Clinical trial NCT02553642
Conditions: Bladder Cancer Melanoma
Keywords: Tumor Mutation Nivolumab Nivolumab plus Ipilimumab Predicted Neo-antigen Burden 15-126
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2015-09-14; Completion date: 2024-04-29
Enrollment: 81 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to investigate the characteristics of tumors in patients treated with nivolumab and to identify features that help to predict a good or bad response to this drug.

Detailed description:

Arms: arm 1: All eligible patients with melanoma will receive ipilimumab at a dose of 3 mg/kg combined with nivolumab at a dose of 1 mg/kg. The ipilimumab and nivolumab will be dosed every 3 weeks for 4 doses. Thereafter, patients may be eligible to continue to receive nivolumab monotherapy at a dose of 240 mg administered every 2 weeks OR nivolumab at dose of 480mg every 4 weeks for up to 2 years. arm 2: All eligible patients with bladder cancer will receive nivolumab at a dose of 240 mg administered every 2 weeks for up to 2 years, if the patient is clinically benefitting, the PI and treating investigator may elect to continue treatment beyond 2 years. All eligible patients with bladder cancer will receive nivolumab at a dose of 240 mg administered every 2 weeks for up to 2 years, if the patient is clinically benefitting, the PI and treating investigator may elect to continue treatment beyond 2 years.
Interventions: intervention 1: Nivolumab intervention 2: Nivolumab plus Ipilimumab
Intervention descriptions: intervention 1: Monotherapy Treatment - Nivolumab 240 mg flat dose Dosed q 2 weeks

OR

\- Nivolumab 480 mg flat dose Dosed q 4 weeks

for up to 2 years from 1st dose of nivolumab or until loss of clinical benefit intervention 2: Combination Treatment

* Ipilimumab 3 mg/kg
* Nivolumab 1 mg/kg Dosed q 3 weeks x 4 doses

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
 
 
MSK PROTOCOL COVER SHEET 
A Prospectively Designed Study to Assess the Relationship between Tumor Mutation Burden and 
Predicted Neo-antigen Burden in Patients with Advanced Melanoma or Bladder Cancer Treated with 
Nivolumab or Nivolumab plus Ipilimumab (CA209-260) 
Samuel A. Funt, MD / Medicine/ Genitourinary Oncology Service 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 5 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 6 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 6 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .......................................................... 12 
4.1 
Design ........................................................................................................................... 12 
4.2 
Intervention ................................................................................................................... 13 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ......................................................................... 18 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ......................................................................... 19 
6.1 
Subject Inclusion Criteria ............................................................................................... 19 
6.2 
Subject Exclusion Criteria .............................................................................................. 20 
7.0 
RECRUITMENT PLAN ..................................................................................................... 22 
8.0 
PRETREATMENT EVALUATION .................................................................................... 23 
9.0 
TREATMENT/INTERVENTION PLAN .............................................................................. 24 
10.0 EVALUATION DURING TREATMENT/INTERVENTION .................................................. 25 
11.0 TOXICITIES/SIDE EFFECTS ........................................................................................... 31 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ...................... 33 
13.0 CRITERIA FOR REMOVAL FROM STUDY ..................................................................... 35 
14.0 BIOSTATISTICS .............................................................................................................. 36 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 38 
15.1 Research Participant Registration .................................................................................. 38 
15.2 Randomization .............................................................................................................. 40 
16.0 DATA MANAGEMENT ISSUES ....................................................................................... 40 
16.1 Quality Assurance ......................................................................................................... 42 
16.2 Data and Safety Monitoring ........................................................................................... 43 
17.0 PROTECTION OF HUMAN SUBJECTS .......................................................................... 46 
17.1 Privacy .......................................................................................................................... 47 
17.2 Serious Adverse Event (SAE) Reporting ........................................................................ 47 
17.2.1 SAE Reporting by MSKCC to BMS ............................................................................... 48 
18.0 INFORMED CONSENT PROCEDURES .......................................................................... 50 


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19.0 REFERENCES ................................................................................................................. 51 
20.0 APPENDICES .................................................................................................................. 53 


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Melanoma 
(n = 10) 
Bladder 
(n = 71) 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
This is a prospectively designed, open label study of nivolumab monotherapy or nivolumab 
plus ipilimumab in patients with advanced cancers designed to test the hypothesis that 
tumors with a higher frequency of mutations (or neo-antigens) will have a higher response 
rate to checkpoint blockade than those with lower mutation (or neo-antigen) burden. 
Patients must have at least one lesion that is safe to undergo biopsy and at least one 
additional measurable lesion not intended to be biopsied. A biopsy will be performed prior 
to treatment on study and whole exome and whole transcriptome sequencing will be 
performed on the biopsied material. All patients will have imaging to evaluate disease 
response (by RECIST 1.1) every 6 weeks for the first 6 months of treatment. Patients with 
bladder cancer who receive nivolumab monotherapy and who have disease progression 
may be eligible to subsequently receive ipilimumab in combination with nivolumab. 
 
 
 
 
 
 
Treatments: For patients with melanoma, the planned treatment will be ipilimumab (3 
mg/kg) in combination with nivolumab (1 mg/kg) administered every 3 weeks for 4 doses 
followed by nivolumab administered every 2 weeks at 240mg, or every 4 weeks at 480mg. 
Treatment may continue for up to 2 years, if the patient is clinically benefitting, the PI and 
treating investigator may elect to continue beyond two years. For patients with bladder 
cancer, the planned treatment will be nivolumab administered every 2 weeks at 240mg, or 
every 4 weeks at 480mg. Treatment may continue for up to 2 years, if the patient is 
clinically benefitting, the PI and treating investigator may elect to continue beyond two 
years. Patients who have disease progression after their 6 week scan may continue to 
receive nivolumab monotherapy, at the discretion of their treating physician and the study 
PI. Patients who have disease progression at 6 weeks that is confirmed to be progression 
on a second scan(by RECIST 1.1 criteria) may be eligible to subsequently receive 
ipilimumab (3 mg/kg) in combination with nivolumab (1 mg/kg) administered every 3 weeks 
for 4 doses followed by nivolumabadministered every 2 weeks (240mg) or every 4 weeks 


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(480mg). The crossover treatment may begin approximately 12 or more weeks after initial 
treatment on study. Treatment may continue for up to 2 years from the initial dose of 
nivolumab, if the patient is clinically benefitting, the PI and treating investigator may elect 
to continue beyond two years. 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary Correlative Objective: Obtain preliminary prospective data on whether 
mutational load is associated with RECIST 1.1 response to immunotherapy. 
Primary Clinical Objective: Obtain prospective data on the overall response Rate (per RECIST 
1.1) to 1) nivolumab monotherapy and 2) ipilimumab and nivolumab combination therapy in 
patients progressing on initial nivolumab monotherapy. 
 
Secondary Clinical Objectives: 
 
1. Evaluate duration of response (DOR), progression free survival (PFS), overall survival (OS), 
rate of grade 3/4 toxicity. 
2. Evaluate ORR, DOR, PFS, OS according to the immune related RECIST criteria. 
Secondary Correlative Objectives: 
1. Obtain preliminary prospective data on whether neo-antigen score is associated with RECIST 
1.1 response to immunotherapy. 
2. Compare tumor characteristics (mutation burden, neo-antigen score, PD-L1, TCR repertoire, 
immune infiltrate) between pre-treatment and on-treatment (optional) tumor biopsies. 
3. Evaluate tumor PD-L1 expression across range of mutation burden/predicted neo- antigens. 
4. Evaluate TCR repertoire across a range of mutation burdens/predicted neo-antigen scores. 
5. Evaluate for the presence of predicted neo-antigen specific T cells in peripheral blood samples. 
6. Compare IMPACT assay to whole exome sequencing for the evaluation of patients according to 
mutation burden. 
 
 
3.0 
BACKGROUND ANDRATIONALE 
Mutations, Cancer and Anti-Tumor Immune Responses 
 
Tumors harbor a diverse range of unique, tumor specific mutations, from dozens to 
thousands per tumor.1-3 In silico analyses predicts that a subset of these mutations are 
detectable by the immune system as tumor- specific neo-antigens (Figure1).4,5 The 
repertoire of neo-antigens for any individual tumor has been dubbed the “immunome”, to 
highlight the vast diversity of potential epitopes. In preclinical models, utilizing syngeneic 
transplantable murine tumors, it is clear that tumor-specific neo-antigens can be functional “tumor 
rejection” antigens.6-9 In murine models, responses to neo-antigens in combination with 
checkpoint blockade can generate potent tumor rejection.10 


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Figure 1. Converting the TCGA into an Immunome database 
(Srivastava et al. unpublished data). 
 
There is longstanding evidence that tumor specific neo-antigens may be relevant in human 
cancers with over 40 publications describing T cells specific for tumor neo-antigens derived from 
a mutated proteins documented since 1993. (http://cancerimmunity.org/peptide/mutations/) In 
pioneering work by Ton Schumacher and colleagues, T cell responses to neo-antigens were 
temporally associated with the activity of the checkpoint blocking antibody ipilimumab in a patient 
with melanoma.11 For adoptive T cell therapies, these neo-antigen specific T cells can also have 
potent anti-tumor activity, as demonstrated in a compelling case report by Steve Rosenberg.12 
More recently, important work by Jedd Wolchok, Tim Chan and Alex Snyder at MSKCC suggests 
that the benefit of ipilimumab for patients with advanced melanoma may be associated with the 
frequency of mutations in the tumor and the presence of mutations that function as neo- 
antigens.13 Moreover, differences in the mutational profiles of 3 distinct tumors in a patient treated 
with the combination of ipilimumab and nivolumab were linked to differences in clinical responses 
in case study under development by Maggie Callahan, Jedd Wolchok and Pramod Srivastava 
(manuscript in preparation). 
Nivolumab, Ipilimumab, and Combination Therapy 
 
Nivolumab enhances antitumor immunity by blocking the co-inhibitory molecule expressed on T 
cells, programmed death 1 (PD-1), thereby interrupting its interaction with its ligand programmed 
death ligand 1 (PD-L1). Nivolumab has shown anti-tumor activity in advanced solid tumors 
including melanoma, renal cell cancer, non-small cell lung cancer, head and neck cancers, and 
ovarian cancer. In addition, several other drugs blocking either PD-1, or its binding partner PD-L1, 
have been developed and have demonstrated activity in additional tumor types including bladder 
cancer and gastric cancer (Table 1). Tumor PD-L1 expression has been explored as a potential 
biomarker for nivolumab, however PD-L1 expression alone lacks both the positive predictive 
value and negative predictive value to be a useful clinical tool. 
Hundreds of patients with advanced solid tumor have been treated with nivolumab, and its safety 
and tolerability have been well established. Although nivolumab is generally well tolerated, a 
unique set of side effects, termed immune-related adverse events (irAEs) has been seen during 
its clinical development. CA209003 (MSKCC IRB 09-102) is a Phase 1 open label, multiple dose 
escalation study of nivolumab in patient with previously treated advanced solid tumors.14Patients 
received nivolumab at doses of 0.1, 0.3, 1, 3 or 10 mg/kg intravenously every 2 weeks, up to a 
maximum of 2 years of total therapy, if the patient is clinically benefitting, the PI and treating 
investigator may elect to continue beyond two years. No maximal tolerated dose was identified. 
The incidence, severity and relationship of AEs were generally similar across dose levels and 
tumor types. The most frequently reported treatment-related AEs were fatigue (28.1%), rash 
(14.7%), diarrhea (13.4%), and pruritus (10.5%). Most treatment-related AEs were low grade. 
Treatment-related high grade (Grade 3-4) AEs were reported in 52 (17.0%) of subjects. The most 
common treatment-related high grade AEs were fatigue (2.3%) and diarrhea (1%), and 
pneumonitis (1%). 
Ipilimumab enhances antitumor immunity by blocking the normally negative regulator of T cell 
function, cytotoxic T-lymphocyte antigen 4 (CTLA-4) and has demonstrated a survival benefit for 
patients with advanced melanoma in two phase 3 trials.15,16 The objective response rate to 
ipilimumab is unfortunately quite low and identifying which patients are expected to benefit from 


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this treatment is an area of ongoing research. 
Responses to ipilimumab are often delayed and may be seen after initial apparent disease 
progression. The unique pattern of disease response seen in patients with ipilimumab led to a 
retrospective study analyzing patients treated across several phase 2 trials. In this evaluation, 
improved survival was associated with a variety of disease response patterns such as patients 
who initially appeared to have progressive disease but later achieved response and those who 
had prolonged stable disease. To better reflect the distinct kinetics of response, the immune- 
related response criteria (irRC) were proposed.17 The irRC are undergoing prospective validation 
in ongoing clinical trials. IrRC may also have utility in nivolumab treated patients. A recent 
abstract at ASCO 2014 presented by F. Stephen Hodi described a survival benefit in patients 
treated with nivolumab who achieve responses by irRC, but not by traditional response criteria, 
compared to those who have disease progression by irRC. 
Thousands of patients have been treated with ipilimumab and its toxicity profile is well described. 
The most severe irAE is generally considered to be an inflammatory colitis, which requires prompt 
treatment with steroids and, in some cases, anti-TNF-alpha therapy. Other side effects related to 
ipilimumab consist of hypophysitis, hepatitis, and dermatitis. Other rarer side effects have also 
been reported including peripheral neuropathy and uveitis. Published algorithms for the treatment 
of ipilimumab-related irAEs are available (https://www.hcp.yervoy.com/pages/rems.aspx). 
Due to the distinct mechanisms of action of CTLA-4 and PD-1 blockade, combined blockade of 
both CTLA-4 (ipilimumab) and PD-1 (nivolumab) has been tested as a therapeutic approach in 
patients with advanced melanoma, RCC, and NSCLC.18-20 At the time of initial publication, the 
objective response rate by for patients treated with the concurrent combination of ipilimumab and 
nivolumab across all doses tested was 40%, with a response rate > 50% in patients treated at the 
doses (3 mg/kg ipilimumab, 1 mg/kg nivolumab) chosen for further clinical development. The rate 
of grade 3/4 treatment-related adverse events related to therapy was 53% of patients in the 
concurrent-regimen group. This rate is numerically higher than that typically described for 
monotherapy with ipilimumab at 3 mg/kg, nivolumab, or pembrolizumab. However, it is important 
to consider that the majority of grade 3/4 adverse events that composed the 53% number from 
this trial were asymptomatic, elevated laboratory values. These included patients with elevations 
in lipase (13%), none of whom had clinical pancreatitis, as well as aspartate aminotransferase 
(13%) and alanine aminotransferase (11%), none of whom were symptomatic. There appeared to 
be no new toxicities attributed to the combination of ipilimumab and nivolumab that have not been 
seen with ipilimumab or nivolumab alone. 
This combination also appears promising in RCC where a small study comprising 21 patients 
treated with 3 mg/kg nivolumab plus 1 mg/kg ipilimumab and 23 patients treated with 1 mg/kg 
nivolumab plus 3 mg/kg ipilimumab described response rates of 43% and 48% respectively. 
These numbers compare favorably to the ORR of 21% described for nivolumab monotherapy. 
This combination has also been tested in NSCLC where a lower response rate (13-20%) and 
relatively high toxicity rate were observed. The activity of the combination of nivolumab and 
ipilimumab in bladder cancer is presently being tested in a Phase 2 study CA209-032 (MSKCC 
IRB 13-187), presently open to accrual at MSKCC. Up to date data on the safety and activity of 
the combination of ipilimumab and nivolumab in bladder cancer will be available prior to its use 
in this study. 


