Clinical trial NCT03241745
Conditions: Uterine Cancer Endometrial Carcinoma Carcinosarcoma Leiomyosarcoma Undifferentiated Sarcoma High Grade Endometrial Stromal Sarcoma Clear Cell Carcinoma
Keywords: Nivolumab 17-180
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2017-08-03; Completion date: 2024-04-01
Enrollment: 35 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to test the safety of nivolumab and find out what affects, if any, nivolumab has on people and their risk of gynecologic cancer. The investigators also want to find out what effects, good or bad, nivolumab has on the patient and their cancer.

Detailed description:

Arms: arm 1: Nivolumab treatment: Nivolumab 480 mg IV once every 4 weeks. Treatment will continue until time of disease progression or until development of unacceptable toxicity, whichever comes first.
Interventions: intervention 1: Nivolumab
Intervention descriptions: intervention 1: Nivolumab 480 mg IV once every 4 weeks

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 17-180 A(10) 
Approval date: 07-Sep-2021 
Page 1 of 44 
 
 
 
 
MSK PROTOCOL COVER SHEET 
 
Phase II Trial of Single-Agent Nivolumab in Patients with Microsatellite 
Unstable/Mismatch Repair Deficient/Hypermutated Uterine Cancer 
Principal Investigator/Department: 
 
Claire Friedman, MD/ Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-180 A(10) 
Approval date: 07-Sep-2021 
Page 2 of 44 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ............................................................................. 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ...................................................................................... 3 
3.0 
BACKGROUND AND RATIONALE............................................................................................. 4 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................ 104 
4.1 
Design ......................................................................................................................... 104 
4.2 
Intervention .................................................................................................................. 104 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ................................................................................ 115 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ................................................................................ 137 
6.1 
Subject Inclusion Criteria .............................................................................................. 137 
6.2 
Subject Exclusion Criteria ............................................................................................ 137 
7.0 
RECRUITMENT PLAN ............................................................................................................. 148 
8.0 
PRETREATMENT EVALUATION ............................................................................................ 148 
9.0 
TREATMENT/INTERVENTION PLAN ...................................................................................... 20 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .......................................................... 21 
11.0 
TOXICITIES/SIDE EFFECTS ..................................................................................................... 18 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT .......................... 31 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ............................................................................. 36 
14.0 
BIOSTATISTICS ........................................................................................................................... 37 
15.0 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 40 
15.1 Research Participant Registration .................................................................................. 40 
15.2 Randomization ............................................................................................................... 41 
16.0 
DATA MANAGEMENT ISSUES ................................................................................................ 41 
16.1 Quality Assurance .......................................................................................................... 41 
16.2 Data and Safety Monitoring ............................................................................................ 42 
17.0 
PROTECTION OF HUMAN SUBJECTS ................................................................................... 43 
17.1 Privacy ........................................................................................................................... 43 
17.2 Serious Adverse Event (SAE) Reporting ........................................................................ 43 
17.2.1 
 415 
18.0 
INFORMED CONSENT PROCEDURES ................................................................................... 45 
19.0 
REFERENCES ............................................................................................................................. 46 
20.0 
APPENDICES ............................................................................................................................ 448 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-180 A(10) 
Approval date: 07-Sep-2021 
Page 3 of 44 
 
 
Recurrent or Persistent Endometrial Carcinoma, Uterine Carcinosarcoma, or 
Uterine Sarcoma 
Identify cases that are any of the following: 
1. Microsatellite unstable (MSl-high or MSI-H) 
2. Mismatch Repair Deficient (MMR-D) 
3. Hypermutated (20 or more mutations on MSK-IMPACT) 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
Phase II Trial of Single-Agent Nivolumab in Patients with Microsatellite 
Unstable/Mismatch Repair Deficient/Hypermutated Uterine Cancer 
 
 
 
! 
 
 
 
 
 
 
 
 
 
CT or MRI CAP for assessment of disease response every 12 weeks 
1 Cycle = 4 weeks (therefore there is 1 dose of nivolumab per treatment cycle) 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
2.1 
Primary Objectives 
2.1.1 To define the Progression-Free Survival rate at 24 weeks in patients with MSl-high, MMR- 
D, or hypermutated persistent or recurrent uterine cancer treated with single-agent 
nivolumab. 
2.1.2 To define the proportion of patients who have objective tumor response (complete or 
partial) by RECIST 1.1 in patients with MSl-high, MMR-O, or hypermutated persistent or 
recurrent uterine cancer treated with single-agent nivolumab. 
 
2.2 
Secondary Objectives 
2.2.1 To determine the progression-free survival rate by RECIST 1.1 and overall survival in this 
population of recurrent uterine cancer patients treated with nivolumab. 
2.2.2 To determine the frequency and severity of adverse events associated with treatment with 
nivolumab as assessed by Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03. 
Nivolumab treatment: Nivolumab 480 mg IV once every 4 weeks. 
Treatment will continue until time of disease progression or until development of 
unacceptable toxicity, whichever comes first. Patients who demonstrate radiologic 
progression by RECIST 1.1 criteria may be considered for continued therapy (but 
not primary efficacy analysis) if they are deemed to be clinically benefiting, 
according to predetermined permitted criteria (section 12.4) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-180 A(10) 
Approval date: 07-Sep-2021 
Page 4 of 44 
 
 
 
 
2.2.3 To determine the duration of response and duration of disease control 
 
2.3 
Exploratory objectives 
2.3.1 Correlate the somatic mutational burden* with clinical benefit from nivolumab, both overall 
response rate (ORR) and progression-free survival (PFS) rate at 24 weeks. 
2.3.2 
Correlate the somatic mutational burden identified by MSK-IMPACT* with the MSlsensor 
algorithm score*. 
2.3.3 Correlate the MSlsensor score* with the MMR IHC status (immunohistochemical staining 
for mismatch repair enzyme proteins). 
2.3.4. Correlate the pre-treatment immune phenotype (tumor infiltrating lymphocyte and PD-L1 
status) with best overall response rate (ORR) and progression free survival rate at 24 
weeks. 
 
* Tissue will be analyzed for number of somatic mutations and MSlsensor score using MSK- 
IMPACT under the auspice of IRB #12-245. We will abstract the data collected under 12-245 
from the EMR to answer questions in this study. 
 
3.0 
BACKGROUND AND RATIONALE 
3.1 
Rationale for lmmunotherapy 
Cancer of the uterine corpus is the most common gynecologic malignancy with an estimated 
60,050 new cases in 2016 and 10,470 deaths in the United States 1. The current standard of care 
for advanced carcinomas and carcinosarcomas of the uterus is combination chemotherapy with 
carboplatin and paclitaxel 2 and gemcitabine plus docetaxel for uterine leiomyosarcomas 3•4. The 
overall response rate to these regimens is 57% and 27-36%, respectively, with complete 
responses being infrequent and all patients eventually dying from disease. More recent studies 
have used 6-month PFS as a criterion in the assessment of efficacy in advanced endometrial 
cancer; single-agent bevacizumab in this setting showed a PFS rate of 40.4% at 6 months and 
overall response rate of 13.5%5. There is a significant need for new therapeutic strategies that will 
provide long-lasting remissions in uterine cancer. 
 
Nivolumab, a fully human, lgG4 (kappa) monoclonal antibody that binds to PD-1, has shown 
significant clinical activity as a single-agent in non-small cell lung cancer 6•8, melanoma 9, renal 
cell carcinoma 10-12, and non-Hodgkin lymphoma 13. While it has been shown that host immune 
response plays a role in controlling malignant progression of epithelial ovarian cancer, thus 
suggesting immunotherapy as a rational therapeutic approach for this gynecologic malignancy14, 
similar data in the setting of advanced uterine cancer has been lacking. In a study of 63 
endometrial cancers, polymerase-e (POLE) mutated ultramutated tumors and microsatellite 
instability high (MSI-H) hypermutated tumors were found to be associated with high neoantigen 
loads, high number of tumor-infiltrating lymphocytes (TILs), and corresponding overexpression of 
PD-1 and PD-L1, suggesting POLE-mutant and MSI-H endometrial cancers as excellent 
candidates for PD-1 targeted immunotherapies 15. This data is in keeping with previous data in 
melanoma demonstrating that an "inflammatory" gene signature corresponds to higher expression 
of PD-L1, which may serve as a mechanism of adaptive immune resistance and indicate a tumor 
that will respond to immunotherapeutic approaches 16. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-180 A(10) 
Approval date: 07-Sep-2021 
Page 5 of 44 
 
 
 
 
 
In a study of mutational burden and mismatch repair status in colorectal cancer (CRC), 149 cases 
of CRC were analyzed by MSK-IMPACT, a targeted-exome capture assay of 341 cancer- 
associated genes. Ninety-eight percent of mismatch repair-proficient (MMR-P) cases had 16 or 
fewer somatic mutations detected with a median number of 6 mutations (range 0-16) whereas 
MMR-deficient (MMR-D) tumors had a median number of 49 somatic mutations (range 23-67) 17. 
This study concluded that using a cutoff for mutational load, such as 20 somatic mutations in the 
MSK-IMPACT panel, could provide a highly sensitive and specific means of screening for MMR 
deficiency. While a straightforward approach such as this is appealing, a bioinformatic approach 
to interpreting mutational burden is likely to more accurately predict tumor MMR status or 
microsatellite instability (MSI). Such an approach to determining MSI status using paired tumor- 
normal sequence data generated by next generation sequencing has been developed 18 and 
provides a promising method of identifying MMR-D/MSl-high (MSI-H) cases that may be missed 
by conventional testing. Phase 2 trial results have demonstrated that clinical activity of the anti- 
programmed death 1 (anti-PD-1) immune checkpoint inhibitor pembrolizumab is enriched in 
MMR-D colorectal and other solid tumors 19. These results, taken with the data from Howitt et al. 
summarized above, suggests that selecting patients with hypermutated, MMR-D, or MSI-H uterine 
cancers will enrich for response to anti-PD-1 therapy. While nivolumab has not been used in 
uterine cancer in a clinical trial setting, phase I trials in other solid tumors20 and a case series 
using nivolumab in hypermutated uterine cancers21 have shown the drug to be safe and have 
suggested efficacy in this setting, thus obviating the need for a phase I trial in this setting. 
 
To determine how many patients with recurrent or persistent uterine cancer have a high burden of 
somatic mutations, we have analyzed 253 patients with uterine cancer by MSK-IMPACT to date 
under IRB protocol #12-245. These cases include 165 endometrial cancers and 88 uterine 
sarcomas, 23 (9.1%) of which have 20 or more somatic mutations (range 20-445; 22 endometrial 
cancers, 1 uterine sarcoma). We performed mutational signature decomposition analysis to 
determine the underlying mutational process in 17 of these hypermutated endometrial cancers. 
One outlier tumor with 445 somatic mutations was found to have a POLE V411L somatic hotspot 
mutation and had a predominantly POLE signature. The other 16 tumors, including 12 with MMR- 
deficiency by immunohistochemical (IHC) staining, 2 with unknown MMR status, and 2 that were 
MMR-proficient by IHC, had a predominant MSI-H mutational signature (Figure 1). Overall, 
mutational signature decomposition analysis from targeted sequencing data in hypermutated 
tumors revealed MMR deficiency even in cases where conventional testing with 
immunohistochemistry produced normal (MMR-proficient) results. 
 
