Conditions: Biliary Tract Cancer Biliary Tract Neoplasms
Keywords: advanced biliary tract cancer refractory biliary tract cancer digestive diseases immunotherapy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 54
Healthy volunteers: no

Brief summary:
This research study is designed to see if a drug called Nivolumab is effective in treating patients with advanced refractory biliary tract cancers. Nivolumab has been approved by the U.S. Food and Drug Administration (FDA) for treatment of certain types of cancer but is not approved by the FDA for treatment of your type of cancer.

Detailed description:

Arms:
arm 1: This is a single arm study with two stage design using nivolumab in advanced biliary tract cancer (BTC), for participants who have failed or are intolerant to at least one line of therapy and no more than 2 lines of therapy. In the first stage, 18 participants will be accrued. If there is at least one response (or several participants with stable disease based on the study team's discretion), an additional 34 patients will be accrued for a total of 52 patients.

Interventions: intervention 1: Nivolumab
Intervention descriptions: intervention 1: Participants will receive nivolumab at a dose of 240 mg intravenously (IV) every 2 weeks (Q 2W) for 16 weeks (16W) and then 480 every 4 weeks (Q4W) from 17 weeks to end of study.

Protocol document:
Prot_SAP_000.pdf: 
A Phase II Investigator Sponsored Study of Nivolumab in Patients with Advanced 
Refractory Biliary Tract Cancers 
 
  
NCT02829918 
 
Version 5 
August 13, 2019 


1 
 
 
Protocol #: 
MCC 18684 
 
 
 
TITLE: A Phase II Investigator Sponsored Study of Nivolumab in Patients with Advanced 
Refractory Biliary Tract Cancers 
 
Sponsor/IND Holder: 
H. Lee Moffitt Cancer Center 
 
*Principal Investigator: 
Richard Kim, MD 
12902 Magnolia Drive 
FOB2-GI 
813-745-6898 
813-745-7229 (fax) 
Richard.kim@moffitt.org 
 
Co-Investigator: 
 
 
Dae Won Kim, MD 
Jonathan Strosberg, MD 
Rutika Mehta, MD 
 
Statistician:                   Michael Schell, PhD 
12902 Magnolia Dr. 
MRC 
813-745-2646 
Michael.Schell@moffitt.org 
 
MCRN Sites: 
City of Hope Cancer Center 
Emory University- Winship Cancer Institute 
 
Supplied Agent: 
Nivolumab 
 
Protocol Version Date: 
08/13/2019 


2 
 
 
 
 
 
 
 
 
 
 
 
Study Synopsis 
 
 
Title 
A  Phase  II  Investigator  Sponsored  Study  of  Nivolumab  in 
Patients with Advanced Refractory Biliary Tract Cancers 
Clinical study phase 
Phase II 
Study objective(s) 
Primary Objective 
The primary endpoint will be overall response rate (ORR). ORR 
is defined as complete responses (CR) plus partial responses 
(PR). 
Secondary Objectives 
• To determine the frequency and severity of adverse events 
and tolerability of the regimen in patients with advanced 
refractory BC receiving nivolumab 
• To determine the progression-free survival (PFS) in 
patients with advanced refractory BC receiving 
nivolumab. PFS is defined as the duration of time from 
start of treatment to time of progression or death, 
whichever comes first. 
• To determine the overall survival in patients with 
advanced refractory BC receiving nivolumab 
• To determine the overall response rate by the immune 
response criteria 
Exploratory Objectives 
Immunohistochemical staining and next generation sequencing 
will be performed with tumor samples to evaluate the correlation 
with clinical outcome in a descriptive analysis. . 


3 
 
 
Background 
The outcome of patients with advanced biliary cancer remains 
dismal with the current standard of care options. There is 
currently an unmet medical need for patients with advanced BC 
who have failed systemic therapy. 
BC includes a heterogeneous group of cancers but data has 
suggested that there is an immune component to the development 
of these tumors and high PD-1 protein expression has been found. 
The second line setting therefore offers a unique opportunity to 
evaluate the activity of anti-PD1 immunotherapy agents like 
nivolumab. 
Indication 
Patients with advanced biliary tumor who have failed at least one 
prior line of systemic therapy. 
Diagnosis and main criteria 
for inclusion 
Patients must have histologically or cytologically documented 
carcinoma primary to the intra- or extra-hepatic biliary system or 
gall bladder with clinical and/or radiologic evidence of 
unresectable locally advanced or metastatic disease. Patients with 
ampullary carcinoma are not eligible. 
Patients must have failed one but no more than 3 prior lines of 
systemic chemotherapy for advanced biliary cancer. Patients who 
are intolerant to first line therapy will be allowed. Patients who 
had disease recurrence after first line therapy will be allowed. 
Patients who received adjuvant chemotherapy and had evidence 
of disease recurrence within 6 months of completion of the 
adjuvant treatment are also eligible. If patient received adjuvant 
treatment and had disease recurrence after 6 months, patients will 
only be eligible after failing one line of systemic chemotherapy 
used to treat the disease recurrence. 
Patients must have measurable disease, as defined by RECIST 1.1 
criteria. 
Patients must not have been treated with any prior anti-PD1, anti- 
PDL1, or anti-CTLA4 agents 
Study design 
This is a multi-institutional phase II single arm two-stage design 
trial using nivolumab as a single agent. 


4 
 
 
Type of control 
Patients will receive nivolumab at a dose of 240 mg IV every 2 
weeks for 16 weeks and then 480 mg IV every 4 weeks until 
disease progression or unacceptable toxicity. After 2 cycles (1 
cycle= 28 days), tumor response will be evaluated using the new 
international criteria proposed by the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guidelines 
(version 1.1) as well as immune response criteria. Treatment 
beyond progressive disease (PD) will be allowed for pseudo 
progression as determined by clinical benefit or immune response 
criteria. 
Number of subjects 
52 evaluable 
 
Plan for statistical analysis 
The primary endpoint for this study will be response rate (CR + 
PR) at 4 months. We will use a Simon’s Two-Stage Design in 
which the power is 0.9 and the type 2 error is 10%. The study 
will be expanded to the second stage if there is a 20% 
probability of response. At least 1 patient of the first 18 
enrolled will need to have a complete or partial response for 
study continuation. 
Alternatively, if there are at least 4 patients with stable disease 
for 16 weeks (2 restaging assessments), the principal 
investigator will discuss proceeding to the second stage of the 
study with the BMS medical team. 
 
The second stage of this study will involve an additional 14 
patients. The study will have met its primary endpoint of 
response rate if there are at least four patients in the 
nivolumab  only arm who achieve a response. 
 
We anticipate an attrition rate of 10%, so about 40 patients 
will  be recruited. Based on previous trials, we expect to 
enroll about 12 patients per year at our center and so will 
involve 2 other centers to complete enrollment within 18 
months. Please see section 8.2 for rationale for the expansion 
of the study. 


5 
 
 
 
 
 
Schema 
 
 
 
 
 
Assessed for eligibility (n= 40) 
 
 
 
 
Anticipated Excluded (10%, n=6) 
 
 
 
 
 
 
 
 
 
Stage I (n=18) 
Nivolumab 240mg q2wk 
for 16 weeks and then 
480mg q4wk 
 
 
 
 
 
 
Progression 
Complete or 
partial response 
Stable disease 
 
Off 
treatment 
 
 
 
Continue 
treatment 
 
 
Continue 
treatment 
 
 
 
 
 
 
 
 
Stage II (n=34) 
Nivolumab 240mg q2wk 
for 16 weeks and then 
q4wk 


6 
 
Table of Contents 
Study Synopsis  .................................................................................................................................... 2 
Schema  ................................................................................................................................................ 5 
1. 
Introduction  ................................................................................................................................. 8 
1.1 
Background  ............................................................................................................ 8 
1.2 
Nivolumab  ............................................................................................................. 9 
2. 
Study Objectives  ........................................................................................................................ 10 
3. 
Study Design  ............................................................................................................................. 10 
4. 
Eligibility  ................................................................................................................................... 11 
4.1 
Inclusion Criteria  ................................................................................................. 11 
4.2 
Exclusion Criteria  ................................................................................................ 12 
4.3 
Withdrawal of Subjects from Study  ..................................................................... 13 
4.3.1 
Withdrawal  .......................................................................................................... 13 
4.3.2 
Screen Failures/Dropouts/Replacements  ............................................................. 14 
5. 
Treatment  ................................................................................................................................... 15 
5.1 
Treatment to be administered  ............................................................................... 15 
5.1.1 
Flat Dose Regimen  .............................................................................................. 15 
5.2 
Management of Toxicities Associated with Study Drug ...................................... 15 
5.2.1 
Dose Delay Criteria  ............................................................................................. 20 
5.2.2 
Criteria to Resume Dosing  ................................................................................... 21 
5.2.3 
Treatment Beyond Disease Progression  .............................................................. 21 
5.2.4 
Treatment Discontinuation Criteria ...................................................................... 22 
5.2.5 
Treatment of Nivolumab-Related Infusion Reactions  ......................................... 23 
5.3 
Study Treatment, Drug Ordering, and Pharmacy Reference Information ............ 24 
5.3.1 
Handling and Dispensing  ..................................................................................... 24 
5.3.2 
Blinding  ............................................................................................................... 25 
5.3.3 
Drug Logistics and Accountability  ...................................................................... 25 
5.3.4 
Treatment Compliance  ......................................................................................... 25 
5.3.5 
Destruction and Return of Study Drug  ................................................................ 25 
5.3.6 
Return of Study Drug  ........................................................................................... 26 
5.4 
Prior and Concomitant Therapy  ........................................................................... 26 
5.4.1 
Prohibited Concomitant Anti-cancer Therapy  ..................................................... 26 
5.4.2 
Other Restrictions and Precautions  ...................................................................... 27 
5.4.3 
Permitted Therapy  ............................................................................................... 27 
6. 
Study Assessments and Procedures  ........................................................................................... 28 
6.1 
Table 1: Screening Assessments and Procedures  ................................................. 28 
6.2 
Table 2: On Study Assessments  ........................................................................... 29 
7. 
Adverse Events  .......................................................................................................................... 31 


7 
 
7.1 
Safety Monitoring  ................................................................................................ 31 
7.1.1 
Internal Safety Monitoring ................................................................................... 32 
7.2 
Serious Adverse Events  ....................................................................................... 32 
7.2.1 
Serious Adverse Event Collection and Reporting  ............................................... 33 
7.3 
Non-serious Adverse Events  ............................................................................... 35 
7.4 
Laboratory Test Abnormalities  ............................................................................ 35 
7.5 
Pregnancy  ............................................................................................................ 35 
7.6 
Overdose  .............................................................................................................. 36 
7.7 
Other Safety Considerations  ................................................................................ 36 
8. 
Statistical Considerations  ........................................................................................................... 36 
8.1 
Sample Size Determination .................................................................................. 36 
8.2 
Populations for Analyses  ..................................................................................... 37 
8.3 
Endpoint Definitions  ............................................................................................ 37 
8.3.1 
Primary Endpoint  ................................................................................................. 37 
8.3.2 
Secondary Endpoints  ........................................................................................... 37 
8.3.3 
Exploratory Endpoints  ......................................................................................... 38 
9. 
Data Recording  .......................................................................................................................... 39 
9.1 
Institutional Review Board (IRB) Approval and Consent  ................................... 39 
9.2 
Required Documentation  ..................................................................................... 39 
9.3 
Ethical and Legal Aspects  .................................................................................... 42 
References  ......................................................................................................................................... 44 
Appendix 1: Immune Adverse Event Management Algorithms  ........................................................ 48 
Appendix 2: Nivolumab Drug Ordering and Pharmacy Reference Material  ..................................... 56 
TABLE 3: Product Information  ..................................................................................................... 57 


8 
 
1. Introduction 
 
1.1 
Background 
 
Biliary tract cancers (BTC) typically include intra and extrahepatic cholangiocarcinoma and cancers 
of the gallbladder.  In the US in 2015, an estimated 2,600 intrahepatic cholangiocarcinomas and 
10,000 cases of extrahepatic bile duct cancer. Of the latter, two thirds were gallbladder cancers.1 
This is a rare but aggressive group of malignancies with many patients presenting with advanced 
disease and overall dismal outcomes.2 
 
The only cure for patients who present with local disease is surgical resection or liver 
transplantation. However, the rate of disease recurrence remains high even in resectable patients  
and there is no compelling data regarding the role for adjuvant therapy in this setting. Though meta- 
analyses have shown a nonsignificant overall survival benefit to adjuvant therapy,3 there is limited 
prospective data on which agents are active in this disease. 
 
