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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  
| Drug Name:                 | Avelumab                                                    | Recombinant human IL-15                                                                                       |
|----------------------------|-------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------|
| (MSB0010718C; NSC #799232) | (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 1
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precis

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 longterm 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 (PTCLTFH), and enteropathy-associated T-cell lymphoma (EATL).  
Adequate organ and marrow function
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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.
3  
| TABLE OF CONTENTS                                                                                                                                            |                                                                                                                                                              |                 |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------|
| PRÉCIS                                                                                                                                                       |                                                                                                                                                              |                 |
| TABLE OF CONTENTS .........................................................................................................................................4 |                                                                                                                                                              |                 |
| STATEMENT OF COMPLIANCE                                                                                                                                      |                                                                                                                                                              |                 |
| INTRODUCTION .                                                                                                                                               |                                                                                                                                                              |                 |
| l                                                                                                                                                            | Study Objectives.................................................................................................................................7           |                 |
| 1.1                                                                                                                                                          | Background and Rationale .............................................................................................................7                      |                 |
| 1.2                                                                                                                                                          |                                                                                                                                                              |                 |
| 2                                                                                                                                                            | ELIGIBILITY ASSESSMENT AND ENROLLMENT ..............................................................19                                                       |                 |
| Eligibility Criteria                                                                                                                                         |                                                                                                                                                              |                 |
| 2.1                                                                                                                                                          |                                                                                                                                                              |                 |
| 2.2                                                                                                                                                          | Screening Evaluation                                                                                                                                         |                 |
| 2.3                                                                                                                                                          | Participant Registration And Status Update Procedures ...................................................23                                                  |                 |
| 2.4                                                                                                                                                          | Baseline Evaluation                                                                                                                                          |                 |
| 3                                                                                                                                                            | STUDY IMPLEMENTATION .                                                                                                                                       |                 |
| 3.1                                                                                                                                                          | Study Design .............................................................................................................................................25 |                 |
| 3.2                                                                                                                                                          | Drug Administration                                                                                                                                          |                 |
| 3.3                                                                                                                                                          | Dose Modifications ..............................................................................................................................29          |                 |
| 3.4                                                                                                                                                          | ON Study Evaluations                                                                                                                                         |                 |
| 3.5                                                                                                                                                          | Post-Treatment Evaluations .................................................................................................38                               |                 |
| Study Calendar .................................................................................................................40                           |                                                                                                                                                              |                 |
| 3.6                                                                                                                                                          |                                                                                                                                                              |                 |
| 3.7                                                                                                                                                          | Cost and Compensation                                                                                                                                        |                 |
| 3.8                                                                                                                                                          | Criteria for Removal from Protocol Therapy and Off Study Criteria ..........................43                                                               |                 |
| 4                                                                                                                                                            | CONCOMITANT MEDICATIONS/MEASURES                                                                                                                             |                 |
| Acceptable Medications ........................................................................................................44                            |                                                                                                                                                              |                 |
| 4.1                                                                                                                                                          | Prohibited Medications                                                                                                                                       |                 |
| 4.2                                                                                                                                                          |                                                                                                                                                              |                 |
| s                                                                                                                                                            | CORRELATIVE STUDIES FOR RESEARCH ...........................................................................45                                               |                 |
| 5.1                                                                                                                                                          | Biospecimen Collection ......................................................................................................45                              |                 |
| Sample Collection and Processing ......................................................................................47                                    |                                                                                                                                                              |                 |
| 5.2                                                                                                                                                          | Biomarker and Research Methods ....................................................................................49                                        |                 |
| 5.3                                                                                                                                                          |                                                                                                                                                              |                 |
| 5.4                                                                                                                                                          | Sample Storage, Tracking, and Disposition ....................................................................................51                             |                 |
| 5.5                                                                                                                                                          | Samples for Genetic/Genomic Analysis                                                                                                                         |                 |
| DATA COLLECTION AND EVALUATION ...................................................................................................54                         |                                                                                                                                                              |                 |
| 6                                                                                                                                                            | 6.1                                                                                                                                                          | DATA COLLECTION |
| 6.2                                                                                                                                                          | DATA SHARING Plans .                                                                                                                                         |                 |  
| 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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design

| 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 |                                                                              |
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statement of compliance

