A Phase II Randomized Study of Nivolumab (NSC-748726) With Ipilimumab (NSC-732442) or Ipilimumab Alone in Advanced Melanoma Patients Refractory to an Anti-PD1 or Anti-PD-L1 Agent
Phase: PHASE2
Conditions: Clinical Stage III Cutaneous Melanoma AJCC v8, Clinical Stage IV Cutaneous Melanoma AJCC v8, Melanoma of Unknown Primary, Mucosal Melanoma, Unresectable Cutaneous Melanoma, Unresectable Melanoma
Sponsor: National Cancer Institute (NCI)

Version Date:
June 10, 2021
TO:
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS
FROM: 
Catrina Mireles, Protocol Coordinator (E-mail: cmireles@swog.org)
RE:
S1616, “A Phase II Randomized Study of Nivolumab (NSC-748726) with Ipilimumab (NSC-
732442) or Ipilimumab alone in Advanced Melanoma Patients Refractory to an Anti-PD1 
or Anti-PD-L1 Agent” Study Chairs: Drs. A VanderWalde and A. Ribas
REVISION #8
Study Chair:  Ari VanderWalde, M.D., M.P.H.
Phone number: 901/683-0055 ext. 63015
E-mail: avanderw@uthsc.edu
IRB Review Requirements
( )   Expedited review allowed
Protocol changes
( )   Other: Request for Amendment (RA) and Additional Translational Medicine 
( )   Informed Consent changes
( )   Patient notification not required 
Sites using the CIRB as their IRB of record: The protocol and/or informed consent form changes have 
been approved by the CIRB and must be activated within 30 days of the CIRB posting of this notice. 
Sites not using the NCI CIRB: Per CTMB Guidelines, the protocol updates and/or informed consent 
changes must be approved by local IRBs within 90 days of distribution of this notice. 
REVISION #8
The above-referenced study has been revised.  The purposes of this revision are to add a reference to the 
Parker Institute for Cancer Immunotherapy in response to the Request for Amendment (RA) received on 
May 18, 2021 from Dr. Jianqiao Zhang, ACG RAB, and to incorporate additional translational medicine 
details. 
Protocol Changes
1.
The Version Date of the protocol has been updated. 
2.
The Table of Contents has been updated.
3.
Section 1.3a & 1.3b: These sections have been updated to include additional translational medicine 
objectives as outlined in Appendix 18.1.
4.
Appendix 18.1:  In response to the Request for Amendment referenced above, a description of Parker 
Institute for Cancer Immunotherapy’s (PICI) role in analyzing genomic data generated by UCLA has 
been added.  In addition, details about the additional translational medicine objective have been added 
throughout this section.  In summary, ctDNA profile will be captured and analyzed and the IHC analysis 
has been clarified to include the various quantitative multiplexed IHC and staining techniques now 
available to not only achieve the original goals but to exceed the depth of data that can be yielded 
from the same amount of study samples.

S1616
Revision #8 (contd.)
Page 2
Model Consent Form Changes
1.
The version date has been updated. No additional changes were made to the Model Consent Form.
This memorandum serves to notify the NCI, CIRB and SWOG Statistics and Data Management Center.
cc:
PROTOCOL & INFORMATION OFFICE
Jia Chen-UCLA

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PRIVILEGED COMMUNICATION
Activation Date July 17, 2017
FOR INVESTIGATIONAL USE ONLY
SWOG
TITLE PAGE
A PHASE II RANDOMIZED STUDY OF NIVOLUMAB (NSC-748726) WITH IPILIMUMAB (NSC-
732442) OR IPILIMUMAB ALONE IN ADVANCED MELANOMA PATIENTS 
REFRACTORY TO AN ANTI-PD1 OR ANTI-PD-L1 AGENT
Partially funded by SU2C Catalyst Grant – SU2C-AACR-CT06-17
NCT #03033576
STUDY CHAIRS:
AGENTS:
Ari VanderWalde, M.D., M.P.H. (Medical Oncology)
NCI Supplied Investigational Agents:
West Cancer Center
Ipilimumab (BMS-734016, MDX-010, YERVOY®) 
University of Tennessee Health Science Center
(NSC-732442)
7945 Wolf River Blvd
Nivolumab (BMS-936558, MDX1106, Opdivo®)
Germantown, TN 38138
(NSC-748726) 
Phone: 901/683-0055 ext. 63015
FAX: 901/322-2969
E-mail: avanderw@uthsc.edu
IND Sponsor: DCTD, NCI
Antoni Ribas, M.D., Ph.D. (Translational Medicine)
BIOSTATISTICIANS:
UCLA Medical Center
James Moon, M.S.
Division of Hematology-Oncology
Michael Wu, Ph.D.
11-934 Factor Building
SWOG Statistical Center
10833 Le Conte Avenue
1100 Fairview Avenue North, M3-C102
Los Angeles, CA 90095
P.O. Box, 19024
Phone: 310/206-3928
Seattle, WA 98109-1024
FAX: 310/825-2493
Phone: 206/667-4623
E-mail: aribas@mednet.ucla.edu
FAX: 206/667-4408
E-mail: jmoon@fredhutch.org
E-mail: mcwu@fredhutch.org
PARTICIPANTS
ALLIANCE/Alliance for Clinical Trials in Oncology
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group
NRG/NRG Oncology
SWOG/SWOG

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TABLE OF CONTENTS
TITLE PAGE .................................................................................................................................................1
PARTICIPANTS............................................................................................................................................1
TABLE OF CONTENTS ...............................................................................................................................2
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION.......................4
SCHEMA.......................................................................................................................................................5
1.0
OBJECTIVES ..................................................................................................................................6
1.1
Primary Objective(s).........................................................................................................................6
1.2
Secondary Objective(s)....................................................................................................................6
1.3
Translational Objectives...................................................................................................................6
2.0
BACKGROUND...............................................................................................................................6
3.0
DRUG INFORMATION ....................................................................................................................9
Ipilimumab (BMS-734016, MDX-010, YERVOY®) (NSC 732442).................................................10
Nivolumab (BMS-936558, MDX1106, Opdivo®) (NSC 748726) ....................................................19
4.0
STAGING CRITERIA.....................................................................................................................29
5.0
ELIGIBILITY CRITERIA ................................................................................................................30
5.1
Disease Related Criteria ................................................................................................................30
5.2
Prior/Concurrent Therapy Criteria..................................................................................................30
5.3
Clinical/Laboratory Criteria.............................................................................................................31
5.4
Specimen Submission Criteria.......................................................................................................32
5.5
Regulatory Criteria .........................................................................................................................32
6.0
STRATIFICATION FACTORS.......................................................................................................33
7.0
TREATMENT PLAN ......................................................................................................................33
7.1
Pre-Medication and Concomitant Medications ..............................................................................33
7.2
Treatment – Arm 1: Ipilimumab Alone ...........................................................................................34
7.3
Treatment – Arm 2: Ipilimumab + Nivolumab ................................................................................34
7.4
Full CDUS Reporting Requirement................................................................................................34
7.5
Criteria for Removal from Protocol Treatment ...............................................................................34
7.6
Discontinuation of Treatment .........................................................................................................35
7.7
Follow-Up Period............................................................................................................................35
8.0
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS..............................................35
8.1
NCI Common Terminology Criteria for Adverse Events ................................................................35
8.2
General considerations ..................................................................................................................35
8.3
Dose Delay Criteria Ipilimumab (Arm 1) ........................................................................................36
8.4
Dose Delay Criteria for Nivolumab in Combination with Ipilimumab (Arm 2) ................................38
8.5 
Treatment of Infusion Reactions Associated with Ipilimumab and/or Nivolumab..........................44
8.6 
Treatment of Ipilimumab-Related Isolated Drug Fever..................................................................45
8.7
Monitoring and Management of Immune-mediated Adverse Reactions........................................45
8.8
White Blood Cell Growth Factors...................................................................................................49
8.9
Dose Modifications Contacts .........................................................................................................49
8.10
Adverse Event Reporting ...............................................................................................................49
9.0
STUDY CALENDAR......................................................................................................................50
9.1 
Arm 1..............................................................................................................................................50
9.2 
Arm 2:  Cycles 1 through 4 (see Section 9.3 for Arm 1 Cycles 5+) ...............................................53
9.3
Arm 2 Cycles 5+.............................................................................................................................56
10.0
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS .....................................................58
10.1
Measurability of Lesions.................................................................................................................58
10.2
Objective Status at Each Disease Evaluation................................................................................59
10.3
Best Response...............................................................................................................................60
10.4
Performance Status .......................................................................................................................61
10.5
Progression-Free Survival (PFS)...................................................................................................61
10.6
Time to death .................................................................................................................................61
11.0
STATISTICAL CONSIDERATIONS..............................................................................................62
11.1
Accrual Goal...................................................................................................................................62
11.2
Primary Analysis and Interim Analysis...........................................................................................62

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11.3
Secondary Objectives ....................................................................................................................62
11.4
Data and Safety Monitoring ...........................................................................................................63
12.0
DISCIPLINE REVIEW....................................................................................................................63
13.0
REGISTRATION GUIDELINES.....................................................................................................63
13.1
Registration Timing ........................................................................................................................63
13.2
Investigator/Site Registration .........................................................................................................63
13.3
OPEN Registration Requirements .................................................................................................66
13.4
Registration Procedures.................................................................................................................67
13.5
Exceptions to SWOG registration policies will not be permitted....................................................67
14.0
DATA SUBMISSION SCHEDULE ................................................................................................68
14.1
Data Submission Requirement ......................................................................................................68
14.2
Master Forms.................................................................................................................................68
14.3
Data Submission Procedures ........................................................................................................68
14.4
Data Submission Overview and Timepoints ..................................................................................69
15.0
SPECIAL INSTRUCTIONS............................................................................................................71
15.1
Translational Medicine (required for patient): ................................................................................71
16.0
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................75
16.1
Adverse Event Reporting Requirements........................................................................................77
17.0
BIBLIOGRAPHY............................................................................................................................83
18.0
APPENDIX.....................................................................................................................................85
18.1 
Translational Medicine Details.......................................................................................................86
18.2 
Translational Medicine Procedures................................................................................................94
18.3 
Management of Immune-Related Adverse Events, Diarrhea, Hepatotoxicity, Endocrinopathy, and 
Neuropathy for Ipilimumab * ..........................................................................................................96
18.4
Management of Algorithms for Endocrinopathy, Gastrointestinal, Hepatic Neurological, 
Pulmonary, Renal, and Skin Adverse Events for Nivolumab.......................................................102
18.5 
Specimen Banking Instructions for the Ribas Laboratory............................................................110

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION
−
CONTACT INFORMATION
For regulatory requirements:
For patient enrollments:
For study data submission:
Regulatory documentation must 
be submitted to the CTSU via
the Regulatory Submission 
Portal:
(Sign in at www.ctsu.org, and 
select the Regulatory 
Submission sub-tab under the 
Regulatory tab.) 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU 
Regulatory Office immediately
at 866-651-2878 to receive 
further information and support.  
Contact the CTSU Regulatory 
Help Desk at 866-651-2878 for 
regulatory assistance.
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org.
Contact the CTSU Help Desk with 
any OPEN-related questions at 
ctsucontact@westat.com.
Data collection for this study will 
be done exclusively through 
Medidata Rave. Please see the 
data submission section of the 
protocol for further instructions. 
Other Tools and Reports: 
Institutions participating through 
the CTSU continue to have 
access to other tools and reports 
available on the SWOG 
Workbench via the SWOG 
website (www.swog.org).
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment housed in the 
CTSU RSS.
Note:  Non-lead group institutions will order the following supplies from the CTSU Operations Office:   
For patient eligibility or data submission questions contact the SWOG Data Operations Center by 
phone or email:
206/652-2267
melanomaquestion@crab.org
For treatment or toxicity related questions contact the Study Chair by phone or email: 
Ari VanderWalde, M.D., M.P.H
Phone: 901-683-0055
avanderw@uthsc.edu
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.
The CTSU Website is located at https://www.ctsu.org.

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SCHEMA
Locally advanced or metastatic melanoma that has progressed on anti-PD-1 or anti-PD-L1 treatment
Registration & Randomization (1:3)*
      STANDARD OF CARE       
                    EXPERIMENTAL
  Ipilimumab
  Ipilimumab + nivolumab
(every 3 weeks for 4 cycles)
           (every 3 weeks for 4 cycles)
Off treatment
Nivolumab every 4weeks
          Progression
Off treatment
NOTE:  This study includes mandatory specimen submission.  See Section 15.0 for details.
* For every patient randomized to receive standard of care, there will be three randomized to receive the 
experimental regimen (see Section 11.0).

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1.0
OBJECTIVES
1.1
Primary Objective(s)
To compare progression free survival (PFS) of patients with advanced melanoma 
refractory to an anti-PD-1 or anti-PD-L1 agent, treated with combination therapy ipilimumab 
plus nivolumab versus ipilimumab alone.
1.2
Secondary Objective(s)
a.
To estimate difference in T-cell infiltrate between on-study biopsy samples of 
patients who respond to combination therapy (including confirmed and 
unconfirmed, complete and partial response per RECIST 1.1, in each treatment 
arm).
b.
To evaluate the objective response rate (ORR), defined as confirmed complete or
partial response per RECIST 1.1, in each treatment arm.
c.
To evaluate the overall survival (OS) of patients in each treatment arm.
d.
To evaluate the toxicity profile of patients in each treatment arm.
1.3
Translational Objectives
a.
To assess the marginal prognostic value of baseline T-cell density, T-cell receptor 
(TCR) clonality, mutational load, mRNA and other phenotypical expression levels, 
and circulating tumor DNA in terms of response.
b.
To assess the joint prognostic value of T-cell density, TCR clonality, and mutational 
load, mRNA and other phenotypical expression levels, and circulating tumor DNA
in terms of response.
c.
To identify T-cell poor subtype(s) that are associated with response.
2.0
BACKGROUND
The landscape of treatment for metastatic melanoma continues to rapidly change with the 
continued emergence of effective immunotherapeutic agents. Response to PD-1 inhibitors in front-
line metastatic melanoma has been demonstrated to be approximately 30-40% and can produce 
both durable remissions and prolong survival. (1,2) T-cell inflamed tumors show remarkable 
sensitivity to this therapeutic class while T-cell poor tumors are generally non-responsive. (3)
Response to the front-line combination of the CTLA-4 inhibitor ipilimumab and the PD-1 inhibitor 
nivolumab is approximately 60% but with substantial toxicity. (4,5) Additionally, the added benefit 
of the combination over single-agent PD-1 inhibitors may be limited to those without high PD-L1 
expression. (6) Adding ipilimumab to PD-1 therapy, therefore, might be capturing additional 
responders by influencing the peri-tumoral milieu such that the cancer becomes more responsive 
to immune manipulation, while avoiding the added toxicity of the combination in patients who were 
poised to respond to anti-PD-1 therapy alone.
The rapid pace of changing paradigms for first-line treatment has left little room for elucidation of 
later-line choices.  Little data exist on appropriate sequencing of immune therapy following PD-1 
therapy. Given the possible synergistic effects of the combination, and given the possibility that the 
addition of ipilimumab may work by making the tumor more sensitive to PD-1 inhibition, it is rational 
to conclude that ipilimumab may be added as salvage therapy for patients whose tumors have 
progressed on single-agent PD-1 therapy. The effects of combining therapy in the second line 

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following failure of first-line anti-PD-1 treatment could be hypothesized to result in more responders 
than would be expected if patients received ipilimumab alone as salvage. This study will attempt to 
provide evidence of the utility of combining ipilimumab, a CTLA-4 antagonist, with the PD-1 inhibitor 
nivolumab even after primary progression on a PD-1 inhibitor.  Progression free survival on the
combination will be compared to rates seen with ipilimumab as a single agent. If the study reveals 
a longer progression-free survival with a high response rate in patients who receive the 
combination, this could provide preliminary evidence to potentially limit a toxic combination to 
salvage use only. On the other hand, if the study reveals equivalent PFS with a low response rate 
it could provide evidence that combination immunotherapy is most useful in front-line use.  
Additionally, key translational components will work to identify subsets of patients that are more or 
less likely to respond to the combination if exhibiting primary refractoriness to PD-1 antibodies 
alone.
The combination of ipilimumab and nivolumab in the treatment of previously untreated advanced 
melanoma was approved by the U.S. Food and Drug Administration based on the results of the 
Phase II Checkmate 069 trial, which compared this combination to ipilimumab alone and 
demonstrated an improved objective response rate among patients with BRAF wild type tumors
(61% for the combination as compared to 11% for ipilimumab alone) and improved progression 
free survival with a hazard ratio of 0.4 (p<0.001). (7) The combination was also compared to 
ipilimumab alone and nivolumab alone in a Phase III study. The combination showed improved 
progression free survival as compared to ipilimumab and thus met its primary endpoint (HR 0.42, 
p<0.01). (8) The combination also showed improved progression-free survival as compared to 
nivolumab alone (HR 0.57, p<0.001). This benefit, however, may have been limited to patients with 
tumors negative for the PD-1 ligand, though objective response rates were numerically higher in 
the combination arm than in the nivolumab arm. Overall survival data have not yet been reported. 
(9)
PD-1 inhibitors as single agents in the first-line setting have been shown to consistently result in 
response rates of 33-44%. (10,11,12)  Both pembrolizumab and nivolumab have been shown 
superior to ipilimumab in the front-line setting in advanced melanoma. (13,14)  As such, PD-1 
inhibitors have become standard of care in the first-line setting, either alone or in combination with 
ipilimumab.  Data for second-line use of any therapy after PD-1 inhibitors is lacking.  While 
ipilimumab was initially approved based on a study of patients who received the drug after failure 
of prior therapy, no studies of ipilimumab following failure on a PD-1 inhibitor have been reported. 
(15) As such, there are no data that guide the appropriate management of patients who have 
progressed on first-line immune-checkpoint therapy with BRAF wild-type mutations.
Further elucidation of patients who are more likely to benefit from combination checkpoint inhibition 
versus single agent PD-1s are also somewhat immature. While Phase III data point toward PD-L1 
overexpression as a marker that may distinguish between patients who benefit from combination 
therapy versus single-agent, translational data present a more complicated picture. (16) PD-L1 
expression may confer different levels of susceptibility dependent on whether overexpressed by 
tumor cells, tumor-infiltrating immune cells, or expression at the invasive tumor margin. (17)  
Additionally, investigations of T-cell repertoire, whole exome modalities, and mutational load have 
shown preliminary predictive potential of response to checkpoint inhibitors in various tumor types. 
(18,19,20) 
The current standard of care in patients who progress on PD-1 therapy alone is single-agent CTLA-
4 inhibitor therapy (e.g. ipilimumab), despite lack of currently available prospective data in this 
setting. Historical response rates to ipilimumab as a single agent have been approximately 10%, 
and this includes first-line studies with ipilimumab, which could be expected to have a higher 
response rate than in the second line after failure of immunotherapy. (21,22,23) Additionally, one 
retrospective case series has reported a response to single-agent ipilimumab of 10% following 
single-agent nivolumab (PD-1 inhibitor) among 40 patients. (24) A clear benefit over the expected 
background rate of 10% response to ipilimumab alone would provide important preliminary data in 
the development of a synergistic effect between the combination even after failure of PD-1 therapy 
alone, and would have potential clinical utility in guidance of physicians and patients in choice of 

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upfront combinatorial approaches versus combination immunotherapy after failure of single-agent 
immunotherapy.
Our main hypothesis, therefore, is that patients with advanced melanoma who progress on anti-
PD-1 therapy upfront may ultimately respond to the addition of the CTLA-4 inhibitor ipilimumab to 
continued PD-1 inhibition (with nivolumab), and that disease control (as measured using PFS) 
would be longer than that seen with switching to ipilimumab alone. We surmise that this would 
occur because melanomas primarily refractory to PD-1 antibodies may not have a preexisting T 
cell infiltrate, which can be corrected by adding treatment with the anti-CTLA-4 antibody ipilimumab.  
CTLA-4 blockade therapy acts at the activation step of an immune response and allows T cells to 
expand, circulate and infiltrate tumors, where they become negatively regulated by anti-PD-1. By 
adding CTLA-4 blockade to continued PD-1 blockade we hypothesize that T cells will infiltrate 
metastatic lesions and be able to induce their specific antitumor cytotoxic response by having 
released these two major immune checkpoints.
Translational Medicine
The guiding hypothesis of the translational medicine portion of the study is that patients who 
progress on single agent PD-1 blockade therapy have “cold” tumors, which lack a pre-existing or 
induced antitumor immune response, but that they can be turned into “hot” tumors by adding an 
anti-CTLA-4 blocking antibody. CTLA-4 blockade releases an early activation immune checkpoint, 
allowing antitumor-T cells to proceed through cell cycle after initial activation, resulting in a 
remarkable diversification of the peripheral T cell pool and increased T cell infiltration in tumors.
(25,26) This hypothesis will be tested clinically with the primary endpoint of progression-free 
survival when adding ipilimumab to continued anti-PD-1 therapy when compared to rates seen with 
ipilimumab alone and experimentally by analyzing paired tumor biopsies testing for changes in the 
tumor micro-environment between responders and non-responders, and between those who 
receive combination therapy and single-agent ipilimumab.
Mechanisms of acquired resistance to anti-PD-1 following initial response appear to be related to 
acquired mutations. (27) However, primary resistance is likely due to the immunologic milieu of the 
cancer and its environs itself, the presence of tumor infiltrating lymphocytes, and expression of 
various immune markers. (28) Studies have shown that anti-CTLA-4 antibodies are very effective 
in bringing T-cells into tumors. (29)  Though direct evidence that this results in inducing PD-1 
responsiveness in patients who were previously PD-1 refractory is lacking. We hypothesize that 
this T-cell recruitment, along with other immune-stimulating effects of anti-CTLA-4 agents will allow 
the combination to induce responses to overcome prior resistance to PD-1 blockade. To test this 
hypothesis, we aim to collect blood and tissue both prior to and on-study in patients who were 
resistant to anti-PD-1 therapy and now receive anti-CTLA-4 in combination with anti-PD-1 therapy
or anti-PD-1 therapy alone. 
To date, no immune assay has been adopted in the clinic to assist with clinical decision-making. 
We propose to systematically investigate the predictive utility of three immunodiagnostic 
approaches that measure distinct parameters within tumors: i) quantitative multiplexed 
immunohistochemistry (qmIHC) which provides spatially resolved, multiparametric information and 
measures the density, location and phenotype of immune cell types; ii) immunosequencing of the 
T-cell receptor (TCR) repertoire which is based on bulk reads and measures the clonality and 
repertoire of TCRs;  and iii) whole exome sequencing which generates signal based on bulk 
measurements and identifies all non-synonymous mutations, as well as information on potential 
loss of function mutations in the interferon and antigen presentation pathways that may lead to 
genetic mechanisms of resistance to PD-1 blockade therapy. (30) These approaches have shown 
preliminary predictive potential by independent groups across different cancer types. No study to 
date, however, has investigated the relationship between these factors or their predictive value 
when interrogating the same tumor. By defining the relationships between these three factors in 
terms of response, we anticipate that our approach will lead to clinically actionable information as 
well as key insights into why certain tumors are immunogenic and others are not. 

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We hypothesize that the integration of all three approaches into a predictive model will show 
incremental predictive value over any single parameter. Additionally, we will be able to determine 
the relationships between immune cell types, density and location, TCR clonality and mutation load 
and/or type.  Our study objectives will be as follows: to assess the independent prognostic value of 
baseline T-cell density, T-cell receptor (TCR) clonality, and mutational load in terms of response; 
to assess the incremental prognostic value of T-cell density, TCR clonality and mutational load in 
terms of response; and to identify T-cell poor subtype(s) that are associated with response.
Additionally, we will incorporate genomic and transcriptomic evaluation of single-gene and gene-
expression signatures into the correlative plan, including emerging data in the field with evaluation 
and prospective testing of the innate anti-PD-1 resistance (IPRES) gene signature. (31) Whole 
exome sequencing, in addition to exposure of mutation load, will be used to evaluate specific 
mutations that have been correlated with response and resistance, such as B2M and JAK1/2 
mutations (13), BRCA2, mismatch-repair deficiency, and others. (32,33) See Appendix 18.1 for 
methods.
Inclusion of Women and Minorities
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  The anticipated accrual in the ethnicity/race and sex categories 
is shown in the table below. 
DOMESTIC PLANNED ENROLLMENT REPORT
Racial Categories
Ethnic Categories
Total
Not Hispanic or Latino
Hispanic or Latino
Female
Male
Female
Male
American Indian/ 
Alaska Native
0
1
0
0
1
Asian
0
1
0
0
1
Native Hawaiian or 
Other Pacific Islander
0
0
0
0
0
Black or African 
American
1
2
0
0
3
White
27
59
1
2
89
More Than One Race
0
0
0
0
0
Total
28
63
1
2
94
3.0
DRUG INFORMATION
Investigator Brochures
For information regarding Investigator Brochures, please refer to SWOG Policy 15.
For this study, ipilimumab and nivolumab are investigational and being provided under an IND held 
by the National Cancer Institute.  The current versions of the Investigator Brochures for the agents 
will be accessible to site investigators and research staff through the PMB Online Agent Ordering
Processing (OAOP) application
(http://ctep.cancer.gov/branches/pmb/agent_order_processing.htm).
Access to OAOP requires 
the establishment of a CTEP Identity and Access Management (IAM) account and the maintenance 
of an “active” account status and a “current” password.  Questions about IB access may be directed 
to the PMB IB coordinator via e-mail (ibcoordinator@mail.nih.gov).