However, the majority of patients present with unresectable disease and treatment options are very 
limited. Systemic chemotherapy has historically been disappointing in advanced BTC, though new 
combination regimens have shown activity. ABC-02, a randomized phase III study, enrolled 410 
patients and compared gemcitabine plus cisplatin with gemcitabine alone.4 The median overall 
survival (OS) and progression-free survival (PFS) were greater for gemcitabine plus cisplatin than 
for gemcitabine alone without significantly increased toxicity (OS: 11.7 v 8.1 months; log-rank P 
= .002; PFS: 8.0 v 5.0 months; P = .003). This drug combination set a new international standard of 
care for the first line treatment of advanced BTC. Based on phase II data, the combination of 
gemcitabine and oxaliplatin is also used in the first line setting after efficacy and tolerability were 
shown.5 
 
Several phase II trials have evaluated various chemotherapy regimens in the second line setting, 
including FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin), oxaliplatin with capecitabine, and 
5-fluorouracil and cisplatin.6,7 However, there is no established regimen for treatment in patients 
with progression on first line therapy or refractory disease. The survival in this setting remains 
dismal at a median of less than 6 months.8-10 Advances have been slow in part because of the tumor 
heterogeneity of BTCs.11 There remains a significant need to identify novel agents and to treat this 
deadly disease. 
 
Outcomes can perhaps be improved with greater understanding of the underlying disease biology. 
The development of BTC appears to be related to the immune system, and carcinogenesis has been 
linked to chronic parasitic infections as well as autoimmune conditions like primary sclerosing 
cholangitis.12,13 In addition, patients with evidence of immune system activation, measured by 
higher levels of lymphocytes, have been shown to have improved prognosis.14 Recent data suggests 
that the immune regulatory protein PD-1 is upregulated in intrahepatic cholangiocarcinoma tissues 
compared to cancer adjacent tumors.15 It has also been shown that hilar cholangiocarcinomas may 
evade immunologic surveillance through the apoptosis of lymphocytes.16 
 
In pre-clinical work at Moffitt Cancer Center, we found that cholangiocarcinoma tumors which 
stained positive for CD45R0 (lymph node like structure) were associated with improved median OS 
(63 months vs 18 months, P = 0.003).17 These immune active tumors are likely to have escaped the 
inhibitory effects of programmed death ligand complex. 
 
Immunotherapy has been evaluated in a few patients with BTCs. In one case report, a patient with a 
locally advanced intrahepatic cholangiocarcinoma was treated initially with surgical resection 
followed by adjuvant treatment with immunotherapy (CD3 activated T cells as well as dendritic 


 
 
cells). She had no disease recurrence for over 3 years.18 More recently, an anti-PD1 agent was 
recently evaluated in tumors with microsatellite instability in a phase II study.19 Included in this 
cohort was one patient with mismatch repair deficient bile duct cancer who had a partial response 
with a 41% decrease in tumor size and a 93% decrease in tumor marker at 20 weeks. 
 
 
 
1.2 
Nivolumab 
 
Human tumors have a myriad of genetic alterations leading to neoantigens which should be 
recognized by the host immune system. However, cancer can dysregulate immune checkpoint 
proteins as a way of evading the host immune system and ensuring survival.20 Immunotherapy in 
oncology has been evaluated as a means of upregulating the host immune system so that tumors can 
be recognized as foreign and endogenous anti-tumor immunity can attack tumor cells. Immune 
checkpoint pathway inhibitors such as anti-CTLA4 and anti-PD-1 antibodies have been evaluated in 
the treatment of a variety of tumors. 
 
Preclinical Studies 
 
Programmed death 1 is a protein which limits T-cell activity in an effort to minimize 
autoimmunity.21 When activated by ligands, PD-1 along with its costimulatory protein B7, decrease 
T cell activity which can allow tumors to escape immune recognition. Antibodies against PD-1 have 
been developed in an effort to increase T cell activity. 
 
Nivolumab is a human monoclonal antibody that targets the programmed death-1 (PD-1) CD279 
cell surface membrane receptor and inhibits PD-1 interaction with its ligands PD-L1 and PD-L2. 
PD-1 knockout mice develop autoimmune conditions from excessive T cell activity including 
glomerulonephritis and autoimmune cardiomyopathy.22,23 In vitro, nivolumab has resulted in 
increased T-cell proliferation and interferon gamma release in mixed lymphocyte reaction.24 In 
vivo, PD-1 blockade by a nivolumab analog resulted in enhanced anti-tumor response and tumor 
rejection in several murine models (BMS investigator’s brochure). Nivolumab has been generally 
well tolerated in the preclinical setting. In toxicity studies of cynomolgus monkeys, nivolumab was 
tolerated at doses of 50mg/kg every 2 weeks. There was increased neonatal mortality in pregnant 
monkeys, in keeping with the role of PD-L1 in maintaining murine fetomaternal tolerance.25 
 
 
 
Clinical Studies 
 
Clinical Pharmacokinetics 
Nivolumab has been tested in over 8600 human subjects with doses ranging from 0.1 to 10 mg/kg as 
both a single dose as well as multiple doses every few weeks. Steady state drug concentration was 
achieved by 12 weeks when nivolumab was administered at 3mg/kg every 2 weeks. Drug clearance 
has not been affected by age, gender, race, or tumor type. Though glomerular filtration rate and mild 
hepatic impairment have had an effect on clearance, it has not been clinically meaningful. 
 
Clinical Efficacy 
Nivolumab has been FDA approved for the treatment of metastatic melanoma, metastatic non-small 
cell lung cancer, and clear cell renal cancer based on the results of phase III studies.26-29 The 
majority of responses have been durable and have exceeded 6 months. In melanoma, nivolumab has 
been approved in metastatic disease in the first line setting. In non-squamous lung cancer, it has 
been approved in advanced disease after progression on one prior treatment. Similarly, nivolumab is 
approved for the treatment of renal cell carcinoma patients who have progressed on previous 
therapy. 
 
9 


10 
 
Clinical Safety 
No maximum tolerated dose of nivolumab has been established at doses tested up to 10mg/kg. The 
safety profile is similar across tumor types and there has been no pattern of adverse effects with 
regards to incidence or severity based on dose level. Common drug related adverse effects have 
included pulmonary toxicity, GI toxicity, liver toxicity, and dermatologic toxicity, the majority of 
which have been manageable with supportive care, dose delay, or steroid treatments. 
 
The  overall  safety  experience  with  nivolumab  is  based  on  c li n ic a l  experience  in 
approximately 8,600 subjects. In general, for monotherapy, the safety profile is similar across 
tumor types. The   most   frequently  reported treatment-related AE is fatigue, which is almost 
always of low grade. 
 
Rationale: 
 
The outcome of patients with advanced biliary cancer remains dismal with the current standard of 
care options. There is no established second line option for patients with advanced BC who have 
failed one prior systemic therapy. 
 
 
Given that immune modulatory agents are known to have activity in BTCs,30 we propose to 
evaluate the anti-PD1 agent nivolumab in advanced, refractory BTC, a rare malignancy in which 
there is a critical unmet clinical need. 
 
2. Study Objectives 
Primary Objective 
To determine the disease response rate (Complete Response + Partial Response) in patients with 
advanced biliary tract cancers (BTC) receiving nivolumab as a single agent 
 
Secondary Objectives 
1. To determine the median progression free survival (PFS) and overall survival (OS) and response 
rate by immune response criteria in patients with advanced BTC receiving nivolumab 
 
2. To determine the safety and tolerability of nivolumab in BTC 
 
Exploratory Objectives 
 
1. To explore potential correlations between mismatch repair status and outcome 
 
 
2. To explore potential correlation of mutational burden and outcome, as evaluated by the Kew 
CancerPlex immune signature panel. 
 
3. Study Design 
 
 
This is a multi-institutional single arm study with two stage design using nivolumab in advanced 
BTC, who have failed or are intolerant to at least one line of therapy and no more than 3 lines of 
therapy. In the first stage, 18 patients will be accrued. If there is at least one response (or several 
patients with stable disease based on the study team’s discretion), an additional 14 patients will be 
accrued for a total of 32 patients. Patients will receive nivolumab at a flat dose of 240mg every 2 
weeks for 16 weeks (4 cycles). Response and progression will be evaluated using the new 


11 
 
international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guidelines (version 1.1).  The primary endpoint is disease response after 2 cycles of 
treatment (8 weeks). Patients with stable disease or disease response will continue on therapy until 
progression. Patients can continue on therapy if there is pseudo-progression which is defined by the 
immune response criteria or if they are having clinical benefit as determined by the investigator 
after discussion with the principal investigator. 
 
 
 
4. Eligibility 
 
4.1 
Inclusion Criteria 
 
 
• Patients must have histologically or cytologically documented carcinoma primary to the 
intra- or extra-hepatic biliary system or gall bladder with clinical and/or radiologic evidence 
of unresectable, locally advanced or metastatic disease. Patients with ampullary carcinoma 
are not eligible. 
 
• Patients must have failed or are intolerant to one line of systemic treatment but no more than 
3 prior lines of systemic chemotherapy for advanced BTC. Patients who received adjuvant 
chemotherapy and had evidence of disease recurrence within 6 months of completion of the 
adjuvant treatment are also eligible. If the patient received adjuvant treatment and had 
disease recurrence after 6 months, patients will only be eligible after failing or having 
intolerance to one line of systemic chemotherapy used to treat the disease recurrence. 
 
 
• Age ≥ 18 years. 
 
• Eastern Cooperative Oncology Group (ECOG) Performance Status Assessment of 0 or 1. 
 
• The patient must have radiographic measurable disease per RECIST 1.1 criteria 
• Life expectancy of at least 12 weeks (3 months). 
• For patients who have received prior radiation, cryotherapy, radiofrequency ablation, 
therasphere, ethanol injection, transarterial chemoembolization (TACE) or 
photodynamic therapy, the following criteria must be met: 
o 28 days have elapsed since that therapy 
o Lesions that have not been treated with local therapy must be present and 
measureable 
• Subjects must be able to understand and be willing to sign the written informed  
consent form. A signed informed consent form must be appropriately obtained prior to 
the conduct of any trial-specific procedure. Subjects must be willing and able to 
comply with scheduled visits, treatment schedule, laboratory testing, and other study 
requirements. 
• All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 Grade 
1 or less at the time of signing the Informed Consent Form (ICF) except for alopecia. 
• Adequate bone marrow, liver and liver function as assessed by the following 
laboratory requirements: 
o Total bilirubin ≤ 1.5 x the upper limits of normal (ULN), except for subjects with 
Gilbert Syndrome who can have bilirubin <3. 
o Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) ≤ 2.5 x 
ULN (≤ 5 x ULN for subjects with liver involvement of their cancer or stent 
placement) 


12 
 
o Alkaline phosphastase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver 
involvement of their cancer) 
o Serum creatinine <2 x ULN 
o Hematologic parameters as follows: 
 Platelet count ≥ 100,000 /mm3 
 Hemoglobin (Hb) ≥ 9 g/dL 
 Absolute neutrophil count (ANC) ≥1000/mm3 
 Blood transfusion to meet the inclusion criteria will be allowed. 
• Women of childbearing potential must have a negative serum or urine pregnancy test 
(minimum sensitivity of 25 IU/L or equivalent units of HCG) performed within24 
hours prior to the start of nivolumab Post-menopausal women (defined as no menses 
for at least 1 year) and surgically sterilized women are not required to undergo a 
pregnancy test. 
• Subjects (men and women) of childbearing potential must agree to use adequate 
contraception beginning at the signing of the ICF until at least 3 months after the last 
dose of study drug.  The definition of adequate contraception will be based on the 
judgment of the principal investigator or a designated associate. 
• Patients with history of hepatitis B and hepatitis C will be eligible but patients with 
hepatitis B must be started on antiviral therapy prior to beginning study therapy 
• Availability of archival tumor tissue for biomarkers analysis (FFPE block or cell 
block will be required). Specimen from primary site will be allowed. Patients must 
have at least 10 slides available. Repeat biopsy to obtain sufficient tissue for 10 slides 
is allowed. 
 
