Clinical trial NCT03905135
Conditions: Peripheral T-cell Lymphoma NOS Mycosis Fungoides Sezary Syndrome Anaplastic Large Cell Lymphoma
Keywords: T-cell Lymphoproliferative Disorder Cutaneous T-Cell Lymphoma Anti-PD-L1 monoclonal antibody Antibody Dependent Cellular Cytotoxicity (ADCC)
Sponsor: National Cancer Institute (NCI)
Start date: 2019-06-07; Completion date: 2022-05-17
Enrollment: 8 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Background:

Some T-cell lymphomas and leukemias do not respond to standard treatment. Researchers hope to develop a treatment that works better than current treatments.

Objective:

To test if interleukin (IL-5) combined with avelumab is safe and effective for treating certain cancers.

Eligibility:

People ages 18 and older with relapsed T-cell leukemias and lymphomas for which no standard treatment exists or standard treatment has failed

Design:

Participants will be screened with:

* Medical history
* Physical exam
* Blood, urine, heart, and lung tests
* Possible tumor biopsy
* Bone marrow biopsy: A small needle will be inserted into the hipbone to take out a small amount of marrow.
* Computed tomography (CT) or positron emission tomography (PET) scans and magnetic resonance imaging (MRI): Participants will lie in a machine that takes pictures of the body.

Participants will get the study drugs for 6 cycles of 28 days each. They will have a midline catheter inserted: A tube will be inserted into a vein in the upper chest. They will get Interleukin-15 (IL-5) as a constant infusion over the first 5 days of every cycle. They will get avelumab on days 8 and 22 of each cycle. They will be hospitalized for the first week of the first cycle.

Participants will have tests throughout the study:

* Blood and urine tests
* Another tumor biopsy if their disease gets worse
* Scans every 8 weeks
* Possible repeat MRI
* Another bone marrow biopsy at the end of treatment, if there was lymphoma in the bone marrow before treatment, and they responded to treatment everywhere else.

After they finish treatment, participants will have visits every 60 days for the first 6 months. Then visits will be every 90 days for 2 years, and then every 6 months for 2 years. Visits will include blood tests and may include scans.

Detailed description:
Background:

Mature T-cell cancers are a phenotypically heterogeneous group of malignancies which constitute 10-15% of all non-Hodgkin lymphomas (NHL). Patients with relapsed/refractory T cell lymphomas have limited therapeutic options, making new therapeutic approaches extremely important.

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 cluster of differentiation 8 (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 immunoglobulin G1 (IgG1) antibody that inhibits programmed cell death protein 1 (PD1)/PD-L1 interactions while leaving the PD1/programmed cell death ligand 2 (PD-L2) pathway intact and enhances immune activation against tumor cells. It has received United States (U.S.) Food and Drug Administration (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.

A significant number of T-cell malignancies express PD-L1, 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.

Objectives:

To determine the safety and toxicity profile and the maximum tolerated dose (MTD) of continuous intravenous infusion (civ) recombinant human interleukin-15 (rhIL-15) administration in combination with standard intravenous (IV) avelumab treatment

Eligibility:

Age \>= 18 years of age

Eastern Cooperative Oncology Group (ECOG) performance status of \<= 1

Histologically or cytologically confirmed relapsed and/or refractory T-cell lymphoma other than adult T-cell leukemia/lymphoma (ATLL), angioimmunoblastic T-cell lymphoma (AITL), peripheral T-cell lymphoma T follicular helper phenotype (PTCL-TFH) and enteropathy-associated T-cell lymphoma (EATL).

Adequate organ and marrow function

Design:

Open-label, single-center, non-randomized Phase 1 study

Standard 3 + 3 design will be used to determine the MTD of dose-escalated rhIL-15 with fixed dose avelumab with a small expansion cohort at the MTD

Maximum 6 cycles (28-day cycle) of combination therapy

To explore all dose levels, including further evaluation in a dose expansion cohort, the accrual ceiling will be set at 30 patients.

Arms: arm 1: Interleukin-15 (IL-15) by continuous intravenous (civ) infusion at escalating doses of 1, 2, 3 and 4 mcg/kg/day on days 1-5 of each 28-day cycle (max 6 cycles) with avelumab by intravenous (IV) infusion at a dose of 10mg/kg on Day 8 and 22 of each cycle, to determine maximum tolerated dose (MTD) arm 2: Interleukin-15 (IL-15) by continuous intravenous (civ) infusion at the maximum tolerated dose (MTD) on days 1-5 of cycles 1-6 with avelumab at 10mg/kg on Day 8 and 22 of each cycle
Interventions: intervention 1: rhIL-15 intervention 2: rhIL-15 intervention 3: Avelumab
Intervention descriptions: intervention 1: Interleukin-15 (IL-15) will be administered by continuous intravenous infusion in a dose-escalation fashion with a starting dose level of 1 mcg/kg/day, a second dose level of 2 mcg/kg/day, a third dose level at 3 mcg/kg/day, and a fourth dose level at 4 mcg/kg/day on days 1-5 of each of six cycles. intervention 2: Interleukin-15 (IL-15) will be administered by continuous intravenous infusion at the maximum tolerated dose (MTD) or maximum administered dose (MAD) on days 1-5 of each of six cycles intervention 3: Avelumab (intravenous (IV) over 1 hour) will be administered at a dose of 10 mg/kg on days 8 and 22 of each of six cycles.

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated Title:  IL-15 and Avelumab in R/R T-cell NHL
Version Date:  09/23/2021
1
Abbreviated Title: IL-15 and Avelumab in R/R T-cell NHL
NIH Protocol #:  19C0076 
CTEP Protocol #: 10239
         Version Date:    09/23/2021
NCT Number: NCT03905135
A Phase 1 Study of Interleukin-15 in Combination with Avelumab (Bavencio) in 
Relapsed/Refractory Mature T-cell Malignancies
NCI Principal Investigator: Kevin Conlon, M.D. 
Center for Cancer Research (CCR)
National Cancer Institute 
Building 10, Room 3B38
9000 Rockville Pike
Bethesda, MD  20892
Phone:  240-760-6087
Email:  conlonkc@mail.nih.gov 
 
Investigational Agents:    
Drug Name:
Avelumab 
(MSB0010718C; NSC #799232)
Recombinant human IL-15 
(rhIL-15; NSC #745101)
IND Number:
140549
Sponsor:
Center for Cancer Research, NCI
Manufacturer:
EMD Serono, Inc.
(Company Study/Tracking #: 
MS100070_0039)
Biopharmaceutical Development 
Program (BDP)/Leidos Biomedical 
Research, Inc. under contract with 
DCTD, NCI
Supplier: 
EMD Serono, Inc.
DCTD
Commercial Agents:  None


Abbreviated Title:  IL-15 and Avelumab in R/R T-cell NHL
Version Date:  09/23/2021
2
PRÉCIS
Background:

Mature T-cell cancers are a phenotypically heterogeneous group of malignancies which 
constitute 
10-15% 
of 
all 
non-Hodgkin 
lymphomas 
(NHL). 
Patients 
with 
relapsed/refractory T cell lymphomas have limited therapeutic options, making new 
therapeutic approaches extremely important.

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.

A significant number of T-cell malignancies express PD-L1, 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.  
Objectives:

To determine the safety and toxicity profile and the maximum tolerated dose (MTD) of 
continuous intravenous infusion (civ) rhIL-15 administration in combination with standard 
intravenous (IV) avelumab treatment
Eligibility:

Age ≥ 18 years of age

ECOG performance status of ≤ 1  

Histologically or cytologically confirmed relapsed and/or refractory T-cell lymphoma 
other than adult T-cell leukemia/lymphoma (ATLL), angioimmunoblastic T-cell 
lymphoma (AITL), peripheral T-cell lymphoma T follicular helper phenotype (PTCL-
TFH), and enteropathy-associated T-cell lymphoma (EATL). 

Adequate organ and marrow function 
Design:

Open-label, single-center, non-randomized Phase 1 study

Standard “3 + 3” design will be used to determine the MTD of dose-escalated rhIL-15 with 
fixed dose avelumab with a small expansion cohort at the MTD

Maximum 6 cycles (28-day cycle) of combination therapy 


Abbreviated Title:  IL-15 and Avelumab in R/R T-cell NHL
Version Date:  09/23/2021
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
To explore all dose levels, including further evaluation in a dose expansion cohort, the 
accrual ceiling will be set at 30 patients.  


Abbreviated Title:  IL-15 and Avelumab in R/R T-cell NHL
Version Date:  09/23/2021
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TABLE OF CONTENTS 
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE ................................................................................................7
1
INTRODUCTION ...................................................................................................................7
1.1
Study Objectives............................................................................................................7
1.2
Background and Rationale ............................................................................................7
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................19
2.1
Eligibility Criteria........................................................................................................19
2.2
Screening Evaluation...................................................................................................22
2.3
Participant Registration And Status Update Procedures .............................................23
2.4
Baseline Evaluation.....................................................................................................24
3
STUDY IMPLEMENTATION .............................................................................................25
3.1
Study Design ...............................................................................................................25
3.2
Drug Administration....................................................................................................28
3.3
Dose Modifications .....................................................................................................29
3.4
On Study Evaluations..................................................................................................37
3.5
Post-Treatment Evaluations ........................................................................................38
3.6
Study Calendar ............................................................................................................40
3.7
Cost and Compensation...............................................................................................43
3.8
Criteria for Removal from Protocol Therapy and Off Study Criteria .........................43
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................44
4.1
Acceptable Medications ..............................................................................................44
4.2
Prohibited Medications................................................................................................44
5
CORRELATIVE STUDIES FOR RESEARCH ...................................................................45
5.1
Biospecimen Collection ..............................................................................................45
5.2
Sample Collection and Processing ..............................................................................47
5.3
Biomarker and Research Methods ..............................................................................49
5.4
Sample Storage, Tracking, and Disposition ................................................................51
5.5
Samples for Genetic/Genomic Analysis......................................................................53
6
DATA COLLECTION AND EVALUATION .....................................................................54
6.1
Data Collection............................................................................................................54
6.2
Data Sharing Plans ......................................................................................................55


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6.3
Response Criteria ........................................................................................................55
6.4
Toxicity Criteria ..........................................................................................................58
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN.....59
7.1
Definitions...................................................................................................................59
7.2
OHSRP Office Of Compliance And Training/ IRB Reporting...................................59
7.3
NCI Clinical Director Reporting .................................................................................59
7.4
NIH Required Data and Safety Monitoring Plan ........................................................59
8
SPONSOR SAFETY REPORTING......................................................................................60
8.1
Definitions...................................................................................................................60
8.2
Assessment of Safety Events.......................................................................................61
8.3
Reporting of Serious Adverse Events .........................................................................61
8.4
Waiver of Expedited Reporting to CCR......................................................................62
8.5
Safety Reporting Criteria to the Pharmaceutical Collaborators and Manufacturers...62
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 Hypothesis ..................................................................................................64
10.2
Sample Size Determination.........................................................................................65
10.3
Population For Analysis ..............................................................................................65
10.4
Statistical analyses.......................................................................................................66
11
COLLABORATIVE AGREEMENTS..................................................................................67
11.1
Cooperative Research and Development Agreement (CRADA)- EMD Serono ........67
11.2
Material Transfer Agreement (MTA)- CTEP .............................................................67
12
HUMAN SUBJECTS PROTECTIONS................................................................................67
12.1
Rationale For Subject Selection ..................................................................................67
12.2
Participation of Children .............................................................................................67
12.3
Participation of Subjects Unable to Give Consent ......................................................67
12.4
Evaluation of Benefits and Risks/Discomforts ...........................................................68
12.5
Risks/Benefits Analysis...............................................................................................68
12.6
Consent Process and Documentation ..........................................................................69
13
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................70
13.1
Study Discontinuation and Closure.............................................................................70


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13.2
Quality Assurance and Quality Control ......................................................................70
13.3
Conflict of Interest Policy ...........................................................................................71
13.4
Confidentiality and Privacy.........................................................................................71
14
PHARMACEUTICAL INFORMATION .............................................................................72
14.1
rhIL-15 (NSC #745101) ..............................................................................................72
14.2
Avelumab (NSC #799232)..........................................................................................77
15
REFERENCES ......................................................................................................................82
16
APPENDICES .......................................................................................................................87
16.1
APPENDIX A:  Performance Status Criteria..............................................................87
16.2
APPENDIX B:  Assay for ADCC...............................................................................88
16.3
APPENDIX C:  Global Response Score and Definitions of Response in Skin, Lymph 
Nodes, Viscera, and Blood ........................................................................................................89
16.4
APPENDIX D:  IL-15 Dilution Instructions...............................................................92
16.5
APPENDIX E:  Assay For Antibodies To rhIL-15.....................................................93


Abbreviated Title:  IL-15 and Avelumab in R/R T-cell NHL
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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.
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective

Determine the safety and toxicity profile and the maximum tolerated dose (MTD) of 
continuous intravenous infusion (civ) rhIL-15 administration in combination with standard 
intravenous (IV) avelumab treatment 
1.1.2
Secondary Objective

Evaluate the potential antitumor activity of combination rhIL-15 and avelumab 

Assess PD-L1, PD-L2 and PD-1 expression before and after treatment with rhIL-15 and 
avelumab, and correlate expression with treatment response

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)
1.2
BACKGROUND AND RATIONALE
1.2.1
Mature T-cell malignancies
Mature T-cell cancers are a phenotypically heterogeneous group of malignancies which constitute 
10-15% of all non-Hodgkin lymphomas (NHL)(1). Excluding a small proportion of indolent 
subtypes, they are treatment-resistant and are associated with poor prognosis(2). The most 
common mature T-cell malignancies in the United States are: peripheral T-cell lymphoma (PTCL, 
including the angioimmunoblastic variant and anaplastic large cell lymphoma - ALCL), cutaneous 
T-cell lymphoma (CTCL), and adult T-cell leukemia/lymphoma (ATLL), with incidence ranging 
from 0.09/100,000 for ATLL to 1/100,000 for PTCL(3-6).


Abbreviated Title:  IL-15 and Avelumab in R/R T-cell NHL
Version Date:  09/23/2021
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1.2.2
Treatment of relapsed/refractory PTCL
Three agents, pralatrexate, belinostat and romidepsin have received accelerated FDA approval for 
treatment of relapsed or refractory PTCL based on overall response rate (ORR) shown in Phase 2, 
single-arm studies. Pralatrexate is an antifolate investigated in 115 patients, 109 of whom were 
evaluable. ORR was 29% (95% CI, 21-39%), with 12 complete responses (CRs - 11%) and 20 
partial responses (PRs- 18%)(7). Median duration of response was 10.1 months (range 1-673 
days), median progression free survival (PFS) was 3.5 months, and median overall survival (OS) 
was 14.5 months. Seventy-four percent of patients had a grade 3 or 4 adverse event, most of which 
were hematological (19% grade 4 thrombocytopenia, 16% grade 3 anemia, 14% grade 3 
thrombocytopenia and neutropenia).
Belinostat is a histone deacetylase inhibitor (HDACi) studied in 129 patients, 120 of whom were 
evaluable. ORR was 26%, with 12 CRs (10%) and 19 PRs (16%)(8). Median duration of response 
was 8.4 months (range NR-36 months). Median PFS was 1.6 months, and median OS was 7.9 
months. Sixty-one percent of patients had a grade 3 or 4 adverse event. 22 patients died during 
treatment, of which 10 deaths (7.8%) were due to treatment-emergent adverse events arising within 
30 days of the last belinostat dose.  Romedepsin is another HDACi studied in 130 patients with 
PTCL.  ORR was 25% including 15% CRs (19 of 130).  Median PFS was 4 months(9).
A meta-analysis of available treatments for relapsed/refractory PTCL showed that, even though 
approved, belinostat and pralatrexate were less effective and less safe than several other regimens 
(Figure 1). Most effective of these regimens was the anti-CD30 immunotoxin brentuximab 
vedotin in anaplastic large cell lymphoma (ORR 86%), although, when given to unselected patients 
with PTCL-NOS, the ORR was significantly lower (ORR 41%)(6).
Figure 1:  Safety and efficacy of treatments for relapsed/refractory PTCL(6)
1.2.3
Treatment of relapsed/refractory CTCL
There are five FDA-approved drugs for relapsed/refractory CTCL: bexarotene, romidepsin, 
vorinostat, mogamulizumab and brentuximab vedotin (for CD30-positive disease).
Bexarotene, a retinoid receptor X (RXR)-selective retinoid agonist, was given at two different dose 
levels to 94 patients with stage ≥IIB CTCL, of whom 31% had erythroderma and 10% had visceral 


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involvement(10). Only 16% of patients had ≥15% circulating Sézary cells, though 27% had 
detectable Sézary cells . ORR was 45-55%, with 1-5 CRs. One of five patients with circulating 
Sézary cells had a substantial decrease in counts. Six of 19 patients (32%) with generalized 
erythroderma, and four of 17 (24%) with Sézary Syndrome (SS) had a response. The most common 
grade 3 or 4 AEs were hyperlipidemia (34-45%) and pruritus (8-14%). One of 17 deaths were 
judged to be possibly drug related, that of a patient who developed liver failure with coagulopathy.
The HDAC inhibitor vorinostat was investigated in a phase IIB multicenter trial of 74 patients, 61 
with advanced (stage ≥IIB) disease, including 30 with SS. ORR was 29.7% (1 CR, 21 PRs), 
including 10/30 patients with SS(11). Grade 3 or 4 AEs were seen in 28% of the patients, with the 
most common being fatigue (5%), pulmonary embolism (5%), thrombocytopenia (5%), and nausea 
(4%). Another HDAC inhibitor, romidepsin, was investigated in two concurrent Phase 2 trials with 
a combined total of 167 patients, 130 of whom with stage ≥IIB disease(12, 13). ORR was 34-38%, 
and a total of 10 patients (6%) had CRs, three of whom had SS. Reports of grade 3 or 4 AEs varied 
between the studies, with lymphopenia ranging from 21% to <10%, neutropenia 14% to <10%, 
and thrombocytopenia 6% to none. There were 10 deaths which occurred within 30 days of 
receiving the last dose of the drug, two from sepsis, one from hypertrophic cardiac disease, and 
the rest from disease progression.
Mogamulizumab is an anti-CCR4 antibody recently approved by the U.S. FDA, based on an open-
label phase III study of 372 patients, with vorinostat as the control arm.  ORR assessed by 
independent reviewers was 23% for mogamulizumab and 4% for vorinostat. Median PFS was 6.7 
months in the mogamulizumab group versus 3.8 months in patients receiving vorinostat. The most 
common treatment-emergent AEs in the mogamulizumab group were infusion-related reactions, 
drug rash, diarrhea, and fatigue(14).
Chemotherapy, including CHOP-based regimens, have the highest response rates (50-88%), but 
duration of response is <6 months and high toxicity is associated with the treatment. More recently, 
a Phase 3 trial comparing brentuximab vedotin to methotrexate or bexarotene in CD30+ CTCL, 
reported improvement in proportion of patients achieving an objective global response lasting at 
least 4 months (ORR4) at a median follow-up of 22.9 months, which was 56.3% with brentuximab 
vedotin vs. 12.5% with methotrexate or bexarotene(15).
1.2.4
Treatment of relapsed/ refractory anaplastic large cell lymphoma (ALCL)
Brentuximab vedotin is the only drug approved by the FDA for the treatment of CD30+ systemic 
ALCL relapsed after or refractory to chemotherapy. In a Phase 2 trial of 58 patients, 57% 
achieved CR and 29% achieved PR, with a median time to response of 5.9 weeks (which was the 
time of the first CT)(16). Median response duration was 12.6 months overall, and 13.2 months 
for patients who achieved CR.
1.2.5
Immune checkpoint inhibitors in T-cell malignancies
A Phase 1b trial of nivolumab in patients with relapsed and refractory hematologic malignancy 
involved 15 patients with CTCL (2 with mycosis fungoides and 2 with SS), 5 patients with PTCL 
and 3 with other forms of T-cell lymphoma(17). PD-L1 testing by immunohistochemistry (IHC) 
and molecular analysis was not done on all patients, and expression was not required for eligibility. 
There were no differences in AE frequency or severity between the B-cell and T-cell groups. Four 
patients (2 with CTCL and 2 with PTCL) had a PR, making the ORR 17%. Three of them had an 
ongoing response after 24.3, 50, and 78.6 weeks of follow-up, while one of the patients with PTCL 


Abbreviated Title:  IL-15 and Avelumab in R/R T-cell NHL
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10
progressed after 10.6 weeks. Ten patients had stable disease (SD; median duration of 11 weeks), 
and the remaining 9 progressed during treatment.
The anti-PD-1 antibody pembrolizumab was given to 24 patients with MF/SS in a CITN 
multicenter Phase 2 study(18). The majority of patients had stage IIB or higher disease, and 15 
had stage IVA SS. ORR was 38% (1 CR, 8 PR), with six patients having ≥90% improvement in 
skin disease as measured by the modified Severity Weighted Assessment Tool (mSWAT). Median 
TTR was 11 weeks, and 8 of 9 responses were ongoing at the time of the report. Notably, there 
was no association between response and skin tissue expression of PD-1, PD-L1, PD-L2, or 
infiltrating CD8+ T cells. A “skin flare” was reported in 40% of patients with SS. Two treatment-
related SAEs were grade 2 pneumonitis and grade 3 diarrhea secondary to steroid-refractory 
duodenitis.
There is preclinical and clinical evidence to suggest that immune checkpoint inhibition may 
precipitate rapid progression in some forms of T-cell lymphoma, most notably those that are PD-
1 (but not PD-L1) positive. In a phase II trial of nivolumab in patients with PTCL, ORR was 33%, 
with two CRs and two PRs among the 12 patients treated.(19) However, one of six patients with 
AITL progressed after the first dose, and three more experienced significant progression after the 
second or third dose of nivolumab. Notably, AITL tumor cells were shown to have high levels of 
PD-1(20), which may act as a tumor suppressor in T-cell lymphomagenesis.(21) PTCL with T 
follicular helper phenotype (PTCL-TFH) is another form of PTCL in which tumor cells are PD-1 
positive, as is ATLL.  A trial of single-agent nivolumab for ATLL (NCT02631746) was suspended 
for interim analysis when the first 3 patients enrolled developed accelerated disease progression 
within the first two doses of the drug.(22)
There are several ongoing Phase 2 trials that have yet to report results: nivolumab for 
relapsed/refractory PTCL (NCT03075553), pembrolizumab after auto-SCT for any HL, DLBCL, 
and T-NHL (NCT02362997); pembrolizumab for CTCL in combination with romidepsin 
(NCT03278782), radiation therapy (NCT03385226), and decitabine and pralatrexate 
(NCT03240211, which also includes patients with PTCL); atezolizumab for relapsed/refractory 
CTCL (NCT03357224); and avelumab for relapsed/refractory PTCL (NCT03046953). 
1.2.6
Recombinant human IL-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 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 (CD215)(23-27). 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.  IL-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 participates less in the capillary leak syndrome. Several studies in 
murine models highlighted the potential value of IL-15 therapy for neoplasia.  The safety of IL-15 
was evaluated in rhesus macaques. A 12-day bolus intravenous administration of 20 µg/kg/day of 
IL-15 to rhesus macaques was associated with a 4 to 8-fold increase in the number of circulating 
NK cells.  When administered by continuous intravenous infusion (civ) at 20 µg/kg/day for 10 
days, a 10-fold increase in the number of circulating NK cells, a 15-fold increase in the number of 
circulating monocytes and a massive 80 to 100-fold increase in the number of circulating effector 
memory CD8 T-cells was observed.  Subcutaneous infusions at 20 µg/day for 10 days led to a 10-


Abbreviated Title:  IL-15 and Avelumab in R/R T-cell NHL
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11
fold expansion in the number of circulating effector memory CD8 T-cells.  On the basis of 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.   
1.2.7
Clinical trials using IL-15 monotherapy in the treatment of cancer
We initiated, executed and reported a first in-human Phase I study (NCT01021059) of bolus 
administered intravenous rhIL-15 in adults with refractory metastatic malignant melanoma and 
metastatic renal cell cancer(23) . This study was initially planned as a Phase 1 dose-escalation trial 
starting with an initial dose of 3 mcg/kg/day for 12 days. However, after the initial patient 
developed grade 3 hypotension, and another patient of the 5 patients at dose level 3 mcg/kg/day 
developed grade 3 thrombocytopenia, the protocol was amended to add the two lower doses of 1.0 
and 0.3 mcg/kg/day. Two of four patients given 1.0 mcg/kg/day dose developed persistent grade 
3 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations that were dose 
limiting. All 9 patients with IL-15 at 0.3 mcg/kg/day received 12 doses without a DLT, and the 
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, and a drop in blood pressure 5 to 9 
hours after the infusion to a nadir approximately 20 mm/Hg below pretreatment levels. These 
changes were concurrent with a maximum of 50-fold elevations of circulating IL-6 and IFn-γ 
concentrations.
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, followed by an influx and hyperproliferation yielding a 10-fold expansion in the 
number of NK cells that ultimately returned to baseline. There was a modest effect on the 
number of CD8+ T-cells but by day 8 of the infusion virtually all CD8+ T-cells expressed high 
levels of Ki67, CD38 and HLA-DR.  In this first-in-human Phase 1 trial there were no responses, 
with stable disease as the best response. However, 5 patients manifested a decrease of between 
10% and 30% of their marker lesions and 2 had clearing of lung lesions.
1.2.8
Clinical trials involving IL-15 administered by alternate dosing strategies 
Ultimately, we concluded that it proved too difficult to administer IL-15 as an intravenous bolus 
infusion because of clinical toxicities produced by intense cytokine secretion that occurred within 
the first 2 hours after treatment. There were exceedingly high IL-15 Cmax levels initially after bolus 
infusions that were sufficient to signal through the IL-2/IL-15R beta and γc receptor pair that IL-
15 shares with IL-2, thereby contributing to the toxicities observed. To reduce the Cmax and toxicity 
and to increase the period of time when IL-15 is at an optimal concentration for high-affinity IL-
15 receptors we evaluated alternative dosing strategies, first in rhesus macaques. By administering 
IL-15 by civ or subcutaneously to these nonhuman primates the exceedingly high Cmax observed 
by bolus infusion was avoided. In particular, with bolus intravenous infusions to rhesus macaques 
at 20 mcg/kg/day, the Cmax was 720 pg/mL, in contrast with subcutaneous infusion of 20 
mcg/kg/day the Cmax was 50 pg/mL and with continuous infusion at 20 µg/kg/d the IL-15 Cmax was 
between 2 and 4 pg/mL throughout the 10-day study period.
1.2.8.1
A Phase I Study of Subcutaneous Recombinant Human IL-15 (rhIL-15) in Adults with 
Metastatic Cancer (NCT01727076)
To translate this observation in collaboration with the Cancer Immunotherapy Trials Network 


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(CITN), we completed a Phase I trial of subcutaneous recombinant human IL-15 in cycles 
consisting of 5 daily injections of rhIL-15 given Monday-Friday for 2 weeks, then 2 weeks of 
observation with potential for additional cycles. Three patients each were enrolled in 0.25, 0.5, 
1.0, and 2.0 mcg/kg/day dose levels and six patients were evaluated at 3.0 mcg/kg/day.  Eighteen 
patients completed at least one cycle with one DLT at 3.0 mcg/kg/day and one serious adverse 
event, pancreatitis, at 2.0 mcg/kg/day. Flow-cytometry data indicated a consistent increase in the 
frequency of CD56bright CD3- negative NK cells peaking at day 15 (day 12 = last dose). The 
mean fold increase with 3 mcg/kg/day of IL-15 in circulating NK cell numbers peaked at 10.8-
fold.  The maximum fold increase in circulating CD8 + T cells was 3.3-fold. It was concluded that 
subcutaneous IL-15 was well tolerated and that the 3 mcg/kg/day dose level was safe for outpatient 
use. 
1.2.8.2
Protocol ID Number:  NCI-12-C-0113 A Phase I Study of a Continuous Intravenous 
Infusion of Recombinant Human Interleukin IL-15 (rhIL-15) in Adults with Metastatic 
Cancers (NCT01572493)
In a parallel clinical trial that we performed in the Clinical Center NIH, rhIL-15 was administered 
at progressively increasing doses (0.25, 0.5, 1.0, 2.0 and 4.0 mcg/kg/day) to groups of 3 patients 
each, with metastatic malignancy by civ for 10 days. Two dose-limiting toxicities were observed 
at 4.0 mcg/kg/day, hepatotoxicity and visceral arterial ischemia. Therefore, an expansion group 
study of 9 patients at the MTD of 2.0 mcg/kg/day was completed. This 2.0 mcg/kg/day dose level 
was well tolerated. None of the patients had an immune response to the IL-15. The 
pharmacokinetic pattern when IL-15 was administered by civ was quite distinct from that observed 
with bolus infusion. With bolus infusions of 3 mcg/kg/day the arithmetic mean Cmax of 30,420 
pg/mL was observed at the onset of the IL-15 administration, followed by a rapid decline in serum 
IL-15 levels. When IL-15 was administered by subcutaneous infusion the Cmax at 4 hours after the 
subcutaneous administration of 3.0 mcg/kg/day was 6,480 pg/mL. With continuous intravenous 
infusion, there was a progressive increase of serum IL-15 levels with a Cmax at 12 to 48 hours of 
1,510 pg/mL, markedly lower than that observed with bolus infusions. The lower Cmax observed 
with subcutaneous and civ was paralleled inversely by a 10-fold greater MTD at these levels 
compared to that with the bolus infusion. In the civ trial following the Cmax at 12 to 48 hours there 
was a gradual decline to 8% of the maximum level by days 8-10 despite the fact that the IL-15 
infusions were continued. We hypothesized that a factor for this decline in serum IL-15 
concentration was the IL-15-induced increase in the number of IL-15 receptor bearing cells as well 
as the number of receptors (especially IL-2/IL-15Rβ [CD122] receptors) per cell that acted as a 
sink, binding some of the IL-15 administered.
The time course of the increase in host lymphoid cells showed an interesting pattern with civ. 
Within 1 to 3 days of the infusion initiation there was a rapid decline in the number of circulating 
NK cells, followed by a gradual increase until the termination of infusions.  Of interest, during the 
1 to 3 days immediately following termination of the infusion there was a dramatic 30-fold increase 
in the number of circulating NK cells and an over 350-fold increase in the number of CD56bright 
NK cells (Figure 2). 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. Furthermore, although the specific lytic 
activity of CD56bright cells was not as great as that of CD56dim cells, their lytic activity was 


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markedly increased by IL-15 treatment including activity associated with antibody-dependent 
cellular cytotoxicity (ADCC), as assessed in vitro by their cytotoxicity against target cells, anti-
CD20 antibody coated Raji cells, K562 cells (natural cytotoxicity mediated by NKp30 and NKp46) 
and C1R-MICA cells (NKG2D-mediated cytotoxicity)(28). These observations on the effect of 
IL-15 on NK subsets and their function support the proposed trials described below that involve 
the combinations of IL-15 with antitumor monoclonal antibodies to increase their ADCC and 
antitumor efficacy. 
A trial of IL-15 by civ for 5 days has been initiated, and in the 10 patients studied following 
treatment there was a 21 to 44-fold increase in the number of circulating NK cells, and up to an 
8.9-fold increase in the number of CD8+ T cells (Figure 2, Table 1).
Figure 2:  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 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 1:  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
A
B


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Diagnosis
Age
Gender
Dose level
(mcg/kg)
No. of doses
NK cell
increase 
(fold)
CD8+ T-cell
increase 
(fold)
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
1.2.9
Avelumab 
Avelumab is a fully human IgG1, anti-programmed death ligand-1 (PD-L1) antibody that inhibits 
PD1/PD-L1 interactions while leaving the PD1/PD-L2 pathway intact and enhances immune 
activation against tumor cells(29-36). Avelumab (Bavencio®) received U.S. FDA accelerated 
approval for the treatment of patients with metastatic Merkel cell carcinoma (MCC)(34) and 
urothelial carcinoma(30). Unlike other approved anti-PD-L1/PD1 antibodies, avelumab induces 
lysis of tumor cells via ADCC, indicating an additional mechanism of action. However, avelumab 
has not shown ADCC against normal immune cell subsets in humans(31). PD-L1 is found 
predominantly on tumor cells and binds to PD1, which like CTLA-4 is found primarily on T cells. 
When overexpressed in tumors, PD-L1 is a negative prognostic marker, most likely due to T-cell 
anergy induced by the binding of PD-L1 to PD1(37, 38). The standard therapeutic dose and dosing 
strategy involves 10 mg/kg IV infusion of avelumab given every 2 weeks(30).
1.2.9.1
Experience with avelumab in refractory metastatic urothelial carcinoma
Sixty-six patients with metastatic urothelial carcinoma were studied with avelumab(30). An 
independent central review assessment resulted in a confirmed ORR of 18.2% including 5 patients 
(11.4%) with a complete response (Figure 3). Three patients (6.8%) had a partial response and 15 
patients had stable disease as best response. Patients' responses were predominantly found in those 
with PD-L1 positive tumors.  Seven of eight responding patients (87.5%) had PD-L1 positive 
tumors whereas only 4.7% (1 of 24) of patients with PD-L1 negative tumors had a response. The 
median time to response was 13.0 weeks. The median duration of response was not reached.
1.2.9.2
Experience with avelumab in ovarian cancer
A total of 124 relapsed ovarian cancer patients were treated with avelumab resulting in a response 
rate of 9.7% comprised of 12 partial responses with 6 ongoing. Stable disease was observed in 
44% yielding a disease control rate of 54% (unpublished data). 
1.2.9.3
Experience with avelumab in non-small cell lung cancer (NSCLC)
In a Phase 1b trial of 184 patients, objective responses were observed in 22 (12%) patients, 1 CR, 
21 PRs, and stable disease was found in 70 patients (38%)(39). Overall, 50% of patients achieved 
disease control. 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 most common being infusion reactions (2%) and increased lipase level 
(2%).
1.2.9.4
Experience with avelumab in breast cancer
Avelumab was studied in 168 patients with locally advanced breast cancer or MVC refractory to 
or progressing after standard of care. Response rate in the entire cohort was 5.4% (9 patients) with 


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1 complete and 8 partial responses. Stable disease was observed in an additional 40 patients 
(23.8%) yielding an overall disease control rate of 29.2%. Responses were predominantly in PD-
L1 expressing tumors (unpublished data).
1.2.9.5
Experience of with avelumab in Merkel cell carcinoma
Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine tumor of the skin. The 
proportion of patients who achieved an objective response was 28/88 (31.8%) including 8 
complete and 20 partial responses(34).
Further trials of avelumab for mesothelioma, gastric cancer, adrenocortical carcinoma and renal 
cancer are ongoing.
Figure 3:Clinical activity of avelumab. (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 
PD-L1 expression status indicated (on the basis of a >5% staining threshold on tumor cells; non-evaluable 
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 


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threshold on tumor cells). 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 post- baseline 
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%. (30)
1.2.9.6
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).
1.2.10 Rationale of Study 
1.2.10.1 PD-L1 expression in T-cell malignancies
Several IHC analyses have demonstrated that T-cell lymphomas express PD-L1. In a series of 26 
cases of cutaneous T-cell lymphoma (CTCL), virtually all stages showed staining for PD-L1 in 
the majority of atypical lymphocytes (>50% in 5/7 stage I/II, 6/6 stage III, and 11/11 stage IV)(40). 
An older series of 11 patients with CTCL (stage unspecified), and 65 patients with peripheral T-
cell lymphoma-NOS reported 17-27% PD-L1 positivity by immunohistochemistry with a cutoff 
of 30%(41). Low prevalence of PD-L1 expression in PTCL-NOS was confirmed in a series of 11 
patients, with three (28%) being positive using a ≥5% cutoff(42).
Eighteen of 24 patients with ALK-negative ALCL showed PD-L1 expression as assessed by IHC 
using SP142 antibody (Ventana). Interestingly, FISH analysis showed no PD-L1 gene 
amplification, but in silico analysis of the PD-L1 and PD-L2 gene promoters identified multiple 
potential binding sites for STAT3 and MYC(43). Multiple other analyses of the T-cell lymphoma 
genomic landscape did not find mutations or gene copy alterations of the PD-L1-encoding PDCD1 
gene(44-48). Some studies found alterations in the PD-1 encoding PDCD1 gene in 8-36% of 
patients with T-cell lymphoma.
Since a significant number of T-cell malignancies express PD-L1, 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. 
1.2.10.2  Preclinical Trials of IL-15 with Anticancer Monoclonal Antibodies to Augment their 
ADCC
While the in vivo effects of IL-15 in cancer patients are still not entirely clear, the initial clinical 
data has demonstrated that to achieve its full potential in the treatment of cancer, IL-15 will have 
to be used in combination with other therapeutic agents. In light of the data from preclinical animal 
models and clinical trials of the capacity of IL-15 to increase the number of activated NK cells, T 
cells and monocytes, this information supports the administration of IL-15 with antitumor 
monoclonal antibodies to augment their ADCC against tumor cells. To further investigate this 


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strategy, the Waldmann Laboratory used an immunocompetent syngeneic mouse model of B-cell 
lymphoma to investigate the combination of IL-15 with rituximab. Wild-type CD56 and BL/6 mice 
were inoculated intravenously with EL4-CD20 cells, a mouse lymphoma line transfected with 
CD20. The mice were distributed into 4 treatment groups (control, IL-15 alone, rituximab alone 
and the combination) of 10 mice each. IL-15(5 µg/mouse) was administered 5 x per week for 4 
weeks beginning 3 days after EL4-CD20 inoculation. In cohorts receiving rituximab, the 
monoclonal antibody was given once per week for 4 weeks starting 5 days after EL4-CD20 
inoculation. As seen (Figure 4), IL-15 or rituximab monotherapy prolonged survival of mice when 
compared to the control group (p < 0.05) but the combination of IL-15 and rituximab showed the 
greatest prolongation of survival compared to monotherapies (< 0.01), such that 75 days after 
tumor inoculation 90% of the combination treatment group were still alive in contrast to 30% 
survival from the monotherapy groups and no surviving mice in the control group (Figure 4). In a 
parallel preclinical trial, the Waldmann Group administered a combination therapy of 
alemtuzumab with rhIL-15 in the MET-1 bearing xenograft model in wild-type SCID/NOD mice 
(Figure 5). Again, there was an augmentation of survival of the combination of IL-15 with 
alemtuzumab compared to either element alone. The efficacy was lost in FcRγ-/- mice, further 
supporting the hypothesis that the efficacy was due to augmented ADCC.
Additionally, Jochems C, et al. analyzed the in vitro ADCC capacity of an IgG1 anti-PD-L1 
antibody structurally similar to avelumab with and without IL-15, and compared it to that of a 
fusion protein consisting of the anti-PD-L1 and a TGF-beta trap(49). IL-15/IL-15R alpha IgFc 
enhanced the ADCC capacity of both molecules, making them equal.
Figure 4:  Addition of IL-15 increased ADCC and antitumor efficacy of cancer-directed monoclonal 
antibodies.EL4 leukemic cells were transfected with human CD20 and administered intravenously into 
immunologically intact mice. Mice treated with either IL-15 alone (yellow) or rituximab (anti-CD20) alone 
(red) showed modest prolongation of survival. This prolongation was markedly augmented when the two 
agents were administered together (green). 