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RCC 
Ovarian 
21% (168) 
17% (18) 
Motzer et al. ASCO 2014 
Hamanishi ASCO 2014 
Solid Tumors 
Melanoma 
NSCLC 
17% (135) 
40% (113) 
19% (146) 
Brahmer et al. NEJM 2012 
Daud et al. AACR 2014 
Gandhi et al. AACR 2014 
Melanoma 
34% (411) 
Ribas ASCO 2014 
NSCLC* 
Head & Neck 
Solid Tumors 
26% (45) 
18% (55) 
21% (103) 
Rizvi ASCO 2014 
Selwert et al. ASCO 2014 
Herbst et al. ASCO 2013 
Melanoma 
23% (30) 
Hamid et al. ASCO 2013 
NSCLC 
Bladder 
Solid Tumors 
23% (53) 
26% (65) 
11% (179) 
Sorial et al. ECC 2013 
Powels et al. ASCO 2014 
Segal et al. ASCO 2014 
NSCLC 
16% (58) 
Brahmer et al ASCO 2014 
Head & Neck 
14% (22) 
Segal et al. ASCO 2014 
Gastric 
19% (16) 
Segal et al. ASCO 2014 
Table 1. Established Clinical Activity of PD-1 and PD-L1 blocking antibodies. 
 
Drug 
Sponsor 
Target 
Disease Type 
Response (n) 
Reference 
Solid Tumors 
21% (42) 
Topalian et al. NEJM 2012 
Nivolumab 
BMS 
PD-1 
Melanoma 
32% (44) 
Weber et al. JCO 2013 
 
NSCLC 
14% (63) 
Antonia et al. WCLC 2013 
 
 
MDX - 1105 
BMS 
PD-L1 
Pembrolizumab 
Merck 
PD-1 
 
 
MPDL3280a 
Genentech 
PD-L1 
MEDI4736 
Medimmune 
PD-L1 
Rationale for Tumor Types Selected 
 
The selection of melanoma and bladder cancer was driven primarily by the biology of these 
diseases. In reviewing the literature, we sought to identify tumors that had a relatively high 
mutation burden and a diverse frequency of mutations (see Figure 1). Further, we reasoned that, in 
a 2-disease study, it would be prudent to choose one disease type that has a well established 
response rate for nivolumab (melanoma) and one that has high potential, but is more exploratory 
(bladder). Additionally for melanoma, data retrospectively linking mutation burden to response to 
checkpoint blockade (ipilimumab) has already been reported by our group at MSKCC and has 
been used to approximate the differences that we may anticipate between “high” and “low” 
mutation burden tumors in this setting. 
For bladder, we anticipate that results from the upcoming CA209-032 (MSKCC IRB 13-187) 
bladder cohort may serve as a reference and a recent abstract reports a response rate of 50% for 
the PD-L1 blocking antibody MPDL3280A in metastatic urothelial bladder cancer highlighting the 
promise of checkpoint blockade for this tumor type. Other tumor types that could also be 
considered promising in this setting, would include gastric, head and neck, RCC, ovarian, NSCLC, 
breast, and CRC, however, in order to assure that the study is adequately powered to address the 
primary endpoint, we have limited the study to 2 disease types at this time. Additionally, studies 
addressing similar questions in CRC (focusing on patients with MSI high disease), in NSCLC, and 


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in RCC are either open or under development. 
 
 
Figure 1. Frequency of Mutations Across a Diversity of Tumor Types (Lawrence et al. 2013) 
 
 
 
 
Clinical Rationale for Evaluating Mutations in Checkpoint Blockade 
 
This analysis will allow us to shed light on several important biological and mechanistic questions: 
Does tumor mutation burden (or predicted neo-antigen burden) related to responses to 
nivolumab monotherapy or to the combination of nivolumab and ipilimumab ? Does this 
relationship explain differences in response to checkpoint blockade between tumor types or 
within tumor types? How does the mutation burden relate to other tumor specific predictive 
markers (PD-L1)? 
 
Data presented at ASCO in 2014, reflecting the work of Alex Snyder, Tim Chan and Jedd 
Wolchok, suggested that mutation burden correlates with response to ipilimumab in a 
retrospective study of patients with metastatic melanoma. Using a cutoff of 250 mutations (~ 
the median of the population), tumors can be divided into a “high” mutation burden group and 
a “low” mutation burden group with rates of long term benefit of 58% and 23% respectively. If 
the cases that fall closest to the median (250 +/- 20%) are eliminated from the analysis, then 
the high mutation group, defined as > 300 mutations comprises ~ 40% of the group and the 
low mutation burden group (< 200 mutations) comprises 44% of the group (eliminating the 
middle ~20% of the population as “medium” mutation burden). With this approach, tumors 
with a high mutation burden have a 60% long term benefit rate, and those with a low 
mutation burden have an 18% long term benefit rate, a difference of 42%. 


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Ultimately, it is our hope that mutation burden, predicted neo-antigen burden, or both, offer some 
utility as biomarkers to guide patient selection for nivolumab or nivolumab/ipilimumab 
combinations. 
 
Figure 2. Patients with Long term benefit after treatment with ipilimumab have a higher 
mutational burden than those with minimal or no benefit. (Snyder et al. NEJM in press). 


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Melanoma 
(n = 10) 
Bladder 
(n = 71) 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
 
 
 
The study design will include 2 independent study populations (melanoma and bladder). The 
bladder cohort will be analyzed for the primary and secondary endpoints. The melanoma cohort 
will be analyzed in a descriptive fashion. All patients enrolled on study who meet eligibility criteria, 
including pre-study biopsy, will be treated as described in section 4.2. Tumor biopsy material will 
be used for whole exome sequencing and whole transcriptome sequencing to evaluate the tumor 
mutation burden and neo-antigen score for each individual patient/biopsy sample. 
Statistical Plan for Evaluation of Primary and Secondary Objectives 
 
Patients who receive at least 1 dose of nivolumab will be considered evaluable for the primary 
clinical objective and patients who have adequate biopsy material for whole exome sequencing 
and adequate sequencing data for determination of mutation burden will be considered 
evaluable for the primary correlative objective (1). Tumor mutation burden and neo-antigen 
score will be determined for each patient enrolled as described in Appendix 3. 
The primary clinical objective is to determine the confirmed objective response rate defined as 
the proportion of patients who achieve a complete or partial response to protocol therapy. The 
primary correlative objective is to obtain information on mutational load and obtain preliminary 
prospective data on whether this factor is predictive of response to immunotherapy. Patients 
mutational load will be assessed using tissue obtained prior to treatment and the number of 
mutations will be calculated. We will perform a nonparametric receiver operator characteristic 
(ROC) curve analysis with mutational load as a continuous measure and estimate the area 
under the curve (AUC) to assess the detectability of responders. This will allow us to 
prospectively test the hypothesis that a higher mutational burden is associated with a 
higher likelihood of response and also estimate the strength of the relationship between 
mutational burden and response rate. 
 
Patients who develop early clinical progression or death related to disease progression (i.e. 
before initial imaging) will be evaluated as non-responding patients for the purpose of study 


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analysis. Patients who develop early toxicities that require treatment delay or discontinuation 
will continue to be evaluated for response on study and response will be determined based 
upon radiographic evaluation. In the unlikely scenario where a patient is lost to followup in the 
first 12 weeks on study and a determination of response by either radiographic findings, clinical 
progression, or death related to disease cannot be made, this patient would be considered 
non-evaluable. 
 
This analysis of the relationship between mutation burden and response rate will be performed for 
each tumor type (melanoma vs. bladder) independently. A responder is defined as someone who 
achieves a confirmed complete or partial response based on RECIST 1.1 criteria. The cutoff point 
will be identified using Youden’s index. These results will be examined in a descriptive manner in 
order to identify potential predictive measures. In addition, we will run the same analysis using the 
predicted neo-antigen score (as described in Appendix 3) and test if predicted neo-antigen burden 
is predictive of response. 
4.2 
Intervention 
Patient Population 
 
Patients with histologically confirmed locally advanced or metastatic disease of the following 
tumor types who meet the eligibility criteria: 
(1) melanoma 
(2) bladder cancer 
Sample Size 
 
Up to 81 patients will be enrolled in two separate arms: one for melanoma and one for bladder 
cancer. It is estimated that approximately 85% of enrolled patients will be considered evaluable 
for both the clinical and research (WES, RNAseq) study endpoints, with an approximate 10% 
failure rate related to the biopsy, biopsy sample preparation and sequencing, and an 
approximate 5% failure rate for clinical reasons (i.e. patient replaced for clinical reasons and 
non-evaluable for response). Based upon these calculations, we estimate that we will have 
approximately 60 bladder patients and approximately 8 melanoma patients with both clinical 
and research (genomic) data for anlysis, consistent with the protocol statistical plan. 
 
Treatment Schema 
All eligible patients with melanoma will receive ipilimumab at a dose of 3 mg/kg combined with 
nivolumab at a dose of 1 mg/kg. The ipilimumab and nivolumab will be dosed every 3 weeks for 4 
doses. Thereafter, patients may be eligible to continue to receive nivolumab monotherapy at a 
dose of 240 mg administered every 2 weeks, or at a dose of 480mg administered every 4 weeks, 
for up to 2 years. If the patient is clinically benefitting, the PI and treating investigator may elect to 
continue treatment beyond 2 years.. 


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Combination Treatment 
-Ipilimumab 3 mg/kg 
-Nivolumab 1mg/kg 
Dosed q 3 weeks x 4 doses 
Combination Treatment 
- Ipilimumab 3 mg/kg 
- Nivolumab 1 mg/kg 
Dosed q 3 weeks x 4 doses 
Monotherapy Treatment 
-  Nivolumab 3 mg/kg 
Dosed q 2 weeks (240 mg) or q 4 
weeks (480 mg) for up to 2 yrs from 
1st dose of nivolumab 
Monotherapy Treatment 
- Nivolumab 240 mg flat dose q 2 weeks OR 
- Nivolumab 480 mg flat dose q 4 weeks 
Dosed for up to 2 years from 1st dose of nivolumab 
Combination Treatment 
-Ipilimumab 3 mg/kg 
-Nivolumab 1mg/kg 
Dosed q 3 weeks x 4 doses 
Monotherapy Treatment 
-Nivolumab 240 mg (q 2 wks) or 
480 mg (q 4 wks) flat dose 
Dosed for up to 2 years from 1st 
dose of nivolumab 
 
 
Schema for Melanoma (prior to Amendment 11) 
 
 
 
Schema for Melanoma (after Amendment 11) 
 
 
Patients with clinical benefit after ipi/nivo combination and 
subsequent progression on Nivolumab monotherapy (and no 
serious toxicity requiring treatment discontinuation) 
 
 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
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All eligible patients with bladder cancer will receive nivolumab at a dose of 240 mg administered every 
2 weeks, or at a dose of 480 mg administered every 4 weeks,for up to 2 years. If the patient is 
clinically benefitting, the PI and treating investigator may elect to continue treatment beyond 2 years. 
Patients with bladder cancer who have confirmed disease progression after treatment with 
nivolumab monotherapy may be treated with the combination of nivolumab and ipilimumab 
provided all of the following conditions are met: 
o Progressive disease should be confirmed on a second imaging study at least 4 weeks 
later and should demonstrate at least 10% or greater additional increase in disease 
burden. Alternatively, if the reviewing radiologist and the treating physician feel that there 
is unequivocal progression, then the patient may be eligible for crossover after discussion 
with the principal investigator. 
o The patient has not experienced a nivolumab related adverse event(s) leading 
to permanent discontinuation. 
o The patient should have completed at least one cycle of treatment before 
crossing over the combination treatment. It is not required that the patient 
receive all scheduled doses of nivolumab during this time; a minimum of 4 
doses of nivolumab monotherapy must be given before crossover. Patients 
may crossover before 4 doses of nivolumab after discussion with the MSK 
principal investigator. 
o The patient must have an ECOG of 0-1. 
o In the opinion of the treating investigator, treatment with the combination of ipilimumab 
and nivolumab represents a reasonable treatment option for the patient. 
 
