Clinical trial NCT04434560
Conditions: Brain Metastases, Adult
Keywords: Pro00103812 Sammons Non-small-cell lung carcinoma Renal cell carcinoma Urothelial carcinoma Melanoma Ovarian carcinoma Triple negative breast cancer Solid tumor Brain metastases Nivolumab Ipilimumab Opdivo Yervoy
Sponsor: Sarah Sammons, MD
Start date: 2020-11-04; Completion date: 2021-06-17
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this phase 2 study is to assess the feasibility and efficacy of neoadjuvant immunotherapy in patients with previously untreated, surgically-resectable, solid tumor brain metastases. The primary objectives of this study are to 1) assess the feasibility of neoadjuvant ipilimumab and nivolumab treatment before surgery and stereotactic radiosurgery (SRS) in patients with solid tumor brain metastases as measured by the proportion of patients who have their surgery delayed or surgery never occurs, and 2) demonstrate that neoadjuvant immunotherapy will increase proliferation of circulating T-cells compared to baseline measurements. Exploratory objectives include describing patient progression free survival and overall survival, time to local and distant intracranial progression, and the rate of radiation necrosis. The rate of radionecrosis will also be explored, as immune expression profiles.

Detailed description:
Forty patients planned for standard of care resection of at least one solid tumor brain metastasis will be enrolled onto the study after providing informed consent. Primary tumor histology types are restricted to those known to extracranially respond to immunotherapy, and will include, but not be limited to, squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC without known anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), and ROS mutation, renal cell carcinoma (RCC), melanoma, and triple negative breast cancer (TNBC) that is programmed death-ligand 1 positive (PD-L1 +). All participants will receive neoadjuvant immunotherapy and will receive a single infusion of nivolumab at a dose of 3 mg/kg and ipilimumab at a dose of 1 mg/kg 7 days (±3 days) prior to surgical resection of their metastases. Approximately three weeks after resection, patients in will then receive SRS per standard of care guidelines. Patients will be followed for 18 months after initiating study treatment. Up to 20 participants will be recruited and treated. Blood will be collected periodically during the study for correlative assessments.

Arms: arm 1: Patients will proceed to surgical resection with no nivolumab/ipilimumab given prior to surgery. arm 2: Patients will receive a single dose of neoadjuvant nivolumab and ipilimumab 7 days (± 3 days) prior to surgical resection.
Interventions: intervention 1: Nivolumab intervention 2: Ipilimumab
Intervention descriptions: intervention 1: Nivolumab will be given at the FDA-approved dose of 3 mg/kg. intervention 2: Ipilimumab will be given at the FDA-approved dose of 1 mg/kg.

Protocol documents:
Prot_SAP_000.pdf: 
 
A Phase II trial of surgery and stereotactic 
radiosurgery with  neoadjuvant nivolumab and 
ipilimumab in patients with surgically-resectable, solid 
tumor brain metastases (NCT04434560) 
 
 
Sponsor: 
PI – Duke Cancer Institute 
Funding Source: 
Drug Source: 
Translating Duke Health Funding 
BMS 
Protocol Source: 
PI - Duke Cancer Institute 
Duke IRB#: 
BMS Protocol #: 
Pro00103812 
CA184-583 
 
Principal Investigator 
Sarah Sammons, MD 
10 Bryan Searle Drive 
IND# 
147565 
Sub Investigators (cont.) 
David Ashley, MBBS, PhD 
David.ashley@duke.edu 
 
Sub Investigators (cont.) 
Mustafa Khasraw, MD 
Mustafa.khasraw@duke.edu 
Seeley G. Mudd Room 449-A 
Durham, NC 27710 
Phone: 919.668.5247 
Fax: 919.970.8389 
Sarah.sammons@duke.edu 
 
Sub-Investigator(s) 
Carey Anders, MD 
Carey.anders@duke.edu 
 
Peter Fecci, MD, PhD 
Peter.fecci@duke.edu 
 
Katherine Peters, MD, PhD 
Katy.peters@duke.edu 
 
John Kirkpatrick, MD, PhD 
John.kirkpatrick@duke.edu 
 
Scott Floyd, MD, PhD 
Scott.floyd@duke.edu 
 
Rory Goodwin, MD 
Rory.goodwin@duke.edu 
 
April Salama, MD 
April.salama@duke.edu 
 
Tian Zhang, MD PhD 
Tian.zhang@duke.edu 
 
Brent Hanks, MD 
Brent.hanks@duke.edu 
 
Jeffrey Clarke, MD 
Jeffrey.clarke@duke.edu 
 
Statistician 
James Herndon II, PhD 
James.herndon@duke.edu 
 
Study Coordinator 
Kathleen “Katie” Hahn 
Kathleen.hahn@duke.
edu 
 
Regulatory Coordinator 
Kendra Boyd 
Kendra.boyd@duke.edu 
 
Data Manager 
Eric Lipp 
Eric.lipp@duke.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


Pro00103812:  Neoadjuvant Immunotherapy in Brain Metastases 
Version: 03/19/2021 
Version: 1.0 
10/07/2019 
Original draft sent to BMS 
Version: 1.1 
12/02/2020 
Updated based on BMS’ comments from 11/06/2019 
Version: 1.2 
03/20/2020 
Revised serum creatinine per FDA recommendation 
Version: 1.3 
06/15/2020 
Addition of table in Section 6, updated face page 
Version: 1.4 
08/31/2020 
Revised schedule of events and eligibility 
Version: 1.5 
09/29/2020 
Removed melanoma BRAF status for eligibility 
Version: 1.6 
02/11/2021 
Revised schedule of events and eligibility 
Version: 1.7 
03/19/2021 
Removal of control arm 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and 
regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise. 
 


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1. TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ........................................................................................... 2 
2. 
LIST OF FIGURES ................................................................................................... 6 
3. 
LIST OF TABLES ..................................................................................................... 7 
4. 
LIST OF ABBREVIATIONS ...................................................................................... 8 
5. 
PROTOCOL SYNOPSIS AND RESEARCH SUMMARY ......................................... 9 
5.1. Purpose .............................................................................................................. 9 
5.2. Background and Significance ............................................................................. 9 
5.3. Design and Procedure ..................................................................................... 10 
5.4. Selection of Subjects ........................................................................................ 10 
5.5. Duration of Study ............................................................................................. 10 
5.6. Data Analysis and Statistical Considerations ................................................... 10 
6. 
STUDY SCHEMA ................................................................................................... 12 
7. 
BACKGROUND AND SIGNIFICANCE .................................................................. 13 
7.1. Study Disease .................................................................................................. 13 
7.2. Study Agent ...................................................................................................... 13 
7.2.1. 
Nivolumab .................................................................................................. 13 
7.2.2. 
Ipilimumab ................................................................................................. 14 
7.3. Study Purpose/Rationale .................................................................................. 14 
8. 
OBJECTIVES AND ENDPOINTS .......................................................................... 17 
9. 
INVESTIGATIONAL PLAN ..................................................................................... 17 
9.1. Study Design .................................................................................................... 17 
9.1.1. 
Definition of Dose-Limiting Toxicity (DLT) .................................................. 18 
9.1.2. 
Dose Modification ...................................................................................... 18 
9.1.3. 
Safety Considerations ................................................................................ 18 
9.1.4. 
Missed Doses ............................................................................................ 21 
9.1.5. 
Concomitant Medications .......................................................................... 21 
9.1.6. 
Study Drug Blinding ................................................................................... 22 
9.1.7. 
Randomization ........................................................................................... 22 
9.2. Rationale for Selection of Dose, Regimen, and Treatment Duration ................ 22 
9.3. Rationale for Correlative Studies ...................................................................... 22 
9.4. Definition of Evaluable Subjects, On Study, and End of Study ......................... 23 
9.5. Early Study Termination ................................................................................... 24 
10. 
STUDY DRUG ..................................................................................................... 25 


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10.1. 
Nivolumab (Opdivo®).................................................................................... 25 
10.1.1. 
Names, Classification, and Mechanism of Action ................................... 25 
10.1.2. 
Packaging and Labeling ......................................................................... 25 
10.1.3. 
Supply, Receipt, and Storage ................................................................. 25 
10.1.4. 
Dispensing and Preparation ................................................................... 25 
10.1.5. 
Disposal and Destruction ....................................................................... 26 
10.2. 
Ipilimumab (Yervoy®) ................................................................................... 26 
10.2.1. 
Names, Classification, and Mechanism of Action ................................... 26 
10.2.2. 
Packaging and Labeling ......................................................................... 26 
10.2.3. 
Supply, Receipt, and Storage ................................................................. 27 
10.2.4. 
Dispensing and Preparation ................................................................... 27 
10.2.5. 
Disposal and Destruction ....................................................................... 27 
11. 
SUBJECT ELIGIBILITY ....................................................................................... 28 
11.1. 
Inclusion Criteria ........................................................................................... 28 
11.2. 
Exclusion Criteria .......................................................................................... 29 
12. 
SCREENING AND ON-STUDY TESTS AND PROCEDURES ............................ 30 
12.1. 
Screening Examination ................................................................................. 31 
12.2. 
Treatment Period .......................................................................................... 31 
12.3. 
End of Treatment .......................................................................................... 32 
12.4. 
Follow-up Period ........................................................................................... 32 
12.5. 
End of Study ................................................................................................. 32 
12.6. 
Early Withdrawal of Subject(s) ...................................................................... 32 
12.6.1. 
Criteria for Early Withdrawal ................................................................... 33 
12.6.2. 
Follow-up Requirements for Early Withdrawal ........................................ 33 
12.6.3. 
Replacement of Early Withdrawal(s) ...................................................... 33 
12.7. 
Study Assessments ...................................................................................... 33 
12.7.1. 
Medical History ....................................................................................... 33 
12.7.2. 
Physical Exam ........................................................................................ 33 
12.7.3. 
Radiographic Review ............................................................................. 33 
12.7.4. 
Laboratory Evaluations ........................................................................... 33 
12.7.5. 
Correlative Assessments ........................................................................ 34 
13. 
SAFETY MONITORING AND REPORTING ....................................................... 35 
13.1. 
Adverse Events ............................................................................................. 35 
13.1.1. 
AEs of Special Interest ........................................................................... 35 


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13.1.2. 
Reporting of AEs .................................................................................... 35 
13.2. 
Serious Adverse Events ................................................................................ 36 
13.2.1. 
Reporting of SAEs .................................................................................. 37 
13.3. 
Emergency Unblinding of Investigational Treatment ..................................... 38 
13.4. 
Other Reportable Information........................................................................ 38 
13.5. 
Special Warnings and Precautions ............................................................... 38 
13.6. 
Safety Oversight Committee (SOC) .............................................................. 38 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................... 40 
14.1. 
Monitoring ..................................................................................................... 40 
14.2. 
Audits ............................................................................................................ 41 
14.3. 
Data Management and Processing ............................................................... 41 
14.3.1. 
Case Report Forms (CRFs).................................................................... 41 
14.3.2. 
Data Management Procedures and Data Verification ............................ 42 
14.3.3. 
Study Closure ......................................................................................... 42 
15. 
STATISTICAL METHODS AND DATA ANALYSIS ............................................. 43 
15.1. 
Study Design Overview ................................................................................. 43 
15.2. 
Analysis Sets ................................................................................................ 43 
15.3. 
Patient Demographics and Other Baseline Characteristics .......................... 43 
15.4. 
Treatments .................................................................................................... 43 
15.5. 
Primary Objectives ........................................................................................ 44 
15.5.1. 
Primary Objective #1: Feasibility (Surgical Delay) .................................. 44 
15.5.2. 
Primary Objective #2: Proliferation of Circulating T-Cells ....................... 46 
15.6. 
Exploratory Objectives .................................................................................. 46 
15.6.1. 
Exploratory Objective #1: Survival .......................................................... 47 
15.6.2. 
Exploratory Objectives #2 - #5: Disease Progression ............................ 47 
15.6.3. 
Exploratory Objectives #6: Radionecrosis .............................................. 48 
15.6.4. 
Exploratory Objectives #7: Immune Expression Profiles ........................ 48 
15.7. 
Interim Analysis ............................................................................................. 48 
15.8. 
Sample Size Calculation ............................................................................... 49 
16. 
ADMINISTRATIVE AND ETHICAL CONSIDERATIONS .................................... 49 
16.1. 
Regulatory and Ethical Compliance .............................................................. 49 
16.2. 
DUHS Institutional Review Board and DCI Cancer Protocol Committee ....... 49 
16.3. 
Informed Consent ......................................................................................... 50 
16.4. 
Study Documentation .................................................................................... 50 


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16.5. 
Privacy, Confidentiality, and Data Storage .................................................... 51 
16.6. 
Data and Safety Monitoring........................................................................... 51 
16.7. 
Protocol Amendments ................................................................................... 52 
16.8. 
Records Retention ........................................................................................ 52 
17. 
REFERENCES .................................................................................................... 53 
18. 
APPENDICES ..................................................................................................... 54 
18.1. 
Nivolumab Safety Algorithms ........................................................................ 54 
18.2. 
Ipilimumab Safety Algorithms ........................................................................ 62 


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2. LIST OF FIGURES 
Figure 1: Proposed mechanism for neoadjuvant immunotherapy t-cell modulation 
in GBM .......................................................................................................................... 15 
Figure 2: Neoadjuvant treatment of surgically-resectable GBM with 
pembrolizumab results in significantly extended survival compared to adjuvant 
treatment ...................................................................................................................... 16 
Figure 3: Neoadjuvant immunotherapy alters intratumoral interferon-γ-related 
gene expression .......................................................................................................... 23 


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3. LIST OF TABLES 
Table 1: Schedule of Study Tests and Procedures .................................................. 30 
Table 2: GI Adverse Event Management Algorithm ................................................. 54 
Table 3: Renal Adverse Event Management Algorithm ........................................... 55 
Table 4: Pulmonary Adverse Event Management Algorithm ................................... 56 
Table 5: Hepatic Adverse Event Management Algorithm ........................................ 57 
Table 6: Endocrinopathy Adverse Event Management Algorithm .......................... 58 
Table 7: Skin Adverse Event Management Algorithm .............................................. 59 
Table 8: Neurological Adverse Event Management Algorithm ............................... 60 
Table 9: Myocarditics Adverse Event Management Algorithm ............................... 61 
Table 10: GI Adverse Event Management Algorithm ............................................... 62 
Table 11: Hepatic Adverse Event Management Algorithm ...................................... 63 
Table 12: Endocrinopathy Adverse Event Management Algorithm ........................ 64 
Table 13: Skin Adverse Event Management Algorithm ............................................ 65 
Table 14: Neurological Adverse Event Management Algorithm ............................. 66 


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4. LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
BMS 
Bristol-Myers Squibb 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
GBM 
Glioblastoma 
IV (or iv)  Intravenously 
ICS 
Investigational Chemotherapy Service 
IO 
Immunotherapy 
IRAE 
Immune Related Adverse Event 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NSCLC 
Non-Small Cell Lung Cancer 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PRTBTC Preston Robert Tisch Brain Tumor Center 
RCC 
Renal Cell Carcinoma 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SRS 
Stereotactic Radio Surgery 
TNBC 
Triple Negative Breast Cancer 


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5. PROTOCOL SYNOPSIS AND RESEARCH SUMMARY 
 
5.1. 
Purpose 
A phase II study of neoadjuvant nivolumab and ipilimumab in patients with 
surgically-resectable, solid tumor brain metastases is planned to address the 
following objectives. 
 
Primary Objectives: 
1. Assess the feasibility of neoadjuvant ipilimumab and nivolumab treatment before 
surgery and SRS in patients with solid tumor brain metastases as measured by 
the proportion of patients who have their surgery delayed or surgery never 
occurs. 
2. Demonstrate that neoadjuvant immunotherapy will increase proliferation of 
circulating T-cells compared to baseline measurements. 
 