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Figure 5:  Combination alemtuzumab and rhIL-15 in a xenograft model of MET-1 ATL Leukemia. 
On the left: SCID/NOD mice bearing the MET-1 ATL leukemia who received either alemtuzumab 
(CAMPATH) (red) or IL-15 alone (yellow) had only modest efficacy that was markedly augmented by the 
combination of IL-15 plus alemtuzumab (green). Right: This efficacy was lost in FcRγ-/- mice supporting 
the hypothesis that the efficacy was due to ADCC. 


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2
ELIGIBILITY ASSESSMENT AND ENROLLMENT
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Patients must have histologically or cytologically proven relapsed/refractory T-cell 
lymphoma other than adult T-cell leukemia/lymphoma (ATLL), angioimmunoblastic T-
cell lymphoma (AITL), peripheral T-cell lymphoma T follicular helper phenotype 
(PTCL-TFH), or enteropathy-associated T-cell lymphoma (EATL), confirmed by the 
Laboratory of Pathology, NCI
2.1.1.2
Patients with CD30+ mycosis fungoides/Sézary syndrome (MF/SS) or CD30+ anaplastic 
large cell lymphoma (ALCL) must have relapsed after or become intolerant to treatment 
with brentuximab vedotin. 
2.1.1.3
A formalin fixed tissue block or 15 slides of tumor sample (archival or fresh) must be 
available for performance of correlative studies. NOTE: Patients must be willing to have 
a tumor biopsy if prior tissue or adequate archival tissue is not available (i.e., post-
enrollment and prior to treatment).
2.1.1.4
Disease must be measurable with at least one measurable lesion by RECIL 2017 or 
mSWAT criteria (see Section 6.3), or have an abnormal clonal T-cell population 
detectable by peripheral blood flow cytometry
2.1.1.5
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 will be eligible for future pediatric trials 
2.1.1.6
ECOG performance status ≤1 (Karnofsky ≥80%, see APPENDIX A). 
2.1.1.7
Adequate organ and marrow function as defined below: 
Absolute neutrophil count
> 1,000/mcL
Absolute lymphocyte count
≥ 500/mcL
Hemoglobin
≥ 9 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
2.1.1.8
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.


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2.1.1.9
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 30 days 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.
2.1.1.10 Ability of subject to understand and the willingness to sign a written informed consent 
document
2.1.2
Exclusion Criteria
2.1.2.1
Patients 
with 
the 
following 
T-cell 
leukemias/lymphomas: 
adult 
T-cell 
leukemia/lymphoma (ATLL), angioimmunoblastic T-cell lymphoma (AITL), peripheral 
T-cell lymphoma T follicular helper phenotype (PTCL-TFH), and enteropathy-associated 
T-cell lymphoma (EATL).
2.1.2.2
Chemotherapy and anti-tumor antibodies within 4 weeks (6 weeks for nitrosoureas or 
mitomycin C); other tumor-directed systemic therapy and radiation therapy within 2 
weeks. 
2.1.2.3
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 judgment 
2.1.2.4
Patients who are receiving any other investigational agents
2.1.2.5
Patients who have had prior therapy with any antibody/drug targeting PD-1/PD-L1 T-cell 
coregulatory proteins (immune checkpoints) 
2.1.2.6
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)


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2.1.2.7
Patients with known CNS involvement 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 
2.1.2.8
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 
2.1.2.9
Patients with history of any organ transplantation, including allogenic stem cell 
transplantation 
2.1.2.10 Received a live vaccine 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
2.1.2.11 Patients with history of allergic reactions attributed to compounds of similar chemical or 
biologic composition to rhIL-15 or avelumab 
2.1.2.12 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 
2.1.2.13 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
2.1.2.14 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 12.5 for IL-15 administration in HIV positive patients)
2.1.2.15 Patients with active or history of any autoimmune disease unrelated to their malignancy, 
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
2.1.2.16 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
2.1.2.17 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 


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and, in the judgment of the investigator, would make the patient inappropriate for entry 
into this study
2.1.3
Recruitment Strategies
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. In addition, information will be provided on the 
ccr.cancer.gov/ Lymphoid-Malignancies-Branch and ClinicalTrials.gov web pages. This study will 
be posted on NIH websites and on NIH social media forums as well as official Lymphoid 
Malignancy Branch social media accounts.  Study-specific public service announcements and 
informational fliers will be used for recruitment activities.  All information to be posted or 
distributed publicly will be submitted to the IRB for review and approval in advance of use.
2.2
SCREENING EVALUATION
2.2.1
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
2.2.2
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 
01C0129, on which screening activities will be performed.
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 Section 3.6. 
2.2.2
Clinical Evaluations

Disease history, including:  diagnosis, treatment (e.g., systemic treatments, radiation 
and surgeries), disease 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, and blood pressure); review of concomitant 
medications and symptoms/side effects; and, assessment of performance status 
2.2.3
Laboratory Evaluations
NOTE:  Results from outside NIH are accepted.

CBC with differential, platelets and reticulocyte count

Chemistry panels (as noted) or specific analyte required for eligibility, including: 
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 


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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) with reflex free 
thyroxine (T4) per DLM policy

Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody, Hepatitis C antibody 
(HCV) [qualitative], HIV 1/2 antibody (qualitative) and HTLV-1/2 serologies (within 
3 months)  NOTE:  For individuals with a positive hepatitis B core antibody, HBV 
DNA PCR will be performed to screen for subclinical infection.

Urinalysis (with microscopic examination if abnormal)

Antinuclear antibody (ANA), rheumatoid factor (RF) and anti-thyroid antibody

Creatine phosphokinase (CPK), troponin 

Serum or urine pregnancy test (B-HCG) for women of childbearing potential

Clonal T-cell receptor rearrangement by PCR
2.2.4
Imaging Studies 
NOTE:  Results from outside NIH are accepted. Other body areas may be imaged if 
clinically indicated. 

CT neck, chest, abdomen and pelvis (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)

MRI of brain (only in patients with suspected involvement of CNS)
2.2.5
Cardiac Evaluation (within 3 months)

Electrocardiogram (EKG)

Transthoracic echocardiogram
2.2.6
Other Procedures

Pathologic review/confirmation of diagnosis by Laboratory of Pathology, NCI (no time 
limit). If archival sample is not available, a fresh tumor biopsy and/or peripheral blood 
sample will be obtained.

Pulmonary function tests (PFTs): diffusing capacity/alveolar volume (DLCO/VA), 
forced expiratory volume in 1 second (FEV1) for patients with significant pulmonary 
or smoking history
2.3
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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2.3.1
Treatment Assignment Procedures  
NOTE: For NCI CCR registration and enrollment system purposes only
2.3.1.1
Cohorts
Number
Name
Description
1
Mature T-cell 
malignancies:  Dose 
Escalation
Relapsed/refractory T-cell lymphoma other than ATLL, AITL, 
PTCL-TFH, and EATL (up to 24 evaluable patients)
2
Mature T-cell 
malignancies:  Dose 
Expansion
Relapsed/refractory T-cell lymphoma other than ATLL, AITL, 
PTCL-TFH, and EATL (up to 3 additional evaluable patients; 
9 total evaluable at the MTD)
2.3.1.2
Arms
Number
Name
Description
1
Experimental Treatment:  
Dose Escalation
IL-15 by civ infusion at escalating doses of 1, 2, 3 and 4 
mcg/kg/day on days 1-5 of each 28-day cycle (max 6 cycles) 
with avelumab by IV infusion at a dose of 10mcg/kg on Day 8 
and 22 of each cycle, to determine MTD
2
Experimental Treatment:  
Dose Expansion
IL-15 by civ infusion at the MTD on days 1-5 of cycles 1-6 
with avelumab at 10mcg/kg on Day 8 and 22 of each cycle
2.3.1.3
Randomization and 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. 
2.4
BASELINE EVALUATION
The following should be performed within 28 days prior to the first dose of rhIL-15 unless 
otherwise noted; tests performed as part of screening do not need to be repeated if they were 
performed within the specified window prior to initiating treatment.  
2.4.1
Clinical Evaluations

Medical history (interim)

Physical examination including weight, vital signs (i.e., temperature, pulse, respiratory 
rate, and blood pressure); review of concomitant medications and symptoms/side 
effects; and assessment of performance status (ECOG performance score, see 
APPENDIX A).
2.4.2
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
CBC with differential, platelets and reticulocyte count
o
Chemistry panels including: Acute Care (sodium, potassium, chloride, CO2, 
glucose, BUN, creatinine), Mineral Panel (serum calcium, phosphate, 


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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, Uric acid, Total protein
o
Coagulation panel, including: PT/INR and aPTT
o
Iron panel (includes: ferritin, transferrin, iron), folate, vitamin B12
o
C-reactive protein (CRP)
o
Serum Lipase and Amylase
o
TSH with reflex free T4
o
Urinalysis (with microscopic examination if abnormal)
o
HLA typing (A, B, C, DR, DQ)
o
Soluble IL-2R
o
Creatinine phosphokinase (CPK), troponin I
•
Required within 28 days:
o
Lymphocyte Phenotype: T, B and NK cell subsets
o
Antinuclear antibody (ANA), rheumatoid factor (RF) and anti-thyroid antibody 
2.4.3
Imaging Studies
Every participant should have an evaluation of known sites of disease as part of baseline 
evaluation. NOTE:  Only results from NIH are accepted 
•
One or more of the following studies: CT, MRI, FDG-PET and/or clinical photography
•
Patients with neurological symptoms or signs should undergo MRI scan* of the brain 
and lumbar puncture
*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.
2.4.4
Other Procedures
•
Bone marrow biopsy and aspiration to assess lymphoma involvement (within 3 
months)
•
Selected patients with cutaneous disease (as determined by physician PI or AI) will 
have clinical photography and dermatology assessment performed to assess their skin 
disease
2.4.5
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
Blood, buccal swab, or saliva for germline DNA
o
Tumor Tissue (archival or fresh)


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
Optional:  
o
Blood samples for ADCC of avelumab, tissue immune cell subset comparison 
(as outlined in Section 5.1)
o
Bone marrow biopsy
o
Tumor biopsy is required if archival tissue is not available or adequate; 
otherwise, this is optional.
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
In patients with relapsed or refractory T-cell malignancies, IL-15 will be administered by 
continuous intravenous infusion in a dose-escalation 3 + 3 system with a starting dose of 1 
mcg/kg/day, a second dose level of 2 mcg/kg/day, a third dose level at 3 mcg/kg/day, and a fourth 
dose level at 4 mcg/kg/day on days 1-5 of each of six cycles. Avelumab (IV over 1 hour) will be 
administered at a dose of 10 mg/kg on days 8 and 22 of the cycle. Treatment will continue for a 
maximum of 6 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.
Day of cycle: 
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, 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) in the absence of signs of leukostasis or 
other toxicities possibly related to the expansion of activated cells 


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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 DLT-defining toxicity after the first 28 days of treatment will lead 
to permanent discontinuation of protocol therapy; however, will not be deemed a DLT for purposes 
of dose escalation.
3.1.2
Dose Escalation
Dose escalation will proceed according to the following schedule (Table 2). Dose escalation will 
follow the following guidelines (Table 3:  Dose Escalation ). DLT is defined above. 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.
The MTD is the dose level at which no more than 1 of up to 6 patients experience DLT during the 
DLT evaluation window(s), or the dose below that at which at least 2 (of ≤6) patients have DLT. 
The protocol will be amended to note the MTD once determined.
Table 2: IL-15 Dose Escalation Schedule
Dose Level
rhIL-15
(mcg/kg)
Avelumab
(mg/kg)
Level 1
1
10
Level 2
2
10
Level 3
3
10
Level 4
4
10
*Doses are stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) rather than as a percentage.
Table 3:  Dose Escalation Guidelines 
Number of Patients with DLT at a 
Given Dose Level
Escalation Decision Rule
0 out of 3
Enter 3 patients at the next dose level.


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Number of Patients with DLT at a 
Given Dose Level
Escalation Decision Rule
>2
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose.
1 out of 3
Enter at least 3 more patients at this dose level.
If 0 of these 3 patients experience DLT, proceed to 
the next dose level.
If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that dose.
≤1 out of 6 at highest dose level below 
the maximally administered dose
This is generally the recommended phase 2 dose. At 
least 6 patients must be entered at the recommended 
phase 2 dose.
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 will be 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. Appropriate dose modifications are described in Section 3.3. No investigational or 
commercial agents or therapies other than those described below may be administered with the 
intent to treat the patient's malignancy. See Table 4 below for description of drug regimen. 
Table 4: Drug Regimen
Agent
Premedications; 
Precautions
Dose
Route
Schedule
rhIL-15
Premedicate with 
acetaminophen and/or 
ibuprofen
** in *** mL D5W 
with 0.1% HSA 
IV over 
24 hours
Days 1-5
Avelumab
Premedicate with 
acetaminophen and an 
antihistamine*
** in 250 mL 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 D
APPENDIX D


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For a full detailed product description and administration guidelines, see Section 14. Infusions may 
be done peripherally or 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.
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 (including bag changes) as first line. Ibuprofen 400 or 600mg orally may be given in 
addition to or instead of acetaminophen, 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 20 mg 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

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. 
3.3
DOSE MODIFICATIONS
If one study agent is held, the other must be held as well.  The maximum time agents may be 
held cannot exceed 6 weeks.  Patients who exceed 6 weeks must be removed from the study 
(section 3.7).
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 14.1.2.
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, 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.
Note: IL-15 should not be administered within 1 week of steroid administration when steroids are 
given to treat avelumab toxicities as listed in the Section 3.3.2.


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3.3.2
Avelumab
3.3.2.1
Treatment modifications for symptoms of infusion-related reactions 
Table 5: 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.
NOTE:  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.


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Table 6: 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. 
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.
IV equivalent of 1 to 2 
mg/kg/day prednisone
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. 


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Table 7: 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 0.5 to 1.0 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
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 PO, 
or PO/IV 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 8: 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 PO, or PO/IV 
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


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Pulmonary irAEs
Pneumonitis
Initial Management
Follow-up Management
Grade 3 or 4
Grade 3: Severe new 
symptoms; New / 
worsening hypoxia
Grade 4: Life-
threatening
Permanently discontinue protocol therapy
Hospitalize
Pulmonary and Infectious Disease consults
1 to 2 mg/kg/day prednisone PO, or PO/IV 
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)
Table 9: 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 protocol 
therapy
Increase frequency of monitoring 
to every 1 to 2 days 
1 to 2 mg/kg/day prednisone PO, 
or PO/IV 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


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Table 10: 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 PO, or PO/IV 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.
Grade 4
Creatinine increased 
> 6 x ULN
Permanently discontinue protocol therapy
Monitor creatinine daily
1 to 2 mg/kg/day prednisone PO, or PO/IV 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 11: 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 PO, or 
PO/IV 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)


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Cardiac irAEs
Myocarditis
Initial Management
Follow-up Management
*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 
Table 12: 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.


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Endocrine irAEs
Endocrine disorder
Initial Management
Follow-up Management
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 PO, 
or PO/IV 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.
Table 13: 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 PO, or 
PO/IV 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.


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Other irAEs (not described above)
Grade of other irAEs
(NCI CTCAE v5)
Initial Management
Follow-up Management
Recurrence of same Grade 
3 irAEs
Permanently discontinue protocol 
therapy
1 to 2 mg/kg/day prednisone PO or 
PO/IV 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 protocol 
therapy
1 to 2 mg/kg/day prednisone PO, or 
PO/IV 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 protocol 
therapy
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 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.
3.4
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. 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 six cycles or until disease progression, 
unacceptable treatment-related toxicity or other reasons outlined in Section 3.8.1.
Refer to the Study Calendars (Section 3.6) 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.


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3.5
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 in all subjects. 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 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 for 
symptoms.
Unless otherwise noted for subjects who come off treatment without evidence of disease 
progression, 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 2 years, 
then annually (±6 weeks) at the discretion of the investigator. See Section 3.5.3.  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 (i.e., every 3 months [±4 weeks]) until the subject is off study; unless otherwise clinically 
indicated. See Section 3.5.4 and the Study Calendar (Section 3.6) for additional information. Any 
adverse events which are present at the time of discontinuation should be followed in accordance 
with the safety requirements.  
3.5.1
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 3.6). 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. 
3.5.2
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 with subsequent clinic visit requested in case any concerns 
are noted during the telephone call.
3.5.3
Follow-Up Visits- Prior to Disease Progression 
Patients who complete trial 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 2 years, then annually (±6 weeks) 
after finishing treatment by radiologic imaging or other clinical assessments to monitor disease 
status. Imaging assessment will be performed at each scheduled post-treatment follow-up visit for 
up to 3 years. 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. 


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3.5.4
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 to 6 months 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).


