A Phase I Study of a Continuous Intravenous Infusion of Recombinant Human Interleukin IL-15 (rhIL-15) in Adults With Metastatic Cancers
Phase: PHASE1
Conditions: Lymphoma, Carcinoma
Sponsor: National Cancer Institute (NCI)

Abbreviated Title: Ph I Study of CIV rhIL-15 
Version Date: 06/13/2018 
1 
 Abbreviated Title:  Ph I Study of CIV rhIL-15 
 
CC Protocol #:  12-C-0113 J 
 
Version Date:  06/13/2018 
 
NCT Number:  NCT01572493  
 
 
A PHASE I STUDY OF A CONTINUOUS INTRAVENOUS INFUSION OF 
RECOMBINANT HUMAN IL-15 (rhIL-15) IN ADULTS  
WITH METASTATIC CANCERS 
 
 
 NCI Principal Investigator: Kevin Conlon, M.D.  
Lymphoid Malignancies Branch (LYMB)  
Center for Cancer Research (CCR) 
National Cancer Institute (NCI) 
National Institutes of Health (NIH) 
10 Center Drive 
Building 10 Room 4N115 
Bethesda, MD 20892 
Phone: 240-760-6087 
Email: conlonkc@mail.nih.gov 
 
    Investigational Agents:   
Drug Name:  
Recombinant human interleukin-15 (rhIL-15) 
IND Number: 
100820 
Sponsor/IND Holder: 
Center for Cancer Research, NCI 
Manufacturer: 
Biopharmaceutical Development Program, NCI 
 
Commercial Agents: None 
 

Abbreviated Title: Ph I Study of CIV rhIL-15 
Version Date: 06/13/2018 
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PRÉCIS 
Background: 
• Interleukin-15 (IL-15) is a stimulatory cytokine with a number of desirable 
immunotherapeutic features, and clinical trials evaluating recombinant human (rh) IL-15 
are underway. 
• In contrast to IL-2, IL-15 treatment does not stimulate activation-induced cell death of T-
cells; potentially inhibits immunosuppressive CD4+CD25+ T regulatory cells, contributes 
to the proliferation, differentiation and activation of CD8+ T-cells and NK-cells and the 
maintenance of long-term CD8+ memory T-cells. 
• IL-15 is active in a number of syngeneic mouse preclinical tumor models, and vaccinia-
based constructs expressing IL-15 induced long-lasting, high-avidity cytotoxic CD8+ T-
lymphocyte response that appears to be more effective than similar IL-2–expressing 
vaccines.  
• Pharmacology/toxicology (pharm/tox) experiments in non-human primate (NHP) rhesus 
macaques and preliminary results from the first-in-human phase I trial examining rhIL-15 
given as an IV bolus (IVB) for 12 consecutive days indicate significant stimulation and 
expansion of NK-cells and CD8+ T-cells.  
• rhIL-15 given as an IVB at 1 mcg/kg dose level appears to be well tolerated despite the 
presence of some common cytokine-related side effects indicating that 0.1 mcg/kg/day is 
an appropriate initial dose level for a phase I safety trial of continuous intravenous 
infusion (CIV) of rhIL-15.  
• Comparison of the pharmacokinetic and immunologic assessments from the IVB phase I 
trial with the data from both sets of NHP pharm/tox experiments suggest that CIV of 
rhIL-15 may have greater potential for stimulating an anticancer cellular immune 
response with a more manageable safety profile. 
Objective: 
• Determine the safety, toxicity profile, dose-limiting toxicity (DLT) and maximum 
tolerated dose (MTD) of rhIL-15 administered as a CIV for 10 consecutive days (240 
hours) or for 5 days (120 hours) in subjects with metastatic unresectable cancers for 
which curative or palliative measures either do not exist or are not associated with a 
survival advantage. 
Eligibility Criteria: 
• Patients ≥18 years-old, ECOG PS ≤ 1, with pathologically confirmed metastatic 
unresectable cancers for which curative or palliative measures either do not exist or are 
not associated with a survival advantage. 
• Patients with measurable or evaluable disease, normal organ and bone marrow function  
Design: 
 
 
• This is a single-institution, open-label, non-randomized 3 + 3 design phase I dose-
escalation study.  
• Groups of 3 to 6 subjects will receive CIV rhIL-15 at doses of 0.1, 0.25, 0.5, 1, 2, and 4 
mcg/kg/day for 10 days provided that DLT has not been observed.  

Abbreviated Title: Ph I Study of CIV rhIL-15 
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• After assessments of the 10-day dosing cohorts have been completed, new groups of 3 to 
6 subjects will receive CIVrhIL-15 at doses of 3, 4 and 5 mcg/kg/day for 5 days provided 
that a DLT has not been observed. 
• Patients with evidence of response and the absence of significant toxicities will be 
eligible for repeat cycles of treatment. 
• Samples for correlative studies will be obtained prior to treatment and at specific times 
points during and after treatment to assess pharmacokinetics of rhIL-15, the effect of 
rhIL-15 on immune cell subset populations and pro-inflammatory cytokine levels in the 
peripheral blood and for the development of neutralizing anti-rhIL-15 antibodies. 
 
 

Abbreviated Title: Ph I Study of CIV rhIL-15 
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SCHEMA 
 
 
Patient 
Cohort 
Number of 
Patients 
Dose of CIV rhIL-15  
(mcg/kg/day x 10 days)* 
1 
3 to 6 
0.1 
2 
3 to 6 
0.25 
3 
3 to 6 
0.5 
4 
3 to 6 
1 
5 
3 to 6 
2 
6 
3 to 6 
4 
 
 
Dose of CIV rhIL-15  
(mcg/kg/day x 5 days)** 
7 
3 to 6 
3 
8 
3 to 6 
4 
9 
3 to 6 
5 
 
*Nine total patients will be treated at the MTD. The MTD for the 10-day dosing schedule has 
been identified as 2 mcg/kg/day.  
The MTD has not yet been identified for the 5-day dosing schedule. 
** If there is a confirmed response (partial or complete response) in at least one patient in the 
5-day dosing cohorts, a total of nine patients will be treated at the MTD or the maximum 
administered dose. Otherwise, there will not be an expansion cohort for any dose in the 5-day 
dosing cohorts. 
 

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TABLE OF CONTENTS 
PRÉCIS ................................................................................................................................................ 2 
TABLE OF CONTENTS ..................................................................................................................... 5 
1 
INTRODUCTION ........................................................................................................................ 7 
1.1 
Study Objectives .................................................................................................................... 7 
1.2 
Background and Rationale ..................................................................................................... 7 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ............................................................ 22 
2.1 
Eligibility Criteria ................................................................................................................ 22 
2.2 
Screening Evaluation ........................................................................................................... 23 
2.3 
Registration Procedures ....................................................................................................... 24 
2.4 
Baseline Evaluation ............................................................................................................. 24 
3 
STUDY IMPLEMENTATION .................................................................................................. 25 
3.1 
Study Design ........................................................................................................................ 25 
3.2 
Dose-Limiting Toxicity ....................................................................................................... 26 
3.3 
Dose Escalation ................................................................................................................... 28 
3.4 
Drug Administration ............................................................................................................ 28 
3.5 
Dose Modifications .............................................................................................................. 29 
3.6 
Monitoring During Therapy ................................................................................................ 29 
3.7 
Monitoring During Follow-up Period (after completion of treatment) ............................... 30 
3.8 
Study Calendars ................................................................................................................... 31 
3.9 
Concurrent Therapy ............................................................................................................. 35 
3.10 Criteria for Removal from the Protocol Therapy and Off-Study Criteria ........................... 35 
4 
CONCOMITANT MEDICATIONS/MEASURES ................................................................... 36 
5 
BIOSPECIMEN COLLECTION ............................................................................................... 36 
5.1 
Correlative Studies for Research, Pharmacokinetic and Special Studies ............................ 36 
5.2 
Sample Storage, Tracking and Disposition ......................................................................... 38 
6 
DATA COLLECTION AND EVALUATION .......................................................................... 41 
6.1 
Data Collection .................................................................................................................... 41 
6.2 
Response Criteria ................................................................................................................. 42 
6.3 
Toxicity Criteria .................................................................................................................. 50 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN . 50 
7.1 
Definitions ........................................................................................................................... 50 

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7.2 
NCI-IRB and Clinical Director (CD) Reporting ................................................................. 51 
7.3 
IND Sponsor Reporting Criteria .......................................................................................... 52 
7.4 
Data and Safety Monitoring Plan ........................................................................................ 53 
8 
STATISTICAL CONSIDERATIONS ....................................................................................... 54 
9 
COLLABORATIVE AGREEMENTS ...................................................................................... 55 
9.1 
Material Transfer Agreement (MTA) .................................................................................. 55 
10 HUMAN SUBJECTS PROTECTIONS ..................................................................................... 55 
10.1 Rationale for Subject Selection ........................................................................................... 55 
10.2 Participation of Children ..................................................................................................... 56 
10.3 Participation of Subjects Unable to Give Consent .............................................................. 56 
10.4 Evaluation of Benefits and Risks/Discomforts .................................................................... 56 
10.5 Strategies and Procedures for Recruitment ......................................................................... 57 
10.6 Risks/Benefits Analysis ....................................................................................................... 57 
10.7 Consent Process and Documentation .................................................................................. 57 
11 PHARMACEUTICAL INFORMATION .................................................................................. 58 
11.1 Recombinant Human Interleukin-15 ................................................................................... 58 
12 REFERENCES ........................................................................................................................... 63 
13 APPENDICES ............................................................................................................................ 69 
APPENDIX A:  Performance Status Criteria ................................................................................. 69 
APPENDIX B:  Immune-Based Studies ........................................................................................ 70 
APPENDIX C:  Assay for Antibodies to rhIL-15 .......................................................................... 71 
APPENDIX D:  CIV rhIL-15 Biospecimen Worksheet for 12-C-0113 Cycle 1 for 10 Day 
Schedule ......................................................................................................................................... 72 
APPENDIX E:  CIV rhIL-15 Biospecimen Worksheet for 12-C-0113 Cycle 2 and Beyond........ 74 
 
 

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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
• Determine the safety, toxicity profile, dose-limiting toxicity (DLT), and maximum 
tolerated dose (MTD) of recombinant human interleukin-15 (rhIL-15) administered as a 
continuous intravenous infusion (CIV) for 10 consecutive days (240 hours) or for 5 days 
(120 hours) in subjects with metastatic unresectable cancers for which curative or 
palliative measures either do not exist or are not associated with a survival advantage. 
1.1.2 Secondary Objectives 
• Determine rhIL-15 pharmacokinetics (PK) and the biological effects of rhIL-15 on 
immune cells reflected in the changes in the percentages and absolute numbers of 
circulating lymphocytes (T and NK cells) and T cell subsets (naïve, central or effector 
memory subsets) based on flow cytometric analysis of CD56, CD3, CD4, CD8, 
CD45RO, CD45RA, CD28, CD95, CCR7 and CD62L expression and on the plasma 
levels of pro-inflammatory cytokines. 
• Evaluate the potential antitumor activity of rhIL-15 by assessing the clinical response rate 
and time to progression in this patient population.  
• Assess the nature of the T-cell infiltration and cytokine and check-point inhibitor gene 
expression by analysis of pre- and post-treatment biopsies obtained from selected patients 
with easily accessible tumor deposits. 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 Interleukin-15 (IL-15)  
The cytokine that is now called interleukin-15 was initially reported nearly simultaneously by 
two different research groups, one at the NCI and the other at Immunex Corporation (1, 2). Since 
this discovery, IL-15 has been and remains one of the key focuses of the Waldmann laboratory’s 
research efforts. While not the exclusive proprietor of all the important publications regarding 
the biology of IL-15, many subsequent reports from this laboratory have described a number of 
key biologic features and therapeutic potential of IL-15 (3-9). The clinical application of the 
laboratory effort that defined IL-15’s immunologic role and pathophysiologic contribution to 
human T-cell lymphotropic virus 1 (HTLV-1)–related diseases and T-cell large granular 
lymphocyte leukemia (LGL) first led to clinical investigations with the anti-IL-15Rβ chain 
antibody Mikβ1 (10, 11) that still continue. More recently, the long-awaited first-in-human phase 
I trial evaluating rhIL-15 as an immunotherapeutic was initiated. This trial is examining the 
safety and efficacy of rhIL-15 given as an IV bolus to patients with advanced incurable 
metastatic renal cell carcinoma and melanoma and soon will be followed by additional trials by 
other clinical cancer researchers.  
Interleukin-15 is produced primarily by antigen-presenting cells (APCs) like dendritic cells 
(DCs) but also by other mononuclear cells following encounters with double-stranded RNA, 
viral, bacterial and fungal pathogens and also type 1 interferons (IFNs) (12-15). While 
constitutive IL-15 mRNA production is present in a number of cell types, IL-15 protein 
expression does not always correlate well with mRNA levels and its secretory pathway is rather 
unique. IL-15 is bound with high affinity by the IL-15Rα chain, which can be membrane bound 

Abbreviated Title: Ph I Study of CIV rhIL-15 
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or cleaved to produce a soluble version. IL-15 is normally not secreted as a free cytokine in vivo, 
but most often is with IL-15Rα on the cell surface of APCs and presented in trans to nearby 
effector T and NK cells (16, 17). Interleukin-15 has a heterotrimeric receptor (IL-15R) composed 
of a unique alpha subunit (IL-15Rα chain), a beta subunit that it shares with IL-2 (IL-2R/IL-
15Rβ chain) and the common gamma-chain γc) that is also present on the receptors for 
cytokines IL-4, IL-7, IL-9 and IL-21 (18-20). While IL-15 and IL-2 also have a number of other 
similarities as activators of NK cells, CD4+ and CD8+ effector T-cells, there are some important 
biologic features distinctive to each of these cytokines. In contrast to IL-2, IL-15 does not cause 
activation-induced cell death (AICD), and seemingly has greater capacity to maintain high-
avidity CD8+ memory T-cell responses to invading pathogens by supporting the survival of these 
T-cells (6, 21-23). In addition to promoting the global CD8+ response (24), IL-15 preferentially 
expands the most active CD8+, CD95+, CCR7-, CD28- effector memory cells, and increases their 
T-cell receptor avidity by inducing higher expression of CD8αβ, which as expected augments 
these cells’ functional capacity (25). Administration of IL-15 has also been shown to upregulate 
IL-15Rα expression, which allows the effector cells to respond to lower local concentrations of 
IL-15 that resulted in increased production of secondary stimulatory cytokines such as IFNγ and 
tumor necrosis factor alpha (TNFα) and increased production of lytic molecules such as perforin 
(26, 27). 
In addition to IL-15’s well-described effects on cytotoxic CD8+ T-cells and NK cells, a number 
of recent publications have demonstrated that IL-15 promotes CD4+ cellular responses more than 
originally recognized (28-30). Again, the effects are more prevalent in the effector memory 
subset; but more importantly, IL-15 provides limited stimulation of immunosuppressive CD4+ T 
regulatory cells (T regs). IL-2 is clearly a potent stimulator of CD4+ CD25+ FoxP3+ T-cells, and 
some reports have demonstrated that IL-15 can inhibit T regs function (31). As research 
continued into the relationship of IL-15 and T regs, it became clear that the biology is complex 
(32-35). The data regarding the effects of IL-15 on T regs is conflicting with some reports 
demonstrating that IL-15 suppresses T reg function (34, 35). It is clear that IL-15 can stimulate T 
regs directly or indirectly; the specific milieu and associated cells have important contributions 
in determining IL-15’s impact on the nearby T regs. While IL-15 effects on these 
immunosuppressive cells are again pleotropic, at a minimum, the data indicate IL-15 has inferior 
capacity to stimulate T regs compared to IL-2 (31-33).  
1.2.1.1 Interleukin-15 as an Immunotherapeutic Agent 
In the now more than two decades of clinical investigations into immunotherapeutics for the 
treatment of human malignancies, many agents have been tested, but IL-2 remains the 
prototypic agent and a central feature of many effective immunotherapy strategies (36, 37). 
While IL-2 has advantageous features shown to contribute to the in vivo anti-tumor immune 
response, the less desirable consequences of high-dose IL-2 (HD IL-2) treatment such as 
capillary leak syndrome, hypotension, and the previously cited roles in AICD and 
stimulation of immunosuppressive T regs must be recognized. Like IL-2, IL-15 has been 
shown in many model systems to be a potent stimulator of T and NK cell functions, but IL-
15 lacks a number of IL-2’s negative characteristics and suggests that IL-15 has greater 
clinical potential as an immunotherapeutic in oncology (38, 39).  
Preclinical experiments indicate that IL-15 is superior to IL-2 in the maintenance of NK 
cells, NK-T cells, intraepithelial lymphocytes and memory phenotype CD8+ T-cells (1-5). 
The antitumor effect of IL-2 probably results from its ability to expand lymphocyte 

