Conditions: Renal Cell Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 13
Healthy volunteers: no

Brief summary:
This will be a single arm, multi-site phase Ib/II clinical trial of standard doses of High Dose Interleukin-2 (HD IL2) (600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart) in IL-2 eligible clear cell metastatic RCC (Renal Cell Carcinoma) subjects in combination with Nivolumab.

Investigators hypothesize that concurrent PD-1 inhibition synergistically enhances the anti-tumor immune response to HD IL-2 in metastatic clear cell RCC. Investigators postulate that the combination of the two therapies would result in an increase in the overall response rate, complete response rate, and improved survival outcomes compared to either of the individual therapies.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Interleukin-2 intervention 2: Nivolumab
Intervention descriptions: intervention 1: 600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart intervention 2: Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression

Protocol document:
Prot_SAP_000.pdf: 
Phase Ib/II Trial of Interleukin-2 and PD-1 Checkpoint Inhibitor, Nivolumab 
In Metastatic Clear Cell Renal Cell Cancer: UMCC 2016.103 
Principal Investigator: 
Ajjai Alva, MD 
University of Michigan, 
Internal Medicine/Hematology-Oncology 
 
 
 
Co-Investigator(s): 
Sarah Yentz, MD 
University of Michigan, 
Internal Medicine/Hematology-Oncology 
 
Megan Veresh Caram, MD 
University of Michigan 
Internal Medicine/Hematology-Oncology 
 
Co-Investigator(s) 
Weiping Zou, MD PhD 
for Correlatives: 
Charles B de Nacrede Research Professor of Surgery and Professor of 
Surgery, Medical School 
University of Michigan 
  
 
Biostatistician: 
Stephanie Daignault-Newton, MS 
University of Michigan 
 
  
 
 
Study Drugs: 
Interleukin (Proleukin; Aldesleukin), Nivolumab (Opdivo) 
Initial version: 
10/18/2016 
Amended: 
08/23/2018; 12/13/2016  
NCT02989714


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TABLE OF CONTENTS 
ABBREVIATIONS ........................................................................................................................... 1 
STUDY SCHEMA ............................................................................................................................ 2 
STUDY SYNOPSIS .......................................................................................................................... 3 
1.0 
BACKGROUND AND RATIONALE .................................................................................... 9 
1.1 
Disease Background........................................................................................................ 9 
1.2 
Study Agent(s) Background and Associated Known Toxicities ....................................... 9 
1.3 
Rationale ........................................................................................................................ 15 
1.4 
Correlative Studies ........................................................................................................ 16 
2.0 
STUDY OBJECTIVES ....................................................................................................... 16 
Phase Ib portion: ........................................................................................................................ 16 
2.1 
Primary Objective .......................................................................................................... 16 
Phase II portion: ......................................................................................................................... 16 
2.2 
Primary Objective .......................................................................................................... 16 
2.3 
Secondary Objectives .................................................................................................... 16 
2.4 
Exploratory Objectives ................................................................................................... 16 
Study Endpoints ......................................................................................................................... 16 
3.0 
PATIENT ELIGIBILITY ...................................................................................................... 17 
3.1 
Inclusion Criteria ............................................................................................................ 17 
3.2 
Exclusion Criteria ........................................................................................................... 18 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES .................................... 19 
5.0 
TREATMENT PLAN .......................................................................................................... 20 
5.1 
Treatment Dosage and Administration .......................................................................... 20 
5.2 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 22 


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5.3 
Concomitant Medications/Treatments ........................................................................... 29 
5.4 
Other Modalities or Procedures ..................................................................................... 30 
5.5 
Duration of Protocol Specified Therapy (IL2 and/or Nivolumab) ................................... 30 
5.6 
Off Protocol Specified Therapy Criteria ......................................................................... 30 
5.7 
Duration of Follow-Up .................................................................................................... 30 
5.8 
Off Study Criteria ........................................................................................................... 30 
5.9 
Patient Replacement ..................................................................................................... 31 
6.0 
STUDY PROCEDURES ..................................................................................................... 31 
6.1 
Screening/Baseline Procedures (see Time and Events table section 6.4) ................... 31 
6.2 
Procedures During Treatment ....................................................................................... 33 
6.3 
Follow-Up Procedures ................................................................................................... 35 
6.4 
Time and Events Table .................................................................................................. 35 
7.0 
MEASUREMENT OF EFFECT .......................................................................................... 37 
7.1 
Antitumor Effect- Solid Tumors ...................................................................................... 37 
7.2 
Safety/Tolerability .......................................................................................................... 42 
8.0 
ADVERSE EVENTS .......................................................................................................... 42 
8.1 
Experimental Therapy.................................................................................................... 42 
8.2 
Adverse Event Reporting Requirements ....................................................................... 42 
8.3 
Definitions ...................................................................................................................... 43 
8.4 
Adverse Event Characteristics ...................................................................................... 44 
8.5 
Serious Adverse Event Reporting Guidelines ............................................................... 44 
8.6 
Routine Reporting .......................................................................................................... 45 
8.7 
Reporting of Unanticipated Problems ............................................................................ 45 
8.8 
Stopping Rules .............................................................................................................. 46 
9.0 
DRUG INFORMATION ...................................................................................................... 46 
9.1 
Interleukin-2: .................................................................................................................. 46 


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9.2 
Nivolumab: ..................................................................................................................... 47 
10.0 
CORRELATIVES/SPECIAL STUDIES .......................................................................... 49 
10.1 
Sample Collection Guidelines ........................................................................................ 49 
10.2 
Assay Methodology ....................................................................................................... 50 
10.3 
Immunogenicity Analysis ............................................................................................... 50 
10.4 
Specimen Banking ......................................................................................................... 51 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................. 51 
11.1 
Study Design/Study Endpoints/Sample Size and Accrual ............................................ 51 
11.2 
Data Analyses Plans...................................................................................................... 52 
12.0 
DATA AND SAFETY MONITORING ............................................................................. 53 
13.0 
QUALITY ASSURANCE AND AUDITS ........................................................................ 54 
14.0 
CLINICAL MONITORING PROCEDURES ................................................................... 54 
15.0 
DATA MANAGEMENT .................................................................................................. 55 
16.0 
REFERENCES ............................................................................................................... 55 
17.0 
APPENDICES ................................................................................................................ 57 


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ABBREVIATIONS 
ADA 
AE 
Anti-Drug Antibody 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTSUO 
Clinical Trials Support Unit 
DLT 
Dose Limiting Toxicity 
DSMC 
Data and Safety Monitoring Committee 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV (or iv) 
Intravenously 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
p.o. 
per os/by mouth/orally 
PR 
Partial Response 
PRC 
Protocol Review Committee 
RCC 
Renal Cell Carcinoma 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
UaP 
Unanticipated Problem 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cells 
WOCBP 
Women of Child Bearing Potential 
 


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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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STUDY SYNOPSIS 
Title 
Phase Ib/II Trial of Interleukin-2 and PD-1 Checkpoint Inhibitor, 
Nivolumab In Metastatic Clear Cell Renal Cell Cancer  
 
Phase 
Phase Ib/II 
Methodology 
Single arm, multi-site phase Ib/II clinical trial of standard doses of High 
Dose Interleukin-2 (HD IL2) (600,000 IU/kg/dose intravenously during 
two 5-day cycles 9 days apart) in IL-2 eligible clear cell metastatic RCC 
subjects in combination with Nivolumab.  
 
Nivolumab will be administered intravenously at 480 mg/dose over 60 
minutes every 28 days, starting 1 week to 3 weeks after the start date of 
the first cycle of IL2 and continued for up to 48 weeks total in the 
absence of disease progression by RECIST 1.1 criteria, unacceptable 
toxicity, withdrawal of consent or lack of clinical benefit as determined 
by the PI.  
 
Nivolumab may be continued beyond 48 weeks off-study at the 
discretion of the investigator at his or her clinical judgment. 
 
Initially 10 patients will be enrolled in the phase 1b portion of the study.  
 
The first 3 patients will be treated with sequential (rather than 
interspersed) treatment. They will receive 2 cycles of HD-IL2 given in 
standard fashion (two 5-day cycles one week apart) followed by 
nivolumab starting the week after the second IL-2 cycle and continuing 
every 4 weeks as per standard nivolumab dosing. 
 
We will perform a safety analysis after the first 3 patients are treated. If 
2 out of 3 of the first patients suffer a grade 3 or 4 immune related 
toxicity, the study will stop. The 4th patient will not be enrolled until after 
the analysis of the 3 patient cohort is complete and submitted to the 
regulatory bodies. 
 
If <2 patients suffer a grade 3 or 4 immune related toxicity, the study will 
enroll up to 7 more patients treated with Nivolumab administered 
intravenously at 480 mg/dose over 60 minutes every 28 days, starting 1 
to 3 weeks after the start date of the first cycle of IL2. We will monitor 
these patients continuously for immune mediated dose limiting toxicities 
for 28 days from the first dose of nivolumab. If, at any time during 
accrual to the phase1 b portion, 6 patients or more have a grade 3 or 4 
immune mediated event of interest (as described in section 5.2.1) we 
will pause the study and modify/discontinue the protocol in consultation 
with the site principal investigators and applicable regulatory authorities. 
If ≤ 5 of the 10 patients have a grade 3 or 4 immune mediated event of 
interest (as described in section 5.2.1), we will proceed to the phase II 
portion of the study. Please note: immune mediated events of interest 
do not include those that are known to occur during high dose IL-2 
monotherapy and are reversible by holding IL2 dose(s) such as capillary 
leak syndrome. 
 
 


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Study Duration 
 
24 months of accrual 
 
24 months of follow-up (counting from week 1) 
 
Study Center(s) 
4 Sites including lead site: University of Michigan.  
Objectives 
Phase Ib: 
Primary Objective:  
1. To estimate the safety and toxicities of High Dose Interleukin-2 
in combination with the immune checkpoint inhibitor Nivolumab 
in metastatic clear cell renal cell carcinoma.  
Phase II: 
Primary Objective:  
1. To estimate the efficacy of High Dose Interleukin-2 in 
combination with the immune checkpoint inhibitor Nivolumab in 
metastatic clear cell renal cell carcinoma.  
Secondary Objectives:  
1. To determine the safety of High Dose Interleukin-2 in 
combination with Nivolumab in metastatic clear cell renal cell 
carcinoma. 
 
2. To profile circulating T cell repertoire by flow cytometry before 
and during therapy. 
Exploratory Objectives: 
1. To bank tissue and serum specimens for correlative analyses 
and anti-drug antibody testing in the future. 
 
Number of Subjects 
 
Number of evaluable subjects (those who receive at least 1 dose of HD 
IL2 and at least 1 dose of nivolumab) = 23. Subjects in the Phase 1b 
portion will be included in the overall toxicity and efficacy analysis of the 
study. Subjects who are not evaluable will be replaced. Up to 28 
patients may need to be registered (enrolled) in order to obtain the 23 
evaluable patients. 
 


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Key Inclusion Criteria 
 
1. Subjects must have a histologic diagnosis of clear cell renal cell 
carcinoma (pure or mixed) with radiologic or histologic or 
cytologic evidence of metastatic disease.   
2. An archived tissue block must be identified to submit unstained 
slides from prior to registration.  
3. Subjects must have measurable disease per RECIST 1.1 
criteria. 
4. ECOG performance status of 0 or 1. 
5. Subjects may have received up to 2 prior lines of systemic 
therapy (excluding any neoadjuvant/adjuvant therapy) including 
anti-VEGF or VEGFR inhibitor or mTOR inhibitor for metastatic 
RCC.  
6. White blood count of ≥ 3000/mm3, platelet count  ≥  
100,000/mm3, hemoglobin  ≥10 g/dl; total bilirubin ≤1.5x upper 
limit of normal (patients with confirmed Gilbert’s syndrome 
(persistent or recurrent hyperbilirubinemia in the absence of 
evidence of hemolysis or hepatic pathology) will be allowed to 
enroll after discussion with the principal investigator if total 
bilirubin is ≤3x the upper limit of normal), ALT/AST ≤2.5x   x 
upper limit of normal; serum creatinine ≤1.5x laboratory upper 
limit of normal or calculated creatinine clearance of ≥ 50 
ml/min/1.73 m2, PT/INR ≤1.5, Urine Protein/Creatinine ratio ≤1 ) 
7. Subjects must be considered appropriate candidates for HD IL-2 
by the treating investigator. HD IL-2 candidacy evaluation is per 
institutional guidelines at each site and should include a 
dobutamine stress echocardiogram or equivalent. Subjects with 
a positive stress test for cardiac ischemia would be excluded 
from this trial. 
8. Subjects must have recovered to grade 1 or less from adverse 
events of prior therapy and be ≥ 2 weeks from most recent 
systemic therapy or most recent radiation therapy by the time of 
first dose of HD IL2.  
9. Informed consent from subject must be obtained prior to 
entrance onto study. 
10. Women of childbearing potential must have a negative urine or 
serum pregnancy test and must take adequate precautions to 
prevent pregnancy during treatment. 
 


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Key Exclusion Criteria 
 
1. Medical need for systemic corticosteroids >10mg prednisone 
daily or equivalent alternative steroid (except physiologic dose 
for adrenal replacement therapy) or other immunosuppressive 
agents (such as cyclosporine or methotrexate). Topical and 
inhaled corticosteroids are permitted if medically needed. 
2. Patients with autoimmune diseases such as rheumatoid arthritis 
are NOT allowed. Vitiligo, mild psoriasis (topical therapy only) or 
hypothyroidism are allowed 
3. Prior anti-PD-1/PD-L1 targeted therapy is not permitted. 
4. Prior history of psychiatric disorder which could be exacerbated 
by interleukin-2 in the treating investigator’s judgment;  
5. Active uncontrolled infection. 
6. Evidence of significant cardiovascular disease including history 
of recent (< 6 months prior) myocardial infarction, congestive 
heart failure, primary significant cardiac arrhythmias (not due to 
electrolyte disorder or drug toxicity, for example) beyond 
occasional PVCs, angina, or cerebrovascular accident; evidence 
of significant pulmonary disease on pulmonary function testing. 
7. Current untreated brain metastasi(e)s. If treated history of CNS 
metastases, should have completed radiation or surgery at least 
4 weeks prior and off systemic corticosteroids. 
 
Study Product(s), Dose, 
Route, Regimen 
 
High Dose Interleukin-2/IL2 (600,000 IU/kg/dose intravenously every 8 
hours for maximum of 28 doses during two 5-day cycles one week 
apart).  
 
Nivolumab will be administered intravenously at 480 mg/dose over 60 
minutes every 28 days, starting 1 week (or up to 3 weeks) after the first 
cycle of IL2 start date and continued for total of up to 48 weeks. 
 
Duration of 
Administration 
 
High Dose Interleukin-2/IL2 will be administered over two 5-day cycles. 
Further doses of IL-2 will be allowed per investigator discretion. 
Nivolumab will be administered for up to 48 weeks.  
 
Reference Therapy 
Nivolumab and Interleukin-2 as monotherapies 
 


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Statistical Methodology 
This is a single arm phase Ib/II trial of Nivolumab and IL-2 in patients 
with Renal Cell Carcinoma. The phase Ib has an endpoint of safety and 
the phase II primary endpoint is overall response rate (ORR = CR or 
PR) at 12 weeks.  A recently reported trial of Nivolumab after 1 prior 
therapy in RCC reported had an ORR of 25%.  With the addition of IL-2 
treatment to nivolumab, we hypothesize an ORR of approximately 46% 
in this population.   
 