The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical Practice (ICH GCP) and the following:
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects Protection and ICH GCP Training. The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both the protocol and the consent form must be obtained before any participant is enrolled. Any amendment to the protocol will require review and approval by the IRB before the changes are implemented to the study. In addition, all changes to the consent form will be IRB-approved; an IRB determination will be made regarding whether a new consent needs to be obtained from participants who provided consent, using a previously approved consent form.
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1 introduction 1.1 study objectives

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)
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1.2 background and rationale 1.2.1

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).
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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)**  
  
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 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 openlabel 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).
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1.2.4 treatment of relapsed/ refractory

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.
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1.2.5 immune checkpoint inhibitors in

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 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 treatmentrelated 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 PD1 (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).
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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 10fold 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 posttreatment 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.
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1.2.8 clinical trials involving il-15

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 IL15 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 IL15 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 (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 10.8fold. 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 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, antiCD20 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**).  
  
| 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 |
| NK cell                        |     |        |                     |              |                  |      |
| Diagnosis                      | Age | Gender | Dose level (mcg/kg) | No. of doses | 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 |
| NK cell                        |     |        |                     |              |                  |      |
| Diagnosis                      | Age | Gender | Dose level (mcg/kg) | No. of doses | increase  (fold) |      |  
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 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 PDL1 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.  
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)
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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).
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1.2.10 rationale of study 1.2.10.1

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 Tcell 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 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.  
Version Date:  09/23/2021
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2 eligibility assessment and enrollment

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 Tcell 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., postenrollment 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).  
| 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.  
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)  
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 immunemediated 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 and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
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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.
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2.2 screening evaluation 2.2.1 screening

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  
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
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2.3 participant registration and status

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**. 2.3.1 Treatment Assignment Procedures NOTE: For NCI CCR registration and enrollment system purposes only  
| Number          | Name                                                                                                                                                            | Description                                                                                                                                           |
|-----------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------|
| Mature T-cell   |                                                                                                                                                                 |                                                                                                                                                       |
| 1               | malignancies: Dose  Escalation                                                                                                                                  | Relapsed/refractory T-cell lymphoma other than ATLL, AITL,  PTCL-TFH, and EATL (up to 24 evaluable patients)                                          |
| Mature T-cell   |                                                                                                                                                                 |                                                                                                                                                       |
| 2               | 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) |
| Number          | Name                                                                                                                                                            | Description                                                                                                                                           |
| 1               | Experimental Treatment:                                                                                                                                         | IL-15 by civ infusion at escalating doses of 1, 2, 3 and 4                                                                                            |
| Dose Escalation | 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:                                                                                                                                         | IL-15 by civ infusion at the MTD on days 1-5 of cycles 1-6                                                                                            |
| Dose Expansion  | with avelumab at 10mcg/kg on Day 8 and 22 of each cycle                                                                                                         |                                                                                                                                                       |  
2.3.1.2 Arms  
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.
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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
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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,
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.
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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)
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.
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3 study implementation 3.1 study

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.  
  
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 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.
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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.  
| Dose Level                                                                                         | rhIL-15   | Avelumab   |
|----------------------------------------------------------------------------------------------------|-----------|------------|
| (mcg/kg)                                                                                           | (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. |           |            |
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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. |  
| 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  This is generally the recommended phase 2 dose. At  the maximally administered dose least 6 patients must be entered at the recommended  phase 2 dose. |                                                                                                                                                                                                                                                                                                                                                                                                              |
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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.  
| Agent                                                                                                                                                                                                      | Premedications;  Precautions    | Dose             | Route             | Schedule   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------|------------------|-------------------|------------|
| Premedicate with                                                                                                                                                                                           |                                 |                  |                   |            |
| rhIL-15                                                                                                                                                                                                    | acetaminophen and/or  ibuprofen | ** in *** mL D5W | IV over  24 hours | Days 1-5   |
| with 0.1% HSA                                                                                                                                                                                              |                                 |                  |                   |            |
| Premedicate with                                                                                                                                                                                           | ** in 250 mL NS                 | IV over          | Days 8 and        |            |
| Avelumab                                                                                                                                                                                                   | acetaminophen and an            | 1 hour           | 22                |            |
| antihistamine*                                                                                                                                                                                             |                                 |                  |                   |            |
| * 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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table 4 drug regimen