 
 
4.2 Exclusion Criteria 
 
 
• 
Subjects with active CNS metastases are excluded. If CNS metastases are treated and 
subjects are at neurologic baseline for at least 2 weeks prior to enrollment, they will be 
eligible but will need a Brain MRI prior to enrollment. Subjects must be off corticosteroids 
or on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent). 
• Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I 
diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring 
hormone replacement, or conditions not expected to recur in the absence of an external 
trigger are permitted to enroll 
• Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily 
prednisone equivalent, are permitted in the absence of active autoimmune disease. 
• 
Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell 
costimulation or checkpoint pathways). 
• Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for curatively 
treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors [Ta 
(non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)]. 
• Known history of human immunodeficiency virus (HIV) infection or acquired 
immunodeficiency syndrome (AIDS). 


13 
 
• Child Pugh B or C disease 
• History of severe hypersensitivity reactions to other monoclonal antibodies 
• History of allergy or intolerance to study drug components or Polysorbate-80-containing 
infusions 
• Substance abuse, medical, psychological or social conditions that may interfere with the 
patient’s participation in the study or evaluation of the study results. 
• History or concurrent condition of interstitial lung disease of any grade or severely impaired 
pulmonary function. 
• Unresolved toxicity higher than CTCAE grade 1 attributed to any prior therapy/procedure 
excluding alopecia. 
• Pregnant or breast-feeding patients. Women of childbearing potential must have a negative 
serum or urine pregnancy test (minimum sensitivity of 25 IU/L or equivalent units of HCG) 
performed within 24 hours prior to the start of nivolumab and a negative result must be 
documented before start of treatment. 
• Any illness or medical conditions that are unstable or could jeopardize the safety of the 
patient and his/her compliance in the study. 
 
Excluded Therapies and Medications for Cancer 
 
• Anticancer chemotherapy during the study or within 4 weeks of study enrollment. Subjects 
must have recovered from the toxic effects of the previous anti-cancer chemotherapy (with 
the exception of alopecia).  Anti-cancer therapy is defined as any agent or combination of 
agents with clinically proven anti-tumor activity administered by any route with the 
purpose of affecting the malignancy, either directly or indirectly, including palliative and 
therapeutic endpoints. 
• Hormonal therapy during the study or within 2 weeks of first study enrollment. 
• Radiotherapy to target lesions during study or within 2 weeks of enrollment. 
• An irradiated lesion is considered evaluable only if it has shown enlargement since the 
completion of last radiation. 
• Bone marrow transplant or stem cell rescue. 
• Investigational drug therapy outside of this trial during or within 4 weeks of first study 
treatment. 
 
 
 
4.3 
Withdrawal of Subjects from Study 
 
4.3.1 Withdrawal 
 
Subjects must discontinue investigational product for any of the following reasons: 
• 
Withdrawal of informed consent (subject’s decision to withdraw for any reason). A 
subject must be removed from the trial at his/her own request or at the request of his/her 
legally acceptable representative. At any time during the trial and without giving 
reasons, a subject may decline to participate further. The subject will not suffer any 
disadvantage as a result. 
• 
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in 
the opinion of the investigator, indicates that continued participation in the study is not 
in the best interest of the subject 


14 
 
• 
Pregnancy will be reported as an SAE and the patient will be withdrawn. (Note: subjects 
who have been withdrawn from treatment with study drug because of pregnancy should 
not undergo CT scans [with contrast]/MRI or bone scans while pregnant.) 
• 
Termination of the study by Bristol-Myers Squibb (BMS) 
• 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
illness. 
• 
Subject is lost to follow-up 
• 
Death 
 
All subjects who discontinue should comply with protocol specified follow-up and survival 
procedures. The ONLY exception to this requirement is when a subject withdraws consent for all 
study procedures or loses the ability to consent freely (i.e., is imprisoned or involuntarily 
incarcerated for the treatment of either a psychiatric or physical illness). If a subject was withdrawn 
before completing the study, the reason for withdrawal must be entered on the appropriate case 
report form page. 
 
 
Subjects may be withdrawn from the study for the following reasons: 
 
• The subject is non-compliant with study drug, trial procedures, or both; including the use 
of anti-cancer therapy not prescribed by the study protocol. 
• Severe allergic reaction to nivolumab 
• The development of a second cancer. 
• Development of another illness or situation which would, in the judgment of the 
investigator, significantly affect assessments of clinical status and trial endpoints. 
• Deterioration of ECOG performance status to 3 or 4. 
• Use of illicit drugs or other substances that may, in the opinion of the investigator, have a 
reasonable chance of contributing to toxicity or otherwise skewing trial result. 
 
Any subject removed from the trial will remain under medical supervision until discharge or 
transfer is medically acceptable. 
 
Any subject with progression of disease will come off of treatment. In all cases, the reason for 
withdrawal must be recorded in the CRF and in the subject's medical records. 
 
 
 
4.3.2 Screen Failures/Dropouts/Replacements 
 
A subject who discontinues study participation prematurely for any reasons except death, disease 
progression and severe toxicity is defined as a dropout. 
 
Dropouts who did not receive at least one staging assessment (after 2 cycles or 8 weeks of 
treatment) will need to be replaced. 
 
A subject who, consents to participate but does not qualify for treatment based upon the eligibility 
criteria is regarded a “screening failure”. 
 
Patients who are screening failures will need to be replaced. 
 
Patient who receive at least one staging assessment (after 2 cycles or 8 weeks of treatment), will be 
included in the analysis of disease response. 


15 
 
5. Treatment 
 
5.1 
Treatment to be administered 
 
All patients will receive Nivolumab 
 
 
Agent 
Dose 
Route  Schedule* 
 
Nivolumab 
240mg 
IV 
q2weeks   until 16 weeks 
 
*One cycle = 28 days 
 
Agent 
Dose 
Route  Schedule* 
 
Nivolumab 
480mg 
IV 
q4weeks   from 17 weeks to end of study 
 
 
 
 
5.1.1 
Flat Dose Regimen 
 
The safety and efficacy of 240 mg Q2W flat dose of nivolumab is expected to be similar to 
3 mg/kg Q2W dosing regimen. Using the PPK model, exposure of nivolumab at 240 mg flat dose 
is identical to a dose of 3 mg/kg for subjects weighing 80 kg, which is 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. Hence, a flat dose of 240 mg nivolumab is under investigation. Of note, 240 
mg is identical to 3mg/kg for 80 kg patients; 80 kg is the median body weight. 
 
 
 
5.2 
Management of Toxicities Associated with Study Drug 
 
Subjects will receive treatment with nivolumab as a 60 minute IV infusion, on Week 1, Day 1 and 
Week 3, Day 1 of a treatment cycle (every 2 weeks). 
 
There will be no dose escalations or reductions of nivolumab allowed. This includes both the 
240mg q 2 week portion of the study as well as the 480mg q 4 week portion of the study. 
 
Subjects may be dosed no less than 12 days from the previous dose. There are no premedications 
recommended for nivolumab on the first cycle. If an acute infusion reaction is noted, subjects 
should be managed according to Section 5.2.5. 
 
Treatment may be delayed for up to a maximum of 6 weeks from the last dose (See Sections 5.2.1 
and 5.2.4.1). 
Subjects will be monitored continuously for AEs while on study. Treatment modifications (eg dose 
delay or discontinuation) will be based on specific laboratory and adverse event criteria. 
 
In some cases, the natural history of immunotherapy-related AEs of special interest can differ and 
be more severe than AEs caused by other therapeutic classes. Early recognition and management 
may mitigate severe toxicity. The management of organ specific toxicities is detailed through flow 
sheets in Appendix 1. 


16 
 
Summary of Safety 
 
Most related AEs are thought to be due to the effects of inflammatory cells on specific tissues. In 
general, the approach to suspected nivolumab-related AEs is similar across any involved 
organ system. Safety management algorithms for organ-specific AEs are found in Appendix 1. 
Subjects  should   have  a thorough  diagnostic  work-up   to   evaluate  potential  drug-  and 
non-drug-related diagnoses. For suspected nivolumab-related AEs, based on the severity of the 
event, management with immunosuppressant may be necessary. In general, dose delays and 
observation are adequate for low-grade AEs. For moderate- and high-grade AEs, 
immunosuppression with corticosteroids should be utilized. Once the AE has begun to improve, 
corticosteroids can be tapered over approximately 3 weeks to 6 weeks (depending on the severity 
of the AE). 
 
Immune Mediated Event Assessment 
 
This assessment of AE is made by the individual investigator and should be based on clinical 
evidence such as: 
• 
Responsiveness to treatment (e.g. steroids) 
• 
Diagnostic test results (e.g. evidence of inflammation) 
• 
Medical history (other illness, prior therapies, etc.) 
 
An IMAE is an AE consistent with an immune-mediated mechanism or immune- 
mediated  component (alternate etiology exacerbated by the induction of autoimmunity) for 
which non-  inflammatory etiologies (e.g. infection or tumor progression) have been ruled out, 
and  consideration given to evidence of inflammation such as tumor biopsies or responsiveness 
to  steroids. 
Likely reasons an event is not an IMAE: 
• 
Likely due to concomitant drug/chemotherapy/radiation 
• 
Documented evidence of tumor as cause 
• 
Same grade event at baseline/history 
• 
Event likely caused by infection 
 
Likely reasons an event is an IMAE: 
• 
Inflammation per pathology or endoscopy 
• 
Improves/resolves after immunosuppression 
• 
Similar to previous immune mediated event in same organ 
 
 
 
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 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. At this time, no underlying risk factor, including prior 
radiotherapy, presence of lung metastases, or underlying pulmonary medical history, has been 
identified. 
 
Guidelines on the recommended management of pneumonitis and other pulmonary AEs are 
found in Appendix 1. 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. It is important 


17 
 
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 1). All subjects with Grade 3-4 pneumonitis should 
discontinue nivolumab and initiate treatment with high doses of corticosteroids. 
 
Gastrointestinal Adverse Events 
 
Gastrointestinal AEs have been observed following treatment with nivolumab. Most 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 1. 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. 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 1). 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. Grade 3 diarrhea/colitis requires permanent discontinuation regardless of AE 
duration. 
 
Diverticular Perforation 
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 w ith their 
malignancy. 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, vigilance should be used 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, drug induced liver 
injury (DILI), have been observed following treatment with nivolumab. Most 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 1. 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 1). 


18 
 
For any grade increase in AST or ALT, the investigator needs to ensure that it is not due to biliary 
obstruction or the introduction of new drugs. Biliary obstruction should be ruled out by imaging if 
needed. If the elevation of AST or ALT is due to biliary obstruction, and the biliary obstruction is 
treated, the study drug may be restarted upon return of the AST and ALT to baseline or grade 2. 
 
For any grade increase in bilirubin, the investigator needs to ensure that it is not due to biliary 
obstruction or the introduction of new drugs. Biliary obstruction should be ruled out by imaging if 
needed. If the elevation of bilirubin is due to biliary obstruction, and the biliary obstruction is 
treated, the study drug may be restarted upon return of the bilirubin to baseline or Grade 1. 
 
 
 
Endocrinopathies 
 
Endocrinopathies have been observed following treatment with nivolumab.  Most cases were of 
low or moderate grade. The events have typically been identified through either routine periodic 
monitoring of specific laboratories (e.g., TSH) or as part of a work-up for associated 
symptoms (e.g., 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 (e.g., 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 1. 
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. As fatigue is common in subjects with 
cancer, it is important that an evaluation/work-up distinguishes between non-drug-related causes 
(e.g., 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 1). 
 
 
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. 
 
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. 


19 
 
Systemic corticosteroids should be used for diffuse and high-grade rash. 
 
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 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 1. 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 (e.g., 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 1). 
 
Neurologic Adverse Events 
 
Neurologic AEs have been uncommonly observed following treatment with nivolumab. 
Neurologic AEs can manifest as central abnormalities (e.g., aseptic meningitis, encephalopathy, or 
encephalitis)  or  peripheral  sensory/motor  neuropathies   (e.g.,   Guillain-Barre  Syndrome, 
myasthenia gravis complicated with sepsis and fatality). 
 
The recommended management of neurologic AEs is provided in Appendix 1. 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 (e.g., weakness), changes in 
sensation (e.g., 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 (e.g., 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 1). For high-grade related 
neurological AEs, nivolumab should be discontinued. 
 
Uveitis and Visual Complaints 
 
Immune therapies have been uncommonly associated with visual complaints. Inflammation of 
components within the eye (e.g., uveitis) is an uncommon, but clinically important, event. 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. 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. 
 
 
 
Others 


range, delay dosing for drug-related Grade ≥ 3 toxicity 
20 
 
Other clinically significant immune-mediated adverse reactions can occur with nivolumab. 
Immune-mediated adverse reactions may occur after discontinuation of nivolumab therapy. For 
any suspected immune-mediated adverse reactions, exclude other causes. Based on the severity of 
the adverse reaction, permanently discontinue or withhold nivolumab, administer high-dose 
corticosteroids, and if appropriate, initiate hormone-replacement therapy. Upon improvement to 
Grade 1 or less, consider initiation of corticosteroid taper and continue to taper over at least 1 
month. Consider restarting nivolumab after completion of corticosteroid taper based on the 
severity of the event. 
 
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. 
 
Precautions for Women of Childbearing Potential 
 
 
The   nonclinical   findings   of   increased   late-stage   pregnancy  loss   and   early  infant 
deaths/euthanasia in nivolumab-exposed pregnant monkeys suggest a potential risk to human pregnancy if 
there is continued treatment with nivolumab during pregnancy. Given the potential risk suggested by 
preliminary data from nonclinical and clinical data, dosing during pregnancy will continue to be prohibited. 
In addition, women of childbearing potential (WOCBP) receiving nivolumab will be instructed to adhere to 
contraception for a period of 23 weeks after the last dose of nivolumab. Men receiving nivolumab and who 
are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after 
the last dose of nivolumab. 
 
 
These durations have been  calculated using the upper limit of the half-life for nivolumab 
(25 days) and are based on the recommendation that WOCBP use contraception for 5 half-lives 
plus 30 days, and men who are sexually active with WOCBP use contraception for 5 half-lives 
plus 90 days after the last dose of nivolumab. Females should not breastfeed while receiving 
nivolumab and for any subsequent protocol-specified period. 
 
 
 
5.2.1 
Dose Delay Criteria 
 
Tumor assessments for all subjects should continue as per protocol even if dosing is interrupted. 
Nivolumab administration should be delayed for the following: 
• Any Grade ≥ 2 non-skin, drug-related adverse event, with the following exceptions: 
− Grade 2 drug-related fatigue or clinically insignificant laboratory abnormalities do 
not require a treatment delay 
• Any Grade 3 drug-related skin adverse event 
• Any Grade 3 drug-related laboratory abnormality, with the following exceptions for blood 
counts, AST, ALT, or total bilirubin: 
− Grade 3 lymphopenia or leukopenia does not require dose delay 
− Grade 2 anemia does not require a dose delay 
• If a subject has a baseline AST, ALT or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade ≥ 2 toxicity 
• If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 or Grade 2 toxicity 


 
• A sudden increase in transaminases that the investigator determines is secondary to 
dislocation of a stent will not be counted as an AE. Treatment should be held until stent 
replacement can be performed and only resumed once LFTs have returned to the patient’s 
baseline 
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication. 
 
 
 
 
5.2.2 
Criteria to Resume Dosing 
 
Subjects may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to Grade ≤ 
1 or baseline, 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 
• Subjects with baseline AST/ALT or total bilirubin in the Grade 1 or 2 toxicity range may 
resume treatment in the presence of return to Grade 1 or 2 AST/ALT OR total bilirubin, 
respectively 
• Subjects who started out with normal baseline LFTs who develop combined Grade 2 
AST/ALT AND total bilirubin values meeting discontinuation parameters (Section 5.2.4.1) 
should have treatment permanently discontinued 
• Drug-related pulmonary toxicity or diarrhea/colitis must have resolved to baseline before 
treatment is resumed. Grade 3 or 4 diarrhea/colitis require permanent discontinuation of the 
drug regardless of duration. Drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement may resume treatment 
 
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study therapy, 
except as specified in Section 5.2.4.1 
 
 
 
5.2.3 
Treatment Beyond Disease Progression 
 
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of progressive disease (PD). 
 
Subjects treated with nivolumab will be permitted to continue treatment beyond initial RECIST 1.1 
defined PD as long as they meet the following criteria: 
1. Investigator-assessed clinical benefit, and do not have rapid disease progression 
2. Continue to meet all other study protocol eligibility criteria 
3. Tolerance of study drug 
4. Stable performance status 
5. Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., CNS metastases) 
 
If the subject appears to be deriving clinical benefit despite disease progression, the decision to 
continue treatment beyond disease progression should be discussed with the Principal Investigator 
and documented in the study records. 
 
21 


22 
 
A radiographic assessment/ scan should be performed within six (6) weeks of original PD to 
determine whether there has been a decrease in the tumor size, or continued PD. The assessment of 
clinical benefit should be balanced by clinical judgment as to whether the subject is clinically 
deteriorating and unlikely to receive any benefit from continued treatment with nivolumab. 
 
If the principal investigator feels that the subject continues to achieve clinical benefit by continuing 
treatment, the subject should remain on the trial and continue to receive monitoring according to the 
Time and Events Schedule. The decision to continue treatment should be discussed and documented 
in the study records. 
 
 
 
5.2.4 
Treatment Discontinuation Criteria 
 
Tumor assessments for all subjects should continue as per protocol even if dosing is discontinued. 
 
 
 
5.2.4.1 
Nivolumab Dose Discontinuation 
 
Nivolumab treatment should be permanently discontinued for the following: 
 
Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical therapy 
and does not improve to Grade 1 severity within the re-treatment period OR requires systemic 
treatment 
 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following exceptions: 
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity reaction, or infusion 
reaction of any duration requires discontinuation 
 
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation except: 
1. Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation 
2. Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation: 
a. AST or ALT > 10x ULN 
b. Total bilirubin > 5x ULN 
c. In subjects with normal baseline LFTs, the development concurrent AST or ALT > 
3x ULN and total bilirubin > 2x ULN 
 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following events 
which do not require discontinuation: 
1. Grade 4 neutropenia ≥ 7 days 
2. Grade 4 lymphopenia or leukopenia 
3. Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset 
 
Any dosing interruption lasting > 6 weeks with the following exceptions: 


23 
 
1. Dosing interruptions to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed. Prior to re-initiating treatment in a subject with a dosing interruption 
lasting > 6 weeks, the Principal Investigator must be consulted. Tumor assessments should 
continue as per protocol even if dosing is interrupted. 
2. Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be allowed if 
approved by the Principal Investigator. Prior to re-initiating treatment in a subject with a 
dosing interruption lasting > 6 weeks, the Principal Investigator must be consulted. Tumor 
assessments should continue as per protocol even if dosing is interrupted. 
3. Any adverse event, laboratory abnormality, or concurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued nivolumab 
dosing. 
 
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 objective progression (ie radiographic confirmation) even 
after discontinuation of treatment. 
 
 
 
5.2.5 
Treatment of Nivolumab-Related Infusion Reactions 
 
 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were to 
occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthalgias, hypotension, 
hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 infusion reactions 
should be reported as an SAE if it meets the criteria. Infusion reactions should be graded according 
to NCI CTCAE (Version 4.0) guidelines. 
 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate: 
 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated). 
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes 
before additional nivolumab administrations. 
 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti- 
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for 24 hours). 
 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject 
with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg; remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid and/or bronchodilator therapy may also be administered as appropriate. If the 


24 
 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor subject closely. If symptoms recur, 
then no further nivolumab will be administered at that visit. 
 
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to1000 mg 
should be administered at least 30 minutes before nivolumab infusions. If necessary, 
corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used. 
 
For Grade 3 or 4 symptoms: Follow guidelines for Grade 2 infusion reaction as above and 
permanently discontinue study drug. 
 
 
 
5.3 
Study Treatment, Drug Ordering, and Pharmacy Reference Information 
 
Nivolumab 100 mg (10 mg/mL) will be packaged in an open-label fashion. Ten nivolumab, 10 mL 
vials will be packaged within a carton, and are not subject or treatment arm specific. The 
appearance of the solution is clear to opalescent, colorless to pale yellow liquid that may contain 
particles. It should be stored between 2 and 8 degrees Celsius and should be protected from light 
and freezing. 
 
Treatment should be initiated within 28 days of enrollment. Treatment will be continued until 
disease progression, discontinuation due to toxicity, withdrawal of consent, or the study ends. 
 
Treatment will be administered at a dose of 240 mg every 2 weeks for 16 weeks and then at 480 mg 
every 4 weeks until disease progression or unacceptable toxicity for up to 24 months. Treatment can 
continue at the discretion of the investigator if clinical benefit is noted. 
 
For full information regarding nivolumab drug ordering as well as pharmacy reference material, 
please see Appendix 2 and Table 3. 
 
5.3.1 
Handling and Dispensing 
 
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by the sponsor. If 
concerns regarding the quality or appearance of the study drug arise, do not dispense the study drug 
and contact the sponsor immediately. Nivolumab vials must be stored in the refrigerator at 2-8°C, 
protected from light and freezing. If stored in a glass front refrigerator, vials should be stored in the 
carton. 
 
Investigational product documentation must be maintained that includes all processes required to 
ensure drug is accurately administered. This includes documentation of drug storage, administration 
and, as applicable, storage temperatures, reconstitution, and use of required processes (e.g. required 
diluents, administration sets). 
 
Recommended safety measures for preparation and handling of nivolumab include laboratory coats 
and gloves. 


25 
 
After nivolumab has been prepared for administration, the total storage time (combination of 
refrigeration and room temperature) is not to exceed 24 hours. For details on prepared drug storage 
and use time under room temperature/light and refrigeration, please refer to the current Nivolumab 
Investigator Brochure. 
 
Care must be taken to assure sterility of the prepared solution as the product does not contain any 
anti-microbial preservative or bacteriostatic agent. No incompatibilities between nivolumab and 
polyolefin bags have been observed. 
 
Nivolumab is to be administered as a 60 minute IV infusion, using a volumetric pump with a 
0.2/0.22 micron in-line filter at the protocol-specified doses. It is not to be administered as an IV 
push or bolus injection. At the end of the infusion, flush the line with a sufficient quantity of normal 
saline (per institutional standard of care). 
 
Details regarding the mixing and concentrations of the dose (preparation) and administration can be 
found in the current Investigator brochure for nivolumab. 
 
 
 
5.3.2 
Blinding 
 
 
This is an open-label trial. There will be no randomization or blinding. 
 
 
 
5.3.3 
Drug Logistics and Accountability 
 
 
All study drugs will be stored at the investigational site in accordance with good clinical practice 
(GCP) and GMP requirements and the instructions given by the clinical supplies department of the 
sponsor (or its affiliate / Contract Research Organization [CRO]), and will be inaccessible to 
unauthorized personnel. Special storage conditions and a complete record of batch numbers and 
expiry dates can be found in the sponsor study file; the site-relevant elements, of this information 
will be available in the ISF. The responsible site personnel will confirm receipt of study drug and 
will use the study drug only within the framework of this clinical study and in accordance with this 
protocol. Receipt, distribution, return and destruction (if any) of the study drug must be properly 
documented according to the sponsor’s agreed upon and specified procedures. 
 
 
 
5.3.4 
Treatment Compliance 
 
 
 
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF. 
 
5.3.5 
Destruction and Return of Study Drug 
 
 
Destruction of Study Drug For this study, study drugs (those supplied by BMS or sourced by the 
investigator) such as partially used study drug containers, vials and syringes may be destroyed on 
site. Any unused study drugs can only be destroyed after being inspected and reconciled by the 


 
responsible BMS Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (e.g. cytotoxics or biologics). On-site destruction is 
allowed provided the following minimal standards are met: 
 
• On-site disposal practices must not expose humans to risks from the drug. 
• On-site disposal practices and procedures are in agreement with applicable laws and regulations, 
including any special requirements for controlled or hazardous substances. 
• Written procedures for on-site disposal are available and followed. The procedures must be filed 
with the site’s SOPs and a copy provided to BMS upon request. 
• Records are maintained that allow for traceability of each container, including the date disposed 
of, quantity disposed, and identification of the person disposing the containers. The method of 
disposal, i.e. incinerator, licensed sanitary landfill, or licensed waste disposal vendor must be 
documented. 
• Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period. 
 
If conditions for destruction cannot be met, the responsible BMS Study Monitor will make 
arrangements for return of study drug. It is the investigator’s responsibility to arrange for disposal 
of all empty containers, provided that procedures for proper disposal have been established 
according to applicable federal, state, local, and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. 
 
 
 
5.3.6 
Return of Study Drug 
 
If study drug will not be destroyed upon completion or termination of the study, all unused and/or 
partially used study drug that was supplied by BMS must be returned to BMS. The return of study 
drug will be arranged by the responsible BMS Study Monitor.  It is the investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal have 
been established according to applicable federal, state, local, and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
 
 
 
5.4 
Prior and Concomitant Therapy 
 
5.4.1 
Prohibited Concomitant Anti-cancer Therapy: 
 
 
CYP3A4 Inhibitors and Inducers 
 
The following strong CYP3A4 inhibitors should be avoided during the study. This includes (but is 
not limited to): 
 
• Ketoconazole 
• Itraconazole 
• Clarithromycin 
• Atazanvir 
• Indinavir 
• Nefazodone 
• Nelfinavir 
• Ritonavir 
• Saquinavir 
• Teithromycin 
• Voriconazole 
 
The following medications are prohibited during the study (unless utilized to treat a drug-related 
 
26 


27 
 
adverse event): 
 
• Immunosuppressive agents 
• Immunosuppressive doses of systemic corticosteroids (except as stated in Section 5.4.3). 
• Any concurrent antineoplastic therapy (i.e., chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents for treatment of 
biliary tract cancers). 
 
Palliative and supportive care for disease related symptoms (including local radiotherapy, 
bisphosphonates and RANK-L inhibitors) may be offered to all subjects prior to first dose of study 
therapy (prior radiotherapy must have been completed at least 2 weeks prior to enrollment). 
 
 
 
5.4.2 
Other Restrictions and Precautions 
 
 
• Subjects with active, known or suspected autoimmune disease. 
• Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune 
thyroiditis only requiring hormone replacement, or conditions not expected to recur in the 
absence of an external trigger are permitted to enroll. 
• Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
enrollment. 
• Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone 
equivalent, are permitted in the absence of active autoimmune disease. 
 
 
 
5.4.3 
Permitted Therapy 
 
• Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). 
• Physiologic replacement doses of systemic corticosteroids (e.g., prednisone ≤ 10 mg/day) 
are permitted. 
• A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g., contrast dye 
allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity 
reaction caused by a contact allergen) is permitted. 
• The potential for overlapping toxicities with radiotherapy and nivolumab currently is not 
known. Therefore, palliative radiotherapy is not recommended while receiving nivolumab. If 
palliative radiotherapy is required, then nivolumab should be withheld for at least 1 week 
before, during, and 1 week after radiation. Subjects should be closely monitored for any 
potential toxicity during and after receiving radiotherapy, and AEs should resolve to Grade 
≤ 1 prior to resuming nivolumab. Only non-target bone lesions that do not include lung 
tissue in the planned radiation field may receive palliative radiotherapy. Details of palliative 
radiotherapy should be documented in the source records and electronic case report form 
(eCRF). Details in the source records should include: dates of treatment, anatomical site, 
dose administered and fractionation schedule, and adverse events. If warranted, symptoms 
requiring palliative radiotherapy should be evaluated for objective evidence of disease 
progression. 


28 
 
6. Study Assessments and Procedures 
 
6.1 
Table 1: Screening Assessments and Procedures 
 
Screening examinations will only be performed after having received the subject’s written 
informed consent. 
 
Screening Assessments and Procedures 
to be completed within 28 days of enrollment 
Procedure 
Screening 
Visit 
Notes 
Eligibility Assessments 
Informed Consent 
X 
Inclusion/Exclusion 
Criteria 
X 
Medical History 
X 
Safety Assessments 
Vital Signs and Oxygen 
saturation 
X 
Temperature, BP, HR, RR, O2 saturation by pulse oximetry (also 
monitor amount of supplemental oxygen if applicable) 
Obtain vital signs at screening visit and within 72 hours of first 
dose 
Physical  Measurements 
(including  Performance 
Status) 
X 
Includes Height and Weight, and ECOG status 
Clinic Visit 
X 
Laboratory Tests 
X 
Labs performed within 21 days prior to first dose of study drug: 
CBC with differential, Serum chemistry (BUN or serum urea level, 
serum creatinine, sodium, potassium, calcium, magnesium, 
phosphate, chloride, and bicarbonate, glucose), AST, ALT, total 
bilirubin, direct bilirubin, alkaline phosphatase, albumin, LDH, 
TSH, free T3, free T4, HBV surface antigen, HCV RNA. CA 19-9 
Pregnancy Test 
X 
Performed within 7 days prior to first dose study drug (serum or urine 
for WOCBP only) 
Concomitant 
Medication  collection 
X 
Radiographic Tumor 
Assessment (Chest, 
abdomen, pelvis) 
X 
Should be performed within 28 days prior to first dose. CT/MRI of 
brain (with contrast) should only be performed in subjects with a 
known history of treated brain metastases. 
Additional sites of known or suspected disease (including CNS) should 
be imaged at the screening visit and at subsequent on-study 
assessments. 
Archived Tumor Tissue 
or Recent Tumor Biopsy 
(for IHC) 
X 
May be archival or recent sample. 1 formalin-fixed paraffin embedded 
tumor tissue block or cell block is needed (or 10 slides). 


29 
 
6.2 
Table 2: On Study Assessments 
 
 
 
Procedure 
C1D1 
C1D8 
C1D15(±5 days) 
C2D1(±5 days) 
C4D1(±5 days) 
End of every 2nd 
cycle(±5 days) 
Subsequent 
Cyclesa 
EOTb 
Notes 
Vital signs and 
Oxygen 
Saturations 
X 
X 
X 
X 
X 
X 
X 
Temperature, BP, HR, RR, O2 
saturation by pulse oximetry (also 
monitor amount of supplemental 
oxygen if applicable) prior to dosing 
and at any time a subject has any new 
or worsening respiratory symptoms 
AE and SAE 
Assessment 
Continuously 
Assessed using NCI CTCAE v. 4.0 
Physical 
Measurements 
including 
Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
Includes Weight and ECOG status 
Complete 
blood count 
Results obtained 
prior to dosing 
on infusion days 
X 
X 
X 
X 
X 
X 
X 
Includes WBC count with differential, 
hemoglobin, hematocrit, and platelet 
count 
Serum 
Chemistry 
Tests 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry (BUN or serum urea 
level, serum creatinine, sodium, 
potassium, calcium, magnesium, 
phosphate, chloride, and bicarbonate, 
glucose), LDH 
Clinic Visit 
X 
X 
X 
X 
X 
X 
X 
Liver Function 
Testing 
Results obtained 
within 72 hours 
prior to dosing 
on infusion days 
X 
X 
X 
X 
X 
X 
X 
Includes aspartate aminotransferase 
(AST), alanine aminotransferase 
(ALT), total bilirubin, alkaline 
phosphatase, and albumin 
Additional 
Testing 
X 
Tumor measurement/disease assessment 
according to RECIST 1.1, CA 19-9 
assessment, Pregnancy Test Urine or 
Serum (for WOCBP only), TSH (reflex 
to free T3 and free T4 if abnormal 
results) 
aTreatment is to be given every 2 weeks for 16 weeks ( 4 cycles) and then will be given once every 4 weeks thereafter as per Section 5.3 


30 
 
b The EOT disease assessment with radiographic imaging is required if it has been > 28 days since the last disease assessment 


31 
 
 
 
 
 
 
7. Adverse Events 
 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre- 
existing medical condition in a subject or clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the use 
of investigational product, whether or not considered related to the investigational product. 
 
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The casual relationship can be one of the following: 
 
 
The 5 categories for AE grading are: 
 
 
1. Not related 
2. Not Likely 
3. Possible 
4. Probable 
5. Definite 
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.) 
 
All AEs will be monitored until resolution or, if the AE is determined to be chronic, a cause is 
identified. If an AE is considered potentially related to study treatment and remains ongoing at the 
conclusion of the study, the event will be followed until resolution, stabilization, or initiation of 
treatment that confounds the ability to assess the event. AEs will be collected for a minimum of 30 
days from the end of treatment. All SAEs must be collected from when the patient begins the study 
drug to within 100 days of discontinuation of dosing or until the patient begins another anti-cancer 
therapy. 
 
 
 
7.1 
Safety Monitoring 
 
Safety assessments will consist of monitoring and recording all adverse events and serious adverse 
events, the regular monitoring of hematology and blood chemistry parameters and regular physical 
examinations. Adverse events will be evaluated continuously throughout the study. Safety and 
tolerability will be assessed according to the NIH/NCI Common Terminology Criteria for Adverse 
Events version 4.0 (CTCAE v4.0) that is available 
at: http://evs.nci.nih.gov/ftp1/CTCAE/About.html 


32 
 
7.1.1 
Internal Safety Monitoring 
 
The Moffitt Protocol Monitoring Committee (PMC) meets monthly and reviews accrual, patterns 
and frequencies of all adverse events, protocol violations and when applicable, internal audit 
results. 
The PMC, upon review of any agenda item, may approve the study for continuation, require 
revisions, suspend or close a protocol. 
 
Data will be captured in OnCore, Moffitt’s Clinical Trials Database. Regulatory documents and 
case report forms will be reviewed routinely according to Moffitt’s Monitoring Policies. 
 
 
 
 
7.2 
Serious Adverse Events 
 
 
A Serious AE (SAE) is any untoward medical occurrence that at any dose: 
7.2.1 results in death 
7.2.2 is life-threatening (defined as an event in which the subject was at risk of death at 
the  time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe) 
7.2.3 requires subject hospitalization or causes prolongation of existing hospitalization (see 
NOTE below) 
7.2.4 results in persistent or significant disability/incapacity 
7.2.5 is a congenital anomaly/birth defect 
7.2.6 is an important medical event (defined as a medical event(s) that may not be 
immediately  life-threatening or result in death or hospitalization but, based upon 
appropriate medical  and scientific judgment, may jeopardize the subject or may require 
intervention [eg, medical, surgical] to prevent one of the other serious outcomes listed in 
the definition  above.) Examples of such events include, but are not limited to, intensive 
treatment in an  emergency room or at home for allergic bronchospasm; blood dyscrasias 
or convulsions  that do not result in hospitalization.) Potential drug induced liver injury 
(DILI) is also  considered an important medical event. (See Section 7.6 for the definition 
of potential  DILI.) 
 
Suspected transmission of an infectious agent (e.g., any organism, virus or infectious particle, 
pathogenic or non-pathogenic) via the study drug is an SAE. 
 
Information about all serious adverse events will be collected and recorded. To ensure patient 
safety, each serious adverse event must be reported to the PI and to BMS expeditiously (see below 
for BMS requirements). Moffitt Cancer Center and all participating sites will report SAEs by 
completing an SAE report in ONCORE, the electronic data capture system and a Medwatch Form 
online at http://www.fda.gov/medwatch The SAE must be reported by email 
(affiliate.research@moffitt.org) to the MCRN within 2 working days. 


33 
 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 7.4 for 
reporting pregnancies). 
 