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3.6
STUDY CALENDAR
Study Cycles
Post-Treatment
Follow-Up
Procedure
Screening
Baseline
C1
C2-6
Disease 
Evaluations
End of 
Treatment 
and
Disease 
Progression
Safety 1
Follow-Up
(Prior to PD)
Survival
(Post-PD)
Scheduling Window (Days): -28 to -12
-143
5
(-1)
8
(-3)
9
22
(-3)
1
(-3)
8
(-3)
22
(-3)
Every 8 
weeks 4
Treatment 
discon/PD 5
Day 30
(+7)
Every 60 or 
90 days 6
Every 3 
months 7
Confirmation of Diagnosis 8
X
Physical Exam and ECOG PS 9
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 10
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
Uric Acid, Total Protein
X
X
X
X
X
X
X
PT/INR and aPTT
X
X
X
X
X
X
X
Thyroid Function (TSH, reflex  free 
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
HLA typing (A, B, C, DR, DQ) 
X
X
Anti-nuclear antibody (ANA), 
rheumatoid factor (RF) and anti-
thyroid antibody
X
X
Clonal T-cell receptor 
rearrangement by PCR
X
Iron panels, Folate, and B12, C-
reactive Protein, IL-2R
X
X
Creatine phosphokinase (CPK), 
troponin 
X
X
X
X
X


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Study Cycles
Post-Treatment
Follow-Up
Procedure
Screening
Baseline
C1
C2-6
Disease 
Evaluations
End of 
Treatment 
and
Disease 
Progression
Safety 1
Follow-Up
(Prior to PD)
Survival
(Post-PD)
Scheduling Window (Days): -28 to -12
-143
5
(-1)
8
(-3)
9
22
(-3)
1
(-3)
8
(-3)
22
(-3)
Every 8 
weeks 4
Treatment 
discon/PD 5
Day 30
(+7)
Every 60 or 
90 days 6
Every 3 
months 7
Pulmonary function tests (PFTs) 11
X
T, B, NK cell subsets
X
X
X
X
X
X
X
Imaging studies 12
X
X
X
X
X
MRI, Lumbar Puncture 13
X
X
X
X
Bone Marrow Aspiration/Biopsy 14
X
X
X
Flow Cytometry15
X
X
X
X
X
Clinical photography and 
dermatology assessment/ global 
score 16
X
X
X
X
Radiologic Evaluation/ tumor 
measurement17
X
X
X
X
EKG. TTE
X
Symptoms/Adverse Events 
Assessment, Concomitant 
Medication Review
X
X
X
X
X
X
Research Blood/Tissue Samples 18
X
X
X
X
X
X
X
X
X
X
X
X
Survival Status
X
NOTE:  Any other tests should be performed as clinically indicated.  See Section 3.2 for drug administration information.  See Section 5 for information on 
research blood samples/correlative studies to be collected.  


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1 30 days (±7) following last dose, and 90 days (+14) after last dose of avelumab (via clinic or phone). 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.
2 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, HTLV-1/2 serologies, Hepatitis B surface antigen and Hepatitis C antibody, EKG, and bone marrow aspiration/biopsy 
(all within 3 months)  NOTE: Any screening tests performed within the specified time frame for baseline do not need to be repeated.
3 Within 14 days prior to dosing on C1D1, with the following exceptions:  Pregnancy test (within7 days of dosing; must be negative).
4 ± 4 days, from date of prior assessment. Confirmatory scans should also be obtained 4 weeks following initial documentation of objective response. After completion of 
treatment, imaging assessment will be performed at each scheduled post-treatment follow-up visit for up to 3 years.
5 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.
6 Follow-up to occur about every 60 days (±7 days) for first 6 months, every 90 days (±14 days) for 2 years, then every 6 months (± 28 days) for another   2 years and then annually 
(± 6 weeks) until disease progression or initiation of new anti-cancer therapy. After completion of treatment, imaging assessment will be performed at each scheduled post-
treatment follow-up visit for up to 3 years.
7 After disease progression or initiation of new anti-cancer therapy, contact for survival about every 3 to 6 months (±4 weeks).
8 Pathologic review/confirmation of diagnosis by Laboratory of Pathology, NCI (no time limit). If archival sample is not available, a fresh tumor biopsy and/or peripheral blood 
sample will be obtained.
9 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). ECOG to be recorded 
at least once per cycle, on day 1, 8, and/or 22.
10 Chemistry panels include:  Acute care, Hepatic, and Mineral.
11 Diffusing capacity/alveolar volume (DLCO/VA), forced expiratory volume in 1 second (FEV1) for patients with significant pulmonary or smoking history.
12 At screening a CT scans of neck, chest, abdomen, and pelvis 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). Other body areas may be imaged if clinically indicated. MRI of the brain is only required in patients with suspected involvement 
of CNS. Also, at screening, a FDG-PET/CT torso (extremities to be included if there is confirmed or suspected disease involvement). At baseline one or more of the following 
studies: CT, MRI, FDG-PET/CT and or clinical photography.
13 Patients with neurological symptoms or signs should undergo MRI scan of the brain and lumbar puncture.
14 Baseline bone marrow aspiration/ biopsy with flow cytometry must be done within 3 months prior to starting treatment. During post-treatment follow-up, repeat bone marrow 
aspiration/ biopsy needed only to confirm a CR.
15 Peripheral blood flow cytometry may be done for disease evaluation of patients who had circulating leukemic cells detected at baseline, and for patients with CTCL regardless of 
their baseline results.
16 To be performed in selected patients with cutaneous disease (as determined by PI or AI).
17 Dermatology assessment and Global/mSWAT scoring will be used instead of or in addition to radiologic evaluation for patients with predominantly cutaneous disease
18 Samples for correlative research are to be collected as indicated in Section 5. Prior biopsy specimen blocks will be used for PD-L1 staining if available. If archival tissue is not 
available or adequate, baseline punch biopsy of the skin or core needle biopsy of a lymph node/visceral lesion is required, otherwise this is optional. 


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3.7
COST AND COMPENSATION
3.7.1
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.    
3.7.2
Compensation
Participants will not be compensated on this study.
3.7.3
Reimbursement
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.   
3.8
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 3.5.
3.8.1
Criteria for removal from protocol therapy
Patients who meet the following criteria should be discontinued from protocol therapy:

Completion of protocol therapy (i.e., up to 6 cycles) 

Confirmed 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

More than 6 weeks has elapsed since the patient received protocol therapy

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

The drug manufacturer can no longer proved the study agent

Study is cancelled for any reason 
3.8.2
Off-Study Criteria

Subject requests to be withdrawn from study

Subject is lost to follow-up

Death 


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
Study is cancelled for any reason
3.8.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she fails to return for two consecutive 
scheduled visits 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 3 business days 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, with the exception of oral or parenteral steroids if they are administered more 
than 7 days before the start of or more than 7 days after the end of IL-15 infusion (Note: 
Dexamethasone for treatment or prophylaxis of avelumab-associated infusion reactions may be 
administered at any time). If there is a clinical indication for a prohibited medication/ measure 
during the trial, discontinuation from trial therapy 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.   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 


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NOTE: Radiation therapy to a symptomatic solitary lesion may be allowed at the 
investigator’s discretion.  

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: 
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, typhoid vaccine and 
FluMist. 
Patients who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study treatment. Patients may 
receive other medications that the investigator deems to be medically necessary.
5
CORRELATIVE STUDIES FOR RESEARCH
5.1
BIOSPECIMEN COLLECTION
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 mature T-cell 
malignancies. 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.


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Time Points
Sample
Collection Details*
Baseline
C1
D5
C1 
D8
C1 
D9
C1 
D22
C2-6
D1
C2-6 
D8
Follow-
up#
Supervising 
Laboratory/ 
Investigator
Blood Samples
Lymphocyte subset 
testing
2 x 10mL K2EDTA 
(lavender-top) tubes
X
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
(X)2
Waldmann
Tissue immune cell 
subsets (comparison) 1 x 5mL green-top tube
(X)
(X)
(X)
Waldmann
PBMC Banking
3 x 10mL sodium 
heparin green-top tubes
X
(X)
X
X
X
X
(X)
Circulating tumor 
DNA, plasma 
banking
1 x 10mL K2EDTA 
tube
1 x 10mL Streck/BCT 
tube
X
(X)
(X)
X3
Anti-IL-15 
antibodies
1 x 4mL SST tube
X
X
X1
Waldmann
(Leidos CSL)
Tissue Samples
Tissue immune cell 
subsets
Two core biopsy 
samples in RPMI 1640 
with 10% human serum 
and antibiotics
One core biopsy 
sample in formalin
NOTE:  Samples may be 
tumor tissue or bone 
marrow aspirate/biopsy 
X**
(X)
(X)
Waldmann/
(RPMI 1640)
and
DLM/ 
NCI LP 
(formalin)
Other Samples
Germline DNA
Blood, Buccal Swab, or 
Saliva (preferred)
X
Waldmann
(X) = Optional; samples will be collected if adequate time/staff available for processing. If an optional sample 
is not collected at baseline, it would also not be collected in follow-up unless specifically requested by the PI. 
*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.
**Tumor biopsy is required if archival tissue is not available or adequate; otherwise, this is optional  
#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; C1D9 and 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 3.5.3.


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5.2
SAMPLE COLLECTION AND PROCESSING
5.2.1
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.
All samples will be delivered to the laboratory of Dr. Thomas Waldmann, Lymphoid Malignancies 
Branch.  The laboratory staff will handle processing or delivery/shipping of associated labs, if 
applicable.  To arrange for sample processing, contact: Bonnita Bryant, Lymphoid Malignancies 
Branch (Building 10, Room 3B35; phone: 240-858-3479) or Sigrid Dubois, Ph.D., Lymphoid 
Malignancies Branch (Building 10, Room 4B47; phone: 301-435-4441). Tissue samples will also 
be sent to the Hematopathology Section of the National Cancer Institute Laboratory of Pathology, 
by courier service.
5.2.2
Blood Samples
All blood samples will be drawn by NIH Clinical Center phlebotomy, inpatient unit, outpatient 
clinic, or day hospital staff
5.2.3
Lymphocyte subset testing by flow cytometry (FACS)

Collect blood in EDTA tubes; gently invert 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.

Lymphoid Malignancies Branch Clinical Research personnel will arrange for these 
samples to be delivered to: Immunology Lab, NIH Clinical Center Bldg. 10/ Room 2C410. 
If the Immunology Section Laboratory is unable to perform this analysis on the specified 
days, this assessment maybe omitted or replaced with standard TBNK panel
5.2.4
Antibody-dependent cell cytotoxicity (ADCC) of avelumab

Collect blood in sodium heparin tubes; gently invert tubes 8-10 times immediately after 
collection. 

Samples will be processed per established laboratory techniques.

Lymphoid Malignancies Branch 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, or directly to Sigrid Dubois, PhD for immediate 
analysis.


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5.2.5
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. Plasma will be isolated 
and frozen at -80ºC until analysis (e.g., centrifuged at 1800 x g for 10 minutes at room 
temperature; plasma transferred/frozen in aliquots of 1.5-2 mL each).

Lymphoid Malignancies Branch 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 techniques maintained within 
standard operating procedures in the laboratory.
5.2.5.1
Anti-IL-15 antibody testing

Collect blood in a 4mL SST tube; gently invert tubes 8-10 times immediately after 
collection.

Lymphoid Malignancies Branch 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.

Samples will be batch processed and analyzed per the procedure outlined in APPENDIX 
E after the last patient has been enrolled and completed treatment, or sooner if there is 
clinical suspicion for anti-IL-15 antibody formation.
5.2.5.2
PBMC Banking

Collect blood in sodium heparin tubes; gently invert tubes 8-10 times immediately after 
collection.

Lymphoid Malignancies Branch 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 techniques maintained within 
standard operating procedures in the laboratory.
5.2.6
Tissue Samples
5.2.6.1
PDL-1 testing for immunohistochemistry (IHC)

Archival block(s) or slides (i.e., at least 15 unstained slides, 5-microns) is required at 
baseline. Patients with prior skin, lymph node, or visceral biopsies performed at NIH or 
outside institutions must make specimen blocks available to the NCI Pathology 
Department for analysis. If no prior biopsies are available at the time of screening, patients 
with Cutaneous T-cell lymphoma and other lymphoma with skin involvement will undergo 
a punch biopsy of a skin lesion, performed by an NIH Clinical Center dermatologist. 
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). An optional biopsy may be performed in the same manner prior to the 
second dose of avelumab (Cycle 1, Day 22).

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 (if needed for diagnosis) or 
baseline, core tumor tissue (or bone marrow aspirate/biopsy) samples will be collected and 


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placed in appropriate media (e.g., RPMI 1640 with 10% human serum and antibiotics, and 
formalin) and processed per established techniques.  As indicated (Sections 5.1 and 5.2), 
samples will be sent to the Department of Laboratory Medicine (DLM)/ NCI Laboratory 
of Pathology (LP) for concurrent routine histologic analysis and reporting and IHC testing 
for PD-L1 expression by tumor cells and tumor-associated immune cells in addition to 
research testing (i.e., Waldmann Lab).
5.2.7
Other Samples
5.2.7.1
Germline DNA
Germline DNA will be collected by blood, buccal swab, and/or saliva samples (preferred).  These 
will ideally be collected at baseline; however, may be collected at any point on study based on 
supplies.  Standardized, commercial collection kits or tubes will be used (e.g., 1, 5-10 mL K2EDTA 
tube for blood; Isohelix SK-1 for buccal swabs; Salviette/Oragene® for saliva).  In the case of 
buccal swabs, two (2) samples may be collected in order to ensure adequate DNA collection.    
The samples will be processed and DNA extracted/isolated per kit instructions and established 
techniques. 
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
Molecular Profiling
Immunohistochemical (IHC) analyses, including FISH and/or PCR testing, will take part in tumor 
tissue samples, including but not necessarily limited to CD2, CD3, CD4, CD5, CD7, CD8, CD14, 
CD16, CD20, CD25, CD38, CD45RA, 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 
for immune subsets including but not necessarily limited to CD8+ T-cells, CD4+Foxp3- T-cells, 
Tregs, Tex, 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


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
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 and PBMC banking
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 herald progression or disease transformation; 
specifically, amplification and sequencing of the VDJ segment of the immunoglobulin receptor is 
planned. Germline DNA obtained from saliva, blood, or buccal mucosa will be used to 
discriminate somatic from germline mutations during cfDNA and ctDNA analyses. Keeping in 
mind a recent report of immune checkpoint inhibition in a patient with a solid tumor being 
associated with T-cell lymphomagenesis (50), and with our own group’s experience with rapid 
progression in 3 patients with ATLL treated with ICI (22, 51), special attention will be paid to 
following T-cell clonality using amplification and sequencing of the complementarity determining 
region 3 (CDR3) in both cfDNA and banked PBMCs. 
5.3.5
DNA/RNA Sequencing 
Genomic DNA and total RNA will be extracted from tumor samples using a Qiagen All-prep kit. 
For individual target genes that are recurrently mutated in T-cell malignancies, classical Sanger 
sequencing will be performed on PCR amplicons, using primers surrounding the known sites of 
mutation. To broadly assess mutations, next generation sequencing (e.g., on an Illumina HiSeq 
2000 platform) will be employed, using a paired end sequencing strategy of libraries constructed 
from tumor DNA. DNA will either be sequenced in its entirety from a whole genome library or 
will be first enriched for exonic sequences using the Agilent Sure Select system, aiming for 30X 
or 100X average coverage per base, respectively. The sequence fragments will be mapped back to 
the genome using the BWA algorithm. Of sequences overlapping a particular base pair in the 
genome, the percent mutant calls greater that 20% with a minimum of 25X coverage will be 
considered as an arbitrary threshold for single nucleotide variants (SNVs). SNVs that are not 
present in the matched normal sample will be considered candidate somatic mutations. 
A related technology, RNA-Seq, utilizes RNA from the tumor specimen to create a cDNA library 
for high-throughput sequencing. RNA-seq will be performed using Illumina kits followed by high-
throughput sequencing on an Illumina HighSeq 2000 machine. The cutoffs for coverage and 
percent mutant calls mentioned above will also be used to identify putative SNVs. RNA 
sequencing will also be used to read out digital gene expression across the genome as described.
Recent advances in genomic technologies enable GEP at the single cell level, a distinct advantage 
over conventional GEP which cannot always distinguish tumor vs non-tumor gene expression.  
Single-cell approaches allow identification of the evolution of rare populations of resistant tumor 
cells, as well as identification of TME cells critical for the survival of the tumor. The Center for 
Cancer Research (CCR) has recently opened a single cell analysis core facility with expert staff 
headed by Dr. Michael Kelly within the CCR Genomics Core.  This facility has the ability to take 


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purified viably frozen cells banked from patient biopsies and prepare them, using well-validated 
10X Genomics technology, for single-cell RNA sequencing.  This core is directly integrated with 
the NCI Sequencing core facility to provide high-quality, deep-sequencing of the single cell RNA-
SEQ samples, as well as ‘first-pass’ data processing and analysis.  Data will then be transferred to 
lymphoma researchers and bio-informaticians for further analysis of gene expression patterns and 
cellular population dynamics.
5.3.6
Other Analyses
Other analyses include the following:

Cell analysis and histological (e.g., H&E), immunohistochemical review and analysis per 
standard and established research techniques (e.g., PD-1/PD-L1 expression [Dako], FISH 
for del(17p), and other IHC analyses in blood and tissue).

Cytokine analysis (e.g., IL-6, IL-10, interferon beta, TNF-alpha)
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 in section 7.2.  
5.4.2
Lymphoid Malignancies Branch – Waldmann Laboratory
Under the direction of Dr. Waldmann, all samples processed by the laboratory will be uniquely 
barcoded, with data entered using a secure computerized database and backup hardcopy process 
per standard laboratory practice.  
Samples are stored in labeled boxes in secured freezers (i.e., -20ºC to -80ºC, or other, as 
appropriate) according to stability requirements; these freezers are located onsite.  Access to stored 
clinical samples is restricted and limited to research personnel for approved analyses only (as per 
the IRB approved protocol).


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Upon completion of planned analyses by the Waldmann lab, leftover samples may be stored for 
future analyses at the Clinical Support Laboratory, Leidos Biomedical Research, Inc.in Frederick, 
MD (see below).
5.4.3
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 trialsThe 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.

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 Principal Investigator who is responsible for the collections 
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.


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
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.
5.4.4
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.  
IRB approval will be obtained before using any samples to conduct studies that are not described 
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.
5.5
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.5.1
Description of the scope of genetic/genomic analysis
The research correlates for this study are expected to include DNA/RNA sequencing of tumors, 
including circulating tumor (ct) DNA. In addition, whole exome sequencing may include 
evaluation for known lymphoma mutations. For any genetic studies performed, the results will be 
deposited in a database such as dbGaP per NIH requirements.  Although there is controlled access 
to such a database, such a submission carries theoretical risks of revealing the identity of the 
subject.  This is discussed in the consent.
5.5.2
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized
Confidentiality for genetic samples will be maintained as described (Section 5.4.2).  In addition, a 
Certificate of Confidentiality has been obtained for this study.
5.5.3
Management of Results
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for this study are defined as disorders appearing in the American College of 
Medical Genetics and Genomics recommendations for the return of incidental findings that is 
current at the time of primary analysis. (A list of current guidelines is maintained on the CCR 
intranet: https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists).


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5.5.4
Genetic Counseling
Subjects will be contacted with a request to provide a blood sample to be sent to a CLIA certified 
laboratory.  If the research findings are verified in the CLIA certified lab, the subject will be offered 
the opportunity to come to NIH to have genetic education and counseling to explain this result; at 
the time of any such event(s), these activities will be funded by the NCI/CCR in consideration of 
the specific circumstances.  If the subject does not want to come to NIH, a referral to a local genetic 
healthcare provider will be provided (at their expense).
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis.
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 through 30 days after the last study intervention 
was administered.  Beyond 30 days after the last intervention, 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.
6.1.2
Data Collection/Recording 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


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
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.
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
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy.
6.3
RESPONSE CRITERIA
6.3.1
Response Assessments 
Tumor response will be assessed by the investigator using the RECIL 2017 criteria (52) for all 
patients with T-cell lymphoma other than CTCL. Global Response Score (53), and modified 
severity weighted assessment tool (mSWAT) (11) will be used for patients with CTCL. Patient 
will be re-evaluated for response as outlined in the Study Calendar, Section 3.6.
6.3.2
Response Criteria for PTCL and ALCL
RECIL 2017 criteria (52) use the Deauville five-point scale for assessment of response via FDG-
PET. The five-point scale (5-PS) has been validated for use at interim staging and at the end of 
treatment and was adopted as the preferred reporting method at the First International Workshop 
on PET in Lymphoma in Deauville, France (i.e., Deauville criteria), and in several international 
trials.