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., 2550 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.
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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).
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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**. 3.3.2 Avelumab 3.3.2.1 Treatment modifications for symptoms of infusion-related reactions
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table 5 treatment modifications for

| 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   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
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.  
| 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                                                                                                                                                                                                               | If improves to Grade ≤ 1:  Resume avelumab therapy                                                                                                                                                                                                                                                                                                         |
| Symptomatic treatment                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | 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. |  
| 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                                                                                                                                                                                                                    |
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table 8 treatment modifications for

| 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 |  
| Pulmonary irAEs   |                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                            |
|-------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Pneumonitis       | Initial Management                                                                                                                                                                                                                                | Follow-up Management                                                                                                                                                                                                                       |
| Grade 3 or 4 Grade 3: Severe new  symptoms; New /  worsening hypoxia Grade 4: Lifethreatening                   | 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) |
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table 9 treatment modifications for

| 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         | 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                       | Withhold avelumab Increase frequency of monitoring  to every 3 days 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 |  
| 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                                                                               |
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table 10 treatment modifications for

| 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 immunemediated 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                                                                                                                                                                              | Permanently discontinue avelumab.                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                      |
| myocarditis                                                                                                                                                                                  | 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) |  
| 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-PracticeGuidelines American Heart Association guidelines website:  http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001                 |                    |                      |  
| 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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table 12 treatment modifications for

| 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 lifethreatening 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. |
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table 13 treatment modifications for

| 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                                                                                                                                  | If irAE is ruled out, manage as                                                                                |
| investigation                                                                   | 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. |  
| Other irAEs (not described above)                                                                                                                                                                                              |                                                                                                                                                                                                                        |                                                                |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------|
| Grade of other irAEs (NCI CTCAE v5)                                                                                                                                                                                            | Initial Management                                                                                                                                                                                                     | Follow-up Management                                           |
| Recurrence of same Grade                                                                                                                                                                                                       | Permanently discontinue protocol                                                                                                                                                                                       |                                                                |
| 3 irAEs                                                                                                                                                                                                                        | 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                                                                                                                                   |                                                                                                                                                                                                                        |                                                                |  
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.
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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.
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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.
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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.
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3.5.3 follow-up visits- prior to