NOTE: 
The following hospitalizations are not considered SAEs: 
 
• A visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event) 
• Elective surgery, planned prior to signing consent 
• Admissions as per protocol for a planned medical/surgical procedure 
• Routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy) 
• Medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study. Appropriate documentation is required in these cases 
• Admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason) 
 
 
 
 
7.2.1 
Serious Adverse Event Collection and Reporting 
 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol- 
specified procedures. All SAEs must be collected from when the patient begins the study drug to 
within 100 days of discontinuation of dosing or until the patient begins another anti-cancer 
therapy. If applicable, SAEs must be collected that relate to any later protocol-specified procedure 
(e.g., a follow-up skin biopsy). 
 
The investigator should report any SAE occurring after these time periods that is believed to be 
related to study drug or protocol-specified procedure. 
 
An SAE report should be completed for any event where doubt exists regarding its status 
of  seriousness. 
 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy, or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form. 
 
SAEs, whether related or not related to study drug, as well as pregnancies, must be reported to 
BMS (or designee) within 24 hours. SAEs must be recorded on the SAE Report Form; 
pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). When using paper 
forms, the reports are to be transmitted via email or confirmed facsimile (fax) transmission to: 
 
SAE Email Address: Worldwide.Safety@BMS.com 
 
SAE Facsimile Number:  609-818-3804 


34 
 
For studies capturing SAEs/pregnancies through electronic data capture (EDC), electronic 
submission is the required method for reporting. The paper forms should be used and submitted 
immediately, only in the event the electronic system is unavailable for transmission. When paper 
forms are used, the original paper forms are to remain on site. 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes  available,  a follow-up  SAE report should  be sent within  24  hours  to  the  BMS 
(or designee) using the same procedure used for transmitting the initial SAE report. 
 
All SAEs should be followed to resolution or stabilization. 
 
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. 
 
SAEs should be reported on MedWatch Form 3500A, which can be accessed 
at: http://www.accessdata.fda.gov/scripts/medwatch/. 
 
MedWatch SAE forms should be sent to the FDA at: 
 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
 
Global Pharmacovigilance & Epidemiology Bristol-
Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
 
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
 
For studies with long-term follow-up periods in which safety data are being reported, include the 
timing of SAE collection in the protocol. 
 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form. 


35 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to BMS using the same 
procedure used for transmitting the initial SAE report. All SAEs should be followed to resolution or 
stabilization. All SAEs should be followed to resolution or stabilization.The Sponsor will reconcile 
the clinical database SAE cases (case level only) transmitted to BMS Global Pharmacovigilance 
(Worldwide.Safety@bms.com). Frequency of reconciliation should be every 3 months and prior to 
the database lock or final data summary. BMS GPV&E will email, upon request from the 
Investigator, the GPV&E reconciliation report. Requests for reconciliation should be sent to 
aepbusinessprocess@bms.com. The data elements listed on the GPV&E reconciliation report will 
be used for case identification purposes. If the Investigator determines a case was not transmitted to 
BMS GPV&E, the case should be sent immediately to BMS. 
 
 
 
7.3 
Non-serious Adverse Events 
 
A non-serious adverse event is an AE not classified as serious. 
The collection of nonserious AE information should begin at initiation of study drug. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 7.2). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug, or those that are present at the end of study treatment 
as appropriate. All identified nonserious AEs must be recorded and described on the nonserious AE 
page of the CRF (paper or electronic). 
 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study. 
 
 
7.4 
Laboratory Test Abnormalities 
 
The following laboratory abnormalities should be captured on the nonserious AE CRF page or 
SAE Report Form (paper or electronic) as appropriate: 
 
• 
Any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
Any laboratory abnormality that required the subject to have study drug discontinued or 
interrupted 
• 
Any laboratory abnormality that required the subject to receive specific corrective therapy. 
 
Wherever possible the clinical, rather than the laboratory term, should be used by the 
reporting investigator (e.g., anemia versus low hemoglobin value). 
 
 
7.5 
Pregnancy 


36 
 
Following initiation of the investigational product, if it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half-lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for subject 
safety). Protocol-required procedures for study discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. 
 
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
and in accordance with SAE reporting procedures described in Section 7.2.1. 
 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form. 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the sponsor. Information on this pregnancy will be collected on the Pregnancy Surveillance 
Form. 
 
 
7.6 
Overdose 
 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 7.2.1 for reporting details). 
 
 
7.7 
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. 
 
For recommendations regarding suspected pulmonary toxicity, diarrhea and colitis, suspected 
hepatotoxicity (including asymptomatic LFT elevations), or suspected endocrinopathy, please 
see Section 5.2 and Appendix 1. 
 
 
 
 
8. Statistical Considerations 
 
8.1 
Sample Size Determination 
Patients will be accrued to the protocol according to a Simon two-stage design.31 Based on patient 
response (CR + PR after 2 cycles), as defined by RECIST 1.1 criteria, we will either conclude that 
the therapy is effective or ineffective. The two-stage design has the smallest effective sample size 
with the following two properties: 


37 
 
8.1.1if the true response rate is less than or equal to 5% , we will conclude that the therapy 
is ineffective with probability of at least 0.07 (alpha), and 
8.1.2if the true response rate is at least 20%, we will conclude that the therapy is effective 
with probability at least 0.90 (power). 
 
At least one of eighteen patients must respond (CR or PR) in the first stage to proceed to the second 
stage.  At any point when it is realized that this cannot happen, the study will be stopped and the 
therapy will be considered ineffective. 
 
If there are at least 4 patients with stable disease for 16 weeks (2 restaging assessments), the 
principal investigator will discuss proceeding to the second stage of the study with the BMS 
medical team. This would require an amended protocol to define a successful trial result. 
 
The second stage of this study will involve an additional 14 patients. The study will have met its 
primary endpoint of response rate if there are at least four patients out of thirty two patients who 
have a response. 
 
8.2 
Rationale for an expansion of the study 
 
In March, 2018, it was determined that the Simon-2 stage results led to the rejection of the null 
hypothesis, and conclusion that the therapy was promising, as 5 of 32 patients had partial 
responses. Two additional patients were also enrolled due to confusion regarding the evaluability of 
two patients, with best responses of PD and SD. Thus 5 of 34 patients overall have had PRs (note:5 
patients did not have any follow-up RECIST assessments; 4 patients had clinical progression, while a 
5th patient withdrew consent).  The study team would like to enroll an additional cohort of 20 patients, 
which would give us a total sample size of 54 patients, for which the 6-month PFS and OS rates are 
the primary endpoints to be estimated. Presuming no censorship of patients in the first six months 
after starting treatment, we will be able to estimate the 6-month PFS and 6-month OS rates with a 
95% confidence interval half-width of 13.3% (Normal approximation to the binomial 
calculation).  Current 6—month estimates from the study are 41%  for PFS, and 73% for 
OS.  Notably, the last of the 10 deaths to date occurred at 6.4 months, and 15 patients have exceeded 
that time by an average of 5.0 months, suggesting that there will be a high rate of long-term 
survivors.  Thus, the expansion would provide additional valuable information on this promising 
therapy. 
 
 
 
 
8.3 
Populations for Analyses 
 
All enrolled subjects: All subjects who signed an informed consent form and were registered into 
the IVRS. Analyses of the patients enrolled into the study but not treated and the reason for not 
being treated will be performed on the data set of all enrolled subjects. 
 
All treated subjects: All subjects who received at least one dose of nivolumab. 
This is the primary dataset for dosing and safety. 
Response Evaluable Subjects: treated subjects whose change in the sum of diameters of target 
lesions was assessed (ie. target lesion measurements were made at baseline and at least one on- 
study tumor assessment.) 


38 
 
8.4 
Endpoint Definitions 
 
 
 
8.4.1 Primary Endpoint 
 
The primary objective in the study will be measured by the primary endpoint of ORR (CR + PR) as 
measured by RECIST 1.1 criteria. 
 
 
 
8.4.2 Secondary Endpoints 
 
8.4.2.1 Overall Survival (OS) 
 
OS is defined as the time from enrollment to the date of death. A subject who has not died will be 
censored at last known date alive. OS will be followed continuously while subjects are on the study 
drugs and every 3 months via in-person or phone contact after subjects discontinue the study drugs. 


39 
 
 
8.4.2.2 Progression Free Survival (PFS) 
 
PFS is defined as the time from first treatment to the date of the first documented tumor progression 
as determined by the investigator (per RECIST 1.1), or death due to any cause. 
 
Subjects who die without a reported prior progression will be considered to have progressed on the 
date of their death. Subjects who did not progress or die will be censored on the date of their last 
evaluable tumor assessment. Subjects who did not have any on study tumor assessments and did 
not die will be censored on the date they were enrolled. Subjects who started any subsequent anti- 
cancer therapy (including on-treatment palliative RT of non-target bone lesions or CNS lesions) 
without a prior reported progression will be censored at the last evaluable tumor assessment prior to 
or on initiation of the subsequent anti-cancer therapy. 
 
8.4.2.3 Safety and Tolerability 
 
Safety and tolerability objective will be measured by the incidence of adverse events, serious 
adverse events, deaths, and laboratory abnormalities. 
 
Adverse event assessments and laboratory tests are performed at baseline, and continuously 
throughout the study at the beginning of each subsequent cycle. 
 
8.4.2.4 Immune Response Criteria 
 
In addition to evaluation by RECIST criteria, subjects will be evaluated using the immune response 
criteria.32 In this classification, the overall response is determined as follows: 
 
• Immune response CR (irCR) is a complete disappearance of all lesions (whether measurable 
or not, and no new lesions) with confirmation by a repeat, consecutive assessment no less 
than 4 weeks from the first documentation. 
• Immune response PR (irPR) is a decrease in tumor burden of greater than or equal to 50% 
relative to baseline. This must be confirmed by a consecutive assessment at least 4 weeks 
after the first documentation. 
• Immune response SD (irSD) is classified as those who do not meet criteria for irCR or irPR 
and who do not have irPD 
• Immune response PD (irPD) is an increase in tumor burden of greater than or equal to 
25%relative to the minimum recorded tumor burden which must be confirmed by a repeat, 
consecutive assessment no less than 4 weeks from the first documentation. 
 
 
 
 
8.4.3 Exploratory Endpoints 
 
 
 
Immunohistochemical stains 
Archive tumor samples (paraffin-embedded tissue blocks or unstained slides) will be used for 
evaluation of expression of PD-L1, CD4, FOXP3, CD8, granzymen B, CD45RO, CD68 and CD163 
using immunohistochemical (IHC) methods with commercial antibiodies. Paraffin blocks may be 
processed according to standard institutional protocols. This IHC scores including PD-L1, memory 
effector cells (CD8+granzyme B+CD45RO+), M2 macrophage (CD163+) and Treg 


40 
 
(CD4+FOXP3+) will be correlated with the clinical efficacy. Sections of formalin-fixed, paraffin-
embedded tissue from the colon cancer will be cut and stained with the respective antibodies against 
PD-L1, CD4, CD8, granzyme B, FOXP3, CD163, CD68 and CD45RO. In brief, the slides will be 
immersed in citrate buffer solution for antigen retrieval and boiled in microwave for 10 min and 
washed in buffer solution. They will be incubated with primary antibody for 1 hr at room 
temperature and then washed in buffer solution. After 1 hr of incubation in the secondary antibody, 
the sections will be incubated with streptavidin-biotin-complex. Appropriate positive and negative 
controls will be used.  
   
Immune Signature 
An immune signature using next generation sequencing  will be performed on all patients and  
correlated to outcome. Total  RNA will be extracted from FFPE tissue sections  or slides followed 
by hybrid-capture next-generation sequencing to evaluate gene expression profiles.  First-strand 
complementary DNA was synthesized from random hexamer-primed RNA templates. Individual 
target-gene amplification will be multiplexed with 18S rRNA endogenous control and run in 
triplicate in 384-well format on fast real-time PCR systems. Normalized cycle threshold values for 
each amplified target gene replicated will be calculated. Resulting triplicate normalized cycle 
threshold values for individual target genes will be averaged, yielding a final value.  
 
Tumor RNA seq, PD-L1, CD8 T cells, Tregs and macrophages will be reported as percentage 
measure. The percentage measurement will be summarized using mean (standard deviation). 
 