Study Design/Study Endpoints/Sample Size and Accrual 
For the phase Ib portion of the study: We will accrue an initial cohort of 3 
patients who will be treated with sequential (rather than interspersed) 
treatment. They will receive 2 cycles of HD-IL2 given in standard fashion 
(two 5-day cycles one week apart) followed by nivolumab starting the 
week after the second IL-2 cycle and continuing every  weeks as per 
standard nivolumab dosing.   If 2 out of 3 of the first patients suffer a 
grade 3 or 4 immune related toxicity of interest (see 5.2.1) the study will 
stop. The 4th patient will not be enrolled until after the analysis of the 3 
patient cohort is complete and submitted to the regulatory bodies. 
 
If <2 patients suffer a grade 3 or 4 immune related toxicity in the cohort 
of 3 patients, the study will enroll 7 more patients treated with 
Nivolumab administered intravenously at 480 mg/dose over 60 minutes 
every 28 days, starting 1 week to 3 weeks after the start date of the first 
cycle of IL2. We will monitor these patients continuously for immune 
mediated dose limiting toxicities for 28 days from the first dose of 
nivolumab with DLTs being reported as they occur. 10 total patients will 
be treated and observed for toxicity for 28 days from the first dose of 
Nivolumab. If, at any time during accrual, 6 patients or more have a 
grade 3 or 4 immune mediated event of interest (as described in section 
5.2.1) we will pause the study and modify/discontinue the protocol in 
consultation with the site principal investigators and applicable 
regulatory authorities.  If 5 or fewer patients experience grade 3 or 4 
immune mediated toxicity of interest (see 5.2.1) during the toxicity 
window, then the study will continue to the phase II portion.  We choose 
to examine toxicity after 10 patients because if 6 patients or more are 
found to have a DLT then the 95% exact binomial confidence interval 
will be > 25% and be indicative that there is too high an incidence of 
serious immune mediated toxicities.  
 
The phase II portion of the trial will be a Simon mini-max 2-stage design.  
The first stage will accrue 12 patients (INCLUDING any evaluable 
patients accrued in the phase 1b portion). If more than 2 patients have a 
response (CR or PR) out of the 12 patients, then we will accrue 11 more 
patients for a total sample size of 23 evaluable patients. If more than 8 
responses (CR or PR) are observed, then we will recommend further 
study of the combination.  This design has 80% power and 10% type I 
error. If the true ORR of the combined treatment is 25% or less, the 
probability of early termination of the trial is 39%.  If the true ORR is 
46% or greater, then the probability of stopping early is only 3.6%.  
Patients accrued in the Phase Ib portion of the trial will also be included 
in the Phase II if they are evaluable as defined below. 
 
Evaluable Patients:  All patients who receive at least 1 dose of IL-2 
and at least 1 dose of Nivolumab will be evaluable for the primary 
endpoint of overall response proportion in the phase II portion of the 


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trial. If response at 12 weeks is not recorded for the patient then the 
patient will be considered a non-responder. 


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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
An estimated 64,770 cases of kidney cancer (RCC) were diagnosed in the U.S. in 2012 
with an estimated 13,570 deaths (SEER). There has been a steady 2-4% per year 
increase in the incidence of RCC since 1975 that is not explained by increased and 
improved imaging studies. Clear cell cancers are the most common variant of kidney 
cancers comprising up to 80% of RCC. The five-year survival rate for RCC subjects is 
70%, however, this includes the majority of subjects with localized disease whose five-
year survival is 91%. At the time of diagnosis approximately 30% of RCC subjects have 
metastatic disease and another 30% of subjects recur, and five-year survival for 
metastatic disease is less than 10%. Therefore, there remains an urgent need for 
improvement in the therapeutic management of metastatic clear cell RCC (mRCC).  
 
RCC was one of the first cancers in which immuno-stimulatory therapy, such as 
interleukin-2 (IL-2), was shown to induce durable treatment response including durable 
complete responses (DCR) leading to FDA approval of High Dose (HD) IL-2 treatment for 
mRCC subjects as early as 1992. Although HD IL-2 remains the only first-line therapy for 
clear cell mRCC subjects offering a potential durable complete response, only a small 
minority of subjects exhibits complete response (CR). Strategies for enhancing the 
percentage of subjects exhibiting a DCR and enhancing the overall response rate 
associated with HD IL-2 address an urgent unmet clinical need in this subject population. 
1.2 
Study Agent(s) Background and Associated Known Toxicities 
Interleukin-2:  
IL-2 is a cytokine that is a potent growth factor for T cells. It exerts its activity by binding  
to the IL-2 receptor (IL-2R) present on the cell surface of T cells and leads to its auto 
phosphorylation via JAK/STAT5-dependent pathways, eventually leading to activation 
and proliferation of the T cells1. Although the exact mechanism by which HD IL-2 results 
in durable CR is not known, the discovery that recombinant IL-2 can have potent anti-
tumor activity was shown in murine models as early as 1980s2. The stimulatory effects of 
IL-2 have been demonstrated in multiple pathways required for a successful generation 
of adaptive and CTL (cytotoxic lymphocyte)-mediated anti-tumor response. For example, 
IL-2 is produced by the antigen-presenting cells (APCs) after they have phagocytosed 
dying tumor cells (or pathogens), presented their antigen in conjunction with MHC class II 
and have bound to their corresponding T cell receptor (TCR) on the surface of CD4+ T 
cells. In this setting, IL-2 is considered the third essential signal that is necessary for 
clonal expansion and effector function of T cells, the first being TCR recognition of 
antigen in MHC and the second being binding of co-stimulatory molecule CD 28 to B71. 
Similarly, CD8+ CTL function is also critically dependent on IL-2 as shown by 
experiments that effector or cytotoxic function is limited in IL-2 or IL-2R-deficient mice3-5. 
IL-2 is postulated to increase trafficking of CTL to the extralymphatic sites of infection or 
tumor1,6. IL-2 induces Th1 differentiation of CD4 T helper cells which leads to activation of 
macrophages. Th1 cells also activate antibody production by activating B cells. IL-2 is 
produced by Th1 cells in response to activation by DC that results in CD8 activation and 
proliferation. A distinct mechanism of antitumor activity of IL-2 may be mediated by 
activation of natural killer (NK) cells7.  
 
While the exact mechanism of anti-tumor activity of HD IL-2 is unclear, seven phase II 
and multiple phase III trials have clinically proven the efficacy of IL-2 in inducing durable 
CR and PR in clear cell RCC subjects8-10. In contrast, molecularly targeted therapies do 
not induce durable CR. The reported RR for treatment with HD IL-2 (600,000-800,000 
IU/kg q8h x 14 as tolerated) in multiple phase III trials ranges from 20% to 23.2% and the 


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CR ranges from 7%-9%. Among the subjects who achieve CR, >80% remained disease 
free at last follow-up with a median survival over 10 years 9,11,12 suggesting a durable 
response or a cure of mRCC. Alternate schedules and decreased doses of IL-2 have 
been tried without any improvement in outcome 8,10.  
 
There are significant but manageable toxicities from HD IL-2 affecting multiple organ 
systems. These side effects include hypotension, cardiac arrhythmias, metabolic 
acidosis, fever, nausea and vomiting, dyspnea, edema, oliguria and renal  
failure, neurotoxicity, and dermatologic complications, and a mortality rate of less than1% 
in recent trials.  
 
SELECT Trial: 
 
The Cytokine Working Group (CWG) designed and conducted the HD IL2 “Select” Trial13. 
The primary objective of this prospective single-arm study was to evaluate prospectively 
whether an integrated selection model (ISM) based on clear-cell histology and carbonic 
anhydrase-9 (CA-9) IHC staining could identify a group of patients with advanced RCC 
and “good” predictive features who were significantly more likely to respond to HD IL2-
based therapy than a historical, unselected patient population. During the course of this 
trial, retrospective analyses identified potential predictors of increased [e.g., programmed 
death-ligand 1 (PD-L1) expression, CA-9 gene SNP] and decreased (e.g., elevated 
pretreatment levels of fibronectin and VEGF) response to immunotherapy in patients with 
RCC. 
 
One hundred and twenty eligible patients (of any histologic subtype of metastatic renal 
cell carcinoma type and no prior systemic therapy) were enrolled; 70% were Memorial 
Sloan Kettering Cancer Center (New York, NY) intermediate risk, 96% had clear cell 
RCC, and 99% had prior nephrectomy. The independently assessed ORR was 25% 
(30/120, 95% CI, 17.5%–33.7%, P = 0.0014; 3 complete responses (2.5%), 27 partial 
responses (22.5%)) and was higher than a historical ORR. Thirteen patients (11%) 
remained progression free at 3 years and the median overall survival was 42.8 months. 
ORR was not statistically different by ISM classification (“good-risk” 23% vs. “poor-risk” 
30%; P = 0.39). 
 
Overall response rate was not associated with CA-9 SNP status or plasma VEGF or 
fibronectin levels (data not shown). Response was positively associated with tumor 
expression of PD-L1 (P = 0.01) and B7H-3 (P = 0.08; Table 3) by IHC staining (23). 
Durable remission (PFS > 3 years) was positively associated with tumor expression of 
PD-L1 (P < 0.01) but not B7-H3 (P = 0.73) by IHC staining. 
 
Data from the SELECT trial has led to the hypothesis that IL2 administration may be 
more effective in “inflamed” tumors that are infiltrated by CD8+ T cells and express 
immune inhibitory molecules (e.g., PD-L1 or B7-H3) but needs to be confirmed in 
prospective trials14. 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 1: Anti-cancer lymphocyte activation and proliferation15 
Ref: Chen DS, et al. Immunity. 2013;39:1-10. DOI: (10.1016/j.immuni.2013.07.012) 
 
 
 
Nivolumab: 
Tumor immune evasion is the norm in mRCC despite the presence of activated tumor 
infiltrating lymphocytes (TILs) and indeed is a hallmark of cancer14. The increasing 
understanding of immune checkpoints such as CTLA-4 and PD-1 that attenuate the anti-
cancer immune response has been clinically validated in multiple tumor types including 
RCC with the use of checkpoint inhibitors16-18.  
 
Nivolumab is a PD-1 checkpoint inhibitor, approved by the FDA for treatment of patients 
with renal cell carcinoma. It is a fully human IgG4 programmed death 1 (PD-1) immune 
checkpoint inhibitor antibody that selectively blocks the interaction between PD-1, which 
is expressed on activated T cells, and PD-1 ligand 1 (PD-L1) and 2 (PD-L2), which are 
expressed on immune cells and tumor cells. Interaction between PD-1 and PD-L1 or PD-
L2 lead to the inhibition of cellular immune response. Previous studies have shown that 
PD-L1 expression is associated with a poor prognosis in renal cell carcinoma19,20. 
Furthermore, a phase III randomized trial have found significant increase in overall 
survival in patients treated with nivolumab, as compared to everolimus, with fewer grade 
3 or 4 adverse events21. 
 
Nivolumab has been investigated in a randomized phase III clinical trial in patients with 
advanced renal cell carcinoma, previously treated with one or two regimens of 
antiangiogenic therapy (N=821). Patients were randomized to receive nivolumab at 3 
mg/kg of body weight intravenously every 2 weeks or a 10 mg everolimus tablet orally 
once daily. The primary end point was overall survival, while the secondary end points 
included the objective response rate and safety21. The median overall survival was 25 
months with nivolumab as compared to 19.6 months in everolimus treated patients. The 


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hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 
0.93; P = 0.002), which met the pre-specified criterion for superiority (P≤0.0148). The 
objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; 
odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival 
was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) 
with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P = 0.11). Grade 3 or 4 
treatment-related adverse events occurred in 19% of the patients receiving nivolumab 
and in 37% of the patients receiving everolimus; the most common event with nivolumab 
was fatigue (in 2% of the patients), and the most common event with everolimus was 
anemia (in 8%).The results of this trial showed that nivolumab was efficacious in 
improving the overall survival with fewer adverse events, as compared to everolimus in 
patients with renal cell carcinoma. 
The following figures and table show the efficacy and safety of nivolumab in metastatic 
RCC. 
 
 
Figure 2: Kaplan Meier Curve for Overall Survival in the phase 3 trial of nivolumab versus 
everolimus21. Ref: Motzer RJ et al. N Engl J Med 2015;373:1803-1813 
 
 
 


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Figure 3: Kaplan Meier Curve for Overall Survival stratified by PD-L1 expression in tumor at 
baseline in the phase 3 trial of nivolumab versus everolimus21 
Ref: Motzer RJ et al. N Engl J Med 2015;373:1803-1813 
 
 
 
 
 
 


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Table 1 Treatment-Related Adverse Events Reported in 10% or more of treated patients in 
either group in the phase 3 trial of nivolumab versus everolimus 
Ref: Motzer RJ et al. N Engl J Med 2015;373:1803-1813 
 
 
 
              
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 4: Lymphocyte proliferation and activity in the context of IL2 and PD-1 blockade  
Ref: Chen DS, et al. Immunity. 2013;39:1-10. DOI: (10.1016/j.immuni.2013.07.012) 
 
 
1.3 
Rationale 
High dose Interleukin-2 and nivolumab are both active agents in metastatic clear cell 
renal cell cancer with complementary and potentially synergistic mechanisms of action at 
distinct points of the T-lymphocyte activation, trafficking, proliferation and anti-tumor cell 
cytotoxicity process. PD-L1 expression on tumor cells is thought to be induced by 
infiltrating CD8+ T cells in the tumor microenvironment22.  
 
We hypothesize that concurrent PD-1 inhibition synergistically enhances the anti-tumor 
immune response to HD IL-2 in metastatic clear cell RCC. We postulate that the 
combination of the two therapies would result in an increase in the overall response rate, 
complete response rate, and improved survival outcomes compared to either of the 
individual therapies. 
 
We propose a single arm, multi-site, phase Ib/II clinical trial of Nivolumab (480 mg/dose 
intravenously over60 minutes every 28 days), a PD-1 inhibitor, in combination with 
standard doses of High Dose Interleukin-2 (600,000 IU/kg/dose intravenously) every 8 
hours for up to a maximum of 28 doses during two 5-day cycles one week apart in 
interleukin-2 eligible clear cell mRCC subjects.  
 
 
 


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1.4 
Correlative Studies 
 
1) We propose to descriptively profile the circulating T-cell repertoire by performing Flow 
Cytometry and cell sorting in whole blood samples at the time points listed in Section 
6.4 Time and Events Table. These studies will be hypothesis generating and could 
possibly guide timing and combination of immunotherapies in renal cell cancer.  
2) We will archive patient tumor and serum samples for future testing including but not 
limited to PD-L1 testing and anti-drug antibody testing. 
 