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Ipilimumab (BMS-734016, MDX-010, YERVOY®) (NSC 732442)
a.
PHARMACOLOGY
Mechanism of Action: Cytotoxic T-lymphocyte antigen-4 CTLA-4 is a negative 
regulator of T-cell activity. Ipilimumab is a full human monoclonal immunoglobin 
(lg) antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its 
ligands, CD80/CD86.  Blockade of CTLA-4 has been shown to augment T-cell 
activation and proliferation, including the activation and proliferation of tumor 
infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-
regulatory cell function, which may contribute to a general increase in T cell 
responsiveness, including the anti-tumor immune response.
b.
PHARMACOKINETICS
Absorption: No formal pharmacokinetic drug interaction studies have been 
conducted with ipilimumab. Ipilimumab is not expected to have 
pharmacokinetic drug-drug interactions, since it is not metabolized by 
CYP450 or other drug metabolizing enzymes.
Distribution: Ipilimumab is confined mainly to the extracellular fluid. Peak 
concentration (Cmax), trough concentration (Cmin), and area under the 
plasma concentration versus time curve (AUC) of ipilimumab increased 
dose proportionally within the dose range examined ipilimumab is confined 
mainly to the extracellular fluid. Peak concentration (Cmax), trough 
concentration (Cmin), and area under the plasma concentration versus 
time curve (AUC) of ipilimumab increased dose proportionally within the 
dose range examined. Based on population pharmacokinetic analysis, the 
mean volume of distribution (% coefficient of variation) at steady state was 
7.47 liters (10%).
Metabolism: Not applicable.  Monoclonal antibodies are usually degraded 
into amino acids and small peptides, independently from CYP450 or other 
drug-metabolizing enzymes.
Elimination: Clearance increased with body weight, but no dose 
adjustment is required with dosing on a mg/kg basis. Upon repeated 
dosing every 3 weeks, the clearance (CL) of ipilimumab was found to be 
time-invariant, and systemic accumulation was 1.5-fold or less.  The mean 
value (% coefficient of variation) generated through population 
pharmacokinetic analysis for the terminal half-life (t1/2) was 15.4 days 
(34%) and for CL was 16.8 mL/h (38%). 
c.
ADVERSE EFFECTS
Adverse Effects: The Comprehensive Adverse Events and Potential Risks 
list (CAEPR) provides a single list of reported and/or potential adverse 
events (AE) associated with an agent using a uniform presentation of 
events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in 
a separate column and is identified with bold and italicized text. This 
subset of AEs (SPEER) is a list of events that are protocol specific 

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exceptions to expedited reporting to NCI (except as noted below).  Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf for further clarification. Frequency is provided based on 
2678 patients. Below is the CAEPR for Ipilimumab (MDX-010).
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted 
in parentheses next to the AE in the SPEER.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required.
Version 2.10, March 29, 20191
Adverse Events with Possible 
Relationship to Ipilimumab (MDX-010)
(CTCAE 5.0 Term)
[n= 2678]
Specific Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER) 
Likely (>20%)
Less Likely (<=20%)
Rare but Serious 
(<3%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Blood and lymphatic 
system disorders -
Other (acquired 
hemophilia)
CARDIAC DISORDERS
Atrial fibrillation
Myocarditis2
Pericardial effusion
EAR AND LABYRINTH DISORDERS
Hearing impaired
ENDOCRINE DISORDERS
Adrenal insufficiency2
Hyperthyroidism2
Hypophysitis2
Hypopituitarism2
Hypothyroidism2
Testosterone 
deficiency2
EYE DISORDERS
Eye disorders - Other 
(episcleritis)2
Uveitis2
GASTROINTESTINAL DISORDERS
Abdominal pain
Colitis2
Colitis (Gr 3)
Colonic perforation3
Constipation
Diarrhea
Diarrhea (Gr 3)
Enterocolitis
Esophagitis
Ileus
Nausea
Nausea (Gr 3)
Pancreatitis2
Vomiting

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Adverse Events with Possible 
Relationship to Ipilimumab (MDX-010)
(CTCAE 5.0 Term)
[n= 2678]
Specific Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER) 
Likely (>20%)
Less Likely (<=20%)
Rare but Serious 
(<3%)
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS
Chills
Fatigue
Fatigue (Gr 3)
Fever
Fever (Gr 2)
General disorders 
and administration 
site conditions -
Other (systemic 
inflammatory 
response syndrome 
[SIRS])
Multi-organ failure
HEPATOBILIARY DISORDERS
Hepatobiliary 
disorders - Other 
(hepatitis)2
IMMUNE SYSTEM DISORDERS
Autoimmune 
disorder2
Immune system 
disorders - Other 
(GVHD in the setting 
of allotransplant)4
INFECTIONS AND INFESTATIONS
Infections and 
infestations - Other 
(aseptic meningitis)2
INJURY, POISONING AND PROCEDURAL 
COMPLICATIONS
Infusion related 
reaction
INVESTIGATIONS
Alanine 
aminotransferase 
increased
Aspartate 
aminotransferase 
increased
Lymphocyte count 
decreased
Neutrophil count 
decreased
Weight loss
METABOLISM AND NUTRITION DISORDERS
Anorexia
Dehydration
Hyperglycemia

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Adverse Events with Possible 
Relationship to Ipilimumab (MDX-010)
(CTCAE 5.0 Term)
[n= 2678]
Specific Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER) 
Likely (>20%)
Less Likely (<=20%)
Rare but Serious 
(<3%)
Metabolism and 
nutrition disorders -
Other (exacerbation 
of pre-existing 
diabetes mellitus)
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS
Arthralgia
Arthritis
Generalized muscle 
weakness
Musculoskeletal and 
connective tissue 
disorder - Other 
(polymyositis)2
NERVOUS SYSTEM DISORDERS
Ataxia
Facial nerve 
disorder2
Guillain-Barre 
syndrome2
Headache
Myasthenia gravis2
Nervous system 
disorders – Other 
(immune-mediated 
encephalitis) 2
Peripheral motor 
neuropathy
Peripheral sensory 
neuropathy
Trigeminal nerve 
disorder
PSYCHIATRIC DISORDERS
Psychiatric disorders 
- Other (mental 
status changes)
RENAL AND URINARY DISORDERS
Acute kidney injury
Renal and urinary 
disorders - Other 
(granulomatous 
tubulointerstitial 
nephritis)
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS
Pneumonitis
Respiratory failure

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Adverse Events with Possible 
Relationship to Ipilimumab (MDX-010)
(CTCAE 5.0 Term)
[n= 2678]
Specific Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER) 
Likely (>20%)
Less Likely (<=20%)
Rare but Serious 
(<3%)
Respiratory, thoracic 
and mediastinal 
disorders - Other 
(bronchiolitis 
obliterans with 
organizing 
pneumonia)
Respiratory, thoracic 
and mediastinal 
disorders - Other 
(lung infiltration)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Erythema multiforme
Pruritus
Pruritus (Gr 3)
Rash maculo-
papular
Rash maculo-
papular (Gr 3) 
Skin and 
subcutaneous tissue 
disorders - Other 
(Sweet's Syndrome)
Stevens-Johnson 
syndrome
Toxic epidermal 
necrolysis
Urticaria
VASCULAR DISORDERS
Hypotension
1 This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of 
revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail.
2 Ipilimumab can result in severe and fatal immune-mediated adverse 
events probably due to T-cell activation and proliferation.  These can 
include (but are not limited to) autoimmune hemolytic anemia, acquired 
anti-factor VIII immune response, autoimmune aseptic meningitis, 
autoimmune hepatitis, autoimmune thyroiditis, hepatic failure, pure red 
cell aplasia, pancreatitis, ulcerative and hemorrhagic colitis, endocrine 
disorders 
(e.g., 
autoimmune 
thyroiditis, 
hyperthyroidism, 
hypothyroidism, autoimmune hypophysitis/hypopituitarism, and adrenal 
insufficiency), ocular manifestations (e.g., uveitis, iritis, conjunctivitis, 
blepharitis, and episcleritis), sarcoid granuloma, myasthenia gravis, 
polymyositis, and Guillain-Barre syndrome.  The majority of these 
reactions manifested early during treatment; however, a minority 
occurred weeks to months after discontinuation of ipilimumab especially 
with the initiation of additional treatments.
3 Late bowel perforations have been noted in patients receiving MDX-010 
(ipilimumab) in association with subsequent IL-2 therapy.
4 Complications including hyperacute graft-versus-host disease (GVHD), 
may occur in patients receving allo stem cell transplant (SCT) after 

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receiving Ipilimumab (MDX-010).  These complications may occur 
despite intervening therapy between receiving Ipilimumab (MDX-010) 
and allo-SCT.
5 In rare cases diplopia (double vision) has occurred as a result of muscle 
weakness (Myasthenia gravis).
6 Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal 
hemorrhage, Colonic hemorrhage, Duodenal hemorrhage, Esophageal 
hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal 
hemorrhage, 
Ileal 
hemorrhage, 
Intra-abdominal 
hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, 
Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage 
under the GASTROINTESTINAL DISORDERS SOC.
7 Infection includes all 75 sites of infection under the INFECTIONS AND 
INFESTATIONS SOC.
Adverse events reported on ipilimumab (MDX-010) trials, but for 
which there is insufficient evidence to suggest that there was a 
reasonable possibility that ipilimumab (MDX-010)
caused the 
adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Blood and 
lymphatic system disorders - Other (pure red cell aplasia)2; Febrile 
neutropenia
CARDIAC 
DISORDERS
-
Conduction 
disorder; 
Restrictive 
cardiomyopathy
EYE DISORDERS - Extraocular muscle paresis5; Eye disorders - Other 
(retinal pigment changes)
GASTROINTESTINAL DISORDERS
-
Colonic ulcer; Dyspepsia; 
Dysphagia; 
Gastrointestinal 
disorders 
-
Other 
(gastroenteritis); 
Gastrointestinal hemorrhage6; Proctitis
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS -
Flu like symptoms; Non-cardiac chest pain
HEPATOBILIARY DISORDERS - Hepatic failure2
IMMUNE SYSTEM DISORDERS - Allergic reaction
INFECTIONS AND INFESTATIONS - Infection7
INVESTIGATIONS
-
Creatinine increased; Investigations -
Other 
(rheumatoid factor); Lipase increased; Platelet count decreased; Serum 
amylase increased; White blood cell decreased
METABOLISM AND NUTRITION DISORDERS - Tumor lysis syndrome
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS -
Back pain; Joint range of motion decreased; Myalgia; Pain in extremity
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL 
CYSTS AND POLYPS) - Tumor pain
NERVOUS SYSTEM DISORDERS - Dizziness; Dysphasia; Ischemia 
cerebrovascular; Seizure
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia
RENAL AND URINARY DISORDERS - Proteinuria
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
-
Allergic rhinitis; Cough; Dyspnea; Laryngospasm
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; 
Hyperhidrosis; Skin hypopigmentation
VASCULAR DISORDERS - Flushing; Hypertension; Vascular disorders -
Other (temporal arteritis)
Note: Ipilimumab (BMS-734016; MDX-010 Transfectoma-derived) in 
combination with other agents could cause an exacerbation of any 

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adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either 
agent.
Pregnancy and Lactation: There are no adequate and well-controlled 
studies of Ipilimumab in pregnant women. Use of Ipilimumab during 
pregnancy only if the potential benefit justifies the potential risk to the 
fetus.  Human IgG1 is known to cross the placental barrier and ipilimumab 
is an IgG1; therefore, ipilimumab has the potential to be transmitted from 
the mother to the developing fetus.
It is not known whether ipilimumab is secreted in human milk.  Because 
many drugs are secreted in human milk and because of the potential for 
serious adverse reactions in nursing infants from ipilimumab, a decision 
should be made whether to discontinue nursing or to discontinue 
ipilimumab, taking into account the importance of ipilimumab to the 
mother.
Drug Interactions:  No formal pharmacokinetic drug interaction studies 
have been conducted with ipilimumab. Ipilimumab is not expected to have 
pharmacokinetic drug-drug interactions, since it is not metabolized by 
CYP450 or other drug metabolizing enzymes
d.
DOSING & ADMINISTRATION
See Section 7.0 Treatment Plan.
Ipilimumab injection is to be administered as 90 minute infusion with an in-line, 
sterile, nonpyrogenic, low-protein-binding filter (pore size of 0.2 micrometer to 1.2 
micrometer). Do not administer as IV push or bolus injection.

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e.
HOW SUPPLIED
Ipilimumab will be supplied free of charge by Bristol-Myers-Squibb (BMS) 
and distributed by NCI/DCTD.
If a storage temperature excursion is identified, promptly return Ipilimumab 
to 2° to 8°C and quarantine the supplies.  Provide a detailed report of the 
excursion (including documentation of temperature monitoring and 
duration 
of 
the 
excursion) 
to 
PMBAfterHours@mail.nih.gov
for 
determination of suitability.
Ipilimumab injection is supplied as 200 mg/40 mL (5 mg/mL).  It is 
formulated as a clear to slightly opalescent, colorless to pale yellow, 
sterile, nonpyrogenic, single-use, isotonic aqueous solution that may 
contain particles.
Each vial is a Type I flint glass vial with gray butyl stoppers and sealed 
with aluminum seals.
Process C
Component
200 mg/ viala
Ipilimumab
213 mg
Sodium Chloride, USP 
249 mg
TRIS-hydrochloride
134.3 mg
Diethylenetriamine pentacetic acid
1.67 mg
Mannitol, USP
426 mg
Polysorbate 80 (plant-derived)
4.69 mg
Sodium Hydroxide
QS to pH 7
Hydrochloric acid
QS to pH 7
Water for Injection
QS: 42.6 mL
Nitrogenb
Processing agent
a Includes 2.6 mL overfill.
b Nitrogen is used to transfer the bulk solution through the pre-filled and 
sterilizing filters into the aseptic area.
f.
STORAGE, PREPARATION& STABILITY
Store intact vials of ipilimumab refrigerated at (20 to 80C), protected from 
light.  Do not freeze.
If a storage temperature excursion is identified, promptly return Ipilimumab 
to 2° to 8°C and quarantine the supplies.  Provide a detailed report of the 
excursion (including documentation of temperature monitoring and 
duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability.
Ipilimumab is given undiluted or further diluted in 0.9% NaCl Injection, USP 
or 5% Dextrose Injection, USP in concentrations between 1 mg/mL and 4
mg/mL.  Ipilimumab is stable in a polyvinyl chloride(PVC), non-PVC/non 
DEHP (di-(2-ethylhexyl) phthalate) IV bag or glass container up to 24 
hours refrigerated at (20 to 80C) or at room temperature/room light.  
The product may be infused using a volumetric pump at the protocol-
specific dose(s) and rate(s) through a PVC IV solution infusion set with an 

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in-line, sterile, nonpyrogenic, low-protein-binding filter (pore size of 0.2 
micrometer to 1.2 micrometer).
Do not administer ipilimumab as an IV push or bolus injection.
Stability of prepared IV ipilimumab solution is stable up to 24 hours 
refrigerated at (20 to 80C) or at room temperature/ room light. 
Partially used vials or empty vials of ipilimumab injection should be 
discarded at the site according to appropriate drug disposal procedures.
g.
DRUG ORDERING & ACCOUNTABILITY
Drug ordering: NCI-supplied agents may be requested by the Principal 
Investigator (or their authorized designee) at each participating institution.  
Pharmaceutical Management Branch (PMB) policy requires that agent be 
shipped directly to the institution where the patient is to be treated.  PMB 
does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  The CTEP-assigned protocol number 
(S1616) must be used for ordering all CTEP-supplied investigational 
agents.  The responsible investigator at each participating institution must 
be registered with CTEP, DCTD through an annual submission of FDA 
Form 1572 (Statement of Investigator), Curriculum Vitae, Supplemental 
Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If 
there are several participating investigators at one institution, CTEP-
supplied investigational agents for the study should be ordered under the 
name of one lead investigator at that institution.
In general, sites may order initial agent supplies when a subject is being 
screened for enrollment onto the study.
Active 
CTEP-registered 
investigators 
and 
investigator-designated 
shipping designees and ordering designees can submit agent requests 
through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” 
account status and a “current” password.  For questions about drug 
orders, transfers, returns, or accountability, call or email PMB any time.  
Refer to the PMB’s website for specific policies and guidelines related to 
agent management.
Drug Handling and Accountability (NCI logs or other)
Drug Accountability: The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of 
the receipt, dispensing and final disposition of all agents received 
from the PMB using the appropriate NCI Investigational Agent 
(Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational 
Agent Accountability Records for each agent, strength, 
formulation and ordering investigator on this protocol. 
Electronic logs are allowed as long as a print version of the log 
process is the exact same appearance as the current NCI DARF. 

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Drug return and/or disposition instruction
Drug Returns: All unused drug supplies should be returned to the 
PMB. When it is necessary to return study drug (e.g., sealed vials 
remaining when expired vials are recalled by the PMB), 
investigators should return the study drug to the PMB using the 
NCI Return Agent Form available on the NCI home page 
(http://ctep.cancer.gov).
Contact Information 
Useful Links and Contacts:
•
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/
•
NCI CTEP Investigator Registration
PMBRegPend@ctep.nci.nih.gov
•
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm 
•
PMB 
Online 
Agent 
Order 
Processing 
(OAOP) 
application: 
https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx 
•
CTEP Identity and Access Management (IAM) account: 
https://eapps-ctep.nci.nih.gov/iam/
•
CTEP 
Associate 
Registration 
and 
IAM 
account 
help:  
ctepreghelp@ctep.nci.nih.gov
•
PMB email:  PMBAfterHours@mail.nih.gov
•
PMB phone and hours of service: (240) 276-6575 Monday through 
Friday between 8:30 am and 4:30 pm (ET)
PMB IB Coordinator: IBCoordinator@mail.nih.gov
Nivolumab (BMS-936558, MDX1106, Opdivo®) (NSC 748726) 
a.
PHARMACOLOGY
Mode of Action: Nivolumab targets the programmed death–1 (PD-1, cluster of 
differentiation 279 [CD279]) cell surface membrane receptor. PD-1 is a negative 
regulatory receptor expressed by activated T and B lymphocytes. Binding of PD-1 
to its ligands, programmed death–ligand 1 (PD-L1) and 2 (PD-L2), results in the 
down-regulation of lymphocyte activation. Nivolumab inhibits the binding of PD-1 
to PD-L1 and PD-L2.  Inhibition of the interaction between PD-1 and its ligands 
promotes immune responses and antigen-specific T-cell responses to both foreign 
antigens as well as self-antigens.
b.
PHARMACOKINETICS
Distribution:  Nivolumab has linear pharmacokinetics after single and 
multiple dosing within the range 0.1 mg/kg to 10 mg/kg. The volume 
distribution (Vd) is 8L.
Elimination:  Clearance is independent of dose in the range 0.1 mg/kg to 
10 mg/kg. The total body clearance is 9.5 mL/hr, and the elimination half-
life of is approximately 26.7 days. Body weight normalized dosing showed 
approximately constant trough concentrations over a wide range of body 
weights. 

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c.
ADVERSE EFFECTS
Adverse Effects:  The Comprehensive Adverse Events and Potential Risks list 
(CAEPR) provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by body system. 
In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with 
bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  
Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 2069 patients. 
Below is the CAEPR for Nivolumab.
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER.  If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is 
required
Version 2.4, December 2, 20201
Adverse Events with Possible 
Relationship to Nivolumab
(CTCAE 5.0 Term)
[n= 2069]
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%)
Less Likely 
(<=20%)
Rare but Serious 
(<3%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia
Anemia (Gr 3)
CARDIAC DISORDERS
Cardiac disorders -
Other 
(cardiomyopathy)
Myocarditis
Pericardial 
tamponade2
Pericarditis
ENDOCRINE DISORDERS
Adrenal 
insufficiency3
Hyperthyroidis
m3
Hypophysitis3
Hypothyroidis
m3
EYE DISORDERS
Blurred vision
Dry eye
Eye 
disorders 
-
Other (diplopia)3

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Adverse Events with Possible 
Relationship to Nivolumab
(CTCAE 5.0 Term)
[n= 2069]
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%)
Less Likely 
(<=20%)
Rare but Serious 
(<3%)
Eye 
disorders 
-
Other 
(Graves 
ophthalmopathy)3
Eye 
disorders 
-
Other (optic neuritis 
retrobulbar)3
Eye 
disorders 
-
Other 
(Vogt-
Koyanagi-Harada)
Uveitis
GASTROINTESTINAL DISORDERS
Abdominal 
pain
Abdominal pain (Gr 2)
Colitis3
Colonic perforation3
Diarrhea
Diarrhea (Gr 3)
Dry mouth
Dry mouth (Gr 2)
Enterocolitis
Gastritis
Mucositis oral
Nausea
Nausea (Gr 2)
Pancreatitis4
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS
Fatigue
Fatigue (Gr 3)
Fever
Fever (Gr 2)
Injection 
site 
reaction
Injection site reaction (Gr 
2)
HEPATOBILIARY DISORDERS
Hepatobiliary 
disorders -
Other 
(immune-mediated 
hepatitis)
IMMUNE SYSTEM DISORDERS
Allergic reaction3
Autoimmune 
disorder3
Cytokine 
release 
syndrome5
Immune 
system 
disorders -
Other 
(GVHD in the setting 
of allotransplant)3,6

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Adverse Events with Possible 
Relationship to Nivolumab
(CTCAE 5.0 Term)
[n= 2069]
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%)
Less Likely 
(<=20%)
Rare but Serious 
(<3%)
Immune 
system 
disorders -
Other 
(sarcoidosis)3
INJURY, 
POISONING 
AND 
PROCEDURAL 
COMPLICATIONS
Infusion 
related 
reaction7
INVESTIGATIONS
Alanine 
aminotransfer
ase increased3
Alanine aminotransferase 
increased3 (Gr 3)
Aspartate 
aminotransfer
ase increased3
Aspartate 
aminotransferase 
increased3 (Gr 3)
Blood bilirubin 
increased3
Blood bilirubin increased3
(Gr 2)
CD4 
lymphocytes 
decreased
CD4 
lymphocyte 
decreased (Gr 4)
Creatinine 
increased
Lipase 
increased
Lymphocyte 
count 
decreased
Lymphocyte 
count 
decreased (Gr 4)
Neutrophil 
count 
decreased
Platelet count 
decreased
Serum 
amylase 
increased
METABOLISM AND NUTRITION DISORDERS
Anorexia
Hyperglycemia
Hyperglycemia (Gr 2)
Metabolism 
and 
nutrition disorders -
Other 
(diabetes 
mellitus 
with 
ketoacidosis)3
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS
Arthralgia

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Adverse Events with Possible 
Relationship to Nivolumab
(CTCAE 5.0 Term)
[n= 2069]
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%)
Less Likely 
(<=20%)
Rare but Serious 
(<3%)
Musculoskeletal and 
connective 
tissue 
disorder 
-
Other 
(polymyositis)
Myositis
Rhabdomyolysis
NERVOUS SYSTEM DISORDERS
Encephalopathy3
Facial 
nerve 
disorder3
Guillain-Barre 
syndrome3
Myasthenia gravis3
Nervous 
system 
disorders -
Other 
(demyelination 
myasthenic 
syndrome)
Nervous 
system 
disorders -
Other 
(encephalitis)3
Nervous 
system 
disorders -
Other 
(meningoencephaliti
s)
Nervous 
system 
disorders -
Other 
(meningoradiculitis)3
Nervous 
system 
disorders -
Other 
(myasthenic 
syndrome)
Peripheral 
motor 
neuropathy
Peripheral sensory 
neuropathy
Reversible posterior 
leukoencephalopath
y syndrome3
RENAL AND URINARY DISORDERS
Acute kidney injury3
Renal and urinary 
disorders -
Other 
(immune-mediated 
nephritis)

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Adverse Events with Possible 
Relationship to Nivolumab
(CTCAE 5.0 Term)
[n= 2069]
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%)
Less Likely 
(<=20%)
Rare but Serious 
(<3%)
RESPIRATORY, 
THORACIC 
AND 
MEDIASTINAL 
DISORDERS
Pleural 
effusion3
Pneumonitis3
Respiratory, 
thoracic 
and 
mediastinal 
disorders -
Other 
(bronchiolitis 
obliterans 
with 
organizing 
pneumonia)3
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Erythema 
multiforme3
Pruritus3
Pruritus3 (Gr 2)
Rash maculo-
papular3
Rash maculo-papular3 (Gr 
2)
Skin 
and 
subcutaneous tissue 
disorders -
Other 
(bullous 
pemphigoid)
Skin 
and 
subcutaneous 
tissue 
disorders 
-
Other (Sweet's 
Syndrome)3
Skin 
hypopigmenta
tion3
Stevens-Johnson 
syndrome
Toxic 
epidermal 
necrolysis
1 This table will be updated as the toxicity profile of the agent is revised.  Updates 
will be distributed to all Principal Investigators at the time of revision.  The current 
version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, 
the name of the investigator, the protocol and the agent should be included in 
the e-mail.
2 Pericardial tamponade may be related to possible inflammatory reaction at tumor 
site.
3 Nivolumab being a member of class of agents involved in the inhibition of 
“immune checkpoints”, may result in severe and possibly fatal immune-mediated 

