A Phase II Study of the Interleukin-6 Receptor Inhibitor Tocilizumab in Combination With Ipilimumab and Nivolumab in Patients With Unresectable Stage III or Stage IV Melanoma
Phase: PHASE2
Conditions: Melanoma
Sponsor: NYU Langone Health

 
 
Official Title: 
A Phase II Study of the Interleukin-6 Receptor Inhibitor Tocilizumab in 
Combination with Ipilimumab and Nivolumab in Patients with 
Unresectable Stage III or Stage IV Melanoma. 
NCT Number: 
NCT03999749 
Study Number: 
s19-00008 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
Janurary 13, 2023 
 
 

 
 
Clinical Research Protocol 
 
CLINICAL STUDY PROTOCOL 
A Phase II Study of the Interleukin-6 Receptor Inhibitor Tocilizumab in 
Combination with Ipilimumab and Nivolumab in Patients with 
Unresectable Stage III or Stage IV Melanoma. 
 
Principal Investigator: 
 
Jeffrey S. Weber, MD, PhD 
Laura and Isaac Perlmutter Cancer Center 
160 E. 34th Street 
New York, NY 10016 
Tel:  212-263-9333 
Fax:  212-263-9190 
Email:  Jeffrey.Weber@nyulangone.org 
Additional Investigators: 
 
Kathleen Madden, NP 
 
Co-Investigator Statistics 
Judith D. Goldberg ScD 
Medical Monitor 
Nina Beri, MD 
Laura and Isaac Perlmutter Cancer Center 
160 E. 34th Street 
New York, NY 10016 
Email: Nina.Beri@nyulangone.org 
NYULHStudy Number: 
S19-00008; BMS CA209-76Y; Genentech ML41555 
Funding Sponsor:  
Bristol-Myers Squibb Company  
345 Park Ave, New York, NY 10154  
(212) 546-4000 
IND/IDE Number:  
144082 
Regulatory Sponsor:  
Perlmutter Cancer Center  
160 E. 34th Street 
New York, NY 10016 
212-263-9333 
 
NYU Langone Medical Center NYU Langone Health  
550 1st Avenue, New York, NY 10016 
(212) 263-5800 
Study Product: 
Tocilizumab 
Study Product Provider:  
Bristol-Myers Squibb Company  
Genentech 
 
Coordinating Center: 
 
NYU Langone Health 
Perlmutter Cancer Center 
Clinical Trials Office 
PCC-QAU@nyulangone.org 
Participating Sites 
NYU Langone Health, New York NY 
Dana Farber Cancer Center, Boston MA 
The Angeles Clinic and Research Institite, Los Angeles CA 
Massachusetts General Hospital   
ClinicalTrials.gov 
Number                 
NCT03999749 
 

 
 
Clinical Research Protocol 
 
Initial version: 02 January 2019 
Version 2.0: 25 January 2019 
Version 3.0: 9 April 2019 
Version 3.1: 17 April 2019 
Version 3.2: 17 May 2019 
Version 3.3: 10 Jul 2019 
Version 3.4: 09 Sept 2019 
Version 3.5: 19 November 2019 
Version 4.0: 06 February 2020 
Version 4.1: 11 March 2020 
Version 4.2: 09 March 2021 
Version 4.3: 13 Jan 2023 
 
 
 

 
 
Clinical Research Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
STATEMENT OF COMPLIANCE 
 
This study will be conducted in accordance with the Code of Federal Regulations on the 
Protection of Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as 
applicable, any other applicable US government research regulations, and institutional 
research policies and procedures. The International Conference on Harmonisation (“ICH”) 
Guideline for Good Clinical Practice (“GCP”) (sometimes referred to as “ICH-GCP” or 
“E6”) will be applied only to the extent that it is compatible with FDA and DHHS 
regulations. The Principal Investigator will assure that no deviation from, or changes to the 
protocol will take place without prior agreement from the sponsor and documented 
approval from the Institutional Review Board (IRB), except where necessary to eliminate 
an immediate hazard(s) to the trial participants. All personnel involved in the conduct of 
this study have completed Human Subjects Protection Training. 
 
 
 

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INVESTIGATOR  SIGNATURE PAGE 
Protocol Title: 
A Phase II Study of the Interleukin-6 Blocking Antibody Tocilizumab in 
Combination with Ipilimumab and Nivolumab in Patients with 
Unresectable Stage III or Stage IV Melanoma 
Protocol Number: 
S19-00008; [BMS CA209-76Y; Genetech ML41555] 
Confidentiality and cGCP Compliance Statement 
I, the undersigned, have reviewed this protocol (and amendments), including appendices, 
and I will conduct the study as described in compliance with this protocol (and 
amendments), cGCP, and relevant ICH guidelines. 
Once the protocol has been approved by the IRB, I will not modify this protocol without 
obtaining previous approval of BMS. and of the IRB. I will submit the protocol 
amendments and/or any ICF modifications to BMS. And the NYU IRB, and approval will 
be obtained before any amendments are implemented. 
I understand that all information obtained during the conduct of the study with regard to 
the patients’ state of health will be regarded as confidential. No patients’ names will be 
disclosed. All patients will be identified by assigned numbers on all CRFs, laboratory 
samples, or source documents forwarded to the Sponsor. Clinical information may be 
reviewed by the Sponsor or its agents or regulatory agencies. Agreement must be obtained 
from the patient before disclosure of patient information to a third party. 
Information developed in this clinical study may be disclosed by BMS to other clinical 
Investigators, regulatory agencies, or other health authority or government agencies as 
required. 
Investigator Signature 
Date 
Printed Name 
Institution 
 
 

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TABLE OF CONTENTS 
Statement of Compliance .................................................................................................... 3 
Investigator  Signature page .............................................................................................. 4 
List of Tables ................................................................................................................. 11 
List of Abbreviations ........................................................................................................ 12 
Synopsis .............................................................................................................................. 16 
1 
Introduction ......................................................................................................... 25 
1.1 
Nivolumab and Ipilimumab in Melanoma ....................................................... 25 
1.2 
Interleukin-6 and Cancer ................................................................................... 26 
1.3 
Tocilizumab in cancer patients .......................................................................... 27 
1.4 
CRP in Cancer..................................................................................................... 27 
1.5 
Rationale for the Study ....................................................................................... 30 
1.6 
Potential Risks & Benefits .................................................................................. 31 
1.6.1 
Known Potential Risks ........................................................................... 31 
 
     1.6.2      Known Potential Benefits…………………………………………….31 
 
2 
Study Objectives.................................................................................................. 32 
2.1 
Co-primary Objectives ....................................................................................... 32 
2.2 
Secondary Objectives.......................................................................................... 32 
2.3 
Exploratory Objectives ....................................................................................... 32 
3 
Investigational Plan ............................................................................................ 33 
3.1 
Overall Study Design and Plan: Description .................................................... 33 
3.1.1 
Study Materials ....................................................................................... 34 
3.1.2 
Screening Phase ...................................................................................... 34 
3.1.3 
Treatment Phase ...................................................................................... 35 
3.1.4 
Follow-up Phase ..................................................................................... 35 
3.1.5 
Schedule of Assessments ........................................................................ 36 
4 
Selection of Study Population ............................................................................ 40 
4.1 
Number of Planned Subjects.............................................................................. 40 
4.2 
Inclusion Criteria ................................................................................................ 40 
4.3 
Exclusion Criteria ............................................................................................... 42 
4.4 
Inclusion of Women and Minorities .................................................................. 44 
4.5 
Women of Childbearing Potential ..................................................................... 44 

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4.6 
Removal of Patients from Therapy or Assessments ........................................ 44 
4.7 
Post Study Follow-up .......................................................................................... 45 
4.8 
Withdrawal of Consent....................................................................................... 45 
4.8.1 
Lost to Follow-up ................................................................................... 46 
5 
Investigational Products ..................................................................................... 47 
5.1 
Investigational Products Administered............................................................. 47 
5.1.1 
Investigational Product Tocilizumab  ..................................................... 47 
5.1.2 
Investigational Study Drugs Ipilimumab and Nivolumab ...................... 47 
 
    5.2   
Identity of Investigational Product ..................................................... 48 
 
5.2.1  Formulation and Packaging ........................................................................ 48 
              5.2.2  Drug Storage and Accountability…..…………………………………..48 
              5.2.3  Preparation and Dispensing...……………...…………………………...49 
              5.2.4  Medication Compliance……..…………...……………………………..49 
              5.2.5  Destruction…………..……………….………………………………… 49 
              5.2.6  Administration…..………………………………………………………49 
5.2.7 
Storage and Dispensing .......................................................................... 49 
5.2.8 
Destruction of Study Drugs .................................................................... 50 
5.2.9 
Return of Study Drug .............................................................................. 51 
 
     5.3 
Method of Assigning Subjects to Treatment ...................................... 51 
 
     5.4 
Selection and Timing of Doses in the Study ....................................... 52 
               
     5.5 
Dosing Schedule…………………………………………….…………...…..52 
 
     5.6 
Blinding………………………………………………………………...…….52 
 
     5.7 
Previous and Concomitant Therapy ................................................... 53 
 
5.7.1  Prohibited and/or Restricted Medication/Therapy  ..................................... 53 
5.7.2  Permitted Therapy  ...................................................................................... 53 
              5.7.3  Premedication for Nivolumab or Ipilimumab  
………………………..53 
5.7.4Treatment Compliance .................................................................................. 53 
6 
Study Procedures/Evaluations ........................................................................... 54 
6.1 
Medical History ................................................................................................... 54 
6.2 
Physical Examinations ........................................................................................ 54 
6.3 
Vital Signs ............................................................................................................ 54 
6.4 
Oxygen Saturation by Pulse Oximetry ............................................................. 54 
6.5 
Electrocardiograms............................................................................................. 54 
6.6 
Concomitant Medications .................................................................................. 55 
6.7 
Clinical Laboratory Evaluation ......................................................................... 55 
6.7.1 
Hematology ............................................................................................. 55 
6.7.2 
Clinical Chemistry .................................................................................. 55 

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6.7.3 
Serology .................................................................................................. 55 
6.7.4 
Pregnancy Testing .................................................................................. 55 
6.7.5 
Eastern Cooperative Oncology Group Performance Status .................... 56 
7  Study Endpoints and Assessments ............................................................................... 58 
7.1  Co-Primary Endpoints: ........................................................................................ 58 
7.2  Secondary Endpoints: .  ........................................................................................ 59 
    7.3  Exploratory Endpoints: ……………………………………………………….59 
7.4  Efficacy Endpoints: ............................................................................................... 58 
7.4.1  Efficacy Endpoint Based on Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 ............................................................................ 58 
7.4.2  Efficacy Endpoint Based on Immune-Related Response Criteria 
(irRC) ...................................................................................................... 59 
     
    7.5  Efficacy Variables and Assessments…………………………………60 
               
              7.5.1  Disease Assessments……………………………………………………61 
              7.5.2  Measurable Disease per RECIST 1.1……………………………….....61 
              7.5.3  Nonmeasurable Disease per RECIST 1.1:………………………….....62 
              7.5.4  Methods of Measurements……………………………………………62 
      
   7.6  Date of Progression …………………………………………………..……….63 
   7.7 Pharmacodynamic Biomarker Assessments .......................................................... 62 
   7.8 Biomarker Endpoints .............................................................................................. 62 
     
   7.9 Tissue Specimens ...................................................................................................... 63 
      
   7.10 Exploratory Serum Biomarkers ........................................................................... 64 
      
   7.11 Peripheral Blood Mononuclear Cells (PBMCs) .................................................. 65 
   7.12  Safety Endpoints and Assessments ...................................................................... 65 
         7.12.1  Safety Reviews .......................................................................................... 65 
7.12.2  Dose-limiting Toxicities ........................................................................... 65 
7.12.3  Dose-Delay Criteria .................................................................................. 66 
7.12.4  Criteria to Resume Ipilimumab and/orNivolumab Treatment 
After a Delay ........................................................................................... 68 
7.12.5  Dose Omission Criteria for Nivolumab and Ipilimumab .......................... 68 
7.12.5.1 Adverse Event Management Alogorithms for Immuno-
Oncology Agents  ................................................................................... 69 
              7.12.5.2 Criteria to Resume Treatment ……………………………………70 
7.12.6 Dose Modifications .................................................................................... 70 
7.12.7 Treatment of Tocilizumab, Nivolumab or Ipilimumab-Related 
Infusion Reactions .................................................................................. 70 
7.12.8  Discontinuation Criteria ............................................................................ 71 
7.12.9  Treatment of tocilizumab-Related Toxicities ........................................... 72 
7.12.10 Management of Tocilizumab in Event of Hematological 
Toxicities ................................................................................................ 73 

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8 
Assessment of Safety ........................................................................................... 75 
8.1 
Adverse Events .................................................................................................... 75 
8.2  Serious Adverse Events……………………… .......... …………………………76 
     8.3    Nonserious Adverse Events……………………...…………………………….77          
          8.3.1  Nonserious Adverse Event Collection and Reporting…………..……..…….78 
 
    8.4  Laboratory Test Result Abnormalities………………………………...………..78 
          
          8.4.1  Pregnancy…………………………………………………..……….……….78 
8.5  Reporting of Serious Adverse Events and Unanticipated Problems ................ 78 
    8.6  Investigator reporting:  notifying the study sponsor and Perlmutter  
Cancer Center Clinical Trials Office………………………… .......... …………………80 
     8.7  Investigator reporting: notifying the IRB ……………………………………..81 
 
     8.8  Sponsor reporting:  Notifying BMS……………………………………………83 
 
           8.8.1  Non-serious Adverse Event …………………………………………..…….85 
           8.8.1.1 Non-serious Adverse Event Collection and Reporting……………….……85 
 
    8.9  Sponsor reporting:  Notifying Genentech ……………………………………...85 
 
          8.9.1  Assessment of Adverse Events ………………………………………...……85 
          8.9.2  AEs of Special Interest (AESIs) …………………………………….…..…..86 
          8.9.3  Exchange of SINGLE CASE REPORTS ………………………….………..87 
          8.9.4  Post-Study Adverse Events ………………………………………….…..….89 
          8.9.5  Case Transmission Verification of Single Case Reports ………….………..89 
          8.9.6  Aggregate Reports ……………………………………………………...…...89 
          8.9.7  Other Reports ………………………………………………………….….....90 
          8.9.8  Study Close Out ……………………………………………………………90 
          8.9.9  Queries ……………………………………………………………………..90 
          8.9.10 Safety Crisis Management ………………………………………………..90 
 
    8.10    Overdose ……………………………………………………………..……….91 
 
    8.11    Potential Drug-Induced Liver Injury (DILI) ………………………………92 
 
    8.12     Other Safety Consideration …………………………………………………92 
 
9 
Clinical Monitoring ............................................................................................. 91 
9.1  Data Monitoring Committee and Other External Committees ........................ 91 
10 
Statistical Methods .............................................................................................. 92 
10.1 Sample Size Considerations ............................................................................... 92 
10.2 Analysis Schedule ................................................................................................ 93 
10.2.1 
Interim Analysis ...................................................................................... 93 
10.2.2 
Final Analysis ......................................................................................... 93 
10.3 Statistical Methods .............................................................................................. 93 
10.3.1 
General Methods ..................................................................................... 93 

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10.3.2 
Disposition of Patients ............................................................................ 94 
10.3.3 
Demographics and Baseline Characteristics ........................................... 94 
10.3.4 
Extent of Exposure ................................................................................. 94 
10.3.5 
Prior and Concomitant Medications ....................................................... 94 
10.3.6 
Safety Analysis ....................................................................................... 94 
10.3.7 
Efficacy Analysis .................................................................................... 95 
10.3.8 
Pharmacodynamics Biomarker Analysis ................................................ 96 
11 
Quality Assurance and Quality Control ........................................................... 99 
11.1 Audit and Inspection........................................................................................... 99 
11.2 Source Documentation........................................................................................ 99 
11.3 Monitoring ......................................................................................................... 100 
11.3.1 Data Monitoring Committee……………………………………….102 
11.4 Data Management and Coding ........................................................................ 102 
11.5 
Monitoring of Other Participating 
Institutions ........................................................................................................ 10212
 ....................................................................................................................... Records and 
Supplies .............................................................................................................. 103 
12.1 Study Drug Records .......................................................................................... 103 
12.2 Records Retention ............................................................................................. 103 
12.3 Financing and Insurance .................................................................................. 103 
13 
Ethics .................................................................................................................. 104 
13.1 Institutional Review Board/Independent Ethics Committee ........................ 104 
13.2 Compliance with the Protocol and Protocol Revisions .................................. 104 
13.3 Regulatory Authorities ..................................................................................... 104 
13.4 Ethical Conduct of the Study ........................................................................... 105 
13.5 Informed Consent Process ............................................................................... 105 
13.5.1 
Consent/Assent and Other Informational Documents Provided 
to Participants ....................................................................................... 105 
  
13.5.2 
Consent Procedures and Documentation .............................................. 105 
 
13.5.3     Informed Consent................................................................................. 105 
13.6 Subject Recruitment ......................................................................................... 106 
13.6.1 
Documentation of Consent ................................................................... 107 
13.7 Registration Procedures ................................................................................... 107 
13.7.1  General Guidelines ……………………… ............................................. 108 
13.7.2  Multi-Site Surveillance ........................................................................... 107 
13.7.3  Patient Registrations at Other Participating Institutions ......................... 108 

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13.8 Patient Confidentiality...................................................................................... 109 
14 
Reporting and Publication, including Archiving ........................................... 110 
14.1 Clinical Study Report and Publications .......................................................... 110 
15 
References .......................................................................................................... 111 
16 
Appendices ......................................................................................................... 118 
16.1 RECIST Version 1.1 Quick Reference ............................................................ 118 
16.2 Appendix 2: Immune-related Response Criteria (irRC) ............................... 123 
 

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List of Tables 
Table 1: 
Regimen for Tocilizumab with Ipilimumab  and Nivolumab During Induction…………..….18 
Table 2:       Schedule of Assessments……………………………………………………………………...37 
Table 3           Non-investigational Drugs (Standard of Care)………………………………………………..47 
Table 4:          Dosing Schedule………………………………………………………………………………52 
Table5: 
 Eastern Cooperative Oncology Group Performance Status Scale……………………………58 
Table 6: 
 Tocilizumab Dose Modifications:  Non-Hematologic Toxicities ……………………………74 
Table 7:           Tocilizumab Dose Modifications: Hematological Toxicities……………………....................75 
 
 
 
  

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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
AE 
adverse event 
AJCC 
American Joint Committee on Cancer 
alloMLC 
allogeneic mixed lymphocyte culture 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATP 
as-treated population 
AUC 
area under the concentration-time curve 
BOR 
best overall response 
BRAF 
B-Raf proto-oncogene, serine/threonine kinase. A human gene 
that makes a protein called B-Raf. 
CD 
clusters of differentiation 
CI 
confidence interval 
cGCP 
current Good Clinical Practice 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form, paper or electronic 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T lymphocyte associated antigen-4 
CTO 
Clinical Trials Office 
DC 
Dendritic cell 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end-of-treatment 
EOMES 
eomesodermin gene 
FDA 
Food and Drug Administration 
FOXP 
forkhead box P gene 
FSH 
follicle stimulating hormone 
FU 
follow-up 
GLP 
Good Laboratory Practices 
hERG 
human ether-a-Go-go related gene 

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HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
ICOS 
inducible T-cell co-stimulator gene 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IHC 
immunohistochemistry 
IL 
interleukin 
IMAE 
immune-mediated adverse events 
IMP 
investigational medicinal product 
I-O 
immuno-oncology 
IP 
Investigational product 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
irBOR 
immune-related best overall response 
irCR 
immune-related complete response 
irPD 
immune-related progressive disease 
irPFS 
immune-related progression-free survival 
irPR 
immune-related partial response 
irRC 
immune-related response criteria 
irRR 
immune-related response rate 
irSD 
immune-related stable disease 
irSPD 
immune related sum of products of diameters 
irUN 
immune-related unknown response 
IV 
intravenous(ly) 
LD 
longest diameter 
LFT 
liver function test 
MDSC 
Myeloid derived suppressor cell 
MHC 
major histocompatibility complex 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
multiple myeloma 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MTD 
maximum tolerated dose 
mTPI 
modified toxicity probability interval 
N 
number of patients or observations 
N/A 
not applicable 
NCI 
National Cancer Institute 

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NOAEL 
no observed adverse effect level 
NOEL 
no observed effect level 
NK 
natural killer 
NSCLC 
non-small cell lung cancer 
NYU 
New York University 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PCC 
Perlmutter Cancer Center 
PD 
progressive disease 
PD-1 
programmed cell death protein 
PD-L1 
programmed death ligand-1 
PD-L2 
programmed death ligand-2 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PO 
orally 
PR 
partial response 
pT 
Probability of toxicity 
QD 
once daily 
ORR 
objective response rate 
qRT-PCR 
quantitative real-time polymerase chain reaction 
QTc 
corrected QT interval  
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
RT 
radiotherapy  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SFU 
survivor follow-up 
SPD 
summary of products of diameters 
SRC 
Safety Review Committee 
Th1 
Type 1 T helper cells 
TIL 
tumor infiltrating lymphocytes 
TNF 
tumor necrosis factor 
TPI 
toxicity probability interval 
Tregs 
regulatory T cells 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
US 
Unites States 
WBC 
white blood cell 

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WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
WT 
wild-type 

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SYNOPSIS 
 
Protocol Number 
S19-00008 
Title: 
A Phase II Study of the Interleukin-6 Receptor Inhibitor Tocilizumab in 
Combination with Ipilimumab and Nivolumab in Patients with Unresectable 
Stage III or Stage IV Melanoma 
Investigational 
Product: 
Tocilizumab 
Study Center: 
Four study centers in the United States:  NYU-Langone Health.  New York 
City, Dana Farber Cancer Center and Massachussetts General Hospital in 
Boston and The Angeles Clinic, Los Angeles 
Phase: 
II 
Indication: 
Unresectable Stage III or Stage IV Melanoma 
Objectives: 
Primary Objectives: 
• 
Determine the safety, tolerability, and rate of grades 3-5 immune-
related adverse events up to 6 months from therapy initiation when 
tocilizumab is administered every 6 weeks for 5 doses from day 1, 
cycle 1 in combination with a regimen of ipilimumab at 1 mg/kg and 
nivolumab at 3 mg/kg every 3 weeks for 4 doses each during a 12-
week induction period, then administered with nivolumab at 240 mg 
flat dose every 2 weeks up to week 24, and nivolumab alone in 
maintenance  after week 24 at 480 mg every 4 weeks for up to 2 years 
in patients with unresectable Stage III/Stage IV melanoma. 
• 
Determine the preliminary antitumor activity defined by overall 
response rate (CR + PR at week 24) of tocilizumab administered in 
combination with ipilimumab and nivolumab to patients with 
unresectable Stage III or Stage IV melanoma. 
 
 
Secondary Objective 
• 
Determine the progression-free survival of tocilizumab administered in 
combination with ipilimumab and nivolumab to patients with 
unresectable Stage III or Stage IV melanoma. 
• 
Determine the overall survival of tocilizumab administered in 
combination with ipilimumab and nivolumab to patients with 
unresectable Stage III or Stage IV melanoma. 
 
 
Exploratory Objectives: 
• 
Determine the pharmacodynamic effect of the 3-drug combination 
(tocilizumab, ipilimumab, nivolumab) dose regimen on biomarkers in 
peripheral blood samples and tumor biopsy specimens. 
 
Study Design: 
This is a Phase II, open-label, single arm study. The study will consist of an 
assessment of the safety and tolerability of tocilizumab administered 
concurrently at 4 mg/kg every 6 weeks for 5 doses in combination with 
ipilimumab and nivolumab for four induction doses to week 12, then 

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maintenance nivolumab alone up to two years to patients with advanced 
melanoma. Treatment will be divided into induction and maintenance phases.  
It is anticipated that this clinical study will inform the use of this 3-drug 
combination for further phase II and/or phase III clinical testing. The 
trial will include an assessment of the pharmacodynamic activity of 
tocilizumab administered in combination with ipilimumab and 
nivolumab. A study schematic is presented below: 
Figure 1:  Study Schematic 
Figure 1:  Study Schematic 
 
Abbreviations: C = cycle, D= day; FU = follow-up; Ipi = ipilimumab; Nivo = nivolumab; PD = progressive 
disease;. 
 
Each treatment cycle will be 42 days (6 weeks) during the induction 
phase, and 84 days (12 weeks) during the maintenance phase. 
Tocilizumab will be administered (IV) every 42 days at 4 mg/kg for 
each 42-day induction treatment cycle. On days administered in 
combination, nivolumab will be administered first at a dose of 3 mg/kg, 
followed by ipilimumab at 1 mg/kg, and immediately followed by 
tocilizumab. Nivolumab and ipilimumab will be administered 
intravenously (IV) each over 30 minutes, with a 30-minute rest period 
between infusions on Days 1 and 22 of each 42-day induction treatment 
cycle. The induction phase will last for 2 treatment cycles. During the 
maintenance phase, tocilizumab will be administered IV every 42 days 
during the first 84-day maintenance treatment cycle only up to week 24. 
Nivolumab will continue to be administered at 240 mg flat dose every 
2 weeks (i.e., at Days 1, 15, 29, 43, 57, and 71 of each 84-day treatment 
cycle up week 24, then after week 24 at a dose of 480 mg every 4 weeks 
for up to two years). On days administered in combination, nivolumab 
will be administered first, followed by tocilizumab. Patients will 
continue maintenance treatment with their tocilizumab and nivolumab 
dose regimen for up to week 24, then nivolumab alone to 2 years or until 
progression of disease, discontinuation due to toxicity, withdrawal of 
consent, or any other reason as specified per protocol. 
A total of 67 patients in this trial will allow a sufficient number of patients to 
provide a preliminary assessment of rates of grades 3-5 irAEs and overall 
response rates (ORR) as co-primary endpoints.co-primary endpoints. 
Enrollment will proceed with administration of tocilizumab in combination 
with ipilimumab and nivolumab as described in Table 1: 
Table 1. Regimen for Tocilizumab with Ipilimumab and Nivolumab 
During Induction 
1
FU Visit 1 
30 + 7 
Days 
after EOT 
FU Visit 2 
90 + 7 
Days after 
FU Visit 1 
Survival FU 
Visit3 
months + 
14 days 
after FU 2 

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Dose 
Cohort 
Tocilizumab 
Dose 
Ipilimumab Dose 
Nivolumab Dose 
2 
6 mg/kg IV 
1 mg/kg IV 
3 mg/kg IV 
1 
4 mg/kg IV  
1 mg/kg IV 
3 mg/kg IV 
-1 
2 mg/kg IV 
1 mg/kg IV 
3 mg/kg IV 
If Cohort 1 shows unacceptable toxicity in the first 12 patients, defined 
as a 50% rate of drug related DLTs, then Cohort -1 will be tested as 
indicated in this study. Decisions regarding dose de-escalation will be 
guided by the incidence of drug-related DLTs occurring within 42 days 
(6 weeks; through Day 42 of induction cycle 1) of initiation of study 
therapy. This observation interval is based upon inclusion of the known 
median times to onset of common immune-related adverse events 
(irAEs) attributed to ipilimumab and nivolumab and allows for a 
substantial amount of time for unexpected toxicities with the combined 
administration of tocilizumab with ipilimumab and nivolumab to 
emerge. Patients who do not complete the 42 day DLT-observation 
period for reasons other than an adverse event will be replaced.  As 
described below, if at the conclusion of stage I both the efficacy and 
toxicity endpoints have not been met, i.e., we have seen neither a 
reduction in the toxicity (irAE of grades 3-5  ≥6/18) nor an increase in 
efficacy ( responses≤10/18), then we will stop early and consult with 
IRB  and/or FDA.    
 
Safety Review: 
All available clinical and laboratory data, and the nature, time of onset, 
and time to resolution of any DLTs observed will be reviewed to 
determine whether an alternate dose schedule should be examined after 
consultation between the Investigators, the FDA and BMS, if needed. If 
agreed upon, the alternate schedule will be identified by a protocol 
amendment. 
The data will be reviewed by the NYU-Perlmutter DSMC which will 
also review all safety data, specifically to review all Grade 3 or greater 
irAEs, or grade 2 irAEs that do not resolve to grade 1 or less with 
therapy. 
Definition of Dose-Limiting Toxicity 
For the purpose of guiding dose escalation decision making, 
hematologic and non-hematologic DLTs will be defined separately and 
will be determined based on the incidence, severity, and duration of 
study drug-related AEs occurring within 42 days (6 weeks; through 
Day 42 of induction cycle 1) of initiation of study therapy.  The dose 
escalation decision for Tocilizumab will be determined by an 
assessment of whether the addition of tocilizumab has potentially 
increased the toxicity associated with ipilimumab and nivolumab or 
potentially decreased the response rate of the regimen. 
 

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The following AEs, if assessed to be related to tocilizumab, will be considered 
DLTs: 
Hematologic toxicity: 
• Grade 4 neutropenia (absolute neutrophil count [ANC] 
< 500/μL) lasting > 7 days. If neutropenia is attributed to 
tocilizumab, ANC is to be repeated on Day 6 to determine if it is 
a DLT 
• Febrile neutropenia (ANC < 1,000/μL with a single temperature 
> 38.3°C [101.0°F] or 38.0°C [100.4°F] for > 1 hour) 
• Grade 4 thrombocytopenia (platelet count < 25,000/μL)  
• Grade 3 thrombocytopenia (platelet count 25,000/μL to 
50,000/μL) with clinically important bleeding. 
Non-hematologic toxicity: 
The etiology of all other Grade 3 or Grade 4 nonhematologic toxicities 
will be indistinguishable from immune related toxicities. 
 