For patients with bladder cancer, the combination treatment will be 3 mg/kg ipilimumab plus 1 
mg/kg nivolumab. The first dose of the combination treatment will be administered at least 2 
weeks, but no more than 6 weeks, after the most recent dose of nivolumab. The combination 
treatment will be administered once every 3 weeks for 4 doses and thereafter, patients will be 
treated with nivolumab every 2 weeks (240 mg) or every 4 weeks (480 mg) for up to 2 years, if 
the patient is clinically benefitting, the PI and treating investigator may elect to continue beyond 
two years. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 12 of 57 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
 
Page 1 
Monotherapy Treatment 
-  Nivolumab 3 mg/kg 
Dosed q 2 weeks (240 mg) or q 
4 weeks (480 mg) for up to 2 
yrs from 1st dose of nivolumab 
Combinati on Treatment 
-
Ipilimumab 1 mg/kg 
-
Nivolumab 3 mg/kg 
Dosed q 3 weeks x 4 doses 
Monotherapy Treatment 
- 
Nivolumab 240 mg (q 2 weeks) or 480 
mg (q 4 weeks) flat dose 
Dosed for up to 2 years from 1st dose of 
nivolumab or until loss of clinical benefit 
Combination Treatment 
-
Ipilimumab 3 mg/kg 
-
Nivolumab 1 mg/kg 
Dosed q 3 weeks x 4 doses 
Monotherapy Treatment 
-  Nivolumab 3 mg/kg 
Dosed q 2 weeks (240 mg) or q 
4 weeks (480 mg) for up to 2 
yrs from 1st dose of nivolumab 
Monotherapy Treatment 
- 
Nivolumab 240 mg (q 2 weeks) 
or 480 mg (q 4 weeks) flat dose 
Dosed for up to 2 years from 1st dose of 
nivolumab or until loss of clinical benefit 
 
 
 
 
 
Schema for Bladder Cancer (prior to Amendment 11) 
 
Patients with confirmed disease progression at least 
12 weeks after first dose of nivolumab 
 
 
 
 
 
 
 
 
 
 
 
Schema for Bladder Cancer (after Amendment 11) 
 
 
 
Patients with clinical benefit after ipi/nivo combination and 
subsequent progression on Nivolumab monotherapy (and no 
serious toxicity requiring treatment discontinuation) 
 
Monotherapy Treatment 
- 
Nivolumab 240 mg (q 2 
weeks) or 480 mg (q 4 
weeks) flat dose 
 
 
3 of 57 
Combination Treatment 
-
Ipilimumab 3 mg/kg 
-
Nivolumab 1 mg/kg 
Dosed q 3 weeks x 4 doses 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 14 of 57 
 
 
 
See the study flowcharts (Section 10) for a depiction of study event scheduling. 
Dosing Adjustments, Delays and Discontinuations 
 
Dosing reductions/adjustments in response to toxicities of nivolumab or ipilimumab are not 
permitted. Patients who delay or discontinue treatment for toxicities should continue followup as 
per study calendar (i.e. imaging, study visits, laboratory followup). 
Dose Delay Criteria/Criteria to Resume Treatment 
 
Dose delay criteria apply for all drug-related adverse events attributed to nivolumab, ipilimumab, 
or both. All study drugs must be delayed until treatment can resume. Because of the potential for 
clinically meaningful ipilimumab/nivolumab-related AEs requiring early recognition and prompt 
intervention, management algorithms have been developed for suspected AEs of selected 
categories. See appendix 2 for specifics. 
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to Grade 
≤ 1 or baseline value, with the following exceptions: 
• 
Subjects may resume treatment in the presence of Grade 2 fatigue 
• 
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin adverse event 
• 
Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in 
the presence of Grade 2 AST/ALT OR total bilirubin 
• 
Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters should have treatment permanently discontinued 
• 
Drug-related pulmonary AEs, diarrhea, or colitis, must have resolved to baseline before 
treatment is resumed 
• 
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment 
If the criteria to resume treatment are met, the subject should restart treatment at the next scheduled 
timepoint per protocol. However, if the treatment is delayed past the next scheduled timepoint per 
protocol, the next scheduled timepoint will be delayed until dosing resumes. 
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study 
therapy, except as specified in discontinuation section. 
Treatment Discontinuation 
 
Discontinuation criteria apply for all drug-related adverse events attributed to nivolumab, 
ipilimumab, or both. Treatment should be permanently discontinued for the following: 
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment. 
 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following exceptions 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 15 of 57 
 
 
for drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, diarrhea, colitis, 
neurologic adverse event, hypersensitivity reactions, and infusion reactions: 
• Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic 
adverse event, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation 
• Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except those noted below: 
o Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation 
o Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation: 
 
AST or ALT > 8 x ULN 
 
Total bilirubin > 5 x ULN 
 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
• Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events which do not require discontinuation: 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 
within 1 week of onset. 
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset 
• Any dosing interruption lasting > 6 weeks with the following exceptions: 
o Dosing interruptions to allow for prolonged steroid tapers to manage drug-related 
adverse events are allowed. Prior to re-initiating treatment in a subject with a 
dosing interruption lasting > 6 weeks, the Principle Investigator must be consulted. 
Tumor assessments should continue as per protocol even if dosing is interrupted 
o Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be 
allowed if approved by the Investigator. Prior to re-initiating treatment in a subject 
with a dosing interruption lasting > 6 weeks, the Princip le Investigator must be 
consulted. Tumor assessments should continue as per protocol even if dosing is 
interrupted 
o Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the Principle Investigator, presents a substantial clinical risk to the 
subject with continued nivolumab dosing 
Post-Treatment Follow-up 
 
Patients who discontinue treatment early due to toxicity, should continue follow up with 
their study physician as clinically appropriate until the resolution or stabilization of the 
toxicity. Thereafter, they should continue to follow the study calendar until week 12 (i.e. 
study visits) and thereafter they should continue with tumor imaging (scans) q 6 months 
or every other scan, visits and labs. 
 
If patients discontinue treatment due to toxicity after they have been on treatment for 12 
weeks, then the q 12 week follow up will begin after the patient’s end of treatment. If the 
patient did not have an end of treatment visit, the q 12 week follow up will begin after the 
patient’s last dose. Patients who experience progression of disease after discontinuing 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 16 of 57 
 
 
treatment early due to toxicity should move to survival follow-up. Patients in toxicity 
follow-up who initiate treatment with a new therapy will be immediately moved to survival 
follow-up. 
 
For melanoma and bladder cancer patients receiving nivolumab or nivolumab plus 
ipilimumab, there is one follow up visit scheduled 6 weeks after the end of treatment. 
Additional follow up visits may be necessary at the discretion of the treating physician (i.e. 
for follow up of study related toxicities). All patients will be followed as per institutional 
guidelines in accordance with the usual standard of care principles. 
Subjects who decline to return to the site for evalutations will be offered follow-up by phone 
every 3 months as an alternative. This will be documented in the patient’s medical record. 
As of MSK Amendment 21, all patients on active follow up should be taken off study as we 
prepare for study closure. 
Survival Follow-up 
 
Patients will be followed up by telephone (or by office visit) every 12 weeks (+/- 2 weeks) for 4 
years from the start of treatment or until death. Follow-up calls or visits should begin 12 weeks (+/- 
2 weeks) from the last study contact. Follow up calls must be documented in the patients’ medical 
records. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
PRODUCT INFORMATION TABLE: Please also see Pharmacy manual in Appendix 1. 
 
Product 
Description and 
Dosage Form 
Potency 
Primary 
Packaging 
(Volume)/ 
Label Type 
Secondary 
Packaging 
(Qty) /Label 
Type 
Appearance 
Storage 
Conditions 
(per label) 
Nivolumab BMS- 
936558-01 
Solution for 
Injection 
100 mg 
(10 
mg/mL) 
10 mL vial 
5-10 vials per 
carton/ Open- 
label 
Clear to opalescent 
colorless to pale 
yellow liquid. May 
contain particles 
Protect form 
light and 
freezing 
Ipilimumab 
Solution for 
Injection 
200 mg (5 
mg/mL) 
40 mL vial 
4 vials per 
carton/Open- 
label 
Clear, colorless to 
pale yellow liquid. 
May contain particles 
2 to 8°C. 
Protect from 
light and 
freezing. 
*Nivolumab may be labeled as BMS-936558-01 Solution for Injection 
If stored in a glass front refrigerator, vials should be stored in the carton. Recommended safety 
measures for preparation and handling of nivolumab and ipilimumab include laboratory coats and 
gloves. 
For additional details on prepared drug storage and use time of nivolumab or ipilimumab under 
room temperature/light and refrigeration, please refer section 8.8 and to the BMS-936558 
(nivolumab) and Ipilimumab Investigator Brochure section for “Recommended Storage and Use 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 17 of 57 
 
 
Conditions” 
Estimated Requirements for Study Drug: 
 
Drug 
Source 
Required Quantity 
For melanoma cohort: 
Nivolumab 
BMS 
Up to 667,200 mg 
 
Induction - 19,200 mg (60 pt x 80 kg x 1 mg/kg x 4 doses) 
Maintenance – 648,000 mg (60 pt x 80 kg x 3 mg/kg x 45 doses) 
Ipilimumab 
BMS 
Up to 57,600 mg (60 pt x 80 kg x 3 mg/kg x 4 doses) 
For bladder cohort: 
Nivolumab 
BMS 
Up to 705,600 mg 
 
Induction – 57,600 mg (60 pt x 80 kg x 3 mg/kg x 4 doses) 
 
Maintenance/ Monotherapy – 648,000 mg (60 pt x 80 kg x 3 mg/kg x 45 doses) 
 
Ipilimumab 
BMS 
Up to 19,200 mg (60 pt x 80 kg x 1 mg/kg x 4 doses) 
Drug Dosing 
 
For patients receiving nivolumab monotherapy, the drug shall be dosed at a dose of 240 mg (every 
2 weeks) or 480 mg (every 4 weeks). 
 
For patients initiated on treatment, or initiated on crossover treatment after the approval of 
Amendment 11, the dosing for the combination of ipilimumab and nivolumab will be ipilimumab 3 
mg/kg and nivolumab 1 mg/kg for both bladder and melanoma patients. For patients who 
initiated treatment with the combination of ipilimumab and nivolumab prior to Amendment 11, 
they will maintain their current dosing/schedule. 
For patients receiving the combination of nivolumab and ipilimumab, the dosing calculations should 
be based on the actual body weight at screening (within 28 days of starting therapy). For Bladder 
crossover patients, the baseline weight for crossover should be used for dosing calculations 
instead of the weight collected during screening for monotherapy. For all patients receiving the 
combination of nivolumab and ipilimumab, if the subject’s weight within 5 days of dosing differs by 
> 10% from the weight used to calculate the original dose, the dose must be recalculated. All 
subsequent dosing should use the baseline weight unless the patients weight has changed by 
> 10% from the weight used to calculate the original dose. If the patients dose differs by > 10% from 
the weight used to calculate the original dose, the dose must be recalculated. All doses should be 
rounded to the nearest milligram. There will be no dose modifications allowed. See appendix 1 for 
additional details. 
Drug Storage, Preparation and Administration 
 
See appendix 1. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 18 of 57 
 
 
 
Ipilimumab and Nivolumab will both be provided by BMS to the study sites. An IND for each agent 
will be cross filed and will be held by MSKCC, the data coordinating center. 
 
 
6.0 CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
For entry into the study, all of the following criteria must be met: 
1. Subjects must have signed and dated an IRB approved written informed consent in 
accordance with regulatory and institutional guidelines. This must be obtained before the 
performance of any protocol related procedures that are not part of normal subject care. 
2. Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests, tumor biopsies, and other requirements of the study. 
3. Pathologically confirmed locally advanced or metastatic disease per the treating 
institution’s standard of care of the following tumor types: 
a. Subjects with histologically confirmed locally advanced/unresectable or metastatic 
melanoma who meet all of the following criteria: 
i. Subjects have received any number of prior lines of therapy or may be 
treatment naïve 
ii. If the subject has been treated with a prior line of therapy, they must have 
had disease progression or be refractory to treatment 
OR 
b. Subjects with histologically or cytologically confirmed locally 
advanced/unresectable or metastatic urothelial carcinoma (including mixed 
histologies of urothelial carcinoma with elements of other subtypes) of the renal 
pelvis, ureter, bladder or urethra (referred to broadly in this protocol as “bladder 
cancer”) who meet the following criteria: 
i. Subjects must have disease progression or refractory disease after their 
prior line of therapy. Subjects must have had at least 1 platinum based 
chemotherapy regimen for the treatment of metastatic or locally advanced 
unresectable disease. Subjects may have received any number of prior lines 
of therapy 
OR 
ii. Subjects with disease recurrence within 1 year of a platinum based 
neoadjuvant or adjuvant therapy for bladder cancer. 
OR 
iii. The subject actively refuses chemotherapy for the treatment of metastatic or 
locally advanced disease considered as standard treatment for this disease 
stage (i.e. a patient who has relapsed >1 year after treatment with 
neoadjuvant or adjuvant chemotherapy), despite being informed by the 
investigator about the treatment options. The subject’s refusal must be 
documented. 
4. Subjects must have measurable disease by CT scans or MRI per RECIST 1.1 criteria. 
Radiographic tumor assessment must be performed within 28 days prior to first dose of 
study drug. 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 
6. Age ≥ 18 years. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 19 of 57 
 
 
7. Subjects must consent to allow for the acquisition of tumor sample prior to starting 
treatment on study (in most cases patients will require a tumor biopsy). This biopsy site 
may be the only site of measurable disease if the site is > 2 cm. The biopsy site must, in 
the opinion of the investigator, be likely to yield acceptable tumor sample for core biopsies 
as described in Appendix 3. It is also acceptable if tumor sample is obtained by excision 
biopsy or during surgery (i.e. if procedure was previously planned), provided the tumor 
sample can be processed as described in Appendix 3. In the case that a patient had a 
tumor sample acquired prior to consenting to the study and this tumor sample is 
acceptable for processing as described in Appendix 3 (i.e. frozen sample stored) and the 
tumor sample was acquired within 60 days of starting treatment, this is acceptable and a 
new biopsy will not be required. 
8. Willingness to adhere to the study visit schedule and prohibitions as specified in this 
protocol. 
9. Expected survival of at least 4 months. 
10. At the time of day 1 of the study, patients must have completed chemotherapy, targeted 
therapy, investigational therapy, other immunotherapy, radiation therapy or major surgery 
(requiring general anesthesia) at least 28 days before administration of the first dose of 
nivolumab. Patients undergoing minor surgical procedures and biopsies that do not 
require general anesthesia may begin receiving study therapy if sufficiently recovered as 
determined by the treating investigator. Patients may have received prior focal 
radiotherapy for palliation of an isolated site of disease, which must be completed at least 
14 days prior to day 1 of the study. 
Palliative (limited-field) radiation therapy is permitted during treatment with study 
drug(s). 
 