 
 
 
9. Data Recording 
 
9.1 
Institutional Review Board (IRB) Approval and Consent 
 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations.  The IRB should approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations.  Once this essential information has been provided to the patient and the investigator is 
assured that the patient understands the implications of participating in the study, the patient will be 
asked to give consent to participate in the study by signing an IRB-approved consent form. 
 
 
 
9.2 
Required Documentation 
 
Before the study can be initiated at any site, the site will be required to provide regulatory 
documentation to the Moffitt Clinical Research Network (MCRN) at Moffitt Cancer Center. Sites 
must provide a copy of their informed consent to the MCRN Coordinating Center for review 
and approval prior to submission of any documents to the site’s IRB. Any changes re- quested by 
the site’s IRB must be provided to the MCRN staff for review and approval prior to resubmission 


41 
 
to the IRB. 
 
The MCRN Coordinating Center must receive the following trial specific documents either by 
hardcopy, fax, or email before a site can be activated for any trial: 


42 
 
1. IRB Approval Letter that includes the protocol version and date 
2. FDA Related Forms 1572/1571/310 as appropriate 
3. Signed Protocol Title Page 
4. IRB Approved Consent Form 
5. Site Delegation of Responsibility Log 
6. Signed  Financial Interest Disclosure Forms (principal and sub investigators) 
7. Updated  Investigator/Personnel  documents  (CVs,  licenses,  Conflict  of  Interest 
statements, etc.) as needed 
8. Updated Laboratory Documents (certifications, normal ranges, etc.) as needed 
9. Signed protocol specific Task Order 
 
A study initiation visit (or teleconference) will be held prior to the start of any study related 
activity at the site. Attendance is required for: 
• The site PI and appropriate research staff 
• Moffitt PI and MCRN research coordinator 
 
The requirements of the protocol and all associated procedures and processes will be reviewed 
and agreed upon prior to the activation of the study. The MCRN utilizes the EDC system, 
O nC o r e .  OnCore training will be scheduled if indicated with the appropriate staff from the 
site. 
 
a. 
Registration Procedures 
 
All subjects must be registered with the MCRN Coordinating Center to be able to participate in 
a trial. The participating site must fax or email the completed study specific eligibility 
checklist and registration forms, supporting documents and signed informed consent to the 
Coordinating Center. Unsigned or incomplete forms will be returned to the site. Once 
documents are received, the MCRN Research Coordinator will review them to confirm eligibility 
and to complete the registration process. If eligibility cannot be confirmed, the research 
coordinator will query the site for clarification or additional documents as needed. Subjects 
failing to meet all study eligibility requirements will not be registered and will be unable to 
participate in the trial. 
 
Upon completion of registration, the MCRN Research Coordinator will provide the participating 
site with the study sequence number. Within 24-48 hours after registration, it is the site’s 
responsibility to: 
 
 
• Enter the demographic and on-study patient information into the OnCore 
database. 
• Order investigational agent(s) if indicated per protocol. 
 
It is the responsibility of the participating Investigator or designee to inform the subject of the 
research treatment plan and to conduct the study in compliance with the protocol as agreed upon 
with Moffitt Cancer Center and approved by the site’s IRB. 
 
To register a patient send the completed signed eligibility checklist along with supporting 


43 
 
documentation to the MCRN via email at affiliate.research@moffitt.org or via fax at 813-745- 
5666, Monday through Friday between 8:00AM and 5:00PM(EST). 
 
 
b. 
Data Management and Monitoring/Auditing 
 
Data will be captured in OnCore, Moffitt’s Clinical Trials Database. Regulatory documents and 
case report forms will be monitored internally according to Moffitt Cancer Center Monitoring 
Policies. Monitoring will be performed regularly to verify data is accurate, complete, and verifiable 
from source documents; and the conduct of the trial is in compliance with the currently approved 
protocol/ amendments, Good Clinical Practice (GCP), and applicable regulatory requirements. 
 
To obtain access to OnCore, the site research staff must complete an OnCore Access Request 
Form and a Moffitt Information Systems Confidentiality Agreement (provided in the MCRN 
Handbook at the site initiation visit) and submit both to the Coordinating Center. Once the 
completed forms are received, the site coordinator will receive VPN access, logon/password, and 
information on how to access OnCore using the VPN. The MCRN Coordinating Center will 
provide OnCore training to the site once initial access is granted and on an ongoing basis, as 
needed. 
 
c. 
Adherence to the Protocol 
 
Except for an emergency situation in which proper care for the protection, safety, and well-being of 
the study patient requires alternative treatment, the study shall be conducted exactly as described in 
the approved protocol. 
 
d. 
Emergency Modifications 
 
Moffitt Cancer Center and Affiliate investigators may implement a deviation from, or a change of, 
the protocol to eliminate an immediate hazard(s) to trial subjects without prior H. Lee Moffitt 
Cancer Center or their respective institution’s approval/favorable opinion. 
 
For Institutions Relying on Moffitt’s IRB: 
 
For any such emergency modification implemented, a Moffitt IRB modification form must be 
completed by Moffitt Research Personnel within five (5) business days of making the change. 
 
For Institutions Relying on Their Own IRB: 
 
For Affiliate investigators relying on their own institution’s IRB, as soon as possible after the 
modification has been made, the implemented deviation or change and the reasons for it should be 
submitted to Moffitt Principal Investigator for agreement and the Affiliate institution’s IRB for 
review and approval. (Once IRB’s response is received, this should be forwarded to the MCRN.) 
 
e. 
Record Retention 
 
Study documentation includes all eCRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 


44 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study documentation pertaining to 
the conduct of a clinical trial must be retained by the study investigator. In the case of a study with 
a drug seeking regulatory approval and marketing, these documents shall be retained for at least 
two years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept on file until three 
years after the completion and final study report of this investigational study. 
 
f. 
Obligations of Investigators 
 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance 
with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal 
Investigator is responsible for personally overseeing the treatment of all study patients. The 
Principal Investigator must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI regulations and 
guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered into the eCRFs. Periodically, monitoring visits will be 
conducted and the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. 
 
 
 
9.3 
Ethical and Legal Aspects 
 
 
a. 
Ethical and Legal Conduct of the Study 
 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation of 
this study, are designed to ensure that the investigator abide by Good Clinical Practice (GCP) 
guidelines and under the guiding principles detailed in the Declaration of Helsinki. The study will 
also be carried out in keeping with applicable local law(s) and regulation(s). 
 
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating centers 
before start of the study, according to GCP, local laws, regulations and organizations. When 
necessary, an extension, amendment or renewal of the EC/IRB approval must be obtained and also 
forwarded to Bristol-Myers-Squibb. 
 
Strict adherence to all specifications laid down in this protocol is required for all aspects of study 
conduct; the investigator may not modify or alter the procedures described in this protocol. 
 
Modifications to the study protocol will not be implemented by the investigator without discussion 
and agreement by Bristol-Myers-Squibb. However, the investigator may implement a deviation 
from, or a change of, the protocol to eliminate an immediate hazard(s) to the trial subjects without 
prior IEC/IRB/Bristol-Myers-Squibb approval/favorable opinion. As soon as possible, the 
implemented deviation or change, the reasons for it and, if appropriate, the proposed protocol 
amendment should be submitted to the IEC/IRB/head of medical institution. Any deviations from 
the protocol must be explained and documented by the investigator. 


45 
 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance 
with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal 
Investigator is responsible for personally overseeing the treatment of all study patients. The 
Principal Investigator must assure that all study site personnel, including sub-investigators and  
other study staff members, adhere to the study protocol and all FDA/GCP/NCI regulations and 
guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and properly documented. 
 
 
 
b. 
Subject Information and Consent 
 
Each subject/legal representative or proxy consenter will have ample time and opportunity to ask 
questions and will be informed about the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 
 
Only if the subject/legal representative or proxy consenter voluntarily agrees to sign the informed 
consent form and has done so, may he/she enter the study. Additionally, the investigator and other 
information provider (if any) will personally sign and date the form. The subject/legal 
representative or proxy consenter will receive a copy of the signed and dated form. 
 
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution. 
 
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject’s clinical record must clearly show that informed consent 
was obtained prior to these procedures. 
 
1. 
If the patient is not capable of providing a signature, a verbal statement of consent can also 
be given in the presence of an impartial witness (independent of Bristol-Myers-Squibb and the 
investigator).  This is to be documented by a signature from the informing physician as well as by a 
signature from the witness. 
 
2. 
For minors or adults under legal protection, consent shall be given by the legal guardian(s). 
The consent of a minor or adult under legal protection shall also be requested where such a person 
is able to express his/her own will. His/her refusal or the withdrawal of his/her consent may not be 
disregarded. 
 
3. 
In emergency situations, when prior consent of the patient is not possible, the consent of the 
patient’s legal representative(s) or proxy consenter, if present, should be requested. The patient 
should be informed about the study as soon as possible and his/her consent to continue the study 
should be requested. 
 
The informed consent form and any other written information provided to subjects/legal 
representatives or proxy consenters will be revised whenever important new information becomes 
available that may be relevant to the subject’s consent, or there is an amendment to the protocol 
that necessitates a change to the content of the subject information and/or the written informed 
consent form.  The investigator will inform the subject/legal representative or proxy consenter of 
changes in a timely manner and will ask the subject to confirm his/her participation in the study by 
signing the revised informed consent form.  Any revised written informed consent form and written 
information must receive the IEC/IRB`s approval/favorable opinion in advance of use. 


46 
 
c. 
Publication policy 
 
Bristol-Myers-Squibb recognizes the right of the investigator to publish results upon completion of 
the study. However, the investigator must send a draft manuscript of the publication or abstract to 
Bristol-Myers-Squibb at least thirty days in advance of submission in order to obtain approval prior 
to submission of the final version for publication or congress presentation.  This will be reviewed 
promptly and approval will not be withheld unreasonably.  In case of a difference of opinion 
between Bristol-Myers-Squibb and the investigator(s), the contents of the publication will be 
discussed in order to find a solution which satisfies both parties. All relevant aspects regarding data 
reporting and publication will be part of the contract between Bristol-Myers-Squibb and the 
investigator/institution. 
 
The Principal Investigator should ensure that the information regarding the study be publicly 
available on the internet at www.clinicaltrials.gov. 
 
 
d. 
Confidentiality 
 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain such 
permission in writing from the appropriate individual. 
 
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49 
 
 


50 
 
Appendix 1: Immune Adverse Event Management Algorithms 
 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens. A general principle is that differential diagnoses should be 
diligently evaluated according to standard medical practice. Non-inflammatory etiologies should be 
considered and appropriately treated. 
 
 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-grade 
toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids. 
 
 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. The frequency and severity of the related adverse events 
covered by these algorithms will depend on the immuno-oncology agent or regimen being used. 


51 
 
GI Adverse Event ManagementAlgorithm 
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and continue I-O therapy. 
Opiates/narcotics may mask symptoms of perforation. Infliximab should not be used in cases of perforation or sepsis. 
 
 
Grade of Diarrhea/ 
Colitis 
(NCI CTCAE v4) 
 
 
Management 
 
 
Follow-up 
 
Grade 1 
Diarrhea:< 4 stools/day over baseline; 
Colitis: asymptomatic 
 
• Continue  I-O therapy per 
protocol 
• Symptomatic treatment 
• Close monitoring for worsening symptoms. 
• Educate patient to report worsening immediately 
If worsens: 
• Treat as Grade 2 or 3/4 
 
 
 
Grade 2 
 Diarrhea: 4-6 stools per day over 
baseline; IV fluids indicated <24 hrs; 
not interfering with ADL 
Colitis: abdominal pain; blood in stool 
 
 
 
 
• Delay I-O therapy per protocol 
• Symptomatic treatment 
If improves to grade 1: 
• Resume I-O therapy per protocol 
If persists > 5-7 days or recur: 
• 0.5-1.0 mg/kg/day methylprednisolone or oral equivalent 
• When symptoms improve to grade 1, taper steroids over 
at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per 
protocol. 
If worsens or persists > 3-5 days with oral steroids: 
• Treat as grade 3/4 
 
 
Grade 3-4 
Diarrhea (G3): ≥7 stools per day over 
baseline; incontinence; IV fluids ≥24 
hrs; interfering with ADL 
Colitis (G3): severe abdominal pain, 
medical intervention indicated, 
peritoneal signs 
G4: life-threatening, perforation 
 
• Discontinue I-O therapy per 
protocol 
• 1.0 to 2.0 mg/kg/day 
methylprednisolone  IV or IV 
equivalent 
• Add prophylactic antibiotics for 
opportunistic infections 
• Consider lower endoscopy 
 
If improves: 
• Continue steroids until grade 1, then taper over at 
least 1 month 
If persists > 3-5 days, or recurs after improvement: 
• Add infliximab 5 mg/kg (if no contraindication). 
Note: Infliximab should not be used in cases of 
perforation or sepsis 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, 
once sustained clinical improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids 


 
 


50 
 
• Continue I-O therapy per protocol 
• Monitor creatinine weekly 
• Delay I-O therapy per protocol 
• Monitor creatinine every 2-3 days 
• 0.5 to 1.0 mg/kg/day 
methylprednisolone  IV or oral 
equivalent 
• Consider renal biopsy with 
nephrology consult 
• Discontinue I-O therapy per 
protocol 
• Monitor creatinine daily 
• 1.0-2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• Consult nephrologist 
• Consider renal biopsy 
If returns to baseline: 
•Resume routine creatinine monitoring per protocol 
If worsens: 
•Treat as Grade 2 or 3/4 
If returns to Grade 1: 
•Taper steroids over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and resume I-O therapy 
and routine creatinine monitoring per protocol 
If elevations persist > 7 days or worsen: 
•Treat as Grade 4 
If returns to Grade 1 : Taper steroids over at least 1 month and 
add prophylactic antibiotics for opportunistic infections 
 
 
 
 
 
Renal Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy 
 
 
Grade of Creatinine 
Elevation 
(NCI CTCAE v4) 
 
Management 
 
Follow-up 
 
 
Grade 1 
Creatinine > ULN and  > 
than baseline but  ≤ 1.5x 
baseline 
Grade 2-3 
Creatinine > 1.5x baseline 
to ≤ 6x ULN 
Grade 4 
Creatinine > 6x ULN 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids 


51 
 
Grade 1 
Radiographic changes only 
Grade 2 
Mild to moderate  new 
symptoms 
• Re-image at least every 3 weeks 
If worsens: 
• Treat as Grade 2 or 3-4 
• Re-image every 1-3 days 
If improves: 
• When symptoms return to near baseline, taper steroids over 
at least 1 month and then resume I-O therapy per protocol 
and consider prophylactic antibiotics 
If not improving after 2 weeks  or worsening: 
• Treat as Grade 3-4 
 
 
 
 
 
Pulmonary Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Evaluate with imaging 
and pulmonary consultation. 
 
Grade of 
Pneumonitis 
(NCI CTCAE v4) 
 
 
Management 
 
Follow-up 
 
 
• Consider delay of I-O therapy 
• Monitor for symptoms every 2-3 
days 
• Consider Pulmonary and ID 
consults 
 
• Delay I-O therapy per protocol 
• Pulmonary and ID consults 
• Monitor symptoms daily, consider 
hospitalization 
• 1.0 mg/kg/day methyl- 
prednisolone IV or oral equivalent 
• Consider bronchoscopy , lung 
biopsy 
 
 
 
 
 
Grade 3-4 
Severe new symptoms; 
New/worsening hypoxia; 
Life-threatening 
• Discontinue  I-O therapy per 
protocol 
• Hospitalize 
• Pulmonary and ID consults 
• 2-4 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• Add prophylactic antibiotics for 
opportunistic infections 
• Consider bronchoscopy, lung 
biopsy 
 
 
 
If improves to baseline: 
• Taper steroids over at least 6 weeks 
If not improving after 48 hours or worsening: 
• Add additional immunosuppression 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 


52 
 
• Continue I-O therapy per protocol 
• Delay I-O therapy per protocol 
• Increase frequency of monitoring 
to every 3 days 
• Continue LFT monitoring per protocol 
If worsens: 
• Treat as Grade 2 or 3-4 
If returns to baseline: 
•Resume routine monitoring, resume I-O therapy per protocol 
If elevations persist > 5-7 days or worsen : 
• 0.5-1 mg/kg/day methylprednisolone or oral equivalent and 
when LFT returns to grade 1 or baseline, taper steroids over at 
least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per protocol 
 
 
 
 
 
Hepatic Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider imaging for 
obstruction. 
 
Grade of Liver 
Test Elevation 
(NCI CTCAE v4) 
 
Management 
 
Follow-up 
 
Grade 1 
AST or ALT > ULN to 3.0 x 
ULN and/or T. bili > ULN 
- 1.5 x ULN 
Grade 2 
AST or ALT > 3.0 to ≤ 5 x 
ULN and/or T. bili > 1.5 
to ≤ 3 x ULN 
 
 
 
Grade 3-4 
AST or ALT > 5 x ULN 
or T.bili >3 x ULN 
 
• Discontinue  I-O therapy* 
• Increase frequency of monitoring 
to every 1-2 days 
•  1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent** 
• Add prophylactic antibiotics for 
opportunistic infections 
• Consult gastroenterologist 
 
If returns to grade 2: 
• Taper steroids over at least 1 month 
 
 
If does not improve in >3-5 days, worsens or rebounds: 
• Add mycophenolate mofetil 1 g BID 
• If no response within an additional 3-5 days, consider other 
immunosuppressants per local guidelines 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 
*I-O therapy may be delayed rather than discontinued if AST/ALT ≤ 8 x ULN or T.bili ≤ 5 x ULN. 
**The recommended starting dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV. 


53 
 
• Continue I-O therapy per protocol 
• If TSH < 0.5 x LLN, or TSH > 2 x ULN, or consistently out of range in 2 subsequent measurements: include fT4 at 
subsequent cycles as clinically indicated; consider endocrinology consult 
• Evaluate endocrine function 
• Consider pituitary scan 
Symptomatic with abnormal lab/pituitary scan: 
• Delay I-O therapy per protocol 
• 1-2 mg/kg/day methylprednisolone IV or PO equivalent 
• Initiate appropriate hormone therapy 
No abnormal lab/pituitary MRI scan but symptoms persist: 
• Repeat labs in 1-3 weeks / MRI in 1 month 
If improves  (with or without 
hormone replacement): 
• Taper steroids over at least 1 
month and consider prophylactic 
antibiotics for opportunistic 
infections 
• Resume I-O therapy per protocol 
• Patients with adrenal 
insufficiency may need to 
continue steroids with 
mineralocorticoid component 
 
 
 
 
 
Endocrinopathy Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider visual field testing, 
endocrinology consultation, and imaging. 
 
Asymptomatic 
TSH elevation 
 
 
 
 
 
Symptomatic 
endocrinopathy 
 
 
 
 
 
 
 
 
Suspicion of adrenal 
crisis (e.g. severe 
dehydration, 
hypotension, shock 
out of proportion to 
current illness 
 
• Delay or discontinue I-O therapy per protocol 
• Rule out sepsis 
• Stress dose of IV steroids with mineralocorticoid activity 
• IV fluids 
• Consult endocrinologist 
• If adrenal crisis ruled out, then treat as above for symptomatic 
endocrinopathy 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, 
once sustained clinical improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids. 


54 
 
Grade of 
Rash 
(NCI CTCAE v4) 
Grade 1-2 
Covering  ≤ 30% 
BSA* 
Grade 3-4 
Covering >30% BSA; 
Life threatening 
consequences*^ 
Management 
• Symptomatic therapy (e.g. antihistamines, 
topical steroids) 
• Continue I-O therapy per protocol 
• Delay or discontinue I-O therapy per 
protocol 
• Consider skin biopsy 
• Dermatology consult 
• 1.0-2.0 mg/kg/day IV methylprednisolone 
IV or IV equivalent 
 
 
 
 
 
Skin Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. 
 
 
 
Follow-up 
 
 
If persists > 1-2 weeks or recurs: 
• Consider skin biopsy 
• Delay I-O therapy per protocol 
• Consider 0.5-1.0 mg/kg/day methylprednisolone IV or 
oral equivalent. Once improving , taper steroids over 
at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per 
protocol 
If worsens: 
• Treat as Grade 3-4 
 
 
 
If improves to Grade 1: 
• Taper steroids over at least 1 month and add 
prophylactic antibiotics for opportunistic infections 
• Resume I-O therapy per protocol 
 
 
 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 
*Refer to NCI CTCAE v4 for term-specific  grading criteria. ^If SJS/TEN is suspected, withhold I-O therapy and refer patient for specialized care for assessment and treatment. If SJS or TEN is diagnosed, 
permanently discontinue I-O therapy. 


55 
 
Grade of 
Neurological 
Toxicity 
(NCI CTCAE v4) 
Grade 1 
Asymptomatic or 
mild symptoms; 
Intervention not 
indicated 
Grade 2 
Moderate symptoms; 
Limiting instrumental 
ADL 
• Consider IVIG or other immunosuppressive therapies per 
local guideline 
ids (e.g. prednisone) at start of 
ailability of oral corticosteroids 
osteroids. 
Neurological Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. 
 
 
 
Management 
 
 
 
 
• Continue I-O therapy per protocol 
 
 
 
• Delay I-O therapy per protocol 
• Treat symptoms per local guidelines 
• Consider 0.5 to 1.0 mg/kg/day 
methylprednisolone  IV or PO 
equivalent 
Follow-up 
 
 
 
Continue to monitor the patient. 
If worsens: 
• Treat as Grade 2 or 3-4 
 
 
 
If improves to baseline: 
•Resume I-O therapy per protocol when improved to baseline 
If worsens: 
• Treat as Grade 3-4 
 
 
Grade 3-4 
Severe symptoms; 
 
ADL; 
Life-threatening 
 
• Discontinue I-O therapy per protocol 
• Obtain neurology consult 
 
• 1.0-2.0 mg/kg/day IV 
methylprednisolone  IV or IV equivalent 
• Add prophylactic antibiotics for 
opportunistic infections 
If improves to Grade 2: 
• Taper steroids over at least 1 month 
 
If worsens or atypical presentation: 
Patients on IV steroids may be switched to an equivalent dose of oral corticostero 
tapering or earlier, once sustained clinical improvement is observed.  Lower bioav 
should be taken into account when switching to the equivalent dose of oral cortic 


56 
 
 
Appendix 2: Nivolumab Drug Ordering and Pharmacy Reference Material 
 
Initial Orders 
 
• 
Following submission and approval of the required regulatory documents, a supply of 
nivolumab may be ordered from by completing a Drug Request Form provided by BMS for 
this specific trial. 
 
• 
The initial order should be limited to the amount needed for two doses. Allow 5 business 
days for shipment of drug from BMS receipt of the Drug Request Form. Drug is protocol 
specific, but not patient specific. All drug products will be shipped by courier in a 
temperature-controlled container. It is possible that sites may have more than one 
nivolumab clinical study ongoing at the same time. It is imperative that only drug  
product designated for this protocol number be used for this study. 
 
• 
Pharmacy supplies not provided by BMS:  Empty IV bags/containers, approved diluents, In- 
line filters and infusion tubing 
 
Re-Supply 
 
• 
Drug re-supply request form should be submitted electronically at least 7 business days 
before the expected delivery date. Deliveries will be made Tuesday through Friday. 
 
• 
When assessing need for resupply, institutions should keep in mind the number of vials  
used per treatment dose, and that shipments may take 14 business days from receipt of 
request. Drug is not patient-specific. Be sure to check with your pharmacy regarding existing 
investigational stock to assure optimal use of drug on hand. 
 
Drug Excursions 
 
• 
Drug excursions should be reported immediately to BMS on the form provided with the 
study-specific drug order form 
 
Please refer to the most recent version of the nivolumab Investigator Brochure for 
additional information to be included as per institutional or regulatory standards. 


57 
 
 
 
TABLE 3: Product Information 
 
 
Product Description:(Other names = MDX-1106, ONO-4538, anti-PD-1  
 
Product 
Descriptio 
n and 
Dosage 
Form 
Potency Primary 
Packagi 
ng 
(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 
mg/Vial 
(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