A Phase 2 Study of Nivolumab and Ipilimumab in Advanced Leiomyosarcoma of the Uterus
Phase: PHASE2
Conditions: Metastatic Leiomyosarcoma, Unresectable Leiomyosarcoma, Uterine Corpus Leiomyosarcoma
Sponsor: National Cancer Institute (NCI)

i 
 
SUMMARY OF CHANGES – Protocol 
 
For Protocol Amendment #3 to: A Phase 2 Study of Nivolumab in Advanced Leiomyosarcoma 
of the Uterus 
 
NCI Protocol #: 9672 
Local Protocol #: DFCI- 15-707 
 
NCI Version Date:  
Protocol Date:   27 April 2018 
 
Please provide a list of changes from the previous CTEP approved version of the protocol.  The 
list shall identify by page and section each change made to a protocol document with hyperlinks 
to the section in the protocol document.  All changes shall be described in a point-by-point 
format (i.e., Page 3, section 1.2, replace ‘xyz’ and insert ‘abc’).  When appropriate, a brief 
justification for the change should be included. 
 
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The protocol version number and date have been updated to Version 3/  
2.  
 
5.8 
 
7.2 
 
 
31 
 
51 
 
Beginning April 1, 2018, the study has converted from the use of 
CTCAE v4.0 to CTCAE v5.0 for adverse event reporting. The protocol 
has been updated to reflect this change. 
 
(Please retain the section break below, so that the Title Page is page “1” of the document.) 
 

1 
NCI Protocol #: 
9672 
 
Local Protocol #: 
DFCI- 15-707 
 
ClinicalTrials.gov Identifier:  NCT02428192 
 
 
TITLE:  A Phase 2 Study of Nivolumab and Ipilimumab in Advanced Leiomyosarcoma of the 
Uterus 
 
 
Corresponding Organization: Dana-Farber Harvard Cancer Center 
 
Principal Investigator: 
Suzanne George 
Dana-Farber Cancer Institute 
450 Brookline Ave 
Boston, MA 02115 
617-632-5204 
617-632-3408 
suzanne_george@dfci.harvard.edu 
 
Participating Organizations  
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
 
Statistician: 
 
Study Coordinator: 
 
 
 
Constance Barysauskas 
Sarah Solomon 
 
Dana-Farber Cancer Institute 
Dana-Farber Cancer Institute 
 
450 Brookline Ave 
450 Brookline Ave 
 
Boston, MA 
Boston, MA 
 
617-582-9055  
617-582-7503
 
constance_barysauskas@dfci.harvard.edu 
sarah_solomon@dfci.harvard.edu 
 
Responsible Research Nurses: 
 
 
Melissa Hohos, RN 
Dana-Farber Cancer Institute 
450 Brookline Ave 
P:  617-582-7162 
F:  617-632-3408 
E:  mhohos@partners.org 
 
NCI-Supplied Agents:  Nivolumab (BMS-936558, MDX-1106, and ONO-4538) NSC 
#748726; Ipilimumab (BMS-743016; MDX-010 Transfectoma-derived) NSC #732442 

2 
 
 
 
IND #:  125336 
IND Sponsor:  DCTD, NCI 
 
 
 
Protocol Type / Version # / Version Date: Original / Version#3 / 27 April 2018 
 
 
 

3 
 
 
 
SCHEMA COHORT A 
 
 

4 
 
 
SCHEMA COHORT B 
 
Week 12 
Tumor assessment per 
RECIST 
CR, PR, SD per RECIST 1.1 
Continue on study,  
Nivolumab 3mg/kg every 2 wks 
PD per RECIST 1.1 
 
Off study* 
 
*some pts may remain on 
study post RECIST PD as 
noted in protocol 
RECIST per CT/MRI 
every 12 weeks 
Baseline Assessments 
 
Baseline Tumor  
RECIST per CT/MRI 
 
 Tumor biopsy (min. 10 
pts) 
 
Immune Correlatives 
 
Nivolumab 3mg/kg administered every 2 weeks 
Immune correlates drawn per study calendar 
Screen 
Enroll if eligible 
Week 4-6 
Tumor biopsy (min of 
10 pts) 

5 
 
 
 
 
 
 
Week 8 
Tumor assessment per 
RECIST 
CR, PR, SD per RECIST 1.1 
Nivolumab 3mg/kg plus ipilimumab 
1mg/kg every 3 weeks to complete 12 
weeks, then nivolumab 3mg/kg every 2 
weeks  
PD per RECIST 1.1 
 
Off study* 
 
*some pts may remain on 
study post RECIST PD as 
noted in protocol 
RECIST per CT/MRI 
every 8 weeks 
Baseline Assessments 
 
Baseline Tumor  
RECIST per CT/MRI 
 
 Tumor biopsy  
Immune Correlatives 
 
Nivolumab 3mg/kg plus ipilimumab 1mg/kg administered every 3 weeks for four 
cycles, then nivolumab 3mg/kg every 2 weeks 
Immune correlates drawn per study calendar 
Screen 
Enroll if eligible 
Week 4-6 
Tumor biopsy  

6 
TABLE OF CONTENTS 
1. OBJECTIVES ..............................................................................................................................8 
1.1 Primary Objectives .........................................................................................................8 
1.2 Secondary Objectives.....................................................................................................8 
2. BACKGROUND .........................................................................................................................8 
2.1      Study Disease – Leiomyosarcoma of the uterus .......................................................8 
2.2 
CTEP IND Agent .....................................................................................................9 
2.3 
Other Agent(s) .......................................................................................................13 
2.4 
Summary of Nivolumab and ipilimumab combination data ..................................14 
2.5 
Rationale ................................................................................................................15 
2.6 
Correlative Studies Background ............................................................................16 
3. PATIENT SELECTION ............................................................................................................17 
3.1 
Eligibility Criteria ..................................................................................................17 
3.1.1 Patients must have histologically or cytologically confirmed advanced 
leiomyosarcoma of the uterus (ULMS). Advanced ULMS is defined as 
metastatic ULMS or unresectable primary ULMS. ...............................................17 
3.2 
Exclusion Criteria ..................................................................................................19 
3.3 
Inclusion of Women and Minorities ......................................................................21 
4 
REGISTRATION PROCEDURES (Rostered Protocol Model) ........................................21 
4.1 
Investigator and Research Associate Registration with CTEP ..............................21 
4.2 
Site Registration .....................................................................................................22 
4.3 
Patient Registration ................................................................................................24 
4.4 
General Guidelines .................................................................................................25 
5 
TREATMENT PLAN ........................................................................................................25 
5.1 
Agent Administration .............................................................................................25 
5.2 
Definition of Dose-Limiting Toxicity ....................................................................27 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................27 
5.4 
Duration of Therapy ...............................................................................................27 
5.5 
Duration of Follow Up ...........................................................................................29 
5.6 
Criteria for Removal from Study ...........................................................................29 
5.7 
Criteria to Resume Treatment ................................................................................29 
5.8 
Treatment of Nivolumab or Ipilimumab Related Infusion Reactions ...................31 
5.9 
Treatment Beyond Progression ..............................................................................32 
6 
DOSING DELAYS/DOSE MODIFICATIONS................................................................33 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................39 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) .................40 
7.2 
Adverse Event Characteristics ...............................................................................51 
7.3 
Expedited Adverse Event Reporting ......................................................................52 
7.4 
Routine Adverse Event Reporting .........................................................................54 
7.5 
Secondary Malignancy ...........................................................................................54 

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7 
7.6 
Second Malignancy ................................................................................................54 
8 
PHARMACEUTICAL INFORMATION ..........................................................................54 
8.1 
CTEP IND Agent(s) ...............................................................................................55 
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................59 
9.1 
Integrated Laboratory or Imaging Studies .............................................................59 
9.2 
Exploratory/Ancillary Correlative Studies ............................................................62 
9.3 
Integral Correlative Studies ...................................................................................64 
10 
STUDY CALENDAR .......................................................................................................65 
11 
MEASUREMENT OF EFFECT........................................................................................69 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................69 
11.2 
Antitumor Effect – Hematologic Tumors ..............................................................75 
11.3 
Other Response Parameters ...................................................................................75 
12 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................76 
12.1 
Data Reporting .......................................................................................................76 
12.2 
CTEP Multicenter Guidelines ................................................................................78 
12.3 
Collaborative Agreements Language .....................................................................78 
13 
STATISTICAL CONSIDERATIONS...............................................................................80 
13.1 
Study Design/Endpoints.........................................................................................80 
13.2 
Sample Size/Accrual Rate ......................................................................................81 
13.3 
Stratification Factors ..............................................................................................83 
13.4 
Analysis of Secondary Endpoints ..........................................................................83 
13.5 
Analysis of Exploratory Objectives .......................................................................84 
13.6 
Reporting and Exclusions ......................................................................................85 
14 
Study Status Updates and Study Closure ...........................................................................86 
14.1 
Definitions of Study Status Changes .....................................................................86 
14.2 
Responsibility for Filing Protocol Status Update Forms .......................................87 
REFERENCES ..............................................................................................................................88 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................92 
APPENDIX B 
MANAGEMENT ALGORITHMS FOR ENDOCRINOPATHY, 
GASTROINTESTINAL, HEPATIC, NEUROLOGICAL, PULMONARY, RENAL, 
AND SKIN ADVERSE EVENTS .....................................................................................93 
 
 

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1. OBJECTIVES 
 
1.1 Primary Objectives 
 
• To evaluate the objective response rate per RECIST 1.1 of patients with advanced 
leiomyosarcoma of the uterus (ULMS) treated with nivolumab.  
• To evaluate the objective response rate per RECIST 1.1 of patients with advanced 
(ULMS) treated with nivolumab in combination with ipilimumab.  
 
 
1.2 Secondary Objectives 
 
Secondary Objectives:  
• To evaluate the toxicity of nivolumab in patients with advanced ULMS. 
• To evaluate the toxicity of nivolumab in combination with ipilimumab in patients with 
advanced ULMS. 
• To evaluate the progression-free survival of ULMS treated with nivolumab.  
• To evaluate the progression-free survival of ULMS treated with nivolumab in 
combination with ipilimumab. 
• To explore the relationship between PDL1, PD1 in infiltrating lymphocytes and PD2 
status in archival tumor, and pre/post treatment biopsies in a minimum of 10 patients. 
 
 
Exploratory Objectives:  
 
 
  
• To explore the relationship between general immune response and specific markers of 
immunomodulation and response to nivolumab.  
• To explore the relationship between tumor inflammatory gene signature and response to 
nivolumab in archival material. 
 
2. BACKGROUND 
 
2.1      Study Disease – Leiomyosarcoma of the uterus 
 
Sarcomas vary widely in anatomic location as well as histologic subtype, with the current 
WHO classification listing over 50 distinct histologic subtypes. Prognosis and outcomes 
can vary widely based on histologic subtype and location of origin; because of this, 
histology-specific clinical trials in soft tissue sarcomas are necessary to evaluate novel 
therapies in order to optimize the likelihood of identifying both active and inactive agents 
within specific sarcoma subtypes. 
 
Uterine sarcomas constitute approximately 3% of all uterine malignancies (Harlow et al, 
1986). With an estimated incidence of 0.64 cases per 100,000 women, leiomyosarcoma is 
the most common uterine sarcoma and likely accounts for the single largest site-specific 
group of leiomyosarcomas (Amant et al, 2009).  Localized disease is treated with 
hysterectomy, however rates of local and distant failure are high (45 to 80%), with an 

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9 
estimated median overall survival of two years once disease is disseminated (Raut et al, 
2009). Management of metastatic disease focuses on disease control and palliation, often 
with a combination of systemic therapies and local treatments, surgery and radiation, as 
indicated. Doxorubicin and gemcitabine based therapies are the most active regimens in 
this disease with estimated response rates of 20% to 40% with median PFS of 
approximately 5 -8 months (Omura et al, 1993, Look et al 2004, Hensley et al, 2008)). 
The most recently FDA approved agent for soft tissue sarcomas, including ULMS, is 
pazopanib a multi-targeted tyrosine kinase inhibitor. In a phase III placebo controlled 
trial, pazopanib demonstrated an ORR of 6% and a median PFS of 4.6 months in patients 
with advanced soft tissue sarcomas who had failed standard prior therapies (van der 
Graaf et al, 2012). Therefore, ULMS remains a disease with a dire need for additional 
effective systemic therapies. 
 
The primary biologic underpinnings of ULMS continue to be elucidated. The exact 
mechanisms of action of pazopanib leading to benefit in soft tissue sarcomas remain 
unclear. There are no other successfully “targeted” approaches to the disease. ULMS is 
cytogenetically complex. Several pathways and signal intermediates have been 
investigated in leiomyosarcoma, and relevance of PI3K/AKT pathway activation has 
been consistently demonstrated throughout several studies. Indeed, genomic deletion of 
chromosome 10q targets PTEN tumor suppressor gene and leads to hyperactivation of 
PI3K/AKT, which is a common finding in leiomyosarcoma. Somatic TP53 mutations are 
estimated to be present in 50 -60% of cases, however the primary drivers of the malignant 
phenotype of the disease remain poorly understood.  
 
Interestingly, a relationship between tumor immune infiltration, specifically 
macrophages, and outcomes in LMS has been reported (Espinosa et al, 2009, Ganjoo et 
al 2011)).  To date, this data has been limited to prognostication, such that patients with 
more extensive tumor macrophage infiltration, and gene signature consistent with CSF1 
and related proteins have inferior outcomes (Espinosa et al, 2009). The relationship of 
these findings to underlying tumor biology and response to specific therapies continues to 
be explored, however, this finding which has been uniquely reported in LMS subtype of 
soft tissue sarcomas, suggests that immune infiltration and disease control may be 
relevant in this specific subtype of soft tissue sarcoma. In addition, there has been least 
one objective PR (duration unknown at this time ) observed with an antiPD1 monoclonal 
antibody in one patient with metastatic ULMS demonstrating that this class of drugs has 
activity in at least a subset set of patients with advanced ULMS (S. George, personal 
communication, 27aug2014). 
 
 
 
2.2 CTEP IND Agent 
 
2.2.1 Nivolumab 
 
Nivolumab (BMS-936558, MDX-1106, and ONO-4538) is a fully human monoclonal 
immunoglobulin G4 (IgG4) antibody (HuMAb) that is specific for human programmed 

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death-1 (PD-1, cluster of differentiation 279 [CD279]) cell surface membrane receptor 
(Investigator Brochure, 2013).  PD-1 is a negative regulatory molecule that is expressed 
transiently following T-cell activation and on chronically stimulated T cells characterized 
by an “exhausted” phenotype.  Nivolumab binds to cynomolgus monkey PD-1 but not 
mouse, rat, or rabbit molecules.  Clinical activity of nivolumab has been observed in 
patients with melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma 
(RCC).   The combination of nivolumab and ipilimumab (anti-cytotoxic T lymphocyte 
associated antigen-4 [anti-CTLA-4]) in a phase 1/2 trial showed markedly enhanced 
clinical activity with an acceptable safety profile in melanoma patients (Wolchok et al., 
2013).   
 
The clinical use of monoclonal antibodies to T-cell inhibitory receptors has provided 
transformative information on the nature of the immune system and cancer.  An emerging 
picture suggests that endogenous immune responses can mediate effective tumor 
regression and/or improved survival even in patients with large volume tumors resistant 
to other forms of therapy.  Some of the unique features of this type of therapy, based 
largely on experience in advanced melanoma, include:  improved overall survival (OS) 
with or without radiographic responses or improved progression-free survival (PFS); 
responses that may be delayed or occur after radiographic disease progression; 
combinations of immune modulators with enhanced or novel activities (in the example of 
ipilimumab and nivolumab); and toxicity that is almost exclusively immune or 
inflammatory in nature.  It is not yet clear what factors determine responses and which 
components of the immune system are needed for this to occur.  It seems likely that both 
memory helper and effector cells would be needed to sustain long-term responses. 
Increasing  emphasis has been placed on understanding the relationships of the tumor,  
celluar  infiltrate,  and immunologic milieu surrounding each tumor.   
 
PD-1, a 55-kDa type 1 transmembrane protein, is a member of the CD28 family of T-cell 
co-stimulatory receptors that include Ig super family member CD28, CTLA-4, inducible 
co-stimulator (ICOS), and B and T lymphocyte attenuator (BTLA) (Investigator 
Brochure, 2013).  PD-1 is transiently but highly expressed on activated T cells 
functioning to limit immune effectors at the site of activation.  Chronic stimulation may 
prevent the re-methylation of the PD-1 gene leading to continuous  expression and 
characterizes a state of “exhausted” T cells that lose function and proliferative capacity 
while enhancing a suppressive tumor microenvironment.  PD-1 may act together with 
other T-cell modulating molecules, including CTLA-4, TIM-3, lymphocyte-activation 
gene 3 (LAG-3) as well as indoleamine-pyrrole 2,3-dioxygenase 1 (IDO-1), cytokines, 
and transforming growth factor beta (TGF-beta).   
 
Two ligands specific for PD-1 have been identified:  PD-ligand 1 (PD-L1, also known as 
B7-H1 or CD274, expressed on tumor, antigen-presenting cells [APCs], and dendritic 
cells [DCs]) and PD-L2 (also known as B7-DC or CD273, expressed on endothelial 
cells).  The interaction of PD-1 with PD-L1 and PD-L2 results in negative regulatory 
stimuli that down-modulate the activated T-cell immune response through SHP-1 
phosphastase.   
 

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PD-1 knockout mice develop strain-specific lupus-like glomerulonephritis (C57BL/6) 
and cardiomyopathy (BALB/c).  In transplantable tumor models that expressed PD-1 and 
LAG-3 on tumor-infiltrating CD4+ and CD8+ T cells dual anti-LAG-3/anti-PD-1 antibody 
treatment cured most mice of established tumors that were largely resistant to single 
antibody treatment (Woo et al., 2012).  Despite minimal immunopathologic sequelae in 
PD-1 and LAG-3 single knockout mice, dual knockout mice abrogated self-tolerance 
with resultant autoimmune infiltrates in multiple organs, leading to eventual lethality. 
 
PD-L1 expression is found on a number of tumors, and is associated with poor prognoses 
based on OS in many tumors, including melanoma (Taube et al., 2012), renal (Thompson 
et al., 2004; Thompson et al., 2005; Thompson et al., 2006), esophageal (Ohigashi, et al. 
2005), gastric (Wu et al., 2006), ovarian (Dong et al., 2003), pancreatic (Nomi, et al., 
2007), lung (Zitvogel, et al., 2006), and other cancers (Investigator Brochure, 2013). 
 
The PD-1/PD-L1 axis plays a role in human infections, particularly in hepatitis C virus 
(HCV) and human immunodeficiency virus (HIV).  In these cases, high expression levels 
of PD-1 were found in viral-specific CD8+ T cells that also display a non-responsive or 
exhausted phenotype.  Non-responsive PD-1-high T cells were observed in simian 
immunodeficiency virus (SIV) infection in rhesus macaques.  Treatment of SIV-infected 
macaques with an anti-PD-1 mAb (3 mg/kg x4) resulted in decreased viral loads and 
increased survival along with expanded T cells with increased T-cell functionality.   
 
 
2.2.1.1 Nonclinical Development of Nivolumab 
 
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, nivolumab 
alone was well tolerated (Investigator Brochure, 2013).  Combination studies have 
highlighted the potential for toxicity when combined with ipilimumab, MDX-1408, and 
BMS-986016.  Nivolumab bound specifically to PD-1 (and not to related members of the 
CD28 family such as CD28, ICOS, CTLA-4, and BTLA) with a Kd = 3.06 nM.  A 
surrogate rat anti-mouse PD-1 antibody (4H2) was derived and expressed as chimeric 
IgG1 murine antibody.  Antitumor activity was seen for several tumor models, including 
colon carcinoma and fibrosarcoma. 
 
 
2.2.1.2 Clinical Development of Nivolumab 
 
Nivolumab is being evaluated as monotherapy and in combination with cytotoxic 
chemotherapy, other immunotherapy (such as ipilimumab), anti-angiogenesis therapy, 
and targeted therapies in completed and ongoing BMS-sponsored clinical trials in 
NSCLC, melanoma, RCC, hepatocellular carcinoma (HCC), gastrointestinal (GI) 
malignancies including microsatellite instability (MSI) in colorectal cancer, and triple-
negative breast cancer (TNBC) with an expanding group of indications (Investigator 
Brochure, 2013).  In addition, two investigator-sponsored trials (ISTs) of nivolumab in 
combination with a peptide vaccine in melanoma are being conducted in the adjuvant 
setting and advanced disease.  

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Seven nivolumab studies were conducted in Japan, including six studies in advanced 
solid tumors and recurrent or unresectable stage III/IV melanoma sponsored by Ono 
Pharmaceuticals Co. Ltd., and one IST in recurrent or advanced platinum-refractory 
ovarian cancer.   
 
 
2.2.1.2.1 Pharmacokinetics 
 
Pharmacokinetics (PK) of nivolumab was linear in the range of 0.3 to 10 mg/kg, with 
dose-proportional increases in maximum serum concentration (Cmax) and area under the 
concentration-time curve from time zero to infinity (AUC0-∞), with low to moderate inter-
subject variability observed at each dose level (Investigator Brochure, 2013).  Clearance 
of nivolumab is independent of dose in the dose range (0.1 to 10 mg/kg) and tumor types 
studied.  Body weight normalized dosing showed approximately constant trough 
concentrations over a wide range of body weights.  The mean terminal elimination half-
life of BMS-936558 is 17 to 25 days consistent with the half-life of endogenous IgG4.   
 
 
2.2.1.2.2 Efficacy 
 
In a phase 1 (1, 3, and 10 mg/kg nivolumab doses) dose-escalation study the 3 mg/kg 
dose was chosen for expanded cohorts. Among 236 patients, objective responses (ORs) 
(complete or partial responses [CR or PR]) were seen in NSCLC, melanoma, and RCC.  
ORs were observed at all doses (Sznol et al., 2013).  Median OS was 16.8 months across 
doses and 20.3 months at the 3 mg/kg dose.  Median OS across all dose cohorts was 9.2 
months and 9.6 months for squamous and non-squamous NSCLC, respectively (Brahmer 
et al., 2013).  In the RCC cohort, median duration of response was 12.9 months for both 
doses with 5 of the 10 responses lasting ≥1 year (Drake et al., 2013).   
 
In an advanced melanoma phase 1 study, nivolumab and ipilimumab were administered 
IV every 3 weeks for 4 doses followed by nivolumab alone every 3 weeks for 4 doses 
(concurrent regimen) (Wolchok et al., 2013).  The combined treatment was subsequently 
administered every 12 weeks for up to 8 doses.  In a sequenced regimen, patients 
previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses.  
In the concurrent regimen (53 patients), 53% of patients had an OR at doses 1 mg/kg 
nivolumab and 3 mg/kg ipilimumab, with tumor reduction of 80% or more (modified 
World Health Organization [mWHO] criteria).  In the sequenced-regimen (33 patients), 
the objective response rate (ORR) was 20%. 
 
In a phase 1 study of nivolumab plus platinum-based doublet chemotherapy (PT-doublet) 
in chemotherapy-naïve NSCLC patients, 43 patients were treated with nivolumab + PT-
doublet (Rizvi et al., 2013).  No dose-limiting toxicities (DLTs) were reported and 
total/confirmed ORRs were 43/33%, 40/33%, and 31/31% in 
nivolumab/gemcitabine/cisplatin, nivolumab/pemetrexed/cisplatin, and 
nivolumab/carboplatin/paclitaxel arms, respectively. 

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13 
 
 
2.2.1.2.3 Toxicology 
 
A maximum tolerated dose (MTD) of nivolumab was not defined (Topalian et al., 2012).  
Serious adverse events (SAEs) occurred in 32 of 296 patients (11%) similar to the 
immune-related inflammatory events seen with ipilimumab:  pneumonitis, vitiligo, 
colitis, hepatitis, hypophysitis, and thyroiditis (with noted pulmonary toxicity resulting in 
3 deaths. Renal failure, symptomatic pancreatic and DM, neurologic events, and 
vasculitis have also been reported.).   In combination with ipilimumab in the concurrent-
regimen group (Wolchok et al., 2013), grade 3 or 4 treatment-related events were noted 
in 53% of patients.  Skin rash represents the majority of these event.  
 
 
2.2.1.2.4 Pharmacodynamics/Biomarkers 
 
Tumor-cell expression (melanoma) of PD-L1 was characterized in combination with 
ipilimumab with the use of IHC staining and pharmacodynamics changes in the 
peripheral-blood absolute lymphocyte count (Wolchok et al., 2013).  With PD-L1 
positivity defined as expression in at least 5% of tumor cells, biopsy specimens from 21 
of 56 patients (38%) were PD-L1–positive.  Among patients treated with the concurrent 
regimen of nivolumab and ipilimumab, ORs were observed in patients with either PD-
L1–positive tumor samples (6 of 13 patients) or PD-L1–negative tumor samples (9 of 
22).  In the sequenced regimen cohorts, a higher number of overall responses was seen 
among patients with PD-L1–positive tumor samples (4 of 8 patients) than among patients 
with PD-L1–negative tumor samples (1 of 13) suggesting the possibility that these tumors 
have higher response rates to the combination. The relationship between PDL-1 
expression and responses may not be present in patients treated with the combination.  
Tissue expression of PDL-2, interferon-γ (IFN- γ), IDO, and T cell CD8+ are of current 
interest.  Until more reliable data based on standardized procedures for tissue collection 
and assays are available, PD-L1 status cannot be used to select patients for treatment at 
this time.   
 
 
2.3 Other Agent(s) 
 
 
2.3.1 Ipilimumab 
 
Ipilimumab is a fully human anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) IgG1 
monoclonal antibody. Following antigen presentation by peptide/major 
histocompatability complex, full activation of T cell requires co-stimulatory signals 
provided by binding of CD28 (expressed on T cells) and B7 molecules present on antigen 
presenting cells. This interaction is crucial for T cell activation and proliferation. CTLA4 
antigen is induced on the surgace of T cell upon activation and is a member of the 
CD28:B7 immunoglobulin superfamily that competes with greater avidity with CD28 for 

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14 
B7.1 and B7.2 (CD80 and CD86). CTLA4 ligation with B7 molecules down-regulates T-
cell response resulting in diminished cytokine production and T cell proliferation. 
Binding of ipilimumab to CTLA-4 with B7 thereby potentiates antitumor T-cell 
activation and proliferation (Krummel et al., 1995, Kearney et al. 1995). 
 
Ipilimumab efficacy as monotherapy was demonstrated in two phase III studies in 
advanced melanoma, where treatment with ipilimumab resulted in clinically meaningful 
and statistically significant survival benefit. The MDX10-20 evaluated ipilimumab (3 
mg/kg) with or without a melanoma specific vaccine (gp100) compared with gp100 alone 
in pre-treated advanced melanoma patients. The median overall survival was 10 months 
with ipilimumab treatment (with or without gp100) versus 6.4 months for gp100 therapy 
alone (Hodi et al., 2010). 
 
The CA184024 trial compared ipilimumab at a higher dose (10 mg/kg) plus dacarbazine 
versus dacarbazine alone in treatment naive advanced melanoma patients. Overall 
survival was improved in the ipilimumab plus dacarbazine group compared to the 
dacarbazine group (11.2 months vs 9.1 months, respectively) (Robert et al., 2011). Both 
trials demonstrated objective responses of 10-15% with ipilimumab treatment and grade 
3 or 4 immune-related toxicities or colitis (5.3%), diarrhea (4.6%), endocrinopathies 
(3.8%) and rash (0.8%).  
 
A pooled overall survival analysis based on studies with more than 1800 ipilimumab 
treated patients with advanced melanoma showed a plateau of overall survival at 3-years 
confirming durability of response and long term survival in ipilimumab treated patients 
(Schadendorf et al., 2015).  
 
 
2.4 Summary of Nivolumab and ipilimumab combination data 
 
 
 
The combination of nivolumab and ipilimumab in untreated advanced melanoma patients 
was evaluated in a phase III trial (CheckMate-067) and demonstrated significant 
improvement in objective response rate and progression free survival with the 
combination therapy compared with either nivolumab or ipilimumab as monotherapy. In 
this trial, ipilimumab was given at 3 mg/kg every 3-weeks for four cycles and nivolumab 
was given at 1 mg/kg every 3 weeks for four cycles, and then escalated to 3mg/kg every 
2-weeks until disease progression or unacceptable toxicity (Larkin et al., 2015).  
 
The median progression-free survival was 11.5 months with nivolumab plus ipilimumab, 
as compared with 2.9 months with ipilimumab and 6.9 months with nivolumab. The rates 
of investigator-assessed objective response were 43.7% in the nivolumab group, 57.6% in 
the nivolumab-plus-ipilimumab group, and 19.0% in the ipilimumab group. Grade 3 or 4 
treatment related adverse events were more common in the combination arm (55%) than 
with nivolumab (16.3%) or ipilimumab (27.3%) arms, with diarrhea (9.3%), colitis 
(7.7%) and rash (4.8%) the most clinically common, and elevation of ALT (8.3%) and 

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AST (6.1%) levels the most common laboratory abnormalities in the nivolumab plus 
ipilimumab arm. Treatment related adverse events leading to discontinuation were 
observed in 36.4% of patients in the combination arm. Ipilimumab and nivolumab 
combination therapy has also been tested in the CheckMate-012 trial which evaluated 
different doses and schedules for the combination in 148 previously untreated advanced 
non-small cell lung cancer patients (Rizvi et al., 2015). 
 
Four administration/dosing schedules for the combination of nivolumab and ipilimumab 
were evaluated. In arm A, both agents were administered at a dose of 1 mg/kg every 3 
weeks (Q3W, N = 31). In arm B nivolumab was administered at 1 mg/kg every 2 weeks 
(Q2W) plus ipilimumab 1 mg/kg every 6 weeks (Q6W; N = 40). Arm C and D dosed 
nivolumab at 3 mg/kg Q2W and ipilimumab 1 mg/kg every 12 weeks (Q12W; N = 38) or 
Q6W (N = 39). Activity was observed in all arms with arms containing nivolumab at 3 
mg/kg showing the best objective response rate (39% in arm C and 31% in arm D) and 
arms B and A demonstrating 25% and 13% response rates respectively, whereasPFS 
correlated less with nivolumab dose with median PFS of 10.6 months, 4.9 months, 8 and 
8.3 months for arms A, B, C, and D respectively).  
 
Treatment- emergent grade 3 or 4 adverse events occurred in 28% to 35% of patients in 
each group but led to discontinuation in just 3% to 10% of cases. All grade treatment-
related AEs occurred in 77%, &3%, 74%, and 69% of patients in groups A, B, C, and D, 
respectively. The safety profile was consistent with previous studies of the combination, 
and the discontinuation rate associated with AEs was similar to rates observed with 
nivolumab alone. The only grade 3/4 adverse events that occurred in as many as 10% of 
patients were hepatic in arm B (10%) and skin-related in arm C and D (13%). Grade 3/4 
pulmonary AEs occurred in no more than 3% of patients in any of the groups. There were 
no treatment-related deaths in the trial.  
 
2.5 Rationale 
 
ULMS is a complex karyotype malignancy without a clear oncogenic driver, and 
although cytotoxic chemotherapy may lead to disease control in a subset of patients for 
some number of months, it is a disease with a median overall survival of 2 years 
following the development of metastatic disease. Effective therapies are desperately 
needed.   
 
The rationale underlying synergistic immunotherapeutic effects is that each dysfunctional 
antitumor T cell could be kept unresponsive by more than one repressor and could only 
be fully capable to exert its functions when completly released from checkpoint 
inhibition. Combining immune checkpoint inhibitors to block more than one 
immunomodulatory pathway thereby may further enhance the antitumor efficacy of each 
individual treatment. Although PD-1 and CTLA-4 are both coinhibitory mechanisms to 
limit T cell activation, evidence suggests that they use distinct mechanisms to limit T cell 
activation, and preclinical and clinical evidence suggest that the combination of 
nivolumab and ipilimumab may be synergistic. 
 

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Preclinical data have shown that ipilimumab treatment may lead to broadening of specific 
killer T cell response in melanoma, pointing towards a role in the priming of cancer-
specific T cell immunity. In addition, evidence is emerging that CTLA4-specific 
antibodies can promote the depletion of regulatory T cells specifically in tumors, and 
increase PD-1+, PDL1+ and CTLA-4+ tumor infiltrating T cells. Conversely, nivolumab 
has been shown to increase peripheral CTLA-4+ and regulatory T cells in subjects 
without clinical response. There is growing evidence of benefit of nivolumab in solid 
tumors, even those without a clear immunologic driver, and the FDA approval for 
nivolumab in 2015 for non-small cell lung cancer is expected to be followed in other 
solid tumors as well, Furthermore, combination therapy with nivolumab and ipilimumab 
has shown superior efficacy over nivolumab monotherapy in melanoma and was granted 
FDA approval. Advanced clinical trials in other solid tumors (non-small cell lung cancer, 
renal cell carcinoma) are currently ongoing with encouraging preliminary results. Most 
interestingly, results of subgroup analyses in the Checkmate-067 suggest that the greatest 
benefit with the combination of nivolumab and ipilimumab versus nivolumab alone may 
occur in the context of negative PD-L1 tumor expression. In this trial, in the subgroup of 
patients with PD-L1 positive tumors, both nivolumab alone and nivolumab plus 
ipilimumab resulted in a similar prolongation of progression-free survival as compared 
with ipilimumab alone, although objective response rates were numerically higher in the 
combination group than in either monotherapy group. However, among patients with a 
negative PD-L1 tumor status, the median progression-free survival was 11.2 months for 
nivolumab plus ipilimumab compared with 5.3 months with nivolumab, and 2.8 months 
ipilimumab monotherapy. This observation of at least additive activity of the combination 
of nivolumab plus ipilimumab in the context of negative PD-L1 expression may be of 
particular interst in uterine leiomyosarcoma. A profound and durable response observed 
in one patient with metastatic ULMS (S. George, personal communication, 27Aug2014) 
should serve as a proof for anti PD-1 drug class activity in at least a subset of patients 
with advanced ULMS. Cohort A of the current protocol (nivolumab as a single agent in 
advanced ULMS) has been completed with no responses observed; therefore, the protocol 
has been amended to include Cohort B, defined as the combination of nivolumab plus 
ipilimumab, with the rationale that this combination may provide  enhanced immune 
response and increased tumor response rate.  
 
2.6 Correlative Studies Background 
 
Nivolumab was initially thought to be most effective in tumors which express PDL1, a 
marker that may vary in a variety of tumor samples over time, however, with increased 
experience with  this agent, it appears that both PDL1 and nonPDL1 expressing tumors 
may benefit from nivolumab, either as a single agent or in combination with ipilmumab. 
Development of biomarkers for response to nivolumab remain under active investigation 
and are a critical aspect to study design.  
 
We aim to explore the relationship between ORR and PFS to general immune response 
(CD3, CD4, CD8, FOX-P3, CD68, CD63) as well as more specific markers of 
immunomodulation including PD-1, PDL-1, PDL-2. We hypothesize that the expression 
of these markers, either alone or in combination, may lead to the identification of a subset 

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of patients with ULMS who are more likely to respond to nivolumab. This evaluation 
will be performed on archival tumor material for all participants when available, and in 
paired pre/post-treatment biopsies in up to10 participants. In addition, we have extensive 
experience using digital scanning of pathology slides and using image analysis to 
quantify immune infiltrates which will be applied to this cohort and related to response 
(14) . This work will be performed under the direction of Scott Rodig, MD, PhD  and at 
the Center for Immuno-oncology Pathology Core at Dana Farber–Harvard Cancer Center  
housed in the Specialized Histopathology Core at the Brigham and Women’s Hospital.  
The immuno-onology core at Dana-Farber Harvard Cancer Center (DFHCC) has 
optimized IHC for these markers (Chen et al, 2013) and is actively developing IHC for 
IDO.  
 
