Conditions: Mucinous Adenocarcinoma of the Colon Mucinous Adenocarcinoma of the Rectum
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: no

Brief summary:
This is a single-arm phase II study of twenty-one subjects with mucinous adenocarcinoma of the colon, rectum, or appendix with prior systemic therapy with a fluoropyrimidine, oxaliplatin, and irinotecan. Treatment will consist of nivolumab 480mg every 4 weeks and ipilimumab 1mg/kg every 8 weeks until disease progression, unacceptable toxicity, or 2 years of therapy.

Detailed description:
Treatment will consist of nivolumab 480mg every 4 weeks and ipilimumab 1mg/kg every 8 weeks (within a 56-day cycle, (Nivolumab administered on days 1 and 29, and Ipilimumab administered on day 1 of each cycle). Imaging assessments will be conducted every 8 weeks (+/-2 weeks) for the first 24 weeks then every 8-12 weeks (+/-2 weeks). If progression is noted on imaging in the setting of clinical stability, subjects may remain on study and have confirmatory imaging in 4-8 weeks per iRECIST criteria

Arms:
arm 1: Treatment will consist of Nivolumab 480mg every 4 weeks and Ipilimumab 1mg/kg every 8 weeks. Subjects will continue on study therapy until disease progression, unacceptable toxicity, withdrawal of consent, or 24 months of therapy.

Interventions: intervention 1: Nivolumab intervention 2: Ipilimumab
Intervention descriptions: intervention 1: IV infusion per institutional guidelines and the Package Insert intervention 2: IV infusion per institutional guidelines and the Package Insert

Protocol document:
Prot_SAP_001.pdf: 
Cover Page for ClinicalTrials.gov 
 
 
 
NCT Number 
 
NCT03693846 
 
 
Protocol 
Official Title 
 
Phase II Study of Nivolumab and Ipilimumab in Mucinous Colorectal and 
Appendiceal Tumors  
 
Documents 
Included 
 
 
study protocol and statistical analysis plan embedded within protocol section 
9.0 
Document 
Date 
(mm/dd/yyyy) 
 
11/24/2020 
 


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Phase II Study of Nivolumab and Ipilimumab in Mucinous Colorectal 
and Appendiceal Tumors 
Prinicipal Investigator: 
 
 
 
Thomas Karasic 
PCAM South, 10th Floor 
3400 Spruce Street 
Philadelphia, PA  19104 
215-614-1858 
thomas.karasic@uphs.upenn.edu 
 
Sponsor:: 
Peter J. O’Dwyer 
PCAM South, 10th Floor 
3400 Spruce Street 
Philadelphia, PA  19104 
215-662-7606 
peter.odwyer@uphs.upenn.edu 
 
Sub-Investigators: 
Giorgos Karakousis 
Mark O’Hara 
Ursina Teitelbaum 
Kim Reiss-Binder 
Charles Schneider 
Nevena Damjanov 
Jennifer Eads 
Peter O’Dwyer 
Ryan Massa 
 
Medical Monitor: 
Roger Cohen 
Lab Collaborators 
 
 
Statistician: 
John Wherry 
Alexander Huang 
Erica Carpenter 
 
E. Paul Wileyto 
 
Funding Sponsor: 
Bristol-Myers Squibb 
 
Study Products: 
 
Ipilimumab [Trade Name: Yervoy] 
Nivolumab [Trade Name: Opdivo] 
BMS Protocol Number 
CA209-8JF 
IRB Number 
831705 
Penn Protocol Number 
UPCC 28218 


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Clinical Trials.gov Number 
NCT03693846 
Initial Version 
11/29/2018 
Amendment #1 
4/1/2019 
   Amendment #2  
 
           8/30/2019 
   Amendment #3 
 
           11/24/2020 
0.0 Study Summary 
Title 
Phase II Study of Nivolumab and Ipilimumab in Mucinous Colorectal and 
Appendiceal Tumors 
Short Title 
Nivo/Ipi In Mucinous CRC 
IRB Number 
831705 
Protocol Number 
UPCC 28218 
Phase 
Phase II 
Methodology 
Single Arm Phase II 
Study Duration 
18-24 months accrual plus 6 months follow-up 
Study Center(s) 
Abramson Cancer Center at University of Pennsylvania 
Objectives 
Primary Objective  
1. To estimate six-month progression-free survival by iRECIST 
 
Secondary Objectives 
1. To determine overall response rate, duration of response, and progression-free 
survival by iRECIST and RECIST 1.1.  To determine overall survival.  
2. To estimate the toxicity rates by CTCAE v 5.0. 
 
Exploratory Objectives 
1. To measure T-cell subsets and markers of T-cell function in peripheral blood 
as a potential biomarker of response 
2. To define the immune effects in pre- and post-treatment biopsy specimens 
with analysis of tumor-infiltrating lymphocytes, including immune subsets, 
mutational load, and TCR sequencing 
3. To correlate imaging response with quantitative changes in cell-free tumor 
DNA, extracellular vesicles, and/or other circulating tumor materials 
 


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Number of Subjects 
 
21 
Diagnosis and Main 
Inclusion/Exclusion 
Criteria 
Inclusion Criteria: 
1. Colorectal or appendiceal mucinous tumor with peritoneal-only metastatic 
disease 
2. Microsatellite stable by PCR and/or mismatch repair proficient by 
immunohistochemistry 
3. ECOG PS 0-1 
4. Standard laboratory parameters 
5. Prior therapy with a fluoropyrimidine, oxaliplatin, and irinotecan unless 
contraindicated or refused.  Prior treatment with antiangiogenic and/or anti-
EGFR antibody therapy is permitted but not required 
 
Exclusion Criteria: 
1. Significant autoimmune disease 
2. Bowel obstruction within the past 60 days 
3. Use of systemic steroids other than for adrenal hormone replacement 
 
Study Products, Dose, 
Route, Regimen 
Product: Nivolumab 
Dose: 480mg 
Route: IV  
Regimen: Every 4 weeks 
 
Product:  Ipilimumab 
Dose:  1mg/kg 
Route:  IV 
Regimen:  Every 8 weeks 
 
Duration of 
administration 
Subjects will continue on study therapy until disease progression, unacceptable 
toxicity, withdrawal of consent, or 24 months of therapy. 
 


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Statistical 
Methodology 
 
 
 
 
For patients with colorectal adenocarcinoma who have progressed on standard 
chemotherapy, treatment with either TAS-102 or regorafenib in chemotherapy-
refractory patients results in median PFS of approximately 2 months and 6-month 
PFS of approximately 17%.  With 21 evaluable subjects, we will have 81% power 
to reject a 6-month PFS of 17% (H0) versus 40%, assuming exponential 
survivorship and using a two-sided binomial alpha = 0.10. 
 
Toxicity rates will be calculated by category with 95% confidence intervals.  We 
will also utilize a Bayesian toxicity monitoriung plan, and estimate the posterior 
probability that the rate of treatment discontinuation due to toxicity exceeds 30%.  
ORR, PFS and DOR will be assessed by both RECIST v. 1.1 and iRECIST and 
calculated with 90% confidence intervals.  Kaplan Meier methods will be used to 
estimate the survival curves for PFS and OS.  Median PFS, OS, and DOR will be 
calculated with 90% confidence intervals.  If progression is confirmed by imaging 
(iCPD) or clinically (iUPD without follow-up imaging), the date of initial 
progression on imaging (iUPD) will be used. 
 
 
 


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Table of Contents 
0.0 
Study Summary ...............................................................................................................................................2 
1.0 
Objectives .......................................................................................................................................................6 
2.0 
Background .....................................................................................................................................................6 
3.0 
Study Design ...................................................................................................................................................8 
4.0 
Study Population ............................................................................................................................................9 
5.0 
Treatment Plan ............................................................................................................................................ 11 
6.0 
Dosing Delays/Dose Modifications .............................................................................................................. 12 
7.0 
Study Procedures ......................................................................................................................................... 12 
8.0 
Study Treatment Details .............................................................................................................................. 13 
9.0 
Statistical Plan ............................................................................................................................................. 17 
10.0 
Safety and Adverse Events .......................................................................................................................... 19 
11.0 
Data Handling and Record Keeping ............................................................................................................. 26 
12.0 
Study Monitoring, Auditing, and Inspecting ................................................................................................ 27 
13.0 
Ethical Considerations ................................................................................................................................. 27 
14.0 
Study Finances ............................................................................................................................................. 28 
15.0 
Publication Plan ........................................................................................................................................... 28 
16.0 
References ................................................................................................................................................... 28 
17.0 
Schedule of Events ...................................................................................................................................... 30 
Appendix A: Definition of Non-Childbearing Potential and Medically Acceptable Methods of Birth Control ....... 32 
Appendix B: Management Algorithms for Nivolumab and Ipilimumab .................................................................. 33 
Appendix C:   RECIST 1.1 Criteria ............................................................................................................................. 41 
Appendix D:  Immune-Related Response in Measurable Lesions (iRECIST) ............................................................ 43 
 
 
 


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1.0 Objectives 
1.1 Primary Objective  
To determine six-month progression-free survival by iRECIST 
1.2 Secondary Objectives   
1. To determine overall response rate, duration of response, and progression-free survival by iRECIST and 
RECIST 1.1.  To determine overall survival. 
 