Exploratory Objectives: 
1. Describe the survival of patients with solid tumor brain metastases receiving 
neoadjuvant ipilimumab and nivolumab followed by surgery and SRS. 
2. Describe the time to local intracranial progression. 
3. Describe the time to distant intracranial progression. 
4. Describe the time to overall intracranial progression. 
5. Describe progression-free survival. 
6. Quantify the rate of radiation necrosis. 
7. Describe the immune expression profile of patients treated with neoadjuvant 
ipilimumab and nivolumab. 
 
Hypotheses 
This is a hypothesis testing protocol designed to test the following hypotheses: 
1. Neoadjuvant immunotherapy will not delay surgical resection for patients with 
solid tumor brain metastases. 
2. Neoadjuvant immunotherapy will increase Ki67 on circulating PDL-1+/CD8+ T- 
cells among patients with solid tumor brain metastases. 
5.2. 
Background and Significance 
As treatments for primary tumors improve and patients survive longer, the potential 
for primary tumors to metastasize increases, creating a need for newer and better 
therapeutic strategies for patients with metastases. Currently, up to 30% of cancer 
patients will develop at least one brain metastasis [1]. Current standard of care 
therapies include resection and stereotactic radiosurgery (SRS) followed by a variety 
of maintenance treatments. Progression free survival (PFS) and overall survival 
(OS) rates for patients with brain metastases are modest at best. For example, lung 


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cancer, breast cancer and melanoma patients with untreated metastases have 
median survival rates of 12 months [2], 13.8 months [3, 4], and 9.8 months [5], 
respectively, motivating a need for novel therapeutic approaches within these patient 
populations. Recent approaches for treating brain oligometastases (few, small 
metastases) include immunotherapies, but the timing as to when to initiate 
immunotherapy is still up for debate. Most studies have focused on adjuvant 
immunotherapies, following surgical resection and SRS; however, giving 
immunotherapies after surgery may reduce T-cell receptor modulation, activating 
fewer tumor-specific T cells leading to a less robust immune response. Providing 
immunotherapies in the neoadjuvant setting, where antigenic burden is higher in the 
brain, could result in enhanced T-cell receptor modulation, and therefore more 
robust activation of tumor-specific T cells and an overall more effective immune 
response. Indeed, a limited number of studies have shown improved outcomes for 
patients receiving immunotherapy in the neoadjuvant setting, demonstrating 
neoadjuvant immunotherapy merits further investigation. 
 
The two most common immunotherapy checkpoint blockades are PD-1/PD-L1 and 
CTLA-4. Bristol Meyers Squibb (BMS) has developed compounds targeted at 
blocking each of these checkpoints: nivolumab (PD-1) and ipilimumab (CTLA-4). 
This is a feasibility and efficacy study testing the combination of neoadjuvant 
nivolumab and ipilimumab in patients with solid tumor brain oligometastases as 
described in Section 5.3. 
5.3. 
Design and Procedure 
After providing informed consent, up to 20 eligible participants with surgically-
resectable, solid tumor brain metastases will be treated. Participants will receive a 
single dose of neoadjuvant nivolumab and ipilimumab 7 days (± 3 days) prior to 
surgical resection. Nivolumab will be given at the FDA-approved dose of 3 mg/kg; 
ipilimumab will be given at the FDA-approved dose of 1 mg/kg. Patients will then 
continue to have standard of care SRS 3 weeks (±3 weeks) after surgery. See 
Section 6 for the study schema. 
5.4. 
Selection of Subjects 
Please see Section 11 for a list of all inclusion and exclusion criteria. 
5.5. 
Duration of Study 
Patients will be on study for up to 18 months after initiation of study treatment. 
5.6. 
Data Analysis and Statistical Considerations 
Feasibility will be assessed by the proportion of patients who have their surgery delayed. 
With the checkpoint inhibitors being administered on Day -7, the surgery is scheduled for 
Week 1, Day 1 (± 3 days).  S urgery will be considered delayed if it never occurs or occurs 
after Day 4 (i.e. Day 1 + 3). The proportion of patients experiencing surgical delay as 
defined in Section 15.5.1.1 will be computed as the number of patients with delay divided 
by the total number of patients per arm. Methods developed for continuous monitoring of 
toxicity will assess whether the number of surgical delays is excessive. Monitoring rules 
based upon Pocock monitoring rules are provided in Section 15.5.1.2. 
 


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A one-sample t-test will assess whether significant changes fold-change in Ki67 
levels between baseline and Day 1 occurred.  
 
Kaplan-Meier methodology will be used to graphically display survival and 
progression-free survival; whereas, cumulative incidence curves will be used to 
graphically display time to local intracranial progression, time to distant intracranial 
progression, and time to overall intracranial progression as defined in Section 
15.6.2. 


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6. STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
Arm 
Study Drug 
Study Drug Administration Schedule 
Dose 
1 
Nivolumab 
7 days (±3 days) prior to surgery 
3 mg/kg 
1 
Ipilimumab 
7 days (±3 days) prior to surgery 
1 mg/kg 


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7. BACKGROUND AND SIGNIFICANCE 
7.1. 
Study Disease 
Brain metastases are 10 times more common than primary brain tumors and arise in 
10-35% of adult cancer patients [6], affecting approximately 200,000 adult cancer 
patients each year in the US [7]. Though brain metastases can develop from any 
primary tumor, the most frequent primary tumors to metastasize to the brain 
originate in the lung, skin (melanoma), kidney, and breast [7]. Given the 
heterogeneity of brain metastases, prognosis varies widely (anywhere from a few 
months to over a year), and is largely dependent on neurological performance status 
at the time of diagnosis, and the primary tumor location [6]. In a recursive partitioning 
analysis of prognostic factors in patients with brain metastases, the best median 
survival was 7.1 months, while the worst median survival was 2.3 months [8]. 
According to a multicenter, retrospective analysis of 3940 patients with brain 
metastases, median overall survival varied with primary tumor location, with a 
median OS of 7 months for NSCLC, 6.74 months for melanoma, 9.63 months for 
RCC, and 13.8 months for breast cancer [9]. Despite evolution of the standard of 
care for patients with brain oligometastases from whole brain irradiation and 
systemic therapy to include some combination of surgical resection, SRS, and 
carefully selected systemic therapy [7], prognosis remains poor for these patients 
with a median survival of around 10.8 months [10]. Clearly, there is a need to identify 
new therapies for patients with brain oligometastases. 
7.2. 
Study Agent 
Immunotherapies, including checkpoint inhibitors, have shown promise for treating a 
variety of tumors, including CNS tumors [11]. The PD-1/PD-L1 and CTLA-4 
checkpoint blockades are often responsible for preventing an effective anti-tumor 
immune response by inducing T-cell senescence. Checkpoint inhibitors, such as 
pembrolizumab (Keytruda®) and nivolumab (Opdivo®), inhibit PD-1 on T-cells to 
delay T-cell senescence by disrupting PD-1/PD-L1 interaction. Other checkpoint 
inhibitors, like ipilimumab (Yervoy®), bind to CTLA-4 on T-cells to prevent T-cell 
inactivation, promoting a more robust immune response. Both nivolumab and 
ipilimumab currently have FDA approval for various indications outlined in Sections 
7.2.1 and 7.2.2. Nivolumab and ipilimumab will be administered a single time at the 
FDA approved doses of 3 mg/kg and 1 mg/kg, respectively. 
7.2.1. Nivolumab 
Nivolumab (Opdivo®) is a human monoclonal antibody that blocks the interaction 
between PD-1 and its ligands, programmed death-ligand 1 (PD-L1) and 
programmed death-ligand 2 (PD-L2). Nivolumab is currently FDA approved for 
unresectable, metastatic, and progressive melanoma and progressive metastatic 
squamous non-small cell lung cancer. For further details regarding nivolumab, 
including its physical properties, pharmaceutical properties, pre-clinical studies, 
and toxicology, please refer to the Investigator’s Brochure. 


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7.2.2. Ipilimumab 
Ipilimumab (Yervoy®) is a recombinant, human monoclonal antibody that binds 
to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is 
currently FDA approved unresectable, metastatic, or cutaneous melanoma; 
advanced renal cell carcinoma in combination with nivolumab; microsatellite 
instability-high or mismatch repair deficient metastatic colorectal cancer that has 
progressed. For further details regarding ipilimumab, including its physical 
properties, pharmaceutical properties, pre-clinical studies, and toxicology, please 
refer to the Investigator’s Brochure. 
7.3. 
Study Purpose/Rationale 
Treatment of a limited number of brain metastases includes a mélange of focused 
radiotherapy, neurosurgical resection, and carefully selected systemic therapy. The 
advent of immunotherapies merits new investigations into the order and timing of 
standard of care and novel approaches. In an article published in the New England 
Journal of Medicine, Tawbi et al report that systemic treatment of asymptomatic 
melanoma brain metastases with ipilimumab and nivolumab showed clinically 
significant intracranial responses with complete response rate of 26% [12]. Patients 
with symptomatic brain metastases have inferior intracranial response rates and are 
in need of novel strategies [13]. A similar study published in The Lancet Oncology 
showed clinical response of both melanoma and NSCLC metastatic to the brain to 
pembrolizumab (PD-1 inhibitor) treatment [14]. These response rates are 
respectable but leave room for improvement. Single agent PD-1 inhibition with 
nivolumab was ineffective in brain metastases from renal cell carcinoma with 
intracranial response rates of only 12% [15]. While the above trials have focused on 
adjuvant immunotherapy, the intent of the proposed study is to determine whether 
neoadjuvant immunotherapy would improve upon the current standard of care in 
patients with newly diagnosed brain metastases. Giving immunotherapies after 
surgery reduces T-cell receptor modulation, activating fewer tumor-specific T cells 
leading to a less robust immune response (Figure 1). 


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Figure 1: Proposed mechanism for neoadjuvant immunotherapy t-cell modulation in 
GBM. Taken from Cloughesy et. al. 
Providing immunotherapies in the neoadjuvant setting, where antigenic burden is 
higher, should result in enhanced T-cell receptor modulation within the brain, and 
therefore more robust activation of tumor-specific T cells and an overall more 
effective immune response. Cloughesy et al reported in Nature Medicine that 
neoadjuvant treatment of surgically-resectable glioblastoma (GBM) with 
pembrolizumab resulted in significantly extended overall survival compared to 
patients who received adjuvant pembrolizumab (Figure 2) [16]. 


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Figure 2: Neoadjuvant treatment of surgically-resectable GBM with pembrolizumab results in 
significantly extended survival compared to adjuvant treatment. Adapted from Cloughsey et al. 
 
Importantly, no patients in the neoadjuvant group experienced surgical delay, 
suggesting that administration of checkpoint inhibitors prior to surgical resection is 
safe. 
 
Given that immunotherapy, specifically nivolumab and ipilimumab, have been shown 
to have significant anti-tumor activity in brain oligometastases [12], and that 
administration of checkpoint inhibitors prior to surgery results in improved overall 
survival in patients with GBM [16], investigating the timing of immunotherapy 
administration in patients with brain metastases is clinically important. Towards this 
end, we have designed a single-arm clinical trial of neoadjuvant nivolumab and 
ipilimumab in patients with asymptomatic or minimally symptomatic brain metastases 
known to have spread from primary tumors that are traditionally responsive to 
immunotherapies. The percentage of patients experiencing surgical delay in the 
neoadjuvant treatment arm will be recorded to assess feasibility. Immunotherapy 
activity will be established by assessing the change in T-cell proliferation levels in 
circulation between baseline and Day 1 (see Section 12.7.5). 


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8. OBJECTIVES AND ENDPOINTS 
 
 
Objective 
Endpoint 
Analysis 
Primary 
Assess the feasibility of 
neoadjuvant ipilimumab and 
nivolumab treatment before 
surgery and SRS among 
patients with solid tumor 
brain metastases 
Among eligible patients, the 
percentage of patients who 
experience surgical delay. 
Surgery is considered 
delayed if it occurs more than 
10 days after ipilimumab and 
nivolumab, or never occurs, 
for reasons relating to the 
immunotherapy treatment. 
See Section 
15.5.1 
Other Primary 
Demonstrate that 
neoadjuvant immunotherapy 
will increase proliferation of 
circulating T-cells compared 
to baseline measurements 
Mean fold-change between 
baseline and day 1 in Ki67 
levels 
See Section 
15.5.2 
Exploratory 
Describe the survival of 
patients with solid tumor 
brain metastases receiving 
neoadjuvant ipilimumab and 
nivolumab followed by 
surgery and SRS. 
Median survival 
See Section 
15.6.1 
Exploratory 
Describe the time to local 
intracranial progression 
Median time to local 
intracranial progression 
See Section 
15.6.2 
Exploratory 
Describe the time to distant 
intracranial progression 
Median time to distant 
intracranial progression 
See Section 
15.6.2 
Exploratory 
Describe the time to overall 
intracranial progression 
Median time to overall 
intracranial progression 
(local or distant) 
See Section 
15.6.2 
Exploratory 
Describe progression-free 
survival 
Median progression-free 
survival 
See Section 
15.6.2 
Exploratory 
Quantify the rate of radiation 
necrosis 
Percent of patients with 
radiation necrosis 
See Section 
15.6.3 
Exploratory 
Describe immune express 
profiles 
Normalized immune 
expression 
See Section 
15.6.4 
 
9. INVESTIGATIONAL PLAN 
9.1. 
Study Design 
This is a phase 2 study that assesses the feasibility and efficacy of neoadjuvant 
immunotherapy in patients with previously untreated, surgically-resectable, solid 
tumor brain metastases. Histologic types are restricted to those known to 
extracranially respond to immunotherapy, and will include, but not be limited to, 
squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC without 
known 


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ALK+, EGFR+, and ROS alterations, renal cell carcinoma (RCC), melanoma, and 
triple negative breast cancer (TNBC) that is PD-L1 positive, ovarian carcinoma, and 
urothelial carcinoma 
 
Eligible participants will receive a single infusion of nivolumab at a dose of 3 mg/kg 
and ipilimumab at a dose of 1 mg/kg 7 days (±3 days) prior to surgical resection of 
their metastases. Patients will then receive SRS 3 weeks (±3 weeks) after surgery. 
Patients will be followed for 18 months after initiating study treatment. Up to 20 
participants will be recruited and treated. Blood will be collected periodically during 
the study for correlative assessments as described in Section 12.7.5. 
9.1.1. Definition of Dose-Limiting Toxicity (DLT) 
Not applicable. 
9.1.1.1. Non-hematologic: 
Not applicable. 
9.1.1.2. Hematologic: 
Not applicable. 
9.1.1.3. Other Considerations: 
Not applicable. 
9.1.2. Dose Modification 
9.1.2.1. Non-hematologic: 
Not applicable, only one dose of the study drug is given so there will be 
no intra-patient dose reduction. Similarly, the proposed doses of 3 mg/kg 
for nivolumab and 1 mg/kg for ipilimumab are recommended by the FDA. 
9.1.2.2. Hematologic: 
Not applicable, only one dose of the study drug is given so there will be 
no intra-patient dose reduction. Similarly, the proposed doses of 3 mg/kg 
for nivolumab and 1 mg/kg for ipilimumab are recommended by the FDA. 
9.1.2.3. Other considerations: 
Not applicable, only one dose of the study drug is given so there will be 
no intra-patient dose reduction. Similarly, the proposed doses of 3 mg/kg 
for nivolumab and 1 mg/kg for ipilimumab are recommended by the FDA. 
9.1.3. Safety Considerations 


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Nivolumab safety: The most common adverse reactions in cancer subjects in 
other clinical trials with nivolumab include fatigue; skin reactions including rash, 
itching, hives, redness, and dry skin; diarrhea; nausea; abdominal pain; 
decreased appetite; low red blood cells; fever; and joint pain or stiffness. Less 
common side effects include bowel inflammation, lever function blood test 
abnormalities, loss of color (pigment) from areas of skin, dry mouth, vomiting, 
weight loss, thyroid gland abnormalities, blood chemistry abnormalities, high 
blood uric acid level, lung inflammation (pneumonitis), cough, dizziness, 
headache, low white blood cells, chills, muscle soreness, muscle weakness, 
stiffness, muscle spasms, paralysis, pain in arms or legs, tingling in hands and 
feet, burning in hands and feet, numbness in hands and feet, shortness of 
breath, abnormal taste, flushing, high or low blood pressure, allergic reaction 
during or between study drug infusions, increased sensitivity of skin to sunlight, 
constipation, difficulty swallowing, heartburn, and low blood platelets. Rare, but 
potentially serious side effects include low blood oxygen level; acute lung injury 
or failure; collection of fluid around the lungs; inflammation of the appendix; 
increase in inflammatory blood proteins; adrenal gland abnormalities; pituitary 
gland inflammation; liver inflammation; changes in vision, inflammation of the 
eye, or bleeding into the eye; acute kidney injury or failure; abnormal blood cell 
production; inflammation of the mouth and lining of the digestive tract; swelling of 
the face, arms, or legs; inflammation of the pancreas; back pain; autoimmune 
disorders; chest discomfort; heart palpitations; inflammation of the heart or its 
lining; collection of fluid around the heart; increased blood sugar; dehydration; 
infections including sepsis, lung and skin infections; decreased movement of the 
intestines; disorientation; swelling of the optic disc; inflammation of the optic 
nerve; inflammation or loss of the lining of the brain and spinal cord; Drug 
Reaction with Eosinophilia and Systemic Symptoms (DRESS); central 
demyelination; abnormal brain function due to brain inflammation; 
rhabdomyolysis; polymyositis; and toxic epidermal necrolysis. Nivolumab can 
cause fetal harm when administered to pregnant women. Females of 
reproductive potential should use effective contraception while on treatment with 
nivolumab and for at least 5 months after the last dose. For additional 
information about nivolumab safety and adverse event management, please see 
Section 18.1. 
 