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populations in vivo and to increase the effector functions of these cells, thereby inhibiting 
tumor growth. The ongoing cellular therapy effort piloted by the NCI Surgery Branch with 
tumor infiltrating lymphocytes (TILs) and chimeric antigen receptor T-cells (CARs) (37, 40) 
and the recently published randomized phase III gp100 peptide vaccine trial (41) have 
demonstrated clinical efficacy for combination treatments with HD IL-2. Although 
numerous individual reports have listed positive clinical results from less intensive IL-2 
regimens, published results from the limited number of comparative trials indicate the HD 
three times daily (tid) dosing regimen is the most consistently active IL-2 treatment (42, 43). 
In composite, the current data suggest higher doses of IL-2 must be maintained at a cost of 
increased toxicities, to be effective. Unlike the standard practice with IL-2, most new rh 
cytokines being examined in clinical trials are not given as dose-intense inpatient regimens 
(44, 45). Biologically, we now understand better the limits of stimulation of HD IL-2 on 
effector T-cells (AICD, T regs) (12, 34, 38) and NK cells as well as the ability of patients to 
tolerate prolonged IL-2 treatment (36). The current development plan for IL-15 given at an 
active but not intensive dose coincides with the philosophic shift to less toxic regimens for 
new immunotherapeutics being evaluated in clinical trials (44-46). Analogous to the 
investigation into IL-15, a number of new immunotherapeutic agents identified by our 
increased understanding of a productive immune response are directed at homeostatic or 
counter-regulatory cellular processes like CTLA4, PD1, indoleamine 2,3-dioxygenase and 
immunosuppressive T regs or macrophage-derived suppressor cells (MDSC) that are 
induced sometimes indirectly by IL-2 treatment (33, 46-51). IL-15’s considerable ability to 
activate crucial effector T-cells and NK-cells, its inhibition of AICD, the lack of a 
meaningful contribution to the generation of T regs, potential for cyclic restimulation of 
effector cells and its unique capacity to maintain the function of CD8+ memory T-cells; 
indicate that IL-15 has greater potential than IL-2 as a cancer immunotherapeutic. 
1.2.1.2 Interleukin-15 in Preclinical Immunotherapy models 
Attempts to prevent tumor growth in mice by administration of IL-15 have proven effective 
(7, 14, 52). The importance of IL-15 in the elimination of syngeneic MC38 colon carcinoma 
has been examined using IL-15 transgenic mice that produce large quantities of IL-15. 
Wild-type C57Bl/6 mice died due to substantial pulmonary involvement by 40 days after 
infusion of the MC38 carcinoma cells, but similarly exposed IL-15 transgenic mice did not 
develop such metastases and survived. The role of IL-15Rα-mediated transpresentation in 
the therapeutic action of IL-15 was evaluated in a related model when the IL-15Rα 
expression element was transfected into MC38 colon carcinoma cells. The administration of 
unmodified MC38 cells to wild-type mice led to death within 40 days, whereas mice with 
normal IL-15 production given IL-15Rα–transfected tumor cells did not develop tumors 
(53). In this system, IL-15Rα on the surface of tumor cells bound circulating IL-15 present 
in the blood that was subsequently transpresented to circulating NK-cells, leading to the 
destruction of the tumor. In analogous non-transfected model, our group demonstrated that 
intraperitoneal therapy with IL-15 prolonged the survival of mice challenged with the 
syngeneic CT-26 colon carcinoma cells. Klebanoff and coworkers (7) also showed that IL-
15 enhanced the in vivo activity of tumor reactive CD8+ T-cells in the T-cell receptor 
transgenic mouse (Pmel-1) whose CD8+ T-cells recognize an epitope derived from the 
melanoma antigen gp100 and stimulated the in vivo antitumor activity of these T-cells in a 
B16 melanoma model. The synergy of IL-21 and IL-15 in stimulating CD8+ T-cell 
expansion and functional capacity also produced apparent cures of established large B16 

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melanomas (52). In addition, the IL-15 monotherapy control arm in these studies 
demonstrated significant antitumor effect over untreated controls. Systemic IL-15 given in 
combination with a fowlpox TRICOM vaccine encoding B7-1, ICAM-1, and LFA-3 
improved survival in a mouse subcapsular renal cell cancer model compared to TRICOM 
vaccination alone or TRICOM plus systemic IL-2 (54).  
IL-15 has also been shown to promote anti-viral T-cell responses. Vaccinia vectors co-
expressing IL-15 and an HIV antigen glycoprotein 160 (gp 160) induced long-lasting robust 
cytotoxic T-lymphocyte (CTL) response in contrast to the short-lived T-cell immunity from 
a vector expressing IL-2. Administration of DNA vaccines containing an optimized plasmid 
encoding IL-15 improved the function and longevity of CD8+ T-cell response to influenza 
virus hemagglutinin protein (24). IL-15 was shown to increase long-lived antigen specific 
memory CD4+ and CD8+ T-cells in rhesus macaques (29, 55-57), and to increase effector 
memory CD8+ T-cells and NK-cells in Simian immunodeficient virus (SIV)–infected 
macaques (29). In this study, recombinant rhesus macaque (rm) IL-15 treatment in 9 
SIVmac 251–infected cynomolgus monkeys was given twice weekly for 4 weeks at a low 
dose of 10 mcg/kg and a high dose 100 mcg/kg. Compared to saline controls, rmIL-15 
treatment induced a nearly three-fold increase in peripheral CD8+CD3- NK cells. 
Furthermore, CD8+ T-cell numbers increased more than two-fold mainly due to an increase 
in CD45RA- , CD62L-, and CD45RA+ CD62L- effector memory CD8+ T-cells.  
To support this proposal, the Lymphoid Malignancies Branch has recently performed 
additional murine experiments to assess the potential of CIV IL-15 (Zhang and Waldmann 
unpublished) using an analogous subcutaneous (SC) minipump system. Protocol mice were 
infused intraperitoneally (IP) with MC-38 tumor cells and IP injection or SC minipump 
treatment of the 5 experimental groups were initiated 1 day later. The 5 treatment groups 
included a phosphate buffered saline (PB5) control, human IL-15 at 5 mcg/day IP for 14 
days (5 x 14), human IL-15 at 2.5 mcg/day IP for 14 days (2.5 x 14), human IL-15 at 5 mcg 
given every other day IP over 14 days for 7 doses (5 x 7) and human IL-15 via an implanted 
pump (2.5 mcg/day) for 14 days that demonstrated more favorable pharmacokinetics for 2.5 
mcg/day infusion pump route of administration with sustained serum IL-15 levels in 3500 to 
8000 pg/mL range in comparison for short high exposures (> 30, 000 pg/mL) for the daily 
IP injections.  
Increases in absolute lymphocyte count (ALC) were seen in the groups receiving rhIL-15 
and nearly identical absolute numbers of CD8+ lymphocytes were seen in animals receiving 
2.5 mcg/day via the pump as those receiving 5 mcg/day as an IP injection (Figure 1, top 
figure). All treatment regimens produced similar increases in the percentage of NK cells, but 
increases in the percentage of CD8+ and CD44hi CD8+ terminal effector cells were highest in 
the animals treated via the pump at 2.5 mcg/day. It is also important to note that IL-15 
treatment stimulated the vast majority of the CD8+ cells to become CD44hi activated effector 
cells. These data suggest that continuous administration of IL-15 as opposed to bolus dosing 
stimulates different populations of lymphocytes and may be a better dosing schedule to 
stimulate a T-cell or CD8+ cells response that also includes a slower decline CD8+ cell 
numbers after the cytokine treatment has been stopped compared to animals treated with a 
daily IP injection. 
1.2.1.3 Results from Non-Human Primate (NHP) Toxicology Studies 
The Lymphoid Malignancies Branch had previously performed a toxicology study in NHP 

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11 
in support of the IND application for the ongoing IVB clinical protocol (56, 57). In this 
toxicology study, 24 adult rhesus macaques were divided into 4 treatment groups of 6 
animals each. The groups of monkeys received vehicle diluent control alone, or rhIL-15 at 
10, 20 or 50 mcg/kg/day IVB daily for 12 days. The animals were assessed regularly with 
clinical observation, physical examination and laboratory tests that included hematology, 
serum chemistries, coagulation studies, PK analysis of serum rhIL-15, immunologic 
parameters, a survey of autoimmune markers and a complete necropsy with gross and 
histopathological examination. After 8 days of treatment, the animal receiving 200 
mcg/kg/day and to a lesser degree those animals receiving 50 mcg/kg/day exhibited 
lethargy, a disheveled appearance, diarrhea and dehydration that in some cases required IV 
fluids. Laboratory results from this time period showed transient grade 3/4 granulocytopenia 
in the rhesus macaques receiving rhIL-15 at a dose of 50 mcg/kg/day, but no infections were 
seen and concurrent bone marrow samples (aspirate and biopsy) showed a hypercellular 
marrow containing all elements of the granulocytes series. Histologic examination of the 
macaques’ livers demonstrated granulocytes and other leukocytes in the sinusoids adjacent 
to normal appearing hepatocytes suggesting that redistribution to the tissues as a 
contributing factor in the apparent neutropenia. Normal or elevated granulocyte counts were 
restored within 48-72 hours of discontinuation of the rhIL-15 dosing. No antibodies directed 
against rhIL-15 were detected in the animals, and no animals developed anti-nuclear 
antibodies (ANA). At necropsy, the only gross or microscopic abnormalities were loss of 
adipocytes in the hyperplastic marrows and the presence of neutrophils and other white 
blood cells (WBCs) in the liver sinusoids. No animal deaths occurred on this study.  
To support a NIAID-planned sponsored clinical trial, a similar toxicology study was 
performed to evaluate the effects of CIV treatment and more frequent administration of SC 
rhIL-15 to rhesus macaques.  Fifteen male macaques were divided into 5 groups of animals 
and were treated with either CIV or SC rhIL-15 as shown below in Table 1 with one group 
of animals receiving vehicle alone serving as the control. The SC rhIL-15 was administered 
either on a twice weekly schedule for 2 weeks or for 10 consecutive days, and the CIV 
dosing was also given continuously for 10 days. In the initial phase of the study animals 
receiving CIV IL-15 were subdivided into two groups (groups 2 and 3) to evaluate 
responses to different preparations of rhIL-15 distinguished by relative levels of 
deamidation (identified as high-D and low-D forms). Initially the plan was for two treatment 
cycles separated by an 8-week interval, but the protocol was modified at a later time point to 
add a third cycle of CIV low-D IL-15 for treatment groups 2 and 3. This third cycle was 
given approximately 9 months after completion of the second cycle of 10-day continuous 
infusion IL-15. The test animals were assessed for clinical toxicity, had standard 
biochemical and hematologic laboratory tests and several immunologic parameters similar 
to the previous IVB NHP study. The tests also included monitoring serum IL-15 PK, 
production of secondary cytokines in animals receiving CIV rhIL-15, development of 
antibodies to IL-15, and changes in lymphocyte subsets by flow cytometry. 
Table 1: Treatment Groups Rhesus Macaques Toxicology Experiment 
Group 
Treatment 
Dose Level in 
mcg/kg/day 
Route of 
Administration 
Duration of 
Treatment 
Total Doses/ 
Cycle 
# Cycles 
1 
Vehicle 
Control 
0 
Continuous 
Infusion 
10 Days 
Consecutive 
10 
2 

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Group 
Treatment 
Dose Level in 
mcg/kg/day 
Route of 
Administration 
Duration of 
Treatment 
Total Doses/ 
Cycle 
# Cycles 
2 
High-D IL-15 
20 
Continuous 
Infusion 
10 Days 
Consecutive 
10 
3 
3 
Low-D IL-15 
20 
Continuous 
Infusion 
10 Days 
Consecutive 
10 
3 
4 
Low-D IL-15 
20 
Subcutaneous 
2x per week 2 
weeks 
4 
2 
5 
Low-D IL-15 
20 
Subcutaneous 
10 Days 
Consecutive 
10 
2 
6 
Low-D IL-15 
40 
Subcutaneous 
10 Days 
Consecutive 
10 
2 
While no consistent change in the initial phase test animals’ body weights was observed 
during the first 10-day treatment, a number of animals in both CIV arms had decreased food 
consumption, diarrhea, rough hair coat, languid posture most notable from day 7 onward but 
appearing to resolve completely by day 13 or 14. These findings correlated with changes in 
the clinical chemistries that yielded treatment-related abnormal results including elevated 
mean serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), 
decreased albumin, total protein and calcium concentrations in animals given either 20 
mcg/kg high-D or low-D CIV in the day 7 and 10 routine laboratory assessments. The 
changes in the ALT and AST values were not sufficiently abnormal to be considered 
significant at day 7, but had progressed by day 10 and were considered a significant adverse 
treatment effect in these test animals at this time point. The changes observed for albumin, 
total protein and calcium were considered moderate and to be another reflection of the IL-15 
treatment effects on the liver. Diverging somewhat with the clinical observations, the 
adverse treatment-related increases in ALT persisted to day 17 in animals given CIV rhIL-
15. The transaminase elevations had returned back to normal values by day 24 laboratory 
assessments and remained in the normal range when repeated on days 40, 46, 53, 60 and 67 
during treatment cycle 2. However, within 1 day of beginning the second course of high-D 
CIV treatment, one test animal was discovered dead on the second morning of the course. 
The animal had not exhibited any signs of significant toxicities either by inspection or 
laboratory analysis on day 1 and actually had been gaining weight over the course of the 
study. Microscopic examination showed mild to severe autolysis of tissue from many organs 
resulting in loss of cellular detail that did not allow full evaluation of certain organs. There 
were submucosal hemorrhages seen in all parts of the small bowel that was most severe in 
the cecum, but there was an absence of inflammatory cells in all the areas examined 
microscopically. Moderate vascular congestion was seen in several organs and mild alveolar 
edema was noted in the lungs, but both of these findings were felt to be most likely related 
to terminal events. Because of the findings in the small bowel, intussusception was 
considered as a possible cause of this animal’s death, but this was not seen at the initial 
examination of the animal’s abdominal cavity. Ultimately, no clear cause of death was 
identified in this animal based on the gross and microscopic results.  
There was no consistent difference noted in the immune activation or lymphocytosis 
produced by the high and low D rhIL-15 preparations. Compared to the lymphocytosis 
noted in the NHP IVB toxicology study, the increase in WBCs and ALC noted in the groups 
(high D and low D combined in graphs) receiving the 20 mcg/kg CIV dose represented is a 
striking (Figure 1) with ALC showing 20-fold expansion from baseline by the day 10 time 

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13 
point and accounting for approximately 90% of leukocytes. This lymphocytosis is still 
substantially present through day 17, a week after the IL-15 treatment has been stopped and 
it is not until day 24 that the primates WBC and ALC have returned near to their baseline 
levels. FACS results assessing changes in lymphocyte subsets shown below in Figure 2 
demonstrate modest increases in CD4+ cells, substantial increases in (CD3- CD16+) NK 
cells, but dramatic increases in CD8+ lymphocytes that account for the majority of the 
increases in ALC.  The increases in CD4+ lymphocytes were primarily in the central 
memory (CD28+CD95+) subset whereas the increases in CD8+ cells were due to modest 
increases in the central memory subset and 20- to 100-fold increases in the effector memory 
(CD95± CD28-) subset (data not shown) paralleling the results observed in the recently 
performed murine IP experiments.  
Figure 1: White Blood Cell Count and Absolute Lymphocyte Count 
 
 
 
 
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Figure 2: Absolute Number of CD8+, CD4+ and NK Cells    
 
Extensive PK was not performed in the animals receiving CIV rhIL-15, with only single 
time points on days 2 and 10 of infusion assessed. IL-15 levels reached the low ng/mL level 
on day 2 and ranged from 2.1 to approximately 6.3 ng/mL. Day 10 values during course 1 
were generally lower. During subsequent courses the peak values observed were also in the 
ng/mL range, and in some animals, the day 10 values were higher than on day 2 (Figure 3). 
Day 17 and 24 samples (7 and 14 days after last day of infusion) had no detectable human 
IL-15 in the serum. The greater than 20-fold expansion of IL-15–responsive cells 
(presumably IL-15 receptor–positive cells) might contribute to the decrease in free 
circulating rhIL-15 measured at the day 10 time point, but the differences in IL-15 PK 
during course 2 as well as decreased course 2 and 3 leukocytosis are not yet explained and 
remain under investigation. Preclinical testing of rh cytokines in NHP provides valuable 
preclinical information for clinical trials; species differences will occasionally cause 
confounding results, but these issues do not diminish the provocative positive results from 
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these experiments. 
Figure 3: IL-15 Levels  
  