3.2 
Nivolumab 
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal antibody 
(HuMAb; immunoglobulin G4 [lgG4]-S228P) that targets the programmed death-1 (PD-1) cluster 
of differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a negative regulatory 
molecule expressed by activated T and B lymphocytes. 20 Binding of PD-1 to its ligands, 
programmed death-ligands 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of 
lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands promotes 
immune responses and antigen-specific T-cell responses to both foreign antigens as well as self- 
antigens. Nivolumab is expressed in Chinese hamster ovary (CHO) cells and is produced using 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-180 A(10) 
Approval date: 07-Sep-2021 
Page 6 of 44 
 
 
 
 
standard mammalian cell cultivation and chromatographic purification technologies. The clinical 
study product is a sterile solution for parenteral administration. 
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10 POLE 
14 Hypermutated 
22 Aristolochic acid 
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28 Unknown 
others 
Immunohistoc hem istry MSH21==11--+--+--+
 --- t-+-+--
 
PMS2 
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*Somatic loss-of-function mutant 
MSH6 ***
 
□Endometrioid Histology1'------'--'------'---'---'-----L-L----'----------'----'--'--'------'---'---'-----'
 -------- '
 MSISensor
 
□Mixed 
□Clear Cell 
□MMMT 


Memorial Sloan Kettering Cancer Center 
Page 7 of 44 
 
 
Figure 1. Origins of hypermutation. The count of somatic mutations from targeted sequencing is 
shown for 17 patients with apparent hypermutation. In red is the median and median absolute deviation 
of somatic mutations in 112 non-hypermutated endometrial tumors for comparison. Mutational signature 
decomposition analysis in the hypermutated tumors reveals the presence of an MM R/MSI dysfunction in 
all tumors at a frequency of 25% or greater. Other mutational signatures that reflected 10% of the total 
somatic mutations or more are also shown (see legend). Conventional immunohistochemical staining for 
MMR proteins indicates false negatives in tumors with evidence of MSI. Asterisks reflect the tumors in 
which somatic loss-of-function mutations were present in the genes indicated. Histologies of each of the 
tumors analyzed are also shown. MSI sensor for the indicated cases reflecting a complementary but 
orthogonal measure of MMR dysfunction in these tumors that is broadly concordant with mutational 
signature analysis, though the latter resolves equi\,ocal cases. 
IRS Number: 17-180 A(10) 
Approval date: 07-Sep-2021 
 
 
 
 
OPDIVO™ (nivolumab) is approved for use in humans to treat several types of cancers, in the 
United States (US, Dec-2014), the European Union (EU, Jun-2015), Japan (Jul-2014), and 
several other countries. 
3.2.1 Nonclinical Development of Nivolumab 
Nivolumab has been shown to bind specifically to the human PD-1 receptor and not to related 
members of the CD28 family. 21 Nivolumab inhibits the interaction of PD-1 with its ligands, PD-L1 
and PD-L2, resulting in enhanced T-cell proliferation and interferon-gamma (IFN-y) release in 
vitro.23•24 Nivolumab binds with high affinity to activated human T-cells expressing cell surface PD- 
1 and to cynomolgus monkey PD-1. 21 In a mixed lymphocyte reaction (MLR), nivolumab 
promoted a reproducible concentration-dependent enhancement of IFN- y release. 23 
 
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, nivolumab was well 
tolerated at doses up to 50 mg/kg, administered weekly for 5 weeks, and at doses up to 50 mg/kg, 
administered twice weekly for 27 doses. While nivolumab alone was well tolerated in cynomolgus 
monkeys, combination studies have highlighted the potential for enhanced toxicity when 
combined with other immunostimulatory agents. 21 
3.2.2 Clinical Development of Nivolumab 
The PK, clinical activity, and safety of nivolumab have been assessed in subjects with non-small 
cell lung cancer (NSCLC), melanoma, and clear-cell renal cell carcinoma (RCC) in addition to 
other tumor types. Clinical activity and safety information derives primarily from that obtained from 
Phase 2/3 studies in subjects with advanced or metastatic squamous (SQ) and nonsquamous 
(NSQ) NSCLC, Phase 2/3 studies in subjects with unresectable or metastatic melanoma, and a 
Phase 2 study in subjects with advanced or metastatic clear-cell RCC 21. Nivolumab is currently 
being investigated both as monotherapy and in combination with chemotherapy, targeted 
therapies, and other immunotherapies. 
 
Nivolumab is approved in multiple countries including the US for treatment of previously treated, 
unresectable or metastatic melanoma and previously treated, metastatic squamous NSCLC, the 
EU for treatment of previously treated, unresectable or metastatic melanoma, and Japan for 
treatment of unresectable melanoma. See Appendix 1 for US Prescribing Information (USPI) and 
Appendix 2 for the EU Summary of Product Characteristics (SmPC). 
Clinical Pharmacokinetics 
The pharmacokinetics (PK) of nivolumab was studied in subjects over a dose range of 0.1 to 10 
mg/kg administered as a single dose or as multiple doses of nivolumab every 2 or 3 weeks. The 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-180 A(10) 
Approval date: 07-Sep-2021 
Page 8 of 44 
 
 
 
 
geometric mean(% CV%) clearance (CL) was 9.5 mUh (49.7%), geometric mean volume of 
distribution at steady state (Vss)was 8.0 L (30.4%), and geometric mean elimination half-life 
(t1/2) was 26.7 days (101%). Steady-state concentrations of nivolumab were reached by 12 
weeks when administered at 3 mg/kg O2W, and systemic accumulation was approximately 3-fold. 
The exposure to nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg 
administered every 2 weeks. The clearance of nivolumab increased with increasing body weight. 
The PPK analysis suggested that the following factors had no clinically important effect on the CL 
of nivolumab: age (29 to 87 years), gender, race, baseline LOH, PD-L1. A PPK analysis 
suggested no difference in CL of nivolumab based on age, gender, race, tumor type, baseline 
tumor size, and hepatic impairment. 
Although ECOG status, baseline glomerular filtration rate (GFR), albumin, body weight, and mild 
hepatic impairment had an effect on nivolumab CL, the effect was not clinically meaningful. PPK 
and exposure response analyses have been performed to support use of 240 mg Q2W dosing of 
nivolumab in addition to the 3 mg/kg Q2W regimen. Using the PPK model, exposure of nivolumab 
at 240 mg flat dose was identical to a dose of 3 mg/kg for subjects weighing 80 kg, which was the 
approximate median body weight in nivolumab clinical trials. Across the various tumor types in the 
clinical program, nivolumab has been shown to be safe and well tolerated up to a dose level of 10 
mg/kg, and the relationship between nivolumab exposure produced by 3 mg/kg and efficacy and 
safety has been found to be relatively flat. Given the similarity of nivolumab PK across tumor 
types and the similar exposures predicted following administration of 240 mg flat dose compared 
to 3 mg/kg, it is expected that the safety and efficacy profile of 240 mg nivolumab will be similar to 
that of 3 mg/kg nivolumab. 
In addition, nivolumab 360 mg Q3W and nivolumab 480 mg Q4W are currently under 
investigation in monotherapy and combination oncology studies. The less frequent dosing 
regimens are designed to afford more convenience to the target patient populations and allow 
combination of nivolumab with other agents using alternative dosing regimens versus Q2W. 
These nivolumab dosing regimens were selected using PPK and exposure-response analyses 
modeling and simulation approaches such that they are predicted to provide approximately 
equivalent exposures (Cavgss) following administration of nivolumab 3 mg/kg Q2W. The model 
predicted that following administration of nivolumab 360 mg Q3W and 480 mg Q4W, Cavgss are 
expected to be similar to those following nivolumab 3 mg/kg or 240 mg Q2W, while Cminss are 
predicted to be 6% and ~16% lower, respectively, and are not considered to be clinically relevant. 
Following nivolumab 360 mg Q3W and 480 mg O4W, Cmaxss are predicted to be approximately 
~23% and ~43% greater, respectively, relative to that following nivolumab 3 mg/kg Q2W dosing; 
however, the range of nivolumab exposures (median and 90% prediction intervals) following 
administration of 360 mg O3W and 480 mg Q4W regimens across the 35 to 160 kg weight range 
are predicted to be maintained well below the corresponding exposures observed with the well 
tolerated 10 mg/kg nivolumab Q2W dosing regimen, and are not considered to put participants at 
increased risk. Hence, a flat dose of 480 mg nivolumab is under investigation. 
Clinical Efficacy 
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy and in 
combination with ipilimumab in several tumor types, including NSCLC 6-8, melanoma 9, RCC 10-12, 
and some lymphomas 13. In confirmatory trials, nivolumab as monotherapy demonstrated a 
statistically significant improvement in OS as compared with the current standard of care in 
subjects with advanced or metastatic NSCLC 6-8 and in subjects with unresectable or metastatic 
melanoma 9. 
 
Clinical Safety 
The overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 8,600 subjects treated to date. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-180 A(10) 
Approval date: 07-Sep-2021 
Page 9 of 44 
 
 
 
 
For monotherapy, the safety profile is similar across tumor types. There is no pattern in the 
incidence, severity, or causality of AEs to nivolumab dose level. In Phase 3 controlled studies, the 
safety profile of nivolumab monotherapy is acceptable in the context of the observed clinical 
efficacy, and manageable using established safety guidelines. Clinically relevant AEs typical of 
stimulation of the immune system were infrequent and manageable by delaying or stopping 
nivolumab treatment and timely immunosuppressive therapy or other supportive care. 
3.2.3 Shorter Infusion Duration 
Administration of nivolumab using a 30-minute infusion time has been evaluated in subjects with 
cancer. Previous clinical studies of nivolumab monotherapy for the treatment of cancer have used 
a 60-minute infusion duration wherein nivolumab has been safely administered up to 10 mg/kg 
over long treatment periods. Infusion reactions including high-grade hypersensitivity reactions 
have been uncommon across the nivolumab clinical program. In CA209010, a dose association 
was observed for infusion site reactions and hypersensitivity reactions (1.7% at 0.3 mg/kg, 3.7% 
at 2 mg/kg and 18.5% at 10 mg/kg). All the events were Grade 1-2 and were manageable. An 
infusion duration of 30 minutes for 3 mg/kg nivolumab (30% of the dose provided at 10 mg/kg) is 
not expected to present any safety concerns compared to the prior experience at 10 mg/kg 
nivolumab dose infused over a 60-minute duration. The safety of nivolumab 3 mg/kg administered 
as a 30-min infusion was assessed in CA209153 in patients (n=322) with previously treated 
advanced NSCLC (see Section 5.5.1.2). Overall, there were no clinically meaningful differences 
in the frequency of hypersensitivity/infusion-related reactions (of any cause or treatment-related) 
in cancer patients administered nivolumab over a 30 min infusion compared with that reported for 
patients with the 60 min infusion. Thus, it was shown that nivolumab can be safely infused over 
30 min in subjects with cancer. 
3.3 
Translational Science Background 
3.3.1 Mutational Burden and MSlsensor (Exploratory Biomarkers) 
As detailed above, previous studies have shown that a count of the absolute number of somatic 
mutations can predict which tumors are MSI-H or MMR-D 17, and that the clinical benefit of PD- 
1/PD-L1 pathway blockade is enriched in MMR-D tumors 19. In this trial, pre-treatment matched 
pairs of tumor and normal DNA from formalin-fixed paraffin embedded (FFPE) tissue will be 
evaluated by MSK-IMPACT under IRB protocol #12-245. MSK-IMPACT is a next generation 
sequencing assay of 410 cancer-associated genes performed in a CUA-compliant 
laboratory. 
It identifies  somatic point mutations, small insertions and deletions, structural 
rearrangements, and DNA copy number alterations in the tumors as compared to matched normal 
samples. Treating the number of somatic mutations in each patient's tumor as a continuous 
variable, we will seek to correlate the patient's tumor's mutational burden with clinical benefit from 
nivolumab, both overall response rate (ORR) and progression-free survival (PFS) at 24 weeks. 
 
The MSlsensor algorithm is a method for assessing MSI, yielding a "high" or "low" result. We aim 
to correlate the MSK-IMPACT somatic mutation number with the MSlsensor score. The 
MSlsensor algorithm may also be correlated with the MMR IHC results from the tumor. 
We will also explore the correlation of pre-treatment immune phenotype (tumor infiltrating 
lymphocyte and PD-L1 status,) with best overall response rate (ORR) and progression free 
survival rate at 24 weeks. 
 
All patients on this study will also be consented to IRB protocol #12-245 in order to have MSK- 
IMPACT sequencing performed. All of the questions we seek to answer using MSK-IMPACT 
results in this protocol will use data abstracted from the EMR. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-180 A(10) 
Approval date: 07-Sep-2021 
Page 10 of 44 
 
 
 
 
3.3.2 Analyzing the Inflammatory Phenotype in the Tumor Microenvironment (Exploratory 
Biomarker) 
Immune infiltration of tumors has been demonstrated in multiple studies to be both prognostic and 
predictive of response to immunotherapies, with tumors exhibiting inflamed phenotypes being 
most responsive. Assessment of the immune subsets in the tumors will help to establish 
predictive markers on the basis of pre-treatment phenotype as well to determine whether clinical 
efficacy correlates with the degree of infiltration of specific immune cell subsets. In addition, both 
PD-L1 and indoleamine-2,3-dioxygenase (IDO) have been demonstrated to be up-regulated in 
tumors in response to immune infiltration and may serve as negative feedback mechanisms 24. As 
such, pre-treatment FFPE will be evaluated for the presence of Tlls and immune marker PD-L1. 
Evaluation of Tlls and PD-L1 will be performed in the laboratory of Dr. Jedd Wolchok in 
collaboration with Dr. Dmitriy Zamarin. See appendix 4. 
 
3.4 
Inclusion of Women and Minorities 
Participating institutions will not exclude potential subjects from participating in this or any study 
solely on the basis of ethnic origin or socioeconomic status. Every attempt will be made to enter 
all eligible patients into this protocol and therefore address the study objectives in a patient 
population representative of the entire uterine cancer population treated by participating 
institutions. 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is an MSKCC investigator-initiated, single-center, non-randomized, open-label, phase 2 
study to evaluate the activity of nivolumab in patients with recurrent or persistent hypermutated, 
MMR-D, or MSI-H uterine cancer. Activity of nivolumab will be assessed by determining the 
percentage of patients who remain progression-free at 24 weeks (primary endpoint) or who have 
objective RECIST response (co-primary endpoint). The safety and tolerability of single-agent 
nivolumab in this population will also be evaluated. 
Each cycle will be 28 days (4 weeks) in duration. Patients will receive study treatment with 
nivolumab until disease progression, development of intolerable toxicity, elective withdrawal from 
the study, study completion, or study termination. Patients who demonstrate radiologic 
progression by RECIST criteria may be considered for continued therapy (but not primary efficacy 
analysis) if they are deemed to be clinically benefiting, according to predetermined permitted 
criteria (section 12.4). 
 
Safety will be evaluated through the monitoring of all serious and non-serious AEs and irAE's, 
graded according to the current version of National Cancer lnstitute's Common Terminology 
Criteria for Adverse Events (CTCAE v. 4.03). AEs will be collected from the time of study 
enrollment until 30 days after last dose of study drug dose. 
 
4.2 
Intervention 
Eligible patients will undergo screening and baseline procedures per the Study Schedule. Study 
inclusion and exclusion criteria will be applied per section 6.0. Enrolled patients will receive 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-180 A(10) 
Approval date: 07-Sep-2021 
Page 11 of 44 
 
 
 
 
nivolumab 480 mg IV every 4 weeks. Each cycle will be 28 days in duration. Patients will receive 
study treatment until disease progression, intolerable toxicity, elective withdrawal from the study, 
study completion, or study termination. 
Efficacy assessments will be performed at the initiation of study treatment and then every 12 
weeks (approximately every 3 cycles) until radiologic and/or clinical disease progression. Patients 
who discontinue treatment for reasons other than progression will continue efficacy assessments 
until progression is demonstrated. Patients who demonstrate radiologic progression by RECIST 
criteria may be considered for continued therapy (but not primary efficacy analysis) if they are 
deemed to be clinically benefiting, according to pre-determined permitted criteria (section 12.4). 
 
 
Nivolumab 480 mg will be infused IV over 30 minute every 4 weeks. (A treatment window of up to 
3 days from the treatment due date will be permitted, provided there are at least 10 days between 
treatment infusions.) 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1 
Nivolumab 
5.1.1 Physical and Chemical Properties 
Nivolumab was selected for dosage form development and is also referred to as BMS-936558-01 
or BMS-936558. Nivolumab is a soluble protein consisting of 4 polypeptide chains, which include 
2 identical heavy chains and 2 identical light chains. The physical and chemical properties of 
nivolumab are provided in Table 5.1-1. 
Table 5.1-1: 
Physical and Chemical Properties 
 
I 
BMS Number 
I 
BMS-936558-01 
I Other Names 
I Nivolumab, BMS-936558, MDX1106, ONO-4538, anti-PD-1 
Molecular Weight 
146,221 daltons (143,619.17 daltions, protein portion) 
Appearance 
Clear to opalescent, colorless to pale yellow liquid, light (few) particulates may be present 
Solution pH 
5.5 to 6.5 
 
5.1.2 Pharmaceutical Properties and Formulation 
Description of the Dosage Form 
Nivolumab Injection, 100 mg/10 ml (10 mg/ml), Nivolumab Injection, 40 mg/4 ml (10 mg/ml), 
and Placebo for Nivolumab Injection, 100 mgNial (10 ml label fill) Nivolumab Injection, 100 
mg/10 ml (10 mg/ml) or 40 mg/4 ml (10 mg/ml), is a clear to opalescent, colorless to pale 
yellow liquid, which may contain light (few) particulates. The drug product is a sterile, non- 
pyrogenic, single-use, isotonic aqueous solution formulated at 10 mg/ml in sodium citrate, 
sodium chloride, mannitol, diethylenetriaminepentacetic acid (pentetic acid), and polysorbate 80 
(Tween  80), pH 6.0 and includes an overfill to account for vial, needle, and syringe holdup. It is 
supplied in 10-cc Type I flint glass vials, stoppered with butyl rubber stoppers and sealed with 
aluminum seals. The only difference between the two drug product presentations is the vial fill 
volume. 
 
Drug Product Preparation 
Nivolumab Injection, 100 mg/10 ml (10 mg/ml), Nivolumab Injection, 40 mg/4 ml (10 mg/ml), 
and Placebo for Nivolumab Injection, 100 mgNial (10 ml label fill) 
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron 
pore size, low-protein binding in-line filter at the protocol-specified doses and infusion times. It is 


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not to be administered as an IV push or bolus injection. Nivolumab injection can be infused 
undiluted (10 mg/ml) or diluted with 0.9% Sodium Chloride Injection, USP or 5% Dextrose 
Injection, USP to protein concentrations as low as 0.35 mg/ml. During drug product preparation 
and handling, vigorous mixing or shaking is to be avoided. Instructions for dilution and infusion of 
nivolumab injection may be provided in the clinical protocol, pharmacy binder, or pharmacy 
reference sheet. Care must be taken to assure sterility of the prepared solution as the product 
does not contain any antimicrobial preservative or bacteriostatic agent. No incompatibilities 
between nivolumab and polyvinyl chloride (PVC) and non-PVC/non-DEHP (di(2- 
ethylhexyl)phthalate) containers/IV components or glass bottles have been observed. 
 
PRODUCT INFORMATION TABLE: Please see Appendix 1: US Prescribing Information 
 
Product Description:!Other names=: MDX-1106, O_NO-4538, anti-PD-_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)* 
Injection 
drug product 
is a sterile, 
non- 
pyrogenic, 
single-use, 
isotonic 
aqueous 
solution 
formulated at 
10 mg/ml 
100 
mgNial 
(10 
mg/ml). 
Carton of 5 or 
10 vials 
. 
10-cc Type 
1 flint glass 
vials 
stoppered 
with butyl 
stoppers 
and sealed 
with 
aluminum 
seals. 
. 
Clear to 
opalescent, 
colorless to pale 
yellow liquid. 
May contain 
particles 
. 
BMS-936558-01 
Injection must be 
stored at 2 to 8 
degrees C (36 to 
46 degrees F) 
and protected 
from light and 
freezing 
*Nh,olumab 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 include laboratory coats and gloves. 
For additional details on prepared drug storage and use time of nivolumab under room 
temperature/light and refrigeration, please refer to the BMS-936558 (nivolumab) Investigator 
Brochure section for "Recommended Storage and Use Conditions" 
Recommended Storage and Use Conditions 
 
Nivolumab Injection, 100 mg/10 mL (10 mglmL) and 40 mg/4mL (10 mglmL) 
Vials of nivolumab injection must be stored at 2° to 8°C (36° to 46°F) and protected from light and 
freezing. 
 
Undiluted Nivolumab Injection and Diluted Nivolumab Injection in the IV Container 
The administration of nivolumab infusion must be completed within 24 hours of preparation. If not 
used immediately, the infusion solution may be stored under refrigeration conditions (2°to 8°C, 
36°to 46°F) for up to 24 hours, and a maximum of 8 hours of the total 24 hours can be at room 


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temperature (20° to 25°C, 68° to 77°F) and room light. The maximum 8-hour period under room 
temperature and room light conditions includes the product administration period. 
Placebo for Nivolumab Injection, 100 mgNial (10 mL label fill) 
The same storage and use conditions for the active drug product also apply to the placebo for 
nivolumab injection. 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
1. Histologically confirmed diagnosis of metastatic or recurrent uterine cancer (endometrial 
carcinoma, carcinosarcoma, clear cell carcinoma, leiomyosarcoma, undifferentiated sarcoma, 
high grade endometrial stromal sarcoma) by 1\/lemorial Sloan Kettering Cancer Center. 
Carcinosarcomas, endometrioid and clear cell carcinomas that appears to have arisen in the 
ovary/fallopian tube or peritoneum are also eligible. Recurrence should not be amenable to 
curative approaches such as surgical resection or chemoradiotherapy. 
2. Tumor is confirmed to be one of the following: 1. MSI-high, or 2. MMR-deficient, or 3. 
Hypermutated defined as 20 somatic mutations in the tumor by MSK-IMPACT 
3. One or more prior lines of cytotoxic treatment for advanced disease (prior hormonal therapy is 
not considered to count as prior lines of therapy) 
4. 1\/leasurable disease by RECIST 1.1 criteria 
5. No known CNS metastases 
6. ECOG Performance status 0-1 
7. WBC 2000/ul, ANC 1500/ul, PLT 100,000/ul, HGB 8g/dl 
8. Serum creatinine 
1.5 x ULN or creatinine clearance of 
40ml/min by Cockroft-Gault 
formula 
9. AST (SGOT) and ALT (SGPT) 
3 x ULN 
10. Total bilirubin 
1.5 x ULN, except subjects with Gilbert's syndrome who can have total 
bilirubin 
3.0 mg/dl 
11. Able to sign voluntary written informed consent 
12. Female, 18 years of age or older 
13. Available archival tumor tissue or patient is willing to undergo new biopsy 
14. Premenopausal women of child bearing potential must have a normal urine or serum beta- 
HCG prior to enrollment, and must agree to use effective contraception during treatment with 
nivolumab and for at least 5 months following the last dose of nivolumab. 
6.2 
Subject Exclusion Criteria 
1. Disease eligible for potentially curative treatment with standard chemotherapy, surgical 
resection, or chemoradiotherapy. 
2. Known or suspected autoimmune disease, except for subjects with vitiligo, diabetes mellitus, 
resolved childhood asthma/atopy, residual hypothyroidism due to an autoimmune immune 
condition only requiring thyroid hormone replacement, psoriasis not requiring systemic 
treatment, or conditions not expected to recur in the absence of an external trigger. 
3. Serious uncontrolled medical disorder or active infection which would impair the ability of the 
subject to receive protocol therapy or whose control would be jeopardized by protocol therapy 
4. History of bowel obstruction, refractory ascites, or bowel perforation due to advanced disease 
within the past 3 months from start of study treatment. 


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5. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 antibody or 
any other antibody or drug specifically targeting T cell co-stimulation or immune checkpoint 
pathways 
6. Patients who have a condition that requires systemic treatment with either corticosteroids 
within 7 days of enrollment (systemic corticosteroid therapy is defined as >10 mg daily 
prednisone or its equivalent); or who require other immunosuppressive medications within 14 
days of study drug administration. Inhaled or topical steroids and adrenal replacement doses 
> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune 
disease. 
7. Prior history of malignancy or a concurrent malignancy, with the exception of cutaneous basal 
cell carcinoma or squamous cell carcinoma, superficial bladder cancer, or in situ carcinoma of 
the uterine cervix, prostate, or breast, unless a complete remission was achieved at least 3 
years prior to study entry and no additional therapy is required or anticipated to be required 
during the study period 
8. Breastfeeding women, pregnant women 
9. Prisoners or subjects who are involuntarily incarcerated 
10. Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness 
11. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic 
acid (HCV antibody) indicating acute or chronic infection (if patient has documented Hepatitis 
Band C from within 6 months of enrollment, these tests do not need to be repeated.) 
12. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS) 
13. Known allergy or Adverse Drug Reaction to nivolumab, or a history of allergy to study drug 
components. 
 
7.0 
RECRUITMENT PLAN 
Potential research subjects will be identified by a member of the patient's treatment team, the 
protocol investigator or research team within the Gynecologic rvledical Oncology Group at 
rvlemorial Sloan Kettering Cancer Center (MSKCC). Patient recruitment will occur in the 
Gynecologic rvledical Oncology clinics at MSKCC. The investigator will discuss the study with 
suitable participants, and should the patient consent to proceed with protocol therapy, will enroll 
their patients in the research study. Approximately 1-2 patients will accrue onto this study per 
month. All participants will be women. 
8.0 
PRETREATMENT EVALUATION 
Within 28 days prior to treatment start: 
• 
Written informed consent 
• 
History and Physical examination 
• 
Review of concomitant medications 
• 
ECOG Performance status 
• 
Toxicity assessment 
• 
12-lead ECG 
• 
Radiographic tumor measurements (CT or MRI C/A/P) 
• 
Request fresh or archival tumor (10-20 FFPE slides or tissue block). 


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• 
Consent patient to enrollment on 12-245 for MSK-IMPACT testing (if patient not previously 
tested) 
Within 14 days prior to treatment start: 
• 
Complete Blood Count (CBC) with differential 
• 
Comprehensive metabolic profile (Na, K, Cl, bicarbonate, BUN, creatinine, glucose, Ca, 
Mg, phosphate, total protein, albumin, ALT, AST, total bilirubin, alkaline phosphatase) 
• 
LOH 
• 
Amylase and lipase 
• 
Thyroid function tests (TSH, free T3 and free T4) 
• 
CA125 (only for patients with endometrial carcinoma or carcinosarcoma) 
• 
Urinalysis 
• 
Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) will be measured 
on study days noted in the Schedule of Assessments. 
• 
Serum or urine beta-HCG (pregnancy test) ONLY for women of child bearing potential 
 
The following clinical laboratory tests will be performed (see the Schedule of Assessments, 
Section 10.0 for the time points of each test): 
• 
Coagulation parameters: Activated partial thromboplastin time (PTT) and International 
normalized ratio (INR) to be assessed at baseline and as clinically indicated 
• 
Thyroid Stimulating Hormone 
o free T3 and free T4, and TSH 
o repeat thyroid function tests approximately every 8 weeks (every other cycle) 
• 
Other laboratory tests 
o Hepatitis B and C testing (HBV sAg and HCV Ab or HCV RNA) if these were not 
performed within 6 months of enrollment. 
 
Table 1. Hematology Laboratory Tests 
 
 
Basophils 
Eosinophils 
Hematocrit 
Hemoglobin 
Lymphocytes 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular \IOlume 
Monocytes 
Neutrophils 
Platelet count 
Red blood cell count 
Total white cell count 
 
 


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Table 2. Clinical chemistry (Serum or Plasma} Laboratory Tests 
 
 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Amylase 
Aspartate aminotransferase 
Bicarbonate 
CA-125 
Calcium 
Chloride 
Creatinine 
Free T3 
Free T4 
Glucose 
Lactate dehydrogenase 
Lipase 
Magnesium 
Potassium 
Phosphate 
Sodium 
Thyroid stimulating hormone 
Total bilirubina 
Total protein 
Urea or blood urea nitrogen, depending on local practice 
a If Total bilirubin is 2: 1.5 x ULN and < 3xULN (and no evidence of Gilbert's syndrome) then fractionate into 
direct and indirect bilirubin to consider Gilbert's syndrome 
 
 
 
Bilirubin 
Blood 
Glucose 
Ketones 
Table 3. Urinalysis Testsa 
pH 
Protein 
Specific gravity 
Colour and appearance 
a Microscopy should be used as appropriate to investigate white blood cells and use the high power field 
for red blood cells 
9.0 
TREATMENT/INTERVENTION PLAN 
All subjects will receive single-agent nivolumab. Each cycle will be 4 weeks in duration. Patients 
will receive study treatment until disease progression, intolerable toxicity, elective withdrawal from 
the study, study completion, or study termination. Patients who demonstrate radiologic 
progression by RECIST criteria may be considered for continued therapy (but not primary efficacy 
analysis) if they are deemed to be clinically benefiting, according to predetermined permitted 
criteria (section 12.4) 
 
Nivolumab 480 mg will be infused IV over 30 minutes every 4 weeks. A treatment window of up to 
3 days from the treatment due date will be permitted. 
 
Efficacy assessments will be performed every 12 weeks (3 cycles) from initiation of study 
treatment until disease progression. Patients who discontinue treatment for reasons other than 
progression will continue efficacy assessments until progression. 


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Safety will be evaluated in this study through the monitoring of all serious and non-serious AEs 
and irAEs, graded according to the current version of the National Cancer Institute. AEs will be 
collected from the time of study enrollment until 30 days after last dose of study drug delivered. 
 
Pre- and post-treatment blood and serum samples, as well as fresh or archival tumor tissue 
(when available) will be collected for biomarker analysis (as per Appendix 4). 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
All assessments to be performed pre-infusion unless stated otherwise. A Cycle is 28 Days. 
 
 
 
 
 
I 
 
 
I 
End of 
Follow- 
Parameter 
Screening 
Cycle 1 
Cycle 2 
onward 
Treatment h 
up h 
Day 
28 days 
before • 
Within 
14 days 
before 
Day 1 
Day 
15 
Day 1 
Consent 
X 
I Medical History 
X 
X 
Concomitant 
Medications 
X 
X  
I 
X 
X 
X 
Request Archival 
tumor tissue 
X 
Physical 
Examination 
X 
X 
X 
ECOG 
X 
I 
X 
X 
I Weight 
X 
I 
X 
X 
Vital Signs (BP, 
HR,and 
temperature), 
height 
X 
X 
X 
X 
Adverse Event 
Assessment 
X 
X 
X 
X 
Report 
AEs 
until 4 
weeks 
after last 
dose 
study 
drug 
CBC 
X 
X 
X 
X 
X 
CMP (AST, ALT, 
alkaline 
phosphatase, 
calcium, Na, K, 
Cl, glucose 
X 
X 
X 
X 
X 
Serum or urine 
pregnancy test 
X 


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I Amylase 
X 
X 
X 
X 
I Lipase 
X 
X 
X 
X 
 
 
 
I 
 
 
 
 
 
I 
a If screening laboratory assessments are performed within 3 days prior to Day 1 they do not need to be repeated at 
Cycle 1 Day 1. 
b  CA-125 only for endometrial carcinoma, carcinosarcoma or clear cell carcinoma, at start of each cycle 
c Research bloods will consist of 4 CPT tubes and 2 Streck tubes. Research bloods will be drawn at following time 
points: baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1 and every 12 weeks until progression. The baseline draw 
may be up to 14 days prior to Cycle 1 Day 1. Please see IMF requisition form and Appendix 4 for details of blood 
processing and delivery. 
d ±3 day window for all parameters except for Radiographic disease assessment which has a ±7 day window as 
clinically indicated. 
e±3 day window for nivolumab treatment days 
f Thyroid function tests (TSH, Free T3, Free T4) will be drawn at baseline and then every 8 weeks (every othercycle) 
starting Cycle 2 
g Hepatitis screening for Hep Band C must be negative for patient to be eligible. Patients with a positive test for 
hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or 
chronic infection will not be eligible. If patient has documented Hepatitis B and C screening tests from within 6 
months of enrollment, these tests do not need to be repeated. 
WOCBP = women of child-bearing potential 
h  ±7 day window for end of treatment and follow -up. 
 
11.0 
TOXICITIES/SIDE EFFECTS 
11.1 
Nivolumab 
11.1.1 Summary of Adverse Events 
A cumulative review of available data from completed and ongoing studies was performed 21. 
There have been some reports of adverse events with BMS-936558 in clinical studies. Based on 
the nature and frequency of the observed events, the events identified as ADRs are listed by 
system organ class in Table 11.0-1. As there is potential for hepatic toxicity with nivolumab, 
drugs with a predisposition to hepatoxicity should be used with caution in patients treated with 
nivolumab-containing regimen. 
ONLY for 
WOCBP 
Magnesium 
X 
X 
X 
X 
Phosphate 
X 
X 
X 
X 
LDH 
X 
X 
X 
X 
TSHr 
X 
Every 8 weeks 
X 
Free T3r 
X 
Every 8 weeks 
X 
Free T4r 
X 
Every 8 weeks 
X 
I CA-125b 
X 
X I 
I 
X 
X 
PT/INR 
X 
As clinically indicated 
I Urinalysis 
X 
As clinically indicated 
Research bloodsc 
Every 
X 
X 
X 
12 
weeks 
12- Lead ECG 
X 
Hepatitis B,C 
xg 
screerung 
Nivolumab d,e 
X 
X 
Radiographic 
disease assessment 
by CT or MRI 
X 
Every 12 weeks 
CAPd 


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ADRs reported in clinical studies of nivolumab that are considered by the Sponsor to be causally 
related to nivolumab are listed by system organ class and frequency. The frequency of ADRs is 
defined using the following convention: very common (;?:1/10); common (;?:1/100 to< 1/10); 
uncommon (;?:1/1,000 to< 1/100); rare (;?:1/10,000 to< 1/1,000); and very rare(< 1/10,000). 
 
As of 29-April-2015, the following ADRs have been reported in clinical studies where nivolumab 
was given as monotherapy (Table 11.0-1). 
 
Table 11.0-1: Adverse Drug Reactions in Subjects Treated with Nivolumab Monotherapy 
System Organ 
Class 
Preferred Term 
Overall Frequency8 
At least one event with outcome: 
Serious 
Life Threatening 
Fatal 
Cardiac 
disorders 
Arrhythmia b 
(including ventricular 
arrhythmia) 
Uncommon 
X 
X 
Tachycardia b 
Uncommon 
X 
Endocrine 
disorders 
Hypothyroidism 
Common 
X 
Hyperthyroidism 
Common 
X 
Hyperglycemia 
Common 
X 
X 
Adrenal insufficiency 
Uncommon 
X 
Hypopituitarismc 
Uncommon 
X 
Hypophysitis 
Uncommon 
X 
(Autoimmune) 
Thyroiditis c 
Uncommon 
X 
Diabetic ketoacidosis 
Uncommon 
X 
X 
Diabetes rnellitus c 
Uncommon 
X 
X 
Eye disorders 
Uveitis (including 
iridocyclitis) 
Uncommon 
X 
Gastrointestinal 
disorders 
Diarrhea 
Very common 
X 
Nausea 
Very common 
X 
(Autoimmune) Colitis 
Common 
X 
X 
Stomatitis c (including 
mucosa! 
inflarnmation/ 
ulceration, mouth 
ulceration) 
Common 
X 
Vomiting 
Common 
X 
Abdominal pain 
Common 
X 
X 
Constipationc 
Common 
X 
Dry mouth b 
Common 
Pancreatitis 
Uncommon 
X 
Duodenal ulcer b 
Uncommon 
X 
General 
disorders and 
administration 
site conditions 
Fatigue (including 
asthenia) 
Very common 
X 
X 
Pyrexia 
Common 
X 
Edema (including 
peripheral edema, 
generalized edema, 
orbital edema, 
swelling face) 
Common 
X 
Hepatobiliary 
disorders 
(Autoimmune) 
hepatitis 
Common 
X 
X 
Immune system 
disorders 
Infusion related 
reaction 
Common 
X 
X 
Anaphy lactic reaction 
Uncommon 
X 
X 


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Hypersensitivity 
I 
Uncommon 
X 
X 
Infections and 
infestations 
Upper respiratory tractI 
Common 
X 
infection b 
Bronchitis b 
I 
Uncommon 
X 
Investigations 
Lipase increased 
I 
Common 
X 
Amylase increased 
I 
Common 
X 
Alanine 
aminotransferase 
increased 
Common 
X 
X 
Aspartate 
aminotransferase 
increased 
Common 
X 
X 
Blood bilirubin 
increased 
Common 
X 
X 
Metabolism and 
nutrition 
disorders 
Hyponatremia c 
Common 
X 
Decreased appetite 
Common 
X 
X 
Musculoskeletal 
Musculoskeletal pain 
Common 
X 
and connective 
b,d 
tissue disorders 
Arthralgia (including 
arthritis, polyarthritis, 
and osteoarthritis) 
Common 
X 
Polymyalgia 
rheumatica b 
Uncommon 
X 
Neoplasms 
benign, 
malignant, and 
unspecified 
(including cysts 
and polyps) 
Histiocytic 
necrotizing 
lymphadenitis b 
(Kikuchi 
lymphadenitis) 
Uncommon 
Nervous system 
disorders 
Neuropathy peripheral 
e 
Common 
X 
Headache 
Common 
X 
Dizziness b (including 
vertigo, vertigo 
positional) 
Common 
X 
Guillain-Barre 
Uncommon 
X 
syndrome 
Demyelination 
Uncommon 
X 
Myasthenic syndrome 
Uncommon 
X 
b 
Autoimmune 
neuropathy (including 
facial and abducens 
nerve pares is) 
Uncommon 
X 
Encephalitis 
Uncommon 
X 
X 
X 
Renal and 
Nephritis 
Common 
X 
 
urinary 
disorders 
Renal failure 
(including acute 
kidney injury) 
Uncommon 
X 
X 
X 
Tubulointers titial 
nephritis 
Uncommon 
X 
Respiratory, 
thoracic, and 
mediastinal 
disorders 
Pneurnonitis 
(including interstitial 
lung disease) 
Common 
X 
X 
X 
Dyspnea 
Common 
X 
X 
X 


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Cough 
Common 
X 
Lung infiltration 
Uncommon 
X 
Skin and 
subcutaneous 
tissue disorders 
Rash f 
Very common 
X 
Pruritus 
Very common 
X 
Vitiligo b 
Common 
X 
Dry skin b 
Common 
Erytherna b 
Common 
Alopecia b 
Common 
Erythema rnultiforrne 
Uncommon 
X 
Psoriasis b 
Uncommon 
X 
Rosaceab 
Uncommon 
Toxic epidermal 
necrolysis b (including 
Stevens Johnson 
syndrome) 
Rare 
X 
X 
Urticaria b 
Uncommon 
Vascular 
disorders 
Hypertension b 
Common 
X 
Vasculitis b 
Uncommon 
a 
Overall frequency includes reported serious and non-serious ADRs 
b 
New ADR added in this 1B 
c 
New ADR added to rnonotherapy table (previously reported in combination therapy 
d 
Musculoskeletal pain is a composite term which includes back pain, bone pain, rnusculoskeletal chest pain, 
rnusculoskeletal discomfort, myalgia, neck pain, pain in extremity, pain in jaw, and spinal pain. 
e 
Neuropathy peripheral is a composite term which includes burning sensation, peripheral motor 
neuropathy, Polyneuropathy, and peripheral sensory neuropathy. 
f 
Rash is a composite term which includes rnaculo-papular rash, rash generalised, rash erythematous,rash 
pruritic, rash follicular, rash macular, rash papular, rash pustular, rash vesicular, dermatitis, dermatitis 
acneiform, dermatitis allergic, dermatitis exfoliative, and drug eruption. 
 
There have been no additional ADRs identified from postmarketing expenence with BMS-936558. 
 
11.1.2 Immune-Related Adverse Event (irAEs) General Definition, Monitoring, and 
Management 
 
Guidelines for the management of adverse events and toxicities are detailed in Appendix 3. 
 
For the purposes of this protocol, an immune-related adverse reaction irAE is defined as an 
adverse reaction of unknown etiology associated with drug exposure and consistent with an 
immune phenomenon. Efforts should be made to rule out neoplastic, infectious, metabolic, toxin 
or other etiologic causes prior to labeling an event an irAEs. Serologic, immunologic, and 
histologic (biopsy) data should be used to support the diagnosis of an immune-related toxicity. 
Suspected immune-related adverse reactions must be documented on an AE or SAE form. 
 
Overall, immune-related AEs commanly start within 3 to 10 weeks from initiation of therapy and 
are in most cases successfully managed by delaying doses, discontinuing dosing, and/or through 
administering symptomatic or immunosuppressive therapy, including corticosteroids, as 
mentioned below. Immune-related AEs generally resolved within days to weeks in the majority of 
subjects. 
 
Patients should be informed of and carefully monitored for evidence of clinically significant 
systemic immune-mediated adverse reactions (e.g., systemic lupus erythematosus-like diseases) 


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or organ-specific immune-mediated adverse reaction (e.g., rash, colitis, uveitis, hepatitis or thyroid 
disease). If an immune-mediated adverse reaction is noted, appropriate work-up (including biopsy 
if possible) should be performed, and steroid therapy may be considered if clinically necessary. 
 
It is unknown if systemic corticosteroid therapy has an attenuating effect on nivolumab activity. 
However, clinical anti-tumor responses have been maintained in patients treated with 
corticosteroids and discontinued from ipilimumab. If utilized, corticosteroid therapy should be 
individualized for each patient. For example, prior experience suggests that colitis manifested as 
grade 3 diarrhea requires corticosteroid treatment. If an irAE is documented, in general, delay 
protocol therapy and initiate corticosteroids earlier to obtain resolution with the possibility for 
resuming protocol therapy rather than waiting for higher grade events. 
 
Potential safety concerns and recommended management guidelines regarding pulmonary 
toxicities, GI toxicities, hepatotoxicities, endocrinopathies, dermatologic toxicities, and other 
toxicities of concern are summarized below and described in detail in Appendix 3. 
 
Pulmonary Adverse Events 
Pulmonary AEs have been observed following treatment with nivolumab and have occurred after 
a single dose and after as many as 48 treatments. The frequency of pulmonary AEs may be 
greater with nivolumab combination therapies than with nivolumab monotherapy. The majority of 
cases reported were Grade 1 or 2, and subjects presented with either asymptomatic radiographic 
changes (eg, focal ground glass opacities and patchy infiltrates) or with symptoms of dyspnea, 
cough, or fever. Subjects with reported Grade 3 or 4 pulmonary AEs were noted to have more 
severe symptoms, more extensive radiographic findings, and hypoxia. Pulmonary AEs have been 
reported in subjects with a variety of tumor types; however, there have been numerically more 
cases in subjects with NSCLC. It is not clear whether the underlying NSCLC is a distinct risk 
factor, or if subjects with NSCLC are more likely to develop radiographic changes and symptoms 
for which it is difficult to distinguish between nivolumab related and unrelated causes. At this time, 
no other underlying risk factor, including prior radiotherapy, presence of lung metastases, or 
underlying pulmonary medical history, has yet to be identified. 
 
Asymptomatic subjects were typically managed with dose delay. Subjects with Grade 2 
pneumonitis were managed with dose delay, treated with corticosteroids, and had resolution of 
pneumonitis within days to weeks. In cases where nivolumab treatment was restarted, recurrence 
of pneumonitis was infrequently reported across the nivolumab program. Subjects with more 
severe cases of pneumonitis can be difficult to treat. In a few cases, subjects who did not initially 
respond to corticosteroids were administered anti-tumor necrosis factor therapy (infliximab) and/or 
cyclophosphamide. In some of these cases, pneumonitis began to resolve following the use of 
these additional therapies. 
 
Guidelines on the recommended management of pneumonitis and other pulmonary AEs are 
found in Appendix 3. Early recognition and treatment of pneumonitis is critical to its management. 
Subjects should be advised to seek medical evaluation promptly if they develop new-onset 
dyspnea, cough, or fever or if they have worsening of these baseline symptoms. As respiratory 
symptoms are common in subjects with cancer (eg, NSCLC), it is important that an 
evaluation/work-up distinguishes between non-drug-related causes (eg, infection or progression 
of disease) and a possible drug-related pulmonary toxicity as the management of these events 
can be quite different. For symptomatic nivolumab-related pneumonitis, the principal treatment is 
corticosteroids (Appendix 3). All subjects with Grade 3-4 pneumonitis should discontinue 


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nivolumab and initiate treatment with high doses of corticosteroids. Consultation with a BMS 
medical monitor should be sought for all suspected cases of pneumonitis. 
Gastrointestinal Adverse Events 
Gastrointestinal AEs have been observed following treatment with nivolumab. l\t1ost cases of 
diarrhea were of low grade (Grade 1-2). Colitis occurred less frequently than diarrhea. High-grade 
cases of diarrhea and colitis were managed with corticosteroids and, in all cases, the events 
resolved. 
 
The recommended management of GI AEs is provided in Appendix 3. Early recognition and 
treatment of diarrhea and colitis are critical to their management. Subjects should be advised to 
seek medical evaluation if they develop new-onset diarrhea, blood in stool, or severe abdominal 
pain or if they have worsening of baseline diarrhea. As GI symptoms are common in subjects with 
cancer, it is important that an evaluation/work-up distinguishes between non-drug-related causes 
(eg, infection or progression of disease) and a possible drug-related AE as the management can 
be quite different. The principal treatment for high-grade GI AEs is corticosteroids (Appendix 3). 
Caution should be taken in the use of narcotics in subjects with diarrhea, colitis, or abdominal 
pain as pain medicines may mask the signs of colonic perforation. Consultation with a BMS 
medical monitor should be sought for all moderate- and high-grade cases of GI AEs. 
 
Diverticular Perforation 
The prevalence of diverticulosis in the general population is common and increases with age from 
10% under 40 years of age to approximately 50% over 60 years of age. Approximately 10% to 
25% of subjects with diverticulosis develop diverticulitis. Perforation occurs in 50% to 70% of 
instances of complicated diverticulitis. 27•28 Corticosteroids, non-steroidal anti-inflammatory drugs 
(NSAIDs), and opioid analgesics are known risk factors for diverticular perforation. 27 Given the 
high prevalence of diverticulosis and diverticulitis in the general population, it is expected that 
some nivolumab-treated subjects will have these conditions concurrently with their malignancy. 
Cases of diverticular perforation while on concomitant corticosteroids (6 cases) or NSAID (1 case) 
were observed in nivolumab program. While there is insufficient evidence to suggest that 
diverticulosis or diverticulitis is a predisposing factor for GI perforation following nivolumab 
administration, clinical caution should be exercised, as appropriate, for subjects on concomitant 
medications of corticosteroids, NSAID, or opioid analgesics. In addition, be vigilant for signs and 
symptoms of potential perforation, especially in subjects with known diverticular disease. 
 
Hepatic Adverse Events 
Hepatic AEs, including elevated liver function tests (LFTs) and, infrequently, DILi, have been 
observed following treatment with nivolumab. l\t1ost cases were of low or moderate grade. Higher- 
grade hepatic AEs, including DILi, were managed with corticosteroids (with or without 
mycophenolate mofetil) and, in almost all cases, the events resolved. 
 
The recommended management of hepatic AEs is provided in Appendix 3. Early recognition and 
treatment of elevated LFTs and DILi are critical to their management. Subjects should be advised 
to seek medical evaluation if they notice jaundice (yellow appearance of skin or sclera) or if they 
develop bruising, bleeding, or right-sided abdominal pain. Physicians should monitor LFTs prior to 
each nivolumab treatment. As LFT abnormalities are common in subjects with cancer, it is 
important that an evaluation/work-up distinguishes between non-drug-related causes (eg, 
infection, progression of disease, concomitant medications, or alcohol) and a possible drug- 
related AE as the management can be quite different. The principal treatment for high-grade 
hepatic AEs is corticosteroids (Appendix 3). Consultation with a BMS medical monitor should be 
sought for all moderate- and high-grade hepatic AEs. 


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Endocrinopathies 
Endocrinopathies have been observed following treatment with nivolumab (Section 5.5). Most 
cases were of low or moderate grade. The events have typically been identified through either 
routine periodic monitoring of specific laboratories (eg, TSH) or as part of a work-up for 
associated symptoms (eg, fatigue). Events may occur within weeks of beginning treatment, but 
also have been noted to occur after many months (while still on treatment). More than 1 
endocrine organ may be involved (eg, hypophysitis [pituitary inflammation] may need to be 
evaluated at the time adrenal insufficiency or thyroid disorder is suspected). Moderate- to high- 
grade cases were managed with hormone replacement therapy and, in some cases, with the 
addition of corticosteroids. In some cases, nivolumab treatment was held until adequate hormone 
replacement was provided. 
Guidelines on the recommended management of endocrinopathies are provided in Appendix 3. 
Early recognition and treatment of endocrinopathies are critical to its management. Subjects 
should be advised to seek medical evaluation if they notice new-onset fatigue, lightheadedness, 
or difficulty with vision or if baseline fatigue worsens. /ls fatigue is common in subjects with 
cancer, it is important that an evaluation/work-up distinguishes between non-drug-related causes 
(eg, progression of disease, anemia, concomitant medications, or depression) and a possible 
drug-related AE as the management can be quite different. The principal management of 
endocrinopathies is hormone replacement therapy. For subjects with moderate- or high-grade 
events, corticosteroids may also be used (Appendix 3). Consultation with a BMS medical 
monitor should be sought for all moderate- and high-grade cases of endocrinopathies. 
 
Skin Adverse Events 
Rash and pruritus were the most common skin AEs observed following treatment with 
nivolumab. The rash was typically focal with a maculopapular appearance occurring on the trunk, 
back, or extremities. Most cases have been of low or moderate grade. In some cases, rash and 
pruritus resolved without intervention. Topical corticosteroids have been used for some cases of 
rash. Anti-histamines have been used for some cases of pruritus. More severe cases responded 
to systemic corticosteroids. 
 
Subjects should be advised to seek medical evaluation if they notice new-onset rash. Early 
consultation with a dermatology specialist and a biopsy should be considered if there is 
uncertainty as to the cause of the rash, or if there is any unusual appearance or clinical feature 
associated with it. Other drugs that may cause rash should be considered in the differential and, if 
possible, discontinued. Three cases of toxic epidermal necrolysis occurred in subjects receiving 
either nivolumab+ipilimumab and prophylaxis with trimethoprim/sulfamethoxazole, alternate 
dosing with ipilimumab and nivolumab, or nivolumab monotherapy. These cases highlight the 
possible importance of discontinuing suspected drugs in the management of rash. In addition, 
careful evaluation of potential benefit-risk is necessary when considering the use of nivolumab or 
ipilimumab in a patient who has previously experienced a severe or life-threatening skin adverse 
reaction on a prior immune-stimulating therapy. 
 
The principal treatment for skin AEs, such as rash and pruritus, consists of symptomatic 
management. Topical corticosteroids can be used for low- to moderate-grade focal rash. 
Systemic corticosteroids should be used for diffuse and high-grade rash. Consultation with a BMS 
medical monitor should be sought for all moderate- and high-grade cases of skin AEs. 
Renal Adverse Events 
Elevated creatinine and biopsy-confirmed tubulointerstitial nephritis and allergic nephritis have 
been infrequently observed following treatment with nivolumab. The frequency of renal AEs may 
be greater with nivolumab combination therapies than with nivolumab monotherapy. Most cases 


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were Grade 2 or 3 and based on creatinine elevation. subjects with a history of RCC or prior 
nephrectomy did not appear to be at higher risk. Events were managed with corticosteroids and, 
in all cases, renal function partially or fully improved. 
The recommended management of renal AEs is provided in Appendix 3. Physicians should 
monitor creatinine regularly. As creatinine abnormalities are common in subjects with cancer and 
other comorbidities, it is important that an evaluation/work-up distinguishes between non-drug- 
related causes (eg, dehydration, concomitant medications, hypotension, or progression of 
disease) and a possible drug-related AE as the management can be quite different. The principal 
treatment for renal AEs is corticosteroids (Appendix 3). Consultation with a BMS medical monitor 
should be sought for all moderate- and high-grade cases of renal AEs. 
Neurologic Adverse Events 
Neurologic AEs have been uncommonly observed following treatment with nivolumab. The 
frequency of neurologic AEs may be greater with nivolumab + ipilimumab combination therapies 
than with nivolumab monotherapy or other nivolumab combinations. Neurologic AEs can manifest 
as central abnormalities (eg, aseptic meningitis, encephalopathy, or encephalitis) or peripheral 
sensory/motor neuropathies (eg, Guillain-Barre Syndrome, myasthenia gravis complicated with 
sepsis and fatality). 
 
The recommended management of neurologic AEs is provided in Appendix 3. Early recognition 
and treatment of neurologic AEs is critical to its management. Subjects should be advised to seek 
medical evaluation if they notice impairment in motor function (eg, weakness), changes in 
sensation (eg, numbness), or symptoms suggestive of possible central nervous system 
abnormalities such as new headache or mental status changes. As neurologic symptoms can be 
common in subjects with cancer, it is important that an evaluation/work-up distinguishes between 
non-drug-related causes (eg, progression of disease, concomitant medications, or infection) and a 
possible drug-related AE as the management can be quite different. The principal treatments for 
neurologic toxicity are dose delay, corticosteroids, and IV immunoglobulin as outlined in the safety 
algorithm (Appendix 3). For high-grade related neurological AEs, nivolumab should be 
discontinued. Consultation with a BMS medical monitor should be sought for all moderate- and 
high-grade cases of neurologic AEs. 
 
Lipase/Amylase Elevations 
Asymptomatic elevations in lipase and amylase have been reported. In monotherapy studies, 
lipase and amylase levels were not systematically monitored, so an estimate of the frequency of 
asymptomatic lipase/amylase elevations is unknown. In studies evaluating the safety of the 
nivolumab + ipilimumab combination in multiple tumor types, lipase and amylase levels were 
systematically monitored, and elevations in any grade of lipase/amylase were consistently noted 
in approximately 10% to 30% of subjects. Very few subjects reported associated symptoms (eg, 
abdominal pain) or radiographic findings (eg, stranding) consistent with pancreatitis. Thus, there 
does not seem to be clinical significance to the elevated laboratory values. 
 
As lipase/amylase abnormalities are not uncommon in subjects with cancer, it is important that an 
evaluation/work-up distinguishes between non-drug-related causes (eg, progression of disease, 
concomitant medications, or alcohol) and a possible drug-related cause as the management can 
be quite different. The recommended management of nivolumab-related elevated lipase/amylase 
values centers around close observation. Physicians should ensure that subjects have no 
associated symptoms consistent with pancreatitis, such as abdominal pain. Corticosteroids do not 
seem to alter the natural history of lipase/amylase elevations. Laboratory values tend to fluctuate 
on a day-to-day basis and eventually return to baseline or low grade over the course of weeks, 
whether or not subjects receive corticosteroids. Asymptomatic elevations should be monitored 


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approximately on a biweekly basis, and nivolumab should be held per protocol instructions. For 
sustained asymptomatic Grade 4 elevations, nivolumab should be discontinued per protocol 
instructions. For subjects with elevated lipase/amylase and symptoms consistent with possible 
pancreatitis, nivolumab should be discontinued, and consultation with a gastroenterologist should 
be considered. Consultation with a BMS medical monitor should be sought for all high-grade 
cases of elevated lipase/amylase. 
 
Uveitis and Visual Com aints 
Immune therapies have been uncommonly associated with visual complaints. Inflammation of 
components within the eye (eg, uveitis) is an uncommon, but clinically important, event. Uveitis 
may occur more frequently with nivolumab + ipilimumab combination therapy than with nivolumab 
monotherapy or nivolumab in combination with other therapies. An ophthalmologist should 
evaluate visual complaints with examination of the conjunctiva, anterior and posterior chambers, 
and retina. Topical corticosteroids may be used to manage low-grade events. Low-grade events 
that do not resolve and high-grade events should be managed with systemic corticosteroids. 
Consultation with a BMS medical monitor should be sought for all cases of ocular inflammatory 
events. Complaints of double vision should also prompt medical evaluation. In addition to ocular 
inflammatory events, a work-up should also consider pituitary inflammation as a cause. 
 
Infusion Reactions 
Infusion reactions, including high-grade hypersensitivity reactions, following administration of 
nivolumab are uncommon. Investigators are advised to monitor for fever, chills, shakes, itching, 
rash, hypertension or hypotension, or difficulty in breathing during and immediately after 
administration of nivolumab. 
Dose Modifications: dose reductions or dose escalations are not permitted. 
Dose Delay Criteria 
Because of the potential for clinically meaningful nivolumab-related AEs requiring early 
recognition and prompt intervention, management algorithms have been developed for suspected 
AEs of selected categories. [see current Investigator Brochure and Appendix for citation 
examples). 
 
Dose delay criteria apply for all drug-related adverse events (regardless of whether or not the 
event is attributed to nivolumab). All study drugs must be delayed until treatment can resume. 
 
Dose delay criteria apply for all drug-related AEs. Nivolumab must be delayed until treatment can 
resume. 
 
Nivolumab administration should be delayed for the following: 
Any Grade 2 non-skin, drug-related AE, with the following exceptions: 
• Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay 
• Any Grade 3 skin, drug-related AE 
 
Any Grade 3 drug-related laboratory abnormality, with the following exceptions for lymphopenia, 
leukopenia, AST, ALT, total bilirubin, or asymptomatic amylase or lipase: 
• Grade 3 lymphopenia or leukopenia does not require dose delay. 
• If a subject enrolled with a baseline AST, ALT, or total bilirubin that was within normal limits, and 
develops new Grade 2 AST, ALT, or bilirubin toxicity delay dosing until less than or equal to 
grade 1. 


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• If a subject enrolled with a baseline AST, ALT, or total bilirubin greater than normal but less than 
or equal to Grade 1 toxicity range, and develops a new Grade 3 AST, ALT, or bilirubin toxicity, 
delay dosing until less than equal to grade 1. 
• Any Grade 3 drug-related amylase or lipase abnormality that is not associated with symptoms 
or clinical manifestations of pancreatitis does not require dose delay. The Investigator should be 
consulted for such Grade 3 amylase or lipase abnormalities. 
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the investigator 
warrants delaying the dose of study medication. 
 
Subjects who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met. 
Criteria to Resume Treatment 
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to Grade :51 
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 toxicity. 
11.1.3 Overdose, Warnings, and Precautions 
There is no available information concerning overdose with nivolumab. Depending on the 
symptoms and/or signs leading to the suspicion of overdose, supportive medical management 
should be provided. There is no specific antidote. 
 
Overdose 
 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE. 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, 
x rays, and any other potential safety assessments, whether or not these procedures are required 
by the protocol, should also be recorded as a nonserious or serious AE, as appropriate, and 
reported accordingly. 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
Antitumor Effect 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [22]. Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 


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12.1 
Definitions 
 
Evaluable for toxicity. All patients who receive at least one dose of nivolumab will be evaluable for 
toxicity. Patients will be considered evaluable for toxicity from the time of their first treatment on 
study. 
 
Evaluable for objective response. Only those patients who have measurable disease present at 
baseline, have received at least one dose of therapy, and have had their disease reevaluated will 
be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response. Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one dose 
of therapy, and have had their disease reevaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal 
progression of the lesions. 
 
12.2 
Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm 
with CT scan, or >10 mm with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area will not be considered 
measurable unless progression is documented or a biopsy is obtained to confirm persistence at 
least 90 days following completion of radiation therapy. 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with;::: 10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardia! 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
 
'Cystic lesions' thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 


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Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow-up. 
12.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. The same method of 
assessment and the same technique should be used to characterize each identified and reported 
lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by 
clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed 
using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g. for body scans), but NOT lung. 
CA125: CA125 alone cannot be used to assess response. If CA125 is initially above the upper 
normal limit, it must normalize for a patient to be considered in complete clinical response. 
 
12.4 
Response Criteria 
Evaluation of Target Lesions 
Com ete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 


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Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
Evaluation of Non-Target Lesions 
Com ete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Note: If 
CA125 is initially above the upper normal limit, it must normalize for a patient to be considered in 
complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of CA125 
level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase. 
 
Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed 
at a later time by the review panel (or Principal Investigator). 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
I 
I 
 
 
 
I 
 
 
Target LesionsI 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
2:4 wks. Confinmtion** 
CR 
I 
Non-CR/Non-PD 
I 
No 
I 
PR 
2:4 wks. Confinmtion** 
CR 
I 
Not evaluated 
I 
No 
I 
PR 
PR 
Non-CR/Non- 
No 
PR 
PD/not evaluated 
SD 
Non-CR/Non- 
PD/not evaluated 
No 
SD 
Documented at least once 2:4 wks. 
from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
Only for non-randomized trials with response as primary endpoint. 


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For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
 
 
 
 
 
I 
 
 
Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). The duration of overall 
CR is measured from the time measurement criteria are first met for CR until the first date that 
progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started, including the baseline measurements. 
 
Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to time 
of recurrence, progression (as defined by RECIST 1.1), or death, whichever occurs first. 
 
Survival 
Survival is defined as the duration of time from start of treatment to time of death or the date of 
last contact 
Permitted Deviations from RECIST 
The study's efficacy objectives will be evaluated according to the standard, unmodified RECIST 
v1.1 criteria described above, and that, within the context of this protocol, the only purpose of the 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as" symptomatic deterioration." Every effort 
should be made to document the objective progress ion even after discontinuation of treatment. 
Non-Target Lesions 
New Lesions 
O\erall Response 
CR 
 
CR 
jNon-CR/non-PD 
No 
jNon-CR/non-PD* 
jNot all evaluated 
No 
10t evaluated 
!Unequivocal PD 
Yes orNo 
rD 
IYes 
I 
*  'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since SD is 
increasingly used as an endpoint for assessment ofefficacy in some trials so to assign this category when no 
lesions can be measured is not advised. 


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modifications to the criteria is to allow certain patients to continue the study treatment despite 
meeting RECIST criteria for progression of disease. 
 
The response to immunotherapy may differ from the typical responses observed with cytotoxic 
chemotherapy including the following (Wolchoket al 2009, Nishino et al 2013): 
• 
Response to immunotherapy may be delayed 
• 
Response to immunotherapy may occur after POD by conventional criteria 
• 
The appearance of new lesions may not represent POD with immunotherapy 
• 
SD while on immunotherapy may be durable and represent clinical benefit. 
 
As long as they are receiving treatment on protocol, patients will be permitted to continue study 
treatment after RECIST v 1.1 criteria for POD are met at the first 12 week(+/- 7 days) CT if they 
meet all of the following criteria: 
• 
No decrease in performance status 
• 
No requirement for immediate alternative treatment or urgent palliative treatment 
• 
Progression limited to an increase of 40% in the sum of diameters of target lesions 
• 
No more than 4 new lesions included in the sum. 
 
For patients who continue treatment in the case of radiologic progression at the first 12 week 
(+/- 7 days) CT: 
• 
At any subsequent CT scan patients who have stable disease as compared to the 12 week 
(+/- 7 days) CT scan will be allowed to continue on study treatment. 
• 
Patients who continue treatment in the case of radiologic progression at the first 12 week (+/- 
7 days) CT, and later experience a PR or CR (as compared to baseline CT) will be recorded 
as delayed responses. 
 
lv1odification of RECIST as described may discourage the early discontinuation of Nivolumab and 
provide a more complete evaluation of its anti-tumor activity than would be seen with conventional 
response criteria. Nonetheless, the efficacy analysis will be conducted by programmatically 
deriving each efficacy endpoint based on RECIST v 1.1 criteria. 
 
The primary reason for study treatment discontinuation should be documented on the eCRF. 
 
Of note, clinically significant deterioration is considered to be a rapid tumor progression that 
necessitates treatment with anti-cancer therapy other than nivolumab or with symptomatic 
progression that requires urgent medical intervention (e.g., central nervous system metastasis, 
respiratory failure due to tumor, spinal cord compression) 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
Patients may withdraw from the study at any time. Any patient who withdraws will be encouraged 
to return to the study center for a treatment completion visit. Patients who discontinue early 
should return within 30 days following the final dose of study treatment. The primary reason for 
discontinuation must be recorded in the medical record. 


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Patients may be withdrawn from the study if they experience any of the following: 
 
• 
Disease progression, per investigator assessment 
• 
Intolerable toxicity of study drugs 
Other reasons for patient discontinuation may include, but are not limited to, the following: 
 
• 
Change in patient eligibility 
• 
Non-compliance 
• 
Patient decision 
• 
If treatment is delayed for more than 28 consecutive days 
The investigator has the right to discontinue a patient from the study for any medical condition 
that the investigator determines may jeopardize the patient's safety if he or she continues in the 
study; for reasons of noncompliance (e.g., missed doses, visits); or if the investigator determines 
it is in the best interest of the patient. 
14.0 
BIOSTATISTICS 
 
This study aims to assess the activity of single-agent nivolumab in patients with recurrent or 
persistent MSI-H, MMR-D, or hypermutated uterine cancer. All patients will be treated with 
nivolumab at a dose of 480 MG given every 4 weeks, until disease progression, or intolerable 
toxicity. The objective response would be considered the best response observed at either the 12 
or 24 week radiographic evaluation. 
 
The null hypothesis relating to uninteresting levels of activity was chosen in accordance with 
previously published reports of cytotoxic and biologic and anti-vascular agent activity in 
endometrial cancers. Further details are outlined in Aghajanian, et al. Phase II trial of 
bevacizumab in recurrent or persistent endometrial cancer: A Gynecologic Oncology Group 
Study. J Clin Oncol 29: 2259-2265, 2011. In that study, bevacizumab was considered to be an 
active agent with 7/52 evaluable patients (13.5%) achieving objective response, and 21/52 
patients (40.4%) surviving progression free for at least 6 months. 
 
Evaluation of overall response rate (ORR) 
ORR (defined as complete response (CR)+ partial response (PR)) will be the primary endpoint. A 
5% ORR will be considered non-promising and 25% of higher will be considered promising for 
further study. Forty patients provide 95% power and Type 1 error of 2.5% using a Simon two 
stage design. There will be an interim analysis after 23 patients and if 2 or more responders 
(CR+PR) are observed out of 23 patients then the study will continue to the second stage. At the 
end of the study we require 6 or more responders out of 40 patients to declare this study positive 
and the agent worthy for further investigation. 
Unacceptable response rate: 0.05 
Desirable response rate: 0.25 
Error rates: Type I= 0.025 ; Type II = 0.05 
(using minimax Simon 2 stage design) 


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Approval date: 07-Sep-2021 
Page 34 of 44 
 
 
 
 
 
# responses 
required in 
Stage I 
# patients 
accrued in 
Stage I 
# responses 
required in 
Stage 1+11 
Total Sample 
Size 
>=2 
23 
>=6 
40 
Evaluation of progression-free survival (PFS) at 24 weeks 
 
PFS at 24 weeks is the co-primary endpoint. For PFS rate at 24 weeks, we consider a 25% rate 
as non-promising and a rate of 50% or higher as indicative of promising clinical activity. There will 
be an interim analysis after the first 23 patients are accrued, and if 5 or more of the first 17 
patients accrued are progression free at 24 weeks then the study will continue to the second 
stage. At the end of the study we require 16 or more patients to be progression free at 24 weeks 
in order to declare the study positive and the agent worthy for further investigation. This study will 
have 91% power and 2.5% Type 1 error to show activity in terms of 24 weeks PFS rate. The 
study will continue if either overall response rate (ORR) or progression-free survival rate (PFS) is 
promising. If we see 1 or fewer objective responses in stage 1 out of 23 patients then we will hold 
accrual to determine if at least 5/17 remain progression free at 24 weeks. The first 17 patients will 
be included in the assessment of 24 week PFS rate. 
 
Unacceptable 24 week PFS rate: 0.25 
Desirable 24 week PFS rate: 0.50 
Error rates: Type I= 0.025 ; Type II = 0.09 
(using minimax Simon design with binary endpoint)) 
 
# patients with 
# patients with 
Total Sample 
Size 
increase in 
PFS required 
in Stage I 
accrued in 
Stage I 
increase in 
PFS required 
in Stage 1+11 
>=5 
17 
>=16 
40 
The overall Type I error of the study is 5%, the combined Type I error of the two primary 
endpoints of the study. 
 
Based on historical rates of recurrent MSI-H, MMR-D, or hypermutated uterine cancer in our 
study population, we anticipate successful enrollment of 1 patients per month yielding a total 
accrual time of 24 months. If 2 or more responders (CR+PR) are seen in the first 23 patients or 5 
patients of the first 17 enrolled remain progression free at 24 weeks, whichever is met first, then 
accrual will continue to stage II. If we see 1 or fewer responders (CR+PR) in the first 23 patients 
enrolled, then we will halt accrual between stages and wait until we get 24 week PFS results on 
the first 17 patients accrued in order to determine if we can go onto stage II based on promising 
PFS. 
 
Efficacy Variables 
The intent of this protocol is to assess single-agent nivolumab for activity in patients with recurrent 
MSI-H, MMR-D, or hypermutated uterine cancers. There are no treatment comparisons involved. 
 
The principal parameters employed to evaluate the efficacy of the combination are: 


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Page 35 of 44 
 
 
 
 
• 
The rate of ORR and duration of overall objective response (ORR= CR+ PR). 
• 
The frequency and severity of observed adverse effects. 
• 
Progression-free survival rate at 24 weeks for all patients evaluable for this endpoint. 
 
Evaluable for efficacy (response and PFS): those who have measurable disease at baseline and 
have received at least one dose of therapy and had at least one post-baseline efficacy 
assessment. Patients who are evaluable for response and are lost to follow up or die before the 
24 week PFS assessment will be considered as events (failures). The primary analysis for 
efficacy will include only patients who are evaluable for response. A sensitivity analysis will 
include all patients who have measurable disease at baseline and have received at least one 
dose of therapy, but do not have a post baseline assessment of response, considering them as 
non responders for ORR and events for PFS. 
For safety patients who received at least one dose of therapy will be included. 
 
Definitions of Statistics to be Reported 
• Disease Control Rate (OCR), defined as the percentage of patients with complete response 
(CR)+ partial response (PR)+ stable disease (SD) 12 weeks from the start of treatment will 
be reported and the 90% confidence interval will be estimated using exact binomial 
proportions. This will be done following RECIST criteria. 
• Progression free survival (PFS), defined as the duration of time from start of treatment to 
time of recurrence, progression, or death due to any cause, whichever occurs first. Patients 
will be censored at last follow up date. The Kaplan Meier estimate of median PFS will be 
reported as well as the PFS rate at 24 weeks 
• Overall survival (OS), defined as the duration of time from start of treatment until the date of 
death due to any cause. Patients will be censored at last follow up date. The Kaplan Meier 
estimate of median OS will be reported. 
• Duration of response (DOR), defined as the time from which measurement criteria are met 
for CR or PR (whichever status is recorded first using RECIST} until the first date of 
documented disease progression, will be estimated using the Kaplan Meier method. Patients 
without documented progression will be censored at last follow up. 
• Adverse events by the current version of Common Terminology Criteria for Adverse Events 
version 4 (CTCAE v4.03) will be tabulated in order to assess the safety profile and tolerability 
therapy in treated patients. 
 
Safety Analysis 
 
The rates of irAE, SAE, therapy completion rate, and protocol completion will be reported. 
 
Safety will be measured by the frequency of grade 3 or 4 treatment-related clinically significant 
toxicities (NCI Common Terminology Criteria for Adverse Events version 4.0), aside from Grade 3 
or 4 hematologic or laboratory abnormalities, unless they are deemed unexpected or clinically 
significant. 
Frequencies of toxicities will be tabulated. The grade 3 or 4 treatment-related non- 
hematologic/non-laboratory toxicity will be estimated at the end of the trial along with the 95% 
confidence interval. With 40 patients, these rates can be estimated within ±16%. 
 
AEs will be collected from the time of study enrollment until 4 weeks after last dose of study drug 
delivered. 


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Page 36 of 44 
 
 
 
 
Exploratory Objectives: 
Objective 1: Correlate mutational burden with clinical benefit from nivolumab, both overall 
response rate (ORR) and progression-free survival (PFS) rate at 24 weeks. Mutational 
burden will be measured by the number of somatic mutations found in genomic profile by 
IMPACT (continuous number). Two separate analyses will be done for each efficacy 
outcome: ORR or PFS at 24 weeks which are considered binary here and thus the 
analysis will test whether the median number of somatic mutation is different in the group 
of responders vs non responders. A non parametric test will be used to test differences in 
the distribution of somatic mutations in the 2 groups (responders vs non responders) such 
as Wilcoxon rank sum test. 
Objective 2: Correlate the somatic mutational burden identified by MSK-IMPACT with the 
MSlsensor algorithm score. The MSK-IMPACT data will also be analyzed by the 
MSlsensor algorithm. We will assess the relationship between MSlsensor score and the 
number of somatic mutations. MSlsensor score is a binary variable; any score <10 is MSI 
stable, any score 10 or higher is MSI high. We will test whether the median mutational 
burden (continuous variable) is different among patients with MSlsensor score< 10 (MSI 
stable) or MSlsensor score 10 or higher (MSI high). Wilcoxon rank sum test will be used to 
test differences in 2 groups. 
Objective 3: Correlate the MSlsensor score with the MMR IHC status (immunohistochemical 
staining for mismatch repair enzyme proteins). We will test for agreement between the 
MSlsensor score (binary) with MMR status by IHC which is measured as retained or 
absent (binary). The goal of the above aims is to explore the agreement between "MMR 
IHC absent", and "MSlsensor score high" and "mutational burden high". McNemar's test 
will be used to test agreement between MSI sensor and MMR status. 
Objective 4: Test for association between pre-treatment immune phenotype (tumor infiltrating 
lymphocytes and PD-L1) and best overall response rate (ORR) and progression free 
survival rate at 24 weeks. Tlls and PD-L1 are both biomarkers without a specific cutoff 
that defines positive and negative. For these reasons these will be analyzed as 
continuous variables. Two separate analysis will be done for each efficacy outcome: ORR 
or PFS at 24 weeks which are considered binary here and thus the analysis will test 
whether the median biomarker value is different in the group of responders vs non 
responders. Wilcoxon rank sum test will be used to test differences in 2 groups. 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
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 


Memorial Sloan Kettering Cancer Center 
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Page 37 of 44 
 
 
 
 
necessary to enroll a participant to the study have been completed. See related Clinical Research 
Policy and Procedure #401 (Protocol Participant Registration). 
15.2 
Randomization 
 
N/A 
16.0 
DATA MANAGEMENT ISSUES 
A research study assistant (RSA) will be assigned to study. The responsibilities of the RSA 
include project compliance, data collection, extraction and data entry, data reporting, coordination 
of the activities of the protocol study team and, and of the flow of regulatory paperwork. 
The data collected for the study will be entered into a secure database (CRDB). All routine blood 
test results required per the protocol will be captured in CRDB in addition to baseline medical 
conditions and disease information, response assessments, off-study documentation, and toxicity 
grade and attribution. Source documentation will be available to support the computerized patient 
record. 
MSK will hold the IND. MSK will be responsible for all safety monitoring. All SAEs will be reported 
to the MSKCC IRB. The safety of the study will be monitored by the MSKCC Data and Safety 
Monitoring Committee. 
Weekly registration reports will be generated by the RSA and reviewed by the Pl 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. Recurrent lapses in data collection, deviations or violations will be 
discussed with the study team and a corrective plan will be generated. Accrual goals and factors 
impacting accrual goals will be discussed at the weekly New Patient/Protocol meetings. 
If accrual proceeds more quickly than anticipated, it may be slowed or staggered at the discretion 
of the Principal Investigator, to account for safety concerns or data management resources. 
16.1 
Quality Assurance 
The data and safety monitoring plan at Memorial Sloan Kettering Cancer Center was approved by 
the National Cancer Institute in September 2001. The plan addressed the new policies set forth 
by the NCI and the document entitled "Policy of the National Cancer Institute for data and safety 
monitoring of clinical trials" which can be found at 
http://grants.nih.gov/grants/guide/noticefiles/not98-084.html. The DSM plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC data and safety 
monitoring plan can be found on the MSKCC Internet at 
http://inside2/clinresearch/Documents/MSKCC Data and Safety Monitoring Plans.pdf. There are 
several different mechanisms by which clinical trials are monitored for data, safety and quality. 
There are institutional processes in place for quality assurance (e.g., protocol monitoring, 
compliance and data verification audits, therapeutic response, and staff education on clinical 
research QA) and departmental procedures for quality control, plus there are two institutional 


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Page 38 of 44 
 
 
 
 
committees that are responsible for monitoring the activities of our clinical trials programs. 
rvlemorial Sloan Kettering Cancer Center has set up three distinct monitoring processes for our 
clinical trials program. There are two sub-committees that have the responsibility of data and 
safety monitoring. These are joint sub-committees with dual-reporting responsibilities. The Data 
and Safety rvlonitoring Committee (DSMC) is the sub-committee responsible for monitoring all 
Phase 1, 2, 1/2, pilot and non-phase clinical trials. The Data and Safety rvlonitoring Board (DSMB) 
is the sub-committee responsible for monitoring Phase 3 randomized clinical trials. 
The DSMC convenes once per quarter and monitors the risk participants are exposed to, the 
progress of the study, the adequacy of the data storage and whether sufficient data are being 
entered into the CRDB. The DSMC monitors phase 1, 2, 1/2, pilot and non-phase trials that are 
not being monitored by an industrial sponsor, and which meet the NCI definition of a Clinical Trial. 
This trial will qualify for monitoring by the DSMC. 
During the protocol development and review process, each protocol will be assessed for its level 
of risk and degree of monitoring required, and the monitoring procedures will be established at the 
time of protocol activation. A detailed description of the data to be collected, process of data 
collection (i.e., data manager and/or data management office), database that will be utilized for 
data collection and storage (e.g., Clinical Research Database (CRDB), user-supported software), 
reporting requirements of the data to the institution (IRB), the sponsor and/or governing agency. 
16.2 
Data and Safety Monitoring 
 
The Data and Safety rvlonitoring (DSM) Plans at rvlemorial Sloan Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001. 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 rvlonitoring of Clinical Trials" which can be found at: 
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1. The DSM Plans at MSKCC 
were established and are monitored by the Office of Clinical Research. The MSKCC Data and 
Safety rvlonitoring Plans can be found on the MSKCC Intranet at: 
http://smskpsps9/dept/ocr/0CR%20Website%20Documents/Clinical%20Research%20Quality%2 
0Assurance%20(CRQA)/MSKCC%20Data%20and%20Safety%20rvlonitoring%20Plan.pdf 


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17.0 
PROTECTION OF HUMAN SUBJECTS 
 
17.1 
Privacy 
 
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 1\/ledical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an SAE. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is required for 30- 
days after the participant's last investigational treatment or intervention. Any events that occur after 
the 30-day period and that are at least possibly related to protocol treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 'Reporting of Serious Adverse 
Events', the SAE report must be sent to the IRB within 5 calendar days of the event. The IRB 
requires a Clinical Research Database (CRDB) SAE report be submitted electronically to the SAE 
Office as follows: 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to  saegrade5@mskcc.org. 
All other reports should be sent to saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to  saegrade5@mskcc.org. 
All other reports should be sent to sae@mskcc.org. 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject's initials 
• 
1\/ledical record number 


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• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o 
A explanation of how the AE was handled 
o 
A description of the subject's condition 
o 
Indication if the subject 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 
 
The Pl's signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions. If appropriate, the report will 
be forwarded to the FDA by the SAE staff through the IND Office. 
Serious Adverse Event Collection and Reporting -All Serious Adverse Events must be reported to 
BMS Worldwide Safety. 
Site specific forms will be requested for review. 
The sponsor/investigator will be required to reconcile SAEs reported in the clinical database with 
SAE cases transmitted to BMS Global Pharmacovigilance (GPV&E);  worldwide.safety@bms.com. 
BMS requests this is initiated by the sponsor investigator up to quarterly and prior to the database 
lock or final data summary. The process will be further defined. During reconciliation, any events 
found to not be reported previously to BMS must be sent to Worldwide.Safety@BMS.com. 
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 


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IRB Number: 17-180 A(10) 
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Page 41 of 44 
 
 
 
 
Email: Worldwide.safety@bms.com 
 
The report should contain the following information: 
Fields populated from CRDB: 
 
• 
Subject's name (generate the report with only initials if it will be sent outside of 
MSK) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o 
A explanation of how the AE was handled 
o 
A description of the subject's condition 
o 
Indication if the subject remains on the study 
o 
If an amendment will need to be made to the protocol and/or consent form. 
 
The Pl's signature and the date it was signed are required on the completed report. 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements Subject data protection. 
 
17.2.1  
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 IRS/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. 


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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. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
19.0 
REFERENCES 
 
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Hensley, M. L. et al. Fixed-dose rate gemcitabine plus docetaxel as second-line therapy for 
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IRB Number: 17-180 A(10) 
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Page 43 of 44 
 
 
 
 
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Motzer, R. J. et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. The 
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Howitt, B. E., Shukla, S. A, Sholl, L. M. & et al. ASsociation of polymerase e-mutated and 
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Gajewski, T. F., Louahed, J. & Brichard, V. G. Gene signature in melanoma associated with 
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IRB Number: 17-180 A(10) 
Approval date: 07-Sep-2021 
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20.0 
APPENDICES 
 
Appendix 1. US Prescribing Information. 
Appendix 2. EU Summary of Product Characteristics. 
Appendix 3. Management Algorithms for Adverse Effects. 
Appendix 4. Translational science