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5.3.1 molecular profiling

Immunohistochemical (IHC) analyses, including FISH and/or PCR testing, will take part in tumor tissue samples, including but not necessarily limited to CD2, CD3, CD4, CD5, CD7, CD8, CD14, CD16, CD20, CD25, CD38, CD45RA, CD45RO, CD56, CD62L, CD69, CD79a/CD79b, CD122, Foxp3, perforin, gamma/delta, CXCR3, CCR4, and NKG2D. 5.3.2 Immune Subset Analysis Peripheral blood mononuclear cells (PBMC) will be assessed using multiparameter flow cytometry for immune subsets including but not necessarily limited to CD8+ T-cells, CD4+Foxp3- T-cells, Tregs, Tex, Th1, Th2 and Th17+ CD4+ T-cells, NK cells and subsets, monocyte subsets, MDSC
subsets. Assessment may include functional markers, i.e. PD-1, Tim-3, CTLA-4, PD-L1, HLADR, Ki67 and/or CD40.
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5.3.3 adcc analysis

Peripheral blood mononuclear cells (PBMCs) should be isolated by Ficoll-Hypaque Density Gradient Centrifugation. The viable cells should be viably frozen and stored in liquid nitrogen. The ADCC assay will be performed on the same occasion for all samples of a given patient. Vials of frozen cells will be thawed using standard procedures 18 hours before the assay in accord with our experience with normal donors. 1.5 million of patient's PBMCs obtained before and on day 15 following IL-15 injection will be tested in aliquots as follows:
Tested alone  
Tested with untreated PD-L1-expressing Raji cells, and with the Raji cells coated with avelumab for 5 hours.  
In addition, we may utilize an ATL cell line in addition to Raji cells. These cell populations will be stained with CD107, CD3, CD56, and CD94.
5.3.4 cfDNA/ctDNA and PBMC banking Since the methods of molecular monitoring in the peripheral blood is an emerging field with numerous technologies under development, the storage of peripheral blood mononuclear cells (PBMC), serum, and plasma will all be performed allowing for future comparison of the different compartments for analytes that include cell-free circulating tumor DNA (ctDNA), and RNA sequencing of circulating tumor cells. Studies to be performed on these samples include: cfDNA/ctDNA for liquid genotyping as a non-invasive dynamic monitoring of disease as well as monitoring for individual molecular aberrations that herald progression or disease transformation; specifically, amplification and sequencing of the VDJ segment of the immunoglobulin receptor is planned. Germline DNA obtained from saliva, blood, or buccal mucosa will be used to discriminate somatic from germline mutations during cfDNA and ctDNA analyses. Keeping in mind a recent report of immune checkpoint inhibition in a patient with a solid tumor being associated with T-cell lymphomagenesis (50), and with our own group's experience with rapid progression in 3 patients with ATLL treated with ICI (22, 51), special attention will be paid to following T-cell clonality using amplification and sequencing of the complementarity determining region 3 (CDR3) in both cfDNA and banked PBMCs.
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5.3.5 dna/rna sequencing

Genomic DNA and total RNA will be extracted from tumor samples using a Qiagen All-prep kit. For individual target genes that are recurrently mutated in T-cell malignancies, classical Sanger sequencing will be performed on PCR amplicons, using primers surrounding the known sites of mutation. To broadly assess mutations, next generation sequencing (e.g., on an Illumina HiSeq 2000 platform) will be employed, using a paired end sequencing strategy of libraries constructed from tumor DNA. DNA will either be sequenced in its entirety from a whole genome library or will be first enriched for exonic sequences using the Agilent Sure Select system, aiming for 30X or 100X average coverage per base, respectively. The sequence fragments will be mapped back to the genome using the BWA algorithm. Of sequences overlapping a particular base pair in the genome, the percent mutant calls greater that 20% with a minimum of 25X coverage will be considered as an arbitrary threshold for single nucleotide variants (SNVs). SNVs that are not present in the matched normal sample will be considered candidate somatic mutations. A related technology, RNA-Seq, utilizes RNA from the tumor specimen to create a cDNA library for high-throughput sequencing. RNA-seq will be performed using Illumina kits followed by highthroughput sequencing on an Illumina HighSeq 2000 machine. The cutoffs for coverage and percent mutant calls mentioned above will also be used to identify putative SNVs. RNA sequencing will also be used to read out digital gene expression across the genome as described. Recent advances in genomic technologies enable GEP at the single cell level, a distinct advantage over conventional GEP which cannot always distinguish tumor vs non-tumor gene expression. Single-cell approaches allow identification of the evolution of rare populations of resistant tumor cells, as well as identification of TME cells critical for the survival of the tumor. The Center for Cancer Research (CCR) has recently opened a single cell analysis core facility with expert staff headed by Dr. Michael Kelly within the CCR Genomics Core. This facility has the ability to take purified viably frozen cells banked from patient biopsies and prepare them, using well-validated 10X Genomics technology, for single-cell RNA sequencing. This core is directly integrated with the NCI Sequencing core facility to provide high-quality, deep-sequencing of the single cell RNASEQ samples, as well as 'first-pass' data processing and analysis. Data will then be transferred to lymphoma researchers and bio-informaticians for further analysis of gene expression patterns and cellular population dynamics.
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5.3.6 other analyses

Other analyses include the following:  
Cell analysis and histological (e.g., H&E), immunohistochemical review and analysis per standard and established research techniques (e.g., PD-1/PD-L1 expression [Dako], FISH for del(17p), and other IHC analyses in blood and tissue).  
Cytokine analysis (e.g., IL-6, IL-10, interferon beta, TNF-alpha)
5.3.7 Future Use
Any blood, tissue, or other products or portions leftover from other analyses will be stored for future research.
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5.4 sample storage tracking and

Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples will not be sent outside NIH without appropriate approvals and/ or agreements, if required. All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are remaining at the completion of the protocol will be stored in the conditions described below. The study will remain open so long as sample or data analysis continues. Samples from consenting subjects will be stored until they are no longer of scientific value or if a subject withdraws consent for their continued use, at which time they will be destroyed. If the patient withdraws consent the participant's data will be excluded from future distributions, but data that have already been distributed for approved research use will not be able to be retrieved.  
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will be per the requirements in section **7.2.** 5.4.2 Lymphoid Malignancies Branch - Waldmann Laboratory Under the direction of Dr. Waldmann, all samples processed by the laboratory will be uniquely barcoded, with data entered using a secure computerized database and backup hardcopy process per standard laboratory practice. Samples are stored in labeled boxes in secured freezers (i.e., -20ºC to -80ºC, or other, as appropriate) according to stability requirements; these freezers are located onsite. Access to stored clinical samples is restricted and limited to research personnel for approved analyses only (as per the IRB approved protocol). Upon completion of planned analyses by the Waldmann lab, leftover samples may be stored for future analyses at the Clinical Support Laboratory, Leidos Biomedical Research, Inc.in Frederick, MD (see below). 5.4.3 Clinical Support Laboratory, Leidos Biomedical Research, Inc. in Frederick, MD The Clinical Support Laboratory, Leidos Biomedical Research, Inc.-Frederick, processes and cryopreserves samples in support of IRB-approved, NCI clinical trialsThe laboratory is CLIA certified for anti-IL15 and certain cytokine measurements, and all laboratory areas operate under a Quality Assurance Plan with documented Standard Operating Procedures that are reviewed annually. Laboratory personnel are assessed for competency prior to being permitted to work with patient samples. Efforts to ensure protection of patient information include:
The laboratory is located in a controlled access building and laboratory doors are kept locked at all times. Visitors to the laboratory are required to be accompanied by laboratory staff at all times.  
Hard copy records or electronic copies of documents containing patient information are kept in the locked laboratory or other controlled access locations.  
An electronic database is used to store information related to patient samples processed by the laboratory.  
The database resides on a dedicated program server that is kept in a central, locked computer facility.  
The facility is supported by two IT specialists who maintain up to date security features including virus and firewall protection.  
Program access is limited to specified computers as designated by the laboratory director.  
Each of these computers has a password restricted login screen.  
The database sample entry program itself is accessed through a password protected entry screen.  
Upon specimen receipt each sample is assigned a unique, sequential laboratory accession ID number. All products generated by the laboratory that will be stored either in the laboratory freezers or at a central repository facility are identified by this accession ID.  
Inventory information will be stored at the vial level and each vial will be labeled with both a sample ID and a vial sequence number.  
Vial labels do not contain any personal identifier information.  
Samples are stored inventoried in locked laboratory freezers and are routinely transferred to the NCI-Frederick repository facilities for long term storage.  
Access to stored clinical samples is restricted. Investigators establish sample collections under "Source Codes" and the Principal Investigator who is responsible for the collections specifies who has access to the collection.  
Specific permissions will be required to view, input or withdraw samples from a collection.  
Sample withdrawal requests submitted to approved laboratory staff by anyone other than the repository source code owner are submitted to the source code owner for approval. The repository facility will also notify the Source Code holder of any submitted requests for sample withdrawal.  
It is the responsibility of the Source Code holder (the NCI Principal Investigator) to ensure that samples requested and approved for withdrawal are being used in a manner consistent with IRB approval.  
The Clinical Support Laboratory does perform testing services that may be requested by clinical investigators including, but not limited to, immunophenotyping by flow cytometry and cytokine testing using ELISA or multiplex platforms.  
When requests are submitted by the NCI investigator for shipment of samples outside of the NIH it is the policy of the laboratory to request documentation that a Material Transfer Agreement is in place that covers the specimen transfer. The laboratory does not provide patient identifier information as part of the transfer process but may, at the discretion of the NCI investigator, group samples from individual patients when that is critical to the testing process.  
The NCI investigator responsible for the sample collection is responsible for ensuring appropriate approvals and/ or agreements are in place, if required, prior to requesting the laboratory to ship samples outside of the NIH.
5.4.4 Hematopathology Section of the Laboratory of Pathology (Tissue samples) Archival and/or freshly collected and processed tumor tissue may be stored in the Hematopathology Section of Laboratory of Pathology until ready for planned and/or future research assays if the patient has agreed to allowing specimens to be used in future research studies. IRB approval will be obtained before using any samples to conduct studies that are not described within this protocol. Samples will be stored under conditions appropriate to the type of sample and processing (e.g., ambient or frozen). Tissue that is given to the technician will be assigned an accession number (HP\#) in the HP Case Logbook; sample tracking also takes place with a FileMaker Pro data base called HP Patient Information and Specimen Inventory. A Patient background sheet may be filled out and filed with any accompanying paperwork, with final reports and any supplemental reports that follow added as completed.
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5.5 samples for genetic/genomic analysis

The research correlates for this study are expected to include DNA/RNA sequencing of tumors, including circulating tumor (ct) DNA. In addition, whole exome sequencing may include evaluation for known lymphoma mutations. For any genetic studies performed, the results will be deposited in a database such as dbGaP per NIH requirements. Although there is controlled access to such a database, such a submission carries theoretical risks of revealing the identity of the subject. This is discussed in the consent. 5.5.2 Description of how privacy and confidentiality of medical information/biological specimens will be maximized Confidentiality for genetic samples will be maintained as described (Section **5.4.2**). In addition, a Certificate of Confidentiality has been obtained for this study.
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5.5.3 management of results

Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically actionable findings for this study are defined as disorders appearing in the American College of Medical Genetics and Genomics recommendations for the return of incidental findings that is current at the time of primary analysis. (A list of current guidelines is maintained on the CCR intranet: https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists).
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5.5.4 genetic counseling

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

The PI will be responsible for overseeing entry of data into an in-house password protected electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal investigator, associate investigators/research nurses and/or a contracted data manager will assist with the data management efforts. Primary and final analyzed data will have identifiers so that research data can be attributed to an individual human subject participant. All adverse events (AEs), including clinically significant abnormal findings on laboratory evaluations, regardless of severity, will be followed until return to baseline or stabilization of event. Document AEs from the first study intervention through 30 days after the last study intervention was administered. Beyond 30 days after the last intervention, only adverse events which are serious and related to the study intervention need to be recorded. End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH Intramural Records Retention Schedule as applicable. Loss or destruction of data: Should we become aware that a major breach in our plan to protect subject confidentiality and trial data has occurred, this will be reported expeditiously per requirements in section 7.2. 6.1.2 Data Collection/Recording Exceptions 6.1.2.1 Abnormal Laboratory Values An abnormal laboratory value will be considered an AE **only** if the laboratory abnormality is characterized by any of the following:
Results in discontinuation from the study  
Is associated with clinical signs or symptoms Requires treatment or any other therapeutic intervention Is associated with death or another serious adverse event, including hospitalization Is judged by the Investigator to be of significant clinical impact If any abnormal laboratory result is considered clinically significant, the investigator will provide details about the action taken with respect to the test drug and about the patient's outcome.  
6.2 DATA SHARING P**LANS**
6.2.1 Human Data Sharing Plan
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what data will be shared?

I will share human data generated in this research for future research as follows: _X_ Coded, linked data in an NIH-funded or approved public repository. _X_ Coded, linked data in another public repository _X_ Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
_X_ Identified or coded, linked data with approved outside collaborators under appropriate agreements.
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how and where will the

Data will be shared through: _X_ An NIH-funded or approved public repository. Insert name or names: ClinicalTrials.gov, dbGaP. _X_ BTRIS (automatic for activities in the Clinical Center)  
_X_ Approved outside collaborators under appropriate individual agreements. _X_ Publication and/or public presentations.
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when will the data be

_X_ Before publication. _X_ At the time of publication or shortly thereafter.  
6.2.2 Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in compliance with the NIH Genomic Data Sharing Policy.
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6.3 response criteria 6.3.1 response

Tumor response will be assessed by the investigator using the RECIL 2017 criteria (52) for all patients with T-cell lymphoma other than CTCL. Global Response Score (53), and modified severity weighted assessment tool (mSWAT) (11) will be used for patients with CTCL. Patient will be re-evaluated for response as outlined in the Study Calendar, Section 3.6.
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6.3.2 response criteria for ptcl

RECIL 2017 criteria (52) use the Deauville five-point scale for assessment of response via FDGPET. The five-point scale (5-PS) has been validated for use at interim staging and at the end of treatment and was adopted as the preferred reporting method at the First International Workshop on PET in Lymphoma in Deauville, France (i.e., Deauville criteria), and in several international trials. The 5-PS PS scores the most intense uptake in a site of initial disease:  
1. if present, as follows: no uptake or no residual uptake (when used at interim) 2. slight uptake, but below blood pool (mediastinum) 3. uptake above mediastinal, but below or equal to uptake in the liver 4. uptake slightly to moderately higher than liver 5. markedly increased uptake or any new lesion (on response evaluation)
The sum of longest diameter (SLD) is used for assessment of tumor burden. In patients with disseminated disease, a maximum of three target lesions should be selected and used to estimate tumor response. Target lesions should be selected from those with the largest size that can be reproducibly measured and preferably representing multiple sites and/organs. In most cases, lymph nodes can be considered target lesions if the lymph node longest diameter measures ≥15 mm. A lymph node measuring between 10 and 14 mm is considered abnormal but should not be selected as a target lesion. Lymph nodes measuring <10 mm in diameter are considered normal. In certain anatomical sites (inguinal, axillary, and portocaval), normal lymph nodes may exist in a narrow, elongated form, and such nodes should not be selected as target lesions if alternatives are available. Extranodal lesions are selected as target lesions if they have soft tissue component, based on their size, and the ease of reproducibility of repeated measurements, with a minimum measurement of the longest diameter of ≥ 15 mm. All other lesions should be identified as nontarget lesions and should be recorded at baseline, without the need to measure them. Nontarget lesions should be followed and reported as present, absent, or clear progression.  
| % Change in sum of diameters of target lesions from nadir                                                                                                                                |                                                                                                                                          |                                                                                     |                                                                                             |                                                                                           |           |                                                                    |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------|-----------|--------------------------------------------------------------------|
| CR                                                                                                                                                                                       | PR                                                                                                                                       | MR                                                                                  | SD                                                                                          | PD                                                                                        |           |                                                                    |
|                                                                                                                                                                                         | Complete  disappearance of  all target lesions  and all nodes with  long axis <10mm                                                      |                                                                                     |                                                                                             |                                                                                           |           |                                                                    |
|                                                                                                                                                                                         | >30% decrease in  the sum of longest  diameters of target  lesions (PR) with  normalization of  FDG-PET                                  | >30%  decrease in  the sum of  longest  diameters of  target  lesions but  not a CR | >10%  decrease in  the sum of  longest  diameters  of target  lesions but  not a PR  (<30%) | <10%  decrease  or < 20%  increase in  the sum of  longest  diameters  of target  lesions |          | >20% increase in the  sum of longest  diameters of target  lesions |
|                                                                                                                                                                                         | For small lymph nodes  measuring <15 mm  post therapy, a  minimum absolute  increase of 5 mm and  the long diameter  should exceed 15 mm |                                                                                     |                                                                                             |                                                                                           |           |                                                                    |
|                                                                                                                                                                                         | Appearance of a new  lesion                                                                                                              |                                                                                     |                                                                                             |                                                                                           |           |                                                                    |
| % change from  baseline                                                                                                                                                                  | Normalization of                                                                                                                         |                                                                                     |                                                                                             |                                                                                           |           |                                                                    |
| FDG-PET                                                                                                                                                                                  | FDG-PET (Deauvile  score 1-3)                                                                                                            | Positive  (Deauville                                                                | Any                                                                                         | Any                                                                                       | Any       |                                                                    |
| score 4-5)                                                                                                                                                                               |                                                                                                                                          |                                                                                     |                                                                                             |                                                                                           |           |                                                                    |
| Bone marrow  involvement                                                                                                                                                                 | Not involved                                                                                                                             | Any                                                                                 | Any                                                                                         | Any                                                                                       | Any       |                                                                    |
| New lesions                                                                                                                                                                              | No                                                                                                                                       | No                                                                                  | No                                                                                          | No                                                                                        | Yes or No |                                                                    |
| CR, complete response; CT, computerized tomography; FDG-PET, [18F]2-fluoro-2-deoxy-D-glucose; MR, minor  response; PD, progression of disease; PR, partial response; SD, stable disease. |                                                                                                                                          |                                                                                     |                                                                                             |                                                                                           |           |                                                                    |
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6.3.3 response criteria for ctcl

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

| Abbreviated Title: IL-15 and Avelumab in R/R T-cell NHL Version Date: 09/23/2021 Weighing factor                                                                                                                                                                                                                                                                                                                                                                                                                                                 | x1   | x2   | x4   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------|------|------|
| Subtotal lesion BSA x  weighing factor NOTE: mSWAT score equals summation of each column line. Abbreviations: BSA, body surface area; mSWAT, modified Severity Weighted Assessment Tool. 1 Any size lesion without induration or significant elevation above the surrounding uninvolved skin; poikiloderma  may be present 2 Any size lesion that is elevated or indurated; crusting, ulceration, or poikiloderma may be present. 3 Any solid or nodular lesion > 1cm in diameter with evidence of deep infiltration in the skin and/or vertical |      |      |      |  
  
  
As recent preclinical data has shown that PD-1 may act as a tumor suppressor in T-cell malignancies(21), and three patients with ATLL who received the anti-PD-1 antibody Nivolumab experienced progression of disease shortly after receiving the first dose (NCT02631746, unpublished data), rapid progression will be followed as a distinct outcome. Rapid progression is defined as any PD within 14 days of the first avelumab administration (i.e., up to and including Cycle 1, Day 21), excluding skin flares. Patients who are suspected of having a skin flare during this period but have confirmed PD on re-evaluation will be noted to have had rapid progression.
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6.3.5 best overall response

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.
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6.3.6 duration of response

The duration of response (DOR) is measured from the time measurement criteria are met for CR or PR (whichever is recorded first) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started), death, or, in the absence of PD, date of last assessment. 6.3.7 Progression-Free Survival Progression-free survival (PFS) is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, or death, whichever occurs first. 6.3.8 Overall Survival Overall survival (OS) is defined as the time from the date of study enrollment until time of death from any cause. 6.3.9 Event-Free Survival Event-free survival (EFS) is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, alternative therapy for lymphoma given (such as radiation), or death, whichever occurs first.
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6.4 toxicity criteria

The following adverse event management guidelines are intended to ensure the safety of each patient while on the study. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).
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7 nih reporting requirements/data and

Please refer to definitions provided in Policy 801: Reporting Research Events found **here**.
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7.2 ohsrp office of compliance

Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802 Non-Compliance Human Subjects Research found **here**. Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported per these policies. 7.2.2 IRB Requirements for PI Reporting at Continuing Review Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.
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7.3 nci clinical director reporting

Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical Director. A separate submission is not necessary as reports in iRIS will be available to the Clinical Director. In addition to those reports, all deaths that occur within 30 days after receiving a research intervention should be reported via email to the Clinical Director unless they are due to progressive disease. To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death.
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7.4 nih required data and

The clinical research team will meet at least weekly when patients are being actively treated on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if applicable will be made based on the toxicity data from prior patients. All data will be collected in a timely manner and reviewed by the principal investigator or a lead associate investigator. Events meeting requirements for expedited reporting as described in section 7.2.1 will be submitted within the appropriate timelines. The principal investigator will review adverse event and response data on each patient to ensure safety and data accuracy. The principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff.
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8 sponsor safety reporting 8.1

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (ICH E6 (R2)).
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8.1.2 serious adverse event

An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following:
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death

A life-threatening adverse event (see **8.1.3**) Inpatient hospitalization or prolongation of existing hospitalization o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery arranged prior to the start of the study), a planned hospitalization for pre-existing condition, or a procedure required by the protocol, without a serious deterioration in health, is not considered a serious adverse event.  
o A hospitalization/admission that is solely driven by non-medical reasons (e.g.,
hospitalization for patient or subject convenience) is not considered a serious adverse event.  
o Emergency room visits or stays in observation units that do not result in admission to the hospital would not be considered a serious adverse event. The reason for seeking medical care should be evaluated for meeting one of the other serious criteria.  
Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions A congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.  
8.1.3 Life-threatening
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death. (21CFR312.32). 8.1.4 Severity The severity of each Adverse Event will be assessed utilizing the CTCAE version 5. 8.1.5 Relationship to Study Product All AEs will have their relationship to study product assessed using the terms: related or not related.  
Related - There is a reasonable possibility that the study product caused the adverse event.  
Reasonable possibility means that there is evidence to suggest a causal relationship between the study product and the adverse event.  
Not Related - There is not a reasonable possibility that the administration of the study product caused the event.
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8.2 assessment of safety events

AE information collected will include event description, date of onset, assessment of severity and relationship to study product and alternate etiology (if not related to study product), date of resolution of the event, seriousness and outcome. The assessment of severity and relationship to the study product will be done only by those with the training and authority to make a diagnosis and listed on the Form FDA 1572 as the site principal investigator or sub-investigator. AEs occurring during the collection and reporting period will be documented appropriately regardless of relationship. AEs will be followed through resolution. SAEs will be:  
Assessed for severity and relationship to study product and alternate etiology (if not related to study product) by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  
Recorded on the appropriate SAE report form, the medical record and captured in the clinical database.  
Followed through resolution by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events recorded from the time of first investigational product administration must be reported to the sponsor with the exception of any listed in section 8.4.
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8.3 reporting of serious adverse

Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of Special Interest that require expedited reporting must be submitted immediately (within 24 hours of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited reporting requirements are found in section **8.4.** All SAE reporting must include the elements described in section 8.2. SAE reports will be submitted to the Center for Cancer Research (CCR) at: OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. CCR SAE report form and instructions can be found at: https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions Following the assessment of the SAE by OSRO, other supporting documentation of the event may be requested by the OSRO Safety and should be provided as soon as possible.
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8.4 waiver of expedited reporting

As death due to disease progression is part of the study objectives, and captured as an endpoint in this study, it will not be reported in expedited manner to the sponsor. However, if there is evidence suggesting a causal relationship between the study drug and the event, report the event in an expedited manner according to section 8.3.
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8.5 safety reporting criteria to

All events listed below must be reported in the defined timelines to OSROsafety@mail.nih.gov. The CCR Office of Regulatory Affairs will send all reports to the manufacturer(s) as described below. 8.5.1 Safety Reporting to the Pharmaceutical Collaborator EMD Serono (Avelumab) The investigational agent, avelumab, is being supplied by EMD Serono and the following are their requirements for safety reporting. The following reportable events must be submitted to EMD Serono within 2 business days or 3 calendar days (whichever comes first) using the applicable safety report form provided. The Principal Investigator/study team will submit reportable events to the Sponsor as well as ensure that any other local reporting requirements are completed, if required (e.g., IRB). The Sponsor will assume responsibility for submitting the reportable event(s) to EMD Serono as well as ensuring that any local reporting requirements are completed in parallel.  
Serious Adverse Event Reports Exposure during pregnancy or breastfeeding (even if not associated with an adverse event)
Occupational exposure (even if not associated with an adverse event) Potential drug-induced liver injury (Hy's Law cases): These events are considered important medical events and should be reported as SAEs.
Contact information for submission of reportable events to EMD Serono:
Fax: +49 6151 72 6914 or Email: ICSR_CT_GPS@merckgroup.com.  
The following items should be specified:  
1. Protocol Number and/or Title 2. EMD Serono assigned Study Number 3. Subject number 4. Site number/PI name
8.5.1.1 Second Malignancies A second malignancy is one unrelated to the treatment of a prior malignancy (and is **NOT** a metastasis from the initial malignancy). Second malignancies require **ONLY** routine AE reporting unless otherwise specified.  
8.5.2 Safety/Other Reporting Criteria to the Manufacturer Collaborator CTEP (rhIL-15) The NCI Cancer Therapy Evaluation Program (CTEP) is providing clinical grade recombinant human IL-15 for this study. Because CTEP is responsible for the Clinical Material and Confidential Information which it develops, CTEP must ensure that the Clinical Material and Confidential Information are used, communicated and reproduced appropriately and completely. The PI agrees to use the Clinical Material in accordance with all Federal laws and regulations that govern the use of investigational agents in clinical trials. The following will be provided to CTEP during the course of the clinical study: Additional safety and efficacy data may also be requested by CTEP to facilitate the development of the Clinical Material across CTEP supported trials.
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8.6 reporting pregnancy

All required pregnancy reports/follow-up to OSRO will be submitted to:
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. Forms and instructions can be found here: https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
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8.6.1 maternal exposure

If a patient becomes pregnant during the course of the study, the study treatment should be discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later than 24 hours of when the outcome of the Pregnancy becomes known. Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects and spontaneous miscarriages that meet serious criteria (section **8.1.2**) should be reported as SAEs.  
1. Initial FDA submission/approval, including: FDA-submitted protocol document; any FDA
comments regarding the protocol and IND submission, including correspondence regarding the IND submission safe-to-proceed notice; and, a copy of the FDA acknowledgement of the IND submission(s) stating the IND number, sponsor, title and date of submission.  
2. Documentation of initial IRB approval of the FDA-submitted protocol document and annual continuing IRB review approvals.  
3. All significant protocol amendments, including changes in study size, eligibility criteria, study design and end points.  
4. Notification of any changes in protocol status or other significant events related to the Protocol.  
5. Notification of any changes in IND status. 6. Copies of any FDA communications. 7. Copies of IND Annual Reports. 8. All IND Safety Reports submitted to the FDA per 21 CFR 312.32. Copies of all IND
Safety Reports submitted to the FDA should be forwarded electronically to CTEPSupportAE@tech-res.com (please provide protocol number in subject line).  
9. Any abstracts, manuscripts, and publications.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed up and documented. 8.6.2 Paternal Exposure Male patients should refrain from fathering a child or donating sperm during the study and for 30 days after the last dose of rhIL-15 and/ or avelumab. Pregnancy of the patient's partner is not considered to be an AE. However, the outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from the date of the first dose until four months after the last dose should, if possible, be followed up and documented.
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8.7 regulatory reporting for studies

Following notification from the investigator, CCR, the IND sponsor, will report any suspected adverse reaction that is both serious and unexpected. CCR will report an AE as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the study product and the adverse event. CCR will notify FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or under any investigator's IND) in an IND safety report of potential serious risks from clinical trials or any other source, as soon as possible, in accordance to 21 CFR Part 312.32. All serious events will be reported to the FDA at least annually in a summary format.
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9 clinical monitoring

As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring program. The CCR's program allows for confirmation of: study data, specifically data that could affect the interpretation of primary and secondary study endpoints; adherence to the protocol, regulations, ICH E6 and SOPs; and human subjects protection. This is done through independent verification of study data with source documentation focusing on:  
Informed consent process Eligibility confirmation Drug administration and accountability Adverse events monitoring
Response assessment.  
The monitoring program also extends to multi-site research when the CCR is the coordinating center. This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified by training and experience to monitor the progress of clinical trials. Personnel monitoring this study will not be affiliated in any way with the trial conduct.
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10 statistical considerations 10.1 statistical

Primary Endpoint(s):  
o Maximum tolerated dose (MTD) of rhIL-15 administered intravenously for 5 days in combination with avelumab for up to 6 cycles o Frequency (number and percentage) of treatment-emergent AEs Secondary Endpoint(s):
o Overall response rate (including CR and PR)
o Overall response rate in patients with ≥50% PD-L1-expressing tumor cells o Duration of response o Progression-free, event-free, and overall survival
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10.2 sample size determination

The MTD will be based on the assessment of DLT during the first cycle of treatment and will be defined as the dose level at which less than one-third of patients (0 of 3 or 0-1/6 patients) treated experience a DLT, with the next higher dose level demonstrating one-third or a greater number of patients (≥ 2-3 or ≥ 2-6 patients) having a DLT. If a subject did not experience a DLT and did not finish one cycle of treatment (28 days) he or she will not be evaluable for determination of the MTD and would be replaced in the dose level. An additional 3 to 6 patients will be enrolled at the MTD, so that a total of 9 patients will be treated at this dose. Using this dose-escalation scheme the probability of escalating to the next dose level will be based on the true rate of DLT at the current doses given by the following table (each group will be considered independently of the other); Thus, if the true underlying proportion of DLTs is 50% at the current dose there is a 17% probability of escalating to the next dose.  
| True toxicity at a given dose   | 10%   | 20%   | 30%   | 40%   | 50%   | 60%   |
|---------------------------------|-------|-------|-------|-------|-------|-------|
| Probability of escalating       | 0.91  | 0.71  | 0.49  | 0.31  | 0.17  | 0.08  |  
If all four dose levels are evaluated with 6 patients per dose level and 9 total patients at the MTD, a maximum of 27 evaluable patients will be enrolled. Similarly, if all dose levels are evaluated with 3 patients per dose level and 9 total patients at the MTD, the minimum number of evaluable patients required will be 18. To account of unevaluable patients, accrual ceiling will be set at 30. It is expected that the accrual can be completed in 24 months. A maximum of 30 patients will be enrolled over 24 months, at a rate of 1-2 patients per month.
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10.3 population for analysis

