Immune Checkpoint Blockade for Kidney Transplant Recipients With Selected Unresectable or Metastatic Cancers
Phase: PHASE1
Conditions: Clinical Stage III Cutaneous Melanoma AJCC v8, Clinical Stage III Cutaneous Merkel Cell Carcinoma AJCC v8, Clinical Stage IV Cutaneous Melanoma AJCC v8, Clinical Stage IV Cutaneous Merkel Cell Carcinoma AJCC v8, Metastatic Basal Cell Carcinoma, Metastatic Melanoma, Metastatic Merkel Cell Carcinoma, Metastatic Skin Squamous Cell Carcinoma, Pathologic Stage III Cutaneous Melanoma AJCC v8, Pathologic Stage III Cutaneous Merkel Cell Carcinoma AJCC v8, Pathologic Stage IIIA Cutaneous Melanoma AJCC v8, Pathologic Stage IIIA Cutaneous Merkel Cell Carcinoma AJCC v8, Pathologic Stage IIIB Cutaneous Melanoma AJCC v8, Pathologic Stage IIIB Cutaneous Merkel Cell Carcinoma AJCC v8, Pathologic Stage IIIC Cutaneous Melanoma AJCC v8, Pathologic Stage IIID Cutaneous Melanoma AJCC v8, Pathologic Stage IV Cutaneous Melanoma AJCC v8, Pathologic Stage IV Cutaneous Merkel Cell Carcinoma AJCC v8, Unresectable Basal Cell Carcinoma, Unresectable Melanoma, Unresectable Merkel Cell Carcinoma
Sponsor: National Cancer Institute (NCI)

NCI Protocol #:  10214 
Version Date: January 28, 2021 
 
i 
DATE: 
January 28, 2021 
 
TO: 
CTEP Protocol and Information Office 
 
FROM: 
Evan Lipson, MD 
 
SUBJECT: 
Amendment in response to the request for rapid amendment from Dr. Streicher, 
NCI, dated 01/28/2021. 
 
I. 
SUMMARY OF CHANGES – Protocol 
 
# 
Section 
Comments 
1. 
Header, 
Title Page 
Updated version date. 
2. 
10.1.1 
Updated revised CAEPR to Version 2.4, December 2, 2020, with the following 
changes: 
• The SPEER grades have been updated. 
• Added New Risk: 
• Less Likely: CD4 lymphocytes decreased 
• Rare: Enterocolitis; Eye disorders - Other (Vogt-Koyanagi-
Harada); Hepatobiliary disorders - Other (immune-mediated 
hepatitis); Renal and urinary disorders - Other (immune-
mediated nephritis) 
• Modified Specific Protocol Exceptions to Expedited Reporting 
(SPEER) reporting requirements:  
• Added: CD4 lymphocytes decreased 
• Provided Further Clarification: 
• Immune system disorders - Other (sarcoid granuloma) is now 
reported as Immune system disorders - Other (sarcoidosis). 
 
II. 
SUMMARY OF CHANGES – Consent Form 
 
# 
Section 
Comments 
1. 
Header 
Updated version date. 
2. 
Possible Side Effects of 
Nivolumab 
Added new risks to Rare, and Serious as requested in the RRA: 
• A syndrome starting with flu-like symptoms and followed 
by swelling, tenderness which may cause flu-like 
symptoms, blurred vision, ringing in the ears, changes in 
hair or hair loss 
• Swelling of the bowels 
 
 
 

NCI Protocol #:  10214 
Version Date: January 28, 2021 
 
ii 
Provided Further Clarification: 
• 
Hormone gland problems (especially the thyroid, pituitary and 
adrenal glands, and pancreas). Signs and symptoms may 
include: headaches that will not go away or unusual headaches, 
extreme tiredness or changes in mood or behavior; decreased sex 
drive; weight loss or weight gain; excessive thirst or urine; 
dizziness or fainting is now reported as Hormone gland 
problems (especially the thyroid, pituitary and adrenal glands, 
and pancreas). Signs and symptoms may include: headaches that 
will not go away or unusual headaches, extreme tiredness or 
changes in mood or behavior; decreased sex drive; weight loss 
or weight gain; excessive thirst or urination; dizziness or 
fainting. 
• 
A syndrome starting with flu-like symptoms and followed by 
swelling, tenderness which may cause flu-like symptoms, blurred 
vision, ringing in the ears, changes in hair or hair loss is now 
reported as A syndrome starting with flu-like symptoms and 
followed by swelling, tenderness which may cause blurred vision, 
ringing in the ears, changes in hair or hair loss 
• 
Swelling of the brain (meningitis/encephalitis) which may cause: 
headache, stiff neck confusion, sleepiness, seizures or injury to 
the brain which may cause headache, seizure, blindness (also 
known as Reversible Posterior Leukoencephalopathy Syndrome) 
is now reported as Swelling of the brain (meningitis/encephalitis) 
which may cause: headache, stiff neck confusion, sleepiness, 
seizures or injury to the brain which may cause headache, 
blindness (also known as Reversible Posterior 
Leukoencephalopathy Syndrome) 

NCI Protocol #:  10214 
Version Date: January 28, 2021 
 
1 
NCI Protocol #: 
10214 
 
Local Protocol #: 
ETCTN10214 
 
ClinicalTrials.gov Identifier:  NCT03816332 
 
TITLE: Immune Checkpoint Blockade for Kidney Transplant Recipients with Selected 
Unresectable or Metastatic cancers 
 
Corresponding Organization: LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer 
Center LAO 
 
Principal Investigator: 
Evan J. Lipson, MD 
Johns Hopkins University School of Medicine 
1550 Orleans St 
Room 507 
Baltimore, MD 21287 
Tel:  410-502-5977 
Fax:  410-502-1958 
evanlipson@jhmi.edu 
 
Participating Organizations 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
EDDOP / Early Drug Development Program 
 
 
Statistician: 
Study Contact: 
 
Hao Wang 
Judy Murray 
 
550 N Broadway 
Johns Hopkins University 
 
Rm 1101 
201 N. Broadway, Suite 9130 
 
Baltimore, MD 21205 
Baltimore, MD 21287 
 
Tel:  410-614-3426 
Tel: 410-955-4044 
 
Fax:  410-955-0859 
jmurra33@jhmi.edu  
 
hwang76@jhmi.edu 
 

NCI Protocol #:  10214 
Version Date: January 28, 2021 
 
2 
 
NCI-Supplied Agents: Nivolumab (NSC 748726) 
 
Ipilimumab (NSC 732442) 
 
Other Agents: 
Tacrolimus (NSC 717865), Commercial 
 
Prednisone (NSC 10023), Commercial 
 
 
IND #:   
IND Sponsor:  DCTD, NCI 
 
 
Protocol Type / Version # / Version Date: 
Original / July 27, 2018 
 
Revision 1 / October 17, 2018 
 
Revision 2 / January 7, 2019 
 
Amendment 1 / February 27, 2019 
 
Amendment 2 / March 20, 2019 
 
Amendment 3 / April 23, 2019 
 
Amendment 4 / May 17, 2019 
 
Amendment 5 / August 5, 2019 
 
Amendment 6 / October 9, 2019 
 
Amendment 7 / December 10, 2019 
 
Amendment 8 / September 23, 2020 
 
Amendment 9 / January 28, 2021 
 
 

NCI Protocol #:  10214 
Version Date: January 28, 2021 
 
3 
SCHEMA 
 
 
 
 
CR=complete response, PR=partial response, SD=stable disease 
Consent 
Registration1 
Immunosuppression regimen modification1 
Nivolumab for up to 16 weeks 
Continue nivolumab 
for up to 96 total 
weeks 
Decrease or discontinue 
immunosuppression; 
continue nivolumab for 
up to 96 total weeks 
OR 
Initiate nivolumab + 
ipilimumab (up to 12 weeks) 
followed by maintenance 
nivolumab (up to 84 weeks 
regardless of duration of 
nivolumab monotherapy) 
Continue nivolumab 
monotherapy beyond 
progression 
(see section 6.6) 
CR, PR, or SD 
Progressive disease 
CR, PR, or SD 
Progressive 
disease 
OR 
1 Protocol-specified immunosuppression regimen may begin prior to registration. Patients whose 
tacrolimus trough level is not yet within the protocol-specified range of 2-5 ng/ml may start 
nivolumab after consultation with the Principal Investigator.  
- Patients who experience CR/PR/SD followed by disease progression within 1 year of last 
Nivolumab dose may be eligible to restart nivolumab therapy (see Section 6.5) 
- All patients will be followed for survival for 5 years from the date of trial registration or until 
death, whichever occurs first (see Section 6.8) 

NCI Protocol #:  10214 
Version Date: January 28, 2021 
 
4 
TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................6 
1.1 
Primary Objective ....................................................................................................6 
1.2 
Secondary Objectives ...............................................................................................6 
1.3 
Exploratory Objective ..............................................................................................6 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Study Disease ...........................................................................................................7 
2.2 
CTEP IND Agents ...................................................................................................9 
2.3 
Other Agents ..........................................................................................................14 
2.4 
Rationale ................................................................................................................15 
2.5 
Correlative Studies Background ............................................................................17 
3. 
PATIENT SELECTION ....................................................................................................19 
3.1 
Eligibility Criteria ..................................................................................................19 
3.2 
Exclusion Criteria ..................................................................................................21 
3.3 
Inclusion of Women and Minorities ......................................................................22 
4. 
REGISTRATION PROCEDURES ...................................................................................24 
4.1 
Investigator and Research Associate Registration with CTEP ..............................24 
4.2 
Site Registration .....................................................................................................25 
4.3 
Patient Registration ................................................................................................27 
4.4 
General Guidelines .................................................................................................29 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................30 
5.1 
Summary Table for Specimen Collection ..............................................................30 
5.2 
Specimen Procurement Kits and Scheduling .........................................................31 
5.3 
Specimen Tracking System Instructions ................................................................31 
5.4 
Specimen Collection ..............................................................................................35 
5.5 
Shipping of Specimens from Clinical Site to Other Laboratories .........................38 
5.6 
Biomarker Plan ......................................................................................................40 
5.7 
Exploratory/Ancillary Correlative Studies ............................................................41 
6. 
TREATMENT PLAN ........................................................................................................43 
6.1 
Agent Administration .............................................................................................43 
6.2 
Week 16 Assessment .............................................................................................45 
6.3 
Nivolumab with Ipilimumab ..................................................................................46 
6.4 
Treatment Beyond Progression ..............................................................................47 
6.5 
Criteria to Resume Treatment ................................................................................47 
6.6 
General Concomitant Medication and Supportive Care Guidelines ......................48 
6.7 
Duration of Therapy ...............................................................................................48 
6.8 
Duration of Follow Up ...........................................................................................49 
6.9 
Treatment of Nivolumab- or Ipilimumab-Related Infusion 
Reactions ................................................................................................................49 
7. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................52 
7.1 
Nivolumab and Ipilimumab Dose Modifications ..................................................52 

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5 
7.2 
Prednisone and Tacrolimus Dose Modifications for Allograft 
Rejection ................................................................................................................59 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................61 
8.1 
CTEP IND Agent(s) ...............................................................................................61 
8.2 
Commercial Agent(s) .............................................................................................65 
9. 
STATISTICAL CONSIDERATIONS...............................................................................67 
9.1 
Study Design/Endpoints.........................................................................................67 
9.2 
Sample Size/Accrual Rate ......................................................................................67 
9.3 
Stratification Factors ..............................................................................................68 
9.4 
Analysis of Primary Endpoints ..............................................................................68 
9.5 
Analysis of Secondary Endpoints ..........................................................................68 
9.6 
Reporting and Exclusions ......................................................................................69 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................71 
10.1 
Comprehensive Adverse Events and Potential Risks Lists 
(CAEPRs) ..............................................................................................................71 
10.2 
Adverse Event Characteristics ...............................................................................82 
10.3 
Expedited Adverse Event Reporting ......................................................................82 
10.4 
Routine Adverse Event Reporting .........................................................................85 
10.5 
Pregnancy ...............................................................................................................85 
10.6 
Secondary Malignancy ...........................................................................................85 
10.7 
Second Malignancy ................................................................................................86 
11. 
STUDY CALENDARS .....................................................................................................87 
11.1 
Nivolumab Monotherapy .......................................................................................87 
11.2 
Nivolumab-Ipilimumab Combination Therapy .....................................................89 
12. 
MEASUREMENT OF EFFECT........................................................................................92 
12.1 
Antitumor Effect – Solid Tumors ..........................................................................92 
12.2 
Other Response Parameters ...................................................................................98 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................99 
13.1 
Study Oversight .....................................................................................................99 
13.2 
Data Reporting .....................................................................................................100 
13.3 
CTEP Multicenter Guidelines ..............................................................................102 
13.4 
Collaborative Agreements Language ...................................................................102 
14. 
REFERENCES ................................................................................................................104 
APPENDIX A. 
PERFORMANCE STATUS CRITERIA ................................................108 
APPENDIX B. 
MANAGEMENT ALGORITHMS FOR ENDOCRINOPATHY, 
GASTROINTESTINAL, HEPATIC, NEUROLOGICAL, PULMONARY, 
RENAL, AND SKIN ADVERSE EVENTS ...................................................................109 
APPENDIX C. 
MEDICATION DIARIES .......................................................................116 
C.1 
Medication Diary for Tacrolimus ........................................................................117 
C.2 
Medication Diary for Prednisone .........................................................................118 
APPENDIX D. 
PATIENT CLINICAL TRIAL WALLET CARD ...................................119 
APPENDIX E. 
cfDNA Collection ....................................................................................120 

NCI Protocol #:  10214 
Version Date: January 28, 2021 
 
6 
1. OBJECTIVES 
 
1.1 
Primary Objective 
 
1.1.1 To estimate the percent of kidney transplant recipients with selected advanced cancers for 
whom standard therapies would be insufficient who, 16 weeks after administration of 
prednisone, tacrolimus, and nivolumab, experience complete response (CR), partial 
response (PR), or stable disease (SD) without allograft loss. 
 
1.2 
Secondary Objectives 
 
1.2.1 To estimate the objective response rate (ORR), rate of allograft loss, and durations of 
progression-free survival (PFS) and overall survival (OS) in the study population. 
 
1.2.2 To estimate the ORR and rate of allograft loss in patients who experience progressive 
disease (PD) after administration of nivolumab and 1) receive ipilimumab and 
nivolumab, or 2) decrease or discontinue immunosuppression. 
 
1.3 
Exploratory Objective 
 
1.3.1 To characterize correlates of the host immune response, possibly including, but not 
limited to: 
• Histopathological characteristics of allograft rejection/loss; 
• Immunological changes in the tumor microenvironment (e.g., changes in T-cell 
subset populations or expression of immune checkpoint molecules) in paired biopsies 
obtained pre-treatment and on-treatment; 
• Changes in donor-derived cell-free DNA (dd-cfDNA) as a marker for allograft 
rejection; 
• Characteristics of anti-programmed death-1 (PD-1)-associated immune-mediated 
adverse reactions (IMARs) in this patient population treated with 
immunosuppression. 
 
 

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Version Date: January 28, 2021 
 
7 
2. 
BACKGROUND 
 
2.1 
Study Disease 
 
2.1.1 Solid Organ Transplant Recipients (SOTRs) 
 
Compared to the general population, SOTRs are at significantly increased risk of developing 
various cancers (Euvrad et al., 2003; Vajdic et al., 2006; Vajdic and van Leeuwen, 2009).  
Although multiple pathogenic factors are likely at play, immune dysregulation from the chronic 
immunosuppressive drug regimens required to maintain allograft tolerance is among the most 
important.  Clinical evidence and murine transplant model data show that the PD-1 pathway is 
important to maintaining allograft tolerance among SOTRs (Tanaka et al., 2007).  Indeed, 
limited published data (Table 1) suggest that while anti-PD-1 therapy may be an effective cancer 
treatment strategy for SOTRs, they may also trigger allograft rejection and loss. 
 
2.1.2 Selected Advanced Cancers 
 
Several factors led to the inclusion of only selected tumor types in the proposed study.  First, the 
risk-benefit ratio may be more favorable among patients with tumor types known to have higher 
response rates in the general population to anti-PD-1, such as melanoma, and Merkel cell 
carcinoma (MCC), than among patients with tumor types with lower response rates, such as lung 
or urothelial cancers.  See Section 2.2.1.2.2 for nivolumab efficacy data.  Second, by including 
only patients with higher response rates, the study cohort size can be limited to 16 patients (see 
Section 9, Statistical Considerations), thereby increasing the feasibility of the trial.  Of note, 
cutaneous cancers are the most common malignancies found in organ transplant recipients 
(Chapman et al., 2013). 
 

NCI Protocol #:  10214 
Version Date: January 28, 2021 
 
8 
Table 1:  Summary of outcomes from published reports of anti-PD-1 therapy in SOTRs. 
 
Transplanted 
organ 
Years from 
transplant 
Type of cancer 
Checkpoint 
inhibitor treatment 
Tumor regression 
Immuno-suppression 
Graft 
rejection/loss 
Reference 
Kidney (HLA 
mismatch) 
15 
Melanoma 
Ipilimumab followed 
by pembrolizumab 
NR 
Prednisone 
Yes / Yes 
Alhamad et al., 
2016. 
Kidney 
8 
Melanoma 
Ipilimumab followed 
by nivolumab 
No 
Prednisone 5 mg daily, 
tacrolimus 2 mg twice 
daily 
No / No 
Herz et al., 
2016. 
Kidney 
26 
Cutaneous squamous cell 
carcinoma 
Pembrolizumab 
Yes 
Prednisone 5 mg daily 
Yes / Yes  
Lipson et al., 
2016. 
Kidney 
14 
Melanoma 
Ipilimumab followed 
by nivolumab 
Yes 
Prednisolone 5 mg daily 
Yes / Yes 
Spain et al., 
2016. 
Kidney 
3 
NSCLC 
Nivolumab 
NR 
Prednisone, cyclosporine 
(goal trough level <50 
ng/mL) 
Yes / NR  
Boils et al., 
2016. 
Kidney 
12 
Melanoma 
Nivolumab 
Yes 
Prednisone 5 mg daily 
Yes / Yes 
Ong et al., 
2016. 
Kidney (HLA 
mismatch) 
6 
Microsatellite-stable 
duodenal adenocarcinoma 
Nivolumab 
Resolution of FDG-
avidity associated with 
hepatic metastases 
Prednisone, sirolimus 
No / No 
Barnett et al., 
2017. 
Heart 
19 
Cutaneous squamous cell 
carcinoma 
Nivolumab 
NR 
Prednisone, tacrolimus 
Yes / NR 
Owonikoko et 
al., 2017. 
Liver 
3 
Hepatocellular carcinoma, 
fibrolamellar type 
Nivolumab 
NR 
Sirolimus 
Yes / Yes 
Friend et al., 
2017. 
Liver 
1 
Hepatocellular carcinoma, 
fibrolamellar type 
Nivolumab 
NR 
Tacrolimus 
Yes / Yes 
Kidney 
14 
Cutaneous squamous cell 
carcinoma 
Nivolumab 
Stable disease 
Prednisone 5 mg daily, 
Sirolimus 
No / No 
Kittai et al., 
2017. 
Heart 
10 
Squamous NSCLC 
Nivolumab 
Stable disease at 8 
months 
Mycophenolate mofetil, 
cyclosporine 
No / No 
Liver 
20 
Melanoma 
Pembrolizumab 
Yes 
Prednisone, tacrolimus, 
Yes / No 
Schvartsman et 
al., 2017. 
Kidney 
14 
Melanoma 
Pembrolizumab 
No 
Azathioprine, everolimus Yes / Yes 
Kwatra et al., 
2017. 
HLA=human leukocyte antigen, NR=not reported, NSCLC=non-small cell lung cancer 
 
 

NCI Protocol #:  10214 
Version Date: January 28, 2021 
 
9 
 
2.2 
CTEP IND Agents 
 
2.2.1 Nivolumab 
 
Nivolumab (BMS-936558, MDX-1106, ONO-4538, Opdivo™) is a fully human monoclonal 
immunoglobulin G4 (IgG4) antibody (HuMAb) that is specific for human PD-1, cluster of 
differentiation 279 (CD279) cell surface membrane receptor (Nivolumab Investigator’s 
Brochure, 2018).  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 a variety of 
cancers.  The combination of nivolumab and ipilimumab, an anti-cytotoxic T lymphocyte 
associated antigen-4 (anti-CTLA-4) agent, in a phase 1/2 trial showed markedly enhanced 
clinical activity with an acceptable safety profile in melanoma patients (Wolchok et al., 2013).  
See Section 2.2.2 for more information about ipilimumab. 
 
The clinical use of monoclonal antibodies to T-cell inhibitory receptors has provided 
transformative information on the nature of the immune system and cancer (Nivolumab 
Investigator’s Brochure, 2018).  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 OS with or 
without radiographic responses or improved 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, cellular 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) (Nivolumab Investigator’s 
Brochure, 2018).  PD-1 is transiently, but highly expressed on activated T-cells and functions 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 (T-cell immunoglobulin mucin 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 

NCI Protocol #:  10214 
Version Date: January 28, 2021 
 
10 
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. 
 