11. All baseline laboratory requirements will be assessed and should be obtained within 14 
days of the first dose of study drug. Screening laboratory values must meet the following 
criteria: 
 
• 
• 
• 
White blood cells (WBCs) 
Neutrophils 
Platelets 
≥ 2000/μL 
≥ 1000/μL 
≥ 100 x 103/μL 
• 
Hemoglobin 
≥ 9.0 g/dL 
• 
Serum creatinine 
≤ 1.5 x ULN (or glomerular filtration rate ≥ 40mL/min) 
• 
Bilirubin 
≤ 1.5 x ULN (except subjects with Gilbert’s syndrome who 
must have total bilirubin ≤ 3.0mg/dL) 
• 
AST and ALT 
 ≤  3 x ULN 
• 
Albumin 
≥ 3.0 g/dL 
 
6.2 
Subject Exclusion Criteria 
 
Patients may not enter the study if they fulfill any of the following criteria: 
 
1. Active brain metastases or leptomeningeal metastases. Subjects with treated brain 
metastases are eligible if they meet all of the following criteria: 
a. Must be at least 28 days since craniotomy and resection, stereotactic 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 20 of 57 
 
 
radiosurgery, or whole brain radiotherapy. 
b. Must have no evidence of progression for at least 4 weeks after treatment is 
complete and within 28 days prior to first dose of study drug administration. 
c. Must have no requirement for immunosuppressive doses of systemic corticosteroids 
(> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug 
administration. 
 
2.  Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair 
the ability of the subject to receive protocol therapy or interfere with the interpretation of 
study results. 
3. Other prior malignancy active within the previous 2 years except for local or organ 
confined early stage cancer that has been definitively treated with curative intent or does 
not require treatment, does not require ongoing treatment, has no evidence of active 
disease and has a negligible risk of recurrence and is therefore unlikely to interfere with 
the endpoints of the study. 
4. Subjects with active autoimmune disease, symptoms or conditions. Subjects with vitiligo, 
type I diabetes, residual hypothyroidism due to autoimmune thyroiditis only requiring 
hormone replacement, asymptomatic laboratory evidence of autoimmune disease (e.g.: 
+ANA, +RF, antithyroglobulin antibodies), or conditions not expected to recur in the 
absence of an external trigger are permitted to enroll. 
5. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
first dose of study drug. Inhaled or topical steroids, and adrenal replacement steroid doses 
are permitted in the absence of active autoimmune disease. 
 
6. Subjects who have received prior therapy with any T cell co-stimulation or checkpoint 
pathways such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, anti-CD137; or other 
medicines specifically targeting T cells are prohibited. Prior therapy with BCG is permitted. 
Prior IL-2 is permitted. 
7.  All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to grade 1 (CTCAE version 4) or baseline before administration of study 
drug. Subjects with toxicities attributed to prior anti-cancer therapy and which are not 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 21 of 57 
 
 
expected to resolve and result in long lasting sequelae such as neuropathy after platinum- 
based therapy, are permitted to enroll. 
8. Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBV sAg) test or 
positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV 
antibody test indicating acute or chronic infection. 
 
9. Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). 
 
10. History of allergy to study drug component or history of severe hypersensitivity reaction to 
any monoclonal antibody 
11. Women who are breast feeding or pregnant as evidenced by positive serum pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of HCG) done within 14 days of first 
dosing and urine test within 72 hours of first dosing. 
 
12. Women of childbearing potential (WOCBP) not using a medically acceptable means of 
contraception throughout the study treatment and for at least 23 weeks following the last 
dose of study treatment (5 half-lives of study drug plus 30 days duration of ovulatory 
cycle). 
WOCBP are defined as those who has experienced menarche and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy) or is not postmenopausal. Post-menopausal is defined as: 
 
-Amenorrhea ≥ 12 consecutive months without another cause, or 
-For women with irregular menstrual periods and on hormone replacement therapy 
(HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL 
 
13. Male subjects who are unwilling to use contraception during the treatment and for at least 
31 weeks after the last dose of study treatment (5 half-lives of study drug plus 90 days 
duration of sperm turnover). 
14. Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(e.g., infectious disease) illness. 
 
Restricted Concomitant Treatments 
 
1. Immunosuppressive agents (except to treat a study-drug related adverse event) 
2. Systemic corticosteroids > 10 mg daily prednisone equivalent (except to treat a study-drug 
related adverse event or as per section 4.2) 
3. Any concurrent antineoplastic therapy, chemotherapy, immunotherapy, biologic therapy, 
except for palliative radiotherapy as described in section 6.1. 
 
7.0 
RECRUITMENT PLAN 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 22 of 57 
 
 
 
Potential research subjects will be identified by a member of the patient’s treatment team, the 
protocol investigator, or research teams at Memorial Sloan-Kettering Cancer Center and 
participating institutions. If the investigator is a member of the treatment team, s/he will screen 
their patient’s medical records for suitable research study participants and discuss the study and 
their potential for enrolling in the research study. Potential subjects contacted by their treating 
physician will be referred to the investigator/research staff of the study. 
 
The MSKCC Principal Investigator may also screen the medical records of patients with whom 
they do not have a treatment relationship for the limited purpose of identifying patients who would 
be eligible to enroll in the study and to record appropriate contact information in order to approach 
these patients regarding the possibility of enrolling in the study. 
 
During the initial conversation between the investigator/research staff and the patient, the patient 
may be asked to provide certain health information that is necessary to the recruitment and 
enrollment process. The investigator/research staff may also review portions of their medical 
records at MSKCC in order to further assess eligibility. They will use the information provided by 
the patient and/or medical record to confirm that the patient is eligible and to contact the patient 
regarding study enrollment. If the patient turns out to be ineligible for the research study, the 
research staff will destroy all information collected on the patient during the initial conversation 
and medical records review, except for any information that must be maintained for screening log 
purposes. 
 
In most cases, the initial contact with the prospective subject will be conducted either by the 
treatment team, investigator or the research staff working in consultation with the treatment 
team. The recruitment process outlined presents no more than minimal risk to the privacy of the 
patients who are screened and minimal PHI will be maintained as part of a screening log. For 
these reasons, we seek a (partial) limited waiver of authorization for the purposes of (1) 
reviewing medical records to identify potential research subjects and obtain information relevant 
to the enrollment process; (2) conversing with patients regarding possible enrollment; (3) 
handling of PHI contained within those records and provided by the potential subjects; and (4) 
maintaining information in a screening log of patients approached (if applicable). 
 
This limited waiver will apply only to MSK. Any participating sites that require a limited waiver 
must obtain it from their own local IRB/Privacy Board (PB) via a separate protocol addendum or 
request. It is the responsibility of the MSK staff to confirm the participating data collection site(s) 
have a limited waiver approved by their local IRB(s)/PBs. 
 
8.0 
PRETREATMENT EVALUATION 
 
Disease Staging 
Disease Assessment by RECIST 1.1 
Tumor Biopsy 
Other Examinations 
Eligibility Assessment and Informed Consent 
Demographics 
Medical History 


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IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 23 of 57 
 
 
 
Vitals 
ECOG & Physical Exam 
Adverse Events Assessment 
Labs & Assays 
Pregnancy Test (see Section 6.2, serum based.) 
Urine pregnancy test (within 3 days prior to dosing) 
Chemistry: Sodium, Potassium, Chloride, CO2, BUN, 
Creatinine, Glucose, Calcium, Magnesium, AST, ALT, 
Alkaline Phosphatase, Total Bilirubin, LDH, TSH, Free or 
Total T31, Free or Total T41, albumin 
Blood Hematology (CBC with differential) 
Research Blood Draw 
HIV, Hepatitis B and Hepatitis C tests 
 
1. Total T3 or Free T3 and Total T4 of Free T4 may be collected according to treating physician preference 
and institutional availability. 
 
9.0 
TREATMENT/INTERVENTION PLAN 
Treatment of protocol eligible patients with nivolumab or nivolumab and ipilimumab will follow the 
treatment plan described in section 4.2. Treatment with nivolumab or nivolumab and ipilimumab 
are deemed experimental treatments. Treatment with nivolumab or nivolumab and ipilimumab will 
occur in the outpatient setting. 
The following interventions on treatment are considered routine and will be performed according 
to the schedules in section 10.0 with indicated time windows. 
• 
Disease assessment by RECIST 1.1 (CT scan CAP, or alternative imaging as 
needed for disease assessment and MRI or CT brain, if applicable) 
• 
Medical History 
• 
Vitals (including Height and Weight) 
• 
Physical Exam 
• 
Pregnancy test (serum or urine)- only if WOCBP 
• 
Chemistry Panel Comprehensive Metabolic Panel (including AST, ALT, total 
bilirubin) LDH, TSH, Total or Free T3, Total or Free T4, albumin 
Note: 1. Total T3 or Free T3 and Total T4 of Free T4 may be collected 
according to treating physician preference and institutional availability. 
• 
Hematology Panel – CBC with differential 
• 
HIV, Hepatitis B and Hepatitis C tests 
The following interventions on treatment are considered research and will be performed according 
to the schedules in section 10.0 with indicated time windows. Additional details are available in 
Appendix 3. 
• 
Tumor Biopsy 
• 
Research Blood draw for collection of PBMCs and serum (6 time points for bladder 
crossover cohort and melanoma cohort, 8 time points for bladder monotherapy cohort) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 24 of 57 
 
 
 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 25 of 57 
 
 
10.1 Standard Evaluation 
Flowchart 1 - Nivolumab Monotherapy for Patients with Bladder Cancer 
Study Section 
Screening 
Baseline 
Initial Treatment 
Treatment beyond 
Week 12 
(up to 2 yrs)h 
(+/- 3 d) 
End of Nivolumab Treatment e 
If patient has not proceeded 
to Crossover Theraoy 
Study Week 
0 
2 
(+/-3 d) 
4 
(+/-3 d) 
6 
(+/-3 d) 
8 
(+/-3 d) 
10 
(+/-3 d) 
12 
(+/-3 d) 
Last Day 
(EOT Only) 
Last Day + 6 
Weeks (+/- 1 wk, 
EOT only) 
Study Day 
-28 to -1 
-14 to -1 
(or as stated) 1 
15 
29 
43 
57 
71 
82 
Drug Administration 
Nivolumab (240 mg or 480 mg) a 
X 
X 
X 
X 
X 
X 
x 
q 2 wks (240 mg) 
OR q 4 wks (480 mg) 
Tumor Assessments 
Disease Staging 
X 
Disease Assessment by RECIST 
1.1(including MRI or CT brain at 
screening) 
X 
Every 6 weeks (+/- 7 days) from first dose for the first 24 weeks and then every 12 weeks (+/- 7 days) thereafter until 
study discontinuation. i 
MRI or CT brain required at screening, but only necessary for subsequent disease assessments in patients with known disease 
metastatic to the CNS f 
Tumor Biopsy 
X 
2 weeks (- 5, +5 days) from first dose and before 2nd dose of therapy g 
At tumor progression (+ 14 days) g 
Other Examinations 
Eligibility Assessment and 
Informed Consent 
X 
Demographics 
X 
Medical History 
X 
ECOG, Vital Signs (including 
Height, Weight), Physical Exam & 
collection of concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
q 2 weeks/ 
q 4 weeks j 
X 
X 
EKG 
X 
Adverse Events Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
q 2 weeks/4weeks j 
X 
X 
Labs & Assays 
Pregnancy Test (see Section 
5.2.17, serum based. b 
3mL 
X 
X 
Urine pregnancy test (within 3 
days prior to dosing) b 
X 
X 
X 
X 
X 
X 
X 
q 2 weeks/4 weeks j 
Chemistry (Comprehensive 
Metabolic Panel, LDH, TSH) c 
X 
X 
X 
X 
X 
X 
X 
X 
q 2 weeks/4 weeks j 
X 
X 
Blood Hematology (CBC with 
differential) c 
X 
X 
X 
X 
X 
X 
X 
X 
q 2 weeks/4 weeks j 
X 
X 
Research Blood Draw [mL] c 
60mL 
60mL 
60mL 
60mL 
60mL 
60mL 
60mL 
60mL 
60 mL 
HIV, Hepatitis B and Hepatitis C 
X 
Survival Follow-up d 
X 
X 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 26 of 57 
 
 
a. Nivolumab may be dosed no less than 11 days from the previous dose of drug. 
b. Pregnancy tests are not required if the patient is a male or a woman not of child-bearing potential 
c. Blood drawn prior to dosing drug. Blood must be drawn at all required timepoints. Results of thyroid functions tests are not required prior to dosing drug. 
d. Patients will be followed up by telephone (or by office visit) every 12 weeks (+/- 2 weeks) for 4 years from the start of treatment or until death. Follow-up calls or visits should begin 12 weeks +/- 2 weeks from the last study contact. 
e. If the patient will not initiate treatment with the combination, end of treatment should be initiated as per Study Flowchart 3 
f. Patients who discontinue treatment due to toxicity will continue to follow the study procedures (without treatment) for 12 weeks from the start date. They will require all disease assessments according to study protocol, however, 
after 12 weeks, all other study assessments (PE, Laboratory assays) will be performed every 12 weeks (+/-7 days). If patients discontinue treatment due to toxicity after they have been on treatment for 12 weeks, then the q 12 
week follow up will begin after the patient’s end of treatment. If the patient did not have an end of treatment visit, the q 12 week follow up will begin after the patient’s last dose.  Patients who experience progression of 
disease after discontinuing treatment early due to toxicity should move to survival follow-up. Patients in toxicity follow-up who initiate treatment with a new therapy will be immediately moved to survival follow-up. 
g. Optional 
h. Patients with a proven ability to tolerate treatment who have been on study for longer than one year will have visits with physicians every 4 weeks and treatment-only visits in between. 
I. Patients who have completed 26 weeks of treatment may elect to complete disease assessment scans every 6 months (24 weeks). This will continue until study discontinuation, under the treating investigator’s discretion 
j. Frequency of ECOG, Vital Signs, Physical Exam, AE Assessments and all lab panels should follow the frequency of Nivolumab treatment (q 2 weeks or q 4 weeks) and should occur simulataneously within the same visit 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 27 of 57 
 