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

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                                    | End of                     |           |          |         |      |         |             |      |           |           |        |             |         |
| Treatment  and                               | Safety 1                   | Follow-Up | Survival |         |      |         |             |      |           |           |        |             |         |
| Disease                                      | (Prior to PD)              | (Post-PD) |          |         |      |         |             |      |           |           |        |             |         |
| Progression                                  |                            |           |          |         |      |         |             |      |           |           |        |             |         |
| Screening                                    | Baseline                   | C1        | C2-6     | Disease |      |         |             |      |           |           |        |             |         |
| Evaluations                                  |                            |           |          |         |      |         |             |      |           |           |        |             |         |
| Scheduling Window (Days): -28 to -12         | -143                       | 5         | 8        | 9       | 22   | 1       | 8           | 22   | Every 8   | Treatment | Day 30 | Every 60 or | Every 3 |
| (-1)                                         | (-3)                       | (-3)      | (-3)     | (-3)    | (-3) | weeks 4 | discon/PD 5 | (+7) | 90 days 6 | 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 antithyroid antibody                                              | X                          | X         |          |         |      |         |             |      |           |           |        |             |         |
| Clonal T-cell receptor  rearrangement by PCR | X                          |           |          |         |      |         |             |      |           |           |        |             |         |
| Iron panels, Folate, and B12, Creactive Protein, IL-2R                                              | X                          | X         |          |         |      |         |             |      |           |           |        |             |         |
| Creatine phosphokinase (CPK),  troponin      | X                          | X         | X        | X       | X    |         |             |      |           |           |        |             |         |  
| Study Cycles                                                                                                                                                                                                          | Post-Treatment Follow-Up   |           |          |         |      |      |    |    |         |           |        |             |         |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------|-----------|----------|---------|------|------|----|----|---------|-----------|--------|-------------|---------|
| Procedure                                                                                                                                                                                                             | End of                     |           |          |         |      |      |    |    |         |           |        |             |         |
| Treatment  and                                                                                                                                                                                                        | Safety 1                   | Follow-Up | Survival |         |      |      |    |    |         |           |        |             |         |
| Disease                                                                                                                                                                                                               | (Prior to PD)              | (Post-PD) |          |         |      |      |    |    |         |           |        |             |         |
| Progression                                                                                                                                                                                                           |                            |           |          |         |      |      |    |    |         |           |        |             |         |
| Screening                                                                                                                                                                                                             | Baseline                   | C1        | C2-6     | Disease |      |      |    |    |         |           |        |             |         |
| Evaluations                                                                                                                                                                                                           |                            |           |          |         |      |      |    |    |         |           |        |             |         |
| Scheduling Window (Days): -28 to -12                                                                                                                                                                                  | -143                       | 5         | 8        | 9       | 22   | 1    | 8  | 22 | Every 8 | Treatment | Day 30 | Every 60 or | Every 3 |
| weeks 4                                                                                                                                                                                                               | discon/PD 5                | 90 days 6 | months 7 |         |      |      |    |    |         |           |        |             |         |
| (-1)                                                                                                                                                                                                                  | (-3)                       | (-3)      | (-3)     | (-3)    | (-3) | (+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                                                                                                                                                              | X                          | X         | X        | X       |      |      |    |    |         |           |        |             |         |
| score 16 Radiologic Evaluation/ tumor  measurement17                                                                                                                                                                  | X                          | X         | X        | X       |      |      |    |    |         |           |        |             |         |
| EKG. TTE                                                                                                                                                                                                              | X                          |           |          |         |      |      |    |    |         |           |        |             |         |
| Symptoms/Adverse Events  Assessment, Concomitant                                                                                                                                                                      | X                          | X         | X        | X       | X    | X    |    |    |         |           |        |             |         |
| Medication Review 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. |                            |           |          |         |      |      |    |    |         |           |        |             |         |  
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 anticancer 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 posttreatment 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

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.
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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.
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3.8 criteria for removal from

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 followup 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
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.
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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**.
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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.
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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
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.
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5 correlative studies for research

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 rhIL15/avelumab therapy on the immune system, and to identify potential biomarkers that would be predictive of response.  
| Time Points                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Supervising  Laboratory/  Investigator                                                                                                                                                  |                                                    |          |          |      |          |      |              |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------|----------|----------|------|----------|------|--------------|
| Sample                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Collection Details*                                                                                                                                                                     | Baseline                                           | C1       | C1       | C1   | C1       | C2-6 | C2-6  Followup#              |
| D5                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | D8                                                                                                                                                                                      | D9                                                 | D22      | D1       | D8   |          |      |              |
| Blood Samples                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Immunology                                                                                                                                                                              |                                                    |          |          |      |          |      |              |
| Lymphocyte subset                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |  2 x 10mL K2EDTA  (lavender-top) tubes                                                                                                                                                 | X                                                  | X        | (X)      | (X)  | (X)      | (X)1 | section, NIH |
| testing                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | 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)          |
|  1 x 10mL K2EDTA  tube  1 x 10mL Streck/BCT  tube                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                         |                                                    |          |          |      |          |      |              |
| Circulating tumor  DNA, plasma  banking                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Waldmann (Leidos CSL)                                                                                                                                                                   |                                                    |          |          |      |          |      |              |
| X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | (X)                                                                                                                                                                                     | (X)                                                | X3       |          |      |          |      |              |
| Anti-IL-15  antibodies                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |  1 x 4mL SST tube                                                                                                                                                                      | X                                                  | X        | X1       |      |          |      |              |
| Tissue Samples                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |  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 | Waldmann/ (RPMI 1640) and DLM/  NCI LP  (formalin) |          |          |      |          |      |              |
| Tissue immune cell  subsets                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | X**                                                                                                                                                                                     | (X)                                                | (X)      |          |      |          |      |              |
| 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

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 eightweek 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.
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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.
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.
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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.
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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.
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5.2.6 tissue samples 5.2.6.1 pdl-1

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 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).
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5.2.7 other samples 5.2.7.1 germline

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.
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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: