 times this day). We will draw 
an extra blood sample for research (2 times this day).
Second Surgery
One week after the first surgery, you will have the second study surgery. You will be taken to the 
operating room. You will get general anesthesia. Once you are under anesthesia, we will remove the 
tube from your back. You may need a small stitch to close the hole that the tube went into. Then we 
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will remove the microdialysis tubes from the brain. We may need to make new cuts into the scalp to 
remove the tubes.
Next, you will have standard surgery to remove as much of the GBM as possible.
After the second surgery, you will go back to the intensive care unit. Most participants will stay in the 
ICU for one night after the second surgery. Once you are well enough to leave the ICU, you will be 
moved to the neurosurgery unit. You will stay in the hospital until you are well enough to leave. Most 
people stay in the hospital for 3-5 days after surgery.
Outpatient Drug Phase of the Study
Nivolumab and BMS-986016 infusions
Two weeks after the first dose of nivolumab, that you got while you were in the ICU and inpatient 
floor, you will return to Emory for an outpatient visit. You will come to Emory for outpatient visits every 
2 weeks. You will start getting infusions of nivolumab and BMS-986016 through an IV. Nivolumab will 
be given first. Nivolumab infusion will take 30 minutes. About 15-30 minutes later, you will get BMS-
986016. The BMS-986016 infusion will take one hour. You will be monitored closely for side effects 
during and for 2 hours after the infusions. You will have a physical exam and blood draw at each visit 
to monitor for effects of these drugs. An ECG may also be done. Each visit to receive nivolumab and 
BMS-986016 will take about 5 hours. You will have an MRI scan of the brain once a month.
You will continue to receive nivolumab and BMS-986016 every other week until there are signs that 
the tumor has come back. We will also stop nivolumab and BMS-986016 if you have side effects that 
would make it unsafe for the infusions to continue.
It is difficult to tell if a brain tumor is responding to immune therapy. We may need to stop the study
medications if your MRI looks like the tumor has come back. We may give you steroids while we wait 
to see if the MRI changes. We may need to perform a biopsy or resection to know whether the tumor 
has come back again. If we find that the tumor has come back, we will stop the nivolumab and BMS-
986016. 
Transfer of Care
We would like to continue to follow you even after the study drugs are stopped. We may be able to 
continue to care for you at Emory under another protocol. You may choose to transfer your care to 
your own doctors. If you transfer your care outside of Emory, we will continue to contact to you from 
time-to-time to see how you are doing. We may ask you to send us your medical records. If we stop 
nivolumab and BMS-986016 because your tumor has returned, we will ask you to return for an MRI 
and safety check at least 4 weeks after we stop giving you the study drugs.
How will my medicine be provided? 
The medicine that you will take will be dispensed by the pharmacy and delivered to the principal 
investigator or study team member. The research team will provide the medicine to you.  If you have 
questions about the medicine, you should ask the study doctor or study nurse.  You may also call the 
pharmacy at (404) 712-4718 if you have questions about the medicine. The number for the pharmacy 
is included on your medicine package.
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Who owns my study information and samples?
If you join this study, you will be donating your samples and study information.  You will not receive 
any compensation if your samples or information are used to make a new product. If you withdraw 
from the study, data and samples that were already collected may be still be used for this study.  
What are the possible risks and discomforts?
First surgery: Microdialysis tube placement and brain biopsy, and placement of lumbar drain
The microdialysis tube placement and brain biopsy are done during your first surgery under this 
study. The microdialysis tubes are being placed only for research purposes. You would not have 
these brain tubes placed if you were not a part of this study. The risks of placing the tubes and doing 
the brain biopsy are similar. The most serious risk is a bleed in the brain. As with all brain surgery, 
there is the risk of a blood clot in the brain. This surgery could also cause a blood clot inside the skull 
that pushes on the brain. The surgery could cause a stroke. There is the risk of an infection in or 
around the brain and spinal cord. There is a risk of brain injury. The surgery could lead to serious 
disability or even death.
Complications from surgery can cause symptoms. Please let us know right away if you develop a 
severe headache, drowsiness, weakness, loss of vision, or difficulty talking. If we are concerned 
