Phase II Trial of Avelumab (Bavencio) With IL-15 in Subjects With Clear-Cell Renal Carcinoma
Phase: PHASE2
Conditions: Clear-Cell Renal Carcinoma
Sponsor: National Cancer Institute (NCI)

Abbreviated Title:IL-15+Avelumab in ccRCC
Version Date: 06/02/2021
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Abbreviated Title: IL-15 + Avelumab in ccRCC 
NIH Protocol #:   20C0007
CTEP Protocol #: 10284
Version Date: 06/02/2021 
NCT Number: NCT04150562
Phase II Trial of Avelumab (Bavencio®) with IL-15 in Subjects with Clear-Cell Renal 
Carcinoma
NCI Principal Investigator: Kevin Conlon, M.D., MS A-F 
Lymphoid Malignancies Branch (LYMB)
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
Building 10, Room 3B38
National Institutes of Health (NIH)
Bethesda, MD  20892
Phone:  240-541-4559
Email:  conlonkc@mail.nih.gov 
Investigational Agents:    
Drug Name:
Avelumab
(MSB0010718C, Bavencio®, 
NSC #799232)
Recombinant human IL-15 (rhIL-
15-NSC #745101)
IND Number:
100820
Sponsor:
Center for Cancer Research, NCI
Manufacturer:
EMD Serono, Inc.
(Company Study/Tracking #: 
MS100070-0207)
Biopharmaceutical Development 
Program (BDP)/Leidos 
Biomedical Research, Inc. under 
contract with DCTD,NCI
Supplier:
EMD Serono, Inc.
Cancer Therapy Evaluation 
Program (CTEP), Division of 
Cancer Treatment and Diagnosis 
(DCTD), NCI
Commercial Agents:  None

Abbreviated Title:IL-15+Avelumab in ccRCC
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PRÉCIS
Background:

Clear-cell renal cell carcinoma (ccRCC) is among the 10 most frequent diagnostic cancers 
in the United States with more than an estimated 62,000 new cases in 2016. The prognosis 
for patients with metastatic disease is poor with survival rates of 8%.

The immunologic effects of recombinant human Interleukin-15 (rhIL-15), a stimulatory 
cytokine that promotes the differentiation and activation of NK cells, monocytes and long-
term CD8+ memory T-cells, has been assessed in several Phase 1 trials in cancer patients.

Avelumab is an anti-programmed death ligand-1 (PD-L1) fully human IgG1 antibody that 
inhibits PD1/PD-L1 interactions while leaving the PD1/PD-L2 pathway intact and 
enhances immune activation against tumor cells. It has received U.S. FDA accelerated 
approval for the treatment of patients with metastatic Merkel cell carcinoma (MCC) and 
urothelial carcinoma. 

Unlike other approved anti-PD-L1/PD1 antibodies, avelumab induces lysis of tumor cells 
via antibody-dependent cell-mediated cytotoxicity (ADCC), indicating an additional 
mechanism of action. However, avelumab has not shown ADCC against normal immune 
cell subsets in humans.

More than 50% of ccRCC is PD-L1+ with higher expression in unfavorable prognostic 
tumors. Since the anti-PD-L1 antibody avelumab has shown ADCC activity in vitro, agents 
that may enhance ADCC by increasing number and activity of Fc-binding effector cells — 
such as rhIL15 — could improve efficacy of avelumab in this disease.  
Objectives:

Determine the efficacy of combined continuous intravenous infusion (CIV) rhIL-15 and 
avelumab treatment in patients with anti-PD-1/PD-L1 refractory metastatic clear cell renal 
carcinoma (ccRCC) by assessing the overall response rate
Eligibility:

Age ≥ 18 years of age

ECOG performance status of ≤ 1  

Histologically proven metastatic clear cell renal carcinoma with ≥ 5% expression of PD-
L1 in the tumor area confirmed by IHC

Patients must have failed or relapsed and have progressive disease after at least 2 prior 
therapies that include multityrosine kinase inhibitor like axitinib or sunitinib and an anti-
PD1 or PD-L1 immune checkpoint inhibitor therapy like nivolumab which could have been  
administered in combination with an anti-CTLA4 agent like ipilimumab 

Adequate organ and marrow function 
Design:

Open-label, single-center, non-randomized Phase II study

Abbreviated Title:IL-15+Avelumab in ccRCC
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
Safety Run-in Cohort with 3-6 patients at dose level 2mcg/kg and 4mcg/kg CIV IL-15 
(recommended phase II dose) will ensure safety of recommended phase II dose rhIL-15 
with fixed dose avelumab with Dose Expansion Cohort at 4mcg/kg dose level

Efficacy of the combination will be assessed in a Simon two-stage phase II design with 9 
or 17 patients depending on demonstration of clinical activity in the initial group of 9 
patients

Maximum 4 cycles (28-day cycle) of combination therapy 

To explore both Safety Run-in Cohort and further evaluation in a Dose Expansion 
Cohort, the accrual ceiling will be set at 25 patients 

Abbreviated Title:IL-15+Avelumab in ccRCC
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TABLE OF CONTENTS 
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE ................................................................................................7
1
INTRODUCTION ...................................................................................................................8
1.1
Study Objectives............................................................................................................8
1.2
Background and Rationale ............................................................................................8
1.3
Considerations and Rationale for Phase II Design......................................................19
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................21
2.1
Eligibility Criteria........................................................................................................21
2.2
Strategies for Recruitment and Retention ...................................................................24
2.3
Screening Evaluation...................................................................................................24
2.4
Participant Registration and Status Update Procedures ..............................................26
2.5
Baseline Evaluation.....................................................................................................27
3
STUDY IMPLEMENTATION .............................................................................................28
3.1
Study Design ...............................................................................................................28
3.2
Drug Administration....................................................................................................31
3.3
Dose Modifications .....................................................................................................33
3.4
Study Intervention Compliance...................................................................................41
3.5
On Study Evaluations..................................................................................................42
3.6
Post-Treatment Evaluations ........................................................................................42
3.7
Study Calendar ............................................................................................................43
3.8
Cost And Compensation..............................................................................................43
3.9
Criteria for Removal from Protocol Therapy and Off Study Criteria .........................44
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................45
4.1
Acceptable Medications ..............................................................................................45
4.2
Prohibited Medications................................................................................................45
5
CORRELATIVE STUDIES ..................................................................................................45
5.1
Summary .....................................................................................................................45
5.2
Sample Collection and Processing ..............................................................................46
5.3
Biomarker and Research Methods ..............................................................................49
5.4
Sample Storage, Tracking, and Disposition ................................................................50

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6
DATA COLLECTION AND EVALUATION .....................................................................52
6.1
Data Collection............................................................................................................52
6.2
Data Sharing Plans ......................................................................................................53
6.3
Response Criteria ........................................................................................................54
6.4
Immune-related Response Criteria (irRECIST)..........................................................59
6.5
Toxicity Criteria ..........................................................................................................60
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN.....60
7.1
Definitions...................................................................................................................60
7.2
OHSRP Office of Compliance and Training...............................................................60
7.3
NIH Required Data and Safety Monitoring Plan ........................................................60
8
SPONSOR SAFETY REPORTING......................................................................................61
8.1
Definitions...................................................................................................................61
8.2
Assessment of Safety Events.......................................................................................62
8.3
Reporting of Serious Adverse Events .........................................................................62
8.4
Waiver of expedited reporting to CCR........................................................................63
8.5
Safety Reporting to the Pharmaceutical Collaborators ...............................................63
8.6
Reporting Pregnancy ...................................................................................................63
8.7
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND ...............64
9
CLINICAL MONITORING..................................................................................................64
10
STATISTICAL CONSIDERATIONS ..................................................................................64
10.1
Statistical Hypotheses..................................................................................................64
10.2
Sample size determination...........................................................................................65
10.3
Population for Analyses ..............................................................................................66
10.4
Statistical Analyses......................................................................................................66
11
COLLABORATIVE AGREEMENTS..................................................................................67
11.1
Cooperative Research and Development Agreement (CRADA) - EMD Serono .......67
12
HUMAN SUBJECTS PROTECTIONS................................................................................67
12.1
Rationale For Subject Selection ..................................................................................67
12.2
Participation of Children .............................................................................................67
12.3
Risk/Benefit Assessment.............................................................................................67
12.4
Consent Process and Documentation ..........................................................................68
13
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................69

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13.1
Study Discontinuation and Closure.............................................................................69
13.2
Quality Assurance and Quality Control ......................................................................69
13.3
Conflict of Interest Policy ...........................................................................................69
13.4
Confidentiality and Privacy.........................................................................................70
14
PHARMACEUTICAL INFORMATION .............................................................................70
14.1
rhIL-15 (NSC #745101) IND# 100820.......................................................................70
14.2
Avelumab IND#100820 (NSC #799232)....................................................................75
15
REFERENCES .....................................................................................................................83
16
APPENDICES .......................................................................................................................92
16.1
APPENDIX A: Performance Status Criteria...............................................................92
16.2
APPENDIX B: Assay for ADCC................................................................................93
16.3
APPENDIX C: IL-15 Dilution Instructions ................................................................94
16.4
APPENDIX D: Assay For Antibodies To rhIL-15 .....................................................96
16.5
APPENDIX E: Modified Immune-Related Response Criteria (irRECIST) ...............97
16.6
APPENDIX F: Study Calendar ...................................................................................98

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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.

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1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective

Determine the efficacy of combined continuous intravenous infusion (CIV) rhIL-15 and 
avelumab treatment in patients with anti-PD-1/PD-L1 refractory metastatic clear cell renal 
carcinoma (ccRCC) by assessing the overall response rate.  
1.1.2
Secondary Objectives

Evaluate duration of response, progression-free survival and overall survival following 
combined CIV IL-15 and avelumab treatment

Assess the safety and tolerability of combined CIV IL-15 and avelumab treatment 

Analyze the changes in peripheral blood lymphocyte subsets before and after treatment 
with rhIL-15 and avelumab

Define the effects of rhIL-15 on the antibody-dependent cell-mediated cytotoxicity 
(ADCC) mediated by avelumab, using ex-vivo peripheral blood mononuclear cells 
(PBMCs)

Examine treatment related changes in tumor deposits by immunohistochemical and 
molecular analysis of core biopsies obtained before and during treatment with rhIL-15 and 
avelumab 
1.2
BACKGROUND AND RATIONALE
1.2.1
Disease Characteristics of Clear-cell Renal Carcinoma
Clear-cell renal cell carcinoma (ccRCC) is among the 10 most frequent diagnostic cancers in the 
United States with more than an estimated 62,000 new cases in 2016 [1, 2].  The prognosis for 
patients with metastatic disease is poor with survival rates of 8% [3, 4]. ccRCC is associated with 
mutations of VHL, an essential component of the cellular oxygen pathway. VHL, located on 
chromosome 3p, is inactivated by a mutation in 52% of ccRCC [5]. Several other genes show 
mutations at lower frequencies than VHLs. These genes include PBRM1 (40%), SETD2 (15%) 
and BAP1 (15%) which are all part of the chromatin remodeling histone methylation pathway [6].  
Like VHL, these three genes are located within a 50-Mb region on the short arm of chromosome 
3p.
1.2.2
Systemic Treatment of ccRCC
In the past 10 years treatment options for metastatic kidney cancer have expanded and improved 
substantially. Interferon alpha (IFNα) has been replaced by antiangiogenics, tyrosine kinase 
inhibitors, molecular therapeutics, new cytokines and recently immune checkpoint inhibitors 
(ICIs) with higher response rates (RRs), longer progression free survival and overall survival [7]. 
Other drugs used to treat ccRCC include antiangiogenic drugs, that target vascular endothelial 
growth factor (VEGF), VEGF receptors or platelet derived growth factor (PDGF) and include 
bevacizumab, axitinib, pazopanib, sorafenib, sunitinib, Cabozantinib and lenvatinib. The 
molecular target of rapamycin (mTOR) inhibitors utilized in the treatment of ccRCC are 
everolimus and temsirolimus [8-20]. High-dose IL-2 (HDIL-2) therapy, with a durable complete 
response rate (CR) of 9% and recognized partial response rate (PR) of 12%, remains a less 
commonly employed treatment largely due to the fact that this treatment is only appropriate for a 

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minority of very fit patients who are able to safely tolerate this intense regimen. Retrospective 
analysis of outcome for this treatment has more precisely defined the patient profile with higher 
likelihood of responding rates but has not identified strategies to expand the number of treatable 
patients or demonstrated more stringent patient selection has substantial impact on RR or survival 
in a prospective clinical trial [21-24]. Preclinical animal experiments identified Programmed cell 
death protein 1 (PD1) expression on CD8+ effector cells as a sign of exhaustion of the viral specific 
immune responses. The expression of Program death ligand (PD-L1) on tumor cells, sometimes 
on adjacent stroma cells or other leukocytes in the tumor milieu was also shown to deliver an 
immune dampening signal through PD-1 on effector lymphocytes. The combination of these 2 
findings established the rationale for anti-PD1/PD-L1 treatment of metastatic cancers [25, 26]. 
Interestingly the preclinical animal data did not demonstrate the striking benefit that has 
subsequently been seen in the treatment of cancer patients [27, 28]. The initial reports of single 
agent clinical trials with nivolumab demonstrated response rates in the 20 to 35% range for 
metastatic melanoma or renal cell carcinoma and 15 to 20% range for patients with relapsed 
refractory non-small cell lung cancer (NSCLC) [27, 29, 30]. Subsequent publications have 
demonstrated clinical activity for pembrolizumab, atezolizumab, durvalumab and avelumab 
(Bavencio) and other anti-PD1/PD-L1 agents in patients with (transitional cell) bladder cancer, 
Hodgkin’s lymphoma (HL), non-Hodgkin’s follicular lymphoma (FL) and squamous cell head and 
neck cancer (SCCH&N) [31-33]. The combination of nivolumab plus ipilimumab, an anticytotoxic 
lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitor, has been shown to be more 
effective than nivolumab alone in several solid tumors including metastatic renal cell carcinoma 
(mRCC), albeit at the cost of significantly more toxicity [28].
1.2.3
Expression of PD-L1 in Renal Cell Carcinoma
There is a wide range of reported levels of PD-L1 positivity (PD-L1+) depending on the particular 
PD-L1 antibody used in the immunohistochemical analysis, the histologic subtype of the RCC and 
whether assessment is scored only for the malignant cells or includes stromal and infiltrating 
immune effector cells. Conservative estimates for PD-L1 expression are usually based on data 
obtained from nephrectomy specimens most often reporting that 20% of mRCC are PD-L1+ [34].  
Closer appraisal of PD-L1 expression in ccRCC revealed that PD-L1 positivity was associated 
with female gender, lymph node metastases, distant metastases, higher AJCC stage and advanced 
stage. Most importantly, the poorer prognostic tumors were more likely to express PD-L1 [35]. In 
a review of 177 patients more than half of the pathologically stage 3 or 4 (pT3/4) and more than 
75% of the G2 tumors were PD-L1+. In an analysis of 85 ccRCC patients who received high dose 
IL-2, 58% of tumors were PD-L1+ [36]. Another retrospective analysis of 115 surgical specimens 
similarly 56.5% of the patients’ tumors were PD-L1+ [37].  A higher percentage of tumors from 
patients with sarcomatoid variant mRCC are reported to be PD-L1+ [38].
1.2.4
Immune Checkpoint Inhibitor Treatment in Renal Cell Carcinoma
When the initial clinical data for MDX-1106, now nivolumab were first reported, it was clear that 
this agent had significant activity in mRCC [27]. Confirming what had been intimated in the first-
in-human phase I trial for multiple tumor types, the subsequent report for 296 nivolumab patients 
showed a response rate (RRs) of 27% (9/33) in the cohort of renal cell patients [30]. The issue of 
the appropriate dose for nivolumab in the treatment of mRCC was largely settled in a randomized 
phase II trial that assessed 3 dose levels (0.3, 2 and 10 mg/kg) which demonstrated almost identical 
RRs of 20, 22 and 20% respectively for the 3 dose levels [39]. A subsequent comparative trial of 
nivolumab versus everolimus demonstrated a similar level of nivolumab activity with a RR of 25% 

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[40]. The Nivolumab Ipilimumab combination was tested in the CheckMate trials 016 and 214 and 
showed appreciable activity (40.4 and 42% RRs) albeit with a significantly higher rate of adverse 
events (AEs) [28]. As a result of these clinical trials, nivolumab either as monotherapy or in 
combination with ipilimumab for higher risk patients is now FDA approved for the treatment of 
mRCC. 
Based on the generally positive results with anti-PD-L1/PD1 treatments including the nivolumab 
data, many commercial sponsors have developed agents targeting the PD-L1/PD1 axis that also 
have shown efficacy in mRCC. A phase I trial of atezolizumab in mRCC that included some 
patients with non-clear cell histology tumors showed an overall RR of 15% and a median 
progression free survival (PFS) of 5.6 months [41]. Most of the PD-1 and PD-L1 agents have now 
established effective fixed dosage schedules that eliminates the need for weight-based dose 
adjustments for individual patients and simplified treatment delivery [42]. There is additional 
clinical data for combination treatment with anti-PD-L1/PD1 agents and other biological response 
modifiers (BRMs)or targeted therapies that shows clinical activity in the treatment of mRCC. A 
phase I trial of pembrolizumab with the 4-1BB/CD137 agonist antibody PF-05082556) showed 
1CR, 1 PR and 2 stable disease (SD) in 4 of the 5 mRCC patients treated in the trial [43]. The 
positive results from a phase 1b trial of Avelumab plus Axitinib [44] showed impressive activity 
in post nephrectomy treatment naïve mRCC with an overall response rate of 58% (32 of 55 
patients) was validated by the recent results of the large (886 patients) randomized phase III Javelin 
101 that compared this combination treatment to sunitinib in advanced previously untreated RCC 
patients and led to FDA approval of this combination as first line treatment for mRCC. The 
Avelumab plus Axitinib treatment produced a significantly better objective response rate (ORR) 
51.4% versus 25.7% (p< 0.001) and progression free survival (PFS) 13.8 versus 8.4 months 
(p=0.0001) in all patients [45]. It is too early to analyze differences in overall survival for the 2 
treatment arms. Treatment related AEs for patients receiving the Avelumab plus Axitinib 
combination in both  trials were similar and substantial with 71% of the patients having > grade 3 
AE and discontinuation of treatment of study treatment in 22.8%, but the rate of these events were 
comparable to the Sunitinib patients (71.5% rate of > grade 3 AEs and 13.4% discontinued 
treatment). Deaths due to treatment related toxicities in the phase III were almost identical (0.7% 
versus 0.2%). Additional clinical trials examining combination regimens with Nivolumab, 
Pembrolizumab, Atezolizumab, Durvalumab and Avelumab in multiple malignancies are currently 
ongoing [46, 47]. 
1.2.5
Avelumab (Bavencio)
When overexpressed in tumors, PD-L1 is a negative prognostic marker due to T-cell anergy 
induced by the binding of PD-L1 to PD1 [31, 33]. Avelumab (Bavencio) is a fully human IgG1 
antibody directed against programmed death ligand-1 (PD-L1) protein. Avelumab inhibits 
PD1/PD-L1 interactions while leaving the PD1/PD-L2 pathway intact, enhances immune 
activation against tumor cells and has been evaluated in the treatment of multiple refractory solid 
tumor patients [31-33, 48-51]. Avelumab (Bavencio) has received accelerated approval in the 
United States from the FDA for the treatment of patients with metastatic Merkel cell carcinoma 
(MCC) [52] and urothelial carcinoma [49].  Unlike other approved anti-PD-L1/PD1 antibodies, 
avelumab has an additional potential mechanism of action that induces lysis of tumor cells in vitro 
via antibody-dependent cell-mediated cytotoxicity (ADCC) that has yet to be confirmed in vivo in 
patients with normal immune T-cell subsets [53] but has been demonstrated by in vitro testing 
[54]. The standard avelumab treatment regimen is 10 mcg/kg given every 2 weeks. The drug is 

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well tolerated by patients and has a toxicity spectrum similar to other anti-PD-1 or PD-L1 
treatments summarized below in Table 1 and Table 2 with most notable AEs being fatigue, 
infusion reactions, followed by skin changes and GI toxicity [54-56].
1.2.6
 Adverse Events in Avelumab Clinical Trials
The safety experience in phase I Javelin Solid Tumor protocol (1650 patients) and phase 2 Javelin 
Merkel 200 clinical trial (88 patients) was recently updated [57]. The most common treatment 
related adverse events (TRAEs) of any grade were fatigue in 307 patients (17.7%) and infusion 
related reactions (IRR) in 295 patients (17.0%). Table 1 from this report shown below lists the 
most common clinical and laboratory TRAEs. These therapy related events led to permanent 
discontinuation of treatment in 107 patients (6.2%). The most common cause of treatment 
discontinuation was immune related events (IRR) seen in 32 patients (1.8%), gamma-glutamyl 
transferase increase seen in 7 patients (0.4%), increased alanine aminotransferase in 4 patients 
0.2%), increased creatine phosphokinase (CPK) in 4 patients (0.2%), and fatigue in 4 patients 
(0.2%). One hundred and eight patients (6.2%) had serious TRAEs again most commonly immune 
related (15 patients; 0.9%), pneumonitis (11 patients; 0.6%), pyrexia (6 patients; 0.3%), and 
adrenal insufficiency (5 patients; 0.3%). Table 2 below lists the Immune Related Adverse Events 
(irAE assessed by the CTC version 4.0 grading criteria) which were seen in a small number of 
patients and generally were grade 3 AEs
Table 1: Avelumab Most Common TRAEs 
Most Common Adverse Treatment Related Events N= 1738
TRAE
Any Grade No (%)
> Grade 3 No (%)
Any TRAE
1164 (67.0)
177 (10.2)
Fatigue
307 (17.7)
17 (1.0)
IRRb
295 (17.0)
10 (0.6)
Nausea
150 (8.6)
2 (0.1)
Diarrhea
123 (7.1)
5 (0.3)
Chills
116 (6.7)
0
Pyrexia
106 (6.1)
0
Decreased appetite
90 (5.2)
3 (0.2)
Hypothyroidism
87 (5.0)
3 (0.2)
AST increased
38 (2.2)
8 (0.5)
Lipase increased
25 (1.4)
17 (1.0)
GGT increased
17 (1.0)
10 (0.6)
Table 2: Immune-Related Adverse Events
Immune Related Adverse Events (irAEs)
N = 1738     No. (%)
irAEa
Any Grade
Grade 3
Grade 4
Grade 5
Any irAE
247 (14.2)
32 (1.8)
4 (0.2)
3 (0.2)
Rash
90 (5.2)
1 (0.1)
0
0

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Immune Related Adverse Events (irAEs)
Colitis
26 (1.5)
7 (0.4)
0
0
Pneumonitis
21 (1.2)
5 (0.3)
1 (0.1)
1 (0.1)
Hepatitis
16 (0.9)
11 (0.6)
0
2 (0.1)
Endocrinopathies
106 (6.1)
6 (0.3)
0
0
Thyroid disorders
98 (5.6)
3 (0.2)
0
0
Adrenal insufficiency
8 (0.5)
1 (0.1)
0
0
Type 1 diabetes mellitus
2 (0.1)
2 (0.1)
0
0
All other irAEs
19 (1.1)
5 (0.3)
3 (0.2)
0
Blood CPK increased
5 (0.3)
1 (0.1)
2 (0.1)
0
Myositis
5 (0.3)
1 (0.1)
1 (0.1)
0
Psoriasis
5 (0.3)
1 (0.1)
0
0
Guillain-Barre syndrome
1 (0.1)
1 (0.1)
0
0
Systemic inflammatory response 
syndrome
1 (0.1)
1 (0.1)
0
0
1.2.7
Immune related risks
In addition, some clinically relevant irAEs were reported after the data cutoff or outside of the
Pooled Safety Dataset. These included: 3 events of nonfatal graft versus host disease (2 in the 
liver and 1 in skin) and 1 event of immune thrombocytopenic purpura in Study B9991007 
(avelumab in subjects with cHL), 4 events of myasthenia gravis/myasthenic syndrome in the 
clinical studies, and overall 15 events of pancreatitis including one case of fatal pancreatitis 
necrotising in Study B9991003 with the combination of avelumab with axitinib in subjects with 
RCC (Investigator Brochure, 29May 2020).
1.2.8
Efficacy in Avelumab Clinical Trials
1.2.8.1
Metastatic Urothelial Cancer
The activity of avelumab in refractory metastatic urothelial carcinoma was assessed in 66 patients 
as part of the phase 1 Javelin trial [49]. An independent central assessment confirmed an overall 
response rate (ORR) of 18.2% including 5 patients (11.4%) with a complete response as seen in 
Figure 1. Three patients (6.8%) had a partial response and 15 patients with stable disease as best 
response. Patients’ responses were predominantly those with PD-L1 positive tumors with seven of 
eight responding patients (87.5%) having PD-L1 positive tumors compared to only 1 of 24 (4.7%) 
patients with PD-L1 negative tumors having a response.