2.0 
STUDY OBJECTIVES 
Phase Ib portion: 
2.1 
Primary Objective 
 
2.1.1 
To estimate the safety and toxicities of High Dose Interleukin-2 in combination 
with the immune checkpoint inhibitor Nivolumab in metastatic clear cell renal cell 
carcinoma  
 
Phase II portion: 
2.2 
Primary Objective 
 
2.3.1 
To assess the efficacy of High Dose Interlukin-2 in combination with the immune 
checkpoint inhibitor Nivolumab in metastatic clear cell renal cell carcinoma.  
2.3 
Secondary Objectives 
 
2.4.1 
To determine the safety of High Dose Interlukin-2 in combination with the 
immune checkpoint inhibitor Nivolumab in metastatic clear cell renal cell 
carcinoma. 
 
2.4.2  
To profile circulating T cell repertoire by flow cytometry before and during 
therapy. 
2.4 
Exploratory Objectives 
 
2.5.1 
To bank tissue and serum specimens for future correlative analyses and anti-
drug antibody testing. 
Study Endpoints 
 
Phase Ib portion: 
 
Primary Endpoint: To establish that the combination of High Dose Interlukin-2 and 
Nivolumab is safe and tolerable by monitoring 10 patients for immune mediated grade 3/4 
events of interest for 28 days from the first dose of Nivolumab.   
 
 
 
 
Phase II portion: 


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Primary Endpoint: Efficacy of the combination therapy will be determined by the overall 
response (ORR) rate/proportion with response including complete response 
rate/proportion as assessed by RECIST 1.1 criteria.  
 
Secondary Endpoints: 
 
Safety will be defined by the frequency of protocol specified therapy-related grade 3-5 
adverse events including events of clinical interest for duration of protocol specified 
therapy and an additional 60 days beyond that, as assessed by NCI’s CTCAE version 
4.0. 
 
Survival endpoints for efficacy are 24-month Overall Survival (OS) and 24-month 
Progression-Free Survival (PFS) in subjects treated with the combination by RECIST 1.1 
criteria. 
 
 
 
To descriptively characterize the circulating immune cell repertoire before and after start 
of combination therapy with High Dose Interlukin-2 in combination with the immune 
checkpoint inhibitor Nivolumab 
 
3.0 
PATIENT ELIGIBILITY 
Subjects must meet all of the inclusion and exclusion criteria to be enrolled to the study. Study 
treatment may not begin until a subject is enrolled. 
3.1 
Inclusion Criteria 
 
3.1.1 
Subjects must have a histologic diagnosis of clear cell renal cell carcinoma (pure 
or mixed) with radiologic or histologic or cytologic evidence of metastatic disease. 
 
3.1.2 
Subjects may have received up to 2 prior lines of systemic therapy (excluding 
any neoadjuvant/adjuvant therapy) including anti-VEGF or VEGFR inhibitor (e.g. 
sorafenib, pazopanib, sunitinib, bevacizumab, axitinib) or mTOR inhibitor (e.g. 
everolimus or temsirolimus) for metastatic disease. 
 
3.1.3 
Age ≥ 18 years at the time of consent. 
 
3.1.4 
ECOG performance status of 0 or 1. 
 
3.1.5 
Adequate organ and marrow function as defined below: 
 
White blood count 
≥ 3000/mm3  
Platelet count  
≥100,000/mm3 
Hemoglobin 
≥  10.0 g/dl 
ALT, AST  
≤2.5x upper limit of institutional normal reference range 
Total Bilirubin 
≤1.5x the upper limit of normal (patients with confirmed 
Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinemia in the absence of evidence of 
hemolysis or hepatic pathology) will be allowed to enroll 
after discussion with the principal investigator if total 
bilirubin is ≤3x the upper limit of normal), 
Serum creatinine 
≤1.5x laboratory upper limit of normal or calculated 
creatinine clearance of ≥ 50ml/min/1.73 m2) 
PT/INR 
≤1.5 
Urine 
≤1 


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Protein/Creatinine 
ratio  
 
3.1.6 
Women of childbearing potential must have a negative serum or urine pregnancy 
test within 28 days prior to prior to registration. Women of non-childbearing 
potential are defined as those who have no uterus, ligation of the fallopian tubes, 
or permanent cessation of ovarian function due to ovarian failure or surgical 
removal of the ovaries. All others are considered women of child bearing 
potential. 
.  
 
3.1.7 
Females and males of childbearing potential must be willing to use an effective 
method of contraception (hormonal or barrier method of birth control; abstinence) 
from the time consent is signed until 12 weeks (for males) and 5 months (for 
females) after treatment discontinuation. 
 
3.1.8 
Subjects must have measurable disease on physical exam or imaging per 
RECIST 1.1 criteria. 
 
3.1.9 
An archived tissue block with the subject’s renal cell carcinoma must be identified 
prior to registration. Please see Section 10.0 for additional information 
 
3.1.10 Subjects must be considered appropriate candidates for HD IL-2 by one of the 
treating investigators listed on the protocol. HD IL-2 candidacy evaluation is per 
institutional guidelines at each site and should include a dobutamine stress 
echocardiogram or equivalent. Subjects with a positive stress test for cardiac 
ischemia would be excluded from this trial. 
 
3.1.11 No clinically significant infections or any other medical condition(s) that render 
the subject ineligible for high dose IL-2 therapy as judged by the treating 
investigator. 
 
3.1.12 Ability to understand and the willingness to sign a written informed consent. 
3.2 
Exclusion Criteria 
 
3.2.1 
Prior interferon or interleukin-2 therapy is NOT allowed.  
 
3.2.2 
Prior anti-PD-1/PD-L1 targeted therapy is NOT allowed. Prior CTLA-4 therapy or 
CD40/CD40L targeted therapy is allowed. 
 
3.2.3 
Prior systemic treatment must be completed at least 14 calendar days prior to 
registration and the subject must have recovered from the toxicities of treatment 
to grade 1 or better. 
 
3.2.4 
Prior radiation therapy is allowed if completed at least 14 calendar days prior to 
registration. 
 
3.2.5 
Treatment with any investigational agent or on an interventional clinical trial 
within 30 days prior to registration. 
 
3.2.6 
No prior or concurrent malignancy is allowed except for: adequately treated basal 
cell or squamous cell skin cancer, in situ cervical cancer, localized or locally 
advanced prostate cancer definitively treated without recurrence or with 


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biochemical recurrence only, or any other cancer fully treated or from which the 
subject has been disease-free for at least 2 years. 
 
3.2.7 
Current untreated brain metastasi(e)s. If treated history of CNS metastases, 
should have completed radiation or surgery at least 12 weeks prior and off 
systemic corticosteroids. 
 
3.2.8 
Autoimmune diseases such as rheumatoid arthritis are NOT allowed. Vitiligo, 
mild psoriasis (topical therapy only) or hypothyroidism are allowed 
 
3.2.9 
Medical need for systemic corticosteroids >10mg prednisone daily or equivalent 
alternative steroid (except physiologic dose for adrenal replacement therapy) or 
other immunosuppressive agents (such as cyclosporine or methotrexate) Topical 
and inhaled corticosteroids are allowed if medically needed 
 
3.2.10 History of allergic reaction to interleukin-2 or nivolumab 
 
3.2.11 Prior history of psychiatric disorder or seizure disorders which could be 
exacerbated by Interleukin-2 as judged by the treating investigator. 
 
3.2.12 Evidence of significant cardiovascular disease including history of recent (< 6 
months prior) myocardial infarction, congestive heart failure, primary cardiac 
arrhythmias (not due to electrolyte disorder or drug toxicity, for example) beyond 
occasional PVC's, angina, positive low-level stress test, or cerebrovascular 
accident. All patients should have baseline pulmonary function tests. Adequate 
pulmonary function should be documented (FEV1 >2 liters or ≥75% of predicted 
for height and age) prior to initiating therapy. 
 
3.2.13 Any history of HIV or hepatitis B infection 
 
3.2.14 Any other medical or surgical condition or disease that, in the judgment of the 
treating physician, renders subject ineligible for High Dose Interleukin-2 therapy. 
 
3.2.15 Any history of organ allografts 
 
3.2.16 Any history of cerebrovascular accident or transient ischemic attack 
 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES 
After informed consent is obtained and PRIOR to the initiation of protocol therapy all patients 
satisfying the inclusion/exclusion criteria must have eligibility confirmed by the Coordinating 
Center. The patient will not be considered registered and enrolled in the study until all information 
is confirmed by the Coordinating Center’s Multi-Site Coordinator.  
 
Patient registration for this trial will be centrally managed as described below: 
 
A potential study subject who has been screened for the trial and who has signed the Informed 
Consent document will be initially documented by the participating site on a Screening and 
Enrollment Log. 
 
It is the responsibility of the local site investigator to determine patient eligibility prior to submitting 
patient registration request to the Coordinating Center. After patient eligibility has been 
determined, a copy of the completed Eligibility Worksheet together with all the pertinent de-
identified source documents will be submitted by the requesting site to the Coordinating Center, 
by email to CTSU-Oncology-Multisite@med.umich.edu.   


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A Multi-Site Coordinator of the Coordinating Center, who acts as the registrar, will review the 
submitted documents and process the registration. Sites should inform the Multi-Site Coordinator 
of a potential registration by 5 p.m. on the day prior to registration.  Same day registrations 
cannot be guaranteed.   
 
An email will be sent by the registrar to the requesting site registrar to confirm patient registration 
and to provide the study identification number that has been assigned to the patient. In addition, a 
copy of the Eligibility Worksheet signed and dated by the registrar, will be sent back to the 
requesting site registrar. 
 
Patients found to be ineligible for participation after being consented will be considered screen 
failures, and documented as such in the Screening and Enrollment Log. These patients will not 
have study identification number assigned to them, and will not receive study treatment. 
5.0 
TREATMENT PLAN 
5.1 
Treatment Dosage and Administration 
Protocol treatment must start within 14 business days of enrollment to the study. The 
interleukin-2 (Proleukin) and Nivolumab (Opdivo) will be stored and prepared as 
described in the approved labels. 
 
5.1.1 
Therapy will start with high dose interleukin-2 (HD IL2) on week1 (day 1-5) and 
again on week 3 (day 1-5). Nivolumab will start on week 2 (optimally day 1 but 
can be given up to 3 weeks after IL-2 start but NOT be on the same week as any 
HD IL2 cycle) and continue every 4 weeks for up to 48 weeks on study unless 
one of the dose delay or stopping rules apply. 
 
5.1.2 
HD IL-2 will be administered in standard fashion at a fixed dose of 600,000 
IU/kg/dose every 8 hours for a total of up to 14 doses (considered as one cycle) 
over 5 consecutive days (D1-D5), followed by a 9-day break and then another 
cycle at the same dose over another 5 consecutive days (D15-D19). Each HD IL-
2 course consists of two cycles of up to 14 doses each separated by 9 days of 
rest.  
 
 
 
 
Monitoring, supportive care measures for HD IL2 will be per institutional 
guidelines. The standard current guidelines for HD IL-2 administration based on 
Schwartzentruber et al. have proven to be safe at the participating institutions in 
the study over the years and will be used for this protocol23.  
 
Pre-medications and concurrent medications: Per institutional guidelines at each 
site usually include anti-emetics, anti-histamines, antipyretics/anti-inflammatory 
agents, anti-motility/anti-diarrheal agents, proton pump inhibitors, vasopressors 
as needed, medications for rigors as needed, hydration including boluses and 
maintenance fluids.  It is recommended but not mandated that subjects be given 
anti-emetics for as needed (prn) use after each IL-2 therapy week to treat 
residual nausea. Furosemide (a loop diuretic) may also be given per treating 
investigator’s discretion following each IL2 week. Please see IL-2 guidance 
document for more details.  
 
Subjects will undergo placement of a central venous catheter before each course 
or cycle of therapy per institutional preferences. 
 
NOTE: If the treating investigator determines another course of HD IL-2 beyond 
the 2 cycles after week 12 of protocol therapy specified in the protocol are in the 


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subject’s best interests, it is permissible and will be recorded in follow-up. If so, 
nivolumab should be held during IL2 weeks. No protocol specified assessments 
are required for the repeat course. 
 
5.1.3 
Nivolumab will be administered intravenously at a standard dose of 480 mg/dose 
every 4weeks starting on week 2 (ideally day 1 of week 2 but can be given up to 
3 weeks after IL-2 start but NOT be on the same week as any HD IL2 cycle) and 
continued as long as clinical benefit continues as determined by the treating 
investigator for up to 48 weeks on study.  
 
5.1.4. 
The first 3 patients will be treated with sequential (rather than interspersed) 
treatment. They will receive 2 cycles of HD-IL2 given in standard fashion (two 5-
day cycles one week apart) followed by nivolumab starting the week after the 
second IL-2 cycle and continuing every 4 weeks as per standard nivolumab 
dosing. 
 
We will perform a safety analysis after the first 3 patients are treated and if 2/3 
patients suffer a grade 3 or 4 immune related toxicity, the study will stop. The 4th 
patient will not be enrolled until after the analysis of the 3 patient cohort is 
complete and submitted to the regulatory bodies 
 
 
 
 
REGIMEN DESCRIPTION 
 
 
Agent 
 
Premedications 
 
Dose 
 
Route 
 
Schedule 
 
Interleukin-
2 
 
Per institutional 
guidelines, none 
mandated. 
 
600,000 
IU/kg/doseΩ 
every 8 hours 
Prepare 
and 
store according 
to 
approved 
label. 
 
 
IV over 15 
minutes (± 5 
minutes) 
 
Week 1 
(Days 1-5) 
AND 
Week 3  
(Days 1-5) 
 
 
Nivolumab 
 
Per institutional 
guidelines, none 
mandated. 
 
480 mg/dose 
Prepare and 
store according 
to approved 
label. 
 
IV over 60  (± 
10 minutes) 
minutes 
 
Every 28 
days 
starting 
Week 2 
(Optimally 
Day 1 but 
can be 
given up 
to 3 
weeks 
after IL-2 
start) 
 
 
ΩThe IL-2 dose should be calculated separately on D1 and D15. 
 
NOTE: Infusions may be performed ±3 business days for reasons such as observed 
holidays, inclement weather, scheduling conflicts, etc. It should be clearly 
documented in subject’s chart and case report forms. 
 


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5.1.5  
Missed doses 
Missed doses of HD IL-2 are not made up. Missed doses of Nivolumab can be 
made up within 72 hours of scheduled time and skipped if outside of 72 hours 
 
5.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
Table (Section 6.4). Toxicity will be assessed according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0. Dose adjustments should be made 
according to the system showing the greatest degree of toxicity.  
 
Dose modifications in strength are not permitted for either IL2 or nivolumab.  
 
Dosing delays: 
 
DURING IL-2 weeks 
 
Individual doses of IL-2 within each cycle may be skipped by the treating 
investigator at his or her discretion. Skipped doses will not be made up. 
 
 
AFTER IL-2, BEFORE NIVOLUMAB 
 
 
All toxicities (with the exception of fatigue) attributed to IL-2 administration should 
have resolved or recovered to grade 1 or resolved or to baseline prior to starting 
nivolumab 
 
 
Fatigue should have recovered to grade 2 or better  
 
 
If toxicities have not improved to the levels listed above, nivolumab and the 2nd 
cycle of IL-2 should be held until toxicities improve to the above levels 
 
 
If nivolumab or IL-2 is delayed >6 weeks as a result of a toxicity, the subject must 
be permanently discontinued from study therapy with the following exception: 
 
o 
If a steroid taper (to manage drug-related adverse events) is the reason 
for treatment delay of >6 weeks, and the subject’s adverse events 
recover to grade 1 or better, continuation on study could be possible if 
approved by the principal investigator 
 
 
AFTER NIVOLUMAB, PRIOR TO 2nd  IL-2 CYCLE 
 
All immune mediated toxicities should have recovered to grade 1 or better prior 
to starting the second dose of IL-2 and subjects should be off systemic steroids 
or on a dose of ≤ prednisone 10mg (or equivalent alternative steroid). 
 