 
Flowchart 2 - Nivolumab plus Ipilimumab Combination Treatment for Patients with Melanoma 
Study Section 
Screening 
Baseline 
Initial Treatment 
Treatment beyond Week 
12 (up to 2 yrs) e,h 
(+/- 3 d) 
End of Treatment 
Study Week 
0 
3 
(+/-3 d) 
6 
(+/-3 d) 
9 
(+/-3 d) 
Last day 
Last day 
+6 weeks 
(+/- 1 wk) 
Study Day 
-28 to -1 (
-14 to -1 
or as stated) 
1 
22 
43 
64 
Drug Administration 
Nivolumab 1 mg/kg 
X 
X 
X 
X 
Nivolumab 240 mg or 480 mg a 
q 2 wks (240 mg) OR 
q 4 wks (480 mg) 
Ipilimumab 3 mg/kg 
X 
X 
X 
X 
Tumor Assessments 
Disease Staging 
X 
Disease Assessment by RECIST 1.1 
(including MRI or CT brain at 
screening) 
X 
Every 6 weeks (+/- 7 days) from first dose for the first 24 weeks and then every 12 weeks (+/- 7 days) thereafter until study 
discontinuation. i 
MRI or CT brain required at screening, but only necessary for subsequent disease assessments in patients with known disease 
metastatic to the CNS f 
Tumor Biopsy 
X 
2 weeks (- / +5 days) from first dose and before 2nd dose 
of therapy g 
At tumor progression (+ 14 days) g 
Other Examinations 
Eligibility Assessment 
X 
Demographics 
X 
Medical History 
X 
ECOG, Vital Signs (including Height, 
Weight), Physical Exam & collection of 
concomitant medications 
X 
X 
X 
X 
X 
q 2 weeks / q 4 weeks j 
X 
X 
EKG 
X 
Adverse Events Assessment 
X 
X 
X 
X 
X 
q 2 weeks / q 4 weeks j 
X 
X 
Labs & Assays 
Pregnancy Test (see Section 5.2.17, 
serum based.) b 
3 mL 
X 
X 
Urine pregnancy test (within 3 days 
prior to dosing) b 
X 
X 
X 
X 
q 2 weeks / q 4 weeks j 
Chemistry (Comprehensive Metabolic 
Panel, LDH, TSH) c 
X 
X 
X 
X 
X 
q 2 weeks / q 4 weeks j 
X 
X 
Blood Hematology (CBC with 
differential) c 
X 
X 
X 
X 
X 
q 2 weeks / q 4 weeks j 
X 
X 
Research Blood Draw [mL] c 
60mL 
60mL 
60mL 
60mL 
60mL 
60mL 
HIV, Hepatitis B and Hepatitis C tests 
X 
Survival Follow-up d 
X 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 28 of 57 
 
 
 
a. Nivolumab may be dosed no less than 11 days from the previous dose of drug. 
b. Pregnancy tests are not required if the patient is male or a woman of child-bearing potential. 
c. Blood drawn prior to dosing drug. Blood must be drawn at all required timepoints. Results of thyroid functions tests are not required prior to dosing drug. 
d. Patients will be followed up by telephone (or office visit) every 12 weeks (+/- 2 weeks) for 4 years from the start of treatment or until death. Follow-up calls or visits should begin 12 weeks +/- 2 weeks from the last study contact. 
e. First dose of nivolumab monotherapy is on week 12 (+/- 3 days) 
f. Patients who discontinue treatment due to toxicity will continue to follow the study procedures (without treatment) for 12 weeks from the start date. They will require all disease assessments according to study protocol, however, after 
12 weeks, all other study assessments (PE, Laboratory assays) will be performed every 12 weeks (+/-7 days). If patients discontinue treatment due to toxicity after they have been on treatment for 12 weeks, then the q 12 week 
follow up will begin after the patient’s end of treatment. If the patient did not have an end of treatment visit, the q 12 week follow up will begin after the patient ’s last dose.  Patients who experience progression of disease after 
discontinuing treatment early due to toxicity should move to survival follow-up. Patients in toxicity follow-up who initiate treatment with a new therapy will be immediately moved to survival follow-up. 
g. Optional 
h. Patients with a proven ability to tolerate treatment who have been on study for longer than one year will have visits with physicians every 4 weeks and treatment-only visits in between. 
I. Patients who have completed 26 weeks of treatment may elect to complete disease assessment scans every 6 months (24 weeks). This will continue until study discontinuation, under the treating investigator’s discretion 
j. Frequency of ECOG, Vital Signs, Physical Exam, AE Assessments and all lab panels should follow the frequency of Nivolumab treatment (q 2 weeks or q 4 weeks) and should occur simulataneously within the same visit 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 29 of 57 
 
 
 
Flowchart 3 - Nivolumab plus Ipilimumab Combination Treatment for Patients with Bladder Cancer Eligible for Crossover (or Reinduction with 
Combination Treatment for Bladder or Melanoma Patients) 
Study Section 
Baselinea 
Initial Treatment 
Treatment beyond 
Week 12 
(up to 2 yrs) f, i 
(+/- 3 d) 
End of Treatment 
Study Week 
0 
3 
(+/-3 d) 
6 
(+/-3 d) 
9 
(+/-3 d) 
Last day 
Last day 
+6 weeks 
(+/- 1 wk) 
Study Day 
-28 to 0 
1 
22 
43 
64 
Drug Administration 
Nivolumab 1 mg/kg b 
X 
X 
X 
X 
Ipilimumab 3 mg/kg 
X 
X 
X 
X 
Re-induction (if applicable) 
Nivolumab 240 mg or 480 mg 
q 2 wks (240 mg) OR 
q 4 wks (480 mg) 
Tumor Assessments 
Disease Assessment by RECIST 1.1 (MRI or CT 
brain only necessary in patients with known disease 
metastatic to the CNS) 
X 
Every 6 weeks (+/- 7 days) from first dose for the first 24 weeks and then every 12 weeks (+/- 7 days) thereafter until study 
discontinuation MRI or CT brain only necessary in patients with known disease metastatic to the CNS g, j 
Tumor Biopsy 
X h 
2 weeks (- 5, +5 days) from first dose and before 2nd dose of 
therapy h 
At tumor progression (+ 14 days) h 
Other Examinations 
Eligibility Assessment 
X 
Demographics 
X 
Medical History 
X 
ECOG, Vital Signs (Height, Weight), Physical Exam 
& collection of concomitant medications 
 
X 
X 
X 
X 
X 
q 2 weeks / q 4 weeks k 
X 
X 
EKG 
X 
Adverse Events Assessment 
X 
X 
X 
X 
X 
q 2 weeks / q 4 weeks k 
X 
X 
Labs & Assays 
Pregnancy Test (see Section 5.2.17, serum 
based.) c 
3 mL 
X 
X 
Urine pregnancy test (within 3 days prior to 
dosing) c 
X 
X 
X 
X 
q 2 weeks / q 4 weeks k 
Chemistry (Comprehensive Metabolic Panel, 
LDH, TSH) d 
X 
X 
X 
X 
X 
q 2 weeks / q 4 weeks k 
X 
X 
Blood Hematology (CBC with differential) d 
X 
X 
X 
X 
X 
q 2 weeks / q 4 weeks k 
X 
X 
Research Blood Draw [mL] d 
60mL 
60mL 
60mL 
60mL 
60mL 
60mL 
HIV, Hepatitis B and Hepatitis C tests 
Survival Follow-up e 
X 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 30 of 57 
 
 
 
a. Baseline procedures do not need to be repeated for reinduction combination treatment for bladder or melanoma patients. 
b. For patients with melanoma, ipilimumab will be dosed at 3 mg/kg and nivolumab at 1 mg/kg, for patients with bladder cancer ipilimumab will be dosed at 3 mg/kg and nivolumab at 1 mg/kg. Nivolumab may be dosed no less than 11 
days from the previous dose of drug. 
c. Pregnancy tests are not required if the patient is male or a woman not of child-bearing potential 
d. Blood drawn prior to dosing drug. Blood must be drawn at all required timepoints. Results of thyroid functions tests are not required prior to dosing drug. 
e. Patients will be followed up by telephone (or office visit) every 12 weeks (+/- 2 weeks) for 4 years from the start of treatment or until death. Follow-up calls or visits should begin 12 weeks +/- 2 weeks from the last study contact. 
f. First dose of nivolumab monotherapy is on week 12 (+/- 3 days) 
g. Patients who discontinue treatment due to toxicity will continue to follow the study procedures (without treatment) for 12 weeks from the start date. They will require all disease assessments according to study protocol, however, after 
12 weeks, all other study assessments (PE, Laboratory assays) will be performed every 12 weeks (+/-7 days). If patients discontinue treatment due to toxicity after they have been on treatment for 12 weeks, then the q 12 week follow 
up will begin after the patient’s end of treatment. If the patient did not have an end of treatment visit, the q 12 week follow up will begin after the patient’s last dose. Patients who experience progression of disease after 
discontinuing treatment early due to toxicity should move to survival follow-up. Patients in toxicity follow-up who initiate treatment with a new therapy will be immediately moved to survival follow-up. 
h. Optional 
i. Patients with a proven ability to tolerate treatment who have been on study for longer than one year will have visits with physicians every 4 weeks and treatment-only visits in between. 
j. Patients who have completed 26 weeks of treatment may elect to complete disease assessment scans every 6 months (24 weeks). This will continue until study discontinuation, under the treating investigator’s discretion 
k. Frequency of ECOG, Vital Signs, Physical Exam, AE Assessments and all lab panels should follow the frequency of Nivolumab treatment (q 2 weeks or q 4 weeks) and should occur simulataneously within the same visit 


Memorial Sloan Kettering Cancer Center 
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Page 31 of 57 
 
 
 
10.2 
Shipping of Specimens 
 
All samples must be labeled with the unique MSKCC CRDB participant study identification 
number and date of the specimen collection. 
 
Frozen, banked PBMC samples are to be shipped on dry ice to MSK along with the appropriate 
Study Requisition Form to the address indicated on the form . Shipments should be made in 
batches every 3-6 months. 
 
FFPE slides or blocks are to be shipped at ambient temperature to MSK along with the 
appropriate Study Requisition Form to the address indicated on the form . Shipments should 
be made in batches every 3-6 months. 
 
Frozen purified DNA and RNA samples for sequencing are to be shipped on dry ice to UConn 
along with the appropriate Study Requisition Form to the address indicated on the form . 
Shipments should be made in batches every 2-4 weeks. 
All participating sites will notify the MSK study coordinator when samples are shipped by 
completing and emailing the sample requisition form. 
10.3 Future Unspecified Use of Biospecimens 
 
The protocol includes an informed consent document and research authorization that meets 
statutory guidelines. Each participating site will have its own consent form meeting the 
requirements described in this section. The consent form will inform patients of the purpose of 
the bank, their rights in relation to it, and the safeguards in place to protect the confidentiality 
of their health information. The consent will state that some of the biospecimens will be saved 
to use for future research. 
 
Type of future use 
The consent specifically describes the types of future research that may be performed, 
including use of tissues to develop new drugs with cancer-associated molecular targets, 
development of cell lines, future use of cell lines to define cancer phenotype and (somatic) 
genotype, DNA sequence analysis of tumor compared to normal and identification of tumor- 
associated proteins as diagnostic or prognostic markers. It will be stated that researchers at 
MSK may either keep indefinitely or dispose of any leftover blood or tissues or other 
samples, including DNA that the samples contain. Blood and tissues will be stored with 
identifiers in secure tissue or fluid banks. It is stated that the samples could be lost or ruined 
because of mechanical failure, and that MSK cannot guarantee that samples will be stored 
indefinitely. The samples will be stored for as long as deemed useful for research purposes. 
Consent for future use and re-contact 
Patients are asked in a series of check boxes at the end of the consent if 1) they permit their 
biospecimen samples to be stored and used in future research to learn about or prevent 
cancer or side effects of treatment, or to develop new treatments; 2) if they permit their 
samples to be stored and used in future research to learn about, prevent, or treat diseases 
other than cancer; or 3) if they permit their samples, with personal identifiers protected, to be 


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IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 32 of 57 
 
 
used for research about inherited genetic factors, 4) if they permit their samples to be used 
for genetic analysis of the tumor and normal tissue to learn about the causes of cancer, 5) 
participants are asked if they agree to be contacted in the future as part of research studies 
for additional health information or to be asked to participate in future biospecimen research 
studies and 6) if they consent to be contacted to discuss research findings which may come 
from their sample. Finally, if not available (e.g. deceased), if they wish to have their designee 
designated on the consent to be contacted. 
Participants will not be provided with specific results of research tests performed on their 
collected human biologic specimens. 
 
Use of identifiable information for genetic studies 
In the course of this research it is possible that some patients whose tumors are analyzed 
through investigational “next-generation” profiling in a research (non-CLIA) environment will 
be found to have somatic or germline mutations in genes that are known to be associated 
with an increased risk of cancer or other diseases. It will be stated in the consent that the 
participants will not receive any specific results from research tests. The consent will tell 
participants that if they wish to have genetic testing done for personal reasons than they 
should make an appointment with the MSK Clinical Genetics Service or Clinical Genetics 
Service at their site. 
 
If in the course of this research a research finding is obtained that, in the opinion of the 
investigator, may be critical to the preventive care of the participant or their family, the 
investigator can communicate that finding to the MSK IRB Genomic Advisory Panel (GAP). 
The finding will be reviewed by the GAP to determine whether the incidental finding should 
be discussed with the participant. For MSK patients, in the event that the GAP determines 
that the finding should be discussed with the participant, and the participant has consented to 
be re-contacted, then the treating/consenting physician shall be contacted by the panel and 
asked to refer the participant to the Clinical Genetics Service for further discussion of the 
research finding. 
 
The following information must be provided to GAP for review: 
• 
Participant Name/MRN # 
• 
Type of Biospecimen (tissue, blood, saliva) 
• 
Incidental Finding 
• 
Collection Protocol # 
• 
Contact: ocrgapirb@mskcc.org 
For non-MSK patients being treated at one of the participating institutions, if the GAP 
determines the finding to be reportable to the participant and the participant has consented to 
be re-contacted, results will be returned to the Site Principal Investigator via the study team. 
Site policies on returning these research findings to the patient should be followed. 
 
We anticipate that other research assays may be incorporated into this protocol as 
technology evolves. 
 
Voluntariness of research participation 


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Approval date: 23-Feb-2024 
Page 33 of 57 
 
 
It is stated that taking part in this tissue and blood bank is voluntary and patients have the 
right to withdraw at any time. Participation in the study will not impact on the clinical care 
patients receive. 
 
Withdrawal 
Participants may decide at a later date that they do not want identified blood and tissue 
samples to be stored in the tissue bank and /or used for future research. If participants 
decide to withdraw from the study, specimens that have not yet left the specimen archive will 
not be used in new studies and any remaining portions of samples that have not been used 
for research will be used only for clinical purposes or, if requested by the patient, destroyed. 
For specimens already shipped out from the archive, it may not be possible to locate the 
samples or stop already ongoing research. The withdrawal request will be documented in 
CRDB and the system updated accordingly. In addition, a note-to-file documenting the 
patient withdrew must be filed in his/her medical records. 
 
Rights after death 
The consent states that if the research participant dies or is unable to make his/her wishes 
known, all of their rights to decide about future uses of the blood or tissues will pass to the 
authorized representative of the estate. If there is no representative of the estate, the rights 
pass to the next of kin. 
 
Risks of research participation 
The greatest risk is release of information from health or research records in a way that 
violates privacy rights. MSK and any participating sites will protect records so that name, 
address, phone number, and any other information that identifies the participant will be kept 
private. It will be stated to the participant that the chance that this information will be given to 
an unauthorized individual without the participant’s permission is very small. 
Costs/compensation 
There is no cost to the participant to enroll in this research. Tissue or blood obtained in this 
research may be used to make a cell line, and these may be patented or licensed and thus 
may have significant commercial value. The participant is informed that there are no plans to 
provide financial compensation for use of their human biologic specimens, nor are there 
plans for the participant to receive money for any new products, tests, and discoveries that 
might come from this research. 
 
Biospecimen Privacy 
Medical information is confidential. The participant’s personal identity will not be used in 
reports that are written about the research. The MSK IRB/PB will review all requests for 
research performed involving biospecimens ascertained through this protocol. Blood and 
tissue samples may be stored with a code linked to the patient’s medical record. The results 
of any research using blood or tissues will not be placed in the medical record. 
 
The consent indicates that samples and genetic information collected may be shared with 
other qualified researchers and placed in online databases. An example of an online 
database is the NIH dbGAP database, which is monitored by the National Institutes of 
Health, and may be made accessible to investigators approved by the U.S. government. 
Such information will not include identifying information such as name. It is also stated in the 


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IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 34 of 57 
 
 
Research Authorization (HIPAA Authorization) that research data (e.g. genomic sequence) 
may be shared with regulators. The requirements for submission of genotype/phenotype data 
into the NIH dbGAP or any other public database will be followed as per the IRB SOP for 
Genomic Data Sharing. 
 
Use of banked samples (at MSK) 
When samples are to be analyzed, the individual investigator needs to write an IRB 
biospecimen protocol. This protocol is fast-tracked through MSK Research Council review 
and is reviewed at the MSK IRB by the expedited review process. This protocol is only for 
research that will be done on biospecimens obtained under identified protocols and their 
informed consent and research authorization that include the institutional future use 
questions. The consent and research authorization for the use of the biospecimens will be 
waived as per 45 CFR 46.116(d) and 45 CFR 164.512(i)(2)(ii). 
 
 
11.0 TOXICITIES/SIDE EFFECTS 
Anticipated Toxicities for Ipilimumab and Nivolumab and detailed in the attached Investigators 
Brochures provided by BMS. 
11.1 
Definition of an Adverse Event 
An Adverse Event (AE) is any untoward medical occurrence in a patient administered the study 
intervention, which does not necessarily have a causal relationship with the treatment. An AE 
can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the study 
intervention. AEs may also include pre- or post-treatment complications that occur as a result of 
protocol specified procedures, lack of efficacy, overdose, or drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during 
or as a consequence of participation in the clinical study will also be considered AEs. 
 
An AE does not include the following: 
• 
Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and 
transfusion. The condition that led to the procedure may be an AE and must be 
reported. 
• 
Pre-existing diseases, conditions, or laboratory abnormalities present or detected 
before the screening visit that do not worsen 
• 
Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery, social and/or convenience admissions) 
• 
Overdose without clinical sequelae 
• 
Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure 
is not an AE. It is considered to be pre-existing and should be documented as part of 
the patient’s medical history. 


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Approval date: 23-Feb-2024 
Page 35 of 57 
 
 
 
Adverse event reporting will be performed in accordance with institutional guidelines for 
reporting to each participating sites local IRB. Toxicities and laboratory abnormalities will be 
assessed according to CTCA 4.0. All toxicities that meet criteria of Grade 2 or higher, 
regardless of causal relationship to nivolumab and/or ipilimumab, will be reported to MSK. 
Grade 1 toxicities unrelated to study drug will not be required to be reported. Any toxicity 
related to study drug will be reported to MSK. All serious adverse events will be reported to 
both MSK and to BMS in accordance with guidelines outlined in section 17.2.1. 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
Patients are considered evaluable for the primary and secondary endpoints if adequate 
sequencing data is generated from pre-study biopsy material to determine mutation burden/neo- 
antigen score. 
 
Responses will be assessed by RECIST 1.1. 
 
Additional clinical endpoints will be evaluated in an exploratory manner. 
 
Duration of Response (DOR) Duration of Response will be determined for each patient with 
time origin at the first occurrence of confirmed response (CR,PR) until the first occurrence of 
confirmed progression or date of death if the patient dies due to any causes before 
progression. Every effort will be made to follow patients for progression after they discontinue 
the study. 
Progression-free Survival (PFS) Progression-free Survival will be determined for each 
patient with time origin at the start of the treatment (day 1) until the first occurrence of 
confirmed progression or date of death if the patient dies due to any causes before 
progression. If a patient does not progress and is still alive, they will be censored on the date 
of last follow-up. Every effort will be made to follow patients for progression after they 
discontinue the study. 
Overall Survival (OS) Overall survival (OS) will be measured for each patient with time origin 
at the start of the treatment (day 1) until recorded date of death. If a patient is still alive, they 
will be censored on the date of last follow-up. Every effort will be made to follow patients for 
overall survival after they discontinue the study. 
Patient Evaluation & Statistics 
 
All patients who receive at least one dose of nivolumab will be evaluated for tumor response 
(ORR, DOR), including patients who (1) develop rapid symptomatic disease progression, or 
(2) drop out early due to death or treatment-related toxicities. All patients who received at least 
one dose of nivolumab will be included in the clinical efficacy analyses of PFS and OS. 
Kaplan- Meier methodology will be implemented to estimate the median OS and PFS. 
Of note, atypical responses are well known to occur in patients treated with immune 
checkpoint blockade, including early radiographic progression due to immune infiltration 
followed by subsequent radiographic response and durable clinical benefit. Thus, patients who 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-126 A(23) 
Approval date: 23-Feb-2024 
Page 36 of 57 
 
 
have early radiographic progression but are felt to be clinically benefitting and convert to 
confirmed stable disease, partial response, or complete response will be considered 
progression-free and will be assgiend a best confirmed overall response of SD, PR, or CR. 
13.0 
CRITERIA FOR TREATMENT DISCONTINUATION OR REMOVAL FROMSTUDY 
 
Treatment Discontinuation Criteria 
Discontinuation criteria apply for all drug-related adverse events attributed to nivolumab, 
ipilimumab, or both. 
Treatment should be permanently discontinued for the following: 
• 
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment 
• 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, 
diarrhea, colitis, neurologic adverse event, hypersensitivity reactions, and infusion 
reactions 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, 
neurologic adverse event, hypersensitivity reaction, or infusion reaction of any 
duration requires discontinuation 
o Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except those noted below 
• 
Grade 3 drug-related thrombocytopenia > 7 days or associated with 
bleeding requires discontinuation 
• 
Any drug-related liver function test (LFT) abnormality that meets the 
following criteria require discontinuation: 
• 
AST or ALT > 8 x ULN 
• 
Total bilirubin > 5 x ULN 
• 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
• 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
• 
Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 
within 1 week of onset. 
• 
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and a corrected with supplementation/appropriate management 
within 72 hours of their onset 
• Any dosing interruption lasting > 6 weeks with the following exceptions: 
• 
Dosing interruptions to allow for prolonged steroid tapers to manage drug- 


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Page 37 of 57 
 
 
related adverse events are allowed. Prior to re-initiating treatment in a subject with 
a dosing interruption lasting > 6 weeks, the Investigator must be consulted. Tumor 
assessments should continue as per protocol even if dosing is interrupted 
• 
Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be 
allowed if approved by the Investigator. Prior to re-initiating treatment in a subject 
with a dosing interruption lasting > 6 weeks, the Investigator must be consulted. 
Tumor assessments should continue as per protocol even if dosing is interrupted 
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the Investigator, presents a substantial clinical risk to the subject with 
continued nivolumab dosing 
 
Patients who discontinue treatment due to toxicity, as outlined above, will remain eligible for 
continued followup on study. Followup on study will be modified as described in Study 
Flowchart 1 and 2. 
CRITERIA FOR REMOVAL FROM STUDY 
 
Patients with confirmed disease progression will be removed from the study with limited 
exceptions outlined below.Progressive disease must be confirmed on a second imaging 
study at least 4 weeks later and should demonstrate at least 10% or greater additional 
increase in disease burden. If, based upon the treating physicians judgment, the patient is 
deriving clinical benefit despite disease progression,treatment beyond progression may be 
considered provided that (1) the decision is discussed with the MSK and or site PI, who 
agrees (2) in the opinion of the treating physician, no alternative therapy would offer greater 
benefit and (3) the treating physician discusses the risks and benefits of continuing on study 
with the patient, this conversation is documented in the patients’ medical records, and the 
patient wishes to continue treatment. 
 
Removal from study for patients symptomatic progression warranting alternative anti-cancer 
treatment should be considered in subjects whose overall tumor burden appears to be 
substantially increased and/or in subjects whose performance status is decreased. These 
patients will be removed from treatment at the Investigator’s discretion in accordance with 
standard practice. 
A patient may withdraw from the study at any time for any reason without prejudice to his/her 
future medical care by the physician or at the study site. 
Patients who are unable or unwilling to comply with study treatment and care plan will be 
removed from treatment at the Investigator’s discretion in accordance with standard practice. 
 
Patient death. 
14.0 
BIOSTATISTICS 
 
Statistical Plan for Evaluation of Primary and Secondary Endpoints 
A total of 81 patients will be accrued to this study (10 melanoma patient and 71 bladder 


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patients).Only patients with bladder cancer will be evaluated for the primary and secondary 
objectives as decribed here. Melanoma and bladder patients will be evaluated for the 
exploratory endpoints described in the next section. The primary clinical objective is to 
determine the confirmed response rate defined per RECIST 1.1 to protocol therapy. Of note, 
atypical responses are well known to occur in patients treated with immune checkpoint 
blockade, including early radiographic progression due to immune infiltration followed by 
subsequent radiographic response and durable clinical benefit. Thus, patients who have early 
radiographic progression but are felt to be clinically benefitting and convert to confirmed stable 
disease, partial response, or complete response will be considered progression-free and will 
be assgiend a best confirmed overall response of SD, PR, or CR. 
The primary correlative objective is to obtain information on mutational load and obtain 
preliminary prospective data on whether this factor is predictive of response to 
immunotherapy. Patient’s mutational load will be assessed using tissue prior to treatment 
and the number of mutations will be calculated. We will perform a nonparametric receiver 
operator characteristic (ROC) curve analysis with mutational load as a continuous measure 
and estimate the area under the curve (AUC) to assess the detectability of responders. The 
cutoff point will be identified using Youden’s index. It is estimated that approximately 85% of 
enrolled patients will be considered evaluable for both the clinical and research (WES, 
RNAseq) study endpoints, with an approximate 10% failure rate related to the biopsy, biopsy 
sample preparation and sequencing, and an approximate 5% failure rate for clinical reasons 
(i.e. patient replaced for clinical reasons and non-evaluable for response). Based upon these 
calculations, we estimate that we will have approximately 60 bladder patients and 
approximately 8 melanoma patients with both clinical and research (genomic) data for 
anlysis, consistent with the protocol statistical plan. With 60 bladder patients, 80% power 
and 5% significance level, we can detect a difference in AUC from: 0.5 to 0.7 if the 
response rate 50%; 0.5 to 0.71 if the response rate is 33%; and from .0.5 to 0.73 if the 
response rate is 25%. 
 
All patients who receive at least one dose of nivolumab will be evaluated for the primary 
clinical endpoint defined as the proportion of patients who achieve a confirmed complete or 
partial response based on RECIST 1.1 criteria. Patients who develop rapid symptomatic 
disease progression or drop out early due to death will be treated as progressive disease. 
Patients who develop early toxicities that require treatment delay or discontinuation will 
continue to be evaluable for response on study. 
 
Patients who receive at least 1 dose of nivolumab and have adequate biopsy material for 
whole exome sequencing and adequate sequencing data for determination of mutation 
burden will be considered evaluable for clinical and correlative objectives. Tumor mutation 
burden and neo-antigen score will be determined for each patient enrolled as described in 
section Appendix 3. We will perform the same analysis for patients according to their neo- 
antigens score (as described in Appendix 3). This analysis of the relationship between 
mutation burden and response rate will be performed for each tumor type independently. 
It is anticipated that 4-5 patients per month will be accrued per cohort and accrual will be 
completed within two years. 
Exploratory Endpoints 


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Patient Evaluation & Statistics for Clinical Endpoints 
 
All patients who received at least one dose of nivolumab will be evaluated for clinical endpoints 
including tumor response (ORR, DOR, OS and PFS), rate of grade 3/4 toxicity, and survival. 
Patients who (1) develop rapid symptomatic disease progression, or (2) drop out early due to 
death will be treated as non responders. Patients who develop early toxicities that require 
treatment delay or discontinuation will continue to be evaluated for response on study. Kaplan- 
Meier methodology will be implemented to estimate the median survival time, median 
progression-free survival, and the PFS and OS rates. Overall survival will defined as the time 
from treatment start to death or last follow-up; progression-free survival will be defined as the 
time from treatment start to the date of progression/death or last follow-up. 
 