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 (Nivolumab Investigator’s Brochure, 2018). 
 
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 × 4) 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 (Nivolumab Investigator’s Brochure, 2018).  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 dissociation constant (Kd) of 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 has demonstrated clinical activity, and has been approved for use in non-small cell 
lunch cancer (NSCLC), melanoma, renal cell carcinoma (RCC), classical Hodgkin’s Lymphoma 
(cHL), squamous cell carcinoma (SCC) of the head and neck, and urothelial carcinoma as 
monotherapy and in combination with ipilimumab and other therapeutics (Nivolumab 
Investigator’s Brochure, 2018).  It has also demonstrated activity in other tumor types.  The 
majority of responses were durable and exceeded 6 months.  In randomized, controlled studies, 
nivolumab monotherapy demonstrated statistically significant improvement in OS over standard 

NCI Protocol #:  10214 
Version Date: January 28, 2021 
 
11 
of care in subjects with advanced or metastatic melanoma, subjects with advanced or metastatic 
NSCLC, subjects with advanced RCC, and subjects with recurrent or metastatic SCCHN.  In 
randomized, controlled studies, nivolumab in combination with ipilimumab demonstrated 
statistically significant improvement in PFS and ORR over ipilimumab monotherapy in subjects 
with advanced or metastatic melanoma. 
 
Nivolumab monotherapy (Opdivo™) was first approved on July 4, 2014 in Japan for 
unresectable melanoma and followed by approval in multiple countries, including the U.S., and 
in the E.U.  Since then it has been approved for several other indications, including metastatic 
NSCLC, advanced RCC, cHL, and urothelial carcinoma.  Nivolumab is also approved in 
combination with ipilimumab (Yervoy™) for unresectable or metastatic melanoma. 
 
Nivolumab is also being evaluated in several other cancers, including small cell lung cancer 
(SCLC), gastric and esophageal cancer, hepatocellular carcinoma, colorectal cancer, 
glioblastoma, and MCC. 
 
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, 2018).  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 nivolumab is 17 to 25 days consistent 
with the half-life of endogenous IgG4.   
 
2.2.1.2.2 
Efficacy 
 
In a randomized, open-label, phase 3 trial, patients with unresectable or metastatic melanoma 
who had progressed after treatment with ipilimumab were given either IV nivolumab (3 mg/kg 
every 2 weeks) or investigator’s choice chemotherapy (ICC; dacarbazine 1000 mg/m2 every 3 
weeks or paclitaxel 175 mg/m2 combined with carboplatin area under the curve [AUC] = 6 every 
3 weeks) (Weber et al., 2015).  Of the first 120 patients treated with nivolumab, objective 
responses (CR or PR) were seen in 38 (31.7%) versus 5 (10.6%) out of 47 patients in the ICC 
arm.  Grade 3-4 adverse events (AEs) related to nivolumab included increased lipase, increased 
alanine aminotransferase, anemia, and fatigue.  Grade 3-4 drug-related serious adverse events 
(SAEs) were noted in 12 (5%) nivolumab-treated patients.  No treatment-related deaths occurred. 
 
In a phase 1/2 trial, patients with virus-positive and -negative solid tumors, including MCC, were 
given 240 mg nivolumab IV every 2 weeks (Nivolumab Investigator’s Brochure, 2018).  As of 
the February 16, 2017 data cutoff, of 25 patients with MCC who had received nivolumab, 
objective responses (PR or CR) were seen in 16 patients (64%, 95% confidence interval [CI] 
42.5%-82%).  Median duration of response (DOR), PFS, and OS have not been reached. 
 

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In a randomized, open-label, phase 3 trial, patients with recurrent SCC of the head and neck were 
given either IV nivolumab (3 mg/kg every 2 weeks) or standard systemic therapy (methotrexate, 
docetaxel, or cetuximab) (Ferris et al., 2016).  The median OS was 7.5 months (95% CI, 5.5 to 
9.1 months) in the nivolumab group versus 5.1 months (95% CI, 4 to 6 months) in the group that 
received standard therapy.  OS was significantly longer with nivolumab than with standard 
therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the estimates of the 
1-year survival rate were approximately 19% higher with nivolumab than with standard therapy 
(36.0% vs. 16.6%).  The median PFS was 2 months (95% CI, 1.9 to 2.1 months) with nivolumab 
versus 2.3 months (95% CI, 1.9 to 3.1 months) with standard therapy (hazard ratio for disease 
progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32).  The PFS rate at 6 months was 19.7% 
with nivolumab versus 9.9% with standard therapy.  The response rate was 13.3% in the 
nivolumab group versus 5.8% in the standard-therapy group.  Treatment-related AEs of grade 3 
or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the 
standard-therapy group.  Physical, role, and social functioning was stable in the nivolumab 
group, whereas it was meaningfully worse in the standard-therapy group. 
 
In an open-label, phase 2 trial, patients with recurrent or metastatic colorectal cancer assessed as 
MSI-high were given 3 mg/kg IV nivolumab every 2 weeks as monotherapy, or in combination 
with 1 mg/kg IV ipilimumab every 3 weeks for 4 doses followed by 3 mg/kg IV nivolumab 
every 2 weeks (Nivolumab Investigator’s Brochure, 2018; Overman et al., 2017).  As of the 
September 19, 2016 data cut-off, 74 patients had received nivolumab monotherapy and 30 had 
received combination nivolumab/ipilimumab therapy.  At a median follow-up of 12 months, 23 
of 74 nivolumab-treated patients (31.1%, 95% CI, 20.8%-42.9%) achieved an objective response 
and 51 patients (69%, 95% CI, 57%-79%) had disease control for 12 weeks or longer.  As of the 
data cut-off, median DOR had not yet been reached; all responders were alive, and eight had 
responses lasting 12 months or longer (Kaplan-Meier 12-month estimate 86%, 95% CI, 62%-
95%).  Median PFS was 7.6 months (95% CI, 3 months-NR).  The 6- and 12-month PFS rates 
were 51.5% (95% CI, 38.9%-62.8%) and 45.6% (95% CI, 32.2%-58.1%), respectively.  The 6- 
and 12-month OS rates were 83.4% (95% CI, 72.5%-90.2%) and 73.8% (95% CI, 59.8%-
83.5%), respectively.  The most common grade 3 or 4 drug-related AEs were increased 
concentrations of lipase (six patients, 8%) and amylase (two patients, 3%).  Twenty-three 
patients (31%) died during the study; none of these deaths were deemed to be treatment related 
by the investigator.  Out of 30 patients who had received nivolumab and ipilimumab 
combination therapy, 27 were evaluable for response (Nivolumab Investigator’s Brochure, 
2018).  Of these, objective responses were seen in 9 patients (33.3%, 95% CI, 18.6%-50.9%).  
The 6-month PFS rate was 66.6% (95% CI, 45.5%-81.1%) and the 6-month OS rate was 85.1% 
(95% CI, 65.0%-94.2%). 
 
2.2.1.2.3 
Toxicology 
 
A maximum tolerated dose (MTD) of nivolumab was not reached at any dose up to 10 mg/kg 
(Topalian et al., 2012; Nivolumab Investigator’s Brochure, 2018).  There was no pattern in the 
incidence, severity, or causality of AEs to nivolumab dose level.  Most AEs were low-grade 
(Grade 1-2) with relatively few drug-related high-grade (Grade 3-4) AEs.  The safety profile of 
nivolumab combination therapy varies with the agent combined with nivolumab but is generally 
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frequency and severity of AEs were greater than that observed with either agent alone.  The 
safety profile of nivolumab + ipilimumab combination therapy was consistent with the 
mechanisms of action of nivolumab and ipilimumab (Nivolumab Investigator’s Brochure, 2018).  
A dose of 3 mg/kg nivolumab/3 mg/kg ipilimumab exceeded the MTD, and both 1 mg/kg 
nivolumab/3 mg/kg ipilimumab and 3 mg/kg nivolumab/1 mg/kg ipilimumab were identified as 
the MTD.  For nivolumab monotherapy and combination therapy, most high-grade events were 
manageable with use of corticosteroids or hormone replacement therapy (endocrinopathies). 
 
The overall safety experience with nivolumab is based on experience in approximately 16,900 
subjects as either monotherapy or in combination with other therapeutics (Nivolumab 
Investigator’s Brochure, 2018).  In general, for monotherapy, the safety profile is similar across 
tumor types.  The only exception is pulmonary inflammation AEs, which may be numerically 
greater in subjects with NSCLC, possibly because in some cases, it can be difficult to distinguish 
between nivolumab-related and unrelated causes of pulmonary symptoms and radiographic 
changes. The most frequently reported treatment-related AE is fatigue, which is almost always of 
low grade. 
 
2.2.1.2.4 
Pharmacodynamics/Biomarkers 
 
Tumor-cell expression (melanoma) of PD-L1 was characterized in combination with ipilimumab 
with the use of immunohistochemistry (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.   
 
2.2.2 Ipilimumab 
 
Ipilimumab (BMS-734016, MDX010, MDX-CTLA4, Yervoy™) is an Ig-G1κ HuMAb specific 
for human cytotoxic T lymphocyte antigen 4 (CTLA-4, CD152), which is expressed on a subset 
of activated T-cells (Ipilimumab Investigator’s Brochure, 2019).  CTLA-4 is a negative regulator 
of T-cell activation.  Ipilimumab binds to CTLA-4 and inhibits its interaction with ligands on 
APCs.  The proposed mechanism of action for ipilimumab’s effects in subjects with melanoma is 
indirect, possibly through T-cell potentiation and mediation of antitumor immune responses. 
 

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14 
Ipilimumab has been approved for the treatment of unresectable metastatic melanoma in over 40 
countries including the United States (US, March 2011), the European Union (July 2011), and 
Australia (July 2011). 
 
BMS and Medarex (acquired by BMS in September 2009) have co-sponsored an extensive 
clinical development program for ipilimumab, encompassing >22,500 subjects in several cancer 
types in completed and ongoing studies, including a compassionate use program (Ipilimumab 
Investigator Brochure, 2019).  The focus of the clinical program is in melanoma, prostate cancer, 
and lung cancer, with advanced melanoma being the most comprehensively studied indication.  
Ipilimumab is being investigated both as monotherapy and in combination with other modalities 
such as chemotherapy, radiation therapy, and other immunotherapies. 
 
CTEP’s clinical development of ipilimumab focuses on cervical, GI, ovarian, prostate cancer, 
chronic lymphocytic leukemia, head and neck squamous cell carcinoma, solid tumors, Hodgkin 
and non-Hodgkin lymphomas, melanoma, and myelodysplastic syndrome.  While the toxicity 
and clinical responses overlap, mechanisms of immune activation and range of responses appear 
to be different for each of the single agents.  
 
Available preclinical data support the combinations of nivolumab and ipilimumab (Curran et al., 
2010).  The combination of ipilimumab with nivolumab has been reported to result in improved 
responses in advanced melanoma, including decreased time to response, increased number of 
responses, improved depth and duration of responses, and increased PFS and OS compared to 
single agent ipilimumab (Wolchok et al., 2013).  
 
The combination is being evaluated in other disease settings typically with 3 mg/kg nivolumab 
and 1 mg/kg ipilimumab every 3 weeks for 4 induction doses. 
 
2.3 
Other Agents 
 
2.3.1 Prednisone 
 
Prednisone is a synthetic adrenocortical steroid drug with predominantly corticosteroid 
properties (Rayos™ package insert, 2012).  Naturally occurring corticosteroids such as 
hydrocortisone and cortisone, which also have salt-retaining properties, are used as replacement 
therapy in adrenocortical deficiency states.  Their synthetic analogs, such as prednisone, are 
primarily used for their potent anti-inflammatory effects in disorders of many organ systems.  
Corticosteroids, such as prednisone, cause profound and varied metabolic effects.  In addition, 
they modify the body’s immune responses to diverse stimuli.  Some of these properties 
reproduce the physiological actions of endogenous glucocorticosteroids, but others do not 
necessarily reflect any of the adrenal hormones’ normal functions and are seen only after 
administration of large therapeutic doses of the drug.  The pharmacological effects of prednisone 
which are due to its corticosteroid properties include: promotion of gluconeogenesis; increased 
deposition of glycogen in the liver; inhibition of the utilization of glucose; anti-insulin activity; 
increased catabolism of protein; increased lipolysis; stimulation of fat synthesis and storage; 
increased glomerular filtration rate and resulting increase in urinary excretion of urate (creatinine 
excretion remains unchanged); and increased calcium excretion.  Depressed production of 

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eosinophils and lymphocytes occurs, but erythropoiesis and production of polymorphonuclear 
leukocytes are stimulated.  Inflammatory processes (edema, fibrin deposition, capillary 
dilatation, migration of leukocytes and phagocytosis) and the later stages of wound healing 
(capillary proliferation, deposition of collagen, cicatrization) are inhibited.  For more 
information, see the package inserts for Rayos™ (2012) or PredniSONE™ (2012) 
 
2.3.2 Tacrolimus 
 
Tacrolimus, previously known as FK506, is a macrolide immunosuppressant produced by 
Streptomyces tsukubaensis (Prograf® package insert, 2018).  Tacrolimus binds to an intracellular 
protein, FKBP-12.  A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (a 
ubiquitous mammalian intracellular enzyme) is then formed, after which the phosphatase activity 
of calcineurin is inhibited. Such inhibition prevents the dephosphorylation and translocation of 
various factors such as the nuclear factor of activated T-cells (NF-AT), and nuclear factor kappa-
light-chain enhancer of activated B-cells (NF-κB).  Tacrolimus inhibits the expression and/or 
production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, 
IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony 
stimulating factor (GMCF).  Tacrolimus also inhibits IL-2 receptor expression and nitric oxide 
release, induces apoptosis and production of transforming growth factor beta that can lead to 
immunosuppressive activity.  The net result is the inhibition of T-lymphocyte activation and 
proliferation as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).  For 
more information, see the Prograf® package insert. 
 
2.4 
Rationale 
 
Activating anti-tumor immunity through blockade of the pathway mediated by the interaction 
between PD-1 and its primary ligands, PD-L1 and PD-L2, has demonstrated efficacy in multiple 
tumor types (Lipson et al., 2015).  However, there is a paucity of data about the safety and 
efficacy of anti-PD-1 in SOTRs.  The same is true of agents blocking another immune 
checkpoint molecule, CTLA-4, such as ipilimumab.  Further, little is known about the impact of 
combining immune checkpoint inhibitors with medications used to prevent allograft rejection on 
rates of tumor regression and allograft loss.  These unmet needs have arisen over the last few 
years as clinical trials testing the above-referenced drugs have excluded SOTRs.  This protocol 
aims to test the safety, tolerability, and efficacy of an anti-allograft-rejection regimen combined 
with nivolumab (anti-PD-1) +/- ipilimumab (anti-CTLA-4) in kidney transplant recipients with 
selected advanced cancers for whom standard anti-neoplastic treatment options would be 
insufficient. 
 
The cases described in Table 1 illustrate two important concepts that underpin the current study.  
First, anti-PD-1 can be effective against malignancies arising in the setting of long-term 
immunosuppression.  This efficacy signal provides a clear rationale for administration of anti-
PD-1 to treat SOTRs with advanced cancer for whom standard treatment options would be 
insufficient.  Second, the PD-1 pathway is critical in maintaining allograft tolerance in humans.  
It is for this reason that only patients with a transplanted kidney, generally considered a “life-
enhancing” rather than “life-sustaining” organ, will be included in the proposed study. 
 

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The first published report of a PD-1 inhibitor administered to a kidney transplant recipient 
involved a 57-year-old woman who received a kidney allograft from a deceased donor in 1989 
(Lipson et al., 2016).  The patient was maintained on standard long-term immunosuppression, 
including cyclosporine and prednisone.  In 2014, she presented with metastatic cutaneous 
squamous cell carcinoma and, after progressing through two lines of therapy, received 
pembrolizumab (anti-PD-1).  Two months after initiation of anti-PD-1, the patient developed 
acute allograft rejection.  Despite administration of high-dose glucocorticoids, the patient’s 
transplanted kidney did not recover.  Histologic and immunohistochemical evaluation of the 
explanted kidney demonstrated changes consistent with advanced cell-mediated rather than 
antibody-mediated rejection (Figure 1). 
 
 
Figure 1.  Explanted renal allograft showing evidence of rejection and expression of PD-1 
pathway molecules after administration of PD-1 antibody. 
A: Hematoxylin and eosin (H&E) staining of arteries showing intimal arteritis and focal intimal foam 
cells, consistent with chronic vasculopathy in the allograft.  B:  Artery endothelium showing strong 
immunostaining for C4d (a product of the classical complement pathway).  C:  H&E staining 
showing glomerulitis, severe tubular loss, tubulitis, interstitial edema, and interstitial inflammation.  
D:  Peritubular capillaries showing capillaritis but negative C4d immunostaining, which, along with a 
lack of serum HLA antibody, suggests an absence of anti-donor humoral activity and argues against a 
component of antibody-mediated rejection.  E and F:  Immunostaining for PD-L1 and PD-L2, 
respectively, show that these molecules are present on endothelial cells and infiltrating immune cells 
associated with glomeruli.  G:  Infiltrating T-cells expressing PD-1 are associated with cells 
expressing PD-L1 and PD-L2.  H:  Infiltrating immune cells are predominantly CD8-positive (brown) 
and are co-expressed with Ki-67 (blue), consistent with an activated cytotoxic T-cell phenotype. 
 
Computed tomography (CT) scans performed 8 months after initiation of pembrolizumab 
revealed an 85% reduction in tumor burden according to Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1.  Her response is ongoing (off-therapy) >3 years after having 
initiated pembrolizumab.  The patient tolerates hemodialysis without unacceptable AEs.  Her 
Eastern Cooperative Oncology Group (ECOG) performance status returned to 0. 
 
Similarly, limited data are available regarding the impact of anti-CTLA-4 in SOTRs with 
advanced cancer.  The first published report of a CTLA-4 pathway blocker (ipilimumab) 

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17 
administered to kidney transplant recipients involved two patients with melanoma (Lipson et al., 
2014).  Both patients experienced a partial response to therapy, one of which is ongoing at 
>6 years.  Neither patient experienced allograft rejection as a consequence of anti-CTLA-4 
administration.  These cases and others suggest that blocking the CTLA-4 pathway in SOTRs 
with advanced melanoma may be an effective cancer treatment strategy, and perhaps less likely 
to trigger allograft rejection and loss than PD-1-pathway blockers (Morales et al., 2015; 
Ranganath and Panella, 2015). 
 
One important consideration for the proposed trial is balancing the potential safety concerns 
associated with immune checkpoint blockers with the potential benefits in this study population. 
The third most common cause of death among kidney transplant recipients is cancer (Rama and 
Grinyo, 2010).  Thus, uncovering an effective anti-cancer strategy in this population—even at 
the cost of a functioning allograft—would have a profound impact on future practice.  Because 
we are only including kidney transplant recipients, dialysis will be offered to patients in the case 
of allograft failure.  Data from the United States Renal Data System (USRDS) suggest that 
survival for patients who start dialysis is approximately 10.5-11 years for patients aged 40-44 
years and 5.5-5.7 years for those 60-64 years-of-age (Saran et al., 2018).  These data will be 
clearly explained to potential trial participants in the context of each patient’s own risk of death 
from cancer. 
 
The current study will illuminate the complex interactions between immune checkpoint 
molecules, allo-antigens, and cancer neoantigens, and provide critical insight into the 
contributions of immunoregulatory molecules in order to better understand how to selectively 
activate anti-tumor immunity while minimizing immune-related toxicities. 
 
2.5 
Correlative Studies Background 
 
Correlative studies undertaken as part of this protocol will help elucidate the biology behind 
allograft rejection in the setting of immune checkpoint blockade, which may affect the design of 
future clinical trials for recipients of life-enhancing and life-sustaining transplanted organs 
including lung, heart, liver, and other organs. 
 
2.5.1 Histopathological Analyses of Allograft in Setting of Rejection 
 
Although the histopathological characteristics of allograft rejection in the general kidney 
transplant population have been well described, little is known about the features of allograft 
rejection in SOTRs receiving immune checkpoint blockade therapy.  The rationale underlying 
this correlative analysis is based upon the need to uncouple the anti-tumor response from the 
anti-allograft response brought about by administration of anti-PD-1 therapy.  
 
In the case described above (Lipson et al., 2016), anti-allograft activity was thought to be T cell-
mediated.  Additionally, expression of PD-L1 was detected in both the tumor and the allograft, 
suggesting that the immunoregulatory pathway comprised of PD-1 and its ligands is active in 
both microenvironments.  Thus, one approach to uncoupling anti-tumor and anti-allograft 
immuno-activation is to find immune checkpoints that are differentially expressed in the tumor 
and the kidney.  To identify these pathways, immunostains for an extended array of 

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immunoactive markers including PD-L1, PD-1, PD-L2, LAG-3, TIM-3 and others will be 
performed. 
 