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adverse events probably due to T-cell activation and proliferation.  This may 
result in autoimmune disorders that can include (but are not limited to) 
autoimmune hemolytic anemia, acquired anti-factor VIII immune response, 
autoimmune aseptic meningitis, autoimmune hepatitis, autoimmune nephritis, 
autoimmune 
neuropathy, 
autoimmune 
thyroiditis, 
bullous 
pemphigoid, 
exacerbation of Churg-Strauss Syndrome, drug rash with eosinophilia systemic 
symptoms [DRESS] syndrome, facial nerve disorder (facial nerve paralysis), 
limbic encephalitis, hepatic failure, pure red cell aplasia, pancreatitis, ulcerative 
and hemorrhagic colitis, endocrine disorders (e.g., autoimmune thyroiditis, 
hyperthyroidism, hypothyroidism, autoimmune hypophysitis/hypopituitarism, 
thyrotoxicosis, and adrenal insufficiency), sarcoid granuloma, myasthenia 
gravis, polymyositis, and Guillain-Barre syndrome.
4 Pancreatitis may result in increased serum amylase and/or more frequently 
lipase.
5 Cytokine 
release 
syndrome 
may 
manifest 
as 
hemophagocytic 
lymphohistiocytosis with accompanying fever and pancytopenia.
6 Complications including hyperacute graft-versus-host disease (GVHD), some 
fatal, have occurred in patients receiving allo stem cell transplant (SCT) after 
receiving Nivolumab.  These complications may occur despite intervening 
therapy between receiving Nivolumab and allo-SCT.
7 Infusion reactions, including high-grade hypersensitivity reactions which have 
been observed following administration of nivolumab, may manifest as fever, 
chills, shakes, itching, rash, hypertension or hypotension, or difficulty breathing 
during and immediately after administration of nivolumab.
Adverse events reported on Nivolumab trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that 
Nivolumab caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Heart 
failure; Ventricular arrhythmia
EAR AND LABYRINTH DISORDERS - Vestibular disorder
EYE DISORDERS - Eye disorders - Other (iridocyclitis); Optic nerve disorder; 
Periorbital edema
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; Flatulence; 
Gastrointestinal disorders - Other (mouth sores); Vomiting
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; 
Edema limbs; Malaise; Pain
HEPATOBILIARY DISORDERS - Bile duct stenosis
IMMUNE SYSTEM DISORDERS - Anaphylaxis; Immune system disorders - Other 
(autoimmune thrombotic microangiopathy); Immune system disorders - Other 
(limbic encephalitis)
INFECTIONS AND INFESTATIONS - Bronchial infection; Lung infection; Sepsis; 
Upper respiratory infection
INVESTIGATIONS - Blood lactate dehydrogenase increased; GGT increased; 
Investigations - Other (protein total decreased); Lymphocyte count increased; 
Weight loss
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperuricemia; 
Hypoalbuminemia; Hypocalcemia; Hyponatremia; Hypophosphatemia
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; 
Musculoskeletal and connective tissue disorder - Other (musculoskeletal pain); 
Musculoskeletal and connective tissue disorder - Other (polymyalgia rheumatica); 
Myalgia; Pain in extremity
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
- Other (Histiocytic necrotizing lymphadenitis)

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NERVOUS SYSTEM DISORDERS
-
Dizziness; Headache; Intracranial 
hemorrhage
PSYCHIATRIC DISORDERS - Insomnia
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary disorders -
Other (tubulointerstitial nephritis)
RESPIRATORY, 
THORACIC 
AND 
MEDIASTINAL 
DISORDERS
-
Bronchospasm; Cough; Dyspnea; Hypoxia
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; 
Hyperhidrosis; Pain of skin; Photosensitivity; Rash acneiform; Skin and 
subcutaneous tissue disorders - Other (rosacea)
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Vasculitis
Note: Nivolumab in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent.
Pregnancy and Lactation:
Pregnancy: Adverse events were observed in animal reproduction studies. 
Nivolumab may be expected to cross the placenta; effects to the fetus may 
be greater in the second and third trimesters. Based on its mechanism of 
action, nivolumab is expected to cause fetal harm if used during 
pregnancy. Women of childbearing potential (WOCBP) receiving 
nivolumab must continue contraception for a period of 5 months after the 
last dose of nivolumab. Men receiving nivolumab and who are sexually 
active with WOCBP must continue contraception for a period of 7 months 
after the last dose of nivolumab.
Lactation: It is not known if nivolumab is excreted into breast milk. Due to 
the potential for serious adverse reactions in the nursing infant, the 
manufacturer recommends women to discontinue breastfeeding during 
treatment with nivolumab.
Potential Drug Interactions: The indirect drug-drug interaction potential of 
nivolumab was assessed using systemic cytokine modulation data for 
cytokines known to modulate CYP enzymes. There were no meaningful 
changes in cytokines known to have indirect effects on CYP enzymes 
across all dose levels of nivolumab. This lack of cytokine modulation 
suggests that nivolumab has no low potential for modulation CYP 
enzymes, thereby indicating a low risk of therapeutic protein-drug 
interaction. 
d.
DOSING & ADMINISTRATION
See Section 7.0 Treatment Plan
Route of Administration: Intravenous infusion over 30 minutes. Do Not administer 
as an IV push or bolus injection.
Method of Administration: Administer through a 0.2 micron to 1.2 micron pore size, 
low-protein binding (polyethersulfone membrane) in-line filter. 

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e.
HOW SUPPLIED
Description: Nivolumab Injection is a clear to opalescent, colorless to pale 
yellow liquid; light (few) particulates may be present. The drug product is 
a sterile, nonpyrogenic, single-use, isotonic aqueous solution formulated 
in 
sodium 
citrate
dihydrate, 
sodium 
chloride, 
mannitol, 
diethylenetriaminepentacetic acid (pentetic acid) and polysorbate 80 
(Tween® 80), and water for injection. Dilute solutions of hydrochloric acid 
and/or sodium hydroxide may be used for pH adjustment (pH 5.5-6.5).
How Supplied: Nivolumab is supplied by Bristol-Myers Squibb and 
distributed by the Pharmaceutical Management Branch, CTEP/DCTD/NCI 
as 100 mg vials (10 mg/mL) with a 0.7 mL overfill.  It is supplied in 10 mL 
type I flint glass vials, with fluoropolymer film-laminated rubber stoppers 
and aluminum seals.
f.
STORAGE, PREPARATION & STABILITY
Storage: Vials of Nivolumab injection must be stored at 2°-8°C (36°-46°F) 
and protected from light and freezing.  The unopened vials can be stored 
at room temperature (up to 25°C, 77°F) and room light for up to 48 hours.
If a storage temperature excursion is identified, promptly return Nivolumab 
to 2° - 8°C and quarantine the supplies.  Provide a detailed report of the 
excursion (including documentation of temperature monitoring and 
duration 
of 
the 
excursion) 
to 
PMBAfterHours@mail.nih.gov 
for 
determination of suitability.
Preparation: Nivolumab injection can be infused undiluted (10 mg/mL) or 
diluted with 0.9% Sodium Chloride Injection, USP or 5% Dextrose. When 
the dose is based on patient weight (i.e. mg/kg), nivolumab injection can 
be infused undiluted or diluted to protein concentrations as low as 0.35 
mg/mL. When the dose is fixed (e.g, 240 mg, 360 mg, or 480 mg flat 
dose), nivolumab injection can be infused undiluted or diluted so as not to 
exceed a total infusion volume of 160 mL. For patients weighing less than 
40 kilograms (kg), the total volume of infusion must not exceed 4 mL per 
kg of patient weight. During drug product preparation and handling, 
vigorous mixing or shaking is to be avoided. 
Compatibility: Nivolumab infusions are compatible with polyvinyl chloride 
(PVC) or polyolefin containers and infusion sets, and glass bottles.
Stability: Shelf-life surveillance of the intact vials is ongoing. 
The administration of undiluted and diluted solutions of Nivolumab must 
be completed within 24 hours of preparation.  If not used immediately, the 
infusion solution may be stored up to 24 hours in a refrigerator at 2°-8°C 
(36°-46°F) and a maximum of 8 hours of the total 24 hours can be at room 
temperature (up to 25°C, 77°F) and room light.  The maximum 8-hour 
period under room temperature and room light conditions includes the 
product administration period. 
CAUTION: The single-use dosage form contains no antibacterial 
preservative or bacteriostatic agent.  Therefore, it is advised that the 
product be discarded 8 hours after initial entry.

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g.
DRUG ORDERING & ACCOUNTABILITY
Drug ordering: NCI-supplied agents may be requested by the Principal 
Investigator (or their authorized designee) at each participating institution.  
Pharmaceutical Management Branch (PMB) policy requires that agent be 
shipped directly to the institution where the patient is to be treated.  PMB 
does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  The CTEP-assigned protocol number 
(S1616) must be used for ordering all CTEP-supplied investigational 
agents.  The responsible investigator at each participating institution must 
be registered with CTEP, DCTD through an annual submission of FDA 
Form 1572 (Statement of Investigator), Curriculum Vitae, Supplemental 
Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If 
there are several participating investigators at one institution, CTEP-
supplied investigational agents for the study should be ordered under the 
name of one lead investigator at that institution.
In general, sites may order initial agent supplies when a subject is being 
screened for enrollment onto the study.
Active 
CTEP-registered 
investigators 
and 
investigator-designated 
shipping designees and ordering designees can submit agent requests 
through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” 
account status and a “current” password.  For questions about drug 
orders, transfers, returns, or accountability, call or email PMB any time.  
Refer to the PMB’s website for specific policies and guidelines related to 
agent management.
Drug Handling and Accountability
Drug Accountability: The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of 
the receipt, dispensing and final disposition of all agents received 
from the PMB using the appropriate NCI Investigational Agent 
(Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational 
Agent Accountability
Records for each agent, strength, 
formulation and ordering investigator on this protocol.
Drug return and/or disposition instruction
Drug Returns: All unused drug supplies should be returned to the 
PMB. When it is necessary to return study drug (e.g., sealed vials 
remaining when expired vials are recalled by the PMB), 
investigators should return the study drug to the PMB using the 
NCI Return Agent Form available on the NCI home page 
(http://ctep.cancer.gov).
Drug Expiration: Shelf life stability studies of the intact vials of 
ipilimumab are on-going

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Contact Information 
Useful Links and Contacts:
•
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/
•
NCI CTEP Investigator Registration:  
PMBRegPend@ctep.nci.nih.gov
•
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm
•
PMB Online Agent Order Processing (OAOP) application: 
https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx
•
CTEP Identity and Access Management (IAM) account: 
https://eapps-ctep.nci.nih.gov/iam/
•
CTEP Associate Registration and IAM account help:  
ctepreghelp@ctep.nci.nih.gov
•
PMB email:  PMBAfterHours@mail.nih.gov
•
PMB phone and hours of service: (240) 276-6575 Monday through 
Friday between 8:30 am and 4:30 pm (ET)
PMB IB Coordinator: IBCoordinator@mail.nih.gov
4.0
STAGING CRITERIA
STAGE IIIC
Any T                 N3                 M0
Stage IV
Any T                Any N               M1
Primary Tumor (T)
TX
Primary tumor cannot be assessed (e.g., curettaged or severely regressed melanoma)
T0
No evidence of primary tumor
Tis
Melanoma in situ
T1a 
Melanomas ≤1.0 mm in thickness without ulceration; mitosis <1/mm2
T1b 
Melanomas ≤1.0 mm in thickness with ulceration or mitoses ≥1/mm2
T2a 
Melanomas 1.01–2.0 mm in thickness without ulceration.
T2b 
Melanomas 1.01–2.0 mm in thickness with ulceration
T3a 
Melanomas 2.01–4.0 mm in thickness without ulceration
T3b 
Melanomas 2.01–4.0 mm in thickness with ulceration
T4a 
Melanomas >4.0 mm in thickness without ulceration
T4b
Melanomas >4.0 mm in thickness with ulceration
Regional Lymph Nodes (N)
NX
Patients in whom the regional nodes cannot be assessed (e.g., previously removed for 
another reason)
N0
No regional metastases detected
N1a 
1 regional lymph node metastasis with micrometastasisc
N1b 
1 regional lymph node metastasis with macrometastasisd
N2a 
2–3 regional lymph node metastases with micrometastasisc
N2b 
2–3 regional lymph node metastases with macrometastasisd
N2c
In transit met(s)/satellite(s) without metastatic lymph nodes
N3
≥4 regional lymph node metastases; or matted nodes; or in transit met(s)/satellite(s) with 
metastatic lymph node(s)

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Distant Metastasis (M)
M0
No detectable evidence of distant metastases
M1a
Metastases to skin, subcutaneous or distant lymph nodes and normal serum LDH
M1b
Metastases to lung and normal serum LDH
M1c
Metastases to all other visceral sites and normal serum LDH or distant metastases to any 
site combined with an elevated serum LDH
5.0
ELIGIBILITY CRITERIA
Each of the criteria in the following section must be met in order for a patient to be considered eligible for 
registration.  For each criterion requiring test results and dates, please record this information on the 
Onstudy Form and submit via Medidata Rave® (see Section 14.0).  Any potential eligibility issues should 
be addressed to the Data Operations Center in Seattle at 206/652-2267 or melanomaquestion@crab.org 
prior to registration.
In calculating days of tests and measurements, the day a test or measurement is done is considered Day 
0.  Therefore, if a test is done on a Monday, the Monday 4 weeks later would be considered Day 28.  If Day 
14 or 28 falls on a weekend or holiday, the limit may be extended to the next working day.
5.1
Disease Related Criteria
a.
Patients must have pathologically confirmed melanoma that is either Stage IV or 
unresectable Stage III. Patients may have primaries of cutaneous, mucosal or 
unknown origin. Patients with uveal (ocular) primary are not eligible.
b.
Patients must have measurable disease per RECIST 1.1 (see Section 10.1). All 
measurable lesions must be assessed by physical examination, CT scans or MRIs 
within 28 days prior to registration. If the only measurable disease is cutaneous or 
subcutaneous, lesions must be at least 10 mm in greatest dimension and able to 
be serially recorded using calipers and photographs. Tests used to assess non-
measurable disease must have been performed within 42 days prior to registration. 
All disease must be assessed and documented on the Baseline Tumor 
Assessment Form.
c.
Patients with central nervous system (CNS) metastases must have all lesions 
adequately treated with stereotactic radiation therapy, craniotomy, Gamma Knife® 
therapy, or whole brain radiotherapy, with no subsequent evidence of CNS 
progression.  Patients must not have required steroids for at least 14 days prior to 
registration. Patients with a history of central nervous system metastases must 
have MRI of the brain within 42 days prior to registration.
5.2
Prior/Concurrent Therapy Criteria
a.
Patients must have had prior treatment with anti-PD1 or anti-PD-L1 agents and 
had documented disease progression per the treating physician either while on 
these agents or after stopping therapy with these agents without intervening 
therapy. Patients who received adjuvant therapy for previously resected disease 
with PD-1 or PD-L1 agents may also be eligible if disease recurrence occurred 
while still receiving the PD-1 or PD-L1 therapy and no intervening therapy was 
received. Patients must have discontinued anti-PD-1 or anti-PD-L1 therapy at least 
21 days prior to registration.
b.
Patients must not have achieved a partial or complete response to the anti-PD-1 
or anti-PD-L1 agents prior to progression per the treating physician.

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c.
Patients must not have had any systemic therapy, including anti-PD-1 or anti-PD-
L1 agents, within 21 days prior to registration.
d.
Patients must not have had prior radiation therapy within 14 days prior to 
registration (see Section 5.1c).
e.
Patients must not have had:
Prior treatment with ipilimumab or other CTLA-4 antagonists.
Systemic therapy between progression on the anti-PD-1 or anti-PD-L1 
agents and registration. 
Note: Systemic therapy (including BRAF-targeting agents) prior to anti-PD-1 or 
anti-PD-L1 therapy is allowed.
f.
Patients must not be planning to require any additional form of systemic anti-tumor 
therapy while on protocol treatment. 
5.3
Clinical/Laboratory Criteria
a.
Patients must be ≥ 18 years of age.
b.
Patients must have Zubrod Performance Status of ≤ 2 (see Section 10.4). 
c.
Patients must have complete history and physical examination within 28 days prior 
to registration.
d.
Patients must have adequate hematologic function as evidenced by all of the 
following within 28 days prior to registration: absolute neutrophil count (ANC) ≥ 
1,500/mcL; hemoglobin ≥ 8 g/dL; and platelets ≥ 100,000/mcL.
e.
Patients must have adequate hepatic function as evidenced by all of the following 
within 28 days prior to registration: total bilirubin ≤ 2.5 x Institutional Upper Limit of 
Normal (IULN) (except patients with Gilbert’s syndrome); and AST and ALT both 
≤ 5 x IULN.
f.
Patients must have adequate kidney function as evidenced by serum creatinine ≤ 
2.0 x IULN within 28 days prior to registration. 
g.
Patients with a known history of HIV must have CD4 count ≥ institutional lower limit 
of normal within 28 days prior to registration. 
h.
Patients must not have known active Hepatitis B Virus (HBV) or Hepatitis C Virus 
(HCV) infection prior to registration.
i.
Patients must not have an active infection requiring systemic therapy at time of 
registration. 
j.
Patients must not have organ allografts. 
k.
Patients must not have received systemic treatment with corticosteroids (> 10 mg 
daily prednisone or equivalent) or other immunosuppressive medications within 14 
days prior to registration. Inhaled or topical steroids, and adrenal replacement 
doses ≤ 10 mg daily prednisone or equivalent are permitted in the absence of 
active autoimmune disease.

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l.
Patients must not have a history of immune-mediated pneumonitis or colitis that 
required interruption of therapy or treatment of steroids. 
m.
Patients with a known history of congestive heart failure (CHF), cardiomyopathy, 
myocarditis, myocardial infarction (MI), exposure to cardiotoxic medications, or 
with a clinical history suggestive of the above must have an EKG and 
Echocardiogram (ECHO) performed within 42 days prior to registration and as 
clinically indicated while on treatment.
n.
Patients with new symptoms of congestive heart failure (CHF), cardiomyopathy, 
myocarditis, myocardial infarction (MI), or exposure to cardiotoxic medications 
must have a cardiology consultation, creatinine phosphokinase (CPK), and 
troponin testing at prestudy and as clinically indicated.
o.
No other prior malignancy is allowed except for the following:  adequately treated 
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated 
Stage 0, I or II cancer from which the patient is currently in complete remission, or 
any other cancer from which the patient has been disease free for two years.
p.
Patients must not be pregnant or nursing due to risk of fetal or nursing infant harm.  
Females of reproductive potential must have negative serum pregnancy test within 
2 days prior to registration and agree to use an effective contraceptive method 
throughout the study and for 5 months after completion of protocol treatment. A 
woman is considered to be of “reproductive potential” if she has had menses at 
any time in the preceding 12 consecutive months. In addition to routine 
contraceptive methods, “effective contraception” also includes heterosexual 
celibacy and surgery intended to prevent pregnancy (or with a side-effect of 
pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or 
bilateral tubal ligation.  If at any point a previously celibate patient chooses to 
become heterosexually active during or within 5 months after protocol treatment, 
she is responsible for beginning effective contraceptive measures.
q.
Males who are sexually active with women of reproductive potential must have 
agreed to use birth control throughout the study and for 7 months after completion 
of protocol treatment. In addition to routine contraceptive methods, “effective 
contraception” also includes heterosexual celibacy and surgery intended to 
prevent pregnancy (vasectomy).  If at any point a previously celibate patient 
chooses to become heterosexually active during or within 7 months after 
completion of protocol treatment, he is responsible for beginning effective 
contraceptive measures.
5.4
Specimen Submission Criteria
a.
Patients must submit archival tissue (if available) for translational medicine as 
described in Section 15.1.  Patients must also be willing to undergo biopsies and 
submit tissue and blood for translational medicine as described in Section 15.1.  
b.
Patients must be offered the opportunity to participate in specimen banking of 
leftover tissue for future research as described in Section 15.1b.
5.5
Regulatory Criteria
a.
Patients must be informed of the investigational nature of this study and must sign 
and give written informed consent in accordance with institutional and federal 
guidelines.

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b.
As a part of the OPEN registration process (see Section 13.4 for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that the 
current (within 365 days) date of institutional review board approval for this study 
has been entered in the system.
6.0
STRATIFICATION FACTORS
There are no stratification factors for this study.
7.0
TREATMENT PLAN
For treatment or dose modification questions, please contact Dr. VanderWalde (901/683-0055 ext. 
63015 or avanderw@uthsc.edu) or Dr. Ribas (310/206-3928 or aribas@mednet.ucla.edu).
For 
dosing principles or questions, please consult the SWOG Policy #38 "Dosing Principles for Patients 
on Clinical Trials" at http://swog.org (then click on "Policies and Manuals" under the "Visitors" menu 
and choose Policy 38).
7.1
Pre-Medication and Concomitant Medications
a.
Pre-Medication
Premedication associated with standard drug administration and supportive care 
(including anti-diarrheals, antibiotics, diuretics or other medications) may be given 
as indicated by the current American Society of Clinical Oncology (ASCO) 
guidelines. Premedication for the use of prophylaxis for infusion reactions (e.g.,
diphenhydramine, acetaminophen, or other medications) may be given per 
institutional standard.
For patients that experience infusion reactions the following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or 
equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 
minutes before additional nivolumab or ipilimumab administrations. 
As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab 
combination, drugs with a predisposition to hepatic toxicity should be used with 
caution in patients treated with nivolumab containing regimen.
b.
Concomitant Medications
The following medications are prohibited during the study (unless utilized to treat 
a drug related adverse event):
•
Immunosuppressive agents
•
Immunosuppressive doses of systemic corticosteroids (e.g., prednisone >10 
mg daily or equivalent)
•
Any concurrent anti-neoplastic therapy (i.e., chemotherapy, hormonal therapy, 
immunotherapy, extensive, non-palliative radiation therapy, or standard or 
investigational agents for treatment of melanoma)

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7.2
Treatment – Arm 1: Ipilimumab Alone
Patients will receive the following treatment until completion of 4 cycles of treatment or 
meeting one of the criteria in Section 7.5. 
Agent
Dose
Route   
Day
Schedule*
Ipilimumab
3 mg/kg
IV over 90 mins     1 
q 21 days for 4 
cycles
* Note: 1 cycle = 21 days
7.3
Treatment – Arm 2: Ipilimumab + Nivolumab
Patients will receive the following treatment until meeting one of the criteria in Section 7.5. 
Cycles 1-4
Agent
Dose
Route
Day
Schedule*
Nivolumab
1 mg/kg
IV over 30 mins
1 
q 21 days for
4 cycles only.
Ipilimumab**
3 mg/kg
IV over 90 mins
1
q 21 days for 
4 cycles only 
* Note: 1 cycle = 21 days 
**Ipilimumab to start 30 minutes after the end of nivolumab infusion.
Cycles 5+
Agent
Dose
Route
Day
Nivolumab
480 mg
IV over 30 mins
1 of every cycle
Note: 1 cycle = 28 days 
7.4
Full CDUS Reporting Requirement
Because this study contains an investigational drug for which CTEP holds the IND, it falls 
under CTEP requirements for full reporting.  This involves required submission of cycle-
specific toxicity and dose information (see Section 14.4, the S1616 Treatment Form, and 
the S1616 Adverse Event Form). 
A cycle is defined as:
•
Arm 1: 21 days
•
Arm 2: 21 days for first 4 cycles; 28 days for Cycles 5+
7.5
Criteria for Removal from Protocol Treatment
a.
Progression of disease as defined in Section 10.2d. However, the patient may 
continue to stay on protocol treatment as long as, in the opinion of the treating 
investigator, the patient is continuing to clinically benefit from treatment. This may 
occur if there are lesions that continue to respond to the therapy despite others 
progressing, or if there is symptomatic relief of symptoms on therapy.

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b.
Completion of 4 cycles on Arm 1.
c.
Symptomatic deterioration (as defined in Section 10.2e). 
d.
Unacceptable toxicity (see also Section 8.0).
e.
Treatment delay for any reason > 12 weeks. 
f.
The patient may withdraw from the study at any time for any reason.
7.6
Discontinuation of Treatment
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice.
7.7
Follow-Up Period
All patients will be followed until death or 3 years after registration, whichever occurs first.
8.0
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS
8.1
NCI Common Terminology Criteria for Adverse Events
Two different versions of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) will be used on this study.
a.
Serious Adverse Event (SAE) reporting
The CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0 
will be utilized for SAE reporting only. The CTCAE Version 5.0 can be 
downloaded from the CTEP home page (https://ctep.cancer.gov). All appropriate 
treatment areas should have access to a copy of the CTCAE Version 5.0.
b.
Routine toxicity reporting
This study will utilize the CTCAE Version 4.0 for routine toxicity reporting. A copy 
of the CTCAE Version 4.0 can be downloaded from the CTEP home page 
(https://ctep.cancer.gov). All appropriate treatment areas should have access to a 
copy of the CTCAE Version 4.0.
8.2
General considerations
a.
No dose reductions are allowed.
b.
The maximum dose delay for any reason is 84 calendar days (12 weeks).
c.
Patients on IV steroids may be switched to an equivalent dose of oral 
corticosteroids (e.g., prednisone) at start of tapering or earlier, once sustained 
clinical improvement is observed.  Lower bioavailability of oral corticosteroids 
should be taken into account when switching to the equivalent dose of oral 
corticosteroids.