Exploratory Tumor and Peripheral Blood Immune Markers 
 
The following endpoints will be evaluated in an exploratory fashion as sample availability 
permits. Descriptive statistics and graphical measures will be employed. Details related to 
methods are described in Appendix 3. 
1. Compare tumor characteristic (mutation burden, neo-antigen score, PD-L1, TCR 
repertoire, immune infiltrate) between pre-treatment and on-treatment (optional) 
tumor biopsies 
 
We aim to collect ~ 20 matched tumor biopsies (pre-treatment/on treatment) (target 10 per 
tumor type), and the comparison will be primarily descriptive and hypothesis generating. Mean 
and median mutation burden will be quantified in both pre-treatment and on-treatment 
biopsies. The difference in mean and median between these timepoints will be compared 
usingnonparametric tests such as Wilcoxon signed rank test. Qualitative comparisons (i.e. 
types of mutations, neo-antigens) will be descriptive. Adaptive Biotechnologies and 
MedGenome will serve as collaborators for this TCR analysis. 
2. Evaluate tumor PD-L1 expression across range of mutation burden/predicted neo- 
antigens. 
 
PD-L1 expression will be evaluated in pre-treatment and on-treatment biopsies. PD-L1 
expression on tumor cells will be graded as positive or negative, according to the most up to 
date standards for the assay in use. The tumor positivity of PD-L1 expression (on either 
tumor or immune cells) will be compared in the pre- and post-treatment biopsies using a 
Wilcoxon signed rank test. Comparisons of immune infiltrate and TCR repertoire will be 
descriptive. Summary statistics will be generated and differences between mutation burden or 
neo-antigen score as they relate to PD-L1 expression will be compared using the Wilcoxon 
rank sum test. 
3. Evaluate TCR repertoire across a range of mutation burdens/predicted neo-antigen 
scores. 
 
Tcell receptor frequencies in the repertoire per patient will be tabulated. Summary statistics 
will be generated and differences between mutation burden or neo-antigen score as they 


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relate to TCR repertoire will be compared using the Wilcoxon rank sum test. Adaptive 
Biotechnologies and MedGenome will serve as collaborators for this TCR analysis. 
4. Evaluate for the presence of predicted neo-antigen specific T cells in peripheral 
blood samples. 
 
Ex vivo and in vitro analysis of peripheral blood T cells will be employed to evaluate for the 
presence of predicted neo-antigen specific T cells as described in detail in appendix 3. 
5. Compare IMPACT assay to whole exome sequencing for the evaluation of patients 
according to mutation burden. 
 
The number of mutations quantified according to whole exome sequencing and according to 
IMPACT assay will be quantified and correlation analysis between whole exome analysis and 
IMPACT will be assessed. This will be exploratory. If a cutoff of high versus low mutation 
burden is determined from earlier analyses using the whole exome this will be used to guide 
the IMPACT preliminary analysis. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
 
15.1 
Research Participant Registration 
 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. During the registration process registering individuals will be 
required to complete a protocol specific Eligibility Checklist. The individual signing the 
Eligibility Checklist is confirming whether or not the participant is eligible to enroll in 
the study. Study staff are responsible for ensuring that all institutional requirements 
necessary to enroll a participant to the study have been completed. See related 
Clinical Research Policy and Procedure #401 (Protocol Participant Registration). 
15.1.1 Registration for Participating Sites 
 
Central registration for this study will take place at MSK. 
 
To complete registration and enroll a participant from another institution, the site must 
contact the MSK study coordinator to notify him/her of the participant registration. 
The following documents must be sent for each enrollment within 24 hours of the 
informed consent form being signed: 
• 
The completed or partially completed MSK eligibility checklist 
• 
The signed informed consent and HIPAA Authorization form 


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• 
Supporting source documentation for eligibility questions (e.g. laboratory results, 
pathology report, radiology reports, MD notes, physical exam sheets, medical 
history, prior treatment records, and EKG report). 
 
Upon receipt, the MSK study coordinator will conduct an interim review of all documents. 
If the eligibility checklist is not complete or source documentation is missing, the 
participant will be registered PENDING and the site will be responsible for sending the 
completed registration documents within 30 days of the consent. 
 
If the external registration submission is complete, the participating site IRB has granted 
approval for the protocol, and the participating site is in good standing, the MSK study 
coordinator will send the completed registration documents to the MSK Protocol 
Participant Registration Office for participant enrollment as stated in section 15.1. 
 
Once the participant is registered, the participant will be assigned a protocol participant 
number in the MSK Clinical Research Database (CRDB). This number will be relayed 
back to study staff at the registering participating site via e-mail and will serve as the 
enrollment confirmation. The number is unique to the participant and must be written on 
all data and correspondence for the participant. 
 
15.2 
Randomization 
 
Not applicable 
16.0 
DATA MANAGEMENT ISSUES 
 
A MSK Clinical Research Coordinator (CRC) will be assigned to the study. The responsibilities 
of the MSK CRC include project compliance, data collection, abstraction and entry, data 
reporting, regulatory monitoring, problem resolution and prioritization, and coordinate the 
activities of the protocol study team. 
 
The data collected for this study will be entered into a secure internet based 
system, Medidata Rave. Source documentation will be available to support the 
computerized patient record. 
 
MSKCC will be the data coordinating center under the guidance of the Multicenter Protocol 
Executive Committee (MPEC). MSKCC will be responsible for reporting to BMS and/or 
governing agencies. 
16.0.1 
Data and Source Documentation for Participating Sites 
 
Data 
The participating site(s) will enter data remotely into electronic Case Report Forms 
(eCRFs) using the internet based system, Medidata Rave. Data entry guidelines have 
been generated for this study and site staff will receive database training prior to enrolling 
its first participant. The participating site PI is responsible for ensuring these forms are 


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completed accurately and in a timely manner. A Data and Source Documentation 
Submission Timeline is shown in section 16.0.3. 
Source Documentation 
Source documentation refers to original records of observations, clinical findings and 
evaluations that are subsequently recorded as data. Source documentation should be 
consistent with data entered into eCRFs. Relevant source documentation to be submitted 
throughout the study includes: 
• 
Baseline measures to assess pre-protocol disease status (ex. CT, PSA, bone 
marrow) 
• 
Treatment records 
• 
Toxicities/adverse events of grades that meet study reporting requirements not 
previously submitted with SAE Reports 
• 
Response designation 
• 
Any other forms of source documentation required per protocol 
Source documentation should include a minimum of two identifiers to allow for data 
verification. MSK will maintain the confidentiality of any subject-identifiable information it 
may encounter. 
16.0.2 
Data and Source Documentation Submission for Participating Sites 
 
Participating sites should enter data directly into Medidata Rave. Source documentation 
should be sent to MSK to the contact information provided by the MSK study coordinator. 
Submissions should include a cover page listing relevant records enclosed per 
participant. 
16.0.3 
Data and Source Documentation Submission Timelines for Participating 
Sites 
 
Data and source documentation to support data should be transmitted to MSK according 
to chart below. 
Data and Source Documentation Submission Timelines 
 
Time point 
Data 
Source Documentation 
Baseline 
Within 24 hours of consent 
(see section 15.1.1) 
Within 24 hours of consent 
(see section 15.1.1) 
Study Visits 
Within 14 days of the study visit 
Within 14 days of the study visit 
Serious 
Adverse 
Events 
Within 3 days of event (see section 
17.3); 
Updates to be submitted as available 
Within 3 days of event (see section 
17.3) 


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16.0.4 
Data Review and Queries for Participating Site Data 
 
Research staff at MSK will review data and source documentation as it is submitted. 
Data will be monitored against source documentation and discrepancies will be sent as 
queries to the participating sites. Queries will be sent by MSK Research staff twice a 
month. 
Participating sites should respond to data queries within 14 days of receipt. 
16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and 
completeness of registration data. Routine data quality reports will be generated to 
assess missing data and inconsistencies. Accrual rates and extent and accuracy of 
evaluations and follow-up will be monitored periodically throughout the study period 
and potential problems will be brought to the attention of the study team for discussion 
and action 
 
Random-sample data quality and protocol compliance audits will be conducted by the 
study team, at a minimum of two times per year, more frequently if indicated. 
16.1.1 Quality Assurance for Participating Sites 
Monitoring 
Each data collection site including MSK will be monitored periodically by MSK. 
Monitoring visits will be conducted every 4-8 weeks, dependent upon the protocol and 
patient accrual and activity. The monitor and the participating site will identify a mutually 
agreeable time for each monitoring visit. At least 10 business days ahead of the visit, 
the monitor will send the site a notification letter that details the date and expectations of 
the visit. Monitoring may be conducted remotely or in-person. The monitor must be 
allowed access to all protocol regulatory and source documents to assess compliance 
with the protocol, federal regulations and GCPs. The monitor will assess all data for 
completeness of source documents and to confirm data being recorded in the eCRFs is 
accurate. If monitoring will be done remotely, sites must agree in advance to provide 
source documents as required. During onsite visits, the monitor will also inspect and 
review the facilities and investigational product storage area. The participating site will 
maintain accurate records of dispensing of study drugs for drug accountability. Drug 
accountability will be reviewed at monitoring visits. Study drug and bottles must be 
retained until the monitor performs drug accountability of the study drug(s). 
 
The site Investigator(s) and/or an authorized member of the Investigator’s staff should 
allow sufficient time during monitoring visits to discuss findings. The Investigator(s) or an 
authorized member of the Investigator’s staff will make any necessary corrections during 
and between monitoring visits. 
Auditing 


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Each participating site accruing participants to this protocol may be audited by MSK for 
protocol and regulatory compliance, data verification and source documentation. Audits 
of selected participant records may be conducted on-site or remotely. 
 
Each audit will be summarized and a final report will be sent to the PI at the audited 
participating site within 30 days of the audit. The report will include a summary of 
findings, participant-specific case review, recommendations on any performance and/or 
shortcomings and request for corrective action, when necessary. When corrective action 
is required, the participating site must reply within 45 days of receipt of the audit report 
with their corrective action plan. 
16.1.2 
Response Review 
 
Since therapeutic efficacy is a stated primary objective, all sites participants’ responses 
are subject to review by MSK’s Therapeutic Response Review Committee (TRRC). 
Radiology, additional lab reports and possibly bone marrow biopsies and/or aspirates 
will need to be obtained from the participating sites for MSK TRRC review and 
confirmation of response assessment. These materials must be sent to MSK promptly 
upon request. 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring Plan utilized for this study must align with the MSK  
DSM Plan, where applicable. 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering were 
approved by the National Cancer Institute in August 2018. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National  
Cancer Institute for Data and Safety Monitoring of Clinical Trials.” 
 
There are several different mechanisms by which clinical studies are monitored for 
data, safety and quality. At a departmental/PI level there exists procedures for quality 
control by the research team(s). Institutional processes in place for quality assurance 
include protocol monitoring, compliance and data verification audits, staff education 
on clinical research QA and two institutional committees that are responsible for 
monitoring the activities of our clinical trials programs. The committees: Data and 
Safety Monitoring Committee (DSMC) for Phase I and II clinical trials, and the Data 
and Safety Monitoring Board (DSMB) for Phase III clinical trials, report to the Deputy 
Physician-in-Chief, Clinical Research. 
 
During the protocol development and review process, each protocol will be assessed 
for its level of risk and degree of monitoring required. 
 
The MSK DSMB monitors phase III trials and the DSMC monitors non-phase III trials. 
The DSMB/C have oversight over the following trials: 
• MSK Investigator Initiated Trials (IITs; MSK as sponsor) 
• External studies where MSK is the data coordinating center 
• Low risk studies identified as requiring DSMB/C review 


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The DSMC will initiate review following the enrollment of the first participant/or by 
the end of the year one if no accruals and will continue for the study lifecycle until 
there are no participants under active therapy and the protocol has closed to 
accrual. The DSMB will initiate review once the protocol is open to accrual. 
16.3 
Regulatory Documentation 
 
Prior to implementing this protocol at MSK, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by 
the MSK Institutional Review Board/Privacy Board (IRB/PB). There will be one protocol 
document and each participating site will utilize that document. 
 
The following documents must be provided to MSK before the participating site can be 
initiated and begin enrolling participants: 
• 
Participating Site IRB approval(s) for the protocol, appendices, informed consent 
form and HIPAA authorization 
• 
Participating Site IRB approved informed consent form and HIPAA authorization 
• 
Participating Site IRB’s Federal Wide Assurance number and OHRP Registration 
number 
• 
Participating Site 1572 
• 
Conflict of Interest forms for Participating Site Investigators on the 1572 
• 
Curriculum vitae and medical license for each investigator and consenting 
professional 
• 
Documentation of Human Subject Research Certification training for investigators 
and key study personnel at the participating site 
• 
Documentation of Good Clinical Practice (GCP) training for the PI and co-PI at the 
participating site 
• 
Participating site laboratory certifications and normals 
Upon receipt of the required documents, MSK will formally contact the site and grant 
permission to proceed with enrollment. 
16.3.1 
Amendments 
 
Each change to the protocol document must be organized and documented by MSK and 
first approved by the MSK IRB/PB. Protocol amendments that affect MSK only (e.g. 
change in MSK Co-Investigator, MSK translation, etc.) do not require IRB review at the 
participating site(s). All other protocol amendments will be immediately distributed to 
each participating site upon receipt of MSK IRB/PB approval. 
 
Each participating site must obtain IRB approval for all amendments within 45 calendar 
days of MSK IRB/PB approval. If the amendment is the result of a safety issue or makes 
eligibility criteria more restrictive, sites will not be permitted to continuing enrolling new 
participants until the site IRB approval of the revised protocol documents is granted and 
submitted to MSK. 


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The following documents must be provided to MSK for each amendment within the 
stated timelines: 
• 
Participating Site IRB approval 
• 
Participating Site IRB approved informed consent form and HIPAA authorization 
16.3.2 
Additional IRB Correspondence 
 
Continuing Review Approval 
The Continuing Review Approval letter from the participating site’s IRB and the most 
current approved version of the informed consent form should be submitted to MSK 
within 7 days of expiration. Failure to submit the re-approval in the stated timeline will 
result in suspension of new participant enrollment. 
 