Immune-related toxicity: 
 
All Grade 3 or Grade 4 immune-related toxicities will be considered as 
potential DLTs. Immune-related toxicities among patients treated with 
nivolumab and ipilimumab have clustered among skin, gastrointestinal, 
endocrine, and liver-related events as follows: 
 
• Skin: alopecia, dry skin, hyperhidrosis, night sweats, pruritus, 
rash/desquamation, toxic epidermal necrolysis, urticaria, vitiligo. 
• Gastrointestinal: abdominal discomfort or pain, anal ulcer, colitis 
(including ulcerative, hemorrhagic, ischemic, and megacolon), 
constipation, cramping, diarrhea (including hemorrhagic), 
diverticulitis/diverticulum, duodenitis, dyspepsia, dysphagia, 
enteritis, esophagitis, gastritis (including erosive), 
gastrointestinal hemorrhage (including rectal), hematochezia, 
ileitis, ileus, intestinal obstruction, intestinal perforation 
(including small and large intestines), melena, nausea, 
pancreatitis, peritonitis, stomatitis (including aphthous), 
vomiting, vasculitis gastrointestinal. 
• Endocrine: adrenal insufficiency (including Addison disease), 
glucose tolerance impaired, hyperthyroidism hypogonadism, 
hypophysitis/hypopituitarism (autoimmune), hypothyroidism, 
pituitary enlargement, thyroiditis (autoimmune). 
• Liver: hepatitis, jaundice. 
 

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Other treatment-related asymptomatic Grade 3 and Grade 4 laboratory 
investigations, excluding cardiac function tests, may be evaluated by the 
SRC to determine whether dose cohorts should be expanded. 
 
 
Number of 
Patients: 
 
Up to 67 patients are expected to be treated for the evaluation of 
immune related toxicity at the selected dose.  If the first dose level is 
modified based on the first 12 patient evaluation, then a max of 79 
patients would be treated in total. 
 
Treatment: 
 
Tocilizumab is supplied for intravenous injection: as 80 mg/4 mL (20 mg/mL), 
200 mg/10 mL (20 mg/mL), 400 mg/20 mL (20 mg/mL) in single-dose vials 
for further dilution. Nivolumab is available as sterile dose formulations of 
10 mg/mL and will be supplied to sites in 100mg/10mL vials to be 
administered IV as an infusion over 30 minutes. Ipilimumab is available as a 
sterile dose formulation at 5 mg/mL and will be administered IV as an infusion 
over 30 minutes. Nivolumab and ipilimumab are not to be administered as an 
IV push or bolus injection. On days administered in combination, nivolumab 
will be administered first at a dose of 3 mg/kg, followed by ipilimumab at 
1 mg/kg with a 30-minute rest period between infusions immediately followed 
by tocilizumab at 4 mg/kg. 
Study Duration: 
 
The total duration of the study from the first dose of study drug to final 
analysis of toxicity and tolerability is expected to be 36 months.  Survival will 
be assessed for 3 years beyond a maximum of 2 years of treatment, i.e., a total 
of up to 5 years.  Patients may discontinue from treatment because of disease 
progression, unacceptable toxicity, withdrawal of consent, or at the discretion 
of the Investigator. The last visit for each patient will be defined as the follow-
up visit which is no less than 90 days after the patient’s end-of-treatment visit. 
The last visit is either 90 days after the last dose or whenever a study 
drug-related toxicity has resolved, stabilized, or been deemed reversible, 
whichever is latest. The end of the trial will occur on the last visit of the last 
patient. 
 
Study Population: 
 
Inclusion Criteria:  
1. Patients must have signed and dated an Institutional Review 
Board/Independent Ethics Committee -approved written informed consent 
form in accordance with regulatory and institutional guidelines. This must 
be obtained before the performance of any protocol-related procedures that 
are not part of normal patient care 
2. Patients must be willing and able to comply with scheduled visits, 
treatment schedule, laboratory tests, tumor biopsies, and other 
requirements of the study. 
3. All patients must be either Stage IIIb/c/d or Stage IV according to the 
American Joint Committee on Cancer (AJCC) (8th edition) and have 
histologically-confirmed melanoma that is felt to be surgically 
unresectable in order to be eligible. Please refer to the AJCC Cancer 
Staging Manual, 8th edition for a description of tumor, lymph node, 
metastasis and staging.  

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• 
All melanomas, except ocular/uveal melanoma, regardless of primary 
site of disease will be allowed; mucosal melanomas are eligible. 
• 
Patients must not have received prior anticancer treatment for 
metastatic disease (for example, but not limited to, systemic, local, 
radiation, radiopharmaceutical).  
o Exceptions: Surgery for melanoma and/or post-resection brain 
radiotherapy (RT) if central nervous system (CNS) metastases 
and local radiation for locoregional disease and/or prior 
treatment with adjuvant nivolumab, dabrafenib and trametinib, 
pembrolizumab, interferon (IFN) or ipilimumab (IPI) (as 
described in Exclusion Criterion 8). 
• 
All patients must have their disease status documented by a complete 
physical examination and imaging studies within 4 weeks prior to the 
first dose of study drug. Imaging studies must include computerized 
tomography (CT) scan of chest, abdomen, pelvis, and all known sites 
of resected disease in the setting of Stage IIIb/c/d or Stage IV disease, 
and brain magnetic resonance imaging ([MRI]; brain CT is allowable 
if MRI is contraindicated).  
• 
The complete set of baseline radiographic images must be available 
before treatment initiation. 
Exclusion Criteria: 
1. Patients with carcinomatosis meningitis or current ocular/uveal melanoma 
are excluded. 
2. Patients with previous non-melanoma malignancies are excluded unless a 
complete resection or remission was achieved at least 2 years prior to study 
entry and no additional therapy is required or anticipated to be required 
during the study period (exceptions include, but are not limited to, non-
melanoma skin cancers, in situ bladder cancer, in situ gastric cancer or 
gastrointestinal stromal tumor, in situ colon cancers, in situ cervical 
cancers/dysplasia, or breast carcinoma in situ). 
3. Patients with active, known, or suspected autoimmune disease. Patients with 
type I diabetes mellitus, residual hypothyroidism due to autoimmune 
thyroiditis only requiring hormone replacement, or skin disorders (such as 
vitiligo, psoriasis, or alopecia) not requiring systemic treatment are 
permitted to enroll. For any cases of uncertainty, it is recommended that the 
Principal Investigator be consulted prior to signing informed consent. 
4. Patients with a condition requiring systemic treatment with either 
corticosteroids (> 10 mg daily prednisone or equivalent) or other 
immunosuppressive medications within 14 days of study drug 
administration. Inhaled or topical steroids are permitted in the absence of 
active autoimmune disease. 
 
 
 
Endpoint 
Co-primary Endpoints: 
• 
To estimate the rate of grades 3-5 irAEs with tocilizumab at 4 mg/kg for 5 
doses over 24 weeks administered in combination with ipilimumab at 1 
mg/kg and nivolumab at 3 mg/kg every 3 weeks for 4 doses each during a 

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12-week induction period, then administered for up to 24 weeks with 
nivolumab at 240 mg fixed dose every 2 weeks up to week 24, then after 
week 24 at 480 mg flat dose every 4 weeks thereafter in maintenance for up 
to 2 years in patients with unresectable Stage III/Stage IV melanoma. 
Safety will be measured by physical examinations, vital sign measurements, 
ECOG performance status evaluations, AE assessments, laboratory testing, 
ECGs, oxygen saturation, and concomitant medications. 
• 
Tumor response of study treatment will be measured by Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1 and irRC. RECIST 1.1 
will be used for response, and irRC will only be used to decide if a patient 
may be treated beyond RECIST progression. 
 
Secondary Endpoints: 
Progression-free Survival 
 
RECIST 1.1 efficacy endpoints include best overall response rate, disease 
control rate, progression-free survival, duration of response, and duration of 
disease control. 
 
irRC efficacy endpoints include immune-related best overall response rate, 
immune-related response rate, immune-related disease control rate, immune-
related progression-free survival, duration of immune-related overall response, 
and duration of immune-related disease control. 
 
Overall survival 
 
Exploratory Endpoints: 
 
• 
Biomarkers will be measured in peripheral blood and in tumor specimens 
to examine associations with clinical endpoints of response, PFS and 
toxicity. 
Assessments 
Efficacy Assessments: Overall response rate (CR + PR at week 24) will be 
determined for all subjects by RECIST 1.1 as a co-primary endpoint to 
evaluate efficacy along with irRC to decide if a patient with RECIST 
progression could continue therapy. If there is RECIST progression but the 
investigator feels that patients may benefit by further therapy then there must 
be PR or SD by irRC.  Assessments of tumor status will be made during 
screening and at week 12 during treatment, and subsequently every 12 weeks. 
Tumor assessments at the end-of-treatment or 90-day follow-up visit will be 
performed only if not assessed within the prior 12 weeks. The individual 
subject’s overall response rate (ORR) by 24 weeks will be assessed, and 
progression free survival (PFS) will also be calculated as a secondary endpoint. 
Other endpoints are disease control defined as outcome of complete response, 
partial response or stable disease by week 24. Duration of response and 
duration of disease control will also be calculated, as will progression-free and 
overall survival.  
Safety Assessments: All patients who receive any study drug therapy will be 
evaluated for safety and response. Safety assessments will be based on medical 
review of AE reports and the results of vital sign measurements, oxygen 
saturation, physical examinations, clinical laboratory tests, concomitant 
mediations, and ECOG performance status.  

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Adverse events will be categorized using the most current version of Medical 
Dictionary for Regulatory Activities (MedDRA), and AEs and laboratory tests 
will be graded using National Cancer Institute Common Terminology Criteria 
for Adverse Events version 5.0. Hepatic AEs (AST, ALT, total bilirubin) will 
also be recorded relative to ULN. Immune-related adverse experiences among 
treated patients will be specifically assessed as well. 
Biomarker Measures: Pharmacodynamic effects will be assessed for 
measures of 1) absolute lymphocyte count; 2) serum cytokine and other 
analyte changes; 3) assessment of peripheral T-cell subsets, their 
activation status, cytokine production allogeneic mixed lymphocyte 
culture (alloMLC) assay changes; and 4) gene expression in peripheral 
blood. Pharmacodynamic effects will also be assessed for tumor-based 
biomarker measures of 1) infiltration of immune cells and release of 
immune-regulatory factors, and 2) intra-tumoral gene expression 
changes of immune cells. 
 
Statistical Analysis: 
 
Sample Size Considerations: 
The first 12 patients at the initial dose level will be evaluated for DLTs. 
Unacceptable toxicity will be defined by a DLT rate of ≥50%.  If we observe 
≥6 DLTs in these first 12 patients, we reject the null hypothesis that the DLT 
rate is <50% (one sided α=0.05, power=80%).  If we do not reject the null 
hypothesis, the current dosing continues with 6 additional patients up to 18 
patients (which count as the first stage of the optimal 2-stage Simon design). 
There will be no adjustment to the operating characteristics of the optimal 2-
stage Simon design. 
 
To evaluate the co-primary endpoint of the rate of grades 3-5 treatment related 
immune-related adverse events, a two-stage Simon Optimal design will be 
used. With a total of 67 patients in two stages, (Stage 1: 12+6 patients, Stage 2: 
49 patients) we can detect a reduction in the rate of the primary toxicity 
endpoint from 35% to 20% in grades 3-5 treatment related irAEs, with alpha of 
0.05 and power of 80%.  
With the planned 67 patients for the co-primary toxicity evaluation of immune-
related adverse events, we can simultaneously evaluate the co-primary efficacy 
endpoint evaluated by overall response rate (ORR) at 6 months over the 18 
months of treatment.  Using a Simon 2-stage optimal and minimax design, we 
can test the null hypothesis that the ORR rate at 24 weeks is less than or equal 
to 50% versus the alternative that it is 70% or greater with a maximum of 67 
patients with alpha of 0.045 and power of 0.85. 
 
The evaluation of stage 1 will occur when the first 18 patients could have been 
observed for the 6-month period following entry. If 6 or more of the first 18 
patients in stage 1 experience a grade 3-5 treatment related immune-related 
adverse event, the rate of toxicity would be considered unacceptable (irAE 
rate>=35%). 
If fewer than 6 patients experience a treatment related immune-related adverse 
event, the rate of toxicity would be considered acceptable (irAE<=20%).  
With an evaluation of the first 18 patients entered on study (who would 
complete the study before the end of study year 2) in stage 1, if we observe 10 

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or fewer responses, the response rate would be considered unacceptable 
(ORR<=50%).  Otherwise, if we observe more than 10 responses, the response 
rate would be considered acceptable (ORR>=70%).   
 
If both toxicity rate and response rate are acceptable - continue to complete 
stage 2 with up to 67 patients. 
 
If toxicity rate is acceptable, and response rate is unacceptable - increase dose 
to level 2 (tocilizumab 6 mg/kg every 6 weeks) and restart DLT evaluation 
with 12 patients.  
 
If toxicity rate is unacceptable (due to irAE rate of grades 3-5 >=35% felt due 
to tocilizumab), and response rate - decrease dose level to -1(tocilizumab 2 
mg/kg every 6 weeks) and restart DLT evaluation with 12 patients.  
 
If toxicity rate is unacceptable (due to irAE rate of grades 3-5 >=35% felt due 
to IPI and/or NIVO), and response rate is acceptable - increase dose level to 2 
(tocilizumab 6 mg/kg every 6 weeks) and restart DLT evaluation with 12 
patients.  
 
If both toxicity rate and response rate are unacceptable - stop early and consult 
with IRB  and/or FDA.   
 
At the end of Stage 2, if there are 39 or fewer responses out of the total of 67 
patients, the regimen would be considered unsuccessful. Similarly, if at the end 
of stage 2, there are 19 or more treatment related irAE, the trial would be 
considered unsuccessful to have met its objective of reducing the toxicity rate 
to 20% or less.  
 
 
 

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1 
INTRODUCTION 
Tocilizumab is a FDA approved inhibitor of the receptor for the cytokine IL-6, currently 
approved for the treatment of rheumatoid arthritis, giant cell arteritis and cytokine release 
syndrome from the use of CAR-T cells. It is also approved by the FDA for the treatment 
of polyarticular juvenile idiopathic arthritis (PJIA) and systemic juvenile idiopathic 
arthritis (SJIA). 
The purpose of this study is to evaluate the safety profile, tolerability, efficacy and 
immunoregulatory (pharmacodynamic) activity of tocilizumab administered in 
combination with ipilimumab (cytotoxic T lymphocyte associated antigen-4 [CTLA4] 
blocking antibody) and nivolumab (anti-programmed cell death protein-1 [PD-1] 
antibody) to patients with unresectable stage III or stage IV melanoma.  
1.1 
Nivolumab and Ipilimumab in Melanoma 
Currently, the front-line and second-line standard of care treatments for unresectable 
Stage III/IV patients in the United States (US) include immunotherapies such as the PD-1 
blocking antibodies nivolumab and pembrolizumab, the CTLA-4 blocking antibody 
ipilimumab, and the combination of ipilimumab combined with nivolumab. For patients 
whose tumors harbor a V600 mutation in the BRAF gene, vemurafenib, dabrafenib, or 
trametinib have been approved as single agents (Chapman, P et al 2011, Flaherty, K et al 
2012), and the combination of dabrafenib with trametinib is the most commonly used 
regimen in that mutated population in the US and the European Union (Flaherty, K et al 
2012, Ascierto, P et al 2015). The combination of ipilimumab and nivolumab at 1 mg/kg 
and 3 mg/kg, respectively, as induction therapy for 4 doses every 3 weeks followed by 
nivolumab alone as maintenance therapy at 3 mg/kg every 2 weeks results in high 
response rates and prolonged duration of remissions in the Checkmate-067 study 
(Wolchok, J et al 2013, Postow, M et al 2013, Larkin, J et al 2015).  
Ipilimumab at 3 mg/kg or 10 mg/kg has shown a survival benefit in two Phase 3 
randomized clinical trials in the advanced melanoma setting (Hodi et al, 2010, and Robert 
et al 2011), and in the U.S., it is used as a second line therapy, particularly in BRAF wild-
type (WT) patients with unresectable metastatic disease.  Recent data from 2018 ESMO 
suggested that ipilimumab and nivolumab continued to have superior progression-free and 
overall survival with over 4 years of follow-up in the Checkmate-067 study, with an 
absolute survival advantage of 7 percentage points, and an estimated median overall 
survival for the combination of nearly 5 years (Hodi FS et al 2018).  
Nivolumab has shown a survival benefit in treatment naive patients with BRAF WT 
metastatic melanoma in a Phase 3, randomized clinical trial (Robert C et al 2014). In the 
US, it is increasingly used as a front-line regimen, as is pembrolizumab, the other US 
Food and Drug Administration (FDA)-approved PD-1 blocking antibody, in BRAF WT, 
but also in BRAF mutated patients (Robert C et al 2015). 
With the recent approval of the combination of nivolumab and ipilimumab in previously 
untreated BRAF WT melanoma, that combination regimen may replace single agent PD-1 
blocking antibodies as the treatment of choice for front line melanoma treatment in a 
significant proportion of patients. In the current study, we propose to build upon the 
combination regimen by adding a interleukin-6 receptor blocking antibody tocilizumab at 

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doses that are likely to be well tolerated, with a dose of nivolumab at 3 mg/kg, the 
approved dose as monotherapy in melanoma, and a reduced dose of ipilimumab at 1 
mg/kg during the 4-dose induction regimen to reduce the potential toxicity of the 
combination regimen observed with the approved doses of 3 mg/kg of ipilimumab and 1 
mg/kg nivolumab during the induction phase. Maintenance dosing of nivolumab when 
administered with Tocilizumab will be at a fixed dose of 240 mg every 2 weeks.  
At the recent 2018 ESMO meeting, results were reported from the Checkmate-511 clinical 
trial of 1 mg/kg of ipilimumab and 3 mg/kg nivolumab during the induction phase 
compared with the approved doses of 3 mg/kg of ipilimumab and 1 mg/kg nivolumab 
during the induction phase administered for up to two years (Lebbe, C et al ESMO 2018).  
The curves of progression-free and overall survival were basically overlapping at a median 
follow up of 15 months.  The incidence of grade 3-4 immune related adverse events was 
48% for the standard regimen versus 33% for the “flipped dose” regimen and the rate of 
stopping treatment for toxicity was 33% versus 23%, suggesting that the regimen to be 
used in the current trial will be less toxic and just as effective as the standard dose of 
ipilimumab and nivolumab during induction therapy. 
1.2 
Interleukin-6 and Cancer 
 IL-6 is a glycosylated polypeptide chain having a molecular weight of nearly 25 kDa, 
depending on the glycosylation and the species. It has a characteristic structure made up 
of four long α-helices arranged in an up–up–down–down topology (Scheller J, et al 
2011). It was first discovered as a B cell differentiation factor (BSF-2) which induces the 
maturation of B cells into antibody-producing cells (Hirano, T et al, 1985). Besides its 
role in immune regulation, it plays an important role in the maintenance of hepatocytes, 
haematopoietic progenitor cells, the skeleton, the placenta, the cardiovascular system 
and the endocrine as well as nervous systems. In the mouse haematopoietic system, IL-6 
induces the expansion of progenitor cells by stimulating cells from the resting stage to 
enter the G1 phase (Kishimoto, T et al, 1995). IL-6 also supports various physiological 
functions by acting as a hepatocyte stimulatory factor and by inducing the acute-phase 
protein synthesis. It is also known to stimulate osteoclast formation, induce bone 
resorption and is responsible for neural differentiation (Wunderlich, F et al 2010). IL-6 
supports the survival of cholinergic neurons, induces adrenocorticotropic hormone 
synthesis, and, in placenta, causes the secretion of chorionic gonadotropin from 
trophoblasts (Kishimoto, T et al 1995). IL-6 also plays a very important role in 
metabolism. 
 
IL-6 binds to the IL-6 receptor (IL-6R) on the plasma membrane, and the resultant IL-
6/IL-6R complex associates with gp130 and causes gp130 homodimerization to form an 
activated IL-6 receptor complex, which is a hexameric structure consisting of two 
molecules each of IL-6, IL-6R and gp130 (Taga, T et al 1996). The binding of IL-6 to 
IL-6R occurs at three distinct receptor-binding sites of IL-6R and gp130. However, the 
Ig-like domain of the human IL-6R is not involved in the direct binding of IL-6 [28]. 
Upon binding to the receptor and gp130, IL-6 induces various functions by activating 
cell signalling events (Mihara, M et al 2012). IL-6 triggers signal transduction via two 
forms of IL-6R: one a transmembrane 80-kDa receptor with a short cytoplasmic domain 
(mbIL-6R, also known as IL-6Rα, gp80 or CD126) and the other a small, extracellular, 
secretory soluble receptor (sIL-6R) (Hibi, M et al 1990). Classical IL-6 signaling, which 

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is the predominant form of IL-6 signaling, requires membrane-bound IL-6R (mbIL-6R) 
and is restricted to hepatocytes, some epithelial cells and certain leukocytes (Taga, T et 
al 1996).  IL-6R contains a very short cytosolic domain that lacks the major potential 
motifs for transduction of intracellular cell signaling. However, gp130 (also known as 
IL-6Rβ or CD130) in the same hexameric complex is rich in all these potential motifs 
required for intracellular signaling, such as SHP-2 domain and YXXQ motif for 
JAK/STAT signaling. Upon binding with IL-6/IL-6R, the dimerization of gp130 leads to 
the activation of associated cytoplasmic tyrosine kinases, resulting in the 
phosphorylation of various transcription factors (Mihara, M et al 2012). 
Elevated levels of IL‐6 have been observed in patients with various types of cancer such as 
renal cell cancer (Blay, J et al 1997), melanoma (Rossi, J et al 2010), ovarian, 
(Luitgendorf, S et al 2008), colorectal, (Knupfer, H et al 2010) and head and neck cancer, 
(Tsukamoto, H et al 2017) or in patients with cachexia or wasting syndrome (Blay, J et al 
1997).  Elevated levels of IL‐6 are inversely proportional to survival rates of cancer 
patients (Hoejberg L et al 2012, Dijkgraaf, E et al 2015). IL‐6 signals to tumor cells 
through at least three major signaling pathways: JAK2/STAT3, Ras/MAPK, and PI3K/Akt 
cascades, which are attributed to expansion and survival of tumor cells, neo‐angiogenesis, 
and inflammation (Ara, T et al 2013, Lesina, M et al 2011). 
IL‐6 exerts multiple effects not only on tumor cells, in which its action is mediated in 
autocrine and paracrine ways (Dijkgraaf, E et al 2015, Ara, T et al 2013, Lesina, M et al 
2011) but can be secreted from myeloid cells such as macrophages (Lesina, M et al 2011), 
DC, and MDSC, and other tumor‐associated stroma such as cancer‐associated 
fibroblasts, endothelial, or senescent cells.  IL6 is felt to be a major contributor to the 
dynamic cross-talk between tumor cells and activated fibroblasts in the tumor 
microenvironment (Karakasheva T  et al 2018). 
1.3 
Tocilizumab in cancer patients 
Tocilizumab has been used extensively in patients receiving CAR-T cells to diminish the 
cytokine release syndrome seen with that treatment, and is currently FDA-approved for 
that indication (Brudno, J et al 2012, Teachey, D et al 2016).  There are no data suggesting 
that anti-tumor immunity is compromised by the use of tocilizumab in patients receiving 
CAR-T cells, and several studies have shown that CAR-T efficacy and function are 
unimpaired in patients treated with tocilizumab (Betts, B et al 2011). A number of 
anecdotal reports have suggested that tocilizumab is effective at reducing the intensity and 
duration of immune- related colitis in patients receiving checkpoint inhibition with PD-1 
antibodies alone or in combination with ipilimumab (Rotz, S et al 2017). Tocilizumab was 
well tolerated in those patients, and has been used with rapid resolution of symptoms in 
patients that in some cases had colitis that was steroid-refractory.  
1.4 
CRP in Cancer  
C-reactive protein (CRP), the prototypical acute phase reactant, is a pentameric protein 
(pentraxin) in serum whose levels rise in inflammatory states. It is synthesized by the 
liver, and also to a lesser degree by smooth muscle cells, macrophages, endothelial cells, 
lymphocytes, and adipocytes in response to interleukin-6 and interleukin-1β (DuClos,  
 
 

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Figure 2:  Association of IL-6 levels Pre- and Post Treatment With Response 
 
2000).  CRP binds lysophosphatidylcholine on the surface of dead or dying eukaryotic 
cells and bacteria and activates complement via C1q. It was first identified as a molecule 
in the serum of patients with infection that reacted with the somatic 'C' carbohydrate 
antigen of pneumococcus.  Normal levels in healthy individuals are up to 10 mcg/mL, but 
cancer patients can have very high CRP levels of greater than 500 mcg/mL.  
 
CRP is an accepted marker for coronary disease risk, as recognized by the American Heart 
Association and the US Centers for Disease Control and Prevention (Yamashita, H et al 
2003). A number of studies have shown that high CRP levels are associated with increased 
cancer risk, but the mechanisms by which that occurs is unclear, and little is known about 
the effects of elevated CRP on immunity in cancer patients. Recent data suggest that chronic 
inflammation and high CRP levels are associated with poor survival in renal cell, lung, 
pancreatic and breast cancer, in head and neck cancer patients treated with radiotherapy, 
and that CRP is associated with bony destruction in multiple myeloma (Katano AS et al 
2017, Yang J et al 2017, Agnoli C et al 2017, Yasuda Y et al 2017, Hang J et al 2017, 
Pasterino U et al 2017, Akamine t et al 2018).  There are few published data about the impact 
of CRP and other acute phase reactants on adaptive immunity in cancer or non-cancer states. 
CRP directly suppressed Th1 polarization in a murine model of experimental autoimmune 
encephalomyelitis (Zhang L et al 2015), and has been shown to decrease activation and 
maturation markers in human and murine dendritic cells by binding to CD32 (Zhang R et al 
2006).  A recent study showed a significant association between pre-treatment CRP levels 
and progression-free and overall survival in lung cancer patients treated with PD-1 immune 
checkpoint blockade (ICB), consistent with our published data in melanoma, which showed 
that acute phase reactants including CRP, serum amyloid A and P, and complement 
components were associated with a poor clinical outcome (Akamine T et al 2018, Weber, J 
et al 2018). Yet, in spite of decades of monitoring CRP and other chronic inflammatory 
mediators in cancer patients, little is known about the direct effects of CRP on adaptive 
      Baseline week 0 levels of IL-6 
           p=0.03 
The picture can't be displayed.
       Week 13  levels of IL-6 
         p=0.004     p=0.006    
The picture can't be displayed.

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immunity in cancer. In the current work, we explored how CRP and other acute phase 
reactants impacted on the phenotype and function of T effector cells and dendritic cells from 
melanoma patients, and generated a hypothesis as to the mechanism by which they suppress 
adaptive immunity. We found that high CRP in the serum was associated with a low 
response rate and shorter overall survival in a recent study of the use of checkpoint inhibition 
in melanoma (Weber J et al 2018), consistent with the data presented herein, which support 
an immune suppressive role for CRP and acute phase reactants. Reduction in CRP and acute 
phase reactants synthesized by the liver can be achieved by the use of inhibitors of IL-1β 
and/or IL-6, and may result in reversal of resistance to checkpoint blockade by overcoming 
inhibitory effects on T cells. In the current proposal, we will employ a humanized IL-6 
receptor alpha blocking antibody to decrease IL-6 levels and reduce the generation of CRP 
and other acute phase reactants from the liver and other cells. 
 
Levels of CRP have long been observed to be elevated in patients with a variety of 
advanced cancers with levels as high as 500 mcg/mL, yet a role of CRP and other APPs in 
modulating the anti-tumor immune response have not been previously explored (Weber J 
et al 2016, McFadyen J et al 2018, Litvack M et al 2010, Agrawal A et al 2003, Whitehead 
A et al 1990). In the work described in the attached preprint, we show that APPs, 
particularly CRP, have a profound suppressive effect on adaptive immunity in melanoma 
patients.  CRP not only diminished the proliferation and effector function of CD4+ and 
CD8+ T cells from melanoma patients, but it also down-regulated dendritic cell function 
and altered the phenotype of T cells and dendritic cells. In T cells, CRP bound to T cells 
and inhibited the immune synapse leading to suppression of the earliest events in T-cell 
receptor engagement, including calcium flux and T cell receptor signaling, resulting in a 
chronic state of immune suppression which has been shown to be associated with a poor 
outcome with the use of PD-1 blockade in melanoma and lung cancer. The RNA seq 
analysis suggested that CRP down- regulated cell cycle pathway genes and T cell 
activation genes such as CD38, ICOS and CTLA-4, indicating that CRP may act both to 
suppress immune synapse formation and T cell receptor signaling at the time of TCR 
engagement, and may also down modulate proliferation and function of T cells 
independent of TCR engagement.  
 
The data presented in the attached pre-print suggest that CRP and other APPs may be 
responsible for a profound state of systemic immune suppression in cancer patients for 
both effector T cells and antigen presentation, and are consistent with previous reports that 
CRP and APPs are associated with a poor outcome for different cancers and with 
checkpoint blockade in melanoma and other cancers. Our work evaluated the impact of 
CRP and APPs on peripheral blood cells from melanoma patients, and did not explore the 
effects of CRP on neo-antigen specific T cells or immunity within the tumor 
microenvironment.  Those studies, including an assessment of the impact of APPs on anti-
tumor immunity using tumor spheroids are planned as part of an ongoing clinical trial.  
The role of CRP on T cell responses and resistance to PD-1 blockade has not been 
evaluated in murine models, and the differences in protein sequence and function of CRP 
in mice and humans may render such studies problematic (Whitehead A et al 1990). 
 
CRP has been shown in mice to facilitate the opsonization of bacteria by binding to Fc 
gamma receptors, yet in work we performed that is described in the attached pre-print, 
blockade of Fc gamma receptors did not impact on the adaptive immunosuppression 
observed with CRP (Thomas-Rudolph D et al 2007). The levels of CRP that were 

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associated with suppression of T cell and dendritic cell function (10-100 micrograms per 
mL) in this study are observed in the serum of many patients with advanced cancer.  The 
finding in our study that serum CRP levels are associated with response and overall 
survival in stage IV melanoma patients treated with nivolumab or ipilimumab further 
support an immune suppressive role for CRP and possibly other APPs and suggest a novel 
mechanism for resistance to PD-1 blockade in melanoma that nay be applicable to other 
cancers.  CRP has been shown to alter dendritic cell maturation and function in murine 
models (Jimenez R et al 2018), although it has not been shown to behave similarly with 
human DCs, and few investigations have explored the impact of high levels of CRP on 
human T cells.   
 