2.5.2 Histopathological Analyses of Tumor 
 
In addition to the analysis described above (interrogation of the tumor microenvironment to find 
immune checkpoints that are differentially expressed in the tumor and the kidney allograft), we 
are also interested in the histological characteristics of response in immunosuppressed patients 
(i.e., SOTRs).  Thus, H&E stained slides of tumor (pre- and on-therapy) for each subject will be 
reviewed.  IHC will be performed for both immune checkpoint molecules (PD-L1, PD-1, LAG-
3) and immune cell subsets (CD3, CD4, CD8, and CD68). 
 
2.5.3 Circulating dd-cfDNA 
 
In the general kidney transplant population, the dd-cfDNA assay has been shown to be predictive 
of Banff Grade 1B and higher active acute cellular rejection, and of antibody-mediated rejection 
(Bloom et al., 2017).  However, the assay’s utility in SOTRs receiving immune checkpoint 
blockade therapy is unknown.  We hypothesize that an early sign of allograft rejection may allow 
for more rapid initiation of immunosuppression and avoidance of allograft loss.  We plan to 
compare the ability of the dd-cfDNA assay to predict allograft rejection as measured by standard 
clinical metrics (see Section 7.2). 
 
2.5.4 Serum and Peripheral Blood Mononuclear Cells (PBMCs) 
 
We aim to analyze serum and PBMC to accomplish some or all of the following: 
 
• Define new tumor antigens and their relevance to disease biology, and correlate antigen 
expression with immune responses and disease outcomes. 
• Evaluate potential immune-related prognostic or treatment response indicators. 
• Evaluate the causative mechanisms of immune-related toxicities in patients receiving 
cancer therapy with immune checkpoint blockade. 
• Characterize factors and molecular pathways in the tumor immune microenvironment 
that lead to immune suppression, tolerance to tumor antigens, and cancer progression. 
 
 

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19 
3. 
PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must be kidney transplant recipients with a functioning allograft who do not 
currently require dialysis. 
 
3.1.2 Patients must have histologically or cytologically confirmed melanoma, basal cell 
carcinoma, Merkel cell carcinoma, cutaneous squamous cell carcinoma, or MSI-high 
cancers for which standard non-immunological medical, surgical, or radiation therapy 
would be insufficient (i.e., patients who are not surgical candidates).  This trial is not 
intended to provide therapy as a neoadjuvant approach. 
 
3.1.3 Measurable disease as defined by RECIST 1.1 criteria, i.e., 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 by chest x-ray or as ≥10 mm 
with CT scan, magnetic resonance imaging (MRI), or calipers by clinical exam is 
preferred, but not required.  Patients with evaluable disease but no target lesions (e.g., 
evaluable bone metastases) may be included after discussion with the Principal 
Investigator (PI).  See Section 12 for detailed criteria. 
 
3.1.4 Patients must have documentation, in consultation with the PI, that they received, 
refused, or were ineligible for the following non-immunologic therapies: 
 
For patients with: 
Prior therapies include: 
BRAF-mutant melanoma 
BRAF/MEK inhibitors 
Merkel cell carcinoma 
Platinum + VP-16 
Basal cell carcinoma 
Hedgehog pathway 
inhibitors 
Cutaneous squamous cell 
carcinoma 
Cetuximab 
MSI colorectal carcinoma 
FOLFOX 
 
3.1.5 Patient’s age must be ≥18 years.  Because no dosing or AE data are currently available on 
the use of nivolumab and ipilimumab in kidney transplant recipients <18 years of age, 
children are excluded from this study, but may be eligible for future pediatric trials. 
 
3.1.6 Patients must have ECOG performance status ≤2 (Karnofsky ≥60%), see Appendix A, 
Performance Status Criteria. 
 
3.1.7 Patients must have normal organ and marrow function as defined below: 
 
− 
leukocytes 
≥2,000/mcL 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
platelets 
≥100,000/mcL 

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− 
total bilirubin 
≤1.5 × institutional upper limit of normal (ULN) 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional ULN 
− 
serum creatinine 
≤3 × ULN 
Note: patients with creatinine levels above 3 × ULN may be eligible after 
consultation with the study PI. 
 
3.1.8 The effects of nivolumab and ipilimumab on the developing human fetus are unknown.  
For this reason, and because other therapeutic agents used in this trial are known to be 
teratogenic, women of child-bearing potential (WOCBP) and men must agree to use 
adequate contraception (e.g., hormonal or barrier methods of birth control, or abstinence) 
prior to study entry, for the duration of study participation, and for 31 weeks after the last 
dose of nivolumab or ipilimumab.  Women who are not of childbearing potential (i.e., 
who are postmenopausal or surgically sterile) as well as azoospermic men do not require 
contraception. 
 
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 
IU/L or equivalent units of beta-human chorionic gonadotropin [B-HCG]) during the 
screening period.  Follow-up evaluations will include interval sexual/menstrual histories 
as needed. 
 
Men who receive nivolumab or ipilimumab and are sexually active with WOCBP must 
use a contraceptive method with a failure rate of <1% per year for the duration of the 
study and for a period of 7 months after the last dose of nivolumab or ipilimumab. 
 
Should a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she (or the participating partner) should inform the treating 
physician immediately. 
  
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.  Women under 
the age of 55 must have a documented serum follicle stimulating hormone (FSH) level 
less than 40 mIU/mL to be considered postmenopausal. 
 
3.1.9 Human immunodeficiency virus (HIV)-infected patients will be eligible for this trial if 
they are on effective antiretroviral regimens utilizing non-CYP-interactive agents and 
have an undetectable viral load. 
 
If there is evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be 
undetectable on suppressive therapy, if indicated.  If there is history of hepatitis C virus 
(HCV) infection, the patient must have been treated and have undetectable HCV viral 
load. 
 

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21 
3.1.10 Patients must be able to understand and be willing to sign a written informed consent 
document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients must not have received a liver, lung, heart, or pancreas transplant; or allogeneic 
stem cell transplant; or any kind of bone marrow transplant. 
 
3.2.2 Patients must not be unwilling or unable to undergo dialysis. 
 
3.2.3 Patients must not have prior evidence of HLA or non-HLA donor-specific antibodies 
(DSA).  Patients with detectable DSA but negative dd-cfDNA may be eligible after 
consultation with the study PI. 
 
3.2.4 Patients must not have a history of antibody- or cell-mediated allograft rejection within 3 
months of study entry. 
 
3.2.5 Patients must not have had chemotherapy or radiotherapy within 4 weeks of study entry 
or those who have not recovered from AEs due to agents administered more than 4 weeks 
earlier. 
 
3.2.6 Patients must not have had prior treatment for their current cancer with an anti-PD-1, 
anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug 
specifically targeting T-cell co-stimulation or immune checkpoint pathways. 
 
3.2.7 Patients must not be receiving any other investigational agents. 
 
3.2.8 Patients must not have known central nervous system (CNS) metastases or 
leptomeningeal metastases because of poor prognosis and concerns regarding progressive 
neurologic dysfunction that would confound the evaluation of neurologic and other AEs.  
Patients with brain metastases are permitted to enroll if metastases have been treated and 
there is no MRI evidence of progression for 4 weeks after treatment is complete and no 
evidence of progression within 28 days prior to study entry. 
 
3.2.9 Patients must not have a history of severe hypersensitivity reaction to any monoclonal 
antibody. 
 
3.2.10 Patients must not have a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to other agents used in study. 
 
3.2.11 Patients must not have 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. 
 

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3.2.12 Pregnant women are excluded from this study because nivolumab and ipilimumab have 
the potential for teratogenic or abortifacient effects.  Because there is an unknown but 
potential risk for AEs in nursing infants secondary to treatment of the mother, 
breastfeeding should be discontinued if the mother is treated with nivolumab or 
ipilimumab.  These potential risks may also apply to other agents used in this study. 
 
3.2.13 Patients must not have active autoimmune disease, or history of autoimmune disease that 
might recur, which may affect vital organ function, and will only be eligible after 
consultation with the study PI. 
 
This includes but is not limited to: 
• immune-related neurologic disease, 
• multiple sclerosis, 
• autoimmune (demyelinating) neuropathy, 
• Guillain-Barre (GB) syndrome, 
• myasthenia gravis, 
• systemic autoimmune diseases such as systemic lupus erythematosus (SLE), 
• connective tissue diseases, 
• scleroderma, 
• inflammatory bowel disease (IBD; e.g., ulcerative colitis or Crohn’s disease), 
• rheumatoid arthritis, and 
• Sjögren’s syndrome. 
 
3.2.14 Patients must not have had evidence of active or acute diverticulitis, intra-abdominal 
abscess, GI obstruction 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 
 
National Institutes of Health (NIH) policy requires that women and members of minority groups 
and their subpopulations be included in all NIH-supported biomedical and behavioral research 
projects involving NIH-defined clinical research unless a clear and compelling rationale and 
justification establishes to the satisfaction of the funding Institute & Center (IC) Director that 
inclusion is inappropriate with respect to the health of the subjects or the purpose of the research.  
Exclusion under other circumstances must be designated by the Director, NIH, upon the 
recommendation of an IC Director based on a compelling rationale and justification.  Cost is not 
an acceptable reason for exclusion except when the study would duplicate data from other 
sources.  Women of childbearing potential should not be routinely excluded from participation in 
clinical research.  Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
Women and minorities will have the same opportunities as all others to participate in this study.  
This study is race and gender neutral.  Subject selection is based solely on meeting the diagnosis 
specific eligibility criteria for this study.  All patients aged 18 or older presenting to one of the 
above-referenced centers with an appropriate diagnosis (see inclusion criteria) will be assessed 

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for eligibility for the study.  Although demographic distributions vary by institution, the gender 
and racial/ethnic composition of the patients seen at the Johns Hopkins Oncology Center is 
representative of the population of the Baltimore, MD metropolitan area.  Specifically, in the 
past 5 years, patients enrolled on clinical trials of the Oncology program have consisted of 
approximately 50% male, 50% female, 30% African American, 5% Hispanic and 5% Asian 
American.  With the exception of patients with skin cancers which primarily affect light-skinned 
individuals, we anticipate that the patient population from Hopkins will reflect the above 
estimates. 
 
See Section 9.2 for more information about accrual of women and minorities. 
 

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24 
4. 
REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to Oncology Patient Enrollment Network (OPEN), Rave, or acting as a 
primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.    
RCR utilizes five person registration types. 
• IVR:  MD, DO, or international equivalent, 
• NPIVR: advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD), 
• AP: clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
(e.g., Roster Update Management System [RUMS], OPEN, Rave,), 
• Associate (A): other clinical site staff involved in the conduct of NCI-sponsored trials, 
and 
• Associate Basic (AB): individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
Documentation Required 
IV
R 
NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, 
and certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
 

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25 
• Addition to a site roster, 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN, 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval, and 
• Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug shipment, or as 
the CI on the DTL must be rostered at the enrolling site with a participating organization (i.e., 
Alliance).  
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 
 
4.2 
Site Registration 
 
This study is supported by the NCI CTSU. 
 
IRB Approval   
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet for Local Context (SSW) to the CIRB using IRBManager to indicate 
their intent to open the study locally. The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network. Site preferences can be set at the network 
or protocol level. Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by emailing the email address above or calling 1-888-651-CTSU (2878). 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following five criteria to complete processing of the IRB/REB approval record: 
• Holds an Active CTEP status, 
• Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) and 
on at least one participating roster, 
• If using NCI CIRB, rostered on the NCI CIRB Signatory record, 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile, and 
• Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• An active Federalwide Assurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization, and 
• Compliance with all protocol-specific requirements (PSRs). 

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26 
4.2.1 Downloading Regulatory Documents 
 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website.  Permission to view and download this protocol and its supporting documents 
is restricted based on person and site roster assignment.  To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a Participating 
Organization on the protocol.  
• Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password, 
• Click on Protocols in the upper left of your screen 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select LAO-MD017, and 
protocol number 10214, 
• Click on Documents, select Site Registration, and download and complete the forms 
provided.  (Note:  For sites under the CIRB initiative, IRB data will load automatically to 
the CTSU as described above.)  
 
4.2.2 Requirements for Protocol 10214 Site Registration 
 
• A Site initiation visit (SIV) is required for each participating site prior to activation.  The 
local site PI must participate on the call as well as their research nurse, study coordinator, 
and pharmacist.  To schedule a SIV, please email the Protocol Liaison and 
crocc@jhmi.edu and reference the protocol in the subject line of the email. 
• Specimen Tracking System Training Requirement: 
o All data entry users (Clinical Research Associate role) at each participating site will 
need to complete the Theradex-led training. 
o Theradex will provide a certificate of completion, which will need to be submitted to 
the CTSU through the Regulatory Submission Portal. 
o The training is a one-time only requirement per individual.  If an individual has 
previously completed the training for another ETCTN study, the training does not 
need to be completed again nor does the certificate of completion need to be 
resubmitted to the CTSU.  However, new versions of the Specimen Tracking System 
may require new training. 
o This training will need to be completed before the first patient enrollment at a given 
site. 
o Peter Clark and Diana Vulih are the main points of contact at Theradex for the 
training (PClark@theradex.com and DVulih@theradex.com, Theradex phone: 609-
799-7580). 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website.  

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27 
To access the Regulatory Submission Portal, log on to the CTSU members’ website → 
Regulatory → Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission 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 
 
You can verify your site registration status on the members’ section of the CTSU website. 
 
1. Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
2. Click on the Regulatory tab at the top of your screen 
3. Click on the Site Registration tab 
4. 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 their affiliated networks. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and with the Lead 
Protocol Organization (LPOs) registration/randomization systems or Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment.  OPEN 
will populate the patient enrollment data in NCI’s clinical data management system, Medidata 
Rave. 
Requirements for OPEN access:   
• A valid CTEP-IAM account. 
• To perform enrollments or request slot reservations:  Be on an LPO roster, ETCTN 
Corresponding roster, or Participating Organization roster with the role of Registrar.  
Registrars must hold a minimum of an AP registration type. 
• If a DTL is required for the study, the registrar(s) must hold the OPEN Registrar task on 
the DTL for the site. 
• Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in 
OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR.  If a DTL is required for the study, the IVR or NPIVR must be 
assigned the appropriate OPEN-related tasks on the DTL. 

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28 
Prior to accessing OPEN, site staff should verify the following: 
• Patient has met all eligibility criteria within the protocol stated timeframes, and  
• All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website.  
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with the registration system in OPEN. Prior to discussing protocol entry with the 
patient, all site staff must use the CTSU OPEN Slot Reservation System to ensure that a slot on 
the protocol is available to the patient. Once a slot reservation confirmation is obtained, site staff 
may then proceed to enroll the patient to this study.  
 
4.3.2 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://www.theradex.com/clinicalTechnologies/?National-
Cancer-Institute-NCI-11. 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 at 
609-619-7862 or Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.3.3 Patient Enrollment Instructions 
 
This study will use the ETCTN Specimen Tracking System (STS). 
 
• All biospecimens collected for this trial must be submitted using the ETCTN Specimen 
Tracking System (STS) unless otherwise noted. 
• The system is accessed through special Rave user roles:  “CRA Specimen Tracking” for 
data entry at the treating institutions and “Biorepository” for users receiving the 
specimens for processing and storage at reference labs and the Biorepository. 
• Please refer to the Medidata Account Activation and Study Invitation Acceptance link on 
the CTSU website under the Rave/DQP tab. 
• Important:  Failure to complete required fields in STS may result in a delay in 
sample processing.  Any case reimbursements associated with sample submissions will 
not be credited if samples requiring STS submission are not logged into STS. 
 

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29 
Detailed instructions can be found in Section 5.3. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 28 days.  Issues that 
would cause treatment delays should be discussed with the study PI.  If a patient does not receive 
protocol therapy following registration, the patient’s registration on the study may be canceled.  
The Study Contact should be notified of cancellations as soon as possible. 

NCI Protocol #:  10214 
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30 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
5.1 
Summary Table for Specimen Collection 
 
Time Point 
Specimen 
Send Specimens To: 
Archival 
 
• Formalin-fixed paraffin-embedded (FFPE) tumor 
tissue block1 (if available) 
Tumor 
microenvironment 
Core at Johns 
Hopkins University 
Baseline 
 
• 2-3 punch biopsies of tumor tissue, at least 3-4 mm 
in size or 2-3 passes with a 1 cm 16-18-gauge core 
needle (if no archival tissue available) (optional) 
Tumor 
microenvironment 
Core at Johns 
Hopkins University 
• ~20 mL whole blood in two SST tubes for serum 
analyses 
• ~100 mL whole blood in 10 CPT tubes for PBMC 
analyses 
Topalian lab at Johns 
Hopkins University 
Week 4 
 
• 2-3 punch biopsies of tumor tissue, at least 3-4 mm 
in size or 2-3 passes with a 1 cm 16-18-gauge core 
needle (optional) 
Tumor 
microenvironment 
Core at Johns 
Hopkins University 
• ~20 mL whole blood in two SST tubes for serum 
analyses 
• ~100 mL whole blood in 10 CPT tubes for PBMC 
analyses 
Topalian lab at Johns 
Hopkins University 
Immune-mediated adverse reaction (including allograft rejection) 
 
• ~20 mL whole blood in two SST tubes for serum 
analyses 
• ~100 mL whole blood in 10 CPT tubes for PBMC 
analyses 
Topalian lab at Johns 
Hopkins University 
Allograft rejection 
 
• One ~1 cm, ~18-gauge core needle kidney biopsy 
sample plus biopsy material leftover after standard-
of-care analysis 
• 2-3 punch biopsies of tumor tissue, at least 3-4 mm 
in size or 2-3 passes with a 1 cm 16-18-gauge core 
needle (optional) 
Tumor 
microenvironment 
Core at Johns 
Hopkins University 

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31 
Time Point 
Specimen 
Send Specimens To: 
Disease progression 
 
• ~20 mL whole blood in two SST tubes for serum 
analyses 
• ~100 mL whole blood in 10 CPT tubes for PBMC 
analyses 
Topalian lab at Johns 
Hopkins University 
1 For archival tissue, a copy of the corresponding anatomic pathology report must be sent with 
the tissue and uploaded to Rave. 
2 For new biopsies, a copy of the radiology and operative reports from the tissue removal 
procedure must be sent with the tissue.  When completed, upload the corresponding pathology 
reports to Rave. 
 
5.2 
Specimen Procurement Kits and Scheduling 
 
5.2.1 Specimen Shipping Kits  
 
5.2.1.1 
SST tubes and CPT tubes 
 
Vacutainer SST and CPT tubes for serum and PBMC collection should be obtained from 
commercial sources. 
 
5.2.2 Scheduling of Specimen Collections 
 
Please adhere to the following guidelines when scheduling procedures to collect tissue: 
• Tumor tissue specimens collected during biopsy procedures should be fixed (submerged) in 
formalin. 
• Tissue can be stored at room temperature in formalin and should be shipped within 
approximately 72 hours for next-day delivery Monday through Friday. 
 
Please adhere to the following guidelines when scheduling blood collection procedures: 
• Fresh blood specimens may be collected Monday through Friday. 
• Specimens collected Monday through Thursday should be shipped the same day as collection 
and shipped for next-day delivery Monday through Friday. 
• Blood specimens collected on Friday should be processed as described in Section 5.4.5 and 
shipped frozen on dry ice within approximately a week following collection. 
 
5.3 
Specimen Tracking System Instructions 
 
5.3.1 Specimen Tracking System Overview and Enrollment Instructions 
 
For the ETCTN STS, the following information will be requested: 
• Protocol Number 
• Investigator Identification  
o Institution and affiliate name 
o Investigator’s name 

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32 
• Eligibility Verification:  Patients must meet all the eligibility requirements listed in 
Section 3. 
• Additional Requirements: 
o Patients must provide a signed and dated, written informed consent form. 
 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate and 
unique identification numbers to the patient, a Universal patient ID (UPID) and a Treatment 
patient ID.  The UPID is associated with the patient and used each and every time the patient 
engages with the portion of this protocol that uses the ETCTN Specimen Tracking System.  The 
UPID contains no information or link to the treatment protocol.  IWRS will maintain an 
association between the UPID for ETCTN biobanking and molecular characterization and any 
treatment protocols the patient participates in, thereby allowing analysis of the molecular 
characterization results with the clinical data.   
 
Immediately following enrollment, the institutional anatomical pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into Rave.  The report must include 
the surgical pathology ID (SPID), collection date, block number, and the IWRS-assigned UPID 
and patient study ID for this trial.  For newly acquired biopsies, the radiology and operative 
report(s) must also be uploaded into Rave.  Important:  Remove any personally identifying 
information, including, but not limited to, the patient’s name, initials, medical record 
number, and patient contact information from the institutional pathology report prior to 
submission. 
 