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8.3
Dose Delay Criteria Ipilimumab (Arm 1)
Dose modifications for ipilimumab by adverse event type are detailed in Table 8.1.  General 
considerations for dose modifications are as follows. 
a.
It is necessary to avoid study drug dosing and initiate appropriate evaluation and/or 
treatment for the following adverse events:
•
Any ≥ Grade 3 skin related adverse event regardless of causality.
•
Any ≥ Grade 2 non-skin related adverse event (including immune-
mediated adverse reactions), except for easily corrected laboratory 
abnormalities that do not reflect underlying organ pathology.
•
Any ≥ Grade 3 laboratory abnormality.
•
Any adverse event, laboratory abnormality or intercurrent illness that, in 
the opinion of the treating investigator, presents a substantial clinical risk 
to the patient with continued dosing.
•
It may be necessary to hold study drug to evaluate Grade 1 events that 
suggest ongoing or incipient autoimmune disease including GI toxicity, 
diarrhea, pancreatitis, hepatitis, pituitary insufficiency, early evidence of 
neurologic events, skin toxicity until diagnosis and progression are 
determined. 
b.
Ipilimumab may be restarted if/when the adverse event(s) resolve(s) in severity or 
returns to baseline within 2 weeks of initial dose administration:
•
If the adverse event has been determined not be related to ipilimumab or is 
not an autoimmune/inflammatory event.  If more than 1 dose is to be skipped 
or > 2 week delay is expected due to current events not related to study the 
dosing schedule modifications must be discussed with the study chairs prior 
to implementation. 
•
If the adverse event has resolved to ≤Grade 1 , ipilimumab dosing may be 
restarted at the next scheduled timepoint per protocol.  Please follow 
guidelines for specific events. Please note that re-initiating treatment may be 
associated with recurrence or exacerbation of autoimmune or inflammatory 
events.  In some instances clinical resolution of events such as colitis may 
be associated with residual pathologic changes and should require 
evaluation of complete resolution prior to restarting therapy. 
•
If the adverse event has not resolved in the protocol-specified dosing 
window (3 weeks [±3 calendar days]), the next scheduled dose will be 
skipped and dosing will be resumed at the subsequently scheduled dose.
•
Events which require intervention with immunosuppressant therapy, 
steroids, surgery, or hormone replacement generally require permanently 
stopping study treatment.  
c.
Permanently discontinue ipilimumab for any of the following:
•
Persistent adverse reactions that require holding more than 2 treatment doses.   
•
Any related Grade 3 or 4 event (see exceptions below) 
•
Any event that requires immunosuppressive treatment or systemic steroids 
which cannot be discontinued during the time in which it takes to hold more than 
2 treatment doses
•
Severe or life-threatening adverse reactions, including any of the following:
o
Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in 
stool frequency (7 or more over baseline), stool incontinence, need for IV 
hydration for more than 24 hours, gastrointestinal hemorrhage, and 
gastrointestinal perforation

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o
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 
times the upper limit of normal or total bilirubin >3 times the upper limit of 
normal
o
Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash 
complicated by full thickness dermal ulceration, or necrotic, bullous, or 
hemorrhagic manifestations
o
Severe motor or sensory neuropathy, Guillain-Barré syndrome, or 
myasthenia gravis
o
Severe immune-mediated reactions involving any organ system (e.g., 
nephritis, pneumonitis, pancreatitis, non-infectious myocarditis)
o
Immune-mediated ocular disease that is unresponsive to topical 
immunosuppressive therapy
o
Any adverse event, laboratory abnormality or intercurrent illness which, in 
the judgment of the investigator, presents organ specific injury and/or a 
substantial clinical risk to the patient with continued dosing. 
NOTE: The following neurological adverse events require permanent 
discontinuation 
of 
ipilimumab 
and 
define 
unacceptable 
neurotoxicity:
•
Any motor neurologic toxicity ≥ Grade 3 regardless of causality
•
Any ≥ Grade 3 treatment related sensory neurologic toxicity
Please refer to Appendix 18.3 and Appendix 18.4 for specific treatment 
algorithms.
d.
Exceptions to Permanent Discontinuation of Ipilimumab
•
Potentially reversible inflammation (< Grade 4), attributable to a local anti-
tumor reaction and a potential therapeutic response. This includes 
inflammatory reactions at sites of tumor resections or in draining lymph nodes, 
or at sites suspicious for, but not diagnostic of metastasis.
•
Hospitalization for ≤Grade 2 adverse events where the primary reason for 
hospitalization is to expedite the clinical work-up.
•
Patients with the following conditions where in the treating investigator’s 
opinion continuing study drug administration is justified based on the potential 
for continued clinical benefit: 
o
Patients treated with systemic steroids for less than 2 weeks without 
evidence of autoimmune disease requiring steroids treatment 
o
Grade 2 skin rash treated with topical steroids for less than 4 weeks 
o
Grade 2 ocular toxicity that has completely responded to topical therapy 
within 4 weeks
o
Endocrinopathies where clinical symptoms are controlled with 
appropriate hormone replacement therapy. Note: Ipilimumab may not 
be restarted while the patient is being treated with systemic 
corticosteroids except for patients on stable doses of hormone 
replacement therapy such as hydrocortisone. 
e.
Allowance for ipilimumab dose delay
•
In general, patients who meet criteria to resume ipilimumab will also have met 
criteria to resume nivolumab with ipilimumab, so it should be feasible to 
synchronize dosing of both drugs when resuming ipilimumab. In order to 
facilitate this, the dosing calendar days of nivolumab and ipilimumab may be 
adjusted within a +/- 5 day window, as long as consecutive nivolumab doses 
are given at least 12 calendar days apart.
•
If an ipilimumab dose is delayed beyond 6 weeks from the prior ipilimumab 
dose, then subsequent nivolumab doses should be rescheduled to maintain at 
least a 3-week interval between consecutive ipilimumab doses.

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•
Dosing delays to manage drug-related adverse events, such as prolonged 
steroid tapers, are allowed. Disease assessments should continue as per 
protocol even if dosing is delayed.
•
Dosing delays resulting in no ipilimumab dosing for > 6 weeks that occur for 
non-drug-related reasons may be allowed if approved by the Study Chairs. 
Disease assessments should continue as per protocol even if dosing is 
delayed.
•
In event of any Grade 2 adverse event experienced while on combination 
nivolumab plus ipilimumab therapy, patient may resume treatment/may be 
continued on nivolumab monotherapy alone, at the discretion of the treating 
investigator 
•
Ipilimumab will not be given as monotherapy for Arm 2. 
NOTE: If adverse events result in permanent discontinuation of ipilimumab, then 
subsequently manage dose delays under Management/Next Dose for nivolumab 
alone
8.4
Dose Delay Criteria for Nivolumab in Combination with Ipilimumab (Arm 2)
Dose modifications for nivolumab in combination with ipilimumab by adverse event type 
are detailed in Table 8.1.  General considerations for dose modifications are as follows.
For the initial induction period, patients with Grade 2 or 3 events requiring 
discontinuation of treatment with the combination may consider continuing 
treatment with single agent nivolumab when the event resolves to baseline.  
However, patients with renal, CNS, or pulmonary toxicity must be removed from 
study.
a.
In addition to the AEs identified in the table below, ipilimumab and nivolumab dose
should be delayed for any AE, laboratory abnormality or inter-current illness which, 
in the judgment of the treating investigator, warrants delaying the dose of study 
medication.
b.
Patients requiring a delay of > 6 weeks or who experience immune-related toxicity 
with inability to decrease prednisone ≤10 mg PO daily must go off protocol therapy 
entirely. 
c.
Patients who received systemic corticosteroids for management of any drug-
related immunologic toxicity must be off corticosteroids or have tapered down to
an equivalent dose of prednisone 10 mg/day.  
d.
Nivolumab monotherapy may be continued at treating investigator discretion if 
there is evidence of clinical benefit. In this event, patient will continue nivolumab 
until AE is resolved and ipilimumab may be re-started or if ipilimumab is 
permanently discontinued (in congruence with guidelines in table below), then 
patient will continue nivolumab alone until cycles are completed.  At completion of 
4 cycles, patient may continue on nivolumab alone, as per protocol. If ipilimumab 
is permanently discontinued prior to receipt of 4 doses, nivolumab dosing should 
remain at the Cycle 1-4 dosing (1 mg/kg every 2 weeks) until completion of Cycle 
4 and should then switch to Cycle 5+ dosing (480 mg every 4 weeks).

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Table 8.1 Dose Modification for Related Adverse Events
Treatment-
related Adverse 
Event
Grade of 
Event
Nivolumab and/or Ipilimumab
Nausea
≤ Grade 1
No dose modification
Grade 2
Hold until ≤ Grade 1 OR baseline
(exceptions as noted below) 1     
Grade 3
Off protocol therapy (exceptions as noted 
below) 1
Grade 4
Off protocol therapy
*Patients requiring a delay of >2 weeks must go off protocol therapy.
Recommended management:  antiemetics.
Diarrhea 
(immune-related 
enterocolitis)
≤ Grade 1
No dose modification
Grade 2
Hold until ≤ Grade 1 OR baseline
(exceptions as noted below) 1     
Grade 3
Off protocol therapy (exceptions as noted 
below) 1
Grade 4
Off protocol therapy
*Patients requiring a delay of >2 weeks must go off protocol therapy
Recommended management:  Loperamide antidiarrheal therapy
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose 
motion until diarrhea-free for 12 hours (maximum dosage:  16 mg/24 hours)
Adjunct anti-diarrheal therapy is permitted and should be recorded when used.
See GI AE Algorithm for management of symptomatic colitis. 
Patients with Grade 2 symptoms but normal colonoscopy and biopsies may be 
retreated after resolution. 
Patients who require steroids must be taken off study treatment. 
Please evaluate pituitary function prior to starting steroids if possible without 
compromising acute care.  
Evaluation for all patients for additional causes includes C. diff, acute and self-
limited infectious and foodborne illness, ischemic bowel, diverticulitis, and IBD.
Vomiting
≤ Grade 1
No dose modification
Grade 2
Hold until ≤ Grade 1 OR baseline
(exceptions as noted below) 1     
Grade 3
Off protocol therapy (exceptions as noted 
below) 1
Grade 4
Off protocol therapy
*Patients requiring a delay of >2 weeks must go off protocol therapy.
Recommended management:  antiemetics.
Other GI 
≤ Grade 1
No dose modification
Grade 2
Hold until ≤ Grade 1 OR baseline
(exceptions as noted below) 1   
Grade 3
Off protocol therapy (exceptions as noted 
below1)  
Grade 4
Off protocol therapy
Patients with Grade 2 or 3 N-V should be evaluated for upper GI inflammation 
and other immune related events.  
Neurologic 
events (new, 
≤ Grade 1
No dose modification
Grade 2
Hold until ≤ Grade 1 OR baseline
(exceptions as noted below) 1     

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Treatment-
related Adverse 
Event
Grade of 
Event
Nivolumab and/or Ipilimumab
motor, sensory, 
encephalitis)
Grade 3
Off protocol therapy (exceptions as noted 
below) 1
Grade 4
Off protocol therapy
Fatigue
≤ Grade 1
No dose modification
Grade 2
No dose modification
≥Grade 3
Off protocol therapy (exceptions as noted 
below) 1 – if fatigue is found related to 
endocrinopathy and clinical symptoms are 
managed with hormone replacement, 
patient resume therapy
Grade 4
Off protocol therapy
Fatigue is the most common adverse event associated with immune 
checkpoint therapy.  Grade 2 or greater fatigue should be evaluated for 
associated or underlying organ involvement including pituitary, thyroid, and 
hepatic, or muscle (CPK) inflammation
Fever
≤ Grade 1
Evaluate and continue 
Grade 2
Hold until ≤ Grade 1.  
Treatment-
related Adverse 
Event
Grade of 
Event
Nivolumab and/or Ipilimumab
Fever
(continued)
Grade 3
Hold until ≤ Grade 1.  
Grade 4
Off protocol therapy
Patients with fever should be evaluated as clinically appropriate.  Patients may 
experience isolated fever during infusion reactions or up to several calendar 
days after infusion.  Evaluation over the course of 1-2 weeks should be done 
for other autoimmune events that may present as fever
Skin drug-
related AE
≤ Grade 1
No dose modification
Grade 2
Hold until ≤ Grade 1 OR baseline
(exceptions as noted below) 1     
Grade 3
Off protocol therapy (exceptions as noted 
below) 1
Grade 4
Off protocol therapy
*Patients with purpuric or bullous lesions must be evaluated for vasculitis, 
Steven-Johnson syndrome, TEN, and autoimmune bullous disease including 
oral lesions of bullous pemphigus/pemphagoid.  Pruritus may occur with or 
without skin rash and should be treated symptomatically if there is no 
associated liver or GI toxicity.  Note skin rash typically occurs early and may 
be followed by additional events particularly during steroids tapering.  
Recommended management:  See AE management guidelines
Pneumonitis,
broncho-spasm, 
pulmonary 
toxicity or 
interstitial lung 
disease
≤ Grade 1
No dose modification. See Section 18.3 for 
Management recommendations.
Grade 2
Hold dose pending evaluation. Resume 
after pulmonary and/or ID consultation 
excludes autoimmune related causes. 
Patient must be removed from protocol 
therapy if steroids are required
Grade 3
Off protocol therapy
Grade 4
Off protocol therapy

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Treatment-
related Adverse 
Event
Grade of 
Event
Nivolumab and/or Ipilimumab
Above does not include infusion reactions. 
Distinguishing inflammatory pneumonitis is often a diagnosis of exclusion for 
patients who do not respond to antibiotics and have no causal organism 
identified including influenza.  Most patients with respiratory failure or hypoxia 
will be treated with steroids.  Bronchoscopy may be required and analysis of 
lavage fluid for lymphocytic predominance may be helpful.  Patients with new 
lung nodules should be evaluated for sarcoid like granuloma.  Please consider 
recommending seasonal influenza killed vaccine for all patients.
Recommended management:  See Pulmonary Adverse Event Management 
Algorithm 
Thrombocyto-
penia
≤ Grade 1
No dose modification
Grade 2
Hold until ≤ Grade 1 OR baseline
(exceptions as noted below) 1     
Grade 3
Off protocol therapy 
Grade 4
Off protocol therapy
Neutropenia
≤ Grade 1
No dose modification
Grade 2
Hold until ≤ Grade 1 OR baseline
(exceptions as noted below) 1     
Grade 3
Off protocol therapy 
Grade 4
Off protocol therapy
*Patients requiring a delay of >2 weeks must go off protocol therapy.
Renal
≤ Grade 1
No dose modification
Grade 2
Hold until ≤ Grade 1.  
Grade 3
Off protocol therapy  
Grade 4
Off protocol therapy
See Section 18.3 for Management recommendations.5
Endocrine 
Hypophysitis 
Adrenal 
Insufficiency
≤ Grade 1
No dose modification
Grade 2
Hold until patients are on a stable 
replacement hormone regimen. If treated 
with steroids patients must be stable off 
steroids for two weeks.     
Treatment-
related Adverse 
Event
Grade of 
Event
Nivolumab and/or Ipilimumab
Endocrine 
Hypophysitis 
Adrenal 
Insufficiency
(continued)
Grade 3
Hold until patients are on a stable 
replacement hormone regimen.  If treated 
with steroids patients must be stable off 
steroids for two weeks.
Grade 4
Off protocol therapy
Note all patients with symptomatic pituitary enlargement, exclusive of hormone 
deficiency, but including severe headache or enlarged pituitary on MRI should 
be considered Grade 3 events.  Isolated thyroid or testosterone deficiency may 
be treated as Grade 2 if there are no other associated deficiencies and adrenal 
function is monitored. 
Please evaluate pituitary function before beginning steroid therapy or 
replacement therapy of any kind. 
*Note patients with thyroiditis may be retreated on replacement therapy.  
Patients must be evaluated to rule out pituitary disease prior to initiating thyroid 
replacement.

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Treatment-
related Adverse 
Event
Grade of 
Event
Nivolumab and/or Ipilimumab
Recommended management: See Endocrine Management Algorithm 
Abnormal liver 
function 
(AST/ALT, Total 
bilirubin, 
immune-related 
hepatitis)
≤ Grade 1
No dose modification
Grade 2
Hold until ≤ Grade 1 OR baseline
(exceptions as noted below) 1     
Grade 3
Off protocol therapy 
Grade 4
Off protocol therapy
Continued treatment of active immune mediated hepatitis may exacerbate 
ongoing inflammation.  Holding drug to evaluate LFT changes and early 
treatment are recommended.  
LFT changes may occur during steroid tapers from other events and may 
occur together with other GI events including cholecystitis/pancreatitis.
Recommended management:  see Hepatic AE management algorithm
Amylase or 
lipase, 
associated with 
GI symptoms
≤ Grade 1
No dose modification
Grade 2
Hold until ≤ Grade 1 OR baseline
(exceptions as noted below) 1     
Grade 3
Hold until baseline and asymptomatic. 
Patients who develop symptomatic 
pancreatitis or DM must be taken off 
treatment5
Grade 4
Off protocol therapy
Patients may develop symptomatic and radiologic evidence of pancreatitis as 
well as DM and DKA.  Lipase elevation may occur during the period of steroid 
withdrawal and with other immune mediated events or associated with colitis, 
hepatitis, and patients who have asymptomatic lipase elevation typically have 
self-limited course and may be retreated. 
For treatment management of symptomatic pancreatitis please follow the 
Hepatic Adverse Event Management Algorithm
Any other 
laboratory 
abnormality 
(except 
AST/ALT, Total 
bilirubin, 
thrombocytope
nia, 
neutropenia, 
lymphopenia) 
≤ Grade 1
No change.
Grade 2
No change.
Grade 3
Off protocol therapy unless is unrelated to 
underlying organ pathology and can be 
managed with electrolyte replacement, 
hormone replacement, insulin, or no 
therapy  
Grade 4
Off protocol therapy unless is unrelated to 
underlying organ pathology and can be 
managed with electrolyte replacement, 
hormone replacement, insulin, or no 
therapy  
2 
Grade 4 lymphopenia or leukopenia or does not require 
drug discontinuation.
3 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 do not 
require drug discontinuation.
4
Resolved, 
well-controlled, 
or 
asymptomatic 
hypothyroidism does not require approval by Study 

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Treatment-
related Adverse 
Event
Grade of 
Event
Nivolumab and/or Ipilimumab
Chairs prior to restarting therapy.
Treatment-
related Adverse 
Event
Grade of 
Event
Nivolumab and/or Ipilimumab
Cardiac*
≤ Grade 1 
Hold dose pending evaluation and 
observation.**  Evaluate for signs and 
symptoms of CHF, ischemia, arrhythmia 
or myositis.  Obtain history EKG, CK (for 
concomitant myositis), CK-MB.  Repeat 
troponin, CK and EKG 2-3 calendar days.  
If troponin and labs normalize may 
resume therapy.  If labs worsen or 
symptoms develop then treat as below.  
Hold pending evaluation. 
Grade >2 
with 
suspected 
myocarditis
Hold dose.**  Admit to hospital.  
Cardiology consult.  Rule out MI and 
other causes of cardiac disease.  Cardiac 
Monitoring.  Cardiac Echo.  Consider 
cardiac MRI and cardiac biopsy.  Initiate 
high dose methylprednisolone.  If no 
improvement within 24 hours, add either 
infliximab, ATG or tacrolimus. Resume 
therapy if there is a return to baseline and
myocarditis is excluded or considered 
unlikely.
Grade >2 with 
confirmed 
myocarditis  
Off protocol therapy.  Admit to CCU 
(consider transfer to nearest Cardiac 
Transplant Unit).  Treat as above.  
Consider high dose methylprednisolone.  
Add ATG or tacrolimus if no improvement.  
Off treatment.
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin 
**Patients with evidence of myositis without myocarditis may be treated 
according as “other event”  
Note:  The optimal treatment regimen for immune mediated myocarditis has not 
been established.  
Since this toxicity has caused patient deaths, an aggressive approach is 
recommended.  
Infusion 
Reaction
≤ Grade 1
No dose modification
Grade 2
Interrupt study drug. Upon recovery from 
symptoms, resume study drug at one half 
the initial infusion rate, then increase 
incrementally to the initial infusion rate  
Grade 3
Off protocol therapy  
Grade 4
Off protocol therapy
Patients with fever should be evaluated as clinically appropriate.  Patients may 
experience isolated fever during infusion reactions or up to several calendar 
days after infusion.  Evaluation over the course of 1-2 weeks should be done 
for other autoimmune events that may present as fever
All other events 
≤ Grade 1
No dose modification

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Treatment-
related Adverse 
Event
Grade of 
Event
Nivolumab and/or Ipilimumab
Grade 2
Hold until ≤ Grade 1 OR 
baseline(exceptions as noted below) 1     
Grade 3
Off protocol therapy 
Grade 4
Off protocol therapy
Table 8.1 Footnotes
1Recommended management:  As clinically indicated
Exceptions: 
o
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 the re-treatment period 
OR requires systemic treatment must go off protocol 
treatment 
o
Any adverse event, laboratory abnormality, or intercurrent 
illness which, in the judgment of the treating investigator, 
presents a substantial clinical risk to the patient with 
continued study drug dosing must go off protocol treatment. 
o
Any Grade 3 or 4 drug-related laboratory abnormality or 
electrolyte abnormality, that can be managed independently 
from underlying organ pathology with electrolyte 
replacement, hormone replacement, insulin or that does not 
require treatment does not require discontinuation. 
5 Recommended management:  As clinically indicated
o
See Section 18.3 for recommended management
o
See Section 8.4 for treatment management
8.5
Treatment of Infusion Reactions Associated with Ipilimumab and/or Nivolumab
Since ipilimumab contains only human protein sequences, and since nivolumab is a fully 
human monoclonal antibody, it is less likely that any allergic reaction will be seen in patients
receiving these agents.  However, it is possible that infusion of ipilimumab or nivolumab
will induce a cytokine release syndrome that could be evidenced by fever, chills, rigors, 
rash, pruritus, hypotension, hypertension, bronchospasm, or other symptoms. 
No 
prophylactic pre-medication should be given unless indicated by previous experience in an 
individual 
patient. 
Reactions 
should 
be 
treated 
based 
upon 
the 
following 
recommendations. 
•
For mild symptoms (e.g., localized cutaneous reactions such as mild pruritus, flushing, 
rash):
o
Decrease the rate of infusion until recovery from symptoms, remain at bedside and 
monitor patient.
o
Complete the infusion at the initial planned rate.
o
Diphenhydramine 50 mg IV may be administered at the discretion of the treating 
physician and patients may receive additional doses with close monitoring.
o
Premedication with diphenhydramine may be given at the discretion of the 
investigator for subsequent doses.

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•
For moderate symptoms (any symptom not listed above [mild symptoms] or below 
[severe symptoms] such as generalized pruritus, flushing, rash, dyspnea, hypotension 
with systolic BP >80 mmHg): 
o
Interrupt infusion of offending agent.
o
Administer diphenhydramine 50 mg IV.
o
Monitor patient closely until resolution of symptoms.
o
Corticosteroids may abrogate any beneficial immunologic effect, but may be 
administered at the discretion of the treating physician.
o
Resume infusion after recovery of symptoms.
o
At the discretion of the treating physician, infusion may be resumed at one half the 
initial infusion rate, then increased incrementally to the initial infusion rate.
o
If symptoms develop after resumption of the infusion, the infusion should be 
discontinued and no additional ipilimumab or nivolumab should be administered that 
day.
o
The next dose will be administered at its next scheduled time and may be given with 
pre-medication (diphenhydramine and acetaminophen) and careful monitoring, 
following the same treatment guidelines outlined above.
o
At the discretion of the treating physician additional oral or IV antihistamine may be 
administered prior to dosing.
•
For severe symptoms (e.g., any reaction such as bronchospasm, generalized urticaria, 
systolic blood pressure 80 mm Hg, or angioedema):
o
Immediately discontinue infusion, and disconnect infusion tubing from the patient.
o
Consider bronchodilators, epinephrine 1 mg IV or subcutaneously, and/or 
diphenhydramine 50 mg IV, with solumedrol 100 mg IV, as needed.
o
Patients should be monitored until the investigator is comfortable that the symptoms 
will not recur.
o
No further ipilimumab (if related to ipilimumab) or nivolumab (if related to nivolumab)
will be administered.
8.6
Treatment of Ipilimumab-Related Isolated Drug Fever
In the event of isolated drug fever, the investigator must use clinical judgment to determine 
if the fever is related to the ipilimumab or to an infectious etiology.  If a patient experiences 
isolated drug fever, for the next dose, pre-treatment with acetaminophen or non-steroidal 
anti-inflammatory agent (investigator discretion) should be instituted and a repeated 
antipyretic dose at 6 and 12 hours after ipilimumab infusion, should be administered.  The 
infusion rate will remain unchanged for future doses.  If a patient experiences recurrent 
isolated drug fever following premedication and post dosing with an appropriate antipyretic, 
the infusion rate for subsequent dosing should be decreased to 50% of the previous rate.  
If fever recurs following infusion rate change, the investigator should assess the patient’s 
level of discomfort with the event and use clinical judgment to determine if the patient 
should receive further ipilimumab.
8.7
Monitoring and Management of Immune-mediated Adverse Reactions
Immune-mediated Enterocolitis
The clinical presentation of GI immune-related AEs included diarrhea, increase in the 
frequency of bowel movements, abdominal pain, or hematochezia, with or without fever. 
However, inflammation may occur in any part of the GI tract including esophagitis and 
gastritis.  Fatalities due to GI perforation have been reported in clinical trials of ipilimumab. 