An important cause of the PK and stimulation differences to be eliminated was the 
development of rhesus macaque (rm) antibodies against human IL-15. The rhesus monkeys 
were evaluated for the presence of rm anti-IL-15 antibodies, and in the monkeys receiving 
CIV IL-15, 3 of 6 animals developed detectable levels of antibodies at some point during the 
test period. One animal became positive after the first course with a boost in the IL-15 titer 
in this animal positive after the second course. Another CIV animal became low titer 
positive after the second course and remained positive in the pre-course 3 assessment, and a 
third animal was observed to have antibodies to IL-15 that were just above the lower limit of 
detection of the assay in the pre-course 3 assessment. All 3 animals continued to have 
elevated titers after completing the third course of CIV IL-15. While the test animal that 
demonstrated anti-IL-15 antibodies after the first course of treatment and had the highest 
anti-cytokine titers throughout the experiments had somewhat lower WBC and ALC values 
measured for the first treatment course, this particular macaque and none of the other 
antibody-positive animals showed substantial differences in their lymphocyte expansion or 
pattern of lymphocyte subpopulations compared to animals that tested negative for anti-IL-
15 antibodies. The underlying causes of the difference in the immune response observed in 
courses 2 and 3 treatment has not been fully explained and is still being assessed with 
samples obtained during these experiments.  
The macaques also had an inflammatory cytokine analysis performed. At the time points 
measured in this study, IL-8 was the only cytokine that gave values that were within the 
detection range of the standard curve, while all other samples had signals below the 2.4 
pg/mL test standard. It is possible that evaluation of secondary cytokine induction would be 
more successful if the focus was on early time points such as 4, 8 and 24 hours after 
initiation of continuous infusion that have been measured in the ongoing IVB trial and are 
planned for this trial.  
Compared to NHP that had received 20 mcg/kg/daily as an IVB for 12 days, the animals 
receiving 20 mcg/kg/daily CIV for 10 days had more constitutional and gastrointestinal side 
effects, as well as biochemical laboratory abnormalities that were most noticeable after the 

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first week of course 1 treatment coinciding with the period of greatest lymphocytosis. These 
side effects, biochemistry abnormalities and lymphocytosis, were somewhat blunted during 
the second and third treatment course for reasons that are again not yet entirely clear.  
1.2.1.4 Clinical Experience from the Completed IV Bolus Phase I Study 
The first in-human (FIH) trial that tested a daily 30-minute infusion (IVB) for 12 days in 
subjects with metastatic melanoma and renal cell cancer has been completed after treating 
18 subjects (58). Doses assessed in this trial were 3, 1 and 0.3 µg/kg; with the 0.3 µg/kg 
dose determined to be the MTD for this schedule. DLTs at the 3 µg/kg dose were grade 3 
hypotension and grade 3 thrombocytopenia; DLTs at the 1 µg/kg dose were grade 3 
elevations of transaminases. One Serious Adverse Event (SAE) grade 3 pneumonitis 
possibly related to rhIL-15 treatment occurred during a subject’s second cycle of treatment. 
The frequency and severity of common cytokine related toxicities such as fever, rigors, 
capillary leak syndrome and edema were generally proportional to the dose of rhIL-15.  
Abnormal laboratory results were seen in all subjects and most often were CTC grade 1 or 2 
events. Laboratory adverse events (AEs) were less clearly proportional to the dose of rhIL-
15 both in frequency and severity as indicated by low and transient occurrence of grade 2 
laboratory AEs in the 3 µg/kg cohort, whereas both DLTs in the 1 µg/kg dosing cohort were 
elevated AST/ALT. The 0.3 µg/kg dosing cohort also had a high frequency of laboratory 
abnormalities including non-DLT grade 3 elevation of ALT/AST in one patient. There was a 
consistent temporal pattern of post-treatment AEs most clearly seen in 3 µg/kg cohort with 
fever beginning approximately 2 to 2½ hours after the rhIL-15 infusions, then rigors 
followed almost immediately by decreased blood pressure (BP). 
A similar but less severe set of post treatment toxicities were seen in the 1 µg/kg subjects 
with chills rather than rigors, less significant increases in temperature, but no appreciable 
BP changes. There was a very low frequency or absence of these post infusional events in 
the 0.3 µg/kg dosing cohort. Serial analyses of inflammatory cytokine levels (IL-1β, IL-6, 
IL-8, IL-10 and TNFα) showed marked increases in serum levels of these inflammatory 
cytokines that coincided with these clinical toxicities and was most closely matched with the 
IL-6 levels. As predicted by the NHP toxicology studies performed to support this trial 
appreciable expansion and activation was seen for T-cells and NK cells, but the increase in 
lymphocytes was statistically significant only for the group that received the 3 µg/kg dose 
that produced a 10-fold increase in NK cells, a more than 3-fold increase in T-cells mostly 
due to expansion of the terminally differentiated (memory and effector memory) CD8+ cells. 
The half-life (t ½) was approximately 2 1/2 hours with Cmax 47,800, 15,900 and 1260 
pg/mL respectively for the 3 dose levels tested. There were no clinical responses, with stable 
disease as a best response. However, 5 subjects manifested a decrease between 10 and 30% 
in their marker lesions, with 2 of these subjects having improvement or clearance of some 
lung lesions.  
1.2.1.5 Previous Clinical Experience for Patients treated in this Protocol 
Twenty-five patients have been enrolled and treated in this protocol. Patients 1-10 were 
treated at the first 3 dose levels (0.1 mcg/kg, 0.25 mcg/kg and 0.5 mcg/kg) and had no DLTs 
or significant toxicities.  
Patients # 11 through 16 were treated at the 1 mcg/kg dose level without additional issues 
except patient #11 who was taken off treatment because he experienced DLT: grade 3 

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hypoxia on Cycle 1 Day 6. The patient’s respiratory status was improving daily in the 8 
days he was observed after this event, but it was not completely resolved by the time he was 
discharged home. The research team continued to be in contact with the patient after 
discharge. The patient reported some dyspnea on exertion during the trip from the airport, 
but was comfortable on the same low flow oxygen when finally settled at home and had no 
new complaints. When next contacted, the patient’s family reported that when the patient 
was checked approximately one hour after going to bed, he was found to be unresponsive. 
Paramedics were called and determined that the patient had already expired. No 
resuscitation attempts were made and a post mortem exam was not performed due to the 
family’s wishes. This death was reported on NIH Problem Form iRIS # 335749.   
Patients #17 through 19 tolerated the 2 mcg/kg dose level without significant toxicities or 
DLT. 
Patients #20 and 21 treated at the 4 mcg/kg dose level both had serious DLTs that required 
early discontinuation of their treatment. Patient # 20 was a 64-year-old male with a history 
of relapsed refractory high mitotic rate spindle cell gastrointestinal stromal tumor (GIST) of 
the small bowel which was initially diagnosed in August 2010. The patient began CIV rhIL-
15 treatment on 3 February 2015 and initially tolerated his treatment with the expected side 
effects; but by treatment day 4 he had become very fatigued, agitated and had an inverted 
sleep cycle. In addition, he had significant increases in his LFTs especially his bilirubin that 
required interruption of his treatment by day 5. The patient also became hypoxic later that 
day and required oxygen by nasal cannula to maintain adequate oxygen levels. Interruption 
of his treatment and attempts to diurese the patient did not improve his symptoms, hypoxia 
or his laboratory abnormalities and when the patient became frankly encephalopathic on 
cycle 1 day 6, his treatment was permanently discontinued. A CT pulmonary angiogram 
confirmed the patient had no pulmonary emboli and over the course of the next few days his 
abnormal LFTs, encephalopathy, hypoxia and general condition improved to the point that 
the patient was discharged home. His overall improvement continued for the next 10 to 14 
days and he had returned to his pretreatment functional status when he began to complain of 
increased abdominal/RUQ pain, decreased appetite and worsening performance status. 
Restaging CT scans performed on cycle 1 day 28 confirmed physical exam findings of 
worsening hepatomegaly and dramatic progression of his intrahepatic as well as an increase 
in intra-abdominal disease compared to his pretreatment scans. He was taken off protocol at 
this time. The patient was assessed as recovered from his acute rhIL-15 toxicities and his 
late general decline was attributed to massive progression of his hepatic and abdominal 
disease. The patient was unable to qualify for any additional research studies due to his poor 
performance status and worsening organ dysfunction. He died in Home Hospice on 28 April 
2015. 
Patient #21 was a 61year old female with squamous cell carcinoma (SCC) at the base of the 
tongue (BOT) initially diagnosed in August of 2012 and treated with aggressive combined 
modality treatment for a complete remission. The patient was discovered to have inoperable 
locally recurrent or metastatic disease in December of 2014. This patient began treatment 
rhIL-15 (4 mcg/kg/day by CIV for 240 hours) on 9 February 2015. Her treatment was 
complicated by significant diarrhea initially considered osmotic due to a change in her G-
tube nutritional supplement and later antibiotic related enteritis from empiric treatment with 
Amoxicillin/Sulbactam (Unasyn®) that eventually required interruption of her CIV rhIL-15 

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treatment on day 3. The patient’s diarrhea improved with a 24-hour interruption of her CIV 
rhIL-15, but within a few hours of restarting rhIL-15 treatment the patient developed signs 
of an acute abdomen. She underwent a laparotomy that evening and was found to have 
patchy ischemia involving all of her stomach, small and large bowel that could not be 
addressed by surgical resection. A detailed description of her course and her grade 5 
Visceral Arterial Ischemia was reported to the IRB in an NIH Problem Form.  
The 4 mcg/kg dose level was clearly above the MTD for these 2 patients. As a result, we 
dropped to the next lower dose level of 2mg/kg for subsequent patients. 
Patient # 22 tolerated his 2 cycles of treatment at the 2 mcg/kg dose level relatively well 
with intermittent temperature spikes concluded to be due to his disease after multiple 
negative blood cultures and negative UA. This patient did however have prolonged fatigue 
after both cycles which gradually improved to baseline or near baseline Performance Score 
(PS) level by his day 28 visits. Post cycle 1 restaging demonstrated stable disease, but his 
post cycle 2 restaging demonstrated disease progression and the patient was taken off study. 
Patient # 23 had metastatic recurrent uterine mixed papillary serous clear cell carcinoma and 
tolerated both cycles of treatment at the 2 mcg/kg dose level fairly well with the expected 
side effects of fatigue, fevers, chills but had appreciable rises in her serum creatinine during 
both cycles of treatment. She also developed progressive dyspnea associated with a 
moderate right sided pleural effusion and mild hypoxia near the end cycle 1 treatment that 
required supplemental oxygen by nasal cannula for a brief period. The patient had a 
therapeutic thoracentesis the day after completing her 240 hours of CIV rhIL-15 after which 
her dyspnea and hypoxia resolved. The patient had returned to her baseline PS within a few 
days of completing her cycle 1 and after her restaging scans documented stable disease, she 
went on to receive her second cycle of treatment. She tolerated her second cycle of 
treatment with less dyspnea, developed a smaller pleural effusion and only a relative 
decrease in her oxygen saturation that did not require supplemental oxygen, but again had a 
therapeutic thoracentesis after completing treatment to improve her respiratory status. 
Analyses of both thoracenteses showed exudative pleural fluid with ≈ 400 to 650 
WBCs/mm3 primarily lymphocytes, few neutrophils, some “other cells” possibly tumor 
cells and were microbiologically sterile. The patient was known to have fairly extensive 
right sided sub-diaphragmatic metastatic disease and had previously undergone debulking 
surgery that included resection of some of her right hemi-diaphragm. We concluded that 
these treatment-related effusions represented rhIL-15 related inflammation at this site of 
tumor because the patient did not develop a left sided pleural or any other body cavity 
effusion during her treatment. The patient’s post cycle 2 restaging showed stable disease; 
she was taken off treatment and remains on study without any treatment related issues.  
Patient # 24 who had a diagnosis of NSCLC with EGFR mutation (exome 19 deletion 
normally associated with EGFR-TKI responsiveness) received one cycle of therapy at the 2 
mcg/kg dose level. The patient was noted to have a new right inferior temporal lesion on her 
cycle 1 day 28 CT scan of the neck. She had an MRI of the brain which showed at least 7 
new enhancing lesions that were consistent with new CNS metastases. The patient was 
started on dexamethasone and sent for consultation with Radiation Oncology. She was taken 
off study for disease progression and initiation of another salvage therapy. 
Patient #25 tolerated 2 cycles of treatment without any significant toxicities. Treatment was 

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discontinued after the post cycle 2 restaging which demonstrated no significant 
improvement in her disease and she was subsequently taken off protocol when restaging 
scans performed at home showed disease progression. 
The protocol and the IND were placed on clinical hold in May 2015 due to concerns about 
pharmacy infusion preparation procedures after discovery of several vials of human serum 
albumin contaminated with fungus in the lot that had been used to prepare infusion mixtures 
for 4 of the patients treated in this protocol (NIH Problem Form iRIS # 346817). No 
evidence of infection or unusual clinical events was seen in a period of prolonged 
observation and the FDA has recently specified changes in the drug preparation procedure 
that will allow the protocol to resume. 
Since resumption of the protocol in 2017, the last two patients #26 and 27 in the 2 mcg/kg 
expansion cohort for the 10-day regimen have completed their treatment without unexpected 
problems. The first two patients #28 and 29 treated with 3 mcg/kg on the 5-day regimen 
have completed at least one cycle of treatment without unexpected problems or DLT.  
1.2.1.6 Rationale for Phase I Evaluation of Repeated Cycles of rhIL-15 given on either a 
10-day or 5-day CIV Schedule  
When rh cytokines first became widely available for clinical trials, in addition to identifying 
appropriate dosing, different routes of administration (IVB, CIV, SC, intracavitary or IP) 
and schedules were evaluated. At the time the NCI Surgery Branch was piloting the three 
times daily (tid) IVB regimen that has become the standard HD IL-2 regimen, the so called 
“West” regimen with CIV HD IL-2 given over 5 days (120 hours) was being investigated in 
numerous clinical trials. The initial publication for this CIV regimen reported a higher 
response rate (RR) along with a similar spectrum of typical cytokine-induced side effects, 
but did not show the roller coaster (peak valley) course of BP, capillary leak and widened 
A-a gradient characteristic of the tid HD IL-2 regimen (59, 60). An important feature that 
made this treatment plan popular with certain practitioners was the gradual emergence of 
more serious or DLTs as the patient’s limit of tolerance was approached more slowly. The 
every 8 hour IVB HD IL-2 regimen can be characterized by acute onset of respiratory and 
vascular toxicities with significant variation depending on the active drug levels related to 
the most recent dose; these toxicities can occur early in the treatment cycle. In addition, 
patients can rapidly transition from a tolerable treatment course to severe complications in 
the space of a few consecutive doses (36). With CIV HD IL-2, there is no rapid variation in 
immune activation or secondary cytokine levels, and the patients approach their 
unacceptable toxicity threshold at a steadier and usually slower rate. This CIV HD IL-2 
regimen has not been popular for quite some time, but lower-dose CIV regimens have been 
evaluated by the French Immunotherapy Group (60), in the treatment of patients with HIV 
(61). It is also interesting to note that recently a positive phase III licensing trial for the anti-
GD2 chimeric antibody ch14.18 in the treatment of advanced pediatric neuroblastoma (62) 
used a CIV IL-2 regimen as part of a multi-agent treatment. This trial was initiated with a 6-
week cycle length based on data from the NHP toxicology study that validated the treatment 
regimen given every 6 weeks. An ongoing clinical multicenter trial (NCI protocol 13-C-
0045 or CITN 11-02) evaluating a similar rhIL-15 SC outpatient regimen (M-F for 2 
consecutive weeks) has demonstrated that rhIL-15 can safely be given on a 4-week 
schedule. Patients need to demonstrate some evidence of a clinical response during their 
first 2 cycles of treatment to be eligible for additional treatment cycles. The clinical course 