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Figure 1: Clinical activity of avelumab [49]: 
(A) Time to response, duration of treatment, and duration of response to avelumab (eight confirmed responses 
and four unconfirmed responses as of data cutoff), with programmed death-ligand 1 (PD-L1) expression 
status indicated (on the basis of a > 5% staining threshold on tumor cells; nonevaluable specimens [n = 7] 
included those that were missing, of poor quality, or otherwise not available to provide results). The vertical 
dotted line represents 1 year from the initiation of treatment. (B) Plot of tumor regression from baseline as 
measured by Response Evaluation Criteria in Solid Tumors (RECIST) in all assessable patients (n = 38), 
with PD-L1 expression status indicated (on the basis of a > 5% staining threshold on tumor cells). Eastern 
Cooperative Oncology Group (ECOG) performance status, presence of non-lymph node metastasis, and 
albumin and hemoglobin levels at baseline are shown for each patient. The upper dotted line represents 
progression at 20% and the lower dotted line represents the RECIST boundary for complete response or 
partial response at 30%. (C) Percentage change in sum of target lesion diameters from baseline over time for 
all assessable patients (n = 38), defined as those patients with baseline tumor assessments and at least one 
postbaseline assessment. The upper dotted line represents progression at 20% and the lower dotted line 
represents the RECIST boundary for complete response or partial response at 30%
In addition to the tumor regressions, Avelumab had an impact on median progression free 
survival (mPFS) and median overall survival (mOS) in this patient population as seen below 
in Figure 2.
Figure 2: Progression-free survival (PFS) and overall survival (OS)  [49]:
Kaplan-Meier estimate of PFS (A) and OS (B) for the overall study population (N = 44). Kaplan-Meier 
estimate of PFS (C) and OS (D) on the basis of programmed death-ligand 1 (PD-L1) expression on tumor 
cells (n = 37). Vertical lines show censored events. Positive PD-L1 expression was defined as >5% of tumor 
cells expressing PD-L1 at any intensity. ne, not estimable

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1.2.8.2
Ovarian Cancer
A preliminary report has demonstrated clinical activity in patients with epithelial ovarian cancer 
[55]  Additional ovarian cancer patients were subsequently treated and produced data for 124 
relapsed ovarian cancer patients treated with avelumab. The response rate for this disease cohort 
is 9.7% (12 patients), all partial responses with 6 ongoing. Stable disease was observed in 44% of 
these patients that resulted in a disease control rate of 54% (unpublished data).
1.2.8.3
Non-small Cell Lung Cancer
In a phase Ib trial of 184 patients, objective responses were seen in 22 (12%) patients that were 1 
CR, 21 PRs and 70 patients had stable disease (38%)[56]  and resulted in a disease control rate 
(DCR) of 50%. The most common treatment-related AEs of any grade were fatigue (25%), 
infusion reactions (21%), and nausea (13%). Grade 3 or worse treatment-related AEs occurred in 
13% of patients, with the two most common being infusion reactions (2%) and increased lipase 
level (2%). 
1.2.8.4
Breast Cancer
Avelumab was studied in 168 patients with locally advanced or metastatic breast cancer refractory 
to or progressing after standard of care including 58 patients with triple negative breast cancer 
(TNBC) [58]. Response rate in the entire cohort was 3.0% and 5.2% in TNBC.  Stable disease was 
observed in an additional 42 patients (25.0%) resulting in a DCR of 28.0%.  Again, responses were 
predominantly in PD-L1 expressing tumors (unpublished data).
1.2.8.5
Merkel Cell Carcinoma
Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine tumor of the skin. The initial 
report of avelumab treatment of 88 MCC patients showed an objective response of 31.8% 
including 8 CRs and 20 PRs [52].
1.2.8.6
Renal Cell Carcinoma
There is preliminary evidence of clinical activity for avelumab in the treatment mRCC [59] as 
additional trials of avelumab for mesothelioma, gastric cancer, adrenocortical carcinoma and renal 
cancer are ongoing. Additionally, preclinical data from combination treatment with the chimeric 
anti-PD-L1/anti-TGFβ fusion molecule M7824 and IL-15 [53] demonstrated significantly 
augmented ADCC with human effector cells in vitro that support this combination treatment 
strategy.
1.2.8.7
Gastric Adenocarcinoma 
Adenocarcinoma of the stomach and the closely related gastroesophageal junction (GEJ) are 
aggressive tumors that are rarely curable and require new and effective treatment options. The 
results of the phase 1 trial JAVELIN Solid Tumor JPN and the dose expansion cohort of metastatic 
gastric or GEJ adenocarcinoma was recently published [60].
1.2.9
Recombinant Human Interleukin-15 (rhIL-15)
IL-15 is a 14-15kDA member of the 4-alpha-helix bundle family of cytokines that acts through a 
heterotrimeric receptor involving IL-12/IL-15R beta (β)subunit shared with IL-2, the common 
gamma chain (γc) shared with IL-2, IL-4, IL-9, IL-21, and  IL-15 specific receptor subunit IL-15R 
alpha (IL-15Rα) or CD215 [61] . IL-15 acts as a cell-surface molecule as part of an immunological 
synapse with IL-15 and IL-15R alpha produced in trans on adjacent mononuclear cells like 
monocytes and DCs which have been stimulated with interferon and/or CD40 ligation [62-65]. IL-

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15 has been shown in many model systems to be a potent stimulator of T and NK-cell functions 
and in contrast to IL-2 does not activate Tregs and produces less capillary leak syndrome [61-63, 
65, 66]. Multiple murine preclinical studies have demonstrated the efficacy of IL-15 in the 
treatment of cancer that led to clinical development of this cytokine.   An intravenous bolus (IVB) 
regimen of IL-15 was evaluated in a rhesus macaque’s toxicology experiment that administered 
20 mcg/kg/day of IL-15 for 12 days and produced a 4 to 8-fold increase in the number of circulating 
NK cells [67, 68]. Administration of the same dose by continuous intravenous infusion (CIV) for 
10 days produced a 10-fold increase in the number of circulating NK cells, a 15-fold increase in 
circulating monocytes and a massive 80 to 100-fold increase in circulating effector memory CD8 
T-cells  [69].When this same dose was given as a subcutaneous (SC) injection for 10 days, a 10-
fold expansion in circulating effector memory CD8 T-cells and modest increases in NK cells was 
observed [69]. Based on animal and laboratory trials of IL-15, great interest was generated among 
leading immunotherapeutic experts participating in the NCI Immunotherapy Agent Workshop who 
ranked IL-15 as the most promising unavailable immunotherapeutic agent to be brought to 
therapeutic trials.
1.2.10 Clinical Experience with Single Agent rhIL-15 in the Treatment of Cancer
1.2.10.1 First in Human Intravenous Bolus (IVB) trial
The first in-human (FIH) phase I trial of rhIL-15 administered the treatment as rapid (30 minute) 
IV bolus (IVB) to adults with refractory metastatic malignant melanoma and metastatic renal cell 
cancer [70]. This study was initially planned with a starting dose of 3 mcg/kg/day given for 12 
consecutive days. However, after the first patient treated developed grade 3 hypotension and after 
patient #5 at this dose level developed grade 3 thrombocytopenia, the protocol was amended to 
add the two lower doses of 1.0 and 0.3 mcg/kg/day with the expectation of returning to higher dose 
levels later. When two of four patients treated at the 1.0 mcg/kg/day dose unexpectantly developed 
asymptomatic grade 3 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
elevations that were dose limiting, all subsequent patients were treated at the 0.3 mcg/kg dose 
level. All 9 patients with IL-15 at 0.3 mcg/kg/day received 12 doses without a DLT, and the 
maximum tolerated dose (MTD) of rhIL-15 was defined as 0.3 mcg/kg/day.
There was a consistent temporal pattern of post-treatment adverse events in patients receiving 3 
mcg/kg/day doses of IL-15 with fever and rigors beginning 2 ½ to 4 hours following the start of 
IV infusions, soon after drops in blood pressure were seen with nadirs approximately 20 mm/Hg 
below pretreatment levels that responded slowly to rapid normal saline (NS) infusions.  These 
physiologic changes were concurrent with an up to 50-fold elevation of serum IL-6 and interferon 
gamma (IFNγ) levels. Flow cytometry of peripheral blood lymphocytes in patients receiving 3 
mcg/kg/day revealed a dramatic efflux of NK and memory CD8 T-cells from the circulation within 
minutes of IL-15 administration, gradual rise in NK cell numbers in the first 4 to 5 days of 
treatment, followed by an influx and hyperproliferation yielding a 10-fold expansion in the number 
of NK cells at the end of or after completion of the treatment cycle. A modest increase in the 
number of CD8+ T-cells was also seen but virtually all of these CD8+ T-cells were activated and 
expressed high levels of Ki67, CD38 and HLA-DR. In this first-in-human phase I trial there were 
no clinical responses with stable disease as the best response. However, 5 patients had decreases 
of between 10% and 30% of their marker lesions that included 2 patients that cleared their lung 
lesions.

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1.2.10.2 Subsequent Clinical Trials with Subcutaneous (SC) or Continuous Intravenous (CIV) 
rhIL-15
The clinical toxicities that limited dose escalation in the IVB trial were associated with intense 
cytokine production within the first few hours of treatment and marked by exceedingly high IL-15 
levels.  Serum IL-15 concentrations at these levels would be sufficient to signal through the 
intermediate affinity (IL-2) IL-15Rβ and gamma chain (γc) receptor pair that resulted in the 
undesirable toxicities seen in the FIH trial and suggested that dosing strategies that limited the 
Cmax, increased the duration of  lower IL-15 levels that were optimal for high-affinity IL-15 αβγ 
receptor would improve the IL-15 stimulatory signal [71]. Alternative SC and CIV dosing 
regimens were evaluated first in non-human primate (NHP) rhesus macaques and subsequently in 
phase I clinical trials.  The preclinical NHP experiments assessed the pharmacokinetics (PK) for 
multiple dose levels including the 20 mcg/kg dose given as an IVB (Cmax 720 pg/mL) and produced 
more advantageous IL-15 concentration; Cmax of 50 pg/mL for SC injections and Cmax  of 4 pg/mL 
for CIV infusion with more balanced PK parameters that stimulated greater expansion of NK and 
CD8+ effector cells [67-69].
A phase I dose escalation trial (Clinical Trials Identifier: NCT01727076) performed in adults with 
refractory metastatic solid tumors that assessed a SC rhIL-15 treatment regimen (Monday-Friday 
for 2 consecutive weeks of a 4-week cycle) was performed under the direction of Cancer 
Immunotherapy Trials Network (CITN) at dose levels of 0.25, 0.5, 1, 2 and 3 mcg/kg/day[71]. 
Nineteen patients were treated with 14 patients receiving ≥ 2 cycles of treatment. Patients 
experienced common cytokine side effects of fevers, chills, fatigue, mild anorexia, transient 
biochemical laboratory abnormalities and transient lymphopenia.  The MTD was 2 mcg/kg/day; 
with notable serious adverse events of pancreatitis at the 2.0 mcg/kg dose level and grade 3 cardiac 
chest pain at the 3mcg/kg dose level.  Flow-cytometry data demonstrated > 10-fold increase in NK 
cells, an approximately 3-fold increase in CD8 cells at the 2 highest dose levels and a dramatic 
increase in the frequency of CD56bright CD3 negative NK cells that peaked about 3 days after the last 
injection on day 15 of the treatment cycle. Again, stable disease was the best response, but 1 patient 
remained on treatment for 2 years without progression but relapsed soon after the rhIL-15 was 
stopped.  This protocol defined a safe immunostimulatory regimen that could be given as an 
outpatient in future combination treatment protocols [71].
A parallel phase I dose escalation trial (Clinical Trials Identifier NCT01572493) was performed 
in adults with refractory metastatic cancers the Clinical Center NIH, rhIL-15 was administered to 
patients with metastatic malignancy by CIV for 10 days at progressively increasing doses to 3 
patients each of 0.25, 0.5, 1.0, 2.0 and 4.0 mcg/kg/day.  Two dose-limiting toxicities were observed 
at 4.0 mcg/kg/day, one hepatotoxicity and the other visceral arterial ischemia making 2 mcg/kg 
the MTD that was well tolerated in the 9 patients treated at this dose [72].  The PK data from the 
CIV regimen was notably different from the IVB regimen having an appreciably lower Cmax 5662 
pg/mL (2 mcg/kg cohort) compared to 30,420 pg/mL (for 3 mcg/kg cohort). The serum IL-15 level 
was largely maintained in the CIVrhIL-15 treated patients over the first 48 hours compared to the 
rapid decline seen in the IVB patients with serum half-life of approximately 2 ½ hours. Patients in 
the CIV trial showed a much lower serum IL-15 level during the last 2 to 3 days of the infusion 
that was approximately 10% of their Cmax level. which is believed to be related to the high number 
of high affinity IL-15 receptor bearing effector cells acting as a sink rapidly binding and clearing 
the free serum IL-15. More limited PK data from the SC treatment protocol showed fairly 
comparable Cmax 6480 pg/mL (for 3 mcg/kg cohort) 4 hours after injection that is largely gone by 

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24 hours post injection. As predicted in the NHP toxicology studies the lower but sustained IL-15 
levels produced by the SC and CIV regimens produced the large increase in activated effector cells 
at the higher dose levels in the respective trials  
The CIV regimen produced characteristic changes in lymphocyte numbers with early lymphopenia 
(days 1 to 3) for both T and NK cells, followed by a gradual increase in cell numbers and dramatic 
rise in cells (30 to 80-fold increase in NK cells, 2 to 6-fold increase in CD8+ cells and 350-fold 
increase in CD56bright NK cells) during the 48 hours after completion of the treatment as shown 
below in Figure 3(77).  The rate of proliferation of different subsets of NK cells assessed by Ki67 
was consistent with their levels of CD122 (IL-2/IL-15Rβ) expression with CD56bright > CD56dim, 
CD94high, > CD56dim, CD94low.  The functional capacity of the dominant CD56bright subset was 
augmented following IL-15 administration and was associated with an increase in their expression 
of perforin and granzyme. Although the specific lytic activity of CD56bright cells was not as great 
as that of CD56dim cells, their single cell lytic and antibody-dependent cellular cytotoxicity 
(ADCC) activity were markedly increased by rhIL-15 treatment. This ADCC activity was 
confirmed in assays with anti-CD20 antibody coated Raji cells, natural cytotoxicity to K562 cells, 
mediated by NKp30 and NKp46 as well as by MICA/NKG2D-mediated cytotoxicity [73].  These 
clinical trial results and preclinical data combining ICI, anti-CTLA4 and anti-PD1, with rhIL-15 
[74, 75]and antitumor antibodies promote the development of clinical trials with these 
combinations [76].
The CIVrhIL-15 trial was subsequently amended to evaluate a 5-day (120 hour) regimen with 
further dose escalation at 3, 4 and 5 mcg/kg/day.  Ten additional patients have been safely treated 
at these dose levels without DLTs or remarkable toxicities. Common adverse events (AEs) as 
expected have been the fatigue, fevers, chills or occasional rigors, capillary leak syndrome and 
reversible laboratory abnormalities.  As seen in table 2, this 5-day regimen has produced 
impressive increases in absolute lymphocyte count (maximum ALC 25,000 to 30,000 cells/mL, 
NK cells (30 to > 80-fold increase) and CD8 cells (5 to 8-fold increase) that generally has been 
higher than seen in the patients treated at the 2 mcg/kg dose level for 10 days.
A                                                                    B
Figure 3: Increase in lymphocytes, predominantly NK cell count, during continuous infusion of rhIL-
15. rhIL-15 was administered at progressively increasing doses of 0.25, 0.5, 1.0, 2.0 and 4.0 mcg/kg/day by 
10-day civ infusion (A) and 5-day civ infusion (B) to patients with metastatic malignancy. Patients 2-4 
received 0.125 mcg/kg, patients 5-7 received 0.25 mcg/kg, patients 8-10 received 0.5 mcg/kg, patients 11-16 

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received 1.0 mcg/kg and patients 17-19 received 2.0 mcg/kg. Following termination of the treatment (red 
arrow) there was a dramatic 30-fold increase in the number of circulating lymphocytes predominantly NK 
cell count and an over 350-fold increase in the number of circulating CD56bright NK cells in the 10-day 
cohort, and an up to 44-fold increase (33-fold mean increase) in the number of circulating NK cells in the 5-
day cohort.
Table 3: Characteristics and Outcomes of 11 patients treated with a 5-day civ rhIL-15 
infusion
Diagnosis
Age
Gender
Dose level
(mcg/kg)
No. of doses
NK cell
increase 
(fold)
CD8+ T-cell
increase 
(fold)
Melanoma
63
M
5
5
32.01
4.21
Small bowel
69
M
5
10
39.13
4.74
Colorectal
60
F
5
4
-
-
Small bowel
51
F
5
10
32.03
5.66
Colorectal
66
F
4
10
44.90
3.65
Renal cell
56
M
4
15
43.65
8.94
Esophageal
60
M
4
10
39.63
2.01
Colorectal
67
F
3
20
21.40
1.65
Colorectal
56
F
3
15
23.66
2.03
Endometrial
70
F
3
3
-
-
Colorectal
47
F
3
10
24.15
1.66
The complete absence of anti-IL-15 antibodies seen in patients treated with IV E. coli rhIL-15 
which contrasts with the experience in patients receiving any formulation of rhIL-15 as a SC 
injection is justification for the increased patient effort required to receive CIV rather than SC 
rhIL-15 treatment. The clinical experience is that all SC rhIL-15 treatment regimens have been 
reported to generate neutralizing anti-IL-15 antibodies that are associated with a decrement in 
immune activation after continuing multicycle treatment  [71-78].
1.3
CONSIDERATIONS AND RATIONALE FOR PHASE II DESIGN
The safety database for the rhIL-15 being used in this trial has data from more than 80 patients, 
mostly monotherapy IV patients, but recently patients have been treated with rhIL-15 in 
combination with antitumor monoclonal antibodies and checkpoint inhibitors [76, 78]. The side 
effects of rhIL-15 have been all closely linked to the patients’ period of treatment without any 
episodes of delayed toxicity which commonly resolve soon after IV treatment is discontinued and 
therefore are distinct from the expected toxicities of avelumab. With the CIVrhIL-15 regimen, 
fevers, fatigue, myalgias, chills with occasional rigors, dry skin with infrequent rashes are the most 
common symptomatic side effects. Capillary leak characterized by decreased serum albumin and 
fluid input exceeding urinary output, modest decrease in blood pressure and possibly some 
pulmonary capillary leak seen in the 4 or 5 mcg/kg dosing cohorts evidenced by slight drops in 
oxygen saturation have been observed in the previously treated CIV rhIL-15 patients. Common 

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laboratory abnormalities include early (treatment days 1-4) leukopenia, lymphopenia, 
thrombocytopenia, transaminitis, anemia, hypoalbuminemia during the whole treatment cycle, late 
cycle rises in bilirubin in patients treated with doses ≥ 2 mcg/kg and the dramatic spike in 
lymphocytes that occurs in the 72 hours after completion of the CIV infusion. The norm is for 
most of these laboratory abnormalities to begin returning or to resolve to baseline while treatment 
continues. There has been no evidence of increased risk of infection or requirement for antibiotic 
treatment during the period of cytopenias or increased bleeding during the period of decreased 
platelets. Decreases in hemoglobin (Hgb), which most likely is related to increased sequestration 
of red blood cells in the liver and spleen, generally require more time to return to pretreatment 
levels. This incidence of anemia has possibly been greater in the patients treated with the 5-day 
regimen and the 3, 4 or 5 mcg/kg dose levels, but this assessment has been complicated by the fact 
that 8 of the 10 patients treated in these dosing cohorts have GI malignancies and were found to 
be iron deficient. Some patients were transfused during their 2nd or later cycle of treatment and 
those who tolerated oral iron replacement therapy had replenishment of their iron stores to improve 
their Hgb level.  A number of the patients previously treated in the rhIL-15 trials had past history 
of autoimmune phenomena related to their prior cancer treatment with checkpoint inhibitors and 
none of these patients developed new or recurrent autoimmune toxicities.
As seen in Figure 4, the rate and severity of irAEs is also generally lower for anti-PD-L1 agents 
[77], including avelumab (Table 4), with the onset of the clinical events of greatest concern 
occurring generally 2 to 3 months after initiation of treatment. Avelumab has been approved by 
the FDA for the treatment of metastatic refractory urothelial cancers, has a safety database that 
exceeds 2000 patients and has a very well characterized AE profile [57]. 

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Figure 4: Distribution of irAEs for anti-PD-L1agents [77]
Distribution of (A) grade 1 to 2 and (B) grade 3 to 5 immune-related adverse events (irAEs) for all tumor types 
in the main clinical trials with anti– cytotoxic T-cell lymphocyte-4 (anti–CTLA-4), anti–programmed death 1 
(PD-1), or anti–PD ligand 1 (PD-L1) antibodies as single therapies. The values quoted are the median (range) 
irAE rates for the set of clinical trials as a whole. 
Table 4: Summary of irAEs in Avelumab Safety Database
Onset of Symptoms
irAE
Overall rate %
Grade 3 through 5%
Median
Range
Pneumonitis
1.2
0.5
2.5 months
3 days – 11 months
Hepatitis
0.9
0.5 (grade 3 only)
3.2 months
7 days -15 months
Colitis
1.5
0.4 (grade 3 only)
2.1 months
2 days – 11 months
Adrenal 
0.5
0.1 (grade 3 only)
2.5 months
1 day – 8 months
Thyroid
6
0.2 (grade 3 only)
2.8 months
14 days – 13 months
Diabetes
0.1
0.1 (grade 3 only)
NA
NA
Nephritis
0.1
NA
NA
NA
Infusion reaction initially occurred in one quarter of the patients receiving avelumab including 9 
patients with grade 3 (0.5%) and 3 patients with grade 4 (0.2%) events that were successfully 
controlled with antihistamines and IV corticosteroids. The avelumab package insert now 
recommends routine premedication with an antihistamine during the first 4 infusions. Anti-PD-1 
(nivolumab, pembrolizumab or PDR001) antibodies have been given in combination with all 
versions of rhIL-15, E. coli (NCI produced) single chain agent, heterodimeric IL-15 (Novartis) 
and the ALT-803 superagonist (Altor now NantKWest).  While the number of patients treated with 
these combinations is still modest, there has not been a new safety signal or evidence of synergistic 
toxicities. Given the close temporal relationship of CIV rhIL-15 treatment to the transient grade 3 
hematologic and occasional metabolic abnormalities, we anticipate that these events will not 
complicate the recognition of the rare autoimmune events seen with avelumab which would 
normally become apparent during the second or third cycle of treatment. We believe it is 
reasonable to use our standard DLT exclusion algorithm even in the initial dose level safety 
evaluation of patients and will view sustained or delayed grade 3 elevations of liver function tests 
(LFTs) as DLTs.
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Patients must have histologically proven metastatic clear cell renal carcinoma with ≥ 5% 
expression of PD-L1 in the tumor area confirmed by IHC in the NCI Lab of Pathology or 
performed by an outside CLIA certified laboratory using the FDA licensed Dako 28-8 or 

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22C3 antibodies PharmDx [79, 80]. Archival tumor sample may be used but if archival 
tissue is not available or is not adequate, tissue biopsy will be required.
2.1.1.2
Patients must have failed or relapsed and have progressive disease after at least 2 prior 
therapies that include multityrosine kinase inhibitor (mTKI) like axitinib or sunitinib and 
an anti-PD1 or PD-L1 (ICI) therapy like nivolumab which could have been administered 
in combination with an anti-CTLA4 agent like ipilimumab. Patients who received an ICI 
in combination with a mTKI would be eligible for the trial if they received another 
appropriate treatment. Adjuvant or neoadjuvant with either type of agent would not fulfill 
this requirement only treatment for metastatic disease will be considered to satisfy this 
criterion. 
2.1.1.3
Disease must be measurable with at least one measurable lesion by RECIST v1.1 criteria 
(see Section 6.3) that is different from the lesion biopsied. 
2.1.1.4
Age >18 years 
NOTE: Because no dosing or adverse event data are currently available on the use of 
rhIL-15 in combination with avelumab in patients <18 years of age, children are 
excluded from this study, but may be eligible for future pediatric trials 
2.1.1.5
ECOG performance status <1 (Karnofsky >80%, see APPENDIX A) 
2.1.1.6
Adequate organ and marrow function as defined below: 
absolute neutrophil count
>1,500/mcL
absolute lymphocyte count
>500/mcL
Hemoglobin
>10 g/dL
Platelets
>100,000/mcL
total bilirubin
<1.5 X institutional upper limit of normal (ULN) 
AST(SGOT)/ALT(SGPT)
<2.5 X institutional ULN
Serum creatinine
< 1.5 X institutional ULN
OR
Creatinine clearance
>50 mL/min/1.73 m2 for patients with creatinine levels >1.5 
institutional ULN
2.1.1.7
Negative serum or urine pregnancy test at screening for women of childbearing potential 
(WOCBP).
NOTE: WOCBP is defined as any female who has experienced menarche and who has 
not undergone successful surgical sterilization or who is not postmenopausal.  WOCBP 
must have a negative pregnancy test (HCG blood or urine) during screening.
2.1.1.8
Women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry, for the 
duration of study participation, and 1 month after completion of rhIL-15 and avelumab 
administration. Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her treating physician 
immediately.
2.1.1.9
Ability of subject to understand and the willingness to sign a written informed consent 

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document.
2.1.2
Exclusion Criteria
2.1.2.1
Chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C).
2.1.2.2
Persisting toxicity related to prior therapy of grade > 1, with the exception of the 
following:  alopecia, sensory neuropathy grade ≤ 2, or other grade ≤ 2 not constituting a 
safety risk based on investigator's judgement.
2.1.2.3
Patients who are receiving any other investigational agents
2.1.2.4
Current use of immunosuppressive medication, EXCEPT for the following: 

Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular 
injection)

Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or 
equivalent; or,

Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication).
2.1.2.5
Patients with known brain metastases should be excluded from this clinical trial because 
of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events. 
2.1.2.6
Patients with previous malignant disease other than the target malignancy within the last 
5 years with the exception of basal or squamous cell carcinoma of the skin or cervical 
carcinoma in situ. 
2.1.2.7
Patients with history of any organ transplantation, 
2.1.2.8
Vaccination within 4 weeks of the first dose of avelumab. Vaccination with a live vaccine 
while on trial is prohibited. NOTE: Seasonal influenza vaccines for injection are 
generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines 
(e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

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2.1.2.9
Patients with history of allergic reactions attributed to compounds of similar chemical or 
biologic composition to rhIL-15 or avelumab. 
2.1.2.10 Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection requiring systemic therapy, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
2.1.2.11 Inability or refusal to practice effective contraception during therapy or the presence of 
pregnancy or active breastfeeding.  Based on its mechanism of action, avelumab can 
cause fetal harm when administered to a pregnant woman. Animal studies have 
demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of 
immune-mediated rejection of the developing fetus resulting in fetal death. These 
potential risks may also apply to other agents used in this study.
2.1.2.12 Patients with active bacterial infections, documented HIV infection or positive screening 
serology, PCR evidence for active or chronic hepatitis B or hepatitis C, or positive 
screening HBV/HCV serology without documentation of successful curative treatment 
(see Section 12.1 for IL-15 administration in HIV positive patients).
2.1.2.13 Patients with active or history of any autoimmune disease, including asthma requiring 
chronic inhaled or oral corticosteroids, or with history of asthma requiring mechanical 
ventilation; patients with a history of mild asthma that are on or can be switched to non-
corticosteroid bronchodilator regimens are eligible
2.1.2.14 Cardiovascular disease: Clinically significant (i.e., active) cardiovascular disease: 
cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction 
(< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York 
Heart Association Classification Class II), or serious cardiac arrhythmia requiring 
medication
2.1.2.15 Other severe acute or chronic medical conditions including  immune colitis, inflammatory 
bowel disease,  immune pneumonitis, pulmonary fibrosis or psychiatric conditions 
including recent (within the past year) or active suicidal ideation or behavior; or 
laboratory abnormalities that may increase the risk associated with study participation or 
study treatment administration or may interfere with the interpretation of study results 
and, in the judgment of the investigator, would make the patient inappropriate for entry 
into this study.
2.2
STRATEGIES FOR RECRUITMENT AND RETENTION
Study participants will be recruited from the population of patients screened in the lymphoid 
malignancies clinic of the National Institutes of Health. These will include both referrals from 
outside physicians as well as patient self-referrals. This study will be posted on NIH websites and 
on NIH social media forums. In addition, information will be provided on the ccr.cancer.gov/ 
Lymphoid-Malignancies-Branch and ClinicalTrials.gov web pages, and on the official Lymphoid 
Malignancy Branch social media accounts.

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2.3
SCREENING EVALUATION
2.3.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 

Email, written, in person or telephone communications with prospective subjects 

Review of existing medical records to include H&P, laboratory studies, etc.  

Review of existing MRI, x-ray, or CT images

Review of existing photographs or videos

Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes.
2.3.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the consent for study 
#01-C-0129 on which screening activities will be performed.  Assessments performed at outside 
facilities or on another NIH protocol within the timeframes below may also be used to determine 
eligibility once a patient has signed consent.
The following tests/procedures should be performed to determine treatment eligibility. 
Assessments and procedures to confirm study eligibility should be completed within 28 days prior 
to registration (unless otherwise noted). See also the Study Calendar provided in APPENDIX F.
2.3.3
Clinical Evaluations

Disease history, including:  diagnosis, treatment (e.g., systemic treatments, radiation 
and surgeries), status, and significant prior/ongoing side effects and symptoms

Complete medical history including:  all active conditions considered to be clinically 
significant by the treating investigator

Physical examination, including: height (screening only), weight, vital signs (i.e., 
temperature, pulse, respiratory rate, oxygen saturation and blood pressure); review of 
concomitant medications and symptoms/side effects; and, assessment of performance 
status 
2.3.4
Laboratory Evaluations
NOTE:  Results from outside NIH are accepted.

Hematological Profile: CBC with differential and reticulocyte count

Biochemical Profile: Creatinine (i.e., Acute Care Panel); serum calcium, phosphate, 
magnesium and albumin (i.e., Mineral Panel); ALT, AST, total and direct (if required) 
bilirubin (i.e., Hepatic Panel); 24-hour urine creatinine clearance (if needed to measure 
CrCl in cases where serum creatinine >1.5mg/dl); and LDH

Serum Lipase and Amylase

Coagulation panel, including: PT/INR and a PTT

Thyroid function tests, including: thyroid stimulating hormone (TSH) and free 
thyroxine (T4) 

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
HIV, and hepatitis: Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody, 
Hepatitis C antibody (HCV) [qualitative], HIV 1/2 antibody (qualitative) NOTE:  For 
individuals with a positive hepatitis B core antibody, HBV DNA PCR will be 
performed to screen for subclinical infection. For individuals with a positive hepatitis C 
antibody, HCV RNA RT-PCR will be performed to determine infectious status.

Serum or urine pregnancy test (B-HCG) in women of childbearing potential

Urinalysis (with microscopic examination if abnormal)

Antinuclear antibody (ANA), rheumatoid factor (RF) and anti-thyroid antibody

Creatine phosphokinase (CPK), troponin 

Flow cytometry and lymphocyte sets, and subsets 
2.3.5
Imaging Studies 
NOTE:  Results from outside NIH are accepted. Other body areas may be imaged if clinically 
indicated. 

CT, chest, abdomen, pelvis and neck (if required).  CT should be performed with IV 
and PO contrast, unless patient is allergic or has renal insufficiency; other imaging 
may be substituted at the discretion of the investigator [such as MRI].

PET/CT torso (extremities to be included if there is confirmed or suspected disease 
involvement) maybe performed in selected cases to better evaluate lesions of 
uncertain etiology

Patients with neurological symptoms or signs should undergo MRI scan of the brain 
and lumbar puncture. 
2.3.6
Other Procedures

Pathological review/confirmation of diagnosis by Laboratory of Pathology, NCI (no 
time limit) and PD-L1 staining as outlined in Section 5.2.4.1. If no prior samples are 
available, punch or core biopsy of an appropriate easily accessible tumor deposit will 
be performed.

Patients with significant pulmonary or smoking history, including significant 
pulmonary involvement by tumor, pleural effusion, history of chronic obstructive 
pulmonary disease (COPD) or lobar or greater surgical resection of lung will require 
qualifying pulmonary function tests (PFTs) that include adjusted diffusing capacity 
(DLCO/Adj), forced expiratory volume in 1 second (FEV1). 

Cardiac Evaluation: Electrocardiogram (EKG), and for patients with significant history 
of vascular disease or clinical suspicion of cardiac dysfunction, a transthoracic 
echocardiogram will be obtained to ensure adequate cardiac performance to receive the 
protocol treatment without increased risk. 
2.4
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
 Registration and status updates (e.g. when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found here.   

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2.4.1
Treatment Assignment Procedures  
NOTE: For NCI CCR registration purposes only
2.4.1.1
Cohorts
Number
Name
Description
1
Safety Run-in
Patients 
with 
relapsed/refractory 
PD-L1-expressing 
metastatic ccRCC  who have progressive disease after at least 
2 prior therapies that include multityrosine kinase inhibitor 
and an anti-PD1/PD-L1 inhibitor to determine safety of dose
2
Dose Expansion
Patients 
with 
relapsed/refractory 
PD-L1-expressing 
metastatic ccRCC  who have progressive disease after at least 
2 prior therapies that include multityrosine kinase inhibitor 
and an anti-PD1/PD-L1 inhibitor to determine efficacy of 
combination treatment
2.4.1.2
Arms
Number
Name
Description
1
Safety Run-in
IL-15 by CIV infusion at escalating doses of 2, and 4 
mcg/kg/day on days 1-5 of each 28-day cycle (max 4 cycles) 
with avelumab by IV infusion at a dose of 800mg on Day 8 
and 22 of each cycle, to determine safety of dose (3-6 patients 
per dose level)
2
Dose Expansion
IL-15 by CIV infusion at  4 mcg/kg/day on days 1-5 of cycles 
1-4 with avelumab at 800mg on Day 8 and 22 of each cycle 
(Total 17 patients) to determine efficacy of treatment 
2.4.1.3
Treatment Assignment
Treatment assignment is open-label, and non-randomized/non-stratified. Subjects in Cohort 1 are 
directly assigned to Arm 1. Subjects in Cohort 2 are directly assigned to Arm 2. 
2.5
BASELINE EVALUATION
The following should be performed within 28 days prior to the first dose of rhIL-15 unless 
otherwise noted; test performed as part of screening do not need to be repeated if they were 
performed within the specified window prior to initiating treatment. 
2.5.1
Clinical Evaluations

Medical history (interim)

Physical examination including weight, vital signs (i.e., temperature, pulse, respiratory 
rate, oxygen saturation and blood pressure); review of concomitant medications and 
symptoms/side effects; and assessment of performance status (ECOG performance 
score see APPENDIX A).
2.5.2
Laboratory Evaluations 
NOTE:  Results from outside NIH are accepted

Required within 7 days:
o
Serum or urine pregnancy test (B-HCG) for women of childbearing potential

Required within 14 days:
o
Hematological Profile: CBC with differential and reticulocyte count

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o
Biochemical Profile: Chemistry panels including: Acute Care (sodium, potassium, 
chloride, CO2, glucose, BUN, creatinine), Mineral Panel (serum calcium, 
phosphate, magnesium and albumin), Hepatic Panel (alkaline phosphatase, ALT, 
AST, total and direct bilirubin), and 24-hour urine creatinine clearance (if needed 
measure CrCl if serum creatinine >1.5mg/dl)
o
Others: LDH, troponin
o
Serum Lipase and Amylase
o
Thyroid panel: TSH and free T4
o
Coagulation panel, including: PT/INR and aPTT
o
Urinalysis (with microscopic examination if abnormal)
o
IL-2R alpha

Required within 28 days:
o
Antinuclear antibody (ANA), rheumatoid factor (RF) and anti-thyroid antibody 
2.5.3
Imaging Studies
Every participant should have an evaluation of known sites of disease as part of baseline 
evaluation. NOTE:  Results from outside the NIH are accepted if the films provide high 
quality images that can be used to measure tumor marker lesions. 

One or more of the following studies: CT, MRI, FDG-PET 

Patients with neurological symptoms or signs should undergo MRI scan* of the 
brain 
*NOTE: The MRIs to be done in this study may involve the use of the contrast agent 
gadolinium, if clinically indicated. The risks associated with MRIs and contrast are 
discussed in the consent form.
2.5.4
Research Correlates
NOTE: See Section 5 for additional information. The following sample types will be 
collected for correlative research studies:  

Required:  
o
Blood samples for lymphocyte subset testing and circulating tumor DNA
o
Tumor Tissue (archival or fresh) to assess PD-L1 expression for eligibility
o
Blood samples for ADCC of avelumab, tissue immune cell subset comparison 
(as outlined in Section 5)

Optional:  
o
Pretreatment tumor biopsy to assess immune response to therapy can use the 
archival tissue or the fresh sample obtained to assess PD-L1 expression for 
protocol entry. Tissue sample for the optional on treatment biopsy obtained 
between cycle 1 day 22 and cycle 2 day 4 will be a core biopsy of easily 
accessible tumor deposits.

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3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
In this Phase II trial of combination rhIL-15 and avelumab in patients with relapsed or refractory 
metastatic PD-L1+ ccRCC, IL-15 will be administered by CIV. The trial will begin with a small 
safety run-in cohort with a rhIL-15 starting dose of 2 mcg/kg/day, and a second dose level of 4 
mcg/kg/day (the desired Phase II dose). There is clinical experience for the combination of anti-
PD1 plus IL-15, but there is no prior safety experience for the combination of avelumab and E. 
coli derived rhIL-15. Consequently, the first 3 patients will begin CIV rhIL-15 treatment at a dose 
of 2 mcg/kg/day on days 1-5 and avelumab (800mg, by IV) on day 8 and 22 of the 28-day cycle 
(i.e., every 2 weeks). If one of these patients has a dose limiting toxicity (DLTs), three additional 
patients will be treated to establish the safety of the combination. Assuming there are no DLTs, 
subsequent patients will be treated at the 4 mcg/kg/day dose level. Again, the safety of this dose 
of rhIL-15 in combination will be established in a 3 to 6 patient cohort to confirm this treatment 
regimen does not pose unacceptable risk to the enrolled subjects. If a second patient in these safety 
run-in cohorts at either the 2 or 4 mcg/kg dose level experiences a DLT all treatment and 
enrollment will be halted to review the data and determine if further clinical evaluation of the 
combination should be attempted. Treatment will continue for a maximum of 4 cycles or until 
toxicity (i.e., dose limiting toxicity as found in Section 3.1.1 or toxicity requiring hold as defined 
in Section 3.3) or progressive disease.
After the safety of the 4 mcg/kg dose level is established all subsequent patients will be treated 
with CIVrhIL-15 at the dose of 4 mcg/kg on days 1-5  (120 hours) and avelumab (800mg, by IV) 
on day 8 and 22 of each 28-day cycle for a maximum of 4 cycles ( in the absence of toxicity 
requiring hold as defined in Section 3.3 or progressive disease). 
Day of cycle: 
cycles 1-4
The standard immune related adverse event (irAE) treatment decision algorithm [66] will be 
followed to address avelumab related AEs and any patient who requires corticosteroid treatment 
for irAE will discontinue their rhIL-15 treatment. Since the expected frequency of grade 3 or 4 
irAEs with single agent avelumab is extremely low (< 1%), irAE requiring corticosteroid treatment 
during the first cycle of treatment for the run-in cohort of patients will also be considered a DLT.  
All patients in the run-in cohort (Cohort 1) must complete their first 28-day cycle of treatment 
without experiencing a DLT before enrollment into the 4 mcg/kg cohort is initiated.
The efficacy of the combination will be assessed in a Simon two-stage phase II clinical trial scheme 
that treats a total of minimum 9 or maximum 17 patients at the 4 mcg/kg dose level depending on 
demonstration of clinical activity in the initial group of patients. 

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See Section 10.2.1 for details regarding early stopping criteria for the whole trial. 
3.1.1
Dose-Limiting Toxicity
A dose-limiting toxicity (DLT) is defined as:  any grade 3, 4, or 5 toxicity if not incontrovertibly 
due to disease progression or an extraneous cause, and deemed possibly, probably or definitely 
related to IL-15 or  avelumab by the PI or designee during the first 28 days of treatment, only for 
the Safety Run-in cohort (Cohort 1) with the following exceptions.:
3.1.1.1
Hematologic exceptions 

Grade 3 or 4 lymphocytopenia without clinical signs of infection grade 2 or above.
o
rhIL-15 and avelumab will be continued in the event of asymptomatic grade 3 
or 4 lymphocytopenia, unless there are clinical signs of significant infection 
(persistent fevers, labile blood pressure, localized complaints or findings on 
physical examination, hypoxia or organ dysfunction).

Grade 3 or 4 neutropenia without clinical signs of infection grade 2 or above.
o
rhIL-15 and avelumab will be continued in the event of grade 3 neutropenia 
unless there are clinical signs of significant infection, as listed above.

Grade 3 leukocytosis (WBC > 100,000/mm3) rhIL-15 and avelumab will be continued 
in the absence of signs of leukostasis or other toxicities possibly related to the 
expansion of activated cells 
3.1.1.2
Non-Hematologic exceptions

Transient (< 24 hours) grade 3 hypoalbuminemia, hypokalemia, hypomagnesemia, 
hyponatremia or hypophosphatemia which responds to medical intervention. rhIL-15 
and avelumab will be continued while the metabolic abnormalities are corrected by 
intravenous or oral supplementation 

Non-sustained (< 7 days) grade 3 liver function test (ATL, AST, alkaline phosphatase, 
total or direct bilirubin) abnormalities deemed unrelated or unlikely related to 
avelumab, in the absence of clinical signs of hepatic dysfunction (lethargy, confusion, 
anorexia, pruritus, tremor); for patients with baseline grade 1 elevations, any increase 
≥ 10 x baseline will be considered dose-limiting and these patients will be closely 
monitored for liver function abnormalities.rhIL-15 and avelumab will be continued as 
long as these abnormalities do not persist for more than 7 days or the patient does not 
exhibit findings consistent with hepatic toxicity
Management and dose modifications associated with the above adverse events are outlined in 
Section 3.3. Occurrence of any of the adverse events listed above after the first 28 days of treatment 
in the Dose Expansion cohort (Cohort 2) will lead to permanent discontinuation of protocol 
therapy, but will not be deemed a DLT for purposes of dose escalation. See Section 3.3.3  for more 
details. 
3.1.2
Dose Escalation and DLT Assessment in Safety Run-in Cohorts
Dose escalation in the initial patients treated at the 2 and 4 mcg/kg/day dose levels will proceed 
according to the following schedule (Table 5). Dose escalation will follow the following 
guidelines (Table 6). Dose-limiting toxicity (DLT) is defined above. Each patient will continue 
treatment at the dose level they were enrolled — there will be no intra-patient dose escalation. 

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Table 5: IL-15 Dose Escalation Schedule
Dose Level
rhIL-15
(mcg/kg)
Avelumab
(mg)
Level 1
2
800
Level 2
4
800
*Doses are stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) rather than as a percentage.
 Table 6:  Dose Escalation Guidelines 
Number of Patients with DLT at a 
Given Dose Level
Escalation Decision Rule
0 out of 3 for dose level 1
Enter 3 patients at dose level 2.
0 out of 3 for dose level 2
All subsequent patients will be treated at dose level 2 
(4mcg/kg). This is the phase 2 dose. 
1 out of 3 at either dose level 1 or 2 
Enter at least 3 more patients at this dose level.
If 0 of these 3 patients experience DLT at dose level 1, 
proceed to the dose level 2.
If 0 of these 3 patients experience DLT at dose level 2, all 
subsequent patients will be treated at dose level 2 (4 
mcg/kg)
> 2 of 3 or 6 for either dose level 1 or 
dose level 2 
Enrollment and all treatment will be halted. The safety data 
will be analyzed and the protocol either substantially 
amended or terminated depending on the results of this safety 
review and discussion with CTEP and EMD Serono
3.2
 DRUG ADMINISTRATION
Each cycle is 28 days (4 weeks). The minimum window between initiation of new cycles is 26 
days; a cycle delay due to scheduling or other administrative reasons (i.e., reasons other than 
toxicity/dose management as defined below) is 7 days. Treatment with rhIL-15 will be given as a 
continuous IV infusion days 1 through 5 (120 hours) Avelumab had previously been given at a 
dose of 10 mg/kg, but recently was given permission by the FDA to administer the drug as a flat 
dose of 800 mg over 60 minutes every 2 weeks. All patients treated in this protocol will receive 
the flat 800 mg avelumab dose. The diluted avelumab solution will be administered over 60 
minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-
line filter (pore size of 0.2 micron). Do not co-administer other drugs through the same intravenous 
line. 
rhIL-15 will be given intravenously as a continuous infusion through a central venous (midline) 
catheter and administered on an inpatient basis during week 1 of the first cycle, and as outpatient 
during subsequent weeks and cycles unless decided otherwise by the principal investigator based 
on clinical judgment. Reported adverse events and potential risks are described in Sections 14. 

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Appropriate dose modifications for later cycles of treatment are described in Section 3.3. See 
Table 7 below for description of drug regimen.
For a full detailed product description and administration guidelines, see Section 14. Infusions will 
be administered via central venous access device (if present; not required to be placed by the 
study). When administered on an outpatient basis, rhIL-15 will be infused via an ambulatory 
infusion pump.
Criteria to be eligible for outpatient ambulatory treatment at 2 mcg/kg dose level are:

no physiologic organ system or fatigue AE > grade 1, 

absence of blood pressure (BP) changes < 20% of baseline or systolic BP < 
100 mm Hg, 

more than 5% decline in room air oxygen saturation. 
Table 7: Drug Regimen
Agent
Premedications; Precautions
Dose
Route
Schedule
rhIL-15
Premedicate with 
acetaminophen and/or 
ibuprofen
** in *** D5W with 
0.1% HSA 
IV over 
24 hours
Days 1-5
Avelumab
Premedicate with 
acetaminophen and an 
antihistamine*
** in 250 mL 0.9% 
or 0.45% NS
IV over 1 
hour
Days 8 and 22
* Mandatory for the first four infusions; subsequently based on clinical judgement
** Doses as appropriate for assigned dose level
*** Infusion volume of rhIL-15 per calculation in APPENDIX C
3.2.1
Prophylactic and supportive care for IL-15
Patients will be given acetaminophen 500-650mg IV or orally, 30-60 minutes prior to each IL-15 
infusion as first line, and ibuprofen 400 or 600mg orally, depending on reactions with 
acetaminophen as premedication. 
3.2.2
Prophylactic and supportive care for avelumab
In order to mitigate infusion related reactions, a premedication with an antihistamine and with 
acetaminophen 30 to 60 minutes prior to the first 4 infusions of avelumab is mandatory (e.g., 25-
50 mg diphenhydramine and 500-650 mg acetaminophen IV or orally). At the discretion of the 
investigator, famotidine 20mg PO or IV (or other H2 receptor blocker of equivalent efficacy) may 
also be administered 30 minutes prior to avelumab. Premedication should be administered for 
subsequent avelumab infusions based upon clinical judgment and presence/severity of prior 
infusion reactions. 
3.2.3
Other modalities or procedures

Patients will be observed in the day hospital or the inpatient unit for at least 30 minutes 
after administration of avelumab for potential infusion-related reactions

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
Avelumab should be administered in a setting that allows for immediate access to an 
intensive care unit or equivalent environment and administration of therapy for 
anaphylaxis, such as the ability to implement immediate resuscitation measures.  Steroids 
(dexamethasone 10 mg), epinephrine (1:1,000 dilution), allergy medications (IV 
antihistamines), bronchodilators, or equivalents, and oxygen should be available for 
immediate access. 
3.2.4
Clinical Monitoring for the Avelumab Infusion 
On Day 8 and Day 22 of Cycle 1 only, vital signs ([VS] blood pressure, pulse, respiratory rate, 
temperature, oxygen saturation) will be assessed predose of avelumab (within 15 minutes of 
injection and/or infusion), and then every 15 minutes from the start of avelumab infusion for at 
least 2 hours. If vital signs are not stable after 2 hours, then continue monitoring every 15 minutes 
until stable on 2 consecutive repeated measurements and consideration for hospital observation for 
prolonged vital sign changes or instability if the patient is being treated as an outpatient during 
subsequent treatment cycles. If a patient requires more than 2 hours of observation during both 
cycle 1 avelumab treatments, they will be observed for 2 hours with similar vital signs timepoints 
for cycle 2 day 8 treatment. Once it is clear that a patient can tolerate their Avelumab infusions 
without any > grade 1 infusion reactions during subsequent treatments, patients will be observed 
for 30 minutes post completion of their avelumab infusion and vital signs will be obtained per 
local standard.
Subjects enrolled in this trial must be observed for 2 hours post avelumab infusion in an area with 
resuscitation equipment and emergency agents. At all times during avelumab and rhIL-15, 
immediate emergency treatment of an infusion-related reaction or a severe hypersensitivity 
reaction according to institutional standards must be assured. To treat possible hypersensitivity 
reactions, for instance, dexamethasone 10 mg and epinephrine in a 1:1000 dilution or equivalents 
should always be available along with equipment for assisted ventilation. Infusion of avelumab 
will be stopped in case of Grade >  2 hypersensitivity, inflammatory response, or infusion-related 
reaction. 
3.2.5 Clinical Monitoring for the CIV rhIL-15 infusion 
The rhIL-15 is given by continuous infusion, and the safety of combined administration will be 
confirmed by administering Cycle 1 treatment as an inpatient and the patient may continue 
treatment as an outpatient if they satisfy the criteria listed above in Section 3.2. It is likely that the 
majority of patients will receive their CIV rhIL-15 as inpatients and will have regular VS 
assessment as per nursing unit norms. Patients who experience a decrease in their BP below 100 
mmHg or have symptomatic orthostatic changes in the BP will receive NS infusion to increase 
their BP and alleviate their symptoms. These patients may also receive salt poor albumin (25%) 
and or transfused packed red blood cells (RBCs) as clinically indicated by their monitoring 
laboratories.  Patients who experience shortness of breath or have decrease in their oxygen 
saturations below 92% will receive Lasix IV, intermittent low flow oxygen (grade 2 CTC event) 
and respiratory treatments as clinically indicated to improve their blood oxygen levels. Patients 
who experience these events will have more frequent VS and clinical assessments as per 
institutional norms. After Cycle 1 monitoring for dose limiting toxicities, patients may also have 
brief interruptions (< 2 hours) of their CIV rhIL-15 to allow symptoms to decrease to acceptable 
levels.

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3.2.5.1 Vital Signs during Inpatient treatment
Inpatient: patients will have vital signs (BP, HR, RR, temperature and oxygen saturation) obtained 
as per inpatient unit norms.
3.2.5.2 Vital Signs for Outpatient treatment
Outpatient: patients will have vital signs (BP, HR, RR, temperature and oxygen saturation) 
obtained at the time of their visit to have their infusion bag changed.
3.3
DOSE MODIFICATIONS
3.3.1
rhIL-15-specific Adverse Events
Please refer to the Comprehensive Adverse Event and Potential Risk list (CAEPR) for rhIL-15 
presented in Section 14.1.8.
For patients treated later in the phase II dose expansion cohort (Cohort 2) at 4 mcg/kg, CIVrhIL-
15 infusion may be interrupted and the dose reduced to 3 mcg/kg for patients who have reversible 
grade 3 thrombocytopenia, hypoxia, symptomatic hypotension or 3 LFT abnormalities during the 
CIV rhIL-15 infusion for improved general tolerability. After the safety of the 4 mcg/kg dose level 
has been established, patients treated in the phase II dose expansion cohort who poorly tolerate the 
4 or 3 mcg/kg dose level (significant fatigue or anorexia) will also have the option of further dose 
reduction to the 2 mcg/kg dose level. Patients who are unable to tolerate the reduced dose of rhIL-
15 will discontinue cytokine treatment and may continue treatment with Avelumab.
Dose of rhIL-15 is based on the dose level and patient’s weight at the beginning of each cycle and 
can only be modified for rounding and/or consistency with prior cycles or as specified above, and 
not for adverse events or renal/hepatic dysfunction. Infusion may continue during correction of 
electrolyte and other laboratory abnormalities listed in Section 3.1.1. Infusion may be interrupted 
for up to two hours each day, but treatment should end 120 (±1) hours after initiation on Day 1.

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3.3.2
Avelumab
3.3.2.1
Treatment modifications for symptoms of infusion-related reactions 
Table 8: Treatment modifications for infusion-related reactions
NCI-CTCAE Grade
Treatment Modification for Avelumab
Grade 1 – mild
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.
Decrease the avelumab infusion rate by 50% and monitor 
closely for any worsening.
Grade 2 – moderate
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (for 
example, antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications indicated for  
24 h.
Temporarily discontinue avelumab infusion.
Resume infusion at 50% of previous rate once infusion-
related reaction has resolved or decreased to at least Grade 1 
in severity, and monitor closely for any worsening.
Grade 3 or Grade 4 – severe or life-threatening
Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or 
brief interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae.
Grade 4: Life-threatening consequences; urgent 
intervention indicated.
Stop avelumab infusion immediately and disconnect infusion 
tubing from the subject.
Subjects have to be withdrawn immediately from study 
avelumab and must not receive any further avelumab 
treatment.
 If avelumab infusion rate has been decreased by 50% or interrupted due to an infusion reaction, it must remain 
decreased for the next scheduled infusion.  If no infusion reaction is observed in the next scheduled infusion, the 
infusion rate may be returned to baseline at the subsequent infusions based on investigator’s medical judgment.
 If hypersensitivity reaction occurs, the subject must be treated according to the best available medical practice. 
IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse 
Event; NSAIDs = nonsteroidal anti-inflammatory drugs
3.3.2.2
Treatment modifications for immune-related adverse reactions (irAE)
All grading scales in the following tables are according to the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Table 9: Treatment Modification for Gastrointestinal Immune-related AEs
Gastrointestinal irAEs
Severity of Diarrhea/Colitis
Initial Management
Follow-up Management
Grade 1
Diarrhea: increase < 4 stools/day over 
Baseline; mild increase in ostomy 
output compared to baseline
Colitis: asymptomatic 
Continue avelumab therapy
Symptomatic treatment (e.g., 
loperamide)
Close monitoring for worsening symptoms
Educate subject to report worsening immediately
If worsens:
Treat as Grade 2, 3 or 4. 

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Gastrointestinal irAEs
Severity of Diarrhea/Colitis
Initial Management
Follow-up Management
Grade 2 
Diarrhea: 4 to 6 stools per day over 
Baseline; moderate increase in ostomy 
output compared to baseline; limiting 
instrumental ADL IV fluids indicated < 
24 hours; not interfering with ADL
Colitis: abdominal pain; mucus or 
blood in stool 
Withhold avelumab therapy
Symptomatic treatment
If improves to Grade ≤ 1: 
Resume avelumab therapy
If persists > 5-7 days or recurs:
Treat as Grade 3 or 4.
Grade 3 to 4
Diarrhea (Grade 3): increase of ≥ 7 
stools per day over Baseline; 
hospitalization indicated; severe 
increase in ostomy output compared to 
baseline; limiting self-care ADL 
incontinence; IV fluids ≥ 24 h; 
interfering with ADL
Grade 4: Life-threatening 
consequences; urgent intervention 
indicated
Colitis (Grade 3):  severe abdominal 
pain, medical intervention indicated, 
peritoneal signs
Grade 4: life-threatening, urgent 
intervention indicated perforation
Withhold avelumab for 
Grade 3.
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3.
1 to 2 mg/kg/day prednisone IV 
or equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Consider lower endoscopy 
If improves: 
Continue steroids until Grade ≤ 1, then taper over 
at least 1 month; resume avelumab therapy 
following steroids taper (for initial Grade 3). 
If worsens, persists > 3 to 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. 
Table 10: Treatment Modifications for Dermatological Immune-related AEs
Dermatological irAEs
Rash
Initial Management
Follow-up Management
Grade 1 to 2
Covering < 30% body surface 
area
Continue avelumab
Symptomatic therapy (for example, 
antihistamines, topical steroids)
If persists > 1 to 2 weeks or recurs: Consider 
skin biopsy
Withhold avelumab
Consider skin biopsy
Consider 0.5 to 1 mg/kg/day prednisone or 
equivalent. Once improving, taper steroids 
over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and 
resume avelumab following steroids taper.
If worsens: 
Treat as Grade 3 to 4

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Dermatological irAEs
Rash
Initial Management
Follow-up Management
Grade 3 to 4
Covering > 30% body surface 
area; life threatening 
consequences
Withhold avelumab for Grade 3
Permanently discontinue for Grade 4 or 
recurrent Grade 3
Consider skin biopsy
Dermatology consult
1 to 2 mg/kg/day prednisone or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections
If improves to Grade ≤ 1:
Taper steroids over at least 1 month and add 
prophylactic antibiotics for opportunistic 
infections
Table 11: Treatment Modifications for Pulmonary Immune-related AEs
Pulmonary irAEs
Pneumonitis
Initial Management
Follow-up Management
Grade 1
Radiographic changes only
Consider withholding avelumab
Monitor for symptoms every 2 to 3 days
Consider Pulmonary and Infectious 
Disease consults
Re-assess at least every 3 weeks
If worsens:
Treat as Grade 2 or Grade 3 to 4
Grade 2
Mild to moderate new 
symptoms
Withhold avelumab
Pulmonary and Infectious Disease 
consults
Monitor symptoms daily, consider 
hospitalization
1 mg/kg/day prednisone or equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Consider bronchoscopy, lung biopsy
Re-assess every 1 to 3 days
If improves:
When symptoms return to Grade ≤ 1, taper 
steroids over at least 1 month and then 
resume avelumab following steroids taper
If not improving after 2 weeks or worsening: 
Treat as Grade 3 to 4
Grade 3 or 4
Grade 3:Severe new symptoms; 
New / worsening hypoxia;
Grade4: Life-threatening
Permanently discontinue avelumab
Hospitalize
Pulmonary and Infectious Disease 
consults
1 to 2 mg/kg/day prednisone o equivalent
Add prophylactic antibiotics for 
opportunistic infections
Consider bronchoscopy, lung biopsy
If improves to Grade ≤ 1:
Taper steroids over at least 1 month
If not improving after 48 hours or worsening:
Add additional immunosuppression (for 
example, infliximab, cyclophosphamide, IV 
immunoglobulin, or mycophenolate mofetil)

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Table 12: Treatment Modifications for Hepatic Immune-related AEs
Hepatic irAEs
Liver test elevation
Initial Management
Follow-up Management
Grade 1
Grade 1 AST or ALT > ULN to 
3.0 x ULN and / or total 
bilirubin > ULN to 1.5 x ULN
Continue avelumab
Continue liver function monitoring
If worsens:
Treat as Grade 2 or 3 to 4
Grade 2
AST or ALT > 3.0 to ≤ 5 x 
ULN and/or total bilirubin > 
1.5 to ≤ 3 x ULN
Withhold avelumab
Increase frequency of monitoring to 
every 3 days
If returns to Grade ≤1:
Resume routine monitoring, resume avelumab
If elevations persist > 5 to 7 days or worsen:
Treat as Grade 3 or 4
Grade 3 to 4
AST or ALT > 5 x ULN and/or 
total bilirubin > 3 x ULN
Permanently discontinue avelumab
Increase frequency of monitoring to 
every 1 to 2 days 
1 to 2 mg/kg/day prednisone or  
equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Consult gastroenterologist/ hepatologist
Consider obtaining MRI/CT scan of liver 
and liver biopsy if clinically warranted
If returns to Grade ≤ 1:
Taper steroids over at least 1 month and add 
prophylactic antibiotics for opportunistic 
infections
If does not improve in > 3 to 5 days, worsens 
or rebounds:
Add mycophenolate mofetil 1 gram (g) twice 
daily
If no response within an additional 3 to 5 
days, consider other immunosuppressants per 
local guidelines
Table 13: Treatment Modifications for Renal Immune-related AEs 
Renal irAEs
Creatinine Increase
Initial Management
Follow-up Management
Grade 1
Creatinine increased > ULN to 
1.5 x ULN
Continue avelumab
Continue renal function monitoring
If worsens:
Treat as Grade 2 or 3 to 4
Grade 2 to 3
Creatinine increased > 1.5 and 
≤  6 x ULN
Withhold avelumab
Increase frequency of monitoring to 
every 3 days
1 to 2 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
If returns to Grade ≤1:
Taper steroids over at least 1 month, and 
resume avelumab following steroids taper.
If worsens: 
Treat as Grade 4.

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Renal irAEs
Creatinine Increase
Initial Management
Follow-up Management
Grade 4
Creatinine increased > 6 x ULN
Permanently discontinue avelumab
Monitor creatinine daily
1 to 2 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
Nephrology consult
If improves to Grade ≤ 1:
Taper steroids over at least 1 month
Table 14: Treatment Modifications for Cardiac Immune-related AEs
Cardiac irAEs
Myocarditis
Initial Management
Follow-up Management
New onset of cardiac signs or 
symptoms and / or new 
laboratory cardiac biomarker 
elevations (e.g., troponin, CK-
MB, BNP) or cardiac imaging 
abnormalities suggestive of 
myocarditis
Withhold avelumab.
 Hospitalize.
In the presence of life threatening cardiac 
decompensation, consider transfer to a 
facility experienced in advanced heart 
failure and arrhythmia management.
Cardiology consult to establish etiology 
and rule out immune- mediated 
myocarditis.
Guideline based supportive treatment as 
per cardiology consult.*
Consider myocardial biopsy if 
recommended per cardiology consult.
If symptoms improve and immune-mediated 
etiology is ruled out, re-start avelumab.
If symptoms do not improve/worsen, viral 
myocarditis is excluded, and immune-
mediated etiology is suspected or confirmed 
following cardiology consult, manage as 
immune-mediated myocarditis.
Immune-mediated myocarditis
Permanently discontinue avelumab.
Guideline based supportive treatment as 
appropriate as per cardiology consult.*
 1 to 2 mg/kg/day. prednisone or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections. 
Once improving, taper steroids over at least 1 
month.
If no improvement or worsening, consider 
additional immunosuppressants (e.g., 
azathioprine, cyclosporine A)
*Local guidelines, or e.g., European Society of Cardiology or American Heart Association guidelines
European Society of Cardiology guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-
Guidelines
American Heart Association guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 

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Table 15: Treatment Modifications for Endocrine Immune-related AEs
Endocrine irAEs
Endocrine disorder
Initial Management
Follow-up Management
Grade 1 or Grade 2 
endocrinopathies (hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Continue avelumab
Endocrinology consult if needed
Start thyroid hormone replacement therapy (for 
hypothyroidism), anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for adrenal 
insufficiency) or insulin (for Type I diabetes 
mellitus) as appropriate.  
Rule-out secondary endocrinopathies (i.e., 
hypopituitarism / hypophysitis)
Continue hormone 
replacement/suppression and 
monitoring of endocrine function 
as appropriate.
Grade 3 or Grade 4 
endocrinopathies (hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Withhold avelumab
Consider hospitalization
Endocrinology consult
Start thyroid hormone replacement therapy (for 
hypothyroidism), anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for adrenal 
insufficiency) or insulin (for type I diabetes 
mellitus) as appropriate.  
Rule-out secondary endocrinopathies (i.e., 
hypopituitarism / hypophysitis)
Resume avelumab once 
symptoms and/or laboratory tests 
improve to Grade < 1 (with or 
without hormone 
replacement/suppression).
Continue hormone 
replacement/suppression and 
monitoring of endocrine function 
as appropriate.
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies)
If secondary thyroid and/or adrenal insufficiency 
is confirmed (i.e., subnormal serum FT4 with 
inappropriately low TSH and/or low serum 
cortisol with inappropriately low ACTH) :
Refer to endocrinologist for dynamic 
testing as indicated and measurement of 
other hormones (FSH, LH, GH/IGF-1, 
PRL, testosterone in men, estrogens in 
women) 
Hormone replacement/suppressive therapy 
as appropriate 
Perform pituitary MRI and visual field 
examination as indicated
If hypophysitis confirmed:
Continue avelumab if mild symptoms with 
normal MRI. Repeat the MRI in 1 month
Withhold avelumab if moderate, severe or 
life-threatening symptoms of 
hypophysitis and/or abnormal MRI. 
Consider hospitalization. Initiate 
corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) followed by 
corticosteroids taper during at least 1 
month.
Add prophylactic antibiotics for 
opportunistic infections.
Resume avelumab once 
symptoms and hormone tests 
improve to Grade < 1 (with or 
without hormone replacement).
In addition, for hypophysitis with 
abnormal MRI, resume avelumab 
only once shrinkage of the 
pituitary gland on MRI/CT scan 
is documented. 
Continue hormone 
replacement/suppression therapy 
as appropriate.

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Table 16: Treatment Modifications for Other Immune-related AEs
Other irAEs (not described above)
Grade of other irAEs
(NCI CTCAE v5)
Initial Management
Follow-up Management
Grade 2 or Grade 3 clinical 
signs or symptoms suggestive 
of a potential irAE
Withhold avelumab pending clinical 
investigation
If irAE is ruled out, manage as appropriate 
according to the diagnosis and consider re-
starting avelumab
If irAE is confirmed, treat as Grade 2 or 3 
irAE.
Grade 2 irAE  
Or
 first occurrence of Grade 
3 irAE
Withhold avelumab
1 to 2 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections
Specialty consult as appropriate
If returns to Grade < 1:
Taper steroids over at least 1 month, and 
resume avelumab following steroids taper.
Recurrence of same Grade 
3 irAEs
Permanently discontinue avelumab
1 to 2 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections
Specialty consult as appropriate
If returns to Grade < 1:
Taper steroids over at least 1 month
Grade 4
Permanently discontinue avelumab
1 to 2 mg/kg/day prednisone or 
equivalent and/or other 
immunosuppressant as needed.
Add prophylactic antibiotics for 
opportunistic infections
Specialty consult
If improves to Grade ≤ 1:
Taper steroids over at least 1 month
Requirement for 10 mg 
per day or greater 
prednisone or equivalent 
for more than 12 weeks for 
reasons other than 
hormonal replacement for 
adrenal insufficiency
Persistent Grade 2 or 3 
irAE lasting 12 weeks or 
longer
Permanently discontinue avelumab
Specialty consult
Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine 
aminotransferase; AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; CK-MB=creatine kinase MB;  
CT= computed tomography; FSH=follicle-stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth 
factor 1; irAE=immune related adverse event; IV=intravenous; LH=luteinizing hormone; MRI=magnetic resonance 

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imaging; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; 
PRL=prolactin;T4=thyroxine; TSH=thyroid stimulating hormone; ULN=upper limit of normal.
3.3.3
Unacceptable Toxicity
Occurrence of any of the adverse events listed in Section  3.1.1 after the first 28 days of treatment 
in the Dose Expansion cohort (Cohort 2) will lead to permanent discontinuation of protocol 
therapy, but will not be deemed a DLT for purposes of dose escalation. Any patient who requires 
corticosteroid treatment for an avelumab related irAE will have their rhIL-15 discontinued 
regardless of their perceived tolerance of the cytokine. Patients may continue single agent 
avelumab after halting rhIL-15 treatment if considered appropriate in the standard avelumab irAE 
decision algorithm.
3.4
STUDY INTERVENTION COMPLIANCE
Adherence to the protocol will be verified by reviewing the Medical Administration Record 
(MAR) section of the medical record, which will serve as source documentation.
3.5
ON STUDY EVALUATIONS
Prior to avelumab administration (Day 8 and 22), pre-dose assessments must be performed (up to 
3 days prior). After Cycle 1, pre-dose assessments may be performed up to 3 days prior to a cycle 
except where otherwise noted. In the event that the patient’s condition is deteriorating, laboratory 
evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. The 
results from all procedures/tests must be reviewed prior to initiation of each cycle of treatment for 
consideration of dose modifications and delay of therapy. 
Treatment with rhIL-15 and avelumab will continue for 4 cycles or until disease progression, 
unacceptable treatment-related toxicity or other reasons outlined in Section 3.9.1.
Refer to the Study Calendars (Section APPENDIX F) for a complete list of procedures to be 
performed at each scheduled study visit. See also Section 5  for all samples to be collected for 
correlative research. During treatment, it is expected that all laboratory and clinical assessments 
be conducted at the NIH (including post-treatment imaging evaluations); results from outside NIH 
will only be accepted at the discretion of the investigator.
3.6
POST-TREATMENT EVALUATIONS
Post treatment evaluations (i.e., End of Treatment Visit) will be performed approximately 30 days 
after the last dose of protocol treatment. If a subject initiates a new anti-cancer therapy within 30 
days after the last dose of trial treatment, the 30-day safety follow-up visit must occur before the 
first dose of the new therapy, if possible.  If the patient cannot return to the Clinical Center for this 
visit, a request will be made to have a local physician or laboratory collect a CBC with differential 
and send the results. If this is not possible, patients may be assessed by telephone or email for 
symptoms.
Unless otherwise noted, follow-up will occur at the following time point: every 60 days (± 7 days) 
for 6 months; then every 90 days (± 14 days) for 2 years; then every six months (± 28 days) for the 
duration of the study until the start of a new anti-neoplastic therapy, disease progression, death or 
end of study. Any other evaluations and tests should be performed as clinically indicated. 
Upon disease progression or initiation of other anti-cancer therapy, contact will be for survival 
only until the subject is off study (i.e., every 3 months [±4 weeks]) for the duration of the study. 
See Study Calendar (Section APPENDIX F) for additional information. Any adverse events 

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which are present at the time of discontinuation should be followed in accordance with the safety 
requirements.  
Patients who are removed from study before completing protocol treatment will be followed 
until completion of the Safety Follow-up Visit or until death, whichever occurs first. Patients 
removed from study for unacceptable adverse event(s) will be followed until resolution or 
stabilization of the adverse event.
3.6.1
Safety Follow-Up Visit
The safety follow-up visit should occur 30 days (±7 days) after the last dose of trial treatment, or 
before the initiation of a new anti-cancer treatment, whichever comes first. Required testing is as 
noted in the Study Calendars (Section APPENDIX F). All AEs that occur prior to the Safety 
Follow-Up Visit should be recorded.  Patients with an ongoing, treatment-related AE of Grade > 
1 will be followed until the resolution of the AE to Grade 0-1, stabilization of the AE in the opinion 
of the investigator, or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  
SAEs that occur within 30 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded. 
3.6.2
Extended Safety Follow-up
Given the potential risk for delayed immune-related toxicities, safety follow-up must be performed 
up to 90 (+14) days after the last dose of avelumab administration. This may be performed either 
via a clinic visit or via a telephone call/email with subsequent clinic visit requested in case any 
concerns are noted during the telephone call/email.
3.6.3
Follow-Up Visits- Prior to Disease Progression 
Patients who complete trial treatment or discontinue treatment without evidence of disease 
progression will move into the Follow-up Phase and may be assessed every 60 days (± 7 days) for 
6 months; then every 90 days (± 14 days) for 2 years; then every six months (± 28 days) for the 
duration of the study after finishing treatment by radiologic imaging or other clinical assessments 
to monitor disease status. Every effort should be made to collect information regarding disease 
status until the start of new anti-neoplastic therapy, disease progression, death, or end of the study 
If the patient cannot return to the Clinical Center for any of these visits, a request will be made to 
have a local physician or laboratory collect a CBC with differential and send the results. If this is 
not possible, patients may be assessed by telephone or email for symptoms. 
3.6.4
Follow-Up Visits – Survival/Post-Disease Progression
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase and should be contacted (e.g., phone, email, etc.; 
in-person visit not required) at least every 3 months for the duration of the study to collect 
information on new anti-cancer treatments received and to assess for survival status until death, 
withdrawal of consent, or the end of the study, whichever occurs first (see Study Calendar).
3.7
STUDY CALENDAR
See APPENDIX F.

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3.8
COST AND COMPENSATION 
3.8.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not 
covered by insurance company.  Medicines that are not part of the study treatment will not be 
provided or paid for by the NIH Clinical Center.
3.8.2
Compensation
Subjects will not be compensated.
3.8.3
Reimbursement
On this study, the NCI will cover the cost for some of the expenses.  Some of the costs may be 
paid directly by the NIH and some may be reimbursed to the subject.  Someone will work with 
subjects to provide more information
3.9
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all patients complete a safety visit 
approximately 30 days following the last dose of study therapy. Additional safety visits and follow-
up will continue as per Section 3.6.
3.9.1
Criteria for removal from protocol therapy
In the absence of treatment delays due to adverse event(s), treatment may continue for 4 cycles or 
until one of the following criteria applies. Patients who meet the following criteria should be 
discontinued from protocol therapy:

Completion of protocol therapy (i.e., up to 4 cycles) 

Clinical or Disease progression

Intercurrent illness that prevents further administration of treatment

Unacceptable toxicities as listed in Section 3.1.1 or those toxicities listed in Section 3.3 
that require treatment to be stopped.

Subject’s request to withdraw from protocol therapy

Investigator’s decision to withdraw the patient

Subject’s non-compliance with trial treatment or procedure requirements that requires 
removal in the opinion of the PI 

Pregnancy

Study is cancelled for any reason 

The drug manufacturer can no longer proved the study agent
3.9.2
Off-Study Criteria

Subject requests to be withdrawn from study

Subject is lost to follow-up*

Death 

Study is cancelled for any reason

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3.9.3
Lost to Follow-up
* A participant will be considered lost to follow-up if he or she fails to return for 3 consecutive 
scheduled visits without good cause and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site will attempt to contact the participant within 1-3 business days (to take into 
account the weekend) to reschedule the missed visit, and counsel the participant on the 
importance of maintaining the assigned visit schedule and ascertain if the participant 
wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file. 

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/MEASURES
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial. If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.
For premedication and supportive care measures, see Section 3.2.1, 3.2.2 and 3.2.3.
4.1
ACCEPTABLE MEDICATIONS
All treatments that the investigator considers necessary for a subject’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care.  All 
concomitant medication will be recorded on the case report form (CRF) including all prescription, 
over-the-counter (OTC), herbal supplements, and IV medications and fluids. If changes occur 
during the trial period, documentation of drug dosage, frequency, route, and date may also be 
included on the CRF.
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  
4.2
PROHIBITED MEDICATIONS
Patients are prohibited from receiving the following therapies during treatment on this trial:

Other therapy for the disease under study not specified in this protocol, unless specifically 
noted as permitted

Investigational agents other than rhIL-15 and avelumab

Radiation therapy 

Live vaccines within 30 days prior to the first dose of trial treatment and while participating 
in the trial.  Examples of live vaccines include, but are not limited to, the following: 

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measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine 
and Flu Mist. 
Patients who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from study treatment. Patients may receive 
other medications that the investigator deems to be medically necessary.
5
CORRELATIVE STUDIES
5.1
SUMMARY
This study will attempt to use rhIL-15 to increase NK cell number and activity, thereby enhancing 
the ADCC of avelumab in treatment of patients with relapsed and refractory metastatic PD-L1+ 
ccRCC. ADCC capacity of ex vivo PBMCs will be tested on PD-L1-expressing cell lines before, 
during and after protocol treatment. Differences in immune cell subsets associated with 
administration will be followed throughout treatment to both study the effects of combined rhIL-
15/avelumab therapy on the immune system, and to identify potential biomarkers that would be 
predictive of response.
Time Points
Sample
Collection Details*
Baselin
e
C1 
D8
C1 
D22
C2-4
D1
C2-4 
D8
Follow 
up#
Supervising 
Laboratory/ 
Investigator
Blood Samples
Lymphocyte subset 
testing
2 x 10mL K2EDTA 
(lavender-top) tubes
X
X
(X)
(X)
(X) 1
Immunology 
section, NIH 
CC
ADCC of avelumab
3 x 10mL sodium 
heparin green-top 
tubes
(X)2
(X)2
(X) 2
Waldmann
(Leidos CSL)
Circulating tumor DNA, 
plasma banking
1 x 10mL K2EDTA 
tube
1 x 10mL 
Streck/BCT tube
X
(X)
(X)
X3
 (Leidos CSL)
Anti-IL-15 antibodies
1 x 4mL SST tube
X
X
X1
(Leidos CSL)
Tissue Samples
Tissue immune cell 
subsets by 
Immunohistochemistry
Two core biopsy 
samples in formalin
X**
(X)***
(X)***
(X)
 (Laboratory 
of Pathology)

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Time Points
Supervising 
(X) = Optional
*Tubes/media may be adjusted at the time of collection based upon materials available or to ensure the best samples are 
collected for planned analyses.
** Pretreatment tumor biopsy sample: may use the archival tissue or the freshly obtained tumor biopsy used to assess PD-L1 
expression for eligibility   
*** The on-treatment tumor biopsy may be obtained anywhere between cycle 1 day 22 and cycle 2 day 4 at whichever time is 
most expedient for the patient and Interventional Radiology
#Subjects who discontinue treatment for a reason other than disease progression and who do not start new treatment should 
continue to have study bloods collected at the scheduled time points.
1 At the end of treatment only. 
2 For ADCC of avelumab, Baseline and C1D8 samples should be collected for at least one patient per dose level, and for at 
least three patients at the MTD; C2-6 samples may be collected at the discretion of the PI but are not required.
3 At each follow-up visit prior to disease progression, as specified in Section 3.6.3 
5.2
SAMPLE COLLECTION AND PROCESSING
5.2.1
Blood Samples
All blood samples will be drawn by NIH Clinical Center phlebotomy, outpatient clinic, or day 
hospital staff
5.2.2
Summary
The planned analyses described below may be done on leftover and/or shared sample portions 
from the respective laboratories, as needed.  In addition to the prospectively collected samples 
below, leftover portions of samples sent for routine laboratory testing (e.g., plasma from 
CBC/hematologies) may also be retrieved for research tests prior to being discarded. The planned 
prospective analyses are identified below; laboratories may share resources or collaborate on 
analyses, if appropriate.
Portions of all samples may be banked for future research analyses; prospective consent will be 
obtained during the informed consent process.  
The blood drawing limits for research purposes are as follows:  

For adult subjects:  The amount of blood that may be drawn from adult patients for 
research purposes shall not exceed 10.5 mL/kg or 550 mL, whichever is smaller, over 
any eight-week period.
Unless otherwise noted, Clinical Research personnel will use courier or escort service to arrange 
delivery of samples to destinations listed in subsections below. 
5.2.3
Blood Samples
5.2.3.1
Lymphocyte subset testing by flow cytometry (FACS)

Whole blood will be collected for each timepoint in 10mL EDTA tubes that are 
gently invert tubes 8-10 times immediately after collection to thoroughly mix the 
sample to prevent clotting and loss of mononuclear cells intended to be analyzed.  

Labels will be affixed to these tubes with the patient's name, date of birth, date and 
time of the blood draw by the hospital staff who obtained the samples. 

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
One each of the 2 EDTA tubes drawn at the timepoints summarized in table 2 will be 
delivered to 2 separate locations: 
o
Routine LYMB flow cytometry panels will be transported to Immunology Lab, 
NIH Clinical Center Bldg. 10/ Room 2C410 for analysis. If the Immunology 
Section Laboratory is unable to perform the complete LYMB flow cytometry 
panels for the specified timepoint, the analysis maybe omitted or replaced with 
the more limited “TBNK panel.”
o
Clinical Research Staff will arrange for the cells collected for more extensive 
bulk flow cytometry studies performed at the completion of all subjects’ protocol 
treatments to be picked up by the Frederick courier from either Phlebotomy or 
the 12 Floor Outpatient Clinic (OP12) and conveyed to the CLS laboratory 
Frederick for controlled freezing and storage .
5.2.3.2
Antibody-dependent cell cytotoxicity (ADCC) of avelumab

Whole blood will be collected for each timepoint in 10mL sodium heparin tubes that 
are gently invert tubes 8-10 times immediately after collection .

Labels will be affixed to these tubes with the patient's name, date of birth, date and time 
of the blood draw by the hospital staff who obtained the samples. 

Clinical Research personnel will arrange for these samples to be delivered to Clinical 
Support Laboratory, Leidos Biomedical Research, Inc.in Frederick, MD, for processing 
per established laboratory techniques storage, and batch analysis by the Waldmann 
Laboratory.
5.2.3.3
Cell-free DNA (cfDNA), and circulating tumor DNA (ctDNA) and plasma banking

Collect 10 mL of blood in one cell-free DNA (e.g., Streck BCT/collection tubes) and 
10 mL of blood in one K2EDTA tube; gently invert the tubes 8-10 times 
immediately after collection. 

Labels listing the patient's name, date of birth, date and time of the blood draw will 
be affixed to all the tubes by the staff person who obtained the samples. each).

Clinical Research personnel will arrange for these samples to be delivered to Clinical 
Support Laboratory, Leidos Biomedical Research, Inc.in Frederick, MD for sample 
processing per established laboratory techniques and maintained within standard 
operating procedures in the laboratory. 
5.2.3.4
Anti-IL-15 antibody testing

Collect blood in a 4mL SST tube; gently invert tubes 8-10 times immediately after 
collection.

Clinical Research personnel will arrange for these samples to be delivered to Clinical 
Support Laboratory, Leidos Biomedical Research, Inc.in Frederick, MD, for storage 
and further analysis.

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
Samples will be batch processed and analyzed per the procedure outlined in 
APPENDIX D after the last patient has been enrolled and completed treatment, or 
sooner if there is clinical suspicion for anti-IL-15 antibody formation.
5.2.4
Tissue Samples
5.2.4.1
PDL-1 testing for immunohistochemistry (IHC)

If a prospective patient’s tumor has not already assessed for PD-L1 expression as listed 
in the eligibility Section 2.1 archival block(s) or slides (i.e., at least 15 unstained slides, 
5-microns) is/are required at screening. Patients with prior tumor biopsies performed 
at NIH or outside institutions may make specimen blocks available to the NCI 
Pathology Department for analysis. If no prior biopsies are available at the time of 
screening, a punch or core biopsy of an appropriate easily accessible tumor deposit will 
be performed during screening period to confirm PDL-1 status for eligibility. Patients 
with lymph node and/or visceral involvement will undergo an 18g core biopsy 
performed by the Department of Radiology and Imaging Sciences’ Interventional 
Radiologists (IR).  

Prior specimen blocks will be sent to NCI Pathology Department via FedEx. For 
patients with no prior samples who undergo biopsy as part of screening, fresh samples 
will be placed in transport saline or 10% formalin PBS and  sent to the Department of 
Laboratory Medicine (DLM)/ NCI Laboratory of Pathology (LP) (Section 5.1 and 5.2) 
for concurrent routine histologic analysis and reporting and IHC testing for PD-L1 
expression by tumor area  Lab).
5.2.4.2
Optional Tissue Samples 

Archival block(s)/ slides or fresh tumor tissue that was obtained to determine 
eligibility expression of PD-L1 will also be used for pre-treatment IHC analysis of 
lymphocyte subsets and other immune molecules as described below in section 5.3.5. 
If no prior sample is available, core biopsies will be performed during the screening 
period by IR and the specimens will be transported to NCI pathology as described 
previously in section 5.2.4.1. 

The optional, on-treatment research biopsy will be obtained during the period from 
cycle 1 day 22 to cycle 2 day 4 and sent to the Laboratory of Pathology as described 
above  in section 5.2.4.1.  and under the analyses described below in section 5.3.5. 
5.3
BIOMARKER AND RESEARCH METHODS
The technology platforms that are able to interrogate genomic structure and function are constantly 
in flux; therefore, the exact nature of the methodologies that will be employed will be assessed at 
the time that the samples are collected and ready for analysis. The protocol will be amended at that 
time, if needed, to describe the intended techniques prior to initiating the analyses
The following are technologies that are currently in use for each planned analysis:  
5.3.1
Flow Cytometry of Peripheral Blood Lymphocytes
Immunohistochemical (IHC) analyses of tumor tissue samples, including but not necessarily 
limited to CD2, CD3, CD4, CD5, CD7, CD8, CD14, CD16, CD20, CD25, CD38, CD45RA, 

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CD45RO, CD56, CD62L, CD69, CD79a/CD79b, CD122, Foxp3, perforin, gamma/delta, CXCR3, 
CCR4, and NKG2D.
5.3.2
Immune Subset Analysis
Peripheral blood mononuclear cells (PBMC) will be assessed using multiparameter flow cytometry 
listed in section 5.3.1 and used to define cytotoxic CD8+ T-cells,  Tregs, T-effector cells, Th1, Th2 
and Th17+ CD4+ T-cells, NK cells and subsets, monocyte subsets, MDSC subsets. Assessment 
may include functional markers, i.e. PD-1, Tim-3, CTLA-4, PD-L1, HLA-DR, Ki67 and/or CD40.
5.3.3
ADCC Analysis
Peripheral blood mononuclear cells (PBMCs) should be isolated by Ficoll-Hypaque Density 
Gradient Centrifugation. The viable cells should be viably frozen and stored in liquid nitrogen. 
The ADCC assay will be performed on the same occasion for all samples of a given patient. Vials 
of frozen cells will be thawed using standard procedures 18 hours before the assay in accord with 
our experience with normal donors. 1.5 million of patient’s PBMCs obtained before and on day 
15 following IL-15 injection will be tested in aliquots as follows:  

Tested alone

Tested with untreated PD-L1-expressing Raji cells, and with the Raji cells coated with 
avelumab for 5 hours. 

In addition, we may utilize an ATL cell line in addition to Raji cells.  These cell populations 
will be stained with CD107, CD3, CD56, and CD94.
5.3.4
cfDNA/ctDNA
Since the methods of molecular monitoring in the peripheral blood is an emerging field with 
numerous technologies under development, the storage of peripheral blood mononuclear cells 
(PBMC), serum, and plasma will all be performed allowing for future comparison of the different 
compartments for analytes that include cell-free circulating tumor DNA (ctDNA), and RNA 
sequencing of circulating tumor cells. Studies to be performed on these samples include: 
cfDNA/ctDNA for liquid genotyping as a non-invasive dynamic monitoring of disease as well as 
monitoring for individual molecular aberrations that may be present for individual patients. 
Changes in the level of ctDNA have been shown to correlate with response to tyrosine kinase 
inhibitor (TKI) treatment for mRCC and will be quantitated to assess response to therapy [81, 82]. 
Analysis of ctDNA for characteristic mutations present in ccRCC will also be performed [83]. 
Additional samples will be stored for later bulk analysis of chromosomal copy number instability 
(CNI) which recently has been identified as a possible surrogate marker of response to 
immunotherapy [84, 85] and to analyze for loss of function PBrm1 mutations that was recently 
reported to be associated with increased clinical benefit in ccRCC patients after ICI treatment [86].
5.3.5
Immunohistochemical Analyses of Optional Tissue Samples
Standard H&E pathologic examination and IHC listed in section 5.3.1 for peripheral blood 
lymphocytes, will also be performed on the tissue samples obtained to characterize the in situ 
immune response.  In addition, other important immune molecules such as PD-1, Fas, FasL, 
KIR2DL1, NKG2A, NKG2D, TIGID will be performed using established procedures for the 
Laboratory of Pathology. In situ cytokine analysis (e.g., IL-6, IL-10, interferon beta, TNF-alpha) 
using established laboratory procedures.

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5.3.6
Other Analyses
Testing for anti-IL-15 antibodies will be on a regular basis or in bulk to determine if any subject 
developed anti-IL-15 antibodies that may have affected their response to therapy. Since no 
subject’s treatment with CIV rhIL-15 [70, 87]have developed antibodies to the cytokine, this test 
is no longer required prior to the administration of any cycle of treatment. 
5.3.7
Future Use
Any blood, tissue, or other products or portions leftover from other analyses will be stored for 
future research.  
5.4
SAMPLE STORAGE, TRACKING, AND DISPOSITION
5.4.1
General
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples 
will not be sent outside NIH without appropriate approvals and/ or agreements, if required.
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are 
remaining at the completion of the protocol will be stored in the conditions described below. The 
study will remain open so long as sample or data analysis continues. Samples from consenting 
subjects will be stored until they are no longer of scientific value or if a subject withdraws consent 
for their continued use, at which time they will be destroyed. 
If the patient withdraws consent the participant’s data will be excluded from future distributions, 
but data that have already been distributed for approved research use will not be able to be 
retrieved.
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will be 
per the requirements of section 7.2.1
All samples that are noted in Section 5.1 to be analyzed by the Waldmann Laboratory will first be 
processed and stored at Clinical Support Laboratory, Leidos Biomedical Research, Inc. in Frederick, 
MD, as per Section 5.4.2.
5.4.2
Clinical Support Laboratory, Leidos Biomedical Research, Inc. in Frederick, MD
The Clinical Support Laboratory, Leidos Biomedical Research, Inc.-Frederick, processes and 
cryopreserves samples in support of IRB-approved, NCI clinical trials. The laboratory is CLIA 
certified for anti-IL15 and certain cytokine measurements and all laboratory areas operate under a 
Quality Assurance Plan with documented Standard Operating Procedures that are reviewed 
annually. Laboratory personnel are assessed for competency prior to being permitted to work with 
patient samples. Efforts to ensure protection of patient information include:

The laboratory is located in a controlled access building and laboratory doors are kept 
locked at all times. Visitors to the laboratory are required to be accompanied by 
laboratory staff at all times.

Hard copy records or electronic copies of documents containing patient information are 
kept in the locked laboratory or other controlled access locations.

An electronic database is used to store information related to patient samples processed 
by the laboratory.

The database resides on a dedicated program server that is kept in a central, locked 
computer facility.

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
The facility is supported by two IT specialists who maintain up to date security features 
including virus and firewall protection.

Program access is limited to specified computers as designated by the laboratory 
director. Each of these computers has a password restricted login screen.

The database sample entry program itself is accessed through a password protected 
entry screen.

Upon specimen receipt each sample is assigned a unique, sequential laboratory 
accession ID number. All products generated by the laboratory that will be stored either 
in the laboratory freezers or at a central repository facility are identified by this 
accession ID.

Inventory information will be stored at the vial level and each vial will be labeled with 
both a sample ID and a vial sequence number.

Vial labels do not contain any personal identifier information.

Samples are stored inventoried in locked laboratory freezers and are routinely 
transferred to the NCI-Frederick repository facilities for long term storage.

Access to stored clinical samples is restricted. Investigators establish sample 
collections under “Source Codes” and the investigator responsible for the collections, 
the protocol Principal Investigator, specifies who has access to the collection. 

Specific permissions will be required to view, input or withdraw samples from a 
collection. Sample withdrawal requests submitted to approved laboratory staff by 
anyone other than the repository source code owner are submitted to the source code 
owner for approval. The repository facility will also notify the Source Code holder of 
any submitted requests for sample withdrawal.

It is the responsibility of the Source Code holder (the NCI Principal Investigator) to 
ensure that samples requested and approved for withdrawal are being used in a manner 
consistent with IRB approval.

The Clinical Support Laboratory does perform testing services that may be requested 
by clinical investigators including, but not limited to, immunophenotyping by flow 
cytometry and cytokine testing using ELISA or multiplex platforms.

When requests are submitted by the NCI investigator for shipment of samples outside 
of the NIH it is the policy of the laboratory to request documentation that a Material 
Transfer Agreement is in place that covers the specimen transfer. The laboratory does 
not provide patient identifier information as part of the transfer process but may, at the 
discretion of the NCI investigator, group samples from individual patients when that is 
critical to the testing process.

The NCI investigator responsible for the sample collection is responsible for ensuring 
appropriate approvals and/ or agreements are in place, if required, prior to requesting 
the laboratory to ship samples outside of the NIH.
5.4.3
Hematopathology Section of the Laboratory of Pathology (Tissue samples)
Archival and/or freshly collected and processed tumor tissue may be stored in the 
Hematopathology Section of Laboratory of Pathology until ready for planned and/or future 
research assays if the patient has agreed to allowing specimens to be used in future research studies.  
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within this protocol.  Samples will be stored under conditions appropriate to the type of sample 
and processing (e.g., ambient or frozen).
Tissue that is given to the technician will be assigned an accession number (HP#) in the HP Case 
Logbook; sample tracking also takes place with a FileMaker Pro data base called HP Patient 
Information and Specimen Inventory.   A Patient background sheet may be filled out and filed with 
any accompanying paperwork, with final reports and any supplemental reports that follow added 
as completed.
6
DATA COLLECTION AND EVALUATION
6.1
DATA COLLECTION
6.1.1
Summary
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts.    Primary and final analyzed data will have identifiers so that 
research data can be attributed to an individual human subject participant.
All adverse events (AEs), including clinically significant abnormal findings on laboratory 
evaluations, regardless of severity, will be followed until return to baseline or stabilization of 
event. 
Document AEs from the first study intervention, Study Day 1, through 30 days after the last dose 
of study treatment. After 30 days, only adverse events which are serious and related to the study 
intervention need to be recorded.
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1.
6.1.2
Data Collection/Reporting Exceptions
6.1.2.1
Abnormal Laboratory Values
An abnormal laboratory value will be considered an AE only if the laboratory abnormality is 
characterized by any of the following:

Results in discontinuation from the study

Is associated with clinical signs or symptoms 

Requires treatment or any other therapeutic intervention

Is associated with death or another serious adverse event, including hospitalization

Is judged by the Investigator to be of significant clinical impact

If any abnormal laboratory result is considered clinically significant, the investigator 
will provide details about the action taken with respect to the test drug and about the 
patient’s outcome.

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6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows:
_X_ Coded, linked data in an NIH-funded or approved public repository.  
_X_ Coded, linked data in another public repository
_X_ Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
_X_ Identified or coded, linked data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 
Data will be shared through:
_X_ An NIH-funded or approved public repository.  Insert name or names: ClinicalTrials.gov, 
dbGaP.
_X_ BTRIS (automatic for activities in the Clinical Center)
_X_ Approved outside collaborators under appropriate individual agreements.  
_X_ Publication and/or public presentations.
When will the data be shared?
_X_ Before publication.
_X_ At the time of publication or shortly thereafter.
6.2.2
Genomic Data Sharing Plan
The NIH Genomic Data Sharing plan does not apply to this protocol.
6.3
RESPONSE CRITERIA
6.3.1
Response Assessments 
Tumor response will be assessed radiographically after cycle 2 and 4 treatments are completed 
by the investigator using the Immune-Modified Response Evaluation Criteria In Solid Tumors, 
i.e., imRECIST criteria [88] for Immune-related Best Overall Response (irBOR, Section 6.4.1) 
will be derived based on reported lesion responses at different evaluation time points from the 
first trial treatment administration until immune-related disease progression per irRECIST [88]  
according to the following rules:
irCR = at least two radiographic determinations of  CR at least 4 weeks apart and before irPD
irPR = at least two radiographic determinations of PR or better at least 4 weeks apart and 
before irPD (and not qualifying for an irCR)
irSD = at least one radiographic assessment o f  S D  (or better) ≥ 6 weeks after the 
first trial treatment administration and before irPD (and not qualifying for irCR or irPR).
irPD = at least two consecutive radiographic determinations of PD at least 4 weeks apart.
Only tumor assessments performed before the start of any further anti-cancer treatment will be 
considered in the assessment of irBOR.

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Immune-related Objective Response (irOR) is defined as irCR or irPR according to irRECIST 
from the first trial treatment administration until irPD or death due to any cause. Both irCR and 
irPR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria 
for immune-related response are first met. Also, irPD must be confirmed by a second, 
consecutive assessment at least 4 weeks apart. Immune-related OR rate (irORR) is the 
proportion of subjects with irOR in the analysis set.
6.3.2
Treatment Beyond Radiographic Progression
Recognition of unconventional response events mainly overall tumor regression after the 
appearance of new lesions that previously were assessed as progressive disease by RECIST criteria 
led to the development of Immune-related RECIST (irRECIST) [89] and the Immune-modified 
RECIST (imRECIST) criteria [88]. Adoption of these disease criteria have been seen to allow a 
better assessment of the clinical efficacy of immunotherapy by capturing additional data from 
patients who experienced a tumor flare or delayed impact of the evolving immune response mostly 
in terms of improved DCR and PFS. In order for this approach to not negatively affect patient 
safety certain criteria must be fulfilled to safely allow treatment beyond conventionally assessed 
disease progression. Patients who are treated beyond RECIST defined progressive disease must be 
stable performance status without evidence of clinical deterioration or have any new physiology 
process that requires urgent additional therapy. Patients will have a follow-up restaging assessment 
after the completion of their next cycle of treatment (≥ 4 weeks) to confirm their disease has not 
progressed further and they can safely continue treatment. 
Patient will be re-evaluated for response as outlined in the Study Calendar, APPENDIX F.
6.3.3
Disease Parameters for RECIST criteria
Measurable disease: Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10    mm with 
CT scan, or >10 mm with calipers by clinical exam. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters).
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed.
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are 
considered as non-measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions.

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Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease.
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow- up.
6.3.4
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans).
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used, and the image acquisition 

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protocol should be followed as closely as possible to prior scans. Body scans should be performed 
with breath-hold scanning techniques, if possible.
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and because they are operator dependent, it cannot be guaranteed 
that the same technique and measurements will be taken from one assessment to the next. If new 
lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in 
selected instances.
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:
a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG- 
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD.
c.
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively 
d e s c r i b e d  in the protocol and supported by disease-specific medical literature for 
the indication. However, it must be acknowledged that both approaches may lead to 
false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.
6.3.5
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.

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Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progressions).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
6.3.6
Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).
Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response.
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, not a single lesion increase.
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator).
6.3.7
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria.
For Patients with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
>4 wks. Confirmation**
CR
Non-CR/Non-
PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
>4 wks. Confirmation**
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks. from baseline**

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Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
PD
Any
Yes or 
No
PD
Any
PD***
Yes or 
No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
*
See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion.
**
Only for non-randomized trials with response as primary endpoint.
***
In exceptional circumstances, unequivocal progression in non-target lesions 
may 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.
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised
6.3.8
Duration of Reponses
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.
6.3.9
Relapse Disease (after CR)/ Progressive Disease (after PR/SD)
Relapse Disease (after CR)/ Progressive Disease (after PR/SD) requires the following:

Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size. Increased FDG uptake in a 
previously unaffected site should only be considered relapsed or progressive disease after 
confirmation with other modalities. Thus, a therapeutic decision should not be made 
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
At least a 20% increase from nadir in the SPD of any previously involved nodes, or in a 
single involved node, or the size of other lesions (e.g., splenic or hepatic nodules). To be 
considered progressive disease, a lymph node with a diameter of the short axis of less 
than 1.0 cm must increase by 50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in 
the long axis.

At least a 50% increase in the longest diameter of any single previously identified node 
more than 1 cm in its short axis.
6.3.10 Time to Progression
Time to progression will be measured from the date of protocol consent until death of progressive 
disease is documented.
6.3.11 Progression-Free Survival
Progression-free survival (PFS) is defined as the duration of time from the date of study enrollment 
until time of disease relapse, disease progression, or death, whichever occurs first.
6.3.12 Overall Survival
Overall survival (OS) is defined as the time from the date of study enrollment until time of death 
from any cause.
6.3.13 Event-Free Survival
Event-free survival (EFS) is defined as the duration of time from the date of study enrollment 
until time of disease relapse, disease progression, alternative therapy for renal cell carcinoma 
given (such as radiation), or death, whichever occurs first
6.4
IMMUNE-RELATED RESPONSE CRITERIA (IRRECIST)
Modified immune-related response criteria (irRECIST) will also be employed in this study. This 
new classification is based on the recent learning from clinical studies with cancer 
immunotherapies that even if some new lesions appear at the beginning of a treatment or if the 
total tumor burden does not increase substantially, tumor regressions or stabilizations might still 
occur later. For this trial, the concepts of the irRECIST are combined with RECIST 1.1. Please 
refer to APPENDIX E  for further details.
6.4.1
Immune-related BOR (irBOR) 
The duration of Immune-related best overall response is measured from the time measurement 
criteria are met for irCR or irPR (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). irSD, not meeting criteria for irCR 
or irPR, in absence of irPD.
The duration of overall irCR is measured from the time measurement criteria are first met for irCR 
until the first date that progressive disease is objectively documented. Confirmation of assessment 
might be delayed up to 12 weeks to confirm PD to account for flare.
6.5
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 

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(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN 
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found here.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING
7.2.1
Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that 
meet the definition of an unanticipated problem will need to be reported per these policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here. 
7.2.3
NCI Clinical Director Reporting
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the 
Clinical Director.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut 
at NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.3
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.3.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular weekly basis when patients are being actively 
treated on the trial to discuss each patient. Decisions about dose level enrollment and dose 
escalation if applicable will be made based on the toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator.  Events meeting requirements for expedited reporting as described in section 
7.2.1 will be submitted within the appropriate timelines. 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
8
SPONSOR SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including 

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an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E6 (R2))
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:

Death,

A life-threatening adverse event (see section 8.1.3)

Inpatient hospitalization or prolongation of existing hospitalization
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration 
in health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious 
adverse event.
o
Emergency room visits or stays in observation units that do not result in 
admission to the hospital would not be considered a serious adverse event. The 
reason for seeking medical care should be evaluated for meeting one of the other 
serious criteria.

Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions

A congenital anomaly/birth defect.

Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.3
Life Threatening
An adverse event or suspected adverse reactions 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 or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death. (21CFR312.32)
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.
8.1.5
Relationship to Study Procedure
All AEs will have their relationship to study product assessed using the terms:  related or not 
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
Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.

Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution.
SAEs will be:

Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator.

Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.

Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor.
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited 
reporting requirements are found in section 8.4.
All SAE reporting must include the elements described in section 8.2 
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 
and instructions can be found at: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
Following the assessment of the SAE by OSRO, other supporting documentation of the event may 
be requested by the OSRO Safety and should be provided as soon as possible.

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8.4
WAIVER OF EXPEDITED REPORTING TO CCR
As death due to disease progression is part of the study objectives, and captured as an endpoint in 
this study, it will not be reported in expedited manner to the sponsor. However, if there is 
evidence suggesting a causal relationship between the study drug and the event, report the event 
in an expedited manner according to section 8.3.
8.5
SAFETY REPORTING TO THE PHARMACEUTICAL COLLABORATORS
Reporting will be per the collaborative agreement.
8.5.1
CTEP
Copies of all IND Safety Reports submitted to the FDA should be forwarded electronically to 
CTEPSupportAE@tech-res.com (please provide protocol number in subject line).
8.6
REPORTING PREGNANCY
All required pregnancy reports/follow-up to OSRO will be submitted to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  Forms and instructions 
can be found here: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions  
8.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy become known.
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as SAEs. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented.
8.6.2
Paternal exposure
Male patients should refrain from fathering a child or donating sperm during the study and for 30 
days after the last dose of avelumab.
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 30 after the last dose should, 
if possible, be followed up and documented.
8.7
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected adverse 
reaction only if there is evidence to suggest a causal relationship between the study product and 
the adverse event.  CCR will notify FDA and all participating investigators (i.e., all investigators 
to whom the sponsor is providing drug under its INDs or under any investigator’s IND) in an IND 
safety report of potential serious risks from clinical trials or any other source, as soon as possible, 
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All serious events will be reported to the FDA at least annually in a summary format.
9
CLINICAL MONITORING 
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary and secondary study endpoints; adherence to the protocol, 
regulations, ICH E6, and SOPs; and human subjects protection. This is done through 
independent verification of study data with source documentation focusing on:

Informed consent process

Eligibility confirmation

Drug administration and accountability

Adverse events monitoring

Response assessment
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center.
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct.  
10 STATISTICAL CONSIDERATIONS  
10.1 STATISTICAL HYPOTHESES
10.1.1 Primary Endpoints
Overall Response (CR + PR) by irRECIST 1.1 criteria in patients who receive at least 1 cycle of 
therapy with the 4 mcg/kg dose of rhIL-15.
10.1.2 Secondary Endpoints

Rate and severity of AEs, duration of response, progression-free survival and overall 
survival in patients who receive at least 1 cycle of therapy

Changes in percentage and absolute number of peripheral blood lymphocyte subsets.

Quantitation of ADCC performed ex vivo on PBMCs obtained from the patients before and 
during treatment.

Characterization of changes in immune cell infiltrates of tumor deposits by 
immunohistochemical and molecular analysis of core biopsies obtained before and during 
treatment
10.2 SAMPLE SIZE DETERMINATION
The primary objective of this trial is to determine the efficacy of combination treatment of CIV 
rhIL-15 on days 1-5 and IV anti PDL-1 avelumab on day 8 and 22 of the 28-day cycle in patients 
with treatment refractory PD-L1+ (≥ 5%) metastatic clear-cell renal carcinoma in terms of overall 
response. All patients must have failed or relapsed and have progressive disease after at least 2 
prior therapies that include multityrosine kinase inhibitor like axitinib or sunitinib and an anti-PD1 

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or PD-L1 ICI  therapy like nivolumab. The primary endpoint will be overall response (OR) per 
irRECIST 1.1 criteria. 
A Simon two stage Simon Optimal Design will be used for the analysis of the primary endpoint of 
overall response rate. A minimum of 12 (3 in the 2mcg/kg safety run-in cohort (Cohort 1) and 9 
evaluable in the first stage) and maximum of 25 patients will be enrolled in order to have 17 
evaluable patients treated at the recommended phase 2 dose for the CIV rhIL-15 schedule at dose 
4 mcg/kg/day. A maximum of 19 patients may be enrolled in the phase 2 part of this trial to 
compensate for inevaluable patients. The sample size for this trial is based on the plan for 3 to 6 
patients treated in the 2 mcg/kg/day safety run-in cohort and to accurately assess target 25% 
response rate in the 4 mcg/kg dosing cohort with a power of 80% to determine the feasibility if 
this rate were true. The overall Type I error was set at 5% and power at 80% that assumes a null 
hypothesis success rate of 5% versus a treatment with a 25% response rate.  Patients treated in the 
2 mcg/kg/day safety cohort will not be included in the primary end point analysis but will be 
included in the safety cohort and be assessed for the secondary endpoints.
Stage 1 for the 4 mcg/kg dose level will consist of 9 evaluable patients to provide evidence of 
effectiveness and safety. If at least 1 of the 9 patients achieves a radiographic response (> 20% 
reduction in tumor volume) the study will be allowed to recruit the total sample size of 17 evaluable 
patients, otherwise it will be stopped for futility (Stage I boundary). The second stage of the design 
requires 3 or more of the 17 patients to have a positive response for the treatment to be considered 
worthy of further investigation. If the null hypothesis is true, there is a 63% chance of terminating 
after Stage I. If the probability of success is actually 0.25, there is a 92% chance that 1 or more 
patients will exhibit a 20% reduction in tumor volume at Stage I. Patients discontinued from the 
trial will not be replaced and counted in an "Intent to Treat" analysis as evaluable and treatment 
failures. At the end of the trial, we will report poor performance if the treatment is rejected at Stage 
I, not meeting the criteria of at least 1 success in 9 cases. If there is no success at Stage II (at most 
2 responses in 17 patients), we will report a failure to reject the null hypothesis using the 
conditional probability of the added patients.
To ensure that this combination, which has not been administered to patients previously, and the 
dose levels chosen for CIV rhIL-15 are safe, 3 to 6 patients will be treated at the 2 mcg/kg/day 
dose level to confirm the absence of dose limiting toxicities. Once the safety of the 2 mcg/kg dose 
level is confirmed the first 3 or 6 patients treated at the intended phase II dose of 4 mcg/kg/day 
will be evaluated likewise for dose limiting toxicities. If unacceptable toxicity is observed in ≥ 2 
of the first 3 or 6 patients treated at these dose levels, entry into the trial and all treatment will be 
halted to review the safety data to determine if the treatment plan should be altered or the study 
terminated. If DLT that halts the trial is not observed in these safety run-in cohorts, the trial will 
proceed to the efficacy assessment as specified above. The protocol will be amended to include 
information from the Safety Run-in cohorts prior to opening phase II. 
10.2.1 Early stopping criteria
An early stopping criterion for toxicity for the whole trial itself would be if ≥ 2 of the first 9 or ≥ 
4 of the first 17 patients has unacceptable toxicity or an irAE that required discontinuation of 
avelumab and/or initiation corticosteroid treatment.

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10.3 POPULATION FOR ANALYSES
10.3.1 Evaluable for Toxicity
All patients will be evaluable for toxicity from the time of their first treatment with rhIL-15 and 
avelumab.
10.3.2 Evaluable for objective response
Only those patients who have measurable disease present at baseline and have received at least 
one cycle of therapy with 4mcg/kg dose of rhIL-15, will be assessed on an intent to treat basis. 
Patients who discontinue treatment or die and are not restaged will be considered to be non-
responders and included in calculating the response rate. Patients will have their response classified 
according to the definitions stated above, Section 6.3. (NOTE:  Patients who exhibit objective 
disease progression prior to the end of Cycle 1 will also be considered evaluable).
10.3.3 Evaluable for Non-Target Disease Response
Patients who have lesions present at baseline that are evaluable but do not meet the definitions of 
measurable disease and have received at least one cycle of therapy will be assessed on an intent to 
treat basis. Patients who discontinue treatment or die and are not restaged will be considered to be 
non-responders. The response assessment is based on the presence, absence, or unequivocal 
progression of the lesions.
10.4 STATISTICAL ANALYSES
10.4.1 General Approach
The response rate will be determined and reported along with a 95% confidence interval using the 
Agresti-Coull method [90]. Other time-to-event outcomes will be reported using Kaplan-Meier 
curves.  
10.4.2 Analysis of Secondary Endpoints
Secondary clinical endpoints of the rate and severity of AEs will be summarized by grade and type 
of toxicity. The progression-free survival (PFS) and overall survival (OS) will be calculated from 
the on-study date using the Kaplan Meier method. For PFS and OS, censoring time is defined as 
time from baseline to date of last follow-up. Duration of response for responders also calculated 
using the Kaplan-Meier approach is defined as time from the initial response to progression or 
death, whichever occurs first. Censoring time for duration of response is defined as time from the 
initial response to date of last follow-up.
The secondary objectives include characterization of biological effects of this treatment and 
determination of effects of IL-15 on the ADCC capacity of ex vivo PBMCs. These 
exploratory analyses will be summarized.
11 COLLABORATIVE AGREEMENTS
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) - EMD SERONO
This study will be incorporated into an existing CRADA (#02666) between the National Cancer 
Institute and EMD Serono, the manufacturer of avelumab.

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12 HUMAN SUBJECTS PROTECTIONS
12.1 RATIONALE FOR SUBJECT SELECTION
All subjects from both sexes and all racial/ethnic groups are eligible for this study if they meet the 
eligibility criteria outlined in the protocol and provide informed consent to protocol participation. 
Pregnant or nursing mothers are excluded because of the potential teratogenic effects of therapy. 
There have been no studies of IL-15 in patients with HIV on or off ART. Two non-human primates 
with SIV who were not on ART and received rhIL-15 on Study 2078-10804 both died, while 
subsequent animals who received viral suppression were seemingly unaffected. rhIL-15 may 
therefore contribute to morbidity/mortality in patients with a detectable viral load. Since potential 
toxicity of IL-15 and avelumab may interfere with ART adherence and optimal viral suppression, 
patients with HIV may be exposed to additional toxicity for unknown potential benefit of IL-15 
and should therefore be excluded from this study.
We expect men and women to be equally represented among the enrolled patients. 
12.2 PARTICIPATION OF CHILDREN
Subjects under the age of 18 are excluded because ccRCC is rare in young patients, and the 
inclusion of an occasional younger patient will not provide generalizable information that would 
justify their inclusion on this study. Additionally, because no dosing or adverse event data are 
currently available on the use of rhIL-15 in combination with avelumab in patients <18 years of 
age, children are excluded from this study, but may be eligible for future pediatric trials.
12.3 RISK/BENEFIT ASSESSMENT
12.3.1 Known Potential Risks
The potential risks of adding rhIL-15 to avelumab include, in particular infusion reactions 
(including chills, fever, hypotension, headache, flushing, dizziness), fatigue, rash, Liver Function 
Test (LFT) abnormalities, and cytopenias.
Since fevers, rigors, lymphopenia, and LFT elevations occurred only during IL-15 infusion in the 
continuous IV trial, and since avelumab is not given concomitantly, these toxicities are not 
expected to overlap. Avelumab manufacturer recommendations for discontinuing therapy will be 
followed, including for grade 3-4 LFT elevations. Fatigue and rash are potential overlapping 
toxicities, and both will be monitored closely.
12.3.2 Risks related to Imaging
CT scans often use a contrast agent.  There is a small risk of having a reaction to the contrast and 
most often include nausea, pain in the vein where the contrast is given, headache, metallic and/ or 
bitter taste in the mouth and a warm, flushing feeling.  Rarely, some people have more severe 
allergic reactions to the contrast which may include skins rashes, shortness of breath, wheezing or 
low blood pressure.
12.3.3 Risks from Radiation Exposure
The procedures for performing the CT scans will follow clinical policies, no special procedures 
apply to these additional assessments for research purposes.  In summary, subjects may receive 
additional radiation exposure from up to seven (7) additional CT scans of the neck, chest, 
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The total additional radiation dose for research purposes will be approximately 9.1 rem.
12.3.4 Blood draws
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting.
12.3.5 MRI
People are at risk for injury from the MRI magnet if they have some kinds of metal in their body. 
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner.  The noise from the 
scanner is loud enough to damage hearing, especially in people who already have hearing loss. 
There are no known long-term risks of MRI scans.
12.3.6 Gadolinium enhanced MRI 
During part of the MRI patient may receive gadolinium, a contrast agent, through an intravenous 
(IV) catheter (small tube). It will be done for research purposes. 
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with 
pain and swelling. Participants undergoing gadolinium enhanced MRIs may also be at risk for 
kidney damage.
Most of the gadolinium contrast is eliminated in the urine. However, recent studies have found 
very small amounts of residual gadolinium in the body, including the brain and bone, by imaging 
and at autopsy. Macrocyclic gadolinium-containing contrast agents are substantially less likely to 
leave gadolinium behind than linear agents. There is presently no evidence that the retained 
gadolinium is associated with any adverse effects or other health risks. Participants undergoing 
gadolinium enhanced MRIs may also be at risk for kidney damage.
12.3.7 Tumor Biopsy (Optional) 
All care will be taken to minimize risks that may be incurred by tumor sampling. However, there 
are procedure-related risks (such as bleeding, infection, and injury) that will be explained fully 
during informed consent.
12.3.8 Electrocardiogram
Some skin irritation can occur where the ECG/EKG electrodes are placed. The test is completely 
painless, and generally takes less than a minute to perform.
12.3.9 Central line
A non-tunneled central catheter is a soft tube a doctor puts into a vein leading to your heart. It is a 
way to take blood samples or give you fluids, medicines, or nutrients over a long period of time.  
Possible side effects include pain, bleeding, bruising, and, on rare occasions, swelling in your arm, 
chest, neck, or face on the same side as the catheter or infection.   
12.3.10
Known Potential Benefits
The potential benefit of adding rhIL-15 to avelumab in treatment of metastatic refractory ccRCC 
is unknown, but single-agent ICI have shown activity as outlined in Section 1.2.4. 
12.3.11
Assessment of Potential Risks and Benefits

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An estimated 20 to 50 % of mRCC are PD-L1+ [34],  and since the anti-PD-L1 antibody avelumab 
has shown ADCC activity in vitro, agents that may enhance ADCC by increasing number and 
activity of Fc-binding effector cells — such as rhIL15 — could improve efficacy of avelumab in 
these diseases. Although the clinical benefit of these drug(s) has not yet been established, the intent 
of offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be 
carefully monitored for tumor response and symptom relief in addition to safety and tolerability. 
In addition to the tumor cells, PD-L1 is also expressed on normal immune cells. Since avelumab 
has potential for in vivo ADCC activity, immune cell subsets may change. However, when 123 
different immune cell subsets were analyzed in 28 patients with solid tumors who received 
avelumab during a phase I trial, there were no changes at any of the time points in any of the 123 
subsets tested regardless of their PD-L1 expression before and during treatment [43]. PBMC 
samples were obtained before Avelumab, and after 1, 3, and 9 doses of the drug. A limited number 
of immune cell subsets will also be tested in our trial, both in PBMCs and optional tissue biopsies.
12.4 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided to the participant as applicable for review prior 
to consenting.  A designated study investigator will carefully explain the procedures and tests 
involved in this study, and the associated risks, discomforts and benefits. In order to minimize 
potential coercion, as much time as is needed to review the document will be given, including an 
opportunity to discuss it with friends, family members and/or other advisors, and to ask questions 
of any designated study investigator. A signed informed consent document will be obtained prior 
to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant.  Whether in person or remote, the privacy of the subject will be 
maintained. Consenting investigators (and participant, when in person) will be located in a private 
area (e.g., clinic consult room). When consent is conducted remotely, the participant will be 
informed of the private nature of the discussion and will be encouraged to relocate to a more private 
setting if needed.
  
13 REGULATORY AND OPERATIONAL CONSIDERATIONS
13.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to investigators, funding 
agencies, the Investigational New Drug (IND) sponsor and regulatory authorities, as applicable.  
If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly 
inform study participants, the Institutional Review Board (IRB), and sponsor and will provide 
the reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:

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
Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping   

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA).
13.2 QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan 
will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities.
13.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial.  The study leadership in conjunction with the National Cancer Institute has established 
policies and procedures for all study group members to disclose all conflicts of interest and will 
establish a mechanism for the management of all reported dualities of interest.
13.4 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.

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The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the NCI CCR. This will not include the 
participant’s contact or identifying information. Rather, individual participants and their research 
data will be identified by a unique study identification number. The study data entry and study 
management systems used by the clinical site(s) and by NCI CCR research staff will be secured 
and password protected. At the end of the study, all study databases will be archived at the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
14 PHARMACEUTICAL INFORMATION
14.1
RHIL-15 (NSC #745101) IND# 100820
14.1.1 Source/Acquisition and Accountability  
rhIL-15 is an investigational agent supplied to investigators by the Cancer Therapy Evaluation 
Program (CTEP), Division of Cancer Treatment and Diagnosis (DCTD), NCI.
14.1.2 Drug Summary Information
14.1.2.1 Chemical Name or Amino Acid Sequence
The 115 amino acid coding sequence of the pET28b/IL-15 cistron is as follows:
MNWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDA
SIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS
14.1.2.2 Other Names
Recombinant Human Interleukin -15; Recombinant Human IL-15; rhIL-15

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14.1.2.3 Classification
Recombinant human interleukin-15 (rhIL-15) is a cytokine of the 4-alpha helix bundle family of 
cytokines whose mature form consists of 115 amino acids.  It has two cystine disulfide cross 
linkages at positions Cys 42-Cys 88 and Cys 35-Cys 85.
14.1.2.4 Molecular Weight (M.W.)
12,898.8 Daltons
14.1.2.5 Mode of Action
IL-15 interacts with a private receptor subunit IL- 15R alpha as well as the IL-2/IL-15R beta chain 
shared with IL-2 and the common gamma chain shared with IL-2, IL-4, IL-7, IL-9 and IL-21.  IL-
15 shares a number of biological activities with IL-2, including stimulation of the proliferation of 
activated CD4+, CD8+ as well as gamma-delta subsets of T cells.  IL-15 also stimulates the 
proliferation of NK cells and acts as a co-stimulator with IL-12 to facilitate the production of 
Interferon-gamma and TNF-alpha.
14.1.3 How Supplied
IL-15 is manufactured by the Biopharmaceutical Development Program (BDP) and distributed by 
the Pharmaceutical Management Branch (PMB) ant CTEP. IL-15 is supplied as a sterile, frozen 
liquid product in single use vials containing no preservatives. Currently, IL-15 is supplied as 147 
mcg / 0.3 mL (490 mcg/mL) in a 3 mL glass vial.  The IL-15 is formulated in 25 mM sodium 
phosphate containing 0.5 M sodium chloride at a pH of 7.4.
NOTE: IL-15 vial content may vary between lots and protocols.  Use caution and consult the 
protocol document for specific preparation instructions when preparing each dose.
14.1.4 Preparation
Vials of frozen IL-15 should be thawed at ambient room temperature and used within 5 hours of 
thawing.  Upon thawing, the solution should be clear and colorless with no evidence of particulates 
or foreign matter.  The infusion solutions should be mixed in a PVC bag.
14.1.5 Storage
IL-15 vials should be stored at or below (-70°C).
14.1.6 Stability
14.1.6.1 Vials
Stability studies of the intact vials are ongoing.
14.1.6.2 Prepared Infusion
The rhIL-15 infusion solution is stable at a concentration of 1 mcg/mL with 0.1% HSA for 4 hours 
at controlled room temperature (15°C–30°C) prior to initiation of the 24-hour infusion or 24 hours 
at 2-8°C prior to initiation of the 24-hour infusion. This stability information was previously 
documented by the Biopharmaceutical Development Program (BDP) of Leidos Biomedical 
Research, Inc., the drug manufacturer.
14.1.7 Administration 
For all dose levels, the dose of rhIL-15 will be diluted in the appropriate volume of 0.1% human serum 
albumin (HSA) in 5% dextrose in water, USP (D5W) or in 0.9% sodium chloride (NS) to reach a final 
rhIL-15 concentration of 1 mcg/mL (see Dilution instruction, APPENDIX C). The rhIL-15 infusion 
will be administered to the patient by continuous intravenous infusion (civ) at a dose in mcg/kg/day 

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determined by the dose level at which the patient is enrolled. Each bag (total 5 bags over 5 days) 
will be infused over 24 hours using a portable ambulatory pump on the inpatient unit (cycle 1) or in the 
outpatient setting (cycles 2-4, if deemed appropriate by the PI) for a total of 120 hours. Bags must be 
changed every 24 hours. Treatment with rhIL-15 will begin within 4 hours of preparation of the 
infusion bag and the infusion must be completed within 24 hours from the time drug administration 
begins. Otherwise a new infusion bag must be prepared to complete administration of the remaining 
dose.
See Table 7  for Drug Regimen, and Section 3.2.1 for supportive care measures.
14.1.8 Toxicity 
The Comprehensive Adverse Event and Potential Risks List (CAEPRs) for Recombinant Human 
IL-15 provides a single list of reported and/or potential adverse events (AE) associated with the 
agent using a uniform presentation of events by body system. .  In addition to the comprehensive 
list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a 
list of events that are protocol specific exceptions to expedited reporting to NCI (except as noted 
below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for 
further clarification. The CAEPR does not provide frequency data; refer to the Investigator's 
Brochure for this information. Below is the CAEPR for Recombinant Human IL-15.
Version 1.3, January 2, 2019*
Adverse Events with Possible 
Relationship to Recombinant Human IL-15
(CTCAE 5.0 Term)
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia
Anemia (Gr 2)
Bone marrow hypocellular
CARDIAC DISORDERS
Sinus tachycardia
Sinus tachycardia (Gr 2)
GASTROINTESTINAL DISORDERS
Abdominal pain
Diarrhea
Nausea
Nausea (Gr 2)
Vomiting
Vomiting (Gr 2)
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Chills
Chills (Gr 2)
Edema limbs
Fatigue
Fatigue (Gr 2)
Fever
Fever (Gr 2)
Injection site reaction
INFECTIONS AND INFESTATIONS
Sepsis
INVESTIGATIONS
Alanine aminotransferase increased
Aspartate aminotransferase increased

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Adverse Events with Possible 
Relationship to Recombinant Human IL-15
(CTCAE 5.0 Term)
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Blood bilirubin increased
Creatinine increased
Lymphocyte count decreased
Lymphocyte count decreased (Gr 2)
Lymphocyte count increased
Neutrophil count decreased
Platelet count decreased
White blood cell decreased
METABOLISM AND NUTRITION DISORDERS
Hypoalbuminemia
Hypophosphatemia
Hypophosphatemia (Gr 2)
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
Generalized muscle weakness
NERVOUS SYSTEM DISORDERS
Dizziness
Headache
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Dyspnea
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Dry skin
Erythema multiforme
Erythema multiforme (Gr 2)
Skin and subcutaneous tissue disorders - Other (rash)
VASCULAR DISORDERS
Capillary leak syndrome
Hypertension
Hypertension (Gr 2)
Hypotension
Hypotension (Gr 2)
*This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail
Adverse events reported on Recombinant Human IL-15 trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that Recombinant 
Human IL-15 caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia
CARDIAC DISORDERS - Atrial fibrillation; Chest pain - cardiac; Palpitations; Pericardial effusion; Pericardial 
tamponade; Sinus bradycardia; Ventricular tachycardia
GASTROINTESTINAL 
DISORDERS 
- 
Ascites; 
Constipation; 
Duodenal 
hemorrhage; 
Gastritis; 
Gastrointestinal disorders - Other (increased appetite); Ileus; Mucositis oral; Pancreatitis
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Infusion related 
reaction; Infusion site extravasation; Multi-organ failure; Pain
IMMUNE SYSTEM DISORDERS - Autoimmune disorder
INFECTIONS AND INFESTATIONS - Tooth infection; Upper respiratory infection; Urinary tract infection
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising

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INVESTIGATIONS - Alkaline phosphatase increased; Cardiac troponin I increased; Electrocardiogram QT 
corrected interval prolonged; GGT increased; INR increased; Lipase increased; Serum amylase increased; Weight 
gain; Weight loss
METABOLISM AND NUTRITION DISORDERS - Anorexia; Dehydration; Hyperkalemia; Hypocalcemia; 
Hypokalemia
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone pain; Muscle 
weakness upper limb; Myalgia; Pain in extremity
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain
NERVOUS SYSTEM DISORDERS - Dysgeusia; Peripheral sensory neuropathy; Presyncope; Vasovagal 
reaction
PSYCHIATRIC DISORDERS - Anxiety; Psychosis
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Genital edema
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Bronchopulmonary hemorrhage; Cough; Hypoxia; Laryngeal inflammation; Pleural effusion; Pneumonitis; 
Pulmonary edema; Wheezing
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythroderma; Palmar-plantar erythrodysesthesia 
syndrome; Pruritus; Rash acneiform; Skin and subcutaneous tissue disorders - Other (skin plaques)
VASCULAR DISORDERS - Hot flashes; Visceral arterial ischemia
Note: Recombinant Human IL-15 in combination with other agents could cause an exacerbation 
of any adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent
14.1.9 CTEP Information
14.1.9.1 Agent ordering and Agent Accountability
NCI-supplied agents may be requested by eligible participating Investigators (or their authorized 
designee).  The CTEP-assigned protocol number must be used for ordering all CTEP-supplied 
investigational agents.  The eligible participating investigators must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), NCI 
Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF).  If there are several 
participating investigators, CTEP-supplied investigational agents for the study should be ordered 
under the name of one lead participating investigator at that institution.
IL-15 may be ordered from PMB when a patient is being worked up for the study.
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) 
account and the maintenance of an “active” account status, a “current” password, and active person 
registration status.  For questions about drug orders, transfers, returns, or accountability, call or 
email PMB any time.  Refer to the PMB’s website for specific policies and guidelines related to 
agent management.  
14.1.9.1.1 Agent Inventory Records
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing and final disposition of all agents received from the PMB using 
the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on the 
CTEP forms page.  Store and maintain separate NCI Investigational Agent Accountability Records 

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for each agent, strength, formulation and ordering investigator on this protocol.
14.1.9.2 Investigator Brochure Availability
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB OAOP application.  Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account status, a 
“current” password and active person registration status.  Questions about IB access may be 
directed to the PMB IB Coordinator via email.
14.1.9.3 Useful Links and Contacts

CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/

NCI CTEP Person Registration:  RCRHelpDesk@nih.gov

PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm

PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP

CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/

CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov

IB Coordinator:  IBCoordinator@mail.nih.gov

PMB email:  PMBAfterHours@mail.nih.gov

PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET)
14.2 AVELUMAB IND#100820 (NSC #799232)
14.2.1 Source/Acquisition and Accountability 
Investigational supplies of Avelumab will be supplied by EMD Serono for use in this clinical trial. 
14.2.2 Toxicity 
Please refer to the IB (version 10, May 2020) for detailed toxicity information. In brief, in 
clinical studies thus far, most observed adverse events were either in line with those expected in 
patients with advanced tumors or with similar class effects of mAb blocking the PD-1/PD-L1 
axis. Infusion-related reactions including drug hypersensitivity reactions and immune-mediated 
adverse reactions (immune-related pneumonitis, immune-related colitis, immune-related 
hepatitis, immune-related endocrinopathies (thyroid disorders, adrenal insufficiency, new onset 
type I diabetes mellitus, pituitary disorders), immune-related nephritis and renal dysfunction and 
other immune-related AEs (myositis, myocarditis, Guillain-Barré syndrome, uveitis, pancreatitis 
and myasthenia gravis/myasthenic syndrome) have been identified as important risks for 
avelumab. Detailed guidelines for the management of immune-related adverse events and 
infusion-related reactions have been incorporated in this study protocol.
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 

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presentation of events by body system. Frequency is provided based on 1738 patients. Below is 
the CAEPR for Avelumab.
Version 2.0, April 23, 2019
 Adverse Events with Possible 
 Relationship to Avelumab
 (CTCAE 5.0 Term)
[n= 1738]
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia
CARDIAC DISORDERS
Myocarditis2
Pericarditis2
ENDOCRINE DISORDERS
Adrenal insufficiency2
Hyperthyroidism2
Hypophysitis2
Hypopituitarism2
Hypothyroidism2
EYE DISORDERS
Uveitis2
GASTROINTESTINAL DISORDERS
Abdominal pain
Colitis2
Diarrhea
Nausea
Pancreatitis2
Vomiting

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 Adverse Events with Possible 
 Relationship to Avelumab
 (CTCAE 5.0 Term)
[n= 1738]
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Chills
Fatigue
Fever
Flu like symptoms3
HEPATOBILIARY DISORDERS
Hepatic failure2
Hepatobiliary disorders - Other 
(autoimmune hepatitis, immune-
related hepatitis)2
IMMUNE SYSTEM DISORDERS
Autoimmune disorder2
Cytokine release syndrome3
Immune system disorders - 
Other (sarcoidosis)2
INFECTION AND INFESTATIONS
 Infection4
INJURY, POISONING AND PROCEDURAL COMPLICATIONS
Infusion related reaction3
INVESTIGATIONS
Alanine aminotransferase 
increased
Alkaline phosphatase 
increased

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 Adverse Events with Possible 
 Relationship to Avelumab
 (CTCAE 5.0 Term)
[n= 1738]
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
Aspartate aminotransferase 
increased
Blood bilirubin increased
CPK increased
Creatinine increased
GGT increased
Lipase increased
Lymphocyte count decreased
Neutrophil count decreased
Platelet count decreased
Serum amylase increased
Thyroid stimulating hormone 
increased
METABOLISM AND NUTRITION DISORDERS
Anorexia
Hyperglycemia2
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
Arthralgia2
Generalized muscle 
weakness
Muscle cramp
Myalgia2
Myositis2
Pain in extremity

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 Adverse Events with Possible 
 Relationship to Avelumab
 (CTCAE 5.0 Term)
[n= 1738]
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
NERVOUS SYSTEM DISORDERS
Encephalopathy2
Guillian-Barre syndrome2
Myasthenia gravis2
Nervous system disorders - 
Other (non-infectious 
encephalitis)2
Nervous system disorders - 
Other (non-infectious 
meningitis)2
Peripheral motor neuropathy
Peripheral sensory neuropathy2
RENAL AND URINARY DISORDERS
Renal and urinary disorders - 
Other (immune related 
nephritis)2
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Cough
Pneumonitis2
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Eczema
Pruritus
Rash acneiform
Rash maculo-papular
*This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 

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PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail.
2Immune-mediated adverse reactions have been reported in patients receiving avelumab.  Adverse events 
potentially related to avelumab may be manifestations of immune-mediated adverse events. In clinical 
trials, most immune-mediated adverse reactions were reversible and managed with interruptions of 
avelumab), administration of corticosteroids and supportive care.
3Infusion reactions, including high-grade hypersensitivity reactions, anaphylaxis, and cytokine release 
syndrome, which have been observed following administration of avelumab, may manifest as fever, chills, 
shakes, itching, rash, hypertension or hypotension, or difficulty breathing during and immediately after 
administration of avelumab.
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC.
Adverse events reported on avelumab trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that avelumab caused the adverse event:
CARDIAC DISORDERS - Palpitations; Sinus tachycardia
EYE DISORDERS - Blurred vision; Dry eye
GASTROINTESTINAL DISORDERS - Abdominal distension; Constipation; Dry mouth; 
Dyspepsia; Flatulence; Mucositis oral
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; 
Localized edema; Malaise; Non-cardiac chest pain; Pain
INVESTIGATIONS - Electrocardiogram QT corrected interval prolonged; Investigations - 
Other (c-reactive protein increased); Weight gain; Weight loss
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypoalbuminemia; 
Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone 
pain
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (tumor 
flare); Tumor pain
NERVOUS SYSTEM DISORDERS - Dizziness; Dysesthesia; Dysgeusia; Headache; Tremor
RENAL AND URINARY DISORDERS - Proteinuria
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; Hypoxia
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis
VASCULAR DISORDERS - Flushing; Hot flashes; Hypertension
Note: Avelumab in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent.

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14.2.3 Formulation and Preparation 
Avelumab drug product is a sterile, clear, and colorless concentrate for solution presented at 
concentration of 20 mg/mL in European Pharmacopeia (Ph. Eur.) and United States Pharmacopeia 
(USP) type I glass vials closed with a rubber stopper and sealed with an aluminum Flip Off® crimp 
seal closure.
Each single-use vial contains 200 mg of avelumab as a preservative-free acetate-buffered 
solution (pH 5.2) containing Mannitol, and Polysorbate 20 (Tween 20).
For avelumab drug product, only excipients that conform to the current Ph. Eur. and/or the 
current USP are used.
14.2.4 Stability and Storage 
Supplies must be stored in a secure, limited-access location under the storage conditions specified 
on the label.  Receipt and dispensing of trial supplies must be recorded by an authorized person at 
the trial site. Supplies may not be used for any purpose other than that stated in the protocol.
Avelumab drug product must be stored at 2°C to 8°C until use. Store diluted solution at room 
temperature up to 77°F (25°C) for no more than 4 hours from the time of dilution. OR Under 
refrigeration at 36°F to 46°F (2°C to 8°C) for no more than 24 hours from the time of dilution. If 
refrigerated, allow the diluted solution to come to room temperature prior to administration. The 
storage condition is based on data from ongoing long-term stability studies with avelumab. 
Avelumab drug product stored at room (23°C to 27°C) or higher temperatures for extended periods 
of time might be subject to degradation. Avelumab drug product must not be frozen. Rough 
shaking of the solution must be avoided.
14.2.5 Administration Procedures
For administration in clinical trials, avelumab drug product may be diluted with 0.9% saline 
solution (sodium chloride injection) supplied in 250 mL infusion bags, alternatively, a 0.45% 
saline solution can be used if needed. The chemical and physical in-use stability for the infusion 
solution of avelumab in 0.45% or 0.9% saline solution has been demonstrated for a total of 24 
hours at room temperature. However, from a microbiological point of view, the diluted solution 
should be used immediately. If not used immediately, it can be considered that the diluted product 
is sufficiently stable from a microbiological perspective for up to 8 hours when stored at ambient 
room temperature or up to 24 hours at 2°C to 8°C. The in-use storage times and conditions prior 
to administration are the responsibility of the user.
Prior to the preparation of the dilution for final infusion, allow each vial to equilibrate to room 
temperature. Use a disposable syringe equipped with a needle of suitable size to remove a volume 
of sodium chloride solution to be replaced by avelumab from the infusion bag and discard the 
removed solution. Use a new disposable syringe equipped with a needle of suitable size to inject a 
volume of avelumab drug product identical to the discarded volume of sodium chloride solution 
into the infusion bag. Gently invert the mixture 10 times. Infusion bags must not be shaken, in 
order to avoid foaming or excessive shearing of the protein solution. The preparation must be 
carefully inspected as it should result in a homogeneous looking clear solution, free of visible 
particles.
14.2.6 Returns and Reconciliations  
Unused investigational products will be destroyed per routine pharmacy procedure.

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

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16.2 APPENDIX B: ASSAY FOR ADCC

Peripheral blood mononuclear cells (PBMCs) should be isolated by Ficoll-High-Paque 
Density Gradient Centrifugation.

The viable cells should be viably frozen and stored in liquid nitrogen.

The ADCC assay will be performed on the same occasion for all samples of a given 
patient.

Vials of frozen cells will be thawed using standard procedures 18 hours before the assay 
in accordance with our experience with normal donors.

1.5 million of patient’s PBMCs obtained before and on day 15 following IL-15 injection 
will be tested in aliquots as follows:
o
Tested alone
o
Tested with untreated PD-L1-expressing Raji cells and with PD-L1-expressing 
Raji cells coated with avelumab for 5 hours.
o
In addition, we may utilize an ATL cell line in addition to Raji cells. These cell 
populations will be stained with CD107, CD3, CD56 and CD94.

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16.3 APPENDIX C: IL-15 DILUTION INSTRUCTIONS
All dose preparations will be performed in a laminar flow hood in compliance with all legal 
requirements and in accordance with guidelines of recognized organizations.
0.1% human serum albumin (HSA) in 5% dextrose in water, USP (D5W), or in 0.9% sodium 
chloride (NS) may be used for the dilutions listed below.
Please note: The dosing examples listed below are for the 147 mcg/0.3 mL in a 3mL vial size 
and dilution ONLY. The following dosing chart may be used as a reference, but doses should 
always be re-calculated at the time of preparation. In the future, different concentrations of IL-15 
may be available and doses and dilutions will need to be recalculated.
Dose Level 1 (2 mcg/kg) and Dose Level 2 (4 mcg/kg)
To prepare an IL-15 dose for Dose Level 1 (2 mcg/kg):
1. Thaw vial(s) of IL-15, 147 mcg/0.3 mL (490 mcg/mL) at room temperature.
2. Using a 27-gauge needle, slowly draw up the required dose in a 1 mL syringe. Doses 
should be rounded to the nearest 0.01 mL. 
3. Add the calculated volume of diluted IL-15 to 0.1% HSA in D5W, or in NS, in a PVC or 
polyolefin bag.
4. Label the bag with a 4-hour beyond-use date. The infusion may be started within 4 hours 
at room temperature, or within 24 hours if bag was kept at 2-8°C. The infusion must be 
completed within 24 hours of initiation.
Administered dose = _______ kg (Patient’s weight) X _______ mcg/kg (DL) = _______ mcg
Prepared dose = _______ mcg (Administered dose) + 10 mcg (Overfill dose) = _______ mcg
IL-15 volume = _______ mcg (Prepared dose)  490 mcg/mL (vial concentration) = _______ mL
Total infusion volume = 
     _______ mcg (Prepared dose)  1 mcg/mL (final infusion concentration) = _______ mL
Diluent volume = 
     _______ mL (Total infusion volume) - _______ mL (IL-15 volume) = _______ mL
IL-15 volume
(490 mcg/ml)
Diluent volume
Total infusion volume 
(1 mcg/ml)
Patient’s 
weight
2mcg/kg
4 mcg/kg
2 mcg/kg
4 mcg/kg
2 mcg/kg
4 mcg/kg
60 kg
0.27
0.51
129.73
249.49
130 ml
250 ml
75 kg
0.33
0.63
159.67
309.37
160 ml
310 ml
90 kg
0.39
0.76
189.61
369.24
190 ml
370 ml
105 kg
0.45
0.88
219.55
429.12
220 ml
430ml

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Dose calculation for obese patients:
For patients whose body mass index (BMI) is >30 kg/m2, the factor for body weight used in 
calculating IL-15 doses will be determined as follows:
Corrected body weight (kg) = 30 x (height [m])2

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16.4 APPENDIX D: ASSAY FOR ANTIBODIES TO RHIL-15

Plates are coated with human IL-15 for 3 hours at 37°C, washed, blocked with 3% FBS 
and washed again.

A standard curve for assay quantitation and quality control is constructed using serial 
dilutions of a commercial affinity purified goat anti-human IL-15 that is diluted in heat-
inactivated normal human serum.  The standard curve samples are incubated for 2 hours 
at 37°C and washed.

Biotin conjugated IL-15 is added to each well, incubated 2 hours at 37°C, and the plates 
are washed.

Alkaline phosphatase–conjugated streptavidin is added to each well for 2 hours at 37°C 
and then washed.

The assay is developed with the addition of diethanolamine buffer with p-Nitrophenyl 
Phosphatase for 1 hour at 37°C and then immediately read at 405 nm.

To detect antibodies to human IL-15 in test samples, serum from the test subject will be 
assayed in duplicate at dilutions of 1/3 and 1/9 concomitantly with the standard curve 
samples as above and the resultant OD obtained used to quantitate the level of antibody 
present.

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16.5 APPENDIX E: MODIFIED IMMUNE-RELATED RESPONSE CRITERIA (IRRECIST)
This new classification is based on the recent learning from clinical studies with cancer 
immunotherapies that even if some new lesions appear at the beginning of a treatment or if the 
total tumor burden does not increase substantially, tumor regressions or stabilizations might still 
occur later. The irRC were created using bi-dimensional measurements (as previously widely used 
in the World Health Organization criteria). For this trial, the concepts of the irRC are combined 
with RECIST 1.1 to come up with the modified irRC. 
For modified irRC, only target and measurable lesions are taken into account. In contrast to the 
RECIST 1.1 criteria, the modified irRC criteria (a) require confirmation of both progression and 
response by imaging at 6-8 weeks after initial imaging and (b) do not necessarily score the 
appearance of new lesions as progressive disease if the sum of lesion diameters of target lesions 
(minimum of 10 mm per lesion, maximum of 5 target lesions, maximum of 2 per organ) and 
measurable new lesions does not increase by ≥ 20%. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported target lesion(s) at baseline, during the trial, and at the end of trial visit. All 
measurements should be recorded in metric notation. The modified irRC based on RECIST 1.1 are 
displayed below. 

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16.6 APPENDIX F: STUDY CALENDAR
Study Cycles
Post-Treatment 
Follow-Up
Procedure
Screening
Baseline
C11
C2-4
Disease 
Evaluations
End of 
Treatment 
and Disease 
Progression
Safety 2
Follow-Up
(Prior to 
PD)
Survival
(Post-PD)
Scheduling Window (Days):
-28 to -13
-14 4
8
(-3)
22
(-3)
1 
(-3)
8
(-3)
22
(-3)
After C2 and C4 5
Treatment 
discon/PD 6
Day 30
(+7)
Every 60 or 
90 days 7
Every 3 
months 8
Confirmation of Diagnosis 9
X
Physical Exam and ECOG 
PS 10
X
X
X
X
X
X
X
X
X
X
CBC with Differential
X
X
X
X
X
X
X
X
X
X
X
Reticulocyte Count
X
X
X
X
X
X
X
X
X
X
X
Chemistry Panels 11
X
X
X
X
X
X
X
X
X
X
X
LDH, Serum Lipase and 
Amylase
X
X
X
X
X
X
X
X
X
X
X
PT/INR and aPTT
X
X
X
X
X
X
X
Thyroid Function (i.e., TSH, 
T4)
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
Pregnancy Test (urine/serum; 
WOCBP)
X
X
X
Hepatitis B and C, HIV 
Antibody, HTLV-1/2
X
Anti-nuclear antibody 
(ANA), rheumatoid factor 
(RF) and anti-thyroid 
antibody
X
X
IL-2R
X
X
X
Creatine phosphokinase 
(CPK), troponin 
X
X
X
X
X
Pulmonary function tests 
(PFTs) and TTE12
X
T, B, NK cell subsets
X
X
X
X
X
X
X
Imaging studies 13
X
X
X
X
X
MRI Lumbar Puncture 14
X
X
X
X

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Study Cycles
Post-Treatment 
Follow-Up
Procedure
Screening
Baseline
C11
C2-4
Disease 
Evaluations
End of 
Treatment 
and Disease 
Progression
Safety 2
Follow-Up
(Prior to 
PD)
Survival
(Post-PD)
Scheduling Window (Days):
-28 to -13
-14 4
8
(-3)
22
(-3)
1 
(-3)
8
(-3)
22
(-3)
After C2 and C4 5
Treatment 
discon/PD 6
Day 30
(+7)
Every 60 or 
90 days 7
Every 3 
months 8
Flow Cytometry15
X
X
X
X
X
X
X
X
X
Clinical photography16
X
X
X
X
Radiologic Evaluation/ tumor 
measurement17
X
X
X
X
EKG
X
Symptoms/Adverse Events 
Assessment, Concomitant 
Medication Review
X
X
X
X
X
X
Research Blood/Tissue 
Samples 18
X
Refer to Table Section 5.1
Survival Status
X
1 On Day 8 and Day 22 of Cycle 1, vital signs ([VS] blood pressure, pulse, respiratory rate, temperature, oxygen saturation) will be assessed predose of avelumab 
(within 15 minutes of injection and/or infusion), and then every 15 minutes from the start of avelumab infusion for at least 2 hours. If vital signs are not stable after 
2 hours, then continue monitoring every 15 minutes until stable on 2 consecutive repeated measurements.
2 30 days (+7) following last dose, and 90 days (+14) after last dose of avelumab (via clinic or phone/email). If initiating new anti-cancer therapy within 30 days 
after last dose of avelumab, 30-day safety follow-up visit must occur before first dose of new therapy.
3 Screening and Baseline evaluations should be performed within 28 days prior to enrollment and dosing, respectively, unless otherwise noted and with the 
following exceptions:  Confirmation of diagnosis (no time limit); HIV antibody, Hepatitis B surface antigen and Hepatitis C antibody and EKG (all within 3 
months)  NOTE: Any screening tests performed within the specified time frame for baseline do not need to be repeated.
4 Within 14 days prior to dosing on C1D1, with the following exceptions:  Pregnancy test (within 7 days of dosing; must be negative).
5 ± 2 days. Confirmatory scans should also be obtained 4 weeks following initial documentation of objective response.
6 To be done at end of treatment (30 days after last dose of study treatment; may be combined with 30 day safety follow-up, if timing coincides). If subject to 
initiate new anti-cancer therapy assessments should occur before the first dose of the new therapy.
7 Follow-up to occur about every 60 days ( ±7 days) for first 6 months, every 90 days (±14 days) for 2 years; then every six months (± 28 days) for the duration 
of the study until disease progression or initiation of new anti-cancer therapy.

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8 After disease progression or initiation of new anti-cancer therapy, contact for survival about every 3 months (±4 weeks) for the duration of the study after 
stopping treatment.
9 Pathologic review/confirmation of diagnosis by Laboratory of Pathology, NCI (no time limit) and PD-L1 as outlined in Section 5.2.4.1. If archival sample is not 
available, a fresh punch or core biopsy of an appropriate easily accessible tumor deposit will be obtained.
10 Physical exams to include medical history (i.e., complete at Screening/Baseline; interim on study and in follow-up), vitals, weight, and height (screening only).
11 Chemistry panels include:  Acute care, Hepatic, and Mineral.
12 Diffusing capacity/alveolar volume (DLCO/VA), forced expiratory volume in 1 second (FEV1) for patients with significant pulmonary or smoking history or 
suspected tumor related pulmonary dysfunction and Transthoracic Echocardiograph for patients with suspected cardiac dysfunction that would increase their risk 
in receiving protocol treatment. 
13 Patients should have an evaluation of known sites of disease (CT, MRI, and in certain cases FDG-PET to better evaluate lesions of uncertain etiology) as part of 
the screening and baseline evaluations. Other body areas may be imaged if clinically indicated. MRI of the brain is only required in patients with suspected 
involvement of CNS. 
14 Patients with neurological symptoms or signs should undergo MRI scan of the brain and lumbar puncture
15 Flow cytometry to be performed at baseline, and on Day 8 and 22 of each cycle, see Section 5.2.3.
16 To be performed in selected patients with skin lesions (as determined by PI or AI).
17 Radiologic documentation must be provided for patients removed from study for progressive disease 
18 Samples for correlative research are to be collected as indicated in Section 5