The immuno-oncology core lab at DFHCC evaluation of gene expression profiling with 
the aim of identification of an immune gene signature with the goal of identify patients 
more likely to respond to therapy with immune checkpoint inhibitors. Therefore, when 
material is available, we plan to evaluate targeted expression profiling for immune 
response signature on FFPE using nanostring platform at the immuno-onolocogy core at 
DFHCC (Scott et al, 2014). 
 
3. PATIENT SELECTION 
 
 
3.1 Eligibility Criteria 
3.1.1 Patients must have histologically or cytologically confirmed advanced leiomyosarcoma 
of the uterus (ULMS). Advanced ULMS is defined as metastatic ULMS or unresectable 
primary ULMS. 
 
 
3.1.2 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for non-
nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) with conventional 
techniques or as ≥10 mm (≥1 cm) with spiral CT scan, MRI, or calipers by clinical exam.  
See Section 11 for the evaluation of measurable disease 
 
3.1.3 Patients must have received at least one prior line of chemotherapy, for ULMS (either in 
the adjuvant or metastatic setting). 
 
3.1.4 Age > 18 years. Because no dosing or adverse event data are currently available on the 
use of nivolumab and ipilimumab in patients <18 years of age, children are excluded 
from this study, but will be eligible for future pediatric trials. 
 
3.1.5 ECOG performance status of 0 or 1 (see Appendix A). 
 
3.1.6 Life expectancy of greater than 9 months.  
 
3.1.7 Patients must have normal organ and marrow function as defined below: 

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- 
absolute neutrophil count 
≥1,500/mcL 
- 
platelets 
≥100,000/mcL 
- 
total bilirubin 
≤1.5× institutional upper limit of normal (ULN) 
(except patients with Gilbert Syndrome, who can have total bilirubin <3.0 mg/dL) 
 
- 
AST(SGOT)/ALT(SGPT) 
≤2.5× ULN/ ≤5xULN for subjects with liver 
metastases 
 
- 
Serum creatinine 
≤1.5× ULN  
OR 
- 
creatinine clearance (CrCl) 
≥50 mL/min (if using the Cockcroft-Gault formula 
below): 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
72 x serum creatinine in mg/dL 
 
3.1.8 Patients with a requirement for steroid treatment or other immunosuppressive treatment:  
Patients should be excluded if they have a condition requiring systemic treatment with 
either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive 
medications within 14 days of study drug administration. Inhaled or topical steroids and 
adrenal replacement doses >10 mg daily prednisone equivalents are permitted in the 
absence of active autoimmune disease. 
 
3.1.9 The effects of nivolumab on the developing human fetus are unknown. For this reason 
women of child-bearing potential (WOCBP) must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation.  WOCBP should use an adequate method to avoid 
pregnancy for 31weeks after the last dose of investigational drug.  Women of 
childbearing potential must have a negative serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of 
nivolumab.  Women must not be breastfeeding.    Women who are not of childbearing 
potential (i.e., who are postmenopausal or surgically sterile) do not require contraception.   

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Women of childbearing potential (WOCBP) is defined as any female who has 
experienced menarche and who has not undergone surgical sterilization (hysterectomy or 
bilateral oophorectomy) or who is not postmenopausal.  Menopause is defined clinically 
as 12 months of amenorrhea in a woman over 45 in the absence of other biological or 
physiological causes.  In addition, women under the age of 55 must have a documented 
serum follicle stimulating hormone (FSH) level less than 40 mIU/mL.   
 
WOCBP receiving nivolumab will be instructed to adhere to contraception for a period of 
31 weeks after the last dose of investigational product.  These durations have been 
calculated using the upper limit of the half-life for nivolumab (25 days) and are based on 
the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 days. 
 
Should a woman become pregnant or suspect she is pregnant while participating in this 
study, she should inform the treating physician immediately. 
 
The effects of nivolumab on the developing human fetus are unknown.   
 
3.1.10 Ability to understand and the willingness to sign a written informed consent document. 
  
3.1.11 For enrollment in the first stage of Cohort B, patients must have accessible pre-treatment 
and post-treatment (4-6 weeks) tumor for biopsy. 
 
 
 
3.2 Exclusion Criteria 
3.2.1 Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered 
from adverse events (AEs) due to agents administered more than 3 weeks earlier.  
Patients who have had prior pelvic radiation may be at increased risk for bowel 
perforation, and therefore may not have residual inflammatory disease of the bowel or 
residual bowel toxicity based on baseline imaging and clinical assessment. Palliative 
(limited-field) radiation therapy is permitted, if all of the following criteria are met: 
 
1) Repeat imaging demonstrates no new sites of bone metastases. 
2) The lesion being considered for palliative radiation is not a target lesion. 
3) Bowel toxicity is not expected from the target field due to increased risk of 
perforation 
 
3.2.2 Patients who are receiving any other investigational agents. 
 
3.2.3 Patients are excluded if they have had prior treatment with an anti-PD-1, anti-PD-L1, 
anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting 
T-cell co-stimulation or immune checkpoint pathways.   
 

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3.2.4 Active brain metastasis or leptomeningeal disease. Patients with known brain metastases 
are allowed if metastases have been treated and there is no magnetic resonance imaging 
(MRI) evidence of progression for at least 12 weeks after treatment is complete and 
within 28 days prior to the first dose of nivolumab administration.  There must also be no 
requirement for immunosuppressive doses of systemic corticosteroids (>10 mg/day 
prednisone equivalents) for at least 2 weeks prior to study drug administration. 
 
3.2.5 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to nivolumab. 
 
3.2.6 History of severe hypersensitivity reaction to any monoclonal antibody. 
 
3.2.7 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.2.8 Pregnant women are excluded from this study because the effects of nivolumab on the 
developing fetus are unknown. Because there is an unknown but potential risk for adverse 
events in nursing infants secondary to treatment of the mother with nivolumab, 
breastfeeding should be discontinued if the mother is treated with nivolumab. 
 
3.2.9 Because the effects of nivolumab on chronic viral infection are not well known, patients 
should be excluded if they have known history of testing positive for human 
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) 
or if they have a positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis 
C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. 
 
 
3.2.10 Patients with active autoimmune disease or history of autoimmune disease that might 
recur, which may affect vital organ function or require immune suppressive treatment 
including systemic corticosteroids, are excluded.  These include but are not limited to 
patients with a history of immune related neurologic disease,  multiple sclerosis, 
autoimmune (demyelinating)  neuropathy, Guillain-Barre syndrome, myasthenia gravis; 
systemic autoimmune disease such as SLE, connective tissue diseases, scleroderma, 
inflammatory bowel disease (IBD), Crohn’s, ulcerative colitis, hepatitis; and patients 
with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or 
phospholipid syndrome should be excluded because of the risk of recurrence or 
exacerbation of disease.  Patients with vitiligo, endocrine deficiencies including 
thyroiditis managed with replacement hormones including physiologic corticosteroids are 
eligible.  Patients with rheumatoid arthritis and other arthropathies, Sjögren’s syndrome 
and psoriasis controlled with topical medication and patients with positive serology, such 
as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the 
presence of target organ involvement and potential need for systemic treatment but 
should otherwise be eligible. 
 

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3.2.11 Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual 
hypothyroidism due to autoimmune condition only requiring hormone replacement, 
psoriasis not requiring systemic treatment, or conditions not expected to recur in the 
absence of an external trigger (precipitating event). 
 
3.2.12 Patients should be excluded if they have a condition requiring systemic treatment with 
either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive 
medications within 14 days of study drug administration.  Inhaled or topical steroids and 
adrenal replacement doses <10 mg daily prednisone equivalents are permitted in the 
absence of active autoimmune disease.  Patients are permitted to use topical, ocular, intra-
articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption).  
Physiologic replacement doses of systemic corticosteroids are permitted, even if <10 
mg/day prednisone equivalents.  A brief 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 contact allergen) is permitted. 
 
3.2.13 Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, 
GI obstruction, fistula and abdominal carcinomatosis which are known risk factors for 
bowel perforation should be evaluated for the potential need for additional treatment 
before coming on study. 
 
3.3 Inclusion of Women and Minorities 
 
Every attempt will be made to enter all eligible patients into this protocol and therefore address 
the study objectives in a patient population representative of the  population of women with 
advanced leiomyosarcoma of the uterus treated by participating institutions.  
 
Please see the Planned Enrollment Report (table in Section 13.2). 
 
4 REGISTRATION PROCEDURES (ROSTERED PROTOCOL MODEL) 
 
4.1 Investigator and Research Associate Registration with CTEP 
4.1.1 CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
 
Registration requires the submission of: 
 
• a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• a current Curriculum Vitae (CV) 
• a completed and signed Supplemental Investigator Data Form (IDF) 
• a completed Financial Disclosure Form (FDF) with an original signature 
 

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22 
Fillable PDF forms and additional information can be found on the CTEP website at 
http://ctep.cancer.gov/investigatorResources/investigator_registration.htm. For questions, 
please contact the CTEP Investigator Registration Help Desk by email at 
pmbregpend@ctep.nci.nih.gov. 
 
4.1.2 CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
 
An active CTEP-IAM user account is needed to access all CTEP and CTSU (Cancer 
Trials Support Unit) websites and applications, and is critical to the conduct of this study, 
including document access, patient enrollment, and clinical data submission. 
 
Additional information can be found on the CTEP website at 
http://ctep.cancer.gov/branches/pmb/associate_registration.htm.  For questions, please 
contact the CTEP Associate Registration Help Desk by email at 
ctepreghelp@ctep.nci.nih.gov. 
 
4.1.3 For Questions and Support 
 
For questions about Investigator Registration, please contact the CTEP Investigator 
Registration Help Desk: pmbregpend@ctep.nci.nih.gov. 
 
For questions about Associate Registration or CTEP-IAM Account Creation, please 
contact the CTEP Registration Help Desk: ctepreghelp@ctep.nci.nih.gov. 
 
4.2 Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Each investigator or group of investigators at a clinical site must obtain Institutional Review 
Board (IRB) approval for this protocol and submit all required regulatory documents (including 
any protocol specific documents) to the CTSU Regulatory Office before they can be approved to 
enroll patients. Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled all regulatory 
criteria including but not limited to: an active Federal Wide Assurance (FWA) number, an active 

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23 
roster affiliation with the Lead Network or a participating organization, a valid IRB approval, 
and compliance with all protocol specific requirements.  
 
Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study are not 
required to submit separate IRB approval documentation to the CTSU Regulatory Office.  For 
sites using the CIRB, IRB approval information is received from the CIRB and applied to the 
RSS in an automated process. Signatory Institutions must submit a Study Specific Worksheet for 
Local Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study 
locally. The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office. 
In order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study.   
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the 9672 protocol page located on the 
CTSU Web site.  Permission to view and download this protocol is restricted and is based 
on person and site roster data housed in the CTSU RSS.  To participate, Investigators and 
Associates must be associated with the Corresponding or Participating protocol 
organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password 
• Click on the Protocols tab in the upper left of your screen  
• Either enter the protocol # in the search field at the top of the protocol tree, or  
• Click on the By Lead Organization folder, then select LAO-MA036 and protocol 
#9672 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 
4.2.2 Requirements For 9672 Site Registration: 
• CTSU Transmittal Sheet (optional)  
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted ) 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org (members’ area) → Regulatory Tab → 
Regulatory Submission 

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When applicable, original documents should be mailed to:  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
 
4.2.4 Checking Site Registration Status 
 
Sites can verify their site registration status on the members’ section of the CTSU 
website:  
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP 
IAM username and password. 
• Click on the Regulatory tab at the top of your screen. 
• Click on the Site Registration subtab. 
• Enter your 5-character CTEP Institution Code and click on Go. 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or other affiliated networks.  
 
4.3 Patient Registration 
 
4.3.1 OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
For trials with slot reservation requirements, OPEN will connect to IWRS at enrollment 
initiation to check slot availability.  Registration staff should ensure that a slot is 
available and secured for the patient before completing an enrollment. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
4.3.2 OPEN/IWRS User Requirements 
 

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OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations:  Be on an ETCTN Corresponding 
or Participating Organization roster with the role of Registrar. 
• To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes. Site 
staff should use the registration forms provided on the CTSU web site as a tool to 
verify eligibility. 
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which 
is available on the Theradex website:  http://theradex.com/CTMS/Downloads.aspx. This 
link to the Theradex website is also on the CTSU website OPEN tab. For questions about 
the use of IWRS for slot reservations, contact the Theradex Helpdesk: 609-619-7802 or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 General Guidelines 
 
Following registration, patients should begin protocol treatment within 21 days. Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  If a patient 
does not receive protocol therapy following registration, the patient’s registration on the study 
may be canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
 
5 TREATMENT PLAN 
 
 
5.1 Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
5.1.1 COHORT A (nivolumab alone)- Closed to Accrual 

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26 
 
Cohort A opened for accrual on 13-May-2015; accrual to this cohort was completed on 21-Oct-
2015. All participants in Cohort A received Nivolumab monotherapy as per the below dosing 
instructions. 
 
Nivolumab will be given every two weeks (±2 days) at a dose of 3 mg/kg. Patients may be dosed 
no less than 12 days from the previous dose of drug. 
The dosing calculations should be based on the actual body weight.  If the patient’s weight on the 
day of dosing differs by >10% from the weight used to calculate the original dose, the dose must 
be recalculated. Actual body weight at each visit may be used to calculate dose, as per 
institutional standard.  All doses should be rounded as per institutional standard.  There will be 
no dose modifications allowed.   
 
Nivolumab is to be administered over an approximately 60-minute IV infusion, using a 
volumetric pump with a 0.2-1.2 micron in-line filter at the protocol-specified dose.  The drug can 
be diluted with 0.9% normal saline for delivery but the total drug concentration of the solution 
cannot be below 0.35 mg/mL. 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.  . 
 
5.1.2 COHORT B (nivolumab and ipilimumab) 
 
Cohort B explores combination therapy with nivolumab and ipilimumab. All participants 
enrolled to this cohort will receive nivolumab in combination with ipilimumab as per the dosing 
instructions below.  
 
 Nivolumab will be given every three weeks (±2 days) at a dose of 3 mg/kg together with 
ipilimumab at a dose of 1 mg/kg for 4-cycles. Starting at cycle 5, nivolumab will be given as a 
monotherapy every two weeks at a dose of 3 mg/kg.  Patients may be dosed no less than 12 days 
from the previous dose of drug. The dosing calculations should be based on the actual body 
weight.  If the patient’s weight on the day of dosing differs by >10% from the weight used to 
calculate the original dose, the dose must be recalculated. Actual body weight at each visit may 
be used to calculate dose, as per institutional standard.  All doses should be rounded as per 
institutional standard.  There will be no dose modifications allowed.   
 
Nivolumab is to be administered over an approximately 60-minute IV infusion, using a 
volumetric pump with a 0.2-1.2 micron in-line filter at the protocol-specified dose.  The drug can 
be diluted with 0.9% normal saline for delivery but the total drug concentration of the solution 
cannot be below 0.35 mg/mL. 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. 
 
Ipilimumab injection can be used for IV administration without dilution after transferring to a 
PVC (polyvinyl chloride), non-PVC/non-DEHP (di-(2-ethylhexyl)phthalate) or glass containers 
and is stable for 24 hours at 2-8°C or room temperature/room light (RT/RL). Ipilimumab is to be 
administered as a 90-minute IV infusion, using a volumetric pump with a 0.2 to 1.2 micron in-
line filter at the protocol-specified dose. The drug can be diluted with 0.9% normal saline or 5% 
dextrose injection to concentrations between 1 mg/mL and 4 mg/mL. It is not to be administered 

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as an IV push or bolus injection. Care must be taken to assure sterility of the prepared solutions, 
since the drug product does not contain any antimicrobial preservatives or bacteriostatic agents. 
At the end of the infusion, flush the line with a sufficient quantity of normal saline or 5% 
dextrose solution.  
 
Separate infusion bags and filters must be used for each infusion of nivolumab and ipilimumab. 
Nivolumab is to be administered first. The nivolumab infusion must be promptly followed by a 
saline flush to clear the line of nivolumab before starting the ipilimumab infusion. 
 
 
5.1.3 Other Modality(ies) or Procedures 
 
Not applicable 
 
5.1.4 Investigational Imaging Agent Administration 
 
Not applicable 
 
5.2 Definition of Dose-Limiting Toxicity 
 
Not applicable 
 
5.3 General Concomitant Medication and Supportive Care Guidelines 
 
Nivolumab is a human monoclonal antibody and as such is not expected to be metabolized by 
cytochrome P450 (CYP) enzymes or other typical drug metabolizing enzymes. Thus, it is not 
expected to have any effect on CYP or other drug metabolizing enzymes in terms of inhibition or 
induction, and is, therefore, not expected to induce this type of PK-based drug interactions.  
 
5.4 Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for up to 46 
doses in Cohort A or until one of the following criteria applies. In Cohort B, treatment may 
continue for up to 4 doses of combination therapy (nivolumab + ipilimumab), and up to 46 doses 
of nivolumab monotherapy after the combination therapy, or until one of the following criteria 
applies:  
 
• 
Disease progression, as per section 5.9 
 
• 
Intercurrent illness that prevents further administration of treatment, 
 
• 
Any patients who require additional immune suppressive treatment beyond steroids 
should go off study treatment 
 
 
• Unacceptable adverse event(s) which include the following (see also section 6 and 

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specific algorithms in Appendix E): 
 
• Any grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment 
period OR requires systemic treatment 
 
• Patients requiring > two dose delays for the same type of event should go off protocol 
therapy. 
 
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the investigator, presents a substantial clinical risk to the subject with 
continued study drug dosing  
 
• Any dosing interruption lasting >6 weeks, with the following exceptions:   
 
• Patients being tapered after high dose corticosteroids over one month followed by a 
two-week observation period will be allowed an additional two weeks to restart 
treatment ( a maximum  eight week interruption).  
 
• Dosing interruptions >6 weeks that occur for non-drug-related reasons may be 
allowed if approved by the Investigator.  Prior to re-initiating treatment in a subject 
with a dosing interruption lasting >6 weeks, the Principal Investigator must be 
consulted. 
 
• Grade 3 drug-related autoimmune or inflammatory events including uveitis, 
pneumonitis, diarrhea, colitis, neurologic adverse events, hypersensitivity reaction, or 
infusion reaction of any duration requires discontinuation except as noted below: 
 
• Any other grade 3 non-skin, drug-related AE lasting >7 days including fatigue. 
 
• Any grade 3 or 4 drug-related laboratory abnormality or electrolyte abnormality, not 
associated with underlying organ pathology, that does not require treatment except for 
electrolyte replacements does not require treatment discontinuation.  
 
• Grade 3 amylase or lipase abnormalities that are not associated with diabetes mellitus 
(DM), associated liver or gall bladder inflammation clinical manifestations of 
pancreatitis and which decrease to < Grade 2 within 1 week of onset may resume 
study treatment when resolved.   
 
• Any grade 4 events except as noted above. 
 
• Patient decides to withdraw from the study, or 
 
• General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 

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5.5 Duration of Follow Up 
 
Patients will be followed for 100 days based on 5 half lives after removal from study or until 
death, whichever occurs first.  Patients removed from study for unacceptable adverse event(s) 
will be followed until resolution or stabilization of the adverse event. Patients who complete all 
protocol therapy (46 doses), without disease progression or unacceptable toxicity will continue to 
be followed until disease progression or the initiation of a new anticancer therapy. 
 
5.6 Criteria for Removal from Study 
 
Patients will be removed from study when any of the applicable criteria, including progressive 
disease as per section 5.9, adverse events, patient withdrawal or inability to follow study protocol 
as listed in Section 5.4.  The reason for study removal and the date the patient was removed must 
be documented in the Case Report Form. 
 
5.7 Criteria to Resume Treatment 
 
Management of adverse events is summarized in section 6 and may include holding of 
nivolumab and ipilimumab, and/or the use of steroids for the management of immune related 
AEs. 
 
If drug administration is held until the next scheduled time point, please continue to count 
weeks/doses. If patients must be delayed due to toxicity, all assessments can be obtained with the 
modified treatment dose schedule as noted in this section. 
 
Some patients may continue to benefit from treatment, maintaining or improving responses after 
progression including those treated with steroids. 
 
Restarting nivolumab may be considered in patients who experience grade 2 events and some 
grade 3 events (skin rash and thyroiditis). Because of this, stopping treatment and starting 
steroids earlier, as per section 6, to obtain resolution with the possibility for restarting rather than 
waiting for higher grade events is encouraged. 
 
For non-autoimmune or non-inflammatory events patients may resume treatment with study drug 
when the drug-related AE(s) resolve to Grade ≤1 or baseline value, with the following 
exceptions: 
• Evaluation to exclude any additional immune mediated events endocrine, GI, and liver / 
pancreas function as clinically indicated must be made prior to restarting.  
• Non-drug-related toxicity including hepatic, pulmonary toxicity, diarrhea, or colitis, must 
have resolved to baseline before treatment is resumed. 
 
If the criteria to resume treatment are met, the patient should restart treatment no sooner than the 
next scheduled time point per protocol.  However, if the treatment is delayed past the next 
scheduled time point per protocol the treatment should resume at the earliest convenient point 
that is within the six week delay period.  

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For protocols using combination nivolumab/ipilimumab for the initial induction period patients 
with grade 2 or 3 events requiring discontinuation of treatment with the combination, the PI may 
consider continuing treatment with single agent nivolumab at the same dose when the event 
resolves to baseline. However, patients with renal, CNS, or pulmonary toxicity must be removed 
from study.   
For patients treated with corticosteroids: 
 
For patients treated with high dose steroids with nivolumab/ipilimumab, toxicity must resolve to 
baseline within 8 weeks of treatment.  
 
Patients should be off steroids for at least 2 weeks with no recurrence or new events. New 
immune related events or exacerbation of existing events during steroid treatment or taper 
suggest the presence of ongoing immune activation and should require permanent 
discontinuation of nivolumab.  
 
Grade 2 events must resolve to grade < 1 before considering retreatment.  
 
All patients treated with steroids for grade ≥2 events should have nivolumab held until resolution 
to  grade < 1 for at least 2 weeks following complete removal from steroid treatment except for 
maintenance replacement doses for adrenal insufficiency (preferably no greater than 10mg 
prednisone equivalent daily).   
 
All patients treated with steroids for grade ≥3 events should have nivolumab discontinued.  
Patients with grade 3 thyroiditis and skin rash may continue therapy as for grade 2 events with 
resolution and stable replacement treatment. 
 
Patients with hepatitis, pancreatitis, pneumonitis, and colitis are at risk for exacerbation with 
retreatment if there is residual inflammation and should resolve to Grade 0 or baseline before 
retreatment.  Baseline can mean the initial grade i.e. grade <1 where permitted on study. 
 
Patients with thyroiditis or hypopituitarism who are stable as above may be restarted with 
replacement hormones including thyroid hormone and physiologic doses only of corticosteroids.  
Please note that grading and for hypophysitis with symptoms of headache, visual or neurologic 
changes or radiologic evidence of pituitary enlargement and other CNS events such as aseptic 
meningitis or encephalitis should be considered grade 3 events.  
 
New immune related events or exacerbation of existing events during steroid treatment or taper 
suggest the presence of ongoing immune activation and should require permanent 
discontinuation of nivolumab.  
 
A patient who is treated with steroids, evaluated, and found to not have an autoimmune or 
inflammatory event requiring steroid treatment, may be restarted if asymptomatic off steroids for 
2 weeks and other restarting criteria are met.  
 
Prior to starting corticosteroids or hormone replacement for any reason, appropriate endocrine 

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testing including cortisol, ACTH, TSH and T4 must be drawn if clinically feasible  to document 
baseline function and distinguish the pituitary  from  peripheral organ dysfunction and later from 
steroid (or thyroid)  treatment associated  ACTH ( or TSH)  suppression.  Steroids should be 
started prior to obtaining results based on clinical indications.  
 
5.8 Treatment of Nivolumab or Ipilimumab Related Infusion Reactions 
 
Since nivolumab and ipilimumab 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, urticaria, 
angioedema, pruritis, arthralgias, hypo- or hypertension, bronchospasm, or other symptoms.  
 
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met.  Infusion 
reactions should be graded according to NCI CTCAE version  5.0 guidelines. 
 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as medically appropriate: 
 
For Grade 1 symptoms:  (Mild reaction; infusion interruption not indicated; intervention not 
indicated) 
 
Remain at bedside and monitor subject until recovery from symptoms.  Infusion rate may be 
slowed.  If the 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 patient closely.   
 
The following prophylactic premedications are recommended for future infusions:  
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at 
least 30 minutes before additional nivolumab administrations, slowing infusion rate as above. 
 
 
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]; close observation for 
recurrence and treatment  medications may need to be continued for 24-48 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 paracetamol 325 to 1000 mg (acetaminophen); 
remain at bedside and monitor patient until resolution of symptoms.  Corticosteroid or 
bronchodilator therapy may also be administered as appropriate.  If the 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 patient closely.  If symptoms recur, then no further nivolumab will be 
administered at that visit.  Administer diphenhydramine 50 mg IV, and remain at bedside and 
monitor the patient until resolution of symptoms.  The amount of study drug infused must be 
recorded on the electronic case report form (eCRF).  The following prophylactic premedications 

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are recommended for future infusions: diphenhydramine 50 mg (or equivalent) and 
(acetaminophen) (or paracetamol) 325 to 1000 mg should be administered at least 30 minutes 
before additional nivolumab administrations.  If necessary, corticosteroids (recommended dose: 
up to 25 mg of IV hydrocortisone or equivalent) may be used. 
 
For Grade 3 or Grade 4 symptoms: (Severe reaction), Grade 3 symptoms: prolonged [i.e., not 
rapidly responsive to symptomatic medication and/or brief interruption of infusion]; recurrence 
of symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[e.g., renal impairment, pulmonary infiltrates]).   
 
Grade 4 symptoms: (life threatening; pressor or ventilatory support indicated).  
 
Immediately discontinue infusion of nivolumab.  Begin an IV infusion of normal saline, and treat 
the subject as follows.  Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 
solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly 
for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV 
(or equivalent), as needed.  Patient should be monitored until the investigator is comfortable that 
the symptoms will not recur.  Nivolumab will be permanently discontinued.  Investigators should 
follow their institutional guidelines for the treatment of anaphylaxis.  Remain at bedside and 
monitor patient until recovery from symptoms.  In the case of late-occurring hypersensitivity 
symptoms (e.g., appearance of a localized or generalized pruritis within 1 week after treatment), 
symptomatic treatment may be given (e.g., oral antihistamine, or corticosteroids). 
 
Please note that late occurring events including isolated fever and fatigue may represent the 
presentation of systemic inflammation.  Please evaluate accordingly.  
 
 
5.9 Treatment Beyond Progression 
 
 
A minority of subjects treated with immunotherapy may derive clinical benefit either delayed 
responses, stable disease, or increased overall survival despite initial evidence of progressive 
disease (PD) with nivolumab or combination treatment.   
 
Patients may be permitted to continue treatment beyond initial RECIST 1.1-defined PD that 
occurs during the initial (24 weeks) of treatment as long as they meet the following criteria: 
 
• No more than 4 new lesions total sum of the longest diameter (SHORT diameter 
for LN) cannot exceed  40% of the initial sum including new lesions   
• Patients must be clinically stable with no change in performance status due to 
disease progression 
• No indication for immediate alternative treatment 
• Patient [assessed by the investigator] is showing clinical benefit and tolerates 
study drug.  The assessment of clinical benefit should take into account whether 
the subject is clinically stable or deteriorating and  likely or unlikely to receive 
further benefit from continued treatment.  

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• The time of progression is noted from the first assessment that exceeds standard 
criteria 
 
New lesions are considered measurable at the time of initial progression if the longest 
diameter is at least 10 mm (except for pathological lymph nodes, which must have a 
short axis of at least 15 mm).  Any new lesion considered non-measurable at the time 
of initial progression may become measurable and therefore included in the tumor 
burden measurement if the longest diameter increases to at least 10 mm (except for 
pathological lymph nodes, which must have an increase in short axis to at least 15 
mm). 
 
 
6 
DOSING DELAYS/DOSE MODIFICATIONS 
 
 
Dose delays for nivolumab and ipilimumab for adverse events are described below. There are no 
dose reductions of nivolumab or ipilimumab allowed. See section 5.6 for guidelines regarding 
resumption of nivolumab and ipilimumab following dose delays. 
 
 
Please refer to the Nivolumab Investigator Brochure, Ipilimumab Investigator Brochure or 
Appendix B to the protocol for toxicity management algorithms which include specific 
treatment guidelines.  These algorithms should be followed unless there are specific clinical 
circumstances which the treating physician indicates variations or alternative treatment is 
needed.  
 
 
Evaluation of possible AEs should occur early, with early withholding of drug, and 
appropriate treatment as indicated in the management tables and following event specific 
guidelines.  In some cases, nivolumab and ipilimumab may be resumed as per section 5.6 
 
ALL OTHER 
EVENTS* 
Management/Next Dose for Nivolumab and combination 
Nivolumab/ipilimumab 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1 OR baseline (exceptions as noted below); Evaluate 
and continue at investigator discretion 
Grade 3 
Off protocol therapy (exceptions as noted below)  
Grade 4 
Off protocol therapy 
* Not agent related,  or agent related non-immunologically mediated 
Recommended management:  As clinically indicated  
ALL OTHER 
EVENTS** 
Management/Next Dose for Nivolumab and combination 
Nivolumab/ipilimumab 
≤ Grade 1 
No change in dose  
Grade 2 
Hold until ≤ Grade 1 OR baseline* When  resolved  <  or  following 
steroids resume at same dose level . 
Grade 3 
 Off protocol therapy (exceptions noted in 5.4)  

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ALL OTHER 
EVENTS* 
Management/Next Dose for Nivolumab and combination 
Nivolumab/ipilimumab 
Grade 4 
Off protocol therapy 
** immunologically mediated 
Recommended management:  As clinically indicated  
• Any grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment should go off protocol treatment. 
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment 
of the investigator, presents a substantial clinical risk to the subject with continued study 
drug dosing should go off protocol treatment. 
• Tumor pain or associated tumor flare does not require permanent discontinuation. 
• Any grade < 2 laboratory only abnormality may continue study treatment at the discretion 
of the investigator. Any grade 3 or 4 drug-related laboratory abnormality or electrolyte 
abnormality, that can be managed independently from underlying organ pathology with 
electrolyte replacement, hormone replacement, insulin, or that does not require treatment 
does not require discontinuation.   
 
Skin Rash and Oral 
Lesions 
 
Management/Next Dose for Nivolumab and combination 
Nivolumab/ipilimumab 
≤ Grade 1 
No change in dose;* evaluate and continue at investigator discretion 
Grade 2 
Hold* until 1≤ Grade resolved^.  Evaluate and continue at investigator 
discretion.   
Grade 3 
Hold* until ≤ Grade 1; evaluate and resume at investigator discretion 
same dose level.  
Grade 4 
Off protocol therapy 
*Patients with purpuric or bullous lesions must be evaluated for vasculitis, Steven-Johnson syndrome, 
TEN, and autoimmune bullous disease including oral lesions of bullous pemphigus/pemphagoid.  
Pruritus may occur with or without skin rash and should be treated symptomatically if there is no 
associated liver or GI toxicity.  Note skin rash typically occurs early and may be followed by additional 
events particularly during steroids tapering.   
Recommended management:  AE management guidelines – Appendix B 
 
 
Liver Function 
AST, ALT, and 
Bilirubin (total)  
Management/Next Dose for Nivolumab and combination 
Nivolumab/ipilimumab 
≤ Grade 1 
Hold pending evaluation. Continue treatment at same level at 
investigator decision.  
Grade 2 
Hold until UNL or baseline. Evaluate and resume at investigator 
discretion same dose level.  
Grade 3 
Off protocol therapy  
Grade 4 
Off protocol therapy 
Continued treatment of active immune mediated heapatitis may exacerbate ongoing inflammation.  
Holding drug to evaluate LFT changes and early treatment are recommended.   

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Liver Function 
AST, ALT, and 
Bilirubin (total)  
Management/Next Dose for Nivolumab and combination 
Nivolumab/ipilimumab 
LFT changes may occur during steroid tapers from other events and may occur together with other GI 
events including cholecystitis/pancreatitis. 
Recommended management:  see Hepatitic AE  management algorithm 
 
 
Diarrhea/ Colitis  
Management/Next Dose for Nivolumab and combination 
Nivolumab/ipilimumab 
≤ Grade 1 
Evaluate and continue treatment at same level at investigator discretion.  
Grade 2 
Hold until Grade <1 or baseline following treatment algorithm; evaluate 
and resume at investigator discretion if additional therapy is not 
required.  
Grade 3 
Hold until Grade <1 or baseline following treatment algorithm; evaluate 
and resume at investigator discretion.  
Grade 4 
Off protocol therapy 
See GI AE Algorithm for management of symptomatic colitis.  
Patients with grade 2 symptoms but normal colonoscopy and biopsies may be retreated after resolution.  
Please evaluate pituitary function prior to starting steroids if possible without compromising acute care.   
Evaluation for all patients for additional causes includes C. diff, acute and self-limited infectious and 
foodborne illness, ischemic bowel, diverticulitis, and IBD.  
Recommended management:  see GI AE management Algorithm 
 
 
Pancreatitis 
Amylapse/Lipase  
Management/Next Dose for Nivolumab and combination 
Nivolumab/ipilimumab 
≤ Grade 1 
Continue treatment at same level at investigator discretion.  
Grade 2 
Continue treatment at same level at investigator discretion if 
asymptomatic. 
Grade 3 
Hold until Grade< 2.  Resume at same dose level if asymptomatic. 
Patients who develop symptomatic pancreatitis or DM should be taken 
off treatment.  
Grade 4 
Hold until Grade< 2.  Resume at same dose level if asymptomatic. 
Patients who develop symptomatic pancreatitis or DM should be taken 
off treatment.  
Patients may develop symptomatic and radiologic evidence of pancreatitis as well as DM and 
DKA.  Lipase elevation may occur during the period of steroid withdrawal and with other 
immune mediated events or associated with colitis, hepatitis, and patients who have 
asymptomatic lipase elevation typically have self-limited course and may be retreated.  
For treatment management of symptomatic pancreatitis please follow the Hepatic Adverse 
Event Management Algorithm.  
 
 

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Pneumonitis 
Management/Next Dose for Nivolumab and combination 
Nivolumab/ipilimumab 
≤ Grade 1 
Hold dose pending evaluation and resolution to baseline including 
baseline pO2.  Resume no change in dose after pulmonary and/or ID 
consultation excludes agent associated lymphocytic pneumonitis.  
Grade 2 
Hold dose pending evaluation. Resume no change in dose after 
pulmonary and/or ID consultation excludes nivolumab/ipilimumab 
associated lymphocytic pneumonitis As the cause of the pneumonitis. 
Off study if steroids are required.  
Grade 3 
Hold dose pending evaluation. Resume no change in dose after 
pulmonary and/or ID consultation excludes nivolumab/ipilimumab 
associated  lymphocytic pneumonitis as the cause of the penumonitis. 
Off study if steroids are required. 
Grade 4 
Off protocol therapy 
Distinguishing inflammatory pneumonitis is often a diagnosis of exclusion for patients who do not 
respond to antibiotics and have no causal organism identified including influenza.  Most patients with 
respiratory failure or hypoxia will be treated with steroids.  Bronchoscopy may be required and analysis 
of lavage fluid for lymphocytic predominance may be helpful.  Patients with new lung nodules should 
be evaluated for sarcoid like granuloma.  Please consider recommending seasonal influenza killed 
vaccine for all patients. 
Recommended management:  See Pulmonary Adverse Event Management Algorithm  
 
 
Other GI N-V  
Management/Next Dose for Nivolumab and combination 
Nivolumab/ipilimumab 
≤ Grade 1 
No change in dose.  
Grade 2 
Hold pending evaluation for gastritis duodenitis and other immune 
adverse events or other causes.  Resume at investigator discretion.  
Grade 3 
Hold pending evaluation   until ≤ Grade 2.  Resume at same dose level. 
If symptoms do not resolve within 7 days with symptomatic treatment  patients 
should go off protocol therapy 
Grade 4 
Off protocol therapy 
Patients with grade 2 or 3 N-V should be evaluated for upper GI inflammation and other immune related 
events.   
 
Fatigue  
Management/Next Dose for Nivolumab and combination 
Nivolumab/ipilimumab 
≤ Grade 1 
No change in dose. 
Grade 2 
No change in dose 
Grade 3 
Hold until ≤ Grade 2.  Resume at same dose level at investigator 
discretion.  
Grade 4 
Off protocol therapy 
Fatigue is the most common adverse event associated with immune checkpoint therapy.  Grade 
2 or greater fatigue should be evaluated for associated or underlying organ involvement 
including pituitary, thyroid, and hepatic, or muscle (CPK) inflammation  
 

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Neurologic events  
 
Management/Next Dose for Nivolumab and combination 
Nivolumab/ipilimumab 
≤ Grade 1 
Hold dose pending evaluation and observation.  Resume with no change 
in dose when resolved to baseline at investigator dicrestion 
Grade 2 
Hold dose pending evaluation and observation. Hold until ≤ Grade 1.Off 
protocol therapy if treatment with steroids is required. Resume at same 
dose level for peripheral isolated n. VII (Bell’s palsy) 
Grade 3 
Off protocol therapy  
Grade 4 
Off protocol therapy  
*Patients with any CNS events including aseptic meningitis, encephalitis, symptomatic 
hypophysitis, or myopathy, peripheral demyelinating neuropathy, cranial neuropathy (other 
than peripheral n. VII), GB syndrome, myasthenia gravis should be off study.   
Recommended management:  See Neurologic Adverse Event Management Algorithm  
 
 
 
Cardiac *   
Management/Next Dose for BMS-936558 (Nivolumab) + 
Ipilimumab Cardiac Toxicities  
≤ Grade 1  
Hold dose pending evaluation and observation.**  Evaluate for signs 
and symptoms of CHF, ischemia, arrhythmia or myositis.  Obtain 
history EKG, CK (for concomitant myositis), CK-MB.  Repeat 
troponin, CK and EKG 2-3 days.  If troponin and labs normalize may 
resume therapy.  If labs worsen or symptoms develop then treat as 
below.  Hold pending evaluation.  
Grade >2 with 
suspected 
myocarditis 
 Hold dose.**  Admit to hospital.  Cardiology consult.  Rule out MI and 
other causes of cardiac disease.  Cardiac Monitoring.  Cardiac Echo.  
Consider cardiac MRI and cardiac biopsy.  Initiate high dose 
methylprednisolone.  If no improvement within 24 hours, add either 
infliximab, ATG or tacrolimus. Consult algorithm for more details.  
Resume therapy if there is a return to baseline and myocarditis is 
excluded or considered unlikely. 
Grade >2 with 
confirmed 
myocarditis   
Off protocol therapy.  Admit to CCU (consider transfer to nearest 
Cardiac Transplant Unit).  Treat as above.  Consider high dose 
methylprednisolone.   
Add ATG or tacrolimus if no improvement.  Off treatment. 
 
 
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
**Patients with evidence of myositis without myocarditis may be treated according as “other 
event”   
Note:  The optimal treatment regimen for immune mediated myocarditis has not been 
established.  Since this toxicity has caused patient deaths, an aggressive approach is 
recommended.   

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Endocrine 
Hypophysitis 
Adrenal 
Insufficiency  
 
Management/Next Dose for Nivolumab and combination 
Nivolumab/ipilimumab 
≤ Grade 1 
Asymptomatic TSH elevation*; continue at investigator discretion with 
evaluation of thyroid function.   
Grade 2 
Hold until patients are on a stable replacement hormone regimen.  If 
treated with steroids, patients must be stable off steroids for two weeks. 
Resume at same dose level.  
Grade 3 
Off protocol therapy. 
Grade 4 
Off protocol therapy 
Note all patients with symptomatic pituitary enlargement, exclusive of hormone deficiency, but 
including severe headache or enlarged pituitary on MRI should be considered grade 3 events.  Isolated 
thyroid or testosterone deficiency may be treated as grade 2 if there are no other associated deficiencies 
and adrenal function is monitored.  
Please evaluate pituitary function before beginning steroid therapy or replacement therapy of any kind.  
*Note patients with thyroiditis may be retreated on replacement therapy.  Patients must be evaluated to 
rule out pituitary disease prior to initiating thyroid replacement. 
Recommended management: TSH, T3, and T4 will be collected at baseline. After baseline, 
TSH will be collected every 6 weeks; T3/T4 will be collected when indicated. See Endocrine 
Management Algorithm  
 
Renal  
Management/Next Dose for Nivolumab and combination 
Nivolumab/ipilimumab 
≤ Grade 1 
Continue at same dose at investigator discretion 
Grade 2 
Hold pending evaluatio. Resume at same dose level at investigator 
discretion.  
Grade 3 
Off study treatment 
Grade 4 
Off study treatment 
Patients with fever should be evaluated as clinically appropriate.  Patients may experience 
isolated fever during infusion reactions or up to several days after infusion.  Evaluation over the 
course of 1-2 weeks should be done for other autoimmune events that may present as fever  
Infusion reaction  
Management/Next Dose for Nivolumab and combination 
Nivolumab/ipilimumab 
≤ Grade 1 
Continue at slower rate at investigator discretion 
Grade 2 
Hold until < Grade 1. Resume at same dose level 
Grade 3 
Hold until < Grade 1. Resume at same dose level 
Grade 4 
Off protocol therapy 
Patients with fever should be evaluated as clinically appropriate.  Patients may experience 
isolated fever during infusion reactions or up to several days after infusion.  Evaluation over the 
course of 1-2 weeks should be done for other autoimmune events that may present as fever  
See section 5.8- Treatment of Nivolumab or Ipilimumab Infusion reactions 
 
Fever  
Management/Next Dose for Nivolumab 
≤ Grade 1 
Evaluate and continue at same dose level 

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Fever  
Management/Next Dose for Nivolumab 
Grade 2 
Continue at investigator discretion 
Grade 3 
Hold until ≤ Grade 1.  Resume at same dose level at investigator 
discretion. 
Grade 4 
Off protocol therapy  
Patients with fever should be evaluated as clinically appropriate.  Patients may experience 
isolated fever during infusion reactions or up to several days after infusion.  Evaluation over the 
course of 1-2 weeks should be done for other autoimmune events that may present as fever  
See section 5.8: Treatment of Nivolumab or Ipilimumab Infusion reactions   
 
If treatment is delayed >8 weeks for an adverse event, the patient must be permanently 
discontinued from study therapy.  
 
Patients requiring high dose steroid treatment for autoimmune or inflammatory events should be 
managed as described in section 5.7, except for a short course of tapering steroids for infusion 
reaction, skin rash, or endocrine events.  
  
Patients with grade 3 thyroiditis and skin rash may continue therapy as for grade 2 events with 
resolution and stable replacement treatment.  
 
Patients with thyroiditis or hypopituitarism who are stable as above may be restarted with 
replacement hormones including thyroid hormone and physiologic doses of corticosteroids. 
Please note that grade for hypophysitis with symptoms of headache, visual, or neurologic 
changes or radiologic evidence of pituitary enlargement and other CNS events such as aseptic 
meningitis or encephalitis should be considered grade 3 events.   
 
Any patient who requires additional immune suppressive treatment beyond steroids should go off 
protocol therapy.  
 
Patients requiring > two dose delays, other than for evaluation for the same event, should go off 
protocol therapy. Patients may be dose-delayed for evaluation and restarted depending on results.  
 
Prior to starting corticosteroids or hormone replacement for any reason, appropriate endocrine 
testing including cortisol, ACTH, TSH and T4 must be obtained to document baseline.  
 
Please note that in some cases the treatment algorithms recommend steroids if symptoms do not 
resolve in 7 days. However, this recommendation is not meant to delay steroid treatment at any 
time it is clinically indicated.  
 
Any patient started on corticosteroids initially who is determined to not require steroids 
treatment for an autoimmune adverse event may resume therapy after a 2 week observation 
period without further symptoms at the discretion of the PI or investigator. 
 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 

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40 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting via the CTEP Adverse Event Reporting 
System (CTEP-AERS) in addition to routine reporting. 
 
7.1 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
 
 
 
7.1.2 CAEPRs for CTEP IND Agent 
 
7.1.2.1 CAEPR for Nivolumab 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
BMS-936558 (Nivolumab, MDX-1106, NSC 748726) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 2069 patients. Below is the CAEPR for 
BMS-936558 (Nivolumab, MDX-1106). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
Version 2.2, November 15, 20161 
 
 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 4.0 Term) 
[n= 782] 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
CARDIAC DISORDERS 
  
 
 
Cardiac disorders- 
other 
(cardiomyopathy) 
  
 
 
Myocarditis 
  
 
 
Pericardial tamponade2   

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41 
 
 
Pericarditis 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency 
 
  
 
Endocrine disorders - Other 
(hypophysitis) 
 
  
 
Hyperthyroidism 
 
  
 
Hypothyroidism 
 
  
EYE DISORDERS 
 
 
 
 
Eye disorders - Other 
(diplopia) 
  
 
 
Eye disorders – Other 
(Graves 
ophthalmopathy) 
  
 
 
Eye disorders - Other 
(optic neuritis 
retrobulbar) 
  
 
Uveitis 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 
Abdominal pain (Gr 
2) 
 
Colitis 
 
  
 
 
Colonic perforation 
  
 
Diarrhea 
 
 Diarrhea (Gr 2) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
 
Gastritis 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis3 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
 
Infusion related reaction4 
 
  
 
Injection site reaction 
 
 
Injection site reaction 
(Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  
 
 
Autoimmune disorder5   
 
 
Cytokine release 
syndrome6 
  
 
 
Immune system 
disorders - Other 
(GVHD in the setting 
of autotransplant)7 
  

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42 
 
 
Immune system 
disorders – Other 
(sarcoid granuloma)5   
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 
Alanine 
aminotransferase 
increased (Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 
Aspartate 
aminotransferase 
increased (Gr 2) 
 
Blood bilirubin increased 
 
 
Blood bilirubin 
increased (Gr 2) 
 
Creatinine increased 
 
  
 
Lipase increased 
 
  
 
Lymphocyte count 
decreased 
 
 
Lymphocyte count 
decreased (Gr 2) 
 
Neutrophil count decreased  
  
 
Platelet count decreased 
 
  
 
Serum amylase increased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
 
Hyperglycemia 
 Hyperglycemia (Gr 2) 
 
 
Metabolism and 
nutritional disorders - 
Other (diabetes 
mellitus with 
ketoacidosis) 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS   
 
Arthralgia 
 
  
 
 
Musculoskeletal and 
connective tissue 
disorder- Other 
(polymyositis) 
  
 
 
Musculoskeletal and 
connective tissue 
disorder- Other 
(rhabdomyolysis) 
  
 
 
Myositis 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Encephalopathy 
  
 
 
Facial nerve disorder5   

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43 
 
 
Nervous system 
disorders – Other 
(demyelination 
myasthenic syndrome)   
 
 
Nervous system 
disorders – Other 
(encephalitis) 
  
 
 
Nervous system 
disorders – Other 
(Guillain-Barre 
syndrome)5 
  
 
 
Nervous system 
disorders - Other 
(meningoencephalitis)   
 
 
Nervous system 
disorders - Other 
(meningoradiculitis) 
  
 
 
Nervous system 
disorders – Other 
(myasthenia gravis)5 
  
 
 
Nervous system 
disorders - Other 
(myasthenic 
syndrome) 
  
 
 
Peripheral motor 
neuropathy 
  
 
 
Peripheral sensory 
neuropathy 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pleural effusion 
 
  
 
Pneumonitis 
 
  
 
 
Respiratory, thoracic 
and mediastinal 
disorders – Other 
(brochiolitis obliterans 
with organizing 
pneumonia) 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme   
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash maculo-papular 
 
 
Rash maculo-papular 
(Gr 2) 

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44 
 
Skin hypopigmentation 
 
  
 
Skin and subcutaneous 
disorders – Other (Sweet’s 
Syndrome) 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2Pericardial tamponade may be related to possible inflammatory reaction at tumor site. 
 
3Pancreatitis may result in increased serum amylase and/or more frequently lipase. 
 
4Infusion reactions, including high-grade hypersensitivity reactions which have been observed 
following administration of nivolumab, may manifest as fever, chills, shakes, itching, rash, 
hypertension or hypotension, or difficulty breathing during and immediately after administration 
of nivolumab. 
 
5BMS-936558 (Nivolumab, MDX-1106) being a member of class of agents involved in the 
inhibition of “immune checkpoints”, may result in severe and possibly fatal immune-mediated 
adverse events probably due to T-cell activation and proliferation.  This may result in 
autoimmune disorders that can include (but are not limited to) autoimmune hemolytic anemia, 
acquired anti-factor VIII immune response, autoimmune aseptic meningitis, autoimmune 
hepatitis, autoimmune nephritis, autoimmune neuropathy, autoimmune thyroiditis, bullous 
pemphigoid; exacerbation of Churg-Strauss Syndrome, drug rash with eosinophilia, systemic 
symptoms [DRESS] syndrome, facial nerve disorder (facial nerve paralysis), limbic encephalitis, 
hepatic failure, pure red cell aplasia, pancreatitis, ulcerative and hemorrhagic colitis, endocrine 
disorders (e.g., autoimmune thyroiditis, hyperthyroidism, hypothyroidism, autoimmune 
hypophysitis/hypopituitarism, thyrotoxicosis, and adrenal insufficiency), sarcoid granuloma, 
myasthenia gravis, polymyositis, and Guillain-Barre syndrome. 
 
6Cytokine release syndrome may manifest as hemophagocytic lymphohistiocytosis with 
accompanying fever and pancytopenia. 
 
7Complications including hyperacute graft-versus-host disease (GVHD), some fatal, have 
occurred in patients receiving allo stem cell transplant (SCT) after receiving BMS-936558 
(Nivolumab, MDX-1106).  These complications may occur despite intervening therapy between 
receiving BMS-936558 (Nivolumab, MDX-1106) and allo-SCT. 
 
Also reported on BMS-936558 (Nivolumab, MDX-1106) trials but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that BMS-936558 
caused the adverse event: 
CARDIAC DISORDERS – Atrial fibrillation; Atrioventricular block complete; Heart failure; 
Pericarditis; Ventricular arrhythmia 

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45 
EAR AND LABYRINTH DISORDERS – Vestibular disorder 
EYE DISORDERS -  Eye disorders – Other (iridocyclitis); Optic nerve disorder 
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; Flatulence; 
Gastrointestinal disorders - Other (mouth sores); Mucositis oral; Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS – Chills; Edema 
limbs; Malaise; Pain 
HEPATOBILIARY DISORDERS – Bile duct stenosis 
IMMUNE SYSTEM DISORDERS - Anaphylaxis; Immune system disorders - Other 
(autoimmune thrombotic microangiopathy); Immune system disorders – Other (limbic 
encephalitis) 
INFECTIONS AND INFESTATIONS – Bronchial infection; Lung infection; Sepsis; Upper 
respiratory infection 
INVESTIGATIONS - GGT increased; Investigations - Other (blood LDH increased); 
Investigations - Other (protein total decreased); Investigations - Other (WBC count increased); 
Lymphocyte count increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperuricemia; 
Hypoalbuminemia, Hypocalcemia; Hyponatremia; Hypophosphatemia  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; 
Musculoskeletal and connective tissue disorder - Other (musculoskeletal pain); Musculoskeletal 
and connective tissue disorder - Other (polymyalgia rheumatica); Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other 
(histiocytic necrotizing lymphadenitis) 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS – Hematuria; Renal and urinary disorders - Other 
(tubulointerstitial nephritis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS – Bronchospasm; 
Cough; Dyspnea; Hypoxia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS – Alopecia; Dry skin; Hyperhidrosis; 
Pain of skin; Periorbital edema; Photosensitivity; Rash acneiform; Skin and subcutaneous tissue 
disorders - Other (rosacea); Toxic epidermal necrolysis 
VASCULAR DISORDERS – Flushing; Hypertension; Hypotension; Vasculitis 
 
Note: BMS-936558 (Nivolumab, MDX-1106) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent. 
 
 
7.1.2.2 CAEPR for Ipilimumab 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Ipilimumab (MDX-010, NSCs 732442 and 720801) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 

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46 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  for 
further clarification. Frequency is provided based on 2678 patients. Below is the CAEPR for 
Ipilimumab (MDX-010). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
Version 2.8, December 21, 20161 
 
 Adverse Events with Possible  
 Relationship to Ipilimumab (MDX-010) 
 (CTCAE 4.0 Term) 
[n= 2678] 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
 
 
Blood and lymphatic 
system disorders - 
Other (acquired 
hemophilia) 
  
CARDIAC DISORDERS 
  
 
Atrial fibrillation 
 
  
 
 
Myocarditis2 
  
EAR AND LABYRINTH DISORDERS 
  
 
Hearing impaired 
 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency2 
 
  
 
Endocrine disorders - Other 
(hypopituitarism/hypophysitis)2  
  
 
Endocrine disorders - Other 
(testosterone deficiency)2 
 
  
 
Hyperthyroidism2 
 
  
 
Hypothyroidism2 
 
  
EYE DISORDERS 
  
 
Eye disorders - Other 
(episcleritis)2 
 
  
 
Uveitis2 
 
  

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47 
 
 Adverse Events with Possible  
 Relationship to Ipilimumab (MDX-010) 
 (CTCAE 4.0 Term) 
[n= 2678] 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Colitis2 
 
 Colitis (Gr 3) 
 
 
Colonic perforation3 
  
 
Constipation 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Enterocolitis 
 
  
 
Esophagitis 
 
  
 
 
Ileus 
  
Nausea 
 
 
 Nausea (Gr 3) 
 
Pancreatitis2 
 
  
 
Vomiting 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS   
 
Chills 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Infusion related reaction 
 
  
 
 
Multi-organ failure 
  
HEPATOBILIARY DISORDERS 
 
 
 
Hepatobiliary disorders - Other 
(hepatitis)2 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Autoimmune disorder2 
 
  
 
 
Immune system 
disorders - Other 
(GVHD in the setting of 
allotransplant)4 
  
INFECTIONS AND INFESTATIONS 
  
 
 
Infections and 
infestations - Other 
(aseptic meningitis)2 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
  

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48 
 
 Adverse Events with Possible  
 Relationship to Ipilimumab (MDX-010) 
 (CTCAE 4.0 Term) 
[n= 2678] 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
 
Aspartate aminotransferase 
increased 
 
  
 
Neutrophil count decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Dehydration 
 
  
 
Hyperglycemia 
 
  
 
 
Metabolism and 
nutrition disorders – 
Other (exacerbation of 
pre-existing diabetes 
mellitus) 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Arthritis 
 
  
 
Musculoskeletal and connective 
tissue disorder - Other 
(polymyositis)2 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Facial nerve disorder 
 
  
 
Headache 
 
  
 
Nervous system disorders - 
Other   (Guillain-Barre 
syndrome)2 
 
  
 
Nervous system disorders - 
Other (myasthenia gravis)2 
 
  
 
Trigeminal nerve disorder 
 
  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
 
Renal and urinary disorders - 
Other (granulomatous 
tubulointerstitial nephritis) 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pneumonitis 
 
  

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49 
 
 Adverse Events with Possible  
 Relationship to Ipilimumab (MDX-010) 
 (CTCAE 4.0 Term) 
[n= 2678] 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
 
 
Respiratory, thoracic 
and mediastinal 
disorders – Other 
(bronchiolitis obliterans 
with organizing 
pneumonia) 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme 
  
 
Pruritus 
 
 Pruritus (Gr 3) 
Rash maculo-
papular 
 
 
 Rash maculo-papular (Gr 
3)  
 
Skin and subcutaneous 
disorders - Other (Sweet’s 
Syndrome) 
 
  
 
 
Stevens-Johnson 
syndrome 
  
 
 
Toxic epidermal 
necrolysis 
  
 
Urticaria 
 
  
VASCULAR DISORDERS 
  
 
Hypotension 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2Ipilimumab can result in severe and fatal immune-mediated adverse events probably due to T-
cell activation and proliferation.  These can include (but are not limited to) autoimmune 
hemolytic anemia, acquired anti-factor VIII immune response, autoimmune aseptic meningitis, 
autoimmune hepatitis, autoimmune thyroiditis, hepatic failure, pure red cell aplasia, pancreatitis, 
ulcerative and hemorrhagic colitis, endocrine disorders (e.g., autoimmune thyroiditis, 
hyperthyroidism, hypothyroidism, autoimmune hypophysitis/hypopituitarism, and adrenal 
insufficiency), ocular manifestations (e.g., uveitis, iritis, conjunctivitis, blepharitis, and 
episcleritis), sarcoid granuloma, myasthenia gravis, polymyositis, and Guillain-Barre syndrome.  
The majority of these reactions manifested early during treatment; however, a minority occurred 
weeks to months after discontinuation of ipilimumab especially with the initiation of additional 

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50 
treatments. 
 
3Late bowel perforations have been noted in patients receiving MDX-010 (ipilimumab) in 
association with subsequent IL-2 therapy. 
 
4Complications including hyperacute graft-versus-host disease (GVHD), may occur in patients 
receiving allo stem cell transplant (SCT) after receiving Ipilimumab (MDX-010).  These 
complications may occur despite intervening therapy between receiving Ipilimumab (MDX-010) 
and allo-SCT. 
 
5In rare cases diplopia (double vision) has occurred as a result of muscle weakness (Myasthenia 
gravis). 
 
6Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic 
hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, 
Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, 
Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic 
hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal 
hemorrhage under the GASTROINTESTINAL DISORDERS SOC 
 
7Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS 
SOC. 
 
Adverse events reported on Ipilimumab (MDX-010) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that Ipilimumab 
(MDX-010) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Blood and lymphatic system 
disorders - Other (pure red cell aplasia)2; Febrile neutropenia 
CARDIAC DISORDERS - Conduction disorder; Restrictive cardiomyopathy 
EYE DISORDERS - Extraocular muscle paresis5; Eye disorders - Other (retinal pigment 
changes) 
GASTROINTESTINAL DISORDERS - Dyspepsia; Dysphagia; Gastrointestinal hemorrhage5 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like 
symptoms; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure2 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INFECTIONS AND INFESTATIONS - Infection7 
INVESTIGATIONS - Creatinine increased; Investigations - Other (rheumatoid factor); Lipase 
increased; Platelet count decreased; Serum amylase increased; Weight loss; White blood cell 
decreased 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Joint 
range of motion decreased; Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysphasia; Ischemia cerebrovascular; 

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51 
Peripheral motor neuropathy; Peripheral sensory neuropathy; Seizure 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia 
RENAL AND URINARY DISORDERS - Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; 
Cough; Dyspnea; Laryngospasm 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia, Dry skin; Hyperhidrosis; 
Skin hypopigmentation 
VASCULAR DISORDERS - Flushing; Hypertension; Vascular disorders - Other (temporal 
arteritis) 
 
Note: Ipilimumab (MDX-010) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 
 
 
7.1.3 Adverse Event List(s) for [Other Investigational Agent(s)] 
 
Not Applicable 
 
7.1.4 Adverse Event List(s) for Commercial Agent(s) 
 
Not Applicable 
 
7.1.5 CAEPR for [CIP IND Agent #1)] 
 
Not Applicable 
 
7.1.6 Adverse Event List(s) for CIP (e.g. Study-Specific) Commercial Imaging 
Agents 
 
Not Applicable 
 
7.2 Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized until March 31, 2018 for AE reporting. CTCAE version 5.0 will be 
utilized for AE reporting beginning April 1, 2018. All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can 
be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 

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52 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 Expedited Adverse Event Reporting 
 
7.3.2 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse 
Event Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are 
presented in the “NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” which 
can be downloaded from the CTEP Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_
events.htm).  These requirements are briefly outlined in the tables below 
(Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.3 CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization, the local treating physician, and the 
Reporter and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients.  
 
The Coordinating Center of the Corresponding Organization is responsible for submitting 
to the CTSU documentation of AEs that they deem reportable for posting on the CTSU 
protocol web page and inclusion on the CTSU bi-monthly broadcast. 
 
7.3.4 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be 
provided. 
 
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, 

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53 
malignant and unspecified (including cysts and polyps) - Other (Progressive 
Disease)” under the system organ class (SOC) of the same name.  Evidence that the death 
was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 

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54 
 
 
7.4 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
7.5 Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
 
 
7.6 Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
8 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 

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55 
8.1 CTEP IND Agent(s) 
 
 
8.1.1 Nivolumab 
Amino Acid Sequence:  4 polypeptide chains, which include 2 identical heavy chains with 440 
amino acids and 2 identical light chains. 
 
Other Names:  BMS-936558, MDX1106 
 
Classification:  Anti-PD-1MAb 
 
M.W.:  146,221 daltons 
 
Mode of Action:  Nivolumab targets the programmed death–1 (PD-1, cluster of differentiation 
279 [CD279]) cell surface membrane receptor.  PD-1 is a negative regulatory receptor expressed 
by activated T and B lymphocytes.  Binding of PD-1 to its ligands, programmed death–ligand 1 
(PD-L1) and 2 (PD-L2), results in the down-regulation of lymphocyte activation.  Nivolumab 
inhibits the binding of PD-1 to PD-L1 and PD-L2.  Inhibition of the interaction between PD-1 
and its ligands promotes immune responses and antigen-specific T-cell responses to both foreign 
antigens as well as self-antigens. 
 
Description:  Nivolumab Injection is a clear to opalescent, colorless to pale yellow liquid; light 
(few) particulates may be present.  The drug product is a sterile, nonpyrogenic, single-use, 
isotonic aqueous solution formulated in sodium citrate, sodium chloride, mannitol, 
diethylenetriamine pentacetic acid (pentetic acid) and polysorbate 80 (Tween® 80), pH 6.0. 
 
How Supplied:  Nivolumab is supplied by Bristol-Myers Squibb and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI as 100 mg vials (10 mg/mL) with a 0.7 
mL overfill.  It is supplied in 10 mL type I flint glass vials, with butyl rubber stoppers and 
aluminum seals. 
 
Preparation:  Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 0.9% 
Sodium Chloride Injection, USP or 5% Dextrose, USP to concentrations no less than 0.35 
mg/mL. 
 
Storage:  Vials of Nivolumab injection must be stored at 2°-8°C (36°-46°F) and protected from 
light, freezing, and shaking.  
 
Stability:  Shelf-life surveillance of the intact vials is ongoing. 
 
The administration of undiluted and diluted solutions of Nivolumab must be completed within 24 
hours of preparation.  If not used immediately, the infusion solution may be stored up to 24 hours 
in a refrigerator at 2°-8°C (36°-46°F) and a maximum of 4 hours of the total 24 hours can be at 
room temperature (20°-25°C, 68°-77°F) and room light.  The maximum 4-hour period under 
room temperature and room light conditions includes the product administration period. 
 

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56 
CAUTION:  The single-use dosage form contains no antibacterial preservative or bacteriostatic 
agent.  Therefore, it is advised that the product be discarded 8 hours after initial entry.  
 
Route of Administration:  Intravenous infusion.  Do not administer as an IV push or bolus 
injection.   
 
Method of Administration:  Administer through a 0.2 micron to 1.2 micron pore size, low-
protein binding polyethersulfone membrane in-line filter. 
 
Potential Drug Interactions:  No incompatibilities between Nivolumab injection and polyvinyl 
chloride (PVC), non-PVC/non-DEHP (di[2-ethylhexyl]phthalate) IV components, or glass 
bottles have been observed. 
 
Availability 
 
Nivolumab is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
 
Nivolumab is provided to the NCI under a Collaborative Agreement between the Pharmaceutical 
Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.1.2 Ipilimumab (NSC 732442) 
 
Chemical Name or Amino Acid Sequence: 4 polypeptide chains, 2 identical heavy chains with 447 
amino acids and 2 identical light chains consisting of 215 amino acids. 
 
Other Names: Anti-CTLA-4 monoclonal antibody, MDX-010, Yervoy™ 
 
Classification: Human monoclonal antibody 
 
M.W.: 147,991 Daltons 
 
Mode of Action: Ipilimumab is specific for the CTLA4 antigen expressed on a subset of activated 
T-cells. CTLA4 interaction with the B7 molecule, one of its ligands expressed on professional 
antigen presenting cells, can down-regulate T-cell response. Ipilimumab is, thought to act by 
blocking the interaction of CTLA4 with the B7 ligand, resulting in a blockade of the inhibitory 
effect of T-cell activation.  The CTLA4/B7 creates the interaction.  
 
Description: Ipilimumab is a fully human immunoglobulin (IgG1) with two manufacturing 
processes – ongoing trials have been using substances manufactured using Process B.  New clinical 
trials will be using ipilimumab that is manufactured by Process C. The Process C has been 
developed using a higher producing sub-clone of the current Master Cell Bank, and modified cell 
culture and purification steps.  
  
How Supplied: Bristol-Myers-Squibb (BMS) supplies Ipilimumab to the DCTD/NCI.  Ipilimumab 
injection, 200 mg/40 mL (5 mg/mL), is formulated as a clear to slightly opalescent, colorless to 

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57 
pale yellow, sterile, nonpyrogenic, single-use, isotonic aqueous solution that may contain particles. 
 
Each vial is a Type I flint glass vial with gray butyl stoppers and sealed with aluminum seals. 
 
 
Process C 
Component 
200 mg/ viala 
Ipilimumab 
213 mg 
Sodium Chloride, USP  
249 mg 
TRIS-hydrochloride 
134.3 mg 
Diethylenetriamine pentacetic acid 
1.67 mg 
Mannitol, USP 
426 mg 
Polysorbate 80 (plant-derived) 
4.69 mg 
Sodium Hydroxide 
QS to pH 7 
Hydrochloric acid 
QS to pH 7 
Water for Injection 
QS: 42.6 mL 
Nitrogenb 
Processing agent 
aIncludes 2.6 mL overfill. 
bNitrogen is used to transfer the bulk solution through the pre-filled and sterilizing filters  
into the aseptic area. 
 
Preparation:  Ipilimumab is given undiluted or further diluted in 0.9% NaCl Injection, USP or 5% 
Dextrose Injection, USP in concentrations between 1 mg/mL and 4 mg/mL.  Ipilimumab is stable in 
a polyvinyl chloride (PVC), non-PVC/non DEHP (di-(2-ethylhexyl) phthalate) IV bag or glass 
container up to 24 hours refrigerated at (20 to 80 C) or at room temperature/ room light.  
 
Recommended safety measures for preparation and handling include protective clothing, gloves, and 
safety cabinets. 
 
Storage: Store intact vials refrigerated at (20 to 80 C), protected from light.  Do not freeze. 
 
Stability: Shelf-life surveillance of the intact vials is ongoing.  Solution as described above is stable 
up to 24 hours refrigerated at (20 to 80 C) or at room temperature/ room light.  
 
CAUTION:  Ipilimumab does not contain antibacterial preservatives.  Use prepared IV solution 
immediately. Discard partially used vials.  
 
Route(s) of Administration: Intravenous infusion.  Do not administer ipilimumab as an IV push or 
bolus injection. 
 
Method of Administration:  Can use a volumetric pump to infuse ipilimumab at the protocol-
specific dose(s) and rate(s) via a PVC IV infusion set with an in-line, sterile, non-pyrogenic, low-
protein-binding filter (0.2 micron to 1.2 micron). 
 
Patient Care Implications:  Monitor patients for immune-related adverse events, e.g., rash/vitiligo, 
diarrhea/colitis, uveitis/episcleritis, hepatitis and hypothyroidism.  If you suspect toxicity, refer to 

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58 
the protocol guidelines for ruling out other causes. 
 
8.1.3 Agent Ordering and Agent Accountability 
 
8.1.3.1 NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If 
there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).  
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” 
account status and a “current” password.  For questions about drug orders, transfers, 
returns, or accountability, call (240) 276-6575 Monday through Friday between 8:30 am 
and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
8.1.3.2 Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Drug Accountability Record Form (DARF).  (See 
the NCI Investigator’s Handbook for Procedures for Drug Accountability and Storage.) 
 
8.1.3.3 Investigator Brochure Availability – The current versions of the IBs for the agents will be 
accessible to site investigators and research staff through the PMB Online Agent Order 
Processing (OAOP) application.  Access to OAOP requires the establishment of a CTEP 
Identity and Access Management (IAM) account and the maintenance of an “active” 
account status and a “current” password.  Questions about IB access may be directed to 
the PMB IB coordinator via email. 
 
8.1.4 Useful Links and Contacts 
• CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration: PMBRegPend@ctep.nci,nih.gov 

NCI Protocol #:9672 
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59 
• PMB policies and guidelines:  
http://ctep.cancer.gov/branches/pmb/agent_management.htm 
• PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx 
• CTEP Identity and Access Management (IAM) account: https://eapps-
ctep.nci.nih.gov/iam/ 
• CTEP Associate Registration and IAM account help: 
ctepreghelp@ctep.nci.nih.gov 
• PMB email: PMBAfterHours@mail.nih.gov 
• IB coordinator: IBCoordinator@mail.nih.gov 
• PMB phone and hours of services: (240)276-6575 Monday through Friday 
between 8:30AM and 4:30PM (ET) 
 
 
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
 
9.1 Integrated Laboratory or Imaging Studies 
 
 
9.1.1 Immunohistochemical Staining for PDL1 (CD274), PDL2 (CD273) and PD1 (CD279)  
 
We hypothesize that CD274, CD273 and CD279 protein expression in tumor tissues might be 
associated with favorable clinical response to immune checkpoint inhibition, and might serve as 
biomarkers for patient selection for CD279 blockade in clinical treatment.  PDL1 assessment by 
BMS DAKO kit will be considered an integrated biomarker for this study because PDL1 
assessment by this method has been used across multiple studies evaluating nivolumab and 
therefore will support standardization, reproducibility, and comparison across studies. Additional 
staining for PDL1 by the antibody method noted below will occur in parallel for exploratory 
comparison of these two techniques. 
 
9.1.1.1 Collection of Specimen(s) 
 
Assay, patient and specimen information 
Immunohistochemical (IHC) staining of CD274 will be used as an integrated biomarker in this 
clinical trial, and to identify a group of patients most likely to respond to the immune checkpoint 
inhibition with nivolumab or nivolumab and ipilimumab. This information  may be used in the 
future phase II trials as a stratification variable. IHC staining of CD273, CD279 will also be 
performed as exploratory biomarkers to explore a possible relationship between expression and 
response to nivolumab or nivoluamb and ipilimumab in this population. Pre-treatment archival 
tumor material will be collected for all eligible patients. In addition, because expression of these 
markers may change over time, paired immediate pre-treatment and post- treatment biopsies will 
be obtained in all patients enrolled to Cohort B. In Cohort A, pre-treatment archival tumor material 
was collected for ten out of the twelve patients treated. In Cohort A, paired biopsies were not 
required for all participants; one set of paired biopsies was conducted. These paired biopsies will 

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60 
be collected and fixed by 10% neutral buffered formalin overnight, dehydrated and paraffin 
embedded.  Four-micrometer-thick sections will be cut.  The paraffin blocks and unstained slides 
will be stored at room temperature.  All IHC staining will be performed in the Center for Immuno-
Oncology Pathology Core at Dana-Farber/Harvard Cancer Center Specialized Histopathology 
Core, which will be a central research laboratory for this multiple-center clinical trial.  Unstained 
slides from other two centers will be shipped to Dr Xiaoyun Liao, Thorn building 603B, Brigham 
and Women Hospital, 75 Francis Street, Boston, MA, 02215. 
 
Primary antibody characteristics 
Mouse monoclonal anti-CD279, anti-CD274 and anti-CD273 antibodies were generated in the 
laboratory of Dr. Gordon Freeman (Dana-Farber Cancer Institute).  The antibodies are human gene 
product and can recognize all isoforms.  The specificity of these antibodies was confirmed by 
western blotting in human cancer cell lines and bands were at expected mass.  The IHC staining 
was abolished in knock-down cancer cells.  CD279 is expressed on the surface of activated T cells.  
CD274 is present in macrophages, dendritic cells, T cells, B cells and in multiple cancers (Sznol 
M, 2013).  CD273 is expressed on dendritic cells, macrophages and bone marrow-derived mast 
cells whereas its expression on cancers is under exploration (Rozali EN, 2012).   No cross-reactive 
proteins that may confound interpretation of IHC staining were identified.  The antigens are stable 
when the period between tissue sectioning and staining is more than 30 days. 
 
Design of immunohistochemical assay 
The IHC assay for CD274, CD273 is semi-quantitative while CD279 stained slides will be scanned 
by an automated scanning microscope and quantitatively analyzed by Aperio image analysis 
system (Leica Biosystems) after they are evaluated and positive cells are manually counted by a 
pathologist.   
Standard EnVision two-step (indirect) staining method will be utilized.  Four-micrometer-thick 
sections will be cut, deparaffinized, rehydrated and subjected to heat mediated antigen retrieval in 
citrate buffer (pH 6) (Invitrogen) by steaming for 30 minutes.  After cooling, tissue sections will 
be incubated with peroxidase block (DAKO, Carpinteria, CA) for five minutes, then serum free 
protein block (DAKO) for 20 minutes.  Slides will be incubated at room temperature for one hour 
with a primary antibody.  Antibodies will be diluted in Da Vinci Green Diluent (Biocare Medical, 
Concord, CA).  EnvisionTM anti-mouse HRP-labeled polymer (DAKO) will be applied to the 
sections for 30 minutes, followed by visualization by using the chromogen 3, 3-diaminobenzidine 
(DAKO). All the sections will then be counterstained with haematoxylin, dehydrated, mounted 
and coverslipped.   Positive and negative controls shall be included in each staining.  Known 
positive stained Hodgkin lymphoma (CD274), tonsil (CD279) and melanoma (CD273) slides will 
be used as external control (separate slides).  Stained slides will be stored at room temperature. 
In our pilot study, immunoreactivity for CD274 was detected in the cytoplasm and cell membrane 
while CD273 and CD279 expression was observed in the cytoplasm.  Scoring for CD274, CD273 
will be semi-quantitative/ordered categorical.  The percentage of the tumor cells staining positive 
for CD274, CD273 and the intensity of the tumor cells will be recorded as 0 (no staining), 1 (weak 
staining), 2 (moderate staining) and 3 (intense staining).   Absolute CD279 positive cells will be 
counted under microscope lens x 20 power field.  Representative 5 areas will be chosen to count.  
The average number from 5 areas will be recorded and be compared with data from image analysis.   

NCI Protocol #:9672 
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61 
CD279
CD274
CD273
 
Assay performance 
The results will be obtained on retrospective data sets.  Protocols of these three antibodies have 
been optimized, standardized to minimize staining variance.  Positive control and negative controls 
were used and stained separately with each batch of slides. The IHC staining of three markers 
(CD274, CD273 and CD279) has been performed in two different labs by three different 
technicians on whole tissue sections of Hodgkin lymphomas, melanomas, lung cancers and renal 
cell carcinomas. Three readers were involved, confirming the good reproducibility of the assay. 
Tumor will be considered positive if >5% (CD274) (Topalian S, 2012) or 10% (CD273) of the 
tumor cell population demonstrates unequivocally staining, respectively.  CD279 positivity was 
defined as >3% positive cells/HPF (Bachireddy P, 2013).  Statistically, Fisher’s Exact Test will be 
used to measure the association between CD274, CD273, CD27 expression and objective response 
Figure shows the 
immunohistochemical 
staining of CD279, 
CD274 and CD273 in 
advanced melanoma. 

NCI Protocol #:9672 
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62 
of patients.  All p values will be two sided, and statistical significance will be set at p<0.05. 
All IHC stained slides will be evaluated and scored by a pathologist (Dr Xiaoyun Liao). A subset 
of slides will be reviewed by a second pathologist (Dr Scott Rodig) to ensure concordance of 
interpretation. 
For CD279 staining, slides will be scanned by an automated scanning microscope and analyzed 
by Aperio image analysis system (Leica Biosystems). Tumor areas will be marked by a pathologist 
to exclude non-neoplastic areas, such as stroma, normal epithelial and necrotic regions.  The 
software will be used to count the number of positive cells in each tissue.  The percentage of 
CD279 positive cells will be calculated.  Data will be compared with that of manual counting by 
a pathologist to exclude tissue artifacts that cannot be recognized by computer image software. 
 
 
9.1.1.2 Site Performing Correlative Study 
 
 
Laboratory information  
The IHC staining, including the CD274 by BMS DAKO kit, will be conducted in a research 
laboratory with GLP standard by Dr. Xiaoyun Liao.  Dr. Liao received her medical degree and 
anatomical pathology training from Peking University Health Science Center, Beijing, China, and 
obtained her PhD degree from the University of Hong Kong Faculty of Medicine, Hong Kong, 
China.  Before she joined Dana-Farber Cancer Institute in 2010, she served Peking University as 
a general pathologist for over 15 years.  She completed her postdoctoral research fellow training 
at Dana-Farber Cancer Institute in 2013 and joined Center for Immuno-Oncology Pathology Core.  
Dr. Liao has extensive experience in tumor pathology and immunohistochemistry (Liao X, 2012).  
Dr. Scott Rodig is a hematopathologist at the Brigham and Women’s hospital with prior expertise 
evaluating PD1, PDL1 and other immunologic markers in paraffin embedded tumor samples (Chen 
BJ, 2013).  
 
9.2 
Exploratory/Ancillary Correlative Studies 
 
9.2.1 
Monitoring Peripheral Blood for Changes in Immune Function 
 
Subpopulations of PBMCs will be isolated, including but not limited to dendritic cells, T cells, and 
B cells.  Phenotype changes in these cell populations by flow cytometry will be determined as a 
function of treatment.  These include regulatory and effector immune panels, naïve and memory 
CD4, CD8 and NK lymphocyte populations.  Both humoral and cellular immune responses will 
be investigated by ELISAs, ELISPOTs, and cytotoxic T cell chromium release assays.   
 
IHC staining of PDL2 (CD273) and PD1 (CD279) will be performed as exploratory assays as 
noted above in section 9.1. 
 
 
9.2.1.2 Handling of Specimens(s) 
Peripheral blood: 
In Cohort A, serial blood/serum samples was  collected every 2 weeks prior to each nivolumab 

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63 
administration starting on day 1 (pre-treatment), through week 12, and then with decreased 
frequency as per section 10.  In Cohort B, serial blood/serum samples will be collected at week 1 
of each cycle prior to study drug infusion starting on day 1 (pre-treatment), through cycle 4. A 
panel of cytokines and chemokines will be tested in serum using Luminex cytokine assay. Changes 
in cytokine production in immune cell subsets as a function of treatment will be determined by 
ELISA and intracellular cytokine staining. Absolute lymphocyte count (ALC) will be monitored. 
 
Peripheral blood mononuclear cells (PBMCs) will be collected from whole blood to assess immune 
cell populations. Surface staining with a panel of antibodies (CD3, CD4, CD8, CD25, FoxP3, 
CD11c, CD83, CD86, CD56) and intracytoplasmatic cytokine staining, followed by flow 
cytometry will be performed in order to identify different T cell populations, their activation status, 
and the production of different cytokines as well as other immune cell populations as described 
below.  
 
Serum marker levels will be summarized descriptively and graphically for the patient population.  
The time course of expression levels will also be summarized graphically by patient, noting times 
of disease response and disease progression.    
 
9.2.1.3 Sites Performing Correlative Study 
The Center for Immuno-oncology Immune Assessment core facilitates the collection, processing, 
and trafficking of patient blood samples on CIO clinical trials.  The Immune Assessment Core has 
standardized multi-color flow assays for phenotying immune cells as well as standardized ELISA 
and Luminex platform analyses. Studies will be performed in the Center for Immuno-oncology 
Immune Assessment core facilitates at Dana-Farber Cancer Institute 
 
9.2.2 Targeted gene-expression profiling. 
 

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64 
As an exploratory end-point, targeted gene expression profiling will be performed on biopsy 
samples, when sufficient material is available, to determine the relative expression of a 
comprehensive set of gene products (161) involved in all aspects of immuno-regulation.  The 
Nanostring nCounter platform will be used for this analysis as it has proven effective for targeted 
gene expression profiling using RNA isolated from formalin-fixed, paraffin embedded tissues 
(Scott DW et al., 2014, PMID:24398326).  The nCounter platform is located at the Center for 
Advanced Molecular Diagnostics (CAMD), a CLIA-certified laboratory in the Department of 
Pathology at BWH.  Dr. Rodig's laboratory has extensive experience with the operation of the 
analytical platform and the analysis of the resulting data (Carey CD et al., J. Mol. Diagn., 2014, in 
press). 
RNA will be isolated from 3 X 10um sections of formalin-fixed, paraffin embedded material. The 
resulting RNA will be quantified using a bioanalyzer and 250ng used for targeted gene expression 
analysis following manufacturer's protocols.  The resulting data will be interrogated to establish 
whether a limited and defined gene-expression signature is predictive of clinical responses to 
therapy. 
 
 
9.3 
Integral Correlative Studies 
 
Not applicable 
 
 
 
 
 

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65 
10 
STUDY CALENDAR 
 
Cohort A- Nivolumab Monotherapy 
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy.  
Baseline assessments include: hematology panel, serum chemistry panel, pregnancy test, 
physical examination, medical history, concurrent medications evaluations, and vital signs Scans 
and x-rays must be done <4 weeks prior to the start of therapy. CBC and serum chemistries must 
be obtained on Week 1 Day 1 and reconfirm eligibility criteria. In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next dose of therapy. 
 
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12d 
Off Studyc 
Nivolumab 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------X 
 
Physical exam 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Vital signs 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Performance status 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
CBC w/diff, pltsa 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum chemistrya 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
HIV, Hep B, Hep C screen J 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG (as indicated)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X---------------------------------------------------------------------------------------------X 
X 
Tumor measurements 
X 
Tumor measurements are repeated every 12 weeks.  Documentation (radiologic) must 
be provided for patients removed from study for progressive disease. 
X 
B-HCG 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor E 
XF 
 
 
 
XH 
 
 
 
 
 
 
 
 
 
Immune correlativesG  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Archival Tumor TissueI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
A: Nivolumab:  3mg/kg IV administered over 60 minutes, every two weeks (+/- 2days) 
 
a: 
Laboratory testing prior to each dose: Within 72 hrs prior to re-dosing to include CBC w/ differential, LFTs, 
BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, Glucose, amylase, and lipase. TSH will be 
collected at screening and repeated every 6 weeks unless clinically indicated. Reflexive Free T4 and Free T3 
will be collected at screening and repeated when clinically indicated. 
 
b:   A serum or urine pregnancy test is required at baseline for women of childbearing potential. 
 
 
 
c: 
Off-study evaluation.  AE assessment will be performed at 100 days following last dose of study drug. This 

NCI Protocol #:9672 
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66 
may be done by phone. Patients who complete all planned protocol therapy (46 doses), will continue to be 
monitored for tumor measurements beyond completion of treatment until disease progression or the initiation 
of a new anticancer therapy.  
 
d:     Schedule post week 12 will repeat as per weeks 1 -12, with the exception of pre/post tumor biopsy and 
correlative studies  
 
E:    Pre/post tumor biopsies will be performed whenever possible, and in a minimum of 10 patients 
 
F:    Pre-study tumor biopsy to be performed after eligibility is confirmed and patient is registered on study and 
prior to first dose of nivolumab.  
 
G:   Peripheral blood will be drawn prior to each dose of nivolumab for the first 12 weeks to assess changes in 
immune function as per section 9.2. After week 12, this will be drawn every 6 weeks prior to dosing for the 
next 12 weeks, then every 3 months. Samples will also be drawn within 7 days of an objective response, and 
at off-study. 
 
H:    Post-treatment biopsy will be performed at approximately week 4-6 (+/- 7 days) 
 
I:     Archival tissue specimen will be collected if available. This is not required prior to study drug dosing. 
 
J:     Testing for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS), 
hepatitis B virus surface antigen (HBV sAg) and  hepatitis C virus ribonucleic acid (HCV antibody) indicating 
acute or chronic infection. 
 
K.    Tumor assessments are repeated every 12 weeks (+/- 2 days) and should continue as per protocol even if 
dosing is interrupted. 
 
 
 
 
 

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67 
Cohort B: Nivolumab + Ipilimumab  
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy.  
Baseline assessments include: hematology panel, serum chemistry panel, pregnancy test, 
physical examination, medical history, concurrent medications evaluations, and vital signs. Scans 
and x-rays must be done <4 weeks prior to the start of therapy. CBC and serum chemistries must 
be obtained on Week 1 Day 1 and reconfirm eligibility criteria. In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next dose of therapy. 
 
 
Pre- 
Study 
Part I: Nivolumab + Ipilimumab 
Cycles 1-4 
1 cycle = 3 weeks 
Part II: Nivolumab 
Monotherapy 
Cycles 5+ 
1 cycle = 2 weeks 
Off Studyc 
Wk 1 
Wk 2 
Wk 3 
Wk 1 
Wk 2  
Nivolumab  
 
A 
 
 
A 
 
 
Ipilimumab 
 
B 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Concurrent meds 
X 
X-----------------------------------------------------------------X 
 
Physical exam 
X 
X 
 
 
X 
 
X 
Vital signs 
X 
X 
 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
 
X 
Performance status 
X 
X 
 
 
X 
 
X 
CBC w/diff, pltsa 
X 
X 
 
 
X 
 
X 
Serum chemistrya 
X 
X 
 
 
X 
 
X 
HIV, Hep B, Hep C screen i 
X 
 
 
 
 
 
 
EKG (as indicated) 
X 
 
 
 
 
 
 
ECHO (as indicated)k 
X 
X---------------------------------------------------------------------------X 
 
Cardiac evaluationsl 
X 
X----------------------------------------------------------------------X 
 
Adverse event evaluation 
 
X-------------------------------------------------------------------X 
X 
Tumor measurementsj 
X 
Tumor measurements are repeated every 8 weeks.  
Documentation (radiologic) must be provided for patients 
removed from study for progressive disease. 
X 
B-HCG 
Xb 
 
 
 
 
 
 
Tumor d 
Xe 
 
 
 
 
 
 
Immune correlativesf  
 
X 
 
 
 
 
X 
Archival Tumor Tissueh 
X 
 
 
 
 
 
 

NCI Protocol #:9672 
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68 
 
A: Nivolumab:  3mg/kg IV administered over 60 minutes, every three weeks (+/- 2 days) for the first four 
cycles. Starting cycle 5, nivolumab will be given as monotherapy every two weeks (+/- 2 days) at a dose of 
3 mg/kg. 
 
B:  Ipilimumab:  1mg/kg IV administered over 90 minutes, every three weeks (+/- 2 days) for cycles 1-4.   
 
a: 
Laboratory testing prior to each dose: Within 72 hrs prior to re-dosing to include CBC w/ differential, 
LFTs, BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, Glucose, amylase, and lipase. TSH 
will be collected at screening and repeated every 6 weeks unless clinically indicated. Reflexive Free T4 and 
Free T3 will be collected at screening and repeated when clinically indicated. 
 
b:    A serum or urine pregnancy test is required at baseline for women of childbearing potential. 
 
  
c: 
Off-study evaluation.  AE assessment will be performed at 100 days following last dose of study drug. This 
may be done by phone. Patients who complete all planned protocol therapy (46 doses), will continue to be 
monitored for tumor measurements beyond completion of treatment until disease progression or the 
initiation of a new anticancer therapy.  
 
d:    Pre/post tumor biopsies will be required for all participants.  
 
e:    Pre-study tumor biopsy to be performed after eligibility is confirmed and patient is registered on study and 
prior to first dose of combination therapy with nivolumab + ipilimumab .  
 
f:   Peripheral blood will be drawn prior to study drug infusion for the first 4 cycles to assess changes in immune 
function as per section 9.2. Samples will also be drawn within 7 days of an objective response, and at off-
study. 
 
g:    Post-treatment biopsy will be performed at approximately week 4-6 (+/- 7 days) 
 
h:     Archival tissue specimen will be collected if available. This is not required prior to study drug dosing. 
 
i:     Testing for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome 
(AIDS), hepatitis B virus surface antigen (HBV sAg) and  hepatitis C virus ribonucleic acid (HCV 
antibody) indicating acute or chronic infection. These viral serologies may be performed within 28 days of 
registration. 
 
j.    Tumor assessments are repeated every 8 weeks (+/- 2 days) and should continue as per protocol regardless 
of dosing interruptions. 
 
k.    For patients with a history of congestive heart failure (CHF) or at risk because of underlying cardiovascular 
disease or exposure to cardiotoxic drugs, EKG and ECHO will be collected as clinically indicated. 
 
l.   For patients with evidence of CHF, myocardial infarction (MI), cardiomyopathy, or myositis, cardiac 
evaluation including lab tests and cardiology consultation (EKG, CPK, troponin levels, ECHO) will be 
conducted as clinically indicated.  
 
 
 
 

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69 
11 
MEASUREMENT OF EFFECT 
 
 
11.1 Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks (+/- 2 
days).  In addition to a baseline scan, confirmatory scans should also be obtained at least 4 weeks 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
All patients who receive at least one dose of nivolumab and ipilimumab each will be included in 
the toxicity analysis. This includes participants who receive study drug and are ultimately 
deemed ineligible. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with nivolumab and ipilimumab. 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area will not be 

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70 
considered measurable, unless there is clear evidence of progression of the lesion since 
completion of radiation and prior to enrollment on study.   
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in 
follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 

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71 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter 
as assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended.  
 
Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT 
scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   

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72 
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 

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73 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria: RECIST version 1.1. 
 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm (<1 cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm).  
(Note:  the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
[<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 

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74 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may 
beaccepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 

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75 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
Progression-Free Survival will be evaluated as a secondary objective.  PFS is defined as 
the duration of time from start of treatment to time of progression or death, whichever 
occurs first. 
 
11.1.7 Response Review 
 
At study completion, all objective responses (RECIST PR or CR) will be reviewed by the 
tumor imaging metrics core (TIMC) at the Dana-Farber Harvard Cancer Center. Patient 
files will be availble to the readers for concurrent review. 
 
11.2 
Antitumor Effect – Hematologic Tumors 
 
Not Applicable 
 
11.3 
Other Response Parameters 
 
Not Applicable 
 
 

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76 
12 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
During the Phase 2 portion of the study, the Protocol Principal Investigator will have, at a 
minimum, quarterly conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and pharmacovigilance.  Decisions to proceed to the 
second stage of a Phase 2 trial will require sign-off by the Protocol Principal Investigator and the 
Protocol Statistician. 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
12.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (https://eapps-ctep.nci.nih.gov/iam) and the 
appropriate Rave role (Rave CRA, Read-Only, or Site Investigator) on either the Corresponding 
Organization or Participating Organization roster at the enrolling site.   
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
 

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77 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.1.1 Method 
 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS). Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/CTMS.  On-site audits will be conducted three times annually 
(one annual site visit and two data audits).  For CTMS monitored studies, after users have 
activated their accounts, please contact the Theradex Help Desk at (609) 799-7580 or by 
email at ctms@theradex.com for additional support with Rave and completion of CRFs. 
 
 
12.1.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and 
assessed on a quarterly basis.  For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
)  and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include the recommended 

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phase 2 dose (RP2D), and a description of any dose-limiting toxicities (DLTs).  CTMS 
will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository 
(caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will 
be included when appropriate to meet unique study requirements.  The PI is encouraged 
to review the eCRFs, working closely with CTMS to ensure prospectively that all 
required items are appropriately captured in the eCRFs prior to study activation.  CTMS 
will prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex 
on a monthly basis.  The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
). 
 
12.2 
CTEP Multicenter Guidelines 
 
N/A  
 
12.3 
Collaborative Agreements Language 
 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 

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(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  

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Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
 
 
13 
STATISTICAL CONSIDERATIONS 
 
 
 
13.1 
Study Design/Endpoints 
 
COHORT A -  Study Design and Endpoints 
This is a phase II two-stage clinical trial with a primary endpoint of objective response per 
RECISTS 1.1 among patients with advanced ULMS treated with nivolumab. 
For the primary endpoint of overall response with a null hypothesis of 5% and an alternative 
hypothesis of 20% we would need 37 patients in a two-stage design with 12 patients in the first 
stage and 25 patients in the second stage. At the first stage analysis we will assess overall 
response, we will need to observe at least 1 response out of 12 patients to continue through the 
second stage. At the second stage we will assess overall response rate again, and we will need to 
observe at least 4 responses out of 37 patients to accept the treatment. The overall power for 
overall response rate is 90%. The overall type I error, the chance of incorrectly rejecting the null 
hypothesis is 9%. The probability of stopping at the first stage under the null hypothesis is 54%. 
The operating characteristics of this design are calculated using the exact binomial distribution. 
Subjects who continue treatment beyond initial investigator-assessed, RECIST 1.1-definedthe 
initial progression event but may be designated as delayed responses for purposes of determining 
ORR and counted as responses for two stage designs. 
Paired immediate pre-treatment and post- treatment biopsies will be obtained whenever 
possible in consenting patients, and in a minimum of 10 patients. If less than 10 patients have 
provided paired tumor biopsies, the remaining slots will give priority to obtain biopsies in the 
last group of 10 patients prior to completion of accrual. For the primary endpoint of overall 
response rate with the parameters as noted in section 13.1, a total sample size of 37 patients is 
needed in a two-stage design with 12 patients in the first stage and 25 patients in the second 
stage. A minimum accrual rate is expected to be 3 subjects per month. With a minimal accrual 
rate of 3 subjects per month, we expect the study enrollment tolast approximately 13 months. 
 
For Cohort A, 12 participants were accrued to the first stage. Since an objective response was not 
seen in the first stage of Cohort A, enrollment to the second stage did not begin.  
 
COHORT B – Study Design and Endpoints 
This phase II two-stage clinical trial will include patients with advanced ULMS treated with 

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nivolumab and ipilimumab with a primary endpoint of objective response per RECISTS 1.1 
among  
 
For the primary endpoint of overall response with a null hypothesis of 5% and an alternative 
hypothesis of 30% we would need 25 patients in a two-stage design with 8 patients in the first 
stage and 17 patients in the second stage.  At the first stage analysis we will assess overall 
response, we will need to observe at least 1 response out of 8 patients to continue through the 
second stage.  At the second stage, we will assess overall response rate again, and we will need 
to observe at least 3 responses out of 25 patients to accept the treatment.  The overall power for 
overall response rate is 94%.  The overall type I error, the chance of incorrectly rejecting the null 
hypothesis is 9%.  The probability of stopping at the first stage under the null hypothesis is 66%.  
The operating characteristics of this design are calculated using the exact binomial distribution. 
 
Subjects who continue treatment beyond initial investigator-assessed, RECIST 1.1-defined 
progression will be considered to have investigator-assessed progressive disease at the time of 
the initial progression event but may be designated as delayed responses for purposes of 
determining ORR and counted as responses for two stage designs. 
 
In order to assess the impact of immune checkpoint inhibition in this population, tissue will 
be acquired to analyze the integrated biomarkers and determine the potential drug effect in this 
disease. Biomarkers will be assessed from pre-treatment and post-treatment biopsies collected in 
a minimum of 10 patients on this study. During enrollment to Cohort A, one set of pre-treatment 
and post-treatment biopsies was collected; the additional 9 were not performed because the study 
did not progress to Stage II. In Cohort B, paired immediate pre-treatment and post- treatment 
biopsies will be collected in the first eight participants who enroll to the study (stage 1-Cohort 
B). For this cohort, participants are required to have disease that can be biopsied safely, as 
discussed in Section 3.1.11. Biopsies will be optional among participants enrolled in the second 
stage of cohort B.   
 
13.2 
Sample Size/Accrual Rate 
 
For the primary endpoint of overall response rate with the parameters as noted in section 13.1, a 
total sample size of 37 patients is needed in a two-stage design with 12 patients in the first stage 
and 25 patients in the second stage for Cohort A. For Cohort B, a total sample size of 25 patients 
is needed in a two-stage design with 8 patients in the first stage and 17 patients in the second 
stage. A minimum accrual rate is expected to be 3 subjects per month.  With a minimal accrual 
rate of 3 subjects per month, we expect the study enrollment to last approximately 9 months.   
PLANNED ENROLLMENT REPORT- COHORT A (Closed to Accrual) 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
1 
NA 
_ 
NA 
1 
Asian 
1 
NA 
_ 
NA 
1 

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82 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
Native Hawaiian or 
Other Pacific Islander 
1 
NA 
_ 
NA 
1 
Black or African 
American 
1 
NA 
1 
NA 
2 
White 
31 
NA 
1 
NA 
32 
More Than One Race 
- 
NA 
- 
NA 
- 
Total 
35 
_ 
2 
_ 
37 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 
 
 

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83 
PLANNED ENROLLMENT REPORT- COHORT B 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
1 
NA 
_ 
NA 
1 
Asian 
1 
NA 
_ 
NA 
1 
Native Hawaiian or 
Other Pacific Islander 
1 
NA 
_ 
NA 
1 
Black or African 
American 
1 
NA 
1 
NA 
2 
White 
19 
NA 
1 
NA 
20 
More Than One Race 
- 
NA 
- 
NA 
- 
Total 
23 
_ 
2 
_ 
25 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 
13.3 
Stratification Factors 
 
There are no planned stratification factors in this study. 
 
13.4 
Analysis of Secondary Endpoints 
 
COHORT A – SECONDARY ENDPOINTS 
We will also assess toxicity in patients with ULMS treated with nivolumab.  Among the 
first phase of 12 patients, there is at least 58% probability of observing one or more rare 
(7% true probability) events, and 83% probability of observing toxicities that have a true 
occurrence of at least 15%.  Among the total cohort of 37 patients, there is at least 85% 
probability of observing one or more rare (5% true probability) events, and 95% 
probability of observing toxicities that have a true occurrence of at least 8%.  With 37 
treated patients, the maximum width of a 90% two-sided exact binomial confidence 
interval for any estimated adverse event proportion will be no wider than ± 14%. 
 
Rate of Progression-free survival at 12 weeks with a null hypothesis of 20% and an 
alternative hypothesis of 40% at 12 weeks will be investigated.  Patients lost to follow-
up or deaths within 12 weeks will be counted as failures.  The overall power for overall 
progression-free rate at 12 weeks is 87%, using the exact binomial distribution.  The 

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operating characteristics of this design are calculated using a one-sided exact test with 
10% type I error. 
 
COHORT B – SECONDARY ENDPOINTS 
 
 
Toxicity: Among the first phase of 8 patients, there is at least 57% probability of observing one 
or more rare (10% true probability) events, and 73% probability of observing one or more 
toxicities that have a true occurrence rate  as low as15%.  Among the total cohort of 25 patients, 
there is at least 84% probability of observing one or more rare (7% true probability) events, and 
93% probability of observing toxicities that have a true occurrence of at least 10%.  With 25 
treated patients, the maximum width of a 90% two-sided exact binomial confidence interval for 
any estimated adverse event proportion will be no wider than ± 18%. 
 
Rate of Progression-free survival at 6 months with a null hypothesis of 18% and an alternative 
hypothesis of 40% at 6 months will be investigated.  Patients lost to follow-up or deaths within 6 
months will be counted as failures.  The overall power for overall progression-free rate at 6 
months is 85%, using the exact binomial distribution.  The operating characteristics of this 
design are calculated using a one-sided exact test with 10% type I error. 
 
In addition, we will explore the relationship between integrated biomarkers PDL1/PD1/PD2 
status (PDL1 status, PDL1 in infiltrating lymphocytes, PD2 status in archival tumor) and 
response to combination treatment of nivolumab and ipilimumab.  We will use Fisher’s Exact 
Test to assess the relationship between each biomarker and response to combination treatment of 
nivolumab and ipilimumab. Each is expected to have similar characteristics. For example, with 
this design, assuming tissue is available on 90% of the sample, the probability of concluding 
combination treatment of nivolumab and ipilimumab response is related to the exploratory 
biomarker is 80%; given the unknown true response is 55% and 4% in positive marker versus 
negative marker patients, respectively, assuming 33% of the population is over-expressed for 
PDL1.  The power to detect the relationship of interest increases as the prevalence of the 
biomarker increases. The operating characteristics of this design are calculated using a two-sided 
exact test with 10% type I error. 
 
13.5 
Analysis of Exploratory Objectives 
COHORT A AND B 

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• Explore the relationship between tumor CSF1 gene signature by RNA analysis and 
response to combination treatment of nivolumab and ipilimumab. 
 
• Explore the relationship of potential biomarkers associated with disease control of 
ULMS treated with combination treatment of nivolumab and ipilimumab by 
evaluating biomarkers within the tumor microenvironment and the periphery. 
 
We will use non-parametric tests to assess the relationships listed above and response to 
combination treatment of nivolumab and ipilimumab. Logistic regression will be used for 
response measured outcomes. Outcome relationships will be largely explorative and 
descriptive.  
 
13.6 
Reporting and Exclusions 
 
13.6.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
nivolumab and ipilimumab. All patients who receive at least one dose of nivolumab and 
ipilimumab will be included in the toxicity analysis. This includes participants who 
receive study drug and are ultimately deemed ineligible. 
 
13.6.2 Evaluation of Response 
 
All eligible patients included in the study must be assessed for response to treatment, 
even if there are major protocol treatment deviations or if they are ineligible.  Each 
patient will be assigned one of the following categories:  1) complete response, 2) partial 
response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 
6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not 
assessable, insufficient data).  [Note:  By arbitrary convention, category 9 usually 
designates the “unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.  The 95% confidence intervals should also be provided.  
 

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14 
STUDY STATUS UPDATES AND STUDY CLOSURE 
 
14.1 
Definitions of Study Status Changes 
 
14.1.1 Temporarily Closed to Accrual 
 
The study status is Temporarily Closed to Accrual when no patient slots are currently 
available, but there is the possibility that the trial will re-open for accrual (patient slots 
become available).  Sites are not permitted to accrue additional patients until CTEP is 
notified of Re-Activation. 
 
Study status will need to be changed to Temporarily Closed to Accrual when any of the 
following criteria are met: 
 
 
• Sites are notified by CTEP (via Request for Rapid Amendment [RRA]) of 
changes in the risk/benefit ratio that necessitate changes to the patient Informed 
Consent document.  Requested changes will be specified in the RRA and must be 
reviewed by the study’s IRB. 
• CTEP and the lead investigator agree that unacceptable toxicities necessitate a 
discussion to change the dosing/regimen. 
• A protocol-defined benchmark has been achieved (such as an interim analysis 
before proceeding to the next stage).  
 
14.1.2 Closed to Accrual 
 
The study status is (permanently) Closed to Accrual when no more patient enrollment 
slots are available, and at least one patient is still actively receiving the study treatment.  
Sites are no longer permitted to enroll additional patients. 
 
Patient slots are no longer available when the following criteria are met: 
 
 
• The pre-specified number of evaluable patients has been successfully enrolled, 
treated, and evaluated. 
• The study treatment has failed to meet the pre-specified efficacy goal at the stage 
1 interim analysis. 
• CTEP and the investigators agree that unacceptable toxicities preclude further 
enrollment. 
 
14.1.3 Closed to Accrual and Treatment 
 
The study status is Closed to Accrual and Treatment when no more patient enrollment 
slots are available and no patients are currently receiving the study treatment.  Patients 
may still be enrolled on the protocol only for the purposes of follow-up. 

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Patient accrual and treatment will be permanently halted when any of the following 
criteria are met: 
 
• Enrollment was previously closed (study status of “Closed to Accrual”), and no 
patients are receiving the study treatment. 
• CTEP and the investigators agree that unacceptable toxicities preclude further 
enrollment.  In this case, CTEP and the investigators must collaborate to alter the 
regimen or to halt the study treatment altogether as soon as it can be safely done 
for patients currently receiving treatment.  
 
CTEP and Theradex must be notified when patients are no longer receiving treatment 
[i.e., when the last patient(s) to be receiving treatment is/are no longer receiving the study 
regimen for any reason]. 
 
14.1.4 Closed to Follow-Up 
 
The study is considered Closed to Follow-Up when all protocol-defined follow-up 
procedures have been completed for all patients who have not been removed from the 
study for other reasons.  That is, there are no outstanding follow-up procedures to be 
performed as mandated by the protocol. 
 
CTEP does not need to be notified of a status change to “Closed to Follow Up.” 
 
14.1.5 Complete 
 
Study is considered Complete if it has been at least thirty (30) days since the last patient 
follow-up evaluation.   
 
A citation to a final study report (manuscript, meeting abstract, etc.) is required with the 
submission of the Protocol Status Update Form to CTEP PIO.   
 
 
14.2 
Responsibility for Filing Protocol Status Update Forms 
 
CTEP must be notified of all study status changes in Section 14.1 (except for Closed to Follow-
Up) by the Corresponding Organization via Protocol Status Update Form, available from the 
CTEP website at http://ctep.cancer.gov/protocolDevelopment/default.htm#amendments.    
 
Theradex must be notified as soon as all patients are off treatment (i.e., when study status 
changes to Closed to Accrual and Treatment).  Theradex will produce a report within 90 days of 
this notification. 
 
 

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 

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APPENDIX B 
MANAGEMENT ALGORITHMS FOR ENDOCRINOPATHY, 
GASTROINTESTINAL, HEPATIC, NEUROLOGICAL, PULMONARY, RENAL, AND 
SKIN ADVERSE EVENTS 

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