2. To determine the toxicity rates by CTCAE v 5.0 
 
1.3 Exploratory Objectives 
1. To measure T-cell subsets and markers of T-cell function in peripheral blood as a potential biomarker of 
response 
 
2. To define the immune effects in pre- and post-treatment biopsy specimens with analysis of tumor-infiltrating 
lymphocytes, including immune subsets, mutational load, and TCR sequencing 
 
3. To correlate imaging response with quantitative changes in cell-free tumor DNA, extracellular vesicles, and/or 
other circulating tumor materials 
 
2.0 Background 
2.1 Mucinous Colorectal and Appendiceal Adenocarcinoma 
Mucinous histology is found in about 15% of colorectal adenocarcinoma, and a higher proportion of appendiceal 
adenocarcinomas, and connotes a poor prognosis in the metastatic setting, with shorter progression-free and overall 
survival and decreased responsiveness to chemotherapy [1,2].  Despite this unfavorable phenotype, a highly select 
subset of patients with peritoneal-only disease can achieve long-term disease control with aggressive surgical 
management using cytoreductive surgery (CRS) in combination with heated intraperitoneal chemotherapy (HIPEC) 
[3].  We hypothesize that the mechanism through which HIPEC results in long-term disease control is not direct 
cytotoxicity but rather immune activation against mucinous tumor antigens.  This immune activation has been 
demonstrated in a “HIPEC-vaccine” murine model, with subsequent immune rejection of distant tumor injections 
after HIPEC [4]. 
The mutational landscape of mucinous adenocarcinomas is poorly-described, as samples are frequently 
paucicellular, but increasing data shows that they are genetically distinct from non-mucinous colorectal cancers [5, 
6].  More importantly, mucinous tumors have increased expression of extracellular proteins such as modified mucins 
that can be highly immunogenic [7].  Only recently have sequencing tools been developed to characterize the 
immunogenicity of these carbohydrate antigens [8], although a variety of vaccine and engineered T-cell studies 
have shown these mucins to be targetable by the immune system [9, 10].  In ovarian tumors, immunopeptidomic 
profiling found that MUC16 was by far the most immunogenic of more than 1,100 tumor-specific antigens, eliciting 
a T-cell response in 80% of healthy blood donors [11].  Recently, PD-1 has also been shown to play a major role in 


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suppressing immunity against Tn and other tumor-associated carbohydrate antigens [12].  No study has yet been 
conducted to evaluate checkpoint blockade in this specific subset of colorectal cancer.  This will be a phase II study 
to determine the efficacy of combination checkpoint blockade nivolumab and ipilimumab in peritoneal-only 
mucinous colorectal and appendiceal adenocarcinoma. 
2.2 Nivolumab Mechanism of Action 
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes CD28, CTLA 4, ICOS, 
and BTLA.  PD-1 signaling has been shown to inhibit CD-28-mediated upregulation of IL-2, IL-10, IL-13, 
interferon-γ (IFN-γ) and Bcl-xL. PD-1 expression also been noted to inhibit T cell activation, and expansion of 
previously activated cells. Evidence for a negative regulatory role of PD-1 comes from studies of PD-1 deficient 
mice, which develop a variety of autoimmune phenotypes.  These results suggest that PD-1 blockade has the 
potential to activate anti-self T-cell responses, but these responses are variable and dependent upon various host 
genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of tolerance to self-
antigens. 
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and inhibits the binding 
of PD-1 to its ligands PD-L1 and PD-L2 (IC50 + 1 nM). Nivolumab binds specifically to PD-1 and not to related 
members of the CD28 family such as CD28, ICOS, CTLA-4 and BTLA. Blockade of the PD-1 pathway by 
nivolumab results in a reproducible enhancement of both proliferation and IFN-γ release in the mixed lymphocyte 
reaction (MLR). In vivo blockade of PD-1 by a murine analog of nivolumab enhances the anti-tumor immune 
response and result in tumor rejection in several immunocompetent mouse tumor models (MC38, SA1/N, and 
PAN02).  Clinical efficacy has been demonstrated in a variety of tumor types, and it is currently FDA approved for 
the treatment of melanoma, non-small cell lung cancer, Hodgkin’s lymphoma, renal cell carcinoma, squamous cell 
carcinoma of the head and neck, urothelial carcinoma, microsatellite instability-high tumors, and hepatocellular 
carcinoma. 
2.3 Ipilimumab Mechanism of Action  
CTLA-4, an activation-induced T-cell surface molecule, is a member of the CD28:B7 immunoglobulin superfamily 
that competes with CD28 for B7. CTLA-4 mediated signals are inhibitory and turn off T cell-dependent immune 
responses.  Ipilimumab is a fully human monoclonal IgG1κ that binds to the CTLA-4 antigen expressed on a subset 
of T cells from human and nonhuman primates. The proposed mechanism of action for ipilimumab is interference 
of the interaction of CTLA-4 with B7 molecules on APCs, with subsequent blockade of the inhibitory modulation 
of T-cell activation promoted by the CTLA 4/B7 interaction.  It is currently FDA approved for the treatment of 
melanoma. 
2.4 Rationale for Adding Ipilimumab to Nivolumab 
Preclinical and clinical evidence suggests synergy between nivolumab and ipilimumab, which target distinct 
mechanisms to limit T cell activation, PD-1 and CTLA-4 respectively.  In vitro combinations of nivolumab plus 
ipilimumab increase IFN-γ production 2- to 7-fold over either agent alone in a mixed lymphocyte reaction. In a 
murine melanoma vaccine model, blockade with either CTLA-4 or PD-1 antibodies increased the proportion of 
CTLA-4 and PD-1-expressing CD4/CD8 tumor infiltrating T effector cells, and dual blockade increased tumor 
infiltration of T effector cells and decreased intratumoral T regulatory cells, as compared to either agent alone.  The 
combination of nivolumab and ipilimumab has been shown to be more effective than either agent in monotherapy 


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in the treatment of a variety of tumors including melanoma, lung, renal cell carcinoma, and MSI-high colorectal 
cancer. 
2.5 Safety of Nivolumab and Ipilimumab 
The combination of nivolumab and ipilimumab has the potential for increased frequencies of AEs compared to 
ipilimumab monotherapy or nivolumab monotherapy.  The toxicity profile of the nivolumab + ipilimumab 
combination has been shown to correlate with the ipilimumab dose: with increasing doses of ipilimumab, there has 
been an increase in frequency of AEs and, potentially, the severity of these events; however, no novel toxicities 
have been demonstrated versus either agent alone.  In the current regimen for this protocol, the dose of ipilimumab 
will be cumulatively lower than the approved dose level for the combination for the treatment of advanced and 
metastatic melanoma. The toxicity profile with lower doses of ipilimumab has been established to be very similar 
to that of nivolumab monotherapy as detailed below in section 2.6. 
The most common (reported at > 10% incidence) treatment related AEs with the combination are fatigue, rash, 
pruritus, diarrhea, lipase increased, pyrexia, ALT increase, AST increased, amylase increased and vitiligo. These 
classes of AEs are expected for the combination of nivolumab and ipilimumab based on the known AE profile of 
each drug alone. In addition, many of the Grade 3-4 AEs are laboratory in nature (ie, LFTs, lipase, amylase), occur 
without clinical sequelae, and are been manageable and reversible following intervention dose delays or with 
systemic steroid treatment. However, immune AEs have the potential to be fatal if not detected early and managed 
per the established algorithm, and fatal AEs have been reported for both ipilimumab and nivolumab monotherapy. 
Adverse drug reactions with fatal outcome in clinical trial participants treated with nivolumab monotherapy and 
nivolumab and ipilimumab combination therapy are listed in the current version of the nivolumab investigator 
brochure (IB). 
A pattern of immune-related AEs has been defined, for which management algorithms have been developed; these 
are provided in Appendix B. Most high-grade events are manageable with the use of corticosteroids or hormone 
replacement therapy (endocrinopathies) as instructed in these algorithms. 
2.6 Rationale for Dose Selections 
The nivolumab doses of 480 mg Q4W was selected for this study based on clinical pharmacokinetic data and 
modeling showing similar drug exposure and no change in safety compared to dosing every 2 weeks using either 
weight-based (3mg/kg) or flat dose (240mg) regimens [13].  In the CA209012 study in non-small cell lung cancer, 
ipilimumab 1 mg/kg using Q6W and Q12W schedules were assessed and were found to be safe in combination with 
nivolumab 3 mg/kg Q2W. Both the Q6W and Q12W arms were associated with improved and manageable 
tolerability compared to the arms with more frequent ipilimumab dosing (Q3W). Both arms also had encouraging 
efficacy in all participants and enhanced benefit in participants with PD-L1 expression, with Q6W arm having 
numerically higher median PFS compared to the Q12W arm. There were some imbalances observed between the 
Q6W and Q12W arms, as follows.  With both schedules showing a similar safety and efficacy profile, a Q8W 
schedule was chosen to align with nivolumab dosing and maintain expected safety and efficacy. 
3.0 Study Design 
This is a single-arm phase II study of twenty-one subjects with mucinous adenocarcinoma of the colon, rectum, or 
appendix with prior systemic therapy with a fluoropyrimidine, oxaliplatin, and irinotecan.  Treatment will consist 


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of nivolumab 480mg every 4 weeks and ipilimumab 1mg/kg every 8 weeks until disease progression, unacceptable 
toxicity, or 2 years of therapy.  Imaging assessments will be conducted every 8 weeks (+/-2 weeks).  If progression 
is noted on imaging in the setting of clinical stability, subjects may remain on study and have confirmatory imaging 
in 4-8 weeks per iRECIST criteria. 
 
4.0 Study Population 
4.1 Inclusion Criteria   
1. Subjects must have signed and dated an IRB-approved written informed consent form prior to the 
performance of any protocol-related procedures that are not part of standard care. 
2. Colorectal or appendiceal mucinous adenocarcinoma with peritoneal-only metastatic disease. It is recognized 
that in some patients, peritoneal disease will predominate without distinction of the site of origin, and such 
patients will be eligible. 
3. Microsatellite stable by PCR and/or mismatch repair proficient by immunohistochemistry 
4. ECOG performance status of 0 or 1 
5. Prior therapy with a fluoropyrimidine, oxaliplatin, and irinotecan unless contraindicated or refused.  Prior 
treatment with antiangiogenic and/or anti-EGFR antibody therapy is permitted but not required 
6. Measurable disease by RECIST v. 1.1 
7. Laboratory parameters (within 14 days prior to the start of treatment): 
a. Absolute neutrophil count > 1500/μL 
b. Platelets > 100,000/μL 
c. Hemoglobin > 9.0 g/dL 
d. PT/INR or PTT < 1.5xULN 
e. Creatinine < 1.5xULN OR creatinine clearance > 50 mL/min by Cockcroft-Gault formula 
f. Total bilirubin < 1.5xULN 
i. Subjects with Gilbert’s Syndrome must have a total bilirubin level of < 3.0xULN 
g. Albumin > 3.0 g/dL 
h. AST and/or ALT: < 3.0×ULN 
8. Subjects with HIV are permitted provided they meet the following criteria: 
a. CD4+ cell count > 250 cells/mm3 
b. No history of AIDS-defining conditions other than low CD4+ count 
c. If subject is on antiretroviral therapy, there must not be expected significant drug-drug interactions 
with study treatment 
 
4.2 Exclusion Criteria 
1. Bowel obstruction within the past 60 days 


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2. Subjects who are currently pregnant, planning to become pregnant, or breast-feeding.  
a. Females participants of child-bearing potential are required to use an effective contraception method 
(see Appendix A) or abstain from intercourse during treatment and for at least 5 months following the 
last dose 
b. Males participants with partners of child-bearing potential are required to use an effective 
contraception method (see Appendix A) or abstain from intercourse during treatment and for at least 
7 months following the last dose 
3. Subjects who, in the opinion of the physician, would not be clinically appropriate for receipt of the therapy 
regimen associated with participation 
4. Subjects with contraindications to immune checkpoint therapy, as follows: 
a. Interstitial lung disease that is symptomatic or may interfere with the detection and management 
of suspected drug-related pulmonary toxicity 
b. Prior organ allograft or allogeneic bone marrow transplantation 
c. Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal 
range with medication 
d. Active autoimmune disease, except for vitiligo, type 1 diabetes mellitus, asthma, atopic 
dermatitis, or endocrinopathies manageable by hormone replacement; other autoimmune 
conditions may be allowable at the discretion of the principal investigator 
e. Condition requiring systemic treatment with corticosteroids 
 
Systemic steroids at physiologic doses (equivalent to dose of oral prednisone 10 mg) are 
permitted. 
 
Intranasal, inhaled, topical, intra-articular, and ocular corticosteroids with minimal 
systemic absorption are permitted. 
5. Established non-peritoneal metastatic disease, including but not limited to metastases to the liver, lung, brain, 
extra-abdominal lymph nodes, and bone 
6. A second primary malignancy that, in the judgment of the investigator, may affect interpretation of results 
7. Prior treatment with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody 
8. Toxicities attributed to prior anti-cancer therapy other than alopecia, fatigue, and peripheral neuropathy must 
have resolved to Grade 1 or baseline before administration of study drug.  In addition, a washout period will 
be required for prior therapies as specified:  
a. No chemotherapy within 14 days prior to first dose 
b. No investigational product(s) (IPs) and/or biologic therapy within 28 days or 5 half-lives, whichever 
is longer, prior to first dose 
c. No major surgery within 28 days prior to first dose. Any surgery-related AE(s) must have resolved at 
least 14 days prior to first dose.   
d. No radiation therapy with curative intent within 28 days prior to first dose.  Prior focal palliative 
radiotherapy must have been completed at least 14 days prior to first dose. 
9. Active hepatitis B or hepatitis C, defined as the following: 
a. Hepatitis B surface antigen positive or HBV DNA PCR >100 IU/mL 
b. Hepatitis C antibody positive unless HCV RNA PCR is negative (i.e. undetectable viral load) 
10. Prisoners or participants who are involuntarily incarcerated. (Note: under specific circumstances a person who 
has been imprisoned may be included as a participant. Strict conditions apply and BMS approval is required.) 
11. Participants who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious 
disease) illness 
 


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4.3 Withdrawal, Removal, Evaluability and Replacement of Subjects 
Subjects may withdraw from the study at any time at their own request in which case investigators will seek 
permission from such subjects for investigators to continue to contact them every 6 months for follow-up; however, 
subjects may choose to withdraw completely from all procedures and follow-up.  Subjects may also be withdrawn 
at any time at the discretion of the Investigator for safety, behavioral, or administrative reasons.  If a subject does 
not return for a scheduled visit, every effort should be made to contact the subject.  In any circumstance, every 
effort should be made to document the subject outcome, if possible.  The Investigator should inquire about the 
reason for withdrawal, and request the subject to return for a final visit and follow-up regarding any unresolved 
AEs.  If the subject withdraws from the study and also withdraws consent for disclosure of future information, no 
further evaluations should be performed and no additional data should be collected.  The Sponsor may retain and 
continue to use any data collected before such withdrawal of consent. 
An individual subject will not receive any further study drug if any of the following occur in the subject in question: 
 
Progressive Disease by iRECIST (See Appendix C) 
 
Complete Withdrawal of consent from the study (no further data collection permitted) 
 
Withdrawal of consent from further treatment with study drug (data collection as per study 
schedule permitted) 
 
Lost to Follow up 
 
An AE that, in the opinion of the Investigator or the Sponsor, contraindicates further 
dosing including but not limited to hypersensitivity to any of the therapeutic agents 
 
Pregnancy or intent to become pregnant 
 
Subject Non-Compliance that, in the opinion of the investigator warrants withdrawal (e.g., 
refusal to adhere to the scheduled visits) 
 
Initiation of another anti-cancer therapy (excluding surgery or palliative radiotherapy), 
including another investigational agent 
 
4.3.1 Evaluability and Replacement of subjects 
Subjects will be evaluable for toxicity if they receive at least one dose of either nivolumab or ipilimumab.  Subjects 
will be evaluable for efficacy if they receive at least one dose of nivolumab and one dose of ipilimumab and undergo 
repeat imaging at least 4 weeks and no more than 12 weeks after initiating therapy on study.  Subjects who do not 
meet the criteria for evaluability for efficacy will be replaced. 
5.0 Treatment Plan 
Treatment will consist of nivolumab 480mg every 4 weeks and ipilimumab 1mg/kg every 8 weeks.  Imaging 
assessments will be conducted every 8 weeks (+/-2 weeks) for the first 24 weeks then every 8-12 weeks (+/-2 
weeks).  If progression is noted on imaging in the setting of clinical stability, subjects may remain on study and 
have confirmatory imaging in 4-8 weeks per iRECIST criteria (see Appendix C) 
Table 1: Treatment Plan 


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Agent 
Dose 
Route 
Frequency (within a 56-
day cycle) 
Nivolumab 
480mg 
IV infusion per 
institutional guidelines 
and the Package Insert  
Days 1, 29 
Ipilimumab 
1mg/kg 
IV infusion per 
institutional guidelines 
and the Package Insert 
Day 1 
 
5.1 Duration of Treatment 
Subjects will continue on therapy until disease progression, unacceptable toxicity, withdrawal of consent, or two 
years of therapy.  Subjects may remain on either ipilimumab or nivolumab monotherapy if the other agent is 
discontinued such as for toxicity. 
6.0 Dosing Delays/Dose Modifications 
The potential immune toxicities of nivolumab and ipilimumab are numerous, and no set of guidelines can account 
for all possible scenarios.  Ultimately, subjects who experience toxicity related to nivolumab and/or ipilimumab 
will be managed according to standard clinical practice at the discretion of the treatment clinician, including the 
administration of corticosteroids.   The toxicities for nivolumab and ipilimumab overlap considerably and it is 
uncommon that a toxicity be clearly attributed to only one of the agents. 
Treatment algorithms for immune-related adverse events are provided in Appendix B for guidance.  No dose 
modifications for nivolumab or ipilimumab are allowed.  Specific dose delays and the use of corticosteroids for 
toxicity is ultimately at the discretion of the treating physician.  
At the end of the study period, Bristol-Myers Squibb Company will not continue to supply study drug to 
subjects/investigators unless the Sponsor chooses to extend their study.  The investigator is responsible to ensure 
that the subject receives appropriate standard of care or other appropriate treatment in the independent medical 
judgement of the investigator to treat the condition under study. 
7.0 Study Procedures 
Study procedures are further detailed in section 17.0 (Schedule of Events). 
7.1 Tumor Analysis and Correlative Studies 
7.1.1 Tumor Biopsy 
Pre-treatment tissue biopsy is mandatory.  Archival material cannot be substituted for the pre-treatment biopsy.  
Subjects in whom pre-treatment biopsy cannot be safely performed require approval of the Principal Investigator 
to enroll.  On-treatment biopsies will be performed on cycle 1 between days 10-14 where safe and feasible, and we 
expect that this will be in the majority of patients.  Testing of these samples may include studies of infiltrating T-


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cells such as subtyping, functional assays and receptor sequencing, whole exome or other genomic sequencing of 
the tumor, immunohistochemistry, and/or other assays that may be developed over the course of this study.  Optional 
biopsies will be requested if a patient undergoes surgery that would permit tumor sampling such as laparoscopy and 
at disease progression.  Procedures for tumor biopsy processing is described in detail in the laboratory manual. 
7.1.2 Research Blood Sampling 
Sixty mL total of blood in EDTA tubes for circulating tumor materials (circulating tumor cells, extracellular 
vesicles, and/or cell-free DNA) and peripheral blood mononuclear cells (PBMCs) will be collected at baseline prior 
to cycle 1 day 1 treatment on the same day as baseline biopsy (or within 3 days if not possible to perform same 
day), on cycle 1 between days 10-14 (same day as research biopsy if repeat biopsy performed), cycle 1 day 29, on 
day 1 of each subsequent cycle prior to treatment, and at the end of treatment visit.  
A one-time 5mL sample in an EDTA tube will be drawn during screening, or, if not previously obtained, at a later 
treatment visit for storage of PBMCs for future germline sequencing with the Nathanson lab. 
Procedures for research laboratory samples and processing is described in detail in the laboratory manual. 
7.2 Assessment of Laboratory Measures and Disease Progression 
7.2.1 Laboratory Safety Monitoring 
CBC with differential will be assessed at screening, on days 1 and 29 of each treatment cycle, and at the end of 
treatment visit.  Serum pregnancy will be assessed for women of childbearing potential at screening and every 4 
weeks.  Non-childbearing potential is defined in Appendix A.  Serum chemistry labs will be assessed at screening, 
on days 1 and 29 of each treatment, and at the end of treatment visit.  Serum TSH will be assessed at screening, on 
day 1 of cycle 2 and all subsequent cycles, and at the end of treatment visit. 
For all laboratory measures, a window of +/- 3 days is acceptable. 
7.2.2 Imaging Assessments 
CT/MRI will be performed for disease assessment at screening (within 21 days of first doses of study drugs) and 
every 8 weeks (+/- 2 weeks).  If progression is noted on imaging in the setting of clinical stability, subjects may 
remain on study and have confirmatory imaging in 4-8 weeks per iRECIST criteria.  PET-CT is an acceptable 
substitute for CT/MRI if determined to be the standard of care by the treating physician. 
7.3 Duration of Follow-Up 
For this protocol, all subjects, including those who discontinue protocol therapy early, will be followed through 
review of the medical record for recurrence and survival for up to 3 years from their end of study visit (every 6 
months for the first year, then annually for the second two years).   
8.0 Study Treatment Details 
8.1  Nivolumab 
8.1.1 Other Names 