10.3.1 Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first treatment with rhIL-15 and avelumab. 10.3.2 Evaluable for objective response: Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated above, Section 6.3. (NOTE: Patients who exhibit objective disease progression prior to the end of Cycle 1 will also be considered evaluable.) 10.3.3 Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease reevaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.
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10.4 statistical analyses 10.4.1 general

The response rate will be determined and reported along with a 95% Agresti-Coull confidence interval (54). Other time-to-event outcomes will be reported using Kaplan-Meier curves. 10.4.2 Analysis of the Primary Endpoints Safety summaries will include summaries in the form of tables and listings. Reports will include the frequency (number and percentage) of treatment emergent AEs grouped by severity of the AE (per CTCAE, v5.0) and by relationship to study drug (e.g., either rhIL-15, avelumab, or both). Laboratory shift tables containing counts and percentages will be prepared by treatment assignment, laboratory parameter, and time. Summary tables will be prepared for each laboratory parameter. Figures of changes in laboratory parameters over time will be generated. Results of vital sign assessments, ECGs, and physical exams will be tabulated and summarized. 10.4.3 Analysis of the Secondary Endpoints The duration of response (DOR; beginning at the date clinical response is first identified), overall survival (OS), event free survival (EFS), and progression free survival (PFS) will be estimated using Kaplan-Meier curves with appropriate confidence intervals reported. Every report of response rates and time to progression should contain all patients included in the study. For the response calculation, the report should contain at least a section with all eligible patients. Another section of the report may detail the response rate for evaluable patients only. However, a response rate analysis based on a subset of patients must explain which patients were excluded and for which reasons. 95% confidence limits will be given.  
10.4.4 Safety Analyses The type, grade and frequency of toxicities will be reported. 10.4.5 Baseline Descriptive Statistics Descriptive statistics (including means, standard deviations, and medians for continuous variables and proportions and CIs for discrete variables) will be used to summarize data as appropriate. 10.4.6 Planned Interim Analyses No interim analyses are planned because of the single stage design of the trial. 10.4.7 Sub-Group Analyses All secondary endpoints will be analyzed and reported separately according to the presenting diagnosis (PTCL-NOS, MF/SS, ALCL, or Other) and baseline PD-L1 expression (<1%, ≥1%, ≥5%, ≥10%, ≥50%). 10.4.8 Tabulation of Individual Participant Data None.
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10.4.9 exploratory analyses

The exploratory objectives such as seeking to identify potential biomarkers or T-cell clones in peripheral blood which are associated with response, will be assessed using descriptive statistics as well as non-parametric methods such as exact Wilcoxon rank sum tests. The analyses will be done without formal adjustment for multiple comparisons, but in the context of the number of tests performed.
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11 collaborative agreements 11.1 cooperative

This study will be incorporated into an existing CRADA (\#02666) between the National Cancer Institute and EMD Serono, the manufacturer of avelumab.
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11.2 material transfer agreement (mta)-

A MTA with Division of Cancer Treatment and Diagnosis (DCTD) for the IL-15 was executed on June 8, 2018 .
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12 human subjects protections 12.1

All subjects from both sexes and all racial/ethnic groups are eligible for this study if they meet the eligibility criteria outlined in the protocol and provide informed consent to protocol participation. Subjects with HIV infection will be excluded due to potential toxicity and unknown effects of rhIL-15 and avelumab on the underlying HIV infection and interference with ART. Pregnant or nursing mothers are excluded because of the potential teratogenic effects of therapy. We expect men and women to be equally represented among the enrolled patients.
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12.2 participation of children

Subjects under the age of 18 are excluded because recurrent T-cell lymphomas are rare in young patients, and the inclusion of an occasional younger patient will not provide generalizable information that would justify their inclusion on this study. Additionally, because no dosing or adverse event data are currently available on the use of rhIL-15 in combination with avelumab in patients <18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.
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12.3 participation of subjects unable

Adults who are unable to consent are excluded from enrolling in this study. However, re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation (Section **12.5**) and because overall survival is one of the secondary outcomes, all subjects ≥ age 18 will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course
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of the study.

Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for evaluation to assess ongoing capacity of the subjects and to identify a LAR, as needed. Please see Section **12.6** for consent procedure.
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12.4 evaluation of benefits and

The potential benefit of adding rhIL-15 to avelumab in treatment of mature T-cell malignancies is unknown, but single-agent immune checkpoint inhibitors have shown activity as outlined in Section **1.2.5**. There is a risk of additive toxicity of the two drugs, in particular infusion reactions (including chills, fever, hypotension, headache, flushing, dizziness), fatigue, rash, Liver Function Test (LFT) abnormalities, and cytopenias. Since fevers, rigors, lymphopenia, and LFT elevations occurred only during IL-15 infusion in the continuous IV trial, and since avelumab is not given concomitantly, these toxicities are not expected to overlap. Avelumab manufacturer recommendations for discontinuing therapy will be followed, including for grade 3-4 LFT elevations. Fatigue and rash are potential overlapping toxicities, and both will be monitored closely. It has recently been shown that PD-1 may act as a haplo-insufficient tumor suppressor of T lymphocytes, with PD-1/PD-L1 checkpoint blockade causing transient lymphoproliferation in ITK-SYK transgenic mice(21). Clinically, three patients with ATLL treated with the anti-PD-1 antibody Nivolumab had rapid disease progression shortly after receiving the first dose ("rapid progression"). Additionally, four patients with AITL have experienced rapid progression after 13 doses of nivolumab.(19) Patients with ATLL, AITL, and PTCL-TFH (which has a similar phenotype to AITL) are therefore excluded from this Phase 1 trial. Additionally, growth of malignant cells in enteropathy-associated T-cell lymphoma (EATL) is dependent on epithelial cellderived IL-15. Patients with EATL are therefore also excluded. There are ongoing trials of different immune checkpoint inhibitors in patients with other forms of T cell lymphoma with no reports of rapid progression. Study team will note any rapid and unexpected disease progression observed in patients on the trial as described in Section **6.3.4**. In addition to the tumor cells, PD-L1 is also expressed on normal immune cells. Since avelumab has potential for *in vivo* ADCC activity, immune cell subsets may change. However, when 123 different immune cell subsets were analyzed in 28 patients with solid tumors who received avelumab during a Phase I trial, there were no changes at any of the time points in any of the 123 subsets tested regardless of their PD-L1 expression before and during treatment(55). PBMC samples were obtained before avelumab, and after 1, 3, and 9 doses of the drug. A limited number of immune cell subsets will also be tested in our trial, both in PBMCs and optional tissue biopsies.
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12.5 risks/benefits analysis

A significant number of T-cell malignancies express PD-L1, and since the anti-PD-L1 antibody avelumab has shown ADCC activity *in vitro*, agents that may enhance ADCC by increasing number and activity of Fc-binding effector cells - such as rhIL15 - could improve efficacy of avelumab in these diseases. Although the clinical benefit of these drug(s) has not yet been established, the intent of offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully monitored for tumor response and symptom relief in addition to safety and tolerability.  
There have been no studies of IL-15 in patients with HIV on or off ART. Two non-human primates with SIV who were not on ART and received rhIL-15 on Study 2078-10804 both died, while subsequent animals who received viral suppression were seemingly unaffected. rhIL-15 may therefore contribute to morbidity/mortality in patients with a detectable viral load. Since potential toxicity of IL-15 and avelumab may interfere with ART adherence and optimal viral suppression, patients with HIV may be exposed to additional toxicity for unknown potential benefit of IL-15 and should therefore be excluded in this study.
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12.5.1 risks related to ct

CT and PET scans often use a contrast agent. There is a small risk of having a reaction to the contrast and most often include nausea, pain in the vein where the contrast is given, headache, metallic and/ or bitter taste in the mouth and a warm, flushing feeling. Rarely, some people have more severe allergic reactions to the contrast which may include skins rashes, shortness of breath, wheezing or low blood pressure.  
12.5.2 Risks from Radiation Exposure The procedures for performing the chest CT and 18F-FDG PET/CT scans will follow clinical policies, no special procedures apply to these additional assessments for research purposes. In summary, subjects may receive additional radiation exposure from up to six (6) additional CT
scans of the neck, chest, abdomen, and pelvis, and three (3) additional 18F-FDG PET/CT scans.  
The total additional radiation dose for research purposes will be approximately 11.4 rem.
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12.6 consent process and documentation

The informed consent document will be provided as a physical or electronic document to the participant or consent designee(s) as applicable for review prior to consenting. A designated study investigator will carefully explain the procedures and tests involved in this study, and the associated risks, discomforts and benefits. In order to minimize potential coercion, as much time as is needed to review the document will be given, including an opportunity to discuss it with friends, family members and/or other advisors, and to ask questions of any designated study investigator. A signed informed consent document will be obtained prior to entry onto the study. The initial consent process as well as re-consent, when required, may take place in person or remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with policy, including HRPP Policy 303) per discretion of the designated study investigator and with the agreement of the participant/consent designee(s). Whether in person or remote, the privacy of the subject will be maintained. Consenting investigators (and participant/consent designee, when in person) will be located in a private area (e.g., clinic consult room). When consent is conducted remotely, the participant/consent designee will be informed of the private nature of the discussion and will be encouraged to relocate to a more private setting if needed. Consent will be documented with required signatures on the physical document (which includes the printout of an electronic document sent to participant) or as described below, with a manual (non-electronic signature) on the electronic document. When required, witness signature will be obtained similarly as described for the investigator and participant.
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manual (non-electronic) signature on electronic

When a manual signature on an electronic document is used for the documentation of consent at the NIH Clinical Center, this study will use the following to obtain the required signatures:  
Adobe platform (which is not 21 CFR Part 11 compliant); or, iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the approved consent document on screens at their respective locations (if remote consent); the same screen may be used when in the same location but is not required. Both the investigator and the participant will sign the document using a finger, stylus or mouse. Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process for additional information (e.g., verification of participant identity when obtaining consent remotely) found **here**.  
12.6.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation For participants addressed in Section **12.3**, an LAR will be identified consistent with Policy 403 and informed consent obtained from the LAR, as described in Section 12.6.
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13 regulatory and operational considerations

This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. Written notification, documenting the reason for study suspension or termination, will be provided by the suspending or terminating party to study participants, investigator, the Investigational New Drug (IND) sponsor and regulatory authorities. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension. Study participants will be contacted, as applicable, and be informed of changes to study visit schedule. Circumstances that may warrant termination or suspension include, but are not limited to:  
Determination of unexpected, significant, or unacceptable risk to participants Demonstration of efficacy that would warrant stopping Insufficient compliance to protocol requirements Data that are not sufficiently complete and/or evaluable Determination that the primary endpoint has been met Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
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13.2 quality assurance and quality

Each clinical site will perform internal quality management of study conduct, data and biological specimen collection, documentation and completion. An individualized quality management plan will be developed to describe a site's quality management. Quality control (QC) procedures will be implemented beginning with the data entry system and data QC checks that will be run on the database will be generated. Any missing data or data anomalies will be communicated to the site(s) for clarification/resolution.  
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is conducted and data are generated and biological specimens are collected, documented (recorded), and reported in compliance with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). The investigational site will provide direct access to all trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities.
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13.3 conflict of interest policy

The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be required to have such conflicts managed in a way that is appropriate to their participation in the design and conduct of this trial. The study leadership in conjunction with the National Cancer Institute has established policies and procedures for all study group members to disclose all conflicts of interest and will establish a mechanism for the management of all reported dualities of interest.
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13.4 confidentiality and privacy

Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological samples and genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, documentation, data, and all other information generated will be held in strict confidence. No information concerning the study or the data will be released to any unauthorized third party without prior written approval of the sponsor. All research activities will be conducted in as private a setting as possible. The study monitor, other authorized representatives of the sponsor, representatives of the Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and records required to be maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site will permit access to such records. The study participant's contact information will be securely stored at each clinical site for internal use during the study. At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be d at the NCI CCR This will not include the participant's contact or identifying information. Rather, individual participants and their research data will be identified by a unique study identification number. The study data entry and study management systems used by clinical sites and by NCI CCR research staff will be secured and password protected. At the end of the study, all study databases will be archived at the NCI CCR. To further protect the privacy of study participants, a Certificate of Confidentiality has been issued by the National Institutes of Health (NIH). This certificate protects identifiable research information from forced disclosure. It allows the investigator and others who have access to research records to refuse to disclose identifying information on research participation in any civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level. By protecting researchers and institutions from being compelled to disclose information that would identify research participants, Certificates of Confidentiality help achieve the research objectives and promote participation in studies by helping assure confidentiality and privacy to participants.
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14 pharmaceutical information

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

14.1.1 Source/ Acquisition and Accountability rhIL-15 is an investigational agent supplied to investigators by the Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis (DCTD), NCI. 14.1.2 Drug Summary Information  
14.1.2.1 Chemical Name or Amino Acid Sequence The 115 amino acid coding sequence of the pET28b/IL-15 cistron is as follows:
MNWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDA SIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS
14.1.2.2 Other Names Recombinant Human Interleukin -15; Recombinant Human IL-15; rhIL-15 14.1.2.3 Classification Recombinant human interleukin-15 (rhIL-15) is a cytokine of the 4-alpha helix bundle family of cytokines whose mature form consists of 115 amino acids. It has two cystine disulfide cross linkages at positions Cys 42-Cys 88 and Cys 35-Cys 85.  
14.1.2.4 Molecular Weight (M.W.)
12,898.8 Daltons
14.1.2.5 Mode of Action IL-15 interacts with a private receptor subunit IL- 15R alpha as well as the IL-2/IL-15R beta chain shared with IL-2 and the common gamma chain shared with IL-2, IL-4, IL-7, IL-9 and IL-21. IL-15 shares a number of biological activities with IL-2, including stimulation of the proliferation of activated CD4+, CD8+ as well as gamma-delta subsets of T cells. IL-15 also stimulates the proliferation of NK cells and acts as a co-stimulator with IL-12 to facilitate the production of Interferon-gamma and TNF-alpha.
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14.1.3 how supplied

IL-15 is manufactured by the Biopharmaceutical Development Program (BDP) and distributed by the Pharmaceutical Management Branch (PMB) ant CTEP. IL-15 is supplied as a sterile, frozen liquid product in single use vials containing no preservatives. Currently, IL-15 is supplied as 147 mcg / 0.3 mL (490 mcg/mL) in a 3 mL glass vial. The IL-15 is formulated in 25 mM sodium phosphate containing 0.5 M sodium chloride at a pH of 7.4. NOTE: IL-15 vial content may vary between lots and protocols. Use caution and consult the protocol document for specific preparation instructions when preparing each dose. 14.1.4 Preparation Vials of frozen IL-15 should be thawed at ambient room temperature. Upon thawing, the solution should be clear and colorless with no evidence of particulates or foreign matter. The infusion solutions should be mixed in a PVC bag. 14.1.5 Storage IL-15 vials should be stores at or below (-70°C).  
14.1.6 Stability
14.1.6.1 Vials Stability studies of the intact vials are ongoing.  
14.1.6.2 Prepared Infusion The rhIL-15 infusion solution is stable at a concentration of 1 mcg/mL with 0.1% HSA for 4 hours at controlled room temperature (15°C–30°C) prior to initiation of the 24-hour infusion or 24 hours at 2-8°C prior to initiation of the 24-hour infusion. This stability information was previously documented by the Biopharmaceutical Development Program (BDP) of Leidos Biomedical Research, Inc., the drug manufacturer.
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14.1.7 administration

For all dose levels, the dose of rhIL-15 will be diluted in the appropriate volume of 0.1% human serum albumin (HSA) in 5% dextrose in water, USP (D5W) to reach a final rhIL-15 concentration of 1 mcg/mL (see Dilution instructions, **APPENDIX D**). The rhIL-15 infusion will be administered to the patient by continuous intravenous infusion (civ) at a dose in mcg/kg/day determined by the dose level at which the patient is enrolled. Each bag (total 5 bags over 5 days) will be infused over 24 hours using a portable ambulatory pump on the inpatient unit (cycle 1) or in the outpatient setting (cycles 2-6, if deemed appropriate by the PI) for a total of 120 hours. Bags must be changed every 24 hours. Treatment with rhIL-15 will begin within 4 hours of preparation of the infusion bag and the infusion must be completed within 24 hours from the time drug administration begins. Otherwise a new infusion bag must be prepared to complete administration of the remaining dose. See **Table 4** for Drug Regimen, and Section **3.2.1** for supportive care measures.
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14.1.8 toxicity

The Comprehensive Adverse Event and Potential Risks List (CAEPRs) for Recombinant Human IL-15 provides a single list of reported and/or potential adverse events (AE) associated with the agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. The CAEPR does not provide frequency data; refer to the Investigator's Brochure for this information. Below is the CAEPR for Recombinant Human IL-15.  
| Version 1.3, January 2, 2019*                                                                                                                                                                                                                       |                                                              |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|
| Adverse Events with Possible                                                                                                                                                                                                                        |                                                              |
| Relationship to Recombinant Human IL-15 (CTCAE 5.0 Term)                                                                                                                                                                                            | Specific Protocol Exceptions to  Expedited Reporting (SPEER) |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia                                                                                                                                                                                                         | Anemia (Gr 2)                                                |
| Bone marrow hypocellular CARDIAC DISORDERS Sinus tachycardia                                                                                                                                                                                        | Sinus tachycardia (Gr 2)                                     |
| GASTROINTESTINAL DISORDERS Abdominal pain Diarrhea Nausea                                                                                                                                                                                           | Nausea (Gr 2)                                                |
| Vomiting                                                                                                                                                                                                                                            | Vomiting (Gr 2)                                              |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Chills                                                                                                                                                                                         | Chills (Gr 2)                                                |
| Edema limbs Fatigue                                                                                                                                                                                                                                 | Fatigue (Gr 2)                                               |
| Fever                                                                                                                                                                                                                                               | Fever (Gr 2)                                                 |
| Injection site reaction INFECTIONS AND INFESTATIONS Sepsis INVESTIGATIONS Alanine aminotransferase increased Aspartate aminotransferase increased Blood bilirubin increased Creatinine increased Lymphocyte count decreased                         | Lymphocyte count decreased (Gr 2)                            |
| Lymphocyte count increased Neutrophil count decreased Platelet count decreased White blood cell decreased METABOLISM AND NUTRITION DISORDERS Hypoalbuminemia Hypophosphatemia                                                                       | Hypophosphatemia (Gr 2)                                      |
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Generalized muscle weakness NERVOUS SYSTEM DISORDERS Dizziness Headache RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Dyspnea SKIN AND SUBCUTANEOUS TISSUE DISORDERS Dry skin Erythema multiforme | Erythema multiforme (Gr 2)                                   |
| Skin and subcutaneous tissue disorders - Other (rash) VASCULAR DISORDERS                                                                                                                                                                            |                                                              |  
| Adverse Events with Possible                             |                                                              |
|----------------------------------------------------------|--------------------------------------------------------------|
| Relationship to Recombinant Human IL-15 (CTCAE 5.0 Term) | Specific Protocol Exceptions to  Expedited Reporting (SPEER) |
| Capillary leak syndrome Hypertension                     | Hypertension (Gr 2)                                          |
| Hypotension                                              | Hypotension (Gr 2)                                           |  
*This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail Adverse events reported on Recombinant Human IL-15 trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that Recombinant Human IL-15 caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia CARDIAC DISORDERS - Atrial fibrillation; Chest pain - cardiac; Palpitations; Pericardial effusion; Pericardial tamponade; Sinus bradycardia; Ventricular tachycardia GASTROINTESTINAL DISORDERS - Ascites; Constipation; Duodenal hemorrhage; Gastritis; Gastrointestinal disorders - Other (increased appetite); Ileus; Mucositis oral; Pancreatitis; Visceral arterial ischemia GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Infusion site extravasation; Multi-organ failure; Pain IMMUNE SYSTEM DISORDERS - Autoimmune disorder INFECTIONS AND INFESTATIONS - Tooth infection; Upper respiratory infection; Urinary tract infection INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Infusion related reaction INVESTIGATIONS - Alkaline phosphatase increased; Cardiac troponin I increased; Electrocardiogram QT corrected interval prolonged; GGT increased; INR increased; Lipase increased; Serum amylase increased; Weight gain; Weight loss METABOLISM AND NUTRITION DISORDERS - Anorexia; Dehydration; Hyperkalemia; Hypocalcemia; Hypokalemia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone pain; Muscle weakness upper limb; Myalgia; Pain in extremity NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain NERVOUS SYSTEM DISORDERS - Dysgeusia; Peripheral sensory neuropathy; Presyncope; Vasovagal reaction PSYCHIATRIC DISORDERS - Anxiety; Psychosis REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Genital edema RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; Bronchopulmonary hemorrhage; Cough; Hypoxia; Laryngeal inflammation; Pleural effusion; Pneumonitis; Pulmonary edema; Wheezing SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythroderma; Palmar-plantar erythrodysesthesia syndrome; Pruritus; Rash acneiform; Skin and subcutaneous tissue disorders - Other (skin plaques) VASCULAR DISORDERS - Hot flashes NOTE: Recombinant Human IL-15 in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.
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14.1.9 ctep information 14.1.9.1 agent

NCI-supplied agents may be requested by eligible participating Investigators (or their authorized designee). The CTEP-assigned protocol number must be used for ordering all CTEP-supplied investigational agents. The eligible participating investigators must be registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are several participating investigators, CTEP-supplied investigational agents for the study should be ordered under the name of one lead participating investigator at that institution.  
IL-15 may be order from PMB when a patient is being worked up for the study.  
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application. Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account and the maintenance of an "active" account status, a "current" password, and active person registration status. For questions about drug orders, transfers, returns, or accountability, call or email PMB any time. Refer to the PMB's website for specific policies and guidelines related to agent management.
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14.1.9.1.1 agent inventory records

The investigator, or a responsible party designated by the investigator, must maintain a careful record of the receipt, dispensing and final disposition of all agents received from the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP forms page. Store and maintain separate NCI Investigational Agent Accountability Records for each agent, strength, formulation and ordering investigator on this protocol.
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14.1.9.2 investigator brochure availability

The current versions of the IBs for the agents will be accessible to site investigators and research staff through the PMB OAOP application. Access to OAOP requires the establishment of a CTEP IAM account and the maintenance of an "active" account status, a "current" password and active person registration status. Questions about IB access may be directed to the PMB IB Coordinator via email.  
14.1.9.3 Useful Links and Contacts CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/  
NCI CTEP Person Registration: RCRHelpDesk@nih.gov PMB policies and guidelines:
http://ctep.cancer.gov/branches/pmb/agent_management.htm PMB Online Agent Order Processing (OAOP) application:
https://ctepcore.nci.nih.gov/OAOP
CTEP Identity and Access Management (IAM) account:
https://ctepcore.nci.nih.gov/iam/
CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov  
IB Coordinator: IBCoordinator@mail.nih.gov PMB email: PMBAfterHours@mail.nih.gov
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET)
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14.2 avelumab (nsc #799232)

14.2.1 Source / Acquisition and Accountability Investigational supplies of Avelumab will be supplied by EMD Serono for use by subjects in this clinical trial.
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14.2.2 toxicity

Please refer to the IB for detailed toxicity information. In brief, in clinical studies thus far, most observed adverse events were either in line with those expected in patients with advanced tumors or with similar class effects of mAb blocking the PD-1/PD-L1 axis. Infusion-related reactions including drug hypersensitivity reactions and immune-mediated adverse reactions (immunerelated pneumonitis, immune-related colitis, immune-related hepatitis, immune-related endocrinopathies (thyroid disorders, adrenal insufficiency, new onset type I diabetes mellitus, pituitary disorders), immune-related nephritis and renal dysfunction and other immune-related AEs (myositis, myocarditis, Guillain-Barré syndrome, uveitis, pancreatitis and myasthenia gravis/myasthenic syndrome) have been identified as important risks for avelumab. Detailed guidelines for the management of immune-related adverse events and infusion-related reactions have been incorporated in this study protocol. The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. Frequency is provided based on 1738 patients. Below is the CAEPR for Avelumab:
Version 2.0, April 23, 20191  
  
| Adverse Events with Possible   Relationship to Avelumab  (CTCAE 5.0 Term) [n= 1738]                                                                                                                 |                     |                        |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|------------------------|
| Likely (>20%)                                                                                                                                                                                       | Less Likely (<=20%) | Rare but Serious (<3%) |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia CARDIAC DISORDERS Myocarditis2 Pericarditis2 ENDOCRINE DISORDERS Adrenal insufficiency2 Hyperthyroidism2 Hypophysitis2 Hypopituitarism2 Hypothyroidism2 |                     |                        |  
Adverse Events with Possible  
Relationship to Avelumab  
(CTCAE 5.0 Term)  
[n= 1738]  
| [n= 1738]                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                     |                        |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|------------------------|
| Likely (>20%)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Less Likely (<=20%) | Rare but Serious (<3%) |
| EYE DISORDERS                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Uveitis2            |                        |
| GASTROINTESTINAL DISORDERS Abdominal pain                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Colitis2            |                        |
| Diarrhea Nausea Pancreatitis2 Vomiting                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                     |                        |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Chills Fatigue Fever Flu like symptoms3 HEPATOBILIARY DISORDERS Hepatic failure2 Hepatobiliary disorders - Other (autoimmune hepatitis,  immune-related hepatitis)2 IMMUNE SYSTEM DISORDERS Autoimmune disorder2 Cytokine release syndrome3 Immune system disorders - Other (sarcoidosis)2 INFECTION AND INFESTATIONS  Infection4 INJURY, POISONING AND PROCEDURAL COMPLICATIONS Infusion related reaction3 INVESTIGATIONS Alanine aminotransferase  increased Alkaline phosphatase  increased Aspartate aminotransferase  increased Blood bilirubin increased CPK increased Creatinine increased GGT increased Lipase increased Lymphocyte count decreased Neutrophil count decreased Platelet count decreased Serum amylase increased |                     |                        |  
| Relationship to Avelumab  (CTCAE 5.0 Term) [n= 1738]                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                     |                        |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|------------------------|
| Likely (>20%)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Less Likely (<=20%) | Rare but Serious (<3%) |
| Thyroid stimulating hormone  increased                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                     |                        |
| METABOLISM AND NUTRITION DISORDERS Anorexia Hyperglycemia2 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia2 Generalized muscle weakness Muscle cramp Myalgia2 Myositis2 Pain in extremity NERVOUS SYSTEM DISORDERS Encephalopathy2 Guillian-Barre syndrome2 Myasthenia gravis2 Nervous system disorders - Other (non-infectious  encephalitis)2 Nervous system disorders - Other (non-infectious  meningitis)2 Peripheral motor neuropathy Peripheral sensory neuropathy2 RENAL AND URINARY DISORDERS Renal and urinary disorders - Other (immune related  nephritis)2 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough Pneumonitis2 SKIN AND SUBCUTANEOUS TISSUE DISORDERS Eczema Pruritus Rash acneiform Rash maculo-papular 1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all  Principal Investigators at the time of revision. The current version can be obtained by contacting |                     |                        |  
  
[n= 1738]
2Immune-mediated adverse reactions have been reported in patients receiving avelumab. Adverse events potentially related to avelumab may be manifestations of immune-mediated adverse events. In clinical trials, most immune-mediated adverse reactions were reversible and managed with interruptions of avelumab), administration of corticosteroids and supportive care.  
3Infusion reactions, including high-grade hypersensitivity reactions, anaphylaxis, and cytokine release syndrome, which have been observed following administration of avelumab, may manifest as fever, chills, shakes, itching,  
rash, hypertension or hypotension, or difficulty breathing during and immediately after administration of avelumab.  
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC.  
Adverse events reported on avelumab trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that avelumab caused the adverse event: CARDIAC DISORDERS - Palpitations; Sinus tachycardia EYE DISORDERS - Blurred vision; Dry eye GASTROINTESTINAL DISORDERS - Abdominal distension; Constipation; Dry mouth; Dyspepsia; Flatulence; Mucositis oral GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; Localized edema; Malaise; Non-cardiac chest pain; Pain INVESTIGATIONS - Electrocardiogram QT corrected interval prolonged; Investigations - Other (c-reactive protein increased); Weight gain; Weight loss METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypoalbuminemia; Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone pain NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (tumor flare); Tumor pain NERVOUS SYSTEM DISORDERS - Dizziness; Dysesthesia; Dysgeusia; Headache; Tremor RENAL AND URINARY DISORDERS - Proteinuria RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; Hypoxia SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis VASCULAR DISORDERS - Flushing; Hot flashes; Hypertension Note: Avelumab in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.  
14.2.3 Formulation and Preparation Avelumab drug product is a sterile, clear, and colorless concentrate for solution presented at concentration of 20 mg/mL in European Pharmacopeia (Ph. Eur.) and United States Pharmacopeia (USP) type I glass vials closed with a rubber stopper and sealed with an aluminum Flip Off® crimp seal closure. Each single-use vial contains 200 mg of avelumab as a preservative-free acetate-buffered solution (pH 5.2) containing Mannitol, and Polysorbate 20 (Tween 20). For avelumab drug product, only excipients that conform to the current Ph. Eur. and/or the current USP are used. 14.2.4 Stability and Storage Supplies must be stored in a secure, limited-access location under the storage conditions specified on the label. Receipt and dispensing of trial supplies must be recorded by an authorized person at the trial site. Supplies may not be used for any purpose other than that stated in the protocol. Avelumab drug product must be stored at 2°C to 8°C until use. Store diluted solution at room temperature up to 77°F (25°C) for no more than 8 hours from the time of dilution OR under refrigeration at 36°F to 46°F (2°C to 8°C) for no more than 24 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration. The storage condition is based on data from ongoing long term stability studies with avelumab. Avelumab drug product stored at room (23°C to 27°C) or higher temperatures for extended periods of time might be subject to degradation. Avelumab drug product must not be frozen. Rough shaking of the solution must be avoided.
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14.2.5 administration procedures

For administration in clinical trials, avelumab drug product may be diluted with 0.9% saline solution (sodium chloride injection) supplied in 250 mL infusion bags, alternatively, a 0.45% saline solution can be used if needed. The chemical and physical in-use stability for the infusion solution of avelumab in 0.45% or 0.9% saline solution has been demonstrated for a total of 24 hours at room temperature. However, from a microbiological point of view, the diluted solution should be used immediately. If not used immediately, it can be considered that the diluted product is sufficiently stable from a microbiological perspective for up to 8 hours when stored at ambient room temperature or up to 24 hours at 2°C to 8°C. The in-use storage times and conditions prior to administration are the responsibility of the user. Prior to the preparation of the dilution for final infusion, allow each vial to equilibrate to room temperature. Use a disposable syringe equipped with a needle of suitable size to remove a volume of sodium chloride solution to be replaced by avelumab from the infusion bag and discard the removed solution. Use a new disposable syringe equipped with a needle of suitable size to inject a volume of avelumab drug product identical to the discarded volume of sodium chloride solution into the infusion bag. Gently invert the mixture 10 times. Infusion bags must not be shaken, in order to avoid foaming or excessive shearing of the protein solution. The preparation must be carefully inspected as it should result in a homogeneous looking clear solution, free of visible particles. 14.2.6 Returns and Reconciliations Unused investigational products will be destroyed per routine pharmacy procedure.
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39. Gulley JL, Rajan A, Spigel DR, Iannotti N, Chandler J, Wong DJL, et al. Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial. The Lancet Oncology. 2017;18(5):599-610. 40. Kantekure K, Yang Y, Raghunath P, Schaffer A, Woetmann A, Zhang Q, et al. Expression patterns of the immunosuppressive proteins PD-1/CD279 and PD-L1/CD274 at different stages of cutaneous T-cell lymphoma/mycosis fungoides. The American Journal of dermatopathology. 2012;34(1):126-8.  
41. Wilcox RA, Feldman AL, Wada DA, Yang ZZ, Comfere NI, Dong H, et al. B7-H1 (PDL1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders. Blood.  
2009;114(10):2149-58. 42. Vranic S, Ghosh N, Kimbrough J, Bilalovic N, Bender R, Arguello D, et al. PD-L1 Status in Refractory Lymphomas. PloS one. 2016;11(11):e0166266. 43. Atsaves V, Tsesmetzis N, Chioureas D, Kis L, Leventaki V, Drakos E, et al. PD-L1 is commonly expressed and transcriptionally regulated by STAT3 and MYC in ALK-negative anaplastic large-cell lymphoma. Leukemia. 2017;31:1633. 44. Choi J, Goh G, Walradt T, Hong BS, Bunick CG, Chen K, et al. Genomic landscape of cutaneous T cell lymphoma. Nature genetics. 2015;47(9):1011-9. 45. da Silva Almeida AC, Abate F, Khiabanian H, Martinez-Escala E, Guitart J, Tensen CP, et al. The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome. Nature genetics. 2015;47(12):1465-70. 46. Kataoka K, Nagata Y, Kitanaka A, Shiraishi Y, Shimamura T, Yasunaga J, et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nature genetics. 2015;47(11):1304-15. 47. Vaque JP, Gomez-Lopez G, Monsalvez V, Varela I, Martinez N, Perez C, et al. PLCG1 mutations in cutaneous T-cell lymphomas. Blood. 2014;123(13):2034-43. 48. Wang L, Ni X, Covington KR, Yang BY, Shiu J, Zhang X, et al. Genomic profiling of Sezary syndrome identifies alterations of key T cell signaling and differentiation genes. Nature genetics. 2015;47(12):1426-34. 49. Jochems C, Tritsch SR, Pellom ST, Su Z, Soon-Shiong P, Wong HC, et al. Analyses of functions of an anti-PD-L1/TGFbetaR2 bispecific fusion protein (M7824). Oncotarget. 2017;8(43):75217-31. 50. Anand K, Ensor J, Pingali SR, Hwu P, Duvic M, Chiang S, et al. T-cell lymphoma secondary to checkpoint inhibitor therapy. J ImmunoTher Cancer. 2020;8(1):e000104.  
51. Ratner L, Waldmann TA, Janakiram M, Brammer JE. Rapid Progression of Adult T-Cell Leukemia–Lymphoma after PD-1 Inhibitor Therapy. New England Journal of Medicine. 2018;378(20):1947-8. 52. Younes A, Hilden P, Coiffier B, Hagenbeek A, Salles G, Wilson W, et al. International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017). Annals of Oncology. 2017;28(7):1436-47. 53. Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, et al. Clinical End Points and Response Criteria in Mycosis Fungoides and Sézary Syndrome: A Consensus Statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. Journal of Clinical Oncology. 2011;29(18):2598-607. 54. Agresti A, Coull BA. Approximate Is Better than "Exact" for Interval Estimation of Binomial Proportions. The American Statistician. 1998;52(2):119-26. 55. Donahue RN, Lepone LM, Grenga I, Jochems C, Fantini M, Madan RA, et al. Analyses of the peripheral immunome following multiple administrations of avelumab, a human IgG1 anti-PD-L1 monoclonal antibody. Journal for ImmunoTherapy of Cancer. 2017;5(1):20.
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16 appendices

| ECOG Performance Status Scale      | Karnofsky Performance Scale                                                                                            |                                                            |                                                                     |
|------------------------------------|------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------|---------------------------------------------------------------------|
| Grade                              | Descriptions                                                                                                           | Percent                                                    | Description                                                         |
| 100                                | Normal, no complaints, no                                                                                              |                                                            |                                                                     |
| Normal activity. Fully active,     | evidence of disease.                                                                                                   |                                                            |                                                                     |
| 0                                  | able to carry on all pre-disease                                                                                       | Able to carry on normal activity;                          |                                                                     |
| performance without restriction.   | 90                                                                                                                     | minor signs or symptoms of  disease.                       |                                                                     |
| Symptoms, but ambulatory.          | Normal activity with effort;                                                                                           |                                                            |                                                                     |
| Restricted in physically strenuous | 80                                                                                                                     | some signs or symptoms of  disease.                        |                                                                     |
| 1                                  | activity, but ambulatory and able  to carry out work of a light or                                                     | Cares for self, unable to carry on                         |                                                                     |
| sedentary nature (e.g., light      | 70                                                                                                                     | normal activity or to do active                            |                                                                     |
| housework, office work).           | work.                                                                                                                  |                                                            |                                                                     |
| In bed <50% of the time.           | Requires occasional assistance,                                                                                        |                                                            |                                                                     |
| Ambulatory and capable of all      | 60                                                                                                                     | but is able to care for most of  his/her needs.            |                                                                     |
| 2                                  | self-care, but unable to carry out  any work activities. Up and                                                        | 50                                                         | Requires considerable assistance                                    |
| about more than 50% of waking      | and frequent medical care.                                                                                             |                                                            |                                                                     |
| hours.                             | 40                                                                                                                     | Disabled, requires special care  and assistance.           |                                                                     |
| 3                                  | In bed >50% of the time.  Capable of only limited self-care,  confined to bed or chair more  than 50% of waking hours. | 30                                                         | Severely disabled,  hospitalization indicated. Death  not imminent. |
| 100% bedridden. Completely         | 20                                                                                                                     | Very sick, hospitalization  indicated. Death not imminent. |                                                                     |
| 4                                  | disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                                           | 10                                                         | Moribund, fatal processes  progressing rapidly.                     |
| 5                                  | Dead.                                                                                                                  | 0                                                          | Dead.                                                               |
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16.1 appendix a performance status

Peripheral blood mononuclear cells (PBMCs) should be isolated by Ficoll-High-Paque Density Gradient Centrifugation.  
The viable cells should be viably frozen and stored in liquid nitrogen. The ADCC assay will be performed on the same occasion for all samples of a given patient.  
Vials of frozen cells will be thawed using standard procedures 18 hours before the assay in accordance with our experience with normal donors.  
1.5 million of patient's PBMCs obtained before and on day 15 following IL-15 injection will be tested in aliquots as follows:
o Tested alone o Tested with untreated PD-L1-expressing Raji cells and with PD-L1-expressing Raji cells coated with avelumab for 5 hours.  
o In addition, we may utilize an ATL cell line in addition to Raji cells. These cell populations will be stained with CD107, CD3, CD56 and CD94.  
16.3 APPENDIX C: GLOBAL RESPONSE SCORE AND DEFINITIONS OF RESPONSE IN SKIN,
LYMPH NODES, VISCERA, AND B**LOOD**  
| Global Response Score                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                             |                         |                                           |       |         |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------|-------------------------|-------------------------------------------|-------|---------|
| Global Score                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Definition                                                                                  | Skin                    | Nodes                                     | Blood | Viscera |
| CR                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Complete disappearance of all                                                               | CR                      | All categories have CR/NI                 |       |         |
| clinical evidence of disease                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                             |                         |                                           |       |         |
| PR                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Regression of measurable                                                                    | CR                      | All categories do not have a CR/NI and no |       |         |
| disease                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | category has a PD                                                                           |                         |                                           |       |         |
| PR                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | No category has a PD and if any category  involved at baseline at least one has a CR  or PR |                         |                                           |       |         |
| SD                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Failure to attain CR, PR, or PD                                                             | PR                      | No category has a PD and if any category  |       |         |
| representative of all disease                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | involved at baseline, no CR or PR in any                                                    |                         |                                           |       |         |
| SD                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | CR/NI, PR, SD in any category and no  category has a PD                                     |                         |                                           |       |         |
| PD                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Progressive disease                                                                         | PD in any category      |                                           |       |         |
| Relapse                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Recurrence of disease in prior                                                              | Relapse in any category |                                           |       |         |
| CR                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                             |                         |                                           |       |         |
| Abbreviations: CR, complete response; NI, noninvolved; PR, partial response; PD, progressive disease;  SD, stable disease. Response in Skin Response Definition Complete response 100% clearance of skin lesions Partial response 50%-99% clearance of skin disease from baseline without new tumors (T3) in  patients with T1, T2 or T4 only skin disease Stable disease <25% increase to <50% clearance in skin disease from baseline without new  tumors (T3) in patients with T1, T2, or T4 only skin disease Progressive disease ≥25% increase in skin disease from baseline or New tumors (T3) in patients with T1, T2, or T4 only skin disease or Loss of response: in those with complete or partial response, increase of skin  score of greater than the sum of nadir plus 50% baseline score Relapse Any disease recurrence in those with complete response Notes: Percentages refer to mSWAT score. |                                                                                             |                         |                                           |       |         |  
Notes: Percentages refer to mSWAT score. A biopsy of normal appearing skin is unnecessary to assign a complete response. However, a skin biopsy should be performed of a representative area of the skin if there is any question of residual disease (persistent erythema or pigmentary change) where otherwise a complete response would exist. If histologic features are suspicious or suggestive of mycosis fungoides/Sézary syndrome, the response should be considered a partial response only.  
| Response in Lymph Nodes                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                        |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Response                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Definition                                                                                                                                                                                                                                                                                                                                                             |
| CR                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | All lymph nodes are now ≤1.5 cm in greatest transverse (long axis) diameter by method  used to assess lymph nodes at baseline or biopsy negative for lymphoma; in addition,  lymph nodes that were N3 classification and ≤1.5 cm in their long axis and >1 cm in  their short axis at baseline, must now be ≤1 cm in their short axis or biopsy negative for  lymphoma |
| PR                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Cumulative reduction ≥50% of the SPD of each abnormal lymph node at baseline and  no new lymph node >1.5 cm in the diameter of the long axis or >1.0 cm in the diameter  of the short axis if the long axis is 1-1.5 cm diameter                                                                                                                                       |
| SD                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Fails to attain the criteria for CR, PR, and PD                                                                                                                                                                                                                                                                                                                        |
| PD                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | >50% increase in SPD from baseline of lymph nodes OR Any new node >1.5cm in the long axis or >1cm in the short axis if 1-1.5 cm in the long  axis that is proven to be N3 histologically OR Loss of response: >50% increase from nadir in SPD of lymph nodes in those with PR  (whichever occurs first)                                                                |
| Relapse                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Any new lymph node >1.5 cm in the long axis in those with CR proven to be N3  histologically                                                                                                                                                                                                                                                                           |
| Abbreviations: CR, complete response; PR, partial response; SPD, sum of the maximum linear  dimension (major axis) ⨉ longest perpendicular dimension (minor axis); SD, stable disease; PD,  progressive disease. Response in Viscera Response Definition CR Liver or spleen or any organ considered involved at baseline should not be enlarged on  physical exam and should be considered normal by imaging; no nodules should be  present on imaging of liver or spleen; any post treatment mass must be determined by  biopsy to be negative for lymphoma PR >50% regression in any splenic or liver nodules, or in measurable disease (SPD) in any  organs abnormal at baseline; no increase in size of liver or spleen and no new sites of  involvement SD Fails to attain the criteria for CR, PR, and PD PD >50% increase in size (SPD) of any organs involved at baseline OR New organ involvement OR Loss of response: >50% increase from nadir in the size (SPD) of any previous organ  involvement in those with PR (whichever occurs first) Relapse New organ involvement in those with CR Abbreviations: CR, complete response; PR, partial response; SPD, sum of the maximum linear  dimension (major axis) ⨉ longest perpendicular dimension (minor axis); SD, stable disease; PD,  progressive disease. |                                                                                                                                                                                                                                                                                                                                                                        |  
| Response in Blood*                                                                                                                                                   |                                                                                                                                                                                                                             |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Response                                                                                                                                                             | Definition                                                                                                                                                                                                                  |
| CR†                                                                                                                                                                  | B0                                                                                                                                                                                                                          |
| PR‡                                                                                                                                                                  | >50% decrease in quantitative measurements of blood tumor burden from baseline in  those with high tumor burden at baseline (B2)                                                                                            |
| SD                                                                                                                                                                   | Fails to attain the criteria for CR, PR, and PD                                                                                                                                                                             |
| PD§                                                                                                                                                                  | B0 to B2 or > 50% increase from baseline and at least 5,000 neoplastic cells/μL or Loss of response: in those with PR who were originally B2 at baseline, > 50% increase  from nadir and at least 5,000 neoplastic cells/μL |
| Relapse                                                                                                                                                              | Increase of neoplastic blood lymphocytes to ≥ B1 in those with CR                                                                                                                                                           |
| Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive  disease. *  As determined by absolute number of neoplastic cells/μL |                                                                                                                                                                                                                             |  
CR† B0  
PR‡ >50% decrease in quantitative measurements of blood tumor burden from baseline in  
those with high tumor burden at baseline (B2)  
SD Fails to attain the criteria for CR, PR, and PD  
PD§ B0 to B2 or  
> 50% increase from baseline and at least 5,000 neoplastic cells/μL or Loss of response: in those with PR who were originally B2 at baseline, > 50% increase from nadir and at least 5,000 neoplastic cells/μL  
Relapse Increase of neoplastic blood lymphocytes to ≥ B1 in those with CR  
Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive  
disease.  
* As determined by absolute number of neoplastic cells/μL  
† If a bone marrow biopsy was performed at baseline and determined to unequivocally be indicative of lymphomatous involvement, then to confirm a global CR where blood assessment now meets criteria  
for B0, a repeat bone marrow biopsy must show no residual disease or the response should be  
considered a PR only.  
‡ There is no PR in those with B1 disease at baseline as the difference within the range of neoplastic  
cells that define B1 is not considered significant and should not affect determination of global objective response. § Whichever occurs first
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16.4 appendix d il-15 dilution

All dose preparations will be performed in a laminar flow hood in compliance with all legal requirements and in accordance with guidelines of recognized organizations. 0.1% human serum albumin (HSA) in 5% dextrose in water, USP (D5W), should be used for the dilutions listed below. Please note: The dosing examples listed below are for the 147 mcg/0.3 mL in a 3mL vial size and dilution ONLY. The following dosing chart may be used as a reference, but doses should always be re-calculated at the time of preparation. In the future, different concentrations of IL-15 may be available and doses and dilutions will need to be recalculated.
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dose level 1 (1 mcg/kg)

To prepare an IL-15 dose for Dose Level 1 (1 mcg/kg):  
1. Thaw vial(s) of IL-15, 147 mcg/0.3 **mL (490 mcg/mL)** at room temperature. 2. Using a 27-gauge needle, slowly draw up the required dose in a 1 mL syringe. Doses should be rounded to the nearest 0.01 mL.  
3. Add the calculated volume of diluted IL-15 to 0.1% HSA in D5W in a PVC or polyolefin bag.  
4. Label the bag with a 4-hour beyond-use date. The infusion may be started within 4 hours at room temperature, or within 24 hours if bag was kept at 2-8°C. The infusion must be completed within 24 hours of initiation.
Administered dose = _______ kg (Patient's weight) X _______ mcg/kg (DL) = _______ mcg Prepared dose = _______ mcg (Administered dose) + 10 mcg (Overfill dose) = _______ mcg IL-15 volume = _______ mcg (Prepared dose)  490 mcg/mL (vial concentration) = _______ mL
Total infusion volume =
_______ mcg (Prepared dose)  1 mcg/mL (final infusion concentration) = _______ mL  
Diluent volume = _______ **mL (Total infusion volume) -** _______ **mL (IL-15 volume) =** _______ mL  
|                   | _______ mL (Total infusion volume) - _______ mL (IL-15 volume) = _______ mL IL-15 volume (490 mcg/ml) Diluent volume Total infusion volume  (1 mcg/ml)   |      |      |      |        |        |        |        |        |        |        |        |
|-------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------|------|------|------|--------|--------|--------|--------|--------|--------|--------|--------|
| Patient's  weight | DL1                                                                                                                                                      | DL2  | DL3  | DL4  | DL1    | DL2    | DL3    | DL4    | DL1    | DL2    | DL3    | DL4    |
| 60 kg             | 0.14                                                                                                                                                     | 0.27 | 0.39 | 0.51 | 69.86  | 129.73 | 189.61 | 249.49 | 70 ml  | 130 ml | 190 ml | 250 ml |
| 75 kg             | 0.17                                                                                                                                                     | 0.33 | 0.48 | 0.63 | 84.83  | 159.67 | 234.52 | 309.37 | 85 ml  | 160 ml | 235 ml | 310 ml |
| 90 kg             | 0.20                                                                                                                                                     | 0.39 | 0.57 | 0.76 | 99.80  | 189.61 | 279.43 | 369.24 | 100 ml | 190 ml | 280 ml | 370 ml |
| 105 kg            | 0.23                                                                                                                                                     | 0.45 | 0.66 | 0.88 | 114.77 | 219.55 | 324.32 | 429.12 | 115 ml | 220 ml | 325 ml | 430ml  |  
Dose calculation for obese patients: For patients whose body mass index (BMI) is >30 kg/m2, the factor for body weight used in calculating IL-15 doses will be determined as follows:
Corrected body weight (kg) = 30 x (height [m])2 16.5 APPENDIX E: ASSAY FOR ANTIBODIES TO RH**IL-15**  
  
  
Plates are coated with human IL-15 for 3 hours at 37°C, washed, blocked with 3% FBS
and washed again.  
A standard curve for assay quantitation and quality control is constructed using serial dilutions of a commercial affinity purified goat anti-human IL-15 that is diluted in heatinactivated normal human serum. The standard curve samples are incubated for 2 hours at 37°C and washed.  
Biotin conjugated IL-15 is added to each well, incubated 2 hours at 37°C, and the plates are washed.  
Alkaline phosphatase–conjugated streptavidin is added to each well for 2 hours at 37°C
and then washed.  
The assay is developed with the addition of diethanolamine buffer with p-Nitrophenyl Phosphatase for 1 hour at 37°C and then immediately read at 405 nm.  
To detect antibodies to human IL-15 in test samples, serum from the test subject will be assayed in duplicate at dilutions of 1/3 and 1/9 concomitantly with the standard curve samples as above and the resultant OD obtained used to quantitate the level of antibody present.