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of patients treated with repeated treatment cycles 4 weeks in length restaged every other 
cycle allowed by previous amendments has not demonstrated any new or unexpected 
problems. 
The safety data from the NHP toxicology study demonstrated increased systemic, GI, 
constitutional and biochemistry side effects in the test animals that appeared to coincide 
with lymphocytosis arising near the end of the first week of treatment. In this proposed 
study to maximize patient safety, all patients will be treated as inpatients, have frequent 
clinical (blood pressure, heart rate, respiratory status including pulse oximetry) monitoring 
and at least daily laboratory assessments. The current rhIL-15 clinical experience has 
provided good fundamental understanding of the biologic effects of this cytokine, the 
limitations of preclinical models and NHP pharm-tox experiments to predict all events in 
humans is clearly evident. Current results strongly indicate that transient biochemical 
abnormalities such as elevated liver function tests, decreased leucocytes, lymphocytes and 
platelets can normalize even if CIV rhIL-15 is continued and will resolve to baseline after 
discontinuation of treatment. Unlike the patients treated with the higher doses in the IVB 
trial, none of the CIVrhIL-15 treated patients through the 2 mcg/kg dose level have 
demonstrated meaningful blood pressure changes, spiking fevers or rigors noted in the rhIL-
15 IVB patients. There has been no correlation between IL-15–induced lymphocytosis and 
the intensity of side effects for patients treated in this study or with the IVB regimen that 
indicate CIV rhIL-15 reproduced the striking lymphocytosis seen in the NHP toxicology 
studies would automatically be at higher risk for SAEs. Hematologic and immunologic data 
from patients previously treated in this trial and the SC trial (protocol 13-C-0045) (63-65) 
also have indicated some divergence in the rhIL-15 effects in humans compared to NHP that 
should be investigated. In contrast to the NHP data, the CIV and SC rhIL-15 treated patients 
are showing appreciably greater in vivo increases in absolute NK cell numbers (20-50x 
pretreatment), but much lower increases in CD8 T-cells (≈ 2-3x pretreatment) albeit at lower 
rhIL-15 doses than was well tolerated in the NHP. There is preliminary data suggesting 
differences in the kinetics for upregulation of the IL-15 receptor β chain (CD122) between 
NK and CD8 cells for the patients treated in this trial that may play a role in this finding. 
The safety profile and AEs for the patients treated at the 0.5, 1 and 2 mcg/kg dose levels 
were not appreciably different and suggested the true MTD for the CIV regimen was higher. 
The SAEs that occurred for the 2 patients treated at the 4 mcg/kg dose level were totally 
unacceptable and by conventional assessments indicated the MTD had been exceeded for 
the CIV regimen, but there are unique features to each patient that should be recognized. 
The start of patient #20’s treatment was delayed 6 weeks for approval of a prior amendment 
during which time his disease became abruptly more aggressive resulting in substantial 
progression of his hepatic disease burden. The patient had recovered from his hepatic 
encephalopathy within a week to 10 days after stopping rhIL-15 with slower improvement 
of his liver function tests. When the patient was taken off protocol due to disease 
progression his scans demonstrated multiple hepatic and mesenteric masses in excess of 10 
cm in diameter and large volume replacement of his liver with the patient’s malignancy. 
Patient #21’s grade 5 SAE was problematic on many levels including the ultimate inability 
to define the primary pathophysiology that occurred with this event. The patient was 
assessed as initially having an osmotic diarrhea related to change in her G-tube oral 
supplementation that was potentiated by the empiric addition of ampicillin/sulbactam 
(Unasyn) that frequently causes antibiotic associated enteritis. Prior experience in NCI and 

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extramural rhIL-15 clinical trials had not shown any real evidence of IL-15 related diarrhea 
or potentiation of diarrhea due to another cause despite NHP toxicology results that 
demonstrated diarrhea in the macaques. The diffuse patchy ischemia seen in the patient’s 
stomach, small and large bowel at laparotomy infers that rhIL-15 may have potentiated 
localized inflammation that compromised small vessel blood flow. We believe that both of 
these patients represent very unique situations that can be avoided by additional changes in 
eligibility, dose adjustment algorithm and DLT criteria to allow evaluation of rhIL-15 above 
2 mcg/kg in a 5-day treatment schedule with sufficient safety margin.  
The effort to identify the optimal regimen for any new immunotherapeutic requires clinical 
evaluation of the various routes of administration and different schedules. Most of the 
murine preclinical IL-15 studies did not perform comparative examination of different 
schedules, routes of administration or repeat cycles of treatment that could have helped 
identify the most promising route and schedules of rhIL-15 to be assessed in the initial 
clinical trials, and our recent murine experiments were also not comprehensive. While the 
IVB and CIV toxicology studies were performed sequentially, there are data that allows 
some comparative deductions. Preclinical data from the initial NHP toxicology experiment 
evaluating IVB rhIL-15 showed the increase in absolute numbers of lymphocytes was most 
notable for NK and CD8+ cells predominantly in the stem, central and effector memory 
subsets. Early data from the current IVB clinical trial has demonstrated less consistent 
expansion of CD8+ cells. Comparison of the immune activation derived from IVB and CIV 
dosing in these NHP toxicology experiments showed that CIV produced a significantly 
greater ALC expansion (2.5-fold vs.10 to 25-fold) after a single cycle of rhIL-15 treatment.  
 
 

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2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Age ≥ 18 years. 
2.1.1.2 Patients must have histologically confirmed (by the NCI Pathology Department) 
solid tumor malignancy or lymphoma that is metastatic or unresectable and for 
which standard curative or palliative measures do not exist or are associated with 
minimal patient survival benefit (as defined by the Lymphoid Malignancies Branch 
physicians) or if the patient refuses standard of care treatment. Enrollment of 
patients with tumors that can be safely biopsied is encouraged.  
2.1.1.3 Patients must have evaluable or measurable disease, defined as at least one lesion 
that can be accurately measured in at least one dimension (longest diameter to be 
recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm with 
conventional techniques or as >10 mm with spiral CT scan. See Section 6.2 for the 
evaluation of measurable disease. 
2.1.1.4 Patients must have recovered to ≤ grade 1 CTCAE v4 from toxicity of prior 
chemotherapy or biologic therapy and must not have had prior chemotherapy or 
biologic therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C, 8 weeks 
for UCN-01).  
2.1.1.5 Patients on bisphosphonates for any cancer or on hormone therapy for prostate 
cancer will not need to discontinue this therapy to be eligible. However, patients 
with prostate cancer will need to have metastatic prostate cancer that has 
progressed despite hormonal therapy. Castrate testosterone levels occur within 
hours after castration and within 2 to 3 weeks of a luteinizing hormone-releasing 
hormone agonist. The current standard is to continue androgen suppression despite 
progressive disease. 
2.1.1.6 DLCO/VA and FEV-1.0 ≥ 60% of predicted on pulmonary function tests. 
2.1.1.7 Serum creatinine of ≤ 1.5 X the upper limit of normal. 
2.1.1.8 AST and ALT < 2.5 x the upper limit of normal. 
2.1.1.9 Absolute neutrophil count ≥ 1,500/mm3 and platelets ≥ 100,000/mm3. 
2.1.1.10 Karnofsky performance status ≥ 70% or ECOG ≤ 1 (see APPENDIX A) 
2.1.1.11 Subjects with inactive central nervous system (CNS) metastasis are eligible. 
Inactive CNS metastasis is defined as: no signs of cerebral edema after successful 
definitive treatment of brain metastases (surgical resection, whole brain irradiation, 
stereotactic radiation therapy, or a combination of these) with stable or improved 
radiographic appearance on MRI scan at least 1 month after completion of 
treatment. 
2.1.2 Exclusion Criteria 
2.1.2.1 Patients who have received any systemic corticosteroid therapy within 3 weeks 
prior to the start of therapy with the exception of physiological replacement doses 

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23 
of cortisone acetate or equivalent. 
2.1.2.2 Patients who have received any cytotoxic therapy, immunotherapy, antitumor 
vaccines, monoclonal antibodies or major surgery in the 4 weeks prior to the start 
of the study. 
2.1.2.3 Life expectancy of less than 3 months.  
2.1.2.4 Patients with more than 30% replacement of hepatic parenchyma by tumor or any 
history of drug related hepatic encephalopathy. 
2.1.2.5 History of complex ventricular or supraventricular arrhythmias. 
2.1.2.6 Documented HIV, active bacterial infections, active or chronic hepatitis B, or 
hepatitis C. 
• A positive hepatitis B serology indicative of previous immunization (i.e., HBsAb 
positive and HBc Ab negative), or a fully resolved acute hepatitis B infection is 
not an exclusion criterion. 
• A positive hepatitis C serology is an exclusion criterion. 
2.1.2.7 Concurrent anticancer therapy (including other investigational agents), with the 
exception of hormone therapy for prostate cancer (see Section 2.1.1.5). 
2.1.2.8 Active CNS metastasis (inactive CNS metastasis is defined in Section 2.1.1.11). 
2.1.2.9 History of severe asthma or presently on chronic inhaled corticosteroid medications 
(patients with a history of mild asthma controlled with inhaled bronchodilators are 
eligible). 
2.1.2.10 History of autoimmune disease, with the exception of an autoimmune event 
associated with prior ipilimumab (anti-CTLA-4) therapy that has been completely 
resolved for more than 4 weeks. 
2.1.2.11 Inability or refusal to practice effective contraception during therapy or the 
presence of pregnancy or active breastfeeding (men and women of childbearing 
potential must use an effective method of birth control or abstinence during 
treatment and for 4 months after completion of treatment). 
2.1.2.12 Cognitive impairment, history of medical or psychiatric disease, other uncontrolled 
intercurrent illness, active substance abuse, or social circumstances, which in the 
view of the Principal Investigator (PI), would preclude safe treatment or the ability 
to give informed consent. 
2.2 
SCREENING EVALUATION 
Screening evaluation must be performed to determine eligibility within 28 days prior to patient 
receiving any study intervention, except as indicated below. 
2.2.1 Complete medical history and physical examination with vital signs and documentation 
of all measurable or evaluable abnormalities.  
2.2.2 Computerized tomography (CT) scan of the chest, abdomen, and pelvis. (CT and/or MRI 
films from outside institution performed within 28 days prior to enrollment may be used 
to determine eligibility. Same films may be used as baseline if done within 28 days prior 
to starting treatment.) 

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24 
2.2.3 MRI or contrast-enhanced CT scan of the brain for melanoma subjects or subjects with 
complaints and/or physical findings suspicious for occult CNS metastasis. 
2.2.4 Documentation of Karnofsky Performance Score ≥ 70% or ECOG ≤ 1 (see APPENDIX 
A). 
2.2.5 Verification that the NCI Laboratory of Pathology has confirmed the histology prior to 
patient registration (No Time Frame). Pathological confirmation of diagnosis can be 
carried out on available slides from either the primary diagnostic biopsy or subsequent 
biopsies performed either at the Clinical Center or outside institutions. If necessary, the 
specimen blocks will be obtained for special stains and other evaluation as deemed 
necessary to confirm the diagnosis of cancer. If the original pathological material or other 
diagnostic biopsies are not available, or if there is uncertainty concerning the diagnosis, a 
repeat biopsy may be undertaken to confirm the diagnosis of cancer. 
2.2.6 Complete blood count (CBC) with differential and platelet count Acute Care Panel 
(sodium, potassium, chloride, CO2, glucose, BUN, creatinine); Hepatic panel (alkaline 
phosphatase, ALT, AST, total and direct bilirubin), LDH, Mineral panel (serum calcium, 
phosphate, magnesium and albumin) and ammonia level. 
2.2.7 Serum pregnancy test in women of childbearing potential.  
2.2.8 Thyroid function tests to include a serum thyroxine (T4) and thyroid-stimulating 
hormone (TSH). 
2.2.9 Anti-nuclear antibodies (ANA), rheumatoid factor (RF) and anti-thyroid antibodies 
2.2.10 Urinalysis. 
2.2.11 12 lead EKG. 
2.2.12 Hepatitis B Surface Antigen, Hepatitis B Surface Antibody, Hepatitis B core Antibody 
and Hepatitis C: HIV 1/2 serology. 
2.2.13 Pulmonary function tests with DLCO. 
2.3 
REGISTRATION PROCEDURES 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent. A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to: NCI Central Registration Office at ncicentralregistration-l@mail.nih.gov. 
After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to 
advise them of the acceptance of the subject on the protocol prior to the release of any 
investigational agents. Verification of Registration will be forwarded electronically via e-mail to 
the research team. A recorder is available during non-working hours.  
2.4 
BASELINE EVALUATION 
The following tests and procedures will be done within 28 days of initiating treatment with rhIL-
15 (except as marked below). If baseline tests were already performed and meet the required 
time frames, they will not need to be repeated. 
2.4.1 Baseline history with documentation of sites of disease, physical examination, vital signs 
and performance score. 

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25 
2.4.2 Serum pregnancy test in women of childbearing potential must be repeated within 3 days 
prior to starting study drug. 
2.4.3 CBC with differential, Acute Care Panel, Hepatic Panel, LDH and Mineral Panel must be 
repeated if not done within 2 weeks of starting study drug. 
2.4.4 Reticulocyte Count 
2.4.5 Serum immunoglobulin levels 
2.4.6 Troponin T or I, based on availability of test in Department of Lab Medicine (DLM) 
2.4.7 HLA typing (A, B, C, DR, DQ) 
2.4.8 Serum tumor marker (PSA, CEA, and CA125) assessment if applicable (within 7 days 
prior to initiating treatment with rhIL-15) 
2.4.9 CT scan of the chest, abdomen and pelvis, or MRI if CT scan is not sufficient or 
contraindicated 
2.4.10 Other imaging studies may be done to document disease as appropriate and at the 
direction of the PI. 
2.4.11 Baseline flow cytometry to assess lymphocyte sets and subsets (see Section 5.1.2):  
2.4.11.1 One 10-mL lavender-top tubes to Clinical Center Dept. of Lab. Medicine for 
Lymphocyte Phenotype IL-15 FACS panel. 
2.4.11.2 Two lavender-top tubes to the Clinical Support Laboratory in Frederick for special 
FACS analysis. 
2.4.12 One 4-mL Serum Separator Tube (SST) tube to the Clinical Support Laboratory in 
Frederick for inflammatory marker and cytokine analysis (see Section 5.1.3).  
2.4.13 Optional Tumor Biopsy (see Section 5.1.5)  
3 
STUDY IMPLEMENTATION  
3.1 
STUDY DESIGN 
This is a Phase I open-label, non-randomized, dose-escalation safety trial of CIV rhIL-15 that 
will enroll 41 to 47 evaluable patients with metastatic unresectable cancers for which curative or 
palliative measures either do not exist or are not associated with a survival advantage.  
Patients will receive CIV rhIL-15 for 10 consecutive days (240 hours) and will be assigned to a 
dose level sequentially based on their order of entry into the study. The starting dose will be 0.1 
mcg/kg/day and in the absence of significant toxicities, dose escalation will proceed to evaluate 
dose levels of 0.25, 0.5, 1, 2 and 4 mcg/kg/day. Cycles 1 and 2 will be 42 days in length, but all 
subsequent treatment cycles will be 28 days in length with an additional 7 days on either 
schedule allowed for reasons other than recovery for treatment-related toxicities. Subjects will 
have to demonstrate an absence of anti-IL-15 antibodies in their post-treatment (day 12 and week 
4) assessments before additional cycles of rhIL-15 can be initiated.  
Radiologic reassessments for 10-day treatment cycle patients will be performed during week 4 
(days 26 to 35) of Cycles 1 and 2 and at off-treatment and off-study visits.  

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26 
After treatment of patients in the expansion cohort for the 10-day schedule is completed, new 
cohorts of 3 to 6 patients each will begin treatment with the 5-day (120 hour) schedule at dose 
levels of 3, 4 or 5 mcg/kg/day to define the MTD for this shorter CIV rhIL-15 regimen. All 
treatment cycles for these cohorts will be 21 days in length.  
As of April 2016, twenty-four evaluable patients have enrolled on Dose Levels 1-6; with 2 more 
to be enrolled in Dose Level 6 after Amendment G. When the study is re-opened for enrollment, 
an additional 17-23 evaluable patients will be enrolled. 
A total of 9 patients will potentially be treated at the MTD or maximum administered dose for 
both schedules to better characterize the clinical activity of CIV rhIL-15 in this patient 
population. 
Radiologic reassessments for both the 10day and 5-day dosing cohorts will be performed after 
every other cycle (2, 4, 6, 8 etc.) including the subjects that go onto to receive additional cycles 
of treatment. 
Patients receiving the 10-day treatment schedule without evidence of an ongoing response after 
any 2 consecutive cycles of treatment will discontinue rhIL-15 and be followed until disease 
progression is documented or they go off study for another reason. (Ongoing response is defined 
as: > 15% decrease in sum of marker lesions and/or improvement or disappearance of some non-
measurable lesions and/or > 10% decrease in tumor markers.) Patients receiving the 5-day 
treatment schedule will have 4 cycles of treatment to demonstrate responsiveness to rhIL-15, so 
that patients are given an equal number of rhIL-15 doses to confirm the treatment has sufficient 
activity to justify more prolonged treatment.  
Patients who demonstrate a complete response (CR) to treatment will receive 2 additional cycles 
after the cycle where the CR is first documented. 
Patients whose best response after 2 consecutive cycles of treatment is stable disease and those 
who stop treatment due to toxicity will be followed with routine exams and restaging x-rays 
(every 60 days x 3 and then quarterly) unless progressive disease is documented or they begin 
another treatment for their cancer. 
3.2 
DOSE-LIMITING TOXICITY  
There are some well-described, clinically inconsequential side effects associated with 
immunotherapy that are addressed differently than with other types of cancer therapies and affect 
the consideration of DLTs. Patients receiving rh cytokines often have an initial decrease in their 
total white blood cell (WBC) counts, significant lymphopenia and occasionally some degree of 
neutropenia early in the course of their treatment (66, 67). Unlike cytopenias noted in patients 
receiving cytotoxic chemotherapies, these drops are usually transient and presumed to be related 
to increased margination (adherence to blood vessel endothelium) or alterations in trafficking 
that reduces the number of circulating cells rather than the destruction of the mature effector and 
bone marrow precursor cells (68). The impediment to normal trafficking (chemotaxis) of various 
classes of leucocytes best described for patients treated with HD IL-2 marginally increases the 
risk for infections, especially central catheter–associated bacteremia; but the rate of infections in 
cytokine-treated patients is substantially less than leucopenic and neutropenic chemotherapy-
treated patients (69).  
As such, rh cytokine treatment resulting in grade 3 or 4 cytopenias, especially lymphopenia, in 
the absence of signs of infection is usually not interrupted. Less commonly, patients receiving 