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Opdivo 
8.1.2 Classification 
Nivolumab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that targets programmed cell death-
1 (PD-1). 
8.1.3 Mechanism of Action 
Nivolumab selectively inhibits PD-1 activity by binding to the PD-1 receptor to block the ligands PD-L1 and PD-
L2 from binding. The negative PD-1 receptor signaling that regulates T-cell activation and proliferation is therefore 
disrupted.  This releases PD-1 pathway-mediated inhibition of the immune response, including the antitumor 
immune response. 
8.1.4 Storage and Stability 
The product does not contain a preservative.  After preparation, store the nivolumab infusion either at room 
temperature for no more than 8 hours from the time of preparation (this includes room temperature storage of the 
infusion in the IV container and time for administration of the infusion) or under refrigeration at 2°C to 8°C (36°F 
to 46°F) for no more than 24 hours from the time of infusion preparation.  Do not freeze. 
8.1.5 Dose Specifics 
480 mg IV over 30 minutes every 4 weeks 
8.1.6 Preparation 
Visually inspect drug product solution for particulate matter and discoloration prior to administration.  Nivolumab 
[Opdivo] is a clear to opalescent, colorless to pale-yellow solution.  Discard the vial if the solution is cloudy, 
discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles. 
Do not shake the vial. 
Withdraw the required volume of nivolumab [Opdivo] and transfer into an intravenous container.  Dilute nivolumab 
[Opdivo] with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare an infusion 
with a final concentration ranging from 1 mg/mL to 10 mg/mL.  Mix diluted solution by gentle inversion.  Do not 
shake.  Discard partially used vials or empty vials of OPDIVO. 
8.1.7 Administration 
Administer the infusion over 30 minutes or per institutional guidelines through an intravenous line containing a 
sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer).  Do not 
coadminister other drugs through the same intravenous line.  Flush the intravenous line at end of infusion. 
8.1.8 Availability 
Nivolumab [Opdivo] is commercially available as a 40 mg/4 mL (10 mg/mL) and 100 mg/10 mL (10 mg/mL) 
solution in a single-dose vial.  Only 100mg vials will be provided for this study. 
8.1.9 Side Effects 


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 
Cardiovascular: Edema, peripheral edema, ventricular arrhythmia, pulmonary embolism, vasculitis 
 
Central nervous system: Fatigue, headache, peripheral neuropathy, peripheral sensory neuropathy, 
dizziness, peroneal nerve palsy, motor dysfunction, migraine, myasthenia, encephalitis, facial paralysis, 
Guillain-Barré syndrome, neuropathy 
 
Dermatologic: Skin rash, pruritis, vitiligo, exfoliative dermatitis, erythema, erythema multiforme, 
psoriasis, urticarial, palmar-plantar erythrodysesthesia 
 
Endocrine and metabolic: Hyponatremia, increased serum triglycerides, hyperkalemia, increased thyroid 
stimulating hormone level, hypocalcemia, increased serum cholesterol, hypercalcemia, hypothyroidism, 
hypomagnesemia, hypokalemia, hyperglycemia, hyperthyroidism, adrenocortical insufficiency, diabetes 
mellitus, diabetic ketoacidosis, weight loss, hypophysitis, pituitary insufficiency 
 
Gastrointestinal: Diarrhea, colitis, decreased appetite, increased serum lipase, nausea, constipation, 
vomiting, increased serum amylase, abdominal pain, duodenitis, gastritis, pancreatitis 
 
Hematologic: Lymphocytopenia, anemia, neutropenia, thrombocytopenia 
 
Hepatic: Increased serum AST, increased serum ALT, increased serum alkaline phosphatase, increased 
serum bilirubin, hepatitis, hepatic failure 
 
Immunologic: Antibody development 
 
Neuromuscular and skeletal: Weakness, musculoskeletal pain, back pain, arthralgia, spondyloarthropathy, 
limb pain, polymyalgia rheumatica 
 
Renal: Increased serum creatinine, renal disease, nephritis, renal insufficiency 
 
Respiratory: Upper respiratory tract infection, productive cough, cough, dyspnea, dyspnea on exertion, 
bronchopneumonia, pneumonia, pleural effusion, pneumonitis, respiratory failure, pneumonia due to 
Pneumocystis jiroveci 
 
Ophthalmic: Iridocyclitis, iritis 
 
Miscellaneous: Fever, infusion related reactions, hypersensitivity reaction, sarcoidosis 
 
8.2 Ipilimumab 
8.2.1 Other Names 
Yervoy 
8.2.2 Classification 
Ipilimumab is a recombinant human IgG1 immunoglobulin monoclonal antibody that binds to the cytotoxic T-
lymphocyte associated antigen 4 (CTLA-4) 
8.2.3 Mechanism of Action 
CTLA-4 is a down-regulator of T-cell activation pathways. Blocking CTLA-4 allows for enhanced T-cell activation 
and proliferation. In melanoma, ipilimumab may indirectly mediate T-cell immune responses against tumors. 
Combining ipilimumab (anti-CTLA-4) with nivolumab (anti-PD-1) results in enhanced T-cell function that is 
greater than that of either antibody alone, resulting in improved antitumor responses in metastatic melanoma. 


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8.2.4 Storage and Stability 
The product does not contain a preservative.  Store ipilimumab under refrigeration at 2°C to 8°C (36°F to 46°F).  
Do not freeze.  Protect vials from light. 
8.2.5 Dose Specifics 
1mg/kg IV every 8 weeks 
8.2.6 Preparation 
Visually inspect drug product solution for particulate matter and discoloration prior to administration.  Solution 
may have a pale yellow color.  Discard the vial if the solution is cloudy, discolored, or contains extraneous 
particulate matter other than a few translucent-to-white, proteinaceous particles.  Do not shake the vial. 
Allow the vials to stand at room temperature for approximately 5 minutes prior to preparation of infusion.  Withdraw 
the required volume of ipilimumab [Yervoy] and transfer into an intravenous bag.  Dilute ipilimimab [Yervoy] with 
either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare an infusion with a final 
concentration ranging from 1 mg/mL to 2 mg/mL.  Mix diluted solution by gentle inversion.  Store the diluted 
solution for no more than 24 hours under refrigeration (2°C to 8°C, 36°F to 46°F) or at room temperature.  Do not 
shake.  Discard partially used vials or empty vials of ipilimumab [Yervpy]. 
8.2.7 Administration 
Administer the infusion over 30 minutes or per institutional guidelines through an intravenous line containing a 
sterile, non-pyrogenic, low protein binding in-line filter.  Do not coadminister other drugs through the same 
intravenous line.  Flush the intravenous line at end of infusion. 
8.2.8 Availability 
Ipilimumab [Yervoy] is commercially available as a 50 mg/10 mL (5 mg/mL) and 200 mg/40 mL (5 mg/mL) 
solution in a single-dose vial.  Only 200mg vials will be provided for this study 
8.2.9 Side Effects 
 
Cardiovascular: Edema, peripheral edema, ventricular arrhythmia, pulmonary embolism, vasculitis 
 
Central nervous system: Fatigue, headache, peripheral neuropathy, peripheral sensory neuropathy, 
dizziness, peroneal nerve palsy, motor dysfunction, migraine, myasthenia, encephalitis, facial paralysis, 
Guillain-Barré syndrome, neuropathy 
 
Dermatologic: Skin rash, pruritis, vitiligo, exfoliative dermatitis, erythema, erythema multiforme, 
psoriasis, urticarial, palmar-plantar erythrodysesthesia 
 
Endocrine and metabolic: Hyponatremia, increased serum triglycerides, hyperkalemia, increased thyroid 
stimulating hormone level, hypocalcemia, increased serum cholesterol, hypercalcemia, hypothyroidism, 
hypomagnesemia, hypokalemia, hyperglycemia, hyperthyroidism, adrenocortical insufficiency, diabetes 
mellitus, diabetic ketoacidosis, weight loss, hypophysitis, pituitary insufficiency 
 
Gastrointestinal: Diarrhea, colitis, decreased appetite, increased serum lipase, nausea, constipation, 
vomiting, increased serum amylase, abdominal pain, duodenitis, gastritis, pancreatitis 


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 
Hematologic: Lymphocytopenia, anemia, neutropenia, thrombocytopenia 
 
Hepatic: Increased serum AST, increased serum ALT, increased serum alkaline phosphatase, increased 
serum bilirubin, hepatitis, hepatic failure 
 
Immunologic: Antibody development 
 
Neuromuscular and skeletal: Weakness, musculoskeletal pain, back pain, arthralgia, spondyloarthropathy, 
limb pain, polymyalgia rheumatica 
 
Renal: Increased serum creatinine, renal disease, nephritis, renal insufficiency 
 
Respiratory: Upper respiratory tract infection, productive cough, cough, dyspnea, dyspnea on exertion, 
bronchopneumonia, pneumonia, pleural effusion, pneumonitis, respiratory failure, pneumonia due to 
Pneumocystis jiroveci 
 
Ophthalmic: Iridocyclitis, iritis 
 
Miscellaneous: Fever, infusion related reactions, hypersensitivity reaction, sarcoidosis 
 
9.0 Statistical Plan 
9.1 Endpoints 
9.1.1  Primary Endpoint:  Progression-Free Survival at 6 Months 
Progression-free survival at 6 months (PFS6) is defined as the proportion of patients free from disease progression 
by iRECIST crieteria (see Appendix D) or death at the time of week 24 restaging imaging (within acceptable 2 
week window).  Subjects who withdraw from the study prior to week 24 imaging will be considered to have 
progressed unless imaging is obtained at or after 24 weeks (within acceptable 2-week window), no progression is 
observed, and the subject has not initiated any other anti-cancer therapy prior to 6-month imaging.  The final efficacy 
analysis will not be performed until all subjects have experienced progression or death, initiated additional anti-
cancer therapy prior to 6 months from the start of study therapy (which will be considered progression), been lost 
to follow-up, or undergone at least six months of follow-up. 
9.1.2  Secondary Endpoints 
9.1.2.1  Progression-Free Survival 
Progression-free survival is defined as the duration of time from start of treatment to time of progression, death, or 
last patient contact when progression-free. PFS will be calculated using both RECIST v. 1.1 (Appendix C) and 
iRECIST (Appendix D).  For patients who are progression-free, PFS will be censored at the most recent date which 
documents progression-free status (i.e., scan date or clinical visit date). 
9.1.2.2  Overall Survival 
Overall survival (OS) is defined as the duration of time from start of treatment to death due to any cause or last 
patient contact alive. Public records (e.g. obituaries) may be used to ascertain dates of death for subjects where such 
data is not available in the medical record unless the subject withdraws consent for follow-up.  For subjects who 
enroll in hospice care in whom the specific date of death cannot be determined, date of death will be recorded as 
the date the patient entered hospice.  In subjects who are alive or lost to follow-up, OS will be censored at last date 
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9.1.2.3 Overall Response Rate 
The overall response rate is determined by iRECIST (Appendix D) and RECIST v1.1 (Appendix C). Criteria 
definitions of CR and PR and is defined as the percentage of individuals on study attaining a CR or PR. 
9.1.2.4 Duration of Response 
Duration of Overall Response: The duration of overall response is measured from the time measurement criteria are 
met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements recorded since the treatment 
started).  
The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date 
that progressive disease is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline 
measurements. 
9.1.2.5  Safety Analysis 
Safety analysis will be performed on the safety – evaluable population, defined as all enrolled subjects who received 
at least one dose of study treatment. Summaries of AEs, SAEs, deaths, changes in laboratory test results, vital signs 
and exposure to study drug will be presented. Drug exposure will be summarized to include treatment duration, 
number of doses and dose intensity. Laboratory data with values outside reference ranges will be summarized by 
NCI-CTCAE v 5.0 grades. 
We will conduct a Bayesian toxicity monitoring plan every 3 patients with a target discontinuation rate due to 
toxicity of 30%.  We assume a Beta(1,2) prior, equivalent to one discontinutation of treatment (both ipilimumab 
and nivolumab) due to toxicity in 3 treated patients.  Early study termination for toxicity will be considered based 
on a posterior probability that the rate of treatment discontinuation due to toxicity exceeds 30%.  Early termination 
will be considered if treatment discontinuation due to toxicity occurs in 2 of 3 patients (0.84 posterior probability), 
3 of 6 patients (0.81), 4 of 9 patients (0.79), 5 of 12 patients (0.78), or 6 of 15 patients (0.78).   
9.2 Sample Size Determination and Methods 
For patients with colorectal adenocarcinoma who have progressed on standard chemotherapy, treatment with either 
TAS-102 or regorafenib in chemotherapy-refractory patients results in median PFS of approximately 2 months and 
6-month PFS of approximately 17%.  In phase III trials of nivolumab in chemotherapy-refractory solid tumors (e.g. 
non-small cell lung cancer [15], urothelial carcinoma [16]) six-month PFS of 30-40% have correlated with an 
overall survival benefit, as many patients without progression by 6 months will have durable benefit.  We therefore 
would find a 6-month progression-free-survival of 40% to be highly promising in this study population.  With 21 
evaluable subjects, we will have 81% power to reject a 6-month PFS of 17% (H0) versus 40%, assuming exponential 
survivorship and using a two sided binomial test with alpha  = 0.10. 
 
The primary endpoint of 6-month PFS will be assessed using iRECIST criteria to account for potential 
pseudoprogression (See Appendix D).  If progression is confirmed by imaging (iCPD) or clinically (iUPD without 


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follow-up imaging), the date of initial progression on imaging (iUPD) will be used.  ORR, PFS and DOR will be 
assessed by both RECIST v. 1.1 and iRECIST and calculated with 90% confidence intervals.  PFS at 6 months will 
be estimated as a crude rate with a 90% CI.  Kaplan Meier methods will be used to estimate the survival curves for 
PFS and OS.  ORR will be summarized as a binomial proportion.  Median PFS, OS, and DOR will be calculated 
with 90% confidence intervals. 
 
Analysis of T-cell function, TCR sequencing, and circulating tumor materials will be an exploratory and hypothesis-
generating analysis of potential biomarkers.  Immune assays in tissue and blood will seek to demonstrate immune 
activation, generate potential biomarkers to predict response and identify responding T-cell populations and their 
respective target(s).  Circulating tumor measurements will seek to improve upon measurability of response and 
generate potential genomic biomarkers of response.  Logistic regression will be used to evaluate any association of 
response status and PFS6 with marker, and markers will be summarized by response status and PFS6.  Cox 
regression will be used to test any association between a time-to-event outcome (PFS, OS) and marker expression. 
Other analyses will be descriptive. 
 
10.0 Safety and Adverse Events 
 
10.1 Definitions 
 
10.1.1 Unanticipated Problems Involving Risk to Subjects or others 
 
Any incident, experience, or outcome that meets all of the following criteria: 
 
Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such as the IRB-
approved protocol or consent form, the investigators brochure, etc)  
 
Related or possibly related to participation in the research (i.e. possibly related means there is a reasonable 
possibility that the incident experience, or outcome may have been caused by the procedures involved in 
the research)  
 
Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm).  
 
10.1.2 Adverse Event 
An adverse event (AE) is any unfavorable symptom, sign, illness or experience that occurs at any dose and develops 
or worsens in severity during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse 
events.  Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
 
results in study withdrawal 
 
is associated with a serious adverse event 
 
is associated with clinical signs or symptoms 
 
leads to additional treatment or to further diagnostic tests 
 
is considered by the investigator to be of clinical significance 
 
10.1.3 Adverse Events of Special Interest 


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AESIs (serious or non-serious) are defined as AEs of scientific and medical concern specific to the investigational 
product or program, for which ongoing monitoring and rapid communication by the Principal Investigator to drug 
manufacturer can be appropriate. Such an event might warrant further investigation in order to characterize and 
understand it. Depending on the nature of the event, rapid communication by the Principal Investigator to other 
parties (eg, regulators) might also be warranted. 
 
Details on currently agreed list of AESIs for investigational agents can be found in the current IB. These AESIs are 
to be reported to drug manufacturer expeditiously within 1 business day of knowledge of the event, during the study 
through 100 days after receiving the last dose of study treatment, according to the procedures below 
 
10.1.4 Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE, that is:  
 
fatal 
 
life-threatening 
 
requires or prolongs hospital stay 
 
results in persistent or significant disability or incapacity 
 
a congenital anomaly or birth defect 
 
an important medical event 
 
suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug is an 
SAE 
 
all occurrences of potential drug-induced liver injury (DILI), meeting the defined criteria below, must be 
reported as SAEs 
 
 
Potential drug induced liver injury is defined as:  
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase) 
AND 
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, including, but not 
limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the administration of other drug(s) 
known to be hepatotoxic. 
 
All Serious Adverse Events or pregnancies that occur following the subject’s written consent to participate in the 
study through 100 days of discontinuation of dosing must be reported to BMS Worldwide Safety, whether related 
or not related to study drug, within 1 business day of becoming aware of the event.  A Medwatch form will be used 
to report SAEs to BMS. 
 
All SAEs should be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
SAE Email Address: Worldwide.Safety@BMS.com 
 


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Important medical events are those that may not be immediately life threatening, but are clearly of major clinical 
significance.   They may jeopardize the subject, and may require intervention to prevent one of the other serious 
outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result in in-patient 
hospitalization, or intensive treatment of bronchospasm in an emergency department would typically be considered 
serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious adverse events.  
 
Events or Outcomes Not Qualifying as Serious Adverse Events 
The following are not considered SAEs and therefore do not need to be reported as such: 
 
Pre-planned or elective hospitalization including social and/ or convenience situations (eg, respite care) 
 
Hospital visits of less than 24 hours duration (eg, patient presents to the emergency room, but is not admitted 
to a ward)  
 
Overdose of study drugs or concomitant medication unless the event meets SAE criteria (eg, 
hospitalization). However, the event should still be captured as a nonserious AE 
 
Events of progression of the patient’s underlying cancer as well as events clearly related to progression of 
the patient’s cancer (signs and symptoms of progression) should not be reported as a serious adverse event 
unless the outcome is fatal within the safety reporting period. If the event has a fatal outcome within the 
safety reporting period, then the event of Progression of Disease must be recorded as an AE and as a SAE 
with CTC Grade 5 (fatal outcome) indicated. 
 
10.2 Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from the initiation 
of any study procedures to the end of the study treatment follow-up.  For this study, the study treatment follow-up 
is defined as 100 days following the last administration of study treatment.  
 
10.3 Preexisting Condition 
A preexisting condition is one that is present at the start of the study. A preexisting condition should be recorded as 
an AE if the frequency, intensity, or the character of the condition worsens during the study period 
 
10.4 General Physical Examination Finding  
At screening, any clinically significant abnormality should be recorded as a preexisting condition. At the end of the 
study, any new clinically significant findings/abnormalities that meet the definition of an AE must also be recorded 
and documented as an AE. 
 
10.5 Post-Study Adverse Event 
All unresolved AEs should be followed by the investigator until the events are resolved, the subject is lost to follow-
up, or the AE is otherwise explained. At the last scheduled visit, the investigator should instruct each subject to 
report any subsequent event(s) that the subject, or the subject’s personal physician, believes might reasonably be 
related to participation in this study. The investigator should notify the Principal Investigator of any death or AE 
occurring at any time after a subject has discontinued or terminated study participation that may reasonably be 
related to this study. The Principal Investigator should also be notified if the investigator should become aware of 
the development of cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has 
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10.6 Abnormal Laboratory Values 
 
An abnormal laboratory value that is not already associated with an AE is to be recorded as an AE only if any one 
of the following criteria is met: 
 
an action on the study drug is made as a result of the abnormality 
 
intervention for management of the abnormality is required 
 
at the discretion of the investigator should the abnormality be deemed clinically significant 
 
10.7 Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented and reported as an SAE 
unless specifically instructed otherwise in this protocol. Any condition responsible for surgery should be 
documented as an AE if the condition meets the criteria for an AE. 
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an AE in the following 
circumstances: 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a preexisting 
condition. Surgery should not be reported as an outcome of an AE if the purpose of the surgery was elective or 
diagnostic and the outcome was uneventful.  
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study.  
Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it is a worsening 
or increase in frequency of hospital admissions as judged by the clinical investigator.  
 
10.8 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by specific questioning 
and, as appropriate, by examination.  Information on all adverse events should be recorded immediately in the 
source document, and also in the appropriate adverse event module of the case report form (CRF).  All clearly 
related signs, symptoms, and abnormal diagnostic procedures results should recorded in the source document, 
though should be grouped under one diagnosis. All adverse events occurring during the study period must be 
recorded.  The clinical course of each event should be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause.  Serious adverse events that are still ongoing 
at the end of the study period must be followed up to determine the final outcome.  Any serious adverse event that 
occurs after the study period and is considered to be possibly related to the study treatment or study participation 
should be recorded and reported immediately. 
 
10.9 Stopping Rule for Adverse Events 
Bayesian toxicity monitoring with a target treatment discontinuation rate (both ipilimumab and nivolumab 
discontinued) of 30% will be implemented as outlined in the statistical plan.  If the posterior probability that the 
treatment discontinuation rate due to toxicity exceeds 30%, the Abramson Cancer Center Data Safety Monitoring 
Committee will be notified and may decide to terminate the study for toxicity.  
 
10.10 Reporting of Adverse Events  
Investigators must conform to the AE reporting timelines, formats and requirements of the various entities to which 
they are responsible, but at a minimum those events that must be reported are those that are: 


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 
Related to study participation, 
 
Unexpected, and 
 
Serious or involve risks to subjects or others  
 
If the AE meets institutional reporting citeria,  the event will be reported to their IRB. An event may qualify for 
expedited reporting to regulatory authorities if it is a suspected unexpected serious adverse reaction (SUSAR) in 
line with relevant regulations.  
 
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of the initial 
report includes:  
 
Study identifier 
 
Study center 
 
Subject number 
 
Investigational study product 
 
A description of the event 
 
Date of onset 
 
Current status 
 
Whether study treatment was discontinued 
 
The reason why the event is classified as serious 
 
Investigator assessment of the association between the event and study treatment. 
 
10.10.1 Investigator Reporting: Notifying Drug Manufacturer  
All SAEs, AESIs, and pregnancies, regardless of relationship to study drug, must be reported to the drug 
manufacturer during the study through 100 days after receiving the last dose of study treatment, according to the 
procedures below. After the specified window, only SAEs considered to be treatment related and all AESIs, 
regardless of treatment relationship, should be reported. It is important that the investigator provide an assessment 
of relationship of the SAE or AESI to study treatment at the time of the initial report. 
 
10.10.2 Investigator Reporting: Notifying the Penn IRB 
This section describes the requirements for safety reporting by investigators who are Penn faculty, affiliated with a 
Penn research site, or otherwise responsible for safety reporting to the Penn IRB. The University of Pennsylvania 
IRB (Penn IRB) requires expedited reporting of those events related to study participation that are unforeseen and 
indicate that participants or others are at increased risk of harm.  The Penn IRB will not acknowledge safety reports 
or bulk adverse event submissions that do not meet the criteria outlined below.  The Penn IRB requires researchers 
to submit reports of the following problems within 10 working days from the time the investigator becomes aware 
of the event: 
Any adverse event (regardless of whether the event is serious or non-serious, on-site or off-site) that occurs any 
time during or after the research study, which in the opinion of the principal investigator is: 
 
Unexpected (An event is “unexpected” when its specificity and severity are not accurately reflected in the protocol-
related documents, such as the IRB-approved research protocol, any applicable investigator brochure, and the 
current IRB-approved informed consent document and other relevant sources of information, such as product 
labeling and package inserts.) 


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AND 
 
Related to the research procedures (An event is “related to the research procedures” if in the opinion of the principal 
investigator or sponsor, the event was more likely than not to be caused by the research procedures.) 
 
Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be reported to the Penn IRB using the 
form: “Unanticipated Problems Posing Risks to Subjects or Others Including Reportable Adverse Events” or as a 
written report of the event (including a description of the event with information regarding its fulfillment of the 
above criteria, follow-up/resolution and need for revision to consent form and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical Investigator’s 
study file. 
 
Other Reportable Events: 
 
For clinical drug trials, the following events are also reportable to the Penn IRB: 
Any adverse experience that, even without detailed analysis, represents a serious unexpected adverse event that is 
rare in the absence of drug exposure (such as agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome). 
Any adverse event that would cause the sponsor to modify the investigators brochure, protocol or informed consent 
form, or would prompt other action by the IRB to assure protection of human subjects. 
Information that indicates a change to the risks or potential benefits of the research, in terms of severity or frequency. 
For example:  
An interim analysis indicates that participants have a lower rate of response to treatment than initially expected. 
Safety monitoring indicates that a particular side effect is more severe, or more frequent than initially expected. 
A paper is published from another study that shows that an arm of your research study is of no therapeutic value. 
Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic used in a research 
protocol. 
Breach of confidentiality  
Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard to a research 
participant. 
Incarceration of a participant when the research was not previously approved under Subpart C and the investigator 
believes it is in the best interest of the subject to remain on the study. 
Complaint of a participant when the complaint indicates unexpected risks or the complaint cannot be resolved by 
the research team. 
Protocol violation (meaning an accidental or unintentional deviation from the IRB approved protocol) that in the 
opinion of the investigator placed one or more participants at increased risk, or affects the rights or welfare of 
subjects. 
 
10.10.3 Abramson Cancer Center Data Safety Monitoring Committee (DSMC): 
 
Every effort should be made to report an event as a diagnosis, not as a list of symptoms. Symptoms that led to the 
diagnosis should be included in the event description, but should not be the actual event. 


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On-Site subjects (this includes any subjects enrolled at other sites on an ACC multi-site study). Only events on 
studies categorized as HIGH risk based on the ACC Risk table must be submitted to the DSMC as follows: 
All grade 3 or higher events regardless of attribution or expectedness within 10 business days of knowledge. 
All unexpected deaths within two business day of knowledge. 
All others deaths within 30 days of knowledge. Deaths of subjects greater than 90 days from the last study 
treatment/intervention are not reportable unless a longer time frame is specified in the protocol. 
 
Study PIs have the option to request DSMC review of AEs that do not meet the high risk definition if they would 
like an independent opinion of the event. The DSMC review will be limited to the scope specifically requested by 
the PI. 
 
All events must be entered into the ACC Clinical Trials Management System (CTMS using the centralized reporting 
form.SAEs will be submitted to the DSMC through the Velos Clinical Trial Management System.Once an event is 
reported, you must keep the information accurate and current in Velos. 
Exception 
A one time, intentional action (planned prospectively) or process that departs from the IRB and CTSRMC approved 
study protocol, intended for one occurrence. Advance documented IRB and DSMC approval is required. 
 
For in-house studies with a Medical Monitor or Safety Monitoring Committee (not DSMB), approval must be 
obtained from the Medical Monitor or Safety Monitoring Committee prior to submitting your exception request to 
the DSMC.  
The following information must be contained in your exception request: 
 
When it is needed and why it is needed in that timeframe 
 
Has the Medical Monitor or Sponsor approved and provide the documentation of approval 
 
Is this an exception from eligibility, treatment, disease progression, study calendar windows, etc.  
 
Why the exception is needed (cite the section(s) of the protocol) along with the full clinical details of the 
subject. This must be determined by the sub-Investigator or PI.  
 
The reason why the protocol currently doesn't allow the situation for which an exception is being requested. 
This must be determined by the sub-Investigator or PI. 
 
If there are plans to amend the protocol and if not, why not. 
 
If additional follow-up or interventions will be required in order to protect the subject as a result of this 
exception. 
 
Study Exceptions the DSMC may Reject: 
 
Exceptions to eligibility, treatment/dosing, contraindicated treatment/therapies/interventions or safety tests for the 
following types of studies may be rejected by the DSMC: 
 
 
Any investigator-initiated treatment study. 
 
Any treatment study involving on-campus manufacturing of any component, regardless of sponsor. 
To seek approval, you must provide the DSMC with strong and compelling scientific and clinical information to 
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If the protocol will not be amended your reasoning must be provided. If this situation is likely to happen again, the 
DSMC will require a protocol amendment. 
 
 
Deviation 
Any unintentional action or process that departs from IRB approval and is identified retrospectively. The deviation 
is reportable to the DSMC and the IRB within 10 days from the time the event becomes known to the study team 
only when: one or more participants were placed at increased risk of harm, or, the event has the potential to occur 
again, or the event has the potential to qualify as serious or continuing noncompliance. 
 
If the PI determines that a deviation has any potential to impact participant safety (harm and/or risk), or the integrity 
of data produced from the participant, or some other overall impact on the study, the PI must report the deviation 
to the IRB and DSMC as described above. The IRB will make the final assessment of the impact. The DSMC will 
assess for additional safety and scientific integrity concerns. 
 
The following information must be contained in your deviation report: 
 
When it happened? When the study team (any member) became aware 
 
The full description of the deviation including important dates, test results, actions taken towards the 
subject, etc. Also, why it happened and how it was identified. 
 
Was the Medical Monitor or Sponsor notified. If so, their response? 
 
The PIs assessment of the impact on risk, safety and/or outcome. If no impact, why. If impact, what and 
what will happen next. 
 
The corrective actions that have been implemented to date and the impact of those corrective action plans. 
 
Future corrective action plans (if applicable) and the impact of those plans. 
 
If there are plans to amend the protocol (if applicable to prevent future deviations) and if not, why not. 
 
If the PI determines that the event had no potential to impact participant safety (harm and/or risk) or the integrity 
of data produced from the participant, the PI must fully document his/her rationale for each category (risk, harm, 
and participant data). 
 
11.0 Data Handling and Record Keeping  
11.1 Confidentiality  
Information about study subjects will be kept confidential and managed according to the requirements of the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require a signed subject 
authorization informing the subject of the following:  
 
What protected health information (PHI) will be collected from subjects in this study  
 
Who will have access to that information and why 
 
Who will use or disclose that information 
 
The rights of a research subject to revoke their authorization for use of their PHI 
 


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In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the 
ability to use all information collected prior to the revocation of subject authorization. For subjects that have revoked 
authorization to collect or use PHI, attempts should be made to obtain permission to collect at least vital status (i.e. 
that the subject is alive) at the end of their scheduled study period 
11.2 Data Collection and Management  
This study will use Velos as the data management system.  The study case report form (CRF) is the primary data 
collection instrument for the study and will be electronically created and completed in Velos. CRFs will be provided 
for each patient. Subjects must not be identified by name on any CRFs. Subjects will be identified by their patient 
identification number (PID). All data requested on the CRF must be recorded. All missing data must be explained. 
If a space on the CRF is left blank because the procedure was not done or the question was not asked, write “N/D”. 
If the item is not applicable to the individual case, write “N/A.”.)  
12.0 Study Monitoring, Auditing, and Inspecting 
12.1 Study Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted above, as well as 
the construction and implementation of a site data and safety-monitoring plan.  Medical monitoring will include a 
regular assessment, at least every 6 months, of the number and type of serious adverse events by an independent 
clinician, Roger Cohen, MD, Department of Medicine, Division of Hematology-Oncology.  Additionally, the 
Medical Monitor will be consulted for protocol exceptions and deviations and as needed for decision-making 
regarding dose modifications, study eligibility, and any need to stop enrollment or the study for safety concerns. 
This study will be monitored in accordance with the Cancer Center’s Clinical Trials Scientific Review and 
Monitoring Committee (CTSRMC) Plan, approved by NCI during the Core Grant’s most recent review. This plan 
requires that the investigator submit a study-specific plan outlining how data will be reviewed In addition, the 
CTSRMC plan calls for an internal audit by the Cancer Center’s Data Safety Committee twice yearly. The 
investigator will allocate adequate time for such monitoring activities. The Investigator will also ensure that the 
monitor or other compliance or quality assurance reviewer is given access to all the above noted study-related 
documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has adequate space to 
conduct the monitoring visit. 
12.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, government regulatory 
bodies, and University compliance and quality assurance groups of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.). The investigator will ensure the 
capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
Participation as an investigator in this study implies acceptance of potential inspection by government regulatory 
authorities and applicable University compliance and quality assurance offices. 
13.0 Ethical Considerations 


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This study is to be conducted according to US and international standards of Good Clinical Practice (FDA Title 
21 parts 50 and 56 and International Conference on Harmonization guidelines), applicable government 
regulations and Institutional research policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted independent IRB, in agreement 
with local legal prescriptions, for formal approval of the study conduct.  
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.  This consent form 
will be submitted with the protocol for review and approval by the IRB and CTSRMC for the study.  The formal 
consent of a subject, using the IRB-approved consent form, must be obtained before that subject undergoes any 
study procedure.  The consent form must be signed by the subject and the investigator-designated research 
professional obtaining the consent.  
14.0 Study Finances 
14.1 
Funding Source 
This clinical study, including correlative work, will be supported by funds provided by Bristol-Myers Squibb.   
14.2 
Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on Conflicts of 
Interest Related to Research.  
15.0 Publication Plan 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the 
information provided by the sponsor for the purposes of performing the study, will be published or passed on to 
any third party without the consent of the study sponsor.  Any investigator involved with this study is obligated to 
provide the sponsor with complete test results and all data derived from the study. 
16.0 References 
1.  Hugen N, Brown G, Glynne-Jones R, et al. Advances in the care of patients with mucinous colorectal cancer. 
Nat Rev Clin Oncol. 2016 Jun;13(6):361-9. 
2.  Franko J, Shi Q, Goldman CD, et al. Treatment of Colorectal Peritoneal Carcinomatosis With Systemic 
Chemotherapy: A Pooled Analysis of North Central Cancer Treatment Group Phase III Trials N9741 and N9841. 
Journal of Clinical Oncology. 2012;30(3):263-267. 
3.  Elias D, Gilly F, Boutitie F, et al. Peritoneal colorectal carcinomatosis treated with surgery and perioperative 
intraperitoneal chemotherapy: retrospective analysis of 523 patients from a multicentric French study. J Clin 
Oncol. 2010 Jan 1;28(1):63-8. 
4.  Zunino B, Rubio-Patiño C, Villa E, et al. Hyperthermic intraperitoneal chemotherapy leads to an anticancer 
immune response via exposure of cell surface heat shock protein 90. Oncogene. 2016 Jan 14;35(2):261-8. 


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5.  Yoshioka Y, Togashi Y, Chikugo T, et al. Clinicopathological and genetic differences between low-grade and 
high-grade colorectal mucinous adenocarcinomas. Cancer. 2015 Dec 15;121(24):4359-68. 
6.  Alakus H, Babicky ML, Ghosh P, et al. Genome-wide mutational landscape of mucinous carcinomatosis 
peritonei of appendiceal origin. Genome Med. 2014 May 29;6(5):43. 
7.  Shibahara H, Higashi M, Yokoyama S, Rousseau K, et al. A comprehensive expression analysis of mucins in 
appendiceal carcinoma in a multicenter study: MUC3 is a novel prognostic factor. PLoS One. 2014 Dec 
31;9(12):e115613. 
8.  Ferreira JA, Magalhães A, Gomes J, et al. Protein glycosylation in gastric and colorectal cancers: Toward 
cancer detection and targeted therapeutics. Cancer Lett. 2017 Feb 28;387:32-45. 
9.  Morse MA, Niedzwiecki D, Marshall JL, et al. A randomized phase II study of immunization with dendritic 
cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for 
resected metastatic colorectal cancer. Ann Surg. 2013 Dec;258(6):879-86. 
10. Posey AD Jr, Schwab RD, Boesteanu AC, et al. Engineered CAR T Cells Targeting the Cancer-Associated 
Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma. Immunity. 2016 Jun 21;44(6):1444-54. 
11. Schuster H, Peper JK, Bösmüller HC, et al. The immunopeptidomic landscape of ovarian carcinomas. Proc 
Natl Acad Sci U S A. 2017 Nov 14;114(46):E9942-E9951. 
12. Haro MA, Littrell CA, Yin Z, et al. PD-1 Suppresses Development of Humoral Responses That Protect 
against Tn-Bearing Tumors. Cancer Immunol Res. 2016 Dec;4(12):1027-1037. 
13.  Long GV, Tykodi SS, Schneider JG, et al. Assessment of nivolumab exposure and clinical safety of 480 mg 
every 4 weeks flat-dosing schedule in patients with cancer. Ann Oncol. 2018 Sep 12. 
14. Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol. 2017 Mar;18(3):e143-e152. 
15. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J 
Med. 2015 May 21;372(21):2018-28. 
16. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial 
Carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026.


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17.0 Schedule of Events 
Note: study timepoints may be performed within a +/- 3 day window.  
 
Screening1 
Cycle 1 
(56 days) 
Cycles 2+ 
(56-day cycles) 
End of 
Study Visit 
Follow
-up 
 
 
1 
10-
14 
29 
1 
29 
 
 
 
Treatments 
Nivolumab 
 
X 
 
X 
X 
X 
 
 
Ipilimumab 
 
X 
 
 
X 
 
 
 
 
Tests and Observations 
Informed Consent2 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
X6 
Physical Exam and 
Performance Status 
X 
X 
 
 
X 
X 
X 
 
AE Assessment 
 
X 
 
X 
X 
X 
X 
 
CBC w/ differential 
X 
X 
 
X 
X 
X 
X 
 
Serum Chemistry4 
X 
X 
 
X 
X 
X 
X 
 
TSH 
X 
 
 
 
X 
X 
X 
 
CEA8 
X 
X 
 
X 
X 
X 
X 
 
Pregnancy test5 
X 
X 
 
X 
X 
X 
X 
 
Disease Assessment 
(routine CT/MRI)3 
X 
 
 
 
X 
 
X 
X7 
 
Research Correlates 
Tumor biopsy 
X 
 
X 
 
 
 
 
 
Research Blood (60mL) 
X9 
 
X 
X 
X 
 
X 
 
 
1 Laboratory screening evaluations (section 4.1 #7) are to be conducted within 14 days prior to start of 
protocol therapy or should be repeated on cycle 1 day 1 prior to treatment to confirm eligibility.  Baseline 
disease assessment with imaging must be conducted within 21 days prior to start of protocol therapy.  
Screening procedures may also occur on cycle 1 day 1 prior to therapy. 
2  Informed consent will be documented prior to initiation of any other research related activity.  If there 
have been tests/procedures that have been performed as part of subjects work-up or routine practice prior to 
informed consent and within the screening evaluation window then those tests/procedures do not have to be 
repeated 
3  CT/MRI, and/or PET/CT in the event that PET/CT is determined to be standard of care.   
4 Sodium, potassium, BUN, serum creatinine, calcium, glucose, AST, ALT, total bilirubin, alkaline 
phosphatase, albumin 
5Within 72 hours prior to first dose of cycle 1 immunotherapy.  Men and women of childbearing potential 
must agree to use a medically accepted form of birth control (see Appendix A) OR must agree to completely 
abstain from intercourse for two weeks before beginning study treatment, during participation in this study, 
and for 5 months (women) or 7 months (men) after the final study treatment.   


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6Limited to following of survival and disease recurrence through review of the medical record for up to 3 
years after the end of study visit (every 6 months for the first year, then annually for the second two years).  
7MRI/CT scan will be performed at frequency determined by clinical care with data to be collected from the 
medical record for the purposes of the research. 
8CEA will be repeated with each cycle if abnormal at screening 
9Research blood is to be drawn on the same day as the tumor biopsies during screening and cycle 1 days 10-
14.  It should not be drawn at the initial screening visit.  If the biopsy is omitted, research blood draw is still 
required and can occur during screening window or on cycle 1 day 1 prior to treatment.  Research blood can 
be drawn within 3 days before or after biopsy if required for scheduling. 
 
 


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Appendix A: Definition of Non-Childbearing Potential and Medically 
Acceptable Methods of Birth Control 
Non-childbearing potential is defined as any of the following (by other than medical reasons): 
1.  ≥45 years of age and has not had menses for >2 years 
2.  Amenorrheic for <2 years without a hysterectomy and oophorectomy and a follicle-stimulating 
hormone value in the postmenopausal range upon pre-study (screening) evaluation 
3.  Post hysterectomy, oophorectomy or tubal ligation. Documented hysterectomy or oophorectomy must 
be confirmed with medical records of the actual procedure or confirmed by imaging. Tubal ligation 
must be confirmed with medical records of the actual procedure otherwise the patient must be willing 
to use 2 other adequate methods. 
Females: 
Women of child-bearing potential must agree to use 2 of the following forms of contraception OR 
completely refrain from intercourse during the study and for at least 5 months following the last dose of 
study drug.   
Males: 
Men with partners of child-bearing potential must agree along with their partner to use 2 of the following 
forms of contraception OR completely refrain from intercourse during the study and for at least 7 months 
following the last dose of study drug. 
Acceptable methods include: 
 
Condoms 
 
Diaphragm 
 
Cervical cap 
 
Intra-uterine device 
 
Surgical sterilization (tubal ligation or vasectomy) 
 
Oral contraceptives 
Abstinence at certain times of the cycle, such as during ovulation or after ovulation, or withdrawal are not 
acceptable methods.  The list of methods above is not exhaustive and additional contraception methods 
may also be acceptable.  The study doctor must approve the contraceptive methods in subjects with child-
bearing potential. 
 
 


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Appendix B: Management Algorithms for Nivolumab and Ipilimumab 
These general guidelines constitute guidance to the Investigator and may not be appropriate in all 
circumstances.  Deviation from these guidelines will not be considered a protocol deviation.  A general 
principle of immune adverse events is that differential diagnoses should be diligently evaluated according 
to standard medical practice. Non-inflammatory etiologies should be considered and appropriately treated.  
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-grade 
toxicity. The lower bioavailability of oral corticosteroids should be taken into account when switching to 
the equivalent dose of oral corticosteroids.


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Appendix C:   RECIST 1.1 Criteria 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm 
with calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters).  
Note: Tumor lesions that are situated in a previously irradiated area might or might not be considered measurable.  
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be >15 mm 
in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and followed.  
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest diameter <10 mm 
or pathological lymph nodes with ≥ 10 to <15 mm 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 as non-measurable. 
Note: 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.  
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if they meet the 
definition of measurability described above. However, if non-cystic lesions are present in the same patient, these 
are preferred for selection as target lesions. 
Target lesions. All measurable and/or evaluable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and measured at 
baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease.  
Non-target lesions. 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 and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
Methods for Evaluation of Measurable Disease 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers (e.g., skin nodules). In the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is 
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Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the assumption 
that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable. 
Response Criteria 
Evaluation of Target Lesions (RECIST 1.1) 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to <10 mm.  
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the 
baseline sum diameters  
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one 
or more new lesions is also considered progressions).  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study. 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to <10 mm.  
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the 
baseline sum diameters  
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one 
or more new lesions is also considered progressions).  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest sum diameters while on study. 
 
 


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Appendix D:  Immune-Related Response in Measurable Lesions (iRECIST) 
iRECIST guidelines were established in 2017 to guide response assessments in clinical trials testing 
immunotherapeutics.  Full details of the iRECIST criteria for this study can be found in Seymour L et al, Lancet 
Oncology 2017 [14].   
If initial RECIST 1.1-defined progression (ie, iUPD) is noted on imaging in the setting of clinical stability, subjects 
may remain on study treatment and have confirmatory imaging in 4-8 weeks (study specified scans every 8 weeks 
should continue on initial schedule if patient remains on study).  An assignment of clinical stability requires that no 
worsening of performance status has occurred, that no clinically relevant increases in disease-related symptoms 
such as pain or dyspnea occur that are thought to be associated with disease progression, and that no requirement 
for intensified management of disease-related symptoms exists, including increased analgesia, radiotherapy, or 
other palliative care.  The imaging findings and the recommendation to continue with treatment despite iUPD should 
be discussed with the patient before a decision is made about whether or not to continue therapy. Patients who have 
iUPD and are not clinically stable should be designated as not clinically stable in the case report form. This 
designation will allow the best overall response to be calculated and the date of iUPD to be used in estimates of 
progression-free survival. 
If radiologic progression is confirmed (iCPD), they will be determined to have progressive disease and discontinued 
from study therapy, but if repeat imaging shows stable disease or response by RECIST 1.1 they may remain on 
study therapy with imaging continuing as previously scheduled every 8 weeks (cycle 3 day 1, cycle 5 day 1, etc.). 
Table 1: Comparison of RECIST 1.1 and iRECIST 
 
RECIST 1.1 
iRECIST 
Definitions of measurable and non-
measurable disease; numbers and 
site of target disease 
Measurable lesions are ≥10 mm in 
diameter (≥15 mm 
for nodal 
lesions); maximum of five lesions 
(two per organ); all other disease is 
considered non-target (must be ≥10 
mm in short axis for nodal disease) 
No change from RECIST 1.1; 
however, new lesions are assessed 
as per RECIST 1.1 but are recorded 
separately on the case report form 
(but not included in the sum of 
lesions for target lesions identified at 
baseline) 
Complete 
response, 
partial 
response, or stable disease 
Cannot 
have 
met 
criteria 
for 
progression 
before 
complete 
response, partial response, or stable 
disease 
Can have had iUPD (one or more 
instances), but not iCPD, before CR, 
PR, or SD 
New lesions 
Result in progression; recorded but 
not measured 
Results in iUPD but iCPD is only 
assigned on the basis of this 
category if at next assessment 
additional new lesions appear or an 
increase in size of new lesions is 
seen (≥5 mm for sum of new lesion 
target or any increase in new lesion 
non-target); the appearance of new 
lesions when none have previously 
been recorded, can also confirm 
iCPD 
Confirmation of progression 
Not required (unless equivocal) 
Required 
Consideration of clinical status 
Consideration of clinical status 
Clinical stability is considered when 
deciding 
whether 
treatment 
is 
continued after iUPD 


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“i” indicates immune responses assigned using iRECIST. RECIST=Response Evaluation Criteria in Solid Tumours. iUPD=unconfirmed 
progression. iCPD=confirmed progression. iCR=complete response. iPR=partial response. iSD=stable disease. 
Table 2: Assignment of timepoint response using iRECIST 
 
Timepoint 
response 
with 
no 
previous iUPD in any category 
Timepoint response with previous 
iUPD in any category 
Target lesions: i CR; non-target 
lesions: iCR; new lesions: no 
iCR 
iCR 
Target lesions: iCR; non-target 
lesions: non-iCR/non-iUPD; new 
lesions: no 
iPR 
iPR 
Target lesions: iPR; non-target 
lesions: non-iCR/non-iUPD; new 
lesions: no 
iPR 
iPR 
Target lesions: iSD; non-target 
lesions: non-iCR/non-iUPD; new 
lesions: no 
iSD 
iSD 
Target lesions: iUPD with no 
change, or with a decrease from last 
timepoint; non-target lesions: iUPD 
with no change, or decrease from 
last timepoint; new lesions: yes 
Not applicable 
New lesions confirm iCPD if new 
lesions were previously identified 
and they have increased in size (≥5 
mm in sum of measures for new 
lesion target or any increase for new 
lesion non-target) or number; if no 
change is seen in new lesions (size 
or number) from last timepoint, 
assignment remains iUPD 
Target lesions: iSD, iPR, iCR; non-
target lesions: iUPD; new lesions: 
no 
iUPD 
Remains iUPD unless iCPD is 
confirmed on the basis of a further 
increase in the size of non-target 
disease (does not need to meet 
RECIST 1.1 criteria for unequivocal 
progression) 
Target lesions: iUPD; non-target 
lesions: non-iCR/non-iUPD, or iCR; 
new lesions: no 
iUPD 
Remains iUPD unless iCPD is 
confirmed on the basis of a further 
increase in sum of measures ≥5 mm; 
otherwise, 
assignment 
remains 
iUPD 
Target lesions: iUPD; non-target 
lesions: iUPD; new lesions: no 
iUPD 
Remains iUPD unless iCPD is 
confirmed based on a further 
increase in previously identified 
target lesion iUPD in sum of 
measures >5 mm or non-target 
lesion iUPD (previous assessment 
need not have shown unequivocal 
progression) 
Target lesions: iUPD; non-target 
lesions: iUPD; new lesions: yes 
iUPD 
Remains iUPD unless iCPD is 
confirmed on the basis of a further 
increase in previously identified 
target lesion iUPD sum of measures 
≥5 mm, previously identified non-
target lesion iUPD (does not need to 
be unequivocal), or an increase in 
the size or number of new lesions 
previously identified 


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Target 
lesions: 
non-iUPD 
or 
progression; 
non-target 
lesions: 
non-iUPD or progression; new 
lesions: yes 
iUPD 
Remains iUPD unless iCPD is 
confirmed on the basis of an 
increase in the size or number of 
new lesions previously identified 
Target lesions, non-target lesions, and new lesions defined according to RECIST 1.1 principles; if no pseudoprogression occurs, RECIST 1.1 
and iRECIST categories for complete response, partial response, and stable disease would be the same. 
*Previously identified in assessment immediately before this timepoint. “i” indicates immune responses assigned using iRECIST. 
iCR=complete response. iPR=partial response. iSD=stable disease. iUPD=unconfirmed progression. non-iCR/non-iUPD=criteria for neither 
CR nor PD have been met. iCPD=confirmed progression. RECIST=Response Evaluation Criteria in Solid Tumours.