 
Fatigue should have recovered to grade 2 or better 
 
 
If specific toxicities are of unclear attribution (including for example: diarrhea, 
increased LFTs, cardiovascular disorders, mental status changes, pulmonary 
disorders and rash) they should be treated as possibly related to nivolumab and 
treated as per the tables in section 5.2.2. These toxicities must improve to grade 
1 or better prior to proceeding with the second week of IL-2 therapy. 
 
 
If toxicities have not improved to the levels listed above, nivolumab and the 2nd 
cycle of IL-2 should be held until toxicities improve to the above levels 
 


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 
If nivolumab or IL-2 is delayed >6 weeks as a result of a toxicity, the subject must 
be permanently discontinued from study therapy with the following exception 
o 
If a steroid taper (to manage drug-related adverse events) is the reason 
for treatment delay >6 weeks, and the subject’s adverse events recover 
to grade 1 or better, continuation on study could be possible if approved 
by the principal investigator 
 
 
DURING NIVOLUMAB ONLY TIME PERIOD:  
 
With any grade 2 or higher non-hematologic toxicity, hold nivolumab and refer 
to section 5.2.1 Events of Interest for relevant management guidelines. If adverse 
event is not an event of interest and improves to grade 1 or better with 
symptomatic management and/or supportive medications, nivolumab may be 
resumed in ≥ 2 weeks. If non-hematologic toxicity does not improve to grade 1 or 
better within 6 weeks from prior dose, nivolumab should be discontinued. 
 
 
5.2.1 
IMMUNE MEDIATED EVENTS OF INTEREST (ONCE AT LEAST 1 DOSE OF 
NIVOLUMAB HAS BEEN   ADMINISTERED) - APPLY TO NIVOLUMAB ONLY: 
 
 
 
Certain adverse events that are possibly immune mediated warrant special monitoring and 
management, and are outlined below to guide investigators. 
 
5.2.1.1 Pulmonary: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
protocol therapy. Evaluate with imaging and pulmonary consultation. 
 
Grade of pneumonitis 
 (NCI CTCAE v4) 
Management 
Follow-up 
Grade 1 
Radiographic Changes Only 
 
Consider delay of 
nivolumab  
 
Monitor for symptoms 
every 2-3 days 
 
Consider pulmonary and 
infectious disease 
consultations 
 
Re-image at least every 3 
weeks 
 
If worsening, treat as grade 
2,3 or 4 
Grade 2 
Mild to moderate new symptoms 
 
Delay nivolumab  
 
Consult pulmonary and 
infectious disease 
 
Monitor symptoms daily, 
consider hospitalization 
 
1.0mg/kg/day 
methylprednisolone IV or 
oral equivalent 
 
Consider bronchoscopy 
and/or lung biopsy 
 
Re-image every 1-3 days 
 
Consider prophylactic 
antibiotics while on 
steroids 
 
If improves: 
 When symptoms return 
to near baseline, taper 
steroids over at least one 
month 
 Resume nivolumab and 
IL-2 if the event 
improves to grade 0 or 1 
within 12 weeks and 
corticosteroids have 
been reduced to the 
equivalent of ≤ 10mg 
oral prednisone per day 
 
If not improving after 2 
weeks or worsening, treat 
as grade 3 or 4 
 


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Grade 3 or 4 
Severe new symptoms and/or 
new or worsening hypoxia 
 
Discontinue nivolumab.  
 
Hospitalize 
 
Consult pulmonary and 
infectious disease 
 
1-2mg/kg/day 
methylprednisolone IV or 
IV equivalent 
 
Add prophylactic antibiotics 
for opportunistic infections 
like PCP 
 
Consider bronchoscopy 
and/or lung biopsy 
 
If improves to baseline: 
 Taper steroids for at 
least 6 weeks 
 
If not improving after 48 
hours or worsening 
 Add additional 
immunosuppressive 
agent(s) (e.g. infliximab, 
cyclophosphamide, 
intravenous 
immunoglobulin or 
mycophenolate mofetil) 
 
 
 
5.2.1.2 Gastrointestinal: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
protocol therapy. Opiates or narcotics may mask symptoms of perforation. Infliximab should not 
be used in case of perforation or sepsis. 
 
Grade of diarrhea/colitis 
 (NCI CTCAE v4) 
Management 
Follow-up 
Grade 1 
Diarrhea of less than 4 stools 
per day over baseline or 
asymptomatic colitis 
 
Continue nivolumab  
 
Symptomatic treatment 
such as loperamide 
 
Close monitoring for 
worsening symptoms 
 
Educate patient to report 
worsening immediately 
 
If worsening, treat as grade 
2,3 or 4 
Grade 2 
 
Diarrhea of 4-6 stools 
per day over baseline 
OR  
 
IV fluids needed < 24 
hours due to diarrhea 
OR 
 
Colitis with abdominal 
pain or blood in stool 
 
Hold nivolumab  
 
Symptomatic treatment 
such as loperamide. 
 
 
If improves to grade 1, 
resume nivolumab and/or 
IL-2 
 
If symptoms persist for > 7 
days 
o 
1-2 mg/kg per day of 
oral prednisone or 
equivalent 
o 
Consider prophylactic 
antibiotics for 
opportunistic 
infections like PCP 
o 
Resume nivolumab 
and IL-2 if the event 
improves to grade 0 
or 1 within 12 weeks 
and corticosteroids 
have been reduced to 
the equivalent of ≤ 
10mg oral prednisone 
per day 
o 
When symptoms 
improve to grade 1, 
taper steroids over at 
least one month 
 
If worsening, treat as grade 
3 or 4 
Grade 3  
 
Hold nivolumab   
 
If improves 


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Grade of diarrhea/colitis 
 (NCI CTCAE v4) 
Management 
Follow-up 
 
Diarrhea ≥ 7 stools per 
day over baseline 
OR 
 
IV fluids needed for ≥ 24 
hours due to diarrhea 
OR 
 
Colitis with severe 
abdominal pain or 
medical intervention 
indicated 
 
 
methylprednisolone IV or 
IV equivalent 
 
Start prophylactic 
antibiotics for opportunistic 
infections such as PCP 
 
Consider lower endoscopy 
 
 
Continue steroids until 
symptoms are grade 1, 
then taper over at least 
one month 
 
Resume nivolumab and 
IL-2 if the event 
improves to grade 0 or 1 
within 12 weeks and 
corticosteroids have 
been reduced to the 
equivalent of ≤ 10mg 
oral prednisone per day 
 
If persists for >3-5 days or 
recurs after improvement, 
add infliximab 5mg/kg if no 
contraindication (Note: 
infliximab should not be 
used in cases of 
perforation or sepsis) 
Grade 4 
Life threatening or perforation 
 
Discontinue nivolumab  
 
1-2mg/kg/day 
methylprednisolone IV or 
IV equivalent 
 
Start prophylactic 
antibiotics for opportunistic 
infections such as PCP 
 
Consider lower endoscopy 
 
If improves 
 
Continue steroids until 
symptoms are grade 1, 
then taper over at least 
one month 
 
If persists for >3-5 days or 
recurs after improvement, 
add infliximab 5mg/kg if no 
contraindication (Note: 
infliximab should not be 
used in cases of 
perforation or sepsis) 
 
 
 
5.2.1.3 Endocrinopathy: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
protocol therapy. Consider visual field testing, endocrinology consultation and imaging. 
 
Endocrinopathy 
Management 
Follow-up 
Asymptomatic thyroid-
stimulating hormone (TSH) 
elevation 
 
Continue nivolumab  
 
If TSH <0.5 x LLN or TSH 
>2x ULN, or consistently 
out of range in subsequent 
measurements, include 
free T4 in subsequent 
measurements as clinically 
indicated 
 
Consider endocrinology 
consult 
 
Symptomatic Hypothyroidism 
 
Initiate thyroid replacement 
 
Symptomatic Hyperthyroidism 
 
Delay nivolumab 
 
Consider endocrinology 
consult 
 Resume nivolumab and IL-
2 when symptoms of 
hyperthyroidism are 


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Endocrinopathy 
Management 
Follow-up 
 
Initiate anti-thyroid drug 
controlled and thyroid 
function is improving 
Hypophysitis 
 
Administer corticosteroids 
and hormone replacement 
as clinically indicated 
 
Delay nivolumab for grade 
2 or 3 hypophysitis 
 
Permanently discontinue 
nivolumab and IL-2 for 
grade 4 hypophysitis 
 
Symptomatic Adrenal 
Insufficiency 
 
Delay nivolumab  
 
Administer 
methylprednisolone 1-2 
mg/kg/day IV followed by 
oral prednisone 1-2mg/kg 
per day or equivalent once 
symptoms improve 
 
If improves to ≤ grade 1, 
taper steroids over at least 
one month 
 
Resume nivolumab and IL-2 
if the vent improves to grade 
0 or 1 within 12 weeks and 
corticosteroids have been 
reduced to the equivalent of 
≤10 mg oral prednisone per 
day and the patient is on 
stable replacement therapy 
if required 
 
 
 
 
 
5.2.1.4 Hepatic: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
protocol therapy. Consider imaging for obstruction. 
 
Grade of Liver Test Elevation 
(NCI CTCAE v4) 
Management 
Follow-up 
Grade 1 
AST or ALT >ULN to 3x ULN 
and/or total bilirubin >ULN to 
1.5x ULN 
 
Continue nivolumab  
 Continue liver function test 
monitoring per protocol 
 If worsening, treat as grade 
2,3, or 4 
Grade 2 
AST or ALT >ULN to 3-5x ULN 
and/or total bilirubin >ULN to 
1.5-3x ULN 
 
Delay nivolumab  
 
Administer corticosteroids 
at a dose of 1-2mg/kg/day 
prednisone 
 Resume nivolumab and IL-
2 if returns to baseline 
 If persists >5-7 days or 
worsens, treat as grade 3 or 
4 


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Grade 3 or 4 
AST or ALT >5x ULN and/or 
total bilirubin >3x ULN 
 
Discontinue nivolumab  
 
Increase frequency of 
monitoring to every 1-2 
days 
 
1-2mg/kg/day 
methylprednisolone IV or 
IV equivalent for grade 3 
and 2 mg/kg/day 
methylprednisolone IV for 
grade 4 
 
Add prophylactic antibiotics 
for opportunistic infections 
like PCP 
 
Consult gastroenterologist 
 If improves to grade 2, taper 
steroids over at least one 
month 
 If does not improve within 
3-5 days or worsens after 
improvement: 
o 
Add mycophenolate 
mofetil 1g twice 
daily 
o 
If no response 
within an additional 
3-5 days, consider 
other 
immunosuppressive 
agents per local 
guidelines 
 
 
 
 
 
 
 
5.2.1.5 Neurological: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
protocol therapy. 
 
Grade of neurological toxicity 
(NCI CTCAE v 4) 
Management 
Follow-up 
Grade 1 
 
Asymptomatic or mild 
symptoms 
 
Intervention not 
indicated 
 
 
Continue nivolumab 
 
Continue to monitor the 
patient, if worsening treat as 
grade 2, 3, or 4 
Grade 2 
 
Moderate symptoms 
 
Limiting 
instrumental 
ADLs 
 
Delay nivolumab  
 
Treat 
symptoms 
per 
institutional guidelines 
 
Consider 0.5-1mg/kg per day 
methylprednisolone 
IV 
or 
oral equivalent 
 
If returns to baseline, 
resume nivolumab and 
IL-2 
 
If worsens, treat as grade 
3 or 4 
Grade 3 or 4 
 
Severe symptoms 
 
Limiting self-care ADLs 
 
Discontinue nivolumab  
 
Consult Neurology 
 
Treat 
symptoms 
per 
institutional guidelines 
 
1-2mg/kg 
per 
day 
IV 
methylprednisolone 
or 
IV 
equivalent 
 
Add prophylactic antibiotics 
for opportunistic infections 
 
If improves to grade 2, 
taper steroids over at 
least one month 
 
If worsens, consider 
IVIG or other 
immunosuppressive 
therapies per 
institutional guidelines 
Meningitis or Encephalitis 
 
Discontinue nivolumab 
 
1-2mg/kg 
per 
day 
IV 
methylprednisolone 
or 
IV 
equivalent 
 
If improves, convert to 
oral steroids (prednisone 
60mg/day or equivalent) 
 
When symptoms 


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improve to ≤ grade 1, 
taper steroids over at 
least one month 
 
5.2.1.6 Skin: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
protocol therapy 
 
Grade of Rash 
(NCI CTCAE v4) 
Management 
Follow-up 
Grade 1-2 
Covering ≤ 30% body surface 
area (BSA) 
 
Symptomatic therapy (such 
as antihistamines, topical 
steroids) 
 
Continue nivolumab  
 
If persists 1-2 weeks or 
recurs 
o 
Consider skin biopsy 
o 
Delay nivolumab and 
IL-2 
o 
Consider 0.5-
1mg/kg/day 
methylprednisolone IV 
or oral equivalent 
o 
Once improving, taper 
steroids for at least 
one month 
o 
Consider prophylactic 
antibiotics for 
opportunistic infections 
like PCP 
o 
Resume nivolumab 
and IL-2 if rash 
improves to ≤ grade 1 
within 12 weeks and 
corticosteroids have 
been reduced to ≤ 10 
mg oral prednisone or 
equivalent per day 
 
If worsens, treat as 
grade 3 or 4 
Grade 3-4 
Covering >30% BSA or life 
threatening consequences 
 
Delay 
or 
discontinue 
nivolumab. 
 