Deviations 
A protocol deviation on this study is defined as any incident involving non-adherence to 
an IRB approved protocol. Deviations typically do not have a significant effect on the 
rights, safety, or welfare of research participants or on the integrity of the resultant data. 
Deviations that represent unanticipated problems involving risks to participants or others, 
or serious adverse events should be reported according to sections 17.2 and 17.5 of this 
protocol. 
Deviations that do not adversely affect the rights and/or welfare of the participant or the 
scientific validity of the study and are related to protocol scheduling changes outside of 
the allowed window due to a holiday (e.g., New Year’s, Thanksgiving, etc.) and/or 
inclement weather or other natural event do not require reporting to the MSK IRB/PB. 
However, they must be clearly documented in the patient’s medical record. 
Prospective Deviations 
Deviations to the research protocol that involve an informed consent procedure change 
and/or treatment/pharmacy alterations that are not allowed by the protocol require 
prospective approval from the MSK IRB/PB prior to the change being carried out. 
Participating sites should contact the MSK PI who will in turn seek approval from the 
MSK IRB/PB. Deviations to the research protocol that involve patient eligibility will not be 
permitted. 
Retrospective Deviations 
Deviations that include a change or departure from the research protocol without prior 
approval from the MSK IRB/PB are considered retrospective deviations. Retrospective 
deviations should be reported to the MSK PI as soon as possible, who will in turn report 
the deviation to the MSK IRB/PB as per MSK guidelines. 
Participating Site IRB Reporting 
Participating sites should report all deviations to their institution’s IRB per local 
guidelines. Approvals/acknowledgments from the participating site IRB for protocol 
deviations should be submitted to MSK upon receipt. 
Other correspondence 


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Participating sites should submit other correspondence to their institution’s IRB according 
to local guidelines, and submit copies of official site correspondence, including approvals 
and acknowledgements. to MSK. 
16.3.3 
Regulatory Documentation Submission for Participating Sites 
 
Participating sites should submit all aforementioned regulatory documentation to MSK via 
the Multicenter Office at the e-mail provided below. Submissions should include the 
provided Participating Site Submission Form as a cover page listing all enclosed 
documents. 
 
Regulatory Contact:  
Email: Multicntrproc@mskcc.org to the attention of 15-126 Document Submission 
 
For questions regarding regulatory documentation submissions, please call 646-888- 
0924. 
For protocol related questions, please contact your MSK Study Coordinator. 
16.4 
Document maintenance 
 
The MSK PI and participating site PI will maintain adequate and accurate records to 
enable the implementation of the protocol to be fully documented and the data to be 
subsequently verified. 
The participating sites will ensure that all regulatory documents and participating site IRB 
correspondences are maintained in an onsite regulatory binder and sent to MSK as 
outlined within the protocol. The on-site regulatory binder will be reviewed by the MSK 
designated study monitor at monitoring visits. A regulatory binder for each site will also 
be maintained at MSK within the institution’s Protocol Information Management System 
(PIMS). 
 
After study closure, the participating sites will maintain all source documents, study 
related documents and eCRFs for 7 years. 
16.5 
Noncompliance 
 
If a participating site is noncompliant with the protocol document, accrual privileges may 
be suspended and/or contract payments may be withheld, until the outstanding issues 
have been resolved. 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
The informed consent for this study will describe in detail to all potential study 
participants the risk/benefits, toxicities/side effects, alternatives/options for treatment, 
and potential financial costs/burdens. As the study will include whole exome sequencing 
of matched tumor and normal tissue samples, special considerations/additional risks 
related to maintaining patient privacy and protecting genomic data will be described in 


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the informed consent. The informed consent will also describe the voluntary nature of 
the study. 
17.1 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health 
information pursuant to a completed and signed Research Authorization form. The use 
and disclosure of protected health information will be limited to the individuals described 
in the Research Authorization form. A Research Authorization form must be completed 
by the Principal Investigator and approved by the IRB and Privacy Board (IRB/PB). 
The consent indicates that individualized de identified information collected for the 
purposes of this study may be shared with other qualified researchers. Only researchers 
who have received approval from MSK will be allowed to access this information which will 
not include protected health information, such as the participant’s name, except for dates. 
It is also stated in the Research Authorization that their research data may be shared with 
other qualified researchers. 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• Death 
• A life-threatening adverse event 
• An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
• Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered 
an SAE. 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention. SAE reporting is required for 30-days after the participant’s last 
investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational 
treatment/intervention and is related to a screening test or procedure (i.e., a screening 
biopsy) must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office 
per IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be 


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submitted within 5 calendar days of the event. All other SAEs must be submitted within 
30 calendar days of the event. 
The report should contain the following information: 
 
• The date the adverse event occurred 
• The adverse event 
• The grade of the event 
• Relationship of the adverse event to the treatment(s) 
• If the AE was expected 
• Detailed text that includes the following 
oAn explanation of how the AE was handled 
oA description of the participant’s condition 
oIndication if the participant remains on the study 
• If an amendment will need to be made to the protocol and/or consent form 
• If the SAE is an Unanticipated Problem 
For IND/IDE protocols: The SAE report should be completed as per above instructions. If 
appropriate, the report will be forwarded to the FDA by the IND Office 
 
17.2.1 SAE Reporting by MSKCC to BMS 
 
Serious Adverse Event Collection and Reporting 
 
Following the subject’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, must be collected, including those thought to be 
associated with protocol-specified procedures. All SAEs must be collected that occur 
within 100 days of discontinuation of dosing. Any SAEs that occur after the 100-day period 
and that are at least possibly related to protocol treatment must also be reported. 
 
All SAEs must be collected that occur during the screening period. SAEs must be 
collected that relate to any protocol-specified procedure (e.g., a follow-up skin biopsy). 
The investigator should report any SAE that occurs after these time periods that is 
believed to be related to study drug or protocol-specified procedure. 
SAEs, whether related or not related to study drug, pregnancies, and overdosing of study 
drug(s) must be reported to BMS by MSK within 3 business days of MSK’s 
determination of the event. An SAE report should be completed for any event where 
doubt exists regarding its seriousness. SAEs must be recorded on BMS or an approved 
form; pregnancies on a Pregnancy Surveillance Form. 
SAE Email Address: Worldwide.Safety@BMS.com 
 
SAE Facsimile Number: 609-818-3804 
 
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.) 


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If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent by MSK within 24 hours to 
the BMS (or designee) using the same procedure used for transmitting the initial SAE 
report. All SAEs should be followed to resolution or stabilization. 
 
For studies with long-term follow-up periods in which safety data are being reported, 
include the timing of SAE collection in the protocol. If the investigator believes that an 
SAE is not related to study drug, but is potentially related to the conditions of the study 
(such as withdrawal of previous therapy or a complication of a study procedure), the 
relationship should be specified in the narrative section of the SAE Report Form. 
For studies conducted under an Investigator IND in the US, any event that is both serious 
and unexpected must be reported to the Food and Drug Administration (FDA) as soon as 
possible and no later than 7 days (for a death or life-threatening event) or 15 days (for all 
other SAEs) after the investigator’s or institution’s initial receipt of the information. BMS 
will be provided with a simultaneous copy of all adverse events filed with the FDA. 
 
 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
In accordance with local regulations, BMS will notify investigators of all reported SAEs 
that are suspected (related to the investigational product) and unexpected (i.e., not 
previously described in the IB). In the European Union (EU), an event meeting these 
criteria is termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR). 
Investigator notification of these events will be in the form of an expedited safety report 
(ESR). 
 
Other important findings which may be reported by BMS as an ESR include: increased 
frequency of a clinically significant expected SAE, an SAE considered associated with 
study procedures that could modify the conduct of the study, lack of efficacy that poses 
significant hazard to study subjects, clinically significant safety finding from a nonclinical 
(e.g., animal) study, important safety recommendations from a study data monitoring 
committee, or sponsor decision to end or temporarily halt a clinical study for safety 
reasons. 
 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with 
the IB. Where required by local regulations or when there is a central IRB/IEC for the 
study, the investigator will submit the ESR to the appropriate IRB/IEC. The investigator 
and IRB/IEC will determine if the informed consent requires revision. The investigator 
should also comply with the IRB/IEC procedures for reporting any other safety information. 
In addition, suspected serious adverse reactions (whether expected or unexpected) shall 
be reported by BMS to the relevant competent health authorities in all concerned countries 


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according to local regulations (either as expedited and/or in aggregate reports). 
17.3 
SAE Reporting for Participating Sites 
 
Responsibilities of Participating Sites 
• 
Participating sites are responsible for reporting all SAEs to their local IRB per local 
guidelines. Local IRB SAE approvals/acknowledgments must be sent to MSK upon 
receipt. 
• 
Participating sites are responsible for submitting the SAE Report Form to MSK 
within 3 calendar days of learning of the event. 
• 
Participating sites should notify the MSK PI of any grade 5 event immediately. 
• 
When a life-threatening event or death is unforeseen and indicates participants or 
others are at increased risk or harm, participating sites should notify the MSK PI as 
soon as possible but within 24 hours of the time the site becomes aware of the 
event. 
 
SAE contact information: 
Email the 15-126 MSK Study Coordinators 
AND 
Email: Dr. Callahan at callaham@mskcc.org 
 
Responsibilities of MSK 
• 
MSK Research Staff are responsible for submitting all SAEs to the MSK IRB/PB as 
specified in 17.2 and to the funding entity as described in 17.2.1. 
• 
The MSK PI is responsible for informing all participating sites about all unexpected 
SAEs that are either possibly, probably, or definitely related to the study 
intervention within 15 days of receiving the stamped SAE from the MSK IRB/PB. 
The MSK PI is responsible for informing all participating sites within 24 hours or on 
the next business day about a life-threatening event or death that is unforeseen 
and indicates participants or others are at increased risk of harm. 
17.4 
Safety Reports 
 
MSK must submit external safety reports to the MSK IRB/PB according to institutional 
guidelines. All outside safety reports will be made available to the participating sites. 
Outside safety reports that are reportable to the MSK IRB/PB will be distributed to the 
participating sites immediately upon receiving a stamped copy from the MSK IRB/PB. 
Participating sites will receive a special alert for any outside safety reports that warrant a 
significant change to the conduct of the study. Outside safety reports that are not 
reportable to the MSK IRB/PB, will be sent to the participating sites monthly. 
 
Participating sites are responsible for submitting safety reports to their local IRB per their 
local IRB guidelines. All local IRB approvals/acknowledgments of safety reports must be 
sent to MSK upon receipt. 
17.5 
Unanticipated Problems 


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Unanticipated problems involving risks to participants or others (UPs) are defined as any 
incident, experience or outcome that meets all of the following criteria: 
 
• 
Unanticipated (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB- 
approved research protocol and informed consent document; and (b) the characteristics 
of the subject population being studied; and 
• 
Related or possibly related to participating in the research (possibly related means there 
is a reasonable probability that the incident, experience or outcome may have been 
caused by procedures involved in the research); and 
• 
Suggests that the research place participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
Participating sites are responsible for reporting all UPs to MSK as soon as possible but 
within 3 calendar days of learning of the event. UPs that are SAEs should be reported to 
MSK via SAE Report form as per section 7.0 of this addendum. All other UPs should be 
reported to MSK in a memo signed by the site PI. 
 
MSK is responsible for submitting UPs to the MSK IRB/PB according to institutional 
guidelines. In addition, MSK is responsible for notifying participating sites of all non-SAE 
UPs that may affect the sites. 
18.0 INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from 
the study at any time. All participants must sign an IRB/PB-approved consent form indicating 
their consent to participate. This consent form meets the requirements of the Code of Federal 
Regulations and the Institutional Review Board/Privacy Board of this Center. The consent form 
will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive care 
for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information. In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 


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IRB Number: 15-126 A(23) 
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Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 
18.1 
INFORMED CONSENT PROCEDURES FOR PARTICIPATING SITES 
 
The investigators listed on the Consenting Professionals Lists at each participating site 
may obtain informed consent and care for the participants according to Good Clinical 
Practice and protocol guidelines. 
 
A note will be placed in the medical record documenting that informed consent was 
obtained for this study, and that the participant acknowledges the risk of participation. 
 
19.0 REFERENCES 
 
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Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the 
search for new cancer-associated genes. Nature 2013;499:214-8. 
4. 
Segal NH, Parsons DW, Peggs KS, et al. Epitope landscape in breast and colorectal 
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5. 
Srivastava N, Srivastava PK. Modeling the repertoire of true tumor-specific MHC I 
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Dubey P, Hendrickson RC, Meredith SC, et al. The immunodominant antigen of an 
ultraviolet-induced regressor tumor is generated by a somatic point mutation in the DEAD box 
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Ikeda H, Ohta N, Furukawa K, et al. Mutated mitogen-activated protein kinase: a tumor 
rejection antigen of mouse sarcoma. Proc Natl Acad Sci U S A 1997;94:6375-9. 
8. 
Matsutake T, Srivastava PK. The immunoprotective MHC II epitope of a chemically 
induced tumor harbors a unique mutation in a ribosomal protein. Proc Natl Acad Sci U S A 
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9. 
Matsushita H, Vesely MD, Koboldt DC, et al. Cancer exome analysis reveals a T-cell- 
dependent mechanism of cancer immunoediting. Nature 2012;482:400-4. 
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Duan F, Duitama J, Al Seesi S, et al. Genomic and bioinformatic profiling of mutational 
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van Rooij N, van Buuren MM, Philips D, et al. Tumor exome analysis reveals neo- 
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Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific 
CD4+ T cells in a patient with epithelial cancer. Science 2014;344:641-5. 
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Snyder A, Makarov V, Merghoub T, et al. Genetic Basis for Clinical Response to 
CTLA-4 Blockade in Melanoma. N Engl J Med 2014. 
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Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of 
anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-54. 
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Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients 
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16. 
Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus Dacarbazine for Previously 
Untreated Metastatic Melanoma. N Engl J Med 2011. 
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Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy 
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Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced 
melanoma. N Engl J Med 2013;369:122-33. 
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Antonio S. ASCO abstract. 2014. 
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Aird D, Ross MG, Chen WS, et al. Analyzing and minimizing PCR amplification bias in 
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Cibulskis K, Lawrence MS, Carter SL, et al. Sensitive detection of somatic point 
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J D, T H, G M, E S, MR H. ReFHap: A Reliable and Fast Algorithm for Single 
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Nicolae M, Mangul S, Mandoiu, II, Zelikovsky A. Estimation of alternative splicing 
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20.0 
APPENDICES 
 
Appendix 1: Pharmacy Manual 
Appendix 2: Algorithms for Management of Select Toxicities 
Appendix 3: Laboratory Procedures 
Appendix 4: Serious Adverse Event Form for Non-MSK Sites 
Appendix 5: Shipping Manual