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The 5-PS PS scores the most intense uptake in a site of initial disease:
1. if present, as follows: no uptake or no residual uptake (when used at interim)
2. slight uptake, but below blood pool (mediastinum)
3. uptake above mediastinal, but below or equal to uptake in the liver
4. uptake slightly to moderately higher than liver
5. markedly increased uptake or any new lesion (on response evaluation) 
The sum of longest diameter (SLD) is used for assessment of tumor burden. In patients with 
disseminated disease, a maximum of three target lesions should be selected and used to estimate 
tumor response. Target lesions should be selected from those with the largest size that can be 
reproducibly measured and preferably representing multiple sites and/organs. In most cases, lymph 
nodes can be considered target lesions if the lymph node longest diameter measures ≥15 mm. A 
lymph node measuring between 10 and 14 mm is considered abnormal but should not be selected 
as a target lesion. Lymph nodes measuring <10 mm in diameter are considered normal. In certain 
anatomical sites (inguinal, axillary, and portocaval), normal lymph nodes may exist in a narrow, 
elongated form, and such nodes should not be selected as target lesions if alternatives are available. 
Extranodal lesions are selected as target lesions if they have soft tissue component, based on their 
size, and the ease of reproducibility of repeated measurements, with a minimum measurement of 
the longest diameter of ≥ 15 mm. All other lesions should be identified as nontarget lesions and 
should be recorded at baseline, without the need to measure them. Nontarget lesions should be 
followed and reported as present, absent, or clear progression.
Table 14: Response categories based on assessment of target lesions
% Change in sum of diameters of target lesions from nadir
CR
PR
MR
SD
PD
% change from 
baseline

Complete 
disappearance of 
all target lesions 
and all nodes with 
long axis <10mm

>30% decrease in 
the sum of longest 
diameters of target 
lesions (PR) with 
normalization of 
FDG-PET
>30% 
decrease in 
the sum of 
longest 
diameters of 
target 
lesions but 
not a CR
>10% 
decrease in 
the sum of 
longest 
diameters 
of target 
lesions but 
not a PR 
(<30%)
<10% 
decrease 
or < 20% 
increase in 
the sum of 
longest 
diameters 
of target 
lesions

>20% increase in the 
sum of longest 
diameters of target 
lesions

For small lymph nodes 
measuring <15 mm 
post therapy, a 
minimum absolute 
increase of 5 mm and 
the long diameter 
should exceed 15 mm

Appearance of a new 
lesion
FDG-PET
Normalization of 
FDG-PET (Deauvile 
score 1-3)
Positive 
(Deauville 
score 4-5)
Any
Any
Any
Bone marrow 
involvement
Not involved
Any
Any
Any
Any
New lesions
No
No
No
No
Yes or No
CR, complete response; CT, computerized tomography; FDG-PET, [18F]2-fluoro-2-deoxy-D-glucose; MR, minor 
response; PD, progression of disease; PR, partial response; SD, stable disease.


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6.3.3
Response Criteria for CTCL
Global Response (GR) score (APPENDIX C) will be used for assessing response in patients 
with CTCL (53). GR score incorporates separate responses in each component of the TNBM 
staging (i.e., skin, nodes, viscera and blood; APPENDIX C). No patient with a global OR should 
have less than a PR in the skin.
The mSWAT (11) is an instrument utilized to track the skin tumor burden in MF/SS. It measures 
the percentage total body-surface area (TBSA, %) involvement separately for patches, plaques, 
and tumors within 12 body regions using the patient's palm and fingers representing 1% of TBSA. 
Patients with erythroderma are assessed for percentage of TBSA involved with patches and/or 
plaques. The percentage of TBSA for each lesion type is multiplied by a number (patch = 1, plaque 
= 2; tumor = 4) and summed to derive the mSWAT score. The mSWAT for each patient will be 
determined by the same individual at all study visits.
A complete response (CR) requires 100% clearing of skin disease and a partial response (PR) 
requires ≥ 50% reduction in the mSWAT score compared with baseline. CR/PR requires 
confirmation by repeat assessment after ≥ 4 weeks. Stable disease is defined as less than 50% 
reduction to less than 25% increase in the mSWAT score compared with baseline. PD is defined 
as ≥ 25% increase in the mSWAT score from baseline or ≥ 50% increase in the sum of the products 
of the greatest diameters of pathologically positive lymph nodes compared with baseline.
Time to response is the time from the first treatment dose until the patient first meets the criteria 
for a 50% decrease in the GR score. The duration of response (DOR) is the time from first CR/PR 
until the GR score is increased from nadir to more than 50% of the difference between the baseline 
and nadir scores. Time to progression (TTP) is the time from start of treatment until PD. If patients 
goes off treatment for any purpose, this date is used for determination of TTP and/or DOR.
As “skin flares” have been described in patients with SS receiving the anti-PD-1 antibody 
Pembrolizumab (18), patients with SS whose only sign of PD is an increase in mSWAT score (i.e., 
who have normal/decreasing number of circulating Sézary cells) will continue treatment and be 
re-evaluated in 2-4 weeks to confirm disease progression. Patients whose PD is not confirmed on 
re-evaluation will be noted to have had a skin flare 
Table 15: Calculating mSWAT Score
Assessment of Involvement in Patient’s Skin
Body Region
% BSA in Body Region
Patch1
Plaque2
Tumor3
Head
7
Neck
2
Anterior trunk
13
Arms
8
Forearms
6
Hands
5
Posterior trunk
13
Buttocks
5
Thighs
19
Legs
14
Feet
7
Groin
1
Subtotal of lesion BSA


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Weighing factor
x1
x2
x4
Subtotal lesion BSA x 
weighing factor
NOTE:  mSWAT score equals summation of each column line.
Abbreviations: BSA, body surface area; mSWAT, modified Severity Weighted Assessment Tool.
1 Any size lesion without induration or significant elevation above the surrounding uninvolved skin; poikiloderma 
may be present
2 Any size lesion that is elevated or indurated; crusting, ulceration, or poikiloderma may be present.
3 Any solid or nodular lesion > 1cm in diameter with evidence of deep infiltration in the skin and/or vertical 
growth.
6.3.4
Rapid progression
As recent preclinical data has shown that PD-1 may act as a tumor suppressor in T-cell 
malignancies(21), and three patients with ATLL who received the anti-PD-1 antibody Nivolumab 
experienced progression of disease shortly after receiving the first dose (NCT02631746, 
unpublished data), rapid progression will be followed as a distinct outcome. Rapid progression is 
defined as any PD within 14 days of the first avelumab administration (i.e., up to and including 
Cycle 1, Day 21), excluding skin flares. Patients who are suspected of having a skin flare during 
this period but have confirmed PD on re-evaluation will be noted to have had rapid progression.
6.3.5
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.
6.3.6
Duration of Response
The duration of response (DOR) is measured from the time measurement criteria are met for CR 
or PR (whichever is recorded first) 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), death, or, in the absence of PD, date of last assessment.
6.3.7
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.
6.3.8
Overall Survival
Overall survival (OS) is defined as the time from the date of study enrollment until time of death 
from any cause.
6.3.9
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 lymphoma given (such as 
radiation), or death, whichever occurs first.
6.4
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 


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Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
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/ IRB REPORTING
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.
7.3
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.
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet at least weekly 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. 


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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 
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
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 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 reaction 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).


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8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.  

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 with the exception of any listed in section 8.4.
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


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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.
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 CRITERIA TO THE PHARMACEUTICAL COLLABORATORS AND 
MANUFACTURERS
All events listed below must be reported in the defined timelines to OSROsafety@mail.nih.gov.  
The CCR Office of Regulatory Affairs will send all reports to the manufacturer(s) as described 
below.
8.5.1
Safety Reporting to the Pharmaceutical Collaborator EMD Serono (Avelumab)
The investigational agent, avelumab, is being supplied by EMD Serono and the following are 
their requirements for safety reporting.
The following reportable events must be submitted to EMD Serono within 2 business days or 3 
calendar days (whichever comes first) using the applicable safety report form provided. The 
Principal Investigator/study team will submit reportable events to the Sponsor as well as ensure 
that any other local reporting requirements are completed, if required (e.g., IRB). The Sponsor will 
assume responsibility for submitting the reportable event(s) to EMD Serono as well as ensuring 
that any local reporting requirements are completed in parallel.

Serious Adverse Event Reports

Exposure during pregnancy or breastfeeding (even if not associated with an adverse event)

Occupational exposure (even if not associated with an adverse event)

Potential drug-induced liver injury (Hy's Law cases): These events are considered 
important medical events and should be reported as SAEs.
Contact information for submission of reportable events to EMD Serono:
Fax: +49 6151 72 6914 or Email: ICSR_CT_GPS@merckgroup.com. 
The following items should be specified:
1. Protocol Number and/or Title
2. EMD Serono assigned Study Number
3. Subject number
4. Site number/PI name
8.5.1.1
Second Malignancies
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 


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8.5.2
Safety/Other Reporting Criteria to the Manufacturer Collaborator CTEP (rhIL-15)
The NCI Cancer Therapy Evaluation Program (CTEP) is providing clinical grade recombinant 
human IL-15 for this study.  Because CTEP is responsible for the Clinical Material and 
Confidential Information which it develops, CTEP must ensure that the Clinical Material and 
Confidential Information are used, communicated and reproduced appropriately and completely. 
The PI agrees to use the Clinical Material in accordance with all Federal laws and regulations that 
govern the use of investigational agents in clinical trials.
The following will be provided to CTEP during the course of the clinical study:  
1. Initial FDA submission/approval, including:  FDA-submitted protocol document; any FDA 
comments regarding the protocol and IND submission, including correspondence 
regarding the IND submission safe-to-proceed notice; and, a copy of the FDA 
acknowledgement of the IND submission(s) stating the IND number, sponsor, title and date 
of submission.
2. Documentation of initial IRB approval of the FDA-submitted protocol document and 
annual continuing IRB review approvals.
3. All significant protocol amendments, including changes in study size, eligibility criteria, 
study design and end points.
4. Notification of any changes in protocol status or other significant events related to the 
Protocol.
5. Notification of any changes in IND status.
6. Copies of any FDA communications.
7. Copies of IND Annual Reports.
8. All IND Safety Reports submitted to the FDA per 21 CFR 312.32.  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).
9. Any abstracts, manuscripts, and publications.
Additional safety and efficacy data may also be requested by CTEP to facilitate the development 
of the Clinical Material across CTEP supported trials.
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 becomes 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. 


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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 rhIL-15 and/ or 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 four months 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, in accordance to 21 CFR Part 312.32. 
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 HYPOTHESIS

Primary Endpoint(s): 


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o
Maximum tolerated dose (MTD) of rhIL-15 administered intravenously for 5 days 
in combination with avelumab for up to 6 cycles
o
Frequency (number and percentage) of treatment-emergent AEs

Secondary Endpoint(s):
o
Overall response rate (including CR and PR)
o
Overall response rate in patients with ≥50% PD-L1-expressing tumor cells
o
Duration of response
o
Progression-free, event-free, and overall survival
10.2 SAMPLE SIZE DETERMINATION
The MTD will be based on the assessment of DLT during the first cycle of treatment and will be 
defined as the dose level at which less than one-third of patients (0 of 3 or 0-1/6 patients) treated 
experience a DLT, with the next higher dose level demonstrating one-third or a greater number of 
patients (≥ 2-3 or ≥ 2-6 patients) having a DLT.  If a subject did not experience a DLT and did not 
finish one cycle of treatment (28 days) he or she will not be evaluable for determination of the 
MTD and would be replaced in the dose level.  An additional 3 to 6 patients will be enrolled at the 
MTD, so that a total of 9 patients will be treated at this dose. 
Using this dose-escalation scheme the probability of escalating to the next dose level will be based 
on the true rate of DLT at the current doses given by the following table (each group will be 
considered independently of the other); Thus, if the true underlying proportion of DLTs is 50% at 
the current dose there is a 17% probability of escalating to the next dose. 
True toxicity at a given dose
10%
20%
30%
40%
50%
60%
Probability of escalating
0.91
0.71
0.49
0.31
0.17
0.08
If all four dose levels are evaluated with 6 patients per dose level and 9 total patients at the MTD, 
a maximum of 27 evaluable patients will be enrolled. Similarly, if all dose levels are evaluated 
with 3 patients per dose level and 9 total patients at the MTD, the minimum number of evaluable 
patients required will be 18. To account of unevaluable patients, accrual ceiling will be set at 30. 
It is expected that the accrual can be completed in 24 months. 
A maximum of 30 patients will be enrolled over 24 months, at a rate of 1-2 patients per month.
10.3 POPULATION FOR ANALYSIS
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, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. 
These patients will have their response classified according to the definitions stated above, Section 
6.3. (NOTE:  Patients who exhibit objective disease progression prior to the end of Cycle 1 will 
also be considered evaluable.)


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10.3.3 Evaluable Non-Target Disease Response:  
Patients who have lesions present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for non-target disease. The response assessment is based 
on the presence, absence, or unequivocal progression of the lesions. 
10.4 STATISTICAL ANALYSES
10.4.1 General Approach
The response rate will be determined and reported along with a 95% Agresti-Coull confidence 
interval (54). Other time-to-event outcomes will be reported using Kaplan-Meier curves.
10.4.2 Analysis of the Primary Endpoints
Safety summaries will include summaries in the form of tables and listings. Reports will include 
the frequency (number and percentage) of treatment emergent AEs grouped by severity of the AE 
(per CTCAE, v5.0) and by relationship to study drug (e.g., either rhIL-15, avelumab, or both).
Laboratory shift tables containing counts and percentages will be prepared by treatment 
assignment, laboratory parameter, and time. Summary tables will be prepared for each laboratory 
parameter. Figures of changes in laboratory parameters over time will be generated.
Results of vital sign assessments, ECGs, and physical exams will be tabulated and summarized.
10.4.3 Analysis of the Secondary Endpoints
The duration of response (DOR; beginning at the date clinical response is first identified), overall 
survival (OS), event free survival (EFS), and progression free survival (PFS) will be estimated 
using Kaplan-Meier curves with appropriate confidence intervals reported.
Every report of response rates and time to progression should contain all patients included in the 
study. For the response calculation, the report should contain at least a section with all eligible 
patients. Another section of the report may detail the response rate for evaluable patients only.  
However, a response rate analysis based on a subset of patients must explain which patients were 
excluded and for which reasons.  95% confidence limits will be given.
10.4.4 Safety Analyses
The type, grade and frequency of toxicities will be reported.
10.4.5 Baseline Descriptive Statistics
Descriptive statistics (including means, standard deviations, and medians for continuous variables 
and proportions and CIs for discrete variables) will be used to summarize data as appropriate.
10.4.6 Planned Interim Analyses
No interim analyses are planned because of the single stage design of the trial.
10.4.7 Sub-Group Analyses
All secondary endpoints will be analyzed and reported separately according to the presenting 
diagnosis (PTCL-NOS, MF/SS, ALCL, or Other) and baseline PD-L1 expression (<1%, ≥1%, 
≥5%, ≥10%, ≥50%). 


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10.4.8 Tabulation of Individual Participant Data
None.
10.4.9 Exploratory Analyses
The exploratory objectives such as seeking to identify potential biomarkers or T-cell clones in 
peripheral blood which are associated with response, will be assessed using descriptive statistics 
as well as non-parametric methods such as exact Wilcoxon rank sum tests. The analyses will be 
done without formal adjustment for multiple comparisons, but in the context of the number of tests 
performed.
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.
11.2 MATERIAL TRANSFER AGREEMENT (MTA)- CTEP
A MTA with Division of Cancer Treatment and Diagnosis (DCTD) for the IL-15 was executed on 
June 8, 2018 .
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. 
Subjects with HIV infection will be excluded due to potential toxicity and unknown effects of 
rhIL-15 and avelumab on the underlying HIV infection and interference with ART. Pregnant or 
nursing mothers are excluded because of the potential teratogenic effects of therapy. 
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 recurrent T-cell lymphomas are 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 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults who are unable to consent are excluded from enrolling in this study.  However,  re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired.   For this reason and because there is a prospect of direct benefit from 
research participation (Section 12.5) and because overall survival is one of the secondary 
outcomes, all subjects ≥ age 18 will be offered the opportunity to fill in their wishes for research 
and care, and assign a substitute decision maker on the “NIH Advance Directive for Health Care 
and Medical Research Participation” form so that another person can make decisions about their 
medical care in the event that they become incapacitated or cognitively impaired during the course 


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of the study.  
Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for 
evaluation to assess ongoing capacity of the subjects and to identify a LAR, as needed. 
Please see Section 12.6 for consent procedure.
12.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
The potential benefit of adding rhIL-15 to avelumab in treatment of mature T-cell malignancies is 
unknown, but single-agent immune checkpoint inhibitors have shown activity as outlined in 
Section 1.2.5. There is a risk of additive toxicity of the two drugs, 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.
It has recently been shown that PD-1 may act as a haplo-insufficient tumor suppressor of T 
lymphocytes, with PD-1/PD-L1 checkpoint blockade causing transient lymphoproliferation in 
ITK-SYK transgenic mice(21). Clinically, three patients with ATLL treated with the anti-PD-1 
antibody Nivolumab had rapid disease progression shortly after receiving the first dose (“rapid 
progression”). Additionally, four patients with AITL have experienced rapid progression after 1-
3 doses of nivolumab.(19) Patients with ATLL, AITL, and PTCL-TFH (which has a similar 
phenotype to AITL) are therefore excluded from this Phase 1 trial. Additionally, growth of 
malignant cells in enteropathy-associated T-cell lymphoma (EATL) is dependent on epithelial cell-
derived IL-15. Patients with EATL are therefore also excluded.  There are ongoing trials of 
different immune checkpoint inhibitors in patients with other forms of T cell lymphoma with no 
reports of rapid progression. Study team will note any rapid and unexpected disease progression 
observed in patients on the trial as described in Section 6.3.4.
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(55). 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.
12.5 RISKS/BENEFITS ANALYSIS
A significant number of T-cell malignancies express PD-L1, 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 
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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 in this study.
12.5.1 Risks related to CT and PET scans
CT and PET 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.
12.5.2 Risks from Radiation Exposure
The procedures for performing the chest CT and 18F-FDG PET/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 six (6) additional CT 
scans of the neck, chest, abdomen, and pelvis, and three (3) additional 18F-FDG PET/CT scans. 
The total additional radiation dose for research purposes will be approximately 11.4 rem.
12.6 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee(s) 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/consent designee(s).  Whether in person or remote, the privacy of 
the subject will be maintained. Consenting investigators (and participant/consent designee, when 
in person) will be located in a private area (e.g., clinic consult room). When consent is conducted 
remotely, the participant/consent designee will be informed of the private nature of the discussion 
and will be encouraged to relocate to a more private setting if needed.  
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic signature) on the electronic document.  When required, witness signature will be 
obtained similarly as described for the investigator and participant.
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent 
at the NIH Clinical Center, this study will use the following to obtain the required signatures:


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
Adobe platform (which is not 21 CFR Part 11 compliant); or,  

iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the 
same screen may be used when in the same location but is not required.  
Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent 
Process for additional information (e.g., verification of participant identity when obtaining 
consent remotely) found here.
12.6.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation
For participants addressed in Section 12.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 12.6. 
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 study participants, 
investigator, the Investigational New Drug (IND) sponsor and regulatory authorities.  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:

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 as applicable, Food and Drug Administration (FDA).
13.2 QUALITY ASSURANCE AND QUALITY CONTROL
Each 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.


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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.
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 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 d 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 clinical sites 
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 NCI CCR.
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 


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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
This study is being conducted under a CCR-held IND:  IND #140549.
14.1
RHIL-15 (NSC #745101)
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
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 


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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.  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 stores 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) to reach a final rhIL-15 concentration of 
1 mcg/mL (see Dilution instructions, APPENDIX D).  The rhIL-15 infusion will be administered 
to the patient by continuous intravenous infusion (civ) at a dose in mcg/kg/day 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 2-6, 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 4 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 
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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
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


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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) 
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; Visceral arterial 
ischemia
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; 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; Infusion related reaction
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
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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 order 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 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/


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
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 (NSC #799232)
14.2.1 Source / Acquisition and Accountability
Investigational supplies of Avelumab will be supplied by EMD Serono for use by subjects in this 
clinical trial. 
14.2.2 Toxicity 
Please refer to the IB 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 
presentation of events by body system.  Frequency is provided based on 1738 patients. Below is 
the CAEPR for Avelumab:
Version 2.0, April 23, 20191
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


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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%)
EYE DISORDERS
Uveitis2
GASTROINTESTINAL DISORDERS
Abdominal pain
Colitis2
Diarrhea
Nausea
Pancreatitis2
Vomiting
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
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


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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%)
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
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
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail.
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, 


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80
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.
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.


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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 8 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:  GLOBAL RESPONSE SCORE AND DEFINITIONS OF RESPONSE IN SKIN, 
LYMPH NODES, VISCERA, AND BLOOD
Global Response Score
Global Score
Definition
Skin
Nodes
Blood
Viscera
CR
Complete disappearance of all 
clinical evidence of disease
CR
All categories have CR/NI
PR
Regression of measurable 
disease
CR
All categories do not have a CR/NI and no 
category has a PD
PR
No category has a PD and if any category 
involved at baseline at least one has a CR 
or PR
SD
Failure to attain CR, PR, or PD 
representative of all disease
PR
No category has a PD and if any category 
involved at baseline, no CR or PR in any
SD
CR/NI, PR, SD in any category and no 
category has a PD
PD
Progressive disease
PD in any category
Relapse
Recurrence of disease in prior 
CR
Relapse in any category
Abbreviations: CR, complete response; NI, noninvolved; PR, partial response; PD, progressive disease; 
SD, stable disease.
Response in Skin
Response
Definition
Complete response
100% clearance of skin lesions
Partial response
50%-99% clearance of skin disease from baseline without new tumors (T3) in 
patients with T1, T2 or T4 only skin disease
Stable disease
<25% increase to <50% clearance in skin disease from baseline without new 
tumors (T3) in patients with T1, T2, or T4 only skin disease
Progressive disease
≥25% increase in skin disease from baseline or
New tumors (T3) in patients with T1, T2, or T4 only skin disease or
Loss of response: in those with complete or partial response, increase of skin 
score of greater than the sum of nadir plus 50% baseline score
Relapse
Any disease recurrence in those with complete response
Notes:
Percentages refer to mSWAT score.
A biopsy of normal appearing skin is unnecessary to assign a complete response. However, a skin 
biopsy should be performed of a representative area of the skin if there is any question of residual 
disease (persistent erythema or pigmentary change) where otherwise a complete response would exist. 
If histologic features are suspicious or suggestive of mycosis fungoides/Sézary syndrome, the response 
should be considered a partial response only.


Abbreviated Title:  IL-15 and Avelumab in R/R T-cell NHL
Version Date:  09/23/2021
90
Response in Lymph Nodes
Response
Definition
CR
All lymph nodes are now ≤1.5 cm in greatest transverse (long axis) diameter by method 
used to assess lymph nodes at baseline or biopsy negative for lymphoma; in addition, 
lymph nodes that were N3 classification and ≤1.5 cm in their long axis and >1 cm in 
their short axis at baseline, must now be ≤1 cm in their short axis or biopsy negative for 
lymphoma
PR
Cumulative reduction ≥50% of the SPD of each abnormal lymph node at baseline and 
no new lymph node >1.5 cm in the diameter of the long axis or >1.0 cm in the diameter 
of the short axis if the long axis
is 1-1.5 cm diameter
SD
Fails to attain the criteria for CR, PR, and PD
PD
>50% increase in SPD from baseline of lymph nodes OR
Any new node >1.5cm in the long axis or >1cm in the short axis if 1-1.5 cm in the long 
axis that is proven to be N3 histologically OR
Loss of response: >50% increase from nadir in SPD of lymph nodes in those with PR 
(whichever occurs first)
Relapse
Any new lymph node >1.5 cm in the long axis in those with CR proven to be N3 
histologically
Abbreviations: CR, complete response; PR, partial response; SPD, sum of the maximum linear 
dimension (major axis) ⨉ longest perpendicular dimension (minor axis); SD, stable disease; PD, 
progressive disease.
Response in Viscera
Response
Definition
CR
Liver or spleen or any organ considered involved at baseline should not be enlarged on 
physical exam and should be considered normal by imaging; no nodules should be 
present on imaging of liver or spleen; any post treatment mass must be determined by 
biopsy to be negative for lymphoma
PR
>50% regression in any splenic or liver nodules, or in measurable disease (SPD) in any 
organs abnormal at baseline; no increase in size of liver or spleen and no new sites of 
involvement
SD
Fails to attain the criteria for CR, PR, and PD
PD
>50% increase in size (SPD) of any organs involved at baseline OR
New organ involvement OR
Loss of response: >50% increase from nadir in the size (SPD) of any previous organ 
involvement in those with PR (whichever occurs first)
Relapse
New organ involvement in those with CR
Abbreviations: CR, complete response; PR, partial response; SPD, sum of the maximum linear 
dimension (major axis) ⨉ longest perpendicular dimension (minor axis); SD, stable disease; PD, 
progressive disease.


Abbreviated Title:  IL-15 and Avelumab in R/R T-cell NHL
Version Date:  09/23/2021
91
Response in Blood*
Response
Definition
CR†
B0
PR‡
>50% decrease in quantitative measurements of blood tumor burden from baseline in 
those with high tumor burden at baseline (B2)
SD
Fails to attain the criteria for CR, PR, and PD
PD§
B0 to B2 or
> 50% increase from baseline and at least
5,000 neoplastic cells/μL or
Loss of response: in those with PR who were originally B2 at baseline, > 50% increase 
from nadir and at least 5,000 neoplastic cells/μL
Relapse
Increase of neoplastic blood lymphocytes to ≥ B1 in those with CR
Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive 
disease.
* As determined by absolute number of neoplastic cells/μL
† If a bone marrow biopsy was performed at baseline and determined to unequivocally be indicative of 
lymphomatous involvement, then to confirm a global CR where blood assessment now meets criteria 
for B0, a repeat bone marrow biopsy must show no residual disease or the response should be 
considered a PR only.
‡ There is no PR in those with B1 disease at baseline as the difference within the range of neoplastic 
cells that define B1 is not considered significant and should not affect determination of global 
objective response.
§ Whichever occurs first


Abbreviated Title:  IL-15 and Avelumab in R/R T-cell NHL
Version Date:  09/23/2021
92
16.4 APPENDIX D:  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), should 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 (1 mcg/kg), Dose Level 2 (2 mcg/kg), Dose Level 3 (3 mcg/kg), and Dose Level 4 
(4 mcg/kg)
To prepare an IL-15 dose for Dose Level 1 (1 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 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
DL1
DL2
DL3
DL4
DL1
DL2
DL3
DL4
DL1
DL2
DL3
DL4
60 kg
0.14
0.27
0.39
0.51
69.86
129.73 189.61 249.49
70 ml
130 ml 190 ml 250 ml
75 kg
0.17
0.33
0.48
0.63
84.83
159.67 234.52 309.37
85 ml
160 ml 235 ml 310 ml
90 kg
0.20
0.39
0.57
0.76
99.80
189.61 279.43 369.24 100 ml 190 ml 280 ml 370 ml
105 kg
0.23
0.45
0.66
0.88 114.77 219.55 324.32 429.12 115 ml 220 ml 325 ml
430ml
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


Abbreviated Title:  IL-15 and Avelumab in R/R T-cell NHL
Version Date:  09/23/2021
93
16.5 APPENDIX E:  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.

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1) 
Version Date: 09/28/2020
Page 1 of 26
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR: 
Milos Miljkovic, M.D. 
STUDY TITLE:
A Phase 1 Study of Interleukin-15 (IL-15) in Combination 
with Avelumab (Bavencio) in Relapsed/Refractory Mature 
T-cell Malignancies
STUDY SITE:
NIH Clinical Center, (CC), National Cancer Institute
Cohort:
Standard 
Consent Version: 
09/28/2020
WHO DO I CONTACT ABOUT THIS STUDY? 
Principal Investigator: 
Milos Miljkovic, M.D., MSc
Phone:  301-250-5216
Email:  milos.miljkovic@nih.gov 
KEY INFORMATION ABOUT THIS RESEARCH 
This consent form describes the research study and is designed to help you decide if you would 
like to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). This 
section provides the information we believe is most helpful and important to you in making your 
decision about participating in this study. Additional information that may help you make a 
decision can be found in other sections of the document. Taking part in research at the NIH is your 
choice.
You are being asked to take part in this study because you have a relapsed T-cell lymphoma, such 
as peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), mycosis fungoides/Sézary 
syndrome (MF/SS) or anaplastic large cell lymphoma (ALCL), that has not responded to standard 
treatments.
The purpose of this study is to test whether IL-15 and avelumab, drugs that have shown positive 
results in the treatment of other cancers, but have never been used to treat your disease and have 
never been administered together in humans, can be used safely in this study. We will also look at 
if they are effective in treating your disease.  The goals of this study are to determine the safe dose 
of IL-15 when combined with avelumab to be used in humans, to identify the side effects of the 
combination treatment and its effects on your immune system, and to determine if this treatment 
has activity against your cancer.
Recombinant human interleukin 15 (IL-15) is considered investigational, which means that it has 
not been approved by the U.S. Food and Drug Administration (FDA) to treat  T-cell lymphomas. 
However, the use of avelumab is approved to treat urothelial and Merkel cell carcinoma. We are 
testing it in this research study to see whether giving recombinant human interleukin 15 (IL-15) in 
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1) 
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
combination with the immune checkpoint inhibitor avelumab (also known as Bavencio) will 
improve outcome of therapy for your disease. Since IL-15 and avelumab have never before been 
given together, this treatment is considered investigational, or experimental. The FDA has given 
us permission to use IL-15 and avelumab together in this study.  
There are other drugs and treatments that may be used for your disease, and these can be prescribed 
by your regular cancer doctor, even if you are not in this study. They all work in different ways in 
the body as compared to IL-15 and avelumab, and with different side effects. In clinical trials, they 
were able to shrink tumors in 20-30% of p (up to 50% for one drug in p with MF/SS), and delayed 
progression of disease in a majority of p by 2-7 months, but none of the other available treatments 
has been shown to prolong life. If you would prefer other drugs or treatments, you should consider 
not joining this study.  
If you decide to join this study, here are some of the most important things that you should know 
that will happen:
•
In the first groups of participants enrolled (dose escalation), we want to find out the highest 
dose of IL-15 that is safe to use with avelumab. We will test increasing doses of IL-15 in small 
groups. We also want to find out what kind of side effects IL-15 and avelumab might cause. 
After phase 1 is done, we will enroll additional participants in a second portion of the study 
(dose expansion) to learn more about out whether IL-15 and avelumab can shrink your 
tumor(s).
•
Before you begin the study, we will perform tests to find out whether you are eligible to 
participate (screening) that will include tests such as:  a complete physical examination, blood 
and urine tests, bone marrow testing and imaging.  Some of these may be done on a separate 
screening protocol before signing the informed consent document for this study.
•
If you are eligible to receive treatment, during the study, both drugs will be administered as 
intravenous infusions for up to six cycles of 28 days each. You will receive IL-15 over the 
course of the first five days of each cycle, and avelumab on days 8 and 22 of each cycle.
•
You will be required to be hospitalized at the NIH Clinical Center for one week to receive the 
first cycle of IL-15. As long as you are accompanied by a caregiver or unless decided otherwise 
by the doctor, you will have the option of receiving the remaining cycles as an outpatient, but 
will still need to report to the hospital each day for the first five days of each cycle.
•
You may experience side effects from taking part in this study. Some can be mild or very 
serious, temporary, long-lasting, or permanent, any may include death.  Examples of some of 
the side effects that you may have include:  changes in blood counts (such as low red or white 
cells), gastrointestinal (such diarrhea, nausea, vomiting), fatigue, and infections. Since this is 
the first time that IL-15 and avelumab are administered together, there may be side effects that 
we cannot predict.
•
You will be seen regularly during the study.  You will have clinical, laboratory, and imaging 
tests to see how you are doing and to assess your disease. We will also collect required samples 
from you (including blood, bone marrow, and tumor biopsies) for both clinical and research 
purposes.
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IRB APPROVAL DATE: 11/17/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1) 
Version Date: 09/28/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
•
After the study treatment has ended, we will need to see you at the NIH Clinical Center 
periodically for up to about four (4) years to assess your health and to determine what impact, 
if any, the study drugs may have had on your disease. After this time, we may contact you to 
see how you are doing for the rest of your life.  
Just as we do not know what side effects you might have, we cannot know if you may benefit from 
taking part in this study. If you do not benefit directly, this study and the results from our research 
may help others in the future.
You are free to stop participating in the trial at any time.  If you decide to stop, the study doctor 
may ask you to agree to certain tests to make sure it is safe for you to stop.
The remaining document will now describe this research study in more detail. The additional 
information should be considered before you make your choice. Members of the study team will 
talk with you about all the information described in this document. Some people have personal, 
religious, or ethical beliefs that may limit the kinds of medical or research treatments they would 
want to receive (such as blood transfusions). Take the time needed to ask any questions and discuss 
this study with NIH staff, and with your family, friends, and personal health care providers.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision maker.  In 
this case, the term “you” refers to you as the decision-maker and/or the individual being asked to 
participate in this research, throughout the remainder of this document.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to receive care at the NIH, 
you must be taking part in a study or are being considered for a study. If you do choose to leave 
the study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY IS BEING DONE?
This is a research study. The purpose of this research study is to develop treatment for T-cell 
leukemias and lymphomas such as mycosis fungoides/Sézary syndrome (MF/SS) , peripheral T-
cell lymphoma not otherwise specified (PTCL-NOS), and anaplastic large cell lymphoma (ALCL), 
that are more effective than existing therapies. 
We are asking you to join this research study because you have relapsed and/or refractory T-cell 
lymphoma for which no standard therapy exists, or standard therapy has failed.
IL-15 is a man-made version of a small protein (cytokine) that is naturally produced in your body 
by certain white blood cells and increases the activity and strength of the immune system. People 
with cancer can have a weak immune system. This weakness can be caused by the cancer itself, or 
by treatments such as radiation, chemotherapy or other drugs that work against the immune system. 
It is hoped that IL-15 can “boost” or strengthen a persons’ immune systems as they fight against 
cancer. In fact, in other clinical trials, all of the people who received IL-15 showed an increase in 
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1) 
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
the number of their immune system cells. In some of the people, the growth was dramatic. We 
hope the same is true in this study.  
Avelumab is a monoclonal antibody that works in two ways: it attaches to the surface of a tumor 
cell and marks the tumor cell for destruction by other cells of the immune system, and it prevents 
tumor cells from inactivating the immune system cells. Monoclonal antibodies are purified 
proteins that are specially made to attach to pieces of foreign substances (such as cancer cells). 
Recent evidence shows that IL-15 boosts the number of immune system cells which are 
responsible for destroying antibody-coated tumor cells. 
Recombinant human interleukin 15 (IL-15) is considered investigational, which means that it has 
not been approved by the U.S. Food and Drug Administration (FDA) to treat peripheral T-cell 
lymphoma not otherwise specified (NOS), mycosis fungoides/ Sézary syndrome (MF/SS), or 
anaplastic large cell lymphoma. However, the use of avelumab is approved to treat urothelial and 
Merkel cell carcinoma. We are testing it in this research study to see whether giving recombinant 
human interleukin 15 (IL-15) in combination with avelumab (also known as Bavencio) will 
improve outcome of therapy for your disease. Since IL-15 and avelumab have never before been 
given together, this treatment is considered investigational, or experimental. The FDA has given 
us permission to use IL-15 and avelumab together in this study.
WHAT WILL HAPPEN DURING THE STUDY?
If you decide to take part in this study, you will be asked to: 

Receive different doses of IL-15 when given as a continuous intravenous infusion (civ) 
over 24 hours on days 1-5 of a 28-day cycle, followed by intravenous infusion (IV) of 
avelumab. Avelumab will be given at a set dose only on days 8 and 22 of each cycle.  The 
avelumab will infuse over 1 hour.

In order to confirm that the doses are safe, participants will be enrolled in groups:
o
Dose escalation group: First, groups of 3-6 study participants will receive IL-15 
and avelumab. The dose of IL-15 will be escalated (or increased) with each new 
group of participants, as long as it is safe to do so, until the best dose of IL-15 is 
found.  All participants will receive the same dose of avelumab.  Each group of 
participants will be checked closely for side effects for at least 4 weeks before 
enrolling at the next higher dose of IL-15 with avelumab.
o
Dose expansion group: Once the dose of IL-15 with avelumab is found, up to 9 
more participants will receive IL-15 dose with avelumab to learn more about the 
drugs and their effect on the types of cancer being studied.

All participants will be given treatment on an inpatient basis for the first week of the first 
cycle, and on an outpatient basis for subsequent weeks and cycles unless decided 
otherwise by the physician, based on clinical judgement. Treatment can continue for up 
to 6 (28-day) cycles. You will only be eligible for outpatient treatment if you have a 
caregiver to accompany you and help you manage the ambulatory infusion pump.
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1) 
Version Date: 09/28/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Another way to find out what will happen to you during the study is to read the chart below.  Start 
reading at the left side and read across to the right, following the lines and arrows:  
HOW LONG WILL THE STUDY TAKE?
If you agree to take part in this study, your involvement will last for at least four years. 
Screening  
Before you begin the study, you will have several tests performed to check whether the study is 
suitable for you. Some of these will be done before signing the informed consent document for 
this study.   This is called screening. Your doctor will review your medical history and the drugs 
that you are currently taking as well as the previous treatments of your disease to determine 
whether you can participate in this study.
A previously collected blood sample or small part of your tumor tissue (depending on your disease) 
that was collected from any previous surgery or biopsy will be tested at NCI to confirm your 
diagnosis. If no sample is available or if additional sample is needed to confirm your diagnosis, a 
fresh blood sample or biopsy will be taken. A biopsy will also be done prior to treatment if there 
is not enough tissue available from your diagnostic biopsy for study purposes (seeing whether the 
target of avelumab can be found on the surface of the tumor cell; the results of this test will not 
affect your eligibility). Any leftover tissue may be stored for future research studies, but a biopsy 
will not be performed solely for these studies. You will be told if this mandatory biopsy is needed. 
Some of these tests or procedures are part of regular care and may be done even if you are not 
being considered to join the study. If you have had some of these tests or procedures recently, they 
may or may not have to be repeated. The following tests and procedures will be performed prior 
to starting treatment:

Your medical history, including previous cancer treatments, any current or previous 
medications (prescription, supplement, and over-the-counter medicines), will be reviewed. 
If you have medical records from another clinic or hospital, you will be asked to get copies 
of these records, or your study doctor may be able to request them on your behalf.

A complete physical examination will be performed that will include your vital signs 
(blood pressure, pulse, body temperature, and respiratory rate) and recording your height 
and weight, and evaluation of your ability to carry out daily activities.

Blood and urine tests will be collected to:
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Consent to Participate in a Clinical Research Study
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File in Section 4: Protocol Consent (1) 
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
o
measure your liver, kidney, and thyroid function, red and white blood cells, 
platelets, electrolytes and others;
o
measure how well your blood clots;
o
test for human T-lymphotropic virus (HTLV) and Hepatitis B and C infection
o
test for human immunodeficiency virus (HIV) infection. This is the virus that 
causes AIDS. If you are infected with HIV you will not be able to participate in this 
study. We will tell you what the results mean, how to find care, how to avoid 
infecting others, how we report HIV infection, and the importance of informing 
your partners at possible risk because of your HIV infection.
o
run routine tests done in people with your type of cancer to confirm your diagnosis 
and the status of your disease.

If you have received a live vaccine within 30 days of starting study treatment, you will not 
be able to immediately participate. Examples of live vaccines include but are not limited 
to: the intranasal influenza vaccine known as Flu-Mist, measles, mumps, rubella, 
varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.

For females of child-bearing potential, a pregnancy test will be done (urine or blood 
sample). You will not be able to participate if you are pregnant or you are breast feeding 
because we don’t know how this medicine would affect your baby or your unborn child.

Pulmonary function test to test how well your lungs function, if applicable. 

An electrocardiogram (EKG) and echocardiogram (ECHO) to check your heart function.

Bone marrow testing and imaging will be done to check your disease, as needed.  
o
A bone marrow aspiration and/or biopsy will be done prior to starting treatment if 
not done within the last 3 months since completing the last treatment received to 
confirm the stage and status of your disease. These are done by numbing your 
hipbone using a small needle containing local anesthesia, and then a needle will be 
put into the hipbone, and a small amount of bone marrow will be taken out through 
the needle
o
Imaging will include a CT scan of neck, chest, abdomen and pelvis, and a PET/CT 
scan of the torso. Other body areas may be imaged if clinically indicated. For 
participants with suspected involvement of disease in the central nervous system, 
an MRI of the brain will be taken.
During the study
If the screening process shows that you are eligible for the study, and you choose to be in it, you 
may need to have a few additional standard tests completed if not done recently. You will also 
have additional samples collected for research tests. 
You will come to the NIH Clinical Center for treatment and procedures. The treatment will be 
given in the inpatient setting for the first week of the first cycle and then in the outpatient setting 
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at the Clinical Center for the remainder of the study. You will be given IL-15 as a continuous 
intravenous infusion as described in section “What will happen during the study?”, over a 24-hour 
period. Your dose of IL-15 will be assigned depending on what dose level is open at the time of 
your enrollment (gradually increasing doses during the dose escalation or the maximum tolerated 
dose during the dose expansion portion). Avelumab is also an IV infusion and will be given to you 
over about a 1-hour period.
A midline catheter may need to be inserted for each IL-15 infusion and maintained for the duration 
of the infusion. If you receive part of the treatment as an outpatient, you will get training on how 
to maintain the midline catheter and the ambulatory infusion pump before being discharged from 
the hospital.  For the first five days of each cycle, you will need to report to the day hospital each 
day for an IL-15 bag change. Each IL-15 infusion is expected to start between 8am and 8pm, and 
bags will be replaced at the same time each day; however, if for any reason IL-15 infusion begins 
after hours (8pm-8am), you will need to come into the hospital during the night for nursing staff 
to manage the pump. 
We will give you standard pre-medications before the IL-15 and avelumab infusions. These may 
include acetaminophen (Tylenol), nonsteroidal anti-inflammatory drugs (NSAIDs such as 
ibuprofen), an antihistamine (Benadryl), and in some cases histamine-2 blockers (Zantac). These 
are given to help prevent infusion related side effects. Your study doctor or a member of the study 
staff can explain these to you in more detail. Because of the unknown side effects, we will ask you 
to stay at the clinic for an additional 30 minutes after your infusion so we may monitor you.
Similar to the tests done at the beginning of the study, the following will be repeated during the 
study to see how you are doing and how the cancer may be responding to treatment:

Review of medical history, and a physical exam (check weight and vitals), including 
obtaining information about how you function in your daily activities, side effects and 
symptoms, and review of medications

Routine blood and urine tests

Bone marrow testing and imaging:
o
Bone marrow testing will be repeated at the end of study treatment if needed to 
confirm response, if and only if other tests show a complete response. 
o
Tumor imaging (such as, CT scan, PET/CT) will be done to assess the sites of your 
disease every 8 weeks during treatment An MRI of the brain and lumbar puncture 
is only required in participants with neurological symptoms. In participants with 
disease primarily on their skin, clinical photography and evaluation by a 
dermatologist will be used to assess the disease sites present on the skin, Other body 
areas may be imaged if clinically indicated. If your disease does not progress, 
follow-up imaging may be done at 6 months after treatment, then every 90 days for 
2 years, then every six months for another 2 years and then annually, at the 
discretion of the clinical team.
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Additional research testing
In addition, the following research samples will be collected, and some are optional:

Blood Samples: Blood will be collected for required research studies to learn more about 
how IL-15 and avelumab affect your cancer at the beginning of the study prior to starting 
treatment, during the first cycle of treatment, and at about the same time as each imaging 
assessment. If at any time your doctor thinks you have responded or may have progressed 
during or after treatment, we will again collect samples. Optional blood samples may be 
obtained more frequently throughout the treatment cycles depending upon the days that 
you are seen in the clinic.  You will be told which samples are required and which are 
optional.

Cheek Swab or Saliva Samples: A required cheek swab and/or saliva sample to collect 
normal tissue will be done, likely at the beginning of the study only. To obtain a cheek 
swab, a small brush is rubbed against the inside of the cheek to wipe off some cells. To 
obtain saliva, a special collection tube will be used and it may take a few minutes to collect 
the saliva.

Tumor Biopsies: These are an optional part of the study and you will only be asked to do 
so if it is felt to be safe. We will ask you to undergo a tumor biopsy during the first Cycle 
of treatment and again if your disease should progress during or after treatment on this 
study. The tissue is being collected for special research tests. Your doctor or the study team 
will discuss the biopsies with you. The biopsies to be performed are exclusively for 
research purposes and will not benefit you. They might help other people in the future. You 
may agree to biopsies now and change your mind later. If at any time you do not want to 
have a biopsy done, please tell us.
Usually tissue can be obtained safely and comfortably with local anesthesia. If you require 
sedation before undergoing a biopsy, you will be informed of the risks and you will be 
asked to sign an additional consent prior to undergoing the procedure. Biopsies will NOT 
be done on this study if they require general anesthesia. We may ask that you have 
ultrasound to help clearly locate your tumor when doing a biopsy.  
All of your samples collected for research purposes on this study may be used to look for specific 
changes in the DNA in tumors that could be used to develop new ways of diagnosing and treating 
cancer. DNA (also called deoxyribonucleic acid) in the cells carries genetic information and passes 
it from one generation of cells to the next – like an instruction manual. Normal tissue contains the 
DNA (instructions) that you were born with, DNA in tumor cells has changed – or mutated – and 
we think that change in the DNA is what causes tumors to form and to grow. 
To look at your DNA, we may do what is called “whole genome sequencing.”  This where we will 
do special tests in the lab to look at the entire sequence, or order, of how your DNA is put together.  
This is what makes you unique.  
To determine which parts of the DNA have mutated, we will compare the DNA in your tumor cells 
to DNA from your normal cells. We will then analyze the results from similar tumors to see if 
there are any changes in the DNA that are common to a particular type of tumor. To examine the 
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tumor and normal tissue we may use several different techniques depending on the type of tissue 
we collect. These could include growing cell lines (cells which keep dividing and growing in the 
laboratory, sometimes for years allowing us to continually study those cells), xenograft studies 
(placing or growing cells in another animal, such as mice), and looking in detail at the parts of the 
genes that produce specific proteins.
However, you should know that the analyses that we perform in our laboratory are for research 
purposes only; they are not nearly as sensitive as the tests that are performed in a laboratory that 
is certified to perform genetic testing or testing for routine clinical care. For these reasons, we will 
not give you the results of the research tests done on your research samples in most cases.  There 
may be exceptions to what we share with you and this is described later in this consent form in the 
section for “Return of research results.”
When you are finished taking the drugs (treatment)
When you finish taking the experimental therapy, we will need to see you 30 days after your last 
dose for a safety visit. We will then ask you to come to the clinic for follow-up visits and 
assessments at about the following times after treatment: every 60 days for the first 6 months, then 
every 90 days for 2 years and then every six months for another 2 years. After almost 5 years we 
may contact you by phone or by email to see how you are doing for the rest of your life. Only in 
certain cases, a participant may be asked to come in annually indefinitely. These clinic visits will 
include having required blood samples collected for routine analysis and for research, and may 
include CT or PET/CT scans. Visits usually take about 3 hours but should take no longer than 8 
hours. 
HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY?
Approximately 30 people will participate in this study at the NIH. 
WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY?
If you choose to take part in this study, there is a risk that the recombinant human IL-15 may not 
be as good as the usual approach for your cancer or condition at shrinking or stabilizing your 
cancer.
You also may have the following discomforts:

Spend more time in the hospital or doctor’s office.

Be asked sensitive or private questions about things you normally do not discuss.

May not be able to take part in future studies.
The recombinant human IL-15 used in this study may affect how different parts of your body work 
such as your liver, kidneys, heart, and blood.  The study doctor will test your blood and will let 
you know if changes occur that may affect your health.
There is also a risk that you could have side effects from the study drug(s)/study approach.
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Here are important things to know about side effects:

The study doctors do not know who will or will not have side effects.

Some side effects may go away soon, some may last a long time, and some may never go 
away.

Some side effects may make it hard for you to have children.

Some side effects may be mild.  Other side effects may be very serious and even result in 
death.
You can ask your study doctor questions about side effects at any time.  Here are important ways 
to make side effects less of a problem:

If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect.

Your study doctor will work with you to treat your side effects.

Your study doctor may adjust the study drugs to try to reduce side effects.
The tables below show the most common and the most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you.
Risks of IL-15
You may have side effects from the IL-15 while on the study. We pay close attention to any side 
effects you have. However, we don’t know all the side effects that may happen. Side effects may 
be mild or very serious. We may give you medicines to help lessen side effects. Many side effects 
go away soon after you stop taking the IL-15. In some cases, side effects can be serious, long 
lasting, or may never go away. It is possible that IL-15 could increase the growth of your leukemic 
cells, that is the IL-15 could make your cancer worse. There also is a risk of death.
Please talk to us about any symptoms you have while you are in the study.   
In studies with humans, common and not very common risks and side effects related to the IL-15 
included the following:
POSSIBLE, SOME MAY BE SERIOUS

Anemia (low red blood cells) which may require blood transfusion

Abnormal heartbeat

Pain in belly

Diarrhea, nausea, vomiting

Chills, tiredness, fever

Swelling of arms, legs

Swelling and redness at the site of the medication injection

Severe blood infection
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POSSIBLE, SOME MAY BE SERIOUS

Bruising, bleeding

Infection, especially when white blood cell count is low

Muscle weakness

Dizziness, headache

Shortness of breath

Dry skin, rash

Fluid in the organs which may cause low blood pressure, shortness of breath, swelling of ankles

High blood pressure which may cause blurred vision

Low blood pressure which may cause feeling faint
Other risks seen with IL-15 that are possibly related to the drug include:

Chest pain

bronchopulmonary hemorrhage and diffuse alveolar hemorrhage (bleeding in the lungs)

Confusion, psychosis (i.e., delusions, hallucinations)

Kidney failure - signs of kidney problems may include: decrease in the amount of urine, 
blood in your urine, ankle swelling

Papilledema (changes in vision due to increased pressure in the brain)

Uveitis (inflammation of the eye – symptoms may include redness, pain, blurred vision)

Pneumonitis (inflammation of the lungs) - symptoms may include new or worsening 
cough, chest pain, shortness of breath.

Inflammation of the lining of the first part of the small intestine symptoms may include 
nausea, vomiting, stomach burning, pain, indigestion

Liver damage which may cause yellowing of eyes and skin, swelling and may result in 
liver failure

Decreases in blood levels of albumin, phosphorus (these are standard blood tests)

Low number of white blood cells, cells that help fight infection (lymphopenia, 
leukopenia, neutropenia) 

Low platelets, cells that help blood to clot (thrombocytopenia)

Low blood oxygen – symptoms may include changes in skin color, confusion, cough, fast 
heartbeat, shortness of breath

Immune related adverse events: hives, hypothyroidism and production of autoantibodies 
– symptoms made include joint pain, tiredness fever, rashes,  allergy-type symptoms, 
muscle weakness
Risks of Avelumab
Three types of risks are associated with avelumab: general signs and symptoms, reactions that 
occur during or following the infusion (infusion-related reactions), and immune side effects.
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In studies with humans, common and not very common risks and side effects related to avelumab 
included the following:
Common (In 100 people receiving avelumab, more than 20 and up to 100)

Fatigue (tiredness)
Occasional (In 100 people receiving avelumab, 4 to 20)

Anemia (which may require blood transfusion)

Nausea, diarrhea , vomiting

Loss of  appetite

Flu-like symptoms including body aches

Reaction during or following a drug infusion (fever, low blood pressure, flushing, dizziness, 
chills) 

Chills (feeling cold), fever

Infection

Bruising, bleeding

Cough

Dry skin

Rash, itching, acne
Avelumab may cause your immune system to attack normal organs and cause side effects in many parts 
of the body. These problems may include but are not limited to:

Hormone gland problems (especially the thyroid, pituitary and adrenal glands, and pancreas).  
Signs and symptoms may include: headaches that will not go away or unusual headaches, 
extreme tiredness or changes in mood or behavior decreased sex drive; weight loss or weight 
gain; excessive thirst or urine; dizziness or fainting 

Damage to the pancreas which may cause belly pain and hospitalization 

Pain or swelling of the joints

Problem of the muscle (myositis), which can cause muscle pain and severe muscle weakness 
sometimes with dark urine 
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RARE, AND SERIOUS
In 100 people receiving avelumab, 3 or fewer may have:
Avelumab may cause your immune system to attack normal organs and cause side effects in many parts 
of the body. These problems may include but are not limited to:

Heart problems including inflammation and heart failure.  Symptoms and signs of heart problem 
may include: Shortness of breath, swelling of the ankle and body

Swelling and redness of the eye

Intestinal problems (colitis) that can rarely lead to tears or holes in your intestine. Signs
and symptoms of colitis may include: diarrhea or increase in bowel movements, blood in
your stools or dark, tarry, sticky stools, severe belly pain or tenderness

Liver problems (hepatitis) which can cause liver failure. Signs and symptoms of hepatitis
may include: yellowing of your skin or the whites of your eyes, severe nausea or
vomiting; drowsiness; pain in the right upper belly

A condition with high blood sugar (diabetes) which leads to tiredness, frequent urination or 
excessive thirst which may require treatment with insulin

Problem of the nerves that can cause paralysis.  Signs and symptoms may include: numbness, 
tingling of hands and feet; weakness of the arms, legs and facial muscle movement

Inflammation of the brain (meningitis/encephalitis), which may cause: headache, confusion, 
sleepiness, seizures, and stiff neck

Kidney problems, including nephritis and kidney failure requiring dialysis.  Signs of kidney 
problems may include: decrease in the amount of urine, blood in your urine, ankle swelling

Lung problems (pneumonitis and pleural effusion). Symptoms may include: new or
worsening cough, chest pain, shortness of breath
Other risks seen with Avelumab that are possibly related to the drug include:

A condition that causes weakness (myasthenia gravis) in the skeletal muscles (muscles 
your body uses for movement) and eye muscles, drooping of one or both eyelids, blurred 
or double vision, a change in facial expression, difficulty swallowing, shortness of breath, 
impaired speech, or weakness in the arms, hands, fingers, legs, and neck.
o
A disease in which the immune system attacks the body’s own tissues (Myasthenic 
syndrome).It can cause weakness in the upper legs, hips, and eye muscles.

Inflammation in the pancreas (Pancreatitis), which may cause: upper abdominal pain, 
abdominal pain that radiates to your back, abdominal pain that feels worse after eating, 
fever, rapid pulse, nausea, vomiting, and tenderness when touching the abdomen.
Allergic reactions or reactions related with the infusions of avelumab might occur during 
treatment. Although avelumab is a fully human protein, the risk cannot be completely excluded. 
In general, these reactions are mild to moderate and can be handled with appropriate drugs, but in 
very rare cases severe to life-threatening and even fatal reactions might occur, which require 
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advanced cardiac life support. 
For the prevention of infusion-related adverse effects and possible allergic reactions you will 
receive a premedication of an antihistamine drug (H1 blocker) and acetaminophen 30 to 60 minutes 
before every infusion. 
Other Study Risks

Blood draws: The possible side effects of drawing blood include pain, bleeding, bruising, 
dizziness, light-headedness, fainting and, on rare occasions, local blood clot formation or 
infection with redness and irritation of the vein.

Bone marrow: A numbing agent that can cause a stinging or burning sensation may be 
injected at the site of your bone marrow biopsy. The biopsy needle will go through the skin 
into the bone and may produce a brief, sharp pain. As the bone marrow liquid is taken from 
the bone, there may be a brief, sharp pain. Since the inside of the bone cannot be numbed, 
this procedure may cause some discomfort, however not all people experience discomfort. 
The possible side effects associated with a bone marrow biopsy include pain, bleeding, 
bruising, and infection, as well as a reaction to the numbing agent.  

Tumor biopsy: The likely side effects include discomfort or pain, redness, swelling, and/or 
bruising at the site of the needle insertion. Bleeding from the site of the needle insertion is 
a less likely risk. Rarely, significant infection or bleeding from this procedure, allergic 
reaction to the anesthetic, or formation of a scar at the site of needle entry occurs. If you 
will have sedation with the procedure, these risks will be discussed with you prior to the 
procedure. You will be asked to sign a separate consent form prior to any biopsy procedure.

Midline Catheter Insertion: 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 your catheter or infection.

CT, PET and MRI scans:  CT, PET, and/ or MRI scans will be used to monitor your disease 
while you are in this study. CT and PET scans expose you to radiation; the amount depends 
on the number of body areas scanned. In addition, CT and PET scans involve use of contrast 
(oral and/or IV) so that the cancer may be seen better on the images. However, these are 
considered standard of care to monitor your disease.  MRI scans are not associated with 
radiation risk but may involve a special dye or contrast agent may have to be injected into 
you intravenously.  It is likely that you have had these types of scans already in your 
diagnosis or treatment.  If you have any questions, please ask the study team.  
Radiation Exposure from Imaging 
During your participation in this research study, you will be exposed to radiation from CT of the 
neck, chest, abdomen, and pelvis, and from 18F-FDG PET/CT of the torso and the extremities. The 
amount of radiation exposure you will receive from these procedures is equal to approximately 
11.4 rem. A rem is a unit of absorbed radiation. 
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Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT and 18F-FDG PET/CT that you get in this study will expose you to the roughly the same 
amount of radiation as 38 years’ worth of background radiation. Being exposed to too much 
radiation can cause harmful side effects such as an increase in the risk of cancer.  The risk depends 
on how much radiation you are exposed to. Please be aware that about 40 out of 100 people (40%) 
will get cancer during their lifetime, and 20 out of 100 (20%) will die from cancer. The risk of 
getting cancer from the radiation exposure in this study is 1.1 out of 100 (1.1%) and of getting a 
fatal cancer is 0.6 out of 100 (0.6%).
MRI Risks
Your doctor may want you to get a magnetic resonance imaging (MRI) scan.  MRI uses a strong 
magnetic field and radio waves to take pictures of the body.  We will obtain pictures of your brain 
for this study.  The MRI scanner is a metal cylinder surrounded by a strong magnetic field.  During 
the MRI, you will lie on a table that can slide in and out of the cylinder.  We will place soft padding 
or a coil around your head. You will be in the scanner about 45 minutes. You may be asked to lie 
still for up to 15 minutes at a time. While in the scanner you will hear loud knocking noises, and 
you will be fitted with earplugs or earmuffs to muffle the sound. You will be able to communicate 
with the MRI staff at all times during your scan, and you may ask to be moved out of the machine 
at anytime.
It is very important for the experiment that you do not move your head or body inside the scanner. 
We will use padding around your head to help keep it in place.
We may place a bar in your mouth to help keep your head still.
People are at risk for injury from the MRI magnet if they have some kinds of metal in their body.  
It may be unsafe for you to have an MRI scan if you have pacemakers or other implanted electrical 
devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall 
of a large artery), metal prostheses (including metal pins and rods, heart valves, and cochlear 
implants), permanent eyeliner, tattoos, an implanted delivery pump, or shrapnel fragments. 
Welders and metal workers may have small metal fragments in the eye. You will be screened for 
these conditions before having any MRI scan.  If you have a question about metal in your body, 
you should inform the staff. You will be asked to complete an MRI screening form before each 
MRI scan you have. 
In addition, all magnetic objects (like watches, coins, jewelry, and credit cards) must be removed 
before entering the MRI scan room.
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. Everyone 
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having a research MRI scan will be fitted with hearing protection. If the hearing protection comes 
loose during the scan, you should let us know right away.
There are no known long-term risks of MRI scans.
Risks for gadolinium enhanced MRI scans:
Procedure
During part of the MRI you may receive gadolinium, a contrast agent, through an intravenous (iv) 
catheter. It will be done for medical purposes.
Risks
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with 
pain and swelling.  
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and 
usually go away quickly.  Mild symptoms may include coldness in the arm during the injection, a 
metallic taste, headache, and nausea.  In an extremely small number, fewer than one in 300,000 
people, more severe symptoms have been reported including shortness of breath, wheezing, hives, 
and lowering of blood pressure. You should not receive gadolinium if you previously had an 
allergic reaction to it.  You will be asked about such allergic reactions before gadolinium is given.   
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis” which has resulted in a very small number of deaths.  A blood test 
of your kidney function may be done within the month before an MRI scan with gadolinium 
contrast. You will not receive gadolinium for a research MRI scan if your kidney function is not 
normal or if you received gadolinium within the previous month. 
Most of the gadolinium contrast leaves the body in the urine.  However, the FDA recently issued 
a safety alert that indicates small amounts of gadolinium may remain in the body for months to 
years.  The effects of the retained gadolinium are not clear. At this time, retained gadolinium has 
not been linked to health risks in people whose kidneys work well. 
Some types of gadolinium contrast drugs are less likely to remain than others.  In this study, we 
will use the gadolinium contrast drugs that are less likely to remain. 
We will also give you additional information called a “Medication Guide.”  Upon request, we will 
give you individual information about retained gadolinium we see on your studies.
Psychological or Social Risks Associated with Loss of Privacy 
As part of the research study, it is possible that you could learn that you have genetic risks for 
another disease or disability. This may be upsetting and, depending on what you learn, might create 
a need to make challenging decisions about how to respond. 
Although your genomic information is unique to you, you share some genomic similarities with 
your children, parents, brothers, sisters, and other blood relatives. Therefore, learning your 
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research results could mean something about your family members and might cause you or your 
family distress. Before joining the study, it may be beneficial to talk with your family members 
about whether and how they want you to share your results with them. 
Privacy Risks Associated with Return of Incidental or Secondary Findings
Although your genetic information is unique to you, you do share some genetic information with 
your children, parents, brothers, sisters, and other blood relatives. Consequently, it may be possible 
that genetic information from them could be used to help identify you.  Similarly, it may be 
possible that genetic information from you could be used to help identify them.  Patterns of genetic 
variation also can be used by law enforcement agencies to identify a person or his/her blood 
relatives.  
Protections against misuse of genetic information 
This study involves genetic testing on samples.  Some genetic information can help predict future 
health problems of you and your family and this information might be of interest to your employers 
or insurers. The Genetic Information Nondiscrimination Act (GINA) is a federal law that prohibits 
plans and health insurers from requesting genetic information or using genetic information. It also 
prohibits employment discrimination based on your health information. However, GINA does not 
address discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not protect you against discrimination based on an already-diagnosed 
condition or disease that has a genetic component.
What are the risks related to pregnancy? 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how these medicines would affect your baby or your unborn child. 
If you are capable of becoming pregnant, we will ask you to have a pregnancy test before beginning 
this study. If you are a woman who can become pregnant or are the partner of a woman who can 
become pregnant, you will need to practice an effective form of birth control before starting study 
treatment, during study treatment, and for 30 days after the last avelumab infusion. 
Effective forms of birth control include: 

abstinence 

intrauterine device (IUD)

hormonal [birth control pills, injections, or implants]

tubal ligation

vasectomy
There may also be unknown risks to a fetus or risks we did not anticipate. If you think that you or 
your partner is pregnant, you should tell your study doctor or nurse at once.  
If you are capable of becoming pregnant, we will ask you to have a pregnancy test before beginning 
this study. For a portion of this study, you will need to use effective birth control methods and try 
not to become pregnant. Your team will provide additional details on how long this will be required 
and what methods may  be used.  If you become pregnant, there may be unknown risks to the fetus 
or unborn child, or risks that we did not anticipate. There may be long-term effects of the treatment 
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
being studied that could increase the risk of harm to a fetus. You must tell the study doctor if your 
birth control method fails while you are in the study. If you think or know you have become 
pregnant while participating in this research study, please contact the research team member 
identified at the top of this document as soon as possible. If you plan to become pregnant in the 
future, please discuss with the research team how long you need to wait before becoming pregnant 
after completing the course of this study drug or procedures on this study.
If you are a sexually active person with a partner capable of becoming pregnant, it is important 
that your partner not become pregnant for the time period discussed with your study team. There 
may be unknown risks to a fetus or risks we did not anticipate. You and your partner must agree 
to use birth control if you want to take part in this study. If you think your partner has become 
pregnant during the restricted time period, please contact the research team member identified at 
the top of this document as soon as possible.  If you and your partner plan for your partner to 
become pregnant after the restricted time period, please discuss this with the study team.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
Because there is not much information about the drug’s effect on your cancer, we do not know if 
you will benefit from taking part in this study. Talk to your doctor about other approved agents 
and treatments that are available to you and that may provide clinical benefit without taking part 
in this study.  
Are there any potential benefits to others that might result from the study?
In the future, other people might benefit from this study because of the knowledge gained from 
the study drug combination or the results of the research studies. 
WHAT OTHER OPTIONS ARE THERE FOR YOU?
Before you decide whether or not to be in this study, we will discuss the other options that are 
available to you. Instead of being in this study, you could:

Get treatment or care for your cancer without being in a study.  These can be prescribed by 
your regular cancer doctor, even if you are not in this study. Some of the other treatments 
were able to shrink tumors and delay progression of disease in some people, but none has 
been shown to prolong life. Your study doctor can talk to you more about these other 
treatment options, how they are given and their possible side effects.  

Take part in another study

Get comfort care, also called palliative care. This type of care helps reduce pain, tiredness, 
appetite problems and other problems caused by the cancer.  It does not treat the cancer 
directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep you as active 
and comfortable as possible.
Please talk to your doctor about these and other options.
IRB NUMBER: 19C0076
IRB APPROVAL DATE: 11/17/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1) 
Version Date: 09/28/2020
Page 19 of 26
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
DISCUSSION OF FINDINGS
New information about the study
If we find out any new information that may affect your choice to participate in this study, we 
will get in touch with you to explain what we have learned. This may be information we have 
learned while doing this study here at the NIH or information we have learned from other 
scientists doing similar research in other places.
Return of research results
When we are examining your DNA, it is possible that we could identify possible changes in other 
parts of your DNA that are not related to this research. These are known as “incidental medical 
findings”. 
These include: 

Changes in genes that are related to diseases other than cancer 

Changes in genes that are not known to cause any disease. These are known as normal 
variations. 

Changes in genes that are new and of uncertain clinical importance. This means that we do 
not know if they could cause or contribute to a disease or if they are normal variations. 
Since the analyses that we perform in our laboratory are not nearly as sensitive as the tests that 
are performed in a laboratory that is certified to perform genetic testing, the genetic changes that 
we find may or may not be valid.  Therefore, we do not plan to inform you of all of the genetic 
results of testing on your tissue and blood that is performed in our research lab. However, in the 
unlikely event that we discover a finding believed to be clinically important based on medical 
standards at the time we first analyze your results, we will contact you. This could be many years 
in the future. We will ask you to have an additional tube of blood drawn to verify the findings 
we have seen in our lab. If the results are verified, you will be re-contacted and offered a referral 
to a genetic healthcare provider to discuss the results.  
EARLY WITHDRAWAL FROM THE STUDY 
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease worsens or comes back during treatment

if you have side effects from the treatment that your doctor thinks are too severe

if you become pregnant

if the IL-15 and/ or avelumab becomes unavailable

if new information shows that another treatment would be better for you

if you do not follow the study rules

if the study is stopped for any reason
IRB NUMBER: 19C0076
IRB APPROVAL DATE: 11/17/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1) 
Version Date: 09/28/2020
Page 20 of 26
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
In this case, you will be informed of the reason therapy is being stopped.
After therapy is stopped, we would like to see you for a safety visit 30 days after your last dose.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your primary doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines information 
collected on you up to that point may still be provided to Division of Cancer Treatment and 
Diagnosis (DCTD) or designated representatives, and EMD Serono or designated representatives. 
WILL YOUR SPECIMENS OR DATA BE SAVED FOR USE IN OTHER RESEARCH 
STUDIES?
As part of this study, we are obtaining specimens and data from you. We plan to use these 
specimens and data for studies going on right now, as well as studies in the future. These studies 
may provide additional information that will be helpful in understanding T-cell leukemias and 
lymphomas, or other diseases or conditions. This could include studies to develop other research 
tests, treatments, drugs, or devices that are not approved by the FDA yet. There are no plans to 
provide financial compensation to you if this happens. Also, it is unlikely that we will learn 
anything from these studies that may directly benefit you. By agreeing to let us use your 
specimens and data, you give up any rights you may have in the specimens and data.
We may share your specimens and data with other researchers. They may be doing research in 
areas similar to this research or in other unrelated areas. These researchers may be at NIH, other 
research centers and institutions, or industry sponsors of research. 
We may put your research data in a large database for broad sharing with the research 
community. These databases are commonly called data repositories. These data repositories 
might or might not be located at the NIH. The information in this database could include but is 
not limited to genetic information, ethnicity and sex.  If your individual research data is placed 
in one of these repositories, it will not be labeled with your name or other information that could 
be used to easily identify you, and only qualified researchers will be able to look at your data. 
These researchers must receive prior approval from individuals or committees to access the data.
Your summary genomic data is being placed in an unrestricted database, so researchers will be 
able to access summary information about all the participants included in the study (including 
you), or summary information combined from multiple studies, without applying for permission. 
The risk of anyone identifying you with this information is very low.
In addition to the use and sharing of your specimens and data described above, we might remove 
any information from your specimens and data that can identify you such as name, address, or 
medical record number, and then use the specimens and data for additional research studies at 
the NIH or other places. If we do this, we might not contact you to ask your permission or 
otherwise inform you.
If you change your mind and do not want us to store and use your specimens and data for future 
research, you should contact the research team member identified at the top of this document. 
IRB NUMBER: 19C0076
IRB APPROVAL DATE: 11/17/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1) 
Version Date: 09/28/2020
Page 21 of 26
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
We will do our best to comply with your request but cannot guarantee that we will always be 
able to destroy your samples. For example, if some research with your specimens and data have 
already been completed, the information from that research may still be used. Also, for example, 
if the specimens and data have been shared already with other researchers, it might not be 
possible to withdraw the specimens and data.
Please place your initials in the blank next to Yes or No for each of the questions below:
My specimens and data may be stored and used for future research as described above.
_____ Yes
_____ No
Initials
Initials
My specimens and data may be shared with other researchers and used by these researchers for 
future research as described above.
_____ Yes 
_____ No
Initials
Initials
How Long Will Your Specimens and Data be Stored by the NIH?
Your specimens and data will be stored at NIH as long as the study is open. When this study is 
closed, we may keep the data and any samples that are leftover for future research indefinitely. 
Risks of Storage and Sharing of Specimens and Data
When we store your specimens and data, we take precautions to protect your information from 
others that should not have access to it. When we share your specimens and data, we will do 
everything we can to protect your identity, for example, when appropriate, we remove information 
that can identify you. Even with the safeguards we put in place, we cannot guarantee that your 
identity will never become known or someone may gain unauthorized access to your information. 
New methods may be created in the future that could make it possible to re-identify your data or 
samples.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of my participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
IRB NUMBER: 19C0076
IRB APPROVAL DATE: 11/17/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1) 
Version Date: 09/28/2020
Page 22 of 26
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid.  Someone will work 
with you to provide more information
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or clinical care 
that you receive at the NIH Clinical Center. 

You will receive study treatment at no charge to you. This may include surgery, medicines, 
laboratory testing, x-rays or scans done at the Clinical Center, National Institutes of Health 
(NIH), or arranged for you by the research team to be done outside the Clinical Center, 
NIH if the study related treatment is not available at the NIH. 

There are limited funds available to cover the cost of some tests and procedures performed 
outside the Clinical Center, NIH.  You may have to pay for these costs if they are not 
covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or paid for by the 
Clinical Center, NIH.

Once you have completed taking part in the study, medical care will no longer be provided 
by the Clinical Center, NIH.
CONFLICT OF INTEREST (COI)
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a COI Guide.  You may ask your research team for a copy 
of the COI Guide or for more information.  Members of the research team who do not work for 
NIH are expected to follow these guidelines or the guidelines of their home institution, but they 
do not need to report their personal finances to the NIH.
Cooperative Research and Development Agreement (CRADA) 
The NIH and the research team for this study are using a study drug developed by EMD Serono 
through a joint study with your study team and the company. The company also provides financial 
support for this study.
Clinical Trial Agreements 
The Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment and 
Diagnosis (DCTD) is providing IL-15 for this study to NIH without charge. No NIH 
investigator involved in this study receives payments or other benefits from any company 
whose drug, product or device is being tested. However, there are some research partners 
not associated with the NIH working on this study who may receive payments or benefits, 
limited by the rules of their workplace. 
No NIH investigator involved in this study receives payments or other benefits from any 
company whose drug, product or device is being tested. However, there are some research 
partners not associated with the NIH working on this study who may receive payments or 
benefits, limited by the rules of their workplace.
IRB NUMBER: 19C0076
IRB APPROVAL DATE: 11/17/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1) 
Version Date: 09/28/2020
Page 23 of 26
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as required by 
U.S. Law. This website will not include information that can identify you. At most, the website 
will include a summary of the results. You can search this website at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY
Some of your health information, and/or information about your specimen, from this study will 
be kept in a central database for research. Your name or contact information will not be put in 
the database. Your test results will be identified by a unique code and the list that links the code 
to your name will be kept separate from your sample and health information. Your information 
may be given out if required by law. For example, certain states require doctors to report to health 
boards if they find a disease like tuberculosis. However, the researchers will do their best to 
make sure that any information that is released will not identify you.
Will my medical information be kept private?
We will do our best to make sure that the personal information in your medical record will be kept 
private. However, we cannot guarantee total privacy. Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA) 
and the Office for Human Research Protections, which are involved in keeping research 
safe for people.

National Institutes of Health Intramural Institutional Review Board

Qualified representatives from EMD Serono, the pharmaceutical company who produces 
avelumab.

Qualified representatives from Cancer Therapy Evaluation Program (CTEP), Division of 
Cancer Treatment and Diagnosis (DCTD), NCI, the manufacturer of IL-15.
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any 
information about your research involvement without your written permission.  However, if you 
sign a release of information form, for example, for an insurance company, the NIH will give the 
insurance company information from your medical record.  This information might affect (either 
favorably or unfavorably) the willingness of the insurance company to sell you insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
any information that shows your identity before sharing your specimens and data. You should be 
aware that there is a slight possibility that someone could figure out the information is about you. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act.
IRB NUMBER: 19C0076
IRB APPROVAL DATE: 11/17/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1) 
Version Date: 09/28/2020
Page 24 of 26
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances. 
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect our information when it: 
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is necessary for your medical treatment and you have consented to this disclosure; 
4. is for other research;
5. is disclosed with your consent 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures.  Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.  
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical information 
that we collect under the authority of the Public Health Service Act.  In some cases, the Privacy 
Act protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy 
Act allows release of information from your record without your permission, for example, if it is 
requested by Congress.  Information may also be released for certain research purposes with due 
consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting,  to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
Policy Regarding Research-Related Injuries  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
IRB NUMBER: 19C0076
IRB APPROVAL DATE: 11/17/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1) 
Version Date: 09/28/2020
Page 25 of 26
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Problems or Questions
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Milos 
Miljkovic, M.D., milos.miljkovic@nih.gov, Building 10, Room 4N115, Telephone:  301-250-
5216. You may also call the NIH Clinical Center Patient Representative at 301-496-2626, or the 
NIH Office of IRB Operations at 301-402-3713, if you have a research-related complaint or 
concern.
Consent Document 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 19C0076
IRB APPROVAL DATE: 11/17/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1) 
Version Date: 09/28/2020
Page 26 of 26
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: 
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 19C0076
IRB APPROVAL DATE: 11/17/2020