There are considerable data that support reduction of CRP as an anti-cancer strategy. CRP 
has been described as a prognostic factor for outcome in patients with melanoma, as has 
serum amyloid a (SAA) (Fang S et al 2015, Findeisen P et al 2009).  Antibodies against 
IL-1β and IL-6 receptor that block liver and monocyte synthesis of CRP and other APPs 
have been tested in patients and are FDA-approved for a variety of indications. 
Tocilizumab, a humanized anti-IL-6Rα antibody that is FDA-approved for the treatment of 
rheumatoid arthritis, juvenile idiopathic arthritis, and polyarticular juvenile rheumatoid 
arthritis, has been tested in cancer patients, to suppress the cytokine release syndrome 
(CRS) observed with the use of CAR-T cell therapy, and more recently for the reversal of 
PD-1 blockade-associated immune related adverse events (Brudno J et al 2015, Teachey D 
et al 2015).  
The IL-1β blocking antibody canakinumab was used in a cardiac prevention trial to test 
the hypothesis that it could reduce the incidence of heart attack, stroke, or cardiovascular 
death in patients with elevated C‐reactive protein, a biomarker for cardiovascular risk. 
There was a significant reduction in incidence of lung cancer noted in that trial (Ridker P 
et al 2017).  Reduction in both cardiac events and lung cancer diagnoses was associated 
with extent of reduction of serum CRP levels (Ridker P et al 2017). There are many 
different explanations for the reduction in incidence of lung cancer, but the adaptive 
immune suppressive role for CRP suggested by our data herein suggest that a re-
invigorated immune response may be at least in part responsible.  The data that we have 
generated in the attached pre-print would support the use of tocilizumab in combination 
with CPI to augment its clinical effect, and based on prior clinical experience, reduce the 
irAEs associated with checkpoint blockade. 
1.5 
Rationale for the Study 
Advanced tumors evade host immune responses by a variety of mechanisms systemically 
and by creating an immune suppressive microenvironment around the tumor.  The 
immunomodulatory properties of interleukin-6 may in part be responsible for immune 
related adverse events, given the reversal of those toxicities observed with IL-6 receptor 
blockade in clinical practice and given the known activity of IL-6 blockade in reversing 
CAR-T-cell related cytokine release syndrome.  Importantly, IL-6 may play a role as a 
chronic inflammatory mediator in raising levels of acute phase proteins synthesized by the 
liver and circulating cells of the myeloid lineage which have been shown to be associated 
with a short survival with checkpoint inhibition and which are immune suppressive. 
Therefore, it is felt that there is a strong rationale for combining an IL-6 receptor blocking 
antibody, tocilizumab, with checkpoint inhibition with ipilimumab and nivolumab in 

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metastatic melanoma to reduce toxicity and potentially augment the therapeutic effect of 
combination checkpoint inhibition. 
1.6 
Potential Risks & Benefits 
1.6.1 Known Potential Risks 
See the relevant package inserts for the three FDA approved drugs, as well as the 
Investigator brochure and Dear Investigator letter for Tocilizumab. 
1.6.2  Known Potential Benefits  
The potential benefits to subjects with study participation are improved overall 
progression-free and overall survival and decreased toxicity from treatment with FDA-
approved ipilimumab and nivolumab.  The information obtained from this research may 
help others with this disease in the future. 

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2 
STUDY OBJECTIVES 
2.1 
Co-primary Objectives 
The co-primary objectives of the study are: 
• Determine the safety, tolerability, and grades 3-5 immune related toxicities of 
tocilizumab administered every 6 weeks up to week 24 in combination with 
ipilimumab at 1 mg/kg and nivolumab at 3 mg/kg every 3 weeks for 4 doses each 
during a 12 week induction period, then nivolumab at 240 mg flat dose every 2 weeks 
in maintenance for up to 24 weeks, and nivolumab at 480 mg flat dose every 4 weeks 
thereafter for up to 2 years in patients with unresectable Stage III/Stage IV melanoma. 
• Determine the preliminary antitumor activity of tocilizumab administered in 
combination with ipilimumab and nivolumab to patients with unresectable stage III or 
stage IV melanoma defined as overall response rate (ORR, CR + PR) at 24 weeks by 
RECIST 1.1 
2.2 
Secondary Objectives 
The secondary objectives of the study are: 
• Determine the preliminary antitumor activity of tocilizumab administered in 
combination with ipilimumab and nivolumab to patients with unresectable stage III or 
stage IV melanoma measured by progression-free and overall survival (Eisenhauer, E 
et al 2009). 
2.3 
Exploratory Objectives 
• Determine the pharmacodynamic effect of the 3-drug combination dose regimen on 
biomarkers in peripheral blood samples and tumor biopsy specimens. 
 

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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan: Description 
In this Phase II, open-label study, the treatment period will consist of an induction phase 
and a maintenance phase. The induction phase consists of 2 induction treatment cycles of 
42 days (6 weeks) each, of which the first cycle of 6 weeks is the DLT period. The 
maintenance phase consists of treatment cycles of 84 days (12 weeks) each, and may 
extend up to 2 years.  
During the induction phase, ipilimumab will be administered for 4 induction doses (during 
the 2 treatment cycles) at a dose of 1 mg/kg intravenously (IV) every 3 weeks, 4 times 
during the 12-week induction period, concurrent with nivolumab at 3 mg/kg administered 
at the same interval with a 30 minute rest period between infusions. On days administered 
in combination, nivolumab will be administered first at a dose of 3 mg/kg, followed by 
ipilimumab at 1 mg/kg, and immediately followed by tocilizumab at 4 mg/kg. Nivolumab 
and ipilimumab will be each administered IV each over 30 minutes consecutively with a 
30-minute rest period between infusions, on Days 1 and 22 of each 42-day induction 
treatment cycle. Tocilizumab will be administered intravenously for each 42-day induction 
treatment cycle.  
After 12 weeks of therapy, starting at Week 13, subjects enter the maintenance phase. 
Tocilizumab will be administered intravenously every 6 weeks during the first 84-day 
maintenance treatment cycle only at 4 mg/kg. On days when administered in combination, 
nivolumab will be administered first, followed by tocilizumab, within 15 minutes . 
Nivolumab will continue to be administered IV at 240 mg flat dose every 2 weeks; i.e., at 
Days 1, 15, 29, 43, 57, and 71 of the 84-day treatment cycle for the first maintenance cycle 
until week 24, then nivolumab will be administered at 480 mg flat dose every 4 weeks to a 
maximum of 2 years. Subjects will continue maintenance treatment with their tocilizumab 
for up to 24 weeks, and their nivolumab dose regimen for up to 2 years or until 
progression of disease, discontinuation due to toxicity, withdrawal of consent, or any other 
reason as specified in Section 7.5.6 and Section 4.6.2. 
A schematic of the study design is presented below in Figure 3. 

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Abbreviations: C = cycle; D = day; FU = follow-up; PD = progressive disease; QD = once daily; W = week. 
The planned study assessments are presented in Table 2 and described below. 
This study will consist of 3 periods: screening, treatment (includes induction phase and 
maintenance phase), and follow-up. 
If de-escalation of tocilizumab from level 1 is needed, it will go to level -1 (Table 1). If 
neither co-primary endpoint is satisfied after stage 1, then we will start again at dose level 
2. 
3.1.1 Study Materials 
• National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 (ref) 
• Nivolumab package insert  
• Ipilimumab package insert  
• Tocilizumab package insert 
3.1.2 Screening Phase 
• Begins by establishing the patient’s initial eligibility and signing of the informed 
consent form (ICF). 
• Patient is assessed for complete study eligibility within the required timeframe  
Enrollment 
& Screening 
C1D1 – C1D42 
Tocilizumab D1, 
Nivolumab + 
Ipilimumab  
D1 & D22 
C2D1 – C2D42 
Tocilizumab D1, 
Nivolumab + 
Ipilimumab  
D1 & D22 
C3D1 – C3D84 
Tocilizumab D1, D43 , 
D84 + Nivolumab (240 
mg every 2 weeks) D1,  
D15, D29, D43, D57, 
D71, then nivolumab 
(480 mg every 4 weeks  
Until PD, toxicities, or 2 
years 
FU Visit 1 
30 ± 7 
days 
after EOT 
FU Visit 2 
90 ± 7 
days 
after FU 
Visit 1 
Survival 
FU Visit 
3 months 
± 14 days 
after FU2 

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• A pregnancy test for WOCBP should be documented within 24 hours prior to the start 
of the first dose of study medication. Pregnancy tests may be performed on serum or 
urine. 
• Baseline tumor tissue must be received at NYU for programmed death ligand-1 (PD-
L1) immunohistochemistry (IHC) testing and other assays in order for the patient to be 
treated. If the tissue specimen cannot be made available to NYU prior to the patient’s 
first dose of the study drug, subjects are allowed to start treatment as long as there is 
confirmation that tissue is available and of sufficient quantity. 
• The pathology reports confirming unresectable melanoma must be reviewed by the site 
Investigator prior to treatment. 
Retesting of laboratory parameters and/or other assessments within any single screening 
will be permitted (in addition to any parameters that require a confirmatory value). 
Any new result will override the previous result (i.e., the most current result prior to the 
first dose of study drug) and is the value by which study inclusion will be assessed, as it 
represents the patient’s most current, clinical state.  
Laboratory parameters and/or assessments are included in Table 2; Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified patients.  
3.1.3 Treatment Phase 
• Following confirmation of the participant’s eligibility, the subject will receive the first 
doses of study medication (Day 1 of Week 1). 
• On-study laboratory assessments should be drawn within 72 hours prior to dosing. 
• Adverse event assessments should be documented at each clinic visit and WOCBP 
must have a pregnancy test every 3 weeks ± 1 week. Pregnancy tests may be 
performed on serum or urine. 
• Treated subjects will have a clinical and radiologic disease evaluation every 12 weeks 
± 7 days.  
• This phase ends when the subject is discontinued early from study therapy or at a 
maximum of 2 years of treatment. For a complete list of reasons for treatment 
discontinuation, see Section 7.7.6. 
3.1.4 Follow-up Phase 
• Begins after 2 years of treatment or when the decision is made to discontinue a subject 
from study therapy. 
• After completion of the first 2 follow-up visits, subjects will be followed every 
3 months for survival, or by their referring physician. 
• Subjects who discontinue treatment for reasons other than progression of disease will 
continue to have disease assessments until local, regional, or distant progression.  
• Surveillance assessments should occur every 12 weeks ± 7 days during the first year 
after the first dose of study drug, every 12 weeks ± 14 days during the second year, 

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every 6 months ± 4 weeks between Year 3 through Year 5 with the last study 
assessment at Year 5.  
• Subjects will be followed for drug-related toxicities until these toxicities resolve, 
return to baseline or are deemed irreversible. All toxicities will be documented for a 
minimum of 100 days after the last dose of study medication. 
The subjects will be treated in all cohorts until disease progression, unacceptable toxicity, 
or subject withdrawal of consent with a maximum of 2-year total duration of study 
medications. 
The total duration of the study from the first dose of study drug to final analysis of toxicity 
and tolerability is expected to be 18 months. 
The study will end once survival follow-up has concluded at year 5 in all patients. 
 
 
3.1.5 Schedule of Assessments 
The schedule of planned study assessments is shown in Table 2. 

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Table 2: 
Schedule of Assessments 
Screening Phase 
(Day –28 to Day –1 before 
First Dose 
Treatment Period 
Follow-Up 
Perioda 
Induction Phase 
Cycle 1 
Induction 
Phase Cycle 
2 
Maintenance Phase Cycle 3 
Study Day 
–28 
to –
1 
Day 
1 
Wk 
1 
Day 
1 
Wk 
4 
Day 
1 Wk 
5 to 6 
Day 
1 
Wk 
7 
Day 
1 
Wk 
10 
Day 1 
Wk 13 
Day 1 
Wk 25 
Day 1 
Wk 37 
Day 1 
Wks 49 
to 103 
EOTu FU 
1 
FU 
2 SFU 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteriab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of pathology 
reportc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor tissue 
samples for 
biomarkersd 
X 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
Physical 
examinationf, 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vital signsh 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Oxygen saturationi 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ECOG performance 
statusg 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Baseline signs and 
symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
assessmentj 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 
Concomitant 
medications review 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
12-lead ECGg,k 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Hematology,l,w 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
 
Clinical 
chemistry,l,v,w 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
 
Pregnancy test for 
WOCBP onlym 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Serologyn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor assessment 
(CT or MRI 
imaging)p,x 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 

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Screening Phase 
(Day -28 to Day -1 
before First Dose 
Treatment Period 
Follow-Up 
Perioda 
Induction Phase 
Cycle 1 
Induction 
Phase Cycle 2 
Maintenance Phase Cycle 3+ 
Study Day 
–
28 
to 
–1 
D
ay 
1 
W
k 
1 
Da
y 1 
W
k 4 
Day 
1 
Wk 
5 to 
6 
Day 
1 
Wk 
7 
Day 
1 
Wk 
10 
Day 
1 
Wk 
13 
Day 1 
Wk 25 
Day 1 Wk 
37 
Day 
1 
Wks
49 
to 
103 
EOT
u 
FU 
1 
FU 
2 SFU 
Blood (serum) and 
urine for 
exploratory 
biomarker 
assessments and 
Peripheral Blood 
Mononuclear cells 
(PBMCs) q 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
Peripheral Blood 
Mononuclear cells 
(PBMCs) 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
Biopsies of affected 
organs 
(OPTIONAL)s 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of 
tocilizumabr 
 
X 
                                      X                                                  
Xr 
 
 
 
 
Administration of 
nivolumabr 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Administration of 
ipilimumabr 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; CT = computerized tomography; ECG = electrocardiogram; ECOG = 
Eastern Cooperative Oncology Group; EOT = end-of-treatment; FU = follow-up visit; MRI = magnetic 
resonance imaging; NYU = New York University; PD-L1 = programmed death ligand-1; SAE = serious adverse 
event; SFU = survival follow-up visit; WOCBP = women of child-bearing potential. 
a 
 
Follow-up visit 1 (FU1) = 30 days (± 7 days) from end of treatment (EOT), Follow-up visit 2 (FU2) = 90 
days (± 7 days) from FU1. First SFU is 12 weeks (±14 days) after FU2. Phone contacts during the SFUs 
are only allowed at time periods between surveillance assessment visits. Surveillance assessments with 
imaging and exam evaluations should occur every 12 weeks ± 7 days during the first year after the last 
dose of study drug was administered, every 12 weeks ± 14 days during the second year, every 
6 months ± 4 weeks between Year 3 and Year 5, with the last assessment at Year 5. 
b 
All inclusion/exclusion criteria should be assessed during the screening and confirmed before the first 
dose of study drug. 
c 
Patients must have unresectable Stage IIIb/c or Stage IV melanoma. The pathology report must be 
reviewed and dated by the Investigator before treatment.  
d 
Sufficient tumor tissue from a prior resected site of disease (archived) will be collected for biomarker 
analysis. Please reference the Laboratory Manual. 
e 
On-treatment biopsies (optional) will be collected during the induction cycle 1 between Days 35 and 42 
(+ 3 days).  
f 
Height and weight are to be measured at the screening visit. Thereafter, only weight is measured.  
g 
Initial biomarker testing must be performed within 14 days prior to the first dose of study drug. 
Subsequent EKG testing will only  be performed if clinically indicated, or at the FU1 visit 
h 
Vital signs include temperature, systolic and diastolic blood pressure, heart rate, and body temperature.  
i 
Oxygen saturation is measured by pulse oximetry at rest, and must be done before dosing.; pulse 
oximetry on exertion will be performed only if there are respiratory symptoms, fatigue and/or 
radiographic abnormalities suggestive of pneumonitis 

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j 
Patients will be followed for drug-related toxicities until these toxicities resolve, return to baseline or are 
deemed irreversible. All toxicities will be documented for a minimum of 100 days after the last dose of 
study medication unless other therapy begins during that period. 
k 
Single 12-lead ECGs will be collected at screening, and at FU1. 
l 
Hematology and chemistry testing are done at each treatment visit, every three weeks during the first 12 
weeks of induction, and every 2 weeks from weeks 12-24, then every 4 weeks until 2 years, toxicity or 
progression on site or at a local laboratory. Refer to Section 6.7.1 and Section 6.7.2, respectively, for 
individual tests to be included. Laboratory testing does not need to be repeated on Day1, Week 1 if 
performed within 14 days before the first dose. 
m 
Pregnancy testing must be performed within 24 hours before the initial dose of study drug, and then 
every 3 weeks ± 1 week. Pregnancy tests may be performed on serum or urine. 
n 
Serology testing is done on site or at a local laboratory. Refer to Section 6.7.3 for individual tests to be 
included. Serology testing, if needed, must be performed within 28 days before the first dose of study 
drug. Laboratory testing does not need to be repeated if performed within 14 days before first dose.  
p 
Tumor assessments are performed by CT scan on the chest, abdomen, pelvis, and all other known sites of 
disease, and brain MRI (brain CT is allowable if MRI is contraindicated). 
q 
Serum and urine samples for exploratory biomarkers should be taken before dosing at Week 1, 7, and 37, 
and upon occurrence of ≥ Grade 3 drug-related AEs and/or laboratory abnormalities regarded as a drug-
related SAE, when clinically safe and feasible. 
r 
First dose to be administered within 3 business days of initiation. Subsequent doses may be administered 
within 3 days before or after the scheduled date if necessary. Ipilimumab is only given during the 
Induction Phase, at three week intervals, four times.  Nivolulab is given every 3 weeks for the first 4 
induction doses, then every 2 weeks for weeks 12-24 at 240 mg fixed dose, then every 4 weeks at a fixed 
dose of 480 mg until 2 years (week 103), toxicity or progression. Tocilizumab is given D1 of the 2 
induction cycles, then day 1 and D43 of the first maintenance cycle only, at 42 day intervals for a total of 
24 weeks up until week 25. 
s 
Upon occurrence of a ≥ Grade 3 drug-related AE and/or any lab abnormality regarded as a drug related 
SAE, a biopsy of the affected organ(s) may be optionally collected. 
t         End of treatment occurs at the time a patient discontinues therapy due to progression-of disease, toxicity 
or refusal to continue, or when a patient reaches 2 years of therapy 
u         Serum lipid panel/profile will be performed at baseline, week 4, and then weeks 12, 24 and 36 
v        The CBC and CMP will be checked before administration of any protocol drugs on this trial including 
tociluzumab.  
w              Scans will be done every 3 months on treatment for up to 3 years, then every six months thereafter 

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4 
SELECTION OF STUDY POPULATION 
4.1 
Number of Planned Subjects  
Safety evaluation and efficacy: This is a Phase II open label optimal Simon two-stage design 
trial. A total of 67 patients allows sufficient number of patients to assess the grades 3-5 irAE 
toxicity rates of the triple drug combination, and provide an estimate of the overall response 
rate by RECIST 1.1. 
4.2 
Inclusion Criteria 
1. Patients must have signed and dated an Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC)-approved written ICF in accordance with regulatory and 
institutional guidelines. This must be obtained before the performance of any protocol-
related procedures that are not part of normal patient care. 
2. Patients must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests, tumor biopsies, and other requirements of the study. 
3. All patients must be either Stage IIIb/c/d or Stage IV melanoma according to the 
American Joint Committee on Cancer (AJCC) (8th edition) and have histologically-
confirmed melanoma that is felt to be surgically unresectable in order to be eligible. 
Please refer to the AJCC 8th edition Cancer Staging Manual for a description of tumor, 
lymph node, metastasis, and staging. 
• All melanomas, except ocular/uveal melanoma, regardless of primary site of disease 
will be allowed; mucosal melanomas are eligible. 
• Patients must not have received prior anticancer treatment for metastatic disease (for 
example, but not limited to, systemic, local, radiation, radiopharmaceutical).  
• Exceptions: Surgery for melanoma and/or post-resection brain radiotherapy (RT) if 
CNS metastases and adjuvant RT for locoregional disease after resection and/or prior 
treatment with adjuvant IFN-alpha, dabrafenib and trametinib, pembrolizumab, 
ipilimumab or nivolumab (as described in Exclusion Criterion 8). 
• All patients must have their disease status documented by a complete physical 
examination and imaging studies within 4 weeks prior to the first dose of study drug. 
Imaging studies must include computerized tomography (CT) scan of chest, abdomen, 
pelvis, and all known sites of resected disease in the setting of Stage IIIb/c/d or Stage 
IV disease, and brain magnetic resonance imaging ([MRI]; brain CT is allowable if 
MRI is contraindicated).  
• The complete set of baseline radiographic images must be available before treatment 
initiation. 
4. Prior treatment with adjuvant IFN-alpha, adjuvant ipilimumab and/or nivolumab or 
pembrolizumab or dabrafenib and trametinib are allowed at any time; that is, a patient may 
have relapsed with unresectable disease during or at any time after receiving adjuvant 
therapy  
5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. 
6. Tumor tissue from the resected site of disease must be provided for biomarker analyses. 
In order to be treated, a patient must have tissue available for PD-L1 expression analysis 
by IHC and other assays obtained within 6 months of starting treatment. If insufficient 

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tumor tissue content is provided for analysis, acquisition of additional archived tumor 
tissue (block and/or slides) for the biomarker analysis is required. 
7. Prior treated CNS metastases must be without MRI evidence of recurrence for at least 
4 weeks after treatment. Patients must be off immunosuppressive doses of systemic 
steroids (≥ 10 mg/day prednisone or equivalent) for at least 14 days prior to study drug 
administration, and must have returned to neurologic baseline status postoperatively. 
a. The 4-week period of stability is measured after the completion of the neurologic 
interventions (i.e., surgery and/or radiation). 
8. In addition to neurosurgery to treat CNS metastases, adjuvant radiation after the resection 
of CNS metastasis is allowed. Immunosuppressive doses of systemic steroids (doses 
> 10 mg/day prednisone or equivalent) must be discontinued at least 14 days before study 
drug administration. 
9. Prior surgery that required general anesthesia must be completed at least 4 weeks before 
study drug administration. Surgery requiring local/epidural anesthesia must be completed 
at least 72 hours before study drug administration.   
10. All baseline laboratory requirements will be assessed and should be obtained within 
14 days of the first dose of study drug. Screening laboratory values must meet the 
following criteria:  
• WBCs ≥ 2000/µL 
• Neutrophils ≥ 1500/µL 
• Platelets ≥ 100 × 10³/µL 
• Hemoglobin ≥ 9.0 g/dL 
• Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or creatinine clearance 
> 40 mL/minute (using Cockcroft/Gault formula) 
• AST ≤ 1.5 × ULN  
• ALT ≤ 1.5 × ULN 
• Total bilirubin ≤ 1.5 × ULN (except patients with Gilbert Syndrome who must have 
total bilirubin < 3.0 mg/dL) 
11. Patient Re-enrollment: This study permits the re-enrollment of a patient that has 
discontinued the study as a screen failure (i.e., patient has not been dosed/has not been 
treated). If re-enrolled, the patient must be re-consented and satisfy all eligibility criteria. 
12. Males and females ≥ 18 years of age  
13. Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin [hCG] hormone) within 24 hours prior to the start of study drug during 
induction phase at each scheduled visit and during the maintenance phase every 4 weeks 
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14. Women of childbearing potential must agree to follow instructions for method(s) of 
contraception for the duration of treatment with study drug(s) plus 5 half-lives of study 
drug plus 30 days (duration of ovulatory cycle). The half-life of nivolumab and 
ipilimumab is up to 25 days and 18 days, respectively. WOCBP should therefore use an 
adequate method to avoid pregnancy for a total of 23 weeks post treatment completion 
(Section 4.5). 
15. Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However, they must still undergo pregnancy 
testing as described in this section.  
Investigators shall counsel WOCBP on the importance of pregnancy prevention and the 
implications of an unexpected pregnancy. Investigators shall advise WOCBP on the use of 
highly effective methods of contraception. Highly effective methods of contraception have a 
failure rate of < 1% when used consistently and correctly. (Refer to Section 4.5). 
4.3 
Exclusion Criteria 
1. Patients with active or history of steroid-requiring non-infectious pneumonitis. 
 
2. Patients who have previously discontinued immunotherapy due to an immune-mediated 
adverse reaction, regardless of grade  
3. Patients with carcinomatosis meningitis or a history of current ocular/uveal melanoma are 
excluded. 
4. Patients with previous nonmelanoma malignancies are excluded unless a complete 
resection or remission was achieved at least 2 years prior to study entry and no additional 
therapy is required or anticipated to be required during the study period (exceptions include, 
but are not limited to, nonmelanoma skin cancers, in situ bladder cancer, in situ gastric 
cancer or gastrointestinal stromal tumor, in situ colon cancers, in situ cervical 
cancers/dysplasia, or breast carcinoma in situ). 
5. Patients with active, known, or suspected autoimmune disease. Patients with type I diabetes 
mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone 
replacement, or skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring 
systemic treatment are permitted to enroll. For any cases of uncertainty, it is recommended 
that the Principal Investigator be consulted prior to signing informed consent. 
6. Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone or equivalent) or other immunosuppressive medications within 14 days of 
study drug administration. Inhaled or topical steroids are permitted in the absence of active 
autoimmune disease. 
7. Prior therapy for melanoma with the following exceptions which are allowed: 1) surgery 
for the melanoma lesion(s), 2) adjuvant RT after neurosurgical resection for CNS lesions 
or for resected locoregional disease, and 3) prior adjuvant IFN-alpha, ipilimumab and 
nivolumab (see qualifier below).  
8. Treatment directed against the melanoma (e.g., chemotherapy, targeted agents, biotherapy, 
limb perfusion) that is administered after a prior complete resection other than adjuvant 
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ipilimumab and/or nivolumab, pembrolizumab and dabrafenib and trametinib for resected 
melanoma. 
9. Any of the following laboratory abnormalities: 
• ANC < 1,500/µL or WBC < 2,000 µL 
• Platelet count < 100,000/µL 
• Hematologic growth factors are not allowed at screening or during the first cycle of 
treatment 
• Hemoglobin < 9 g/dL (< 5.5 mmol/L; previous RBC transfusion is permitted) 
• Creatinine > 1.5 × ULN 
• AST or ALT > 1.5 × ULN. For patients with liver metastasis AST or ALT > 3 × ULN 
• Serum total bilirubin > 1.5 mg/dL or > 3 × ULN for patients with hereditary benign 
hyperbilirubinemia 
10. Corrected QT interval using Fridericia’s formula value > 480 msec at screening; family or 
personal history of long QTc syndrome or ventricular arrhythmias including ventricular 
bigeminy at screening; previous history of drug-induced QTc prolongation or the need for 
treatment with medications known or suspected of producing prolonged QTc intervals on 
electrocardiogram (ECG). 
11. Congestive heart failure (New York Heart Association Class III or IV), myocardial 
infarction within 12 months before starting study treatment, or unstable or poorly 
controlled angina pectoris, including Prinzmetal variant angina pectoris. 
12. Any serious or uncontrolled medical disorder or active infection that, in the opinion of the 
Investigator, may increase the risk associated with study participation, study drug 
administration, or would impair the ability of the patient to receive protocol therapy. 
13. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other 
infections 
14. Any positive test result for hepatitis B virus or hepatitis C virus indicating acute or chronic 
infection 
15. Positive QuantiFERON TB  test , history of tuberculosis, or active TB infection without at 
least 4 weeks of adequate therapy for TB. 
16. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary 
(including obstructive pulmonary disease), renal, hepatic, endocrine (include uncontrolled 
diabetes mellitus) or gastrointestinal disease (including complicated diverticulitis, 
ulcerative colitis, or Crohn’s disease.) 
17. Immunization with a live or attenuated vaccine within 4 weeks of baseline. 
18. Known history of testing positive for human immunodeficiency virus or known acquired 
immunodeficiency syndrome 
19. Known hypersensitivity to monoclonal antibodies 
20. History of diverticulitis in the last 10 years 
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22. Prisoners or patients who are involuntarily incarcerated 
23. Patients who are compulsorily detained for treatment of either a psychiatric or physical 
(e.g., infectious disease) illness. 
24. Pregnant or nursing women 
25. Psychological, familial, sociological, or geographical conditions that potentially hamper 
compliance with the study protocol and follow-up schedule; those conditions should be 
discussed with the patient before registration in the trial. 
 
