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5.4 sample storage tracking and

5.4.1 General Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples will not be sent outside NIH without appropriate approvals and/ or agreements, if required. All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are remaining at the completion of the protocol will be stored in the conditions described below. The study will remain open so long as sample or data analysis continues. Samples from consenting subjects will be stored until they are no longer of scientific value or if a subject withdraws consent for their continued use, at which time they will be destroyed. If the patient withdraws consent the participant's data will be excluded from future distributions, but data that have already been distributed for approved research use will not be able to be retrieved.  
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will be per the requirements of section **7.2.1** All samples that are noted in Section 5.1 to be analyzed by the Waldmann Laboratory will first be processed and stored at Clinical Support Laboratory, Leidos Biomedical Research, Inc. in Frederick, MD, as per Section **5.4.2**.  
5.4.2 Clinical Support Laboratory, Leidos Biomedical Research, Inc. in Frederick, MD
The Clinical Support Laboratory, Leidos Biomedical Research, Inc.-Frederick, processes and cryopreserves samples in support of IRB-approved, NCI clinical trials. The laboratory is CLIA
certified for anti-IL15 and certain cytokine measurements and all laboratory areas operate under a Quality Assurance Plan with documented Standard Operating Procedures that are reviewed annually. Laboratory personnel are assessed for competency prior to being permitted to work with patient samples. Efforts to ensure protection of patient information include:  
The laboratory is located in a controlled access building and laboratory doors are kept locked at all times. Visitors to the laboratory are required to be accompanied by laboratory staff at all times.  
Hard copy records or electronic copies of documents containing patient information are kept in the locked laboratory or other controlled access locations.  
An electronic database is used to store information related to patient samples processed by the laboratory.  
The database resides on a dedicated program server that is kept in a central, locked computer facility.
The facility is supported by two IT specialists who maintain up to date security features including virus and firewall protection.  
Program access is limited to specified computers as designated by the laboratory director. Each of these computers has a password restricted login screen.  
The database sample entry program itself is accessed through a password protected entry screen.  
Upon specimen receipt each sample is assigned a unique, sequential laboratory accession ID number. All products generated by the laboratory that will be stored either in the laboratory freezers or at a central repository facility are identified by this accession ID.  
Inventory information will be stored at the vial level and each vial will be labeled with both a sample ID and a vial sequence number.  
Vial labels do not contain any personal identifier information.  
Samples are stored inventoried in locked laboratory freezers and are routinely transferred to the NCI-Frederick repository facilities for long term storage.  
Access to stored clinical samples is restricted. Investigators establish sample collections under "Source Codes" and the investigator responsible for the collections, the protocol Principal Investigator, specifies who has access to the collection.  
Specific permissions will be required to view, input or withdraw samples from a collection. Sample withdrawal requests submitted to approved laboratory staff by anyone other than the repository source code owner are submitted to the source code owner for approval. The repository facility will also notify the Source Code holder of any submitted requests for sample withdrawal.  
It is the responsibility of the Source Code holder (the NCI Principal Investigator) to ensure that samples requested and approved for withdrawal are being used in a manner consistent with IRB approval.  
The Clinical Support Laboratory does perform testing services that may be requested by clinical investigators including, but not limited to, immunophenotyping by flow cytometry and cytokine testing using ELISA or multiplex platforms.  
When requests are submitted by the NCI investigator for shipment of samples outside of the NIH it is the policy of the laboratory to request documentation that a Material Transfer Agreement is in place that covers the specimen transfer. The laboratory does not provide patient identifier information as part of the transfer process but may, at the discretion of the NCI investigator, group samples from individual patients when that is critical to the testing process.  
The NCI investigator responsible for the sample collection is responsible for ensuring appropriate approvals and/ or agreements are in place, if required, prior to requesting the laboratory to ship samples outside of the NIH.  
5.4.3 Hematopathology Section of the Laboratory of Pathology (Tissue samples)
Archival and/or freshly collected and processed tumor tissue may be stored in the Hematopathology Section of Laboratory of Pathology until ready for planned and/or future research assays if the patient has agreed to allowing specimens to be used in future research studies. 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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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, Study Day 1, through 30 days after the last dose of study treatment. After 30 days, only adverse events which are serious and related to the study intervention need to be recorded. End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH Intramural Records Retention Schedule as applicable. Loss or destruction of data: Should we become aware that a major breach in our plan to protect subject confidentiality and trial data has occurred, this will be reported expeditiously per requirements in section **7.2.1**.  
6.1.2 Data Collection/Reporting Exceptions 6.1.2.1 Abnormal Laboratory Values An abnormal laboratory value will be considered an AE **only** if the laboratory abnormality is characterized by any of the following:  
Results in discontinuation from the study Is associated with clinical signs or symptoms Requires treatment or any other therapeutic intervention Is associated with death or another serious adverse event, including hospitalization Is judged by the Investigator to be of significant clinical impact If any abnormal laboratory result is considered clinically significant, the investigator will provide details about the action taken with respect to the test drug and about the patient's outcome.
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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 The NIH Genomic Data Sharing plan does not apply to this protocol.
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6.3 response criteria

6.3.1 Response Assessments Tumor response will be assessed radiographically after cycle 2 and 4 treatments are completed by the investigator using the Immune-Modified Response Evaluation Criteria In Solid Tumors, i.e., imRECIST criteria [88] for Immune-related Best Overall Response (irBOR, Section **6.4.1**) will be derived based on reported lesion responses at different evaluation time points from the first trial treatment administration until immune-related disease progression per irRECIST [88] according to the following rules:  
irCR = at least two radiographic determinations of CR at least 4 weeks apart and before irPD irPR = at least two radiographic determinations of PR or better at least 4 weeks apart and before irPD (and not qualifying for an irCR)
irSD = at least one radiographic assessment o f S D (or better) ≥ 6 weeks after the first trial treatment administration and before irPD (and not qualifying for irCR or irPR).  
irPD = at least two consecutive radiographic determinations of PD at least 4 weeks apart.
Only tumor assessments performed before the start of any further anti-cancer treatment will be considered in the assessment of irBOR. Immune-related Objective Response (irOR) is defined as irCR or irPR according to irRECIST from the first trial treatment administration until irPD or death due to any cause. Both irCR and irPR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for immune-related response are first met. Also, irPD must be confirmed by a second, consecutive assessment at least 4 weeks apart. Immune-related OR rate (irORR) is the proportion of subjects with irOR in the analysis set.
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6.3.2 treatment beyond radiographic progression