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Patients should be carefully monitored for GI symptoms that may be indicative of immune-
related colitis, diarrhea, or GI perforation.  Diarrhea or colitis occurring after initiation of 
ipilimumab therapy should be evaluated to exclude infectious or alternate etiologies. In 
clinical trials, immune-related colitis was associated with evidence of mucosal 
inflammation, with or without ulcerations, and lymphocytic infiltration.
Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, 
mucus or blood in stool, with or without fever) and bowel perforation (such as peritoneal 
signs and ileus). In symptomatic patients, rule out infectious etiologies and consider 
endoscopic evaluation to establish etiology and for persistent or severe symptoms.  
C.difficile toxin has been detected in several patients with colitis and may be an 
independent entity or may co-exist with ipilimumab induced inflammatory colitis.  
Withhold ipilimumab and/or nivolumab dosing for any patients with enterocolitis pending 
evaluation; administer anti-diarrheal treatment and, if persistent evaluate with colonoscopy 
and initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent.
Permanently discontinue ipilimumab and nivolumab in patients with severe enterocolitis 
and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or 
equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue 
to taper over at least one month. In clinical trials, rapid corticosteroid tapering has resulted 
in recurrence or worsening symptoms of enterocolitis in some patients. 
Patients have been treated with anti-TNF agents for persistent colitis not responding to 
steroids.
Please note autoimmune pancreatitis may cause abdominal pain and should be included 
in all evaluations. Enteritis may occur occasionally with other autoimmune events including 
hepatitis, pancreatitis, and endocrine insufficiency, which should be evaluated as clinically 
indicated. 
Immune-mediated Hepatitis and Pancreatitis 
Hepatic immune-related AEs were mostly clinically silent and manifested as transaminase 
or bilirubin laboratory abnormalities.  Fatal hepatic failure has been reported in clinical trials 
of ipilimumab.  Serum transaminase and bilirubin must be evaluated before each dose of 
ipilimumab and nivolumab as early laboratory changes may be indicative of emerging 
immune-related hepatitis/ pancreatitis and elevations in liver function tests (LFTs) may 
develop in the absence of clinical symptoms.  Increase in LFT or total bilirubin should 
be evaluated to exclude other causes of hepatic injury, including infections, disease 
progression, or other medications, and monitored until resolution.  Liver biopsies from 
patients who had immune-related hepatotoxicity showed evidence of acute inflammation 
(neutrophils, lymphocytes, and macrophages).
Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients 
for signs and symptoms of hepatotoxicity/ pancreatitis before each dose of ipilimumab and 
nivolumab.  In patients with hepatotoxicity, rule out infectious or malignant causes and 
increase frequency of liver function test monitoring until resolution.  Withhold ipilimumab
and nivolumab in patients with Grade 2 hepatotoxicity. 
Permanently discontinue ipilimumab and nivolumab in patients with
Grade 3–5 
hepatotoxicity/pancreatitis and administer systemic corticosteroids at a dose of 1 to 2 
mg/kg/day of prednisone or equivalent.  When liver function tests show sustained 
improvement or return to baseline, initiate corticosteroid tapering and continue to taper 
over 1 month.  Across the clinical development program for ipilimumab, mycophenolate 

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treatment has been administered in patients who have persistent severe hepatitis despite 
high-dose corticosteroids. 
Immune-mediated Dermatitis
Skin immune-related AEs presented mostly frequently as a rash and/or pruritus.  Some 
patients reported vitiligo associated with ipilimumab administration.  Fatal toxic epidermal 
necrolysis has been reported in clinical trials of ipilimumab. 
Monitor patients for signs and symptoms of dermatitis such as rash and pruritus.  Unless 
an alternate etiology has been identified, signs or symptoms of dermatitis should be 
considered immune-mediated.  
Permanently discontinue ipilimumab and nivolumab in patients with Stevens-Johnson 
syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal 
ulceration, or necrotic, bullous, or hemorrhagic manifestations.  Administer systemic 
corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent.  When dermatitis 
is controlled, corticosteroid tapering should occur over a period of at least 1 month.  
Withhold ipilimumab and nivolumab dosing in patients with moderate to severe signs and 
symptoms. 
For mild to moderate dermatitis, such as Grade 2 localized rash and pruritus, treat 
symptomatically. For persistent Grade 2, Grade 3, or greater, topical steroids may be 
administered.  Administer topical or systemic corticosteroids as indicated if there is no 
improvement of symptoms within 1 week.
Immune-related Neurological Events 
Fatal Guillain-Barré syndrome has been reported in clinical trials of ipilimumab. Patients 
may present with muscle weakness and myasthenia gravis, cranial nerve palsy (n VII Bell’s 
palsy), and aseptic meninigits, encephalopathy.  Unexplained motor neuropathy, muscle 
weakness, or sensory neuropathy lasting more than 4 calendar days should be evaluated 
and non-inflammatory causes such as disease progression, infections, metabolic 
syndromes, nerve entrapment, and medications should be excluded as causes. 
Withhold ipilimumab and nivolumab dosing in patients with any evidence of neuropathy 
pending evaluation.  
Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral 
weakness, sensory alterations, or paresthesia.  Permanently discontinue ipilimumab and 
nivolumab in patients with severe neuropathy (interfering with daily activities) such as 
Guillain-Barré-like syndromes.  Institute medical intervention as appropriate for 
management of neuropathy and other neurologic events.  Consider initiation of systemic 
corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe 
neuropathies. 
Immune-mediated Endocrinopathies
Ipilimumab and/or nivolumab can cause inflammation of endocrine organs including thyroid 
(Hashimoto’s thryroiditis with positive antibodies) and adrenal glands, hypophysitis, 
hypopituitarism, and resulting thyroid and adrenal insufficiency, low ADH, prolactin, FSH, 
LH.  Hyperthyroid with Graves’ disease and positive antibody has been reported.  Patients 
may present with subtle and nonspecific symptoms.  The most common clinical 
presentation includes headache and fatigue.  Symptoms may also include visual field 
defects, behavioral changes, and electrolyte disturbances including hyponatremia and 
hypotension.  Adrenal crisis as a cause of the patient’s symptoms should be excluded.  
Based on the available data with known outcome, most of the patients symptomatically 

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improved with hormone replacement therapy.  Long-term hormone replacement therapy 
with 
HC 
and 
Synthroid 
will 
typically 
be 
required 
for 
patients 
developing 
hypophysitis/hypopituitarism after treatment with ipilimumab alone or with nivolumab.  
Some patients have regained partial function following steroid treatment. 
Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency 
(including adrenal crisis), and hyper- or hypothyroidism.  Headache is often the first 
symptoms of hypophysitis.  Patients may present with fatigue, headache, mental status 
changes, loss of libido, abdominal pain, unusual bowel habits, and hypotension, or 
nonspecific symptoms which may resemble other causes such as brain metastasis or 
underlying disease.  Unless an alternate etiology has been identified, signs or symptoms 
of endocrinopathies should be considered immune-mediated and drugs withheld pending 
evaluation.  Patients may demonstrate both central (hypophysitis) and peripheral adrenal 
and thyroid insufficiency.  Evaluation of hypophysitis should include pituitary MRI. 
Endocrine evaluation, including TSH, should be performed at baseline prior to initial 
treatment.  Monitor thyroid function tests and clinical chemistries at the start of treatment 
and hold blood for possible evaluation should clinical events require determining baseline 
function and anti-thyroid antibodies.  In a limited number of patients, hypophysitis was 
diagnosed by imaging studies through enlargement of the pituitary gland.  
Withhold ipilimumab and nivolumab dosing in patients symptomatic for hypophysitis.  
Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, 
and initiate appropriate hormone replacement therapy. 
Other Immune-mediated Adverse Reactions, Including Ocular Manifestations 
Ocular inflammation, manifested as Grade 2 or Grade 3 episcleritis or uveitis, was 
associated with concomitant diarrhea in a few patients (< 1%) and occasionally occurred 
in the absence of clinically apparent GI symptoms.  Other presumed immune-related AEs 
reported include, but were not limited to, arthritis/arthralgias, pneumonitis, pancreatitis, 
autoimmune (aseptic) meningitis, autoimmune nephritis, pure red cell aplasia, noninfective 
myocarditis, polymyositis, and myasthenia gravis, of which were individually reported for <
1% of patients. 
The following clinically significant immune-mediated adverse reactions were seen in less 
than 1% of ipilimumab-treated patients in Study 1: nephritis, pneumonitis, pulmonary 
granuloma resembling sarcoidosis, meningitis, pericarditis, uveitis, iritis, ITP, neutropenia 
and hemolytic anemia.
Across the clinical development program for ipilimumab, the following likely immune-
mediated adverse reactions were also reported with less than 1% incidence: myocarditis, 
angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, 
blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, 
pancreatitis, arthritis, and autoimmune thyroiditis.  
Permanently discontinue ipilimumab and nivolumab for clinically significant or severe 
immune-mediated adverse reactions.  Initiate systemic corticosteroids at a dose of 1 to 2 
mg/kg/day prednisone or equivalent for severe immune-mediated adverse reactions.
Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis.  
Permanently discontinue ipilimumab for immune-mediated ocular disease that is 
unresponsive to local immunosuppressive therapy.

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a.
Overall, immune-related AEs commonly started within 3 to 10 weeks from first 
dose, were successfully managed in most instances by omitting doses, 
discontinuing 
dosing, 
and/or 
through 
administering 
symptomatic 
or 
immunosuppressive therapy, including corticosteroids, as mentioned above and 
detailed in Section 7.0.  Immune-related AEs generally resolved within days to 
weeks in the majority of patients
8.8
White Blood Cell Growth Factors
If used, white blood cell growth factors, including biosimilars, must be used per ASCO 
guidelines (http://jco.ascopubs.org/content/24/19/3187.full) and NCCN Guidelines® 
Myeloid Growth Factors 
(http://www.nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf).
8.9
Dose Modifications Contacts
For treatment or dose modification questions, please contact Dr. VanderWalde (901/683-
0055 
ext 
63015
or 
avanderw@uthsc.edu) 
or
Dr. 
Ribas 
(310/206-3928 
or 
aribas@mednet.ucla.edu).
8.10
Adverse Event Reporting
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.1 of the protocol must be reported to the Operations Office, Study 
Chair and NCI via CTEP-AERS, and to the IRB per local IRB requirements.

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9.0
STUDY CALENDAR
9.1 
Arm 1 
Pre-
registration G
Cycle (1 cycle = 21 days)
Follow-up 
prior to 
progression
Follow-up 
after 
progression
1
2
3
4
Week K
1
2
3
4
5
6
7
8
9
10
11
12
PHYSICAL
History and physical 
exam
X
X 
L
X
X
X
X N
X Q
Weight and performance 
status R
X
X 
L
X
X
X
X N
X Q
Toxicity notation
X
X
X
X
X P
X P
Baseline abnormalities
X
Disease assessments
X
X M
X N
Biopsy A
X
X
LABORATORY
ANC, platelets, and 
hemoglobin
X
X 
L
X
X
X
X P
X P
AST, ALT, and total 
bilirubin
X
X 
L
X
X
X
X P
X P
Serum creatinine
X
X 
L
X
X
X
X P
X P
Pregnancy test
X H
Creatinine 
phosphokinase (CPK), 
Troponin, and Cardiology 
consultation B
X
CD4
X J
TSH, Free T4, Free T3 C
X
X
X
X
Calendar continued on next page. Click here for Footnotes

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Pre-
registration G
Cycle (1 cycle = 21 days)
Follow-up 
prior to 
progression
Follow-up 
after 
progression
1
2
3
4
Week K
1
2
3
4
5
6
7
8
9
10
11
12
X-RAYS AND SCANS
MRI or CT for disease 
assessment S
X
X M
X N
Electrocardiogram (ECG) 
and Echocardiogram 
(Echo) D
X
SPECIMEN 
SUBMISSION
Archival tissue E
X
Tissue block or slides 
from biopsy
X
X
Blood F
X
X
Fresh Frozen Tissue from 
biopsy T
X
X
TREATMENT
Ipilimumab
X
X
X
X
Calendar continued on next page. Click here for Footnotes
Note: Forms are found on the protocol abstract page of the SWOG website (www.swog.org). The schedule for submission of these forms 
is listed in Section 14.0.
Note: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment 
for continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG 
guidelines as outlined in https://swog.org/Visitors/Download/QA/Best%20Practices%20upddate.pdf.

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Footnotes
A  To be performed on or prior to Day 1 and on Day 21-35 (Day 28 +/- 7 days). The first biopsy should be performed within 28 
days prior to Day 1. If it is not feasible to obtain this biopsy, tissue that was collected at any time since demonstrated 
progression on PD-1 or PD-L1 therapy may be substituted provided that 30 unstained slides are available.
B 
Only for patients with symptoms of congestive heart failure (CHF), cardiomyopathy, myocarditis, myocardial infarction, or exposure 
to cardiotoxic medications.  Required pre-registration (see Section 5.3n).  After that, perform as clinically indicated.
C
Free T3 and Free T4 are only required if TSH results are abnormal.
D  Only for patients with a known history of congestive heart failure (CHF), cardiomyopathy, myocarditis, myocardial infarction,
exposure to cardiotoxic medications, or with a clinical history suggestive of any of these conditions.  Required pre-registration 
(see Section 5.3m).  After that, perform as clinically indicated.
E Collected prior to previous anti-PD-1 or anti-PD-L1 treatment
F  To be drawn on or prior to Day 1 (after registration and within 28 days) and on Day 21-35 (Day 28 +/- 7 days). If feasible, Day 1 blood 
should be drawn on the same day as the baseline tissue biopsy. Day 28  Blood must be drawn on same day as the Day 28 tissue biopsy.
G  Required time frame is detailed in Section 5.0.
H  Only for females of reproductive potential (see Section 5.3p)
J  Only required for patients with a known history of HIV (see Section 5.3g)
K  Weeks measured from start of treatment, provided that the patient does not have any treatment delays
L 
If pre-registration exam/lab was performed within 14 days prior to Cycle 1 Day 1, this exam/lab does not need to be repeated 
on Cycle 1 Day 1.
M Performed at completion of Week 12
N Every 12 weeks until progression
P
Every 3 weeks until resolution of adverse events
Q At least every 6 months (+/- 2 weeks) until 2 years after registration, then annually (+/- 4 weeks) until 3 years after registration.
R
Though weight should be checked at each visit, weight-based dosing should be calculated using baseline weight unless weight 
has changed from last dose by more than 10%.
S
CT or MRI of the chest, abdomen, and pelvis should be performed at baseline and all subsequent assessments. Additionally, for 
patients with known assessable scalp or neck disease, a CT or of the head/face/neck should be performed at baseline and all 
subsequent assessments. Patients with known assessable extremity disease should have the affected extremity also measured by 
CT or MRI at baseline and all subsequent visits. Patients with a history of central nervous system metastases must have MRI of the 
brain at baseline and at all subsequent assessments.
T
Select sites will, at each prospective biopsy timepoint, obtain additional cores. See Section 15.1c.4 for details.

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9.2 
Arm 2:  Cycles 1 through 4 (see Section 9.3 for Arm 1 Cycles 5+)
Pre-registration 
G
Cycle (1 cycle = 21 days)
1
2
3
4
Week K
1
2
3
4
5
6
7
8
9
10
11
12
PHYSICAL
History and physical exam
X
X L
X
X
X
Weight and performance status N
X
X L
X
X
X
Toxicity notation
X
X
X
X
Baseline abnormalities
X
Disease assessments
X
X M
Biopsy A
X
X
LABORATORY
ANC, platelets, and hemoglobin
X
X L
X
X
X
AST, ALT, and total bilirubin
X
X L
X
X
X
Serum creatinine
X
X L
X
X
X
Pregnancy test
X H
Creatinine phosphokinase (CPK), 
Troponin, and Cardiology 
consultation B
X
CD4
X J
TSH, Free T4, Free T3 C
X
X
X
X
Calendar continued on next page.  Click here for footnotes.

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Pre-registration G
Cycle (1 cycle = 21 days)
1
2
3
4
Week K
1
2
3
4
5
6
7
8
9
10
11
12
X-RAYS AND SCANS
MRI or CT for disease assessment
O
X
X M
Electrocardiogram (ECG) and 
Echocardiogram (Echo) D
X
SPECIMEN SUBMISSION
Archival tissue E
X
Tissue block or slides from biopsy
X
X
Blood F
X
X
Fresh Frozen Tissue from biopsy P
X
TREATMENT
Nivolumab 1 mg/kg
X
X
X
X
Ipilimumab
X
X
X
X
Click here for footnotes.
Note: Forms are found on the protocol abstract page of the SWOG website (www.swog.org). The schedule for submission of these forms is listed 
in Section 14.0
Note: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for continuous 
treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined in 
https://swog.org/Visitors/Download/QA/Best%20Practices%20upddate.pdf.

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Footnotes
A To be performed on or prior to Day 1 and on Day 21-35 (Day 28 +/- 7 days). The first biopsy should be performed within 28 days prior 
To Day 1. If it is not feasible to obtain this biopsy, tissue that was collected at any time since demonstrated progression on PD-1 or PD-L1 
therapy may be substituted provided that 30 unstained slides are available.
B Only for patients with symptoms of congestive heart failure (CHF), cardiomyopathy, myocarditis, myocardial infarction, 
or exposure to cardiotoxic medications.  Required pre-registration (see Section 5.3n).  After that, perform as clinically indicated.
C Free T3 and Free T4 are only required if TSH results are abnormal.
D Only for patients with a known history of congestive heart failure (CHF), cardiomyopathy, myocarditis, myocardial infarction,
exposure to cardiotoxic medications, or with a clinical history suggestive of any of these conditions.  Required pre-registration 
(see Section 5.3m).  After that, perform as clinically indicated.
E Collected prior to previous anti-PD-1 or anti-PD-L1 treatment. See Section 15.1.
F  To be drawn on or prior to Day 1 (after registration and within 28 days prior) and on Day 21-35 (Day 28 +/- 7 days). f feasible, 
Day 1 blood should be drawn on the same day as the baseline tissue biopsy. Day 28 blood must be drawn on same day as the 
Day 28 tissue biopsy.
G
Required time frame is detailed in Section 5.0.
H Only for females of reproductive potential (see Section 5.3p)
J  Only required for patients with a known history of HIV (see Section 5.3g)
K Weeks measured from start of treatment, provided that the patient does not have any treatment delays
L
If pre-registration exam/lab was performed within 14 days prior to Cycle 1 Day 1, this exam/lab does not need to be repeated
on Cycle 1 Day 1.
M Performed at completion of Week 12
N
Though weight should be checked at each visit, weight-based dosing should be calculated using baseline weight unless weight has 
changed from baseline by more than 10%.
O
CT or MRI of the chest, abdomen, and pelvis should be performed at baseline and all subsequent assessments. Additionally, for patients with 
known assessable scalp or neck disease, a CT or of the head/face/neck should be performed at baseline and all subsequent assessments. 
Patients with known assessable extremity disease should have the affected extremity also measured by CT or MRI at baseline and all 
subsequent visits. Patients with a history of central nervous system metastases must have MRI of the brain at baseline and at all subsequent 
assessments.
O
CT or MRI of the chest, abdomen, and pelvis should be performed at baseline and all subsequent assessments. Additionally, for patients with 
known assessable scalp or neck disease, a CT or of the head/face/neck should be performed at baseline and all subsequent assessments. 
Patients with known assessable extremity disease should have the affected extremity also measured by CT or MRI at baseline and all 
subsequent visits. Patients with a history of central nervous system metastases must have MRI of the brain at baseline and at all subsequent 
assessments.
P
Select sites will, at each prospective biopsy timepoint, obtain additional core. See Section 15.1c.4 for details.

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9.3
Arm 2 Cycles 5+
Cycle (1 cycle = 28 days) R
Follow-up 
prior to 
progression
Follow-up 
after 
progression
5
6
7+
Week K
13
14
15
16
17
18
19
20
21
22
23
24
PHYSICAL
History and physical exam
X
X
X
X N
X Q
Weight and performance status
X
X
X
X N
X Q
Toxicity notation
X
X
X
X P
X P
Disease assessments
X M
X M
LABORATORY
ANC, platelets, and hemoglobin
X
X
X
X P
X P
AST, ALT, and total bilirubin
X
X
X
X P
X P
Serum creatinine
X
X
X
X P
X P
Creatinine phosphokinase (CPK), 
Troponin, and Cardiology consultation B
TSH, Free T4, Free T3 C
X
X
X
X-RAYS AND SCANS
MRI or CT for disease assessment S
X M
X M
Electrocardiogram (ECG) and 
Echocardiogram (Echo) D
TREATMENT
Nivolumab 480 mg
X
X
X
Click here for footnotes.
Note:  Forms are found on the protocol abstract page of the SWOG website (www.swog.org).  The schedule for submission of these forms is listed 
in Section 14.0.
Note:  Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment, disease 
assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined in http://swog.org/Visitors/QA/
Documents/Best%20Practices%20upddate.pdf.

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Footnotes
B 
Only for patients with symptoms of congestive heart failure (CHF), cardiomyopathy, myocarditis, myocardial infarction, or exposure to 
cardiotoxic medications.  Required pre-registration (see Section 5.3n).  After that, perform as clinically indicated.
C 
Free T3 and Free T4 are only required if TSH results are abnormal.
D 
Only for patients with a known history of congestive heart failure (CHF), cardiomyopathy, myocarditis, myocardial infarction, exposure to 
cardiotoxic medications, or with a clinical history suggestive of any of these conditions.  Required pre-registration (see Section 5.3m). 
After that, perform as clinically indicated.
K 
Weeks measured from start of treatment, provided that the patient does not have any treatment delays
M 
Performed every 12 weeks (i.e., at completion of Week 24, 36, etc.) for 3 years from time of registration or until progression.
N  
Every 12 weeks until progression
P 
Every 4 weeks until resolution of adverse events
Q 
At least every 6 months (+/- 2 weeks) until 2 years after registration, then annually (+/- 4 weeks) until 3 years after registration.
R 
Protocol treatment and parameters will continue on this same schedule until one of the criteria in Section 7.5 is met.
S
CT or MRI of the chest, abdomen, and pelvis should be performed at baseline and all subsequent assessments. Additionally, for patients 
with known assessable scalp or neck disease, a CT or of the head/face/neck should be performed at baseline and all subsequent 
assessments. Patients with known assessable extremity disease should have the affected extremity also measured by CT or MRI at 
baseline and all subsequent visits. Patients with a history of central nervous system metastases must have MRI of the brain at baseline and 
at all subsequent assessments.

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10.0
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS
10.1
Measurability of Lesions
a.
Measurable disease: Measurable disease is defined differently for lymph nodes 
compared with other disease and will be addressed in a separate section below.
Lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 2.0 cm by chest x-ray, by ≥ 1.0 cm 
with CT or MRI scans (see below for additional considerations for size 
based on the imaging approach), or ≥ 1.0 cm with calipers by clinical exam. 
All tumor measurements must be recorded in decimal fractions of 
centimeters (or millimeters).
The defined measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 0.5 cm or less.  If CT scans have 
slice thickness greater than 0.5 cm, the minimum size for a measurable 
lesion should be twice the slice thickness.
Malignant lymph nodes are to be considered pathologically enlarged and 
measurable if it measures ≥ 1.5 cm in SHORT AXIS (greatest diameter 
perpendicular to the long axis of the lymph node) when assessed by scan 
(CT scan slice recommended being no greater than 0.5 cm).
b.
Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter < 1.0 cm or pathologic lymph nodes with ≥ 1.0 cm to < 
1.5 cm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered non-measurable as are previously radiated 
lesions that have not progressed.
c.
Notes on measurability
For CT and MRIs, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  Body scans should by performed with breath-hold scanning 
techniques, if possible.
PET-CT:  At present, the low dose or attenuation correction CT portion of 
a PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT, then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT.
Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement.
Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable 
nor non-measurable) since they are, by definition simple cysts.
If a target lesion becomes very small some radiologists indicate that it is 
too small to measure.  If the lesion is actually still present, a default 

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measurement of 0.5 cm should be applied.  If the radiologist believes the 
lesion has gone, a default measurement of 0.0cm should be recorded.
10.2
Objective Status at Each Disease Evaluation
Objective Status is to be recorded at each evaluation.  All measurable lesions up to a 
maximum of 2 lesions per organ 5 lesions in total, representative of all involved organs, 
should be identified as target lesions at baseline.  All other lesions (or sites of disease) 
including any measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions.  Measurements must be provided for target measurable lesions, 
while presence or absence must be noted for non-target measurable and non-measurable 
disease.
For studies that use disease progression as an endpoint, whole body scanning at specific 
intervals is necessary to determine that progression is NOT present outside of the “target” 
areas.  Therefore, in these studies it is not acceptable to image only the “target” areas of 
the body in follow-up scans.  For study-specific imaging requirements, see the Study 
Calendar in Section 9.0.
a.
Complete Response (CR):  Complete disappearance of all target and non-target 
lesions (with the exception of lymph nodes mentioned below).  No new lesions.  
No disease related symptoms.  Any lymph nodes (whether target or non-target) 
must have reduction in short axis to < 1.0 cm.  All disease must be assessed using 
the same technique as baseline.
b.
Partial Response (PR):  Applies only to patients with at least one measurable 
lesion.  Greater than or equal to 30% decrease under baseline of the sum of 
appropriate diameters of all target measurable lesions.  No unequivocal 
progression of non-measurable disease.  No new lesions.  All target measurable 
lesions must be assessed using the same techniques as baseline.
c.
Stable:  Does not qualify for CR, PR, Progression or Symptomatic Deterioration.  
All target measurable lesions must be assessed using the same techniques as 
baseline.
d.
Progression:  One or more of the following must occur:  20% increase in the sum 
of appropriate diameters of target measurable lesions over smallest sum observed 
(over baseline if no decrease during therapy) using the same techniques as 
baseline, as well as an absolute increase of at least 0.5 cm.  Unequivocal 
progression of non-measurable disease in the opinion of the treating physician (an 
explanation must be provided).  Appearance of any new lesion/site.  Death due to 
disease without prior documentation of progression and without symptomatic 
deterioration (see Section 10.2e).
Notes regarding new lesions:  FDG-PET imaging can complement regular scans 
in identifying new lesions according to the following algorithm.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of progression based on a new lesion.
No FDG-PET at baseline and a positive FDG-PET at follow-up 
corresponding to a potential new site of disease must have a confirmation 
by anatomical assessment (e.g., CT, MRI, x-ray) as new site of disease to 
be considered progressive disease.  In such a case, the date of 
progressive disease will be the date of the initial abnormal FDG-PET.

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e.
Symptomatic deterioration:  Global deterioration of health status requiring 
discontinuation of treatment without objective evidence of progression.  Efforts 
should be made to obtain objective evidence of progression after discontinuation.
f.
Assessment inadequate, objective status unknown.  Progression or 
symptomatic deterioration has not been documented, and one or more target 
measurable lesions have not been assessed or inconsistent assessment methods 
were used.
g.
Objective status notes:
Non-measurable and non-target measurable disease do not affect 
Objective Status in determination of CR (must be absent--a patient who 
otherwise has a CR, but who has non-measurable or non-target 
measurable disease present or not assessed, will be classified as having 
a PR). However, non-measurable and non-target lesions are included in 
determination of progression (if new sites of disease develop or if 
unequivocal progression occurs in the opinion of the treating physician).
An objective status of PR or stable cannot follow one of CR.  Stable can 
follow PR only in the rare case that tumor increases too little to qualify as 
progression, but enough that a previously documented 30% decrease no 
longer holds.
In cases for which initial flare reaction is possible (hypercalcemia, 
increased bone pain, erythema of skin lesions), objective status is not 
progression unless either symptoms persist beyond 4 weeks or there is 
additional evidence of progression.
Lesions that appear to increase in size due to presence of necrotic tissue 
will not be considered to have progressed.
For bone disease documented on bone scan only, increased uptake does 
not constitute unequivocal progression.  However, increase in the soft 
tissue component of a lesion as measured by CT or MRI would constitute 
progression.
Appearance of new pleural effusions does not constitute unequivocal 
progression unless cytologically proven of neoplastic origin, since some 
effusions are a toxicity related to therapy or other medical conditions.  
Increase in the size of an existing effusion does not constitute unequivocal 
progression, since the fluid status of the patient could alter the size of the 
effusion.
If CR determination depends on a lesion for which the status is unclear by 
the required tests, it is recommended the residual lesion be investigated 
with biopsy or fine needle aspirate.
10.3
Best Response
This is calculated from the sequence of objective statuses.
a.
CR:  Two or more objective statuses of CR a minimum of four weeks apart 
documented before progression or symptomatic deterioration.

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b.
PR:  Two or more objective statuses of PR or better a minimum of four weeks apart 
documented before progression or symptomatic deterioration, but not qualifying as 
CR.
c.
Unconfirmed CR:  One objective status of CR documented before progression or 
symptomatic deterioration but not qualifying as CR or PR.
d.
Unconfirmed PR:  One objective status of PR documented before progression or 
symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR.
e.
Stable/no response:  At least one objective status of stable/no response 
documented at least 6 weeks after registration and before progression or 
symptomatic deterioration, but not qualifying as anything else above.
f.
Increasing disease:  Objective status of progression within 12 weeks of 
registration, not qualifying as anything else above.
g.
Symptomatic deterioration:  Objective status of symptomatic deterioration within 
12 weeks of registration, not qualifying as anything else above.
Inadequate assessment, response unknown:  Progression or symptomatic deterioration 
greater than 12 weeks after registration and no other response category applies.
10.4
Performance Status
Patients will be graded according to the Zubrod Performance Status Scale.
POINT
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 
housework, office work.
2
Ambulatory and capable of self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours.
3
Capable of 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.
10.5
Progression-Free Survival (PFS)
From date of registration to date of first documentation of progression or symptomatic 
deterioration (as defined above), or death due to any cause. Patients last known to be alive 
without report of progression are censored at date of last contact.
10.6
Time to death
Measured from the date of registration until death from any cause, with patients last known 
to be alive censored at the date of last contact

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11.0
STATISTICAL CONSIDERATIONS
11.1
Accrual Goal
Although the primary objective aims to assess whether combination therapy ipilimumab 
and nivolumab is superior to single therapy ipilimumab in patients who have previously 
progressed on anti-PD-1 or anti-PD-L1 therapy, major additional objectives of this study 
include assessment of key biomarkers and genomic correlatives, particularly for patients 
who receive combination therapy.  This study will use a design in which 63 patients will be 
randomized to receive combination therapy ipilimumab and nivolumab and 21 patients will 
be randomized to receive single therapy ipilimumab. Assuming an ineligibility rate of 10% 
the total accrual goal is 94 patients.
The unbalanced randomization is motivated by the necessity of evaluating the first 
secondary objective.  In particular, the underlying rationale for the combination therapy is 
that initial progression on PD-1 blockade alone results from poor T cell recruitment. If the 
combination therapy is superior to single agent ipilumimab, evaluation of this hypothesis 
by comparing T cell infiltration between patients who have an objective response 
(confirmed and unconfirmed partial or complete response per RECIST 1.1) and patients 
who do not have an objective response to combination therapy will elucidate mechanisms 
that are imperative for design and development of further studies of combination therapy 
in this population.  Thus, unbalanced randomization is necessary to ensure adequate 
sample size for evaluating this hypothesis.  Assuming a response rate of 25% and 90% 
compliance in tissue and biopsy submission, then we anticipate accruing 14 eligible 
objective responders and 43 eligible objective non-responders in the combination therapy 
arm.
11.2
Primary Analysis and Interim Analysis
For our primary objective, we will compare the PFS between arms using a log-rank test.  
Kaplan-Meier plots will be constructed and median PFS for each arm with corresponding 
95% Brookmeyer-Crowley confidence intervals will be estimated.  
Combination therapy will be considered superior to single therapy ipilimumab if median 
progression-free survival (PFS) is doubled.  Based on Hodi et al., we assume the median 
PFS for patients randomized to single therapy ipilimumab to be 3 months such that the 
target alternative PFS for patients randomized to combination therapy is 6 months 
(corresponding to a hazard ratio of 0.5).  We assume exponential survival, 24 months of 
accrual, 12 additional months of follow-up after the last patient is randomized, and that the 
final analysis will be conducted at the one-sided alpha = 10% level.  One interim analysis 
for futility will be performed after approximately 50% information under the null 
(corresponding to approximately 41 events across both arms which is expected to occur 
16-17 months after accrual starts).  If the hazard ratio favors the control arm (is greater 
than 1), the study will be stopped due to futility. Given the modest sample size, no plans 
for formal interim analysis of efficacy are included. Using simulations (10,000 replicates), 
this design has overall type I error of 9.0% and power of 89%.  Under the null, the 
probability of stopping early for futility at the interim analysis is 50% and under the 
alternative, the probability of stopping early is 4.1%.
11.3
Secondary Objectives 
An important hypothesis underlying the rationale for the combination therapy is that initial 
progression on PD-1 blockade alone results from poor T cell recruitment. Consequently, 
our first secondary endpoint will evaluate this by comparing the quantitative CD8+ 
expression levels between patients who eventually respond and patients who do not 
respond using a two-sample t-test and control the type I error at the two-sided 0.05 level.  
Assuming that the trial accrues to completion, 90% compliance in tissue and biopsy 

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submission, there will be 56 patients to evaluate this hypothesis. If it is further assumed
that 25% of these patients respond, then we anticipate 80% power to detect a mean 
difference in CD8+ expression of 0.875 standard deviations. Evaluation of this hypothesis 
motivates the unbalanced randomization.
For the additional secondary objectives, the study will estimate the response rate 
(confirmed and unconfirmed, complete and partial responses) in each arm and construct 
95% binomial confidence intervals. All randomized patients will be included in the analysis 
of response. Patients who cannot have their exact response determined due to inadequate 
disease assessments will be counted in the denominator as non-responders.
We will also construct Kaplan-Meier plots and estimate the median Overall Survival (OS) 
and construct 95% Brookmeyer-Crowley Confidence intervals. We will be able to estimate 
the ORR or the OS rates at a particular time point (e.g. 13 weeks) to within 12.3% (95% 
confidence interval (CI)) and 21.4% in the combination therapy and ipilimumab alone arms, 
respectively. Waterfall plots will be constructed to represent each patient’s best change in 
tumor burden.
Toxicity will be assessed in each arm separately. Any toxicity with at least 5% chance of 
occurring has 93.7% and 60.3% chance of being observed at least once in the combination 
therapy and ipilimumab alone arms, respectively. We will be able to estimate the rate of 
occurrence of any particular toxicity to within 12.3% (95% CI) and 21.4% in the combination 
therapy and ipilimumab alone arms, respectively.
11.4
Data and Safety Monitoring
A Data and Safety Monitoring Committee will oversee the conduct of the study.  The 
Committee consists of four members from outside of the SWOG, 3 SWOG members, 3 
non-voting representatives from the National Cancer Institute (NCI), and the Group 
Statistician (non-voting).  The members of this Committee will receive confidential reports 
every 6 months from the SWOG Statistical Center, and will meet at the Group's bi-annual 
meetings as necessary.  The Committee will be responsible for decisions regarding 
possible termination and/or early reporting of the study.
12.0
DISCIPLINE REVIEW
Discipline review is not applicable.
13.0
REGISTRATION GUIDELINES
13.1
Registration Timing
Patients must be registered prior to initiation of treatment (no more than seven calendar
days prior to planned start of treatment).
13.2
Investigator/Site Registration
Prior to the recruitment of a patient for this study, investigators must be registered members 
of a Cooperative Group. Each investigator must have an NCI investigator number and 
must maintain an “active” investigator registration status through the annual submission of 
a complete investigator registration packet to CTEP.

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a.
CTEP Investigator Registration Procedures
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all investigators participating in any NCI-sponsored clinical trial 
to register and to renew their registration annually.
Registration requires the submission of:
•
a completed Statement of Investigator Form (FDA Form 1572) with an 
original signature
•
a current Curriculum Vitae (CV)
•
a completed and signed Supplemental Investigator Data Form (IDF)
•
a completed Financial Disclosure Form (FDF) with an original signature
Fillable PDF forms and additional information can be found on the CTEP website 
at <http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.
For questions, please contact the CTEP Investigator Registration Help Desk by 
email at <pmbregpend@ctep.nci.nih.gov>.
b.
CTEP Associate Registration Procedures
The Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) application is a web-based application intended for use by both 
Investigators (i.e., all physicians involved in the conduct of NCI-sponsored clinical 
trials) and Associates (i.e., all staff involved in the conduct of NCI-sponsored 
clinical trials).
Associates will use the CTEP-IAM application to register (both initial registration 
and annual re-registration) with CTEP and to obtain a user account.
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering 
with CTEP as an Investigator, which must be completed before a CTEP-IAM 
account can be requested.)
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU 
members’ website.
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.
For 
questions, please contact the CTEP Associate Registration Help Desk by email 
at <ctepreghelp@ctep.nci.nih.gov>.
c.
CTSU Registration Procedures
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll 
patients. Study centers can check the status of their registration packets by 
querying the Regulatory Support System (RSS) site registration status page of the 
CTSU members’ website by entering credentials at https://www.ctsu.org. For sites 
under the CIRB initiative, IRB data will automatically load to RSS.

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Note: Sites participating on the NCI CIRB initiative and accepting CIRB approval 
for the study are not required to submit separate IRB approval documentation to 
the CTSU Regulatory Office for initial, continuing or amendment review. This 
information will be provided to the CTSU Regulatory Office from the CIRB at the 
time the site’s Signatory Institution accepts the CIRB approval. The Signatory site 
may be contacted by the CTSU Regulatory Office or asked to complete information 
verifying the participating institutions on the study.
Other site registration 
requirements (i.e., laboratory certifications, protocol-specific training certifications, 
or modality credentialing) must be submitted to the CTSU Regulatory Office or 
compliance communicated per protocol instructions.
Downloading Site Registration Documents:
Site registration forms may be downloaded from the S1616 protocol 
page located on the CTSU members’ website. Go to 
https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password
•
Click on the Protocols tab in the upper left of your screen
•
Click on the SWOG link to expand, then select S1616. Click on the 
Site Registration Documents link.
Requirements for S1616 Site Registration:
•
CTSU IRB Certification (for sites not participating via the NCI CIRB)
•
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not 
participating via the NCI CIRB)
Submitting Regulatory Documents:
Submit completed forms along with a copy of your IRB Approval to the 
CTSU Regulatory Office, where they will be entered and tracked in the 
CTSU RSS. 
ONLINE: www.ctsu.org (members section) →Regulatory Submission 
Portal
CTSU Regulatory Office
1818 Market Street, Suite 1100
Philadelphia, PA 19103
Phone: 1-866-651-2878
Fax: 215-569-0206
E-mail: 
CTSURegulatory@ctsu.coccg.org
(for 
regulatory 
document submission only)
Checking Your Site’s Registration Status:
Check the status of your site’s registration packets by querying the RSS 
site registration status page of the members’ section of the CTSU 
website. (Note: Sites will not receive formal notification of regulatory 
approval from the CTSU Regulatory Office.)
•
Go to https://www.ctsu.org and log in to the members’ area using your 
CTEP-IAM username and password
•
Click on the Regulatory tab at the top of your screen
•
Click on the Site Registration tab
•
Enter your 5-character CTEP Institution Code and click on Go

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13.3
OPEN Registration Requirements
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data.
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster.
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions:
a.
Institution CTEP ID
b.
Protocol Number
c.
Registration Step
d.
Treating Investigator
e.
Credit Investigator
f.
Patient Initials
g.
Patient’s Date of Birth
h.
Patient SSN (SSN is strongly encouraged, but optional.  Do not enter invalid 
numbers.)
i.
Country of Residence
j.
ZIP Code
k.
Gender (select one):
•
Female Gender
•
Male Gender
l.
Ethnicity (select one):
•
Hispanic or Latino
•
Not Hispanic or Latino
•
Unknown
m.
Method of Payment (select one):
•
Private Insurance
•
Medicare
•
Medicare and Private Insurance
•
Medicaid
•
Medicaid and Medicare
•
Military or Veterans Sponsored NOS
•
Military Sponsored (Including Champus & Tricare)
•
Veterans Sponsored
•
Self Pay (No Insurance)

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•
No Means of Payment (No Insurance)
•
Other
•
Unknown
n.
Race (select all that apply):
•
American Indian or Alaska Native
•
Asian
•
Black or African American
•
Native Hawaiian or other Pacific Islander
•
White
•
Unknown
13.4
Registration Procedures
a.
All site staff will use OPEN to enroll patients to this study. OPEN is integrated with 
the CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient in the Rave database.
OPEN can be accessed at 
https://open.ctsu.org, from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org, or from the OPEN Patient Registration link on the 
SWOG CRA Workbench.
b.
Prior to accessing OPEN site staff should verify the following:
•
All eligibility criteria have been met within the protocol stated timeframes and 
the affirmation of eligibility on the Registration Worksheet has been signed by 
the registering investigator or another investigator designate. Site staff should 
refer to Section 5.0 to verify eligibility.
•
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).
c.
The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. Please print this confirmation for your records.
d.
Further instructional information is provided on the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org or at https://open.ctsu.org. 
For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com.  
13.5
Exceptions to SWOG registration policies will not be permitted.
a.
Patients must meet all eligibility requirements.
b.
Institutions must be identified as approved for registration.
c.
Registrations may not be cancelled.
d.
Late registrations (after initiation of treatment) will not be accepted.

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14.0
DATA SUBMISSION SCHEDULE
14.1
Data Submission Requirement
Data must be submitted according to the protocol requirements for ALL patients registered, 
whether or not assigned treatment is administered, including patients deemed to be 
ineligible.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible.
14.2
Master Forms
Master forms can be found on the protocol abstract page on the SWOG website 
(www.swog.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see Section 14.3a for details.
14.3
Data Submission Procedures
a.
Data collection for this study will be done exclusively through the Medidata Rave® 
clinical data management system. Access to the trial in Rave is granted through 
the iMedidata application to all persons with the appropriate roles assigned in 
Regulatory Support System (RSS). To access Rave via iMedidata, you must have 
an 
active 
CTEP-IAM 
account 
(check 
at 
https://eapps-
ctep.nci.nih.gov/iam/index.jsp) and the appropriate Rave role (Rave CRA, Read-
Only, Site Investigator) on either the LPO or participating organization roster at the 
enrolling site.
Upon initial site registration approval for the study in RSS, all persons with Rave 
roles assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata. To accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on 
the link in the upper right pane of the iMedidata screen.
Users that have not previously activated their iMedidata/Rave account at the time 
of initial registration approval for the study in RSS will also receive a separate 
invitation from iMedidata to activate their account. Account activation instructions 
are located on the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ website under 
the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU help Desk at 1-
888-823-5923 or by e-mail at ctsucontact@westat.com. 
b.
You may also access Rave® via the SWOG CRA Workbench.  Go to the SWOG 
web site (http://swog.org) and logon to the Members Area using your SWOG 
Roster ID Number and password. After you have logged on, click on Workbenches, 
then CRA Workbench to access the home page for the CRA Workbench and follow 
the link to Rave® provided in the left-hand navigation panel.
To access the CRA Workbench the following must be done (in order):
1.
You are entered into the SWOG Roster and issued a SWOG Roster ID 
Number,

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2.
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed,
3.
Your Web User Administrator has added you as a web user and has given 
you the appropriate system permissions to view data for that institution.
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  For 
point 3, contact your local Web User Administrator (refer to the "Who is my Web 
User Administrator?" function on the swog.org Members logon page).
For 
difficulties 
with 
the 
CRA 
Workbench, 
please 
email 
technicalquestion@crab.org.
c.
Institutions participating through the Cancer Trials Support Unit (CTSU) please 
refer to the CTSU Participation Table.
14.4
Data Submission Overview and Timepoints
a.
WITHIN 24 HOURS AFTER BASELINE blood COLLECTION:
Submit Blood within 24 hours of collection at baseline, as outlined in Section15.0.
b.
WITHIN 7 CALENDAR DAYS AFTER REGISTRATION:
Submit the following:
S1616 Onstudy Form
S1616 Baseline Abnormalities Form
Baseline Tumor Assessment Form (RECIST 1.1)
Pathology Report documenting histologic confirmation of melanoma*
Submit radiology reports from all scans performed to assess disease at baseline.*
*NOTE: Upload reports via the Source Documentation: Baseline form in Rave®.
c.
WITHIN 21 to 35 CALENDAR DAYS AFTER REGISTRATION:
Submit tissue specimens as outlined in Section 15.0.
Note: Blood for PBMCs must be submitted within 24 hours of collection at Day 
28 (+/-) 7 calendar days.
d.
WITHIN 14 CALENDAR DAYS AFTER EACH CYCLE OF TREATMENT
Submit the following:
S1616 Treatment Form
S1616 Adverse Event Form

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e.
WITHIN 14 CALENDAR DAYS AFTER EACH DISEASE ASSESSMENT UNTIL 
PROGRESSION/RELAPSE (SEE STUDY CALENDAR FOR SCHEDULE):
Submit the following:
Follow Up Tumor Assessment Form (RECIST 1.1)
Submit radiology reports from all scans performed to assess disease.*
*NOTE: Upload reports via the Source Documentation: Follow-Up form in Rave®.
f.
WITHIN 14 CALENDAR DAYS AFTER DISCONTINUATION OF TREATMENT:
Submit the following:
S1616 Off Treatment Notice
S1616 Treatment Form
S1616 Adverse Event Form
g.
WITHIN 14 CALENDAR DAYS AFTER PROGRESSION:
Follow Up Tumor Assessment Form (RECIST 1.1)
Submit radiology reports from all scans performed to assess disease.*
*NOTE: Upload reports via the Source Documentation: Follow-Up form in Rave®.
h.
AFTER PROGRESSION, SUBMIT EVERY 6 MONTHS FOR THE FIRST 2 
YEARS AND THEN ANNUALLY UNTIL 3 YEARS FROM REGISTRATION:
Submit the following:
Advanced Melanoma Follow Up Form
Late Effects Form (if prior to treatment for progression or relapse or a second 
primary, and prior to non-protocol treatment, the patient experiences any severe 
[Grade ≥ 3] long term toxicity that has not been previously reported)
i.
WITHIN 4 WEEKS AFTER KNOWLEDGE OF DEATH:
Submit the Notice of Death documenting death information.
Also submit:
If the patient was still on protocol treatment, the materials specified in Section 
14.4e.
or
Advanced Melanoma Follow-Up Form (if the patient was off protocol treatment)

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15.0
SPECIAL INSTRUCTIONS
15.1
Translational Medicine (required for patient):
Timepoint
Specimen
Preferred
Acceptable 
alternate
Prior to previous 
anti-PD-1, anti-PD-
l1 therapy
Archival tissue (if 
available) ***
30 slides, 4 mcm 
each
On or prior to Day 
1 of protocol 
treatment
Cores from 
biopsied lesion
One block from 
each biopsied 
lesion
30 slides, 4 mcm 
each, from each 
block
Day 28 of protocol 
treatment
Cores from 
biopsied lesion
One block from 
each biopsied 
lesion
30 slides, 4 mcm 
each, from each 
block
On or prior to Day 
1 of protocol 
treatment
Blood for PBMCs
50 mL in purple top 
EDTA tubes
Day 28 of protocol 
treatment
Blood for PBMCs
50 mL in purple top 
EDTA tubes
a.
Specimens must be submitted at the timepoints listed below.  Collection 
instructions are outlined in Section 15.1c and submission instructions are outlined 
in Section 15.1e.
b.
Specimens must be submitted at the following times (see Section 9.0)
If available, 30 slides 4 um each, unstained of archival tissue (biopsy from 
prior to anti-PD-1 or anti-PD-L1 therapy).
FFPE tissue. At least 2 passes/cores from 14-gauge coring needle, or 3 
passes/passes from 18-gauge coring needle from each biopsied lesion. 
While cores may be formalin fixed in the same container, each core should 
be embedded in a separate paraffin block. Tissue from each block should 
be submitted.  If no block can be shipped, submit 30 slides (4 mcm) each 
from each block. Tissue must be collected within 28 calendar days prior to 
Day 1 of protocol treatment* and again 28 calendar days (+/- 7 calendar 
days) after starting protocol treatment**.
50 mL of peripheral blood collected in purple-top EDTA tubes at baseline 
(within 28 calendar days prior to starting protocol treatment on Day 1) and 
on the same day as the Day 28 (+/- 7 calendar days) tissue collection**. 
*   Biopsy on or prior to Day 1 should be performed within 28 days prior to Day 1. 
If it is not feasible to prospectively obtain this biopsy, tissue collected at any 
time since demonstrated progression on PD-1 or PD-L1 therapy may be 
substituted provided that 30 unstained slides are available.
**
The tissue samples may be batch shipped after collection of tissue from Day 
28(+/- 7 calendar days) biopsy. Tissue blocks should be stored at 4oC before 
shipping.
*** Blood must be sent via overnight courier (e.g. FedEx) within 24 hours of 
collection. Specimens may be shipped Monday through Thursday using 
only overnight delivery to arrive Monday through Friday. No blood 
should be collected or shipped on Friday or right before a holiday.  
Additionally, since blood must be logged and shipped the day of 

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collection, blood should not be collected prior to subject registration. 
Please see additional collection/shipping instructions in Sections 15.1c and 
15.1e (below). 
**** If archival tissue is not available for submission, proceed as usual per directed 
time points for biopsy collection. Archival tissue is required if available.
With patient consent, remaining specimens will be banked for future use.
c.
Specimen Collection Instructions
Standard collection of Paraffin Embedded Tissue Block.
•
Place the fresh tissue in formalin. Do Not Exceed 24 hours fixation 
time.
•
Fixed tissue must be paraffin embedded within 24 hours.
•
Send H & E (Hematoxylin and Eosin) stained section if it is routine 
practice for the site.  Otherwise, sending the block without the 
H&E slide is adequate.
Standard Instructions for Shipping Paraffin Embedded Tissues:
•
Include in shipment:
o
Tissue as outlined above
o
Archived tissue only: A pathology report (indicating the 
morphological diagnosis).
o
A copy of the packing/shipping list produced by the SWOG 
Online Specimen Tracking System.
•
Ship paraffin embedded tissue according to the shipping 
guidelines for ambient specimens in the General Specimen 
Submission Instructions below.
NOTE: Paraffin tissue blocks will NOT be returned to the submitting institution 
unless it is required for patient care. If the block is needed for patient care, a 
written request must be submitted to the bank with a rationale for the return. 
Standard Instructions for Collecting and Shipping Fresh Whole Blood 
Specimens.
•
Use 10 ml vacutainer tubes with EDTA to collect whole blood.
o
If your site does not have the recommended size of 
vacutainer tubes required by the treatment protocol, other 
sized tubes may be used to collect the required/requested 
amount of blood.
o
Avoid using < 3mL collection tubes.