4.4 
Inclusion of Women and Minorities 
Both women and men of all races and ethnic groups are eligible for this trial. 
4.5 
Women of Childbearing Potential 
Women of childbirth potential is defined as any female who has experienced menarche and 
who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and is 
not postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone (FSH) level > 40mIU/mL 
to confirm menopause. 
Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic 
FSH level. The duration of the washout period is a function of the type of HRT used. The 
washout periods below are suggested guidelines and the Investigators should use their 
judgement in checking serum FSH levels. If the serum FSH level is > 40 mIU/ml at any time 
during the washout period, the woman can be considered postmenopausal: 
• 1-week minimum for vaginal hormonal products (rings, creams, gels) 
• 4-week minimum for transdermal products 
• 8-week minimum for oral products 
Other parenteral products may require washout periods as long as 6 months. 
4.6 
Removal of Patients from Therapy or Assessments 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the Investigator) for any of the following reasons: 
• Subject’s request to stop study treatment 
• Documented progression of disease (local, regional or distant) by immune-related response 
criteria (irRC)  
• Any clinical AE, laboratory abnormality or intercurrent illness which, in the opinion of the 
Investigator, indicates that continued participation in the study is not in the best interest of 
the patient 
• Termination of the study by BMS and/or Genentech 

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• Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
illness 
• Additional protocol specified reasons for discontinuation (see Section 7.7.6). 
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 3.1.4. The only exception to this requirement is when a 
patient withdraws consent for all study procedures including post treatment study follow-up 
or loses the ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the 
treatment of either a psychiatric or physical illness). 
If study drug is discontinued prior to the patient’s completion of the study, the reason for the 
discontinuation must be documented in the patient’s medical records and entered on the 
appropriate CRF page. 
Pregnancy 
In the case of pregnancy, the Investigator must immediately notify the main site of the trial, 
NYU, and the sponsor will report to BMS Worldwide Safety and Genentech Drug Safety of 
this event. In most cases, the study drug will be permanently discontinued in an appropriate 
manner. If the Investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study drug, a discussion between the Investigator and the BMS Medical 
Monitor/designee must occur. 
If a female subject becomes pregnant while receiving the study drug or within 90 days after 
the last dose of study drug, or if the female partner of a male study subject becomes pregnant 
while the study subject is receiving the study drug or 90 days after the last dose of study drug, 
a report should be completed and expeditiously submitted to Genentech, Inc. Follow-up to 
obtain the outcome of the pregnancy should also occur. Abortion, whether accidental, 
therapeutic, or spontaneous, should always be classified as serious, and expeditiously 
reported as an SAE. Similarly, any congenital anomaly/birth defect in a child born to a 
female subject exposed to the study drug should be reported as an SAE. 
4.7 
Post Study Follow-up 
In this study, toxicity defined as grades 3-5 treatment-related irAEs is a primary endpoint, 
and overall response (ORR) rate is the clinical co-primary endpoint. Post-study follow-up is 
of critical importance and is essential to preserving patient safety and the integrity of the 
study. Patients who discontinue study drug must continue to be followed for collection of 
outcome data as required until death or the conclusion of the study, with survival follow-up 
for a minimum of 5 years. 
4.8 
Withdrawal of Consent 
Patients who request to discontinue study drug will remain in the study and must continue to 
be followed for protocol specified follow-up procedures. The only exception to this is when a 
patient specifically withdraws consent for any further contact with him/her or persons 
previously authorized by patient to provide this information. Patients should notify the 
Investigator of the decision to withdraw consent from future follow-up in writing, whenever 
possible. The withdrawal of consent should be explained in detail in the medical records by 
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or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page. In the event that vital status (whether the patient is alive or dead) is 
being measured, publicly available information should be used to determine vital status only 
as appropriately directed in accordance with local law. 
4.8.1 Lost to Follow-up 
All reasonable efforts must be made to locate patients to determine and report their ongoing 
status. This includes follow-up with persons authorized by the patient as noted above. Lost to 
follow-up is defined by the inability to reach the patient after a minimum of three 
documented phone calls, faxes, or emails as well as lack of response by patient to one 
registered mail letter. All attempts should be documented in the patient’s medical records. If 
it is determined that the patient has died, the site will use permissible local methods to obtain 
the date and cause of death. 
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information. If after all attempts, 
the patient remains lost to follow-up, then the last known alive date as determined by the 
Investigator should be reported and documented in the patient’s medical records. 

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5 
INVESTIGATIONAL PRODUCTS 
5.1 
Investigational Products Administered 
Study drugs include all investigational [Medicinal] Products (tocilizumab, ipilimumab and 
nivolumab).  
At the end of the study period, Bristol-Myers Squibb Company and Genentech Inc. 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. 
5.1.1  Investigational Product Tocilizumab 
Tocilizumab is a recombinant humanized anti-human interleukin 6 (IL-6) receptor 
monoclonal antibody of the immunoglobulin IgG1κ (gamma 1, kappa) subclass with a typical 
H2L2 polypeptide structure. Each light chain and heavy chain consists of 214 and 448 amino 
acids, respectively. The four polypeptide chains are linked intra- and inter-molecularly by 
disulfide bonds. Tocilizumab has a molecular weight of approximately 148 kDa. The 
antibody is produced in mammalian (Chinese hamster ovary) cells. 
Intravenous Infusion tocilizumab injection is supplied as a sterile, preservative-free solution 
for further dilution prior to intravenous infusion at a concentration of 20 mg/mL. tocilizumab 
is a clear, colorless to pale yellow liquid, with a pH of about 6.5. Single-dose vials are 
available for intravenous administration containing 80 mg/4 mL, 200 mg/10 mL, or 400 
mg/20 mL of tocilizumab. Injectable solutions of tocilizumab are formulated in an aqueous 
solution containing disodium phosphate dodecahydrate and sodium dihydrogen phosphate 
dehydrate (as a 15 mmol per L phosphate buffer), polysorbate 80 (0.5 mg per mL), and 
sucrose (50 mg per mL). 
The investigational product tocilizumab should be stored in a secure area according to local 
regulations. It is the responsibility of the Investigator to ensure that the non-investigational 
products are only dispensed to study patients. The investigational product must be dispensed 
only from official study sites by authorized personnel according to local regulations.  
Patients will take tocilizumab intravenously at a dose of 4 mg/kg administered in 
combination with ipilimumab and nivolumab. If any intermediate doses and schedules of 
tocilizumab are felt to be indicated after consultation with the investigators, BMS, Genentech 
Inc. and the FDA, the IRB will be informed of any implementation of intermediate doses.  
 5.1.2  Investigational Study Drugs Ipilimumab and Nivolumab 
Investigational, standard of care products may consist of the following as shown in Table 3: 
Table 3: 
Investigational Study Drugs (Standard of Care) 
Product 
Description / Class 
and Dosage Form 
Potency 
IP/Non-IMP 
Blinded or Open 
Label  
Primary Packaging/ 
Appearance 
Storage Conditions 
(per label) 

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Nivolumab Solution 
for Injectiona 
100 mg (10 mg/mL) 
Per IB asnd PI 
Open-labelb 
10 mL/vial  
Store at 2 to 8°C. Protect 
from light and freezing. 
Ipilimumab Solution 
for Injection 
200 mg or 50 mg (5 
mg/mL) 
Per IB and PI 
Open-labelb 
40 mL/vial  
Store at 2 to 8°C. Protect 
from light and freezing. 
0.9% Sodium 
Chloride for 
Injection 
N/A 
 
Non-IMP 
Open-label 
Various (local commercial 
product) 
As per active PI 
 
5% Dextrose for 
Injection 
N/A 
 
Non-IMP 
Open-label 
Various (local commercial 
product) 
As per active PI 
 
Abbreviations: IMP = investigational medicinal product; IP = investigational product; N/A = not applicable. 
a Nivolumab injection drug product is a sterile, nonpyrogenic, single-use, isotonic aqueous solution. Its 
appearance is a clear to opalescent, colorless to pale yellow liquid which may contain particles. Nivolumab is 
secondary packaged in 10-mL Type 1 flint glass vials stoppered with butyl stoppers and sealed with 
aluminum seals. 
b The term “open label” refers to the medication as it is upon receipt at the pharmacy. 
If nivolumab is stored in a glass front refrigerator, vials should be stored in the carton. 
Recommended safety measures for preparation and handling of nivolumab include laboratory 
coats and gloves. For additional details on prepared drug storage and use time of nivolumab 
under room temperature/light and refrigeration, please refer to the nivolumab package insert.  
Premedications or medications used to treat infusion-related reactions should be sourced by 
the investigative site if available and permitted by local regulations. Solutions used as diluent 
or placebo (i.e., 0.9% Sodium Chloride Injection or 5% Dextrose Injection) should also be 
sourced by investigative site if available and permitted by local regulations. 
The Investigator is responsible for ensuring that the noninvestigational products are stored 
under the appropriate environmental conditions (temperature, light, and humidity). The 
Investigational products must be dispensed only from official study sites by authorized 
personnel according to local regulations.  
5.2  Identity of Investigational Product 
5.2.1  Formulation and Packaging 
Tocilizumab  
Medication labels comply with the legal requirements of the United States and will be printed 
in the languages required in the countries in which the study is conducted. 
5.2.2  Drug Storage and Accountability 
Tocilizumab liquid should be stored protected from light, at suggested range is 36--48°F, 2-
8°C) according to instructions on the label.  The storage area should be secure with limited 
access and monitored for temperature using a calibrated thermostat. Available stability data 
support ≥ 12-months shelf-life when stored under the above conditions, depending on vial 
strength.   
All study treatment supplies will be accounted for in the drug accountability inventory forms 
using locally approved forms that include all required information.  The drug accountability 

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inventory forms must identify the study drug, including batch or lot numbers and account for 
its disposition on a patient-by-patient basis, including specific dates and quantities.  The 
forms must be signed by the individual who dispensed the drug. 
5.2.3  Preparation and Dispensing 
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents. 
5.2.4  Medication Compliance 
Study site personnel should provide each patient with written dosing information for 
Tocilizumab and review it with the patient during clinic visits.  
5.2.5 Destruction 
At the end of the study, all unused Tocilizumab drug supplies must be destroyed in 
accordance with local Standard Operating Procedure provided by the Sponsor (NYU), or 
returned to the Sponsor. 
5.2.6  Administration 
Tocilizumab will be administered intravenously over 30 minutes at 4 mg/kg in 42 day cycles.  
The starting dose for tocilizumab is 4 mg/kg.  The dose may be deescalated depending on 
observed safety.     
Tocilizumab for infusion will be supplied by Genentech Inc. to NYU, The Angeles Clinic and 
Dana Farber Cancer Institute investigational pharmacies in appropriately sized vials for 
intravenous administration. Dose preparation instructions are provided in detail in the 
investigational brochure and package inserts for all three drugs. 
The label attached to each bottle will contain the appropriate information, including product 
name and amount, lot number, directions for storage, date of manufacture, name of Sponsor, 
and the region-specific regulatory information. 
Study-drug labels will not contain any statement that is false or misleading in any manner or 
represent that the study drug is safe or effective for the purposes for which it is being 
investigated. All packaging and labeling operations will be performed according to Good 
Manufacturing Practice for Medicinal Products and the relevant regulatory requirements. 
5.2.7  Storage and Dispensing 
The Investigator should ensure that the study drugs tocilizumab,  ipilimumab and nivolumab 
are stored in accordance with the environmental conditions (temperature, light, and humidity) 
as per product information, the IB, per local regulations, and as determined by BMS and 
Genentech. If concerns regarding the quality or appearance of the study drug(s) arise, the 
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Please refer to the current version of the IB and/or shipment reference sheets for additional 
information on storage, handling, dispensing, and infusion information for tocilizumab. 
It is the responsibility of the Investigator to ensure that drug product is only dispensed to 
study patients.  
Study drugs (tocilizumab, nivolumab and ipilimumab) will be stored in accordance with the 
package inserts. Please refer to the current version of the investigator brochures and/or 
pharmacy reference sheets for complete storage, handling, dispensing, and infusion 
information for tocilizumab, nivolumab and ipilimumab. 
Product documentation must be maintained that includes all processes required to ensure drug 
is accurately administered. This includes documentation of drug storage, administration and, 
as applicable, storage temperatures, reconstitution, and use of required processes (e.g., 
required diluents, administration sets). 
Infusion-related supplies (e.g., IV bags, in-line filters, 0.9% sodium chloride injection, 5% 
dextrose injection) will be purchased locally if permitted by local regulations. 
The NYU, The Angeles Clinic and Dana Farber investigational pharmacists or their delegate 
will obtain treatment assignment and prepare investigational drug.  
On days administered in combination, nivolumab will be administered first at a dose of 
3 mg/kg, followed by ipilimumab at 1 mg/kg, and immediately followed by tocilizumab at 4 
mg/kg. The infusion duration for tocilizumab, nivolumab and for ipilimumab is 30 minutes 
each .  
If the study drug(s) are to be destroyed on site, it is the Investigator’s responsibility to ensure 
that arrangements have been made for disposal, and that procedures for proper disposal have 
been established according to applicable regulations, guidelines, and institutional procedures. 
It is the Sponsor Investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to applicable 
federal, state, local, and institutional guidelines and procedures, and provided that appropriate 
records of disposal are kept. 
5.2.8  Destruction of Study Drugs 
For this study, study drugs (those supplied by BMS, Genentech or sourced by the 
Investigator) such as partially used study drug containers, vials and syringes may be 
destroyed on site.  
On-site destruction is allowed provided the following minimal standards are met: 
• On-site disposal practices must not expose humans to risks from the drug. 
• On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances. 

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• Written procedures for on-site disposal are available and followed. The procedures must 
be filed with the site’s standard operating procedures and a copy provided to BMS and/or 
Genentech upon request. 
• Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. 
The method of disposal (i.e., incinerator, licensed sanitary landfill, or licensed waste 
disposal vendor) must be documented. 
• Accountability and disposal records are complete, up-to-date, and available for the 
Monitor to review throughout the clinical trial period. 
If conditions for destruction cannot be met the principal investigator will make arrangements 
for return of study drug. 
It is the Investigator’s responsibility to arrange for disposal of all empty containers, provided 
that procedures for proper disposal have been established according to applicable federal, 
state, local, and institutional guidelines and procedures, and provided that appropriate records 
of disposal are kept. 
5.2.9  Return of Study Drug 
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug tocilizumab that was supplied by Genentech must be 
returned to Genentech, and any study drug ipilimumab and/or nivolumab that was supplied 
by BMS must be destroyed. The return of study drug will be arranged by the responsible 
Study Monitor.  
It is the principal Investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to applicable 
federal, state, local, and institutional guidelines and procedures, and provided that appropriate 
records of disposal are kept.  
5.3  Method of Assigning Subjects to Treatment 
After the participant’s initial eligibility is established and informed consent has been 
obtained, the patient must be enrolled into the study. Every patient that signs the ICF must be 
assigned a patient number. The Investigator or designee will register the patient for 
enrollment by following the enrollment procedures established by the Perlmutter Clinical 
Trials Office. The following information is required for enrollment: 
• Date that informed consent was obtained 
• Date of birth 
• Gender at birth 
• Race/Ethnicity 
• Zip Code 
• AJCC Stage and M classification 
− Stage IIIb/c/d 
− Stage IV M1a-M1b 

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− Stage IV M1c/d 
Once enrolled, enrolled patients that have met all eligibility criteria (the required tumor tissue 
received by the NYULH, Angeles Clinic and Dana Farber Pathology laboratories) will be ready 
to be treated.  
5.4  Selection and Timing of Doses in the Study 
When study drugs (tocilizumab, ipilimumab or nivolumab) are to be administered on the 
same day, separate infusion bags and filters must be used for each infusion. On days 
administered in combination, nivolumab will be administered first at a dose of 3 mg/kg, 
followed by a 30-minute rest period, followed by ipilimumab at 1 mg/kg, and immediately 
followed by tocilizumab  at 4 mg/kg.  
Intravenous tocilizumab will be dosed at 4 mg/kg every 6 weeks at D1 of the first 2 induction 
cycles, and at D1, D43 and D84 of the first maintenance cycle only for a total of 5 doses. 
Patients may be dosed up to ± 3 days before or after the scheduled date if necessary. 
Vital signs will be taken before dosing of each drug.   
5.5  Dosing Schedule 
The dosing schedule is described in Table 4. Weight should be used to calculate the dose and 
if the weight differs 5% or10% (depending on local institutional standards) from baseline, the 
dose should be recalculated. 
Table 4: 
Dosing Schedule 
 
Day 1  
Week 1 
Day 1  
Week 4 
Day 1  
Week 7 
Day 1  
Week 10 
Day 1  
Week 13 
Day 1  
Weeks 25, 
37, 49, 52 
Nivolumab 
+ 
Ipilimumab 
+ 
Tocilizumab 
3 mg/kg  
nivolumab 
3 mg/kg  
nivolumab 
3 mg/kg  
nivolumab 
3 mg/kg  
nivolumab- 
240  mg  
nivolumab 
Every two 
weeks for 12 
weeks 
+ 
4 mg/kg 
Tocilizumab  
A: Weeks 19 
and 25 
240 mg  
nivolumab 
Every two 
weeks for 
each 12 week 
cycle 
+ 
4 mg/kg 
Tocilizumaba 
 
a: Weeks 19 
and 25 
1 mg/kg 
ipilimumab 
1 mg/kg 
ipilimumab 
1 mg/kg 
ipilimumab 
1 mg/kg  
ipilimumab 
4 mg/kg 
Tocilizumab  
- 
4 mg/kg 
Tocilizumab  
 
 
If a patient cannot receive a dose of drugs within 3 days of its scheduled administration date, 
the dose should be completely omitted. When the patient is able to reinitiate treatment, dosing 
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Antiemetic pre-medications should not be routinely administered prior to dosing of drugs. 
See Section 7.12.7 for premedication recommendations following a nivolumab- or 
ipilimumab-related infusion reaction. 
5.6  Blinding 
There is no blinding in this study. 
5.7  Previous and Concomitant Therapy 
5.7.1  Prohibited and/or Restricted Medication/Therapy 
The following medications are prohibited during the treatment and follow-up phases (before 
recurrence) of the study (unless utilized to treat a drug-related AE): 
• Immunosuppressive agents 
• Immunosuppressive doses of systemic corticosteroids (except as stated in Section 5.7.2). 
• Any concurrent anti-neoplastic therapy (including, but not limited to chemotherapy, 
hormonal therapy, immunotherapy, radiation therapy, or standard or investigational agents 
for treatment of melanoma). 
Antiemetic pre-medications should not be routinely administered before dosing of drugs. See 
Section 7.12.7 for premedication recommendations following a nivolumab- or ipilimumab-
related infusion reaction. 
5.7.2  Permitted Therapy 
Patients are permitted the use of topical, ocular, intra-articular, intranasal and inhalational 
corticosteroids (with minimal systemic absorption). Physiologic replacement doses of 
systemic corticosteroids are permitted even if > 10 mg daily prednisone (or equivalent). A 
brief course (< 7 days) of corticosteroids for prophylaxis (e.g., for contrast dye allergy) or for 
treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused 
by a contact allergen) is permitted. 
Intravitreal injections of vascular endothelial growth factor inhibitors are permitted if used 
according to the approved ocular indication, such as macular degeneration. 
5.7.3  Premedication for Nivolumab or ipilimumab 
There will be no routine pre-treatment for the three antibodies in this trial, but if a grade 1 or 
2 infusion reaction occurs to any of the antibodies, then pre-treatment will be carried out 
according to section 7.12.5.2 on page 69. 
5.7.4  Treatment Compliance 
Treatment compliance will be monitored by drug accountability as well as the patient’s 
medical record and eCRF. 
Study center pharmacy personnel will prepare individual patient doses to be taken during 
scheduled study center visits.  

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6 
STUDY PROCEDURES/EVALUATIONS 
6.1 
 Medical History 
At screening, a medical history will be obtained to capture relevant underlying conditions, 
both past and ongoing concurrent medical conditions.  
6.2 
Physical Examinations 
A complete physical examination will be performed according to Table 2. The screening visit 
examination should include height as well as weight; however, at subsequent visits, only 
weight needs to be measured. Physical examination should be performed within 72 hours 
before dosing. Physical examinations are also to be performed as clinically indicated. 
6.3 
Vital Signs 
Vital signs (diastolic and systolic blood pressure, heart rate, and body temperature) will be 
performed as noted in Table 2. Vital signs should also be taken as per institutional standard of 
care before, during, and after dosing. Vital signs will be taken in the same position (supine or 
sitting) at each visit. 
6.4 
 Oxygen Saturation by Pulse Oximetry 
Oxygen saturation by pulse oximetry should be obtained prior to each dosing of combination 
nivolumab + ipilimumab +tocilizumab treatment, nivolumab with tocilizumab treatment, 
nivolumab alone, and at any time a patient has any new or worsening respiratory symptoms. 
Oxygen saturation by pulse oximetry at rest should be obtained at each time point before 
dosing as noted in Table 2. If patients have respiratory symptoms and/or fatigue and/or have 
any radiographic abnormalities consistent with pneumonitis, accurate recording and 
documentation of oxygen saturation at rest and on exertion, i.e.  2 different activity levels, 
will be performed, and is important because drug-related pulmonary toxicity can present 
initially as lower than baseline oxygen saturation. The extent of the exertion should be based 
on the judgment of the Investigator, but should remain consistent for each individual patient 
throughout the study. If the patient’s status changes, the Investigator can alter the extent of 
exertion based on his/her medical judgment. If a patient shows changes on pulse oximetry or 
other pulmonary related signs (hypoxia, fever) or symptoms (e.g., dyspnea, cough, fever) 
consistent with possible pulmonary AEs, the patient should be immediately further evaluated 
to rule out pulmonary toxicity. An algorithm for the management of suspected pulmonary 
toxicity can be found in the nivolumab Prescribing Information in the investigational 
brochure and the package insert. 
6.5 
Electrocardiograms 
Single 12-lead ECGs will be performed at screening (i.e., within 14 days before receiving the 
first dose of study drug), and at the end-of-treatment visit. Additional ECGs may be 
performed at any time point at the Investigator’s discretion. 

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6.6 
Concomitant Medications 
Concomitant medications will be collected from within 14 days before receiving the first 
dose of study drug through the study treatment period and follow-up visits 1 and 2 as noted in 
Table 2  
6.7 
Clinical Laboratory Evaluation 
The hematology, clinical chemistry, lipid panel/profile and serology assessments will be done 
by local laboratories according to the time points specified in Table 2. Baseline blood 
samples at screening should be done within 14 days prior to the first dose of study drug. 
Laboratory tests do not need to be repeated if performed within 14 days prior to the first dose. 
Additional measures not listed here including non-study required laboratory tests should be 
performed as clinically indicated or to comply with local regulations. Laboratory toxicities 
(e.g., suspected drug inducted liver enzyme elevations) will be monitored during the follow-
up phase via on site/local labs until all study drug related toxicities resolve, return to baseline, 
or are deemed irreversible. If hemoglobin levels are < 10 g/dL, blood will only be drawn for 
safety assessment, and will not be drawn for biomarker assessment. 
6.7.1 Hematology 
Hematology assessments done locally will include a complete blood count with differential, 
which includes a hematocrit, hemoglobin, WBC count, platelet count, RBC count, and mean 
corpuscular volume. These local laboratory assessments should be done within 72 hours prior 
to dosing.  
6.7.2 Clinical Chemistry 
Clinical chemistry assessments will include LFTs (ALT, AST, total bilirubin, and alkaline 
phosphatase), carbon dioxide, albumin, Gamma-glutamyl transferase GGT, phosphorus, 
blood urea nitrogen, uric acid, total protein, creatinine, calcium, magnesium, sodium, 
potassium, chloride, lactate dehydrogenase, glucose, amylase, lipase, TSH, free thyroxin, and 
free triiodothyronine, which must be initially performed within 14 days before the first dose 
and within 72 hours before dosing for other time points specified in Table 2. 
6.7.3 Serology 
Only if indicated, serology assessments will include hepatitis B and hepatitis C testing 
(hepatitis B virus surface antigen, hepatitis C virus antibody or RNA). These baseline 
serology tests should be assessed within 28 days before the first dose of study drug is 
administered as specified in Table 2. 
6.7.4 Pregnancy Testing 
Pregnancy tests (done locally, using serum or urine) must be performed on females of 
childbearing potential at screening, within 24 hours before the initial administration of study 
drug at baseline, during induction phase at each scheduled visit and during maintenance 
phase every 4 weeks while on treatment.  

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Females will be assessed as being of childbearing potential or not of childbearing potential 
and will undergo pregnancy testing as described below: 
Pregnancy testing for WOCBP must be performed within 24 hours before the initial 
administration of study drug at baseline and then every 3 weeks (± 1 week) during the 
treatment phase. Serum or urine may be used for pregnancy testing. 
• Females of childbearing potential include all females who are menstruating, 
amenorrheic from previous medical treatments, under 50 years of age, and/or 
perimenopausal, and those who do not qualify for the females not of reproductive 
potential category. Females of childbearing potential must commit either to abstain 
continuously from heterosexual sexual intercourse or to use 2 methods of reliable 
birth control simultaneously (1 highly effective form of contraception – tubal ligation, 
intrauterine device, hormonal birth control pills, injections, hormonal patches, vaginal 
rings, or implants) or partner’s vasectomy and 1 additional effective contraceptive 
method: male latex or synthetic condom, diaphragm, or cervical cap. 
• Females not of reproductive potential include females who have been in natural 
menopause for at least 24 consecutive months or who have had a hysterectomy and/or 
bilateral oophorectomy. 
• Females of childbearing potential must agree to use adequate contraceptive measures 
until 5 months after last study drug is taken. 
. 
6.7.5 Eastern Cooperative Oncology Group Performance Status 
Eastern Cooperative Oncology Group performance status will be assessed at each study visit 
according to Table 2 and within 72 hours before dosing. Patient ECOG performance status 
will be assessed as indicated in Table 5. 

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Table 5: 
Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
ECOG Description 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature; e.g., light house work, 
office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about > 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined 
to bed or chair  
5 
Dead 
Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. 
 

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7  STUDY ENDPOINTS AND ASSESSMENTS 
7.1  Co-Primary Endpoints: 
• To determine the grades 3-5 treatment related irAEs by week 24 when tocilizumab at 
4 mg/kg every 6 weeks for 5 doses is administered in combination with ipilimumab at 
1 mg/kg and nivolumab at 3 mg/kg every 3 weeks for 4 doses each during a 12-week 
induction period, then nivolumab is administered at 240 mg flat dosing every 2 weeks 
in maintenance for up to 1 year in subjects with unresectable Stage III/Stage IV 
melanoma. 
o Safety will be measured by physical examinations, vital sign measurements, 
ECOG performance status evaluations, AE assessments, laboratory testing, 
ECGs, oxygen saturation, and concomitant medications. 
• Overall response (CR + PR) by week 24 to study treatment will be measured by 
RECIST 1.1  
7.2  Secondary Endpoint: 
• Progression-free survival will be assessed. 
• Overall survival will be assessed  
7.3  Exploratory Endpoints: 
• 
Biomarkers will be measured in peripheral blood and in tumor specimens to examine 
associations with clinical endpoints. 
7.4  Efficacy Endpoints: 
7.4.1Efficacy Endpoint Based on Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 
Objective Response Rate (ORR) is defined as the total number of patients whose best 
response outcome is a CR or PR by week 24 divided by the total number of evaluable 
patients. 
Disease Control Rate (DCR) is defined as the total number of patients whose best response 
outcome is a complete response (CR) or partial response (PR), or SD divided by the total 
number of evaluable patients. 
Progression-Free Survival (PFS): is defined for each patient as the time from first dosing to 
the first observation of disease progression or death due to any cause. If a patient has not 
progressed or died at the time of analysis, PFS will be censored on the date of the last disease 
assessment. Patients who do not have any tumor assessment on treatment will be censored on 
the day of the first dose. 

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Duration of Overall Response: will be computed for all patients whose best response is 
either a PR or CR and is calculated from the time the measurement criteria are met for PR or 
CR, whichever is recorded first, until the date of documented PD or death. 
Duration of Disease Control: will be computed for the patients who had ORR outcome of 
CR, PR, or SD and is calculated from the beginning of treatment until the time of 
documented disease progression. 
Overall Survival: is defined for each patient as the time from first dosing to death due to any 
cause. If a patient has not died at the time of analysis, OS will be censored as of their last 
known date alive (i.e. last time patient was contacted for any reason in the study). Patients 
who do not have any tumor assessment on treatment be followed up for OS, and their date of 
death will be incorporated into the OS analysis. 
Appendix 1 contains a quick reference guide to using RECIST 1.1. 
7.4.2  Efficacy Endpoint Based on Immune-Related Response Criteria (irRC) 
Immune Related Best Overall Response (irBOR) is the best irRC designation over 6 
months, recorded between the date of first dose until the last tumor assessment prior to 
subsequent therapy (except for local palliative RT for painful bone lesions) for the individual 
patient in the study. Immune-related complete response (irCR) or immune-related partial 
response (irPR) determinations included in the irBOR assessment must be confirmed by a 
second (confirmatory) evaluation meeting the criteria for response and performed no less than 
4 weeks after the criteria for response are first met. 
Immune-related Response Rate (irRR) is defined as the proportion of response evaluable 
patients whose irBOR outcome is irPR, irCR. 
Immune-related Disease Control Rate is defined as the proportion of the response 
evaluable patients whose irBOR outcome is irPR, irCR, or immune-related stable disease 
(irSD). 
Immune-related Progression-Free Survival (irPFS) is defined as the time between the first 
dosing date and the date of immune-related progressive disease (irPD) or death, whichever 
occurs first. For patients with no recorded post-baseline tumor assessment, irPFS will be 
censored at the day of first dose. A patient who dies without reported irPD will be considered 
to have progressed on the date of death. For those who remain alive and have no irPD, irPFS 
will be censored on the date of last evaluable tumor assessment. Patients who do not have any 
tumor assessment on treatment will be censored on the day of the first dose. 
Duration of Immune-related Overall Response: will be computed for all patients whose 
irBOR outcome is either an irPR or irCR and is calculated from the time the measurement 
criteria are met for irPR or irCR, whichever is recorded first, until the date of documented PD 
or death by irRC. 
Duration of Immune-related Disease Control: will be computed for the patients who had 
irBOR outcome of irCR, irPR, or irSD and is calculated from the beginning of treatment until 
the time of documented disease progression by irRC. 

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Appendix 2 contains a summary of the irRC assessment. 
7.5  Efficacy Variables and Assessments 
7.5.1  Disease Assessments 
Disease assessments will take place in accordance with Table 2. Baseline disease assessments 
should be performed within 28 days prior to the first dose utilizing CT or MRI. This includes 
a CT scan of chest, abdomen, pelvis, and all known sites of disease, and a brain MRI (brain 
CT allowable if MRI is contraindicated). Patients will be evaluated for tumor burden until 
local, regional, or distant recurrence (whichever comes first) by irRC beginning 12 weeks (± 
7 days) relative to the first dose of study treatment, and will continue to have disease 
assessments every 12 weeks (± 7 days) for the first 12 months. After 12 to 24 months after 
receiving the first dose of study drug, efficacy assessments should be every 12 weeks (± 14 
days). After 24 months until Year 5 after the first dose of study treatment, efficacy 
assessments should be performed every 6 months (± 4 weeks). CT scans will be performed 
every 3 months on treatment, then every 6 months after 3 years which is standard of care in 
stage 4 melanoma. 
Progression is defined as an increase in the sum of the longest unidimensional diameters of 
the 5 measurable lesions defined at baseline beyond 20% from baseline or the lowest point at 
any time during treatment. The appearance of 1 or more new melanoma lesions, which can be 
local, regional, or distant in location does not constitute progression; rather the longest 
unidimensional diameters of all new lesions should be added into the sum to determine 
progression. Progression should be verified not less than 4 weeks after the first evaluation 
that showed it.  
7.5.2  Measurable Disease per RECIST 1.1 
Measurable lesions must be accurately measured in at least 1 dimension (longest diameter in 
the plane of the measurement to be recorded) with a minimum size of: 
• 10 mm by CT/MRI scan (CT/MRI scan slice thickness no greater than 5 mm); PET-CT 
may be utilized if the CT parameters are satisfied above. 
• 10 mm caliper measurement by clinical examination (lesions which cannot be accurately 
measured with calipers should be recorded as nonmeasurable) 
• 20 mm by chest x-ray 
Malignant lymph nodes: to be considered pathologically enlarged and measurable per 
RECIST 1.1, a lymph node must be ≥ 15 mm in the short axis when assessed by CT scan (CT 
scan slice thickness recommended to be no greater than 5 mm).   
If the measurable disease is restricted to a solitary lesion (visceral or nodal), its neoplastic 
nature must be confirmed either by cytology/histology or by lesion progression certified on 
the next CT/MRI examination. 

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7.5.3  Nonmeasurable Disease per RECIST 1.1: 
Nonmeasurable lesions include all other lesions, including small lesions (longest diameter 
< 10 mm or pathological lymph nodes with ≥ 10 and < 15 mm on the short axis), as well as 
truly nonmeasurable lesions. Lesions considered truly nonmeasurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusions, inflammatory breast disease, 
lymphangitic involvement of skin or lung, or abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
Note: 
• Cutaneous relapses occurring beyond the periphery of the previous surgical bed (i.e., over 
2 cm) are considered distant metastases. 
• Node relapses occurring beyond the anatomical compartment of the dissected basins are 
considered distant metastases. 
• Node relapses in nodal basins situated in a different anatomical compartment or beyond 
the previously dissected basin or in 2 nodal basins (even if contiguous [i.e., 2 pelvic nodal 
basins, 2 mediastinal nodal basins]) are considered distant metastases. 
7.5.4 Methods of Measurements  
CT and MRI are an essential part of the work-up to establish response or progression. 
Conventional CT with IV contrast and MRI gadolinium should be performed with contiguous 
cuts of 10 mm or less slice thickness. Spiral CT should be performed using a 3-mm or 5-mm 
contiguous reconstruction algorithm; this specification applies to the tumors of the chest, 
abdomen, and pelvis while head and neck tumors and those of the extremities usually require 
specific protocols. In each institute, the same technique for CT/MRI should be used to 
characterize each new lesion. 
Patients allergic to contrast media may have a CT performed without contrast after discussion 
and agreement with the Principal Investigator. 
PET alone will not be considered for the disease assessment. Complementary CT and/or MRI 
or biopsy must be performed in such cases. 
Histological or cytological evidence of progression should be attempted in all cases except 
for brain metastases when safe and clinically feasible. 
Tumor markers or auto-antibodies alone cannot be used to assess recurrence. 
In the case of clinically detected new lesions that occur during the study: 
• Superficial cutaneous lesions: the neoplastic nature must be confirmed by 
cytology/histology. 
• Deep subcutaneous lesions and lymph node lesions should be documented by ultrasound 
and histological/cytological evidence should be attempted. In absence of a pathology 
report, lesion recurrence will be documented with a CT scan/MRI. 

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7.6  Date of Progression 
 
The first date when progression was observed is taken into account regardless the method of 
assessment. Therefore, progression will be declared for any lesion when: 
• Only imaging was performed and progression confirmed. 
• Only pathology was done and malignancy confirmed in a new lesion (in solitary or in 
doubtful lesions, cutaneous, subcutaneous or lymph node lesions). 
• Both pathology and imaging were done and progression/malignancy confirmed. In this 
case, the date of whichever examination comes first is considered the date of progression. 
 
7.7 Pharmacodynamic Biomarker Assessments 
A variety of factors that could potentially predict clinical response and incidence of AEs to 
nivolumab + ipilimumab + tocilizumab will be investigated in peripheral blood and in tumor 
specimens taken from all patients prior to treatment and as outlined in Table 2. Data from 
these investigations will be evaluated for associations with ORR rate, and PFS and/or safety 
(AE) data. In addition, analyses of markers will provide the necessary data to identify and 
validate biomarkers with predictive vs prognostic value. All samples collected may also be 
used for future exploratory analyses (unless restricted by local requirements and/or 
institutional policies) to assess biomarkers associated with melanoma or immunotherapy 
treatment.  
7.8 Biomarker Endpoints 
Baseline (pretreatment) and other measures of peripheral blood, urine and intra-tumoral 
immune responses will be analyzed to examine associations with clinical endpoints. In 
peripheral blood, baseline levels of: 1) absolute lymphocyte count; 2) serum and urine 
cytokines; 3) T-cell subsets, their phenotype, activation status, and cytokine production; and 
4) gene expression profiles will be used in such assessments. In addition, tumor biopsies will 
be collected and measures of tumor-based markers of: 1) intra-tumoral immune cells and 
immune-regulatory factors, and 2) gene expression in tumors will be analyzed to assess 
associations with antitumor activity. 
An assessment of the effect of tocilizumab in combination with ipilimumab and nivolumab 
on biomarkers in peripheral blood, urine and tumor tissue (when collected) will be 
performed. Blood samples will be collected for analysis of immunoregulatory markers 
including, but not limited to, absolute lymphocyte count counts, natural killer (NK) cells and 
T-cell subtypes (CD4, CD8, Tregs), T cell intracellular cytokines (IFN-gamma, tumor 
necrosis factor [TNF]-alpha, IL-10, and IL-6), and serum as well as urine cytokine levels (IL-
10, IFN-gamma, TNF-alpha). Absolute leukocyte counts will be evaluated in all patients on 
study. Flow cytometry will be performed for CD4 and CD8 T-cell expression of inducible T-
cell co-stimulator gene (ICOS), Ki67, and eomesodermin gene (EOMES) as predictive 
markers (Wang W et al 2012). Given the positive correlation between sustained acetylation of 
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regulator and findings that clinical benefit with ipilimumab is associated with pretreatment 
expression of EOMES in T cells, we will determine whether tocilizumab would increase 
EOMES promoter acetylation in T cells and potentially augment the clinical efficacy of 
ipilimumab and/or nivolumab. Multiplex analysis will be performed for serum and urine 
cytokines including IL-6, IL-10, and IFN-γ. Flow cytometry analysis of intracellular 
cytokines will be performed, all as pharmacodynamic markers of the effects of tocilizumab 
on immune cells. Exploratory analysis of mRNA expression in T cells (as assessed by gene 
expression profiling by Affymetrix and/or by quantitative real-time polymerase chain 
reaction [qRT-PCR]) may also be considered based on sample availability. Blood samples 
will be collected prior to the designated tocilizumab and/or ipilimumab with/without 
nivolumab dosing for the day of sample collection. As indicated above, there is particular 
interest in EOMES acetylation and expression in T cells, serum cytokine assays by multiplex 
analysis, and intracellular cytokine staining by flow cytometry for IFN gamma, IL-6, and IL-
10, based on preclinical work with IL-6 receptor blockade.  
In addition, pretreatment and on-treatment fresh tumor biopsies will be collected from up to 
15 patients and examined for biomarkers including, but not limited to, T-cell markers such as 
CD4, CD8, CD45, and FOXP3, and activation markers such as granzyme B by IHC. 
Exploratory analysis of mRNA expression (as assessed by gene expression profiling by 
Affymetrix or by qRT-PCR) may also be considered based on sample availability. On-
treatment biopsies will be collected during the induction cycle 1 between Days 35 and 42. 
On-treatment biopsies will be collected prior to administration of any scheduled morning 
dose of study therapy. The biopsy specimens will be split into two, and one half will be 
frozen, and the other half placed in formalin for paraffin imbedding.  Two passes of a core 
biopsy needle may be taken if required for sufficient material. 
7.9 Tissue Specimens 
Pretreatment tumor tissue specimens in the form of a paraffin embedded block or a minimum 
of 15 unstained slides will be submitted for PD-L1 and other IHC assessments to NYU from 
NYU, The Angeles Clinic or Dana-Farber Cancer Institute’s Pathology Laboratories prior to 
the patient’s first dose of study drug. A minimum of 15 slides is ideal, but fewer slides based 
on substrate availability may be acceptable. In these situations, it is recommended to consult 
with the protocol team to discuss the specifics of the case. 
Programmed death ligand-1 stained tissue sections will be assessed by a pathologist and 
membranous PD-L1 expression scored in tumor and immune cells if a minimum of 100 
evaluable tumor cells are present. Patients with tumor samples containing less than 100 
tumors cells per tissue section will not be enrolled, but patients with positive, negative, or 
indeterminate (membrane staining is obscured by high cytoplasmic staining or melanin 
content) PD-L1 expression will be stratified based on their expression. In addition, this 
pretreatment tumor sample may be used to assess other putative predictive biomarkers of 
nivolumab with ipilimumab efficacy and/or to better characterize the tumor-immune 
microenvironment postresection. Various molecular markers with potential predictive value 
for the treatment of melanoma with nivolumab, ipilimumab, and other immunotherapies are 
currently under investigation and may be assessed in this study. These tumor tissue 
biomarkers include, but are not limited to, PD-1, PD-L2, TILs, or subpopulations of TILs and 
a Th1 immune mRNA expression signature. In addition, other methods of measuring tumor 
PD-L1 expression may also be assessed. These pretreatment tumor samples may also be used 

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to further characterize the tumor-immune microenvironment through assessment of markers 
that may be associated with the efficacy of nivolumab and/or ipilimumab, including, but not 
limited to, other T cell checkpoint receptors and ligands (e.g., Lag-3, Tim-3) intratumoral 
immune cell subsets, including macrophages, NK cells, and B cells. 
Optional tumor tissue samples may also be collected upon recurrence. This sample may be 
used for the assessment of markers implicated in resistance to immunotherapeutic agents, 
including but not limited to other T cell checkpoint receptors and ligands (e.g., Lag-3, Tim-3) 
and intratumoral immune cell subsets, including, but not limited to, T regulatory cells and 
myeloid derived suppressor cells. These samples may also be used to investigate the effect of 
nivolumab or ipilimumab the expression of potentially relevant predictive and/or prognostic 
melanoma biomarkers, including, but not limited to, BRAF mutation and PD-L1. Both the 
pretreatment tumor sample and the sample collected upon recurrence may be retrospectively 
assessed for BRAF mutation status, N-RAS mutation status, as well as for the expression of 
other immune or melanoma related genes, RNAs and/or proteins, or for the presence of 
immune cell populations using a variety of methodologies inclusive of, but not limited to 
IHC, qRT-PCR, genetic mutation detection and fluorescent in-situ hybridization. 
Upon occurrence of a ≥ Grade 3 drug-related AE and/or any lab abnormality regarded as a 
drug-related SAE, a biopsy of the affected organ(s) may be optionally collected. These 
samples may be used for the assessment of immune cell markers, including, but not limited to 
T cell, T regulatory cell and NK cell markers, as well as for the expression of MHC class I/II 
molecules. 
7.10 Exploratory Serum and Urine Biomarkers 
Blood samples for exploratory serum, plasma and urine biomarker analyses will be drawn at 
the specified time points indicated in Table 2. Additionally, serum samples will be collected 
when clinically safe and feasible, upon occurrence of a ≥ Grade 3 drug-related AE and/or any 
lab abnormality regarded as a drug-related SAE. Separate blood samples will be collected and 
processed for serum and plasma and then put in frozen storage. Urine samples will be frozen 
after collection. Serum, plasma and urine samples may be assessed by ELISA, seromics, 
microRNA profiling, circulating tumor DNA measurements, metabolomics, and/or other 
relevant multiplex-based protein assay methods for immune or melanoma-related factors that 
will predict for nivolumab or ipilimumab benefit or correlate with nivolumab or 
ipilimumab-related AEs. Numerous potential serum/plasma-based biomarkers are currently 
under investigation for their potential to predict or correlate with safety or efficacy to 
nivolumab, ipilimumab or other immunotherapies, including but not limited to levels of CRP, 
IL-6, soluble PD-L1, antitumor antibodies, cytokines, chemokines, inflammatory factors, 
NKG2D ligands (e.g., soluble MICA), circulating tumor DNA, and microRNAs (such as, but 
not limited to, miR-513 and miR19b). 
Samples will be stored for up to 10 years at NYU Langone Health at the following location:  
522 First Avenue Room 1310 Smilow Building 
New York, New York, 10016  
The samples will only be stored for research related to this study and will be stored only 
using the subject number. No names or other subject identifiers will be used; a unique code 

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will be applied to the samples at the site. The linking key will be held by NYU. The genetic 
testing is related only to the subject’s cancer and the potential use of tocilziumab as treatment 
and will not be used to predict an individual’s risk for developing a disease or passing it to 
their children. The results of this testing will not be shared with the subjects.  
7.11 Peripheral Blood Mononuclear Cells (PBMCs) 
Peripheral blood samples will be taken prior to initiation of study therapy and at designated 
time points on-treatment (see Table 2 for additional details on the blood sample collection 
schedule) for PBMC preparation, except for sites where the stability of the samples after 
shipment to the Central lab cannot be guaranteed. Samples must be shipped within 48 hours 
to a designated central laboratory for processing.  
These PBMC samples may be used for immunophenotyping or characterization of the 
immune cell subsets in the periphery, including, but not limited to, T cells, B cells, NK cells, 
or subpopulations of the aforementioned immune cell types. These samples may also be used 
to assess immune cell function or antigen specific T cell proliferation or activation pending 
emerging information from other nivolumab or ipilimumab studies.  
7.12  Safety Endpoints and Assessments 
Patients will be evaluated for safety if they have received any study drug.  
7.12.1  Safety Reviews 
All available clinical and laboratory data, and the nature, time of onset, and time to 
resolution of DLTs observed during dose escalation will be reviewed to determine 
whether an alternate dose schedule should be examined after consultation between the 
Investigators and BMS, if needed. If agreed upon, the alternate schedule will be 
identified by a protocol amendment and the MTD determined for the revised dose 
schedule. The dose escalation decision for Tocilizumab will be determined by an 
assessment of whether the addition of tocilizumab has potentially increased the 
toxicity associated with ipilimumab and nivolumab or potentially decreased the 
response rate of the regimen. 
The data will be reviewed by a safety review committee consisting of the NYU Perlmutter 
Cancer Center DSMC, which will also review all safety data, specifically to review all Grade 
3 or greater irAEs. 
7.12.2  Dose-limiting Toxicities 
The following AEs, if assessed to be possibly, probably or definitely related to tocilizumab, 
will be considered to be DLTs at CTCAE 5.0 (ref): 
Hematologic Toxicity: 
• Grade 4 neutropenia (absolute neutrophil count [ANC] < 500/μL) lasting > 7 days. If 
neutropenia is attributed to tocilizumab, ANC is to be repeated on Day 6 to determine 
if this is a DLT. 

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• Febrile neutropenia (ANC < 1,000/μL with a single temperature > 38.3°C [101.0°F] 
or 38.0°C [100.4°F] for > 1 hour). 
• Grade 4 thrombocytopenia (platelet count < 25,000/μL). 
• Grade 3 thrombocytopenia (platelet count 25,000/μL to 50,000/μL) with clinically 
important bleeding. 
Non-hematologic Toxicity: 
All other Grade 3 or Grade 4 non-hematologic toxicities may be due to immune therapy 
or tocilizumab, so etiology cannot be possible to ascribe to tocilizumab 
Immune-related Toxicity: 
All other Grade 3 or Grade 4 immune-related toxicities will be considered as potential 
DLTs. Immune-related toxicities among patients treated with nivolumab and/or 
ipilimumab have clustered among skin, gastrointestinal, endocrine and liver-related 
events as follows: 
• Skin: alopecia, dry skin, hyperhidrosis, night sweats, pruritus, rash/desquamation, 
toxic epidermal necrolysis, urticaria, vitiligo. 
• Gastrointestinal: abdominal discomfort or pain, anal ulcer, colitis (including 
ulcerative, hemorrhagic, ischemic, and megacolon), constipation, cramping, diarrhea 
(including hemorrhagic), diverticulitis/diverticulum, duodenitis, dyspepsia, dysphagia, 
enteritis, esophagitis, gastritis (including erosive), gastrointestinal hemorrhage 
(including rectal), hematochezia, ileitis, ileus, intestinal obstruction, intestinal 
perforation (including small and large intestines), melena, nausea, pancreatitis, 
peritonitis, stomatitis (including aphthous), vomiting, vasculitis gastrointestinal. 
• Endocrine: adrenal insufficiency (including Addison disease), glucose tolerance 
impaired, hyperthyroidism hypogonadism, hypophysitis/hypopituitarism 
(autoimmune), hypothyroidism, pituitary enlargement, thyroiditis (autoimmune). 
• Liver: hepatitis, jaundice. 
Other treatment-related asymptomatic Grade 3 and Grade 4 laboratory investigations, 
excluding cardiac function tests, may be evaluated to determine whether dose cohorts should 
be expanded. 
DLT will also include all immune-mediated adverse reactions (IMARs) that require 
withholding or discontinuation of at least one of the study drugs (tocilizumab, ipilimumab, 
nivolumab) per its label.  
7.12.3  Dose-Delay Criteria 
Because of the potential for clinically meaningful nivolumab and/or ipilimumab-related AEs 
requiring early recognition and prompt intervention, management algorithms have been 
developed for suspected AEs of selected categories.  

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Dose delay criteria apply for all drug-related AEs (regardless of whether or not the event is 
attributed to ipilimumab and/or nivolumab). All study drugs, including ipilimumab and/or 
nivolumab and/or tocilizumab, must be delayed until treatment can resume.  
Ipilimumab and/or nivolumab administration should be delayed for the following: 
Any Grade 2 non-skin, drug-related AE, with the following exceptions: 
• Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay. 
• Any Grade 2 skin, drug-related AE. 
Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
lymphopenia, leukopenia, AST, ALT, total bilirubin, or asymptomatic amylase or lipase: 
• Grade 3 lymphopenia or leukopenia does not require dose delay. 
• If a patient has a baseline AST, ALT, or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade ≥ 2 toxicity. 
• If a patient has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade ≥ 3 toxicity. 
• Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis does not require dose delay. The 
Principal Investigator should be consulted for Grade ≥ 3 amylase or lipase abnormalities. 
• Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, warrants delaying the dose of study medication. 
Patients who require delay of ipilimumab and/or nivolumab should be re-evaluated weekly or 
more frequently if clinically indicated and resume ipilimumab and/or nivolumab dosing when 
retreatment criteria are met. 
7.12.4  Criteria to Resume Ipilimumab and/or Nivolumab Treatment After a Delay 
Patients may resume treatment with study drugs when the drug-related AE(s) resolve to 
Grade ≤ 1 or baseline value, with the following exceptions: 
• Patients may resume treatment in the presence of Grade 2 fatigue. 
• Patients who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity. 
• Patients with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in 
the presence of Grade 2 AST/ALT OR total bilirubin. 
• Patients with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters should have treatment permanently discontinued. 
• Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline 
before treatment is resumed.  

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• Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment if the Principal Investigator allows it. 
• Patients may resume treatment when steroids are at 10 mg/day of prednisone or its 
equivalent or less. 
If the criteria to resume treatment are met, the patient should restart treatment at the next 
scheduled time point per protocol. However, if the treatment is delayed past the next 
scheduled time point per protocol, the next scheduled time point will be delayed until dosing 
resumes. 
If treatment is delayed or interrupted for > 6 weeks, the patient must be permanently 
discontinued from study therapy, except as specified in discontinuation section.  
7.12.5  Dose Omission Criteria for Nivolumab and Ipilimumab 
Doses of ipilimumab and/or nivolumab should be omitted (not delayed) if any of the 
following criteria are met: 
• Any Grade 3 nonskin, drug-related AE. 
• Any Grade 3 skin, drug-related AE. 
• Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
lymphopenia, leukopenia, AST, ALT, or total bilirubin:  
o Grade 3 lymphopenia or leukopenia does not require dose omission. 
o If a patient has baseline AST, ALT, or total bilirubin that is within normal 
limits, omit dosing for drug-related Grade ≥ 2 toxicity. 
o If a patient has baseline AST, ALT, or total bilirubin within the Grade 1 
toxicity range, omit dosing for drug-related Grade ≥ 3 toxicity. 
o Grade 3 amylase or lipase abnormalities that are not associated with symptoms 
or clinical manifestations of pancreatitis do not require a dose omission.  
• Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, warrants omitting the dose of study medication. 
If the criteria to resume treatment (specified in Section 7.12.5.2) are met within the dosing 
window (Day 1, Week X ± 3 days), then the dose may be given.  
Note: the term “interruption” is reserved for interruption of the actual IV infusion during 
administration. The terms omission and interruption should not be used synonymously when 
completing the case report form (CRF). 
7.12.5.1  Adverse Event Management Algorithms for Immuno-Oncology Agents 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and 
duration than AEs caused by other therapeutic classes. Nivolumab and ipilimumab are 
considered immuno-oncology agents in this protocol. Early recognition and management of 
AEs associated with immuno-oncology agents may mitigate severe toxicity. Management 
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following groups of AEs: gastrointestinal, renal, pulmonary, hepatic, endocrinopathies, skin, 
and neurological. The management algorithms can be found in the nivolumab package insert.  
While the ipilimumab IB contains management algorithms for similar AEs, it is 
recommended to follow the AE management algorithms for I-O agents in the nivolumab 
package insert. 
For patients expected to require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an AE, consider recommendations provided in the 
nivolumab package insert. 
Immune-related adverse events (irAEs) are specific events occurring within 100 days of the 
last dose (which includes pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, 
rash, and endocrine abnormalities [adrenal insufficiency, hypothyroidism/thyroiditis, 
hyperthyroidism, diabetes mellitus, and hypophysitis]), regardless of causality, for which 
patients received immunosuppressive medication for treatment of the event. The exception to 
the immunosuppressive medication criteria for irAEs is endocrine events (e.g., 
hypothyroidism/thyroiditis, hyperthyroidism, hypophysitis, diabetes mellitus, adrenal 
insufficiency), which are included regardless of treatment since these events are often 
managed without immunosuppression. 
7.12.5.2  Criteria to Resume Treatment 
Patients may resume treatment with any of the 3 study drugs when the drug-related AE(s) 
resolve to Grade ≤ 1 or baseline value, with the following exceptions: 
• Patients may resume treatment in the presence of Grade 2 fatigue. 
• Patients who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity. 
• Patients with baseline Grade 1 AST/ALT or total bilirubin who require dose omissions for 
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in 
the presence of Grade 2 AST/ALT OR Grade 2 total bilirubin. 
• Patients with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters should have treatment permanently discontinued. 
• Drug-related pulmonary toxicity, diarrhea, colitis, uveitis or neurological toxicity, must 
have resolved to baseline before treatment is resumed. 
• Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment. 
If the criteria to resume treatment are met, the patient should restart treatment at the next 
scheduled time point per protocol. However, if the treatment is withheld past the window 
period of the next scheduled time point per protocol to ensure adequate recovery from the AE 
or tapering of immunosuppression, the dosing should continue to be withheld until the 
subsequent scheduled time point.  
If treatment is withheld > 6 weeks from the last dose, the patient must be permanently 
discontinued from study therapy, except as specified in Section 712.4. 

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7.12.6 Dose Modifications  
Dose reductions or dose escalations of ipilimumab or nivolumab for individual patients are 
not permitted. 
7.12.7 Treatment of Tocilizumab, Nivolumab or Ipilimumab-Related Infusion Reactions 
Since nivolumab and ipilimumab contains only human immunoglobulin protein sequences, 
and tocilizumab is humanized, they are unlikely to be immunogenic and induce infusion or 
hypersensitivity reactions. However, if such a reaction were to occur, it might manifest with 
fever, chills, rigors, headache, rash, pruritus, arthralgias, hypo- or hypertension, 
bronchospasm, or other symptoms. All Grade 3 or 4 infusion reactions should be reported as 
an SAE if criteria are met. Infusion reactions should be graded according to National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE [version 5.0]) 
guidelines. 
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines as appropriate: 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated) 
Remain at bedside and monitor patient until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes 
before additional tocilizumab, nivolumab or ipilimumab administrations. 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g., antihistamines, nonsteroidal 
anti-inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for ≤ 24 hours). 
Stop the tocilizumab, nivolumab or ipilimumab infusion, begin an IV infusion of normal 
saline, and treat the patient with diphenhydramine 50 mg IV (or equivalent) and/or 
paracetamol 325 to 1000 mg (acetaminophen); remain at bedside and monitor patient until 
resolution of symptoms. Corticosteroid or bronchodilator therapy may also be administered 
as appropriate. If the infusion is interrupted, then restart the ipilimumab and/or nivolumab 
infusion at 50% of the original infusion rate when symptoms resolve; if no further 
complications ensue after 30 minutes, the rate may be increased to 100% of the original 
infusion rate. Monitor patient closely. If symptoms recur then no further tocilizumab, 
nivolumab or ipilimumab will be administered at that visit. Administer diphenhydramine 50 
mg IV, and remain at bedside and monitor the patient until resolution of symptoms. The 
amount of study drug infused must be recorded on the case report form (CRF). The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) should be administered 
at least 30 minutes before additional nivolumab or ipilimumab administrations. If necessary, 
corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be 
used. If a patient has symptoms of anaphylaxis or hypersensitivity, or requires an interruption 
of tocilizumab because of symptoms of anaphylaxis or hypersensitivity felt due to 
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For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [i.e., not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[e.g., renal impairment, pulmonary infiltrates]). Grade 4: (life-threatening; pressor or 
ventilatory support indicated).  
Immediately discontinue infusion of tocilizumab, nivolumab or ipilimumab. Begin an IV 
infusion of normal saline, and treat the patient as follows: recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 1:1,000 solution for subcutaneous or intramuscular 
administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV administration, 
and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), as 
needed. Patient should be monitored until the Investigator is comfortable that the symptoms 
will not recur. Tocilizumab, nivolumab or ipilimumab will be permanently discontinued. 
Investigators should follow their institutional guidelines for the treatment of anaphylaxis. 
Remain at bedside and monitor patient until recovery from symptoms. In the case of late-
occurring hypersensitivity symptoms (e.g., appearance of a localized or generalized pruritus 
within 1 week after treatment), symptomatic treatment may be given (e.g., oral antihistamine, 
corticosteroids). 
7.12.8  Discontinuation Criteria 
Treatment with ipilimumab and nivolumab should be permanently discontinued for the 
following: 
• Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within 3 weeks OR requires 
systemic treatment. 
• Any Grade 3 nonskin, drug-related AE lasting > 7 days, with the following exceptions for 
drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, diarrhea, 
colitis, neurologic toxicity, hypersensitivity reactions, and infusion reactions: 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, 
neurologic toxicity, hypersensitivity reaction, or infusion reaction of any 
duration requires discontinuation. 
o Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except:  
 Grade 3 drug-related thrombocytopenia > 7 days or associated with 
bleeding requires discontinuation. 
 Any drug-related liver function test (LFT) abnormality that meets the 
following criteria require discontinuation:  
• AST or ALT > 8 × ULN 
• Total bilirubin > 5 × ULN 
• Concurrent AST or ALT > 3 × ULN and total bilirubin > 2 × 
ULN 
• Creatinine greater than 6 × ULN. 

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• Any severe or Grade 3 immune-mediated adverse reaction that recurs on reintroduction of 
nivolumab with ipilimumab, or nivolumab alone, or an inability to reduce corticosteroid 
dose to 10 mg or less of prednisone or equivalent per day within 12 weeks. 
• Persistent Grade 2 or 3 immune-mediated adverse drug reactions that do not recover to 
Grade 1 or resolve within 12 weeks after the last dose of study drug. 
• Any Grade 4 drug-related AE or laboratory abnormality, except for the following events 
which do not require discontinuation: 
o Grade 4 amylase or lipase abnormalities that are not associated with symptoms 
or clinical manifestations of pancreatitis. It is recommended to consult with 
the BMS Medical Monitor for Grade 4 amylase or lipase abnormalities. 
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset. 
• Dosing that is withheld > 6 weeks from the last dose with the following exceptions: 
o Dosing omissions to allow for prolonged steroid tapers to manage drug-related 
AEs are allowed. Prior to re-initiating treatment in a patient with a dosing 
omission period lasting > 6 weeks from the last dose, the BMS Medical 
Monitor must be consulted.  
o Dosing omissions > 6 weeks from the last dose that occur for nondrug-related 
reasons may be allowed if approved by the BMS Medical Monitor. Prior to re-
initiating treatment in a patient with a dosing omission period lasting > 6 
weeks from the last dose, the BMS Medical Monitor must be consulted.  
• Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the patient with continued nivolumab or 
ipilimumab dosing. 
• Tumor surveillance assessments and biomarker sampling should continue as per protocol 
even if dosing is omitted, and should be delayed for delayed dosing. 
7.12.9  Treatment of tocilizumab-Related Toxicities 
Non-hematological toxicities ≥ Grade 3 and considered to be treatment-related should be 
managed with tocilizumab treatment interruption until resolution of toxicity to ≤ Grade 1 or 
to baseline value.  If the toxicity is adequately managed by routine supportive care (such as 
anti-emetics, anti-diarrheals, or electrolyte supplementation), treatment may be resumed at 
the same dose; if not, treatment may be resumed at a reduced dose (Table 1).  Recurrence of 
the toxicity may be managed similarly.  If treatment is interrupted for ≥ 28 days, permanent 
discontinuation from study treatment should be considered. 

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Table 6 : Tocilizumab Dose Modifications – Non-Hematological Drug-Related 
Toxicities Including Hepatotoxicity 
 
 
Lab Value 
Action 
> 1 to 3x ULN 
Dose modify concomitant hepatotoxic medications  
 
For persistent increases in this range, reduce tocilizumab 
dose to 2 mg/kg or interrupt tocilizumab until ALT/AST 
have normalized 
 
> 3 to 5x ULN 
(confirmed 
by 
repeat testing) 
Interrupt tocilizumab dosing until < 3x ULN and follow 
recommendations above for >1 to 3x ULN 
 
For persistent increases > 3x ULN, discontinue tocilizumab 
> 5x ULN 
Discontinue tocilizumab 
 
Patients withdrawn from tocilizumab treatment due to elevated liver function tests should have repeat tests 
performed, as clinically appropriate, until levels return to baseline.  If the patient’s liver function tests have not 
returned to baseline within 6 months (or sooner, if deemed necessary by the sponsor or designee), an ultrasound 
and/or liver biopsy should be considered 
 
7.12.10 Management of Tocilizumab in Event of Hematological Toxicities 
Hematological toxicities ≥ Grade 3 and considered to be treatment-related should be managed 
with treatment interruption until resolution as described in Table 3.  Recurrence of the 
toxicity may be managed similarly.  If treatment is interrupted for ≥ 28 days, permanent 
discontinuation from study treatment should be considered. 

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ANC (cells/mm3) 
Action 
> 1000 
Maintain dose. 
500 – 1000 
Interrupt tocilizumab dosing. 
When ANC increases to > 1000, resume 
tocilizumab  
 
< 500 
Discontinue tocilizumab. 
 
Patients withdrawn from tocilizumab treatment due to a reduced neutrophil count should be 
monitored for signs of infection, with treatment as deemed appropriate by the sponsor or 
designee, and should have a repeat white blood cell count with differential performed weekly 
until the ANC is above 1000 cells/mm3 (1.0 x 109/L). If the ANC does not return to above 1000 
cells/mm3 (1.0 x 109/L) within 2 months (or sooner if deemed necessary by the sponsor or 
designee), a hematology referral is recommended. 
 
Platelet count (cells/mm3) 
Action 
> 100,000 
Maintain dose. 
 
50,000 – 100,000 
Interrupt tocilizumab dosing. 
 
When platelet count increases to > 100,000, resume 
tocilizumab at 4 mg/kg  
 
< 50,000 
Discontinue tocilizumab. 
Patients withdrawn from tocilizumab treatment due to a reduced platelet count should have a 
repeat platelet count performed weekly until the count is above 100,000 cells/mm3 (100 x 
109/L). If the platelets do not return to above 100,000 cells/mm3 (100 x 109/L) within 2 
months (or sooner if deemed necessary by the sponsor or designee), a hematology referral is 
recommended 
 

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8 
ASSESSMENT OF SAFETY 
 
8.1 
 Adverse Events 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of 
a preexisting medical condition in a clinical investigation patient administered study drug and 
that does not necessarily have a causal relationship with this treatment. An AE can therefore 
be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of study drug, whether or not considered related 
to the study drug. 
The causal relationship to study drug is determined by a physician and should be used to 
assess all AEs. The causal relationship can be one of the following: 
• Related: There is a reasonable causal relationship between study drug administration and 
the AE. 
• Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.  
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a patient. In order to prevent reporting bias, patients should not 
be questioned regarding the specific occurrence of one or more AEs. 
The start and stop time of the study drug infusions should be documented. If there are any 
new or worsening clinically significant changes since the last exam, report changes on the 
appropriate nonserious AE or SAE page. 
Adverse events will be categorized using the most current version of Medical Dictionary of 
Regulatory Activities (MedDRA). Adverse events and laboratory values will be graded 
according to the NCI CTCAE version 5.0. Baseline signs and symptoms are those that are 
assessed within 14 days prior to the first dose of study drug. Immune-related adverse events 
among treated patients will be specifically assessed as well.  
8.2  Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
• Results in death. 
• Is life-threatening (defined as an event in which the patient was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if 
it were more severe). 
• Requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below). 

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• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event (defined as a medical event[s] that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the patient or may require intervention [e.g., 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization. Potential drug-induced liver injury (DILI) is also 
considered an important medical event. See Section 8.10 the definition of potential DILI. 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the 
study drug is an SAE.  
Although pregnancy, overdose, cancer, and potential DILI are not always serious by 
regulatory definition, these events must be handled as SAEs. (See Section 8.4.1 for reporting 
pregnancies). 
Any component of a study endpoint that is considered related to study therapy (e.g., death is 
an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be 
reported as SAE (see Section 8.5 for reporting details). 
NOTE:  
The following hospitalizations are not considered SAEs:  
• A visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event). 
• Elective surgery, planned prior to signing consent. 
• Admissions as per protocol for a planned medical/surgical procedure. 
• Routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy). 
• Medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases. 
• Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
• Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols). 
8.3  Nonserious Adverse Events 
A nonserious AE is an AE not classified as serious. 

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8.3.1  Nonserious Adverse Event Collection and Reporting 
The collection of nonserious AE information should begin when patients give written 
informed consent to participate and continue until 100 days from the last dose of study 
drug. Nonserious AE information should also be collected from the start of a placebo lead-in 
period or other observational period intended to establish a baseline status for the patients. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 8.5). Follow-up is also required for nonserious AEs that cause 
withholding or discontinuation of study drug and for those present at the end of study 
treatment as appropriate. All identified nonserious AEs must be recorded and described on 
the electronic CRF .  
8.4  Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities should be captured on the AE CRF page or 
SAE Report Form (paper or electronic) as appropriate: 
• Any laboratory test result that is clinically significant or meets the definition of an AE  
• Any laboratory test result abnormality that required the patient to have study drug omitted 
or discontinued  
• Any laboratory test result abnormality that required the patient to receive specific 
corrective therapy 
It is expected that wherever possible, the clinical rather than laboratory term would be used 
by the reporting Investigator (e.g., anemia versus low hemoglobin value). 
8.4.1  Pregnancy 
If, following initiation of the study drug, it is subsequently discovered that a study patient is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the Investigator must immediately notify the 
sponsor,  NYU, which will have the responsibility to report this event to BMS Worldwide 
Safety and Genentech Inc. and complete and forward a Pregnancy Surveillance Form to BMS 
and Genentech Inc.within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Section 8.5. 
In most cases, the study drug will be permanently discontinued in an appropriate manner 
(e.g., dose tapering if necessary for patient safety). 
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, 
after consultation with NYU DSMC, the pregnant patient may continue study drug after a 
thorough discussion of benefits and risk with the patient  
Protocol-required procedures for study discontinuation and follow-up must be performed on 
the patient unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. 

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Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable, offspring information must be reported on the 
Pregnancy Surveillance Form. 
Any pregnancy that occurs in a female partner of a male study participant should be reported 
to BMS and Genentech Inc..   
In order to collect any pregnancy surveillance information from the female partner, the 
female partner must sign an informed consent form for disclosure of this information.  
8.5  Reporting of Serious Adverse Events and Unanticipated Problems 
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, 
formats and requirements of the various entities to which they are responsible, but at a 
minimum those events that must be reported within 24 hours of PI notification are those that 
are: 
• related to study participation, 
• unexpected, and  
• Harmful or have the potential to cause harm (see definitions, sections 8.1, 8.2) 
   
Events should be reported using the NYU CTO Medical Events Form. 
 
Adverse events that do not fit the above immediately reportable criteria must still be reported 
to the IRB at each annual review, either in a summary or tabular format. 
 
For studies involving collection of survival data/ follow up until progression free period/ 
Extended follow up period (select applicable) the investigator after the end of the adverse 
event reporting period (defined as {xx- days after the last dose of study drug) should report 
all deaths, (regardless of cause), and any serious adverse event including development of 
cancer or a congenital anomaly in a subsequently conceived offspring of a female subject 
[add if applicable-including pregnancy occurring in the partner of a male study subject] who 
participated in the study that is believed to be related to prior exposure to study drug. 
Case Transmission Verification will be performed by both parties during this period to ensure 
successful transmission of Single case reports  
 
Case Transmission Verification of Single Case Reports 
 
The Sponsor agrees to conduct the Case Transmission verification to ensure that all single 
case reports have been adequately received by Genentech via NYU emailing Genentech a 
Quarterly line-listing documenting single case reports sent by NYU to Genentech in the 
preceding time period.  
The periodic line-listing will be exchanged within seven (7) calendar days of the end of the 
agreed time period. Confirmation of receipt should be received within the time period 
mutually agreed upon. 
                    
If discrepancies are identified, the Sponsor and Genentech will cooperate in resolving the 
discrepancies. The responsible individuals for each party shall handle the matter on a case-
by-case basis until satisfactory resolution.  The sponsor shall receive reconciliation guidance 
documents within the ‘Activation Package’. 

S 1 9- 0 0 0 0 8 
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Pa ge  7 9  of  1 2 4  
 
 
F oll o wi n g Case Tra ns missi o n Verificati o n, si n gle case re p orts w hic h h a ve n ot bee n recei ve d 
b y Ge ne ntec h s hall be f or war d e d b y N Y U t o G e n e ntec h wit hi n fi ve ( 5) cal e n dar da ys fr o m 
re q uest b y Ge n e ntec h I nc. 
 
t he e n d of t he st u d y, a fi n al c u m ulati ve Case Tra ns missi o n Verificati o n re p ort will be se nt t o 
Ge ne ntec h  I nc 
 
A Es of S pecial I nterest ( A E SIs)  
 
A E SIs are a s u bset of E v e nts t o M o nit or ( Et Ms) of scie ntific a n d me di cal c o ncer n s pecific t o 
t he pr o d uct, f or w hic h o n g oi n g m o nit ori n g a n d ra pi d c o m m u nicati o n b y t he I n v esti gat or t o 
t he S p o ns or is re q uire d. S uc h a n e ve nt mi g ht re q uire f urt her i n vesti gati o n i n or der t o 
c haracteri ze a n d u n d ersta n d it. De pe n di n g o n t he n at ure of t he e ve nt, ra pi d c o m m u nicati o n b y 
t he trial S p o ns or t o ot her parties (e. g., Re g ul at or y A ut h orities) ma y als o be warra nte d. 
 
T he { St u d y Dr u g } E ve nts of S pecial I nterest are:  
A d verse e v e nts of s pecial i nterest f or t his st u d y i ncl u de t he f oll o wi n g: 
•  
Cases of p ote ntial dr u g-i n d uce d li ver i nj ur y t hat i ncl u de a n el e vate d A L T or A S T i n 
c o m bi nati o n wit h eit her a n ele vat e d bilir u bi n or cli nical ja u n dice, as defi ne d b y H y’s la w: 
• 
T reat me nt-e mer ge nt A L T or A S T > 3 X  U L N i n c o m bi nati o n wit h t otal bilir u bi n  2  
U L N  
• 
T reat me nt-e mer ge nt A L T or A S T > 3 X U L N i n c o m bi nati o n wit h cli nical ja u n dice  
 
E xc ha n ge O F SI N G L E C A S E R E P O R T S  
 
N Y U will be res p o nsi ble f or c ollecti n g all pr ot oc ol- defi ne d A d v erse E ve nts ( A Es) a n d 
S pecial Sit uati o n Re p orts (i ncl u di n g pre g na n c y re p orts) ori gi nati n g fr o m t he St u d y f or t he 
Pr o d uct.  
 
I n v esti gat ors m ust re p ort all A d verse E v e nts/ Seri o us A d verse e ve nts ( S A Es), A Es of S pecial 
I nterest ( A E SIs)  a n d S pecial Sit uati o n Re p orts (i ncl u di n g pre g na nc y re p orts) a de q uat el y t o 
Ge ne ntec h wit hi n t he ti meli nes descri be d b el o w. T he c o m plete d Me d Watc h or CI O M S I 
f or m or Ge n e ntec h a p pr o ve d re p orti n g f or ms s h o ul d be fa xe d i m me diatel y u p o n c o m pleti o n 
t o Ge ne ntec h Dr u g Saf et y at: 
8. 6   I n vesti g at or re p orti n g:  n otif yi n g t he st u d y s p o ns or a n d Perl m utter C a ncer 
Ce nter Cli nic al Tri als Office  
T he f oll o wi n g descri b es e ve nts t hat m ust be re p orte d t o t he st u d y s p o ns or i n a n e x pe dite d 
fas hi o n. 
 
I niti al Re p ort : wit hi n 2 4 h o urs:  
T he f oll o wi n g e ve nts m ust be re p orte d t o t he st u d y s p o ns or wit hi n 2 4 h o urs of a ware ness of 
t he e ve nt usi n g t he N Y U C T O Me dical E ve nts F or m :  
•  U na ntici pate d pr o ble ms r elate d t o st u d y partici pati o n,  

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Serious adverse events, regardless of whether they are unexpected. The study sponsor will 
then report all medical events to BMS and Genentech Inc. directly. 
All report forms must be signed and dated by the Principal Investigator.  If the Principal 
Investigator is not available at the time of the initial report, then the form can be submitted by 
a Sub-Investigator.  This form should be reviewed by the Principal Investigator, whom 
sign/date initial report upon return. 
   
Report to: 
NYUPCCsafetyreports@nyulangone.org 
 
 
AND 
 
Jeffrey S. Weber, MD, PhD 
Laura and Isaac Perlmutter Cancer Center 
160 E. 34th Street 
New York, NY 10016 
Tel:  212-263-9333 
Email:  Jeffrey.Weber@nyulangone.org 
 
AND  
 
PCC Assigned Medical Monitor 
 
 
 
 
 
 
Genentech Inc. at FAX (650) 225-4682 or (650) 225-4630 
 
Follow-up report: within 48 hours: 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, 
the investigator shall provide further information, as applicable, on the unanticipated device 
event or the unanticipated problem in the form of a written narrative.  This should include 
any other diagnostic information that will assist in the understanding of the event.  Significant 
new information on ongoing unanticipated adverse device effects shall be provided promptly 
to the study sponsor.   
 
Other Reportable events: 
• Deviations from the study protocol 
Any protocol deviations initiated without Sponsor and the investigator’s IRB approval 
that may affect the scientific soundness of the study, or affect the rights, safety, or 
welfare of study subjects, must be reported to the Sponsor and to the investigator’s 
IRB as soon as a possible, but no later than 5 working days of the protocol deviation. 
 
• Withdrawal of IRB approval 
An investigator shall report to the sponsor a withdrawal of approval by the 
investigator’s reviewing IRB as soon as a possible, but no later than 5 working days 
of the IRB notification of withdrawal of approval. 
8.7  Investigator reporting:  notifying the IRB 

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Federal regulations require timely reporting by investigators to their local IRB of 
unanticipated problems posing risks to subjects or others.  The following describes the 
NYULMC IRB reporting requirements, though Investigators at participating sites are 
responsible for meeting the specific requirements of their IRB of record.  The NYU IRB 
address is: 
 
 
 
NYU School of Medicine IRB 
 
 
 
1 Park Avenue, 6th Floor 
New York, NY 10016 
 
Report promptly, but no later than 5 working days: 
Researchers are required to submit reports of the following problems promptly but no later 
than 5 working days from the time the investigator becomes aware of the event: 
• Unanticipated problems including adverse events that are unexpected and related 
– Unexpected: An event is “unexpected” when its specificity and severity are not 
accurately reflected in the protocol-related documents, such as the IRB-approved 
research protocol, any applicable investigator brochure, and the current IRB-
approved informed consent document and other relevant sources of information, 
such as product labeling and package inserts.  
– Related to the research procedures: An event is related to the research procedures 
if in the opinion of the principal investigator or sponsor, the event was more likely 
than not to be caused by the research procedures.  
– Harmful: either caused harm to subjects or others, or placed them at increased risk 
 
Other Reportable events: 
The following events also require prompt reporting to the IRB, though no later than 5 
working days: 
• Complaint of a research subject when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team. 
• Protocol deviations or violations (includes intentional and accidental/unintentional 
deviations from the IRB approved protocol) for any of the following situations:  
– one or more participants were placed at increased risk of harm  
– the event has the potential to occur again 
– the deviation was necessary to protect a subject from immediate harm 
• Breach of confidentiality 
• Incarceration of a participant when the research was not previously approved under 
Subpart C and the investigator believes it is in the best interest of the subject to remain 
on the study. 
• New Information indicating a change to the risks or potential benefits of the research, 
in terms of severity or frequency. (e.g. analysis indicates lower-than-expected response 
rate or a more severe or frequent side effect; Other research finds arm of study has no 
therapeutic value; FDA labeling change or withdrawal from market) 

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Reporting Process 
The reportable events noted above will be reported to the IRB using the form: “Reportable 
Event Form” or as a written report of the event (including a description of the event with 
information regarding its fulfillment of the above criteria, follow-up/resolution and need for 
revision to consent form and/or other study documentation). The contact information for 
submitting IND safety reports is noted below: 
 
 
 
 
 
Email:  NYUPCCsafetyreports@nyulangone.org 
 
 
 
 
 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the 
Clinical Investigator’s study file. 
 
8.8   Sponsor reporting:  Notifying BMS 
 
All SAEs (whether related or not to study drug) and medically important conditions must be 
reported to BMS Worldwide Safety via fax or email within 24 hours/1 business day of 
becoming aware of the event.  SAEs including pregnancies are to be reported using FDA 
MedWatch 3500. 
  
Global Pharmacovigilance & Epidemiology (GPV&E) 
Bristol-Myers Squibb Company 
  
SAE Emailing Address:  Worldwide.Safety@BMS.com 
  
SAE Facsimile Number:  BMS: 1-609-818-3804 
 
 
 
 
 
      Genentech Inc. (650) 225-4682 or (650) 225-4630 
  
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. 
  
The causal relationship to study drug is determined by a physician and should be used to 
assess all adverse events (AE). The casual relationship can be one of the following: 
·        Related: There is a reasonable causal relationship between study drug administration 
and the AE. 
·        Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
  
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
  

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The Sponsor Investigator will reconcile the clinical database SAE cases (case level only) 
transmitted to BMS Global Pharmacovigilance (Worldwide.Safety@bms.com). Frequency of 
reconciliation should be every 3 months and prior to the database lock or final data summary. 
BMS GPV&E will email, upon request from the Investigator, the GPV&E reconciliation 
report. Requests for reconciliation should be sent to aepbusinessprocess@bms.com. The data 
elements listed on the GPV&E reconciliation report will be used for case identification 
purposes. If the Investigator determines a case was not transmitted to BMS GPV&E, the case 
should be sent immediately to BMS. 
  
In addition to the Sponsor Investigator’s responsibility to report events to their local HA, 
suspected serious adverse reactions (whether expected or unexpected) shall be reported by 
BMS to the relevant competent health authorities in all concerned countries according to 
local regulations (either as expedited and/or in aggregate reports). 
  
In accordance with local regulations, BMS will notify sponsor investigators of all reported 
SAEs that are suspected (related to the investigational product) and unexpected (i.e., not 
previously described in the IB). An event meeting these criteria is termed a Suspected, 
Unexpected Serious Adverse Reaction (SUSAR). Sponsor investigator notification of these 
events will be in the form of either a SUSAR Report or a Semi-Annual SUSAR Report.  
  
Other important findings which may be reported by BMS as an Expedited Safety Report 
(ESR) include: increased frequency of a clinically significant expected SAE, an SAE 
considered associated with study procedures that could modify the conduct of the study, lack 
of efficacy that poses significant hazard to study subjects, clinically significant safety finding 
from a nonclinical (e.g., animal) study, important safety recommendations from a study data 
monitoring committee, or sponsor or BMS decision to end or temporarily halt a clinical study 
for safety reasons. 
  
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with the 
IB. Where required by local regulations or when there is a central IRB/IEC for the study, the 
sponsor will submit the ESR to the appropriate IRB/IEC. The investigator and IRB/IEC will 
determine if the informed consent requires revision. The investigator should also comply with 
the IRB/IEC procedures for reporting any other safety information.     
  
Following the patient’s or the legal representative’s written consent to participate in the 
study, all SAEs, whether related or not related to study drug, must be collected, including 
those thought to be associated with protocol-specified procedures. All SAEs must be 
collected that occur during the screening period and within 100 days of discontinuation of 
dosing. If applicable, SAEs must be collected that relate to any later protocol-specified 
procedure (e.g., a follow-up skin biopsy).  
The Investigator should report any SAE that occurs after these time periods and that is 
believed to be related to study drug or protocol-specified procedure.  
An SAE report should be completed for any event where doubt exists regarding its 
seriousness.  
If the Investigator believes that an SAE is not related to study drug, but is potentially related 
to the conditions of the study (such as withdrawal of previous therapy or a complication of a 

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study procedure), the relationship should be specified in the narrative section of the SAE 
Report Form. 
All SAEs should be followed to resolution or stabilization. 
8.8.1  NONSERIOUS ADVERSE EVENT 
·        Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim 
or final study reports as specified in the agreement or, if a regulatory requirement 
[e.g., IND US trial] as part of an annual reporting requirement.  
·        Non-serious AE information should also be collected from the time of signing of 
informed consent and is intended to establish a baseline status for the subjects.  
  
8.8.1.1  Non-serious Adverse Event Collection and Reporting 
The collection of non-serious AE information should begin at the time of signing of informed 
consent. All non-serious adverse events (not only those deemed to be treatment-related) 
should be collected continuously during the treatment period and for a minimum of 100 days 
following the last dose of study treatment.  
  
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if 
they become serious. Follow-up is also required for non-serious AEs that cause interruption 
or discontinuation of study drug and for those present at the end of study treatment as 
appropriate.  
  
8.9  Sponsor reporting:  Notifying Genentech 
 
8.9.1 Assessment of Adverse Events 
 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start 
and end dates), regulatory seriousness criteria if applicable, suspected relationship to the 
tocilizumab (see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
 
Yes 
 
There is a plausible temporal relationship between the onset of the AE and administration of 
the tocilizumab, and the AE cannot be readily explained by the subject’s clinical state, 
intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of 
response to the tocilizumab; and/or the AE abates or resolves upon discontinuation of the 
tocilizumab or dose reduction and, if applicable, reappears upon re- challenge. 
 
 

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No 
 
Evidence exists that the AE has an etiology other than the tocilizumab (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); 
and/or the AE has no plausible temporal relationship to tocilizumab administration (e.g., 
cancer diagnosed 2 days after first dose of study drug). 
 
 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert (P.I) or current Investigator Brochure (I.B). 
 
Unexpected adverse events are those not listed in the P.I or current I.B or not identified. This 
includes adverse events for which the specificity or severity is not consistent with the 
description in the P.I. or I.B. For example, under this definition, hepatic necrosis would be 
unexpected if the P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis. 
 
8.9.2 AEs of Special Interest (AESIs) 
 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific 
to the product, for which ongoing monitoring and rapid communication by the 
Investigator to the Sponsor is required. Such an event might require further investigation 
in order to characterize and understand it. Depending on the nature of the event, rapid 
communication by the trial Sponsor to other parties (e.g., Regulatory Authorities) may 
also be warranted. 
 
The tocilizumab  Events of Special Interest are:  
Adverse events of special interest for this study include the following: 
 
• Cases of potential drug-induced liver injury that include an elevated ALT or AST 
in combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law noted below.  The risk of serious hepatotoxicity associated with the use 
of tocilizumab was also recently described in a “Dear Investigator Letter” 
distributed by F. Hoffmann-La Roche Ltd: 
• Serious or medically significant hepatic events 
• Serious and/or medically significant infections 
• Myocardial infarction/Acute coronary syndrome 
• Gastrointestinal perforations 
• Malignancies 
• Anaphylaxis/Hypersensitvity reactions 
• Demyelinating disorders 
• Stroke 
• Serious and/or medically significant bleeding events 
 

S 1 9- 0 0 0 0 8 
Versi o n 4. 3  
 
 
 
 
 
 
Pa ge  8 6  of  1 2 4  
 
 
8. 9. 3 E xc h a n ge O F SI N G L E C A S E R E P O R T S  
 
 
Perl m utter Ca ncer Ce nt er  will be res p o nsi ble f or c ollecti n g all pr ot oc ol- defi ne d A d vers e 
E ve nts ( A Es) a n d S pecial Sit uati o n Re p orts (i ncl u di n g pre g na nc y re p orts) a n d pr o d uct 
c o m plai nt ( wit h or wit h o ut A Es) ori gi nati n g fr o m t he St u d y f or t he Pr o d uct.  
 
I n v esti gat ors m ust r e p ort all A d verse E v e nts/ Seri o us A d verse e ve nts ( S A Es), A Es of S pecial 
I nterest ( A E SIs)  a n d S pecial Sit uati o n Re p orts (i ncl u di n g pre g na nc y re p orts) a de q uatel y t o 
G e ne nt ec h  wit hi n  t he ti meli nes descri be d  b el o w.   
 
T he  c o m plete d Med W at c h or CI O M S I f or m or G e ne ntec h a p pr o ve d re p orti n g f or ms s h o ul d 
be fa x e d/e maile d i m me diatel y u p o n c o m pleti o n t o Ge ne ntec h at t he f oll o wi n g c o ntacts: 
 
All pr ot oc ol- defi ne d A Es, S A Es, A E SIs, S peci al Sit uati o n Re p orts (i ncl u di n g pre g na nc y 
re p orts) a n d Pr o d u ct C o m plai nts wit h  a n A E s h o ul d be se nt t o: 
 
 
F a x: 6 5 0- 2 3 8- 6 0 6 7 
E m ail: us ds _aere p orti n g- d @ ge ne. c o m  
 
All Pr o d uct C o m plai nts w it h o ut a n A E s h o ul d be se nt t o: 
E m ail:  k aiser a u gst. gl o b al _i m pc o m pl ai nt _ m a n a ge me nt @r oc he.c o m  
 
It is u n derst o o d a n d a gr ee d t hat t he S p o ns or will be res p o nsi ble f or t he e v al uati o n of 
A Es/ S A Es, A E SIs, S peci al Sit uati o n Re p orts (i ncl u di n g pre g na nc y re p orts) a n d Pr o d uct 
C o m plai nts ( wit h or wit h o ut  a n A E) ori gi nati n g fr o m t he st u d y.  
T hese si n gle cas e re p orts will be e xc ha n g e d bet wee n t he parties as o utli ne d bel o w s o t hat 
re g ulat or y o bli gati o ns ar e met. 
 
Seri o us a d ver se e v e nts ( S A Es), A Es  of S pecial  I nt erest ( A E SIs), pre g n a nc y re p orts 
(i ncl u di n g pre g na n c y occ urri n g i n t he part ner of a male st u d y s u bject), a n d ot her S pecial 
Sit uati o n Re p orts w here  t he patie nt  has bee n  e x p os e d t o t he Ge ne ntec h Pr o d uct, will  be se nt 
o n a N Y U C T O Me dical E ve nts F or m  t o  Ge ne ntec h Dr u g Safet y . Tra ns missi o n  of t hese 
re p orts (i nitial a n d f oll ow- u p) will  be eit her electr o nicall y  or b y fa x a n d wit hi n  t he ti meli nes 
s pecifie d bel o w: 
 
 
     S A D Rs  
Se ri o us A E re p orts t hat are relat e d t o t he Pr o d uct s hall be tra ns mitte d t o Ge ne ntec h  
wit hi n  fiftee n ( 1 5) cale n dar da ys of t h e a ware n ess  date.  
 
     O t her S AEs  
Seri o us  A E re p orts  t hat ar e  u nrelate d t o  t he  Pr o d uct s hall  be tra ns mitt ed t o 
Ge ne ntec h  wit hi n  t hirt y ( 3 0) cale n d ar da ys of  t he a ware ness  date.  
 
•  A E SIs  

S 1 9- 0 0 0 0 8 
Versi o n 4. 3  
 
 
 
 
 
 
Pa ge  8 7  of  1 2 4  
 
A E SIs  s hall  be f or w ar d ed t o G e n e nt e c h  wit hi n  fiftee n  ( 1 5) cale n d ar d a ys  of t he 
a ware ness  date. See secti o n 8. 9. 2 f or A E SIs 
 
•  S pe ci al Sit u ati o n Re p orts  
 
Pre g n a nc y  re p orts  
W h ile s uc h re p orts are n ot seri o us A Es  or A d v ers e Dr u g R e a cti o ns ( A D Rs)  per se, 
as defi ne d  herei n,  a n y r e p orts of  pre g n a nc y (i n cl u di n g pr e g n a n c y o c c urri n g i n t h e 
p art n er of a m al e st u d y s u bj e ct),   w here t he fet us m a y  h a v e b ee n e x p os ed  t o t he 
Pr o d u ct , s hall  b e tr a ns mitted  t o Ge n e nt ec h  wit hi n t hirty ( 3 0) cale n d ar d a ys  of  t he 
a war e ness  d ate.  Pre g na n cies will  be f oll o we d u p u ntil t he o ut c o me of t he pre g na nc y is 
k n o w n, w he n e ver   p ossi ble, base d   u p o n  d ue  dili ge nce t a ke n t o  o btai n  t he f oll ow- u p 
i nf or mati o n. 
 
Pre g n a ncies i n Fe m ale P art ners of M ale P ati e nts   
 
Male patie nts will be i nstr ucte d t hr o u g h t he I nf or me d C o nse nt F or m t o i m me diatel y 
i nf or m t he i n vesti gat or if t heir part ner b ec o mes pre g na nt d uri n g t he st u d y or wit hi n 3 0 
da ys after t h e last d ose of st u d y dr u g.  A Cli nical Trial Pre g na nc y R e p orti n g F or m 
s h o ul d be c o m plete d a n d s u b mitte d t o Ge ne ntec h wit hi n t hirt y ( 3 0) cale n dar da ys of 
t he a war e ness dat e. 
 