about a complication of surgery, you will have a MRI scan or a CT scan. You will be treated for any 
complication. Additional surgery might be needed.
The risk of developing a blood clot that requires surgery is about 1% or 1 in 100 patients who have 
similar surgery. With immediate surgery, improvement is usually complete, but there can be 
permanent weakness, loss of vision, and speech problems.
The risk of infection is about 1.2% or 12 in 1000 patients who have similar surgery. If you develop an 
infection, you will receive antibiotics and may need more surgery. The effects of infection are usually 
temporary but there can be permanent weakness, loss of vision, and speech problems.
There is a risk of a biopsy that misses the lesion. This risk is about 1%. If a biopsy misses the lesion, 
you may need to have a repeat biopsy. This would carry the additional 1% risk of hemorrhage.
Lumbar Drain and Lumbar Puncture
The lumbar drain will be placed in your back while you are under general anesthesia for the first 
surgery. It will be removed one week later during the second surgery. You would not have a lumbar 
drain placed if you were not part of this study. Having the lumbar drain in place can lead to an 
infection, headache, blood clot or leak of spinal fluid. The tube can also break. These complications 
could cause pelvic or leg weakness or numbness. You may require additional surgery for a 
complication related to the lumbar drain. The lumbar drain could stop working or fall out. If so, we will 
offer to put a new one in. Placing a new lumbar drain in the intensive care unit would also have risks 
of infection, headache, blood clot or leak of spinal fluid. This can also cause back pain.
If you do not want the lumbar drain replaced, we will need to perform a lumbar puncture during the 
second surgery. We would do the lumbar puncture while you are asleep. About one-third of people 
have a headache for a few days after a lumbar puncture. Usually the headache is not severe and 
improves without treatment other than a mild pain reliever. Headaches lasting longer than 7 days 
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develop with one in 50 to 200 lumbar punctures and usually improve gradually over 2 weeks. In rare 
cases, headaches persist longer. Prolonged headaches may be due to persistent leakage of CSF 
from the area of the lumbar puncture. If your headache is prolonged, you may get a “blood patch.” For 
the blood patch, we will remove blood from a vein in your arm and inject it into the area of your back 
where the lumbar puncture was performed to seal off the leak of CSF.
Second Surgery: Removal of the brain tumor and research catheters
The second surgery is to remove your tumor and research catheters. The surgery to remove the 
tumor will be about 8 days later than if you were not in this study. The delay is so that we can get 
samples and information for the research about your response to a dose of nivolumab. This delay 
could be longer if there is a problem during the first surgery or over the next week. Your tumor could 
get worse during this delay. This delay could make the tumor removal surgery harder or more 
dangerous. Your brain function could become worse because of this delay.
The risks of the second surgery include loss of speech, paralysis, or loss of sensation. The risks 
depend on where the lesion is located. Removing a small tumor that is not near the parts of the brain 
that control speech, movement, or sensation has a 1/10 chance (10%) of causing temporary loss of 
one of these functions and a 4% chance of permanent loss. Removal larger tumor from near parts of 
the brain that controls speech, movement, or sensation has a 25-50% chance of causing temporary 
loss of one of these functions and a 10-25% chance of permanent loss of function. Removal of a 
lesion less than 0.7 centimeters (1/3 inch) from a part of the brain that controls speech, movement, or 
sensation has a 1/2 chance (50%) of having temporary loss of one of these functions and a 25% 
chance of permanent loss of function. We cannot remove parts of the tumor that have grown into 
brain areas that control speech, movement, and sensation because you would permanently lose one 
or more of these important functions. The risks, based on the size and location of your own tumor, will 
be discussed with you before your surgery.
Nivolumab and BMS-986016 Infusions
The lists below show the most common and the most serious side effects of nivolumab that we know 
about so far. BMS-986016 has not been given to very many people. We do not know very much 
about its possible side effects. We do not know how taking BMS-986016 might interact with 
nivolumab. The combination of these 2 drugs may make these side effects more severe or more 
likely. There might be other side effects that we do not yet know about, including serious side effects.
Possible Side Effects of Nivolumab with BMS-986016:
Very common (may affect more than 1 in 10 people)