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27 
activated T-cells and cytokine therapy will have a significant leukocytosis (67). Even though 
these cells are activated and generally large lymphocytes, toxicities seen in leukemic patients 
with elevated WBC counts are not encountered and therapy is not interrupted based purely on an 
arbitrary WBC number. In the completed IVB trial and in this protocol, we have observed most 
commonly during the first 7 days of treatment transient increases in liver function tests (alkaline 
phosphatase, alanine aminotransferase [ALT] and aspartate aminotransferase [AST] which 
usually begin to improve while the subject continues treatment and have not been associated with 
any clinical signs of hepatotoxicity. During the IVB trial, treatment was discontinued for grade 3 
elevations (> 5 times ULN) of AST and/ALT in 2 subjects treated at the 1 mcg/kg dose level 
who otherwise were tolerating their treatment very well. Some subjects previously treated in this 
protocol have had less significant elevations that have also resolved without incident, DLTs or 
clinical sequelae. HDIL-2 subjects commonly have abnormalities of their LFTs in many 
occasions much more abnormal than we have observed in the rhIL-15 subjects and continue their 
treatment (59, 60). Similar transient increases which resolve spontaneously most often with 
continued rhIL-15 or in all cases after treatment is stopped have also not been associated clinical 
hepatotoxicity with the one exception discussed in Section 1.2.1.6. We believe that the clinical 
experience with rhIL-15 in all three trials with the additional limitation on degree of hepatic 
tumor replacement allows continuation of the DLT exception with regards to ALT, AST, 
alkaline phosphatase, total and direct bilirubin. 
3.2.1 DLT will be defined as follows: 
Grade 2 diarrhea lasting more than 24 hours or any grade 3 or 4 toxicity, if deemed possibly, 
probably or definitely related to the study drug by the PI during the first cycle of treatment, with 
the following exceptions: 
Hematologic exceptions: 
• Grade 3 or 4 lymphopenia 
o rhIL-15 will be continued in the event of asymptomatic grade 3 or 4 lymphopenia, 
unless there are clinical signs of significant infection (persistent fevers, labile blood 
pressure, localized complaints or findings on physical exam, hypoxia or organ 
dysfunction).  
• Grade 3 granulocytopenia  
o rhIL-15 will be continued in the event of grade 3 granulocytopenia unless there are 
clinical signs indicating a significant infection, as listed above.  
• Grade 3 leukocytosis (WBC > 100, 000/mm3) in the absence of signs of leukostasis or 
other toxicities possibly related to the expansion of activated cells. 
Non-hematologic exceptions: 
• Transient (< 24 hours) grade 3 hypoalbuminemia, hypokalemia, hypomagnesemia, 
hyponatremia or hypophosphatemia which responds to medical intervention. rhIL-15 will 
be continued while the metabolic abnormalities are corrected by intravenous and oral 
supplementation. 
• Non-sustained (< 7 days) grade 3 liver function test (ALT, AST, alkaline phosphatase, 
total or direct bilirubin) abnormalities in the absence of clinical signs of hepatic 
dysfunction (lethargy, confusion, anorexia, pruritus, tremor). rhIL-15 will be continued as 
long as these abnormalities do not persist more than 7 days or the patient does not exhibit 
findings consistent with hepatic toxicity.  

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28 
3.3 
DOSE ESCALATION  
Dose escalation will proceed in cohorts of 3 to 6 patients. Patients will not begin treatment at the 
next higher dose level until all patients treated at the previous dose level have reached day 21 of 
the protocol, recovered from any clinical or laboratory toxicities and would be able to initiate 
another cycle of treatment unless restaging has demonstrated progression of their disease). The 
MTD is the dose level at which no more than 1 of up to 6 patients experience DLT, and the dose 
below that at which at least 2 (of ≤ 6) patients have DLT as a result of the drug. If a patient did 
not experience DLT and did not finish 1 cycle of treatment (42 days), he or she will not be 
evaluable for determination of the MTD and will be replaced in the dose level. 
Dose escalation will follow the rules outlined in the Table below. 
Number of Patients with 
DLT at a Given Dose 
Level 
Escalation Decision Rule 
0 out of 3 
Enter up to 3 patients at the next dose level 
> 2 
Dose escalation will be stopped. This dose level will be declared the 
maximally administered dose (highest dose administered). Up to 3 
additional patients will be entered at the next lowest dose level if only 3 
patients were treated previously at that dose. 
1 out of 3 
Enter up to 3 more patients at this dose level. 
• 
If 0 of these 3 patients experience DLT, proceed to the next dose level. 
• 
If 1 or more of this group suffer DLT, then dose escalation is stopped, 
and this dose is declared the maximally administered dose. Up to 3 
additional patients will be entered at the next lowest dose level if only 
3 patients were treated previously at that dose. 
<1 out of 6 at highest dose 
level below the maximally 
administered dose 
This is the MTD and is generally the recommended phase 2 dose. At least 
6 patients must be entered at the recommended phase 2 dose. 
The MTD has already been defined for patients treated with the 10-day regimen. For patients 
treated with the 5-day regimen dose escalation will continue through the 5 mcg/kg/day dose level 
in the absence of ≥ 2 DLTs for the patients treated for any of the dose levels being evaluated for 
the 5-day regimen. If an MTD is not identified up to 9 patients may be treated at the maximum 
administered dose (MAD) of 5 mcg/kg/day to better evaluate the therapeutic potential of rhIL-15 
given by this schedule.   
3.4 
DRUG ADMINISTRATION 
For all dose levels, the dose of rhIL-15 will be diluted in the appropriate volume of 0.1% human 
serum albumin (HSA) in 5% dextrose in water, USP (D5W) to reach a final rhIL-15 
concentration of 1 mcg/mL. The rhIL-15 treatment will be administered to the patient by 
continuous 24-hour intravenous infusion (CIV) using portable ambulatory pump on the inpatient 
unit for either a total of 240 or 120 hours depending on the treatment cohort. Treatment with 
rhIL-15 will begin within 4 hours of preparation of the infusion bag and each infusion bag must 
be completed within 24 hours from the time drug administration begins. If the infusion bag is not 
empty at the 24-hour time point, the remaining solution will be discarded and the next infusion 
bag will be started. The 240- or 120-hour infusion time frame will not be extended.  

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29 
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 2-8º 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.-Frederick, the drug manufacturer. 
The rhIL-15 will be infused through a PICC or another appropriate CVAD.  
Samples for PK assessments must not be drawn from the PICC or CVAD through which the 
rhIL-15 is infused. If feasible, venous access will be placed at 2 locations NOT in the same 
extremity during cycle 1. This will prevent contamination of the blood draws with residual rhIL-
15 present in the catheter or double lumen catheters with distal openings in close proximity. 
In Cycle 2 and beyond, the IL-15 infusion may be put on hold for 5-15 mins to collect routine 
(non-PK) daily labs. 
3.5 
DOSE MODIFICATIONS 
Since this is a phase I study intending to define the MTD, there will be no dose modifications or 
interruption of treatment during the first cycle of treatment for the 5-day dosing cohorts. The 
rhIL-15 infusion maybe interrupted for up to 24 consecutive hours for reasons other than 
DLTs without bearing on the patient’s continued treatment during subsequent treatment 
cycles for patients treated with either schedule. Interruptions of the infusion will not be 
made up by extending the 240- or 120-hour infusion and there will be no change in the date 
and time the 10- or 5-day infusion is terminated unless the treatment is stopped early for 
safety reasons. Patients with evidence of clinical benefit at restaging may have interruptions or 
early termination of their CIV rhIL-15 during later retreatment cycles for non-DLT events to 
improve tolerability of the treatment without forfeiting the possibility of subsequent treatment 
cycles. Stoppage of less than 15 minutes occurring during the daily change of the rhIL-15 
infusion device will not be considered an interruption. 
3.6 
MONITORING DURING THERAPY  
The following tests and procedures will be performed during all treatment cycles as indicated in 
Section 3.8, Study Calendars.  
3.6.1 Acute Care, Hepatic and Mineral Panels, ammonia level and LDH  
3.6.2 CBC with differential  
3.6.3 Troponin T or I, based on availability of test in DLM  
3.6.4 ANA, RF, anti-thyroid antibody and thyroid function tests: TSH and T4  
3.6.5 EKG  
3.6.6 Percutaneously Inserted Central Catheter (PICC) or another appropriate central vascular 
access device (CVAD) will be inserted from Day -7 to Day 1 of each treatment cycle for 
infusion of rhIL-15. An additional PICC, CVAD or a peripheral venous catheter may be 
inserted and used for drawing multiple blood samples as needed. Samples for PK 
assessments must not be drawn from the CVAD through which the rhIL-15 is infused. 
3.6.7 Radiographic Evaluation and Laboratory Assessments for Clinical Responses 
3.6.8 Other Studies 

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30 
Patients may have additional laboratory or radiological studies performed as clinically indicated, 
in particular if there were a suspicion of disease progression that would warrant an urgent 
therapeutic intervention. 
3.6.9 Vital signs  
3.6.10 Fluid intake and urine output (I/O)  
3.6.11 Weight  
3.6.12 Interval history and physical examination 
3.7 
MONITORING DURING FOLLOW-UP PERIOD (AFTER COMPLETION OF TREATMENT) 
The following tests and procedures will be performed during the follow-up portion of the study, 
as indicated in Section 3.8, Study Calendars.  
3.7.1 Vital signs 
3.7.2 Weight 
3.7.3 History and physical examination, including documentation of performance status 
3.7.4 ANA, RF, anti-thyroid antibody and thyroid function tests: TSH and T4 
3.7.5 Acute Care, Hepatic and Mineral Panels and LDH 
3.7.6 CBC with differential 
3.7.7 Radiographic evaluation and laboratory assessments for clinical responses 
 

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31 
3.8 
STUDY CALENDARS 
3.8.1 10 Day Schedule 
Procedure 
Pre-treatment 
Day on Treatment (For All Cycles1) 
During-treatment 
Follow-Up 
Period3 
End of 
Study4 
Screening 
Baseline16 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 122 21-27 28-34 
CIV rhIL-15 treatment5 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
Pathology confirmed 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performance status  
x 
x 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
x 
x 
History & physical exam6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Vital Signs7 and Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
Acute Care, Hepatic and Mineral Panels 
and LDH 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Ammonia level 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
I/Os 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
CBC w/differential,  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Reticulocyte Count 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis and HIV serology 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid function panel 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Troponin T 
 
x 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
 
Urinalysis 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
x 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
Pulmonary function tests 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA (A, B, C, DR, DQ) typing 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor imaging and serum tumor markers8 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x8 
x 
 
Serum βHCG9 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANA, RF and anti-thyroid antibodies 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Pharmacokinetics (PK)10 
 
 
x 
x 
x 
 
 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
Serum immunoglobulin levels 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Flow cytometry (Fleisher Lab)11 
 
x 
x 
 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
 
 
Flow cytometry (Roederer Lab)12 
 
x 
 
x 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
 
 
Cytokine and MesoScale inflammatory 
cytokines13 
 
 
x 
x 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
Anti-IL-15 antibodies14 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
x 
 
Optional Tumor Biopsy 15 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 

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32 
 
1. Cycles 1 and 2 for the 10-day dosing schedule will be 42 days in length, but subsequent cycles will be 28 days in length with all cycles allowing an 
additional 7 days allowed for reasons other than recovery for treatment-related toxicities.  
2. Day 12 tests and procedures only occur on Cycle 1. 
3. Patients whose best response after 2 consecutive cycles of treatment is stable disease will be followed with routine exams and restaging scans: Every 60 days 
x 3; then quarterly for up to 2 years after starting treatment unless progressive disease is documented, or they begin another treatment for their cancer. 
4. Denotes testing to be performed at an end of study visit (just prior to the patient being taken off study), if feasible. 
5. Because the treatment is CIV for 240 hours, the day 10 treatment concludes on day 11. 
6. Interval history during inpatient treatment period. 
7. Vital signs, including heart rate, blood pressure, respiration, temperature and arterial oxygen saturation (SO2) by transcutaneous pulse-oximeter.  
a. 
Every 4 hours during treatment days 1 through 11 (SO2 every 8 hours) 
b. Every 8 hours on other inpatient days 
c. 
Once at outpatient clinic follow-up visits on day 28. 
d. Off treatment visit 
e. 
End of study visit.  
8. Repeat radiologic studies to assess response week 4 of cycles 1 and 2. Subjects that go onto to receive additional cycles of treatment will have restaging after 
every other cycles (4, 6, 8 etc.) and may be restaged earlier if the subject has complaints or findings that indicate progressive disease. Subjects with evidence 
of a partial or complete response (RECIST criteria) may undergo a confirmatory scan at least 4 weeks after the scan which first met the criteria for a clinical 
response. Patients with tumors known to have tumor markers (PSA, CEA, and CA125) will have the serum level of these markers assessed at the time of 
their radiographic restaging. 
9. Pretreatment on Day 1 or within 3 days of starting treatment in women of child bearing potential. 
10. PKs are collected on Cycle 1 only. Samples are collected in 4 mL SST tubes at the time points listed in Section 5.1.1. These samples will be held at room 
temperature until picked up by the Figg laboratory for processing (pager 102-11964 for pickup). See Section 5.1 for additional details. 
11. One 10 mL lavender-top tube will be drawn for Lymphocyte Phenotype IL-15 FACS analysis. If the Immunology Section Laboratory is unable to perform 
this analysis on the specified days, this assessment maybe omitted or replaced with standard TBNK panel. See Section 5.1.2 for additional details: 
a. 
At baseline (need to perform twice before initiating study drug if at all possible.) 
b. Day 1: prior to the start of the CIV rhIL-15 infusion 
c. 
Days 8 and 12 drawn with the routine AM laboratories  
d. Days 21and 28: at the same time as the outpatient blood draws.  
12. Two 10 mL lavender-top tubes will be drawn for the Roederer Lab (NIAID) to perform special FACS analysis. See Section 5.1.2 for additional details: 
a. 
At baseline (OK to draw on Day 1 or up to 2 weeks prior to initiating study drug.) 
b. Day 2: 24 hours after starting the CIV rhIL-15 infusion 
c. 
Days 8 and 12: Samples may be drawn with the routine AM laboratories 
d. Days 21and 28: Samples may be drawn at the same time as the outpatient blood draws.  
13. Cytokine and MesoScale inflammatory cytokines are collected on cycle 1 only: Samples to assess for IL-2Rα IL-18, MIP2, MIP1α, TNFα and MesoScale 
Discovery Multiplex Pro-Inflammatory Cytokines (IL-1β, IL-12p70, Interferon γ, IL-6, IL-8 and IL-10) will be obtained from the same SST tubes drawn for 
PK time points drawn at the time listed above in # 10. See Section 5.1.3 for additional details. 
14. For all samples: Assessments that fall on a Friday, Saturday or Sunday due to an individual patient’s treatment schedule will be shifted forward or backward 
to the nearest day that these laboratories are able to process the time sample. 
15. Optional biopsies will be performed (if patient agrees) pre-treatment and one subsequent time between Day 8 and Day 21 as determined by clinical response 
and/or changes in lymphocyte subsets. 
16. If baseline tests were already performed and meet the required time frames, they will not need to be repeated. 