Recognition of unconventional response events mainly overall tumor regression after the appearance of new lesions that previously were assessed as progressive disease by RECIST criteria led to the development of Immune-related RECIST (irRECIST) [89] and the Immune-modified RECIST (imRECIST) criteria [88]. Adoption of these disease criteria have been seen to allow a better assessment of the clinical efficacy of immunotherapy by capturing additional data from patients who experienced a tumor flare or delayed impact of the evolving immune response mostly in terms of improved DCR and PFS. In order for this approach to not negatively affect patient safety certain criteria must be fulfilled to safely allow treatment beyond conventionally assessed disease progression. Patients who are treated beyond RECIST defined progressive disease must be stable performance status without evidence of clinical deterioration or have any new physiology process that requires urgent additional therapy. Patients will have a follow-up restaging assessment after the completion of their next cycle of treatment (≥ 4 weeks) to confirm their disease has not progressed further and they can safely continue treatment. Patient will be re-evaluated for response as outlined in the Study Calendar, **APPENDIX F**.  
6.3.3 Disease Parameters for RECIST criteria Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions. Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as **target lesions** and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as **non-target lesions** and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow- up.  
6.3.4 Methods for Evaluation of Measurable Disease All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. Clinical lesions: Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable. Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up should be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used, and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if possible. PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or serially performed. Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and because they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. FDG-PET: While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD
based on a new lesion.  
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDGPET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDGPET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD.  
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively d e s c r i b e d in the protocol and supported by disease-specific medical literature for the indication. However, it must be acknowledged that both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.  
Note: A 'positive' FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image.  
6.3.5 Evaluation of Target Lesions Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.  
6.3.6 Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).  
Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal *progression* of existing non-target lesions. *Unequivocal progression* should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator).  
6.3.7 Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
| Target   | Non-Target    | New     | Overall   | Best Overall Response when                        |
|----------|---------------|---------|-----------|---------------------------------------------------|
| Lesions  | Lesions       | Lesions | Response  | Confirmation is Required*                         |
| CR       | CR            | No      | CR        | >4 wks. Confirmation**                            |
| CR       | Non-CR/NonPD               | No      | PR        |                                                   |
| CR       | Not evaluated | No      | PR        |                                                   |
| PR       | Non-CR/NonPD/not  evaluated               | No      | PR        | >4 wks. Confirmation**                            |
| SD       | Non-CR/NonPD/not  evaluated               | No      | SD        | Documented at least once >4  wks. from baseline** |  
| Target   | Non-Target                                                                                                                                                                                                                                                                                                                   | New     | Overall   | Best Overall Response when   |
|----------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------|-----------|------------------------------|
| Lesions  | Lesions                                                                                                                                                                                                                                                                                                                      | Lesions | Response  | Confirmation is Required*    |
| PD       | Any                                                                                                                                                                                                                                                                                                                          | Yes or  | PD        |                              |
| No       |                                                                                                                                                                                                                                                                                                                              |         |           |                              |
| Any      | PD***                                                                                                                                                                                                                                                                                                                        | Yes or  | PD        |                              |
| No       | no prior SD, PR or CR                                                                                                                                                                                                                                                                                                        |         |           |                              |
| Any      | Any                                                                                                                                                                                                                                                                                                                          | Yes     | PD        |                              |
| *        | See RECIST 1.1 manuscript for further details on what is evidence of a new  lesion.                                                                                                                                                                                                                                          |         |           |                              |
| **       | Only for non-randomized trials with response as primary endpoint.                                                                                                                                                                                                                                                            |         |           |                              |
| ***      | In exceptional circumstances, unequivocal progression in non-target lesions  may be accepted as disease progression.                                                                                                                                                                                                         |         |           |                              |
| Note:    | Patients with a global deterioration of health status requiring discontinuation of  treatment without objective evidence of disease progression at that time should  be reported as "symptomatic deterioration." Every effort should be made to  document the objective progression even after discontinuation of treatment. |         |           |                              |  
| Non-Target Lesions                                                                                                                                                                                                                             | New Lesions   | Overall Response   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|--------------------|
| CR                                                                                                                                                                                                                                             | No            | CR                 |
| Non-CR/non-PD                                                                                                                                                                                                                                  | No            | Non-CR/non-PD*     |
| Not all evaluated                                                                                                                                                                                                                              | No            | not evaluated      |
| Unequivocal PD                                                                                                                                                                                                                                 | Yes or No     | PD                 |
| Any                                                                                                                                                                                                                                            | Yes           | PD                 |
| * 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since SD is  increasingly used as an endpoint for assessment of efficacy in some trials so to assign  this category when no lesions can be measured is not advised |               |                    |  
6.3.8 Duration of Reponses Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented. Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements.  
6.3.9 Relapse Disease (after CR)/ Progressive Disease (after PR/SD)
Relapse Disease (after CR)/ Progressive Disease (after PR/SD) requires the following:  
Appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, even if other lesions are decreasing in size. Increased FDG uptake in a previously unaffected site should only be considered relapsed or progressive disease after confirmation with other modalities. Thus, a therapeutic decision should not be made solely on the basis of the PET without histologic confirmation.  
At least a 20% increase from nadir in the SPD of any previously involved nodes, or in a single involved node, or the size of other lesions (e.g., splenic or hepatic nodules). To be considered progressive disease, a lymph node with a diameter of the short axis of less than 1.0 cm must increase by 50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the long axis.  
At least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis.
6.3.10 Time to Progression Time to progression will be measured from the date of protocol consent until death of progressive disease is documented.  
6.3.11 Progression-Free Survival Progression-free survival (PFS) is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, or death, whichever occurs first.  
6.3.12 Overall Survival Overall survival (OS) is defined as the time from the date of study enrollment until time of death from any cause.  
6.3.13 Event-Free Survival Event-free survival (EFS) is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, alternative therapy for renal cell carcinoma given (such as radiation), or death, whichever occurs first
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6.4 immune-related response criteria (irrecist)

Modified immune-related response criteria (irRECIST) will also be employed in this study. This new classification is based on the recent learning from clinical studies with cancer immunotherapies that even if some new lesions appear at the beginning of a treatment or if the total tumor burden does not increase substantially, tumor regressions or stabilizations might still occur later. For this trial, the concepts of the irRECIST are combined with RECIST 1.1. Please refer to **APPENDIX E** for further details.
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6.4.1 immune-related bor (irbor)

The duration of Immune-related best overall response is measured from the time measurement criteria are met for irCR or irPR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). irSD, not meeting criteria for irCR or irPR, in absence of irPD. The duration of overall irCR is measured from the time measurement criteria are first met for irCR until the first date that progressive disease is objectively documented. Confirmation of assessment might be delayed up to 12 weeks to confirm PD to account for flare.
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6.5 toxicity criteria

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

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

7.2.1 Expedited Reporting Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802 Non-Compliance Human Subjects Research found here. **Note:** Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported per these policies.  
7.2.2 IRB Requirements for PI Reporting at Continuing Review Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.  
7.2.3 NCI Clinical Director Reporting Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical Director. A separate submission is not necessary as reports in iRIS will be available to the Clinical Director. In addition to those reports, all deaths that occur within 30 days after receiving a research intervention should be reported via email to the Clinical Director unless they are due to progressive disease. To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death.
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7.3 nih required data and

7.3.1 Principal Investigator/Research Team The clinical research team will meet on a regular weekly basis when patients are being actively treated on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if applicable will be made based on the toxicity data from prior patients. All data will be collected in a timely manner and reviewed by the principal investigator or a lead associate investigator. Events meeting requirements for expedited reporting as described in section 7.2.1 will be submitted within the appropriate timelines. The principal investigator will review adverse event and response data on each patient to ensure safety and data accuracy. The principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff.
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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))
8.1.2 Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following:
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death

A life-threatening adverse event (see section **8.1.3**) Inpatient hospitalization or prolongation of existing hospitalization  
o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery arranged prior to the start of the study), a planned hospitalization for pre-existing condition, or a procedure required by the protocol, without a serious deterioration in health, is not considered a serious adverse event.  
o A hospitalization/admission that is solely driven by non-medical reasons (e.g.,
hospitalization for patient or subject convenience) is not considered a serious adverse event.  
o Emergency room visits or stays in observation units that do not result in admission to the hospital would not be considered a serious adverse event. The reason for seeking medical care should be evaluated for meeting one of the other serious criteria.  
Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions A congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
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8.1.3 life threatening

An adverse event or suspected adverse reactions is considered "life-threatening" if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death. (21CFR312.32)
8.1.4 Severity The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.  
8.1.5 Relationship to Study Procedure All AEs will have their relationship to study product assessed using the terms: related or not 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.
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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 to the

Reporting will be per the collaborative agreement.  
8.5.1 CTEP
Copies of all IND Safety Reports submitted to the FDA should be forwarded electronically to CTEPSupportAE@tech-res.com (please provide protocol number in subject line).
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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 8.6.1 Maternal exposure If a patient becomes pregnant during the course of the study, the study treatment should be discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later than 24 hours of when the outcome of the Pregnancy become known. Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects and spontaneous miscarriages that meet serious criteria (section **8.1.2**) should be reported as SAEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed up and documented.  
8.6.2 Paternal exposure Male patients should refrain from fathering a child or donating sperm during the study and for 30 days after the last dose of avelumab. Pregnancy of the patient's partner is not considered to be an AE. However, the outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from the date of the first dose until 30 after the last dose should, if possible, be followed up and documented.
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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

Overall Response (CR + PR) by irRECIST 1.1 criteria in patients who receive at least 1 cycle of therapy with the 4 mcg/kg dose of rhIL-15.  
10.1.2 Secondary Endpoints Rate and severity of AEs, duration of response, progression-free survival and overall survival in patients who receive at least 1 cycle of therapy Changes in percentage and absolute number of peripheral blood lymphocyte subsets.  
Quantitation of ADCC performed *ex vivo* on PBMCs obtained from the patients before and during treatment.  
Characterization of changes in immune cell infiltrates of tumor deposits by immunohistochemical and molecular analysis of core biopsies obtained before and during treatment
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10.2 sample size determination

The primary objective of this trial is to determine the efficacy of combination treatment of CIV rhIL-15 on days 1-5 and IV anti PDL-1 avelumab on day 8 and 22 of the 28-day cycle in patients with treatment refractory PD-L1+ (≥ 5%) metastatic clear-cell renal carcinoma in terms of overall response. All patients must have failed or relapsed and have progressive disease after at least 2 prior therapies that include multityrosine kinase inhibitor like axitinib or sunitinib and an anti-PD1 or PD-L1 ICI therapy like nivolumab. The primary endpoint will be overall response (OR) per irRECIST 1.1 criteria. A Simon two stage Simon Optimal Design will be used for the analysis of the primary endpoint of overall response rate. A minimum of 12 (3 in the 2mcg/kg safety run-in cohort (Cohort 1) and 9 evaluable in the first stage) and maximum of 25 patients will be enrolled in order to have 17 evaluable patients treated at the recommended phase 2 dose for the CIV rhIL-15 schedule at dose 4 mcg/kg/day. A maximum of 19 patients may be enrolled in the phase 2 part of this trial to compensate for inevaluable patients. The sample size for this trial is based on the plan for 3 to 6 patients treated in the 2 mcg/kg/day safety run-in cohort and to accurately assess target 25% response rate in the 4 mcg/kg dosing cohort with a power of 80% to determine the feasibility if this rate were true. The overall Type I error was set at 5% and power at 80% that assumes a null hypothesis success rate of 5% versus a treatment with a 25% response rate. Patients treated in the 2 mcg/kg/day safety cohort will not be included in the primary end point analysis but will be included in the safety cohort and be assessed for the secondary endpoints. Stage 1 for the 4 mcg/kg dose level will consist of 9 evaluable patients to provide evidence of effectiveness and safety. If at least 1 of the 9 patients achieves a radiographic response (> 20% reduction in tumor volume) the study will be allowed to recruit the total sample size of 17 evaluable patients, otherwise it will be stopped for futility (Stage I boundary). The second stage of the design requires 3 or more of the 17 patients to have a positive response for the treatment to be considered worthy of further investigation. If the null hypothesis is true, there is a 63% chance of terminating after Stage I. If the probability of success is actually 0.25, there is a 92% chance that 1 or more patients will exhibit a 20% reduction in tumor volume at Stage I. Patients discontinued from the trial will not be replaced and counted in an "Intent to Treat" analysis as evaluable and treatment failures. At the end of the trial, we will report poor performance if the treatment is rejected at Stage I, not meeting the criteria of at least 1 success in 9 cases. If there is no success at Stage II (at most 2 responses in 17 patients), we will report a failure to reject the null hypothesis using the conditional probability of the added patients. To ensure that this combination, which has not been administered to patients previously, and the dose levels chosen for CIV rhIL-15 are safe, 3 to 6 patients will be treated at the 2 mcg/kg/day dose level to confirm the absence of dose limiting toxicities. Once the safety of the 2 mcg/kg dose level is confirmed the first 3 or 6 patients treated at the intended phase II dose of 4 mcg/kg/day will be evaluated likewise for dose limiting toxicities. If unacceptable toxicity is observed in ≥ 2 of the first 3 or 6 patients treated at these dose levels, entry into the trial and all treatment will be halted to review the safety data to determine if the treatment plan should be altered or the study terminated. If DLT that halts the trial is not observed in these safety run-in cohorts, the trial will proceed to the efficacy assessment as specified above. The protocol will be amended to include information from the Safety Run-in cohorts prior to opening phase II.
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10.2.1 early stopping criteria

An early stopping criterion for toxicity for the whole trial itself would be if ≥ 2 of the first 9 or ≥ 4 of the first 17 patients has unacceptable toxicity or an irAE that required discontinuation of avelumab and/or initiation corticosteroid treatment.
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10.3 population for analyses 10.3.1

All patients will be evaluable for toxicity from the time of their first treatment with rhIL-15 and avelumab.  
10.3.2 Evaluable for objective response Only those patients who have measurable disease present at baseline and have received at least one cycle of therapy with 4mcg/kg dose of rhIL-15, will be assessed on an intent to treat basis.  
Patients who discontinue treatment or die and are not restaged will be considered to be nonresponders and included in calculating the response rate. Patients will have their response classified according to the definitions stated above, Section 6.3. (**NOTE:** Patients who exhibit objective disease progression prior to the end of Cycle 1 will also be considered evaluable).  
10.3.3 Evaluable for Non-Target Disease Response Patients who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease and have received at least one cycle of therapy will be assessed on an intent to treat basis. Patients who discontinue treatment or die and are not restaged will be considered to be non-responders. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.
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10.4 statistical analyses 10.4.1 general