Decreased appetite

Diarrhea (watery, loose or soft stools)

Nausea

Feeling tired or weak

Inflammation of the heart

Fever

Constipation

Cough

Joint pain

Shortness of breath
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Common (may affect up to 1 in 10 people)

Skin rash or itching

Infections of the upper respiratory tract

Allergic reaction or other reaction to drug infusion

Underactive thyroid gland, which can cause tiredness or weight gain

Overactive thyroid gland, which can cause rapid heart rate, sweating and weight loss

High blood sugar level

Inflammation of the nerves causing numbness, weakness, tingling or burning pain of the arms 
and legs

Headache

Dizziness

Blurry vision, dry eyes

High blood pressure (hypertension)

Inflammation of the lungs with coughing, difficulty breathing, shortness of breath

Inflammation of the intestines (colitis)

Mouth ulcers and cold sores, dry mouth

Vomiting or stomach pain

Patches of skin color change (vitiligo), dry skin, redness of the skin

Hair loss or thinning

Pain in the muscles, bones and joints

Swelling (edema)

Abdominal pain and discomfort

Anemia (decrease in red or white blood cell counts)

ALT increased: lab test result associated with abnormal liver function

AST increased: lab test result associated with abnormal liver function
Uncommon (may affect up to 1 in 100 people)

Serious lung infection (pneumonia), bronchitis

Temporary increase in the number of your blood cells (transient leukocytosis)

Altered levels of body hormones

Dehydration

Inflammation of the liver (hepatitis), with yellowing of the skin or eyes (jaundice)

Nerve damage

Eye inflammation with pain, redness, or vision problems

Fast heart rate

Inflammation of blood vessels

Fluid around the lungs

Inflammation of the pancreas

Severe rashes or psoriasis

Inflammation of muscles causing pain or stiffness, painful joints

Inflammation of the kidney, kidney failure

Pain

Chest pain
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Rare (may affect up to 1 in 1000 people)

Lymph node inflammation

Diabetes

Blockage of bile ducts

Inflammation of the nerves or muscles with pain, weakness, and paralysis

Irregular heart beat

Fluid in the lungs

Gastritis (inflammation of the stomach), ulcer of the small intestines

Severe and possibly fatal peeling of the skin (toxic epidermal necrolysis)
History, Physical Examination, Pregnancy Testing, echocardiogram, ECG:
There is minimal medical risk or discomfort from these procedures.
Contrast Agents
Your x‐ray, CT or MRI procedure will require the use of a “contrast agent.” The contrast agent is a 
substance that helps the radiologist interpret the images. The contrast agent will be injected by either 
a hand‐held needle or a machine that does the injection. Most contrast agents stay in your body for 
only a few minutes, but some of them can remain for a few hours or days without any harm to you or 
anyone near you. Contrast agents are generally quite safe, but any injection involves some risks. 
The injection could harm a nerve, artery or vein, or cause infection. The contrast agent could affect 
kidney function or cause an allergic reaction, though these outcomes are rare. The contrast agent 
could also leak from your veins a little causing swelling and discomfort, that is typically treated with 
ice packs.
Magnetic Resonance Imaging (MRI)
MRI exams use powerful magnets to create images of the body. In addition to the possible reactions 
to contrast materials, you may feel claustrophobic while in the magnet, and will hear loud beeping or 
hammering noises. If you have tattoos or any metal items in your body such as implants, 
pacemakers, clips or shrapnel, we will do special screening to make sure your MRI scan is done 
safely.
Radiation-Related Risks
You will be exposed to radiation from CT scans and other x-rays. Some of these procedures are not 
necessary for your medical care and will occur because you participate in this study. The estimated 
radiation dose that you will receive is equal to or less than the natural environmental radiation the 
average person receives in the United States annually.  The principal risk associated with a radiation 
dose is the possibility of developing a radiation-induced cancer later in life.  The risk for radiation-
induced cancer from this study is negligible. 
Gadolinium Enhancement
You may have some discomfort and bruising from the needle insertion for the intravenous (IV) 
catheter. Some people feel light-headed or faint. The risks of an IV catheter also include bleeding, 
infection, or skin or vein inflammation with pain and swelling.
Symptoms from the gadolinium contrast are usually mild. Symptoms may include a cold feeling in the 
arm during injection, a metallic taste, headache, and nausea. In an extremely small number of 
patients, more severe symptoms have been reported including allergic reactions, shortness of breath, 
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wheezing, hives, and lowering of blood pressure. You should not receive gadolinium if you previously 
had an allergic reaction to it. You will be asked about such allergic reactions before a contrast agent 
is administered.
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis” which has resulted in a very small number of deaths. If you are older 
than 60 or have diabetes, kidney disease or liver disease, a blood test of your kidney function will be 
done within 4 weeks before any MRI scan with gadolinium contrast. You may not receive gadolinium 
for a research MRI scan if your kidney function is not normal.
Most of the gadolinium contrast leaves the body in the urine. However, recent studies have found that 
very small amounts of gadolinium remain in the body, including the brain. Some gadolinium contrast 
drugs are less likely to remain than others. In this study, we will use the gadolinium contrast drugs 
that are less likely to remain whenever possible. There is no evidence at this time that the gadolinium 
that stays in the body causes any health problems.
Blood drawing
You may have some discomfort and bruising from the needle insertion. Some people feel light-
headed or faint.
If you are pregnant you will not be permitted to participate in this research study.
Risk to Pregnancy or Fetus
Procedures or drugs used in this study could harm a developing fetus, such as an MRI scan with 
gadolinium and anesthesia used during surgery. We do not know if the study drugs, nivolumab are 
BMS-986016 can harm a pregnancy. We do not know if these drugs can hurt a growing fetus. 
Because of these risks, participants who are physically able to have a baby and those who are able to 
father a baby must agree to remain completely abstinent from sexual intercourse or use a reliable 
method of birth control. Those who are able to father a child must use birth control while in this study 
and for 33 weeks after their last dose of either nivolumab or BMS-986016. Those who are able to 
have a baby will have to use birth control while in this study until 24 weeks after their last dose of a 
study drug.
Effective methods of birth control for this study include:

hormonal contraception (birth control pills, injected hormones or vaginal ring)

intrauterine device

barrier methods (condom or diaphragm) used with spermicide

surgical sterilization (hysterectomy, tubal ligation, or vasectomy)
It is important for you to know that no method of birth control is totally effective in preventing 
pregnancy except for surgical sterilization (hysterectomy, tubal ligation or vasectomy) or total 
abstinence from sexual intercourse.
Participants who can get pregnant will have pregnancy testing on entry to the study and during the 
study. You will not be able to stay in this study if the pregnancy test is positive. If you become 
pregnant during participation, we will stop nivolumab and BMS-986016. We will refer you to the 
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Emory OB/Gyn service. They will check your health and give you advice. We will ask if you are willing 
to continue to have study visits. We will continue to follow you until you are no longer pregnant.
If you father a child while you are in this study, please inform us. We may ask to evaluate your partner 
and follow her until she is no longer pregnant.
Risks of Storage and Sharing of Data
Even though we will remove information that could identify you from samples and data that are sent 
to repositories or shared, there is a very small chance that the samples and data could be identified 
as yours.
It is possible that the researchers will learn something new during the study about the risks of being in 
it.  If this happens, they will tell you about it. Then you can decide if you want to continue to be in this 
study or not.  You may be asked to sign a new consent form that includes the new information if you 
decide to stay in the study.
Will I benefit directly from the study? 
You may benefit from being in this study if nivolumab and BMS-986016 slow the growth of your brain 
tumors. We do not know if nivolumab and BMS-986016 will have any effect on the tumor. Also, any 
benefit from the nivolumab or BMS-986016 may not last very long. The tests of the brain's immune 
response to nivolumab will not directly help you. What we learn from the study may help future 
patients with GBM.
Will I be compensated for my time and effort?
You will not be offered compensation for being in this study.  
What are my other options?
The alternative to being in this study is to receive medical or surgical treatment for your GBM at 
Emory (if available) or elsewhere. Medical care for GBM that has regrown may include radiation, 
chemotherapy and/or surgery. You do not have to participate in this trial to receive GBM surgery at 
the Emory. You may not have to be in this study to receive nivolumab and BMS-986016. You may be 
able receive these study drugs elsewhere under the care of your own physicians.
Drugs that are FDA-approved for GBM that has regrown include bevacizumab and gliadel wafers. 
You will not be able to use bevacizumab, gliadel wafers or other drugs for your tumor while you are in 
this study. You cannot participate in any other treatment or research study for GBM while in this 
study. We will discuss all of these options with you before you decide whether you want to be in this 
study.
Taking part in this study, however, may make you unable to participate in some other research 
studies, if they exclude people who have taken certain treatments.  You should discuss this with the 
researchers if you have concerns. You may wish to research other study options at websites like 
clinicaltrials.gov and ResearchMatch.org.
How will you protect my private information that you collect in this study?
Whenever possible, a study number, rather than your name, will be used on study records.  Your 
name and other identifying information will not appear when we present or publish the study results.
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Certificate of Confidentiality
There is a Certificate of Confidentiality from the National Institutes of Health for this Study.  The 
Certificate of Confidentiality helps us to keep others from learning that you participated in this study.  
Emory will rely on the Certificate of Confidentiality to refuse to give out study information that 
identifies you.  For example, if Emory received a subpoena for study records, it would not give out 
information that identifies you.
The Certificate of Confidentiality does not stop you or someone else, like a member of your family, 
from giving out information about your participation in this study.  For example, if you let your 
insurance company know that you are in this study, and you agree to give the insurance company 
research information, then the investigator cannot use the Certificate to withhold this information. This 
means you and your family also need to protect your own privacy.
The Certificate does not stop Emory from making the following disclosures about you:

Giving state public health officials information about certain infectious diseases,

Giving law officials information about abuse of a child, elderly person or disabled person.

Giving out information to prevent harm to you or others.
Giving the study sponsor or funders information about the study, including information for an audit or 
evaluation.
Storing and Sharing your Information
De-identified data from this study (data that has been stripped of all information that can identify you), 
may be placed into public databases where, in addition to having no direct identifiers, researchers will 
need to sign data use agreements before accessing the data. We will remove or code any personal 
information that could identify you before your information is shared. This will ensure that, by current 
scientific standards and known methods, it is extremely unlikely that anyone would be able to identify 
you from the information we share. Despite these measures, we cannot guarantee anonymity of your 
personal data.
Your data and specimens from this study may be useful for other research being done by 
investigators at Emory or elsewhere. To help further science, we may provide your deidentified data 
and/or specimens to other researchers. If we do, we will not include any information that could identify 
you. If your data or specimens are labeled with your study ID, we will not allow the other investigators 
to link that ID to your identifiable information.
Medical Record
If you have been an Emory Healthcare patient before, then you already have an Emory Healthcare 
medical record.  If you have never been an Emory Healthcare patient, you do not have one.   An 
Emory Healthcare medical record will be made for you if an Emory provider or facility gives you any 
services or procedures for this study.  
Copies of the consent form/HIPAA authorization that you sign will be put in any Emory Healthcare 
medical record you have now or any time during the study.  
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Emory Healthcare may create study information about you that can help with your care.  For example, 
the results of study tests or procedures.  These study results will be put in your Emory Healthcare 
medical record. Anyone who has access to your medical records will be able to have access to all the 
study information placed there.  The confidentiality of the study information in your medical record will 
be protected by laws like the HIPAA privacy rule.  State and federal laws may not protect the 
research information from disclosure. 
Tests and procedures done at non-Emory places may not become part of your Emory medical record. 
Also, if you decide to be in this study, it is up to you to let your other health providers know. 
In Case of Injury
If you believe you have become ill or injured from this research, you should contact Dr. Edjah Nduom 
at telephone number 404-778-1900. You should also let any health care provider who treats you 
know that you are in a research study.  
If you get ill or injured from being in the study, Emory will help you to get medical treatment. Neither 
Emory nor the sponsor have set aside money to pay for this medical treatment.  Your insurer will be 
billed for your treatment costs.  If you do not have insurance, or if your insurance does not pay, then 
you will have to pay these costs.   
For Emory, the only exception is if it is proven that your injury or illness is directly caused by the 
negligence of an Emory employee. “Negligence” is the failure to follow a standard duty of care. You 
do not give up any legal rights you may have by being in this study, including any right to bring a 
claim for negligence. 
Costs
The study sponsor will pay for certain items and services that you may receive if you take part in this 
study.  
You will have to pay for the items or services for which the study sponsor does not pay. The sponsor 
will not pay for your regular medical care. If you have insurance, Emory will submit claims to your 
insurance for items and services that the sponsor does not cover.  Emory will send in only those 
claims for items and services that it reasonably believes your insurance will pay and that the sponsor 
has not paid. 
The actual amount that you have to pay depends on whether or not you have health insurance and 
whether or not that insurance will pay for any research study costs. Generally, insurance companies 
will not pay for items and services that are required just for a research study. Some insurance 
companies will not pay for regular medical treatment or treatment for complications if you are in a 
study.  How much you will have to pay for any co-payments, deductibles or co-insurance depends on 
your plan.  Emory and the sponsor will not pay for these costs. 
It is a good idea to contact your insurance provider and tell them you want to be in this research 
study.  Ask them what they will pay for and what they will not pay for.  You can also ask the study 
team for help in figuring out what you will have to pay. 
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If you do not have insurance, Emory will review your case as part of its program for low-income 
patient care.  The standard policies of that program will apply.  The program will figure out if you have 
to pay any costs for taking part in the study and what those costs will be.
Withdrawal from the Study
You have the right to leave a study at any time without penalty.  
For your safety, however, you should consider the study doctor’s advice about how to go off the study 
treatment.  If you leave the study before the final planned study visit, the researchers may ask you to 
have some of the final steps done.
The researchers also have the right to stop your participation in this study without your consent for any 
reason, especially if they believe it is in your best interest or if you were to object to any future changes 
that may be made in the study plan.  
Authorization to Use and Disclose Protected Health Information
The privacy of your health information is important to us.  We call your health information that 
identifies you, your “protected health information” or “PHI.”  To protect your PHI, we will follow federal 
and state privacy laws, including the Health Insurance Portability and Accountability Act and 
regulations (HIPAA).  We refer to all of these laws as the “Privacy Rules.”  Here we let you know how 
we will use and disclose your PHI for the main study and for any optional studies in which you may 
choose to participate.
Main Study
PHI that Will be Used/Disclosed:  
The PHI that we will use or share for the main research study includes:

Medical information about you including your medical history and present/past medications.

Results of exams, procedures and tests you have before and during the study.

Laboratory test results.
Purposes for Which Your PHI Will be Used/Disclosed:
We will use and share your PHI for the conduct and oversight of the research study.  We will use and 
share your PHI to provide you with study related treatment and for payment for such treatment.  We 
will also use and share your PHI to conduct normal business operations.  We may share your PHI 
with other people and places that help us conduct or carry out the study, such as laboratories, data 
management centers, data monitors, contract research organizations, Institutional Review Boards 
(IRBs) and other study sites. If you leave the study, we may use your PHI to determine your health, 
vital status or contact information.
Use and Disclosure of Your Information That is Required by Law:  
We will use and disclose your PHI when we are required to do so by law. This includes laws that 
require us to report child abuse or abuse of elderly or disabled adults.  
Authorization to Use PHI is Required to Participate:
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By signing this form, you give us permission to use and share your PHI as described in this 
document. You do not have to sign this form. If you do not sign this form, you may still receive non-
research related treatment.  
People Who will Use/Disclose Your PHI:
The following people and groups will use and disclose your PHI in connection with the research 
study:

The Principal Investigator and the research staff will use and disclose your PHI to conduct the 
study and give you study related treatment.

Emory may use and disclose your PHI to get payment for study related treatment and to run 
normal business operations. 

The Principal Investigator and research staff will share your PHI with other people and groups 
to help conduct the study or to provide oversight for the study.

National Institute of Neurological Disorders and Stroke (NINDS) is the Sponsor of the study.  
The Sponsor may use and disclose your PHI to make sure the research is done correctly and 
to collect and analyze the results of the research.  The Sponsor may disclose your PHI to other 
people and groups like study monitors to help conduct the study or to provide oversight for the 
study.  

The following people and groups will use your PHI to make sure the research is done correctly 
and safely:
o
Emory offices that are part of the Human Research Participant Protection Program and 
those that are involved in study administration and billing.  These include the Emory 
IRB, the Emory Research and Healthcare Compliance Offices, and the Emory Office for 
Clinical Research. 
o
Government agencies that regulate the research including:  Office for Human Research 
Protections; Food and Drug Administration; National Institutes of Health (NIH).
o
Public health agencies.
o
Research monitors and reviewer.
o
Accreditation agencies.
o
Study-supporter, Bristol-Myers Squibb.

Sometimes a Principal Investigator or other researcher moves to a different institution. If this 
happens, your PHI may be shared with that new institution and their oversight offices. PHI will 
be shared securely and under a legal agreement to ensure it continues to be used under the 
terms of this consent and HIPAA authorization.
Optional Study of Data and/or Specimens for Future Research
Authorization for This Use of PHI is Required to Participate in Optional Study, but Not in Main 
Study:
You do not have to authorize the use and disclosure of your PHI for the optional study.  If you do not 
authorize the use and disclosure of your PHI for the optional study, then you may not participate in 
the optional research study, but you can still be in the main research study.   
Additional People Who Will Use/Disclose Your PHI for Optional Study:
The same people and groups who will use and disclose your PHI for the Main Study will also do so in 
connection with the optional research study/storage of PHI for future research. 
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Expiration of Your Authorization
Your PHI will be used until this research study ends.
Revoking Your Authorization
If you sign this form, at any time later you may revoke (take back) your permission to use your 
information.  If you want to do this, you must contact the study team at:
Edjah Nduom, MD
Winship Cancer Institute, Emory University
1365-C Clifton Road NE
Atlanta, GA 30322
At that point, the researchers would not collect any more of your PHI.  But they may use or disclose 
the information you already gave them so they can follow the law, protect your safety, or make sure 
that the study was done properly and the data is correct.  If you revoke your authorization you will not 
be able to stay in the main study. 
Other Items You Should Know about Your Privacy
Not all people and entities are covered by the Privacy Rules.  HIPAA only applies to health care 
providers, health care payers, and health care clearinghouses.  If we disclose your information to 
people who are not covered by the Privacy Rules, including HIPAA, then your information won’t be 
protected by the Privacy Rules.  People who do not have to follow the Privacy rules can use or 
disclose your information with others without your permission if they are allowed to do so by the laws 
that cover them.  The Sponsor, and people and companies working with the Sponsor on this study 
are not covered by the Privacy Rules.  They will only use and disclose your information as described 
in this Consent and Authorization. 
To maintain the integrity of this research study, you generally will not have access to your PHI related 
to this research until the study is complete.  When the study ends, and at your request, you generally 
will have access to your PHI that we maintain in a designated record set.  A designated record set is 
data that includes medical information or billing records that your health care providers use to make 
decisions about you. If it is necessary for your health care, your health information will be provided to 
your doctor. 
We may remove identifying information from your PHI.  Once we do this, the remaining information 
will not be subject to the Privacy Rules.  Information without identifiers may be used or disclosed with 
other people or organizations for purposes besides this study.  
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Contact Information
Contact Dr. Edjah Nduom at 404-778-1900:

if you have any questions about this study or your part in it,  

if you feel you have had a research-related injury or a bad reaction to the study drug, or

if you have questions, or concerns about the research
Contact the Emory Institutional Review Board at 404-712-0720 or 877-503-9797 or irb@emory.edu:

if you have questions about your rights as a research participant.

if you have complaints about the research or an issue you rather discuss with someone outside 
the research team.
You may also let the IRB know about your experience as a research participant through our Research 
Participant Survey at https://tinyurl.com/ycewgkke.
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Consent and Authorization
Consent and HIPAA Authorization for Optional Study:  
Please initial below if you opt to participate in and authorize use and disclosure of your PHI in the 
optional study/studies previously described:
Optional Study for Future Research
  
My samples and data may be used for other research projects. This includes those not related to
brain tumors.
 Yes     
 No
________Initials
TO BE FILLED OUT BY SUBJECT ONLY
Please print your name, sign, and date below if you agree to be in this research study, and any 
optional studies you initialed above. By signing this consent and authorization form, you will not give up 
any of your legal rights. We will give you a copy of the signed form to keep.
________________________________________
Name of Subject 
________
____:____ am / pm
Signature of Subject  
    Date           Time  (please circle)
(18 or older and able to consent)
________
____:____ am / pm
Signature of Legally Authorized Representative
    Date           Time  (please circle)
_______________________________________
Authority of Legally Authorized Representative or Relationship to Subject
TO BE FILLED OUT BY STUDY TEAM ONLY
__________________________________________________
Name of Person Conducting Informed Consent Discussion
________
____:____ am / pm
Signature of Person Conducting Informed                    Date             Time  (please circle)
Consent Discussion 
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