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o
Pre-label vacutainer tube(s) according to specimen 
labeling requirements indicated in the General Specimen 
Submission Instructions.
•
Use aseptic techniques and draw blood from the patient into the 
vacutainer tube(s). The amount of blood required will vary per 
protocol.
•
Immediately after the blood is drawn, thoroughly mix the blood 
with the anticoagulant by gently inverting the vacutainer tube(s) 
multiple times.
•
Store whole blood prior to shipping at room temperature. Do not 
freeze the whole blood. Storage time longer than 24 hours should 
be noted on the specimen shipping form.
•
Whole blood should be shipped the same day (day of collection) 
preferably using Federal Express, Priority Overnight service. Use 
of other courier services may delay package receipt.
o
Specimens may be shipped Monday through 
Thursday using only overnight delivery to arrive 
Monday through Friday. No blood should be collected 
or shipped on Friday or right before a holiday. For 
specimens collected before a holiday, please process 
and ship the specimens according the instructions 
outlined below (#2).
o
During the months of April-September, ship fresh 
specimens on a cold pack. During the months of October-
March, insulate fresh specimens to keep from freezing 
due to weather (ex. wrap specimen in bubble wrap).
Standard Instructions for Collecting and Shipping Flash Frozen Tissue 
Samples:
•
Selected sites will, at each prospective biopsy time point, obtain 
additional cores (at least one core, more if deemed possible) to 
be immediately placed in RNAlater (Sigma, Cat # R0901), stored 
at 4ºC overnight for full penetration, and moved to -80ºC the next 
day until shipment. Samples should be shipped on dry ice.
NOTE: Select sites have already been selected and are aware 
of their duties.
For packaging instructions, refer to the shipping guidelines for ambient 
specimens in the General Specimen Submission Instructions outlined above.
d.
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies.
e.
SHIPPING SAMPLES
SWOG Specimen Tracking System (STS)
All specimen submissions for this study must be entered and tracked using 
the SWOG online Specimen Tracking system. SWOG members may log 
on the online system via the CRA Workbench. To access the CRA 
Workbench, go to the SWOG Web site (http://swog.org) Non- SWOG 
users may log into SpecTrack using their CTSU UserID and password on 
the SpecTrack login page located at 

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https://spectrack.crab.org (select the option “SWOG – SWOG – CTSU”).  
SpecTrack start-up instructions (both written and demo) are available after 
signing in to SpecTrack.
A copy of the Shipment Packing List produced by the online Specimen 
Tracking system should be printed and placed in the pocket of the 
specimen bag if it has one, or in a separate resealable bag. The Specimen 
Submission Form is NOT required when the online system is used.
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE 
NO EXCEPTIONS.
To report technical problems with Specimen Tracking, such as database 
errors 
or 
connectivity 
issues, 
please 
send 
an 
email 
to 
technicalquestion@crab.org. For procedural help with logging and 
shipping specimens, there is an introduction to the system on the 
Specimen Tracking main page
(https://spectrack.crab.org/Instructions); or contact the Data Operations 
Center at 206/652-2267 to be routed to the Data Coordinator for further 
assistance.
In the online specimen tracking system, the appropriate SWOG laboratory 
for submission of tissue and blood samples is identified as follows:
Lab #224: 
The Ribas Laboratory
Attention: Agustin Vega-Crespo
Medical Receiving – Study S1616
CHS 54-200
650 Charles E. Young Dr. South.
UCLA Medical Center
Los Angeles, CA 90095
Phone: 310-825-2676
Fax: 310-825-2493
Contact:  Agustin Vega-Crespo
E-mail: avegacrespo@mednet.ucla.edu  
Federal guidelines for the shipment of blood products:
The tube must be wrapped in an absorbent material.
The tube must then be placed in an AIRTIGHT container (like a 
resealable bag).
Pack the resealable bag and tube in a Styrofoam shipping 
container.
Pack the Styrofoam shipping container in a cardboard box.
Mark the box "Biohazard".

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16.0
ETHICAL AND REGULATORY CONSIDERATIONS
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice:
Informed Consent
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations.
Institutional Review
This study must be approved by an appropriate institutional review committee as defined by Federal 
Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) and the 
Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code of Federal 
Regulations 45 CFR 46).
Drug Accountability
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312. 
Publication and Industry Contact
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) between Pharmaceutical Compan(ies)
(hereinafter referred to as "Collaborator(s)") and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines in addition to the provisions in the 
"Intellectual Property Option to Collaborator" 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award apply to the use of the Agent in this study:
1.
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators.  The protocol documents for studies 
utilizing Agents contain confidential information and should not be shared or distributed 
without the permission of the NCI.  If a copy of this protocol is requested by a patient or 
patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov.
2.
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different Collaborative Agreements, 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data"):
a.
NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NCI, the design 
of the proposed combination protocol, and the existence of any obligations which 
would tend to restrict NCI's participation in the proposed combination protocol.

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b.
Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own
Agent.
c.
Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-
Party Data solely for development, regulatory approval, and commercialization of 
its own Agent.
3.
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate 
and unless additional disclosure is required by law or court order as described in the IP 
Option to Collaborator
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  Additionally, all 
Clinical Data and Results and Raw Data will be collected, used and disclosed consistent 
with all applicable federal statutes and regulations for the protection of human subjects, 
including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164.
4.
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them.
5.
Any data provided to the Collaborator(s) for Phase III studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there 
is a DMC for this clinical trial.
6.
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication.  Collaborator(s) will have 30 calendar 
days from the date of receipt for review.  Collaborator shall have the right to request that 
publication be delayed for up to an additional 30 calendar days in order to ensure that 
Collaborator's confidential and proprietary data, in addition to the Collaborator(s)'s 
intellectual property rights, are protected.  Copies of abstracts must be provided to CTEP 
for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at 
least three (3) calendar days prior to submission, but in any case, prior to presentation at 
the meeting or publication in the proceedings.  Press releases and other media 
presentations must also be forwarded to CTEP prior to release.  Copies of any manuscript, 
abstract and/or press release/media presentation should be sent to:
E-mail:  
ncicteppubbs@mail.nih.gov. 
The Regulatory Affairs Branch will then distribute them to the Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of the 
Collaborator's confidential/proprietary information.
Monitoring
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  Cumulative 
protocol- and patient-specific CDUS data will be submitted electronically by the SWOG Data 
Operation Center to CTEP on a quarterly basis by FTP burst of data.  Reports are due January 31, 
April 30, July 31, and October 31.  Instructions for submitting data using the CDUS can be found 
on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html).

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Confidentiality
Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained.
16.1
Adverse Event Reporting Requirements 
a.
Purpose
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as well 
as those who will enroll in future studies using similar agents. Adverse events are 
reported in a routine manner at scheduled times during a trial. (Directions for 
routine reporting are provided in Section 14.0.) Additionally, certain adverse events 
must be reported in an expedited manner to allow for more timely monitoring of 
patient safety and care. The following guidelines prescribe expedited adverse
event reporting for this protocol. 
b.
Reporting method
Expedited AE reporting for this study must only use CTEP-AERS (CTEP-Adverse 
Event Reporting System), accessed via the CTEP Web site, https://eapps-
ctep.nci.nih.gov/ctepaers.  In the rare occurrence when Internet connectivity is lost, 
a 24-hour notification is to be made to CTEP by telephone at 301-897-7497.  Once 
Internet connectivity is restored, the 24-hour notification phoned in must be entered 
electronically into CTEP-AERS by the original submitter at the site.
c.
When to report an event in an expedited manner
Some adverse events require 24-hour notification (refer to Table 16.1) via CTEP-
AERS. 
When the adverse event requires expedited reporting, submit the report within the 
number of calendar days of learning of the event specified in Table 16.1. 
Any supporting documentation should be submitted to CTEP per NCI guidelines 
for AE reporting located at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf. 
d.
Other recipients of adverse event reports
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required.
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local policy 
and procedures.
e.
Expedited reporting for investigational agents
Expedited reporting is required if the patient has received at least one dose of the 
investigational agents as part of the trial. Reporting requirements are provided in 
Table 16.1. The investigational agents used in both arms of this study are 
ipilimumab and nivolumab. [Please note – the post dosage expedited reporting 

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requirement window has been extended to 90 calendar days rather than the 
normal 30 day requirement.]  If there is any question about the reportability of an 
adverse event or if on-line CTEP-AERS cannot be used, please telephone or email 
the SAE Specialist at the Operations Office, 210/614-8808 or adr@swog.org, 
before preparing the report.

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Table 16.1
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under a CTEP IND within 90 Calendar Days of the Last Administration of the 
Investigational Agent/Intervention1 Ipilimumab and Nivolumab (Arm 1 and Arm 2)
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:  
1)
Death
2)
A life-threatening adverse event 
3)
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for 
≥ 24 hours 
4)
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
5)
A congenital anomaly/birth defect. 
6)
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below.
Hospitalization
Grade 1 
Timeframes
Grade 2 
Timeframes
Grade 3 Timeframes
Grade 4 & 5 
Timeframes
Resulting in 
Hospitalization 
≥ 24 hrs
10 Calendar Days
24-Hour 5 
Calendar 
Days
Not resulting in
Hospitalization 
≥ 24 hrs
Not required
10 Calendar Days
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR or [Section 
16.1f.]  
Expedited AE reporting timelines are defined as:
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 
24-hour report.
o
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE.
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for:
•
All Grade 4, and Grade 5 AEs
Expedited 10 calendar day reports for:
•
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization 
•
Grade 3 adverse events
May 5, 2011

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f.
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Phase 1 and Early Phase 2 Studies Utilizing an Agent 
under a CTEP IND:
Group-specific instructions.
Submission of the on-line CTEP-AERS report plus any necessary 
amendments generally completes the reporting requirements In 
addition, you may be asked to submit supporting clinical data to the 
SWOG Operations Offices in order to complete the evaluation of 
the event.  If requested, the supporting data should be sent within 
5 calendar days by fax to 210-614-0006.  Supporting clinical data 
submitted should include:
•
Printed copy of the first page of the CTEP-AERS Report.
•
Copies of clinical source documentation of the event.
•
If applicable, and they have not yet been submitted to the 
SWOG Data Operations Center copies of Off Treatment 
Notice and/or Notice of Death.
The adverse events listed below also require expedited monitoring for this 
trial:
Any > Grade 3 pneumonitis, colitis, dermatitis, hepatitis, infusion-
related reaction, neuro or ocular toxicity, or endocrinopathy.
g.
Reporting Secondary Malignancy, including AML/ALL/MDS
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy).  A secondary malignancy is not considered a 
metastasis of the initial neoplasm.
CTEP requires all secondary malignancies that occur following 
treatment with an agent under an NCI IND to be reported via CTEP-
AERS.  Three options are available to describe the event.
•
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML])
•
Myelodysplastic syndrome (MDS)
•
Treatment-related secondary malignancy
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol.
Second Malignancy: A second malignancy is one unrelated to the 
treatment of a prior malignancy (and is NOT a metastasis from the 
initial malignancy).
Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified.
For more information see:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/d
ocs/aeguidelines.pdf. 

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Any supporting documentation should be submitted to CTEP per NCI 
guidelines for AE reporting located at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/d
ocs/aeguidelines.pdf.
A copy of the report and the following supporting documentation must 
also be submitted to SWOG Operations Office within 30 calendar days 
by fax to 210-614-0006 or mail to the address below:
•
a copy of the pathology report confirming the AML/ALL 
/MDS diagnosis
•
(if available) a copy of the cytogenetics report  
SWOG
ATTN: SAE Program
4201 Medical Drive, Suite 250
San Antonio, Texas 78229
NOTE: If a patient has been enrolled in more than one NCI-sponsored 
study, the report must be submitted for the most recent trial.
h.
Reporting Pregnancy, Fetal Death, and Death Neonatal
Pregnancy Study participants who become pregnant while on study; that 
pregnancy should be reported in an expedited manner via CTEP-AERS 
as Grade 3 “Pregnancy, puerperium and perinatal conditions – Other 
(pregnancy)”
under the Pregnancy, puerperium and perinatal 
conditions SOC.  
Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report.
Fetal Death Fetal Death defined in CTCAE as “A disorder characterized 
by death in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation” should be 
reported expeditiously as Grade 4 “pregnancy, puerperium and 
perinatal conditions – Other (pregnancy loss)” under the Pregnancy, 
puerperium and perinatal conditions SOC.  
Death Neonatal  Neonatal death, defined in CTCAE as “A disorder 
characterized by cessation of life occurring during the first 28 calendar 
days of life” that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention should be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration – Other (neonatal loss)” under the
General disorders and administration SOC.
Fetal death and neonatal death should NOT be reported as a Grade 5 event.  If 
reported as such, the CTEP-AERS interprets this as a death of the patient being 
treated.

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NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should also be completed and 
faxed with any additional medical information to 301-230-0159.  The potential risk 
of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) 
should be documented in the “Description of Event” section of the CTEP-AERS 
report.
The Pregnancy Information Form is available at:  
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm 

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17.0
BIBLIOGRAPHY
1
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mutation. N Engl J Med 372:320-330. PMID: 25399552, 2015.
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Robert C, Schachter J, Long GV et al. Pembrolizumab versus ipilimumab in advanced melanoma. 
N Engl J Med 372:2521-32. PMID: 25891173, 2015.
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Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive 
immune resistance. Nature 515:568-71. PMID: 25428505. PMCID: PMC4246418, 2014.
4
Postow MA, Chesney J, Pavlick AC et al. Nivolumab and ipilimumab versus ipilimumab in untreated 
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Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy 
in untreated melanoma. N Engl J Med 373:23-34. PMID: 26027431, 2015.
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Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy 
in untreated melanoma. N Engl J Med 373:23-34. PMID: 26027431, 2015.
7
Postow MA, Chesney J, Pavlick AC et al. Nivolumab and ipilimumab versus ipilimumab in untreated 
melanoma. N Engl J Med. 372:2006-17. PMID: 25891304, 2015.
8
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy 
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Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy 
in untreated melanoma. N Engl J Med 373:23-34. PMID: 26027431, 2015.
10
Robert C, Long GV, Brady B et al. Nivolumab in previously untreated melanoma without BRAF 
mutation. N Engl J Med 372:320-330. PMID: 25399552, 2015.
11
Robert C, Schachter J, Long GV et al. Pembrolizumab versus ipilimumab in advanced melanoma. 
N Engl J Med 372:2521-32. PMID: 25891173, 2015.
12
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy 
in untreated melanoma. N Engl J Med 373:23-34. PMID: 26027431, 2015.
13
Robert C, Schachter J, Long GV et al. Pembrolizumab versus ipilimumab in advanced melanoma. 
N Engl J Med 372:2521-32. PMID: 25891173, 2015.
14
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy 
in untreated melanoma. N Engl J Med 373:23-34. PMID: 26027431, 2015.
15
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with 
metastatic melanoma. N Engl J Med 363:711-23. PMID: 20525992. PMCID: PMC3549297, 2010.
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Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy 
in untreated melanoma. N Engl J Med 373:23-34. PMID: 26027431, 2015.
17
Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive 
immune resistance. Nature 515:568-71. PMID: 25428505. PMCID: PMC4246418, 2014.

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Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines 
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Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade 
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Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N 
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Robert C, Schachter J, Long GV et al. Pembrolizumab versus ipilimumab in advanced melanoma. 
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22
Postow MA, Chesney J, Pavlick AC et al. Nivolumab and ipilimumab versus ipilimumab in untreated 
melanoma. N Engl J Med. 372:2006-17. PMID: 25891304, 2015.
23
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with 
metastatic melanoma. N Engl J Med 363:711-23. PMID: 20525992. PMCID: PMC3549297, 2010.
24
Bowyer S, Prithviraj P, Lirogan P, et al. Efficacy and toxicity of treatment with anti-CTLA-4 antibody 
ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy. British Journal of 
Cancer 114:1084-1089, 2016. PMID: 27124339
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Robert L, Tsoi J, et al. CTLA4 blockade broadens the peripheral t-cell receptor repertoire. Clin 
Cancer Res 20:2424-32, 2014. PMID: 24583799
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Huang RR, Jalil J, Economou JS, et al. CTLA4 blockade induces frequent tumor infiltration by 
activated lymphocytes regardless of clinical responses in humans. Clin Cancer Res 17:4101-9, 
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Zaretsky J, Diaz AG, Shin DS, et al. Mutations associated with Acquired resistance to PD-1 
blockade in Melanoma. N Engl J Med, 2016; 375(9):819-29. PMID: 27433843.
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Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive 
immune resistance. Nature 2014;515:568-71. PMID: 25428505. PMCID: PMC4246418.
29
Huang RR, Jalil J, Economou JS, et al. CTLA4 blockade induces frequent tumor infiltration by 
activated lymphocytes regardless of clinical responses in humans. Clin Cancer Res 17:4101-9, 
2011. PMID: 21558401
30
Zaretsky J, Diaz AG, Shin DS, et al. Mutations associated with Acquired resistance to PD-1 
blockade in Melanoma. N Engl J Med, 2016; 375(9):819-29. PMID: 27433843
31
Hugo W, Zaretsky JM, Sun L, et al. Genomic and transcriptomic features of response to anti-PD-1 
therapy in metastatic melanoma. Cell 165:35-44, 2016. PMID: 26997480
32
Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N 
Engl J Med 2015;372:2509-20. PMID: 26028255. PMCID: PMC4481136
33
Hugo W, Zaretsky JM, Sun L, et al. Genomic and transcriptomic features of response to anti-PD-1 
therapy in metastatic melanoma. Cell 165:35-44, 2016. PMID: 26997480

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18.0
APPENDIX
18.1 
Translational Medicine Details
18.2 
Translational Medicine Procedures
18.3
Management
of 
Immune-Related 
Adverse 
Events, 
Diarrhea, 
Hepatotoxicity, 
Endocrinopathy, and Neuropathy for Ipilimumab
18.4 
Management of Algorithms for Endocrinopathy, Gastrointestinal, Hepatic Neurological, 
Pulmonary, Renal, and Skin Adverse Events for Nivolumab
18.5
Specimen Banking Instructions for the Ribas Laboratory

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18.1 
Translational Medicine Details
a.
Background
Combined therapeutic checkpoint blockade of cytotoxic T-lymphocyte antigen 4
(CTLA-4, ipilimumab) and
programmed death 1 protein (PD-1, nivolumab) has
demonstrated higher objective response rates when compared to either ipilimumab
or nivolumab as single agents in advanced melanoma patients but is associated
with increased toxicities (Grade 3/4 treatment-related adverse events of55%). (1) 
A key challenge in oncology today is how to select for patients that are likely to
respond to single agent anti-PD1.Furthermore, in patients unlikely to respond to
single agent anti-PD1, it remains unclear which patients are likely to benefit
from
combined ipilimumab/nivolumab. Immunodiagnostics that predict and monitor
response will be key to addressing this
challenge and are urgently needed
considering the number of combinations entering oncology in the next 5 years. (2)
To date, no immune assay has been adopted in the clinic to assist with clinical
decision-making. We propose to systematically investigate the predictive utility of
four immunodiagnostic approaches that measure distinct parameters
within
tumors: i) quantitative multiplexed immunohistochemistry (qmIHC) which provides
spatially resolved, multiparametric information and measures the density, location
and
phenotype
of
immune
cell
types
(Tumeh et al. nature 2014);
ii)
immunosequencing of the T-cell receptor (TCR) repertoire which is based on bulk
reads and measures the clonality and
repertoire of TCRs (Tumeh et al. nature 
2014); and iii) whole exome sequencing which generates signal based on bulk
measurements and identifies
all non-synonymous mutations(Shin et al. Cancer 
Discovery 2017); and iv) RNASeq which, through analysis of mRNA expression 
levels, can identify changes in the functional characteristics of different cells in the 
tumor microenvironment (Hugo et al. Cell 2016). These approaches have shown
preliminary predictive potential by independent groups
across different cancer
types. (3,4,5) No study to date, however, has investigated the relationship between
these factors or
their predictive value when interrogating the same tumor. By
defining the relationships between these four factors in
terms of response, we
anticipate that our approach will lead to clinically actionable information as well as
key insights into why certain tumors are immunogenic and others are not.
Figure 1a and b show CD8 T-cell density and TCR clonality in terms of response
to single agent anti-PD1 in patients with advanced melanoma.  Figure 1c and d
show images of multiplexed immunophenotyping that enable the identification of
distinct immune cell types in a spatially resolved
manner. (6) Table 1 provides
preliminary data comparing CD8+ T-cell density,
clonality and mutational load
derived from the same melanoma tumors. Note that Patient 1 and 2 had relatively
high mutation load but low CD8+ T-cells at the invasive margin and progressed on
single agent anti- PD1 while Patient 5 had low mutational burden but high CD8+ T-
cells and clonality and responded to therapy.
We hypothesize that the integration of all four approaches into a predictive model
will show incremental predictive value over any single parameter. Additionally, we
will be able to determine the relationships between immune cell types density and
location, TCR clonality, mutation load and/or type and mRNA expression levels

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Figure 1. Baseline CD8 density and clonality in melanoma .
a, CD8 density (cells/mm2) in terms of response to single agent anti-PD1. 
b, Clonality in terms of response to single agent anti-PD1. 
c, d, Quantitative multiparametric IHC using spectral imaging. Immunofluorescence (6-plex)
images using spectral deconvolution enables identification of distinct phenotypes and spatial
relationships in melanoma (c, CD8xPD1xPDL1xFoxp3xTopoII and d, CD8xPDL1xSOX10)
Table 1 provides preliminary data comparing CD8+ T-cell density, clonality and
mutational load derived from the same melanoma tumors.
Table 1. Comparison of CD8 density, clonality and mutational load in
melanoma
tumors in terms of response to single agent anti-PD1. Each parameter is assigned a 
“high” and “low” descriptive where “low” would predict progression and “high” would predict 
response. The clinical response is provided.
b.
Experimental Approach and Analysis
Data storage and computational infrastructure: To optimally perform computational 
analysis on the large amount of genomic and imaging data to be generated from 
this study, it is expected that appropriate cloud computing infrastructure with the 
necessary analysis pipeline is required for the storage and computation of these 
data. One such computational infrastructure and resource available for this study 
is through the collaboration with the Parker Institute for Cancer Immunotherapy.
Objective 1: To compare the predictive value of four baseline tumor factors: T-cell 
density, T-cell receptor (TCR) clonality mutational load, mRNA and other 
phenotypical expression levels, and circulating tumor DNA. The following provides 
information about the methods for each approach. Samples will be obtained within 
28 calendar days of starting combined ipilimumab/nivolumab for analysis (or, if not 
feasible, obtained at any point since documented progression on PD-1 or PD-L1 

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therapy alone). Critical to understanding how these antibodies promote tumor 
rejection is the identification of immune cell types that are altered during therapy. 
Samples obtained during treatment will also be analyzed in order to understand 
how distinct immune cell types evolve in terms of density, effector activity, 
proliferative status and cell:cell proximity during intervention according to 
response. Additionally, we will investigate how the T-cell repertoire and mutational 
landscape evolve in responsive vs. non-responsive tumors. Finally, we will obtain 
a subset of samples that are amenable to analysis of mRNA by RNASeq.
Quantitative multiplexed IHC: Measuring the density, phenotype and location of 
different cell types: Samples will be obtained from patients at baseline and during 
ipi/nivo on Day 28 (+/- 7 days) of therapy and fixed in 10% neutral buffered formalin 
and paraffin embedded according to standard institution protocols. Twenty slides 
with tissue section cuts of 3-4 um thick will be provided for analysis from each 
FFPE block. At selected study sites, the biopsy will be processed as fresh frozen 
tissue for RNASeq and other analyses. Slides will be stained with a set of multiple 
biomarkers to comprehensively define the innate and adaptive immune system in 
tumors
and the functional characteristics of different cells in the tumor 
microenvironment. Note that each antibody used is an in vitro diagnostic antibody 
for IHC, meets the highest level of sensitivity and specificity requirements, and 
have been optimized for single staining and multiplexed staining in our lab. Slides 
will be analyzed using quantitative imaging analysis optimized by the translational
as well as previously described. (7, 8)
Lymphocyte receptor sequencing: Defining the T-cell receptor (TCR) repertoire 
in tumors: Genomic DNA will be isolated from FFPE blocks (or from fresh frozen 
samples if available) derived from tumor biopsies performed at baseline and at 
Day 28 (+/- 7 days) of therapy. The V beta and alpha chains of TCRs will be 
captured using the ImmunoSeq assay as previously described. (9) The analysis 
will define the repertoire, diversity and clonality of tumor samples.
Whole exome sequencing: Defining the mutational landscape: Genomic DNA 
will be isolated from FFPE tissue blocks and matched peripheral blood 
mononuclear cells (PBMCs). This will allow us to differentiate germline variants 
(non-cancer variants) from non-synonymous mutations (cancer specific). 
Following whole exome sequencing, the Genome Analysis Toolkit (GTAK) and 
workflow to process the raw dataset for downstream analysis. To ensure accurate 
identification of non-synonymous mutations, each variant will require discovery 
identification with at least two variant discovery software tools (MuTect and 
Vascan2). The analysis will determine the mutation load and provide for further 
investigation into the spatial diversity of mutations and HLA binding predictions of 
specific mutations in terms of response.
mRNA expression analysis: Identifying predictive genes and signatures: A 
subset of clinical sites will provide samples from patients at baseline and during 
ipi/nivo during Week 5 of which a portion of tissue will stabilized and preserved 
using RNAlater reagent and then frozen, while a portion will be flash frozen on site 
using liquid nitrogen. Tissue obtained from both mechanisms will be transferred to 
the laboratory at UCLA where further analysis will be performed. Using single cell 
RNASeq and drop-Seq approaches we will be able to analyze protein expression 
levels by tracking changes in different cells that make up the tumor 
microenvironment. Following standard preprocessing mRNA based signatures will 
be obtained.