Consider skin biopsy 
 
Consult dermatology 
 
1-2mg/kg/day 
methylprednisolone IV or IV 
equivalent 
 
Add prophylactic antibiotics 
for opportunistic infections 
 
If improves to grade 1: 
o 
Taper steroids over 
at least one month  
o 
Resume nivolumab 
and IL-2 if rash 
improves to ≤ grade 
1 within 12 weeks 
and corticosteroids 
have been reduced 
to ≤ 10 mg oral 
prednisone or 
equivalent per day 
 
 
5.2.1.7 Renal: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
protocol therapy 
 


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Grade of elevation in serum 
creatinine 
(NCI CTCAE v4) 
Management 
Follow-up 
Grade 1 
Serum creatinine >ULN and 
>baseline but ≤1.5x baseline 
 Continue nivolumab  
 Monitor 
serum 
creatinine 
weekly 
 
If returns to baseline, 
resume creatinine 
monitoring per protocol 
 
If worsens, treat as grade 
2, 3, or 4 
Grade 2 or 3 
Serum creatinine 1.5x baseline 
to ≤ 6 x ULN 
 Delay or discontinue 
nivolumab  
 Monitor 
serum 
creatinine 
every 2-3 days 
 0.5-1 mg/kg/day 
methylprednisolone IV or 
oral equivalent 
 Add prophylactic antibiotics 
for opportunistic infections 
 Consider renal biopsy 
 
If improves to grade 1 
o Taper steroids over 
at least one month  
o Resume nivolumab 
and IL-2 if improves 
to ≤ grade 1 within 
12 weeks and 
corticosteroids have 
been reduced to ≤ 
10 mg oral 
prednisone or 
equivalent per day 
 
If elevation persists >7 
days or worsens, treat as 
grade 4 
Grade 4 
Serum creatinine <6x ULN 
 Discontinue nivolumab  
 Monitor 
serum 
creatinine 
daily 
 1-2mg/kg/day 
methylprednisolone IV or IV 
equivalent 
 Add prophylactic antibiotics 
for opportunistic infections 
 Consult nephrology 
 Consider renal biopsy 
 
If improves to grade 1 
o Taper steroids over 
at least one month  
o Resume nivolumab 
and IL-2 if improves 
to ≤ grade 1 within 
12 weeks and 
corticosteroids have 
been reduced to ≤ 
10 mg oral 
prednisone or 
equivalent per day 
 
For nivolumab only with any grade 4 hematologic toxicity, hold nivolumab. If the adverse 
event improves to grade 3 or better with symptomatic management and/or supportive 
medications, nivolumab may be resumed in ≥2 weeks. 
  
 
Discontinue both IL-2 and Nivolumab permanently for the following conditions:  
 
Guillain-Barre Syndrome (GBS) 
 
Myasthenia gravis  
 
Pituitary apoplexy or hypopituitarism (clinical including based on 
biochemical values. 
 
5.3 
Concomitant Medications/Treatments 
Corticosteroids greater than the equivalent of 10mg daily of prednisone (except 
physiologic dose for adrenal replacement therapy), other immunosuppressive agents 
(such as cyclosporine or methotrexate) and any other medications that could potentially 
impact the efficacy or safety of the study as judged by the treating investigator are NOT 
permitted from time of registration to subjects completing protocol therapy unless 
clinically indicated to manage adverse events or life threatening or serious conditions as 
determined by the treating investigator. 


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5.4 
Other Modalities or Procedures 
Nivolumab should be held for any surgery or radiotherapy until subject is judged to be 
stable to resume by treating investigator as adequate information does not exist on its 
effects on wound healing and radio sensitization effects. When resumed, same dose 
level will be maintained. Percutaneous procedures like imaging guided biopsies and 
central line placements do not require Nivolumab to be held. 
5.5 
Duration of Protocol Specified Therapy (IL2 and/or Nivolumab) 
In the absence of treatment delays due to adverse events, treatment may continue for up 
to 48 weeks or until one of the following criteria apply: 
 
Disease progression as defined in Section 7.0.  
 
Inter-current illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) 
 
Patient voluntarily withdraws from treatment  
 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
5.6 
Off Protocol Specified Therapy Criteria  
Patients will be removed from protocol specified therapy when any of the criteria listed in 
Section 5.5 apply. The reason for ending protocol therapy and the date the patient was 
removed from treatment should be documented. All patients who discontinue treatment 
should comply with protocol specific follow-up procedures as outlined in Section 6.3. The 
only exception to this requirement is when a subject withdraws consent for all study 
procedures or loses the ability to consent freely. 
5.7 
Duration of Follow-Up 
Patients will be followed for 2 years (counting from week 1) after completion of/removal 
from treatment or until death, whichever occurs first. Patients removed from treatment for 
unacceptable adverse events will be followed until resolution or stabilization of the 
adverse events.  
5.8 
Off Study Criteria 
Patients can be taken off study at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral or administrative 
reasons. The reason(s) for discontinuation from study will be documented and may 
include: 


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5.8.1 
Patient withdraws consent (termination of treatment and follow-up); 
5.8.2 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment; 
5.8.3 
Patient is unable to comply with protocol requirements in the judgment of the 
treating investigator; 
5.8.4 
Treating physician determines continuation on the study would not be in the 
patients best interest; 
5.8.5 
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
5.8.6 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
5.8.7 
Lost to Follow-up. If a research subject cannot be located to document survival in 
the follow-up period per protocol, the subject may be considered “lost to follow-
up.” All attempts to contact such a subject during the follow-up period must be 
documented 
5.8.8 
Termination of the study by The University of Michigan or other regulatory 
bodies; 
5.8.9 
Patient completes protocol treatment and follow-up criteria. 
 
5.9 
Patient Replacement 
Subjects who are not evaluable will be replaced. Evaluable patients are those who 
receive at least 1 dose of HD IL2 and at least 1 dose of nivolumab.  
 
 
6.0 
STUDY PROCEDURES 
6.1 
Screening/Baseline Procedures (see Time and Events table section 6.4) 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 28 calendar days prior to registration 
unless otherwise stated. The screening procedures include: 
6.1.1 Informed Consent 
6.1.2 Medical history 
To include complete medical and surgical history, history of infections, 
autoimmune diseases 
6.1.3 Demographics 
Age, gender 


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6.1.4 Review subject eligibility criteria 
6.1.5 Review previous (within 28 calendar days) and concomitant medications 
6.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight 
6.1.7 Performance status 
ECOG performance status 
6.1.8 Adverse event assessment 
Baseline adverse events will be assessed. See Section 8.0 for Adverse Event 
monitoring and reporting. 
6.1.9 Hematology 
CBC with diff includes total WBC, hemoglobin, hematocrit, platelet count and 
differential of the WBC including absolute counts 
6.1.10 Blood draw for correlative studies and anti-drug antibody analysis 
See Section 10.0 for details. 
6.1.11 Serum chemistries 
Comprehensive metabolic profile (COMP) includes sodium, potassium, chloride, 
bicarbonate, BUN, creatinine, AST, ALT, alkaline phosphatase, total bilirubin. 
 
Magnesium, phosphorus, LDH. 
 
TSH, free T3, free T4 (Only If Clinically Indicated: FSH, LH, ACTH). 
6.1.12   Coagulation 
 
 
PT/INR 
6.1.13 Urine Tests 
 
 
Urine protein/creatinine ratio 
6.1.14 Pregnancy test (for females of child bearing potential) 
Women of non-childbearing potential are defined as those who have no uterus, 
ligation of the fallopian tubes, or permanent cessation of ovarian function due to 
ovarian failure or surgical removal of the ovaries. All others are considered 
women of child bearing potential. 
 
Either urine or serum pregnancy test is acceptable. 
6.1.15 Tumor assessment 
To be performed within 28 calendar days of registration: Computed tomography 
of the chest, computed tomography or magnetic resonance imaging of the 
abdomen and pelvis, computed tomography or magnetic resonance imaging of 
the brain 
6.1.16 Other  
 12-lead Electrocardiography. 


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 High dose Interleukin-2 eligibility assessment: to be done within 4 weeks of 
registration, should include cardiac (including dobutamine stress echocardiogram 
or equivalent at the discretion of the treating investigator) and pulmonary function 
testing evaluation. 
 An archived tissue block must be identified (but not needed to be submitted) to 
submit unstained slides from prior to registration. 
6.2 
Procedures During Treatment 
All assessments have a window of ± 3 business days except for imaging/tumor 
measurements where a window of ± 7 business days will apply. 
6.2.1 
Each HD IL2 week (weeks 1 and 3) 
 Physical exam, vital signs, ECOG Performance Status, Toxicity. 
 
 Minimum of once daily: urine output measurement, pulse oximetry 
measurement. 
 
 Hematology: CBC with diff includes total WBC, hemoglobin, hematocrit, 
platelet count and differential of the WBC including absolute counts 
 
 Serum chemistries: Comprehensive metabolic profile (COMP) includes 
sodium, potassium, chloride, bicarbonate, BUN, creatinine, AST, ALT, alkaline 
phosphatase, total bilirubin. 
 
 Magnesium, phosphorus, LDH 
 
 Day 5 and Day 19 (N.B: these will occur during IL2 weeks): Total Creatinine 
Kinase, Troponin T 
 
 Central line placement prior to any IL2 dose on days 1 and 15. 
 
 HD IL-2 administration will start on Day 1 and continue every 8 hours until Day 
5 (cycle 1), then resume on D15 and continue until D19 (cycle 2). HD IL2 dose 
strength (600,000 IU/kg/dose) will be calculated separately on Day 1 and Day 
15 and not modified at other times during the IL2 week. IL2 dose will be 
administered over 15 minutes (± 5 minutes) via a central line. 
 
 Other clinical, laboratory and imaging assessments during HD IL-2 
administration as per institutional guidelines per treating investigator 
 
6.2.2 
Nivolumab administration days 
 Physical exam, vital signs, ECOG Performance Status, Toxicity 
 
 Hematology: CBC with diff includes total WBC, hemoglobin, hematocrit, 
platelet count and differential of the WBC including absolute counts 
 
 Serum chemistries: Comprehensive metabolic profile (COMP) includes 
sodium, potassium, chloride, bicarbonate, BUN, creatinine, AST, ALT, alkaline 
phosphatase, total bilirubin. 
 


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 Magnesium, phosphorus, LDH 
 
 Every 12 weeks until discontinuation/completion of nivolumab on trial: TSH, 
free T3, free T4 (Only If Clinically Indicated: FSH, LH, ACTH). 
 
 
Whole blood will be collected for correlative analysis at certain time points. 
See Section 6.4 Time and Events Table including footnote #8 for the time 
points and the Lab Manual for collection, labeling and shipping instructions  
 
 
Blood draw for ADA (anti-drug antibody) analysis will be collected at the time 
points listed in Section 6.4 Time and Events Table. 
 
 Prior to dose # 1 (subsequently ONLY if clinically indicated): 12-lead 
Electrocardiography 
 
 At week 12: Echocardiogram 
 
 Nivolumab administration will be over 60 minutes (± 10 minutes) at a dose of 
480 mg intravenously. Pre-medications or rescue medications are not 
specified by protocol and will be per institutional guidelines/treating 
investigator.  
 
 
Continue Nivolumab every 4 weeks until i) progression noted or ii) up to 48 
weeks completed from start of protocol therapy (week 1) - refer to sections 
5.4, 5.5. and 5.7. Nivolumab may be continued by treating investigator beyond 
this period off-study at his or her discretion and clinical judgment. 
 
 
Clinic visits: For patients who continue on nivolumab on trial nivolumab: every 
4 weeks (from week1) with scans as in Section 6.4 Time and Events Table 
below.   
 
 At week 12 and then every 12 weeks: Computed tomography of the chest, 
computed tomography or magnetic resonance imaging of the abdomen and 
pelvis, and only if clinically indicated: computed tomography or magnetic 
resonance imaging of the brain 
 
6.2.3 
In between clinic visits 
 
Study nurse or coordinator will call patient at least once a week in the first 12 
weeks between clinic visits to evaluate for toxicity.  
 
6.2.4 
End of Treatment Visit after protocol specified therapy (IL2 and nivolumab) 
termination 
 Physical exam, vital signs, ECOG Performance Status, Toxicity 
 
 Hematology: CBC with diff includes total WBC, hemoglobin, hematocrit, 
platelet count and differential of the WBC including absolute counts 
 
 Serum chemistries: Comprehensive metabolic profile (COMP) includes 
sodium, potassium, chloride, bicarbonate, BUN, creatinine, AST, ALT, alkaline 
phosphatase, total bilirubin 


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 Magnesium, phosphorus, LDH 
 
 TSH, free T3, free T4 (Only If Clinically Indicated: FSH, LH, ACTH) 
6.3 
Follow-Up Procedures 
 
For patients who have stopped all protocol specified therapy (IL2 and nivolumab for up to 
48 weeks), follow up will be done every 12 weeks (counting from week 1) via phone or 
other forms of communication. In these patients, scans and/or labs will be per the treating 
investigator’s discretion/per standard of care and not dictated by the protocol. 
 
 
6.4 
Time and Events Table 
 
Screen 
(<28d) 
Week 1  
IL2 
Cycle 
#1 
Nivolum
ab 
Dose 
#1 12 
Week 3 
IL2 
Cycle 
#2 
 
Nivolum
ab 
Dose 
#2… 12,  
Week 
12 
Subseq
uent 11  
End of 
treatme
nt visit 
16 
Follow-
Up 9, 11 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
History, PE, 
Con Meds, 
Weight, Vital 
Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
X 
 
Toxicity 
Evaluation 
 
X 
X 
X 
X 
X 
X 
X 
 
HD IL2 
eligibility 
assessment 
X 
 
 
 
 
 
 
 
 
Pregnancy 
Test for 
WOCBP 10 
X 
 
 
 
 
 
 
 
 
CBC with diff 
and plt 2 
X 
X 
X 
X 
X 
X 
X 
X 
 
COMP 3 
X 
X 
X 
X 
X 
X 
X 
X 
 
Mag, Phos, 
LDH 
X 
X 
X 
X 
X 
X 
X 
X 
 
PT/INR 
X 
 
 
 
 
 
 
 
 
Urine 
Protein/Creati
nine Ratio 
X 
 
 
 
 
 
 
 
 
Urine output 
measurement, 
pulse 
oximetry 
measurement.  
 
X 
(qday) 
 
X 
(qday) 
 
 
 
 
 


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Screen 
(<28d) 
Week 1  
IL2 
Cycle 
#1 
Nivolum
ab 
Dose 
#1 12 
Week 3 
IL2 
Cycle 
#2 
 
Nivolum
ab 
Dose 
#2… 12,  
Week 
12 
Subseq
uent 11  
End of 
treatme
nt visit 
16 
Follow-
Up 9, 11 
TSH, free T3, 
free T4 (IF 
Clinically 
Indicated: 
FSH, LH, 
ACTH) 3 
X 
 
 
 
 
 
X 
(q 12 
weeks) 
X 
 
Total 
Creatinine 
Kinase, 
Troponin T 
 
X 
(day 5) 
 
X 
(day 
19) 
 
 
 
 
 
12-lead ECG 
X 
 
X 
 
 
 
X 
(IF 
clinicall
y 
indicate
d) 
 
 
CT chest 4 
X 
 
 
 
 
X 
X 
(q 12 
weeks) 
 
X 9 
CT or MRI 
abdomen/pelv
is 4 
X 
 
 
 
 
X 
X 
(q 12 
weeks) 
 
X 9 
CT or MRI 
brain 4, 
X 
 
 
 
 
X 
X5 
 
X5,9 
Tumor 
Measurement
s 
X 
 
 
 
 
X 
X 
(q 12 
weeks) 
 
X 9 
Central line 
placement 
 
X 
(day 1) 
 
X 
(day 
15) 
 
 
 
 
 
HD-
Interleukin-2 
 
X 
(D1-5) 
 
X 
(D15-
19) 
 
 
 
 
 
Nivolumab 12 
 
 
X 
 
X 
X 
X…6 
 
 
Archived 
Tumor Tissue 
7 
X 
 
 
 
 
 
 
 
 
Blood draw 
for Anti-Drug 
Antibody 
Analysis15 
X 
 
X 
 
X 
X 
X (q12 
weeks) 
 
 
Whole blood, 
8 
X 
 
X 
X 
X 
X 
 
 
 
Serum 8 
X 
 
 
 
 
 
 
 
 
Echocardiogr
am 13 
X 
 
 
 
 
X 
 
 
 
Study RN/ 
Coordinator 
Call 14 
 
X 
X 
X 
X 
X 
 
 
 
 
All assessments have a window of ± 3 business days except for imaging/tumor 
measurements where a window of ± 7 business days will apply. 
 