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software.   
 
For questions regarding the Specimen Tacking System, please contact the Theradex Help Desk at 
CTMSSupport@theradex.com. 
 
A shipping manifest must be included with all sample submissions. 
 
5.3.2 Specimen Labeling 
 
5.3.2.1 Blood Specimen Labels 
 
Include the following on blood specimens (including whole blood and frozen, processed blood 
products – like serum and plasma): 
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., blood, serum) 
• Collection date and time (to be added by hand) 
 

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33 
5.3.2.2 Tissue Specimen Labels 
 
Include the following on all tissue specimens or containers (e.g., formalin jar):  
• Patient Study ID 
• UPID 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., FFPE Block, Formalin Fixed Tissue, Fresh Tissue in Media, etc.) 
• Tissue type (P for primary, M for metastatic, or N for normal) 
• Surgical pathology ID (SPID) number   
• Block number from the corresponding pathology report (archival only) 
• Collection date and time (to be added by hand) 
 
5.3.2.3 Example of Specimen Label 
 
The following image is an example of a tissue specimen label printed on a standard Avery label 
that is 1 inch high and 2.625 inches wide. 
 
 
 
The QR code in the above example is for the Specimen ID shown on the second line. 
 
NOTE:  The QR code label is currently under development at Theradex as of 31-Aug-2018; 
therefore, labels generated by the STS for this study may not include a QR code. 
 
The second line item from the end includes four data points joined together: 
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the beginning of 
the specimen ID; this field is blank if not relevant (e.g., for blood) 
2. Block ID or blank if not relevant 
3. SPID (Surgical Pathology ID) or blank if none 
4. The last alpha-numeric code is protocol specific and is only included if the protocol 
requires an additional special code classification 
 
The last line on the example label is for the handwritten date and optional time. 
 
5.3.3 Overview of Process at Treating Site 
 

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34 
5.3.3.1 OPEN Registration 
 
All registrations will be performed using the Oncology Patient Enrollment Network (OPEN) 
system.  OPEN communicates automatically with the Interactive Web Response System (IWRS) 
which handles identifier assignments, any study randomization, and any prescribed slot 
assignments.  If specimen analysis is required to determine eligibility, the protocol will be setup 
with multi-step registration. 
 
Registration without eligibility specimen analysis:  
1. Site enters registration data into OPEN during one or more steps. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal Patient 
ID, both of which are sent back to OPEN. 
3. IWRS sends all applicable registration data directly to Rave at the end of the final 
registration step. 
 
Any data entry errors made during enrollment should be corrected in Rave. 
 
5.3.3.2 Rave Specimen Tracking Process Steps 
 
Step 1:  Complete the Histology and Disease form (but do not upload reports until a specimen 
label can be applied to them) and the Baseline forms regarding Prior Therapies.  Enter the 
initial clinical specimen data: 
• Specimen Tracking Enrollment CRF:  Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, number of labels needed 
(include extra labels to apply to reports to be uploaded).  CRF generates unique Specimen 
ID.  
 
Step 2:  Print labels using report in EDC and collect specimen. 
• Label specimen containers and write the collection date and time on each label. 
• After collection, store labeled specimens as described in Section 5.4. 
• Apply an extra specimen label to each report before scanning.  Return to the Histology 
and Disease form to upload any initial Pathology, Radiology, Molecular Reports (up to 
four), Surgical (or Operative) reports and Pathology Verification form (when applicable). 
Return to Specimen Tracking Enrollment CRF to upload any molecular report (one per 
specimen) and/or specimen specific pathology or related report (one per specimen).   
Uploaded reports should have protected health information (PHI) data like name, mailing 
address, medical record number or social security number (SSN) redacted. Do not redact 
SPID, block number or relevant dates, and include the UPID and patient ID on each 
document.   
 
Step 3:  Complete specimen data entry. 
• Specimen Transmittal Form:  Enter Collection date and time and other required 
specimen details. 
 
Step 4:  When ready to ship, enter shipment information. 

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35 
• Shipping Status CRF:  Enter tracking number, your contact information, recipient, 
number of containers and ship date once for the 1st specimen in a shipment. 
• Copy Shipping CRF:  Select additional specimens to add to an existing shipment 
referenced by the tracking number. 
 
Step 5:  Print shipping list report and prepare to ship. 
• Print two copies of the shipping list, one to provide in the box, the other for your own 
records. 
• Print pathology or other required reports to include in the box. Be sure the printed copy 
includes the specimen label. 
 
Step 6:  Send email notification. 
• For only one of the specimens in the shipment, click “Send Email Alert” checkbox on the 
Shipping Status CRF to email recipient. 
 
Step 7:  Ship the specimen(s). 
 
5.4 
Specimen Collection 
 
5.4.1 General Methods 
 
5.4.1.1 
Tissue / tumor biopsies 
 
Biopsies of tumor or other tissue should provide sufficient material for histologic examination of 
tissue architecture (i.e., core or punch biopsy rather than fine needle aspiration). Biopsy 
technique should be determined by the investigator based on the following guidance. 
• Core needle sampling is frequently the preferred technique for obtaining tissue from 
lymph nodes and other internal tumors. It is recommended that at least 2-3 core biopsies, 
16-18 gauge in diameter and at least 1 cm in length, are obtained. Specimens should be 
placed immediately into buffered formalin and shipped to the Tumor Microenvironment 
Core at Johns Hopkins University (see Section 5.5). 
• Punch biopsy sampling is frequently the preferred technique for obtaining tissue from 
cutaneous lesions and other externally accessible tumors. It is recommended that at least 
2-3 biopsies, each 3-4mm in diameter are obtained. Specimens should be placed 
immediately into buffered formalin and shipped to the Tumor Microenvironment Core at 
Johns Hopkins University (see Section 5.5). 
• Endoscopic approaches are permitted if necessary in the opinion of the investigator. 
• Excisional biopsies are permitted if necessary in the opinion of the investigator. 
• Imaging-guided (e.g., ultrasound, CT) procedures are permitted if necessary in the 
opinion of the investigator. 
 
5.4.1.2 
Whole Blood 
 
Whole blood should be collected according to local institutional standards.  When collecting 
blood for multiple purposes, blood for serum analysis (SST tubes) should be collected first, then 

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36 
blood for PBMC analysis (CPT tubes), and finally blood for dd-cfDNA (Cell-Free DNA BCT® 
tubes). 
 
5.4.2 Archival Tumor Biopsy 
 
If previously-collected formalin-fixed paraffin-embedded (FFPE) tissue will be submitted, then 
the following criteria must be met: 
• Tissue must have been collected within 12 weeks prior to registration  
• Formalin-fixed paraffin-embedded tumor tissue block(s) must be submitted.  The optimal 
block is at least 70% tumor.  Specimen size requirement is as follows: 
o Surface area:  25 mm2 is optimal.  Minimum is 5 mm2. 
o Volume:  1 mm3 optimal.  Minimum volume is 0.2 mm3. 
 
If an existing block cannot be submitted, the following are requested, if available: 
• One H&E slide, 
• Five 4 µm unstained air-dried charged or uncharged slides 
 
See Section 5.3.1 for labeling instructions. 
 
5.4.3 Kidney Biopsy 
 
If a patient shows markers of allograft rejection (see Section 7.2), a biopsy of their renal allograft 
should be obtained immediately.  Patients may refuse biopsy and still remain on study.  The 
biopsy should be performed according to local institutional standards.  In addition, one ~1 cm, 
~18-gauge core needle research biopsy sample should be procured, if possible.  The research 
core sample plus biopsy material leftover after standard-of-care analysis should be provided to 
the Johns Hopkins team for research purposes.  After collection, specimens will be formalin-
fixed and paraffin-embedded per standard institutional protocol.  Thereafter, samples should be 
sent as follows: 
 
One H&E stained slide AND one unstained slide from every FFPE block from the standard-of-
care surgical pathology specimens, or FFPE blocks if either of the above is not available. In 
addition, the research core sample should be embedded in paraffin and sent to the Tumor 
Microenvironment Core at Johns Hopkins University (see Section 5.5, below). 
 
All slides and FFPE blocks can be sent at ambient temperature.  Please ensure that each slide is 
labeled with the surgical pathology case number as well as the part number and block 
designation (number and/or letter, e.g., 1A, 2A) to ensure that each slide can be matched to a 
particular block as outlined in the gross description on the pathology report. 
 
See Section 5.3.1 for additional labelling instructions. 
 
5.4.4 Fresh Tumor Biopsy 
 
Patients will undergo optional baseline and on-treatment biopsies of tumor per the study calendar 
(See Section 5.1 and Section 11).  The on-treatment biopsies should be obtained around Week 4, 

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and at the time of allograft rejection.  The biopsy obtained at the time of allograft rejection 
should be obtained at the same time as the standard-of-care renal biopsy.  Biopsy site(s), number 
of samples, and technique will be determined by the investigator.  In general, the following 
techniques will yield tissue sufficient for meaningful correlative analysis: 
• 2-3 punch biopsies of at least 3-4 mm in size or 
• 2-3 passes with a 1 cm 16-18-gauge core needle 
 
After collection, specimens will be formalin fixed and paraffin embedded per standard 
institutional protocol.  Thereafter, samples should be sent as follows: 
• One H&E stained slide AND 5 unstained slides from every FFPE block in the surgical 
pathology specimen, or FFPE blocks if either of the above is not available. 
 
All slides and FFPE blocks can be sent at ambient temperature.  Please ensure that each slide is 
labeled with the surgical pathology case number as well as the part number and block 
designation (number and/or letter, e.g. 1A, 2A) to ensure that each slide can be matched to a 
particular block as outlined in the gross description on the pathology report. 
 
Sites should make every effort to either procure an archival specimen or to obtain a new biopsy 
prior to starting therapy but it is not an absolute requirement for joining the trial.  If a biopsy will 
compromise the evaluability of a lesion for response (RECIST v1.1), the biopsy may be omitted. 
 
See Section 5.3.1 for additional labelling instructions. 
 
5.4.5 Blood Collection 
 
5.4.5.1 Collection of Blood in SST Tubes 
 
1. Label two 10 mL SST tubes according to Section 5.3.1.  
2. Collect 10 mL of blood into each pre-labeled tube and gently invert to mix.  Note:  blood 
must be thoroughly mixed to ensure preservation of specimen. 
3. If collection occurs Monday through Thursday, samples should be shipped overnight at 
room temperature.  Specimens should be labeled according to Section 5.3.1. 
 
If collected on a Friday, within 2 hours after collection, SST tubes should be processed as 
follows: 
1. Centrifuge tubes at 25 °C for 10 minutes at 1290 × g in a swinging-bucket rotor.  If using 
a fixed-angle rotor, centrifuge for 15 minutes. 
2. Remove the hemogard closure by twisting and pulling simultaneously, until the tube 
stopper is loosened.  Then, lift the closure off of the tube. 
3. Transfer serum to a suitable sterile tube. 
4. Fill up to four 1.8-mL cryovials, with ~1.2 to 1.6 mL of serum each.  Dispense any 
additional serum in 3.6-mL cryovials. 
5. Serum aliquots should be stored at -80 °C prior to shipping 
6. Serum aliquots should be shipped frozen on dry ice.  Specimens should be labeled 
according to Section 5.3.1. 
 

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5.4.5.2 Collection of Blood in CPT Tubes 
 
1. Label 10 CPT tubes according to Section 5.3.1. 
2. Collect 10 mL of blood into each pre-labeled tube and gently invert to mix. 
3. If collection occurs Monday through Thursday, samples should be shipped overnight at 
room temperature.  Specimens should be labeled according to Section 5.3.1. 
 
If collected on a Friday, within 2-6 hours after collection, CPT tubes should be processed as 
follows: 
1. Centrifuge tubes at 25 °C for 30 minutes at 1500 × g. 
2. Gently invert tubes 5-10 times to resuspend the cells in the plasma, and then transfer 
entire plasma contents into a 50 mL conical tube.  Avoid transferring red blood cells. 
3. Add room temperature RPMI 1640 (Life Technologies) for a 1:3 dilution (Usually up to 
45 mL for every two CPT tubes). 
4. Spin tubes at 1500 rpm (470 × g) for 10 minutes at room temperature.  
5. Aspirate off the supernatant without disturbing the cell pellet. 
6. Resuspend in appropriate volume of RPMI 1640 and combine tubes to count.  In general, 
resuspend combined cells in 5 mL RPMI per CPT, up to a total volume of 40 mL, (e.g., 
for 10 CPT tubes, combine cells in a total volume of 40 mL). 
7. Count cells and check platelet abundance. 
a. If there are ≤20 per high-power field (400×):  spin at 1500 rpm for 10 minutes. 
b. If there are >20 per high-power field (400×):  spin at 1000-1200 rpm for 
10 minutes, then re-count.  Expect some cell loss due to the slow spin. 
8. Freeze cells in 90% FBS + 10% DMSO.  There should be between 5×106 and 3×107 
cells/mL per cryovial tube.  Freeze at least 3 vials and up to 10 vials. 
9. Store at -80°C prior to shipping. 
10. PBMC samples should be shipped frozen on dry ice.  Specimens should be labeled 
according to Section 5.3.1. 
 
 
5.5 
Shipping of Specimens from Clinical Site to Other Laboratories  
 
5.5.1 Kidney and Tumor Biopsies 
 
Kidney and tumor FFPE blocks or tumor tissue slides should be shipped at ambient temperature 
via overnight delivery to be received Monday through Friday to: 
 
Janis Taube, M.D. 
c/o Julie Stein, M.D. 
Johns Hopkins University School of Medicine 
Department of Dermatopathology 
600 N. Wolfe Street – Blalock 907 
Baltimore, MD 21287 
Phone: +01-410-955-3484 
 

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5.5.2 Blood Samples for Serum and PBMC Analysis 
 
Samples collected Monday through Thursday should be shipped at room temperature on the day 
of collection via overnight delivery to be received Monday through Friday.  Samples collected 
on a Friday should be processed as described in Section 5.4.5 and shipped frozen on dry ice 
within approximately a week following collection.   
 
Ship specimens to: 
 
Tracee McMiller 
Manager, Topalian Lab 
Johns Hopkins Medicine 
CRB II, Room 528 
1550 Orleans Street 
Baltimore, MD 21287 
Phone:  410-502-8220 
Fax:   410-502-1958 
 
Send a 24-hour email notification to the Topalian lab’s e-mail: 
 
TopalianLab@lists.johnshopkins.edu 
 
The subject line should specify “Study 10214 patient sample shipment,” and the body of the e-
mail should specify the patient ID(s) and date and time of draw.  
 
 
 
 
 

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5.6 
Biomarker Plan 
 
Priority 
Biomarker 
Name 
Biomarker 
Assay 
Biomarker Type and Purpose M/O 
Specimens and Time Points 
Laboratory Performing Assay 
1 
Histopathological 
analysis of 
allograft in setting 
of rejection 
Immuno-
histochemistry 
 
CLIA:  Ya / Nb 
 
Exploratory 
 
To characterize molecular 
mechanisms and pathogenesis of 
anti-PD-1-mediated allograft 
rejection. 
 
M 
 
FFPE kidney allograft biopsy 
 
After analysis of tissue from 
standard-of-care allograft biopsy at 
the time of rejection 
 
Tumor microenvironment Core at 
Johns Hopkins University 
 
Lab PIs:  Dr. Janis Taube and Dr. 
Serena Bagnasco 
 
PI emails:  jtaube1@jhmi.edu 
sbagnas1@jhmi.edu  
2 
Histopathological 
analysis of tumor 
Immuno-
histochemistry 
 
CLIA:  Ya / Nb 
Exploratory 
 
To characterize immunological 
changes in the tumor 
microenvironment (e.g., changes 
in T-cell subset populations or 
expression of immune 
checkpoint molecules). 
O 
FFPE tumor biopsy block or 1 H&E 
and 10 unstained slides. 
 
Baseline, at week 4 ±7 days of 
treatment, and at the time of allograft 
rejection. 
 
Tumor microenvironment Core at 
Johns Hopkins University 
 
Lab PIs:  Dr. Janis Taube and Dr. 
Serena Bagnasco 
 
PI emails:  jtaube1@jhmi.edu 
sbagnas1@jhmi.edu  
3 
Circulating 
donor-derived 
cell-free DNA 
(dd-cfDNA) 
PCR-based 
 
CLIA:  Y 
Exploratory 
 
To investigate the utility of dd-
cfDNA as an indicator of kidney 
injury in the study population 
 
M Whole blood 
 
Baseline (prior to immune-
suppression adjustment), every 2 
weeks for the first 12 weeks of 
nivolumab or nivolumab/ 
ipilimumab therapy, then every 4 
weeks during every cycle after that, 
and in case of an immune-mediated 
adverse reaction or disease 
progression 
CareDx, Inc., Brisbane, CA 
 
4 
Serum and 
PBMCs 
Various 
Exploratory 
 
Please see section 2.5.4 for 
details of analysis  
M Whole blood 
 
Baseline, Week 4, at time of 
progression, and in case of immune-
mediated adverse reaction 
Topalian lab at Johns Hopkins 
 
Lab PI:  Dr. Suzanne Topalian 
 
PI email:  stopali1@jhmi.edu 
a:  The lab doing immunostains for CD3, CD4, CD8, CD20, FoxP3 CD68, and CD163 is CLIA certified. 
b:  The lab doing immunostains for PD-L1, PD-1, PD-L2, and LAG-3 is not CLIA certified.

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5.7 
Exploratory/Ancillary Correlative Studies 
 
5.7.1 Histopathological Analysis of Allograft in Setting of Rejection 
 
5.7.1.1 
Specimen Receipt and Processing at the Tumor microenvironment Core at Johns 
Hopkins University 
 
Immunostains for CD3, CD4, CD8, CD20, FoxP3 CD68, and CD163 will be performed in a 
CLIA-certified lab using standard automated methods.  Additional immunostains for an extended 
array of immunoactive markers including PD-L1, PD-1, PD-L2, and LAG-3 (Lipson et al., 2017; 
Sunshine et al., 2017), will be performed by the Tumor Microenvironment Core Laboratory at 
Johns Hopkins Hospital (JHH) as previously described (Taube et al., 2014; Taube et al., 2015; 
Yanik et al., 2017).  Specimens will be considered PD-L1-positive for either tumor cell or 
immune cell staining if membranous staining is present in more than 5% of the neoplastic cells 
or 5% of the immune cells, respectively (Taube, et al., 2012). 
 
5.7.1.2 Site Performing Correlative Study 
 
Assays will be performed in the laboratories of the Johns Hopkins Department of Pathology by 
Dr. Serena Bagnasco and Dr. Janis Taube.  Dr. Bagnasco is an Associate Professor of Pathology 
with expertise in kidney transplant pathology.  She serves as director of the Hopkins Renal 
Pathology Service.  Dr. Taube is an Associate Professor of Dermatology and Pathology and 
serves as the Director of the Division of Dermatopathology and as the Assistant Director of the 
Dermato-immunology Laboratory at the Johns Hopkins School of Medicine. 
 
5.7.2 Histopathological Analysis of Tumor 
 
5.7.2.1 
Specimen Receipt and Processing at the Tumor microenvironment Core at Johns 
Hopkins University 
 
Immunostains for CD3, CD4, CD8, CD20, FoxP3 CD68, and CD163 will be performed in a 
CLIA-certified lab using standard automated methods.  Additional immunostains for an extended 
array of immunoactive markers including PD-L1, PD-1, PD-L2, and LAG-3 (Lipson et al., 2017; 
Sunshine et al., 2017), will be performed by the Tumor Microenvironment Core Laboratory at 
JHH as previously described (Taube et al., 2014; Taube et al., 2015; Yanik et al., 2017).  
Specimens will be considered PD-L1-positive for either tumor cell or immune cell staining if 
membranous staining is present in more than 5% of the neoplastic cells or 5% of the immune 
cells, respectively (Taube, et al., 2012). 
 
5.7.2.2 Site Performing Correlative Study 
 
Assays will be performed in the laboratories of the Johns Hopkins Department of Pathology by 
Dr. Janis Taube.  Dr. Taube is an Associate Professor of Dermatology and Pathology and serves 
as the Director of the Division of Dermatopathology and as the Assistant Director of the 
Dermato-immunology Laboratory at the Johns Hopkins School of Medicine. 
 

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5.7.3 Circulating donor-derived cell-free DNA (dd-cfDNA) 
 
5.7.3.1 Site Performing Correlative Study  
 
CareDx, Inc., Brisbane, California (CLIA certified) will perform the study. Please refer to 
Appendix E for additional information regarding collection.  
 
5.7.4 Serum and PBMC Analysis 
 
5.7.4.1 
Specimen Receipt and Processing at the Topalian Lab at Johns Hopkins University 
 
Upon receipt, serum aliquots will be stored at -80 °C and PBMC samples will be stored in liquid 
nitrogen. 
 
5.7.4.2 
Site Performing Correlative Study 
 
The laboratory of Dr. Suzanne Topalian at Johns Hopkins University will perform the assays.  
Samples will be analyzed to: 
• Define new tumor antigens and their relevance to disease biology, and correlate antigen 
expression with immune responses and disease outcomes. 
• Evaluate potential immune-related prognostic or treatment response indicators. 
• Evaluate the causative mechanisms of immune-related toxicities in patients receiving 
cancer therapy with immune checkpoint blockade. 
• Characterize factors and molecular pathways in the tumor immune microenvironment 
that lead to immune suppression, tolerance to tumor antigens, and cancer progression. 
 
 

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6. 
TREATMENT PLAN 
 
6.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported AEs and potential risks are 
described in Section 10.  Appropriate dose modifications are described in Section 7.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient’s malignancy. 
 
Prior to beginning nivolumab therapy, patients will have their immunosuppression medication 
adjusted to the following regimen: 
 
Immunosuppression Regimen Description 
Agent 
Premedications 
and Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Tacrolimus 
None 
Dosed to achieve 
goal trough level 
of 2-5 ng/mL 
PO 
Twice daily 
No more 
than 28 
days 
Prednisone 
None 
5 mg* 
 
PO 
Daily 
*Patients may remain on higher-dose prednisone if already taking. 
PO=orally 
 
Patients receiving the above protocol-specified immunosuppression regimen may participate on 
the study. These patients can register any time prior to starting the study immunotherapy regimen 
below. 
 
The patient will be requested to maintain a medication diary of each dose of medication (see 
Appendix C).  The medication diary will be returned to clinic staff for review.  Once patients are 
on a stable immunosuppression regimen and the tacrolimus trough level (2-5 ng/mL) is reached, 
they may begin nivolumab therapy: 
 
Nivolumab Regimen Description 
Agent 
Premedications 
and Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Nivolumab 
None, except in the 
case of an infusion 
reaction 
(see Section 6.9)  
480 mg 
IV infusion 
over ~30 
minutes 
Day 1, 
Week 1 
4 weeks 
Tacrolimus* None 
Dosed to achieve 
goal trough level 
of 2-5 ng/mL** 
PO 
Twice daily 
Prednisone* None 
5 mg*** 
PO 
Daily 
* Patients who experience PD on this regimen may reduce or discontinue the use of tacrolimus and prednisone as 
detailed in section 6.2. 

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Nivolumab Regimen Description 
Agent 
Premedications 
and Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
** Tacrolimus trough levels should be monitored each cycle while receiving Nivolumab in order to maintain 2-5 
ng/ml. 
*** Patients may remain on higher-dose prednisone if already taking. 
IV=intravenous, PD=progressive disease, PO=orally 
 
Patients whose tacrolimus trough level is not yet within the protocol-specified range of 2-5 ng/ml 
may start nivolumab after consultation with the Principal Investigator.  
 
Patients will be assessed clinically every ~2 weeks and radiographically every ~8 weeks. 
 
6.1.1 Nivolumab 
 
Once patients have finished immunosuppression adjustment, they may begin nivolumab 
treatment.  Nivolumab will be given by IV infusion every 4 weeks (+7 days) at a dose of 480 mg 
for 24 Cycles (96 weeks). 
 
There will be no dose modifications allowed. 
 
Nivolumab is to be administered as an approximately 30-minute IV infusion, using a volumetric 
pump with a 0.2-1.2 micron in-line filter.  The drug can be diluted with 0.9% normal saline for 
delivery, but the total infusion volume should not exceed 160 mL.  For patients weighing less 
than 40 kg, the total infusion volume must not exceed 4 mL per kg of patient weight.  Nivolumab 
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. 
 
6.1.2 Prednisone 
 
Patients will take 5 mg prednisone PO once each day.  Patients may remain on higher-dose (up to 
10 mg daily) prednisone if already taking prior to study entry. Prednisone should be taken per the 
package insert/SOC instructions with or without food. Do not take another dose if vomiting 
occurs. A missed dose may be taken if more than 12 hours to the next expected dose. Prednisone 
should be taken in the morning approximately the same time each day and prior to infusion.  
 
6.1.3 Tacrolimus 
 
Tacrolimus will be dosed to achieve a trough level between 2-5 ng/mL. Higher doses are 
permitted if required for maintenance of the allograft.  Patients who require tacrolimus trough 
levels >5-8 ng/mL should be discussed with the overall study PI.  Sublingual tacrolimus (instead 
of oral) may be administered to patients if needed (e.g., nausea/vomiting, inability to swallow, 
etc.). Tacrolimus should be taken approximately the same time each day and prior to infusion. 
Patients should be instructed not to eat 2 hours before taking tacrolimus and not to eat for 1 hour 
after taking tacrolimus. Missed doses can be taken within 6 hours of the expected dosing time. 
Vomited doses should not be made up. 

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45 
 
Adjustments to tacrolimus dosing should be made under the guidance of each institution’s 
transplant nephrologist.  Typically, a reliable tacrolimus trough level can be measured within 2-4 
days of starting the therapy.  Many investigators recheck the trough level (prior to morning 
tacrolimus dose, 12 hours from the evening dose) 3 days later to ensure stability. 
 
No formal washout period is required for patients who were previously taking other 
immunosuppressive agents (e.g., sirolimus, mycophenolate mofetil) at the time of screening.  
The period of time that will be necessary to ensure that the tacrolimus level is correct will 
provide sufficient time to allow previous immunosuppressive agents to “wash out.” 
 
During the study, serum tacrolimus levels should be checked approximately weekly for the first 
~4-6 weeks, then every ~2 weeks for ~4-6 weeks, then every ~4 weeks thereafter. 
 
6.2 
Week 16 Assessment 
 
At 16 weeks, patients will be assessed for tumor response to therapy.  Patients who experience 
SD, PR, or CR will be allowed to continue study therapy per Section 6.1 (nivolumab 480 mg IV 
every 4 weeks for up to 24 doses total).  Patients whose disease demonstrates progression will be 
given 3 options: 
 
1. Reduce or discontinue immunosuppression and continue nivolumab therapy (480 mg IV 
every 4 weeks for up to 24 total doses) per section 6.1.  Dose reductions of 
immunosuppression will be performed on a case-by-case basis.  This option likely 
increases the risk of allograft loss. 
2. Transition to treatment with nivolumab 3 mg/kg IV every 3weeks for 4 doses + 
ipilimumab 1 mg/kg IV every 3 weeks for 4 doses, followed by 480 mg nivolumab every 
4 weeks for 21 doses per Section 6.3.  This option likely carries a higher risk of immune-
mediated toxicity compared to nivolumab monotherapy. 
3. Discontinue study treatment. 
 
 
If a patient chooses either option 1 or 2 above, the other option may be used later (i.e., if 
immunosuppression is decreased and the patient again experiences PD, ipilimumab could be 
added to therapy or if ipilimumab is added and the patient again experiences PD, 
immunosuppression could be decreased). 
 
Ideally, patients should be assessed 16 weeks after initiation of nivolumab (regardless of the 
number of doses received) and complete at least 2 on-treatment scans with the second scan being 
completed at least 4 weeks after the first scan, before being declared to have PD to allow for the 
possibility of an immune-related tumor response.  However, if, in the opinion of the investigator, 
a patient demonstrates unequivocal evidence of PD after, for example, 8 weeks of nivolumab 
therapy, the patient may transition at that time.  Additionally, patients who experience delayed 
disease progression (e.g., an initial objective response followed by PD) may transition at that 
time. 
 

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Patients should transition from nivolumab monotherapy to one of the above 2 options within ~28 
days of determination of PD.  Patients do not need to be re-screened.  
 
Patients who have experienced allograft loss should discontinue tacrolimus regardless of 
treatment option chosen.  Prednisone may be prescribed as needed. 
 
6.3 
Nivolumab with Ipilimumab 
 
Patients who experience PD on single-agent nivolumab, or patients who have experienced 
allograft loss, may shift to a combination therapy with nivolumab and ipilimumab.  During the 
initial induction period, nivolumab will be dosed at 3 mg/kg and ipilimumab will be dosed at 1 
mg/kg.  Each will be given by IV infusion over approximately 30 minutes once every 3 weeks 
for 4 cycles (12 weeks).  After the 4th and final induction dose, there will be a six-week gap 
before beginning maintenance nivolumab therapy.  This gap includes the 3 weeks in Cycle 4, 
thus Cycle 5 (the first cycle of the maintenance period) should begin 3 weeks after the end of 
Cycle 4.  During the maintenance period, nivolumab will be dosed at 480 mg by IV infusion over 
approximately 30 minutes once every 4 weeks.  This maintenance regimen may be continued for 
up to 21 cycles (84 weeks) regardless of the duration of nivolumab administration prior to 
transitioning to combination therapy. 
 
Tacrolimus and prednisone administration will continue as described in Section 6.1.  Patients 
who have experienced allograft loss should discontinue tacrolimus regardless of treatment option 
chosen.  Prednisone may be prescribed as needed. 
 
Dosing calculations should be based on the actual body weight.  If the patient’s weight differs by 
>10% from the weight used to calculate the original dose, the dose may be recalculated.  All 
doses should be rounded to the nearest milligram.  There will be no other dose modifications 
allowed. 
 
Toxicity management for the combined agents follows the same template guidelines and 
algorithms that are provided in Section 7 and Appendix B for single agent nivolumab. 
 
When both nivolumab and ipilimumab are to be administered on the same day, separate infusion 
bags and filters must be used for each infusion, there should be a 30-minute rest period between 
infusions, and nivolumab is to be administered first.  Nivolumab is to be infused over 
approximately 30 minutes, promptly followed by a saline flush to clear the line of nivolumab and 
a 30-minute rest period before starting the ipilimumab infusion.  Ipilimumab is to be infused over 
approximately 30 minutes, also followed by a saline flush. 
 

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Nivolumab/Ipilimumab Regimen Description 
Agent 
Premedications 
and Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Nivolumab 
(Induction) 
 
None, except in 
the case of an 
infusion reaction 
(see Section 6.9) 
 
3 mg/kg 
IV infusion 
over ~30 
minutes 
Day 1, Week 1 
for 4 cycles 
(Four total 
doses) 
3 weeks 
Ipilimumab 
(Induction) 
 
None, except in 
the case of an 
infusion reaction 
(see Section 6.9) 
 
1 mg/kg 
IV infusion 
over ~30 
minutes 
Day 1, Week 1 
for 4 cycles  
(Four total 
doses) 
 
Nivolumab 
(Maintenance) 
 
None, except in 
the case of an 
infusion reaction 
(see Section 6.9) 
 
480 mg 
IV infusion 
over ~30 
minutes 
Day 1, Week 
1, starting six 
weeks after 
the last dose of 
ipilimumab 
 
4 weeks 
Tacrolimus* 
 
None 
 
Dosed to achieve 
goal trough level 
of 2-5 ng/mL** 
 
PO 
 
Twice daily 
 
N/A  
Prednisone* 
 
None 
 
5 mg** 
 
PO 
 
Daily 
 
* Patients who have experienced allograft loss may discontinue tacrolimus and prednisone. 
** Tacrolimus trough levels should be monitored each cycle while receiving Nivolumab/Ipilimumab in order to 
maintain 2-5 ng/ml. 
*** Patients may remain on higher-dose prednisone if already taking. 
IV=intravenous, PO=orally 
 
6.4 
Treatment Beyond Progression 
 
A minority of subjects treated with immunotherapy may derive clinical benefit (e.g., delayed 
response, stable disease, or increased OS) despite initial evidence of PD with nivolumab or 
combination treatment.   
 
Patients may be permitted to continue treatment beyond initial RECIST 1.1-defined PD if, in the 
opinion of the investigator, they may benefit from doing so.  In general, patients must be 
clinically stable with no change in performance status due to disease progression and there must 
be no indication for immediate alternative treatment. 
 
6.5 
Criteria to Resume Treatment 
 
Some patients may continue to benefit from treatment, maintaining or improving their responses 
after disease progression, including those treated with steroids. 

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48 
 
For non-autoimmune or non-inflammatory events patients may resume treatment with study 
drug(s) when the drug-related AE(s) resolve to ≤ grade 1, or baseline value, with the following 
exceptions: 
 
• An evaluation of endocrine, GI, hepatic, and pancreatic functions must be made prior to 
restarting to exclude any additional IMARs. 
• Non-drug-related toxicity including hepatic or 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 according to the 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. 
 
A patient who is successfully treated for allograft rejection (i.e., still has a functional kidney 
allograft) may restart study therapy after rescreening and consultation with the PI if the patient: 
 
• Experienced an objective response or SD on study therapy, 
• Experiences progressive or recurrent disease after having been off study therapy, and 
• Has been off study therapy for at least 90 days but less than 1 year. 
 
6.6 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of nivolumab or ipilimumab with other concomitantly 
administered drugs, the case report form must capture the concurrent use of all other drugs, over-
the-counter medications, or alternative therapies.  The study PI should be alerted if the patient is 
taking any agent known to affect or with the potential for drug interactions.  The study team 
should check a frequently updated medical reference for a list of drugs to avoid or minimize the 
use of. 
 
6.7 
Duration of Therapy 
 
In the absence of treatment delays due to AE(s), treatment may continue for 24 cycles or until 
one of the following criteria applies: 
 
• Complete radiographic response; 
• Signs of allograft rejection (see Section 7 for further information); 
• Disease progression (see Section 7 for further information); 
• Intercurrent illness that prevents further administration of treatment; 
• AEs which require permanently going off study treatment (see Section 7 and specific 
algorithms in Appendix B); 
• Any dosing interruption lasting >6 weeks, with the following exceptions: 
o Dosing interruptions >6 weeks that occur for non-drug-related reasons may be 
allowed if approved by the Investigator.  Prior to re-initiating treatment in a subject 

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49 
with a dosing interruption lasting >6 weeks, the study PI must be consulted.  Tumor 
assessments should continue according to the protocol even if dosing is interrupted; 
• Patient decides to withdraw from the study; 
• General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the Investigator; 
• Patient non-compliance; 
• Pregnancy: 
o All women of child-bearing potential should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed, or late, menstrual 
period) at any time during study participation; 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study; 
• Termination of the study by the study sponsor; or 
• The drug manufacturer can no longer provide the study agents. 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
6.8 
Duration of Follow Up 
 
Follow-up visits should be scheduled as follows: 
• All patients who receive study therapy will be monitored for SAEs and IMARs for 90 
days after their last dose of nivolumab or ipilimumab.  Patients will be followed via 
monthly phone calls. 
• For patients except those who develop PD (i.e., patients who complete 96 weeks of 
therapy or whose treatment is discontinued after a CR or drug toxicity): every 8 weeks 
(±14 days) during the year immediately following cessation of therapy, then every 12 
weeks (±21 days) during the second year following cessation of therapy, then every 16 
weeks (±21 days) during the third year following cessation of therapy, then every 24 
weeks (±28 days) during the fourth year following cessation of therapy. 
• Patients with documented PD will be contacted by telephone or other means (e.g., email) 
every 12 weeks ±14 days to assess for survival.  Survival follow-up will continue until 
death or 5 years from the date of trial registration, whichever occurs first. 
 
6.9 
Treatment of Nivolumab- or Ipilimumab-Related Infusion Reactions 
 
Nivolumab- or ipilimumab-related infusion or hypersensitivity reactions are rare.  However, 
when such reactions occur, symptoms/signs may include fever, chills, rigors, headache, rash, 
urticaria, angioedema, pruritis, arthralgias, hypo- or hypertension, bronchospasm, back pain, 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 Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 guidelines. 
 

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Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as medically appropriate: 
 
6.9.1 Grade 1 symptoms:  Mild reaction, infusion interruption and/or intervention not 
indicated. 
 
Infusion rate may be slowed or interrupted and restarted 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 the patient closely. 
 
The following prophylactic medications are recommended for future infusions: 
• Diphenhydramine 50 mg (or equivalent) and/or 
• Paracetamol 325-1000 mg (acetaminophen) at least 30 minutes before additional 
nivolumab administrations 
 
6.9.2 Grade 2 symptoms:  Moderate reaction that requires therapy or infusion interruption but 
responds promptly to symptomatic treatment (e.g., antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids). 
 
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, 
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 the patient closely.  If symptoms recur, re-administer diphenhydramine 50 mg IV, 
and monitor the patient until resolution of symptoms.  The amount of study drug infused must be 
recorded on the CRF.  If symptoms recur, treatment medications may need to be continued for 
24-48 hours, and no further nivolumab will be administered at that visit. 
 
The following prophylactic medications are recommended for future infusions: 
• Diphenhydramine 50 mg (or equivalent), 
• Paracetamol 325-1000 mg (acetaminophen) at least 30 minutes before additional 
nivolumab administrations, and 
• Corticosteroids (recommended dose:  up to 25 mg of IV hydrocortisone or equivalent) 
may be used, if necessary. 
 
6.9.3 Grade 3 or 4 symptoms:  Prolonged reaction (i.e., not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); hospitalization indicated for other 
clinical sequelae (e.g., renal impairment, pulmonary infiltrates, etc.); life threatening; 
pressor or ventilatory support indicated. 
 
• Immediately discontinue nivolumab infusion. 
• Begin an IV infusion of saline and bronchodilators 
• Epinephrine 0.2-1 mg diluted 1:1,000 for subcutaneous administration, or 0.1-0.25 mg 
diluted 1:10,000 for IV administration, 

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• 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 should be discontinued permanently. 
 
Investigators should follow their institutional guidelines for the treatment of anaphylaxis.  
Monitor the 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).  Additional treatment prior to next dose may be given 
according to the guidelines above. 
 
Note:  late occurring events including isolated fever and fatigue may represent the presence of 
systemic inflammation.  
 
 

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7. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
Note:  If a patient experiences several AEs and there are conflicting recommendations, the 
investigator should use the recommended treatment modification for the most severe AE. 
 
7.1 
Nivolumab and Ipilimumab Dose Modifications 
 
Below are dose modification tables for nivolumab and combination nivolumab with ipilimumab 
for the following adverse events.  Please use as written and contact the drug monitor for any 
proposed changes. 
 
Please refer to Appendix B, the Nivolumab Investigator’s Brochure, or the Ipilimumab 
Investigator’s Brochure for toxicity management algorithms which include specific treatment 
guidelines.  These algorithms should be followed unless there are specific clinical circumstances 
for which the treating physician decides an alternative treatment approach is clinically 
appropriate.  Consultation with the study PI or drug monitor is recommended.  
 
In several places there are differences from the algorithms regarding protocol directed drug 
modifications and these are identified with (#).  In these cases, please follow the protocol-
specific guidelines in this section.  
 
Generally, early evaluation while withholding drug, and appropriate treatment as indicated in the 
management tables and event specific guidelines is strongly encouraged. 
 
• Any patient with grade 2 drug-related uveitis, eye pain, or blurred vision that does not 
respond to topical therapy and does not improve to grade 1 severity within the re-
treatment period OR that requires systemic treatment should go off protocol therapy 
• Patients with any AE, laboratory abnormality, or intercurrent illness which, in the 
judgment of the investigator, presents a substantial clinical risk to the patient with 
continued study drug dosing should go off protocol therapy. 
• 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, or insulin therapy, or that does not require treatment 
does not require discontinuation of protocol therapy. 
• If any kidney-related AEs (e.g. elevated serum creatine levels, development of DSA or 
non-HLA antibodies, or development of severe proteinuria [>1 g/day]) are observed, 
nivolumab should be held, a renal allograft biopsy should be obtained, and treatment for 
allograft rejection should be started immediately (see Section 7.2). 
 

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Skin Rash and Oral 
Lesions 
Management/Next Dose for Nivolumab and Combination 
Nivolumab/Ipilimumab 
≤ Grade 1 
No change in dose* 
Grade 2 
Hold* until ≤ grade 1 (#).  Resume at same dose level. 
Grade 3 
Hold* until ≤ grade 1.  Resume at same level at investigator’s discretion  
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:  See Skin AE management guidelines. 
 
Liver Function 
AST, ALT, 
Bilirubin 
Management/Next Dose for Nivolumab and Combination 
Nivolumab/Ipilimumab 
≤ Grade 1 
Hold, at investigator’s discretion, until values return to ULN or 
baseline (#).   Resume at same dose level. 
Grade 2 
(3 – 5 × ULN) 
Hold until values return to baseline.  Resume at same dose level. 
Grade 3 
(5 – 20 × ULN) 
Hold until grade 1 (ULN – 3 x ULN) or baseline.  Resume at same dose 
level, at investigator’s discretion.  If persistent (>7 days) or requires 
steroids, patients should go off protocol therapy  
Grade 4 
Off protocol therapy 
Continued treatment of active immune mediated hepatitis may exacerbate ongoing 
inflammation.  Holding drug to evaluate LFT changes and early treatment are recommended.   
LFT changes may occur during steroid tapers from other events and may occur together with 
other GI events including cholecystitis/pancreatitis. 
Note:  Grades for liver function follow multiples of ULN, rather than multiples of baseline. 
Recommended management:  See Hepatic AE Management Algorithm. 
 

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Diarrhea/Colitis 
Management/Next Dose for Nivolumab and Combination 
Nivolumab/Ipilimumab 
≤ Grade 1 
Hold until baseline (#).  No change in dose. 
Grade 2 
Hold until baseline.  No change in dose. 
Grade 3 
Resume at same dose level, at investigator discretion, if resolved within 
7 days without steroids and with no evidence of colitis.  If persistent (>7 
days), or requires steroids, patients should go off protocol therapy. 
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.  
Patients who require systemic steroids should be taken off study treatment.  
If possible without compromising acute care, evaluate pituitary function prior to starting 
steroids. 
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 
Amylase/Lipase  
Management/Next Dose for Nivolumab and Combination 
Nivolumab/Ipilimumab 
≤ Grade 1 
Continue at same dose level, if asymptomatic, at investigator’s 
discretion. 
Grade 2 
Continue at same dose level, if asymptomatic, at investigator’s 
discretion.  If symptomatic, resume at same dose level once resolved. 
Grade 3 
Continue at same dose level, if asymptomatic, at investigator’s 
discretion.  Patients should have imaging done when clinically indicated 
(i.e., grade 3 pancreatitis) before resuming treatment.  Patients who 
develop symptomatic pancreatitis or diabetes mellitus should go off 
protocol therapy. 
Grade 4 
Hold until grade 2.  Resume at same dose level if asymptomatic.  
Patients should have imaging done before resuming treatment, and when 
clinically indicated.  Patients who develop symptomatic pancreatitis or 
diabetes mellitus should go off protocol therapy. 
Patients may develop symptomatic and radiologic evidence of pancreatitis as well as DM and 
diabetic ketoacidosis (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 
re-treated. 
For treatment management of symptomatic pancreatitis please follow the Hepatic AE 
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 O2 saturation.  Resume with no change in dose after pulmonary 
and/or infectious disease consultation excludes lymphocytic 
pneumonitis. 
Grade 2 
Hold dose pending evaluation.  Resume with no change in dose after 
pulmonary and/or infectious disease consultation excludes ipilimumab 
and associated lymphocytic pneumonitis as the cause of the 
pneumonitis.  Patients should go off protocol therapy if steroids are 
required. 
Grade 3 
Hold dose pending evaluation.  Resume with no change in dose after 
pulmonary and/or infectious disease consultation excludes ipilimumab 
and associated lymphocytic pneumonitis as the cause of the 
pneumonitis.  Patients should go off protocol therapy 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.  Seasonal influenza 
killed vaccine should be recommended for all patients. 
Recommended management:  See Pulmonary AE Management Algorithm. 
 
Other GI / Nausea 
and Vomiting 
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 
AEs or other causes.  Resume at same dose level after resolution to 
≤ grade 1. 
Grade 3 
Hold pending evaluation until ≤ grade 1.  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 nausea or vomiting should be evaluated for upper GI inflammation 
and other immune related events. 
 

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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. 
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, or hepatic; or muscle inflammation (as assessed by creatine 
phosphokinase levels). 
 
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. 
Grade 2 
Hold dose pending evaluation and observation.  Hold until ≤ grade 1.  
Patients should go off protocol therapy if treatment with steroids is 
required.  Resume at same dose level for peripheral isolated nerve 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 nerve VII), GB syndrome, or myasthenia gravis should be off study. 
Recommended management:  See Neurologic AE Management Algorithm. 
 

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Endocrine 
Hypophysitis/Adrenal 
Insufficiency  
Management/Next Dose for Nivolumab and Combination 
Nivolumab/Ipilimumab 
≤ Grade 1 
Hold pending evaluation, including consultation with an 
endocrinologist for evidence of adrenal insufficiency or hypophysitis.  
Patients with asymptomatic TSH elevation may continue treatment 
while evaluating the need for thyroid replacement. 
Grade 2 
Hold until patients are on a stable hormone replacement regimen.  If 
treated with steroids, patients must be stable off steroids for 2 weeks.  
Resume at same dose level. 
Grade 3 
Hold until patients are on a stable replacement hormone regimen.  If 
treated with steroids, patients must be stable off steroids for 2 weeks.   
Resume at same dose level. 
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. 
Pituitary function should be evaluated before beginning steroid therapy or replacement therapy 
of any kind. 
*Note patients with thyroiditis may be retreated on hormone replacement therapy.  Patients 
must be evaluated to rule out pituitary disease prior to initiating hormone replacement therapy. 
Recommended management: See Endocrine AE Management Algorithm  
 
Renal 
Management/Next Dose for Nivolumab and Combination 
Nivolumab/Ipilimumab 
≤ Grade 1 
See Section 7.2 
Grade 2 
See Section 7.2 
Grade 3 
See Section 7.2 
Grade 4 
See Section 7.2 
 
Infusion Reaction 
 
Management/Next Dose for Nivolumab and Combination 
Nivolumab/Ipilimumab 
≤ Grade 1 
See Section 6.9 
Grade 2 
See Section 6.9 
Grade 3 
See Section 6.9 
Grade 4 
See Section 6.9 
 

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Fever  
Management/Next Dose for Nivolumab and Combination 
Nivolumab/Ipilimumab 
≤ Grade 1 
Evaluate and continue at same dose level. 
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. 
 
Cardiac* 
Management/Next Dose for Nivolumab and Combination 
Nivolumab/ Ipilimumab 
≤ Grade 1 
Hold dose pending evaluation and observation.**  Evaluate for signs and 
symptoms of congestive heart failure, ischemia, arrhythmia, or myositis.  
Obtain history, EKG, and CK (for concomitant myositis) and CK-MB 
tests.  Repeat troponin and CK tests, and EKG every 2-3 days.  If 
troponin and labs normalize without evidence of myocarditis, the patient 
may resume therapy.  If labs worsen or symptoms develop then treat as 
below.   
≥ Grade 2 with 
suspected 
myocarditis 
Hold dose.**  Admit to hospital and consult with a cardiologist.  Rule 
out MI and other causes of cardiac disease, and begin cardiac monitoring.  
Obtain an echocardiogram and consider cardiac MRI and cardiac biopsy.  
Initiate high dose methylprednisolone and immune suppression as 
clinically indicated.  If no improvement is seen within 24 hours consider 
adding either infliximab, ATG, or tacrolimus.  Patients may 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. 
*Including congestive heart failure, LV systolic dysfunction, myocarditis, or elevated levels of 
phosphocreatine kinase and/or troponin. 
**Patients with evidence of myositis without myocarditis may be treated according to “All 
Other Events,” below. 
Given the heightened risk for cardiac AEs, troponin should be monitored with each dose of 
nivolumab for the first two months to detect any early evidence of myocarditis.  Baseline 
troponin should be obtained on study, after tacrolimus adjustment.  Evaluation of cardiac 
function, including troponin and CPK levels, EKGs, and echocardiograms as clinically 
indicated, is recommended for any patients with a history of congestive heart failure or who are 
at risk because of underlying cardiovascular disease or previous exposure to cardiotoxic drugs. 
 
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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All Other Events 
Management/Next Dose for Nivolumab and Combination 
Nivolimab/Ipililmumab  
≤ Grade 1 
No change in dose. 
Grade 2 
Hold until ≤ grade 1 or baseline (exceptions as noted below). 
Grade 3 
Hold until ≤ grade 1 or baseline and patient no longer on steroid 
treatment, if initiated (exceptions as noted below).  Patients should 
go off protocol therapy for events with a high likelihood of  
morbidity or mortality with recurrent events. 
Grade 4 
Off protocol therapy. 
Recommended management:  As clinically indicated  
 
 
Patients requiring high-dose steroid treatment for autoimmune or inflammatory AEs should go 
off study treatment except for short courses of tapering steroids for infusion reactions, 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 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.  
 
Prior to starting corticosteroids or hormone replacement for any reason, appropriate endocrine 
testing, including cortisol, adrenocorticotropic hormone (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.   
 
Patients may be dose-delayed for evaluation and restarted depending on results.  
 
Any patient started on corticosteroids who is later determined to not require steroid treatment for 
an autoimmune AE may resume therapy after a 2-week observation period without further 
symptoms at the discretion of the study PI or Investigator. 
 
7.2 
Prednisone and Tacrolimus Dose Modifications for Allograft Rejection 
 
Given the potential for rejection due to the administration of nivolumab and ipilimumab in this 
study, patients should be monitored closely for signs of rejection.  
 

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Markers of allograft rejection may include the following: 
 
• Unexplained ≥20% increase in serum creatinine over baseline, 
• Development of donor-specific antigen (DSA) or non-HLA antibodies, 
• Development of severe proteinuria (>1 g/day), 
• Persistent increase in dd-cfDNA. 
 
Serum creatinine (included in the comprehensive metabolic panel) will be monitored according 
to the schedule outlined in the treatment calendars (Section 11). 
 
Donor-specific and non-HLA antibodies should be checked as clinically indicated at the 
direction of the institution's transplant nephrologist.  Patients should be encouraged to report 
possible symptoms of rejection, including elevated temperature, elevated blood pressure, graft 
tenderness, and blood in the urine.  Although experimental in this setting, dd-cfDNA levels (see 
Section 2.5.3 and the Biomarker Plan, Section 5.6)  may be useful to monitor for signs of 
rejection. 
 
Dipstick urinalysis should be performed per the schedule outlined in the treatment calendars.  If 
2+ or greater, a urine protein/creatinine ratio (spot or 24-hour) should be assessed at the direction 
of the institution's transplant nephrologist. 
 
If rejection is suspected based on the above analyses, the following interventions will be 
triggered: 
 
1. Hold or discontinue nivolumab (and ipilimumab, if applicable) 
2. Immediately biopsy the renal allograft 
a. If cell-mediated rejection:  Increase the tacrolimus dose (target trough level = 
5-10 ng/mL) and administer 500 mg IV methylprednisolone daily for 3 days, with a 
prednisone taper thereafter.  If no improvement, administer 5 mg/kg infliximab.  
b. If antibody-mediated rejection:  Increase the tacrolimus dose (target trough level = 
5-10 ng/mL), perform plasmapheresis, and administer IV immunoglobulin (Ig) per 
institutional protocol plus 500 mg IV methylprednisolone daily for 3 days with a 
prednisone taper thereafter. 
 
A patient who experiences clinical benefit from the above regimen and still has a functional 
kidney allograft may restart study therapy after re-screening and consultation with the PI if the 
patient: 
• Experienced an objective response or SD on study therapy, 
• Experiences progressive or recurrent disease after having been off study therapy, and 
• Has been off study therapy for at least 90 days, but less than 1 year. 
 
Patients who experience allograft loss should begin dialysis and may resume nivolumab 
monotherapy or nivolumab plus ipilimumab combination therapy, as appropriate. 
 
Dose modifications of tacrolimus and prednisone should be done per standard of care.  
 

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8. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational and 
commercial agents administered in this study can be found in Section 10.1. 
 
8.1 
CTEP IND Agent(s) 
 
8.1.1 Nivolumab (NSC 748726) 
 
Amino Acid Sequence:  4 polypeptide chains, which include 2 identical heavy chains with 440 
amino acids and 2 identical light chains. 
 
Other Names:  nivolumab, MDX1106 
 
Classification:  Anti-PD-1 MAb 
 
M.W.:  146,221 Daltons 
 
Mode of Action:   Nivolumab targets the PD-1, 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, 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, 
diethylenetriaminepentacetic acid (pentetic acid), polysorbate 80 (Tween™ 80), and water for 
injection.  Dilute solutions of hydrochloric acid and/or sodium hydroxide may be used for pH 
adjustment (pH 5.5-6.5). 
 
How Supplied:  Nivolumab is supplied by Bristol-Myers Squibb and distributed by the 
Pharmaceutical Management Branch (PMB), 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 fluoropolymer film-laminated 
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.  When the dose is based on patient weight (i.e., 
mg/kg), nivolumab injection can be infused undiluted or diluted to protein concentrations as low 
as 0.35 mg/mL.  When the dose is fixed (e.g., 240 mg, 360 mg, or 480 mg flat dose), nivolumab 
injection can be infused undiluted or diluted so as not to exceed a total infusion volume of 160 
mL.  For patients weighing less than 40 kg, the total volume of infusion must not exceed 4 mL 
per kg of patient weight.  During drug product preparation and handling, vigorous mixing or 
shaking is to be avoided. 
 

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Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and 
infusion sets, and glass bottles. 
 
Storage:  Vials of Nivolumab injection must be stored at 2-8 °C (36-46 °F) and protected from 
light and freezing.  The unopened vials can be stored at room temperature (up to 25 °C, 77 °F) 
and room light for up to 48 hours. 
 
If a storage temperature excursion is identified, promptly return Nivolumab to 2-8 °C and 
quarantine the supplies.  Provide a detailed report of the excursion (including documentation of 
temperature monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov for 
determination of suitability. 
 
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 
at 2-8 °C (36-46 °F) and a maximum of 8 hours of the total 24 hours can be at room temperature 
(20-25 °C, 68-77 °F) and room light.  The maximum 8-hour period under room temperature and 
room light conditions includes the product administration period. 
 
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 over 30 minutes.  Do not administer as an IV 
push or bolus injection. 
 
Method of Administration:  Administer through a 0.2-1.2-micron pore size, low-protein binding 
(polyethersulfone membrane) in-line filter.  
 
Potential Drug Interactions:  The indirect drug-drug interaction potential of nivolumab was 
assessed using systemic cytokine modulation data for cytokines known to modulate CYP 
enzymes.  There were no meaningful changes in cytokines known to have indirect effects on 
CYP enzymes across all dose levels of nivolumab.  This lack of cytokine modulation suggests 
that nivolumab has no or low potential for modulating CYP enzymes, thereby indicating a low 
risk of therapeutic protein-drug interaction. 
 
Patient Care Implications:  Women of childbearing potential (WOCBP) receiving nivolumab 
must continue contraception for a period of 5 months after the last dose of nivolumab.  Men 
receiving nivolumab and who are sexually active with WOCBP must continue contraception for 
a period of 7 months after the last dose of nivolumab. 
 
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 Bristol-Myers Squibb and the DCTD, NCI (see Section 13.4). 
 

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8.1.2 Ipilimumab 
 
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. 
 
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:  Ipilimumab is supplied by Bristol-Myers Squibb and distributed by the PMB, 
CTEP/DCTD/NCI.  Ipilimumab for injection, 200 mg/40 mL (5 mg/mL), is formulated as a clear 
to slightly opalescent, colorless to 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. 
 

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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 2-8 °C (36-46 °F) 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 2-8 °C (36-46 °F), 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 2-8 °C (36-46 °F) or at room temperature/ room light.  
 
CAUTION:  Ipilimumab does not contain antibacterial preservatives.  Use prepared IV 
solution immediately.  Discard partially used vials.  
 
Route of Administration: Intravenous infusion over 30 minutes.  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 and rate via a PVC IV infusion set with an in-line, sterile, non-pyrogenic, low-
protein-binding filter (0.2-1.2 micron). 
 
Patient Care Implications:  Monitor patients for immune-related adverse events, e.g., 
rash/vitiligo, diarrhea/colitis, uveitis/episcleritis, hepatitis and hypothyroidism. 
 
8.1.3 Agent Ordering and Agent Accountability 
 
NCI-supplied agents may be requested by eligible participating Investigators (or their authorized 
designee) at each participating institution.  The CTEP-assigned protocol number must be used 
for ordering all CTEP-supplied investigational agents.  The eligible participating investigators at 
each participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment 
Form, 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 participating investigator at that institution. 
 
Sites can request a 5-vial starter supply of nivolumab.  Ipilimumab should not be requested until 
there is an active patient at the site. 
 
Submit agent requests 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, a “current” password, and active 
person registration status.  For questions about drug orders, transfers, returns, or accountability, 

NCI Protocol #:  10214 
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65 
call or email PMB any time.  Refer to the PMB’s website for specific policies and guidelines 
related to agent management.   
 
8.1.3.1 
Agent Inventory Records 
 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing and final disposition of all agents received from the PMB using 
the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on 
the CTEP forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
 
8.1.3.2 
Investigator Brochure Availability 
 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB OAOP application.  Access to OAOP requires the establishment of a 
CTEP IAM account and the maintenance of an “active” account status, a “current” password and 
active person registration status.  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:  https://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines:  
https://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP  
• CTEP Identity and Access Management (IAM) account:  
https://ctepcore.nci.nih.gov/iam/ 
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service:  (240) 276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET) 
 
8.2 
Commercial Agent(s) 
 
8.2.1 Prednisone 
 
Product description:  Prednisone, a synthetic glucocorticoid, is a white crystalline powder.  It is 
available as 1 mg, 2.5 mg, 5 mg, 20 mg, and 50 mg tablets, and as an oral solution.  Tablets are 
available in immediate and delayed release formulations.. 
 
Route of administration:  Prednisone is administered orally once each day.  Delayed release 
tablet formulations should not be crushed or chewed. Prednisone may be taken with our without 
food. 

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Agent Ordering:  Oral prednisone will be obtained from commercial sources. 
 
See prednisone package inserts for more information. 
 
8.2.2 Tacrolimus 
 
Product Description:  Tacrolimus, (FK506) is a macrolide immunosuppressant produced by 
Streptomyces tsukubaensis.  Tacrolimus appears as white crystals or crystalline powder.  It is 
practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and 
chloroform.  Tacrolimus inhibits T lymphocyte activation, although the exact mechanism of 
action is not known.  Tacrolimus binds to FKBP-12, an intracellular protein.  A complex of 
tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase 
activity of calcineurin is inhibited.  This effect may prevent the generation of nuclear factor of 
activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the 
formation of lymphokines (interleukin-2, gamma interferon).  The net result is the inhibition of 
T lymphocyte activation (i.e., immunosuppression).  Refer to the package insert for more 
information. 
 
Availability:  Tacrolimus is available for oral administration as capsules containing the 
equivalent of 0.5 mg, 1 mg, or 5 mg of anhydrous tacrolimus.  Inactive ingredients include 
lactose, hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate. 
 
Storage and Handling:  Tacrolimus capsules should be stored at room temperature (15-30 °C, 
59-86 °F).  Tacrolimus for injection should be stored at 5-25 °C (41-77 °F). 
 
Administration:  Capsules should be taken by mouth every 12 hours without food.  Immediate-
release and extended-release oral formulations are not interchangeable. If a patient cannot take 
oral capsules, please use sublingual tacrolimus.  
 
Potential drug interactions:  Tacrolimus is extensively metabolized by the cytochrome P450 
(CYP) system, primarily CYP3A4.  Drugs that may increase tacrolimus blood concentrations 
include: calcium channel blockers (e.g., diltiazem, nicardipine, nifedipine, verapamil), antifungal 
agents (e.g., ketoconazole, clotrimazole, fluconazole, itraconazole), macrolide antibiotics (e.g., 
clarithromycin, erythromycin, troleandomycin), gastrointestinal prokinetic agents (e.g., cisapride, 
metoclopramide), and/or other drugs (e.g., bromocriptine, cimetidine, cyclosporine, danazol, 
ethinyl estradiol, omeprazole, nefazodone, HIV-protease inhibitors.  Drugs that may decrease 
tacrolimus concentrations include: anticonvulsants (e.g., carbamazepine, phenobarbital, 
phenytoin), antibiotics (e.g., rifabutin, rifapentine), and/or herbal preparations (e.g., St. John’s 
Wort [hypericum perforatum]).  Grapefruit and grapefruit juice should be avoided.  Refer to an 
updated reference for current information about drug-drug interactions with calcineurin 
inhibitors. 
 
Agent Ordering:  Tacrolimus will be obtained from commercial sources. 

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9. 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Endpoints 
 
9.1.1 Overview 
 
A “success” rate (CR/PR/SD without allograft loss at 16 weeks) of 15% or lower (null 
hypothesis) would be considered insufficient for further study in this population, while a 
“success” rate of 40% or higher (alternative hypothesis) would be considered worthy of further 
investigation.  This trial will be performed using a modified Simon’s two-stage minimax design 
(Simon, 1989).   In the first stage, nine patients will be enrolled.  To minimize risk to patients, 
accrual will be paused after the ninth patient is enrolled until a decision is made to continue the 
trial.  If one or no patients experience CR/PR/SD without allograft loss at 16 weeks, the study 
will be temporarily closed to accrual for futility.  Otherwise, 7 additional patients will be 
enrolled for a total of 16.  The null hypothesis will be rejected if 5 or more patients experience 
CR/PR/SD without allograft loss.  This design yields a type 1 error rate of 0.074 and power of 
0.8 to distinguish between the null hypothesis and the alternative hypothesis. 
 
9.1.2 Primary Endpoint 
 
The percentage of kidney transplant recipients with selected advanced cancers for whom 
standard medical, surgical or radiation therapy would be insufficient who experience CR/PR/SD 
without allograft loss at 16 weeks after administration of nivolumab, tacrolimus, and prednisone. 
 
9.1.3 Secondary Endpoints 
 
• Objective response (CR or PR) rate (ORR) based on RECIST 1.1 criteria, and immune-
related objective response rate (irORR) using immune-related response criteria (iRECIST); 
• Allograft rejection rate; 
• Duration of response among patients who experience CR or PR; 
• Progression-free survival; 
• Overall survival; 
 
9.2 
Sample Size/Accrual Rate 
 
A minimum of 9, and up to 16, patients will be recruited for this study.  Estimated accrual is 
approximately one patient every eight weeks. 
 
The study population is expected to comprise 50% men and 50% women, but because this 
protocol involves a small number of patients recruited across multiple institutions with 
geographically, racially, and culturally diverse populations, we cannot estimate the racial 
composition of the cohort. 
 

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68 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or 
Latino 
Hispanic or 
Latino 
 
 
Female 
Male 
Female 
Male 
 
American Indian/ 
Alaska Native 
 
 
 
 
 
Asian 
1 
1 
 
 
2 
Native Hawaiian or 
Other Pacific 
Islander 
 
 
 
 
 
Black or African 
American 
2 
2 
 
 
4 
White 
4 
4 
1 
1 
10 
More Than One Race 
 
 
 
 
 
Total 
7 
7 
1 
1 
16 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015) 
OMB No. 0925-0001/0002 
 
9.3 
Stratification Factors 
 
N/A 
 
9.4 
Analysis of Primary Endpoints 
 
The percent of kidney transplant recipients who experience CR/PR/SD at 16 weeks and do not 
experience allograft loss after administration of nivolumab, tacrolimus, and prednisone will be 
calculated, along with the corresponding exact 95% CI.  A minority of subjects treated with 
immunotherapy may derive clinical benefit and experience a delayed response, stable disease, or 
increased OS despite initial evidence of PD with nivolumab or combination treatment.  Subjects 
who continue treatment beyond initial investigator-assessed, RECIST 1.1-defined progression 
will be considered to have investigator-assessed PD at the time of the initial progression event 
but may be later designated as delayed responses for purposes of determining CR/PR/SD and 
counted as responses for this study. 
 
The evaluable population for the primary endpoint is all subjects who receive at least one dose of 
nivolumab and undergo tumor response assessments and graft assessments at ~8 and ~16 weeks.  
Patients who experience allograft loss within 16 weeks of receiving nivolumab will be evaluable 
for the primary endpoint even if tumor response assessments cannot be performed.  Patients who, 
in the opinion of the investigator, experience PD (with or without allograft failure) prior to 16 
weeks will also be evaluable. 
 
9.5 
Analysis of Secondary Endpoints 
 
Renal allograft rejection rate will be estimated as the proportion of subjects who experience 
markers of allograft rejection as defined in Section 7.2.  

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69 
 Allograft loss is defined as allograft rejection leading to complete, permanent, and irreversible 
loss-of-function of the renal allograft.  All patients who receive at least one dose of nivolumab 
will be evaluable for allograft rejection. 
 
Objective response rate (ORR) is defined as the proportion of subjects whose best overall 
response from baseline is either a CR or PR, based on RECIST 1.1 criteria.  ORR will be 
estimated along with 95% exact CI.  A minority of subjects treated with immunotherapy may 
derive clinical benefit and experience a delayed response, stable disease, or increased OS despite 
initial evidence of PD with nivolumab or combination treatment.  Subjects who continue 
treatment beyond initial investigator-assessed, RECIST 1.1-defined progression will be 
considered to have investigator-assessed PD at the time of the initial progression event but may 
be later designated as delayed responses for purposes of determining ORR and counted as 
responses.  The analysis of ORR will be performed on the response-evaluable population, 
defined as those subjects who have measurable disease at baseline, receive at least one dose of 
nivolumab, and undergo response assessments at ~8 and ~16 weeks.  Patients who, in the 
opinion of the investigator, experience PD prior to 16 weeks will also be evaluable.  Immune-
related ORR based on immune-related response criteria (iRECIST) will also be summarized 
using the same method. 
 
Among the patients who experience CR or PR, DOR is measured from the time criteria are met 
for CR/PR (whichever is first recorded) until the first date that recurrent disease or PD is 
documented.  DOR will be summarized using the Kaplan-Meier method.  All patients who 
experience CR/PR will be evaluable for DOR. 
 
Overall survival (OS) is the time from the first dose of nivolumab to the date of death from any 
cause.  A subject who has not died will be censored at last known date alive.  Progression-free 
survival (PFS) is defined as the time from the first dose of nivolumab to the date of the first 
documented tumor progression or death due to any cause, whichever occurs first.  Subjects who 
did not progress or die will be censored on the date of their last evaluable tumor assessment.  
Kaplan-Meier curves will be used to summarize OS and PFS.  OS and PFS analyses will be 
performed for all patients who receive at least one dose of nivolumab. 
 
Because the number of patients who change over to nivolumab + ipilimumab or continue 
nivolumab with reduction in their immunosuppressive regimen after disease progression on 
nivolumab monotherapy will be small and unpredictable, data from these patients will be 
considered investigative and potentially hypothesis-generating. 
 
 
9.6 
Reporting and Exclusions 
 
9.6.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with tacrolimus 
and prednisone.   
 
 

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70 
9.6.2 Evaluation of Tumor Response 
 
All patients enrolled in the study will be assessed for response to treatment.  Tumor responses 
will be assessed according to RECIST and iRECIST criteria. 
 
9.6.3 Evaluation of Allograft  
 
Allograft rejection will be reported as 1) rejection without loss; 2) rejection with loss; or 3) no 
rejection. 
 

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71 
10. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
AE monitoring and reporting is a routine part of every clinical trial.  The following list of AEs 
(Section 10.1) and the characteristics of an observed AE (Sections 10.2 and 10.3) will determine 
whether the event requires expedited reporting via the CTEP Adverse Event Reporting System 
(CTEP-AERS) in addition to routine reporting. 
 
10.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
 
10.1.1 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 2.4, December 2, 20201 
 
 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
CARDIAC DISORDERS 
  
 
 
Cardiac disorders - Other 
(cardiomyopathy) 
  
 
 
Myocarditis 
  
 
 
Pericardial tamponade2 
  
 
 
Pericarditis 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency3 
 
  
 
Hyperthyroidism3 
 
  

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72 
 
 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Hypophysitis3 
 
  
 
Hypothyroidism3 
 
  
EYE DISORDERS 
  
 
 
Blurred vision 
  
 
 
Dry eye 
  
 
 
Eye disorders - Other (diplopia)3   
 
 
Eye disorders - Other (Graves 
ophthalmopathy)3 
  
 
 
Eye disorders - Other (optic 
neuritis retrobulbar)3 
  
 
 
Eye disorders - Other (Vogt-
Koyanagi-Harada) 
  
 
Uveitis 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Colitis3 
 
  
 
 
Colonic perforation3 
  
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
 
Enterocolitis 
  
 
 
Gastritis 
  
 
 
Mucositis oral 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis4 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Injection site reaction 
 
 Injection site reaction (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatobiliary disorders - Other 
(immune-mediated hepatitis) 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction3 
  
 
 
Autoimmune disorder3 
  
 
 
Cytokine release syndrome5 
  
 
 
Immune system disorders - 
Other (GVHD in the setting of 
allotransplant)3,6 
  
 
 
Immune system disorders - 
Other (sarcoidosis)3 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction7 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased3 
 
 Alanine aminotransferase 
increased3 (Gr 3) 
 
Aspartate aminotransferase 
increased3 
 
 Aspartate aminotransferase 
increased3 (Gr 3) 

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73 
 
 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Blood bilirubin increased3 
 
 Blood bilirubin increased3 
(Gr 2) 
 
CD4 lymphocytes decreased 
 
 CD4 lymphocyte decreased 
(Gr 4) 
 
Creatinine increased 
 
  
 
Lipase increased 
 
  
 
Lymphocyte count decreased 
 
 Lymphocyte count 
decreased (Gr 4) 
 
Neutrophil count decreased 
 
  
 
Platelet count decreased 
 
  
 
Serum amylase increased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
 
Hyperglycemia 
 Hyperglycemia (Gr 2) 
 
 
Metabolism and nutrition 
disorders - Other (diabetes 
mellitus with ketoacidosis)3 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
 
Musculoskeletal and connective 
tissue disorder - Other 
(polymyositis) 
  
 
 
Myositis 
  
 
 
Rhabdomyolysis 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Encephalopathy3 
  
 
 
Facial nerve disorder3 
  
 
 
Guillain-Barre syndrome3 
  
 
 
Myasthenia gravis3 
  
 
 
Nervous system disorders - 
Other (demyelination 
myasthenic syndrome) 
  
 
 
Nervous system disorders - 
Other (encephalitis)3 
  
 
 
Nervous system disorders - 
Other (meningoencephalitis) 
  
 
 
Nervous system disorders - 
Other (meningoradiculitis)3 
  
 
 
Nervous system disorders - 
Other (myasthenic syndrome) 
  
 
 
Peripheral motor neuropathy 
  
 
 
Peripheral sensory neuropathy   
 
 
Reversible posterior 
leukoencephalopathy 
syndrome3 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury3 
  

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74 
 
 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
 
Renal and urinary disorders - 
Other (immune-mediated 
nephritis) 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pleural effusion3 
 
  
 
Pneumonitis3 
 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(bronchiolitis obliterans with 
organizing pneumonia)3 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme3 
  
 
Pruritus3 
 
 Pruritus3 (Gr 2) 
 
Rash maculo-papular3 
 
 Rash maculo-papular3 (Gr 2) 
 
 
Skin and subcutaneous tissue 
disorders - Other (bullous 
pemphigoid) 
  
 
Skin and subcutaneous tissue 
disorders - Other (Sweet's 
Syndrome)3 
 
  
 
Skin hypopigmentation3 
 
  
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
 
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. 
 
3Nivolumab 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. 
 
4Pancreatitis may result in increased serum amylase and/or more frequently lipase. 
 
5Cytokine release syndrome may manifest as hemophagocytic lymphohistiocytosis with accompanying 
fever and pancytopenia. 
 

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75 
6Complications including hyperacute graft-versus-host disease (GVHD), some fatal, have occurred in 
patients receiving allo stem cell transplant (SCT) after receiving Nivolumab.  These complications may 
occur despite intervening therapy between receiving Nivolumab and allo-SCT. 
 
7Infusion 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. 
 
 
Adverse events reported on Nivolumab trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that Nivolumab caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Heart failure; Ventricular 
arrhythmia 
EAR AND LABYRINTH DISORDERS - Vestibular disorder 
EYE DISORDERS - Eye disorders - Other (iridocyclitis); Optic nerve disorder; Periorbital edema 
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; Flatulence; Gastrointestinal 
disorders - Other (mouth sores); 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 - Blood lactate dehydrogenase increased; GGT increased; Investigations - Other 
(protein total decreased); 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; 
Photosensitivity; Rash acneiform; Skin and subcutaneous tissue disorders - Other (rosacea) 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Vasculitis 
 
 
Note: Nivolumab 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. 
 
10.1.2 CAEPR for Ipilimumab 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 

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76 
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 
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 2.10, March 29, 20191 
 
 Adverse Events with Possible  
 Relationship to Ipilimumab (MDX-010) 
 (CTCAE 5.0 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 
  
 
 
Pericardial effusion 
  
EAR AND LABYRINTH DISORDERS 
  
 
Hearing impaired 
 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency2 
 
  
 
Hyperthyroidism2 
 
  
 
Hypophysitis2 
 
  
 
Hypopituitarism2 
 
  
 
Hypothyroidism2 
 
  
 
Testosterone deficiency2 
 
  
EYE DISORDERS 
  

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77 
 
 Adverse Events with Possible  
 Relationship to Ipilimumab (MDX-010) 
 (CTCAE 5.0 Term) 
[n= 2678] 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
Eye disorders - Other 
(episcleritis)2  
 
  
 
Uveitis2 
 
  
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) 
 
 
General disorders and 
administration site 
conditions - Other 
(systemic inflammatory 
response syndrome 
[SIRS]) 
  
 
 
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 
  

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78 
 
 Adverse Events with Possible  
 Relationship to Ipilimumab (MDX-010) 
 (CTCAE 5.0 Term) 
[n= 2678] 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
 
Infections and 
infestations - Other 
(aseptic meningitis)2 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
  
 
Aspartate aminotransferase 
increased 
 
  
 
 
Lymphocyte count 
decreased 
  
 
Neutrophil count decreased 
 
  
 
Weight loss 
 
  
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 
 
  
 
 
Generalized muscle 
weakness 
  
 
Musculoskeletal and 
connective tissue disorder - 
Other (polymyositis)2  
 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
 Ataxia 
  
 
Facial nerve disorder 
 
  
 
Guillain-Barre syndrome2 
 
  
 
Headache 
 
  

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79 
 
 Adverse Events with Possible  
 Relationship to Ipilimumab (MDX-010) 
 (CTCAE 5.0 Term) 
[n= 2678] 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
Myasthenia gravis2 
 
  
 
 
Nervous system 
disorders - Other 
(immune-mediated 
encephalitis)2 
  
 
 
Peripheral motor 
neuropathy 
  
 
 
Peripheral sensory 
neuropathy 
  
 
Trigeminal nerve disorder 
 
  
PSYCHIATRIC DISORDERS 
  
 
 
Psychiatric disorders - 
Other (mental status 
changes) 
  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
 
Renal and urinary disorders - 
Other (granulomatous 
tubulointerstitial nephritis) 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pneumonitis 
 
  
 
 
Respiratory failure 
  
 
 
Respiratory, thoracic 
and mediastinal 
disorders - Other 
(bronchiolitis obliterans 
with organizing 
pneumonia) 
  
 
 
Respiratory, thoracic 
and mediastinal 
disorders - Other (lung 
infiltration) 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme 
  
 
Pruritus 
 
 Pruritus (Gr 3) 
Rash maculo-
papular 
 
 
 Rash maculo-papular  
(Gr 3)  

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80 
 
 Adverse Events with Possible  
 Relationship to Ipilimumab (MDX-010) 
 (CTCAE 5.0 Term) 
[n= 2678] 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<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 
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 
receving 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). 

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81 
 
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 - Colonic ulcer; Dyspepsia; Dysphagia; 
Gastrointestinal disorders - Other (gastroenteritis); Gastrointestinal hemorrhage6; Proctitis 
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; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Tumor lysis syndrome 
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; 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) 
 

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82 
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. 
 
10.1.3 Adverse Event List for Prednisone 
 
Common adverse reactions for corticosteroids include fluid retention, alteration in glucose 
tolerance, elevation in blood pressure, behavioral and mood changes, increased appetite, and 
weight gain.  See a prednisone package insert for more information. 
 
10.1.4 Adverse Event List for Tacrolimus 
 
The most common adverse reactions (≥15%) were abnormal renal function, hypertension, 
diabetes mellitus, fever, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, 
bronchitis, pericardial effusion, urinary tract infection, constipation, diarrhea, headache, 
abdominal pain, insomnia, paresthesia, peripheral edema, nausea, hyperkalemia, 
hypomagnesemia, and hyperlipemia.  See a tacrolimus package insert for more information 
 
10.2 
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 
5.0 will be utilized for AE reporting.  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 10.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
 
• Attribution of the AE: 
o Definite – The AE is clearly related to the study treatment. 
o Probable – The AE is likely related to the study treatment. 
o Possible – The AE may be related to the study treatment. 
o Unlikely – The AE is doubtfully related to the study treatment. 
o Unrelated – The AE is clearly NOT related to the study treatment. 
 
10.3 
Expedited Adverse Event Reporting 
 
10.3.1 Rave-CTEP-AERS Integration 
The Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS) 
integration enables evaluation of post-baseline AEs entered in Rave to determine whether they 

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83 
require expedited reporting, and facilitates entry in CTEP-AERS for those AEs requiring 
expedited reporting.    
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event form, 
which is available for entry at each treatment or reporting period, and used to collect AEs that 
start during the period or persist from the previous reporting period. The Clinical Research 
Associate (CRA) will enter AEs that occur prior to the start of treatment on a baseline form that 
is not included in the Rave-CTEP-AERS integration. AEs that occur prior to enrollment must 
begin and end on the baseline Adverse Event form and should not be included on the standard 
Adverse Events form that is available at treatment unless there has been an increase in grade. 
Prior to sending AEs through the rules evaluation process, site staff should verify the following 
on the Adverse Event form in Rave: 
The reporting period (course/cycle) is correct, and AEs are recorded and complete (no missing 
fields) and the form is query-free (fields added to the form during study build do not need to be 
query-free for the integration call with CTEP-AERS to be a success). 
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules evaluation 
by completing the Expedited Reporting Evaluation form. Both NCI and protocol-specific 
reporting rules evaluate the AEs submitted for expedited reporting. A report is initiated in CTEP-
AERS using information entered in Medidata Rave for AEs that meet reporting requirements. 
The CRA completes the report by accessing CTEP-AERS via a direct link on the Medidata Rave 
Expedited Reporting Evaluation form. 
In the rare occurrence that 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 that was phoned in must be entered immediately into CTEP-AERS using the deep 
link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the CTSU website: 
• Study specific documents:  Protocols > Documents > Education and Promotion, and   
• Expedited Safety Reporting Rules Evaluation user guide:  Resources > CTSU Operations 
Information > User Guides. 
NCI requirements for SAE reporting are available on the CTEP website:  
• NCI Guidelines for Investigators:  Adverse Event Reporting Requirements is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.p
df. 
10.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  PI and AE Coordinator(s) (if applicable) of the Corresponding Organization or Lead 
Organization, the local treating physician, and the Reporter and Submitter.  CTEP-AERS 
provides a copy feature for other e-mail recipients.  
 

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84 
10.3.3 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.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.”  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. 
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 90 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 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:   
• 
Death; 
• 
A life-threatening adverse event; 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours; 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; 
• 
A congenital anomaly/birth defect; 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or 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 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
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: 
• 
“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. 
• 
“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 90 days after the last administration of investigational agent/intervention and have 
an attribution of possible, probable, or definite require reporting as follows:  

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85 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
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 
 
10.4 
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. 
 
10.5 
Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP.  Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome.  Newborn infants should be followed until 30 days old.  Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 
and DCP INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) 
for more details on how to report pregnancy and its outcome to CTEP.  
 
10.6 
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  

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86 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
 
10.7 
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. 
 
 

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87 
11. STUDY CALENDARS 
 
11.1 
Nivolumab Monotherapy 
 
Nivolumab 
monotherapy 
Screening 
Immuno-
suppression 
adjustmentA 
Treatment (cycle length = 28 daysB) 
Follow-up 
Immune-mediated 
Adverse ReactionC 
Disease 
Progression 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycles 6+ 
Within 28 days of 
registration 
Day -28 to Day 0 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
See Section 
6.8 
 
See Section 
6.2 
Medication administration 
Nivolumab 
(480 mg IV) 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Tacrolimus 
 
X 
Continue twice daily oral dosing 
X 
X 
Prednisone 
 
X 
Continue daily oral dosing 
X 
X 
Patient medication diary 
review 
(Appendix C) 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Administrative Assessments 
Informed consent / HIPAAD 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pathology review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record concomitant 
medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical Assessments 
Physical examinationE 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG performance status 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Review of adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead EKG and 
echocardiogramF 
XF 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Assessments 
CT scans:  chest / abdomen / 
pelvis plus additional areas 
as appropriate 
X 
 
 
 
 
 
X 
 
 
 
Day 1 every other cycle 
(Cycles 5, 7, 9, etc.) 
X 
 
 
Clinical color photographs 
with scale ruler of tumors, 
as appropriateG 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
X 
X 
X 
 
 
Brain imagingH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard-of-care Laboratory Assessments (Note:  Day 1 assessments for each cycle may be ±3 days from scheduled timepoint) 
CBC w/ differential 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CMPI 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Dipstick urinalysisJ 
X 
XK 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
Pregnancy testL 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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88 
Nivolumab 
monotherapy 
Screening 
Immuno-
suppression 
adjustmentA 
Treatment (cycle length = 28 daysB) 
Follow-up 
Immune-mediated 
Adverse ReactionC 
Disease 
Progression 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycles 6+ 
Within 28 days of 
registration 
Day -28 to Day 0 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
See Section 
6.8 
 
See Section 
6.2 
serum TSH, free T4 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Troponin and CPK 
 
XK 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
dd-cfDNA collectionO 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
X 
Tacrolimus trough levelR 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Correlative studies 
Serum collectionM 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
PBMC collectionN 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Tumor biopsyP 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Allograft biopsyQ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XQ 
 
A: Immunosuppression adjustment will last no more than 28 days. 
B: The cycle length may be extended by 7 days, except in the case of a drug toxicity, in which case treatment may be delayed up to 6 weeks, then resumed if appropriate in the opinion of the Investigator. 
Nivolumab is not be administered less than every 28 days. Laboratory assessments scheduled for treatment days (i.e., Day 1 of a cycle) may be ±3 days from the scheduled timepoint. 
C: Patients who experience allograft rejection should stop nivolumab treatment and a biopsy of the renal allograft should be obtained. 
• If cell-mediated rejection:  Increase tacrolimus dose (target trough level:  5-10 ng/mL), administer methylprednisolone 500 mg IV daily for 3 days, with prednisone taper thereafter.  If no improvement, 
administer infliximab 5 mg/kg. 
• If antibody-mediated rejection:  Increase tacrolimus dose (target trough level:  5-10 ng/mL), perform plasmapheresis, and administer IV Ig plus methylprednisolone 500 mg IV daily for 3 days, with 
prednisone taper thereafter. 
Note:  Donor-specific and non-HLA antibodies should be checked as clinically indicated at the direction of the institution's transplant nephrologist. 
D: Informed consent form and HIPAA authorization are to be provided before initiation of any screening assessments and may be obtained before Day -28. 
E: Required on days when blood draws occur.  To include vital signs (e.g., temperature, blood pressure, pulse). 
F: All patients must have an EKG and echocardiogram at baseline screening. Additional EKGs and cardiac imaging should be performed as clinically indicated. 
G: Biopsy may be performed when response assessment is confounded by the presence of ulceration, cyst(s), scarring/fibrosis, etc.  See tumor biopsy instructions in protocol section 5.2.2.1. 
H: MRI preferred; CT acceptable for patients unable to undergo MRI. 
I: To include albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, AST, ALT, sodium. 
J: If 2+ or greater, UPCR (spot or 24-hour) should be assessed at the direction of the institution's transplant nephrologist. 
K: Baseline should be obtained after immunosuppression adjustment. 
L: For women of childbearing potential. 
M: Two 10 mL SST tubes; Day 1 collection should be prior to administration of nivolumab and the second collection should be during Week 4. 
N: Ten 10 mL CPT tubes; Day 1 collection should be prior to administration of nivolumab and the second collection should be during Week 4. 
O: Two 10-mL cfDNA BCT tubes.  Samples should be collected every 2 weeks.  If levels are stable at 12 weeks, testing may decrease to every 4 weeks. Standard of Care. Research based off of sample results 
P: If safe and feasible in the investigator’s opinion.  Pre-treatment biopsy may be omitted if sufficient archival tumor tissue exists, procured within 12 weeks of enrollment without intervening therapy.  The on-
treatment biopsies should be obtained during Week 4, and if the patient experiences allograft rejection.  A biopsy should not be obtained for immune-mediated adverse reactions with no renal involvement.  
Patients may refuse biopsy and still remain on study.  If a biopsy will compromise the evaluability of a lesion for response (RECIST 1.1), it may be omitted.  See Section 5.4. 
Q: Patients who experience allograft rejection should stop nivolumab therapy and a biopsy of the renal allograft should be obtained.  An allograft biopsy should only be obtained if allograft rejection is 
suspected, and is not necessary for immune-mediated adverse reactions with no renal involvement. 
R: Tacrolimus trough levels should be monitored each cycle while receiving Nivolumab in order to maintain 2-5 ng/ml.  
ALT=alanine aminotransferase, AST=aspartate aminotransferase, BCT=Blood collection tube, BUN=blood urea nitrogen, CBC=complete blood count, CPK=phosphocreatine kinase, CMP=comprehensive 
metabolic panel, CPT=cell preparation tube, CT=computed tomography, EKG=electrocardiogram, ECOG=Eastern Cooperative Oncology Group, HIPAA= Health Information Portability and Accountability 
Act, Ig=immunoglobulin, IV=intravenous, PBMC=peripheral blood mononuclear cells, PT=prothrombin time, PTT=partial thromboplastin time, RECIST=response evaluation criteria in solid tumors, 
SST=serum separating tube, T4=thyroxine, TSH=thyroid stimulating hormone, UPCR=urine protein/creatinine ratio 
 

NCI Protocol #:  10214 
Version Date: January 28, 2021 
 
89 
11.2 
Nivolumab-Ipilimumab Combination Therapy 
 
Nivolumab + 
Ipilimumab 
Induction (cycle length = 21 daysA) 
3-week gapB 
Maintenance 
(cycle length = 28 daysA) 
Follow-up 
Immune-
mediated 
Adverse 
ReactionC 
Disease 
Progression 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4B 
 
Cycle 5 
Cycles 6+ 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
 
 
See Section 
6.2 
Medication administration 
Nivolumab 
(3 mg/kg IV) 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Ipilimumab 
(1 mg/kg IV) 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Nivolumab 
(480 mg IV) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
Tacrolimus 
Continue twice daily oral dosing 
X 
X 
Prednisone 
Continue daily oral dosing 
X 
X 
Patient medication 
diary review 
(Appendix C) 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
Administrative Assessments 
Record concomitant 
medications 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Clinical Assessments 
Physical 
examinationD 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
ECOG performance 
status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of adverse 
events 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
12-lead EKG and 
echocardiogramE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard-of-care Laboratory Assessments (Note:  Day 1 assessments for each cycle may be ±3 days from scheduled timepoint) 
CBC with differential 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
CMPF 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
Dipstick urinalysisG 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
Pregnancy testH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
serum TSH, free T4 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
Troponin and CPK 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood for 
dd-cfDNAL 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
X 
Tacrolimus trough 
levelO 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
Efficacy Assessments 

NCI Protocol #:  10214 
Version Date: January 28, 2021 
 
90 
Nivolumab + 
Ipilimumab 
Induction (cycle length = 21 daysA) 
3-week gapB 
Maintenance 
(cycle length = 28 daysA) 
Follow-up 
Immune-
mediated 
Adverse 
ReactionC 
Disease 
Progression 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4B 
 
Cycle 5 
Cycles 6+ 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
 
 
See Section 
6.2 
CT scans:  chest / 
abdomen / pelvis plus 
additional areas as 
appropriate 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Day 1 every other cycle, 
beginning with Cycle 6. 
 
 
 
Clinical color 
photographs with 
scale ruler of tumors 
as appropriateI 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
Correlative studies 
Serum collectionJ 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
PBMC collectionK 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Tumor biopsyM 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Allograft biopsy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XN 
 

NCI Protocol #:  10214 
Version Date: January 28, 2021 
 
91 
Nivolumab + 
Ipilimumab 
Induction (cycle length = 21 daysA) 
3-week gapB 
Maintenance 
(cycle length = 28 daysA) 
Follow-up 
Immune-
mediated 
Adverse 
ReactionC 
Disease 
Progression 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4B 
 
Cycle 5 
Cycles 6+ 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
 
 
See Section 
6.2 
A: Cycle length may be extended by 7 days, except in the case of a drug toxicity, in which case treatment may be delayed up to 6 weeks, then resumed if appropriate in the opinion of the Investigator. 
Nivolumab/Ipilimumab is not to be administered less than every 21 days during induction or less than 28 days during maintenance. Laboratory assessments scheduled for treatment days (i.e., Day 1 of a cycle) 
may be ±3 days from the scheduled timepoint. 
B: After nivolumab (3 mg/kg IV) and ipilimumab (1 mg/kg IV) administration on Cycle 4, Day 1, there should be a six-week gap before beginning Cycle 5 and nivolumab (480 mg IV) maintenance therapy.  
This gap includes the 3 weeks in Cycle 4, thus there should be a 3-week gap between the end of Cycle 4 and the beginning of Cycle 5. 
C: Patients who experience allograft rejection should stop nivolumab and ipilimumab treatment and a biopsy of the renal allograft should be obtained (Section 7.2). 
• If cell-mediated rejection:  Increase tacrolimus dose (target trough level:  5-10 ng/mL), administer methylprednisolone 500 mg IV daily for 3 days, with prednisone taper thereafter.  If no improvement, 
administer infliximab 5 mg/kg. 
• If antibody-mediated rejection:  Increase tacrolimus dose (target trough level:  5-10 ng/mL), perform plasmapheresis and administer IV Ig plus methylprednisolone 500 mg IV daily for 3 days, with 
prednisone taper thereafter. 
Note:  Donor-specific and non-HLA antibodies should be checked as clinically indicated at the direction of the institution's transplant nephrologist. 
D: Required on days when blood draws occur.  To include vital signs (e.g., temperature, blood pressure, pulse). 
E: After obtaining a 12-lead EKG and echocardiogram at Cycle 1, additional EKGs and cardiac imaging should be performed as clinically indicated. 
F: To include albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, AST, ALT, sodium. 
G: If 2+ or greater, UPCR (spot or 24-hour) should be assessed at the direction of the institution's transplant nephrologist. 
H: For women of childbearing potential. 
I: Biopsy may be performed when response assessment is confounded by the presence of ulceration, cyst(s), scarring/fibrosis, etc.  See tumor biopsy instructions in Section 5.4. 
J: Two 10 mL SST tubes; Day 1 collection should be prior to administration of nivolumab/ipilimumab and the second collection should be during Week 4. 
K: Ten 10 mL CPT tubes; Day 1 collection should be prior to administration of nivolumab/ipilimumab and the second collection should be during Week 4. 
L: Two 10-mL cfDNA BCT tubes.  Samples should be collected every 3 weeks.  If levels are stable at 12 weeks, testing may decrease to every 4 weeks starting with Cycle 5. Standard of Care. Research based 
off of sample results 
M: If safe and feasible in the opinion of the investigator.  The on-treatment biopsies should be obtained during Week 3, and if the patient experiences allograft rejection.  A biopsy should not be obtained for 
immune-mediated adverse reactions with no renal involvement.  Patients may refuse biopsy and still remain on study.  If a biopsy will compromise the evaluability of a lesion for response (RECIST 1.1), the 
biopsy may be omitted.  See tumor biopsy instructions in Section 5.2.2.1. 
N: Patients who experience allograft rejection should stop nivolumab and ipilimumab therapy and a biopsy of the renal allograft should be obtained (Section 7.2).  An allograft biopsy should only be obtained if 
rejection is suspected, and is not necessary for immune-mediated adverse reactions with no renal involvement. 
O: Tacrolimus trough levels should be monitored every cycle while receiving Nivolumab/Ipilimumab in order to maintain 2-5 ng/ml.  
ALT=alanine aminotransferase, AST=aspartate aminotransferase, BCT=blood collection tube, BUN=blood urea nitrogen, CBC=complete blood count, CPK=phosphocreatine kinase, CMP=comprehensive 
metabolic panel, CPT=cell preparation tube, CT=computed tomography, ECOG=Eastern Cooperative Oncology Group, Ig=immunoglobulin, IV=intravenous, PBMC=peripheral blood mononuclear cells, 
PT=prothrombin time, PTT=partial thromboplastin time, RECIST=response evaluation criteria in solid tumors, SST=serum separating tube, T4=thyroxine, TSH=thyroid stimulating hormone, UPCR=urine 
protein/creatinine ratio 
 

NCI Protocol #:  10214 
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92 
12. MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response approximately every 
8 weeks.  In addition to a baseline scan, confirmatory scans should also be obtained about 8 
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 RECIST guideline (version 1.1) as well as by irRECIST. Both criteria 
will be used at each evaluation. 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. 
 
12.1.1 Definitions 
 
12.1.1.1 
Evaluable for Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with nivolumab. 
 
12.1.1.2 
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.) 
 
12.1.1.3 
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.  
 
12.1.2 Disease Parameters 
 
12.1.2.1 
Measurable disease 
 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥20 mm by chest x-ray or as ≥10 mm 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 may only be considered 
measurable if interval growth has occurred after administration of radiotherapy.   

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93 
 
12.1.2.2 
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. 
 
12.1.2.3 
Non-measurable Disease 
 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.  ‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
 
12.1.2.4 
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. 
 
12.1.2.5 
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. 
 

NCI Protocol #:  10214 
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94 
12.1.2.6 
Clinical Lesions 
 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers (e.g., skin nodules).  
In the case of skin lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is required.  
 
12.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
12.1.3.1 
Conventional CT and MRI 
 
This guideline has defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is 5 mm or less.  If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (e.g. for body scans).   
 
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. 
 
12.1.3.2 
Positron Emission Tomography (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.   

NCI Protocol #:  10214 
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95 
 
12.1.3.3 
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. 
 
12.1.3.4 
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. 
 
12.1.3.5 
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. 
 
12.1.3.6 
Cytology and Histology 
 
These techniques can be used to differentiate between PR and 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. 
 
12.1.3.7 
Fluorodeoxyglucose (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: 
 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
• 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, 

NCI Protocol #:  10214 
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96 
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. 
 
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. 
 
12.1.4 Response Criteria 
 
12.1.4.1 
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. 
 
12.1.4.2 
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. 
 

NCI Protocol #:  10214 
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97 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or PI). 
 
12.1.4.3 
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 
≥4 wks. Confirmation** 
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. 
** Confirmatory scans should be obtained at least 4 weeks following initial documentation of 
response.  
*** In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 

NCI Protocol #:  10214 
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98 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
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 
 
12.1.5 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.  
 
12.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
12.2 
Other Response Parameters 
 
Tumor responses will also be assessed using immune-related response criteria (Seymour et al., 
2017).  Other endpoints can be found in Section 9.1. 
 

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13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
AE lists, guidelines, and instructions for reporting can be found in Section 10, Adverse Events: 
List and Reporting Requirements. 
 
Data Quality Portal  
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries. DQP Queries, DQP Delinquent Forms, and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, and 
timeliness reports. Review the DQP modules on a regular basis to manage specified 
queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization (LPO) for delinquent form details and reports to be available 
on the DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality.  
 
13.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol PI 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.   
 
All decisions regarding dose escalation/expansion/de-escalation require sign-off by the Protocol 
PI through the CTMS/IWRS.  In addition, the Protocol PI will have at least monthly, or more 
frequent, conference calls with the Study Investigators and the CTEP Medical Officer(s) to 
review accrual, progress, AEs, and unanticipated problems.  Decisions to proceed to the second 
stage will require sign-off by the Protocol PI and the Protocol Statistician. 
 

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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. 
 
13.2 
Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments. To access Rave via iMedidata: 
• 
Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM 
account, and  
• 
Assigned one of the following Rave roles on the relevant Lead Protocol Organization 
(LPO) or Participating Organization roster at the enrolling site:  Rave CRA, Rave Read 
Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
o To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must hold a 
minimum of an AP registration type, 
o To hold Rave Investigator role, the individual must be registered as an NPIVR or 
IVR, and 
o To hold Rave Read Only role, site staff must hold an Associates (A) registration 
type. 
Upon initial site registration approval for the study in Regulatory Support System (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 staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, and 
click on the accept link in the upper right-corner of the iMedidata page. Site staff 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. If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under the study name 
in iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name.  
Site staff 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 in the Rave section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance).  Additional information on iMedidata/Rave is available on the 

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CTSU members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
 
13.2.1 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/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  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) 799-7862 or by email at CTMSSupport@theradex.com for additional support 
with Rave and completion of CRFs. 
 
13.2.2 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 4 weeks.  Baseline data should be entered within 2 weeks of registration and Cycle 1, Day 
1 data should be entered within 2 weeks of Cycle 2, Day 1.  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 8 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 a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the recommended 
phase 2 dose (RP2D) and a description of any 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 

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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). 
 
13.3 
CTEP Multicenter Guidelines 
 
N/A 
 
13.4 
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 
(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. 
 

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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 PI 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.  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. 
 

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Ferris, R.L., G. Blumenschein, Jr., J. Fayette, et al.  (2016).  Nivolumab for recurrent squamous-
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Friend, B.D., R.S. Venick, S.V. McDiarmid, et al.  (2017).  Fatal orthotopic liver transplant 
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Grskovic, M., D.J. Hiller, L.A. Eubank, et al.  (2016).  Validation of a clinical-grade assay to 
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Kittai, A.S., H. Oldham, J. Cetnar, and M. Taylor.  (2017).  Immune checkpoint inhibitors in 
organ transplant patients.  J Immunother.  40(7):277-81. 
 
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Lipson, E.J., M.A. Bodell, E.S. Kraus, and W.H. Sharfman.  (2014).  Successful administration 
of ipilimumab to two kidney transplantation patients with metastatic melanoma.  J Clin Oncol.  
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Lipson, E.J., S.M. Bagnasco, J. Moore, Jr., et al.  (2016).  Tumor regression and allograft 
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Lipson, E.J., M.T. Lilo, A. Ogurtsova, et al.  (2017).  Basal cell carcinoma: PD-L1/PD-1 
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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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APPENDIX C. 
MEDICATION DIARIES 
 
 
 

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C.1 
Medication Diary for Tacrolimus 
 
PATIENT’S MEDICATION DIARY 
Today’s date:   _______________________ 
Agent:  Tacrolimus 
Patient Name:   ______________________(initials acceptable) Patient Study ID:   ____________________  
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each month. 
2. 
You will take ___ ___-mg capsule(s) each day, ___ in the morning and ___ in the evening.  You should take the capsules 12 hours apart, 
and at the same time each day.  You should take the capsules with 8 oz. of water and without food. 
3. 
Record the date, the number of capsules you took, and when you took them. 
4. 
If you have any comments or notice any side effects, please record them in the Comments column. 
5. 
Please return the forms to your physician when you go for your next appointment. 
Day 
Date 
Time of morning 
dose 
# of capsules 
taken 
Time of evening 
dose 
# of capsules 
taken  
Comments 
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Physician’s Office will complete this section: 
1. 
Date patient started protocol therapy: 
 
 
2. 
Date patient was removed from study: 
 
 
3. 
Patient’s planned total daily dose: 
 
 
4. 
Total number of pills taken this month: 
 
 
5. 
Physician/Nurse/Data manager’s signature: 
 
 
Patient’s Signature:   ___________________________________________________________________________________  
 
 
CTEP-assigned Protocol # 10214 
Local Protocol # ETCTN10214 

NCI Protocol #:  10214 
Version Date: January 28, 2021 
 
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C.2 
Medication Diary for Prednisone 
 
PATIENT’S MEDICATION DIARY 
 
Today’s date:   
 
Agent:  Prednisone 
Patient Name:   
(initials acceptable) Patient Study ID:   
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each month. 
2. 
You will take your dose of prednisone each day in the morning.  You will take ___ 5-mg tablet(s) every day with or without food.  You 
should take prednisone at the same time each day and you should swallow the tablets whole.  Do not chew. 
3. 
Record the date, the number of tablets of each size you took, and when you took them.   
4. 
If you have any comments or notice any side effects, please record them in the Comments column.   
5. 
Please return the forms to your physician when you go for your next appointment. 
Day 
Date 
What time 
was dose 
taken? 
# of tablets 
taken 
Comments 
1 
 
 
 
 
2 
 
 
 
 
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Physician’s Office will complete this section: 
1. 
Date patient started protocol therapy: 
 
 
2. 
Date patient was removed from study: 
 
 
3. 
Patient’s planned total daily dose: 
 
 
4. 
Total number of pills taken this month: 
 
 
5. 
Physician/Nurse/Data manager’s signature: 
 
 
Patient’s Signature:   ___________________________________________________________________________________  
 
CTEP-assigned Protocol # 10214 
Local Protocol # ETCTN10214 

NCI Protocol #:  10214 
Version Date: January 28, 2021 
 
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APPENDIX D. 
PATIENT CLINICAL TRIAL WALLET CARD 
 
 
 
 
CLINCIAL TRIAL WALLET 
CARD 
Show this card to all of your 
healthcare providers and 
keep it with you in case you 
go to the emergency room. 
Patient Name:        
Diagnosis:        
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:  10214 
Study Drugs: 
Nivolumab 
Ipilimumab 
Tacrolimus 
Prednisone 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov 
 
 
 
 

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APPENDIX E. 
cfDNA COLLECTION  
 
In addition to standard clinical monitoring, this study will investigate whether the cfDNA levels 
can serve as an early indicator of allograft rejection in the study population. The collection is 
standard of care (SOC). 
 
Streck Cell-Free DNA BCT Tubes 
 
Streck Cell-Free DNA BCT® Tubes for dd-cfDNA should be ordered as part of the Allosure® 
test kit directly from the CareDx® web portal:  https://www.caredxinc.com/results-portal.  This 
kit includes materials for collection and shipping. 
 
Collection of Blood in cfDNA BCT® Tubes 
 
1. Label two 10 mL cfDNA Streck tube according to the instructions in Section 5.3.1.  
2. Collect 10 mL of blood into each pre-labeled tube and gently invert to mix.  Note:  blood 
must be thoroughly mixed to ensure preservation of specimen. 
3. After collection, blood in cfDNA BCT tubes should never be refrigerated, as this will 
compromise the specimen.  Blood collected in cfDNA BCT tubes is stable at room 
temperature. 
4. Specimens should be shipped at room temperature on the day of collection 
 
Blood Samples for Donor Derived Cell-Free DNA 
 
Samples should be shipped at room temperature on the day of collection via overnight delivery 
to CareDx®.  The Allosure® collection kits will include packing instructions and shipping labels.