The response rate will be determined and reported along with a 95% confidence interval using the Agresti-Coull method [90]. Other time-to-event outcomes will be reported using Kaplan-Meier curves.  
10.4.2 Analysis of Secondary Endpoints Secondary clinical endpoints of the rate and severity of AEs will be summarized by grade and type of toxicity. The progression-free survival (PFS) and overall survival (OS) will be calculated from the on-study date using the Kaplan Meier method. For PFS and OS, censoring time is defined as time from baseline to date of last follow-up. Duration of response for responders also calculated using the Kaplan-Meier approach is defined as time from the initial response to progression or death, whichever occurs first. Censoring time for duration of response is defined as time from the initial response to date of last follow-up.  
The secondary objectives include characterization of biological effects of this treatment and determination of effects of IL-15 on the ADCC capacity of ex vivo PBMCs. These exploratory analyses will be summarized.
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11 collaborative agreements

11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) - EMD S**ERONO** This study will be incorporated into an existing CRADA (\#02666) between the National Cancer Institute and EMD Serono, the manufacturer of avelumab.
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12 human subjects protections 12.1

All subjects from both sexes and all racial/ethnic groups are eligible for this study if they meet the eligibility criteria outlined in the protocol and provide informed consent to protocol participation.  
Pregnant or nursing mothers are excluded because of the potential teratogenic effects of therapy. There have been no studies of IL-15 in patients with HIV on or off ART. Two non-human primates with SIV who were not on ART and received rhIL-15 on Study 2078-10804 both died, while subsequent animals who received viral suppression were seemingly unaffected. rhIL-15 may therefore contribute to morbidity/mortality in patients with a detectable viral load. Since potential toxicity of IL-15 and avelumab may interfere with ART adherence and optimal viral suppression, patients with HIV may be exposed to additional toxicity for unknown potential benefit of IL-15 and should therefore be excluded from this study. We expect men and women to be equally represented among the enrolled patients.
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12.2 participation of children

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

12.3.1 Known Potential Risks The potential risks of adding rhIL-15 to avelumab include, in particular infusion reactions (including chills, fever, hypotension, headache, flushing, dizziness), fatigue, rash, Liver Function Test (LFT) abnormalities, and cytopenias. Since fevers, rigors, lymphopenia, and LFT elevations occurred only during IL-15 infusion in the continuous IV trial, and since avelumab is not given concomitantly, these toxicities are not expected to overlap. Avelumab manufacturer recommendations for discontinuing therapy will be followed, including for grade 3-4 LFT elevations. Fatigue and rash are potential overlapping toxicities, and both will be monitored closely.
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12.3.2 risks related to imaging

CT scans often use a contrast agent. There is a small risk of having a reaction to the contrast and most often include nausea, pain in the vein where the contrast is given, headache, metallic and/ or bitter taste in the mouth and a warm, flushing feeling. Rarely, some people have more severe allergic reactions to the contrast which may include skins rashes, shortness of breath, wheezing or low blood pressure. 12.3.3 Risks from Radiation Exposure The procedures for performing the CT scans will follow clinical policies, no special procedures apply to these additional assessments for research purposes. In summary, subjects may receive additional radiation exposure from up to seven (7) additional CT scans of the neck, chest, abdomen, and pelvis. The total additional radiation dose for research purposes will be approximately 9.1 rem.  
12.3.4 Blood draws Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting.  
12.3.5 MRI
People are at risk for injury from the MRI magnet if they have some kinds of metal in their body. People with fear of confined spaces may become anxious during an MRI. Those with back problems may have back pain or discomfort from lying in the scanner. The noise from the scanner is loud enough to damage hearing, especially in people who already have hearing loss. There are no known long-term risks of MRI scans.  
12.3.6 Gadolinium enhanced MRI
During part of the MRI patient may receive gadolinium, a contrast agent, through an intravenous (IV) catheter (small tube). It will be done for research purposes. The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with pain and swelling. Participants undergoing gadolinium enhanced MRIs may also be at risk for kidney damage. Most of the gadolinium contrast is eliminated in the urine. However, recent studies have found very small amounts of residual gadolinium in the body, including the brain and bone, by imaging and at autopsy. Macrocyclic gadolinium-containing contrast agents are substantially less likely to leave gadolinium behind than linear agents. There is presently no evidence that the retained gadolinium is associated with any adverse effects or other health risks. Participants undergoing gadolinium enhanced MRIs may also be at risk for kidney damage.
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12.3.7 tumor biopsy (optional)

All care will be taken to minimize risks that may be incurred by tumor sampling. However, there are procedure-related risks (such as bleeding, infection, and injury) that will be explained fully during informed consent.
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12.3.8 electrocardiogram

Some skin irritation can occur where the ECG/EKG electrodes are placed. The test is completely painless, and generally takes less than a minute to perform.
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12.3.9 central line

A non-tunneled central catheter is a soft tube a doctor puts into a vein leading to your heart. It is a way to take blood samples or give you fluids, medicines, or nutrients over a long period of time. Possible side effects include pain, bleeding, bruising, and, on rare occasions, swelling in your arm, chest, neck, or face on the same side as the catheter or infection.  
12.3.10 Known Potential Benefits The potential benefit of adding rhIL-15 to avelumab in treatment of metastatic refractory ccRCC is unknown, but single-agent ICI have shown activity as outlined in Section **1.2.4**. 12.3.11 Assessment of Potential Risks and Benefits An estimated 20 to 50 % of mRCC are PD-L1+ [34], and since the anti-PD-L1 antibody avelumab has shown ADCC activity *in vitro*, agents that may enhance ADCC by increasing number and activity of Fc-binding effector cells - such as rhIL15 - could improve efficacy of avelumab in these diseases. Although the clinical benefit of these drug(s) has not yet been established, the intent of offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully monitored for tumor response and symptom relief in addition to safety and tolerability. In addition to the tumor cells, PD-L1 is also expressed on normal immune cells. Since avelumab has potential for *in vivo* ADCC activity, immune cell subsets may change. However, when 123 different immune cell subsets were analyzed in 28 patients with solid tumors who received avelumab during a phase I trial, there were no changes at any of the time points in any of the 123 subsets tested regardless of their PD-L1 expression before and during treatment [43]. PBMC samples were obtained before Avelumab, and after 1, 3, and 9 doses of the drug. A limited number of immune cell subsets will also be tested in our trial, both in PBMCs and optional tissue biopsies.
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12.4 consent process and documentation

The informed consent document will be provided to the participant as applicable for review prior to consenting. A designated study investigator will carefully explain the procedures and tests involved in this study, and the associated risks, discomforts and benefits. In order to minimize potential coercion, as much time as is needed to review the document will be given, including an opportunity to discuss it with friends, family members and/or other advisors, and to ask questions of any designated study investigator. A signed informed consent document will be obtained prior to entry onto the study. The initial consent process as well as re-consent, when required, may take place in person or remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with policy, including HRPP Policy 303) per discretion of the designated study investigator and with the agreement of the participant. Whether in person or remote, the privacy of the subject will be maintained. Consenting investigators (and participant, when in person) will be located in a private area (e.g., clinic consult room). When consent is conducted remotely, the participant will be informed of the private nature of the discussion and will be encouraged to relocate to a more private setting if needed.
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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 investigators, funding agencies, the Investigational New Drug (IND) sponsor and regulatory authorities, as applicable. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension. Study participants will be contacted, as applicable, and be informed of changes to study visit schedule. Circumstances that may warrant termination or suspension include, but are not limited to:  
Determination of unexpected, significant, or unacceptable risk to participants Demonstration of efficacy that would warrant stopping Insufficient compliance to protocol requirements Data that are not sufficiently complete and/or evaluable Determination that the primary endpoint has been met Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA).
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13.2 quality assurance and quality

The clinical site will perform internal quality management of study conduct, data and biological specimen collection, documentation and completion. An individualized quality management plan will be developed to describe a site's quality management. Quality control (QC) procedures will be implemented beginning with the data entry system and data QC checks that will be run on the database will be generated. Any missing data or data anomalies will be communicated to the site(s) for clarification/resolution. Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is conducted and data are generated and biological specimens are collected, documented (recorded), and reported in compliance with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). The investigational site will provide direct access to all trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities.
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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 the/each clinical site for internal use during the study. At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be transmitted to and stored at the NCI CCR. This will not include the participant's contact or identifying information. Rather, individual participants and their research data will be identified by a unique study identification number. The study data entry and study management systems used by the clinical site(s) and by NCI CCR research staff will be secured and password protected. At the end of the study, all study databases will be archived at the NIH. To further protect the privacy of study participants, a Certificate of Confidentiality has been issued by the National Institutes of Health (NIH). This certificate protects identifiable research information from forced disclosure. It allows the investigator and others who have access to research records to refuse to disclose identifying information on research participation in any civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level. By protecting researchers and institutions from being compelled to disclose information that would identify research participants, Certificates of Confidentiality help achieve the research objectives and promote participation in studies by helping assure confidentiality and privacy to participants.
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14 pharmaceutical information 14.1 rhil-15

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. IL15 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.
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14.1.4 preparation

Vials of frozen IL-15 should be thawed at ambient room temperature and used within 5 hours of thawing. Upon thawing, the solution should be clear and colorless with no evidence of particulates or foreign matter. The infusion solutions should be mixed in a PVC bag.  
14.1.5 Storage IL-15 vials should be stored at or below (-70°C).
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14.1.6 stability

14.1.6.1 Vials Stability studies of the intact vials are ongoing. 14.1.6.2 Prepared Infusion The rhIL-15 infusion solution is stable at a concentration of 1 mcg/mL with 0.1% HSA for 4 hours at controlled room temperature (15°C–30°C) prior to initiation of the 24-hour infusion or 24 hours at 2-8°C prior to initiation of the 24-hour infusion. This stability information was previously documented by the Biopharmaceutical Development Program (BDP) of Leidos Biomedical Research, Inc., the drug manufacturer.  
14.1.7 Administration For all dose levels, the dose of rhIL-15 will be diluted in the appropriate volume of 0.1% human serum albumin (HSA) in 5% dextrose in water, USP (D5W) or in 0.9% sodium chloride (NS) to reach a final rhIL-15 concentration of 1 mcg/mL (see Dilution instruction, **APPENDIX C**). The rhIL-15 infusion will be administered to the patient by continuous intravenous infusion (civ) at a dose in mcg/kg/day determined by the dose level at which the patient is enrolled. Each bag (total 5 bags over 5 days) will be infused over 24 hours using a portable ambulatory pump on the inpatient unit (cycle 1) or in the outpatient setting (cycles 2-4, if deemed appropriate by the PI) for a total of 120 hours. Bags must be changed every 24 hours. Treatment with rhIL-15 will begin within 4 hours of preparation of the infusion bag and the infusion must be completed within 24 hours from the time drug administration begins. Otherwise a new infusion bag must be prepared to complete administration of the remaining dose. See **Table 7** for Drug Regimen, and Section **3.2.1** for supportive care measures.
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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 |                                                              |  
| Adverse Events with Possible                                                                                                                                                                                                                        |                                                              |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|
| Relationship to Recombinant Human IL-15 (CTCAE 5.0 Term)                                                                                                                                                                                            | Specific Protocol Exceptions to  Expedited Reporting (SPEER) |
| Blood bilirubin increased Creatinine increased Lymphocyte count decreased                                                                                                                                                                           | Lymphocyte count decreased (Gr 2)                            |
| Lymphocyte count increased Neutrophil count decreased Platelet count decreased White blood cell decreased METABOLISM AND NUTRITION DISORDERS Hypoalbuminemia Hypophosphatemia                                                                       | Hypophosphatemia (Gr 2)                                      |
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Generalized muscle weakness NERVOUS SYSTEM DISORDERS Dizziness Headache RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Dyspnea SKIN AND SUBCUTANEOUS TISSUE DISORDERS Dry skin Erythema multiforme | Erythema multiforme (Gr 2)                                   |
| Skin and subcutaneous tissue disorders - Other (rash) VASCULAR DISORDERS Capillary leak syndrome Hypertension                                                                                                                                       | Hypertension (Gr 2)                                          |
| Hypotension                                                                                                                                                                                                                                         | Hypotension (Gr 2)                                           |  
*This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail Adverse events reported on Recombinant Human IL-15 trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that Recombinant Human IL-15 caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia CARDIAC DISORDERS - Atrial fibrillation; Chest pain - cardiac; Palpitations; Pericardial effusion; Pericardial tamponade; Sinus bradycardia; Ventricular tachycardia GASTROINTESTINAL DISORDERS - Ascites; Constipation; Duodenal hemorrhage; Gastritis; Gastrointestinal disorders - Other (increased appetite); Ileus; Mucositis oral; Pancreatitis GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Infusion related reaction; Infusion site extravasation; Multi-organ failure; Pain IMMUNE SYSTEM DISORDERS - Autoimmune disorder INFECTIONS AND INFESTATIONS - Tooth infection; Upper respiratory infection; Urinary tract infection INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 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
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reproductive system and breast disorders

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; Bronchopulmonary hemorrhage; Cough; Hypoxia; Laryngeal inflammation; Pleural effusion; Pneumonitis; Pulmonary edema; Wheezing SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythroderma; Palmar-plantar erythrodysesthesia syndrome; Pruritus; Rash acneiform; Skin and subcutaneous tissue disorders - Other (skin plaques) VASCULAR DISORDERS - Hot flashes; Visceral arterial ischemia Note: Recombinant Human IL-15 in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent
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14.1.9 ctep information

14.1.9.1 Agent ordering and Agent Accountability NCI-supplied agents may be requested by eligible participating Investigators (or their authorized designee). The CTEP-assigned protocol number must be used for ordering all CTEP-supplied investigational agents. The eligible participating investigators must be registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are several participating investigators, CTEP-supplied investigational agents for the study should be ordered under the name of one lead participating investigator at that institution. IL-15 may be ordered from PMB when a patient is being worked up for the study. Submit agent requests through the PMB Online Agent Order Processing (OAOP) application. Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account and the maintenance of an "active" account status, a "current" password, and active person registration status. For questions about drug orders, transfers, returns, or accountability, call or email PMB any time. Refer to the PMB's website for specific policies and guidelines related to agent management. 14.1.9.1.1 Agent Inventory Records The investigator, or a responsible party designated by the investigator, must maintain a careful record of the receipt, dispensing and final disposition of all agents received from the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP forms page. Store and maintain separate NCI Investigational Agent Accountability Records for each agent, strength, formulation and ordering investigator on this protocol. 14.1.9.2 Investigator Brochure Availability The current versions of the IBs for the agents will be accessible to site investigators and research staff through the PMB OAOP application. Access to OAOP requires the establishment of a CTEP IAM account and the maintenance of an "active" account status, a "current" password and active person registration status. Questions about IB access may be directed to the PMB IB Coordinator via email.  
14.1.9.3 Useful Links and Contacts CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/
NCI CTEP Person Registration: RCRHelpDesk@nih.gov
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14.2 avelumab ind#100820 (nsc #799232)

14.2.1 Source/Acquisition and Accountability Investigational supplies of Avelumab will be supplied by EMD Serono for use in this clinical trial.  
14.2.2 Toxicity Please refer to the IB (version 10, May 2020) for detailed toxicity information. In brief, in clinical studies thus far, most observed adverse events were either in line with those expected in patients with advanced tumors or with similar class effects of mAb blocking the PD-1/PD-L1 axis. Infusion-related reactions including drug hypersensitivity reactions and immune-mediated adverse reactions (immune-related pneumonitis, immune-related colitis, immune-related hepatitis, immune-related endocrinopathies (thyroid disorders, adrenal insufficiency, new onset type I diabetes mellitus, pituitary disorders), immune-related nephritis and renal dysfunction and other immune-related AEs (myositis, myocarditis, Guillain-Barré syndrome, uveitis, pancreatitis and myasthenia gravis/myasthenic syndrome) have been identified as important risks for avelumab. Detailed guidelines for the management of immune-related adverse events and infusion-related reactions have been incorporated in this study protocol. The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform 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)
presentation of events by body system. Frequency is provided based on 1738 patients. Below is the CAEPR for Avelumab.  
| Version 2.0, April 23, 2019                                                         |                                                                        |                        |
|-------------------------------------------------------------------------------------|------------------------------------------------------------------------|------------------------|
| Adverse Events with Possible   Relationship to Avelumab  (CTCAE 5.0 Term) [n= 1738] |                                                                        |                        |
| Likely (>20%)                                                                       | Less Likely (<=20%)                                                    | Rare but Serious (<3%) |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia CARDIAC DISORDERS                       | Myocarditis2 Pericarditis2                                             |                        |
| ENDOCRINE DISORDERS                                                                 | Adrenal insufficiency2 Hyperthyroidism2 Hypophysitis2 Hypopituitarism2 |                        |
| Hypothyroidism2                                                                     |                                                                        |                        |
| EYE DISORDERS                                                                       | Uveitis2                                                               |                        |
| GASTROINTESTINAL DISORDERS Abdominal pain                                           | Colitis2                                                               |                        |
| Diarrhea Nausea Pancreatitis2 Vomiting                                              | 78                                                                     |                        |  
  
  
Relationship to Avelumab  
(CTCAE 5.0 Term)  
[n= 1738]  
| (CTCAE 5.0 Term) [n= 1738]   |                     |                        |
|------------------------------|---------------------|------------------------|
| Likely (>20%)                | Less Likely (<=20%) | Rare but Serious (<3%) |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Chills Fatigue Fever Flu like symptoms3 HEPATOBILIARY DISORDERS Hepatic failure2 Hepatobiliary disorders - Other  (autoimmune hepatitis, immunerelated 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                              |                     |                        |  
| Adverse Events with Possible   Relationship to Avelumab  (CTCAE 5.0 Term) [n= 1738]                                                                                                                                                                                             |                     |                        |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|------------------------|
| Likely (>20%)                                                                                                                                                                                                                                                                   | Less Likely (<=20%) | Rare but Serious (<3%) |
| Aspartate aminotransferase  increased Blood bilirubin increased CPK increased Creatinine increased GGT increased Lipase increased Lymphocyte count decreased Neutrophil count decreased Platelet count decreased Serum amylase increased Thyroid stimulating hormone  increased |                     |                        |
| METABOLISM AND NUTRITION DISORDERS Anorexia                                                                                                                                                                                                                                     | Hyperglycemia2      |                        |
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia2 Generalized muscle  weakness Muscle cramp Myalgia2 Myositis2 Pain in extremity80                                                                                                                                    |                     |                        |  
| Adverse Events with Possible   Relationship to Avelumab  (CTCAE 5.0 Term) [n= 1738]                                                                          |                                                                                                                                                                                                                                                          |                        |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------|
| Likely (>20%)                                                                                                                                                | Less Likely (<=20%)                                                                                                                                                                                                                                      | Rare but Serious (<3%) |
| NERVOUS SYSTEM DISORDERS                                                                                                                                     | Encephalopathy2 Guillian-Barre syndrome2 Myasthenia gravis2 Nervous system disorders -  Other (non-infectious  encephalitis)2 Nervous system disorders -  Other (non-infectious  meningitis)2 Peripheral motor neuropathy Peripheral sensory neuropathy2 |                        |
| RENAL AND URINARY DISORDERS                                                                                                                                  | Renal and urinary disorders -  Other (immune related  nephritis)2                                                                                                                                                                                        |                        |
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough Pneumonitis2 SKIN AND SUBCUTANEOUS TISSUE DISORDERS Eczema Pruritus Rash acneiform Rash maculo-papular |                                                                                                                                                                                                                                                          |                        |  
*This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
2Immune-mediated adverse reactions have been reported in patients receiving avelumab. Adverse events potentially related to avelumab may be manifestations of immune-mediated adverse events. In clinical trials, most immune-mediated adverse reactions were reversible and managed with interruptions of avelumab), administration of corticosteroids and supportive care.  
3Infusion reactions, including high-grade hypersensitivity reactions, anaphylaxis, and cytokine release syndrome, which have been observed following administration of avelumab, may manifest as fever, chills, shakes, itching, rash, hypertension or hypotension, or difficulty breathing during and immediately after administration of avelumab.  
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC.  
Adverse events reported on avelumab trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that avelumab caused the adverse event: CARDIAC DISORDERS - Palpitations; Sinus tachycardia EYE DISORDERS - Blurred vision; Dry eye GASTROINTESTINAL DISORDERS - Abdominal distension; Constipation; Dry mouth; Dyspepsia; Flatulence; Mucositis oral GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; Localized edema; Malaise; Non-cardiac chest pain; Pain INVESTIGATIONS - Electrocardiogram QT corrected interval prolonged; Investigations - Other (c-reactive protein increased); Weight gain; Weight loss METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypoalbuminemia; Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone pain NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (tumor flare); Tumor pain NERVOUS SYSTEM DISORDERS - Dizziness; Dysesthesia; Dysgeusia; Headache; Tremor RENAL AND URINARY DISORDERS - Proteinuria RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; Hypoxia SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis VASCULAR DISORDERS - Flushing; Hot flashes; Hypertension Note: Avelumab in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.  
14.2.3 Formulation and Preparation Avelumab drug product is a sterile, clear, and colorless concentrate for solution presented at concentration of 20 mg/mL in European Pharmacopeia (Ph. Eur.) and United States Pharmacopeia (USP) type I glass vials closed with a rubber stopper and sealed with an aluminum Flip Off® crimp seal closure. Each single-use vial contains 200 mg of avelumab as a preservative-free acetate-buffered solution (pH 5.2) containing Mannitol, and Polysorbate 20 (Tween 20). For avelumab drug product, only excipients that conform to the current Ph. Eur. and/or the current USP are used.  
14.2.4 Stability and Storage Supplies must be stored in a secure, limited-access location under the storage conditions specified on the label. Receipt and dispensing of trial supplies must be recorded by an authorized person at the trial site. Supplies may not be used for any purpose other than that stated in the protocol. Avelumab drug product must be stored at 2°C to 8°C until use. Store diluted solution at room temperature up to 77°F (25°C) for no more than 4 hours from the time of dilution. OR Under refrigeration at 36°F to 46°F (2°C to 8°C) for no more than 24 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration. The storage condition is based on data from ongoing long-term stability studies with avelumab. Avelumab drug product stored at room (23°C to 27°C) or higher temperatures for extended periods of time might be subject to degradation. Avelumab drug product must not be frozen. Rough shaking of the solution must be avoided.  
14.2.5 Administration Procedures For administration in clinical trials, avelumab drug product may be diluted with 0.9% saline solution (sodium chloride injection) supplied in 250 mL infusion bags, alternatively, a 0.45% saline solution can be used if needed. The chemical and physical in-use stability for the infusion solution of avelumab in 0.45% or 0.9% saline solution has been demonstrated for a total of 24 hours at room temperature. However, from a microbiological point of view, the diluted solution should be used immediately. If not used immediately, it can be considered that the diluted product is sufficiently stable from a microbiological perspective for up to 8 hours when stored at ambient room temperature or up to 24 hours at 2°C to 8°C. The in-use storage times and conditions prior to administration are the responsibility of the user. Prior to the preparation of the dilution for final infusion, allow each vial to equilibrate to room temperature. Use a disposable syringe equipped with a needle of suitable size to remove a volume of sodium chloride solution to be replaced by avelumab from the infusion bag and discard the removed solution. Use a new disposable syringe equipped with a needle of suitable size to inject a volume of avelumab drug product identical to the discarded volume of sodium chloride solution into the infusion bag. Gently invert the mixture 10 times. Infusion bags must not be shaken, in order to avoid foaming or excessive shearing of the protein solution. The preparation must be carefully inspected as it should result in a homogeneous looking clear solution, free of visible particles.  
14.2.6 Returns and Reconciliations Unused investigational products will be destroyed per routine pharmacy procedure.
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77. Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S,
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16 appendices

| 16.1                               | APPENDIX A: PERFORMANCE STATUS CRITERIA ECOG Performance Status Scale Karnofsky Performance Scale                      |                                                            |                                                                     |
|------------------------------------|------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------|---------------------------------------------------------------------|
| Grade                              | Descriptions                                                                                                           | Percent                                                    | Description                                                         |
| 100                                | Normal, no complaints, no                                                                                              |                                                            |                                                                     |
| 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;                                                                                           |                                                            |                                                                     |
| 80                                 | some signs or symptoms of                                                                                              |                                                            |                                                                     |
| Restricted in physically strenuous | 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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16.2 appendix b assay for

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

All dose preparations will be performed in a laminar flow hood in compliance with all legal requirements and in accordance with guidelines of recognized organizations.  
0.1% human serum albumin (HSA) in 5% dextrose in water, USP (D5W), or in 0.9% sodium chloride (NS) may be used for the dilutions listed below. Please note: The dosing examples listed below are for the 147 mcg/0.3 mL in a 3mL vial size and dilution ONLY. The following dosing chart may be used as a reference, but doses should always be re-calculated at the time of preparation. In the future, different concentrations of IL-15 may be available and doses and dilutions will need to be recalculated.
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dose level 1 (2 mcg/kg)

To prepare an IL-15 dose for Dose Level 1 (2 mcg/kg):  
1. Thaw vial(s) of IL-15, 147 mcg/0.3 **mL (490 mcg/mL)** at room temperature. 2. Using a 27-gauge needle, slowly draw up the required dose in a 1 mL syringe. Doses should be rounded to the nearest 0.01 mL.  
3. Add the calculated volume of diluted IL-15 to 0.1% HSA in D5W, or in NS, in a PVC or polyolefin bag.  
4. Label the bag with a 4-hour beyond-use date. The infusion may be started within 4 hours at room temperature, or within 24 hours if bag was kept at 2-8°C. The infusion must be completed within 24 hours of initiation.
Administered dose = _______ kg (Patient's weight) X _______ mcg/kg (DL) = _______ mcg Prepared dose = _______ mcg (Administered dose) + 10 mcg (Overfill dose) = _______ mcg IL-15 volume = _______ mcg (Prepared dose)  490 mcg/mL (vial concentration) = _______ mL
Total infusion volume =
_______ mcg (Prepared dose)  1 mcg/mL (final infusion concentration) = _______ mL
Diluent volume = _______ **mL (Total infusion volume) -** _______ **mL (IL-15 volume) =** _______ mL  
| Patient's   | IL-15 volume (490 mcg/ml)   | Diluent volume   | Total infusion volume   |          |          |        |
|-------------|-----------------------------|------------------|-------------------------|----------|----------|--------|
| weight      | (1 mcg/ml)                  |                  |                         |          |          |        |
| 2mcg/kg     | 4 mcg/kg                    | 2 mcg/kg         | 4 mcg/kg                | 2 mcg/kg | 4 mcg/kg |        |
| 60 kg       | 0.27                        | 0.51             | 129.73                  | 249.49   | 130 ml   | 250 ml |
| 75 kg       | 0.33                        | 0.63             | 159.67                  | 309.37   | 160 ml   | 310 ml |
| 90 kg       | 0.39                        | 0.76             | 189.61                  | 369.24   | 190 ml   | 370 ml |
| 105 kg      | 0.45                        | 0.88             | 219.55                  | 429.12   | 220 ml   | 430ml  |
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dose calculation for obese patients

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

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

| Study Cycles                                                                     | Post-Treatment  Follow-Up   |                          |                    |                               |         |           |          |           |        |                      |    |
|----------------------------------------------------------------------------------|-----------------------------|--------------------------|--------------------|-------------------------------|---------|-----------|----------|-----------|--------|----------------------|----|
| Procedure                                                                        | Screening                   | Baseline                 | C11                | C2-4                          | Disease |           |          |           |        |                      |    |
| Evaluations                                                                      | End of                      |                          |                    |                               |         |           |          |           |        |                      |    |
| Treatment  and Disease  Progression                                              | Safety 2                    | Follow-Up (Prior to  PD) | Survival (Post-PD) |                               |         |           |          |           |        |                      |    |
| Scheduling Window (Days):                                                        | -28 to -13                  | -14 4                    | 8                  | 22                            | 1       | 8         | 22       | Treatment | Day 30 | Every 60 or  Every 3 |    |
| (-3)                                                                             | (-3)                        | (-3) (-3)                | (-3)               | After C2 and C4 5 discon/PD 6 | (+7)    | 90 days 7 | months 8 |           |        |                      |    |
| Confirmation of Diagnosis 9                                                      | X                           |                          |                    |                               |         |           |          |           |        |                      |    |
| Physical Exam and ECOG  PS 10                                                    | X                           | X                        | X                  | X                             | X       | X         | X        | X         | X      | X                    |    |
| CBC with Differential                                                            | X                           | X                        | X                  | X                             | X       | X         | X        | X         | X      | X                    | X  |
| Reticulocyte Count                                                               | X                           | X                        | X                  | X                             | X       | X         | X        | X         | X      | X                    | X  |
| Chemistry Panels 11                                                              | X                           | X                        | X                  | X                             | X       | X         | X        | X         | X      | X                    | X  |
| LDH, Serum Lipase and  Amylase                                                   | X                           | X                        | X                  | X                             | X       | X         | X        | X         | X      | X                    | X  |
| PT/INR and aPTT                                                                  | X                           | X                        | X                  | X                             | X       | X         | X        |           |        |                      |    |
| Thyroid Function (i.e., TSH,  T4)                                                | X                           | X                        | X                  | X                             | X       | X         | X        |           |        |                      |    |
| Urinalysis                                                                       | X                           | X                        | X                  | X                             | X       |           |          |           |        |                      |    |
| Pregnancy Test (urine/serum;  WOCBP)                                             | X                           | X                        | X                  |                               |         |           |          |           |        |                      |    |
| Hepatitis B and C, HIV  Antibody, HTLV-1/2                                       | X                           |                          |                    |                               |         |           |          |           |        |                      |    |
| Anti-nuclear antibody  (ANA), rheumatoid factor  (RF) and anti-thyroid  antibody | X                           | X                        |                    |                               |         |           |          |           |        |                      |    |
| IL-2R                                                                            | X                           | X                        | X                  |                               |         |           |          |           |        |                      |    |
| Creatine phosphokinase  (CPK), troponin                                          | X                           | X                        | X                  | X                             | X       |           |          |           |        |                      |    |
| Pulmonary function tests  (PFTs) and TTE12                                       | X                           |                          |                    |                               |         |           |          |           |        |                      |    |
| T, B, NK cell subsets                                                            | X                           | X                        | X                  | X                             | X       | X         | X        |           |        |                      |    |
| Imaging studies 13                                                               | X                           | X                        | X                  | X                             | X       |           |          |           |        |                      |    |
| MRI Lumbar Puncture 14                                                           | X                           | X                        | X                  | X                             |         |           |          |           |        |                      |    |  
| Study Cycles                                        | Post-Treatment  Follow-Up   |                            |                    |                               |         |           |          |           |        |                      |
|-----------------------------------------------------|-----------------------------|----------------------------|--------------------|-------------------------------|---------|-----------|----------|-----------|--------|----------------------|
| Procedure                                           | Screening                   | Baseline                   | C11                | C2-4                          | Disease |           |          |           |        |                      |
| Evaluations                                         | End of                      |                            |                    |                               |         |           |          |           |        |                      |
| Treatment  and Disease  Progression                 | Safety 2                    | Follow-Up (Prior to  PD)   | Survival (Post-PD) |                               |         |           |          |           |        |                      |
| Scheduling Window (Days):                           | -28 to -13                  | -14 4                      | 8                  | 22                            | 1       | 8         | 22       | Treatment | Day 30 | Every 60 or  Every 3 |
| (-3)                                                | (-3)                        | (-3) (-3)                  | (-3)               | After C2 and C4 5 discon/PD 6 | (+7)    | 90 days 7 | months 8 |           |        |                      |
| Flow Cytometry15                                    | X                           | X                          | X                  | X                             | X       | X         | X        | X         | X      |                      |
| Clinical photography16                              | X                           | X                          | X                  | X                             |         |           |          |           |        |                      |
| Radiologic Evaluation/ tumor  measurement17         | X                           | X                          | X                  | X                             |         |           |          |           |        |                      |
| EKG                                                 | X                           |                            |                    |                               |         |           |          |           |        |                      |
| Symptoms/Adverse Events  Assessment, Concomitant    | X                           | X                          | X                  | X                             | X       | X         |          |           |        |                      |
| Medication Review Research Blood/Tissue  Samples 18 | X                           | Refer to Table Section 5.1 |                    |                               |         |           |          |           |        |                      |
| Survival Status                                     | X                           |                            |                    |                               |         |           |          |           |        |                      |  
1 On Day 8 and Day 22 of Cycle 1, vital signs ([VS] blood pressure, pulse, respiratory rate, temperature, oxygen saturation) will be assessed predose of avelumab
(within 15 minutes of injection and/or infusion), and then every 15 minutes from the start of avelumab infusion for at least 2 hours. If vital signs are not stable after 2 hours, then continue monitoring every 15 minutes until stable on 2 consecutive repeated measurements.  
2 30 days (+7) following last dose, and 90 days (+14) after last dose of avelumab (via clinic or phone/email). If initiating new anti-cancer therapy within 30 days after last dose of avelumab, 30-day safety follow-up visit must occur before first dose of new therapy.  
3 Screening and Baseline evaluations should be performed within 28 days prior to enrollment and dosing, respectively, unless otherwise noted and with the following exceptions: Confirmation of diagnosis (no time limit); HIV antibody, Hepatitis B surface antigen and Hepatitis C antibody and EKG (all within 3 months) **NOTE:** Any screening tests performed within the specified time frame for baseline do not need to be repeated.  
4 Within 14 days prior to dosing on C1D1, with the following exceptions: Pregnancy test (within 7 days of dosing; must be negative). 5 ± 2 days. Confirmatory scans should also be obtained 4 weeks following initial documentation of objective response. 6 To be done at end of treatment (30 days after last dose of study treatment; may be combined with 30 day safety follow-up, if timing coincides). If subject to initiate new anti-cancer therapy assessments should occur before the first dose of the new therapy.  
7 Follow-up to occur about every 60 days ( ±7 days) for first 6 months, every 90 days (±14 days) for 2 years; then every six months (± 28 days) for the duration of the study until disease progression or initiation of new anti-cancer therapy.  
8 After disease progression or initiation of new anti-cancer therapy, contact for survival about every 3 months (±4 weeks) for the duration of the study after stopping treatment.  
9 Pathologic review/confirmation of diagnosis by Laboratory of Pathology, NCI (no time limit) and PD-L1 as outlined in Section **5.2.4.1**. If archival sample is not available, a fresh punch or core biopsy of an appropriate easily accessible tumor deposit will be obtained.  
10 Physical exams to include medical history (i.e., complete at Screening/Baseline; interim on study and in follow-up), vitals, weight, and height (screening only). 11 Chemistry panels include: Acute care, Hepatic, and Mineral. 12 Diffusing capacity/alveolar volume (DLCO/VA), forced expiratory volume in 1 second (FEV1) for patients with significant pulmonary or smoking history or suspected tumor related pulmonary dysfunction and Transthoracic Echocardiograph for patients with suspected cardiac dysfunction that would increase their risk in receiving protocol treatment.  
13 Patients should have an evaluation of known sites of disease (CT, MRI, and in certain cases FDG-PET to better evaluate lesions of uncertain etiology) as part of the screening and baseline evaluations. Other body areas may be imaged if clinically indicated. MRI of the brain is only required in patients with suspected involvement of CNS.  
14 Patients with neurological symptoms or signs should undergo MRI scan of the brain and lumbar puncture 15 Flow cytometry to be performed at baseline, and on Day 8 and 22 of each cycle, see Section **5.2.3**.  
16 To be performed in selected patients with skin lesions (as determined by PI or AI). 17 Radiologic documentation must be provided for patients removed from study for progressive disease 18 Samples for correlative research are to be collected as indicated in Section 5