Ipilimumab safety: Ipilimumab has been most frequently studied in subjects with 
advanced melanoma. Other studies have been conducted in subjects with 
prostate cancer and lung cancer. In previous studies in subjects with advanced 
melanoma, approximately 79-80% experienced a side effect from ipilimumab. 
Most were mild to moderate and resolved with proper medical treatment. Side 
effects that may occur during the infusion of ipilimumab include fever, 
hypotension, chills, flushing, nausea and/or vomiting. If an infusion reaction 
occurs, the infusion will be slowed or stopped until the symptoms have been 
treated. These symptoms can also occur hours after the completion of the 
infusion. The most common side effects of ipilimumab include diarrhea, fatigue, 
skin itchiness, skin rash, nausea, fever, decreased appetite, vomiting, colitis, 


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abdominal pain, headache, constipation. Less common side effects include chills, 
weakness, muscle pain, and redness of skin. Rare side effects (in less than 1% 
of subjects) include tumor lysis syndrome, which can result in elevation in certain 
blood levels (for example, uric acid, phosphorous, potassium) can cause the 
kidneys to shut down, the heart to function irregularly (for example, an irregular 
heartbeat), shortness of breath, and loss of consciousness. 
 
Ipilimumab can cause side effects due to the immune system attacking normal 
cells, called immune-related adverse events or IRAEs. In previous studies in 
subjects with advanced melanoma, 72-76% of treated subjects developed an 
IRAE of any grade of severity. About 25-37% of subjects had a severe IRAE. 
These IRAEs have usually been controlled by stopping ipilimumab temporarily or 
permanently and if needed, with medications, including steroids (medications that 
are used to decrease inflammation). 
 
For additional information about ipilimumab safety and adverse event 
management, please see Section 18.2. 
 
Surgical Complications: The surgical resection carries a risk for cerebrospinal 
fluid leak, infection, hemorrhage, loss of neurologic function, non-neurologic 
complications, and death. These risks depend primarily on the preoperative 
condition of the patient, the size and location of the tumor and associated 
diseases. The potential risk for the patient will be discussed in detail with the 
patient and family. 
 
Stereotactic radiosurgery (SRS): Side effects resulting from complications of 
SRS include tiredness and fatigue, headache, nausea, vomiting, reddening of the 
skin of the scalp, memory or neurological problems (rare), and late development 
of a second cancer (rare). 
 
Anesthesia: Patients undergoing general anesthesia may be subjected to 
associated risks including pneumothorax, pneumonia, airway injury, hypotension, 
myocardial infarction, stroke, hepatic and renal injury and death. 
 
Peritumoral Inflammation and Increased Intracranial Pressure: Peritumoral 
inflammation may be secondary to the disease process itself, the surgical 
procedure, necrosis from radiation, or inflammation due to immune infiltration of 
the brain or destruction of tumor cells. Symptoms may include, but are not limited 
to, severe headache, confusion, lethargy, unresponsiveness, coma, or focal 
neurological deficits. Patients will be monitored throughout the course of the 
study for peritumoral inflammation and upon any signs or symptoms of cerebral 
edema, may have their steroid doses increased or receive treatment with an 
antiangiogenic agent, osmotic diuretic, or surgical decompression. Edema that 
fails to respond to aggressive therapy may lead to permanent neurological 
impairment. The risks will be discussed with the subject and the subject’s family. 


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Risk of Phlebotomy: Drawing blood or inserting an intravenous catheter into an 
arm vein may result in bruising or swelling in the area of the insertion, bleeding at 
the site of the needle puncture, light headedness, fainting and very rarely, local 
infection, which may be severe. These risks are reduced by the fact that the 
blood will be drawn by a qualified physician, nurse or phlebotomist (a 
professional trained to draw blood). 
 
Risks of MRIs: Risks and/or discomforts associated with MRI scans include 
anxiety produced from being in a tight, enclosed space (claustrophobia). In 
addition, the machine operates using a large and powerful magnet, which attracts 
certain metals. Therefore, people with these metals in their bodies (specifically 
pacemakers, infusion pumps, metal aneurysm clips, metal prostheses, joints, 
rods or plates) will be excluded from the study. Patients will also be checked to 
make sure that they do not bring any metal objects into the MRI facility. Dental 
fillings are less affected by the magnetic fields generated and are therefore 
permitted. Patients will be asked to let the physicians conducting this study know 
of any metal in their bodies other than dental fillings. 
 
Unknown Risks: The overall risk classification of this research is unknown. 
 
9.1.4. Missed Doses 
Not applicable as there is only one dose of the study agents given. 
9.1.5. Concomitant Medications 
9.1.5.1. Steroids 
Corticosteroids should be used at the lowest dose to control symptoms of 
edema and mass effect, and discontinued, if possible. Use of corticosteroids 
should be recorded in the electronic research database (see Section 16.5). 
Every effort should be made to keep the dose of steroids at or lower than an 
equivalent of 4 mg daily of dexamethasone. 
9.1.5.2. Anticonvulsants 
Anticonvulsants drugs should be used or continued, if indicated. Use of such 
anticonvulsants should be recorded in the electronic research database. 
9.1.5.3. Growth Factors 
Routine use of growth factors (i.e. G-CSF, GM-CSF, and erythropoietin) is not 
permitted. However, therapeutic use of G-CSF in patients with serious 
neutropenic conditions, such as sepsis, may be used at the investigator’s 
discretion. Use of such growth factors should be recorded in the electronic 
research database (see Section 16.5). 
9.1.5.4. Anti-emetics 


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The use of anti-emetics will be at the investigator’s discretion. Use of anti- 
emetics should be recorded in the electronic research database (see Section 
16.5). 
9.1.5.5. Proton Pump Inhibitors 
The use of proton pump inhibitors (PPI) (e.g. rabeprazole, omeprazole, 
pantoprazole, lansoprazole or esomeprazole) is allowed on this study and 
should be recorded in the electronic research database (see Section 16.5). 
9.1.5.6. Pneumocystis jiroveci pneumonia (PJP) prophylaxis 
The use of medication (i.e., Bactrim) for PJP prophylaxis in patients on 
chronic steroids is recommended, but is at the investigator’s discretion. 
9.1.5.7. Neurosurgical Procedures 
If a neurosurgical procedure is required for a reason other than tumor 
progression (i.e., the onset of hydrocephalus), these procedures should be 
documented, but will not constitute criteria for declaring the patient “off 
therapy.” 
9.1.6. Study Drug Blinding 
Not applicable. 
9.1.7. Randomization 
As of 03/19/2021, randomization was removed from the study when a control arm 
without neoadjuvant nivolumab and ipilimumab was removed from the study 
design. See details in Section 15.1. 
9.2. Rationale for Selection of Dose, Regimen, and Treatment 
Duration 
Both nivolumab and ipilimumab will be dosed at the FDA recommended dosing 
levels of 3 mg/kg and 1 mg/kg for combination therapy, respectively. Nivolumab and 
ipilimumab infusions will occur in the neoadjuvant setting, prior to surgery, with the 
expectation that neoadjuvant dosing will result in a more robust immune response 
than adjuvant dosing, as was seen in a study in GBM patients [16]. 
9.3. 
Rationale for Correlative Studies 
Due to the nature of their activity, checkpoint inhibitors like nivolumab and 
ipilimumab inherently alter the activity of the immune system. Inhibition of CTLA-4 
and PD-1 on T cells using monoclonal antibodies (like ipilimumab and nivolumab) 
results in increased T-cell proliferation [17], and could serve as a surrogate marker 


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for therapeutic efficacy. It is important, therefore, to understand how T cells, both in 
the periphery and intratumoral, are affected by ipilimumab and nivolumab. In a study 
involving neoadjuvant administration of pembrolizumab in patients with recurrent 
GBM, tumor interferon-γ-related gene expression was altered by neoadjuvant 
immunotherapy (Figure 3). Neoadjuvant treatment with pembrolizumab resulted in 
increased gene expression in a panel of 16 genes related to interferon-γ expression 
for 9/14 tumors. Markedly, tumors that did not receive neoadjuvant pembrolizumab 
showed decreased gene expression for 10/14 tumors. 
 
Figure 3: Neoadjuvant immunotherapy alters intratumoral interferon-γ-related gene 
expression. The letter ‘A’ represents a tumor treated in the neoadjuvant setting. The letter 
‘B’ represents a tumor treated in the adjuvant setting. The majority (10/14) of patients 
treated with adjuvant pembrolizumab had tumors with decreased levels of mRNA 
expression. Conversely the majority (9/14) of patients treated with neoadjuvant 
pembrolizumab had tumors with increased levels of mRNA expression. Adapted from 
Cloughesy et. al. 
Immune correlative studies will also aid in understanding, which patients respond 
better to checkpoint inhibition for future studies. For these purposes, blood will be 
drawn at various time points throughout the study, as outlined in Table 1. 
 
Additionally, a sample of the resected tumor will be requested for correlative analysis 
if enough tissue is available after standard pathologic testing. We will also request a 
sample of archival tissuefrom an extracranial site pretreatment. The full correlative 
study plan is detailed in Section 12.7.5 and the Correlative Lab Manual (CLM). 
9.4. 
Definition of Evaluable Subjects, On Study, and End of Study 
Section 15.2 indirectly addresses the definition of evaluable patients. All eligible 
patients who initiate checkpoint treatment will be followed for survival regardless of 
compliance to assigned treatment. In addition, all patients who initiate checkpoint 
treatment will be included in the denominator for assessing feasibility, whether or not 
a surgery occurs. 


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Participants will be considered on study once they have signed the informed consent 
form and eligibility has been confirmed. The study will be ended once all subjects 
have completed follow up and all data analysis is complete. 
9.5. 
Early Study Termination 
This study can be terminated at any time for any reason by the PI-sponsor. If this 
occurs, all subjects on study should be notified as soon as possible. Additional 
procedures and/or follow up should occur in accordance with Section 12.6, which 
describes procedures and process for prematurely withdrawn patients. 


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10. STUDY DRUG 
10.1. 
Nivolumab (Opdivo®) 
10.1.1. 
Names, Classification, and Mechanism of Action 
Nivolumab is a human monoclonal antibody that blocks the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2. Nivolumab is an IgG4 kappa 
immunoglobulin that has a calculated molecular mass of 146 kDa [18]. 
 
T-cell proliferation and cytokine production are inhibited by the binding of PD-1 to 
its ligands, PD-L1 and PD-L2. Some tumors upregulate the PD-1 ligands which 
contributes to reduced T-cell immune response and surveillance in tumors. 
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds 
to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing 
PD-1 pathway-mediated inhibition of the immune response, including the anti- 
tumor immune response. In syngeneic mouse tumor models, blocking PD-1 
activity resulted in decreased tumor growth [18]. 
10.1.2. 
Packaging and Labeling 
Nivolumab is packaged in a clear glass vial with a grey rubber top (100 mg/mL) 
or a purple rubber top (40 mg/mL). 
 
The label includes the following: 
NDC number 
“Rx only” 
Concentration of solution 
“For Intravenous Infusion Only 
Single-Dose Vial; Discard Unused Portion” 
 
The label will also include the following statement: “Caution: New Drug—Limited 
by Federal (or United States) law to investigational use.” 
10.1.3. 
Supply, Receipt, and Storage 
Nivolumab is supplied as a clear to opalescent, colorless to pale-yellow solution 
in a single dose vial of either 100 mg/mL or 40 mg/mL. The vial should be 
discarded if the solution appears cloudy, is discolored, or contains extraneous 
particulate matter other than a few translucent-to-white, proteinacious particles. 
Nivolumab will be shipped directly from BMS to ICS on ice and should be stored 
at 2-8°C, protected from heat and light, upon receipt. Do not freeze or shake. 
10.1.4. 
Dispensing and Preparation 
Nivolumab is given via IV over 30-60 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). The drug product should be visually 
inspected for particulate matter and discoloration prior to administration and 
infusion preparation. If the vial of solution appears cloudy, is discolored, or 


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contains extraneous particulate matter other than a few translucent-to-white, 
proteinacious particles, it should be discarded[18]. Do not shake the vial. 
 
The infusion solution should be prepared as follows [18]: 
• Withdraw the required volume of nivolumab from the vial and transfer into 
an intravenous container. 
• Dilute nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP, to prepare an infusion with a final concentration 
ranging from 1 mg/mL to 10 mg/mL. 
• Mix diluted solution by gentle inversion. Do not shake. 
• Discard partially used or empty vials of nivolumab. 
 
The infusion should be administered immediately once prepared. If the diluted 
nivolumab infusion solution is not used immediately, the solution can be stored at 
room temperature for up to 4 hours from the time of preparation (including 
storage of the infusion in the IV container and infusion time) or at 2-8°C for up to 
24 hours from the time of preparation [18]. 
10.1.5. 
Disposal and Destruction 
All empty vials and used IV bags of nivolumab should be disposed of based on 
pharmacy guidelines. 
10.2. 
Ipilimumab (Yervoy®) 
10.2.1. 
Names, Classification, and Mechanism of Action 
Ipilimumab is a recombinant, human monoclonal IgG1 kappa immunoglobulin 
that binds to CTLA-4. CTLA-4 is a negative regulator of T-cell activity. 
Ipilimumab binds to CLTA-4 and blocks the interaction with its ligands, 
CD80/CD86. CTLA-4 blockade has been shown augment the activation and 
proliferation of tumor-infiltrating T-effector cells. Inhibition of CTLA-4 can also 
reduce T-regulatory cell function, which may contribute to a general increase in T 
cell responsiveness, including the anti-tumor response [19]. 
10.2.2. 
Packaging and Labeling 
Ipilimumab is packaged in a clear glass vial with a purple rubber top with a red 
label (200 mg/40 mL) or a teal rubber top with a yellow label (50 mg/ 10mL). 
 
The label includes the following: 
NDC number 
“Rx only” 
Concentration of solution 
“For Intravenous Infusion Only 
Single-Dose Vial; Discard Unused Portion” 
 
The label will also include the following statement: “Caution: New Drug—Limited 
by Federal (or United States) law to investigational use.” 


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10.2.3. 
Supply, Receipt, and Storage 
Ipilimumab is supplied as a clear to slightly opalescent, colorless to pale-yellow 
solution in a single dose vial of either 50 mg/10 mL or 200 mg/40 mL. The vial 
should be discarded if the solution appears cloudy, there is pronounced 
discoloration (solution may have pale-yellow color), or there is foreign particulate 
matter other than translucent-to-white, amorphous particles. Ipilimumab will be 
shipped directly from BMS to ICS on ice and should be stored at 2-8°C, protected 
from heat and light, in the original carton, upon receipt. Do not freeze or shake. 
10.2.4. 
Dispensing and Preparation 
Ipilimumab is given via IV over 90 minutes through an intravenous line containing 
a sterile, non-pyrogenic, low protein binding in-line filter.  The drug product 
should be visually inspected for particulate matter and discoloration prior to 
administration and infusion preparation. If the vial of solution appears cloudy, is 
discolored, or contains foreign particulate matter other than a few translucent-to- 
white, amorphous particles, it should be discarded [19]. 
 
The infusion solution should be prepared as follows [19]: 
• Allow the vials to stand at room temperature for approximately 5 minutes 
prior to preparation of infusion. 
• Withdraw the required volume of ipilimumab and transfer into an 
intravenous bag. 
• Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, 
USP to prepare a diluted solution with a final concentration ranging from 1 
mg/mL to 2 mg/mL. Mix diluted solution by gentle inversion. 
• Store the diluted solution for no more than 24 hours under refrigeration 
(2°C to 8°C, 36°F to 46°F) or at room temperature (20°C to 25°C, 68°F to 
77°F). 
• Discard partially used vials or empty vials of ipilimumab. 
 
The prepared solution should be administered as follows [19]: 
• Do not mix ipilimumab with, or administer as an infusion with, other 
medicinal products. 
• Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 
5% Dextrose Injection, USP after each dose. 
• Administer diluted solution over 90 minutes through an intravenous line 
containing a sterile, non-pyrogenic, low-protein-binding in-line filter. 
10.2.5. 
Disposal and Destruction 
All empty vials and used IV bags of ipilimumab should be disposed of based on 
pharmacy guidelines. 


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11. SUBJECT ELIGIBILITY 
11.1. 
Inclusion Criteria 
1. Patients must have at least 1 previously untreated, solid tumor brain metastasis 
that is  ≤4 cm in the largest dimension that is planned for standard of care 
surgical resection. Metastasis must be planned for treatment with post-surgical 
SRS per standard of care. Primary tumor histology must be one of the following: 
o Squamous NSCLC 
o Non-squamous NSCLC without known ALK, EGFR, and ROS mutation 
o RCC 
o Urothelial carcinoma 
o Ovarian carcinoma 
o Melanoma 
o Triple negative breast cancer that is PD-L1 positive 
o Other solid tumor histologies may be eligible at the discretion of the PI 
if they are known to respond to immunotherapy containing regimens.  
2. Patient must be asymptomatic or minimally symptomatic, requiring the equivalent 
of ≤ 4 mg dexamethasone daily for at least 7 days prior to enrollment 
3. Patient or partner(s) meets one of the following criteria: 
a) Non-childbearing potential (i.e. not sexually active, physiologically 
incapable of becoming pregnant, including any female who is post- 
menopausal or surgically sterile, or any male who has had a vasectomy). 
Surgically sterile females are defined as those with a documented 
hysterectomy and/or bilateral oophorectomy or tubal ligation. 
Postmenopausal for purposes of this study is defined as 1 year without 
menses.; or 
b) Childbearing potential and agrees to use one of the following methods of 
birth control: approved hormonal contraceptives (e.g. birth control pills, 
patches, implants, or infusions), an intrauterine device, or a barrier method 
of contraception (e.g. a condom or diaphragm) used with spermicide. 
4. Age ≥ 18 years of age at the time of entry into the study 
5. Karnofsky Performance Score (KPS) ≥ 70 
6. Prothrombin and Partial Thromboplastin Times ≤ 1.2 x normal at screening 
7. Neutrophil count ≥ 1000 at screening 
8. Hemoglobin ≥ 9 g/dl at screening 
9. Platelet count ≥ 100,000/µl unsupported is necessary at screening 
10. Creatinine ≤ 1.5 x ULN at screening 
11. A signed informed consent form approved by the Institutional Review Board (IRB) will 
be required for patient enrollment into the study. Patients must be able to read and 
understand the informed consent document and must sign the informed consent 
indicating that they are aware of the investigational nature of this study 
12. Ability to undergo MRI 
11.2. 
Exclusion Criteria 
1. Females who are pregnant or breast-feeding 
2. Patients with an impending, life-threatening cerebral herniation syndrome, based 
on the assessment of the study neurosurgeons or their designate 
3. Patients with severe, active co-morbidity, defined as follow: 


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a) Patients with an active infection requiring intravenous treatment or having an 
unexplained febrile illness (Tmax > 99.5°F/37.5°C) 
b) Patients with known immunosuppressive disease or known uncontrolled 
human immunodeficiency virus infection 
c) Patients with unstable or severe intercurrent medical conditions such as 
severe heart disease (New York Heart Association Class 3 or 4) 
4. Patients who have not recovered from the toxic effects of prior chemo- and/or 
radiation therapy.  
5. Patients must not have received immunotherapy within 3 months prior to 
enrollment 
6. Patients with prior, unrelated malignancy requiring current active treatment in the 
last 3 years with the exception of cervical carcinoma in situ and adequately 
treated basal cell or squamous cell carcinoma of the skin 
7. Patients with a known history of hypersensitivity to nivolumab, or any 
components of nivolumab 
8. Patients with a known history of hypersensitivity to ipilimumab, or any 
components of ipilimumab 
9. Patients with active autoimmune disease requiring systemic immunomodulatory 
treatment within the past 3 months. 
10. History and/or confirmed pneumonitis, or extensive bilateral lung disease on high 
resolution/spiral CT scan. 


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12. 
SCREENING AND ON-STUDY TESTS AND PROCEDURES 
Table 1: Schedule of Study Tests and Procedures 
Description 
Screening 
Treatment Period 
Up to 14 days 
prior to surgical 
resection 
Neoadjuvant IO 
Surgery 
Adjuvant SRS1 
Follow-up 
Week2 
 
-1 
1 
33 
4 
7, 13 +SOC visits 
Day2 
 
-10 to -4 
1 
15 
22 (± 3 weeks) 
29 + SOC visits 
General Evaluations 
 
Informed Consent 
X 
 
 
 
 
 
Physical Exam4 
X 
X 
X 
X 
 
X 
Neurologic Exam4 
X 
X 
X 
X 
 
X 
Performance Status4 
X 
X 
X 
X 
 
X 
Adverse Events 
Continuous5 
Laboratory 
Evaluations 
 
CBC w/diff 
X 
X6 
X 
X 
 
X 
CMP 
X 
X6 
X 
X 
 
X 
Thyroid panel 
X 
 
 
 
 
X 
PT, aPTT 
X 
 
 
 
 
 
Pregnancy test7 
X 
X6 
 
 
 
 
Whole blood for 
correlative analysis 
(3x10 mL yellow top)8 
X 
 
X9 
X 
X10 
X11 
Archival tissue 
sample12 
X 
 
 
 
 
 
Surgical tissue 
sample 
 
 
X13 
 
 
 
Disease Evaluations 
 
MRI of the brain14 
X 
 
 
 
 
X15 
Treatment 
 
Ipilimumab 
 
X 
 
 
 
 
Nivolumab 
 
X 
 
 
 
 
Surgery16 
 
 
X 
 
 
 
SRS 
X 
 
1 Number of fractions for SRS treatment will be assigned at physician’s discretion 
2 Weeks and days listed are approximate. 
3 Post-operative visit 
4 Clinical evaluations will include a general physical examination, complete neurologic examination, and KPS rating. 
5 Adverse events will be continuously monitored after the first study-mandated agent is administered to the patient and reviewed 
monthly by the study PI. AE collection will cease 100-days after surgery, or 100 days after ipilimumab/nivolumab infusion for 
patients who do not undergo surgery. 
6 Only drawn if more than 7-days (24-hours for pregnancy) post screening draw 
7 For women of childbearing potential 
8 Whole blood should be sent to the Substrate Services Core (SSCRS) for processing and then sent to Dr. Kent Weinhold’s laboratory 
9 Blood should be drawn prior to surgical resection 
10 Blood should be drawn prior to SRS 
11 Drawn only at the week 7 follow-up visit 
12 A sample of archival tissue from the primary or other extracranial tumor will be requested for correlative analysis, if available. 
13 A sample of tissue from the resected metastases will be requested for correlative analysis, if available. 
14 MRI of the brain should be accompanied by systemic staging scans per standard of care. Though not dictated by the protocol, 
results of standard of scare systemic staging scans should be recorded in the eCRF. 
15 No MRI taken at week 7. Follow-up MRIs will be taken at week 13 (± 2 weeks) and continue every 12 weeks (± 4 weeks) thereafter. 
16 Surgery is performed per SOC. 


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12.1. 
Screening Examination 
All screening procedures should occur within 14 days prior to the planned surgical 
resection. An informed consent form must be signed by the patient prior to initiating 
any screening tests or procedures. Screening test and procedures include a physical 
exam, neurological exam, performance (KPS) status, a pregnancy test, and blood 
tests. Blood for immune monitoring will also be collected during screening. An 
archival tissue sample from the primary tumor will be requested for correlative 
analysis, if available. 
 
If a subject does not receive nivolumab or ipilimumab, minimal records regarding the 
subject will be retained in the study database. Participants who screen fail after 
providing informed consent but before receiving study-related treatment will be 
withdrawn, and these subjects will be excluded from all analyses. 
12.2. 
Treatment Period 
Day -10 to -4: 
• Physical exam, neurological exam, and KPS 
• Laboratory testing including: 
o CBC with differential 
o CMP 
o Beta-HCG, if appropriate and > 24 hours post screening Beta-HCG 
• Ipilimumab infusion 
• Nivolumab infusion 
 
Day 1 (prior to surgery): 
• Physical exam, neurological exam, and KPS 
• Laboratory testing including: 
o CBC with differential 
o CMP 
o PT, aPTT 
• Whole blood (3 x 8.5 mL yellow top tubes) for immune monitoring, collected prior to 
surgery 
• Surgical resection 
 
Week 3 (± 1 week), surgical follow-up visit: 
• Physical exam, neurological exam, and KPS 
• Laboratory testing including: 
o CBC with differential 
o CMP 
• Whole blood (3 x 8.5 mL yellow top tubes) for immune monitoring 
 
Week 4 (± 3 weeks): 


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• Whole blood (3 x 10 mL yellow top tubes) for immune monitoring 
• SRS treatment (number of fractions given will be at the physician’s discretion) 
 
12.3. 
End of Treatment 
Week 7 (±1 week): 
• Physical exam, neurological exam, and KPS 
• Laboratory testing including: 
o CBC with differential 
o CMP 
o Thyroid panel 
• Whole blood (3 x 10 mL yellow top tubes) for immune monitoring 
 
12.4. 
Follow-up Period 
Week 13 (±2 weeks) and at standard of care visits per the treating physician’s discretion 
for up to 18 months: 
• Physical exam, neurological exam, and KPS 
• Laboratory testing including: 
o CBC with differential 
o CMP 
o Thyroid panel 
• MRI of the brain accompanied by any standard of care systemic staging 
scans. Though standard of care systemic staging scans are not dictated by 
this protocol, the results of such scans should be included in the eCRF. 
12.5. 
End of Study 
At the end of the study period, Bristol-Myers Squibb Company will not continue to 
supply study drug to subjects/investigators unless the Sponsor-Investigator chooses 
to extend their study. The investigator is responsible to ensure that the subject 
receives appropriate standard of care or other appropriate treatment in the 
independent medical judgement of the Investigator to treat the condition under 
study. 
 
The study will be considered complete once enrollment has been met, follow-up 
procedures outlined in Section 12.4 have been conducted on all subjects, and data 
analysis is concluded. The study may also be terminated early for any reason by the 
PI. 
 
Subjects that are lost to follow-up will be documented in the patient record and in the 
21 CFR Part 11 database. In the compliant database, the subject will be marked as 
“Patient Status Unknown,” along with a corresponding explanation, if any. 
12.6. 
Early Withdrawal of Subject(s) 


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12.6.1. 
Criteria for Early Withdrawal 
Subjects may voluntarily withdraw from the study at any time. The PI may also 
withdraw a subject from the study at any time based on his/her discretion. 
Reasons for PI-initiated withdrawal may include, but is not limited to the 
following: 
 
- 
If, in the investigator’s medical judgment, further participation would be 
injurious to the subject’s health or wellbeing 
- 
Protocol deviation 
- 
Administrative issues 
- 
Non-compliance of the subject 
- 
Pregnancy 
- 
They do not receive neoadjuvant nivolumab and ipilimumab infusions  
12.6.2. 
Follow-up Requirements for Early Withdrawal 
Subjects should be seen in clinic or contacted at a minimum of every 3 months 
until 18 months after initiating study treatment, if possible. 
12.6.3. 
Replacement of Early Withdrawal(s) 
Subjects who withdraw from the study without receiving both nivolumab and 
ipilimumab will be considered non-evaluable; those subjects will be replaced. 
12.7. 
Study Assessments 
12.7.1. 
Medical History 
Standard medical history will be obtained and documented per institutional 
guidelines. 
12.7.2. 
Physical Exam 
Standard physical exam and neurological assessment will be conducted and 
documented per institutional and PRTBTC guidelines. 
12.7.3. 
Radiographic Review 
Starting at week 13, an MRI of the brain will be obtained at the subsequent 
standard of care visits outlined in Section 12.4. Given that imaging following 
immunotherapy differs greatly from what is typically seen following 
chemoradiation treatment or treatment with anti-angiogenic compounds, 
evaluation of response using Macdonald criteria or Response Assessment in 
Neuro-Oncology (RANO) criteria is not appropriate in this trial. Due to differences 
in the nature of primary brain tumors and brain metastases, a modified version of 
RANO called RANO-BM will be used. 
12.7.4. 
Laboratory Evaluations 
The timing of laboratory assessments that will be obtained during the course of 
the study is given in Table 1. A list of each evaluation is below. 
• CBC with differential 


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• CMP 
• PT, aPTT 
• Beta-HCG, if appropriate 
• Thyroid panel 
12.7.5. 
Correlative Assessments 
Correlative studies will assess and compare the immune response observed 
within patients treated with neoadjuvant immunotherapy. Inhibition of CTLA-4 
and PD-1 on T cells using monoclonal antibodies (like ipilimumab and 
nivolumab) results in increased T-cell proliferation [17], and could serve as a 
surrogate marker for therapeutic efficacy. To examine T-cell proliferation rates, 
Ki67 staining will be performed on PD-1+/CD8+ T cells extracted both from the 
peripheral blood and from resected tissue (when available). Blood will be drawn 
longitudinally during treatment (see Table 1 in Section 12) to study how a single 
dose of nivolumab and ipilimumab before surgery affect T-cell proliferation over 
time. Assessing how Ki67 levels on peripheral-blood T cells change over time in 
patients receiving neoadjuvant immunotherapy will provide evidence that 
neoadjuvant checkpoint inhibition alters T-cell function. Additional immune 
profiling will be performed to understand how the immune system is responding 
to neoadjuvant immunotherapy compared to the control group. This immune 
profiling will be performed with assays including, but not limited to: RNASeq, 28 
color flow cytometry, and IHC. These assays may be run on cells from peripheral 
blood, resected tissue (if available), and archival tissue (if available). Analysis will 
be performed to correlate peripheral blood immune responses to those within the 
tumor. An alternative protocol will be established to collect fresh tissue in solid 
tumor brain metastases patients who are undergoing standard of car resection 
and not receiving immunotherapy to compare as a control for RNA sequencing 
and 28 color flow panels. 28 color flow panel analysis will be performed by Dr. 
Kent Weinhold or his designee. 


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13. SAFETY MONITORING AND REPORTING 
The PI is responsible for the identification and documentation of adverse events and 
serious adverse events, as defined below. At each study visit, the PI or designee must 
assess, through non-suggestive inquiries of the subject or evaluation of study 
assessments, whether an AE or SAE has occurred. 
13.1. 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject receiving study 
drug and which does not necessarily have a causal relationship with this treatment. For 
this protocol, the definition of AE also includes worsening of any pre- existing medical 
condition. An AE can therefore be any unfavorable and unintended or worsening sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of nivolumab or ipilimumab, whether or not related to use of nivolumab or 
ipilimumab. Abnormal laboratory findings that are able to be graded via CTCAE will be 
collected as AEs and attribution will be reviewed by the PI.   
 
From the time the subject signs the informed consent form until 100-days after 
surgery, or 100 days after ipilimumab and nivolumab infusion for patients who do not 
undergo surgery, all AEs must be recorded in the subject medical record and 
adverse events case report form. 
 
AEs will be assessed according to the CTCAE version 5. If CTCAE grading does 
not exist for an AE, the severity of the AE will be graded as mild (1), moderate (2), 
severe (3), life-threatening (4), or fatal (5). 
 
Attribution of AEs will be indicated as follows, with the study drug specified to be 
ipilimumab, nivolumab, protocol-mandated surgery, or SRS: 
- 
Definite:  The AE is clearly related to the study drug 
- 
Probably:  The AE is likely related to the study drug 
- 
Possible:  The AE may be related to the study drug 
- 
Unlikely: The AE is doubtfully related to the study drug 
- 
Unrelated: The AE is clearly NOT related to the study drug 
 
For additional information on adverse event management algorithms, please see 
Sections 18.1 and 18.2 for nivolumab and ipilimumab, respectively. 
 
13.1.1. 
AEs of Special Interest 
See Section 9.1.3 for management of anticipated adverse events. 
13.1.2. 
Reporting of AEs 
Any AE occurrence (spontaneously volunteered and enquired for, as well as 
observed AEs) during the study must be documented in the patient’s medical 
records in accordance with the Investigator’s normal clinical practice and on the 


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AE page of the eCRF. SAEs that occur during the study must be documented in 
the patient’s medical record, on the AE eCRF, and on the SAE form. 
 
The Investigator should attempt to establish a diagnosis of the event based on 
the signs, symptoms, and/or other clinical information. In such cases, the 
diagnosis should be documented as the AE (and SAE if serious) and not the 
individual signs/symptoms. 
 
If an abnormal laboratory finding or other abnormal assessment meets the 
definition of an AE, then the AE eCRF page must be completed as appropriate. 
In addition, if the abnormal assessment meets the criteria for being serious, the 
SAE form must also be completed. A diagnosis, if known, or clinical signs or 
symptoms if the diagnosis is unknown, rather than the clinically significant 
laboratory finding or abnormal assessment, should be used to complete the 
AE/SAE page. If no diagnosis is known and clinical signs or symptoms are not 
present, then the abnormal finding should be recorded. If an SAE report is 
completed, pertinent laboratory data should be recorded on the SAE form, 
preferably with baseline values and copies of laboratory reports. 
 
A database of all adverse events (not just those considered related to the study 
drug) will be maintained in a 21 CFR Part 11 compliant database. The event will 
be categorized by organ system, relationship to treatment, its grade of severity, 
and resolution. The PI and study statistician will periodically review the collective 
adverse events with the intention of identifying any trends or patterns in toxicity. If 
any such trends are identified, depending on their severity and frequency, a 
protocol amendment will be considered. 
 
13.2. 
Serious Adverse Events 
An AE is considered “serious” if in the opinion of the investigator it is one of the 
following outcomes: 
 
- 
Fatal 
- 
Life-threatening 
- 
Constitutes a congenital anomaly or birth defect 
- 
A medically significant condition (defined as an event that compromises 
subject safety or may require medical or surgical intervention to prevent one 
of the three outcomes above). 
- 
Requires inpatient hospitalization or prolongation of existing hospitalization 
- 
Results in persistent or significant incapacity or substantial disruption to 
conduct normal life functions. 
- 
Suspected transmission of an infectious agent (eg, pathogenic or 
nonpathogenic) via the study drug is an SAE. 


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Note: 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. 
 
13.2.1. 
Reporting of SAEs 
Following the subject’s written consent to participate in the study, all SAEs, 
whether related or not related to study drug, should be collected, including those 
thought to be associated with protocol-specified procedures. The investigator 
should report any SAE occurring after these aforementioned time periods, which 
is believed to be related to study drug or protocol-specified procedure. 
 
All SAEs should be reported immediately to the Principal Investigator or 
designee. Only adverse events that the Principal Investigator determines to be 
serious, unanticipated, and related or possibly/probably (i.e. more likely than not) 
related to the research must be reported to the Duke IRB. An SAE report should 
be completed for any event where doubt exists regarding its seriousness. If the 
investigator believes that an SAE is not related to study drug, but is potentially 
related to the conditions of the study (such as withdrawal of previous therapy or a 
complication of a study procedure), the relationship should be specified in the 
narrative section of the SAE Report Form. Reportable adverse events will be 
submitted in the electronic IRB system, according the following guidelines: 
• Report within 24 hours of learning about any subject’s death that was 
unanticipated and more likely related to the research than unrelated; 
• Report within 5 business days of learning about any serious AE that is 
unanticipated and related or possibly/probably related to study treatment; 
• Report within 10 business day of learning about any other unanticipated 
problem or event that was more likely related to the study treatment than 
unrelated. 
 
The PI-Sponsor must report to the FDA, in an IND safety report, any suspected 
adverse reaction that is both serious and unexpected. Before submitting this 
report, the PI-Sponsor needs to ensure that the event meets all three of the 
definitions contained in the requirement: 
o Suspected adverse reaction (i.e. there is a reasonable possibility that the 
drug caused the adverse event) 
o Serious 
o Unexpected (see nivolumab and/or ipilimumab investigator brochures) 
 
If the adverse event does not meet all three of the definitions, it should not be 
submitted as an expedited IND safety report. The PI-Sponsor is required to 
report to the FDA all IND Safety reports in writing within 15 days (7 days for 
unexpected fatal or life-threatening suspected adverse reaction). The FDA Form 
3500A can be found on the FDA website, www.fda.gov. All other adverse events 
will be reported to the FDA in the Annual Report. 


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All Serious Adverse Events (SAEs) that occur following the subject’s written 
consent to participate in the study through 100 days of discontinuation of dosing 
must be reported to BMS Worldwide Safety, whether related or not related to 
study drug. SAEs must be collected that relate to any later protocol-specified 
procedure (eg, surgery and SRS). SAEs, whether related or not related to study 
drug, and pregnancies (including in a female partner of a male participant) must 
be reported to BMS within 24 hours \ 1 Business Day of becoming aware of the 
event. Pregnancies must be reported and submitted to BMS on any of the 
following form(s): 
1. MedWatch or, CIOMS or 
2. BMS Pregnancy Surveillance Form or, 
3. Approved site SAE form 
 
SAEs should be reported to BMS using a Medwatch form, must include the BMS 
protocol number, and should be either emailed or faxed as below. 
 
SAE Email Address: Worldwide.Safety@BMS.com 
 
SAE Facsimile Number: +1 609-818-3804 
 
If only limited information is initially available, follow-up reports are required. 
(Note: Follow-up SAE reports should include the same investigator term(s) 
initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 
hours \ 1 Business Day to BMS using the same procedure used for transmitting 
the initial SAE report. 
 
All SAEs should be followed to resolution or stabilization. 
13.3. 
Emergency Unblinding of Investigational Treatment 
Not applicable. 
13.4. 
Other Reportable Information 
Not applicable. 
13.5. 
Special Warnings and Precautions 
Not applicable. 
13.6. 
Safety Oversight Committee (SOC) 
The Duke Cancer Institute SOC is responsible for annual data and safety monitoring 
of DUHS sponsor-investigator phase I and II, therapeutic interventional studies that 
do not have an independent Data Safety Monitoring Board (DSMB). The primary 
focus of the SOC is review of safety data, toxicities and new information that may 
affect subject safety or efficacy. Annual safety reviews includes but may not be 
limited to review of safety data, enrollment status, stopping rules if applicable, 


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accrual, toxicities, reference literature, and interim analyses as provided by the 
sponsor-investigator. The SOC in concert with the DCI Monitoring Team (see 
Section 14.1 for Monitoring Team description) oversees the conduct of DUHS 
cancer-related, sponsor-investigator greater-than-minimal-risk intervention studies 
that do not have an external monitoring plan, ensuring subject safety and that the 
protocol is conducted, recorded and reported in accordance with the protocol, 
standing operating procedures (SOPs), Good Clinical Practice (GCP), and 
applicable regulatory requirements. 


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14. QUALITY CONTROL AND QUALITY ASSURANCE 
14.1. 
Monitoring 
This clinical research study will be monitored both internally by the PI, and 
institutionally by the Duke Cancer Institute (DCI). In terms of internal review the PI 
will continuously monitor and tabulate adverse events. Appropriate reporting to the 
Duke University Medical Center IRB will be made. If an unexpected frequency of 
Grade III or IV events occur, depending on their nature, action appropriate to the 
nature and frequency of these adverse events will be taken. This may require a 
protocol amendment, dose de-escalation, or potentially closure of the study. The PI 
of this study will also continuously monitor the conduct, data, and safety of this study 
to ensure that: 
• Interim analyses occur as scheduled; 
• Stopping rules for toxicity and/or response are met; 
• Risk/benefit ratio is not altered to the detriment of the subjects; 
• Appropriate internal monitoring of AEs and outcomes is done; 
• Over-accrual does not occur; 
• Under-accrual is addressed with appropriate amendments or actions; 
• Data are being appropriately collected in a reasonably timely manner. 
 
DCI Protocol Review and Monitoring systems (PRMS) review of this protocol begins 
with an initial review by the Cancer Protocol Committee (CPC). CPC new protocol 
review focuses on scientific relevance, study design, adequacy of biostatistical input, 
protocol prioritization, feasibility of completing the study within a reasonable time 
frame and risk assessment of the trial. The PI will abide by CPC assessment of the 
level of risk, which will determine the intensity of subsequent DCI monitoring. CPC 
also conducts annual scientific progress reviews on protocols that are open to 
enrollment and focus on protocol prioritization, accrual and scientific progress. 
These reviews are conducted at the time of IRB annual renewals and documentation 
of all CPC reviews will be maintained in eIRB/iRIS systems. 
 
A determination for the degree of monitoring conducted by the DCI monitoring team 
is made at the time of initial CPC approval to commensurate with the type and level 
of intervention, phase, endpoints, degree of risk, size and complexity of the protocol. 
A formal, independent monitoring will be conducted by the DCI monitoring team 
according to the risk level and monitoring plan assigned by the CPC until the study is 
closed to enrollment or subjects are no longer receiving study drug or other 
interventions that are more than minimal risk. Additional monitoring may be 
prompted by findings from monitoring visits, unexpected frequency of serious and/or 
unexpected toxicities, or other concerns.  Monitoring visits may also be initiated 
upon request by DUHS and DCI Leadership, CPC, SOC, a sponsor, an investigator, 
or the IRB. 
 
The DCI monitoring team reviews the adequacy of informed consent, enrollment of 
eligible patients, implementation of protocol-specified procedures and treatment, 
adequacy of data collection, and appropriateness of adverse event monitoring and 


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reporting. The DCI monitoring team presents final monitoring reports to the DCI 
Safety Oversight Committee (SOC) highlighting safety concerns and unresolved 
issues. The SOC, at a convened meeting, assigns an overall rating of satisfactory, 
marginal, or unsatisfactory to reflect the overall quality of data, regulatory, consent, 
eligibility, study conduct and AE reporting. Corrective action plans (CAPs) are 
developed, implemented, and evaluated as indicated. The SOC will notify the 
sponsor-investigator and DUHS IRB when significant safety concerns are identified. 
 
The SOC in concert with DCI monitoring team conducts data and safety monitoring 
for DUHS sponsor-investigator phase I and II, therapeutic interventional oncology 
studies that do not have an independent DSMB. These reviews occur at a minimum 
annually and more frequently for the high risk studies. The SOC safety reviews 
include review of safety data, enrollment status, stopping rules if applicable, accrual, 
toxicities, reference literature, and interim analyses as provided by the sponsor- 
investigator. The SOC, at a convened meeting, assigns a rating of satisfactory when 
adequate accrual with lack of excessive toxicity is present. 
14.2. 
Audits 
The Duke Office of Audit, Risk and Compliance (OARC) may conduct confidential 
audits to evaluate compliance with the protocol and the principles of GCP. The PI 
agrees to allow the OARC auditor(s) direct access to all relevant documents and to 
allocate his/her time and the time of the study team to the OARC auditor(s) in order 
to discuss findings and any relevant issues. 
 
OARC audits are designed to protect the rights and well-being of human research 
subjects. OARC audits may be routine or directed (for cause). Routine audits are 
selected based upon risk metrics generally geared towards high subject enrollment, 
studies with limited oversight or monitoring, Investigator initiated Investigational 
Drugs or Devices, federally-funded studies, high degree of risk (based upon adverse 
events, type of study, or vulnerable populations), Phase I studies, or studies that 
involve Medicare populations. Directed audits occur at the directive of the IRB or an 
authorized Institutional Official. 
 
OARC audits examine research studies/clinical trials methodology, processes and 
systems to assess whether the research is conducted according to the protocol 
approved by the DUHS IRB. The primary purpose of the audit/review is to verify that 
the standards for safety of human subjects in clinical trials and the quality of data 
produced by the clinical trial research are met. The audit/review will serve as a 
quality assurance measure, internal to the institution. Additional goals of such audits 
are to detect both random and systemic errors occurring during the conduct of 
clinical research and to emphasize “best practices” in the research/clinical trials 
environment. 
14.3. 
Data Management and Processing 
14.3.1. 
Case Report Forms (CRFs) 


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The electronic CRF (eCRF) will be the primary data collection document for the 
study. The CRFs will be updated in a timely manner following acquisition of 
new source data. Only the PI, the study coordinator, the data management 
team, and the clinical trials coordinator are permitted to make entries, changes, 
or corrections in the eCRF. 
 
An audit trail will be maintained automatically by the electronic CRF 
management system, Advarra OnCore. Designated personnel will complete 
user training, as required or appropriate per regulations. 
14.3.2. 
Data Management Procedures and Data Verification 
Access to the electronic databases will be managed by the PRTBTC Data 
Manager. 
 
Completeness of entered data will be checked be the PRTBTC Data Manager 
or designee, and users will be alerted to the presence of data inconsistencies. 
Additionally, the data manager and the statistical team will cross-reference the 
data to verify accuracy. Missing or implausible data will be highlighted for the 
PI requiring appropriate responses (i.e. confirmation of data, correction of data, 
completion or confirmation that data is not available, etc.). 
 
The database will be reviewed and discussed prior to database closure, and 
will be closed only after resolution of all remaining queries. An audit trail will be 
kept of all subsequent changes to the data. 
14.3.3. 
Study Closure 
Following completion of the studies, the PI will be responsible for ensuring the 
following activities: 
 
- 
Data clarification and/or resolution 
- 
Accounting, reconciliation, and destruction/return of used and unused study 
drugs 
- 
Review of site study records for completeness 
- 
Shipment of all remaining laboratory samples to the designated laboratories 


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15. STATISTICAL METHODS AND DATA ANALYSIS 
 
All statistical analysis will be performed under the direction of the statistician designated 
in key personnel. Any data analysis carried out independently by the investigator must 
be approved by the statistician before publication or presentation. 
 
15.1. 
Study Design Overview 
This randomized phase II trial is conducted among patients with surgically- 
resectable, solid tumor brain metastases to assess the impact of neoadjuvant 
nivolumab and ipilimumab administered before surgery and stereotactic radiosurgery 
on various clinical and biological endpoints. 
 
The study was originally designed as a randomized phase 2 trial in which patients 
were randomized via a permuted block randomization algorithm using a 1:1 
allocation ratio to receive either Arm 1 (with neoadjuvant nivolumab and ipilimumab) 
or Arm 2 (without neoadjuvant treatment). Unfortunately, the study faced challenges 
to enrollment due to delays in treatment caused by the randomizing of patients to a 
control arm. In a Memo to File dated March 4, 2021 that was submitted to the IRB 
and FDA, we proposed the removal of randomization in favor of a single-arm study in 
which all patients will receive neoadjuvant immunotherapy prior to their resection and 
SRS. This change is reflected in the protocol’s amendment date 03/19/2021. This 
change will not affect the primary endpoint of feasibility. Prior to the writing of this 
Memo to File, 1 patient had been randomized to receive standard of care surgery 
and SRS without neoadjuvant immunotherapy. This patient, though eligible, will not 
be part of the analyses described below. 
 
15.2. 
Analysis Sets 
The primary analysis associated with the assessment of feasibility, survival, 
progression-free survival, and time to intracranial progression will include all 
eligible patients who receive both nivolumab and ipilimumab. 
 
Correlative analyses may be limited to only those patients who provide adequate 
specimens for analyses. 
 
15.3. 
Patient Demographics and Other Baseline Characteristics 
Summaries of clinical and socio-demographic characteristics will be generated for all 
enrolled patients. Categorical descriptors will be summarized using frequency 
distributions; whereas, interval variables will be summarized using percentiles, as 
well as means and standard deviations. 
 
15.4. 
Treatments 
A CONSORT diagram will be generated that describes flow of treatment. The 
diagram will provide information about the number of patients who receive 


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neoadjuvant treatment, undergo surgery (on schedule, late, or not at all), and 
receive SRS. Details about the SRS administered will be summarized. 
The number of patients who receive treatment after SRS will also be tabulated with 
some detail about the type of treatment administered. Data about maintenance 
treatment, including the type of immunotherapy, will also be summarized. 
 
15.5. 
Primary Objectives 
This study has two primary objectives. This includes an assessment of the feasibility 
of administering ipilimumab and nivolumab before surgery and SRS in patients with 
solid tumor brain metastases, as well as an assessment of the effect of neoadjuvant 
treatment on the proliferation of circulating T-cells. 
 
15.5.1. 
Primary Objective #1: Feasibility (Surgical Delay) 
15.5.1.1. Variable 
The first primary objective is to demonstrate that neoadjuvant administration 
of ipilimumab and nivolumab administered to patients with solid tumor brain 
metastases before surgery and SRS is feasible. Feasibility will be assessed 
by the proportion of patients who have their surgery delayed or surgery never 
occurs as a direct or indirect result of ipilimumab and/or nivolumab treatment. 
With the checkpoint inhibitors being administered on Day -7, the surgery is 
scheduled for Week 1, Day 1 (± 3 days). S urgery will be considered delayed 
if it never occurs or o ccurs after Day 4 (i.e. Day 1 + 3). 
 
15.5.1.2. Continuous Monitoring of Feasibility and Analysis 
The proportion of patients experiencing surgical delay as defined in Section 
15.5.1.1 will be computed as the number of patients with delayed surgery or 
whom never have surgery as a direct or indirect result of ipilimumab and/or 
nivolumab treatment divided by the total number of patients. 
 
Neoadjuvant treatment patients who have delayed surgery or no surgery due 
to reasons unrelated to ipilimumab and/or nivolumab treatment will be 
excluded from the assessment of feasibility. However, this patient will be 
included in all other analyses if data is available. Reasons for such exclusions 
will be tabulated. All other patients will be considered evaluable for the 
assessment of feasibility. 
 
Methods developed for continuous monitoring of toxicity will assess whether 
the number of surgical delays is not excessive. Based upon the Pocock 
boundary, the following monitoring rules were developed assuming that a true 
surgical delay rate of 10% is acceptable, and a surgical delay rate of 20% is 
too high. Accrual of patients will be suspended if the following conditions are 
satisfied: 
 
 


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1 – 4 
# Evaluable Patients with Delayed Surgery > 1 
5 – 8 
# Evaluable Patients with Delayed Surgery > 2 
6 – 14 
# Evaluable Patients with Delayed Surgery > 3 
15+ 
# Evaluable Patients with Delayed Surgery > 4 
 
These monitoring rules were generated using the R software package. 
Specifically, the toxbdry function in the clinfun package (https://cran.r- 
project.org/web/packages/clinfun/clinfun.pdf) that implements methods 
developed by Jennison and Turnbull [20] and Ivanova et al [21] was used. 
 
If accrual is suspended, the reasons for delay will be carefully reviewed to 
determine whether accrual to should continue without any protocol modification, be 
permanently terminated, or whether modifications to the treatment regimen (e.g., 
removal of ipilimumab from the treatment regimen) should occur. 
 
15.5.1.3. Adverse Events 
In addition to feasibility, we will also be monitoring the study for adverse 
events, both before, during, and after surgery. 
 
Aggregate summaries of adverse events will be generated periodically for 
study team use, for review by the Safety Oversight Committee, and for 
submission to ClinicalTrials.gov. Included with these summaries will be a list 
of all patients experiencing serious adverse events. 
 
Two tabulations will be generated--one that includes all toxicities regardless 
of attribution, and another that includes only toxicities that are possibly, 
probably, and definitely related to treatment. For each of these tabulations, 
the maximum grade (according to CTCAE version 5) of each type of toxicity 
experienced by each patient will be summarized with frequency distributions. 
These tabulations will also summarize adverse events by step in the 
treatment regimen (e.g. neoadjuvant treatment period, surgery / SRS). 
 
For ClinicalTrials.gov, serious adverse events and other adverse events will 
be summarized separately. These tabulations will reflect the number of 
patients who experience each type of toxicity regardless of grade or 
attribution. 
 
As noted in section 15.5.1.2, if the percentage of patients with surgical delay 
due as a direct or indirect result of ipilumumab and/or nivolumab treatment is 
elevated, consideration will be given to modifying the immunotherapy 
treatment regimen. In addition, if the prevalence of adverse events possibly, 
probably, or definitely related to combination immunotherapy is higher than 
Suspend Treatment Assignment if 
# of Patients Enrolled 
to Date 


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anticipated based upon prior experience with this combination, consideration 
will also be given to modifying the immunotherapy regimen. 
 
15.5.2. 
Primary Objective #2: Proliferation of Circulating T-Cells 
The second primary objective involves an assessment of whether neoadjuvant 
immunotherapy will increase proliferation of circulating T-cells compared to 
baseline measurements. 
 
15.5.2.1. Variable 
To examine T-cell proliferation rates, Ki67 staining will be performed on PD- 
1+/CD8+ T cells extracted both from the peripheral blood and from resected 
tissue. 
 
As described in Table 1 of Section 12, blood will be drawn longitudinally 
during treatment to study how a single dose of nivolumab and ipilimumab 
before surgery affect T-cell proliferation over time. 
 
The primary outcome is the fold-change in Ki67 levels on peripheral-blood T 
cells between baseline and Day 1. 
 
15.5.2.2. Statistical Hypothesis, Model, and Method of Analysis 
As noted in Section 15.5.2.1, the primary outcome for each patient is the 
fold- change in Ki67 levels between baseline and Day 1. The mean fold-
change will be tested using a one-sample t-test. If assumptions for 
conducting a t-test are violated, a logarithmic transformation may be 
considered as well as a Wilcoxon one-sample test. 
 
15.5.2.3. Additional Analyses 
 
Ki67 from circulating PD-1/CD8+ T cells at Day 1 will be correlated to 
intratumoral PD-1/CD8+ T cells based on nonparametric correlation, 
Spearman’s rank order correlation. 
 
15.6. 
Exploratory Objectives 
This study has several exploratory objectives including the description of survival, 
time to local intracranial progression, time to distant intracranial progression, time to 
overall intracranial progression, and progression-free survival. The rate of 
radionecrosis will also be explored, as immune expression profiles. 


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Some of the proposed exploratory analyses may generate p-values. If they do, they 
will be viewed as descriptive and exploratory in nature. 
 
15.6.1. 
Exploratory Objective #1: Survival 
Survival is defined as the time between initiation of checkpoint treatment and 
death; survival time will be censored if the patient remained alive at the time of 
last follow-up. A Kaplan-Meier estimator will describe the survival of patients 
and associated survival statistics (e.g. median survival, survival at 6 months, 12 
months, and 18 months) will be estimated. 
 
In addition, exploratory analyses will assess the impact of fold-change in T-cell 
proliferation (KI-67) between baseline and Day 1 on subsequent survival, using a 
Cox model with fold-change as predictors of survival post-surgery. 
 
15.6.2. 
Exploratory Objectives #2 - #5: Disease Progression 
Several different efficacy measures of progression will be computed as part of 
exploratory objectives #2 - #5: 
 
• The time to local intracranial progression is the time between initiation of 
checkpoint treatment and first identification of local intracranial progression, 
which is defined by RANO-BM criteria. If a patient experiences a distant 
intracranial progression or dies before documentation of local progression, 
the time to local intracranial progression will be censored at the time of 
distant intracranial progression or the time of death. 
 
• The time to distant intracranial progression is the time between initiation of 
checkpoint treatment and first identification of distant intracranial progression, 
which is defined by RANO-BM disease progression criteria. If a patient locally 
progresses intracranially or dies before documentation of distant intracranial 
progression, the time to distant intracranial progression will be censored at 
the time of local intracranial progression or the time of death. 
 
• The time to overall intracranial progression is the time between initiation of 
checkpoint treatment and first identification of intracranial progression (distant 
or local), as defined by RANO-BM criteria. If a patient dies before 
documentation of intracranial progression, the time to overall intracranial 
progression will be censored at the time of death. 


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• Progression-free survival is the time between initiation of checkpoint 
treatment and first progression (intracranial or extracranial), or death if the 
patient dies without documented disease progression, as defined by 
RECIST 1.1. If the patient remains alive without disease progression at the 
time of analysis, progression-free survival will be censored at the time of 
last follow-up. 
 
Given that death, local intracranial recurrence, and distant intracranial recurrence 
are competing events, time to local intracranial recurrence, time to distant 
intracranial recurrence, and time to overall intracranial recurrence will be 
graphically described using a cumulative incidence function.  
 
15.6.3. 
Exploratory Objectives #6: Radionecrosis 
Rates of radionecrosis will also be determined based on radiographic and clinical 
suspicion or tissue confirmation when available. The proportion of patients who 
experience radionecrosis will be estimated with confidence intervals in the two 
treatment groups. 
 
15.6.4. 
Exploratory Objectives #7: Immune Expression Profiles 
Various exploratory analyses will be conducted to describe the immune 
expression profiles of patients. As noted previously immune profile assays may 
be run on cells from peripheral blood, resected tissue, and archival tissue using 
RNASeq, 28 color flow cytometry, IHC, and other methods. Some analyses may 
not be pre-specified, and may be motivated by other study findings or the 
evolving clinical literature that is available at the time accrual has been 
completed. 
 
Nanostring expression data will be normalized as per system guidelines. 
Exploratory analysis of highly differentially expressed genes will be utilized in 
assessing association to Ki67 from circulating PD-1/CD8+ T cells and to 
intratumoral PD- 1/CD8+ T cells. Additionally, differentially expressed genes will 
be incorporated in exploratory models of survival outcomes. 
 
15.7. 
Interim Analysis 
No interim efficacy analyses will be performed. However, continuous monitoring of 
surgical timing/delay will occur as described in Section 15.5.1.2. 


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15.8. 
Sample Size Calculation 
Twenty (2) patients will be enrolled onto this study and treated with ipilimumab and 
nivolumab. We anticipate that due to drop-out and/or sample quality issues Ki67 
data will be available from approximately 17 patients. 
 
Kim et al (2019) [23] reports that a higher fold-change in the percentage of Ki-67+ 
cells among PD1+ CD8+ T cells 7 days after the first dose of anti-PD-1 therapy is 
associated with greater efficacy. The distribution of this fold-change is graphically 
presented in Figure 2A of the Kim article. Based upon a crude estimate of the value 
of KI-67 associated with each data point in this figure, mean fold-changes were 
computed. The mean fold- change among the 11 patients with durable clinical 
response is 4.9 (SD=2.0; CV = 0.42); whereas the mean fold-change among the 20 
patients with non-durable response is 2.5 (SD=1.3; CV=0.54). Overall, the mean 
fold-change is 3.4 (SD=2.0; CV=0.6). 
 
Assuming that CV=0.6, a one-sample t-test (α=0.05; two-tailed) has >95% power to 
detect a mean fold- change of 1.7 among the 17 patients with evaluable Ki67 data. 
 
16. ADMINISTRATIVE AND ETHICAL CONSIDERATIONS 
16.1. 
Regulatory and Ethical Compliance 
This protocol was designed and will be conducted and reported in accordance with 
the International Conference on Harmonization (ICH) Harmonized Tripartite 
Guidelines for Good Clinical Practice, the Declaration of Helsinki, and applicable 
federal, state, and local regulations. 
16.2. 
DUHS Institutional Review Board and DCI Cancer Protocol 
Committee 
The protocol, informed consent form, advertising material, and additional protocol- 
related documents must be submitted to the DUHS Institutional Review Board (IRB) 
and DCI Cancer Protocol Committee (CPC) for review. The study may be initiated 
only after the Principal Investigator has received written and dated approval from the 
CPC and IRB. 
 
The Principal Investigator must submit and obtain approval from the IRB for all 
subsequent protocol amendments and changes to the informed consent form. The 
CPC should be informed about any protocol amendments that potentially affect 
research design or data analysis (i.e. amendments affecting subject population, 
inclusion/exclusion criteria, agent administration, statistical analysis, etc.). 


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The Principal Investigator must obtain protocol re-approval from the IRB within 1 
year of the most recent IRB approval. The Principal Investigator must also obtain 
protocol re-approval from the CPC within 1 year of the most recent IRB approval, for 
as long as the protocol remains open to subject enrollment. 
16.3. 
Informed Consent 
The informed consent form must be written in a manner that is understandable to the 
subject population. Prior to its use, the informed consent form must be approved by 
the IRB. 
 
The Principal Investigator or authorized key personnel will discuss with the potential 
subject the purpose of the research, methods, potential risks and benefits, subject 
concerns, and other study-related matters. This discussion will occur in a location 
that ensures subject privacy and in a manner that minimizes the possibility of 
coercion. Appropriate accommodations will be made available for potential subjects 
who cannot read or understand English or are visually impaired. Potential subjects 
will have the opportunity to contact the Principal investigator or authorized key 
personnel with questions, and will be given as much time as needed to make an 
informed decision about participation in the study. 
 
Before conducting any study-specific procedures, the Principal Investigator must 
obtain written informed consent from the subject or a legally acceptable 
representative. The original informed consent form will be stored with the subject’s 
study records, and a copy of the informed consent form will be provided to the 
subject. The Principal Investigator is responsible for asking the subject whether the 
subject wishes to notify his/her primary care physician about participation in the 
study. If the subject agrees to such notification, the Principal Investigator will inform 
the subject’s primary care physician about the subject’s participation in the clinical 
study. 
16.4. 
Study Documentation 
Study documentation includes but is not limited to source documents, case report 
forms (CRFs), monitoring logs, appointment schedules, study team correspondence 
with sponsors or regulatory bodies/committees, and regulatory documents that can 
be found in the DCI-mandated “Regulatory Binder”, which includes but is not limited 
to signed protocol and amendments, approved and signed informed consent forms, 
FDA Form 1572, CAP and CLIA laboratory certifications, and clinical supplies 
receipts and distribution records. 
 
Source documents are original records that contain source data, which is all 
information in original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Source 
documents include but are not limited to hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, 


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photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories and at medico-technical 
departments involved in the clinical trial. When possible, the original record should 
be retained as the source document. However, a photocopy is acceptable provided 
that it is a clear, legible, and an exact duplication of the original document. 
 
An electronic case report form (eCRF) will be the primary data collection document 
for the study. The eCRFs will be updated within two weeks of acquisition of new 
source data. Only approved study staff (See Section 14.3.1) are permitted to make 
entries, changes, or corrections in the CRF. For electronic CRFs, an audit trail will 
be maintained by the electronic CRF management system, Medidata Rave. 
16.5. 
Privacy, Confidentiality, and Data Storage 
The Principal Investigator will ensure that subject privacy and confidentiality of the 
subject’s data will be maintained. Research Data Security Plans (RDSPs) will be 
approved by the appropriate institutional Clinical Research Unit. 
 
To protect privacy, every reasonable effort will be made to prevent undue access to 
subjects during the course of the study. Prospective participants will be consented 
in an exam room where it is just the research staff, the patient and his family, if 
desired. For all future visits, interactions with research staff (study doctor and study 
coordinators) regarding research activities will take place in a private exam room. All 
research related interactions with the participant will be conducted by qualified 
research staff who are directly involved in the conduct of the research study. 
 
To protect confidentiality, subject files in paper format will be stored in secure 
cabinets under lock and key accessible only by the research staff. Subjects will be 
identified only by a unique study number and subject initials. Electronic records of 
subject data will be maintained using a dedicated database, Medidata Rave, which 
is housed in an encrypted and password-protected file on a secure network drive. 
Access to electronic databases will be managed by the PRTBTC Data Manager. 
Subject data may be stored temporarily on encrypted and password-protected 
portable memory devices such as flash drives and external hard drives, but only 
when absolutely necessary. Data stored on portable memory devices will be de- 
identified. Subject data will be deleted from the portable memory device at the 
earliest opportunity. The security and viability of the IT infrastructure will be 
managed by the DCI and/or Duke Medicine. 
 
Upon completion of the study, research records will be archived and handled per 
DUHS HRPP policy. 
 
Subject names or identifiers will not be used in reports, presentations at scientific 
meetings, or publications in scientific journals. 
 
16.6. 
Data and Safety Monitoring 


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Data and Safety Monitoring will be performed in accordance with the DCI Data and 
Safety Monitoring Plan. For a more detailed description of the DSMP for this 
protocol, refer to Section 13 (Section 13.6 in particular) and Section 14. 
16.7. 
Protocol Amendments 
All protocol amendments must be initiated by the Principal Investigator and 
approved by the IRB prior to implementation. IRB approval is not required for 
protocol changes that occur to protect the safety of a subject from an immediate 
hazard. However, the Principal Investigator must inform the IRB and all other 
applicable regulatory agencies of such action immediately. 
 
Though not yet required, the CPC should be informed about any protocol 
amendments that potentially affect research design or data analysis (i.e. 
amendments affecting subject population, inclusion/exclusion criteria, agent 
administration, etc.). 
16.8. 
Records Retention 
 
The Principal Investigator will maintain study-related records for the longer of a 
period of: 
 
- at least two years after the date on which a New Drug Application is approved by 
the FDA (if an IND is involved) 
- at least two years after formal withdrawal of the IND associated with this protocol 
(if an IND is involved) 
- at least six years after study completion (Duke policy) 


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17. REFERENCES 
1. 
Brown, P.D., et al., Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation 
Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical 
Trial. JAMA, 2016. 316(4): p. 401-409. 
2. 
Sperduto, P.W., et al., Estimating Survival in Patients With Lung Cancer and Brain Metastases: 
An Update of the Graded Prognostic Assessment for Lung Cancer Using Molecular Markers 
(Lung-molGPA). JAMA Oncol, 2017. 3(6): p. 827-831. 
3. 
Sperduto, P.W., et al., Effect of tumor subtype on survival and the graded prognostic assessment 
for patients with breast cancer and brain metastases. Int J Radiat Oncol Biol Phys, 2012. 82(5): p. 
2111-7. 
4. 
Shen, Q., et al., Breast cancer with brain metastases: clinicopathologic features, survival, and 
paired biomarker analysis. Oncologist, 2015. 20(5): p. 466-73. 
5. 
Sperduto, P.W., et al., Estimating Survival in Melanoma Patients With Brain Metastases: An 
Update of the Graded Prognostic Assessment for Melanoma Using Molecular Markers 
(Melanoma-molGPA). Int J Radiat Oncol Biol Phys, 2017. 99(4): p. 812-816. 
6. 
Lin, X. and L.M. DeAngelis, Treatment of Brain Metastases. J Clin Oncol, 2015. 33(30): p. 3475- 
84. 
7. 
Arvold, N.D., et al., Updates in the management of brain metastases. Neuro Oncol, 2016. 18(8): 
p. 1043-65. 
8. 
Gaspar, L., et al., Recursive partitioning analysis (RPA) of prognostic factors in three Radiation 
Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys, 1997. 
37(4): p. 745-51. 
9. 
Sperduto, P.W., et al., Summary report on the graded prognostic assessment: an accurate and 
facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol, 
2012. 30(4): p. 419-25. 
10. 
Yamamoto, M., et al., Stereotactic radiosurgery for patients with multiple brain metastases 
(JLGK0901): a multi-institutional prospective observational study. Lancet Oncol, 2014. 15(4): p. 
387-95. 
11. 
Preusser, M., et al., Prospects of immune checkpoint modulators in the treatment of glioblastoma. 
Nat Rev Neurol, 2015. 11(9): p. 504-14. 
12. 
Tawbi, H.A., et al., Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. N 
Engl J Med, 2018. 379(8): p. 722-730. 
13. 
Tawbi, H.A.-H., et al., Efficacy and safety of the combination of nivolumab (NIVO) plus ipilimumab 
(IPI) in patients with symptomatic melanoma brain metastases (CheckMate 204). 2019, American 
Society of Clinical Oncology. 
14. 
Goldberg, S.B., et al., Pembrolizumab for patients with melanoma or non-small-cell lung cancer 
and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. 
Lancet Oncol, 2016. 17(7): p. 976-983. 
15. 
Flippot, R., et al., Safety and Efficacy of Nivolumab in Brain Metastases From Renal Cell 
Carcinoma: Results of the GETUG-AFU 26 NIVOREN Multicenter Phase II Study. 2019: p. JCO. 
18.02218. 
16. 
Cloughesy, T.F., et al., Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with 
intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med, 2019. 25(3): p. 
477-486. 
17. 
Callahan, M.K., M.A. Postow, and J.D. Wolchok, Targeting T Cell Co-receptors for Cancer 
Therapy. Immunity, 2016. 44(5): p. 1069-78. 
18. 
OPDIVO. March 2015 November 2018]; Reference ID: 3710966]. 
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YERVOY. July 10, 2018 November 2018]; Reference ID: 4289391]. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125377s096lbl.pdf. 
20. 
Jennison, C. and B.W. Turnbull, Group sequential methods with applications to clinical trials. 
1999: Chapman and Hall/CRC. 
21. 
Ivanova, A., B.F. Qaqish, and M.J. Schell, Continuous toxicity monitoring in phase II trials in 
oncology. Biometrics, 2005. 61(2): p. 540-5. 
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Fine, J.P. and R.J.J.J.o.t.A.s.a. Gray, A proportional hazards model for the subdistribution of a 
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23. 
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Cells Predicts the Response to Anti-PD-1 Therapy in Solid Tumors. Clin Cancer Res, 2019. 
25(7): p. 2144-2154. 
18. APPENDICES 
18.1. 
Nivolumab Safety Algorithms 
Table 2: GI Adverse Event Management Algorithm. Rule out non-inflammatory causes. If non-inflammatory cause 
is identified, treat accordingly and continue I-O therapy. Opiates/narcotics may mask symptoms of perforation. 
Infliximab should not be used in cases of perforation or sepsis. 
 
Grade of Diarrhea/Colitis 
Management 
Follow-up 
Grade 1 
Diarrhea:< 4 stools/day over 
baseline; 
Colitis: asymptomatic 
• 
Continue I-O therapy per 
protocol 
• 
Symptomatic treatment 
• 
Close monitoring for worsening 
symptoms. 
• 
Educate patient to report 
worsening immediately 
If worsens: 
• 
Treat as Grade 2 or 3/4 
Grade 2 
Diarrhea: 4-6 stools per day 
over baseline; IV fluids 
indicated <24 hrs; 
not interfering with ADL 
Colitis: abdominal pain; 
blood in stool 
• 
Delay I-O therapy per 
protocol 
• 
Symptomatic treatment 
If improves to grade 1: 
• 
Resume I-O therapy per 
protocol 
If persists > 5-7 days or recur: 
• 
0.5-1.0 mg/kg/day 
methylprednisolone or oral 
equivalent 
• 
When symptoms improve to 
grade 1, taper steroids over at 
least 1 month, consider 
prophylactic antibiotics for 
opportunistic infections, and 
resume I-O therapy per 
protocol. 
If worsens or persists > 3-5 days 
with oral steroids: 
• 
Treat as grade 3/4 
Grade 3-4 
Diarrhea (G3): ≥7 stools per 
day over baseline; 
incontinence; IV fluids ≥24 
hrs; interfering with ADL 
Colitis (G3): severe 
abdominal pain, 
medical intervention 
indicated, peritoneal signs 
G4: life-threatening, 
perforation 
• 
Discontinue I-O therapy per 
protocol 
• 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• 
Add prophylactic antibiotics 
for opportunistic infections 
• 
Consider lower endoscopy 
If improves: 
• 
Continue steroids until grade 1, 
then taper over at least 1 month 
If persists > 3-5 days, or recurs 
after improvement: 
• 
Add infliximab 5 mg/kg (if no 
contraindication). Note: 
Infliximab should not be used in 
cases of perforation or sepsis 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 


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Table 3: Renal Adverse Event Management Algorithm. Rule out non-inflammatory causes. If non-inflammatory 
cause, treat accordingly and continue I-O therapy. 
 
Grade of Creatinine 
Elevation 
Management 
Follow-up 
Grade 1 
Creatinine > ULN and > than 
baseline but ≤ 1.5x baseline 
• 
Continue I-O therapy per 
protocol 
• 
Monitor creatinine weekly 
If returns to baseline: 
• 
Resume routine creatinine 
monitoring per protocol 
If worsens: 
• 
Treat as Grade 2 or 3/4 
Grade 2-3 
Creatinine > 1.5x baseline to 
≤ 6x ULN 
• 
Delay I-O therapy per 
protocol 
• 
Monitor creatinine every 2-3 
days 
• 
0.5 to 1.0 mg/kg/day 
methylprednisolone IV or 
oral equivalent 
• 
Consider renal biopsy with 
nephrology consult 
If returns to grade 1: 
• 
Taber steroids over at least 1 
month, consider prophylactic 
antibiotics for opportunistic 
infections, and resume I-O 
therapy and routine creatinine 
monitoring per protocol 
If elevations persists > 7 days or 
worsen: 
• 
Treat as Grade 4 
Grade 4 
Creatinine > 6x ULN 
• 
Discontinue I-O therapy per 
protocol 
• 
Monitor creatinine daily 
• 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• 
Consult nephrologist 
• 
Consider renal biopsy 
If returns to grade 1: 
• 
Taper steroids over at least 1 
month and add prophylactic 
antibiotics for opportunistic 
infections 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 


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Table 4: Pulmonary Adverse Event Management Algorithm. Rule out non-inflammatory causes. If non- 
inflammatory cause, treat accordingly and continue I-O therapy. Evaluate with imaging and pulmonary consultation. 
 
Grade of Pneumonitis 
Management 
Follow-up 
Grade 1 
Radiographic changes only 
• 
Consider delay of I-O 
therapy 
• 
Monitor for symptoms every 
2-3 days 
• 
Consider Pulmonary and ID 
consults 
• 
Re-image at least every 3 
weeks 
If worsens: 
• 
Treat as Grade 2 or 3-4 
Grade 2-3 
Mild to moderate new 
symptoms 
• 
Delay I-O therapy per 
protocol 
• 
Pulmonary and ID consults 
• 
Monitor symptoms daily, 
consider hospitalization 
• 
1.0 mg/kg/day 
methylprednisolone IV or 
oral equivalent 
• 
Consider bronchoscopy, 
lung biopsy 
• 
Re-image every 1-3 days 
If improves: 
• 
When symptoms return to near 
baseline, taper steroids over at 
least 1 month and then resume 
I-O therapy per protocol and 
consider prophylactic antibiotics 
If not improving after 2 weeks or 
worsening: 
• 
Treat as Grade 3-4 
Grade 4 
Severe new symptoms; 
New/worsening hypoxia; 
Life-threatening 
• 
Discontinue I-O therapy per 
protocol 
• 
Hospitalize 
• 
Pulmonary and ID consults 
• 
2-4 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• 
Add prophylactic antibiotics 
for opportunistic infections 
• 
Consider bronchoscopy, 
lung biopsy 
If improves to baseline: 
• 
Taper steroids over at least 6 
weeks 
If not improving after 48 hours or 
worsening: 
• 
Add additional 
immunosupression 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 


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Table 5: Hepatic Adverse Event Management Algorithm. Rule out non-inflammatory causes. If non-inflammatory 
cause, treat accordingly and continue I-O therapy. Consider imaging for obstruction. 
 
Grade of Liver Test 
Elevation 
Management 
Follow-up 
Grade 1 
AST or ALT > ULN to 3.0 x 
ULN and/or T. bili > ULN to 
1.5 x ULN 
• 
Continue I-O therapy per 
protocol 
• 
Continue LFT monitoring per 
protocol 
If worsens: 
• 
Treat as Grade 2 or 3-4 
Grade 2 
AST or ALT > 3.0 to ≤ 5 x 
ULN and/or T. bili > 1.5 to ≤ 
3 x ULN 
• 
Delay I-O therapy per 
protocol 
• 
Increase frequency of 
monitoring to every 3 days 
If returns to baseline: 
• 
Resume routine monitoring, 
resume I-O therapy per protocol 
If elevation persists > 5-7 days or 
worsens: 
• 
0.5-1 mg/kg/day 
methylprednisolone or oral 
equivalent and when LFT 
returns to grade 1 or baseline, 
taper steroids over at least 1 
month, consider prophylactic 
antibiotics for opportunistic 
infections, and resume I-O 
therapy per protocol 
Grade 3-4 
AST or ALT > 5 x ULT or T. 
bili >3 x ULN 
• 
Discontinue I-O therapy per 
protocol* 
• 
Increase frequency of 
monitoring to every 1-2 days 
• 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent* 
• 
Add prophylactic antibiotics 
for opportunistic infections 
• 
Consult gastroenterologist 
If returns to Grade 2: 
• 
Taper steroids over at least 1 
month 
If does not improve in >3-5 days, 
worsens or rebounds: 
• 
Add mycophenolate mofetil 1 g 
BID 
• 
If no response within an 
additional 3-5 days, consider 
other immunosuppressants per 
local guidelines 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 
*The recommended starting dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV. 