•  O t her S peci al Sit u ati o n Re p orts 
I n a d diti o n t o all SA E s, pre g na nc y re p orts a n d A E SIs,  t h e f oll o wi n g ot her S pecial  
Sit uati o ns  Re p orts s h o ul d be c ollecte d  e ve n  i n t he a bse nce of a n A d v erse  E ve nt a n d 
tra ns mitte d t o Ge ne ntec h wit hi n  t hirt y ( 3 0) cale n dar da ys: 
     D ata relat e d t o t he Pr o d uct usa ge d uri n g breastfee di n g  
 Dat a r elate d t o o ver d os e, a b use, mis use  or me dicati o n err or  (i ncl u di n g p ote ntiall y 
e x p ose d or i nter ce pte d m e dicati o n err ors)  
     Dr u g i nteracti o n 
 Us e of a M e dici nal Pr o d uct i n a Pe diatric a n d El d erl y p o p ulati o n (i n a d diti o n, 
reas o na bl e atte m pts s h o ul d be ma de t o o btai n a n d s u b mit t he a ge or a ge gr o u p of 
t he patie nt, i n or der t o be a ble t o i de ntif y p ote ntial safet y si g nals s pecifi c t o a 
partic ular p o p ulati o n) 
•  Data rel ate d t o a s us pecte d tra ns missi o n of a n i nfecti o us a ge nt b y t he st u d y dr u g 
( S TI A M P), as defi n e d bel o w: 
A n y or ga nis m, vir us, or i nfecti o us particle (e. g., pri o n pr otei n tra ns mitti n g tra ns missi ble 
s p o n gif or m e nce p h al o pat h y), pat h o ge nic or n o n- p at h o ge nic, is c o nsi dere d a n i nfecti o us 
a ge nt.  A tra ns missi o n of a n i nfecti o us a g e nt ma y be s us pecte d fr o m cli nical s y m pt o ms or 
la b orat or y fi n di n gs t hat i n dicate a n i nfecti o n i n a patie nt e x p ose d t o a me di ci nal pr o d uct.  
T his ter m a p plies o nl y w he n a c o nta mi nati o n of t h e st u d y dr u g is s us pecte d 
 
          Pr o d uct  Co m pl ai nts  
All  Pr o d uct  C o m plai nts  ( wit h  or  wit h o ut  a n  A E)  s hall  be  f or w ar de d  t o  Ge ne ntec h            
wit hi n fiftee n ( 1 5) cale n d ar da ys of t he a ware n ess date.  
 
A Pr o d uct C o m plai nt is defi ne d as a n y writte n or oral i nf or mati o n recei ve d fr o m a 
c o m plai na nt t hat alle ges deficie nci es relat e d t o i de ntit y, q ualit y, safet y, stre n gt h, p urit y, 
relia bilit y, d ura bilit y, effecti ve ness, or p erf or ma nce of a pr o d uct after it h as b ee n releas e d 
a n d distri b ute d t o t he c o m mercial mar ket or cli nical trial.  

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 Occasionally Genentech may contact the reporter for additional information, clarification, 
or current status of the patient for whom an adverse event was reported. 
It is understood and agreed that the Sponsor will perform adequate due diligence with regard 
to obtaining follow-up information on incomplete AE, Special Situations and 
pregnancy reports. 
 
8.9.4 Post-Study Adverse Events  
 
For studies involving collection of Extended follow up period the investigator after the end of 
the adverse event reporting period (defined as {5 years after the last dose of study drug) 
should report all deaths, (regardless of cause), and any serious adverse event including 
development of cancer or a congenital anomaly in a subsequently conceived offspring of a 
female subject [add if applicable-including pregnancy occurring in the partner of a male 
study subject] who participated in the study that is believed to be related to prior exposure to 
study drug. 
Case Transmission Verification will be performed by both parties during this period to ensure 
successful transmission of Single case reports  
 
8.9.5  Case Transmission Verification of Single Case Reports 
The Sponsor agrees to conduct the Case Transmission verification to ensure that all single 
case reports have been adequately received by Genentech via Perlmutter Cancer Center, 
emailing Genentech a Quarterly line-listing documenting single case reports sent Perlmutter 
Cancer Center,  to Genentech in the preceding time period.  
The periodic line-listing will be exchanged within seven (7) calendar days of the end of the 
agreed time period. Confirmation of receipt should be received within the time period 
mutually agreed upon. 
                    
If discrepancies are identified, the Sponsor and Genentech will cooperate in resolving the 
discrepancies. The responsible individuals for each party shall handle the matter on a case-
by-case basis until satisfactory resolution.  The sponsor shall receive reconciliation guidance 
documents within the ‘Activation Package’. 
 
Following Case Transmission Verification, single case reports which have not been received 
by Genentech shall be forwarded by Perlmutter Cancer Center, to Genentech within five (5) 
calendar days from request by Genentech. 
 
At the end of the study, a final cumulative Case Transmission Verification report will be sent 
to Genentech 
 
8.9.6 Aggregate Reports  
 
IND Annual Reports 
  
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech 
 
Copies of such reports should be emailed to Genentech at:  Genentech Drug Safety CTV mail 
box: ctvist_drugsafety@gene.com 

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8.9.7 Other Reports  
 
Perlmutter Cancer Center,will forward a copy of the Final Study Report to 
Genentech/Roche upon completion of the Study.  
 
8.9.8 Study Close Out 
 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech/Roche. This includes all IND annual reports and the Clinical Study Report (final 
study report). Additionally, any literature articles that are a result of the study should be sent 
to Genentech/Roche. Copies of such reports should be mailed to the assigned Clinical 
Operations contact for the study: 
 
E-mail: ACTEMRA IST Central Mailbox: actemra-gsur@gene.com 
And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com 
8.9.9 Queries 
 
Queries related to the Study will be answered by Perlmutter Cancer Center. 
However, responses to all  safety  queries  from  regulatory  authorities  or  for 
publications will be discussed and coordinated between the Parties. The Parties 
agree that Genentech/Roche shall have the final say and control over safety 
queries relating to the Product. Perlmutter Cancer Center agrees that it shall not 
answer such queries from regulatory authorities and other sources relating to the 
Product independently but shall redirect such queries to Genentech/Roche. 
 
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent 
requests for information or review of data are met. The Parties will clearly indicate on the 
request the reason for urgency and the date by which a response is required. 
 
8.9.10 Safety Crisis Management 
 
In case of a safety crisis, e.g., where safety issues have a potential impact on the 
indication(s), on the conduct of the Study, may lead to labeling changes or 
regulatory actions that limit or restrict the way in which the Product is used, or 
where there is media involvement, the Party where the crisis originates will 
contact the other Party as soon as possible. 
The Parties agree that Genentech/Roche shall have the final say and control 
over safety crisis management issues relating to the Product. Perlmutter Cancer 
Center agrees that it shall not answer such queries from media and other sources 
relating to the Product but shall redirect such queries to Genentech/Roche. 
 
 

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8.10 Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as an SAE (see Section 8.5 for reporting details). 
8.11  Potential Drug-Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event. All occurrences of potential 
DILIs, meeting the defined criteria, must be reported as SAEs (see Section 8.5 for reporting 
details). 
Potential DILI is defined as:  
Aminotransaminase (ALT or AST) elevation > 3 × ULN 
AND 
Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
AND 
No other immediately apparent possible causes of aminotransaminases elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic. 
8.12  Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, ECG, x-ray 
filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious AE or SAE, as appropriate, and reported accordingly.  
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the study Investigator as per 
standard medical/clinical judgment. 
Appropriateness of Measurements 
The efficacy and safety assessments planned for this study are recognized as reliable, 
accurate, and relevant to the disease condition and considered appropriate for this clinical 
study. Tumor assessments will be performed objectively using CT or MRI to measure 
lesions. Assessment of disease progression using ECOG performance status and irRC is 
accepted standard. 
 

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9 
CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of human 
subjects are protected, that the reported trial data are accurate, complete, and verifiable, and 
that the conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with GCP, and with applicable regulatory requirement(s). 
 
9.1  Data Monitoring Committee and Other External Committees 
The Data Safety Monitoring Committee (DSMC) at the Laura and Isaac Perlmutter Cancer 
Center of NYU-Langone Health will provide oversight of safety and efficacy considerations 
in this protocol. Additionally, the DSMC will provide advice to the Sponsor regarding actions 
the committee deems necessary for the continuing protection of patients enrolled in the study. 
The DSMC will be charged with assessing such actions in light of an acceptable benefit/risk 
profile for nivolumab and ipilimumab with tocilizumab. The DSMC will act in an advisory 
capacity and will monitor patient safety and evaluate the available efficacy data for the study. 
When required, adjudicated events will be submitted to the DSMC and Health Authorities for 
review on a specified timeframe in accordance with the adjudication documentation and 
schedule. 
The DSMC will have access to periodic reports of safety and efficacy to allow a risk/benefit 
assessment. The NCI approved DSMC charter is available online at 
https://central.nyumc.org/clin/cancer/NYUR/_layouts/15/WopiFrame.aspx?sourcedoc=/clin/c
ancer/NYUR/Shared%20Documents/Standard%20Operating%20Procedures/DSMC%20SOP
.pdf&action=default   This committee meets monthly. 
Per the NYU PCC Institutional Data Safety and Monitoring Plan, this pilot trial will be 
monitored by DSMC quarterly (from the date the first patient is enrolled), at protocol-
specified interim time points, and at the completion of the study prior to study closure. This 
review includes accrual data, subject demographics and adverse events  Principal 
Investigators are required to attend the review of their studies. Additional reviews can be 
scheduled based on SAE reports, investigator identified issues, external information, etc. The 
DSMC will review safety data every 3 months. DSMC summary reports are available to 
facilitate the review and monitoring of this study. These reports include the following:  
patient listings and summary reports that describe study enrollment and accrual, 
eligibility, demographic characteristics, dose modifications, adverse experiences, 
subject’s death and additional external published data if applicable to the study.  
Cumulative toxicities, SAEs, and AEs are reviewed, to identify possible adverse events 
with elevated frequency that is unexpected.  Once a recommendation is made if further 
action is required, the Investigator must respond within the time period designated by the 
DSMC.   
 

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10 STATISTICAL METHODS 
10.1 Sample Size Considerations 
The first 12 patients at the initial dose level will be evaluated for DLTs. Unacceptable 
toxicity will be defined by a DLT rate of ≥50%.  If we observe ≥6 DLTs in these first 12 
patients, we reject the null hypothesis that the DLT rate is <50% (one sided α=0.05, 
power=80%).  If we do not reject the null hypothesis, the current dosing continues with 6 
additional patients up to 18 patients (which count as the first stage of the optimal 2-stage 
Simon design). There will be no adjustment to the operating characteristics of the optimal 2-
stage Simon design.  
 
To evaluate the co-primary endpoint of the rate of grades 3-5 treatment related immune-
related adverse events, a two-stage Simon Optimal design will be used. With 67 patients in 
two stages (Stage 1: 12+6 patients, Stage 2: 49 patients) we can detect a reduction in the rate 
of the primary toxicity endpoint from 35% to 20% in grades 3-5 treatment related irAEs, with 
alpha of 0.05 and power of 80%.  
With the planned 67 patients for the co-primary toxicity evaluation of immune-related 
adverse events, we can simultaneously evaluate the co-primary efficacy endpoint evaluated 
by overall response rate (ORR) at 6 months over the 18 months of treatment.  Using a Simon 
2-stage optimal and minimax design, we can test the null hypothesis that the ORR rate at 24 
weeks is less than or equal to 50% versus the alternative that it is 70% or greater with a 
maximum of 67 patients with alpha of 0.045 and power of 0.85. 
 
The evaluation of stage 1 will occur when the first 18 patients could have been observed for 
the 6-month period following entry. If 6 or more of the first 18 patients in stage 1 experience 
a grade 3-5 treatment related immune-related adverse event, the rate of toxicity would be 
considered unacceptable (grade 3-5 irAE rate≥35%)  
 
If fewer than 6 patients experience a treatment related immune-related adverse event, the rate 
of toxicity would be considered acceptable (irAE≤20%) .  
 
With an evaluation of the first 18 patients entered on study (who would complete the study 
before the end of study year 2) in stage 1, if we observe 10 or fewer responses, the response 
rate would be considered unacceptable (ORR≤50%) .   Otherwise, if we observe more than 
10 responses, the response rate would be considered acceptable (ORR≥70% 
 
If both toxicity rate and efficacy rate are acceptable, - continue to complete stage 2 with up to 
67 patients.  
 
If toxicity rate is acceptable and response rate is unacceptable , – increase dose to level 2 
(tocilizumab 6 mg/kg every 6 weeks) and restart DLT evaluation with 12 patients.  
 
If toxicity rate is unacceptable (due to irAE rate of grades 3-5 >=35% felt due to 
tocilizumab), and response rate  is acceptable,  – decrease dose level to -1(tocilizumab 2 
mg/kg every 6 weeks) and restart DLT evaluation with 12 patients.  
 
If toxicity rate is unacceptable (due to irAE rate of grades 3-5 >=35% felt due to 
 

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IPI and/or NIVO), and response rate  is acceptable,  – increase dose level to 2(tocilizumab 6 
mg/kg every 6 weeks) and restart DLT evaluation with 12 patients.  
 
If both toxicity rate and response rate are unacceptable  – stop early and consult with 
IRB  and/or FDA.   
 
At the end of Stage 2, if there are 39 or fewer responses out of the total of 67 patients, the 
regimen would be considered unsuccessful. Similarly, if at the end of stage 2, there are 19 or 
more treatment related grade 3-5 irAEs, the trial would be considered unsuccessful to have 
met its objective of reducing the toxicity rate to 20% or less. 
There is no adjustment for these simultaneous assessments of efficacy and safety.   
Accrual will occur over 1.5 years, 22-23 patients per institution or 14 
patients/year/institution. .   
Enrolled Population: All patients who sign an ICF and are registered into the trial. 
As-Treated Population (ATP): All patients who receive any study drug of nivolumab, 
ipilimumab, or tocilizumab. 
DLT Evaluation Population: All patients who receive any study drug of nivolumab, 
ipilimumab, or tocilizumab and either experience a DLT during the first cycle or complete 
the first cycly without experiencing a DLT. Patients who do not complete the DLT period for 
reasons other than toxicity will be replaced. 
Biomarker Population: All patients in the ATP who have available biomarker data (PD-L1 
expression status and other assays). 
10.2 Analysis Schedule  
10.2.1 Interim Analysis  
Interim assessment of the two co-primary endpoints will occur as described in the sample size 
considerations section.  
10.2.2 Final Analysis  
An analysis of the co-primary endpoints is planned after the last patient completes the 
maintenance phase at the end of one year of treatment or discontinues from the study.  
10.3 Statistical Methods  
10.3.1 General Methods  
Statistical analyses will be primarily descriptive in nature, since the goals of the Phase II 
study is to evaluate the toxicity and efficacy of tocilizumab in combination with nivolumab 
and ipilimumab.  
Continuous variables will be summarized using descriptive statistics (n, mean, standard 
deviation, median, minimum, and maximum). Categorical variables will be summarized 

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showing the number and percentage (n, %) of patients within each classification. Graphical 
displays will be provided where useful in the interpretation of results. 
10.3.2 Disposition of Patients  
Patients who are screened for study entry and do not meet the eligibility criteria will be listed 
only. The number and percentage of patients in each population and discontinued early, along 
with the primary reasons for early discontinuation, will be tabulated by study stage.   
10.3.3 Demographics and Baseline Characteristics  
Demographic data (gender, age [years], age group, race, ethnicity, height, weight, body mass 
index), baseline characteristics, and baseline disease characteristics for patients enrolled will 
be summarized by study stage.  
10.3.4 Extent of Exposure  
Study drug administration and information on dose reductions will be summarized for each 
dose level. Descriptive statistics for patients who started and completed each treatment cycle, 
including the number of doses missed/held, will be presented by treatment cycle and overall. 
Furthermore, descriptive statistics for the number of actual doses received and percentage of 
expected dose received will be summarized by treatment cycle. A tabular summary and 
listing of drug administration and dose intensity by treatment cycle, a by-patient listing of the 
dose date and time, and the dose amount administered will also be presented. 
10.3.5  Prior and Concomitant Medications  
Prior and concomitant medications will be coded using the most current World Health 
Organization (WHO) Drug Dictionary. Prior medications will be defined as medications 
documented on the Prior and Concomitant Medications eCRF that started up to 28 days 
before the first dose of study drug and stopped before the first dose of any study drug. 
Concomitant medications will be defined as medications documented on the Prior and 
Concomitant Medications eCRF that a patient started up to 28 days before the first dose of 
study drug or continued to take on or after the first dose of any study drug. Prior and 
concomitant medications will be summarized in separate tables, with concomitant 
medications coded using the WHO Drug Dictionary. All concomitant medications 
administered will be tabulated in a data listing. The statistical analysis plan (SAP) may 
include more details regarding how to summarize medications. 
10.3.6 Safety Analysis  
Safety data will be summarized when 12 patients have completed the second 42-day cycle 
during the induction phase.  In addition, safety data will be summarized for the entire treated 
population at the termination of the study.  
Safety evaluations will be based on the incidence, intensity, and type of AEs, and changes in 
the patient’s physical examination findings, ECOG performance status, vital signs, oxygen 
saturation, ECG findings, and clinical laboratory results. Safety analysis will be performed in 
the ATP. Summarization will focus on occurrence rates of any SAEs; treatment-emergent 

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AEs by system organ class and preferred term; rate of discontinuation study treatment due to 
AE; or toxicity based on clinical laboratory assessment and rates of hematologic toxicity.  
Adverse events will be coded using the MedDRA for purposes of summarization. All AEs 
occurring on study will be listed in by-patient data listings. Treatment-emergent AEs will be 
tabulated, where treatment emergent is defined as any AE that occurs after administration of 
the first dose of study drug through 30 days after the last dose of study drug, any event that is 
considered drug related regardless of the start date of the event, or any event that is present at 
baseline but worsens in intensity or is subsequently considered drug-related by the 
Investigator. 
Adverse events that are considered related to treatment (possibly or probably drug related) 
will also be tabulated; it should be noted, however, that without a control the primary safety 
conclusions must be based on overall incidence rates and not those considered 
treatment-related. The treatment-emergent AEs will also be summarized by system organ 
class, preferred term, and maximum severity.  
A separate listing and summary of all irAEs and inflammatory events regardless of causality 
(IERC) will be provided. In addition, the irAE rate will be estimated and a 95% confidence 
interval will be constructed for the overall all grade irAE and the Grade 3-4 irAE rate, based 
on the Clopper-Pearson method.  
Deaths and AEs resulting in study discontinuation will be tabulated. 
Change from baseline in clinical laboratory parameters will be summarized across time on 
study, and the frequency of clinically significant abnormal laboratory values will be 
tabulated. Shift tables will be produced for selected laboratory parameters, to include 
hemoglobin, WBC count, ANC, absolute lymphocyte count, platelet count, AST, ALT, 
bilirubin, creatinine, alkaline phosphatase, and electrolytes. These tables will summarize the 
number of patients with each baseline NCI CTCAE grade and changes to the maximum NCI 
CTCAE grade.  
Changes in vital sign parameters (including blood pressure, heart rate, and temperature) will 
be summarized over time in a similar fashion to laboratory parameters, and any abnormal 
values will be tabulated. Change in ECOG and oxygen saturation at each visit will be 
tabulated.  
Any significant physical examination findings will be listed. 
ECG findings will be presented in data listing format. Abnormalities of ECG, QT interval, 
and QTc interval by Bazett’s and Fridericia’s formulas will be summarized. 
Additional safety analyses may be determined at any time without prejudice in order to 
clearly enumerate rates of toxicities and to define further the safety profile of study drug.  
10.3.7 Efficacy Analysis 
All patients entered into this Phase II trial will be evaluated for efficacy. Patients will be 
stratified by safety cohort (if applicable) and by stage in the two-stage design summaries. 
Efficacy analysis will be performed on the as treated population. The analysis will be based 

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on the change from baseline in tumor measurements as assessed by imaging (CT scan or 
MRI) studies and the ORR by 6 months assessed according to RECIST version 1.1 criteria 
(Eisenhauer, E et al 2009), which is the primary efficacy criteria and irRC, which will be 
used to determine progression that mandates stopping therapy 
The ORR will be the percentage of patients who achieve overall response of CR or PR at 
month 6. The immune-related response rate will be the percentage of patients who achieve 
the immune-related best overall response of irCR or irPR. 
The number of patients who have at least SD or better per RECIST 1.1 will be included as the 
calculation of DCR. 
Progression-free survival will be defined as the time from the first dose of study treatment to 
the first documentation of disease progression or death from any cause during the study using 
RECIST 1.1.. 
Time to progression will be defined as the time from first dose of study treatment to the first 
documentation of disease progression using RECIST 1.1. 
For responders, time-to-tumor response and response duration will be summarized 
Time-to-tumor response will be defined as the time from first dose of study treatment to the 
first documentation of response (either PR or CR). 
Duration of response will be defined as the time from the first PR or CR to the first 
documentation of disease progression using both RECIST and irRC.  
Kaplan-Meier procedures will be used to characterize these time-to-event curves (PFS, time 
to progression, response duration) when there is censoring (the detailed censoring rules will 
be documented in the SAP); descriptive summary statistics will be provided for time to tumor 
response. The 95% confidence interval for ORR, DCR, and prolonged disease rate based on 
Clopper-Pearson method will be provided.   
10.3.8 Pharmacodynamics Biomarker Analysis  
Biomarker analysis will be performed on the Biomarker population. The biomarker endpoints 
will be summarized descriptively as appropriate.  
The following blood inflammatory proteins/cytokines will be assessed at baseline, week 7 and 
37: 
 
Inflammatory cytokines: IL-1β; IL-6; IL-8, IL-10, IL-12, TNF-alpha and gamma interferon 
Acute phase reactants: C reactive protein, Serum amyloid A, Serum amyloid P, Haptoglobin 
and Mannose binding protein, alpha-1 anti-trypsin 
Complement components: C5a, C3a, C3b, C1q, C1r, complement factor B and C9 
 
Selected urine biomarkers will be measured at baseline, week 7 and 37: IL-1β; IL-6; IL-8, IL-
10, IL-12, TNF-alpha and gamma interferon 
 
Statistical summary: The utility of an inflammatory protein signature will be assessed using a 
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regression methods to select predictors and adjust for potential confounders. We will test 
whether the signature predicts ORR as the primary clinical endpoint using logistic regression 
and PFS as secondary, using Cox models, respectively.  
Expected results: We expect that baseline values and changes in inflammatory proteins from 
the above list, especially CRP, will distinguish patients who benefit from tocilizumab with 
combination checkpoint inhibition and that those with the highest levels of the inflammatory 
proteins and cytokines will benefit the most.  
 
The following flow cytometric T cell phenotype studies will be performed, based on 
preliminary data presented herein and in the literature; they will be assessed at baseline, and at 
week 12: 
T cell function: CD8+ and CD4+ Ki-67; CD8+ and CD4+/STAT 1, 3, 4 and 6; CD8+ and 
CD4+/pLck, pZAP70 and pERK; CD8+ and CD4+/IFN-gamma, TNF-alpha, granzyme B and 
IL-1β 
Immune cell panels: T cell proliferation, checkpoint, activation, memory; MDSC 
(granulocytic/myeloid)    
Statistical summary: Success would consist of defining a selected baseline signature that 
includes selected markers from those noted above associated with co-primary endpoints of 
grades 3-5 irAEs and ORR, and the secondary endpoint of PFS in the trial with a sensitivity of 
at least 0.90 and a specificity of 0.80 with FDR ≤ 0.01 using logistic and Cox regression models 
and adjusting for potential confounders. As a control group, we will use 40 specimens of PBMC 
from a phase II trial of second line PD-1 antibody to determine if biomarkers are checkpoint 
specific or determined by CRP depletion with IL-6 blockade.   
Expected results: We expect that changes in T cell phenotypes and functional determinations 
will distinguish those patients who benefit from combination tocilizumab and checkpoint 
inhibition in this trial.  
 
The following dendritic cell studies will be performed, based on preliminary data presented 
herein and the literature, at baseline and week 12: 
Dendritic cell phenotype: 
CD40, CD80, CD83, CD86, CD205, CD206, HLA-DR 
Dendritic cell function: 
Fluorescinated dextran uptake  
 
Statistical summary: The utility of a signature composed of dendritic cell phenotypes and a 
functional determination will be assessed in the current study using similar approaches to those 
described above. We will test whether the signature predicts grades 3-5 irAE toxicity as the 
primary endpoint and ORR as well as PFS as the secondary clinical endpoints using logistic 
regression and PFS as secondary, using Cox proportional hazards models and adjusting for 
potential confounders as above.  
 
Expected results: We expect that changes in some dendritic cell phenotypes and functional 
determinations will distinguish those patients who benefit from combination tocilizumab and 
ipilimumab/nivolumab checkpoint inhibition in this trial, assessed by a lower toxicity, higher 
response rate and longer progression-free survival. 

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We will merge the data from serum, T cell and dendritic cell assays into one comprehensive 
dataset so that each subject has a vector of measurements for multiple biomarkers, including 
high-dimensional mass spec protein data with repeated measurements. These biomarkers are 
measured on the same subjects, so we expect correlations and interactions among them for 
outcomes that are of biologic interest. One can exploit these interactions to develop a single 
comprehensive, integrated model. Such a comprehensive model can increase predictive accuracy 
by taking advantage of synergistic interactions between the multiple types of correlated 
biomarkers measured in the same patients above. Several approaches can be used to evaluate 
synergies 
and 
other 
interaction 
including 
network 
or 
pathway 
analyses 
in 
bioinformatics/machine learning and/or the formal assessment of interactions using statistical 
tests. Moreover, we can use regression models to evaluate how strongly the CRP signature 
predicts the phenotype of the T-cells or DCs.  Further, we can use regression analysis for ORR 
and PFS to see how much the effect of inhibiting IL-6 by tocilizumab as captured by the CRP 
signature is modulated by the functional changes in T-cells or DCs in the patients in the 
tocilizumab + IPI + NIVO treatment arm with comparison to the 40 samples with the inhibition 
of PD-1 alone. We have expertise in identifying and characterizing interactions as well as in 
modeling and integrating heterogeneous and multi-scale medical data for patients’ response, 
survival and for drug resistance. To build comprehensive predictive models we will use machine 
learning-based feature selection methods, including those described in Weber et al12, to identify 
optimal low-dimensional subsets from candidate high-dimensional features that accurately 
predict ORR and PFS. In particular, approaches to dimensionality reduction include cluster 
analysis, penalized latent class regression models, random forest, and various machine learning 
techniques. We will also incorporate other baseline tumor-based predictors such as BRAF 
mutation status and PD-L1 express levels. We will decide whether they should be baseline 
predictors or as stratification factors. We will use random splitting into discovery and testing 
sets and use cross validation to identify predictive models and evaluating the models via 
averaging the performance in testing sets only as exploratory analyses.  
High resolution flow cytometry including the new CITE-Seq technology will be performed 
on peripheral blood mononuclear cells harvested prior to treatment and at weeks 6 and 12 to 
aid in defining possible predictive pretreatment and pharmacodynamic markers.  We will also 
assess tumor biopsies for infiltrating cells with biopsies pretreatment, and post treatment in 
selected patients. 
The change between pre-dose and post-dose time points in the levels of analytes including 
CRP, IL-6 and other acute phase reactants will be determined in blood samples. A summary 
report will be generated with the pharmacodynamics analysis. 
Procedures for Reporting Deviations to Original Statistical Analysis Plan  
A formal statistical plan for the analysis and presentation of data from this study will be 
prepared before database lock. Deviations from the statistical analyses outlined in this 
protocol will be indicated in this plan; any further modifications will be noted in the final 
clinical study report. 

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11 QUALITY ASSURANCE AND QUALITY CONTROL 
11.1 Audit and Inspection 
Study centers and study documentation may be subject to a Quality Assurance audit during 
the course of the study by the Sponsor, NYU Langone Health or its nominated representative. 
In addition, inspections may be conducted by regulatory authorities at their discretion. 
11.2 Source Documentation 
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original, and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, 
archived, retrieved, or transmitted electronically via computerized systems (and/or any other 
kind of electronic devices) as part of regulated clinical trial activities, such systems must be 
compliant with all applicable laws and regulations governing use of electronic records and/or 
electronic signatures. Such systems may include, but are not limited to, electronic 
medical/health records, AE tracking/reporting, protocol required assessments, and/or drug 
accountability records). 
When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of 
a copy of original information that has been verified, as indicated by a dated signature, as an 
exact copy having all of the same attributes and information as the original.  
An Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation on each 
individual treated or entered as a control in the investigation. Data that are derived from 
source documents and reported on the CRF must be consistent with the source documents or 
the discrepancies must be explained. Additional clinical information may be collected and 
analyzed in an effort to enhance understanding of product safety. CRFs may be requested for 
AEs and/or laboratory abnormalities that are reported or identified during the course of the 
study. 
Electronic CRFs will be prepared for all data collection fields. Spaces may be left blank only 
in those circumstances permitted by study-specific CRF completion guidelines.  
The confidentiality of records that could identify patients must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). 
The Investigator will maintain a signature sheet to document signatures and initials of all 
persons authorized to make entries and/or corrections on CRFs.  
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be 
promptly reviewed, signed, and dated by the Investigator or qualified physician who is a sub-
investigator and who is delegated this task on the Delegation of Authority Form. For eCRFs, 
review and approval/signature is completed electronically. The Investigator must retain a 
copy of the CRFs including records of the changes and corrections. 

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TrialMaster, an electronic database capture system will be created to record the 
data for this trial. Research coordinators will input clinical trial data into the database. 
This database is password protected and only the PI, assigned study team members, 
and CTO staff will have access to the database. DataCore, a core resource of the 
institution, will provide the primary data collection instrument for the study. All data 
requested in the system must be reported. All missing data must be explained. The 
quality assurance (QA) specialists will monitor this trial every 4-6 weeks for data entry 
accuracy. 
 
Source documentation should be consistent with data entered into any electronic 
medical record or Trial master.  Relevant source documentation to be reviewed by the 
QA specialists throughout the study includes: 
 
1. Baseline measures to assess pre-protocol disease status 
2. Concurrent medications 
3. Treatment records 
4. Adverse events 
 
Access to study records will be limited to IRB-approved members of the study team. The 
investigator will permit study-related monitoring, audits, and inspections by the IRB/EC, the 
sponsor, government regulatory bodies, and University compliance and quality assurance 
groups of all study related documents (e.g. source documents, regulatory documents, data 
collection instruments, study data etc.).  The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality 
assurance offices. 
 
11.3 Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events 
as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan.  The NYU Data Safety and Monitoring Committee (DSMC) will review the 
study quarterly.  Medical monitoring will include a regular assessment of the number and 
type of serious adverse events. In addition, the study may be evaluated by BMS and/or 
Genentech Inc.internal auditors and government inspectors who must be allowed access to 
CRFs, source documents, other study files, and study facilities. BMS and/or Genentech 
Inc.audit reports will be kept confidential. 
The Investigator must notify BMS and Genentech Inc. promptly of any inspections scheduled 
by regulatory authorities, and promptly forward copies of inspection reports to BMS.  

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Data for each patient will be recorded on an eCRF. Data collection must be completed for 
each patient who signs an ICF and is administered study drug. 
In accordance with current Good Clinical Practice (cGCP) and The International Conference 
on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) guidelines, the study monitor will carry out source document verification at 
regular intervals to ensure that the data collected in the CRF are accurate and reliable.  
The Investigator must permit the monitor, the IRB, the Sponsor’s internal auditors, and 
representatives from regulatory authorities to have direct access to all study-related 
documents and pertinent hospital or medical records for confirmation of data contained 
within the CRFs. 
11.3.1  Data Monitoring Committee 
This investigator initiated and sponsored study will be monitored by the Data Safety 
Monitoring Committee (DSMC) of the New York University Perlmutter Cancer Center. The 
DSMC operates based on the 2018 National Cancer Institute approved Charter. It is an 
existing and multidisciplinary committee (consisting of clinical investigators/oncologists, 
biostatisticians, nurses and design and in proper conduct of clinical trials) that is responsible 
for monitoring safety, conduct and compliance in accordance with protocol data monitoring 
plans for interventional clinical trials conducted in the New York University Langone 
Perlmutter Cancer Center that are not monitored by another institution or agency. The DSMC 
reports to the director of the New York University Perlmutter Cancer Center (Benjamin Neel, 
MD/PhD). Per the New York University Perlmutter Cancer Center Institutional Data Safety 
and Monitoring Plan, this Phase II trial will be monitored by the DSMC at least every 6 
months and as often as quarterly (from the date the first patient is enrolled), with outcome 
data presented upon completion of each cohort. DSMC will review the study whenever there 
is action to take in terms of dosing of tocilizumab. However, taking the appropriate action 
will not be contingent upon the DSMC review. This review includes accrual data, subject 
demographics, and adverse events. The Principal Investigator is required to attend the review 
of their studies. Additional reviews can be scheduled based on SAE reports, investigator 
identified issues, external information, etc.  The DSMC will review safety data every 3 
months or sooner if indicated. 
At the NYU Perlmutter Cancer Center, all investigator-initiated protocols are subject to a 
standardized data and safety monitoring, which includes scientific peer review, IRB review, 
Phase I/II committee review and DSMC review as well as internal auditing.  
The review of AEs and trial conduct for this trial occurs at several levels:  

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1.  Principal Investigator:  Adverse events are evaluated monthly by the principal 
investigator in conjunction with the research nurses, data managers and research team.  
 
2.  DSMC, quarterly 
 
 
3.  IRB:  An annual report to the IRB is submitted by the trial PI for continuation of the 
protocol. It includes a summary of all AEs, total enrollment with demographics, 
protocol violations, and current status of subjects as well as available research data 
4.  In addition, the quality assurance unit, the quality assurance unit will monitor this 
trial every 4-6 weeks, this includes real- time review of all eCRFs to ensure 
completeness and to verify adherence to the protocol; the completeness, accuracy 
and consistency of the data; and adherence to ICH Good Clinical Practice 
guidelines. Additionally, a first subject audit is to be conducted within four weeks 
of enrollment. 
11.4 Data Management and Coding 
NYU’s Datacore will be responsible for activities associated with the data management of 
this study. This will include setting up a relevant database and data transfer mechanisms, 
along with appropriate validation of data and resolution of queries. Data generated within 
this clinical study will be handled according to the relevant standard operating procedures of 
the Clinical Trials Office at NYU. 
Study centers will enter data directly into an EDC system by completing the CRF via a secure 
internet connection. Data entered into the eCRF must be verifiable against source documents 
at the study center. Any changes to the data entered into the EDC system will be recorded in 
the audit trail and will be US Title 21 Code of Federal Regulations Part 11 compliant. 
Missing or inconsistent data will be queried in writing to the Investigator for clarification. 
Subsequent modifications to the database will be documented. 
11.5  Monitoring of Other Participating Institutions 
Monitoring visits are done remotely unless otherwise specified, via remote EMR access. If 
not possible, secure email exchange will be utilized. The quality assurance specialist will 
confirm an upcoming monitoring visit with a Site Investigator and staff. If remote EMR 
access is not available, then the Site Coordinator will ensure that all source documents 
for subjects are de-identified and labeled only with the subject ID number(s), and emails 
all requested documents to the quality assurance specialist by the specified visit date. All 
documents are reviewed and a monitoring report is submitted within 5 business days from 
the date of the visit. Any outstanding documents will be listed in the report as a high- 
priority request for the next monitoring visit. It is expected that response to data 
clarification requests and other trial-related inquiries will occur throughout the course of 
the study through regular communication with the site monitor, the Sponsor or 
representatives, and review/entry of data into the electronic study database. Continued 
non-compliance and failure to submit documentation will result in the suspension of 
subject enrollment at the site, until the documents have been received. 

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12 RECORDS AND SUPPLIES 
12.1 Study Drug Records 
It is the responsibility of the Investigator to ensure that a current disposition record of 
investigational product (inventoried and dispensed) is maintained at the study site. Records or 
logs must comply with applicable regulations and guidelines and should include: 
• Amount received and placed in storage area 
• Amount currently in storage area 
• Label identification number or batch number  
• Amount dispensed to and returned by each patient, including unique patient identifiers 
• Amount transferred to another area/site for dispensing or storage 
• Nonstudy disposition (e.g., lost, wasted)  
• Amount destroyed at study site, if applicable 
• Amount returned to BMS and/or Genentech 
• Retain samples for bioavailability/bioequivalence, if applicable  
• Dates and initials of person responsible for Investigational Product 
dispensing/accountability, as per the Delegation of Authority Form. 
12.2 Records Retention 
The Investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS and/or Genentech Inc., whichever is longer. The Investigator must contact 
BMS prior to destroying any records associated with the study. 
BMS and/or Genentech Inc. will notify the Investigator when the study records are no longer 
needed. 
If the Investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another Investigator, IRB). Notice of 
such transfer will be given in writing to BMS and/or Genentech Inc.  
12.3 Financing and Insurance 
Financing and insurance of this study will be outlined in a separate agreement between BMS 
and the Sponsor. 

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13 ETHICS 
13.1 Institutional Review Board/Independent Ethics Committee 
Before initiation of the study at each study center, the protocol, the ICF, other written 
material given to the patients, and any other relevant study documentation will be submitted 
to the appropriate IRB/IEC. Written approval of the study and all relevant study information 
must be obtained before the study center can be initiated or the study drug is released to the 
Investigator. Any necessary extensions or renewals of IRB/IEC approval must be obtained 
for changes to the study such as amendments to the protocol, the ICF or other study 
documentation. The written approval of the IRB/IEC together with the approved ICF must be 
filed in the study files. 
The Investigator will report promptly to the IRB/IEC any new information that may 
adversely affect the safety of the patients or the conduct of the study. The Investigator will 
submit written summaries of the study status to the IRB/IEC as required. On completion of 
the study, the IRB will be notified that the study has ended. 
13.2 Compliance with the Protocol and Protocol Revisions 
The study shall be conducted as described in this approved protocol. The Investigator should 
not implement any deviation or change to the protocol without prior review and documented 
approval/favorable opinion from the IRB of an amendment, except where necessary to 
eliminate an immediate hazard(s) to study patients.  
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) 
prior to obtaining IRB approval/favorable opinion, as soon as possible the deviation or 
change will be submitted to: 
• IRB for review and approval/favorable opinion 
• Regulatory Authority(ies), if required by local regulations 
Documentation of approval signed by the chairperson or designee of the IRB(s)) must be sent 
to BMS and Genentech Inc.. 
If an amendment substantially alters the study design or increases the potential risk to the 
patient: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from 
patients currently enrolled in the study if they are affected by the amendment; and (3) the new 
form must be used to obtain consent from new patients prior to enrollment. 
If the revision is done via an administrative letter, Investigators must inform their IRB(s). 
13.3 Regulatory Authorities 
Relevant study documentation will be submitted to the regulatory authorities of the 
participating countries, according to local/national requirements, for review and approval 
before the beginning of the study. On completion of the study, the regulatory authorities will 
be notified that the study has ended. 

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13.4 Ethical Conduct of the Study 
The Investigators and all parties involved in this study should conduct the study in adherence 
to the ethical principles based on the Declaration of Helsinki, cGCP, ICH guidelines, and the 
applicable national and local laws and regulatory requirements. 
13.5 Informed Consent Process 
13.5.1 Consent/Assent and Other Informational Documents Provided to Participants 
Consent forms describing in detail the study agent, study procedures, and risks are given to 
the participant and written documentation of informed consent is required prior to starting 
intervention/administering study product. The following consent materials are submitted with 
this protocol Informed Consent. 
13.5.2 Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate 
in the study and continues throughout the individual’s study participation. Extensive 
discussion of risks and possible benefits of participation will be provided to the participants 
and their families. Consent forms will be IRB-approved and the participant will be asked to 
read and review the document. The investigator will explain the research study to the 
participant and answer any questions that may arise. All participants will receive a verbal 
explanation in terms suited to their comprehension of the purposes, procedures, and potential 
risks of the study and of their rights as research participants. Participants will have the 
opportunity to carefully review the written consent form and ask questions prior to signing. 
The participants should have the opportunity to discuss the study with their surrogates or 
think about it prior to agreeing to participate. The participant will sign the informed consent 
document prior to any procedures being done specifically for the study. The participants may 
withdraw consent at any time throughout the course of the trial. A copy of the signed 
informed consent document will be given to the participants for their records. The rights and 
welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
 
A copy of the signed informed consent document will be stored in the subject’s research 
record. The consent process, including the name of the individual obtaining consent, will be 
thoroughly documented in the subject’s research record. Any alteration to the standard 
consent process (e.g. use of a translator, consent from a legally authorized representative, 
consent document presented orally, etc.) and the justification for such alteration will likewise 
be documented.  
 
The consenting process and documentation will follow Standard Operating Procedures 
(Obtaining Informed Consent for Clinical Trials) of the NYULH PCC CTO 
13.5.3  Informed Consent 
The process of obtaining informed consent must be in accordance with applicable regulatory 
requirements and must adhere to cGCP. 

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The Investigator is responsible for ensuring that no patient undergoes any study-related 
examination or activity before that patient has given written informed consent to participate 
in the study. 
The Investigator or designated personnel will inform the patient of the objectives, methods, 
anticipated benefits, and potential risks and inconveniences of the study. The patient should 
be given every opportunity to ask for clarification of any points he/she does not understand 
and, if necessary, ask for more information. At the end of the interview, the patient will be 
given ample time to consider the study. Patients will be required to sign and date the ICF. 
After signatures are obtained, the ICF will be kept and archived by the Investigator in the 
Investigator’s study file. A signed and dated copy of the patient ICF will be provided to the 
patient or their authorized representative. 
It should be emphasized that the patient may refuse to enter the study or to withdraw from the 
study at any time, without consequences for their further care or penalty or loss of benefits to 
which the patient is otherwise entitled. Patients who refuse to give or who withdraw written 
informed consent should not be included or continue in the study. 
If new information becomes available that may be relevant to the patient’s willingness to 
continue participation in the study, a new ICF will be approved by the IRBs (and regulatory 
authorities, if required). The study patients will be informed about this new information and 
re-consent will be obtained. 
For non-English speaking patients, institutional translation services will be utilized. 
All procedures for consenting non-English speaking patients will be in accordance 
with NYU Langone Health PCC CTO guidelines and policies or the SOP of the local 
institution. 
For patients who cannot read.  A witness, not related to the research study will be present.  
The consent will be read to the patient.  The patient will also be allowed to ask any questions 
s/he may have.  The investigator will ask the patient questions to ensure s/he understands the 
study.  If the investigator determines the subject understands the stud, the patient will mark 
an X where his/her name would go and the witness will sign the consent form. 
13.6 Subject Recruitment 
Target enrollment for this study is 67 patients over 1.5 years.  Patients will be recruited from 
physicians participating in this study.  Consenting, screening, and treatment will take place at 
the NYULMC PCC, The Angeles Clinic in Los Angeles, Dana Farber Cancer Institute in 
Boston or participating sub-sites under supervision of the Site PIs.  Prospective subjects will 
receive detailed information regarding this study; its investigational nature, required study 
procedures, alternative treatments, risks and potential benefits of the study.   
The Principal Investigator will: 
1.  Obtain signed and dated informed consent from the potential subject before any study 
specific procedures are performed. 
2. Determine patient eligibility, see Section 4.2 and 4.3  

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3. Submit registration to NYU Langone Perlmutter Cancer Center CTO 
4. Receive registration confirmation from the NYU Perlmutter Cancer Center CTO, 
including a unique study identification number assigned to the patient that will be 
distributed to the study team upon registration of the patient. 
Recruitment and consenting will take place in a private area such as an exam room to protect 
the patient’s privacy.  The informed consent process and documentation follows the 
established procedures of the NYULMC Perlmutter Cancer Center Clinical Trials Office. 
13.6.1 Documentation of Consent 
The Principal Investigator will be responsible for documentation in the medical record that 
consent has been obtained from all participants.  A signed copy of the consent form will be 
given to each participant.  Original consent forms will be stored in the subject’s medical 
chart. 
13.7 Registration Procedures 
13.7.1  General Guidelines 
Each patient must sign and date an informed consent form before undergoing any study 
specific procedures unless a procedure is being performed as part of the patient’s standard of 
care.  Enrollment in the study requires that all inclusion and exclusion criteria have been met.  
Enrollment occurs upon confirmation of registration from the NYULH PCC Clinical Trials 
Office.  The following materials must be submitted to the CTO for subject registration: 
1. Complete signed and dated informed consent form 
2.  Complete signed and dated eligibility checklist 
3.  All supporting documentation verifying each eligibility criterion has been met 
 
Registration will occur within 48 hours of CTO receipt of all of the above documents.  A written 
confirmation of enrollment including a unique study identification number will be disbursed to 
the study team upon registration. 
Upon receipt of ICF, a unique patient study number will be issued within 24 hours of 
receiving all required registration material.  The patient will not be identified by name.  This 
is the point at which the patient is considered accrued on study.  If tissue is submitted prior to 
eligibility confirmation, a unique study number may also need to be issued. 
13.7.2  Multi-Site Surveillance 
As the lead investigator in a multi-site trial, the Principal Investigator is responsible for 
organizing and conducting monthly teleconferences with all participating sites. Each 
participating site will be responsible for submitting the results and recommendations 
from the DSMC’s quarterly reviews to their IRB of record at the time of continuing 
review. Additionally, the NYU Langone Health PCC Clinical Trial Office, Quality 

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Assurance Unit will provide a remote extensive monitoring including real-time review of all 
eCRFs to ensure completeness and compliance with the protocol (100% source 
documentation verification).  Additionally, a first subject audit is to be completed within four 
weeks of enrollment. Decisions from the DSMB will be disseminated to other study sites 
during routine calls of the investigators at each site, which will occur monthly. 
 
13.7.3 Patient Registrations at Other Participating Institutions 
Enrollment at addition sites can begin once each site’s IRB has approved this 
protocol, a copy of each site’s IRB approval, Citi training certificates, Medical 
Licenses and signed CVs are provided to NYU Langone Health Perlmutter Cancer 
Center (PCC) Clinical Trials Office. Once, all required documents are provided to 
NYU Clinical Trials Office a n d  a n  S I V  i s  c o n d u c t e d ,  an activation 
notification will be sent to the PI and research coordinator of that site. Central 
registration for this study will take place at NYU Langone Health PCC Quality 
Assurance Unit (PCC-QAU@nyulangone.org). 
Each patient must sign and date an informed consent form before undergoing any 
study specific procedures unless a procedure is being performed as part of the 
patient’s standard of care. Once a patient has signed consent, each site must notify 
the NYU Langone Health PCC Quality Assurance Unit and forward a copy of the 
signed consent to NYU Langone Health PCC Clinical Trials Office within 24 hours. 
Enrollment in the study requires that all inclusion and exclusion criteria have been 
met. Enrollment occurs upon confirmation of registration from the NYU Langone 
Health PCC Clinical Trials Office. The following materials must be submitted to the 
Quality Assurance Unit at NYU Langone Health via email (PCC-
QAU@nyulangone.org): 
 
1. Complete signed and dated informed consent form 
2. Complete signed and dated informed consent checklist 
3. Complete signed and dated eligibility checklist 
4. All supporting documentation verifying each criterion has been met. 
Registration will occur once the Senior Research Nurse for Quality Assurance conducts 
a central review of the submitted materials. Once eligibility is verified, a unique 
subject study number will be issued within 48 hours of receiving all required 
registration material. This number is unique to the participant and must be written on 
all data and correspondence for the participant. The NYU Langone Health PCC CTO 
will return a signed eligibility confirmation worksheet email with the subject’s unique 
study number. 
The subject will not be identified by name. This is the point, at which, the patient is 
considered accrued on study. Protocol treatment should begin within the designated 
timeframe; issues that would cause treatment delays should be discussed with the 
overall PI, Dr. Weber. All screen failures/ineligible subjects, as well as subject’s 
who withdraw consent prior to initiation of protocol therapy must be submitted to 

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the CTO in a manner analogous to the procedures noted above. Applicable source 
documentation will be required within the corresponding submissions. 
Subjects must not start any protocol procedures prior to registration; each 
participating institution will order the study agent directly from the supplier, BMS, in 
the case of ipilimumab and nivolumab, and Genentech Inc. in the case of tocilizumab.. 
Each site is responsible for reporting all unexpected problems involving risks to 
participants or others to NYU Langone PCC Clinical Trials Office and to their IRB as 
per site institutional policy. 
Please email all SAEs to NYUPCCsafetyreports@nyulangone.org, BMS, Genentech 
Inc. and Dr. Weber. 
13.8   Patient Confidentiality 
Monitors, auditors, and other authorized agents of the Sponsor and/or its designee, BMS. 
Genentech Inc., the IRBs approving this research, and the US FDA, as well as that of any 
other applicable agency (ies), will be granted direct access to the study patients’ original 
medical records for verification of clinical study procedures and/or data, without violating the 
confidentiality of the patients to the extent permitted by the law and regulations. In any 
presentations of the results of this study or in publications, the patients’ identities will remain 
confidential. 
All personal data collected and processed for the purposes of this study should be managed 
by the Investigator and his/her staff with adequate precautions to ensure confidentiality of 
those data, and in accordance with the Health Insurance Portability and Accountability Act, 
applicable to national and/or local laws and regulations on personal data protection. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at NYU Langone Medical Center. This will not 
include the participant’s contact or identifying information. Rather, individual participants 
and their research data will be identified by a unique study identification number. The study 
data entry and study management systems used by clinical sites and by NYU Langone Health 
research staff will be secured and password protected. At the end of the study, all study 
databases will be de-identified and archived at the NYU Langone Medical Center. 

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14 REPORTING AND PUBLICATION, INCLUDING ARCHIVING 
Essential documents are those documents that individually and collectively permit evaluation 
of the study and quality of the data produced. After completion of the study (end of study 
defined as the date of the last visit of the last patient), all documents and data relating to the 
study will be kept in an orderly manner by the Investigator in a secure study file. This file 
will be available for inspection by the Sponsor or its representatives. Essential documents 
should be retained for 2 years after the final marketing approval in an ICH region or for at 
least 2 years since the discontinuation of clinical development of the investigational product. 
It is the responsibility of the Sponsor to inform the study center when these documents no 
longer need to be retained. The Investigator must contact the Sponsor before destroying any 
study-related documentation. In addition, all patient medical records and other source 
documentation will be kept for the maximum time permitted by the hospital, institution, or 
medical practice. 
The Sponsor must review and approve any results of the study or abstracts for professional 
meetings prepared by the Investigator. Published data must not compromise the objectives of 
the study. Data from individual study centers in multicenter studies must not be published 
separately. 
14.1 Clinical Study Report and Publications 
A Signatory Investigator must be selected to sign the clinical study report.  
For this protocol, the Signatory Investigator will be selected as appropriate based on the 
following criteria: 
• Patient recruitment (e.g., among the top quartile of enrollers) 
• Involvement in trial design 
• Other criteria (as determined by the study team) 
The data collected during this study are confidential. Any publications or abstracts arising 
from this study must adhere to the publication requirements set forth in the clinical trial 
agreement governing [study site or Investigator] participation in the study. These 
requirements include, but are not limited to, submitting proposed publications to BMS at the 
earliest practicable time prior to submission or presentation and otherwise within the time 
period set forth in the clinical trial agreement. 
 

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16 APPENDICES 
16.1 RECIST Version 1.1 Quick Reference 
The following is a quick reference guide for the revised RECIST (version 1.1) guidelines 
with minor modifications. 
Eligibility 
• Only patients with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint.  
o Measurable disease - the presence of at least one measurable lesion. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should 
be confirmed by cytology/histology.  
o Measurable lesions - lesions that can be accurately measured in at least one 
dimension with longest ≥ 10 mm with CT scan or MRI. For lymph nodes, the 
short axis must be > 15 mm to be assessed as pathological. 
o Nonmeasurable lesions - all other lesions, including small lesions (longest 
diameter (LD)  < 10 mm with CT scan or MRI), i.e., bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory 
breast disease, lymphangitis cutis/pulmonis, cystic lesions, and also abdominal 
masses that are not confirmed and followed by imaging techniques. 
• All measurements should be taken and recorded in metric notation, using a ruler. All 
baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment.  
• The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.  
• Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes). For the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
Methods of Measurement 
• CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed 
with cuts of 10 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm.  This applies to tumors of the chest, 
abdomen and pelvis. Head and neck tumors and those of extremities usually require 
specific protocols.  PET-CT with contrast may be used if the CT portion satisfies the 
criteria above. 
• Lesions on chest X-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable. MRI is to be 
avoided for lung lesions. 
• Since one of the secondary endpoints of the study is objective response evaluation, 
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• The utilization of endoscopy and laparoscopy for objective tumor evaluation has not yet 
been fully and widely validated. Their uses in this specific context require sophisticated 
equipment and a high level of expertise that may only be available in some centers. 
Therefore, the utilization of such techniques for objective tumor response should be 
restricted to validation purposes in specialized centers. However, such techniques can be 
useful in confirming complete pathological response when biopsies are obtained. 
• Tumor markers alone cannot be used to assess response. If markers are initially above the 
ULN, they must normalize for a patient to be considered in complete clinical response 
when all lesions have disappeared. 
• Cytology and histology can be used to differentiate between PR and CR in rare cases (eg, 
after treatment to differentiate between residual benign lesions and residual malignant 
lesions in tumor types such as germ cell tumors). 
Baseline Documentation of “Target” and “Nontarget” Lesions 
• All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline.  
• Target lesions should be selected on the basis of their size (lesions with the LD) and their 
suitability for accurate repeated measurements (either by imaging techniques or 
clinically).  
• A sum of the LD for all target lesions will be calculated and reported as the baseline sum 
LD. The baseline sum LD will be used as reference by which to characterize the objective 
tumor. 
• All other lesions (or sites of disease) should be identified as nontarget lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence or absence of each should be noted throughout follow-up.  
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR): 
Disappearance of all target lesions 
Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the 
treatment started or the appearance of one or more new lesions 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started 
Abbreviation: LD = longest diameter 
 

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Evaluation of Nontarget Lesions 
Complete Response (CR): 
Disappearance of all nontarget lesions and normalization of 
tumor marker level 
Incomplete Response/ 
Stable Disease (SD):  
Persistence of one or more nontarget lesions or/and maintenance 
of tumor marker level above the normal limits 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing nontarget lesionsa 
a 
Although a clear progression of “nontarget” lesions only is exceptional, in such circumstances, the opinion 
of the treating physician should prevail and the progression status should be confirmed later on by the 
review panel (or study chair). 
Evaluation of Overall Response Rate 
The ORR is the response recorded from the start of the treatment until month 6 (taking as 
reference for PD the smallest measurements recorded since the treatment started). In general, 
the patient's response assignment will depend on the achievement of both measurement and 
confirmation criteria.  
Target lesions 
Nontarget lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; SD = stable 
disease. 
• Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as 
having “symptomatic deterioration”. Every effort should be made to document the 
objective progression even after discontinuation of treatment.  
• In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to 
confirm the complete response status. 
Confirmation 
• The main goal of confirmation of objective response is to avoid overestimating the 
response rate observed. In cases where confirmation of response is not feasible, it should 
be made clear when reporting the outcome of such studies that the responses are not 
confirmed. 

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• To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that should be performed no less than 4 weeks after the criteria for 
response are first met. Longer intervals as determined by the study protocol may also be 
appropriate.  
• In the case of SD, follow-up measurements must have met the SD criteria at least once 
after study entry at not less than 6 weeks) that is defined in the study protocol.  
Duration of Overall Response 
• The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever status is recorded first) until the first date that recurrence or PD 
is objectively documented, taking as reference for PD the smallest measurements 
recorded since the treatment started. 
Duration of Stable Disease 
• Stable disease is measured from the start of the treatment until the criteria for disease 
progression are met, taking as reference the smallest measurements recorded since the 
treatment started.  
• The clinical relevance of the duration of SD varies for different tumor types and grades. 
Therefore, it is highly recommended that the protocol specify the minimal time interval 
required between 2 measurements for determination of SD. This time interval should take 
into account the expected clinical benefit that such a status may bring to the population 
under study.  
Response Review 
• Since response rate is one of the secondary endpoints, all responses will be reviewed 
locally by an expert. Simultaneous review of the patients’ files and radiological images is 
the best approach.  
Reporting of Results 
• All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible. Each patient will be 
assigned one of the following categories: 1) CR, 2) PR, 3) SD, 4) PD, 5) early death from 
malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 
9) unknown (not assessable, insufficient data). 
• All of the patients who met the eligibility criteria should be included in the main analysis 
of the response rate. Patients in response categories 4 to 9 should be considered as failing 
to respond to treatment (disease progression). Thus, an incorrect treatment schedule or 
drug administration does not result in exclusion from the analysis of the response rate. 
Precise definitions for categories 4 to 9 will be protocol specific. 
• All conclusions should be based on all eligible patients. 
• Subanalyses may then be performed on the basis of a subset of patients, excluding those 
for whom major protocol deviations have been identified (eg, early death due to other 
reasons, early discontinuation of treatment, major protocol violations). However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 

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efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.   
• The 95% CIs should be provided. 
 
 

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16.2 Appendix 2: Immune-related Response Criteria (irRC) 
The following summary of assessment of disease response using irRC is from the Guidelines 
for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response 
Criteria (Wolchok, 2009).[ 
The irRC, antitumor response is based on the total measurable tumor burden of index and 
measurable new lesions. Thus, each net percentage change in tumor burden represents the 
size and growth kinetics of both old and new lesions as they appear. 
The baseline sum of the product of the diameters for all index lesions identified is the 
immune-related sum of products of diameters (irSPD). At each subsequent tumor assessment, 
the sum of products of diameters (SPD) of the index lesions and of new, measurable lesions 
(≥ 5 × 5 mm; up to 5 new lesions per organ: 5 new cutaneous lesions and 10 visceral lesions) 
are added together to provide the total tumor burden). 
Tumor burden = SPDindex lesions + SPDnew, measurable lesions 
Percentage changes in tumor burden per assessment time point describe the size and growth 
kinetics of both conventional and new, measurable lesions as they appear. At each tumor 
assessment, the response in index and new, measurable lesions is defined based on the change 
in tumor burden (after ruling irPD). Decreases in tumor burden must be assessed relative to 
baseline measurements (i.e., the SPD of all index lesions at baseline). 
Time Point Overall Response Using irRC 
The overall assessment of immune-related response reported at each time point will be based 
on the following criteria (as defined in table that follows): 
• Immune-related complete response (irCR)  
Complete disappearance of all tumor lesions (index and non-index together with no 
new measurable/unmeasurable lesions 
• Immune-related partial response (irPR) 
A decrease relative to baseline of the irSPD of 50% or greater 
• Immune-related stable disease (irSD) 
An evaluable response that fails to meet criteria for irCR or irPR, in the absence of 
PD 
• Immune-related progressive disease (irPD) 
At least a 25% increase in the irSPD (based on irSRSPD of all index lesions and any 
measurable new lesions) over the nadir irSPD 
• Immune-related unknown response (irUN) 
Tumor assessments that cannot be evaluated (eg, because of image quality, inability to 
assess all relevant lesions, etc) 
Patients will be able to continue treatment by irRC criteria even if there is progression of 
disease by RECIST 1.1 if the following conditions are met: 

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• Absence of clinical symptoms or signs indicating clinically significant progressive 
disease (PD) 
• No decline in Eastern Cooperative Oncology Group (ECOG) performance status 
 
• Absence of rapid PD or threat to vital organs/critical anatomical sites (e.g., spinal 
cord compression) requiring urgent alternative medical intervention 
 
• Patients will be re-consented prior to continuation of therapy 
 
Immune-Related Response Criteria Definitions 
Index Lesions 
Non-Index 
Lesions 
New Lesions 
% Change in Tumor Burden 
(Including New Lesions) 
Overall irRC 
Response 
CR 
CR 
Any 
– 100% 
irCR 
CR 
Any 
Any 
> –100% to ≤ –50% 
irPR 
 
 
 
> –50% to < +25% 
irSD 
 
 
 
≥ +25% 
irPD 
PR 
Any 
Any 
> –100% to ≤ –50% 
irPR 
 
 
 
> –50% to < +25% 
irSD 
 
 
 
≥ +25% 
irPD 
SD 
Any 
Any 
> –50% to < +25% 
irSD 
 
 
 
≥ +25% 
irPD 
PD 
Any 
Any 
≥ +25% 
irPD 
UN 
Any 
Any 
UN 
irUN 
Abbreviations: CR = complete response; irCR = immune-related complete response; irPD = immune-related 
progressive disease; irPR = immune-related partial response; irRC = immune-related response criteria; 
irSD = immune-related stable disease; irUN = immune-related unknown response; PD = progressive disease; PR 
= partial response; SD = stable disease; UN = unknown response.