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Circulating tumor DNA analysis: Detecting tumor-specific mutations in the 
circulating tumor DNA (ctDNA) as a way to monitor treatment responses: Whole 
blood will be processed to separate peripheral blood mononuclear cells (PBMCs) 
and plasma, which can be used for ctDNA profiling. This study proposes to perform 
ctDNA from patient-matched baseline and on-treatment plasma samples to 
determine the amount or fraction of ctDNA corresponding to the genetic profile of 
the patient tumor biopsies. 
Objective 2: To determine the incremental prognostic value of T-cell density, TCR 
clonality,mutational load, and mRNA expression levels in response
To capture the complexity of the immune system’s response to tumors, our group 
proposes to integrate four parameters (T-cell density, clonality, mutational load, 
mRNA expression signature) into a single predictive model. By doing so, our aim 
is to define the relationship between the immune system and tumor according to 
treatment outcome that would not be possible with any single approach. We 
hypothesize that the integration of all four parameters into a predictive model will 
show incremental predictive value over any single parameter.
Consistent with previous publications, preliminary data in melanoma shows that 
there are patients who show high CD8+ T-cells in tumors despite having a low 
mutational load. (10,11,12) Conversely, there are patients that lack a CD8+ T-cell 
response to their tumor but have high mutational load. We anticipate that our 
approach will lead to defined signatures (TIL, Clonality, Mutation Score) that are 
driven by clinical relevance. Investigating the density and repertoire of T-cells in 
terms of mutational burden will allow us to gain insight into the type of mutations 
that are associated with clinical response.
Objective 3: To identify T-cell poor subtypes associated with response
The T-cell status of tumors represents a key determinant of response to anti-PD1. 
Tumors infiltrated with T-cells show sensitivity to single agent anti-PD1 but 
represent a minority of patients. The majority of tumors lack T-cells and are 
inherently non-responsive to therapy. T-cell poor tumors represent a 
heterogeneous group and remain poorly defined. A challenge in the field is to 
develop immunodiagnostics that have the ability to subtype T-cell poor tumors into 
immune ‘activity’ signatures that are clinically actionable.
The response rates observed with combination checkpoint inhibition indicate that 
there is a responsive subgroup within the T-cell poor group that would otherwise 
be non-responsive to single agent PD1 inhibitor. We propose to define this 
subgroup by using multi-parameter flow cytometry and multiplexed multi-
parameter immunohistochemistry to analyze the peripheral blood and tumor, 
respectively, within the same patient. In this way we can compare circulating 
immune cells and tumor infiltrating immune cells within a given patient and 
according to treatment outcome groups. Immune cell types within the innate the 
adaptive system will be defined and monitored within the blood and in tumors. Our 
rationale for this approach is based on the necessary mobilization of TILs from the 
peripheral blood in order to infiltrate a tumor responding to combination to 
combination therapy. Our goal is to define the innate and adaptive immune 
landscape in baseline tumors that are CD8+ T-cell poor but undergo unique 
alterations during response that are absent in non- responsive tumors.
c.
Statistical Plan: 

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Objective 1: Assess the independent prognostic value of baseline T-cell 
density, T-cell receptor (TCR) clonality, ctDNA fraction, and mutational 
load in terms of response in each arm.
We will consider each treatment arm separately.  Then for each arm, we 
will assess whether each of the IHC markers, T-Cell clonality, ctDNA 
fraction, mutational load and mRNA signatures can be used to identify 
patients who respond. Under our first objective, we will assess each 
variable individually. In particular, we will use logistic regression to regress 
dichotomous response status on each variable, one-at-a-time. Since our 
primary objective is to develop a classification model for identifying 
responders, we will estimate standard model classification characteristics 
including misclassification error, sensitivity, specificity, and AUC for each 
variable where the threshold for the logistic probabilities for defining 
predicted responder vs. non-responder will be tuned via leave-one-out 
cross validation (LOOCV). We will estimate both the in-sample 
classification characteristics as well as the cross-validated (where the full 
procedure is cross-validated, with potential nested LOOCV for tuning 
parameter selection) characteristics with corresponding 95% confidence 
intervals. The in-sample estimates represent optimistic values while the 
LOOCV estimates represent pessimistic values such that the smallest 
lower 95% CI and highest upper 95% CI bound for each characteristic on 
each variable will provide conservative coverage of the true characteristic 
value. For Arm 1 (ipilumimab alone), with a sample size of 21 patients, 
assuming we have 90% compliance on tissue submission, then we will be 
able to estimate the in-sample or cross validated misclassification error to 
within 22.5% (95% CI). For Arm 2 (combination therapy), with a sample 
size of 63 patients and again assuming 90% compliance on tissue 
submission, then we will be able to estimate the in-sample or cross 
validated misclassification error to within 13.0% (95% CI). 
Although our primary analysis will focus on developing classification 
models, we will also assess the association between response and each 
individual marker, clonality, mutational load, mRNA expression signature, 
and ctDNA fraction. The analysis will be again conducted separately by 
treatment arm. For each of the IHC markers, clonality, and ctDNA fraction, 
we will test for difference in mean levels between responders and non-
responders using two-sample t-tests.  We assume we obtain data on 90% 
of patients and that the response rates are 15% and 30% in arms 1 and 2, 
respectively.  Then at the nominal alpha=0.05 level, we anticipate 80% 
power to detect a difference in marker level, clonality, or ctDNA fraction
between responders and non-responders of 1.9 and 0.83 standard 
deviations in Arms 1 and 2, respectively.  Further, we will also assess 
whether individual mRNA transcripts and genes are associated with 
response.  Specifically, we will compare the expression between patients 
who respond and who do not respond using two-sample t-tests again.  We 
will accommodate multiple testing by controlling the false discovery rate.  
With the same response rate and sample size assumptions as before, and 
further assuming that 80% of genes are not associated with response, 
then at the FDR = 5% level, we anticipate 80% power to detect a difference 
in expression level of 2.43 and 1.33 standard deviations in Arms 1 and 2, 
respectively.  Note that t-tests are used since they can be more powerful 
than logistic regression, but for all association analyses in this objective 
and subsequent translational medicine objectives, we will consider the use 
of alternative approaches, e.g. data transformation, Wilcoxon tests or 
logistic regression, if there are outliers or influential points.

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Since mutational load is far from normally distributed, we will use a 
Wilcoxon test to test for difference in mutational burden.  To assess power, 
we conducted simulations under the assumption that we will collect exome 
sequencing data on 90% of patients and that we will control the type I error 
rate at the two-sided alpha=0.05 level. To simulate mutational load, we 
used an internal, private data exome sequencing data set comprised of 13 
non-responder patients to first line anti-PD1 therapy and sampled from the 
interpolated empirical cumulative distribution function (ECDF) via the 
inverse probability integral transform. For power analyses, data from this 
distribution were taken to be null.  To simulate under the alternative, we 
shifted all of the mutational load values by a scalar δ and re-sampled from 
the interpolated ECDF of the shifted data. For Arm 1, assuming response 
rate of 15%, with 18 total patients, we anticipate 80% power to detect a 
shift in mutational load distribution of δ=13.9.  For Arm 2, assuming 
response rate of 30%, with 54 total patients, we anticipate 80% power to 
detect a shift in mutational load distribution of δ=2.7.  We again emphasize 
that alternative approaches will be considered if Wilcoxon tests do not 
perform well, e.g. due to heteroscedasticity etc.
Objective 2: Prognostic Value of T-cell Density, TCR Clonality, and 
Mutational Load
We will assess the joint capacity of the IHC markers, T-Cell clonality, 
ctDNA fraction, and mutational load, and gene expression signatures to 
identify patients who respond to each therapy. In particular, analyzing 
each arm separately, we will use the logistic elastic net to model the joint 
effect on response of the multiple markers and variables simultaneously. 
We will select the tuning parameters for elastic net via a two-dimensional 
grid search and LOOCV. We will again estimate the in-sample and cross-
validated (of the entire procedure with nested LOOCV for tuning) model 
classification characteristics and corresponding 95% confidence intervals, 
again noting that these represent optimistic and pessimistic bounds for 
each characteristic. Since the elastic net essentially enforces linearity in 
the effects of the variables, we will also consider the use of alternative 
strategies, including large margin (e.g. support vector machines) and tree 
based classifiers in order to accommodate potential nonlinear and 
potentially interactive effects. Independent of the specific classification 
method used, for Arm 1, with a sample size of 21 patients and again 
assuming we have 90% compliance on tissue submission, then we will be 
able to estimate the in-sample or cross validated misclassification error to 
within 22.,5% (95% CI). For Arm 2, with a sample size of 63 patients, 90% 
compliance on tissue submission, then we will be able to estimate the in-
sample or cross validated misclassification error to within 13% (95% CI)
Objective 3: Identification of T-cell Poor Subtype(s) Associated with 
Response
We will first define the range of CD-8+ T-cell density in the tumor sample 
characterizing a patient as T-cell poor using a supervised approach: this 
range is currently undefined for patients who have already failed on an 
anti-PD1 or anti-PD-L1 agent. Specifically, we will consider a range of 
thresholds for CD8 expression above which the patients are classified as 
T-cell rich and below which patients are classified as T-cell poor. For each 
candidate threshold, we will estimate the proportion of responders above 
and below the threshold. The final threshold defining T-cell poor status will 
be selected as the threshold which leads to the highest difference in 

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proportion of responders above vs. below the threshold. We will also 
consider un-supervised approaches based on identifying gaps in the 
distribution of CD8 expression and will tune this according to our 
supervised results.
After defining the range characterizing patients as T-cell poor, we will 
restrict further analyses to the patients determined to be T-cell poor. We 
will then repeat the approach used in Objective 2 to develop a signature 
identifying T-cell poor patients who respond to therapy. We will again 
estimate the in-sample and cross validated classifier operating 
characteristics and construct 95% confidence intervals. Assuming that 
90% of patient samples are available for analysis, for Arm 1, we will be 
able to estimate the in-sample or cross-validated misclassification error to 
within 25.2%, 23.7%, or 23.1% (95% CI) if 80%, 90%, or 95%, 
respectively, of patients are determined to be T-cell poor. For Arm 2 we 
will be able to estimate the in-sample or cross-validated misclassification 
error to within 14.6%, 13.7%, or 13.4% (95% CI) if 80%, 90%, or 95%, 
respectively, of patients are determined to be T-cell poor.
We will repeat this analysis using the data collected from blood samples.
References for 18.1
1
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy 
in untreated melanoma. The New England journal of medicine 2015;May 31:[Epub ahead of print]
2
Morrison C. 'Financial toxicity' looms as cancer combinations proliferate. Nat Biotechnol 33:783-4, 
2015.
3
Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines 
sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124-8, 2015.
4
Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade
in melanoma. The New England journal of medicine 371:2189-99, 2014.
5
Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive 
immune resistance. Nature 515:568-71, 2014.
6
Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive 
immune resistance. Nature 515:568-71, 2014.
7
Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive 
immune resistance. Nature 515:568-71, 2014.
8
Angelo M, Bendall SC, Finck R, Hale MB, Hitzman C, Borowsky AD, Levenson RM, Lowe JB, Liu 
SD, Zhao S, Natkunam Y, Nolan GP. Multiplexed ion beam imaging of human breast tumors. Nat 
Med. 2014 Apr;20(4):436-42. doi: 10.1038/nm.3488. Epub 2014 Mar 2. PMID: 24584119; PMCID: 
PMC4110905.
10
Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade 
in melanoma. The New England journal of medicine 2014;371:2189-99.
11
Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade 
in melanoma. The New England journal of medicine 2014;371:2189-99.

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12
Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. The 
New England journal of medicine 372:2509-20, 2015.

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18.2 
Translational Medicine Procedures
Whole exome sequencing to analyze mutational load: To test whether there is a 
correlation of tumor mutational load and response to PD-1 antibody therapy, DNA will be 
isolated from thick slides of FFPE tissues and *PBMC via commercial kit (i.e. Qiagen 
AllPrep DNA/RNA FFPE kit, cat 80234). Whole exome sequencing (WES), including probe-
based exon capture, library preparation, and high throughput 100bp paired-end 
sequencing on the Illumina HiSeq2500 platform will be performed at the UCLA 
Immunogenetics core laboratory (CLIA approved lab). DNA from the same patient’s PBMC 
(preferably) or other non-cancerous tissue will be isolated and sequenced for baseline 
comparison and differentiation of germline SNPs from true somatic mutations. Read 
mapping and data preprocessing will be performed according to the Broad Institute Best 
Practices Guidelines for the Genome Analysis Toolkit (version 3), and mutation detection 
will require a consensus call among several published programs (Varscan2, MuTect, GATK 
HaplotypeCaller). Mutational load will be quantified as the number of nonsynonymous 
somatic mutations per MB.
Quantitative analysis of T cell infiltration: To analyze whether baseline CD8+ cell 
infiltration is correlated with response to anti-PD1 therapy, and whether PD-1 blockade can 
increase CD8+ cell infiltration in DM patients, slides taken from standard formalin-fixed 
paraffin-embedded (FFPE) tissue blocks obtained from baseline, 4 week (on treatment), 
and 9 week biopsies will be stained by immunohistochemistry (IHC) for S100 and CD8 to 
determine the presence of CD8+ T cells inside tumors and in the invasive margin. Slides 
will be analyzed using quantitative digital pathology following the methods described (10). 
This analysis will provide a predictive score for response or lack of response to 
pembrolizumab based on the baseline CD8+ T cell infiltration.
Method: Slides will be stained with S100 and CD8 (one slide per stain) at the UCLA 
Anatomic Pathology IHC Laboratory (CLIA approved lab). Immunostaining will be 
performed on Leica Bond III autostainers using Leica Bond ancillary reagents and REFINE 
polymer DAB detection system (Leica DS9800). Antibodies used will include rabbit
polyclonal S100 (DAKO, 1/1,000 dilution, low pH retrieval), mouse anti-CD8 clone C8/144B 
(DAKO, 1/100, low PH retrieval), and all staining will be performed on Dako autostainers, 
and visualized with DAB. Slides will be baked for 60 minutes at 60C.  Procedure involves 
dewaxing, heat-retrieved in Bond ER1 (pH6) buffer for 20 minutes, and sequential 
incubations with primary antibody, post-primary reagent, and polymer for 15 minutes, 8 
minutes, and 8 minutes, respectively, and subsequent DAB chromogen application and 
Hematoxylin counterstaining. All stained slides will be evaluated in a blinded fashion by 
one dermatopathologist and one investigator trained to identify the features of melanoma, 
and the presence of CD8 within the tumor parenchyma (tumor) and the connective tissue 
surrounding the tumor (invasive margin) will be examined.
All slides will be scanned at an absolute magnification of X200 (resolution of 0.5 mm/pixel). 
An algorithm was designed based on pattern recognition that quantified immune cells 
within S100-positive areas (tumor) and S100-negative areas (invasive margin). Image 
analysis based on RGB (red, green, blue) spectra will be used to detect all cells by 
counterstaining with haemotoxylin (blue), and DAB or fast red. The algorithm calculated 
the density (cells mm-2) and percentage cellularity (% positive cells/all nucleated cells) 
using Indica Labs Halo platform.
Analysis of TCR clonality in tumors: To answer the question whether the T cell response 
is targeting specific tumor antigen (mono-clonal) or a non-specific process (poly-clonal) in 
the tumors, we will analyze TCR clonality by deep sequencing the TCR Vβ CDR region
using the ImmunoSeq assay from Adaptive Biotech as described (10). From thick slides of 

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FFPE tissues taken at baseline, 4 weeks, and 9 weeks, we will isolate DNA and submit it 
for TCR Vβ sequencing. This analysis will provide information about the clonality or 
diversity of T cells infiltrating tumors in DM samples. DNA analysis will be performed by the 
UCLA Immunogenetics core laboratory (CLIA approved lab).
DNA will be isolated from FFPE thick cuts followed by extraction using a DNeasy kit 
(Qiagen). Melanin will be removed from visibly pigmented melanoma samples using a PCR 
Inhibitor Removal kit (ZymoResearch). TCR Vβ CDR3 regions will be amplified and 
sequenced using the survey ImmunoSeq assay in a multiplexed PCR method using 45 
forward primers specific to TCR Vβ gene segments and 13 reverse primers specific to TCR 
Vβ gene segments (Adaptive Biotechnologies). Reads of length 87bp will be obtained 
using the Illumina HiSeq System. For each sample, Shannon entropy will be calculated on 
the clonal abundance of all productive TCR sequences in the data set. Shannon entropy 
will be normalized to the range by dividing Shannon entropy by the logarithm of the number 
of unique productive TCR sequences in the data set. This normalized entropy value will be 
then inverted (12 normalized entropy) to produce our clonality metric.
Analysis of adaptive immune resistance mechanism in tumors: Slides taken from 
standard FFPE tissue blocks obtained from baseline, and the on treatment biopsy will be 
stained by immunohistochemistry (IHC) for PD-L1 (SP142, Spring Bioscience) to evaluate
whether PD-L1 can be induced by PD-1 blockade, and which it is correlated with response. 
Slides will be analyzed using quantitative digital pathology following the methods described 
for Quantitative analysis of T cell infiltration.  Analysis will be performed at the UCLA 
Anatomic Pathology IHC Laboratory (CLIA approved lab). 
Method:
1.
Bake slides for 1 hour at 65°C.
2.
Deparaffinize slides in xylene (3 changes) and rehydrate through graded ethanol 
to deonized-H2O.
3.
Perform antigen retrieval in pressure cooker for 5 minutes with Tris-EDTA pH9 
buffer (Leica ER2).  Cool for 15 minutes at room temperature and rinse in DI-water.
Perform IHC on Leica Bond III autostainer with Refine Polymer Detection 
(Leica DS9800); autostainer was programmed for primary antibody at 
1/200 dilution in daVinci Green Diluent (Biocare Medical) for 60 minutes, 
Polymer  for 15 minutes, Peroxidase block for 5 minutes, DAB for 10 
minutes, and offline manual steps 0.5% cupric sulfate for 10 minutes and 
Hematoxylin for  5 minutes.  Usual Bond washes between steps.  Use 
Bond Refine Polymer Detection kit (DS9800), which includes reagents for 
all steps after primary antibody, except for cupric sulfate and hematoxylin 
counterstain.

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18.3 
Management
of 
Immune-Related 
Adverse 
Events, 
Diarrhea, 
Hepatotoxicity, 
Endocrinopathy, and Neuropathy for Ipilimumab *
*Investigator’s Brochure (2011)
General Recommendations for Management of Suspected Inflammatory Events
Caution: With the appearance of any 
generalized rash, discontinue and avoid 
any concomitant medications
(e.g. antibiotics, anticonvulsants, or proton 
pump inhibitors) that may be associated 
with severe skin reactions
+ Definition: irAEs are associated with 
ipilimumab exposure and are consistent 
with immune phenomenon
Examples of possible irAEs (common 
and rare): rash, pruritus, diarrhea/colitis, 
hepatitis/elevated liver function tests, 
hypopituitarism, hypo/hyperthyroidism, 
uveitis, pneumonitis, nephritis, 
pancreatitis, aseptic meningitis, toxic 
epidermal necrolysis, myopathy/myositis 
or neuromuscular disorder (e.g. 
Myasthenia gravis, Guillain-Barre 
Syndrome) 
Suspicion of an 
immune related 
adverse event
(irAE)+
Rule-out non-immune related causes
If symptoms have a GI, Liver, or Endocrine etiology, then refer
To ‘Diarrhea”, “Hepatotoxicity”, or “Endocrinopathy” 
Management Algorithm for more specific guidance
Low grade
(Grade 1 or 2)
What is the 
severity of the 
adverse event?
(NCI CTCAE 
High grade
(Grade 3 or 4)
- Increase monitoring
- Symptomatic treatment 
- Consider skipping next dose until 
event resolves
- Consider oral steroid therapy* for 
persistent or recurring Grade 2 irAEs
- If symptoms worsen or do not 
improve with treatment after 1-2 weeks 
then consider managing as a high 
grade event
- Increase monitoring
- Strongly consider high dose steroid 
therapy*
- Hold further dosing until adverse event 
resolves
- Consider specialist consult
- If steroid therapy is initiated and symptoms 
improve, then consider a gradual steroid 
taper over 4 weeks
- If symptoms do not respond within 5-7 days 
of intervention, then consider alternative 
immunosuppression therapy (e.g., 
mycophenolate mofetil, tacrolimus, 
infliximab)
* Based on clinical experience to date, systemic steroids for 
treatment of irAEs do not appear to impact the development or 
maintenance of ipilimumab clinical activity in advanced melanoma. 

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Diarrhea Management Algorithm
Diarrhea
GRADE 1
Increase of <4 stools per 
day over baseline;
mild increase in ostomy 
output compared with
baseline
GRADE 2
Increase of 4-6 stools per day 
over baseline; IV fluids 
indicated < 24 hrs; moderate 
increase in ostomy output 
compared to baseline; not 
interfering with activities of 
daily living (ADL)
GRADE 3
Increase of ≥7 stools per day over 
baseline; incontinence; IV fluids ≥
24 hrs; hospitalization;
severe increase in ostomy output 
compared to baseline; interfering 
with ADL
GRADE 4
Life-threatening
consequences
(e.g.,
hemodynamic
collapse)
GRADE 5 
Death
Rule out
clear non-
irAE
Caution:
• The use of narcotics for 
abdominal pain in the setting of 
suspected immune related 
diarrhea/colitis may mask 
symptoms of perforation and 
peritonitis
• Infliximab should not be used if 
perforation or sepsis are present
Patient complains 
of diarrhea or 
blood in stool
Yes
No
Specific 
treatment 
for non-irAE 
cause
Grade of 
diarrhea
Continue 
ipili-
mumab
as per 
protocol
Treat 
symptomatically 
without steroids
Treat 
symptomatically 
without steroids
Stool WBC, 
Stool 
calprotectin, 
Consider 
endoscopy 
Continue 
ipilimumab
as per protocol
Resolved 
to ≤grade
1
2
3-4
No
Yes
Likely 
Colitis?
No
Yes
Grade 
of
Treat with high 
dose steroids 
and taper for at 
least 1 month
Treat with oral 
budesonide or 
other moderate 
dose steroid
Treat with high 
dose steroids 
and taper for at 
least 1 month
If no 
response 
in 1 week, 
consider a 
5 mg/kg 
dose of 
infliximab
Resolve
d to ≤ 
grade 1?
Yes
No 
longer 
eligible 
for 
further 
ipili-
mumab 
treatme
2
3-4
No

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Hepatoxicity Management Algorithm
Situation: rising liver function tests (LFTs) >8X ULN or suspected immune-mediated
Hepatitis
1)
Admit subject to hospital for evaluation and close monitoring
2)
Stop further ipilimumab dosing until hepatotoxicity is resolved. Consider permanent
discontinuation of ipilimumab per protocol 
3)
Start at least 120 mg methylprednisolone sodium succinate per day, given IV as a
single or divided dose
4)
Check liver laboratory test values (LFTs, T-bilirubin) daily until stable or showing
signs of improvement for at least 3 consecutive calendar days
5)
If no decrease in LFTs after 3 calendar days or rebound hepatitis occurs despite treatment with
corticosteroids, then add mycophenolate mofetil 1g BID per institutional guidelines
for immunosuppression of liver transplants (supportive treatment as required,
including prophylaxis for opportunistic infections per institutional guidelines)
6)
If no improvement after 5 to 7 calendar days, consider adding 0.10 to 0.15 mg/kg/day of
tacrolimus (trough level 5-20 ng/mL)
7)
If target trough level is achieved with tacrolimus but no improvement is observed
after 5 to 7 calendar days, consider infliximab, 5 mg/kg, once
8)
Continue to check LFTs daily for at least 2 weeks to monitor sustained response to
treatment
A flow chart of the algorithm is depicted on the following page.

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18.4
Management of Algorithms for Endocrinopathy, Gastrointestinal, Hepatic Neurological, 
Pulmonary, Renal, and Skin Adverse Events for Nivolumab

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18.5 
Specimen Banking Instructions for the Ribas Laboratory
Any leftover tissue from Section 15.1 will be stored at the Ribas Laboratory for future if the 
patient consents.  Upon receipt, the Bank will accession, barcode, and store FFPE material 
at room temperature.  Fresh Frozen tissue from select sites will be stored at -80ºC for future 
use. The SWOG Statistical and Data Management Center will provide a distribution case 
list for specimens for subsequent analysis.