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Table 6: Endocrinopathy Adverse Event Management Algorithm. Rule out non-inflammatory causes. If non- 
inflammatory cause, treat accordingly and continue I-O therapy. Consider visual field testing, endocrinology 
consultation, and imaging. 
 
Asymptomatic TSH 
Elevation 
• 
Continue I-O therapy per protocol 
• 
If TSH < 0.5 x LLN, or TSH > 2 x ULN, or consistently out of range 
in 2 subsequent measurements: include fT4 at subsequent cycles 
as clinically indicated; consider endocrinology consult 
Symptomatic 
endocrinopathy 
• 
Evaluate endocrine function 
• 
Consider pituitary scan 
Symptomatic with abnormal 
lab/pituitary scan: 
• 
Delay I-O therapy per 
protocol 
• 
1-2 mg/kg/day 
methylprednisolone IV or PO 
equivalent 
• 
Initiate appropriate hormone 
therapy 
No abnormal lab/pituitary MRI 
scan but symptoms persist: 
• 
Repeat labs in 1-3 weeks / 
MRI in 1 month 
If improves (with or without 
hormone replacement): 
• 
Taper steroids over at least 1 
month and consider 
prophylactic antibiotics for 
opportunistic infections 
• 
Resume I-O therapy per 
protocol 
• 
Patients with adrenal 
insufficiency may need to 
continue steroids with 
mineralocorticoid component 
Suspicion of adrenal crisis 
(e.g., severe dehydration, 
hypotension, shock out of 
proportion to current 
illness) 
• 
Delay or discontinue I-O 
therapy per protocol 
• 
Rule out sepsis 
• 
Stress dose of IV steroids 
with mineralocorticoid 
activity 
• 
IV fluids 
• 
Consult endocrinologist 
• 
If adrenal crisis ruled out, 
then treat as above for 
symptomatic endocrinopathy 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 


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Table 7: Skin Adverse Event Management Algorithm. Rule out non-inflammatory causes. If non-inflammatory 
cause, treat accordingly and continue I-O therapy. 
 
Grade of Rash 
Management 
Follow-up 
Grade 1-2 
Covering ≤ 30% BSA* 
• 
Symptomatic therapy (e.g., 
antihistamines, topical 
steroids) 
• 
Continue I-O therapy per 
protocol 
If persists > 1-2 weeks or recurs: 
• 
Consider skin biopsy 
• 
Delay I-O therapy per protocol 
• 
Consider 0.5-1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent. Once improving, 
taper steroids over at least 1 
month, consider prophylactic 
antibiotics for opportunistic 
infections, and resume I-O 
therapy per protocol 
If worsens: 
• 
Treat as Grade 3-4 
Grade 3-4 
Covering > 30% BSA; Life 
threatening consequences 
*^ 
• 
Delay or discontinue I-O 
therapy per protocol 
• 
Consider skin biopsy 
• 
Dermatology consult 
• 
1.0-2.0 mg/kg/day IV 
methylprednisolone IV or IV 
equivalent 
If improves to Grade 1: 
• 
Taper steroids over at least 1 
month and add prophylactic 
antibiotics for opportunistic 
infections 
• 
Resume I-O therapy per 
protocol. 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 
*Refer to NCI CTCAE v4 for term-specific grading criteria 
^If SJS/TEN is suspected, withhold I-O therapy and refer patient for specialized care for assessment and 
treatment. If SJS or TEN is diagnosed, permanently discontinue I-O therapy. 


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Table 8: Neurological Adverse Event Management Algorithm. Rule out non-inflammatory causes. If non- 
inflammatory cause, treat accordingly and continue I-O therapy. 
 
Grade of Neurological 
Toxicity 
Management 
Follow-up 
Grade 1 
Asymptomatic or mild 
symptoms; Intervention not 
indicated 
• 
Continue I-O therapy per 
protocol 
• 
Continue to monitor the patient 
If worsens: 
• 
Treat as Grade 2 or 3-4 
Grade 2 
Moderate symptoms; 
Limiting instrumental ADL 
• 
Delay I-O therapy per 
protocol 
• 
Treat symptoms per local 
guidelines 
• 
Consider 0.5 to 1.0 
mg/kg/day 
methylprednisolone IV or PO 
equivalent 
If improves to baseline: 
• 
Resume I-O therapy per 
protocol when improved to 
baseline 
If worsens: 
• 
Treat as Grade 3-4 
Grade 3-4 
Severe symptoms; Limiting 
self-care ADL; Life- 
threatening 
• 
Discontinue I-O therapy per 
protocol 
• 
Obtain neurology consult 
• 
Treat symptoms per local 
guidelines 
• 
1.0-2.0 mg/kg/day IV 
methylprednisolone IV or IV 
equivalent 
• 
Add prophylactic antibiotics 
for opportunistic infections 
If improves to Grade 2: 
• 
Taper steroids over at least 1 
month 
If worsens or atypical 
presentation: 
• 
Consider IVIG or other 
immunosuppressive therapies 
per local guidelines 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 


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Table 9: Myocarditics Adverse Event Management Algorithm. 
 
Grade of Myocarditis 
Management 
Follow-up 
Grade 2 
Symptoms with mild to 
moderate activity or exertion 
• 
Delay I-O therapy; 
hospitalization with cardiac 
monitoring 
• 
Urgent cardiology 
consultation for evaluation 
and management 
o 
Troponin and BNP 
o 
ECG ± continuous 
cardiac monitoring 
o 
Echocardiogram 
o 
Cardiac MRI 
• 
Prompt initiation of 2 
mg/kg/day 
methylprednisolone IV or 
equivalent 
• 
If worsens, intensify treatment 
according to grade 
• 
Upon recovery, taper steroids 
over at least 1 month with close 
monitoring of troponin and BNP 
as well as for new symptoms 
• 
Repeat cardiac MRI for post 
treatment assessment and 
cardiology follow-up 
• 
Retreatment may be 
considered after recovery and 
completion of steroid taper 
Grade 3: Severe with 
symptoms at rest or with 
minimal activity or exertion; 
intervention indicated 
Grade 4: Life-threatening 
consequences; urgent 
intervention indicated (e.g., 
continuous IV therapy or 
mechanical hemodynamic 
support) 
• 
Permanently discontinue I-O 
therapy 
• 
Hospitalize to intensive 
cardiac monitoring 
• 
Cardiac evaluation to 
include: 
o 
Troponin and BNP 
o 
ECG ± continuous 
cardiac monitoring 
o 
Echocardiogram 
o 
Cardiac MRI 
o 
Myocardial biopsy if 
feasible 
• 
Immediate initiation of 2 
mg/kg/day 
methylprednisolone IV or 1 g 
IV bolus 
• 
Consider adding a second 
immunosuppressive agent 
Additionally, for Grade 4: 
• 
Hospitalize/transfer to 
institution with expertise in 
intensive cardiac monitoring 
• 
Consider ATG as second 
agent given its immediate 
effect 
• 
If no improvement, consider 
additional immunosuppression 
• 
Upon recovery, taper steroids 
over at least 1 month with close 
monitoring of troponin and BNP 
as well as for new symptoms 
• 
Repeat cardiac MRI for post 
treatment assessment and 
cardiology follow-up 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 
ATG = anti-thymocyte globulin; BNP = B-type natriuretic peptide; ECG = electrocardiogram; IV = 
intravenous; MRI = magnetic resonance imaging 


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18.2. 
Ipilimumab Safety Algorithms 
Table 10: GI Adverse Event Management Algorithm. Rule out non-inflammatory causes. If non-inflammatory 
cause is identified, treat accordingly and continue ipilimumab. Opiates/narcotics may mask symptoms of perforation. 
Infliximab should not be used in cases of perforation or sepsis. 
 
Grade of Diarrhea/Colitis 
Management 
Follow-up 
Grade 1 
Diarrhea:< 4 stools/day over 
baseline; 
Colitis: asymptomatic 
• 
Continue ipilimumab 
• 
Symptomatic treatment 
• 
Close monitoring for worsening 
symptoms. 
• 
Educate patient to report 
worsening immediately 
Grade 2 
Diarrhea: 4-6 stools per day 
over baseline; IV fluids 
indicated <24 hrs; 
not interfering with ADL 
Colitis: abdominal pain; 
blood in stool 
• 
Withold/delay ipilimumab 
• 
Symptomatic treatment 
Symptoms improve/resolve 
(grade 0/1): 
• 
Resume ipilimumab 
Symptoms persists > 5-7 days, 
worsen, or recur: 
• 
Moderate to high dose steroids 
PO (e.g., prednisone 0.5-1.0 
mg/kg/day) 
• 
Continue to hold/delay 
ipilimumab until grade 1 
• 
When symptoms are grade 1 or 
less, slowly taper steroids over 
at least 1 month and resume 
ipilimumab 
Symptoms worsen: 
• 
Treat as grade 3/4 
Grade 3-4 
Diarrhea (G3*): ≥7 stools per 
day over baseline; 
incontinence; IV fluids ≥24 
hrs; interfering with ADL 
Colitis (G3*): fever, ileus, 
peritoneal signs 
• 
Permanently discontinue 
ipilimumab 
• 
High dose IV steroids (e.g., 
1-2 mg/kg/day 
methylprednisolone) 
• 
Consider endoscopy 
Symptoms improve: 
• 
Continue steroids (same dose) 
until grade 1 
• 
Then taper over at least 1 
month 
Symptoms persist 3-5 days, or 
recur after improvement: 
• 
1 dose* infliximab 5 mg/kg (if no 
contraindication) 
*G4: life-threatening, perforation 
*Some patients have required a second dose of infliximab 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 


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Table 11: Hepatic Adverse Event Management Algorithm. Rule out non-inflammatory causes. If non-inflammatory 
cause, treat accordingly and continue I-O therapy. Consider imaging for obstruction. 
 
Grade of Liver Test 
Elevation 
Management 
Follow-up 
Grade 1 
AST or ALT ≤ 2.5 x ULN 
Or 
Total bilirubin ≤ 1.5 x ULN 
• 
Continue ipilimumab 
• 
Continue LFT monitoring prior 
to each dose 
Grade 2 
AST or ALT > 2.5 to ≤ 5 x 
ULN 
or 
Total bilirubin > 1.5 to ≤ 3 x 
ULN 
• 
Increase frequency of 
monitoring (q3d) 
• 
Withhold/delay ipilimumab 
while investigating 
alternative etiology 
Return to baseline: 
• 
Resume q3w monitoring 
• 
Resume ipilimumab 
Elevations persist > 5-7 days or 
worsen, and no alternative 
etiologies are identified: 
• 
Consider moderate to high 
dose steroids PO (e.g., 0.5-1 
mg/kg/day prednisone or 
equivalent) 
Grade 3-4 
AST or ALT > 5 x ULN 
or 
Total bilirubin > 3 x ULN 
• 
Discontinue ipilimumab* 
• 
Increase frequency of 
monitoring (q1-3d) 
• 
High dose IV steroids (e.g., 
1-2 mg/kg/day 
methylprednisolone**) 
AST/ALT/Tbili returns to Grade 2: 
• 
Taper steroids over at least 1 
month 
Labs do not decrease over 3-5 
days, worsen or rebound: 
• 
Add mycophenolate mofetil 1 g 
BID 
• 
If no response within 3-5 days, 
consider other 
immunosuppressants per local 
guidelines 
*Ipilimumab may be held/delayed rather than discontinued if AST/ALT ≤ 8 X ULN and Tbili < 5 X ULN. 
Resume ipilimumab when AST/ALT/Tbili return to grade 2 and meet protocol specific retreatment criteria. 
**The recommended starting dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV. 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 


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Table 12: Endocrinopathy Adverse Event Management Algorithm. Rule out non-inflammatory causes. If non- 
inflammatory cause, treat accordingly and continue ipilimumab. 
 
Asymptomatic TSH 
Elevation 
• 
Continue ipilimumab 
• 
If TSH < 0.5 x LLN, or TSH > 2 x ULN, or consistently out of range 
in 2 subsequent measurements: include fT4 at subsequent cycles 
as clinically indicated; consider endocrinology consult 
Symptomatic 
endocrinopathy 
• 
Evaluate endocrine function 
• 
Consider pituitary scan 
Symptomatic with abnormal 
lab/pituitary scan: 
• 
Withhold/delay ipilimumab 
• 
High dose IV steroids (e.g., 
1-2 mg/kg/day 
methylprednisolone) 
• 
Initiate appropriate hormone 
therapy 
No abnormal lab/pituitary scan 
but symptoms persist: 
• 
Repeat labs in 1-3 weeks / 
MRI in 1 month 
Symptoms resolve (with or 
without hormone replacement): 
• 
Taper steroids over at least 1 
month 
• 
Resume ipilimumab 
• 
Patients with adrenal 
insufficiency may need to 
continue steroids with 
mineralocorticoid component 
Suspicion of adrenal crisis 
(e.g., severe dehydration, 
hypotension, shock out of 
proportion to current 
illness) 
• 
Rule out sepsis 
• 
Stress dose of IV steroids 
with mineralocorticoid 
activity 
• 
IV fluids 
• 
Consult endocrinologist 
• 
If adrenal crisis ruled out, 
then treat as above for 
symptomatic endocrinopathy 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 


Duke Cancer Institute 
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Table 13: Skin Adverse Event Management Algorithm. Rule out non-inflammatory causes. If non-inflammatory 
cause, treat accordingly and continue ipilimumab. 
 
Grade of Rash 
Management 
Follow-up 
Grade 1-2 
• 
Symptomatic therapy (e.g., 
antihistamines, topical 
steroids) 
• 
Continue ipilimumab 
Symptoms resolve: continue 
ipilimumab 
If persists > 1-2 weeks or recurs: 
• 
Continue ipilimumab 
• 
Moderate to high dose steroids 
PO (e.g., 0.5-1.0 mg/kg/day 
lprednisone) 
• 
Once controlled, taper steroids 
over at least 1 month 
Grade 3-4 
• 
Hold/delay ipilimumab 
(regardless of relationship) 
• 
Take photos of rash 
• 
Consider skin biopsy 
• 
Dermatology consult 
• 
High dose IV steroids (e.g., 
1-2 mg/kg/day 
methylprednisolone) 
Symptoms resolve / return to 
Grade 1: 
• 
Taper steroids over at least 1 
month 
• 
Resume ipilimumab 
• 
Discontinue if grade 4 toxicity 
considered related 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 


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Table 14: Neurological Adverse Event Management Algorithm. Rule out non-inflammatory causes. If non- 
inflammatory cause, treat accordingly and continue ipilimumab. Discontinue ipilimumab for any grade 3-4 motor 
neuropathy, regardless of relationship. 
 
Severity of Neurological 
Toxicity 
Management 
Follow-up 
Grade 1 
• 
Continue ipilimumab 
• 
Continue to monitor the patient. 
If symptoms worsen, treat as 
below 
Grade 2 
• 
Hold/delay ipilimumab 
• 
Treat symptoms per local 
guidelines 
• 
Resume ipilimumab when 
resolved/grade 1. If symptoms 
worsen, treat as below. 
Grade 3-4 sensory 
• 
Discontinue ipilimumab if 
considered related 
• 
Obtain neuro consult 
• 
Treat symptoms per local 
guidelines 
• 
High dose IV steroids (e.g., 
1-2 mg/kg/day 
methylprednisolone) 
Symptoms resolve / return to 
Grade 2: 
• 
Taper steroids over at least 1 
month 
Grade 3-4 motor 
• 
Discontinue ipilimumab 
regardless of relationship 
• 
Obtain neuro consult 
• 
Treat symptoms per local 
guidelines 
• 
High dose IV steroids (e.g., 
1-2 mg/kg/day 
methylprednisolone) 
Symptoms resolve / return to 
Grade 2: 
• 
Taper steroids over at least 1 
month 
Symptoms do not resolve or 
progress; atypical presentation: 
• 
Consider IVIg or other 
immunosuppressive therapies 
per local guidelines 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.