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1: Vital signs will include temperature, pulse, respirations, blood pressure); height will be obtained at 
screening only. 
2: CBC with diff includes total WBC, hemoglobin, hematocrit and differential of the WBC including absolute 
counts. 
3: Comprehensive metabolic profile includes sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
AST, ALT, alkaline phosphatase, total bilirubin. TSH, free T3, free T4 at baseline and then repeated every 12 
weeks. (IF Clinically Indicated ONLY: FSH, LH, ACTH) 
4: With or without intravenous contrast, before or on associated visit. 
5: Only if clinically indicated 
6. Continue Nivolumab on trial every 4 weeks until i) progression noted and no clinical benefit as determined 
by treating investigator or ii) up to 48 weeks completed from start of protocol therapy (week 1). Please note 
that nivolumab could be continued by the treating investigator off-trial beyond the 48-week duration at his 
or her clinical discretion. 
7. An archived tissue block must be identified with intent to submit for analysis prior to registration. See 
the Lab Manual for collection, labeling and shipping instructions. 
8: Whole blood is to be collected at 5 time points: pre-all study therapy, post first HD IL2 cycle but pre-
nivolumab, after the first dose of nivolumab but before the second dose of nivolumab, post second HD-IL2 
cycle (before the next dose of nivolumab) and at 12 weeks on days indicated prior to study drug being 
administered on that day. In some patients, due to the exact timing of dose #1 of nivolumab in that patient, 
two of these time points might coincide and in those patients, only 4 time points will be drawn. Serum will 
be collected at baseline only. See the Lab Manual for collection, labeling and shipping instructions.  
9: For patients who have stopped all protocol specified therapy, follow up will be done every 12 weeks ± 4 
weeks x total of 24 months (counting from week 1) via phone or other form of communication. In those 
patients, scans and/or labs will be per the treating investigator’s discretion/standard of care and will not be 
dictated by protocol. 
10. WOCBP: urine or serum pregnancy test for women of child bearing potential, see section 6.1.12 
11. For as long as subjects continue on nivolumab (i.e. up to 48 weeks on treatment, or beyond the 48 
week duration of treatment per treating investigator’s discretion): Survival status assessment at least every 
12 weeks ± 4 weeks x total of 24 months (counting from week 1) with scans as noted. 
12. Nivolumab should optimally be started on week 2 (after the first 3 subjects, please see statistical section 
11) but can be started up to 3 weeks after first dose of IL-2 but NOT be on the same week as any HD IL2 
cycle. 
13. At baseline, a dobutamine stress echocardiogram or equivalent will be performed. Standard 2-D 
transthoracic or surface echo cardiogram will be performed.  
14. A call from the study nurse or coordinator will occur in between clinic/hospital visits once weekly for the 
first 12 weeks. 
15. Blood draw for Anti-Drug Antibody Analysis to be collected: pre-all study therapy, prior to Nivolumab 
dose 1, prior to Nivolumab dose 2, at week 12 (prior to Nivolumab dose), and every 12th subsequent week 
(prior to Nivolumab dose) until the end of protocol treatment. 
16. Within 60 days after protocol specified therapy (IL2 and nivolumab) termination. 
 
7.0 
MEASUREMENT OF EFFECT 
 
7.1 
Antitumor Effect- Solid Tumors 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee [JNCI 92(3):205-216, 2000]. Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST v1.1 criteria. 
7.1.1 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of 
their first treatment with study drug. 


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Evaluable for objective response. Only those patients who have measurable 
disease present at baseline, have received at least 1 dose of HD IL2 and at least 
1 dose of nivolumab, 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.) 
 
7.1.2 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
 
 
10mm by CT scan (irrespective of scanner type) for studies with a slice 
thickness of <5mm or twice the slice thickness or MRI 
 
10mm caliper measurement by clinical exam (lesions which cannot be 
             accurately measured with calipers should be recorded as  
             non-measurable)          
 
20mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
                           
                         All tumor measurements must be recorded in millimeters (or decimal fractions of     
                         centimeters). 
 
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Note: Tumor lesions that are situated in a previously irradiated area are not 
considered measurable. 
 
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <20 mm with conventional techniques or <10 mm using 
CT scan), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all non-measurable. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total 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 organ, 
but in addition should be those that lend themselves to reproducible repeated 
measurements. 
 
Lymph nodes merit special mention since they are normal anatomical structures 
which may be visible by imaging even if not involved by tumor. Pathological 
nodes which are defined as measurable and may be identified as target lesions 
must meet the criterion of a short axis of ≥15mm by CT scan. Only the short axis 
of these nodes will contribute to the baseline sum. The short axis of the node is 
the diameter normally used by radiologists to judge if a node is involved by solid 
tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI 
the plane of acquisition may be axial, sagittal or coronal). The smaller of these 


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measures is the short axis. For example, an abdominal node which is reported as 
being 20mm x 30mm has a short axis of 20mm and qualifies as a malignant, 
measurable node. In this example, 20mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10mm but <15 
mm) should be considered non-target lesions. Nodes that have a short axis 
<10mm are considered non-pathological and should not be recorded or followed. 
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 as noted above, 
only the short axis is added into the sum. The baseline sum diameters will be 
used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including pathological 
lymph nodes should be identified as non-target lesions and should also be 
recorded at baseline. Measurements are not required and these lesions should 
be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g. 
‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
7.1.3 
Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation, using calipers if 
clinically assessed. All baseline evaluations should be performed as close as 
possible to the treatment start 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 should always be done rather than clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they 
are superficial and >10mm diameter as assessed using calipers (e.g. skin 
nodules). For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesion is suggested. As noted above, 
when lesions can be evaluated by both clinical exam and imaging, imaging 
evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 
 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when 
progression is an important endpoint, since CT is more sensitive than X-ray, 
particularly in identifying new lesions. However, lesions on chest X-ray may be 
considered measurable if they are clearly defined and surrounded by aerated 
lung. 
 
CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined 
measurability of lesions on CT scan based on the assumption that CT slice 
thickness is 5mm or less. When 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). 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. Ultrasound examinations cannot be 


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reproduced in their entirety for independent review at a later date and, because 
they are operator dependent, it cannot be guaranteed that the same technique 
and measurements will be taken from one assessment to the next. If new lesions 
are identified by ultrasound in the course of the study, confirmation by CT or MRI 
is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in 
trials where recurrence following complete response or surgical resection is an 
endpoint. 
 
Cytology, Histology: These techniques can be used to differentiate between PR 
and CR in rare cases. When effusions are known to be a potential adverse effect 
of treatment, the cytological confirmation of the neoplastic origin of any effusion 
that appears or worsens during treatment can be considered if the measurable 
tumor has met criteria for response or stable disease in order to differentiate 
between response (or stable disease) and progressive disease. 
7.1.4 
Response Criteria 
7.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, 
determined by two separate observations conducted not less than 4 
weeks apart. There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as reference the baseline 
sum LD. There can be no appearance of new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD 
of target lesions, taking as reference the smallest sum LD recorded since 
the treatment started, or the appearance of one or more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started. 
7.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. 
 
Incomplete Response/Stable Disease (SD): Persistence of one or more 
non-target lesion(s) and/or maintenance of tumor marker level above the 
normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions. 
7.1.4.3 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 


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treatment started). The patient's best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 
 
 
 
 
Target 
Lesions 
Non-
Target 
Lesions 
New Lesions 
Overall 
Response 
Best 
Response for 
this Category 
Also 
Requires: 
CR 
CR 
No 
CR 
>4 wks. 
confirmation 
CR 
Non-
CR/SD 
No 
PR 
 
>4 wks. 
confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at 
least once >4 
wks. from 
baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, 
PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
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. 
 
Note: If subjects respond to treatment and are able to have their disease 
resected, the patient’s response will be assessed prior to the surgery. 
7.1.5 
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 recurrent 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.  
7.1.6 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression. 


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7.2 
Safety/Tolerability 
 
 Analyses will be performed for all patients having received at least one dose of study 
drug. The study will use the CTCAE version 4.0 for reporting of adverse events 
(http://ctep.cancer.gov/reporting/ctc.html). 
8.0 
ADVERSE EVENTS 
8.1 
Experimental Therapy 
For the most recent safety update on Contraindications, Special Warnings and 
Precautions for Use, Interaction with other medications and Adverse Reactions, please 
refer to the current Investigator’s Brochure or package insert. 
 
8.2 
Adverse Event Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and is 
done to ensure the safety of subjects enrolled in the studies as well as those who will 
enroll in future studies using similar agents. Data on adverse events will be collected from 
the time of initial study treatment administration or intervention through 60 days after the 
last dose of study treatment (study treatment here refers to the two possible cycles of 
interleukin-2 and/or last dose of nivolumab up to 48 weeks of therapy, whichever is later). 
Any serious adverse event that occurs more than 60 days after the last study treatment 
and is considered related to the study treatment must also be reported. Serious Adverse 
Events (SAEs) will continue to be followed until: 
 
Resolution or the symptoms or signs that constitute the serious adverse event 
return to baseline; 
 
There is satisfactory explanation other than the study treatment or intervention 
for the changes observed; or  
 
Death. 
The investigator is responsible for the detection, documentation, grading and assignment 
of attribution of events meeting the criteria and definition of an AE or SAE. The definitions 
of AEs and SAEs are given below. It is the responsibility of the principal investigator to 
ensure that all staff involved in the trial is familiar with the content of this section. 
Any medical condition or laboratory abnormality with an onset date before initial study 
treatment administration or intervention is considered to be pre-existing in nature. Any 
known pre-existing conditions that are ongoing at time of study entry should be 
considered medical history. 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 8.3, 
occurring from the initial study treatment administration or intervention through 60 days 
following the last dose of the study treatment (study treatment here refers to the two 
possible cycles of interleukin-2 and/or last dose of nivolumab up to 48 weeks of therapy  
whichever is later) or study intervention must be recorded as an adverse event in the 
patient’s source documents and on the CRF regardless of frequency, severity (grade) or 
assessed relationship to the study treatment or intervention.  
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of 
a pre-existing condition that occurs after the patient begins study treatment or 
intervention is also considered an adverse event. 


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8.3 
Definitions 
8.3.1 Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an experimental intervention, whether or not related to the intervention.  
 
 
Diagnostic and therapeutic non-invasive and invasive (i.e., surgical) 
procedures will not be reported as adverse events. However, the medical 
condition for which the procedure was performed must be reported if it meets 
the definition of an adverse event unless it is a pre-existing (prior to protocol 
treatment) condition. 
 
 
Abnormal laboratory values or test results constitute adverse events if they 
induce clinical signs or symptoms or require therapy. They are to be captured 
under the signs, symptoms or diagnoses associated with them. 
8.3.2 Serious Adverse Event 
An adverse event is considered “serious” if, in the view of either the investigator 
or Sponsor-Investigator, it results in any of the following outcomes: 
  
o 
Death 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
 
o 
A life-threatening adverse event 
An adverse even is considered ‘life-threatening’ if, in the view of either the 
investigator [or sponsor], its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event that, had it 
occurred in a more severe form, might have caused death.  
 
o 
Inpatient hospitalization or prolongation of existing hospitalization for > 24 
hours. 
 
o 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 
o 
A congenital anomaly/birth defect 
 
o 
Important medical event 
Any event that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition 
of “Serious Adverse Event”. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room 
or at home; convulsions that do not result in inpatient hospitalization or the 
development of drug dependency or drug abuse. 
 
Previously planned (prior to signing the informed consent form) surgeries should 
not be reported as SAEs unless the underlying medical condition has worsened 
during the course of the study.  


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Preplanned hospitalizations or procedures for preexisting conditions that are 
already recorded in the patient’s medical history at the time of study enrollment 
should not be considered SAEs.  
 
Hospitalization or prolongation of hospitalization without a precipitating 
clinical AE (for example, for the administration of study therapy (e.g. HD 
IL2) or other protocol-required procedure) should not be considered SAEs. 
However, if the preexisting condition worsened during the course of the study, it 
should be reported as an SAE. 
 
8.3.3 Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 
 
For approved and marketed drugs or devices, those adverse events are 
described in the approved Package Insert (Label).  
 
For investigational new drugs or devices, those adverse events are 
described in the FDA Investigator’s Brochure.  
 
In clinical research studies, information on expected adverse events is 
also summarized in the protocol and in the consent document.  See 
section 9.1 for the list of expected adverse events related to the drug 
under study. 
8.3.4 Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not described in the 
Package Insert, Investigator’s Brochure, in published medical literature, in the 
protocol, or in the informed consent document.  
8.4 
Adverse Event Characteristics 
8.4.1 CTCAE Term 
(AE description) and grade: The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be down 
loaded from the CTEP web site. (http://ctep.cancer.gov) 
8.4.2 Attribution of the AE 
The investigator or co-investigator is responsible for assignment of attribution. 
Definite – The AE is clearly related to the study treatment/intervention. 
Probable – The AE is likely related to the study treatment/intervention. 
Possible – The AE may be related to the study treatment/intervention. 
Unlikely – The AE is doubtfully related to the study treatment/intervention. 
Unrelated – The AE is clearly NOT related to the study treatment/intervention. 
8.5 
Serious Adverse Event Reporting Guidelines 
8.5.1 
The Sponsor-Investigator and Coordinating Center must be notified within 24 
hours of study team’s knowledge of all events meeting the criteria and definition 
of a serious adverse event that are unexpected and possibly related (definite, 
probable or possible) to study treatment administration, occurring during the 
study or within 60 days of the last administration of the study treatment.  All other 
SAEs not meeting the criteria of unexpected and possibly related should be 
reporting to the Sponsor-Investigator and Coordinating Center within 5 business 


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days of study team’s knowledge. All SAEs should be reported using the CTO 
SAE Form. 
8.5.2 
The investigator must report all events meeting the criteria and definition of a 
serious adverse event that are unexpected and possibly related (definite, 
probable or possible) to study treatment administration or intervention to the local 
IRB within 5 business days of study team’s knowledge if death or life threatening, 
and within 7 calendar days for all others or per local institutional guidelines.  
8.5.3 
A copy of the CTO SAE form as available in the study database should be sent 
to the Sponsor-Investigator (see below for contact info) and also to the 
Coordinating Center via email to CTSU-Oncology-Multisite@med.umich.edu. 
Contact information for the PI for notification of SAEs: 
Ajjai Alva, MBBS, MS 
7316 Cancer Center, 
University of Michigan, 
1500 E. Medical Center Dr. 
Ann Arbor, MI 48109 
 
Ph: (734) 936-0091 
Fax: (734) 615-2719  
Email: ajjai@med.umich.edu   
 
Follow-up information must also be reported within 7 business day of the site’s 
knowledge of the information.  
8.5.4 
The Coordinating Center will disseminate information regarding SAEs to the 
participating sites within 5 days of review of the information by the Sponsor-
Investigator (or designee in the event of extended absence) only in the case that 
the event(s) us believed to be related (i.e., possibly, probably, or definitely) to the 
study treatment.  The Coordinating Center will be responsible for reporting of 
events to supporters, as appropriate (outlined below). The Michigan Institute for 
Clinical and Health Research (MICHR) MIAP group will be responsible for 
reporting any SAEs to the FDA as outlined below. 
8.5.5 
In this trial, serious unexpected adverse events believed to be definitely, probably 
or possibly related to the study treatment will be reported to the Food and Drug 
Administration via the MedWatch 3500A according to the reporting requirements 
in 21 CFR 312.32.  The MICHR MIAP group, in cooperation with the 
Coordinating Center, will be responsible for correspondence regarding adverse 
events with the FDA for all participating sites.  
8.6 
Routine Reporting 
All other adverse events- such as those that are expected, or are unlikely or definitely not 
related to the study participation- are to be reported annually as part of regular data 
submission. 
8.7 
Reporting of Unanticipated Problems 
There are types of incidents, experiences and outcomes that occur during the conduct of 
human subjects’ research that represent unanticipated problems but are not considered 
adverse events. For example, some unanticipated problems involve social or economic 
harm instead of the physical or psychological harm associated with adverse events. In 
other cases, unanticipated problems place subjects or others at increased risk of harm, 
but no harm occurs. 