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33 
3.8.2 5 Day Schedule 
Procedure 
Pre-treatment 
 Days During-treatment1 
After treatment 
Screening 
Baseline15 
1 
2 
3 
4 
5 
6 
8 
21±41 
End of 
Treatment16 
Follow-Up 
Period2 
End of 
Study3 
CIV rhIL-15 treatment4 
 
 
x 
x 
x 
x 
x 
x4 
 
 
 
 
 
Pathology confirmed 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Performance status  
x 
x 
x 
 
 
 
 
 
x 
 
x 
x 
x 
History & physical exam5 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital Signs6 and Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
NIH Advance Directives Form17 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acute Care, Hepatic and Mineral Panels and LDH 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Ammonia level 
x 
 
x 
 
 
 
 
 
x 
 
 
 
 
I/Os 
 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
CBC w/differential  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Reticulocyte Count 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis and HIV serology 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid function tests: TSH and T4 
x 
 
 
 
 
 
 
 
 
 
x 
x 
 
Troponin T or I, based on availability of test in DLM 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
x 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
Pulmonary function tests 
x 
 
 
 
 
 
 
 
 
 
 
 
 
HLA (A, B, C, DR, DQ) typing 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Tumor imaging and serum tumor markers7 
x 
x 
 
 
 
 
 
 
 
 
 
x 
 
Serum βHCG8 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
ANA, RF and anti-thyroid antibodies 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
Pharmacokinetics (PK)9 
 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
Serum immunoglobulin levels 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Flow cytometry (Fleisher Lab)10 
 
x 
x 
 
 
 
 
 
x 
x 
 
 
 
Flow cytometry (Roederer Lab)11 
 
x 
x 
 
 
 
 
 
x 
x 
 
 
 
Cytokine and MesoScale inflammatory cytokines12 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Anti-IL-15 antibodies13 
 
 
x 
 
 
 
 
 
 
x 
 
x 
 
Optional Tumor Biopsies14 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 

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1. All cycles are 21 days in length, but the end of cycle evaluations may be performed ± 4 days from this time point and an additional 7 days allowed for 
reasons other than recovery for treatment-related toxicities. Cycle 1 day 21 and cycle 2 day 1 maybe the same calendar day for certain patients. This also 
applies to later cycles where day 21 of a previous cycle falls on the same calendar day as day 1 of the subsequent cycle.  
2. Patients whose best response after 4 consecutive cycles of treatment is stable disease will be followed with routine exams and restaging scans: Every 60 days 
x 3; then quarterly for up to 2 years after starting treatment unless progressive disease is documented, or they begin another treatment for their cancer. 
3. Denotes testing to be performed at an end of study visit (just prior to the patient being taken off study), if feasible. 
4. Because the treatment is CIV for 120 hours, the day 5 treatment concludes on day 6. 
5. Interval history during inpatient treatment period. 
6. Vital signs, including heart rate, blood pressure, respiration, temperature and arterial oxygen saturation (SO2) by transcutaneous pulse oximeter.  
a. 
Every 4 hours ± 1 hour during treatment days 1 through 6 (SO2 every 8 hours ± 1 hour) 
b. Every 8 hours ± 1 hour on other inpatient days 
c. 
Once at outpatient clinic follow-up visits on days 8 and 21. 
d. Off treatment visit 
e. 
End of study visit.  
7. Repeat radiologic studies to assess response the last week (day 14 through 21) of even numbered cycles (2, 4, 6 and so on) as long as patients meet criteria to 
continue treatment. Patients with evidence of a partial or complete response (RECIST criteria) may undergo a confirmatory scan at least 4 weeks after the 
scan which first met the criteria for a clinical response. Patients with tumors known to have tumor markers (PSA, CEA, and CA125) will have the serum 
level of these markers assessed at the time of their radiographic restaging. 
8. Pretreatment on Day 1 or within 3 days of starting treatment in women of child bearing potential. 
9. PKs are collected on Cycle 1 only. Samples are collected in 4 mL SST tubes at the time points. These samples will be held at room temperature until picked 
up by the Figg laboratory (Blood Processing Core) for processing (pager 102-11964 for pickup). See Section 5.1 for additional details. 
10. One 10 mL lavender-top tube will be drawn for Lymphocyte Phenotype IL-15 FACS analysis. If the Immunology Section Laboratory is unable to perform 
this analysis on the specified days, this assessment maybe omitted or replaced with standard TBNK panel. See Section 5.1.2 for additional details: 
a. 
At baseline (need to perform twice before initiating study drug if at all possible.) 
b. Day 1: prior to the start of the CIV rhIL-15 infusion 
c. 
Days 8 and 21 drawn with the routine laboratories  
11. Two 10 mL lavender-top tubes will be drawn for the Roederer Lab (NIAID) to perform special FACS analysis. See Section 5.1.2 for additional details: 
a. 
At baseline (need to perform twice before initiating study drug if at all possible.) 
b. Day 1: prior to the start of the CIV rhIL-15 infusion 
c. 
Days 8 and 21 drawn with the routine laboratories.  
12. Cytokine and MesoScale inflammatory cytokines are collected on cycle 1 only: Samples to assess for IL-2Rα IL-18, MIP2, MIP1α, TNFα and 
MesoScale Discovery Multiplex Pro-inflammatory Cytokines (IL-1β, IL-12p70, Interferon γ, IL-6, IL-8 and IL-10) will be obtained from the same SST 
tubes drawn for PK time points drawn at the time listed in Section 5.1.3. Refer to this Section for additional details. 
13. For all samples: Assessments that fall on a Friday, Saturday or Sunday due to an individual patient’s treatment schedule will be shifted forward or backward 
to the nearest day that these laboratories are able to process the time sample. 
14. Optional biopsies will be performed (if patient agrees) pre-treatment and one subsequent time between Day 8 and Day 21 as determined by clinical response 
and/or changes in lymphocyte subsets. 
15. If baseline tests were already performed and meet the required time frames, they will not need to be repeated. 
16. End of treatment visit will occur approximately 30 days after the last dose of study drug. If the patient cannot return to the Clinical Center, a request will be 
made to collect clinical labs from a local physician or laboratory. If this is not possible, patients may be assessed by telephone for symptoms.  
17. All subjects will be offered the opportunity to complete an NIH advance directives form (Section 10.3); preferably done at baseline, but can be done at any 
time during the study as long as the capacity to do so is retained. The completion of the form is strongly recommended, but is not required.

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3.9 
CONCURRENT THERAPY 
Concurrent anti-cancer therapy to include immunotherapy, immunosuppressive therapy, 
radiation therapy or chemotherapy, and administration of systemic corticosteroids except for 
physiologic replacement doses of cortisone acetate is not permitted while on the study. Initiation 
of medically indicated, non-oncologic medications such as anti-hypertensive agents or antibiotics 
for urinary tract infections that do not have significant potential for interaction with the rhIL-15 
treatment are allowable with prior approval of the PI.  
3.10 CRITERIA FOR REMOVAL FROM THE PROTOCOL THERAPY AND OFF-STUDY CRITERIA 
Prior to documenting removal from study, effort must be made to have all subjects complete a 
safety visit approximately 30 days following the last dose of study therapy. 
3.10.1 Off-Treatment Criteria 
• DLT as defined in Section 3.2. 
• Persistent (> 14 days) treatment-related grade 2 (non-DLT) adverse events.  
• Completion of protocol therapy  
• Patient requests to be withdrawn from active therapy. 
• Disease progression. 
• No evidence of clinical response (i.e., patient has stable disease) on radiographic 
restaging after 2 consecutive cycles of treatment.  
• The detection of anti-IL-15 neutralizing antibody serum titer ≥ 500 ng/mL as described in 
APPENDIX C prior to subsequent treatment cycles.  
• Evidence the patient has developed auto-immunity that involves a vital organ (heart, 
kidney, brain, eye, thyroid or adrenal gland, colon, lung). Patients who develop new auto-
antibodies without clinical evidence of end organ dysfunction will be seen by the 
appropriate Internal Medicine subspecialists to assess their risk for developing an 
autoimmune syndrome.  
• Interruption of CIV rhIL-15 treatment for any reason for more than 24 consecutive hours 
during cycle 1. Stoppage of less than 15 minutes occurring during the daily change of the 
rhIL-15 infusion device will not be considered an interruption. 
• Positive pregnancy test 
3.10.2 Off-Study Criteria 
• Voluntary withdrawal of consent by the patient to participate in the study 
• Patient non-compliance with treatment and research plans 
• Initiation of another anticancer treatment 
• Any new medical or psychiatric condition that, in the opinion of the PI, precludes the safe 
continuation of the study 
• Death 
3.10.3 Off Protocol Therapy and Off-Study Procedure  
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to: NCI Central Registration Office at 

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ncicentralregistration-l@mail.nih.gov. 
4 
CONCOMITANT MEDICATIONS/MEASURES 
Patients will be followed and managed as clinically appropriate with IV fluids, anti-emetics, anti-
pyretics or other standard interventions based on the experience gathered from the ongoing rhIL-
15 IVB trial and other biological response modifier therapies.  
5 
BIOSPECIMEN COLLECTION 
5.1 
CORRELATIVE STUDIES FOR RESEARCH, PHARMACOKINETIC AND SPECIAL STUDIES  
Please e-mail Julie Barnes at Julie.barnes@nih.gov and Paula Carter (pcartera@mail.nih.gov) at 
least 24 hours before transporting samples to the (Figg Lab) Blood Processing Core (the Friday 
before is preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact Julie Barnes by e-mail or at 240-760-6044. 
5.1.1 Pharmacokinetic (PK) Studies 
All PK samples will be drawn in 4 mL SST tubes and PK testing will be performed only during 
the first treatment cycle. Labels listing the patient’s name, date of birth, date and time of the 
blood draw will be affixed to all the tubes by the staff person who obtained the samples. Please 
page 102-11964 (Figg lab) for pick-up. Because each treatment day is a 24 hour infusion, the 
“day 10 treatment” ends on day 11. Samples will be held at room temperature until picked up by 
the Figg lab (Blood Processing Core) for processing and shipping of the samples to a Contractor 
for performance of the assays. At time points where PK and inflammatory marker cytokine or 
anti-IL-15 antibody analyses coincide (day 1 pretreatment, hours 8, 4, 24 post initiation of 
infusion, day 8 and 12) one or two 4 mL SST tube will be drawn to decrease total amount of 
research blood drawn and the serum aliquoted into vials prior to shipment to the respective 
reference labs. Patient identifiers will be removed prior to shipment per Section 5.2.1.  
Sampling times for the 10-day infusion schedule are as follows (cycle 1 only): 
• Day 1: Timed samples will be drawn just before beginning treatment (baseline), and at 
10 minutes, 1, 2, 4 8 and 12 hours (± 30 minutes) after starting the CIV rhIL-15 infusion.  
• Day 2: A single timed sample will be drawn 24 hours (±1 hour) after starting the CIV 
rhIL-15 infusion. 
• Day 3: A single timed sample will be drawn 48 hours (±2 hours) after starting the CIV 
rhIL-15 infusion  
• Days 7, through 10: Timed samples will be drawn each morning with routine AM 
laboratory samples. The time the sample was obtained must be recorded.  
• Post-treatment day 11 at completion of infusion and day 12: Timed samples will be 
drawn at the end of the 240-hour infusion, 10 and 30 minutes, 1, 2, 4 (± 30 minutes) and 
24 (± 2 hours) hours (day 12) after termination of the CIV rhIL-15 infusion.  
Sampling times for the 5-day infusion schedule are as follows (cycle 1 only): 
• Day 1: Timed samples will be drawn just before beginning treatment (baseline), and at 

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10 minutes, 1, 2, 4 8 and 12 hours (± 30 minutes) after starting the CIV rhIL-15 infusion.  
• Day 2: A single timed sample will be drawn 24 hours (±1 hour) after starting the CIV 
rhIL-15 infusion. 
• Day 3: A single timed sample will be drawn 48 hours (±2 hours) after starting the CIV 
rhIL-15 infusion  
• Days 4 and 5: Timed samples will be drawn each morning with routine AM laboratory 
samples. The time the sample was obtained must be recorded.  
• Post-treatment day 6 at completion of infusion: Timed samples will be drawn at the 
end of the 120 hour infusion at 10 and 30 minutes, 1, 2, 4 hours (± 30 minutes). 
5.1.2 Flow Cytometry Studies for Absolute Numbers and Percentages of Lymphocyte Sets and 
T-cell Subsets 
All FACS samples will be drawn in 10-mL lavender-top tubes and will be performed during all 
treatment cycles as defined in Section 3.8. Labels listing the patient’s name, date of birth, date 
and time of the blood draw will be affixed to all the tubes by the staff person who obtained the 
samples. The same FACS panels will be performed by the Fleisher and Roederer laboratories for 
all time points analyzed.  
• Pre-treatment:  
o Two lavender-top tubes drawn for special FACS analysis in the Roederer Laboratory 
(NIAID). Lymphoid Malignancies Branch Clinical Research personnel will arrange 
for these samples to be sent via courier for cryopreservation to Clinical Support 
Laboratory 560/11-27, Building 1050, Boyles Street, Frederick, Maryland 21702, 
telephone number: 301-846-1707 or 301-846-1917).  
o One 10 mL lavender top tube Lymphocyte Phenotype IL-15 FACS panel will be drawn 
and sent via routine collection routing to the Immunology Laboratory of the NIH 
Clinical Center 10/2C410 (to the Attn. of Dr. Thomas Fleisher M.D., phone number: 
301-496-4879) for CD2, CD3, CD4, CD8, CD8 beta, CD11c, CD14, CD16, CD20, 
CD25, CD27, CD28, CD38, CD45RA, CD45RO, CD56, CD57, CD80, CD86, CD95, 
IL-2R/IL-15R beta (CD122), CD127 (IL-7R alpha), CD123, CD132, CD62L, CCR5, 
CCR7, Ki67, IL-15R alpha, and Foxp3. 
5.1.3 Inflammatory Markers and Cytokine Analysis 
All samples will be drawn in 4 mL SST tubes. Serum samples for these analyses only during the 
first treatment cycle will be obtained from the PK samples (see Section 5.1.1). Labels listing 
the date and time of the blood draw as well as the patient’s name will be affixed to all the tubes 
by the staff person who obtained the samples.  Lymphoid Malignancies Branch Clinical 
Research personnel will arrange for these samples to be sent via courier to (specified above) the 
Clinical Support Laboratory, for analysis of IL-2Rα, IL-18, MIP2, MIP1α and TNFα and to 
storage for the MesoScale Discovery pro-inflammatory cytokines assay (IL-1β, IL-12p70, 
interferon γ, IL-6, IL-8 and IL-10). 
5.1.4 Anti-IL-15 Antibodies 
All samples will be drawn in 4 mL SST tubes; sampling will be performed for the days listed 
below during all treatment cycles. Labels listing the patient’s name, date of birth, date and time 
of the blood draw will be affixed to all the tubes by the staff person who obtained the samples. 
For questions, please contact Dr. Figg’s Clinical Pharmacology Program (CPP) at 240-760-6180; 
additionally, for pre-notification of planned samples (at least 24 hours in advance, the Friday 

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before is preferred) email Julie Barnes (julie.barnes@nih.gov) and Paula Carter 
(pcartera@mail.nih.gov). After sample collection, please page 102-11964 for immediate pick-up. 
For any questions regarding sample processing, you may also contact Julie Barnes by e-mail or 
at 240-760-6044.  
Samples will be held at room temperature until picked up by the Figg lab (Blood Processing 
Core) for processing and shipping of the samples to a Contractor for performance of the assays. 
Lymphoid Malignancies Branch Clinical Research personnel will arrange for these samples to be 
sent via courier to Clinical Support Laboratory in Frederick (specified above) for assay of the 
anti-IL-15 antibodies. 
Sampling times for the 10-day infusion schedule are as follows: 
• Day 1 pre-treatment, days 12, 28 and off-treatment visit: One SST tube will be drawn 
to assess for the formation of anti-IL-15 antibodies. 
• Patients will have to demonstrate an absence of anti-IL-15 antibodies in their post-
treatment (days 12 and 28) assessments before additional cycles of rhIL-15 can be 
initiated.  
Sampling times for the 5-day infusion schedule are as follows: 
• Day 1 pre-treatment, days 6, 21, day 1 of subsequent cycles and off-treatment visit: 
One SST tube will be drawn to assess for the formation of anti-IL-15 antibodies. 
• Patients will have to demonstrate an absence of anti-IL-15 antibodies in their post-
treatment assessments before additional cycles of rhIL-15 can be initiated.  
5.1.5 Optional Tumor Biopsies 
Subjects with easily accessible superficial tumor deposits will be asked to sign a separate consent 
for core biopsies that would be performed by the Department of Radiology and Imaging 
Sciences’ Interventional Radiologists (IR) and evaluated by the NCI Pathology Department at 
two separate time points [pre-treatment and after treatment has started (anytime from Day 8 to 
Day 21)] to assess the dynamics of T-cell infiltration and changes in gene expression associated 
with rhIL-15 treatment. The biopsies should be processed as follows: 
• LYMB laboratory staff will provide sample tubes with an adequate amount of 
RNAlater® for 1 or 2 cores or an excisional biopsy. After the biopsy material is placed in 
RNAlater®, the specimen will be refrigerated for 12 to 72 hours in room 4B40 prior to 
being sent via courier to the Clinical Support Laboratory in Frederick for cataloging and 
long-term storage at -80°C.  
• A separate core biopsy (18g) will also be obtained. This sample will be transported to the 
NCI Pathology Department for confirmation that the specimen contains tumor and for 
performing routine histologic and immunohistochemical analyses. Alternatively, if fine 
needle biopsy is performed, the sample will be transported to Cytology. 
• If excisional biopsy is performed, Dr. Conlon will view the size of the specimen to make 
sure an adequate volume of RNAlater® is used to breakdown tissue/denature proteins 
and decide if there is an adequate amount of tissue to perform immunohistochemistry.  
5.2 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
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 IRB notification and an executed MTA.  

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5.2.1 Procedures for storage and disposition of serum specimens at the Clinical Support 
Laboratory, Leidos Biomedical Research, Inc.in Frederick, MD: 
The Clinical Support Laboratory, Leidos Biomedical Research, Inc. processes and cryopreserves 
samples in support of IRB-approved, NCI clinical trials. All laboratory personnel with access to 
patient information annually complete the NIH online course in Protection of Human Subjects. 
The laboratory is CLIA certified for CD4 immunophenotyping 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.  
• The database program has different levels of access approval to limit unauthorized 
changes to specimen records and the program maintains a sample history.  
• 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, typically 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 (generally the NCI Principal 
Investigator) to ensure that samples requested and approved for withdrawal are being 
used in a manner consistent with IRB approval.  

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• The Clinical Support Laboratory in Frederick 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 IRB approvals are in place and that a Material Transfer Agreement has been 
executed prior to requesting the laboratory to ship samples outside of the NIH.  
5.2.2 Sample Handling, Data Collection and Sample Disposition for the Blood Processing Core 
(Figg Lab) 
•  The samples will be processed, barcoded, and stored in Dr. Figg’s lab until requested by 
the investigator. 
• All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered 
and stored in the LABrador (a.k.a. LabSamples) utilized by the BPC. This is a secure 
program, with access to LABrador limited to defined BPC personnel, who are issued 
individual user accounts. Installation of LABrador is limited to computers specified by 
Dr. Figg. These computers all have a password restricted login screen. All BPC personnel 
with access to patient information annually complete the NIH online Protection of 
Human Subjects course.  
• LABrador creates a unique barcode ID for every sample and sample box, which cannot 
be traced back to patients without LABrador access. The data recorded for each sample 
includes the patient ID, name, trial name/protocol number, time drawn, cycle time point, 
dose, material type, as well as box and freezer location. Patient demographics associated 
with the clinical center patient number are provided in the system. For each sample, there 
are notes associated with the processing method (delay in sample processing, storage 
conditions on the ward, etc.). 
• Following completion of this study, samples will remain in storage as detailed above. 
Access to these samples will only be granted following IRB approval of an additional 
protocol, granting the rights to use the material.  
• Sample barcodes are linked to patient demographics and limited clinical information. 
This information will only be provided to investigators listed on this protocol, via 
registered use of LABrador. It is critical that the sample remains linked to patient 
information such as race, age, dates of diagnosis and death, and histological information 
about the tumor, in order to correlate genotype with these variables. 
5.2.3 Disposition of samples  
• 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 above. 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. The PI will report any loss or destruction of samples 

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to the NCI IRB as soon as he is made aware of such loss 
• Blood and tissue specimens collected in the course of this research project may be banked 
and used in the future to investigate new scientific questions related to this study. 
However, this research may only be done if the risks of the new questions were covered 
in the consent document and the proposed research has undergone prospective IRB 
review and approval. If new risks are associated with the research (e.g., analysis of 
germline genetic mutations), the Principal Investigator must amend the protocol and 
obtain informed consent from all research subjects. 
• Once primary research objectives for the protocol are achieved, intramural researchers 
can request access to remaining samples provided they have an IRB-approved protocol 
and subject consent. Access to these samples will only be granted following IRB 
approval of an additional protocol, granting the rights to use the material. 
• Samples will be stored for future use following completion of the study in only those 
subjects who have consented to do so in the Optional Studies section of the Consent 
Document. 
• If, at any time, a subject withdraws from the study and does not wish for their existing 
samples to be utilized, the individual must provide a written request. Following receipt of 
this request, the samples will be destroyed (or returned to the subject, if so requested), 
and reported as such to the IRB.  
• The PI will report destroyed samples to the IRB if samples become unsalvageable 
because of environmental factors (ex. broken freezer or lack of dry ice in a shipping 
container) or if a patient withdraws consent. Samples will also be reported as lost if they 
are lost in transit between facilities or misplaced by a researcher. Freezer problems, lost 
samples or other problems associated with samples will also be reported to the IRB, the 
NCI Clinical Director, and the office of the CCR, NCI. 
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system 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. All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. Patients 
will be followed for adverse events for at least 30 days after removal from study treatment or 
until off-study, whichever comes first.  
An abnormal laboratory value will be recorded in the database as 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 

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• 
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. 
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, the IRB will be notified. 
6.2 
RESPONSE CRITERIA 
6.2.1 Radiographic Evaluation and Laboratory Assessments for Clinical Responses 
• All patients will have repeat baseline radiologic studies to assess marker lesions 
(measurable) and evaluable lesions (non-measurable) performed on day 28 ± 3 days of 
each treatment cycle for comparison to their pre-treatment studies.  
• Patients with evidence of a partial or complete response (RECIST criteria) may undergo a 
confirmatory scan that will be performed at least 4 weeks after the scan which first met 
the criteria for a clinical response to rhIL-15 treatment. 
• Appropriate patients with tumors known to have tumor markers (PSA, CEA, and CA125) 
will have the serum level of these markers assessed at the time of their radiographic 
restaging to gain further insight into the potential efficacy of rhIL-15 treatment. 
6.2.2 Solid Tumors 
Response and progression for all solid tumors with the exception of non-Hodgkin’s lymphomas 
will be evaluated in this study using the new international criteria proposed by the revised 
Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) (70). Changes 
in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest 
diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
6.2.2.1 Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with rhIL-15. 
Evaluable for objective response: Only those patients who have measurable disease present 
at baseline, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for response. These patients will have their response 
classified according to the definitions stated below. (Note: Patients who exhibit objective 
disease progression prior to the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable 
for non-target disease. The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions.  
6.2.2.2 Disease Parameters  
Measurable disease: Measurable lesions are defined as those that can be accurately 

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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, lymphangitis cutis/pulmonitis, 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.  
6.2.2.3 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. 

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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. 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation 
is not advised. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 

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complete clinical response. Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published (71-
73). In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression 
criteria which are to be integrated with objective tumor assessment for use in first-line trials 
in ovarian cancer (74). 
Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may be 
a side effect of the treatment) and progressive disease. 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described 
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. 
6.2.2.4 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 

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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. 
6.2.2.5 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). 
6.2.2.6 Evaluation of Best Overall Response  
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
Documented at least once >4 wks. 
from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 

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Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
6.2.2.7 Duration of Response 
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.  
6.2.3 Non-Hodgkin’s Lymphoma  
Response and progression for non-Hodgkin’s lymphoma will be evaluated in this study using the 
International Working Group Recommendations (75).  
Complete Response (CR) requires the following:  
• Complete disappearance of all detectable clinical evidence of disease and disease-related 
symptoms if present before therapy.  
• Typically FDG-avid lymphoma: in patients with no pretreatment PET scan or when the 
PET scan was positive before therapy, a post-treatment residual mass of any size is 
permitted as long as it is PET negative.  

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• Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a pretreatment 
PET scan, or if a pretreatment PET scan was negative, all lymph nodes and nodal masses 
must have regressed on CT to normal size ( 1.5 cm in their greatest transverse diameter 
for nodes > 1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in 
their long axis and more than 1.0 cm in their short axis before treatment must have 
decreased to 1.0 cm in their short axis after treatment. 
• The spleen and/or liver, if considered enlarged before therapy on the basis of a physical 
examination or CT scan, should not be palpable on physical examination and should be 
considered normal size by imaging studies, and nodules related to lymphoma should 
disappear. However, determination of splenic involvement is not always reliable because 
a spleen considered normal in size may still contain lymphoma, whereas an enlarged 
spleen may reflect variations in anatomy, blood volume, the use of hematopoietic growth 
factors, or causes other than lymphoma. 
• If the bone marrow was involved by lymphoma before treatment, the infiltrate must have 
cleared on repeat bone marrow biopsy. The biopsy sample on which this determination is 
made must be adequate (with a goal of > 20 mm unilateral core). If the sample is 
indeterminate by morphology, it should be negative by immunohistochemistry. A sample 
that is negative by immunohistochemistry but that demonstrates a small population of 
clonal lymphocytes by flow cytometry will be considered a CR until data become 
available demonstrating a clear difference in patient outcome. 
Partial Response (PR) requires: 
• At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the 
largest dominant nodes or nodal masses. These nodes or masses should be selected 
according to all of the following: they should be clearly measurable in at least 
2 perpendicular dimensions; if possible they should be from disparate regions of the 
body; and they should include mediastinal and retroperitoneal areas of disease whenever 
these sites are involved.  
• No increase should be observed in the size of other nodes, liver, or spleen.  
• Splenic and hepatic nodules must regress by 50% in their SPD or, for single nodules, in 
the greatest transverse diameter.  
• With the exception of splenic and hepatic nodules, involvement of other organs is usually 
assessable and no measurable disease should be present.  
• Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive before treatment. However, if positive, the cell type should be specified (e.g., 
large-cell lymphoma or small neoplastic B cells). Patients who achieve a CR by the above 
criteria, but who have persistent morphologic bone marrow involvement will be 
considered partial responders.  
When the bone marrow was involved before therapy and a clinical CR was achieved, but 
with no bone marrow assessment after treatment, patients should be considered partial 
responders. 
• No new sites of disease should be observed. 
• Typically, FDG-avid lymphoma: for patients with no pretreatment PET scan or if the PET 
scan was positive before therapy, the post-treatment PET should be positive in at least one 
previously involved site. Variably FDG-avid lymphomas/FDG-avidity unknown: for 
patients without a pretreatment PET scan, or if a pretreatment PET scan was negative, CT 

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criteria should be used. 
Stable disease is defined as less than a PR (see above) but is not progressive disease (see 
below): 
• A patient is considered to have SD when he or she fails to attain the criteria needed for a 
CR or PR, but does not fulfill those for progressive disease (see Relapsed Disease [after 
CR]/Progressive Disease [after PR, SD]).  
• Typically, FGD-avid lymphomas: the PET should be positive at prior sites of disease with 
no new areas of involvement on the post-treatment CT or PET.  
• Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a 
pretreatment PET scan or if the pretreatment PET was negative, there must be no change 
in the size of the previous lesions on the post-treatment CT scan. 
Relapsed 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. In patients with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are mostly benign. Thus, a therapeutic 
decision should not be made solely on the basis of the PET without histologic 
confirmation. 
• At least a 50% 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. 
• Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion 
was PET positive before therapy unless the lesion is too small to be detected with current 
PET systems (< 1.5 cm in its long axis by CT).  
6.2.4 Time to Progression 
Time to progression will be measured from the date of protocol consent until death of 
progressive disease is documented.  
6.2.5 Immunologic Response Criteria 
6.2.5.1 Definition of Biologically Active Dose 
• ≥ 50% increase of the circulating absolute NK-cell number (product of absolute number 
of mononuclear cells and the proportion of NK cells) that is maintained for at least 1 
week as determined by flow cytometry over the patient’s pre-treatment NK-cell count 
(APPENDIX B). The baseline will be defined in each patient as the number of NK cells 
determined no more than 1 month prior to rhIL-15 administration. 
• 
The study will aim at determining a range of biologically active doses meeting the above 
criteria. 

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6.2.5.2 Secondary Biologic Study Endpoints 
In mice and non-human primates, another sensitive indicator of biological activity following 
IL-15 administration has been the expansion of the T-memory phenotype CD44hiCD8+ (T-
cell memory phenotype compartment in mice) cell. Therefore, the secondary biological 
endpoint will aim at determining signs of expansion of the counterpart T-cell population in 
humans. 
• Doubling in the absolute number of CD45RO+ CD8+ T-cells that is maintained for at least 
1 week as determined by flow cytometry over the patient’s pre-treatmentCD45RO+ CD8+ 
T-cell count. The baseline will be defined in each patient as the number of these cells 
determined no more than 1 month prior to rhIL-15 administration. 
• The immunogenicity of the infused rhIL-15 will be defined using a 2-arm capture ELISA 
method (APPENDIX B). 
• At least a 2-fold increase in serum soluble IL-2R-alpha (sIL-2R-alpha) levels. 
6.3 
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 4.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
7.1 
DEFINITIONS 
7.1.1 Adverse Event 
An adverse event is defined as any untoward medical occurrence in a human subject, including 
any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or 
disease, temporally associated with the subject’s participation in the research, whether or not 
considered related to the subject’s participation in the research.  
7.1.2  Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
7.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 

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7.1.4 Serious 
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.1.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
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. 
7.1.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
7.1.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death. 
7.1.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.  
7.1.9 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects. 
7.1.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
•  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
7.2 
NCI-IRB AND CLINICAL DIRECTOR (CD) REPORTING 
7.2.1 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths 

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The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director: 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems  
• All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
7.2.2 NCI-IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the 
deviation occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
• 
All Grade 2 unexpected events that are possibly, probably or definitely related to 
the research;  
• 
All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
• 
All Grade 5 events regardless of attribution;  
• 
All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.2.3 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB. 
7.3 
IND SPONSOR REPORTING CRITERIA  
During the first 30 days after the subject receives investigational agent/intervention, the 
investigator must immediately report to the sponsor, using the mandatory MedWatch form 
3500a, any serious adverse event, whether or not considered drug related, including those listed 
in the protocol or investigator brochure and must include an assessment of whether there is a 
reasonable possibility that the drug caused the event. For serious adverse events that occur more 
than 30 days after the last administration of investigational agent/intervention, only report those 
that have an attribution of at least possibly related to the agent/intervention. 
Required timing for reporting per the above guideline: 
• Deaths (except death due to progressive disease) must be reported via email within 
24 hours. A complete report must be submitted within one business day.  
• Other serious adverse events including deaths due to progressive disease must be 
reported within one business day 
Events will be submitted to the Center for Cancer Research (CCR) at: CCRsafety@mail.nih.gov 
and to the CCR PI and study coordinator. 
7.3.1 Reporting Pregnancy 
7.3.1.1 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. The potential risk of 

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exposure of the fetus to the investigational agent(s) or chemotherapy agents (s) should be 
documented in box B5 of the MedWatch form “Describe Event or Problem”. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study treatment 
under study may have interfered with the effectiveness of a contraceptive medication. 
However, as patients who become pregnant on study risk intrauterine exposure of the fetus 
to agents which may be teratogenic, the CCR is requesting that pregnancy should be 
reported in an expedited manner as Grade 3 “Pregnancy, puerperium and perinatal 
conditions - Other (pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC.  
Congenital abnormalities or birth defects and spontaneous miscarriages should be reported 
and handled as SAEs. Elective abortions without complications should not be handled as 
AEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented. 
If any pregnancy occurs in the course of the study, then the investigator should inform the 
Sponsor within 1 day, i.e., immediately, but no later than 24 hours of when he or she 
becomes aware of it. 
The designated Sponsor representative will work with the investigator to ensure that all 
relevant information is provided to the Sponsor within 1 to 5 calendar days for SAEs and 
within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
7.3.1.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and 
for 4 months after the last dose of rhIL-15. 
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 4 months 
after the last dose should, if possible, be followed up and documented. 
7.4 
DATA AND SAFETY MONITORING PLAN 
7.4.1 Principal Investigator/Research Team  
The clinical research team will meet on a 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. Adverse 
events will be reported as required above. Any safety concerns, new information that might 
affect either the ethical and or scientific conduct of the trial, or protocol deviations will be 
immediately reported to the IRB using iRIS and if applicable to the Sponsor.  
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.  
7.4.2 Sponsor Monitoring Plan 

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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 study endpoints; adherence to the protocol, regulations, 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.  
8 
STATISTICAL CONSIDERATIONS 
The primary objective of this trial is to determine the safety, toxicity profile, DLT and MTD of 
CIV rhIL-15 administered for 10 consecutive days (240 hours) or 5 consecutive days (120 hours) 
in subjects with metastatic unresectable cancers for which curative or palliative measures either 
do not exist or are not associated with a survival advantage.  
The secondary objectives include determination of rhIL-15 PK, including time to reach serum 
steady state, decline if any at later time points, changes in serum concentration associated with 
the expected lymphocytosis and decline following discontinuation of the CIV infusion; 
characterization of the biological effects of rhIL-15 on the percentages and absolute numbers of 
circulating lymphocyte sets (NK and T-cells) and T-cell subsets (naïve, central or effector 
memory subsets based on expression of CD56, CD4, CD8, CD45RO, CD45RA, CD28, CD95, 
CCR7 and CD62L) by flow cytometry and the plasma levels of pro-inflammatory cytokines. The 
potential antitumor activity of rhIL-15 will be assessed by the clinical response rate and time to 
progression in this patient population; and assessment of the nature of T-cell infiltration and 
cytokine and check-point inhibitor gene expression by analysis of pre- and post-treatment 
biopsies obtained from selected patients with easily accessible tumor deposits. All evaluations of 
these secondary endpoints will be considered exploratory. 
There are 9 planned dose levels for this trial that will enroll 3 to 6 patients each using a modified 
Fibonacci design to define the MTD for CIV rhIL-15. 
The MTD for each schedule will be based on the assessment of DLT during the first cycle of 
treatment, and will be defined as the dose level at which less than one-third of patients (0/3 or 0-
1/6 patients) treated at that dose experience a DLT, with the next higher dose level demonstrating 
a one-third or greater number of patients (≥ 2/3 or ≥ 2/6 patients) having DLT. If a patient did 
not experience DLT and did not finish 1 cycle of treatment (either 42 or 21 days), he or she will 
not be evaluable for determination of the MTD and will be replaced in the dose level. An 
additional 3 to 6 patients will be enrolled at the MTD or, if no severe or dose-limiting toxicities 
are encountered, the maximum administered dose of rhIL-15, so that a total of 9 patients will 
potentially be treated at MTD for either schedule to better characterize the clinical activity of 

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CIV rhIL-15 in this patient population. If feasible, the patients enrolled in this expansion cohort 
will be limited to histologic cancer subtypes previously shown to be sensitive to immunotherapy 
(renal cell carcinoma, melanoma, prostate, colorectal and ovarian cancer).  
As of April 2016, twenty-four evaluable patients have enrolled on Dose Levels 1-6; with 2 more 
to be enrolled in Dose Level 6 after Amendment G. A maximum of 6 evaluable patients may be 
enrolled at DL 7 & 8 with an additional 9 at DL 9. If all dose levels are evaluated (with 6 patients 
per remaining dose levels and 9 total patients at the MTD or maximum administered dose), a 
maximum of 47 evaluable patients will be enrolled. An additional 5 patients may be enrolled to 
compensate for inevaluable patients; thus, bringing the maximum accrual ceiling to 52. 
Similarly, if all dose levels are evaluated, the minimum number of patients required will be 41 
(24 evaluable patients have enrolled at DL 1-6; with 2 more to be enrolled in Dose Level 6 after 
Amendment G and with 3 patients enrolled at DL 7 & 8; 9 at DL 9; and 5 inevaluable patients a 
minimum of 46 will be reached).  
Patients with tumors known to have tumor markers (PSA, CEA, CA125) will have the serum 
level of these markers assessed at the time of their radiographic restaging to gain further insight 
into the potential efficacy of rhIL-15 treatment. If tumor markers are initially above the upper 
limit of normal, they must normalize for the patient to be considered a complete response. 
Specific guidelines for serum tumor markers previously reported (CA125 and PSA) will be used 
to assess responses to rhIL-15 treatment. 
Using the two dose escalation schedules, the probability of escalating to the next dose level, 
based on the true rate of DLT at the current dose for each schedule, is given by the following 
table (each group will be considered independently of the other): 
True Toxicity at 
a Given Dose 
10% 
20% 
30% 
40% 
50% 
60% 
Probability of 
Escalating 
.91 
.71 
.49 
.31 
.17 
.08 
Thus, if the true underlying proportion of DLTs is 50% at the current dose, there is a 17% chance 
of escalating to the next dose. 
9 
COLLABORATIVE AGREEMENTS 
9.1 
MATERIAL TRANSFER AGREEMENT (MTA) 
There is an NCI Intramural MTA # 14-2-00040 in place between DCTD, CTEP and CCR, NCI.  
10 HUMAN SUBJECTS PROTECTIONS 
10.1 RATIONALE FOR SUBJECT SELECTION 
Men and women age 18 years or older of all races and ethnic groups are eligible for this trial if 
they meet the criteria outlined. Efforts will be made to extend the accrual to a representative 
population. However, in a Phase I trial with limited sample size, a balance must be struck 
between patient safety, considerations and limitations on the number of individuals exposed to 
potentially toxic or ineffective treatments on the one hand and the need to explore gender, racial, 
and ethnic aspects of clinical research on the other. If differences in outcome that correlate to 
gender, racial, or ethnic identity were noted, accrual may be expanded or additional studies may 

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be performed to investigate those differences more fully. Because there is no significant 
preclinical information regarding the risk to a fetus or newborn infant, pregnant or breastfeeding 
women will be excluded from participation in this trial. Since the CIV rhIL-15 treatment acts by 
stimulating the patient’s immune system to attack their tumor, patients with HIV, hepatitis B or 
C that have defective immune systems or immune responses much less likely to have benefit 
from this immune based therapy are not eligible for this trial. 
Adults who are cognitively impaired prior to study entry will not be eligible for the trial, because 
they cannot give informed consent. Some of the subjects could become cognitively impaired 
because of disease progression or other causes. Patients will be offered the opportunity to assign 
Durable Power of Attorney (DPA) prior to study entry.  
10.2 PARTICIPATION OF CHILDREN 
Individuals under the age of 18 years of age are not eligible to participate in this trial. The 
immune physiology of children and the potential toxicity in this population are felt to be 
sufficiently different from those of adult patients that a separate protocol, dedicated to pediatric 
patients, appears warranted. Therefore, children will be the object of a separate protocol once 
toxicity and a dose range with biological activity are defined in adults. 
10.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally-impaired. For this reason and because there is a prospect of direct benefit from 
research participation (Section 10.6), all subjects will be offered the opportunity to fill in their 
wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or 
cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an 
independent assessment of whether an individual has the capacity to provide consent; assistance 
in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the 
capacity to appoint a surrogate. For those subjects that become incapacitated and do not have 
pre-determined substitute decision maker, the procedures described in MAS Policy 87-4 and 
NIH HRPP SOP 14E for appointing a surrogate decision maker for adult subjects who are (a) 
decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, 
will be followed. 
10.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
The discomforts of a 10-day CIV of rhIL-15 are expected to be the same pain and discomfort 
from venipuncture for blood drawing. The primary risk to patients participating in this research 
study is from expected or unforeseen toxicity or biological effects of recombinant human IL-15 
as an investigational agent. Patients will be carefully monitored for any adverse events as 
described in Section 3.5 and appropriate care provided. 
The intent of the study is to evaluate the toxicity of rhIL-15 in this Phase I trial and to find a 
range of doses where it has an effect on humans (biological activity). Recently there has been 
new evidence to suggest that patients with solid tumors may respond to immunotherapeutics or 
that infiltration of their tumor deposits by activated effector T-cells is associated with an 
improved survival. These finding lend additional weight to the notion that the administration of 

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rhIL-15 might be associated with a partial or complete response of the patient’s tumor more 
commonly associated with the immune-based treatment of metastatic melanoma and metastatic 
renal cell cancer. 
10.5 STRATEGIES AND PROCEDURES FOR RECRUITMENT  
Patient accrual will be facilitated by the large number of clinical investigators who refer patients 
to the NCI and CCR. Contact letters or emails will be sent to the regional University referral 
center’s Medical Oncologists informing them of this trial. In addition, the information will be 
provided on the NCI Clinical Trials and ClinicalTrials.gov web pages. 
10.6 RISKS/BENEFITS ANALYSIS 
The success of this effort cannot be predicted at this time. Because all patients in this protocol 
have incurable metastatic cancer and limited life expectancies, the potential benefit is thought to 
outweigh the potential risks. 
Given the prospect of direct benefit, this same risks/benefits analysis applies also to adults who 
may become unable to consent during participation.  
10.7 CONSENT PROCESS AND DOCUMENTATION 
The investigational nature and the research objectives of this trial, the procedures and treatments 
involved and their attendant risks and discomforts, potential benefits, time commitments and 
potential alternative therapies will be carefully explained to the patients during the informed 
consent process. A signed informed consent document will be obtained prior to entry onto the 
study by the Principal Investigator or an Associate Investigator. The original signed consent goes 
to Medical Records and a copy will be placed in the research record.  
If the patient agrees to have the optional biopsy for research, then the patient will consent at the 
time of the procedure. If the patient refuses the optional biopsy at that time, the refusal will be 
documented in the medical record and in the research record.  
10.7.1 Telephone reconsent 
Reconsent on this study may be obtained via telephone according to the following procedure: the 
informed consent document will be sent to the subject. An explanation of the change (s) in the 
study will be provided over the telephone after the subject has had the opportunity to read the 
consent form. The subject will sign and date the informed consent. A witness to the subject’s 
signature will sign and date the consent.  
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.  
A fully executed copy will be returned via mail for the subject’s records.  
The informed consent process will be documented on a progress note by the consenting 
investigator and a copy of the informed consent document and note will be kept in the subject’s 
research record.  
10.7.2 Informed consent of non-English speaking subjects 
If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the principal investigator and/or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 
Policy M77-2, OHSRP SOP 12, 45 CFR 46.117 (b) (2) and 21 CFR 50.27 (b) (2). The summary 
that will be used is the English version of the extant IRB approved consent document. Signed 

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copies of both the English version of the consent and the translated short form will be given to 
the subject or their legally authorized representative and the signed original will be filed in the 
medical record.  
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation. Preferably someone who is independent of the subject (i.e., not a 
family member) will assist in presenting information and obtaining consent. Whenever possible, 
interpreters will be provided copies of the relevant consent documents well before the consent 
conversation with the subject (24 to 48 hours if possible).  
We request prospective IRB approval of the use of the short form process and will notify the IRB 
at the time of continuing review of the frequency of the use of the Short Form. 
11 PHARMACEUTICAL INFORMATION 
11.1 RECOMBINANT HUMAN INTERLEUKIN-15 
Chemical Name: Recombinant human interleukin-15 (rhIL-15) 
Other Names: Interleukin-T (IL-T)—no longer recognized. 
Classification: Recombinant human cytokine. 
Molecular Structure: Member of the four α-helix bundle family of human cytokines 
consisting of 115 amino acids manufactured in E. coli by recombinant technology. Non-
glycosylated. 
Description: Sterile, clear, colorless, particulate-free liquid; endotoxin free. 
11.1.1 Source 
Agent Ordering and Agent Accountability 
NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution. Pharmaceutical Management Branch (PMB) policy 
requires that agent be shipped directly to the institution where the patient is to be treated. PMB 
does not permit the transfer of agents between institutions (unless prior approval from PMB is 
obtained). The CTEP-assigned protocol number must be used for ordering all CTEP-supplied 
investigational agents. The responsible investigator at each participating institution must be 
registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and Financial 
Disclosure Form (FDF). If there are several participating investigators at one institution, CTEP-
supplied investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
In general, sites may order initial agent supplies when a subject is being screened for enrollment 
onto the study. 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can 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 and a “current” 
password. 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 

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management.  
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. 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration: PMBRegPend@ctep.nci.nih.gov 
• PMB policies and guidelines: http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
• CTEP Identity and Access Management (IAM) account: https://eapps-ctep.nci.nih.gov/iam/ 
• CTEP Associate Registration and IAM account help: ctepreghelp@ctep.nci.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) 
11.1.2 Toxicity 
From the experience in the ongoing rhIL-15 IVB trial, side effects of fatigue, fever, rigors or 
chills, capillary leak syndrome, fluid retention and edema are likely. Although there has not been 
any evidence of meaningful pulmonary dysfunction or changes in renal function, the preclinical 
NHP data and experience with other similar biological compounds indicates that these toxicities 
could potentially occur in patients treated with the CIV schedule. Gastrointestinal toxicities in 
the IVB IL-15 patients have included nausea, vomiting and in one case explosive diarrhea 
exclusively in the patient treated with the 3 mcg/kg/day dose, and data from the NHP toxicology 
study also showed diarrhea and dehydration—these could also be more common in patients 
treated with the CIV regimen. Although there has not been significant granulocytopenia in the 
rhIL-15 patients treated to date and lymphopenia has been transient, there is still some potential 
for infectious issues if the granulocytopenia associated with CIV treatment of macaques occurs 
in the patients enrolled in this protocol. 
Comprehensive Adverse Events and Potential Risks List (CAEPRs) For Recombinant 
Human IL-15  
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. 
Version 1.2, February 01, 20161 

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Adverse Events with Possible  
Relationship to Recombinant Human IL-15 
(CTCAE 4.0 Term) 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 Anemia (Gr 2) 
Bone marrow hypocellular 
  
CARDIAC DISORDERS 
  
Sinus tachycardia 
 Sinus tachycardia (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
Abdominal pain 
  
Diarrhea 
  
Nausea 
 Nausea (Gr 2) 
Vomiting 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS   
Chills 
 Chills (Gr 2) 
Edema limbs 
  
Fatigue 
 Fatigue (Gr 2) 
Fever 
 Fever (Gr 2) 
Injection site reaction 
  
INFECTIONS AND INFESTATIONS 
  
Sepsis 
  
INVESTIGATIONS 
  
Alanine aminotransferase increased 
  
Aspartate aminotransferase increased 
  
Blood bilirubin increased 
  
Creatinine increased 
  
Lymphocyte count decreased 
 Lymphocyte count decreased 
(Gr 2) 
Lymphocyte count increased 
  
Neutrophil count decreased 
  
Platelet count decreased 
  
White blood cell decreased 
  
METABOLISM AND NUTRITION DISORDERS 
  
Hypoalbuminemia 
  
Hypophosphatemia 
 Hypophosphatemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
Generalized muscle weakness 
  
NERVOUS SYSTEM DISORDERS 
  
Dizziness 
  
Headache 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
Dyspnea 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
Dry skin 
  
Erythema multiforme 
 Erythema multiforme (Gr 2) 
Skin and subcutaneous tissue disorders - Other (rash) 
  
VASCULAR DISORDERS 
  
Capillary leak syndrome 
  
Hypertension 
 Hypertension (Gr 2) 
Hypotension 
 Hypotension (Gr 2) 

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1This table will be updated as the toxicity profile of the agent is revised.  
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 
Reproductive system and breast disorders - Genital edema 
Respiratory, thoracic and mediastinal disorders - Adult respiratory distress syndrome; 
Bronchopulmonary hemorrhage; Cough; Hypoxia; Laryngeal inflammation; Pleural effusion; 
Pneumonitis; Pulmonary edema; Wheezing 
Skin and subcutaneous tissue disorders - Erythroderma; Palmar-plantar erythrodysesthesia 
syndrome; Pruritus; Rash acneiform; Skin and subcutaneous tissue disorders - Other (skin plaques) 
Vascular disorders - Hot flashes; Visceral arterial ischemia 
Note: Recombinant Human IL-15 in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may result 
in events never previously associated with either agent. 
11.1.3 Formulation  
Sterile rhIL-15 drug product is vialed at a concentration of 0.52 mg/mL (0.16 mg/0.3 ml) 
solution of 25 mM sodium phosphate, dibasic and 500 mM sodium chloride (pH 7.0 ±0.4) in a 5 
mL borosilicate glass vial. rhIL-15 drug product for intravenous administration should be 

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withdrawn from the vial and prepared as described in Section 11.1.5.  
Vials are for single use only.  
11.1.4 Stability and Storage  
Long-term at ≤ -70oC.  
Storage of rhIL-15 diluted in 0.1% HSA in infusion bags is limited to a maximum of 4 hours at 
room temperature or 24 hours at 2-8°C prior to initiation of the 24- hour infusion. 
Drug stability studies are ongoing and will be continued throughout the clinical trial. Long-term 
drug stability information will be periodically updated and communicated to the Clinical Center 
Pharmacy Department.  
11.1.5 Preparation and Administration Procedures 
For all dose levels, the dose of rhIL-15 will be diluted in the appropriate volume of 0.1% human 
serum albumin (HSA) in 5% dextrose in water, USP (D5W) to reach a final rhIL-15 
concentration of 1 mcg/mL. The rhIL-15 infusion will be administered to the patient by 
continuous intravenous infusion (CIV) over 24 hours using a portable ambulatory pump on the 
inpatient unit for either a total of 240 or 120 hours depending on the treatment cohort. 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. 
The infusion solutions will be mixed in an MMI bag.  
The rhIL-15 infusion solution is stable at a concentration of 1.0 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 2-8ºC 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. 
11.1.6 Drug Incompatibilities 
None known. 
 
 

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

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APPENDIX B:  IMMUNE-BASED STUDIES 
1. Flow Cytometry 
• Flow cytometry analysis for peripheral blood lymphocyte subset enumeration will 
be performed using standard techniques in the College of American pathologists 
(CAP) certified flow cytometry laboratory within the Clinical Pathology 
Department, NIH Clinical Center.  
• Special flow cytometry also performed by Dr. Enrico Lugli with Dr. Mario 
Roederer in the Vaccine Research Center, Building 40, Room 5044. 
2. Assay of rhIL-15 by R&D Systems Quantikine ELISA Kit (Catalog # D1500) to define 
concentration of IL-15 in pharmacokinetic assay. 
3. Assay for antibodies to infused IL-15 (see APPENDIX C). 
 
 

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

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APPENDIX D:  CIV RHIL-15 BIOSPECIMEN WORKSHEET FOR 12-C-0113 CYCLE 1 FOR 10 DAY SCHEDULE 
 
 
 

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APPENDIX E:  CIV RHIL-15 BIOSPECIMEN WORKSHEET FOR 12-C-0113 CYCLE 2 AND BEYOND