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Upon becoming aware of any incident, experience, or outcome (not related to an adverse 
event) that may represent an unanticipated problem, the investigator should assess 
whether the incident, experience, or outcome represents an unanticipated problem. The 
incident, experience or outcomes is considered unanticipated if it meets all of the 
following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency); 
2. Related or possibly related to participation in the research; and 
3. Suggests that the research places subjects or others at a greater risk of harm 
than was previously known or recognized. 
If the investigator determines that the incident, experience, or outcome represents an 
unanticipated problem, the investigator must report it to the IRB within 14 calendar days 
of the study team becoming aware of the problem. 
8.8 
Stopping Rules  
Please refer to Section 11.1. 
 
9.0 
DRUG INFORMATION 
9.1 
Interleukin-2: 
 
Chemical Name: Recombinant human interleukin-2 (rhIL-2) 
 
 
Other names for the drug: Proleukin, Aldesleukin 
 
 
Description: Interleukin-2 is supplied as a sterile, white to off-white, lyophilized cake 
in single-use vials intended for intravenous (IV) administration 
 
 
Classification - type of agent: Cytokine, Antineoplastic Agent, Miscellaneous; 
Biological Response Modulator 
 
 
Mode of action: Immune-stimulator; Binds to IL-2-receptor and activates proliferation 
of lymphocytes. Interleukin-2 is a human recombinant interleukin-2 product which 
promotes proliferation, differentiation, and recruitment of T and B cells, natural killer 
(NK) cells, and thymocytes; causes cytolytic activity in a subset of lymphocytes and 
subsequent interactions between the immune system and malignant cells; can 
stimulate lymphokine-activated killer (LAK) cells and tumor-infiltrating lymphocytes 
(TIL) cells. 
 
 
Side effects: Please see the Interleukin-2 Guidance Document for information 
regarding side effects. For the most recent safety update, please refer to the current 
package insert(s). 
 
 
Drug Interactions: Please see the Interleukin-2 Guidance Document for information 
regarding drug interactions. 
 
 
Contraindications  
 
 Please see the Interleukin-2 Guidance Document for information regarding 
contraindications.  
 
 
Special Warnings and Precautions for Use  


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Please see the Interleukin-2 Guidance Document for information regarding special 
warnings and precautions for use. 
 
 
Storage and stability: Refrigerator at 2° to 8°C (36° to 46°F). Avoid exposure to heat 
and light. Stability after reconstitution—24 hours. 
  
 
Preparation and Dispensing:  
Please refer to package insert for preparation of this medication. 
 
 
Handling and disposal of IL-2 should be per institutional guidelines for the handling 
and disposal of cytotoxic agents. 
 
 
Administration:  
Route of administration for this study: IV infusion over 15 minutes via a central line 
 
Precautions: 
Please see the Interleukin-2 Guidance Document for information regarding 
precautions. For the most recent safety update, please refer to the current package 
insert(s). 
 
 
Availability: Commercially available from Prometheus. Standard of care. 
9.2 
Nivolumab: 
 
 
Chemical Name: Nivolumab 
 
 
Other names for the drug: Opdivo, BMS-936558, MDX-1106, ONO-4538 
 
 
Description: Nivolumab is supplied a sterile solution (Opdivo Intravenous) which 
comes in bottles of 40 mg/4 mL (4 mL) or 100 mg/10 mL (10 mL). 
 
 
Classification - type of agent: Immunomodulatory; checkpoint inhibitor 
 
 
Mode of action: Nivolumab is a fully human IgG4 programmed death 1 (PD-1) 
immune checkpoint inhibitor antibody that selectively blocks the interaction between 
PD-1, which is expressed on activated T cells, and PD-1 ligand 1 (PD-L1) and 2 (PD-
L2), which are expressed on immune cells and tumor cells. 
 
 
Side effects: Please see the package insert(s) for nivolumab. For the most recent 
safety update, please refer to the current package insert(s).  
 
Treatment-Related Adverse Events Reported in 10% or more of treated patients in 
either group in the randomized phase 3 trial of nivolumab versus everolimus. 
 


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Ref: Motzer RJ et al. N Engl J Med 2015;373:1803-1813 
 
 
Drug Interactions Please see the Investigator’s brochure and package insert for 
Nivolumab for information regarding drug interactions. 
 
 
Contraindications: Please see the Investigator’s brochure and package insert for 
Nivolumab for information regarding contraindications.  
 
 
Special Warnings and Precautions for Use: Please see the package insert(s) for 
nivolumab for information regarding special warnings and precautions for use. 
 
 
Storage and Stability: Nivolumab vials must be stored at a temperature of 2*C to 8*C 
and should be protected from light. If stored in a glass front refrigerator, vials should 
be stored in the carton. 
 
For details on prepared drug storage and use time of Nivolumab under room 
temperature/light and refrigeration, please refer to the Investigator Brochure section 
for “Recommended Storage and Use Conditions” and/or pharmacy reference sheets. 
Briefly, Withdraw the required volume and transfer into an IV container. Dilute with 
either NS or D5W to a final concentration of 1 to 10 mg/mL. Mix by gentle inversion; 
do not shake. 


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Care must be taken to assure sterility of the prepared solution as the product does 
not contain any anti-microbial preservative or bacteriostatic agent. No 
incompatibilities between Nivolumab and polyvinyl chloride (PVC), non-PVC/non-
DEHP (di(2-ethylhexyl)phthalate) IV components, or glass bottles have been 
observed. 
 
 
Administration:  Nivolumab is to be administered as a 60 (± 10 minute) intravenous 
infusion, using a volumetric pump with a 0.2 to 1.2 micron in-line filter at the protocol-
specified dose. It is not to be administered as an IV push or bolus injection. At the 
end of the infusion, flush the line with a sufficient quantity of 0.9% Sodium Chloride 
Injection or 5% Dextrose Injection. 
 
 
Handling and disposal of nivolumab should be per institutional guidelines for the 
handling and disposal of biologic and cytotoxic agents. Recommended safety 
measures for preparation and handling of Nivolumab include laboratory coats and 
gloves. 
 
 
Availability: Commercially available from Bristol Myers Squibb (BMS). Standard of 
care in metastatic renal cell carcinoma. 
.   
10.0 
CORRELATIVES/SPECIAL STUDIES 
The planned laboratory correlative studies are to profile the circulating T-cell subsets before and 
during therapy with IL2 and nivolumab.  
 
We will also archive patient tumor and serum samples for future unspecified testing including but 
not limited to PD-L1 and anti-drug antibody testing. Submission of samples for correlative studies 
is expected of all subjects. 
10.1 
Sample Collection Guidelines 
An archived tissue block must be identified (to submit unstained slides from) prior to 
registration.  Unstained slides from an archived formalin-fixed paraffin embedded tissue 
block are to be submitted for each subject from prior nephrectomy or biopsy of metastatic 
lesion (estimated tumor content >30% of nucleated cells in specimen). This tissue will be 
archived for future testing, including but not limited to PD-L1 expression and anti-drug 
antibody testing.  
 
Whole blood samples (20 mL at each time point) will be collected at the time points listed 
in Section 6.4 Time and Events Table. 
 
Serum samples (5-10 mL) will be collected at the time points listed in Section 6.4 Time 
and Events Table. 
  
 
ALL samples should be labeled with the subject’s de-identified study number and 
collection date. Samples should be overnighted via a courier service and delivered 
for analysis to:  
 
 
 
Lab of Weiping Zou, MD PhD 
Charles B de Nacrede Research Professor of Surgery and Professor of Surgery  
 
University of Michigan 
 
 
 
 
 


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Phone 
  
 
  
 
 
Email: 
 
 
***Specimen receiving times are limited to Monday to Friday 8am to 4pm. Specimens 
should not be shipped on a Friday or the day before a national holiday without prior 
permission*** 
 
 
 
10.2 
Assay Methodology 
 
Whole blood Flow Cytometry: 
PBMCs will be isolated from the whole blood sample by standard centrifugation. We will 
analyze the changes of different immune cell sub-population components before and 
during the course of treatment by FACS with flow cytometry analyzer. These include APC 
(Antigen Processing Cells) subsets, ILC and NK subsets and T cell subsets.  
 
The staining parameters are as follows: 
Staining 1 
APC subsets 
 
 
 
 
 
Staining 2 
ILC/NK subsets  
 
 
 
 
Staining 3 
T cells subsets - surface 
 
 
 
Staining 4 
T cells subsets - intracellular 
 
 
 
 
 
 
 
 
 
 
 
 
Staining 1 
CD45, CD11c, CD14, CD33, HLA-DR 
 
 
 
Staining 2 
CD45, CD3, CD123, CD127, NKp46, NKp44, CD56, CD161, CD94 
 
Staining 3 
CD3, CD4, CD8, CD45RO, CD45RA, PD-1, CD57, CD127, CXCR5, 
CXCR3 
Staining 4 
CD3, CD4, CD8, CD57, KLRG1, Tim3, Foxp3, Ki67 
 
Staining 5 
CD45, CD3, CD8, IFNγ, IL-17, GranB, TNFb, IL-2, IL-22, GM-CSF 
 
10.3 
Immunogenicity Analysis 
Immunogenicity assessment (ADA sampling [including ADA neutralizing antibodies] to 
identify ADA responses in patient circulation): 
 
Time-points: 
Samples for ADA (Anti-drug antibody) analysis will be collected at the time points listed in 
Section 6.4 Time and Events Table. 
 
Analysis: 
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of patients who develop detectable ADAs against nivolumab. 
 
The immunogenicity titer and presence of neutralizing ADAs will be reported for samples 
confirmed positive for the presence of ADAs. The effect of immunogenicity on efficacy, 
and safety will be evaluated, if the data allow. 
 
Method: 
The presence of ADAs will be assessed in serum samples taken according to the 
assessment schedules. At each time point, 20 mL of blood will be drawn for nivolumab 
ADAs and nivolumab neutralizing antibodies. 
 
Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for 
nivolumab using validated electrochemiluminescent (ECL) immunoassays. Tiered 


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analysis will be performed to include screening, confirmatory, and titer assay 
components, and positive-negative cut points previously statistically determined from 
drug naïve validation samples will be used. 
 
ADA samples, if not exhausted by analyses outlined herein, may be retained for 15 years 
from the patient’s last visit date for research purposes. 
 
ADA samples may be disposed of or destroyed and anonymized by pooling after planned 
analyses. 
 
Incurred sample reproducibility analysis, if any, will be performed alongside the 
bioanalysis of the test samples. The results from the evaluation will not be reported in the 
CSR but will be reported separately in a Bioanalytical Validation Report. 
10.4 
Specimen Banking 
Patient samples (tissue, blood, serum) collected for this study will be retained at the 
University of Michigan. De-identified specimens will be stored indefinitely or until they are 
used up. If consent for future use of specimens is withdrawn by the subject, best efforts 
will be made to stop any additional studies and to destroy the specimens. 
 
Specimens being stored long-term for potential use not outlined in the protocol are 
subject to University Policy Governing Tissue Sample Collection, Ownership, Usage, and 
Disposition within all UMMS Research Repositories 
[http://msa.med.umich.edu/policies/tissue-sample-collection-ownership-usage-
disposition-within-all-umms-research-biorepositories] 
 
11.0 
STATISTICAL CONSIDERATIONS 
This is a single arm phase Ib/II trial of Nivolumab and IL-2 in patients with Renal Cell 
Carcinoma. The phase Ib has an endpoint of safety and the phase II primary endpoint is 
overall response rate (ORR = CR or PR) at 12 weeks.  A recently reported trial of 
Nivolumab after 1 prior therapy in RCC reported had an ORR of 25%.  With the addition 
of IL-2 treatment to nivolumab, we hypothesize an ORR of approximately 46% in this 
population.   
11.1 
Study Design/Study Endpoints/Sample Size and Accrual 
For the phase 1b portion of the study: We will accrue an initial cohort of 3 patients who 
will be treated with sequential (rather than interspersed) treatment as follows: they will 
receive 2 cycles of HD-IL2 given in standard fashion (two 5-day cycles one week apart) 
followed by nivolumab starting the week after the second IL-2 cycle and continuing every 
4 weeks as per standard nivolumab dosing.   If 2 or more out of 3 of the first patients 
suffer a grade 3 or 4 immune related toxicity of interest (see 5.2.1) within 28 days from 
the first dose of nivolumab (DLT period) the study will stop. The 4th patient will not be 
enrolled until after the analysis of the 3 patient cohort is complete and submitted to the 
regulatory bodies. 
 
If <2 patients suffer a grade 3 or 4 immune related toxicity in the cohort of 3 patients, the 
study will enroll 7 more patients treated with Nivolumab administered intravenously at 
480 mg/dose over 60 minutes every 28 days, starting 1 to 3 weeks after the start date of 
the first cycle of IL2. We will monitor these patients continuously for immune mediated 
dose limiting toxicities for 28 days from the first dose of nivolumab (DLT period). Up to 
10 total patients will be treated and observed for toxicity for 28 days from the first dose of 
Nivolumab in the phase 1b portion. 
 


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If, at any time during accrual to the phase 1 b portion, 6 patients or more have a grade 3 
or 4 immune mediated event of interest (as described in section 5.2.1) we will pause the 
study and modify/discontinue the protocol in consultation with the site principal 
investigators and applicable regulatory authorities.  If 5 or fewer patients experience 
grade 3 or 4 immune mediated toxicity of interest (see 5.2.1) during the toxicity window, 
then the study will continue to the phase II portion. 
 
We choose to examine toxicity after 10 patients because if 6 patients or more are found 
to have a DLT then the 95% exact binomial confidence interval (26% - 88%) will be > 
25% and be indicative that immune mediated toxicity with this regimen is too great.   
 
Dose-Limiting Toxicity is defined as a grade 3 or 4 immune mediated event of interest (as 
listed and described in section 5.2.1). Please note: immune mediated events of interest 
do not include those that might occur during high dose IL-2 and are reversible.   
 
DLT evaluable patients:  All patients who receive at least 1 dose of HD IL2 and at least 1 
dose of Nivolumab will be evaluable for the primary endpoint of toxicity in the phase Ib 
portion of the trial. Subjects who are not evaluable will be replaced. 
 
The phase II portion of the trial will be a Simon mini-max 2-stage design.  The first stage 
will accrue 12 patients (including any response evaluable patients accrued in the phase 
1b portion). If more than 2 patients have a response (CR or PR) out of the 12 patients, 
then we will accrue 11 more patients for a total sample size of 23 evaluable patients. If 
more than 8 responses (CR or PR) are observed in the 23 evaluable patients, then we 
will recommend further study of the combination.  This design has 80% power and 10% 
type I error. If the true ORR of the combined treatment is 25% or less, the probability of 
early termination of the trial is 39%.  If the true ORR is 46% or greater, then the 
probability of stopping early is only 3.6%.  Patients accrued in the Phase Ib portion of the 
trial will also be included in the Phase II if they are evaluable as defined below. 
 
Response Evaluable Patients:  All patients who receive at least 1 dose of Nivolumab and 
IL-2 will be evaluable for the primary endpoint of overall response proportion in the phase 
II portion of the trial. If response at 12 weeks is not recorded for the patient, then the 
patient will be considered a non-responder. 
 
We expect accrual to the entire study to be completed over a period of 24 months. 
11.2 
Data Analyses Plans 
Primary Endpoint Analysis:   
Phase 1b: DLT count and proportion will be reported.  Type, grade and attribution will be 
described by body system in the first 10 DLT evaluable patients.  Number of IL-2 cycles 
and doses and Nivolumab doses will be summarized. 
 
Phase II:  Overall response rate at 12 weeks will be reported with the sample size and 
proportion of evaluable patients and the corresponding 95% exact binomial confidence 
interval. 
 
Secondary Endpoint Analyses:   
 
 
Safety will be defined by frequency of drug-related grade 3-5 adverse events including 
adverse events of interest within the duration of protocol, specified therapy and an 
additional 60 days following the last dose with the combination of HD IL2 and nivolumab, 
as assessed by NCI’s CTCAE version 4.0.  Counts and frequencies will be reported by 
body system, type and grade.  Cycles and of each drug and doses/cycle of IL-2 will be 
described using descriptive statistics. 
 


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Survival endpoints are 24-month Overall Survival (OS) and 24-month Progression-Free 
Survival (PFS) as assessed by RECIST 1.1 criteria in subjects treated with the 
combination.  Product-limit estimates from Kaplan-Meier methods will be used to report 
the 24-month OS and PFS proportions with 95% confidence intervals.  Kaplan-Meier 
figures will be produced. 
 
 
Interim Analysis for efficacy:  An interim analysis for efficacy is planned after 12 response 
evaluable patients have been enrolled (total in the phase I b/II portions).  If 2 or less 
patients have a response at 12 weeks then the trial will terminate. . 
 
Analyses for correlative endpoints 
 
Flow Cytometry to profile circulating T cell repertoire including Tregs 
(CD4+/CD25+/FoxP3+) will be described graphically for pre-therapy and post-therapy. 
 
All study information should be recorded in an appropriate source document (e.g. clinic 
chart).  
 
Immunogenicity Analysis: 
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of patients who develop detectable ADAs against nivolumab. 
 
The immunogenicity titer and presence of neutralizing ADAs will be reported for samples 
confirmed positive for the presence of ADAs. The effect of immunogenicity on efficacy, 
and safety will be evaluated, if the data allow. 
 
12.0 
DATA AND SAFETY MONITORING 
 
The Data and Safety Monitoring Committee (DSMC) of The University of Michigan Rogel 
Cancer Center is the DSMC for this study. This committee is responsible for monitoring the 
safety and data integrity of the trial. The committee will meet monthly (during the phase Ib 
portion) or quarterly (during the phase II portion). 
 
 
Until the phase Ib portion is completed i.e. the first 10 patients have been treated and 
monitored for 28 days from the first dose of nivolumab, a biweekly phone call/webinar 
involving site Principal Investigators/Sub-investigator(s) from each site and relevant 
research staff at each site will be conducted to exchange information about 
toxicity/safety, subject clinical course and discern trends if any. The site investigators 
are highly experienced in the administration of HD IL2 and also, with nivolumab 
therapy. 
 
 
At each site the study team is required to meet monthly (during the phase Ib portion) or 
quarterly (during the phase II portion) to discuss matters related to: 
 
o 
>Enrollment rate relative to expectations, characteristics of participants 
o 
>Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
o 
>Adherence to protocol (protocol deviations) 
o 
>Completeness, validity and integrity of study data 
o 
>Retention of study participants 
 
 
These meetings are to be documented by the site data manager or study coordinator using 
the Protocol Specific Data and Safety Monitoring Report (DSMR), signed by the site principal 
investigator or co-investigator.  Each site is required to submit the completed DSMR to the 
Multi-Site Coordinator at the University of Michigan Coordinating Center on a monthly (during 


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the phase Ib portion) or quarterly (during the phase II portion) basis together with other 
pertinent documents. 
 
 
Similarly, protocol deviations are to be documented using the Coordinating Center Deviation 
specified form and requires the signatures of both the sites data manager or study 
coordinator and the site principal investigator or co-investigator. These reports are to be sent 
to the University of Michigan Coordinating Center within 7 calendar days of awareness of the 
event and on a monthly (during the phase Ib portion) or quarterly (during the phase II portion) 
basis with the Protocol Specific Data and Safety Monitoring Report. 
 
 
The Coordinating Center is responsible for collating all the Data and Safety Monitoring 
Reports from all the participating sites, and providing the information to the Data and Safety 
Monitoring Committee. 
 
13.0 
QUALITY ASSURANCE AND AUDITS 
The Data and Safety Monitoring Committee can request a ‘for cause’ audit of the trial if the 
committee identifies a need for a more rigorous evaluation of study-related issues.  
 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its 
conduct or even after its completion. If an inspection has been requested by a regulatory 
authority, the site investigator must immediately inform the Coordinating Center that such a 
request has been made. 
14.0 
CLINICAL MONITORING PROCEDURES 
Clinical studies coordinated by The University of Michigan Rogel Cancer Center must be 
conducted in accordance with the ethical principles that are consistent with Good Clinical 
Practices (GCP) and in compliance with other applicable regulatory requirements. 
 
This study will be monitored by a representative of the Coordinating Center. Monitoring visits will 
be made during the conduct of the study and at study close-out. 
 
Prior to subject recruitment, a participating site will undergo site initiation meeting to be conducted 
by the Coordinating Center. This will be done as an actual site visit; teleconference, 
videoconference, or web-based meeting after the site’s IRB approval and fully executed 
subcontract has been received by the Multi-Site Coordinator.  The site’s principal investigator and 
his study staff should make every effort in attending the site initiation meeting. Study–related 
questions or issues identified during the site initiation meeting will be followed-up by the 
appropriate Coordinating Center personnel until they have been answered and resolved. 
 
Monitoring of this study will include both ‘Centralized Monitoring’, the review of source documents 
at the Coordinating Center and ‘On-site Monitoring’, an actual site visit.  The first ‘Centralized’ 
visit should occur after the first subject enrolled completes first HD IL2 course (consisting of both 
weeks of IL2). The study site will send the de-identified source documents to the Coordinating 
Center for monitoring.  ‘Centralized’ monitoring may be requested by the Coordinating Center if 
an amendment requires changes to the protocol procedures. The site will send in pertinent de-
identified source documents, as defined by the Coordinating Center for monitoring.  
 
The first annual ‘On-site’ monitoring visit should occur after the first five study participants are 
enrolled or twelve months after a study opens, whichever occurs first.  The annual visit may be 
conducted as a ‘Centralized’ visit if less than three subjects have enrolled at the study site.  The 
type of visit is at the discretion of the Coordinating Center.  At a minimum, a routine monitoring 
visit will be done at least once a year, or once during the course of the study if the study duration 
is less than 12 months. The purpose of these visits is to verify: 
 


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 Adherence to the protocol 
 Completeness and accuracy of study data and samples collected 
 Proper storage, dispensing and inventory of study medication 
 Compliance with regulations 
 
During a monitoring visit to a site, access to relevant hospital and clinical records must be given 
by the site investigator to the Coordinating Center representative conducting the monitoring visit 
to verify consistency of data collected on the CRFs with the original source data.  While most 
patient cases will be selected from patients accrued since the previous monitoring visit, any 
patient case has the potential for review.  At least one or more unannounced cases will be 
reviewed, if the total accruals warrant selection of unannounced cases.  
 
The Coordinating Center expects the relevant investigational staff to be available to facilitate the 
conduct of the visit, that source documents are available at the time of the visit, and that a 
suitable environment will be provided for review of study-related documents. Any issues identified 
during these visits will be communicated to the site and are expected to be resolved by the site in 
a timely manner.  For review of study-related documents at the Coordinating Center, the site will 
be required to ship or fax documents to be reviewed.   
 
Participating site will also undergo a site close-out upon completion, termination or cancellation of 
a study to ensure fulfillment of study obligations during the conduct of the study, and that the site 
Investigator is aware of his/her ongoing responsibilities. In general, a site close-out is conducted 
during a site visit; however, site close-out can occur without a site visit.  
15.0 
DATA MANAGEMENT 
All information will be recorded locally and entered into Case Report Forms (CRFs) on the web-
based data management system of the University of Michigan. Online access will be provided to 
each site by the Coordinating Center.  
 
CRFs will be reviewed and source verified by the MSC during annual monitoring visits and prior 
to and between visits. Discrepant, unusual and incomplete data will be queried by the MSC. The 
investigator or study coordinator will be responsible for providing resolutions to the data queries, 
as appropriate. The investigator must ensure that all data queries are dealt with promptly.  
 
The data submission schedule is as follows:  
 
At the time of registration   
o 
Subject entry into the database 
 
Subject Status 
 
Demographics 
 
During study participation 
o 
All data should be entered online within 10 business days of data acquisition. 
Information on Serious Adverse Events must be entered within the reporting 
timeframe specified in Section 8.5 of the protocol.  
  
Long term data will be collected periodically either by chart review or by contacting the patients. 
 
All study information should be recorded in an appropriate source document (e.g. clinic chart). 
 
16.0 
REFERENCES 
 
 
 
1. 
Malek TR, Bayer AL: Tolerance, not immunity, crucially depends on IL-2. Nat 
Rev Immunol 4:665-74, 2004 


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2. 
Rosenberg SA, Mule JJ, Spiess PJ, et al: Regression of established pulmonary 
metastases and subcutaneous tumor mediated by the systemic administration of high-dose 
recombinant interleukin 2. J Exp Med 161:1169-88, 1985 
 
3. 
Cousens LP, Orange JS, Biron CA: Endogenous IL-2 contributes to T cell 
expansion and IFN-gamma production during lymphocytic choriomeningitis virus infection. J 
Immunol 155:5690-9, 1995 
 
4. 
Su HC, Cousens LP, Fast LD, et al: CD4+ and CD8+ T cell interactions in IFN-
gamma and IL-4 responses to viral infections: requirements for IL-2. J Immunol 160:5007-17, 
1998 
 
5. 
Blattman JN, Grayson JM, Wherry EJ, et al: Therapeutic use of IL-2 to enhance 
antiviral T-cell responses in vivo. Nat Med 9:540-7, 2003 
 
6. 
D'Souza WN, Schluns KS, Masopust D, et al: Essential role for IL-2 in the 
regulation of antiviral extralymphoid CD8 T cell responses. J Immunol 168:5566-72, 2002 
 
7. 
Suzuki H, Duncan GS, Takimoto H, et al: Abnormal development of intestinal 
intraepithelial lymphocytes and peripheral natural killer cells in mice lacking the IL-2 receptor 
beta chain. J Exp Med 185:499-505, 1997 
 
8. 
McDermott DF, Regan MM, Clark JI, et al: Randomized phase III trial of high-
dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic 
renal cell carcinoma. J Clin Oncol 23:133-41, 2005 
 
9. 
Klapper JA, Downey SG, Smith FO, et al: High-dose interleukin-2 for the 
treatment of metastatic renal cell carcinoma : a retrospective analysis of response and survival in 
patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. 
Cancer 113:293-301, 2008 
 
10. 
Yang JC, Sherry RM, Steinberg SM, et al: Randomized study of high-dose and 
low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 21:3127-32, 2003 
 
11. 
Belldegrun AS, Klatte T, Shuch B, et al: Cancer-specific survival outcomes 
among patients treated during the cytokine era of kidney cancer (1989-2005): a benchmark for 
emerging targeted cancer therapies. Cancer 113:2457-63, 2008 
 
12. 
Fyfe G, Fisher RI, Rosenberg SA, et al: Results of treatment of 255 patients with 
metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin 
Oncol 13:688-96, 1995 
 
13. 
McDermott DF, Cheng SC, Signoretti S, et al: The high-dose aldesleukin "select" 
trial: a trial to prospectively validate predictive models of response to treatment in patients with 
metastatic renal cell carcinoma. Clin Cancer Res 21:561-8, 2015 
 
14. 
Gajewski TF, Fuertes M, Spaapen R, et al: Molecular profiling to identify 
relevant immune resistance mechanisms in the tumor microenvironment. Curr Opin Immunol 
23:286-92, 2011 
 
15. 
Chen DS, Mellman I: Oncology meets immunology: the cancer-immunity cycle. 
Immunity 39:1-10, 2013 
 
16. 
Brahmer JR, Tykodi SS, Chow LQ, et al: Safety and activity of anti-PD-L1 
antibody in patients with advanced cancer. N Engl J Med 366:2455-65, 2012 
 
17. 
Hamid O, Robert C, Daud A, et al: Safety and tumor responses with 
lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369:134-44, 2013 
 
18. 
Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates 
of anti-PD-1 antibody in cancer. N Engl J Med 366:2443-54, 2012 


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19. 
Thompson RH, Kuntz SM, Leibovich BC, et al: Tumor B7-H1 is associated with 
poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res 66:3381-5, 
2006 
 
20. 
Thompson RH, Gillett MD, Cheville JC, et al: Costimulatory B7-H1 in renal cell 
carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl 
Acad Sci U S A 101:17174-9, 2004 
 
21. 
Motzer RJ, Escudier B, McDermott DF, et al: Nivolumab versus Everolimus in 
Advanced Renal-Cell Carcinoma. N Engl J Med 373:1803-13, 2015 
 
22. 
Taube JM, Anders RA, Young GD, et al: Colocalization of inflammatory 
response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance 
mechanism of immune escape. Sci Transl Med 4:127ra37, 2012 
 
23. 
Schwartzentruber DJ: Guidelines for the safe administration of high-dose 
interleukin-2. J Immunother 24:287-93, 2001 
 
 
 
 
17.0 
APPENDICES 
Appendix A. ECOG Performance Status and Karnofksy Performance Scale 
 
Additional documents not included in the protocol: 
 
Laboratory Manual 
 
IL2 guidance document 
 
 
 


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Appendix A. ECOG Performance Status and Karnofksy Performance Scale 
 
ECOG Performance Status developed by the Eastern Cooperative Oncology Group, Robert L. 
Comis, MD, Group Chair.* 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair 
5 
Dead 
 
 
Percent 
Karnofsky Performance Scale 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
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. 
60 
Requires occasional assistance, but is able to care for most of his/her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated.  Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead.