Clinical trial NCT04185220
Conditions: Adult T-Cell Lymphoma/Leukemia Sezary Syndrome Mycosis Fungoides
Keywords: Antibody-Dependent Cell Cytotoxicity (ADCC) CCR4 Monoclonal Antibody
Sponsor: National Cancer Institute (NCI)
Start date: 2020-02-26; Completion date: 2022-05-18
Enrollment: 6 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Background:

Adult T-cell leukemia/lymphoma (ATLL) and mycosis fungoides/Sezary syndrome (MF/SS) are cancers that form in the T cells, a type of white blood cell that helps with the body's immune response. A combination of drugs might be able to better treat these cancers than existing therapies.

Objective:

To test if the drugs interleukin-15 (IL-15) and mogamulizumab are safe and effective to treat people with Adult T-Cell Leukemia and Mycosis Fungoides/Sezary Syndrome (ATLL or MF/SS).

Eligibility:

People ages 18 and older with relapsed ATLL or MF/SS that has not responded to at least one standard treatment

Design:

Participants will be screened with:

Medical history

Physical exam

Blood (including human immunodeficiency virus (HIV), hepatitis B and C), urine, lung, and heart tests

Bone marrow tests (if needed): A needle inserted in the participants hip will take a small amount of marrow.

Computed tomography (CT), positron emission tomography (PET) and/or magnetic resonance imaging (MRI) scans

Tumor biopsy (if needed): A needle will take out a small piece of the participants tumor.

Participants will get the study drugs by vein for up to six 28-day cycles. They will get IL-15 the first 5 days of each cycle. They will get mogamulizumab on days 1, 8, 15, and 22 of cycle 1 and days 1 and 15 of the other cycles. They will be hospitalized for 1 week in cycle 1. They may need to get a midline catheter. This is a soft tube put into a vein leading to the heart.

Participants will have repeats of the screening tests throughout the study.

After treatment, participants will have visits every 60 days for 6 months, every 90 days for 2 years, and then every 6 months for 2 years.

Detailed description:
Background:

* Advanced mycosis fungoides, its leukemic form Sezary syndrome (MF/SS), and adult T- cell leukemia/lymphoma (ATLL) are all aggressive mature T-cell malignancies which are considered incurable without an allogeneic stem cell transplant.
* Mogamulizumab is a defucosylated monoclonal antibody directed towards C-C Motif Chemokine Receptor 4 (CCR4), a chemokine receptor expressed by the majority of MS/SS and ATLL cells. It is approved by the United States Food and Drug Administration for treatment of relapsed MF/SS and is recommended by the National Comprehensive Cancer Network for treatment of ATLL.
* Defucosylation of mogamulizumab is thought to enhance its capacity for antibody- dependent cell cytotoxicity (ADCC), which is mediated by natural killer (NK) cells and macrophages.
* The immunologic effects of recombinant human Interleukin-15 (rhIL-15), a stimulatory cytokine that promotes the differentiation and activation of natural killer (NK) cells, monocytes and long- term cluster of differentiation 8 (CD) 8+ memory T-cells, has been assessed in several phase I trials in cancer patients.
* Concomitant administration of rhIL-15 with mogamulizumab may further enhance the ADCC capacity of the antibody and result in improved efficacy for patients with CCR4- expressing cancers.

Objectives:

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

Eligibility:

* Age greater than or equal to 18 years of age
* Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 1
* Histologically or cytologically confirmed mycosis fungoides/S(SqrRoot)(Copyright)zary syndrome or adult T- cell leukemia/lymphoma relapsed after or refractory to at least one line of systemic treatment.
* Adequate organ and marrow function

Design:

* Open-label, single-center, non-randomized phase I study
* Standard "3 + 3" design will be used to determine the maximum tolerated dose (MTD) of dose-escalated recombinant human Interleukin-15 (rhIL-15) with fixed dose of mogamulizumab, with an expansion cohort at the MTD
* Maximum 6 cycles (28-day cycles) of combination therapy
* To explore all dose levels, including further evaluation in a dose expansion cohort, and to account for unevaluable patients the accrual ceiling will be set at 20 patients.

Arms: arm 1: Interleukin-15 (IL-15) by continuous intravenous (CIV) infusion at escalating doses of 2 and 4 mcg/kg/day on days 1-5 of each 28-day cycle (max 6 cycles) with mogamulizumab by intravenous (IV) infusion at a dose of 1 mg/kgdays 1, 8, 15 and 22 of cycle 1 and days 1 and 15 of each subsequent cycle to determine MTD. arm 2: Interleukin-15 (IL-15) by continuous intravenous (CIV) infusion at the maximum tolerated dose (MTD) on days 1- 5 of each 28-day cycle (max 6 cycles) with mogamulizumab by intravenous (IV) infusion at a dose of 1 mg/kgdays 1, 8, 15 and 22 of cycle 1 and days 1 and 15 of each subsequent cycle.
Interventions: intervention 1: Recombinant human Interleukin-15 (rhIL-15) intervention 2: Mogamulizumab
Intervention descriptions: intervention 1: Interleukin 15 (IL-15) will be administered by continuous intravenous infusion in a dose-escalation 3 + 3 system with a starting dose of 2 mcg/kg/day and a second dose level of 4 mcg/kg/day on days 1-5 of each of six cycles. intervention 2: Mogamulizumab (intravenous (IV) over at least 1 hour) will be administered at a dose of 1 mg/kg on days 1, 8, 15 and 22 of cycle 1 and days 1 and 15 of each subsequent cycle. Treatment will continue for a maximum of 6 cycles.

Protocol documents:
Prot_SAP_000.pdf: 
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Abbreviated Title: IL-15+Mogamulizumab  
Version Date: 11/16/2020 
Abbreviated Title: IL-15+ Mogamulizumab  
CC Protocol #: 20C0011 D 
CTEP Protocol #: 10336 
Version Date: 11/16/2020 
NCT Number: NCT04185220 
 
Title: Phase 1 Study of Recombinant Human IL-15 (rhIL-15) and Mogamulizumab for 
Patients with Refractory or Relapsed Adult T-Cell Leukemia and Mycosis 
Fungoides/Sézary Syndrome 
 
NCI Principal Investigator: 
 
 
Milos Miljkovic, M.D., MSc 
Lymphoid Malignancies Branch (LYMB) 
Center for Cancer Research (CCR) 
National Cancer Institute (NCI) 
Building 10, Room 4N115 
National Institutes of Health (NIH) 
Bethesda, MD  20892 
Phone:  301-250-5216 
Email:  milos.miljkovic@nih.gov  
 
Investigational Agents: 
Drug Name: 
Recombinant human IL-15  
(rhIL-15; NSC #745101) 
IND Number: 
140549 
Sponsor: 
Center for Cancer Research, NCI 
Manufacturer: 
Biopharmaceutical Development Program 
(BDP)/Leidos Biomedical Research, Inc. 
under contract with DCTD, NCI 
 
Commercial Agents: Mogamulizumab (Poteligeo®) 
 
 
 


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PRÉCIS  
Background: 
• Advanced mycosis fungoides, its leukemic form Sézary syndrome (MF/SS), and adult T-
cell leukemia/lymphoma (ATLL) are all aggressive mature T-cell malignancies which are 
considered incurable without an allogeneic stem cell transplant. 
• Mogamulizumab is a defucosylated monoclonal antibody directed towards CCR4, a 
chemokine receptor expressed by the majority of MS/SS and ATLL cells. It is approved 
by the United States Food and Drug Administration for treatment of relapsed MF/SS, and 
is recommended by the National Comprehensive Cancer Network for treatment of ATLL. 
• Defucosylation of mogamulizumab is thought to enhance its capacity for antibody-
dependent cell cytotoxicity (ADCC), which is mediated by natural killer (NK) cells and 
macrophages. 
• The immunologic effects of recombinant human Interleukin-15 (rhIL-15), a stimulatory 
cytokine that promotes the differentiation and activation of NK cells, monocytes and long-
term CD8+ memory T-cells, has been assessed in several phase I trials in cancer patients. 
• Concomitant administration of rhIL-15 with mogamulizumab may further enhance the 
ADCC capacity of the antibody and result in improved efficacy for patients with CCR4-
expressing cancers. 
Objectives: 
• To determine the safety and toxicity profile and the maximum tolerated dose (MTD) of 
continuous intravenous infusion (civ) rhIL-15 administration in combination with standard 
intravenous (IV) mogamulizumab treatment 
Eligibility: 
• Age ≥ 18 years of age 
• ECOG performance status of ≤ 1   
• Histologically or cytologically confirmed mycosis fungoides/Sézary syndrome or adult T-
cell leukemia/lymphoma relapsed after or refractory to at least one line of systemic 
treatment. 
• Adequate organ and marrow function  
Design: 
• Open-label, single-center, non-randomized phase I study 
• Standard “3 + 3” design will be used to determine the MTD of dose-escalated rhIL-15 with 
fixed dose of mogamulizumab, with an expansion cohort at the MTD 
• Maximum 6 cycles (28-day cycles) of combination therapy  
• To explore all dose levels, including further evaluation in a dose expansion cohort, and to 
account for unevaluable patients the accrual ceiling will be set at 20 patients.   


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TABLE OF CONTENTS  
PRÉCIS ........................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 3 
STATEMENT OF COMPLIANCE ................................................................................................ 1 
1 
INTRODUCTION .................................................................................................................. 2 
1.1 
Study Objectives .............................................................................................................. 2 
1.2 
Background and Rationale ............................................................................................... 2 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 12 
2.1 
Eligibility Criteria .......................................................................................................... 12 
2.2 
Screening Evaluation ...................................................................................................... 14 
2.3 
Participant Registration and Status Update Procedures ................................................. 16 
2.4 
Baseline Evaluation ........................................................................................................ 17 
3 
STUDY IMPLEMENTATION ............................................................................................ 18 
3.1 
Study Design .................................................................................................................. 18 
3.2 
Drug Administration ...................................................................................................... 21 
3.3 
Dose Modifications ........................................................................................................ 22 
3.4 
Study Intervention Compliance ...................................................................................... 24 
3.5 
On Study Evaluations ..................................................................................................... 24 
3.6 
Post-Treatment Evaluations ........................................................................................... 24 
3.7 
Study Calendar ............................................................................................................... 26 
3.8 
Costs and Compensation ................................................................................................ 29 
3.9 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 29 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 30 
4.1 
Acceptable Medications ................................................................................................. 30 
4.2 
Prohibited Medications .................................................................................................. 31 
5 
CORRELATIVE STUDIES ................................................................................................. 31 
5.1 
Summary ........................................................................................................................ 31 
5.2 
Sample Collection and Processing ................................................................................. 33 
5.3 
Sample Storage, Tracking, and Disposition ................................................................... 36 
5.4 
Samples for Genetic/Genomic Analysis ........................................................................ 38 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 39 
6.1 
Data Collection ............................................................................................................... 39 


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6.2 
Data Sharing Plans ......................................................................................................... 40 
6.3 
RESPONSE CRITERIA ................................................................................................ 40 
6.4 
Toxicity Criteria ............................................................................................................. 44 
7 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN .. 44 
7.1 
Definitions ...................................................................................................................... 44 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting ....................................... 44 
7.3 
NCI Clinical Director Reporting .................................................................................... 44 
7.4 
NIH Required Data and Safety Monitoring Plan ........................................................... 45 
8 
SPONSOR SAFETY REPORTING ..................................................................................... 45 
8.1 
Definitions ...................................................................................................................... 45 
8.2 
Assessment of Safety Events .......................................................................................... 46 
8.3 
Reporting of Serious Adverse Events ............................................................................ 47 
8.4 
Waiver of expedited reporting to CCR .......................................................................... 47 
8.5 
Safety Reporting Criteria to the Pharmaceutical Collaborators ..................................... 47 
8.6 
Reporting Pregnancy ...................................................................................................... 47 
8.7 
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND .................. 48 
9 
CLINICAL MONITORING ................................................................................................. 48 
10 STATISTICAL CONSIDERATIONS.................................................................................. 48 
10.1 
Statistical Hypothesis ................................................................................................. 48 
10.2 
Sample Size Determination ........................................................................................ 49 
10.3 
Population For Analysis ............................................................................................. 49 
10.4 
Statistical analyses ...................................................................................................... 50 
11 COLLABORATIVE AGREEMENTS ................................................................................. 51 
11.1 
Material Transfer Agreement (MTA)- CTEP ............................................................. 51 
12 HUMAN SUBJECTS PROTECTIONS ............................................................................... 51 
12.1 
Rationale For Subject Selection ................................................................................. 51 
12.2 
Participation of Children ............................................................................................ 51 
12.3 
Participation of Subjects Unable to Give Consent ..................................................... 51 
12.4 
Risk/ Benefit Assessment ........................................................................................... 52 
12.5 
Consent Process and Documentation ......................................................................... 53 
13 REGULATORY AND OPERATIONAL CONSIDERATIONS ......................................... 54 
13.1 
Study Discontinuation and Closure ............................................................................ 54 


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13.2 
Quality Assurance and Quality Control...................................................................... 54 
13.3 
Conflict of Interest Policy........................................................................................... 55 
14 PHARMACEUTICAL INFORMATION ............................................................................. 55 
14.1 
rhIL-15 (NSC #745101) ............................................................................................. 55 
14.2 
Mogamulizumab (KW-0761, NSC# 791064) ............................................................ 60 
15 REFERENCES ..................................................................................................................... 64 
16 APPENDICES ...................................................................................................................... 68 
16.1 
APPENDIX A:  Performance Status Criteria ............................................................. 68 
16.2 
APPENDIX B:  Assay for ADCC .............................................................................. 69 
16.3 
APPENDIX C:  Global Response Score and Definitions of Response in Skin, Lymph 
Nodes, Viscera, and Blood........................................................................................................ 70 
16.4 
APPENDIX D:  IL-15 Dilution Instructions .............................................................. 73 
16.5 
Appendix E: Assay For Antibodies to rhIL-15 .......................................................... 74 


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


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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
• Determine the safety and toxicity profile and the maximum tolerated dose (MTD) of 
continuous intravenous infusion (civ) rhIL-15 administration in combination with standard 
intravenous (IV) mogamulizumab treatment 
1.1.2 Secondary Objective(s) 
• Determine the efficacy of combined CIV rhIL-15 and mogamulizumab treatment in 
patients with ATLL and MF/SS by assessing the overall response rate (ORR), time-to-
progression (TTP), and progression-free survival (PFS). 
• Determine the effect of CCR4 mutation status (mutated versus wild type) and presenting 
diagnosis (MF/SS versus ATLL, MF versus SS, acute and chronic versus lymphoma 
subtype ATLL) on ORR, TTP, and PFS 
• Define the effects of rhIL-15 on the antibody-dependent cell-mediated cytotoxicity 
(ADCC) mediated by mogamulizumab, using ex-vivo peripheral blood mononuclear cells 
(PBMCs) 
1.1.3 Exploratory Objective(s) 
• Better understand the in vivo biologic effects of mogamulizumab and rhIL-15 treatment 
by:  
o analyzing changes in peripheral blood lymphocyte subsets 
o examining treatment-related changes in tumor deposits by immunohistochemical 
and molecular analysis of core biopsies obtained before and during treatment. 
• Assess circulating tumor DNA as a prognostic and predictive biomarker in MF/SS and 
ATLL. 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 Adult T-cell leukemia/lymphoma (ATLL) 
ATLL is an aggressive T-cell lymphoproliferative disorder characterized by the presence of 
malignant CD4/CD25/CCR4-expressing T cells in the peripheral blood, lymphoid tissues, and 
other organs. Epidemiological studies demonstrated clear association of the disease with the 
presence of the retrovirus human T-cell lymphotrophic virus-1 (HTLV-1). ATLL cells exhibit 
immunophenotypic characteristics of mature T-regulatory cells, with surface expression of 
CD3dim, CD4, and CD25, and loss of CD7. There are four clinical subtypes of ATL (Table 1), with 
median overall survival (OS) ranging from 72 months for chronic/smoldering, 10.2 months for 
lymphomatous, and only 4.1 months for acute subtype in a cohort of 195 patients of predominantly 
Caribbean origin treated with modern therapies between 2000 and 2016.(1) 
 


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Table 1: Clinical subtypes of adult T-cell leukemia/lymphoma 
Subtype 
Clinical features 
Lymphocyte count 
Associated biochemical 
abnormalities 
Smoldering 
Skin and pulmonary lesions 
No LAD or organ involvement 
≥ 5% abnormal T cells 
Normal ALC (< 4 x 109/L) 
Calcium, LDH < 1.5 ⨉ ULN 
Chronic 
Skin and lung involvement, no 
CNS, bone, GI tract involvement, 
no ascites or pleural effusions 
ALC > 4 x 109/L 
T cells > 3 x 109/L 
LDH elevated but < 2 ⨉ ULN 
Calcium normal 
Lymphoma 
Biopsy-proven LAD 
Normal ALC, ≤ 1% 
abnormal circulating T-
cells 
Acute 
Tumor lesions 
Leukemia 
Not required for diagnosis 
ALC, absolute lymphocyte count; LDH, lactate dehydrogenase; ULN, upper limit of normal; 
LAD, lymphadenopathy; CNS, central nervous system. (adapted from Shimoyama et al.(2) 
1.2.1.1 Treatment of ATLL 
There are no curative therapeutic options for patients with ATLL outside of early allogeneic stem 
cell transplantation, ideally immediately after achieving a complete response to first-line 
chemotherapy.(3) Prognosis of ATLL relapsed or refractory to front-line therapy is dismal(4), and 
experience with the standard combination chemotherapeutic regimens known to be useful in the 
treatment of the more common aggressive B-cell non-Hodgkin lymphomas or acute lymphoblastic 
leukemia has been disappointing. In North America, the majority of patients with the three more 
aggressive categories of ATLL (severe chronic, acute, and lymphoma subtype) are still treated 
with CHOP-based regimens (cyclophosphamide, Adriamycin, vincristine and prednisone) with or 
without interferon and zidovudine.(5) In countries where ranimustine and vindesine are available, 
and which have the infrastructure for a more intensive chemotherapy regimen, the LSG15 protocol 
(VCAP-AMP-VECP) is an option shown to be superior to biweekly CHOP in a phase III trial 
(complete response [CR] rate 40% v. 25%, 3-year OS 24% v. 13%).(6) A meta-analysis showed 
that the addition of interferon and zidovudine to first-line therapy improved OS of patients with 
acute, chronic, and smoldering subtypes(7), but there was a lack of efficacy in patients with 
relapsed disease. 
There are no US FDA-approved drugs for relapsed/refractory ATLL, and no randomized phase III 
trials have been conducted in this patient population. Mogamulizumab (KW-0761), a monoclonal 
antibody targeting CCR4, is approved in Japan for treatment of CCR4-positive ATLL. In a phase 
II trial of 27 Japanese patients with relapsed ATLL, overall response rate (ORR) was 50% (95% 
CI 30% to 70%), median progression-free survival (PFS) was 5.2 months, and median OS 13.7 
months.(8) An international randomized phase II study of mogamulizumab versus investigator-
choice chemotherapy in 71 patients from the US, Europe, and Latin America with aggressive 
relapsed/refractory ATLL showed confirmed ORR (response lasting ≥8 weeks) to be 11% versus 
0%, and best ORR 28% versus 8% (in press). 
Lymphoid Malignancies Branch (LYMB) conducted a phase II trial of alemtuzumab (Campath), 
an anti-CD52 monoclonal antibody, in 29 patients with relapsed chronic, acute, and lymphomatous 


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subtypes of ATLL. ORR was 52% (95% CI 32% to 70%), but median duration of response was 
only 1.4 months, with median PFS and OS of 2.0 and 5.9 months respectively.(9) 
Treatment with Lenalidomide, given to 26 patients in a multicenter phase II trial, resulted in an 
ORR of 42% (95% CI 23% to 63%), including four CRs and one unconfirmed CR.(10) Median 
PFS and OS were 3.8 and 20.3 months respectively. Phase II trials of single-agent cladribine, 
arsenic trioxide with alpha interferon, and bortezomib have all shown modest results (ORR 4% to 
7%) with significant toxicity.(11-13) 
1.2.2 Mycosis fungoides/Sézary syndrome (MF/SS) 
Cutaneous T-cell lymphomas are a diverse group of non-Hodgkin lymphomas characterized by 
primary cutaneous infiltration of malignant T cells. Mycosis fungoides (MF), the most common 
type of CTCL, arises from accumulation of aberrant effector/resident memory CD4+ T-cells in 
skin lesions, while malignant clones in Sézary syndrome (SS), the erythrodermic and leukemic 
form of CTCL, are thought to arise de novo as an expansion of central memory T-cells. Although 
very early stage MF patients have an indolent course with median OS of 15-35 years, those with 
≥ stage IIB and SS patients have compromised survival (median OS of 4.7 years for stage IIB-
IIIA, 2.1-3.8 years for stage IIIB-IVA, and 1.4 years for stage IVB).(14)  
1.2.2.1 Treatment of MF/SS 
Other than allogeneic hematopoietic stem cell transplantation(15), no treatment for MF/SS has 
been shown to be curative, and advanced disease can become refractory, leading to serious clinical 
complications.(14) Chemotherapy, including CHOP-based regimens, has high response rates (50-
88%), but duration of response of <6 months and high toxicity.(14, 16, 17) There are five US FDA-
approved drugs for relapsed/refractory MF/SS currently on the market: bexaroten, romidepsin, 
vorinostat, brentuximab vedotin, and the recently approved mogamulizumab. The sixth, anti-CD25 
immunotoxin denileukin diftitox, was withdrawn by the manufacturer and is no longer available. 
The RXR-selective retinoid bexaroten was given at two different dose levels to 94 patients with 
stage ≥IIB CTCL, of whom 31% had erythroderma and 10% had visceral involvement.(18) Only 
16% of patients had ≥15% circulating Sézary cells, though 27% had the cells detectable. ORR was 
45-55%, with 1-5 CRs. One of five patients with circulating Sézary cells had a substantial decrease 
in counts. Six of 19 patients (32%) with generalized erythroderma, and four of 17 (24%) with SS 
had a response. The most common grade 3 or 4 AEs were hyperlipidemia (34- 45%) and pruritus 
(8-14%). One of 17 deaths was judged to be possibly drug related, that of a patient who developed 
liver failure with coagulopathy. 
The HDAC inhibitor vorinostat was investigated in a phase IIB multicenter trial of 74 patients, 61 
with advanced (stage ≥IIB) disease, including 30 with SS. ORR was 29.7% (1 CR, 21 PRs), 
including 10/30 patients with SS. Grade 3 or 4 AEs were seen in 28% of the patients, with the most 
common being fatigue (5%), pulmonary embolism (5%), thrombocytopenia (5%), and nausea 
(4%).(19) 
Another HDAC inhibitor, romidepsin, was investigated in two concurrent phase II trials which 
included a total of 167 patients, 130 of whom had stage ≥IIB disease.(20, 21) ORR was 34-38%, 
and a total of 10 patients (6%) had CRs, three of whom had SS. Reports of grade 3 or 4 AEs varied 
between the studies, with lymphopenia ranging from 21% to <10%, neutropenia 14% to <10%, 
and thrombocytopenia 6% to none. There were 10 deaths within 30 days of receiving the last dose 


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of the drug, two from sepsis, one from hypertrophic cardiac disease, and the rest from disease 
progression. 
Results of a phase III trial of brenutixmab vedotin compared to methotrexate or bexaroten in 
CD30+ CTCL were reported as positive for improvement in global overall response lasting at least 
4 months (ORR4), which was 56.3% vs. 12.5% after a median follow-up of 22.9 months.(22)  
Finally, mogamulizumab has shown efficacy in patients with cutaneous T-cell lymphoma. In the 
phase I/II study, among the 38 evaluable patients the ORR was 36.8%; 47.1% in SS (n = 17) and 
28.6% in MF (n = 21).(23) Eighteen of 19 (94.7%) patients with blood involvement had a response 
in blood, including 11 CRs. Efficacy of mogamulizumab was confirmed in a phase III randomized 
controlled trial which demonstrated a median 4.6-month improvement in PFS as compared to 
vorinostat (7.7 vs. 3.1 months).(24) Importantly, CCR4 expression was not required for treatment, 
though an exploratory analysis showed 97% (280 of 290) patients to be CCR4 positive, defined as 
having at least 10% infiltrating CCR4ᐩ lymphocytes on immunohistochemistry. No differences in 
response were seen in patients on the basis of skin CCR4 expression. Mogamulizumab was well-
tolerated, with the majority of events Grade 1/2 that included nausea, chills, headache and infusion-
related reactions.  
1.2.3 Chemokine Receptor 4 (CCR4) 
CCR4 is a chemokine receptor that has a critical role in immune cell trafficking. Expression of 
CCR4 on normal lymphocytes is modest, as it is found predominantly on T-regs and skin-homing 
memory T-cells that migrate toward the chemokines CCL17 and CCL22, which interact with the 
receptor CCR4. In contrast to the relative non-expression of CCR4 on normal lymphocytes, the 
leukemic cells in 90 percent of patients with ATLL cells express CCR4 on their surface.(25) 
Interestingly, the most frequent sites of ATLL involvement are lymph nodes and skin where 
dendritic cells, M2-phenotype macrophages, Langerhans cells, and cutaneous venules can produce 
CCL17 and/or CCL22. A number of studies have provided insights concerning the mechanisms 
underlying the expression of CCR4 on ATLL cells. In our own studies we discovered recurrent 
somatic mutations in CCR4 in 14 of 53 ATLL cell samples (26 percent) that consisted exclusively 
of nonsense or frameshift mutations that truncated the coding region at C329, Q330, or Y331 in 
the carboxyl terminus.(26) Due to the deletion of the carboxyl terminus the CCR4 expression was 
maintained on the ATLL cells rather than internalizing on the interaction with its cognate 
chemokine. Functionally, the CCR4 Q330 nonsense isoform was a gain-of-function because it 
increased cell migration towards CCR4 ligands CCL17 and CCL22. Furthermore, this mutant 
enhanced PI (3) kinase/AKT activation after receptor engagement by CCL22 and conferred a 
growth advantage in long-term in vivo cultures. Even in the absence of the mutations it has been 
demonstrated that HBZ encoded by HTLV-1 in ATLL cells acts on the promoter of CCR4 
augmenting expression of this receptor. In MF/SS, CCR4 was detected by peripheral blood flow 
cytometry in 63% of patients(27), and by IHC of skin lesions in 97% (with positivity defined as 
≥10% of infiltrating lymphoid cells).(24) Similarly to ATLL, genomic studies of patients with SS 
have described gain-of-function nonsense mutations Q330 and Y331, as well as a new nonsense 
mutation Y347, and two new frame shift mutations, C322fs and D341fs.(28) Taken together these 
findings implicate CCR4 expression in the pathogenesis of ATLL and MF/SS, and suggest that 
inhibition of CCR4 and its signaling may have therapeutic potential in these malignancies. 


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1.2.4 Mogamulizumab 
As noted above, the CC chemokine receptor 4 is expressed in the malignant cells of 90% of patients 
with ATLL and 97% of patients with MF/SS, however, with the exception of Tregs, is minimally 
expressed on normal lymphocytes. Mogamulizumab (KW-0761) is a defucosylated humanized 
mAb with enhanced antibody cellular cytotoxicity (ADCC) that binds to CCR4.(29)  
Mogamulizumab is devoid of complement dependent cytotoxicity. The antibody has shown potent 
antitumor activity mediated by highly enhanced ADCC against primary ATLL cells both in vitro 
and in vivo.(30) The degree of mogamulizumab ADCC against primary ATLL cells in an 
autologous setting was mainly determined by the amount of effector natural killer (NK) cells 
present but not on the amount of targeted molecule CCR4 on the ATLL cell surface.(30) It is 
approved in Japan for treatment of CCR4-positive relapsed/refractory ATLL and MF/SS, and in 
the US for the treatment of any MF/SS after at least one prior systemic therapy. 
In a post-marketing all-case survey conducted in Japan of patients with ATLL who received 
mogamulizumab, the overall response rate in the 308 patients treated with single-agent therapy 
was 57.7%.(31) Forty-two patients had received mogamulizumab after an allogeneic stem cell 
transplant. Grade 3 or 4 acute graft versus host disease (GVHD) occurred in 28.6% of these 
patients, all of whom received mogamulizumab within 90 days of transplant. Chronic GVHD 
occurred in 45% of patients who survived beyond 100 days after transplant. In a different analysis, 
patients with ATLL who carried any CCR4 gain-of-function mutation had superior response to 
mogamulizumab compared with wild-type CCR4 (5-year OS 72.2% vs. 26.2%), despite patients 
with mutated CCR4 doing worse compared to unmutated patients in historic controls. As 
hypothesized when CCR4 gain-of function mutations were first described(26), this was likely the 
effect of impaired CCR4 internalization upon ligand binding, resulting in increased CCR4 
expression even in the presence of the ligand.  
1.2.5 Interleukin-15 
IL-15 is a 14-15 kDa member of the 4 alpha-helix bundle family of cytokines that acts through a 
heterotrimeric receptor involving IL-2/IL-15R beta subunit shared with IL-2, the common gamma 
chain (γc) shared with IL-2, IL-4, IL-9, IL-21, and IL-15 specific receptor subunit IL-15R alpha 
(CD215).(32-36)  IL-15 acts as a cell surface molecule as a part of an immunological synapse with 
IL-15 and IL-15R alpha produced in trans on adjacent mononuclear cells like monocytes and DCs 
which have been stimulated with interferon (and/or) CD40 ligation. IL-15 has been shown in many 
model systems to be a potent stimulator of T and NK-cell functions and in contrast to IL-2 does 
not activate Tregs and participates less in the capillary leak syndrome. A number of studies in 
murine models suggested that IL-15 may prove to be of value in the therapy of neoplasia.  The 
safety of IL-15 was evaluated in rhesus macaques. A 12-day bolus intravenous administration of 
20 µg/kg/day of IL-15 to rhesus macaques was associated with a 4 to 8-fold increase in the number 
of circulating NK cells.(33)  When administered by CIV at 20 µg/day for 10 days it led to a 10-
fold increase in the number of circulating NK cells, a 15-fold increase in the number of circulating 
monocytes and a massive 80 to 100-fold increase in the number of circulating effector memory 
CD8 T-cells.(34)  Subcutaneous injections at 20 µg/day for 10 days led to a 10-fold expansion in 
the number of circulating effector memory CD8 T-cells (Figure 1).(35)  


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Figure 1. Fold-Increase in absolute NK cell counts in rhesus macaques 
1.2.5.1 IL-15 in the Treatment of Patients with Metastatic Malignancy 
Three clinical trials of rhIL15 have had their patient accrual completed with 19-29 patients each: 
one by bolus infusion over 30 minutes(37), one by subcutaneous (SC) administration(38), and the 
third by CIV of rhIL15 to patients with metastatic malignancy.(39) The MTD by bolus infusion 
was 0.3 mcg/kg/day, whereas the MTD with SC administration was 3 mcg/kg/day and by CIV was 
2 mcg/kg/day.  
In the phase I study of bolus infusions of recombinant Escherichia coli produced human IL-15, the 
MTD was determined to be 0.3 µg/kg/day for 12 days. At a dose of 3 µg/kg/day the patients 
developed fever and rigors and a reduction in blood pressure that were concurrent with a maximum 
of 50-fold elevations of circulating IL-6 and IFNγ concentrations.  The bolus infusion of IL-15 at 
3 µg/kg/day led to a 10-fold expansion of NK cells.  When IL-15 was administered subcutaneously 
5 days a week for 2 weeks at 3 mcg/kg/day there was a significant increase (mean 10.8 fold) in the 
number of circulating NK cells. Furthermore, when it was administered at 2 mcg/kg/day by 
continuous intravenous infusion there was an 8-fold increase in this number during the infusion.  
Following termination of the infusion there was a 38-fold increase in the number of NK cells and 
a 358-fold increase in the number of CD56bright NK cells (Figure 2A). A trial of IL-15 by CIV 
for 5 days has been initiated, and in the 11 patients studied following treatment there was a 21 to 
44-fold increase in the number of circulating NK cells, and up to an 8.9-fold increase in the number 
of CD8+ T cells (Figure 2B, Table 2 and Table 3). 


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Figure 2: Increase in lymphocytes, predominantly NK cell count, during continuous infusion of 
rhIL-15. 
rhIL-15 was administered at progressively increasing doses of 0.25, 0.5, 1.0, 2.0 and 4.0 mcg/kg/day by 
10-day civ infusion (A) and 5-day civ infusion (B) to patients with metastatic malignancy. Patients 2-4 
received 0.125 mcg/kg, patients 5-7 received 0.25 mcg/kg, patients 8-10 received 0.5 mcg/kg, patients 11-
16 received 1.0 mcg/kg and patients 17-19 received 2.0 mcg/kg. Following termination of the treatment 
(red arrow) there was a dramatic 30-fold increase in the number of circulating lymphocytes predominantly 
NK cell count and an over 350-fold increase in the number of circulating CD56bright NK cells in the 10-
day cohort, and an up to 44-fold increase (33-fold mean increase) in the number of circulating NK cells in 
the 5-day cohort. 
Table 2: Characteristics and Outcomes of 11 patients treated with a 5-day civ rhIL-15 
infusion. 
Diagnosis 
Age 
Gender 
Dose level 
(mcg/kg) 
No. of doses 
NK cell 
increase 
(fold) 
CD8+ T-cell 
increase 
(fold) 
Melanoma 
63 
M 
5 
5 
32.01 
4.21 
Small bowel 
69 
M 
5 
10 
39.13 
4.74 
Colorectal 
60 
F 
5 
4 
- 
- 
Small bowel 
51 
F 
5 
10 
32.03 
5.66 
Colorectal 
66 
F 
4 
10 
44.90 
3.65 
Renal cell 
56 
M 
4 
15 
43.65 
8.94 
Esophageal 
60 
M 
4 
10 
39.63 
2.01 
Colorectal 
67 
F 
3 
20 
21.40 
1.65 
Colorectal 
56 
F 
3 
15 
23.66 
2.03 
Endometrial 
70 
F 
3 
3 
- 
- 
Colorectal 
47 
F 
3 
10 
24.15 
1.66 
A 
B 


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Table 3: Lymphocyte subset changes observed with four rhIL-15 dosing regimens at the 
recommended dose.  
 
Regimen 
RP2D 
(mcg/kg) 
Mean fold increase at RP2D 
NK 
CD56bright 
CD8 T 
IVB 
0.3 
2.5 
 
8 
SC 
2 
10.8 
37 
3.3 
CIV-10 
2 
31 
400 
3.3 
CIV-5 
4 
42 
Pending 
4.8 
RP2D: recommended phase 2 dose, IVB: intravenous bolus, SC: subcutaneous injection, CIV-10: 10-day 
continuous intravenous infusion, CIV-5: 5-day continuous intravenous infusion. 
The best response has been stable disease. There have been no dose-limiting toxicities. Two 
patients (at 3 and 5 mcg/kg/day dose levels) did not complete cycle 1 for reasons unrelated to IL-
15 and have completely recovered since. One patient at the 4 mcg/kg/day dose level developed 
bilateral arthritis which was thought to be septic and unrelated to IL-15, with mostly PMNs and 
some GPCs in the synovial fluid. Other AEs have been identical to what was seen in patients 
receiving 10-day infusion, though shorter in duration (Table 4 and Table 5). 
Table 4: Clinical adverse events possibly, probably, or definitely related to research (5-day 
CIV cohort) excluding single grade 1 events 
Dose  
3 μg/kg 
n=4 
4 μg/kg 
n=3 
5 μg/kg 
n=4 
CTC V4 Grade 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
Arthritis 
 
 
 
 
 
1 
 
 
0 
0 
 
 
Bladder infection 
 
1 
 
 
0 
0 
 
 
0 
0 
 
 
Chills 
1 
1 
 
 
0 
2 
 
 
0 
2 
 
 
Constipation 
1 
0 
 
 
0 
0 
 
 
1 
0 
 
 
Diarrhea 
2 
0 
 
 
1 
0 
 
 
1 
1 
 
 
Dizziness 
 
 
 
 
2 
0 
 
 
0 
0 
 
 
Dry mouth 
1 
0 
 
 
2 
0 
 
 
0 
0 
 
 
Dry skin 
 
 
 
 
0 
1 
 
 
0 
0 
 
 
Edema limbs 
1 
1 
 
 
0 
0 
 
 
0 
0 
 
 
Fatigue 
1 
1 
 
 
0 
0 
 
 
2 
1 
 
 
Fever 
2 
2 
 
 
1 
1 
 
 
2 
2 
 
 
Headache 
1 
0 
 
 
1 
0 
 
 
0 
0 
 
 
Hypotension 
 
1 
 
 
 
1 
 
 
1 
 
 
 
Nausea 
2 
0 
 
 
2 
0 
 
 
3 
0 
 
 
Pulmonary edema 
 
1 
 
 
 
 
 
 
 
 
 
 
Rash maculo-papular 
2 
0 
 
 
0 
0 
 
 
2 
0 
 
 
Vomiting 
2 
0 
 
 
1 
0 
 
 
2 
0 
 
 
 


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Table 5: Laboratory abnormalities possibly, probably, or definitely related to research 
(5-day CIV cohort) excluding single grade 1 events 
 
 
3 μg/kg 
n=4 
4 μg/kg 
n=3 
5 μg/kg 
n=4 
CTC V4 Grade 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
Anemia 
 
0 
2 
 
0 
2 
0 
0 
1 
1 
1 
 
ALT increased 
1 
1 
0 
 
1 
1 
0 
0 
3 
0 
0 
 
AST increased 
 
2 
0 
 
2 
0 
0 
0 
4 
0 
0 
 
Alkaline phosphatase  
 
1 
0 
 
1 
0 
1 
0 
2 
1 
0 
 
Hyperbilirubinemia 
1 
1 
0 
 
0 
1 
0 
0 
1 
0 
1 
 
Hypoalbuminemia 
 
2 
0 
 
1 
1 
0 
0 
2 
2 
0 
 
Creatinine increased 
 
 
 
 
1 
0 
0 
0 
1 
2 
0 
 
Hyperglycemia 
 
 
 
 
 
 
 
 
 
1 
 
 
Hypernatremia 
2 
0 
0 
 
0 
0 
0 
0 
011 0 
1 
 
Hyponatremia 
1 
0 
1 
 
2 
0 
0 
0 
3 
0 
0 
 
Hypocalcemia 
1 
0 
0 
 
1 
0 
0 
0 
4 
0 
0 
 
Hypokalemia 
2 
1 
0 
 
0 
0 
0 
0 
1 
0 
2 
 
Hypomagnesemia 
 
 
 
 
1 
0 
0 
0 
3 
0 
0 
 
Hypophosphatemia 
 
1 
2 
 
0 
2 
0 
0 
0 
1 
2 
 
Lymphocytosis 
 
 
 
2 
0 
0 
0 
2 
0 
0 
1 
2 
Lymphopenia 
 
1 
0 
 
0 
1 
1 
0 
0 
2 
1 
1 
Neutropenia 
1 
0 
0 
 
1 
0 
1 
0 
0 
1 
0 
 
Thrombocytopenia 
 
2 
0 
 
2 
0 
0 
0 
1 
1 
0 
 
Leucopenia 
 
2 
0 
 
0 
1 
1 
0 
1 
1 
1 
 
 
1.2.5.2 Preclinical Trials of IL-15 with Anticancer Monoclonal Antibodies to Augment their 
ADCC 
While the in vivo effects of IL-15 in cancer patients are still not entirely clear, the initial clinical 
data has demonstrated that to achieve its potential in the treatment of cancer, IL-15 will have to be 
used in combination with other therapeutic agents. In light of the data, from preclinical animal 
models and clinical trials, of the capacity of IL-15 to increase the number of activated NK cells, T 
cells and, monocytes this information supports the administration of IL-15 with antitumor 
monoclonal antibodies to augment their ADCC against tumor cells. To further investigate this 
strategy, the Waldmann Laboratory used an immunocompetent syngeneic mouse model of B-cell 
lymphoma to investigate the combination of IL-15 with rituximab.(40) Wild-type CD56 and BL/6 
mice were inoculated intravenously with EL4-CD20 cells, a mouse lymphoma line transfected 
with human CD20 and the mice were distributed into 4 treatment groups (control, IL-15 alone, 
rituximab alone and the combination) of 10 mice each. IL-15 (5 µg/mouse) was administered 5 
times per week for 4 weeks beginning 3 days after EL4-CD20 inoculation. In cohorts receiving 
rituximab, the monoclonal antibody was given once per week for 4 weeks starting 5 days after 
EL4-CD20 inoculation. IL-15 or rituximab monotherapy prolonged survival of mice when 


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compared to the control group (p < 0.05) but the combination of IL-15 and rituximab showed the 
greatest prolongation of survival compared to monotherapies (< 0.01), so that 75 days after tumor 
inoculation 90% of the combination treatment group were still alive in contrast to 30% survival 
from the monotherapy groups and no surviving mice in the control group (Figure 3). In a parallel 
preclinical trial, the Waldmann Group administered a combination therapy of alemtuzumab with 
rhIL-15 in the MET-I bearing xenograft model in wild-type SCID/NOD mice (Figure 4). Again, 
there was an augmentation of survival of the combination of IL-15 with alemtuzumab compared 
to either element alone. 
In summary, clinical trials in humans indicate that IL-15 administered by CIV is well tolerated and 
is associated with an increase in the number of NK cells. Furthermore, studies combining 
monoclonal antibodies with IL-15 in syngeneic and xenogeneic murine tumor models provide 
scientific support for the combination of antitumor monoclonal antibodies with IL-15 in patients 
with chronic and acute lymphoma forms of ATLL.  All previous trials in patients with acute ATLL 
have been closed for patient accrual. 
 
 
Figure 3:The effect of Rituximab and human IL-15 treatment of CD20+ Lymphoma 
 
 
Figure 4:The effect of Alemtuzumab and human IL-15 treatment of ATL cell line MET-1 
 


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2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Patients must have one of the following histologically or cytologically proven relapsed 
and/or refractory to at least one line of systemic treatment, T-cell malignancies 
confirmed by the Laboratory of Pathology, NCI: mycosis fungoides/Sézary syndrome, 
or adult T-cell leukemia (chronic, acute, or lymphoma subtype by Shimoyama criteria, 
see Table 1) 
2.1.1.2 Patients with CD30+ MF/SS must have relapsed after or become intolerant to treatment 
with brentuximab vedotin 
2.1.1.3 A formalin fixed tissue block or 15 slides of tumor sample (archival or fresh) must be 
available for performance of correlative studies. NOTE: Patients must be willing to have 
a tumor biopsy if prior tissue or adequate archival tissue is not available (i.e., post-
enrollment and prior to treatment). 
2.1.1.4 Disease must be measurable with at least one measurable lesion by RECIL 2017 or 
mSWAT criteria (see Section 6.3), or have an abnormal clonal T-cell population 
detectable by peripheral blood flow cytometry 
2.1.1.5 Age >18 years  
NOTE: Because no dosing or adverse event data are currently available on the use of rhIL-15 in 
combination with mogamulizumab in patients <18 years of age, children are excluded from this 
study, but will be eligible for future pediatric trials 
2.1.1.6 ECOG performance status <1 (Karnofsky >80%, see APPENDIX A  
2.1.1.7 Patients must have normal organ and marrow function as defined below: 
Absolute neutrophil count 
> 1,000/mcL 
Platelets 
> 100,000/mcL 
Total bilirubin 
≤ 1.5 X institutional upper limit of normal (ULN)  
AST(SGOT)/ALT(SGPT) 
≤ 2.5 X institutional ULN 
Serum creatinine 
≤ 1.5 X institutional ULN 
OR  
Creatinine clearance 
≥ 50 mL/min/1.73 m2 for patients with creatinine levels >1.5 
institutional ULN 
 
2.1.1.8 Negative serum or urine pregnancy test at screening for women of childbearing 
potential (WOCBP) 
NOTE: WOCBP is defined as any female who has experienced menarche and who has not 
undergone successful surgical sterilization or who is not postmenopausal.   
2.1.1.9 Women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry, for the 
duration of study participation, and 6 months after completion of rhIL-15 and 
mogamulizumab administration. Should a woman become pregnant or suspect she is 


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pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately. 
2.1.1.10 Ability of subject to understand and the willingness to sign a written informed consent 
document 
2.1.2 Exclusion Criteria 
2.1.2.1 Patients with other T-cell leukemias/lymphomas not specified in the inclusion criteria 
2.1.2.2 Anti-cancer treatment within 2 weeks of the first dose of rhIL-15 and mogamulizumab (4 
weeks for anti-cancer monoclonal antibody or investigational agents, 6 weeks for donor 
lymphocyte infusion, 100 days for allogeneic stem cell transplant) 
2.1.2.3 Systemic treatment for acute or chronic graft versus host disease (GVHD) within 12 
weeks of the first dose of rhIL-15 and mogamulizumab 
2.1.2.4 Cohort 1 (Dose Escalation) only: history of grade 3/4 GVHD, or active grade 1/2 GVHD 
regardless of treatment 
2.1.2.5 Persisting toxicity related to prior therapy of grade > 1, with the exception of the 
following: alopecia, sensory neuropathy grade ≤ 2, or other grade ≤ 2 not constituting a 
safety risk based on investigator's judgment 
2.1.2.6 Patients who are receiving any other investigational agents 
2.1.2.7 Current use of immunosuppressive medication, EXCEPT for the following:  
• Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular 
injection) 
• Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or 
equivalent; or, 
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) 
2.1.2.8 Patients with previous malignant disease other than the target malignancy within the last 
3 years with the exception of basal or squamous cell carcinoma of the skin or cervical 
carcinoma in situ 
2.1.2.9 Cohort 1 (Dose Escalation) only: Active or history of any autoimmune disease thought to 
be unrelated to their malignancy; for Cohort 2 (Dose Expansion), patients with history of 
autoimmune disease who are not on active immunosuppressive therapy per Section 
2.1.2.7 are eligible. 
2.1.2.10 Patients with asthma requiring chronic inhaled or oral corticosteroids, or history of 
asthma requiring mechanical ventilation. Patients with a history of mild asthma that are 
on or can be switched to non-corticosteroid bronchodilator regimens are eligible 
2.1.2.11 Patients with active bacterial infections, documented HIV infection or positive HIV 1/2 
antibodies at screening, PCR evidence for active or chronic hepatitis B or hepatitis C, or 
positive screening HBV/HCV serology without documentation of successful curative 
treatment (see Section 12.1 for IL-15 administration in HIV positive patients) 
2.1.2.12 Presence of uncontrolled intercurrent illnesses including but not limited to ongoing or 
active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, cognitive impairment, active substance abuse, or psychiatric illness/social 


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situations that in the view of the Investigator would preclude safe treatment and limit 
compliance with study requirements 
2.1.2.13 Inability or refusal to practice effective contraception during therapy or the presence of 
pregnancy or active breastfeeding. Because there is no significant preclinical information 
regarding the risks to a fetus or a newborn infant, all pregnant or breastfeeding woman 
will be excluded from participation in this trial 
2.1.2.14 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to rhIL-15 or mogamulizumab, unless felt to be in the best interests of the 
patient in the opinion of the investigator 
2.1.2.15 Patients who received a live vaccine within 30 days of planned start of study therapy. 
Vaccination with a live vaccine while on trial is prohibited. NOTE: Seasonal influenza 
vaccines for injection are generally inactivated flu vaccines and are allowed; however 
intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not 
allowed 
2.1.3 Recruitment Strategies 
Study participants will be recruited from the population of patients screened in the lymphoid 
malignancies clinic of the National Institutes of Health. These will include both referrals from 
outside physicians as well as patient self-referrals. This study will be posted on NIH websites: 
http://ccr.cancer.gov/Lymphoid-Malignancies-Branch and http://ClinicalTrials.gov, on NIH social 
media forums (Lymphoid Malignancy Branch and NIH social media accounts). 
2.2 
SCREENING EVALUATION 
2.2.1 Screening activities performed prior to obtaining informed consent 
Minimal risk activities that may be performed before the subject has signed a consent include the 
following:  
• Email, written, in person or telephone communications with prospective subjects  
• Review of existing medical records, including medical history, physical evaluations, 
laboratory studies, etc.   
• Review of existing MRI, x-ray, or CT images 
• Review of existing photographs or videos 
• Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes. 
If felt to be possible candidates after review of the above and after subjects sign a research 
consent for screening, they will undergo the evaluations described in Section 2.2.2. 
2.2.2 Screening activities performed after a consent for screening has been signed 
The following screening activities will be performed only after the subject has signed the consent 
for study 01-C-0129 on which screening activities will be performed. 
Assessments and procedures to confirm study eligibility should be completed within 28 days 
prior to registration (unless otherwise noted). Assessments performed at outside facilities or on 
another NIH protocol within the timeframes below may also be used to determine eligibility once 


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a patient has signed the consent.  See also the Study Calendar provided in Section 3.7. Clinical 
Evaluations 
• Disease history, including: diagnosis, treatment (e.g., systemic treatments, radiation 
and surgeries), disease status, and significant prior/ongoing side effects and symptoms 
• Complete medical history, including: all active conditions considered to be clinically 
significant by the treating investigator 
• Physical examination, including: height (screening only), weight, vital signs (i.e., 
temperature, pulse, respiratory rate, and blood pressure); review of concomitant 
medications and symptoms/side effects; and, assessment of performance status  
2.2.3 Laboratory Evaluations 
NOTE:  Results from outside NIH are accepted. 
• CBC with differential and reticulocyte count 
• Chemistry panels (as noted) or specific analyte required for eligibility, including: 
Creatinine (i.e., Acute Care Panel); serum calcium, phosphate, magnesium and albumin 
(i.e., Mineral Panel); ALT, AST, total and direct (if required due to elevated total 
bilirubin, at discretion of the lab) bilirubin (i.e., Hepatic Panel); 24-hour urine 
creatinine clearance (if needed to measure CrCl in cases where serum creatinine 
>1.5mg/dl); and LDH 
• Coagulation panel, including: PT/INR and a PTT 
• Thyroid function tests (thyroid stimulating hormone (TSH), with free thyroxine (T4) if 
TSH is abnormal) 
• Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody, Hepatitis C antibody 
(HCV) [qualitative], HIV 1/2 antibody (qualitative) and HTLV-1/2 serologies (within 
3 months)  NOTE:  For individuals with a positive hepatitis B core antibody, HBV 
DNA PCR will be performed to screen for subclinical infection. For individuals with 
positive hepatitis C antibody and history of curative treatment, HCV DNA PCR will 
be performed to confirm the resolution of infection. 
• Urinalysis (with microscopic examination if abnormal) 
• Antinuclear antibody (ANA), rheumatoid factor (RF) and anti-thyroid antibody 
• Creatine phosphokinase (CPK), troponin  
• Serum or urine pregnancy test (B-HCG) for women of childbearing potential 
• Clonal T-cell receptor rearrangement by PCR 
2.2.4 Imaging Studies  
NOTE:  Results from outside NIH are accepted. Other body areas may be imaged if 
clinically indicated.  
• CT neck, chest, abdomen and pelvis (CT should be performed with IV and PO contrast, 
unless patient is allergic or has renal insufficiency; other imaging may be substituted 
at the discretion of the investigator [such as MRI]) 
• PET/CT torso (extremities to be included if there is confirmed or suspected disease 
involvement) 
• MRI of brain (only in patients with suspected involvement of CNS) 


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2.2.5 Cardiac Evaluation (within 3 months) 
• Electrocardiogram (EKG) 
• Transthoracic echocardiogram (TTE) 
2.2.6 Other Procedures 
• Pathologic review/confirmation of diagnosis by Laboratory of Pathology, NCI (no time 
limit). If archival sample is not available, a fresh tumor biopsy and/or peripheral blood 
sample will be obtained. 
• Pulmonary function tests (PFTs): diffusing capacity/alveolar volume (DLCO/VA), 
forced expiratory volume in 1 second (FEV1) for patients with significant pulmonary 
or smoking history 
2.3 
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES 
Registration and status updates (e.g. when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found here.   
2.3.1 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants, to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
 
2.3.2 Treatment Assignment and Randomization/Stratification Procedures 
2.3.2.1 Cohorts 
Number 
Name 
Description 
1 
Mature T-cell 
malignancies:  Dose 
Escalation 
Relapsed/refractory mycosis fungoides/Sézary syndrome, adult 
T-cell leukemia/lymphoma acute, chronic, and lymphoma 
subtype (up to 12 evaluable patients) 
2 
Mature T-cell 
malignancies:  Dose 
Expansion 
Relapsed/refractory mycosis fungoides/Sézary syndrome, adult 
T-cell leukemia/lymphoma acute, chronic, and lymphoma 
subtype (up to 9 additional evaluable patients, 12 total 
evaluable at the MTD) 
2.3.2.2 Arms 
Number 
Name 
Description 
1 
Experimental Treatment:  
Dose Escalation 
IL-15 by CIV infusion at escalating doses of 2 and 4 
mcg/kg/day on days 1-5 of each 28-day cycle (max 6 cycles) 
with mogamulizumab by IV infusion at a dose of 1 mg/kg on 
days 1, 8, 15, and 22 of cycle 1 and days 1 and 15 of cycles 2-
6, to determine MTD 


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Number 
Name 
Description 
2 
Experimental Treatment:  
Dose Expansion 
IL-15 by CIV infusion at the MTD on days 1-5 of cycles 1-6 
with mogamulizumab at 1 mg/kg on days 1, 8, 15, and 22 of 
cycle 1 and days 1 and 15 of cycles 2-6 
2.3.2.3 Randomization and Assignment 
Treatments assignment is open-label, and non-randomized/non-stratified. Subjects in Cohort 1 
are directly assigned to Arm 1; subjects in Cohort 2 are directly assigned to Arm 2.  
2.4 
BASELINE EVALUATION 
The following should be performed within 28 days prior to the first dose of rhIL-15 unless 
otherwise noted; tests performed as part of screening do not need to be repeated if they were 
performed within the specified window prior to initiating treatment.  
2.4.1 Clinical Evaluations 
• Medical history (interim) 
• Physical examination including weight, vital signs (i.e., temperature, pulse, respiratory 
rate, and blood pressure); review of concomitant medications and symptoms/side 
effects; and assessment of performance status (ECOG performance score, see 
APPENDIX A) 
2.4.2 Laboratory Evaluations  
NOTE:  Results from outside NIH are accepted 
• Required within 7 days: 
o Serum or urine pregnancy test (B-HCG) for women of childbearing potential 
• Required within 14 days: 
o CBC with differential and reticulocyte count 
o Chemistry panels including: Acute Care (sodium, potassium, chloride, CO2, 
glucose, BUN, creatinine), Mineral Panel (serum calcium, phosphate, 
magnesium and albumin), Hepatic Panel (alkaline phosphatase, ALT, AST, 
total and direct bilirubin), and 24-hour urine creatinine clearance (if needed to 
measure CrCl if serum creatinine >1.5mg/dl) 
o Others: LDH, Uric acid, Total protein 
o Serum Lipase and Amylase 
o Coagulation panel, including: PT/INR and aPTT 
o Iron panel (includes: ferritin, transferrin, iron), folate, vitamin B12 
o C-reactive protein (CRP) 
o Serum Lipase and Amylase 
o TSH, with free thyroxine if TSH is abnormal 
o Urinalysis (with microscopic examination if abnormal) 
o HLA typing (A, B, C, DR, DQ) 
o Soluble IL-2Rɑ 


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o Creatinine phosphokinase (CPK), troponin I 
• Required within 28 days: 
o Lymphocyte Phenotype: T, B and NK cell subsets 
o Antinuclear antibody (ANA), rheumatoid factor (RF) and anti-thyroid antibody  
2.4.3 Imaging Studies 
Every participant should have an evaluation of known sites of disease as part of baseline 
evaluation. NOTE:  Only results from NIH are accepted  
• One or more of the following studies: CT, MRI, FDG-PET and/or clinical 
photography 
• Patients with neurological symptoms or signs should undergo MRI scan* of the 
brain and lumbar puncture 
*NOTE:   The MRIs to be done in this study may involve the use of the contrast agent 
gadolinium, if clinically indicated.  The risks associated with MRIs and contrast are 
discussed in the consent form. 
2.4.4 Other Procedures 
• Bone marrow biopsy and aspiration to assess lymphoma involvement (within 3 
months) 
• Selected patients with cutaneous disease (as determined by physician PI or AI) will 
have clinical photography and dermatology assessment performed to assess their skin 
disease 
2.4.5 Research Correlates 
NOTE: See Section 5.1 for additional information. The following sample types will be 
collected for correlative research studies:   
• Required:   
o Blood samples for lymphocyte subset testing and circulating tumor DNA 
o Blood, buccal swab, or saliva for germline DNA 
o Tumor Tissue (archival or fresh) 
• Optional:   
o Blood samples for ADCC of mogamulizumab, tissue immune cell subset 
comparison (as outlined in Section 5.2) 
o Bone marrow biopsy 
o Tumor biopsy is required if archival tissue is not available or adequate; 
otherwise, this is optional. 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
In patients with relapsed/refractory MF/SS or ATLL, IL-15 will be administered by continuous 
intravenous infusion in a dose-escalation 3 + 3 system with a starting dose of 2 mcg/kg/day and a 
second dose level of 4 mcg/kg/day on days 1-5 of each of six cycles. Mogamulizumab will be 


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administered IV over at least 1 hour at a dose of 1 mg/kg on days 1, 8, 15 and 22 of cycle 1, and 
days 1 and 15 of each subsequent cycle. Treatment will continue for a maximum of 6 cycles or 
until toxicity (i.e., dose limiting toxicity as found in Section 3.1.1 or toxicity requiring hold as 
defined in Section 3.3) or progressive disease. 
 
 
3.1.1 Dose Limiting Toxicity 
A dose-limiting toxicity (DLT) is defined as:  any grade 3, 4, or 5 toxicity if not incontrovertibly 
due to disease progression or an extraneous cause, and deemed possibly, probably or definitely 
related to IL-15 or mogamulizumab by the PI or designee during the first 28 days of treatment, 
with the following exceptions: 
3.1.1.1 Hematologic exceptions  
• 
Grade 3 or 4 lymphocytopenia without clinical signs of infection grade 2 or above. 
• 
Grade 3 or 4 neutropenia without clinical signs of infection grade 2 or above. 
• 
Grade 3 or 4 thrombocytopenia lasting fewer than 5 days and not associated with 
bleeding or purpura. 
• 
Grade 3 leukocytosis (WBC > 100,000/mm3) in the absence of signs of leukostasis or 
other toxicities possibly related to the expansion of activated cells. 
3.1.1.2 Non-hematologic exceptions  
• 
Transient (< 24 hours) grade 3 hypoalbuminemia, hypokalemia, hypomagnesemia, 
hyponatremia or hypophosphatemia which responds to medical intervention. 
• 
Non-sustained (< 7 days) grade 3 liver function test (ATL, AST, alkaline 
phosphatase, total or direct bilirubin) abnormalities in the absence of clinical signs of 
hepatic dysfunction (lethargy, confusion, anorexia, pruritus, tremor); for patients with 
baseline grade 1 elevations, any increase ≥ 10 x baseline will be considered dose-
limiting and these patients will be closely monitored for liver function abnormalities. 
• 
Grade 3 rash (maculo-papular, acneiform, or urticaria); if the rate of grade 3 rashes 
exceeds the expected rate (10% per mogamulizumab package insert) this will be 
reported as an unanticipated problem. 
• 
First grade 3 infusion reaction associated with mogamulizumab administration 
(occurring within 24 hours of the dose). 
Management and dose modifications associated with the above adverse events are outlined in 
Section 3.3. If a DLT is possibly, probably, or definitely related to IL-15 and unrelated or 


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unlikely to be related to mogamulizumab, patient may continue treatment with mogamulizumab 
alone if PI or designate deems it to be in the patient’s best interest. Any DLT at least possibly 
related to mogamulizumab will lead to permanent discontinuation of protocol therapy regardless 
of attribution to IL-15. The same management will apply to an occurrence of any DLT-defining 
toxicity after the first 28 days of treatment; however, that toxicity will not be deemed a DLT for 
purposes of dose escalation. 
3.1.2 Dose Escalation 
Dose escalation will proceed according to the following schedule (Table 6). Dose escalation will 
follow the following guidelines (Table 7). DLT is defined above. Each patient will continue 
treatment at the dose level they were enrolled – there will be no intra-patient dose escalation. 
The MTD is the dose level at which no more than 1 of up to 6 patients experience DLT during 
the DLT evaluation window(s), or the dose below that at which at least 2 (of ≤6) patients have 
DLT. The protocol will be amended to note the MTD once determined. 
Table 6: IL-15 Dose Escalation Schedule 
Dose Level 
rhIL-15 
(mcg/kg) 
Mogamulizumab 
(mg/kg) 
Level 1 
2 
1 
Level 2 
4 
1 
*Doses are stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) rather than as a percentage. 
 
Table 7:  Dose Escalation Guidelines  
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
>2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that dose. 
≤1 out of 6 at highest dose level below 
the maximally administered dose 
This is generally the recommended phase 2 dose. At 
least 6 patients must be entered at the recommended 
phase 2 dose. 


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3.2 
DRUG ADMINISTRATION 
Each cycle is 28 days (4 weeks). The minimum window between initiation of new cycles is 26 
days; a cycle delay due to scheduling or other administrative reasons (i.e., reasons other than 
toxicity/dose management as defined below) is 7 days.  
Treatment will be administered on an inpatient basis during week 1 of the first cycle, and as 
outpatient during subsequent weeks and cycles unless decided otherwise by the principal 
investigator based on clinical judgment. Reported adverse events and potential risks are described 
in Section 14. Appropriate dose modifications are described in Section 3.3. No investigational or 
commercial agents or therapies other than those described below may be administered with the 
intent to treat the patient's malignancy. See Table 8 below for description of drug regimen.  
Table 8: Drug Regimen 
Agent 
Premedications;  
Precautions 
Dose 
Route 
Schedule 
rhIL-15 
Premedicate with 
acetaminophen 
and/or ibuprofen 
** in *** mL D5W 
with 0.1% HSA  
IV over  
24 hours 
Days 1-5 
Mogamulizumab 
Premedicate with 
acetaminophen and 
an antihistamine* 
1 mg/kg in **** 
mL 0.9% Sodium 
Chloride for 
Injection 
IV over  
1 hour 
Days 1, 8, 15 
and 22 of 
Cycle 1 and 
Days 1 and 
15 of Cycles 
2-6 
* Mandatory for the first infusion; subsequently based on clinical judgement 
** Doses as appropriate for assigned dose level 
*** Infusion volume of rhIL-15 per calculation in APPENDIX D 
**** Infusion volume of mogamulizumab titrated to a final concentration of the diluted solution 
between 0.1 mg/mL and 3.0 mg/mL 
For a full detailed product description and administration guidelines, see Section 14. Infusions will 
be done via midline catheter. When administered on an outpatient basis, rhIL-15 will be infused 
via an ambulatory infusion pump. 
3.2.1 Prophylactic and supportive care for IL-15 
Patients will be given acetaminophen 500-650mg IV or orally, 30-60 minutes prior to each IL-15 
infusion as first line, and ibuprofen 400 or 600mg orally, depending on reactions with 
acetaminophen as premedication.  
3.2.2 Prophylactic and supportive care for mogamulizumab 
In order to mitigate infusion related reactions, a premedication with an antihistamine and with 
acetaminophen 30 to 60 minutes prior to the first infusion of mogamulizumab is mandatory (e.g., 
25-50 mg diphenhydramine and 500-650 mg acetaminophen IV or orally). Premedication should 
be administered for subsequent mogamulizumab infusions based upon clinical judgment and 
presence/severity of prior infusion reactions.  


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3.2.3 Other modalities or procedures 
Patients will be observed in the day hospital or the inpatient unit for at least 30 minutes after 
administration of mogamulizumab for potential infusion-related reactions. 
3.2.4 Delays in Dosing 
During the first treatment cycle, mogamulizumab should be administered beginning on Day 1 
and within +/- 1 day of the other scheduled visits (i.e., Days 8, 15 and 22).  For subsequent 
cycles, mogamulizumab should be administered within +/- 2 days of the scheduled visits. 
3.3 
DOSE MODIFICATIONS 
3.3.1 rhIL-15-specific Adverse Events 
Please refer to the Comprehensive Adverse Event and Potential Risk list (CAEPR) for rhIL-15 
presented in Section 14.1.2. 
Dose of rhIL-15 is based on the dose level and patient’s weight at the beginning of each cycle, and 
can only be modified for rounding and/or consistency with prior cycles, and not for adverse events 
or renal/hepatic dysfunction. Infusion may continue during correction of electrolyte and other 
laboratory abnormalities listed in Section 3.1.1. Infusion may be interrupted for up to two hours 
each day, but treatment should end 120 (±1) hours after initiation on Day 1. 


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3.3.2 Mogamulizumab-specific Adverse Events 
3.3.2.1 Treatment modifications for symptoms of infusion-related reactions  
Table 9: Treatment modifications for infusion-related reactions 
NCI-CTCAE Grade 
Treatment Modification for 
Mogamulizumab 
Grade 1-3 – mild, moderate, or severe 
Grade 1: Mild transient reaction; infusion interruption 
not indicated; intervention not indicated. 
Grade 2: Therapy or infusion interruption indicated 
but responds promptly to symptomatic treatment (for 
example, antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications indicated for ≤24 h. 
Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms 
following initial improvement; hospitalization 
indicated for clinical sequelae. 
Temporarily interrupt the infusion of 
mogamulizumab and treat symptoms. 
Reduce the infusion rate by at least 50% 
when restarting the infusion after symptoms 
resolve. If reaction recurs and is 
unmanageable, discontinue infusion. 
Grade 4 –life-threatening 
Life-threatening consequences; urgent intervention 
indicated. 
Stop mogamulizumab infusion immediately 
and disconnect infusion tubing from the 
subject. 
Subjects have to be withdrawn immediately 
from study treatment and must not receive 
any further mogamulizumab treatment. 
NOTE:  If mogamulizumab infusion rate has been decreased by 50% or interrupted due to an infusion reaction, 
it must remain decreased for the next scheduled infusion.  If no infusion reaction is observed in the next 
scheduled infusion, the infusion rate may be returned to baseline at the subsequent infusions 
IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse 
Event; NSAIDs = nonsteroidal anti-inflammatory drugs 
3.3.2.2 Treatment modifications for dermatologic toxicity  
Table 10: Treatment Modifications for Dermatological AEs 
Dermatological irAEs 
Rash 
Initial Management 
Resuming protocol treatment 
Grade 1 
Covering <10% of body 
surface area 
Continue protocol therapy 
Consider topical steroids 
N/A 
 
Grade 2 to 3 
Covering >10% of body 
surface area 
Hold protocol therapy 
Administer topical steroids for at 
least 2 weeks 
Rash improves to Grade ≤1 
Grade 4 
Life-threatening 
consequences; Stevens-
Jonson syndrome (SJS) or 
Hold protocol therapy for 
suspected SJS/TEN 
Permanently discontinue protocol 
therapy if SJS/TEN has been 
SJS/TEN has been excluded and the rash 
improves to Grade ≤1 


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Dermatological irAEs 
Rash 
Initial Management 
Resuming protocol treatment 
toxic epidermal necrolysis 
(TEN) 
confirmed or if there are life-
threatening consequences 
3.4 
STUDY INTERVENTION COMPLIANCE 
Adherence to the protocol will be verified by reviewing the Medical Administration Record 
(MAR) section of the medical record, which will serve as source documentation. 
3.5 
ON STUDY EVALUATIONS 
Prior to mogamulizumab administration (Days 1, 8, 15 and 22 of cycle 1 and days 1 and 15 of 
cycles 2-6), pre-dose assessments must be performed (up to 3 days prior). After Cycle 1, pre-dose 
assessments may be performed up to 3 days prior to a cycle except where otherwise noted. The 
results from all procedures/tests must be reviewed prior to initiation of each cycle of treatment for 
consideration of dose modifications and delay of therapy.  
Treatment with rhIL-15 and mogamulizumab will continue for six cycles or until disease 
progression, unacceptable treatment-related toxicity or other reasons outlined in Section 3.9.1. 
Refer to the Study Calendars (Section 3.7) for a complete list of procedures to be performed at 
each scheduled study visit. See also Section 5.1 for all samples to be collected for correlative 
research. During treatment, it is expected that all laboratory and clinical assessments be conducted 
at the NIH (including post-treatment imaging evaluations); results from outside NIH will only be 
accepted at the discretion of the investigator. 
3.6 
POST-TREATMENT EVALUATIONS 
Post treatment evaluations (i.e., End of Treatment Visit) will be performed approximately 30 days 
after the last dose of protocol treatment. If a subject initiates a new anti-cancer therapy within 30 
days after the last dose of trial treatment, the 30-day safety follow-up visit must occur before the 
first dose of the new therapy.  If the patient cannot return to the Clinical Center for this visit, a 
request will be made to have a local physician or laboratory collect a CBC with differential and 
send the results. If this is not possible, patients may be assessed by telephone for symptoms. 
Unless otherwise noted, follow-up will occur at the following time point: every 60 days (± 7 days) 
for 6 months; then every 90 days (± 14 days) for 2 years; then every six months (± 28 days) for 2 
years, then annually (±6 weeks) at the discretion of the investigator. Any other evaluations and 
tests should be performed as clinically indicated.  
Upon disease progression or initiation of other anti-cancer therapy, contact will be for survival 
only until the subject is off study (i.e., every 3 months [±4 weeks]); unless otherwise clinically 
indicated. See Study Calendar (Section 3.7) for additional information. Any adverse events which 
are present at the time of discontinuation should be followed in accordance with the safety 
requirements.   
Patients who stop treatment early will be followed until completion of the Safety Follow-up Visit 
or until death, whichever occurs first. Patients removed from study treatment for unacceptable 
adverse event(s) will be followed until resolution or stabilization of the adverse event. 


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3.6.1 Safety Follow-Up Visit 
The safety follow-up visit should occur 30 days (±7 days) after the last dose of trial treatment, or 
before the initiation of a new anti-cancer treatment, whichever comes first. Required testing is as 
noted in the Study Calendars (Section 3.7) All AEs that occur prior to the Safety Follow-Up Visit 
should be recorded.  Patients with an ongoing, treatment-related AE of Grade > 1 will be followed 
until the resolution of the AE to Grade 0-1, stabilization of the AE in the opinion of the investigator, 
or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur 
within 30 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded.  
3.6.2 Follow-Up Visits — Prior to Disease Progression  
Patients who complete trial treatment without evidence of disease progression will move into the 
Follow-up Phase and may be assessed every 60 days (± 7 days) for 6 months; then every 90 days 
(± 14 days) for 2 years; then every six months (± 28 days) for 2 years, then annually (±6 weeks) 
after finishing treatment by radiologic imaging or other clinical assessments to monitor disease 
status. Every effort should be made to collect information regarding disease status until the start 
of new anti-neoplastic therapy, or disease progression. If the patient cannot return to the Clinical 
Center for any of these visits, a request will be made to have a local physician or laboratory collect 
a CBC with differential and send the results. If this is not possible, patients may be assessed by 
telephone or email for symptoms.  
3.6.3 Follow-Up Visits — Survival/Post-Disease Progression 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase and should be contacted (e.g., phone, email, etc.; 
in-person visit not required) at least every 6 months (± 4 weeks) to  collect information on new 
anti-cancer treatments received and to assess for survival status until death, withdrawal of 
consent, or the end of the study, whichever occurs first (see Study Calendar)


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3.7 
STUDY CALENDAR 
Procedure 
Screening 
Baseline 
Study Cycles 
Disease 
Evaluations 
End of 
Treatment 
and 
Disease 
Progression 
Post-Treatment 
Follow-Up 
C1 
C2-6 
Safety 1 
Follow-Up 
(Prior to PD) 
Survival 
(Post-PD) 
Scheduling Window (Days): -28 to -12 
-143 
8 
(-3) 
15 
(-3) 
22 
(-3) 
1 
(-3) 
15 
(-3) 
Every 8 
weeks 4 
Treatment 
discon/PD 5 
Day 30 
(+7) 
Every 60 or 
90 days 6 
Every 6 
months 7 
Confirmation of Diagnosis 8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam and ECOG PS 9 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
CBC with Differential 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Reticulocyte Count 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Chemistry Panels 10, LDH 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Serum Lipase and Amylase 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Uric Acid, Total Protein 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
PT/INR and aPTT 
X 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
 
Thyroid Function (i.e., TSH, T4) 
X 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
 
Urinalysis 
X 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
Pregnancy Test (urine/serum; 
WOCBP) 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C, HIV Antibody, 
HTLV-1/2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HLA typing (A, B, C, DR, DQ)  
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Anti-nuclear antibody (ANA), 
rheumatoid factor (RF) and anti-
thyroid antibody 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Clonal T-cell receptor 
rearrangement by PCR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Iron panels, Folate, and B12, C-
reactive Protein, IL-2Rɑ 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Creatine phosphokinase (CPK), 
troponin  
X 
X 
X 
 
 
 
 
 
 
X 
 
X 
 


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Procedure 
Screening 
Baseline 
Study Cycles 
Disease 
Evaluations 
End of 
Treatment 
and 
Disease 
Progression 
Post-Treatment 
Follow-Up 
C1 
C2-6 
Safety 1 
Follow-Up 
(Prior to PD) 
Survival 
(Post-PD) 
Scheduling Window (Days): -28 to -12 
-143 
8 
(-3) 
15 
(-3) 
22 
(-3) 
1 
(-3) 
15 
(-3) 
Every 8 
weeks 4 
Treatment 
discon/PD 5 
Day 30 
(+7) 
Every 60 or 
90 days 6 
Every 6 
months 7 
Pulmonary function tests (PFTs) 11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
T, B, NK cell subsets 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
 
Imaging studies 12 
X 
X 
 
 
 
 
 
 
X 
X 
 
X 
 
MRI, Lumbar Puncture 13 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
 
Bone Marrow Aspiration/Biopsy 14 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
Flow Cytometry15 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
Clinical photography and 
dermatology assessment/ global 
score 16 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
 
Radiologic Evaluation/ tumor 
measurement17 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
 
EKG. TTE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Symptoms/Adverse Events 
Assessment, Concomitant 
Medication Review 
X 
X 
 
 
 
 
X 
 
 
X 
X 
X 
 
Research Blood/Tissue Samples 18 
 
X 
Refer to Section 5.1 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
NOTE:  Any other tests should be performed as clinically indicated.  See Section 3.2 for drug administration information.  See 
Section 5.1 for information on research blood samples/correlative studies to be collected.   
 
 
 
 


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1 30 days (+7) following last dose, and 90 days (+14) after last dose of mogamulizumab (via clinic or phone). If initiating new anti-cancer therapy within 30 days 
after last dose of mogamulizumab, 30-day safety follow-up visit must occur before first dose of new therapy. 
2 Screening and Baseline evaluations should be performed within 28 days prior to enrollment and dosing, respectively, unless otherwise noted and with the 
following exceptions:  Confirmation of diagnosis (no time limit); HIV antibody, HTLV-1/2 serologies, Hepatitis B surface antigen and Hepatitis C antibody, 
EKG, and bone marrow aspiration/biopsy (all within 3 months)  NOTE: Any screening tests performed within the specified time frame for baseline do not need 
to be repeated. 
3 Within 14 days prior to dosing on C1D1, with the following exceptions:  Pregnancy test (within7 days of dosing; must be negative). 
4 ± 2 days. Confirmatory scans should also be obtained 4 weeks following initial documentation of objective response. 
5 To be done at end of treatment (30 days after last dose of study treatment; may be combined with 30 day safety follow-up, if timing coincides). If subject to 
initiate new anti-cancer therapy assessments should occur before the first dose of the new therapy. 
6 Follow-up to occur about every 60 days (±7 days) for first 6 months, every 90 days (±14 days) for 2 years, then every 6 months (± 28 days) for another   2 years 
and then annually (± 6 weeks) until disease progression or initiation of new anti-cancer therapy. 
7 After disease progression or initiation of new anti-cancer therapy, contact for survival about 6 months (±4 weeks). 
8 Pathologic review/confirmation of diagnosis by Laboratory of Pathology, NCI (no time limit). If archival sample is not available, a fresh tumor biopsy and/or 
peripheral blood sample will be obtained. 
9 Physical exams to include medical history (i.e., complete at Screening/Baseline; interim on study and in follow-up), vitals, weight, and height (screening only). 
10 Chemistry panels include:  Acute care, Hepatic, and Mineral. 
11 Diffusing capacity/alveolar volume (DLCO/VA), forced expiratory volume in 1 second (FEV1) for patients with significant pulmonary or smoking history. 
12 At screening a CT scans of neck, chest, abdomen, and pelvis should be performed (with IV and PO contrast, unless patient is allergic or has renal insufficiency; 
other imaging may be substituted at the discretion of the investigator). Other body areas may be imaged if clinically indicated. MRI of the brain is only required in 
patients with suspected involvement of CNS. At screening, a FDG-PET/CT torso (extremities to be included if there is confirmed or suspected disease involvement). 
At baseline one or more of the following studies: CT, MRI, FDG-PET/ CT and or clinical photography. FDG/ PETs to be done between C3 and C4 and at EOT. 
13 Patients with neurological symptoms or signs should undergo MRI scan of the brain and lumbar puncture 
14 Baseline bone marrow aspiration/ biopsy with flow cytometry must be done within 3 months prior to starting treatment. During post-treatment follow-up, 
repeat bone marrow aspiration/ biopsy needed only to confirm a CR. 
15 Peripheral blood flow cytometry may be done for disease evaluation of patients who had circulating leukemic cells detected at baseline, and for patients with 
CTCL regardless of their baseline results. 
16 To be performed in selected patients with cutaneous disease (as determined by PI or AI). 
17 Dermatology assessment and Global/mSWAT scoring will be used instead of or in addition to radiologic evaluation for patients with predominantly cutaneous 
disease 
18 Samples for correlative research are to be collected as indicated in Section 5.1. Prior biopsy specimen blocks will be used for CCR4 staining if available. If 
archival tissue is not available or adequate, baseline punch biopsy of the skin or core needle biopsy of a lymph node/visceral lesion is required, otherwise this is 
optional.  
 


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3.8 
COSTS AND COMPENSATION 
3.8.1 Costs 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not 
covered by insurance company.  Medicines that are not part of the study treatment will not be 
provided or paid for by the NIH Clinical Center. 
3.8.2 Compensation 
No direct compensation will be provided on the study.   
3.8.3 Reimbursement 
On this study, the NCI will cover the cost for some of the expenses.  Some of the costs may be 
paid directly by the NIH and some may be reimbursed to the subject.  Someone will work with 
subjects to provide more information. 
3.9 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all patients complete a safety visit 
approximately 30 days following the last dose of study therapy. Additional safety visits and follow-
up will continue as per Section 3.6. 
3.9.1 Criteria for removal from protocol therapy 
Patients who meet the following criteria should be discontinued from protocol therapy: 
• Completion of protocol therapy (i.e., up to 6 cycles)  
• Confirmed disease progression 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable toxicities as listed in Section 3.1.1 or those toxicities listed in Section 3.3 
that require treatment to be stopped. 
• Subject’s request to withdraw from protocol therapy 
• Investigator’s decision to withdraw the patient 
• Subject’s non-compliance with trial treatment or procedure requirements that requires 
removal in the opinion of the PI 
• Pregnancy 
• The drug manufacturer can no longer provide the study agent 
• Study is cancelled for any reason  
• Failure to maintain eligibility prior to starting treatment  
3.9.2 Off-Study Criteria 
• Subject requests to be withdrawn from study 
• Subject is lost to follow-up* 
• Death  


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• Study is cancelled for any reason 
3.9.3 Lost to Follow-up 
* A participant will be considered lost to follow-up if he or she fails to return for two consecutive 
scheduled visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site will attempt to contact the participant within 3 business days to reschedule the 
missed visit, and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain if the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file.  
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
4 
CONCOMITANT MEDICATIONS/MEASURES 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial with the exception of oral or parenteral steroids if they are administered more 
than 7 days before the start of or more than 7 days after the end of IL-15 infusion. If there is a 
clinical indication for a prohibited medication/ measure during the trial, discontinuation from trial 
therapy may be required. 
For premedication and supportive care measures, see Sections 3.2.1, 3.2.2, and 3.2.3. 
4.1 
ACCEPTABLE MEDICATIONS 
All treatments that the investigator considers necessary for a subject’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care.  All 
concomitant medication will be recorded on the case report form (CRF) including all prescription, 
over-the-counter (OTC), herbal supplements, and IV medications (not to include continuous 
intravenous fluids). If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.   
Patients who are deemed to be at high risk for CNS involvement by the primary investigator and 
who have not received intrathecal prophylaxis prior to enrollment may receive it as clinically 
indicated after completion of the first cycle of therapy. Patients who have evidence of CNS 
involvement with lymphoma by flow cytometry and have no parenchymal lesions on brain imaging 
may receive intrathecal treatment as clinically indicated after completion of the first cycle of 
therapy. 


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4.2 
PROHIBITED MEDICATIONS 
Patients are prohibited from receiving the following therapies during treatment on this trial: 
• Other therapy for the disease under study not specified in this protocol, unless specifically 
noted as permitted 
• Investigational agents other than rhIL-15 and mogamulizumab 
• Radiation therapy  
NOTE: Radiation therapy to a symptomatic solitary lesion may be allowed at the 
investigator’s discretion.   
• Live vaccines within 30 days prior to the first dose of trial treatment and while participating 
in the trial.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, typhoid vaccine and 
FluMist.  
Patients who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study treatment. Patients may 
receive other medications that the investigator deems to be medically necessary. 
5 
 CORRELATIVE STUDIES 
5.1 
SUMMARY 
This study will attempt to use rhIL-15 to increase NK cell number and activity, thereby enhancing 
the ADCC of mogamulizumab in treatment of patients with relapsed and refractory MF/SS and 
ATLL. ADCC capacity of ex vivo PBMCs will be tested on CCR4-expressing cell lines before, 
during, and after protocol treatment. CCR4 mutation status will be determined for each patient by 
batch processing, and correlated with response and survival. Differences in circulating immune 
cell subsets associated with administration will be followed throughout treatment to both study the 
effects of combined rhIL-15/mogamulizumab therapy on the immune system, and to identify 
potential biomarkers that would be predictive of response. With the same goal in mind, immune 
cell subsets in the tumor microenvironment before and after treatment will be determined using 
single-cell RNA sequencing. 
 
Sample 
Collection Details* 
Time Points 
Supervising 
Laboratory/ 
Investigator 
Baseline C1  
D8 
C1  
D15 
C2-6 
D1 
C2-6  
D15 
Follow-
up# 
Blood Samples 
 
 
 
 
 
 
 
 
Lymphocyte subset 
testing 
• 2 x 10mL K2EDTA 
(lavender-top) tubes 
X 
X 
(X) 
(X) 
(X) 
(X)1 
Immunology 
section, NIH CC 
ADCC of 
mogamulizumab 
• 3 x 10mL sodium 
heparin green-top tubes 
(X)2 
(X)2 
 
 
 
 
Waldmann 
Tissue immune cell 
subsets (comparison) 
• 1 x 5mL sodium heparin 
green-top tube 
(X) 
 
(X) 
 
 
(X) 
Waldmann 


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Sample 
Collection Details* 
Time Points 
Supervising 
Laboratory/ 
Investigator 
Baseline C1  
D8 
C1  
D15 
C2-6 
D1 
C2-6  
D15 
Follow-
up# 
Circulating tumor 
DNA, plasma 
banking 
• 1 x 10mL K2EDTA tube 
• 1 x 10mL Streck/BCT 
tube 
X 
(X) 
X 
(X) 
(X) 
X3 
Waldmann 
(Leidos CSL) 
PBMC banking 
• 2 x 10mL sodium 
heparin green-top tubes 
X 
X 
X 
X 
X 
X 
Anti-IL-15 
antibodies 
• 1 x 4mL SST tube 
X 
 
 
X 
 
X1 
CCR4 expression 
• 2 x 10mL sodium 
heparin green-top tubes 
(X) 
(X) 
 
(X) 
 
 
Stetler-Stevenson 
(Laboratory of 
Pathology) 
CCR4 mutation 
status 
• 2 x 10mL sodium 
heparin green-top tubes 
(X) 
 
 
 
 
 
Raffeld 
(Laboratory of 
Pathology) 
Tissue Samples 
 
 
 
 
 
 
 
 
CCR4 expression 
• One core biopsy sample 
in formalin 
X** 
 
(X) 
 
 
 
Pittaluga 
(Laboratory of 
Pathology) 
CCR4 mutation 
status 
• One core biopsy sample 
in formalin 
X** 
 
(X) 
 
 
 
Raffeld 
(Laboratory of 
Pathology) 
Tissue immune cell 
subsets 
• Two core biopsy samples 
in RPMI 1640 with 10% 
human serum and 
antibiotics 
• One core biopsy sample 
in formalin 
NOTE:  Samples may be 
tumor tissue or bone 
marrow aspirate/biopsy  
X** 
 
(X) 
 
 
(X) 
 Pittaluga 
(Laboratory of 
Pathology) 
Single-cell RNA-Seq 
• One core biopsy sample 
in RPMI 1640 with 10% 
human serum and 
antibiotics 
(X) 
 
(X) 
 
 
 
Pittaluga 
(Laboratory of 
Pathology) and 
CCR single cell 
core 
Other Samples 
 
 
 
 
 
 
 
 
Germline DNA 
• Blood, Buccal Swab, or 
Saliva (preferred) 
X 
 
 
 
 
 
Waldmann 
(Leidos CSL) 


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Sample 
Collection Details* 
Time Points 
Supervising 
Laboratory/ 
Investigator 
Baseline C1  
D8 
C1  
D15 
C2-6 
D1 
C2-6  
D15 
Follow-
up# 
(X) = Optional; samples will be collected if adequate time/staff available for processing. If an optional sample is 
not collected at baseline, it would also not be collected in follow-up unless specifically requested by the PI.  
*Tubes/media may be adjusted at the time of collection based upon materials available or to ensure the best samples 
are collected for planned analyses. 
**Tumor biopsy is required if archival tissue is not available or adequate; otherwise, this is optional   
#Subjects who discontinue treatment for a reason other than disease progression and who do not start new treatment 
should continue to have study bloods collected at the scheduled time points. 
1 At the end of treatment only. 
2 For ADCC of mogamulizumab, Baseline and C1D8 samples should be collected for at least one patient per dose 
level, and for at least three patients at the MTD 
3 At each follow-up visit prior to disease progression, as specified in Section 3.6.2. 
 
Note: If there is an optional biopsy for research in the protocol, 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.  
5.2 
SAMPLE COLLECTION AND PROCESSING 
5.2.1 Summary 
The planned analyses described below may be done on leftover and/or shared sample portions 
from the respective laboratories, as needed.  In addition to the prospectively collected samples 
below, leftover portions of samples sent for routine laboratory testing (e.g., plasma from 
CBC/hematologies) may also be retrieved for research tests prior to being discarded. The planned 
prospective analyses are identified below; laboratories may share resources or collaborate on 
analyses, if appropriate. 
Portions of all samples may be banked for future research analyses; prospective consent will be 
obtained during the informed consent process. 
The blood drawing limits for research purposes are as follows:   
• For adult subjects:  The amount of blood that may be drawn from adult patients for research 
purposes shall not exceed 10.5 mL/kg or 550 mL, whichever is smaller, over any eight-
week period. 
Unless otherwise noted, Lymphoid Malignancies Branch Clinical Research personnel will use 
courier or escort service to arrange delivery of samples to destinations listed in subsections below.  
5.2.2 Blood Samples 
All blood samples will be drawn by NIH Clinical Center phlebotomy, inpatient unit, outpatient 
clinic, or day hospital staff. 
5.2.2.1 Lymphocyte subset testing by flow cytometry (FACS) 
• Collect blood in EDTA tubes; gently invert tubes 8-10 times immediately after collection  


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• Labels listing the patient's name, date of birth, date and time of the blood draw will be 
affixed to all the tubes by the staff person who obtained the samples. 
• Lymphoid Malignancies Branch Clinical Research personnel will arrange for these 
samples to be delivered to: Immunology Lab, NIH Clinical Center Bldg. 10/ Room 2C410. 
If the Immunology Section Laboratory is unable to perform this analysis on the specified 
days, this assessment maybe omitted or replaced with standard TBNK panel. 
5.2.2.2 Antibody-dependent cell cytotoxicity (ADCC) of mogamulizumab 
• Collect blood in sodium heparin tubes; gently invert tubes 8-10 times immediately after 
collection.  
• Lymphoid Malignancies Branch Clinical Research personnel will arrange for these 
samples to be delivered to Clinical Support Laboratory, Leidos Biomedical Research, 
Inc.in Frederick, MD, for processing per established laboratory techniques, storage, and 
batch analysis by the Waldmann Laboratory. 
5.2.2.3 Cell-free DNA (cfDNA), circulating tumor DNA (ctDNA) and plasma banking 
• Collect 10 mL of blood in one cell-free DNA (e.g., Streck BCT/collection tubes) and 10 
mL of blood in one K2EDTA tube; gently invert the tubes 8-10 times immediately after 
collection.  
• Labels listing the patient's name, date of birth, date and time of the blood draw will be 
affixed to all the tubes by the staff person who obtained the samples. Plasma will be isolated 
and frozen at -80ºC until analysis (e.g., centrifuged at 1800 x g for 10 minutes at room 
temperature; plasma transferred/frozen in aliquots of 1.5-2 mL each). 
• Lymphoid Malignancies Branch Clinical Research personnel will arrange for these 
samples to be delivered to Clinical Support Laboratory, Leidos Biomedical Research, 
Inc.in Frederick, MD for sample processing per established techniques maintained within 
standard operating procedures in the laboratory. 
5.2.2.4 PBMC banking and tissue immune cell subsets (comparison) 
• Collect blood in sodium heparin tubes; gently invert tubes 8-10 times immediately after 
collection.  
• Lymphoid Malignancies Branch Clinical Research personnel will arrange for these 
samples to be delivered to Clinical Support Laboratory, Leidos Biomedical Research, 
Inc.in Frederick, MD for sample processing per established techniques maintained within 
standard operating procedures in the laboratory. 
5.2.2.5 Anti-IL-15 antibody testing 
• Collect blood in a 4mL SST tube; gently invert tubes 8-10 times immediately after 
collection. 
• Lymphoid Malignancies Branch Research personnel will arrange for these samples to be 
delivered to Clinical Support Laboratory, Leidos Biomedical Research, Inc.in Frederick, 
MD, for storage and further analysis. 
• Samples will be batch processed and analyzed per the procedure outlined in Appendix E 
after the last patient has been enrolled and completed treatment, or sooner if there is 


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clinical suspicion for anti-IL-15 antibody formation. 
5.2.2.6 CCR4 expression (peripheral blood flow cytometry, optional) 
• Collect blood in two 10ml sodium heparin (green-top) tubes; gently invert tubes 8-10 
times immediately after collection 
• Labels listing the patient's name, date of birth, date and time of the blood draw will be 
affixed to all the tubes by the staff person who obtained the samples. 
• Lymphoid Malignancies Branch Clinical Research personnel will arrange for these 
samples to be delivered to: Flow Cytometry Laboratory, Laboratory of Pathology, NIH 
Clinical Center Bldg. 10/Room 3S240 for real-time processing; or delivered to: Leidos 
Biomedical Research, Inc. in Frederick, MD for storage. 
5.2.2.7 CCR4 mutation status (peripheral blood, optional) 
• Collect blood in two 10ml sodium heparin (green top) tubes; gently invert tubes 8-10 
times immediately after collection. 
• Labels listing the patient's name, date of birth, date and time of the blood draw will be 
affixed to all the tubes by the staff person who obtained the samples. 
• Lymphoid Malignancies Branch Clinical Research personnel will arrange for these 
samples to be delivered to: Molecular Diagnostics Section, Laboratory of Pathology, NIH 
Clinical Center Bldg. 10/ Room 3S247 for real-time processing; or delivered to Leidos 
Biomedical Research, Inc. in Frederick, MD for storage. 
5.2.3 Tissue Samples 
5.2.3.1 CCR4 expression (tissue IHC) and mutation status 
• Archival block(s) or slides (i.e., at least 15 unstained slides, 5-microns) is required at 
baseline. Patients with prior skin, lymph node, or visceral biopsies performed at NIH or 
outside institutions must make specimen blocks available to the NCI Laboratory of 
Pathology for analysis (IHC and mutation testing). If no prior biopsies are available at the 
time of screening, patients with MF/SS and ATLL with skin involvement will undergo a 
punch biopsy of a skin lesion, performed by an NIH Clinical Center dermatologist. Patients 
with lymph node and/or visceral involvement will undergo an 18g core biopsy performed 
by the Department of Radiology and Imaging Sciences’ Interventional Radiologists (IR).  
• Prior specimen blocks will be sent to NCI Pathology Department via FedEx. For patients 
with no prior samples who undergo biopsy as part of screening (if needed for diagnosis) or 
baseline, core tumor tissue (or bone marrow aspirate/biopsy) samples will be collected and 
placed in appropriate media (e.g., RPMI 1640 with 10% human serum and antibiotics, 
normal saline, and/or formalin) and processed per established techniques. As indicated 
(Sections 5.1 and 5.2) samples will be sent to the Department of Laboratory Medicine 
(DLM)/ NCI Laboratory of Pathology (LP) for concurrent routine histologic analysis and 
reporting, IHC testing for CCR4 expression by tumor cells and tumor-associated immune 
cells in addition to research testing (i.e., Waldmann Lab). 


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5.2.3.2 Tissue immune cell subsets and single-cell RNA-sequencing 
• Collect 1-3 4mm punch biopsies (skin) or 1-3 18G core biopsies (lymph node/viscera) in 
RPMI 1640 with 10% human serum and antibiotics or normal saline. 
• Lymphoid Malignancies Branch Clinical Research personnel will arrange for the samples 
to be delivered to NCI LP for processing to a single-cell suspension and storage. Samples 
will be batch processed by the single-cell sequencing core (NIH Clinical Center Bldg 
10/Room 4B44). 
5.2.4 Other Samples 
5.2.4.1 Germline DNA 
Germline DNA will be collected by blood, buccal swab, and/or saliva samples (preferred).  
These will ideally be collected at baseline; however, may be collected at any point on study 
based on supplies.  Standardized, commercial collection kits or tubes will be used (e.g., 1, 5-10 
mL K2EDTA tube for blood; Isohelix SK-1 for buccal swabs; Salviette/Oragene® for saliva).  
In the case of buccal swabs, two (2) samples may be collected in order to ensure adequate DNA 
collection.     
Lymphoid Malignancies Branch Clinical Research personnel will arrange for these samples to 
be delivered to Clinical Support Laboratory, Leidos Biomedical Research, Inc.in Frederick, 
MD to be processed and DNA extracted/isolated per kit instructions and established techniques.  
5.3 
SAMPLE STORAGE, TRACKING, AND DISPOSITION 
5.3.1 General 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples 
will not be sent outside NIH without appropriate approvals and/ or agreements, if required. 
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are 
remaining at the completion of the protocol will be stored in the conditions described below. The 
study will remain open so long as sample or data analysis continues. Samples from consenting 
subjects will be stored until they are no longer of scientific value or if a subject withdraws consent 
for their continued use, at which time they will be destroyed. 
If the patient withdraws consent the participant’s data will be excluded from future distributions, 
but data that have already been distributed for approved research use will not be able to be 
retrieved.  
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will 
be per the requirements of section 7.2. 
5.3.2 Lymphoid Malignancies Branch – Waldmann Laboratory 
All samples that are noted in Section 5.1 to be analyzed by the Waldmann Laboratory will first be 
processed and stored at Clinical Support Laboratory, Leidos Biomedical Research, Inc. in 
Frederick, MD, as per Section 5.3.3. 


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5.3.3 Clinical Support Laboratory, Leidos Biomedical Research, Inc. in Frederick, MD 
The Clinical Support Laboratory, Leidos Biomedical Research, Inc.-Frederick, processes and 
cryopreserves samples in support of IRB-approved, NCI clinical trials. The laboratory is CLIA 
certified for anti-IL15 and certain cytokine measurements and all laboratory areas operate under a 
Quality Assurance Plan with documented Standard Operating Procedures that are reviewed 
annually. Laboratory personnel are assessed for competency prior to being permitted to work with 
patient samples. Efforts to ensure protection of patient information include: 
• The laboratory is located in a controlled access building and laboratory doors are kept 
locked at all times. Visitors to the laboratory are required to be accompanied by laboratory 
staff at all times. 
• Hard copy records or electronic copies of documents containing patient information are 
kept in the locked laboratory or other controlled access locations. 
• An electronic database is used to store information related to patient samples processed by 
the laboratory. 
• The database resides on a dedicated program server that is kept in a central, locked 
computer facility. 
• The facility is supported by two IT specialists who maintain up to date security features 
including virus and firewall protection. 
• Program access is limited to specified computers as designated by the laboratory director. 
Each of these computers has a password restricted login screen. 
• The database sample entry program itself is accessed through a password protected entry 
screen. 
• Upon specimen receipt each sample is assigned a unique, sequential laboratory accession 
ID number. All products generated by the laboratory that will be stored either in the 
laboratory freezers or at a central repository facility are identified by this accession ID. 
• Inventory information will be stored at the vial level and each vial will be labeled with both 
a sample ID and a vial sequence number. 
• Vial labels do not contain any personal identifier information. 
• Samples are stored inventoried in locked laboratory freezers and are routinely transferred 
to the NCI-Frederick repository facilities for long term storage. 
• Access to stored clinical samples is restricted. Investigators establish sample collections 
under “Source Codes” and the Principal Investigator who is responsible for the collections 
specifies who has access to the collection.  
• Specific permissions will be required to view, input or withdraw samples from a collection. 
Sample withdrawal requests submitted to approved laboratory staff by anyone other than 
the repository source code owner are submitted to the source code owner for approval. The 
repository facility will also notify the Source Code holder of any submitted requests for 
sample withdrawal. 
• It is the responsibility of the Source Code holder (the NCI Principal Investigator) to ensure 
that samples requested and approved for withdrawal are being used in a manner consistent 
with IRB approval. 
• The Clinical Support Laboratory does perform testing services that may be requested by 
clinical investigators including, but not limited to, immunophenotyping by flow cytometry 
and cytokine testing using ELISA or multiplex platforms. 


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• When requests are submitted by the NCI investigator for shipment of samples outside of 
the NIH it is the policy of the laboratory to request documentation that a Material Transfer 
Agreement is in place that covers the specimen transfer. The laboratory does not provide 
patient identifier information as part of the transfer process but may, at the discretion of 
the NCI investigator, group samples from individual patients when that is critical to the 
testing process. 
• The NCI investigator responsible for the sample collection is responsible for ensuring 
appropriate approvals and/ or agreements are in place, if required, prior to requesting the 
laboratory to ship samples outside of the NIH. 
5.3.4 Hematopathology Section of the Laboratory of Pathology (Tissue samples) 
Archival and/or freshly collected and processed tumor tissue may be stored in the 
Hematopathology Section of Laboratory of Pathology until ready for planned and/or future 
research assays if the patient has agreed to allowing specimens to be used in future research studies.  
IRB approval will be obtained before using any samples to conduct studies that are not described 
within this protocol.  Samples will be stored under conditions appropriate to the type of sample 
and processing (e.g., ambient or frozen). 
Tissue that is given to the technician will be assigned an accession number (HP#) in the HP Case 
Log book; sample tracking also takes place with a FileMaker Pro data base called HP Patient 
Information and Specimen Inventory.   A Patient background sheet may be filled out and filed with 
any accompanying paperwork, with final reports and any supplemental reports that follow added 
as completed. 
5.4 
SAMPLES FOR GENETIC/GENOMIC ANALYSIS 
5.4.1 Description of the scope of genetic/genomic analysis 
The research correlates for this study are expected to include DNA/RNA sequencing of tumors, 
including circulating tumor (ct) DNA. In addition, whole exome sequencing may include 
evaluation for known lymphoma mutations. For any genetic studies performed, the results will be 
deposited in a database such as dbGaP per NIH requirements.  Although there is controlled access 
to such a database, such a submission carries theoretical risks of revealing the identity of the 
subject.  This is discussed in the consent. 
5.4.2 Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized 
Confidentiality for genetic samples will be maintained as described (Section 5.3). In addition, a 
Certificate of Confidentiality has been obtained for this study. 
5.4.3 Management of Results 
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for this study are defined as disorders appearing in the American College of 
Medical Genetics and Genomics recommendations for the return of incidental findings that is 
current at the time of primary analysis. (A list of current guidelines is maintained on the CCR 
intranet: https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists). 


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5.4.4 Genetic Counseling 
Subjects will be contacted at this time with a request to provide a blood sample to be sent to a 
CLIA certified laboratory.  If the research findings are verified in the CLIA certified lab, the 
subject will be offered the opportunity to come to NIH to have genetic education and counseling 
to explain this result; at the time of any such event(s), these activities will be funded by the 
NCI/CCR in consideration of the specific circumstances.  If the subject does not want to come to 
NIH, a referral to a local genetic healthcare provider will be provided (at their expense). 
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis. 
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
6.1.1 Summary 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts. 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.  
Document AEs from the first study intervention, Study Day 1 through 30 days after the last 
intervention. Beyond 30 days after the last intervention, only adverse events which are serious 
and related to the study intervention need to be recorded. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in Section 7.2.1. 
6.1.2 Data Collection/Recording Exceptions 
6.1.2.1 Abnormal Laboratory Values 
An abnormal laboratory value will be considered an AE only if the laboratory abnormality is 
characterized by any of the following: 
• Results in discontinuation from the study 
• Is associated with clinical signs or symptoms  
• Requires treatment or any other therapeutic intervention 
• Is associated with death or another serious adverse event, including hospitalization 
• Is judged by the Investigator to be of significant clinical impact 


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• If any abnormal laboratory result is considered clinically significant, the investigator 
will provide details about the action taken with respect to the test drug and about the 
patient’s outcome. 
6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows: 
_X_ Coded, linked data in an NIH-funded or approved public repository.   
_X_ Coded, linked data in another public repository 
_X_ Coded, linked data in BTRIS (automatic for activities in the Clinical Center) 
_X_ Identified or coded, linked data with approved outside collaborators under appropriate 
agreements. 
How and where will the data be shared?  
Data will be shared through: 
_X_ An NIH-funded or approved public repository.  Insert name or names: ClinicalTrials.gov, 
dbGaP. 
_X_ BTRIS (automatic for activities in the Clinical Center) 
_X_ Approved outside collaborators under appropriate individual agreements.   
_X_ Publication and/or public presentations. 
When will the data be shared? 
_X_ Before publication. 
_X_ At the time of publication or shortly thereafter. 
6.2.2 Genomic Data Sharing Plan 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 
6.3 
RESPONSE CRITERIA 
6.3.1 Response Assessments  
Tumor response will be assessed by the investigator using the Global Response Score (41) and 
modified severity weighted assessment tool (mSWAT) (19) for patients with MF/SS, and the 
International Consensus Meeting guidelines (42, 43) for patients with ATLL. Patient will be re-
evaluated for response as outlined in the Study Calendar, Section 3.7. 
6.3.2 Response Criteria for MF/SS 
Global Response (GR) score (APPENDIX C) will be used for assessing response in patients 
with CTCL (41). GR score incorporates separate responses in each component of the TNBM 
staging (i.e., skin, nodes, viscera and blood; APPENDIX C). No patient with a global OR should 
have less than a PR in the skin. 


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The mSWAT (19) is an instrument utilized to track the skin tumor burden in MF/SS. It measures 
the percentage total body-surface area (TBSA, %) involvement separately for patches, plaques, 
and tumors within 12 body regions using the patient's palm and fingers representing 1% of TBSA. 
Patients with erythroderma are assessed for percentage of TBSA involved with patches and/or 
plaques. The percentage of TBSA for each lesion type is multiplied by a number (patch = 1, plaque 
= 2; tumor = 4) and summed to derive the mSWAT score. The mSWAT for each patient will be 
determined by the same individual at all study visits. 
A complete response (CR) requires 100% clearing of skin disease and a partial response (PR) 
requires ≥ 50% reduction in the mSWAT score compared with baseline. CR/PR requires 
confirmation by repeat assessment after ≥ 4 weeks. Stable disease is defined as less than 50% 
reduction to less than 25% increase in the mSWAT score compared with baseline. PD is defined 
as ≥ 25% increase in the mSWAT score from baseline or ≥ 50% increase in the sum of the products 
of the greatest diameters of pathologically positive lymph nodes compared with baseline. 
Time to response is the time from the first treatment dose until the patient first meets the criteria 
for a 50% decrease in the GR score. The duration of response (DOR) is the time from first CR/PR 
until the GR score is increased from nadir to more than 50% of the difference between the baseline 
and nadir scores. Time to progression (TTP) is the time from start of treatment until PD. If patients 
goes off treatment for any purpose, this date is used for determination of TTP and/or DOR. 
As “skin flares” have been described in patients with SS receiving the anti-PD-1 antibody 
Pembrolizumab (44), patients with SS whose only sign of PD is an increase in mSWAT score (i.e., 
who have normal/decreasing number of circulating Sézary cells) will continue treatment and be 
re-evaluated in 2-4 weeks to confirm disease progression. Patients whose PD is not confirmed on 
re-evaluation will be noted to have had a skin flare  


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Table 11: Calculating mSWAT Score 
Body Region 
% BSA in Body Region 
Assessment of Involvement in Patient’s Skin 
Patch1 
Plaque2 
Tumor3 
Head 
7 
 
 
 
Neck 
2 
 
 
 
Anterior trunk 
13 
 
 
 
Arms 
8 
 
 
 
Forearms 
6 
 
 
 
Hands 
5 
 
 
 
Posterior trunk 
13 
 
 
 
Buttocks 
5 
 
 
 
Thighs 
19 
 
 
 
Legs 
14 
 
 
 
Feet 
7 
 
 
 
Groin 
1 
 
 
 
Subtotal of lesion BSA 
 
 
 
 
Weighing factor 
 
x1 
x2 
x4 
Subtotal lesion BSA x 
weighing factor 
 
 
 
 
NOTE:  mSWAT score equals summation of each column line. 
Abbreviations: BSA, body surface area; mSWAT, modified Severity Weighted Assessment Tool. 
1 Any size lesion without induration or significant elevation above the surrounding uninvolved skin; poikiloderma 
may be present 
2 Any size lesion that is elevated or indurated; crusting, ulceration, or poikiloderma may be present. 
3 Any solid or nodular lesion > 1cm in diameter with evidence of deep infiltration in the skin and/or vertical 
growth. 
6.3.3 Response Criteria for ATLL 
Table 12: Response Criteria for Adult T-cell Leukemia-Lymphoma 
Response Definition 
Lymph 
nodes 
Extranodal 
masses 
Spleen, 
liver 
Skin 
Peripheral 
blood 
Bone 
marrow 
CR* 
Disappearance 
of all disease 
Normal 
Normal 
Normal 
Normal 
Normal† 
Normal 
CRu* 
Stable 
residual mass 
in bulky 
lesion 
≥75% 
decrease‡ 
≥75% 
decrease‡ 
Normal 
Normal 
Normal† 
Normal 
PR* 
Regression of 
disease 
≥50% 
decrease‡ 
≥50% 
decrease‡ 
No 
increase 
≥50% 
decrease 
≥50% 
decrease 
Irreleva
nt 
SD* 
Failure to 
attain CR/PR 
and no PD 
No change 
in size 
No change 
in size 
No 
change 
in size 
No 
change 
in size 
No 
change 
No 
change 


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RD/PD 
New or 
increased 
lesions 
New or 
≥50% 
increase§ 
New or 
≥50% 
increase§ 
New or 
≥50% 
increase 
≥50% 
increase 
New or 
≥50% 
increase|| 
Reappea
rance 
Not assessable 
CR: complete response, CRu: unconfirmed complete response, PR: partial response, SD: stable 
disease, RD/PD: relapsed disease/progressive disease 
*Require each criterion to be present for a period of at least 4 weeks. 
†Provided that <5% of flower cells remained, complete remission will be judged to have been 
attained if the absolute lymphocyte count, including flower cells is < 4 ⨉109/L. 
‡Calculated by the sum of the products of the greatest diameters of measurable disease. 
§Defined by ≥ 50% increase from nadir in the sum of the products of measurable disease. 
|| Defined by ≥ 50% increase from nadir in the count of flower cells and an absolute lymphocyte 
count, including flower cells, of > 4 ⨉109/L. 
 
6.3.4 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). 
6.3.5 Duration of Response 
The duration of response (DOR) is measured from the time measurement criteria are met for CR 
or PR (whichever is recorded first) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started), death, or, in the absence of PD, date of last assessment. 
 
6.3.6 Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from the date of study enrollment 
until time of disease relapse, disease progression, or death, whichever occurs first. 
6.3.7 Overall Survival 
Overall survival (OS) is defined as the time from the date of study enrollment until time of death 
from any cause. 
6.3.8 Event-Free Survival 
Event-free survival (EFS) is defined as the duration of time from the date of study enrollment until 
time of disease relapse, disease progression, alternative therapy for lymphoma given (such as 
radiation), or death, whichever occurs first. 
6.3.9 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 


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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.  
6.4 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study. The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. 
All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy 
of 
the 
CTCAE 
version 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).  
7 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN 
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING 
7.2.1 Expedited Reporting  
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that 
meet the definition of an unanticipated problem will need to be reported per these policies. 
7.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.  
7.3 
NCI CLINICAL DIRECTOR REPORTING  
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the Clinical 
Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to progressive 
disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut 
at NCICCRQA@mail.nih.gov within one business day of learning of the death. 


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7.4 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
7.4.1 Principal Investigator/Research Team  
The clinical research team will meet at least once weekly when patients are being actively treated 
on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
Section 7.2.1 will be submitted within the appropriate timelines. 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
8 
SPONSOR SAFETY REPORTING 
8.1 
DEFINITIONS 
8.1.1 Adverse Event  
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E6 (R2) 
8.1.2 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse event (see 8.1.3) 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration 
in health, is not considered a serious adverse event. 
o A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient convenience) is not considered a serious adverse event. 
o Emergency room visits or stays in observation units that do not result in 
admission to the hospital would not be considered a serious adverse event. The 
reason for seeking medical care should be evaluated for meeting one of the other 
serious criteria. 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 


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• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
8.1.3 Life-threatening  
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death (21CFR312.32) 
8.1.4 Severity 
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5. 
8.1.5 Relationship to Study Product 
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.   
• Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event. 
• Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
8.2 
ASSESSMENT OF SAFETY EVENTS 
AE information collected will include event description, date of onset, assessment of severity and 
relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution. 
SAEs will be: 
• 
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator. 
• 
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database. 
• 
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator. 


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For timeframe of recording adverse events, please refer to Section 6.1.   All serious adverse 
events recorded from the time of first investigational product administration recorded must be 
reported to the sponsor with the exception of any listed in section 8.4. 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS 
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited 
reporting requirements are found in section 8.4. 
All SAE reporting must include the elements described in section 8.2. 
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 
and instructions can be found at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=157942842 
Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible. 
8.4 
WAIVER OF EXPEDITED REPORTING TO CCR 
As death due to disease progression is part of the study objectives, and captured as an endpoint in 
this study, it will not be reported in expedited manner to the sponsor. However, if there is 
evidence suggesting a causal relationship between the study drug and the event, report the event 
in an expedited manner according to section 8.3. 
8.5 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
Reporting will be per the collaborative agreement.  
8.5.1 CTEP 
Copies of all IND Safety Reports submitted to the FDA should be forwarded electronically to 
CTEPSupportAE@tech-res.com (please provide protocol number in subject line). 
8.6 
REPORTING PREGNANCY  
8.6.1 Maternal exposure 
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy becomes known, 
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria section 8.1.2) should be reported as SAEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented. 


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8.6.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 6 
months after the last dose of mogamulizumab. 
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 90 days after the last dose 
should, if possible, be followed up and documented. 
8.7 
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND 
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected adverse 
reaction only if there is evidence to suggest a causal relationship between the study product and 
the adverse event.  CCR will notify FDA and all participating investigators (i.e., all investigators 
to whom the sponsor is providing drug under its INDs or under any investigator’s IND) in an IND 
safety report of potential serious risks from clinical trials or any other source, as soon as possible, 
in accordance to 21 CFR Part 312.32.  
All serious events will be reported to the FDA at least annually in a summary format. 
9 
CLINICAL MONITORING  
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary and secondary study endpoints; adherence to the protocol, 
regulations, ICH E6, and SOPs; and human subjects protection. This is done through independent 
verification of study data with source documentation focusing on: 
• Informed consent process 
• Eligibility confirmation 
• Drug administration and accountability 
• Adverse events monitoring 
• Response assessment. 
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center. 
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct.   
10 STATISTICAL CONSIDERATIONS 
10.1 STATISTICAL HYPOTHESIS 
• Primary Endpoint(s):  
o Maximum tolerated dose (MTD) of rhIL-15 administered intravenously for 5 days 
in combination with mogamulizumab for up to 6 cycles 
o Frequency (number and percentage) of treatment-emergent AEs 
• Secondary Endpoint(s): 
o Overall response rate (including CR and PR) 


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o ORR, TTP, and PFS by CCR4 mutation status (mutated versus wild type) and 
presenting diagnosis (MF/SS versus ATLL, MF versus SS, acute/chronic versus 
lymphoma subtype ATLL) 
o Duration of response 
o Progression-free, event-free, and overall survival 
o Changes in percentage and absolute number of peripheral blood lymphocyte 
subsets 
o Quantitation ADCC performed ex vivo on PBMCs obtained from the patients 
before and during treatment 
o Characterization of changes in immune cell infiltrates of tumor deposits by 
immunohistochemical and molecular analysis of core biopsies obtained before and 
during treatment 
10.2 SAMPLE SIZE DETERMINATION 
The MTD will be based on the assessment of DLT during the first cycle of treatment and will be 
defined as the dose level at which less than one-third of patients (0 of 3 or 0-1/6 patients) treated 
experience a DLT, with the next higher dose level demonstrating one-third or a greater number of 
patients (≥ 2-3 or ≥ 2-6 patients) having a DLT.  If a subject did not experience a DLT and did not 
finish one cycle of treatment (28 days) he or she will not be evaluable for determination of the 
MTD and would be replaced in the dose level.  An additional 6 to 9 patients will be enrolled at the 
MTD, so that a total of 12 patients will be treated at this dose.  
Using this dose-escalation scheme the probability of escalating to the next dose level will be based 
on the true rate of DLT at the current doses given by the following table (each group will be 
considered independently of the other); Thus, if the true underlying proportion of DLTs is 50% at 
the current dose there is a 17% probability of escalating to the next dose.  
 
True toxicity at a given dose 
10% 
20% 
30% 
40% 
50% 
60% 
Probability of escalating 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
 
If both dose levels are evaluated with 6 patients per dose level and 12 total patients at the MTD, a 
maximum of 18 evaluable patients will be enrolled. Similarly, if all dose levels are evaluated with 
3 patients per dose level and 12 total patients at the MTD, the minimum number of evaluable 
patients required will be 15. To account of unevaluable patients, accrual ceiling will be set at 20. 
It is expected that the accrual can be completed in 18 months.  
A maximum of 18 patients will be enrolled over 18 months, at a rate of 1 patient per month. 
10.3 POPULATION FOR ANALYSIS 
10.3.1 Evaluable for toxicity:  
All patients will be evaluable for toxicity from the time of their first treatment with rhIL-15 and 
mogamulizumab. 


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10.3.2 Evaluable for objective response:  
Only those patients who have measurable disease present at baseline, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. 
These patients will have their response classified according to the definitions stated above, Section 
6.3. (NOTE:  Patients who exhibit objective disease progression prior to the end of Cycle 1 will 
also be considered evaluable for response. All patients who initiate treatment and receive at least 
one dose of study drug are considered evaluable for toxicity and will not be replaced.) 
10.3.3 Evaluable Non-Target Disease Response:   
Patients who have lesions present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for non-target disease. The response assessment is based 
on the presence, absence, or unequivocal progression of the lesions.  
10.4 STATISTICAL ANALYSES 
10.4.1 General Approach 
The response rate will be determined and reported along with a 95% Agresti-Coull confidence 
interval (45). Other time-to-event outcomes will be reported using Kaplan-Meier curves. 
10.4.2 Analysis of the Primary Endpoints 
Safety summaries will include summaries in the form of tables and listings. Reports will include 
the frequency (number and percentage) of treatment emergent AEs grouped by severity of the AE 
(per CTCAE, v5.0) and by relationship to study drug (e.g., either rhIL-15, mogamulizumab, or 
both). 
Laboratory shift tables containing counts and percentages will be prepared by treatment 
assignment, laboratory parameter, and time. Summary tables will be prepared for each laboratory 
parameter. Figures of changes in laboratory parameters over time will be generated. 
Results of vital sign assessments, ECGs, and physical exams will be tabulated and summarized. 
10.4.3 Analysis of the Secondary Endpoints 
The duration of response (DOR; beginning at the date clinical response is first identified), overall 
survival (OS), event free survival (EFS), and progression free survival (PFS) will be estimated 
using Kaplan-Meier curves with appropriate confidence intervals reported. 
Every report of response rates and time to progression should contain all patients included in the 
study. For the response calculation, the report should contain at least a section with all eligible 
patients. Another section of the report may detail the response rate for evaluable patients only.  
However, a response rate analysis based on a subset of patients must explain which patients were 
excluded and for which reasons.  95% confidence limits will be given. 
10.4.4 Safety Analyses 
The type, grade and frequency of toxicities will be reported. 
10.4.5 Baseline Descriptive Statistics 
Descriptive statistics (including means, standard deviations, and medians for continuous variables 
and proportions and CIs for discrete variables) will be used to summarize data as appropriate. 


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10.4.6 Planned Interim Analyses 
No interim analyses are planned because of the single stage design of the trial. 
10.4.7 Sub-Group Analyses 
All secondary endpoints will be analyzed and reported separately according to the presenting 
diagnosis (MF/SS or ATLL, and MF, SS, acute, chronic, or lymphoma subtype ATLL) and CCR4 
mutation status (mutated versus wild-type).  
10.4.8 Tabulation of Individual Participant Data 
None. 
10.4.9 Exploratory Analyses 
The exploratory objectives such as seeking to identify potential biomarkers or T-cell clones in 
peripheral blood which are associated with response, will be assessed using descriptive statistics 
as well as non-parametric methods such as exact Wilcoxon rank sum tests. The analyses will be 
done without formal adjustment for multiple comparisons, but in the context of the number of tests 
performed. 
11 COLLABORATIVE AGREEMENTS  
11.1 MATERIAL TRANSFER AGREEMENT (MTA)- CTEP 
An MTA with Division of Cancer Treatment and Diagnosis (DCTD) for the IL-15 was executed 
on September 11, 2019. 
12 HUMAN SUBJECTS PROTECTIONS  
12.1 RATIONALE FOR SUBJECT SELECTION 
All subjects from both sexes and all racial/ethnic groups are eligible for this study if they meet the 
eligibility criteria outlined in the protocol and provide informed consent to protocol participation. 
Subjects with HIV infection will be excluded due to potential toxicity and unknown effects of 
rhIL-15 and mogamulizumab on the underlying HIV infection and interference with ART. 
Pregnant or nursing mothers are excluded because of the potential teratogenic effects of therapy.  
We expect men and women to be equally represented among the enrolled patients.  
12.2 PARTICIPATION OF CHILDREN 
Subjects under the age of 18 are excluded because recurrent T-cell lymphomas are rare in young 
patients, and the inclusion of an occasional younger patient will not provide generalizable 
information that would justify their inclusion on this study. Additionally, because no dosing or 
adverse event data are currently available on the use of rhIL-15 in combination with 
mogamulizumab in patients <18 years of age, children are excluded from this study, but may be 
eligible for future pediatric trials. 
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults who are unable to consent are excluded from enrolling in this study.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired.  For this reason and because there is a prospect of direct benefit from 


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research participation (Section 12.4), all subjects ≥ age 18 will be offered the opportunity to fill in 
their wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or cognitively 
impaired during the course 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 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. 
12.4 RISK/ BENEFIT ASSESSMENT 
12.4.1 Known Potential Risks 
The potential risks of adding rhIL-15 to mogamulizumab include, in particular, infusion reactions 
(including chills, fever, hypotension, headache, flushing, dizziness), liver enzyme elevations, 
thrombocytopenia, and rash, particularly since the drugs are given concomitantly. As noted in 
Section 3.2, premedication will be given during IL-15 infusions and before each mogamulizumab 
dose to reduce the risk of these AEs occurring. Patients will be monitored closely, and 
manufacturer recommendations for delaying and discontinuing mogamulizumab and initiating 
supportive therapy will be followed.  
In addition to the tumor cells, CCR4 is also expressed on normal immune cells, 
immunosuppressive T regulatory cells (Tregs) in particular. While Treg depletion may have an 
anti-tumor effect, it also increases the risk of GVHD. In a post-marketing study conducted in Japan, 
among 29 patients who received mogamulizumab after a median of 59 days after allo-HSCT, seven 
who already had GVHD before receiving mogamulizumab did not experience worsening of their 
symptoms, and 5 of the 22 who did not have GVHD developed it after mogamulizumab.(46). 
International Consensus Group therefore recommends avoiding mogamulizumab within 50 days 
of allo-HSCT, but deemed it acceptable to use for patients with a more remote transplant history. 
(42). 
12.4.2 Risks related Imaging 
CT and PET scans often use a contrast agent.  There is a small risk of having a reaction to the 
contrast and most often include nausea, pain in the vein where the contrast is given, headache, 
metallic and/ or bitter taste in the mouth and a warm, flushing feeling.  Rarely, some people have 
more severe allergic reactions to the contrast which may include skins rashes, shortness of breath, 
wheezing or low blood pressure. 
12.4.3 Risks from Radiation Exposure 
The procedures for performing the chest CT and 18F-FDG PET/CT scans will follow clinical 
policies, no special procedures apply to these assessments for research purposes.  In summary, 
subjects may receive radiation exposure from up to seven (7) CT scans of the neck, chest, 
abdomen, and pelvis, and three (3) 18F-FDG PET/CT scans.  
The total radiation dose for research purposes will be approximately 12.7 rem. 


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12.4.4 Known Potential Benefits 
The benefit of adding rhIL-15 to mogamulizumab in treatment of MF/SS and ATLL is unknown, 
but single-agent mogamulizumab has shown activity as outlined in Section 1.2.4, is US FDA-
approved for treatment of advanced MF/SS, and is recommended by the NCCN for treatment of 
relapsed/refractory ATLL.  
12.4.5 Assessment of Potential Risks and Benefits 
Mogamulizumab is FDA-approved for treatment of MF/SS and NCCN-recommended for 
treatment of ATLL. Since its primary mode of action is mediated by ADCC, agents that may 
enhance ADCC by increasing number and activity of Fc-binding effector cells — such as rhIL15 
— could improve efficacy of mogamulizumab in these diseases. Although the clinical benefit of 
IL-15 has not yet been established, the intent of offering this treatment is to provide a possible 
therapeutic benefit, and thus the patient will be carefully monitored for tumor response and 
symptom relief in addition to safety and tolerability. 
There have been no studies of IL-15 in patients with HIV on or off ART. Two non-human primates 
with SIV who were not on ART and received rhIL-15 on Study 2078-10804 both died, while 
subsequent animals who received viral suppression were seemingly unaffected. rhIL-15 may 
therefore contribute to morbidity/mortality in patients with a detectable viral load. Since potential 
toxicity of IL-15 and mogamulizumab may interfere with ART adherence and optimal viral 
suppression, patients with HIV may be exposed to additional toxicity for unknown potential 
benefit of IL-15 and should therefore be excluded in this study. 
There have been no reports of severe capillary leak syndrome (CLS) when single-agent rhIL-15 
was given via a continuous infusion. Of the first six patients treated with combination rhIL-
15/mogamulizumab, one, with acute subtype ATLL, developed grade 4 CLS less than 24 hours 
after the first infusion of mogamulizumab and initiation of rhIL-15 infusion at DL2 (4 
mcg/kg/day), which subsequently led to grade 4 acute kidney injury. Both had resolved after 
cessation of therapy and initiation of high dose steroids. This patient had baseline CLS which was 
disease-related, and which seems to have been worsened by the combination therapy. Although no 
definitive conclusions can be drawn from a single event, increased scrutiny will be given to similar 
patients with high circulating leukemic cell counts and baseline CLS, with close clinical follow-
up for serious adverse events. Notably, there is no known effective treatment for such patients after 
combination chemotherapy and single-agent mogamulizumab. 
12.5 CONSENT PROCESS AND DOCUMENTATION 
The informed consent document will be provided to the participant or consent designee(s) (e.g., 
legally authorized representative [LAR] if participant is an adult unable to consent) for review 
prior to consenting.  A designated study investigator will carefully explain the procedures and 
tests involved in this study, and the associated risks, discomforts and benefits. In order to 
minimize potential coercion, as much time as is needed to review the document will be given, 
including an opportunity to discuss it with friends, family members and/or other advisors, and to 
ask questions of any designated study investigator. A signed informed consent document will be 
obtained prior to entry onto the study. 
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms) per discretion of the 
designated study investigator and with the agreement of the participant/consent designee(s).  


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Whether in person or remote, the privacy of the subject will be maintained. Consenting 
investigators (and participant/consent designee, when in person) will be located in a private area 
(e.g., clinic consult room). When consent is conducted remotely, the participant/consent designee 
will be informed of the private nature of the discussion and will be encouraged to relocate to a 
more private setting if needed.   
13 REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to investigators, funding 
agencies, the Investigational New Drug (IND) sponsor and regulatory authorities, as applicable.  
If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly 
inform study participants, the Institutional Review Board (IRB), and sponsor and will provide 
the reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
 Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
13.2 QUALITY ASSURANCE AND QUALITY CONTROL 
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan 
will be developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 


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13.3 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial.  The study leadership in conjunction with the National Cancer Institute has established 
policies and procedures for all study group members to disclose all conflicts of interest and will 
establish a mechanism for the management of all reported dualities of interest. 
14 PHARMACEUTICAL INFORMATION 
This study is being conducted under a CCR-held IND:  IND #140549. 
14.1 RHIL-15 (NSC #745101) 
14.1.1 Source/ Acquisition and Accountability 
rhIL-15 is an investigational agent supplied to investigators by the Cancer Therapy Evaluation 
Program (CTEP), Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
14.1.2 Drug Summary Information 
14.1.2.1 Chemical Name or Amino Acid Sequence 
The 115 amino acid coding sequence of the pET28b/IL-15 cistron is as follows: 
MNWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDA
SIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS 
14.1.2.2 Other Names 
Recombinant Human Interleukin -15; Recombinant Human IL-15; rhIL-15 
14.1.2.3 Classification 
Recombinant human interleukin-15 (rhIL-15) is a cytokine of the 4-alpha helix bundle family 
of cytokines whose mature form consists of 115 amino acids.  It has two cystine disulfide cross 
linkages at positions Cys 42-Cys 88 and Cys 35-Cys 85. 
14.1.2.4 Molecular Weight (M.W.) 
12,898.8 Daltons 
14.1.2.5 Mode of Action 
IL-15 interacts with a private receptor subunit IL- 15R alpha as well as the IL-2/IL-15R beta 
chain shared with IL-2 and the common gamma chain shared with IL-2, IL-4, IL-7, IL-9 and 
IL-21.  IL-15 shares a number of biological activities with IL-2, including stimulation of the 
proliferation of activated CD4+, CD8+ as well as gamma-delta subsets of T cells.  IL-15 also 
stimulates the proliferation of NK cells and acts as a co-stimulator with IL-12 to facilitate the 
production of Interferon-gamma and TNF-alpha. 
14.1.3 How Supplied 
IL-15 is manufactured by the Biopharmaceutical Development Program (BDP) and distributed by 
the Pharmaceutical Management Branch (PMB) CTEP. IL-15 is supplied as a sterile, frozen liquid 
product in single use vials containing no preservatives. Currently, IL-15 is supplied as 147 mcg / 


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0.3 mL (490 mcg/mL) in a 3 mL glass vial.  The IL-15 is formulated in 25 mM sodium phosphate 
containing 0.5 M sodium chloride at a pH of 7.4. 
NOTE: IL-15 vial content may vary between lots and protocols.  Use caution and consult the 
protocol document for specific preparation instructions when preparing each dose. 
14.1.4 Preparation 
Vials of frozen IL-15 should be thawed at ambient room temperature.  Upon thawing, the solution 
should be clear and colorless with no evidence of particulates or foreign matter.  The infusion 
solutions should be mixed in a PVC bag. 
14.1.5 Storage 
IL-15 vials should be stored at or below (-70°C). 
14.1.6 Stability 
14.1.6.1 Vials 
Stability studies of the intact vials are ongoing. 
14.1.6.2 Prepared Infusion 
The rhIL-15 infusion solution is stable at a concentration of 1 mcg/mL with 0.1% HSA for 4 
hours at controlled room temperature (15°C–30°C) prior to initiation of the 24-hour infusion or 
24 hours at 2-8°C prior to initiation of the 24-hour infusion. This stability information was 
previously documented by the Biopharmaceutical Development Program (BDP) of Leidos 
Biomedical Research, Inc., the drug manufacturer. 
14.1.7 Administration 
For all dose levels, the dose of rhIL-15 will be diluted in the appropriate volume of 0.1% human 
serum albumin (HSA) in 5% dextrose in water, USP (D5W) to reach a final rhIL-15 concentration of 
1 mcg/mL (see Dilution instructions, APPENDIX D).  The rhIL-15 infusion will be administered 
to the patient by continuous intravenous infusion (civ) at a dose in mcg/kg/day determined by the 
dose level at which the patient is enrolled.  Each bag (total 5 bags over 5 days) will be infused over 
24 hours using a portable ambulatory pump on the inpatient unit (cycle 1) or in the outpatient 
setting (cycles 2-6, if deemed appropriate by the PI) for a total of 120 hours. Bags must be changed 
every 24 hours. Treatment with rhIL-15 will begin within 4 hours of preparation of the infusion 
bag and the infusion must be completed within 24 hours from the time drug administration begins. 
Otherwise a new infusion bag must be prepared to complete administration of the remaining dose. 
See Appendix 3.2 for Drug Regimen, and Section 3.2.1 for supportive care measures. 
14.1.8 Toxicity  
The Comprehensive Adverse Event and Potential Risks List (CAEPRs) for Recombinant Human 
IL-15 provides a single list of reported and/or potential adverse events (AE) associated with the 
agent using a uniform presentation of events by body system.  In addition to the comprehensive 
list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a 
list of events that are protocol specific exceptions to expedited reporting to NCI (except as noted 
below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for 
further clarification. The CAEPR does not provide frequency data; refer to the Investigator's 


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Brochure for this information. Below is the CAEPR for Recombinant Human IL-15. 
Version 1.3, January 2, 2019* 
Adverse Events with Possible  
Relationship to Recombinant Human IL-15 
(CTCAE 5.0 Term) 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 Anemia (Gr 2) 
Bone marrow hypocellular 
  
CARDIAC DISORDERS 
  
Sinus tachycardia 
 Sinus tachycardia (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
Abdominal pain 
  
Diarrhea 
  
Nausea 
 Nausea (Gr 2) 
Vomiting 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS   
Chills 
 Chills (Gr 2) 
Edema limbs 
  
Fatigue 
 Fatigue (Gr 2) 
Fever 
 Fever (Gr 2) 
Injection site reaction 
  
INFECTIONS AND INFESTATIONS 
  
Sepsis 
  
INVESTIGATIONS 
  
Alanine aminotransferase increased 
  
Aspartate aminotransferase increased 
  
Blood bilirubin increased 
  
Creatinine increased 
  
Lymphocyte count decreased 
 Lymphocyte count decreased (Gr 2) 
Lymphocyte count increased 
  
Neutrophil count decreased 
  
Platelet count decreased 
  
White blood cell decreased 
  
METABOLISM AND NUTRITION DISORDERS 
  
Hypoalbuminemia 
  
Hypophosphatemia 
 Hypophosphatemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
Generalized muscle weakness 
  
NERVOUS SYSTEM DISORDERS 
  
Dizziness 
  
Headache 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
Dyspnea 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
Dry skin 
  
Erythema multiforme 
 Erythema multiforme (Gr 2) 
Skin and subcutaneous tissue disorders - Other (rash) 
  
VASCULAR DISORDERS 
  
Capillary leak syndrome 
  


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Adverse Events with Possible  
Relationship to Recombinant Human IL-15 
(CTCAE 5.0 Term) 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Hypertension 
 Hypertension (Gr 2) 
Hypotension 
 Hypotension (Gr 2) 
 
*This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail 
Adverse events reported on Recombinant Human IL-15 trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that Recombinant 
Human IL-15 caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Chest pain - cardiac; Palpitations; Pericardial effusion; Pericardial 
tamponade; Sinus bradycardia; Ventricular tachycardia 
GASTROINTESTINAL DISORDERS - Ascites; Constipation; Duodenal hemorrhage; Gastritis; 
Gastrointestinal disorders - Other (increased appetite); Ileus; Mucositis oral; Pancreatitis; Visceral arterial 
ischemia 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Infusion site 
extravasation; Multi-organ failure; Pain 
IMMUNE SYSTEM DISORDERS - Autoimmune disorder 
INFECTIONS AND INFESTATIONS - Tooth infection; Upper respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Infusion related reaction 
INVESTIGATIONS - Alkaline phosphatase increased; Cardiac troponin I increased; Electrocardiogram QT 
corrected interval prolonged; GGT increased; INR increased; Lipase increased; Serum amylase increased; Weight 
gain; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Anorexia; Dehydration; Hyperkalemia; Hypocalcemia; 
Hypokalemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone pain; Muscle 
weakness upper limb; Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor 
pain 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Peripheral sensory neuropathy; Presyncope; Vasovagal 
reaction 
PSYCHIATRIC DISORDERS - Anxiety; Psychosis 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Genital edema 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Bronchopulmonary hemorrhage; Cough; Hypoxia; Laryngeal inflammation; Pleural effusion; Pneumonitis; 
Pulmonary edema; Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythroderma; Palmar-plantar erythrodysesthesia 
syndrome; Pruritus; Rash acneiform; Skin and subcutaneous tissue disorders - Other (skin plaques) 
VASCULAR DISORDERS - Hot flashes 
NOTE: Recombinant Human IL-15 in combination with other agents could cause an exacerbation 
of any adverse event currently known to be caused by the other agent, or the combination may 


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result in events never previously associated with either agent. 
14.1.9 CTEP Information 
14.1.9.1 Agent ordering and Agent Accountability 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee).  The CTEP-assigned protocol number must be used for ordering all 
CTEP-supplied investigational agents.  The eligible participating investigators must be 
registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF).  If 
there are several participating investigators, CTEP-supplied investigational agents for the study 
should be ordered under the name of one lead participating investigator at that institution. 
IL-15 may be order from PMB when a patient is being worked up for the study. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) 
account and the maintenance of an “active” account status, a “current” password, and active 
person registration status.  For questions about drug orders, transfers, returns, or accountability, 
call or email PMB any time.  Refer to the PMB’s website for specific policies and guidelines 
related to agent management.   
14.1.9.2 Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing and final disposition of all agents received from the PMB using 
the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on 
the CTEP forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
14.1.9.3 Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB OAOP application.  Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account status, a 
“current” password and active person registration status.  Questions about IB access may be 
directed to the PMB IB Coordinator via email. 
14.1.9.4 Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Person Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm 
• PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/ 
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov 
• IB Coordinator:  IBCoordinator@mail.nih.gov 
• PMB email:  PMBAfterHours@mail.nih.gov 


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• PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
14.2 MOGAMULIZUMAB (KW-0761, NSC# 791064) 
14.2.1 Source/ Acquisition and Accountability  
Mogamulizumab (Poteligeo®) is commercially available and will be purchased by the CCR and 
supplied to the patients enrolled on the study by the NIH Clinical Center Pharmacy Department. 
14.2.2 Toxicity  
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. 
Version 2.3, September 15, 20191 
 
 Adverse Events with Possible  
 Relationship to KW-0761 (mogamulizumab) 
 (CTCAE 5.0 Term) 
[n= 4759] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
CARDIAC DISORDERS 
 
 
Chest pain - cardiac 
 
 
Myocardial infarction 
 
 
Myocarditis2 
 
 
Restrictive cardiomyopathy 
GASTROINTESTINAL DISORDERS 
 
Nausea 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Fatigue 
 
 
Fever 
 
 
Flu like symptoms2 
 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction 
 
 
 
Anaphylaxis3 
 
 
Immune system disorders - Other (graft 
versus host disease)4 
INFECTIONS AND INFESTATIONS 
 
Infection5 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
Infusion related reaction3 
 
INVESTIGATIONS 
 
Alanine aminotransferase increased2,6 
 
 
Alkaline phosphatase increased2,6 
 
 
Aspartate aminotransferase increased2,6 
 
 
Blood bilirubin increased2,6 
 
 
GGT increased2,6 
 
 
Lymphocyte count decreased2 
 
 
Neutrophil count decreased2 
 
 
Platelet count decreased2 
 
 
White blood cell decreased2 
 
METABOLISM AND NUTRITION DISORDERS 


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 Adverse Events with Possible  
 Relationship to KW-0761 (mogamulizumab) 
 (CTCAE 5.0 Term) 
[n= 4759] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthritis2 
 
NERVOUS SYSTEM DISORDERS 
 
Peripheral motor neuropathy2 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Pneumonitis2 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Erythema multiforme2 
 
Rash maculo-papular2 
 
 
 
Skin and subcutaneous tissue disorders - 
Other (drug eruption, toxic skin eruption)2 
 
Skin hypopigmentation2 
 
 
 
Stevens-Johnson syndrome2 
 
 
Toxic epidermal necrolysis2 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2Immune-mediated adverse reactions have been reported in patients receiving KW-0761 
(mogamulizumab).  Adverse events potentially related to KW-0761 (mogamulizumab) may be 
manifestations of immune-mediated adverse events. In clinical trials, most immune-mediated adverse 
reactions were reversible and managed with interruptions of KW-0761 (mogamulizumab), administration 
of corticosteroids and supportive care. 
3Infusion reactions, including high-grade hypersensitivity reactions, anaphylaxis, and cytokine release 
syndrome, which have been observed following administration of KW-0761 (mogamulizumab), may 
manifest as fever, chills, shakes, itching, rash, hypertension or hypotension, or difficulty breathing during 
and immediately after administration of KW-0761 (mogamulizumab). 
4Acute graft-versus-host disease has been observed in patients treated with KW-0761 (mogamulizumab) 
who subsequently received hematopoeitic stem cell transplants. 
5Infection may include any of the infection sites under the INFECTIONS AND INFESTATIONS SOC. 
6Symptoms of hepatic dysfunction may include Alanine aminotransferase increased, Alkaline 
phosphatase increased, Aspartate aminotransferase increased, Blood bilirubin increased, and GGT 
increased under the INVESTIGATIONS SOC. 
Adverse events reported on KW-0761 (mogamulizumab) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that KW-0761 (mogamulizumab) 
caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Disseminated intravascular coagulation; 
Febrile neutropenia; Hemolysis; Thrombotic thrombocytopenic purpura 
CARDIAC DISORDERS - Atrial fibrillation; Sinus tachycardia; Supraventricular tachycardia 
EYE DISORDERS - Retinal vascular disorder 
GASTROINTESTINAL DISORDERS - Abdominal pain; Cheilitis; Colitis2; Constipation; Diarrhea; 
Gastritis; Mucositis oral; Vomiting 


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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Edema 
limbs; Generalized edema; Malaise; Multi-organ failure 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatobiliary disorders - Other (bile duct 
stone); Hepatobiliary disorders - Other (hepatitis) 
INVESTIGATIONS - Blood lactate dehydrogenase increased2; CPK increased; Lipase increased; Serum 
amylase increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Anorexia; Dehydration; Hypercalcemia; 
Hyperglycemia; Hyperkalemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; 
Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - Other (diabetes mellitus) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Flank pain; Generalized 
muscle weakness; Musculoskeletal and connective tissue disorder - Other (tendonitis); Myositis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Treatment 
related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Depressed level of consciousness; Encephalopathy; Headache; 
Nervous system disorders - Other (altered state of consciousness); Nervous system disorders - Other 
(cerebellar syndrome); Paresthesia; Seizure 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Cough; Dyspnea; Hypoxia; Pleural effusion; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Erythroderma; Hyperhidrosis; 
Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Pruritus; Rash acneiform; Skin and 
subcutaneous tissue disorders - Other (lichenoid keratosis); Urticaria 
VASCULAR DISORDERS - Hypertension2; Hypotension2 
Note: KW-0761 (mogamulizumab) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent. 
14.2.3 Formulation and preparation  
Mogamulizumab is supplied as single-use 20 mg vials containing a sterile, clear, colorless 
solution (4 mg/mL).  Mogamulizumab solution for infusion is formulated in 2.1 mmol/L sodium 
citrate buffer, 300 mmol/L glycine, and 0.2 mg/mL polysorbate 80 (Tween 80), pH 5.5, supplied 
in Type I glass vials. 
Mogamulizumab solution for infusion must be diluted prior to administration.  Do not shake the 
vials.  To prepare the infusion solution add the dose volume of Mogamulizumab to an infusion 
bag containing 0.9% Sodium Chloride Injection, USP.  PVC and non-PVC (polyolefin) IV bags 
may be used.  The final concentration of the infusion solution must be between 0.1 mg/mL to 3.0 
mg/mL.   
14.2.4 Stability and Storage  
Store intact vials between 2°C - 8°C (36°F - 46°F).  Do not freeze.  Protect from light by storing 
in the original box.   
If a storage temperature excursion is identified, promptly return Mogamulizumab to between 2-
8°C and quarantine the supplies. 


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After preparation, infuse the mogamulizumab solution immediately, or store under refrigeration 
at 2°C to 8°C (36°F to 46°F) for no more than 4 hours from the time of infusion preparation. Do 
not freeze. Do not shake. 
14.2.5 Administration procedures 
Infuse over at least 1 hour using an infusion set containing a low-protein binding 0.2 to 0.22 µm 
in-line filter.  Do not co-administer other drugs through the same infusion line.  Following the 
infusion, flush the IV line with normal saline. 
14.2.6 Incompatibilities 
No incompatibilities between mogamulizumab and polyvinylchloride (PVC) or non-PVC 
polyolefin bags and administration sets have been observed. No formal drug interaction studies 
have been performed with mogamulizumab. Please refer to the package insert and PDR for full 
drug interactions and toxicities. 
Please refer to the mogamulizumab package insert for complete information. 
 
 


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15 REFERENCES  
1. 
Malpica L, Pimentel A, Reis IM, Gotuzzo E, Lekakis L, Komanduri K, et al. 
Epidemiology, clinical features, and outcome of HTLV-1–related ATLL in an area of prevalence 
in the United States. Blood Advances. 2018;2(6):607-20. 
2. 
Shimoyama M, members of The Lymphoma Study G. Diagnostic criteria and 
classification of clinical subtypes of adult T-cell leukaemia-lymphoma. British journal of 
haematology. 1991;79(3):428-37. 
3. 
Fuji S, Fujiwara H, Nakano N, Wake A, Inoue Y, Fukuda T, et al. Early application of 
related SCT might improve clinical outcome in adult T-cell leukemia/lymphoma. Bone Marrow 
Transplant. 2016;51(2):205--11. 
4. 
Fujiwara H, Fuji S, Wake A, Kato K, Takatsuka Y, Fukuda T, et al. Dismal outcome of 
allogeneic hematopoietic stem cell transplantation for relapsed adult T-cell leukemia/lymphoma, 
a Japanese nation-wide study. Bone Marrow Transplant. 2017;52(3):484--8. 
5. 
Bazarbachi A, Suarez F, Fields P, Hermine O. How I treat adult T-cell 
leukemia/lymphoma. Blood. 2011;118(7):1736-45. 
6. 
Tsukasaki K, Utsunomiya A, Fukuda H, Shibata T, Fukushima T, Takatsuka Y, et al. 
VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan 
Clinical Oncology Group Study JCOG9801. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. 2007;25(34):5458-64. 
7. 
Bazarbachi A, Plumelle Y, Carlos Ramos J, Tortevoye P, Otrock Z, Taylor G, et al. 
Meta-analysis on the use of zidovudine and interferon-alfa in adult T-cell leukemia/lymphoma 
showing improved survival in the leukemic subtypes. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology. 2010;28(27):4177-83. 
8. 
Ishida T, Joh T, Uike N, Yamamoto K, Utsunomiya A, Yoshida S, et al. Defucosylated 
anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a 
multicenter phase II study. J Clin Oncol. 2012;30(8):837--42. 
9. 
Sharma K, Janik JE, O'Mahony D, Stewart D, Pittaluga S, Stetler-Stevenson M, et al. 
Phase II Study of Alemtuzumab (CAMPATH-1) in Patients with HTLV-1-Associated Adult T-
cell Leukemia/lymphoma. Clinical cancer research : an official journal of the American 
Association for Cancer Research. 2017;23(1):35-42. 
10. 
Ishida T, Fujiwara H, Nosaka K, Taira N, Abe Y, Imaizumi Y, et al. Multicenter Phase II 
Study of Lenalidomide in Relapsed or Recurrent Adult T-Cell Leukemia/Lymphoma: ATLL-
002. J Clin Oncol. 2016;34(34):4086--93. 
11. 
Tobinai K, Uike N, Saburi Y, Chou T, Etoh T, Masuda M, et al. Phase II study of 
cladribine (2-chlorodeoxyadenosine) in relapsed or refractory adult T-cell leukemia-lymphoma. 
Int J Hematol. 2003;77(5):512--7. 
12. 
Hermine O, Dombret H, Poupon J, Arnulf B, Lefrère F, Rousselot P, et al. Phase II trial 
of arsenic trioxide and alpha interferon in patients with relapsed/refractory adult T-cell 
leukemia/lymphoma. Hematol J. 2004;5(2):130--4. 


65 
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Version Date: 11/16/2020 
13. 
Ishitsuka K, Utsunomiya A, Katsuya H, Takeuchi S, Takatsuka Y, Hidaka M, et al. A 
phase II study of bortezomib in patients with relapsed or refractory aggressive adult T-cell 
leukemia/lymphoma. Cancer Sci. 2015;106(9):1219--23. 
14. 
Wilcox RA. Cutaneous T-cell lymphoma: 2017 update on diagnosis, risk-stratification, 
and management. Am J Hematol. 2017;92(10):1085--102. 
15. 
Duarte RF, Canals C, Onida F, Gabriel IH, Arranz R, Arcese W, et al. Allogeneic 
hematopoietic cell transplantation for patients with mycosis fungoides and Sézary syndrome: a 
retrospective analysis of the Lymphoma Working Party of the European Group for Blood and 
Marrow Transplantation. J Clin Oncol. 2010;28(29):4492--9. 
16. 
Dummer R, Quaglino P, Becker JC, Hasan B, Karrasch M, Whittaker S, et al. Prospective 
international multicenter phase II trial of intravenous pegylated liposomal doxorubicin 
monochemotherapy in patients with stage IIB, IVA, or IVB advanced mycosis fungoides: final 
results from EORTC 21012. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology. 2012;30(33):4091-7. 
17. 
Whittaker S, Hoppe R, Prince HM. How I treat mycosis fungoides and Sezary syndrome. 
Blood. 2016;127(25):3142-53. 
18. 
Duvic M, Hymes K, Heald P, Breneman D, Martin AG, Myskowski P, et al. Bexarotene 
is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: 
multinational phase II-III trial results. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. 2001;19(9):2456-71. 
19. 
Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S, et al. Phase IIb 
multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory 
cutaneous T-cell lymphoma. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology. 2007;25(21):3109-15. 
20. 
Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum MH, et al. Phase II 
multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for 
patients with cutaneous T-cell lymphoma. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. 2009;27(32):5410-7. 
21. 
Whittaker SJ, Demierre MF, Kim EJ, Rook AH, Lerner A, Duvic M, et al. Final results 
from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell 
lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. 2010;28(29):4485-91. 
22. 
Prince HM, Kim YH, Horwitz SM, Dummer R, Scarisbrick J, Quaglino P, et al. 
Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma 
(ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet 
(London, England). 2017;390(10094):555-66. 
23. 
Duvic M, Pinter-Brown LC, Foss FM, Sokol L, Jorgensen JL, Challagundla P, et al. 
Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated 
patients with cutaneous T-cell lymphoma. Blood. 2015;125(12):1883--9. 
24. 
Kim YH, Bagot M, Pinter-Brown L, Rook AH, Porcu P, Horwitz SM, et al. 
Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma 


66 
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Version Date: 11/16/2020 
(MAVORIC): an international, open-label, randomised, controlled phase 3 trial. The Lancet 
Oncology. 2018. 
25. 
Yoshie O. Expression of CCR4 in adult T-cell leukemia. Leukemia & Lymphoma. 
2005;46(2):185-90. 
26. 
Nakagawa M, Schmitz R, Xiao W, Goldman CK, Xu W, Yang Y, et al. Gain-of-function 
<em>CCR4</em> mutations in adult T cell leukemia/lymphoma. The Journal of experimental 
medicine. 2014;211(13):2497-505. 
27. 
Duvic M, Pinter-Brown LC, Foss FM, Sokol L, Jorgensen JL, Challagundla P, et al. 
Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated 
patients with cutaneous T-cell lymphoma. Blood. 2015;125(12):1883-9. 
28. 
Wang L, Ni X, Covington KR, Yang BY, Shiu J, Zhang X, et al. Genomic profiling of 
Sezary syndrome identifies alterations of key T cell signaling and differentiation genes. Nature 
genetics. 2015;47(12):1426-34. 
29. 
Antoniu SA. Mogamulizumab, a humanized mAb against C-C chemokine receptor 4 for 
the potential treatment of T-cell lymphomas and asthma. Curr Opin Mol Ther. 2010;12(6):770--
9. 
30. 
Ishii T, Ishida T, Utsunomiya A, Inagaki A, Yano H, Komatsu H, et al. Defucosylated 
humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for 
adult T-cell leukemia/lymphoma. Clin Cancer Res. 2010;16(5):1520--31. 
31. 
Sakamoto Y, Ishida T, Masaki A, Murase T, Yonekura K, Tashiro Y, et al. CCR4 
mutations associated with superior outcome of adult T-cell leukemia/lymphoma under 
mogamulizumab treatment. Blood. 2018:2018--02. 
32. 
Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer 
therapy and vaccine design. Nature reviews Immunology. 2006;6(8):595-601. 
33. 
Lugli E, Goldman CK, Perera LP, Smedley J, Pung R, Yovandich JL, et al. Transient and 
persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates. Blood. 
2010;116(17):3238-48. 
34. 
Sneller MC, Kopp WC, Engelke KJ, Yovandich JL, Creekmore SP, Waldmann TA, et al. 
IL-15 administered by continuous infusion to rhesus macaques induces massive expansion of 
CD8+ T effector memory population in peripheral blood. Blood. 2011;118(26):6845--8. 
35. 
Waldmann TA, Lugli E, Roederer M, Perera LP, Smedley JV, Macallister RP, et al. 
Safety (toxicity), pharmacokinetics, immunogenicity, and impact on elements of the normal 
immune system of recombinant human IL-15 in rhesus macaques. Blood. 2011;117(18):4787-95. 
36. 
Waldmann TA. The biology of IL-15: implications for cancer therapy and the treatment 
of autoimmune disorders. The journal of investigative dermatology Symposium proceedings. 
2013;16(1):S28-30. 
37. 
Conlon KC, Lugli E, Welles HC, Rosenberg SA, Fojo AT, Morris JC, et al. 
Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine 
production during first-in-human clinical trial of recombinant human interleukin-15 in patients 
with cancer. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. 2015;33(1):74-82. 


67 
Abbreviated Title: IL-15+Mogamulizumab  
Version Date: 11/16/2020 
38. 
Miller JS, Morishima C, McNeel DG, Patel MR, Kohrt HEK, Thompson JA, et al. A 
First-in-Human Phase I Study of Subcutaneous Outpatient Recombinant Human IL15 (rhIL15) 
in Adults with Advanced Solid Tumors. Clinical Cancer Research. 2018;24(7):1525-35. 
39. 
Conlon KC, Dubois S, Lee C-cR, Fleisher T, Hsu JI, Waldmann TA. Abstract 1596: 
Phase I trial of recombinant human Interleukin 15 (rhIL-15) administered as continuous 
intravenous infusion (CIV) for 10 days (240 hours) in patients with refractory metastatic cancers. 
Cancer Research. 2017;77(13 Supplement):1596-. 
40. 
Miljkovic MD, Zhang M, Conlon KC, Waldmann TA. IL-15-enhanced antibody-
dependent cellular cytotoxicity mediated by NK cells and macrophages: Implications for 
immunotherapy of T-cell lymphoma [abstract].  In: Proceedings of the 2018 AACR Meeting on 
Advances in Malignant Lymphoma; 2018 June 22 - 26; Boston, Massachusetts: Philadelphia 
(PA): AACR; 2018. 
41. 
Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, et al. Clinical End 
Points and Response Criteria in Mycosis Fungoides and Sézary Syndrome: A Consensus 
Statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous 
Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European 
Organisation for Research and Treatment of Cancer. Journal of Clinical Oncology. 
2011;29(18):2598-607. 
42. 
Cook LB, Fuji S, Hermine O, Bazarbachi A, Ramos JC, Ratner L, et al. Revised Adult T-
Cell Leukemia-Lymphoma International Consensus Meeting Report. Journal of Clinical 
Oncology. 2019. 
43. 
Tsukasaki K, Hermine O, Bazarbachi A, Ratner L, Ramos JC, Harrington W, et al. 
Definition, Prognostic Factors, Treatment, and Response Criteria of Adult T-Cell Leukemia-
Lymphoma: A Proposal From an International Consensus Meeting. Journal of Clinical 
Oncology. 2009;27(3):453-9. 
44. 
Khodadoust MS, Rook AH, Porcu P, Foss F, Moskowitz A, Shustov AR, et al. 
Pembrolizumab For Treatment Of Relapsed/Refractory Mycosis Fungoides And Sézary 
Syndrome: Clinical Efficacy In A CITN Multicenter Phase 2 Study. 3rd World Congress of 
Cutaneous Lymphomas. 2016;Abstract O-10. 
45. 
Agresti A, Coull BA. Approximate Is Better than "Exact" for Interval Estimation of 
Binomial Proportions. The American Statistician. 1998;52(2):119-26. 
46. 
Ishitsuka K, Yurimoto S, Kawamura K, Tsuji Y, Iwabuchi M, Takahashi T, et al. Safety 
and efficacy of mogamulizumab in patients with adult T-cell leukemia–lymphoma in Japan: 
interim results of postmarketing all-case surveillance. International journal of hematology. 
2017;106(4):522-32. 
 


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16 APPENDICES 
16.1 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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16.2 APPENDIX B:  ASSAY FOR ADCC 
 
• Peripheral blood mononuclear cells (PBMCs) should be isolated by Ficoll-High-Paque 
Density Gradient Centrifugation. 
• The viable cells should be viably frozen and stored in liquid nitrogen. 
• The ADCC assay will be performed on the same occasion for all samples of a given patient. 
• Vials of frozen cells will be thawed using standard procedures 18 hours before the assay in 
accordance with our experience with normal donors. 
• 1.5 million of patient’s PBMCs obtained before and on day 15 following IL-15 injection 
will be tested in aliquots as follows: 
o Tested alone 
o Tested with untreated PD-L1-expressing Raji cells and with PD-L1-expressing Raji 
cells coated with mogamulizumab for 5 hours. 
o In addition, we may utilize an ATL cell line in addition to Raji cells. These cell 
populations will be stained with CD107, CD3, CD56 and CD94. 
 
 


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


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


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Version Date: 11/16/2020 
Response in Blood* 
Response 
Definition 
CR† 
B0 
PR‡ 
>50% decrease in quantitative measurements of blood tumor burden from baseline in 
those with high tumor burden at baseline (B2) 
SD 
Fails to attain the criteria for CR, PR, and PD 
PD§ 
B0 to B2 or 
> 50% increase from baseline and at least 
5,000 neoplastic cells/μL or 
Loss of response: in those with PR who were originally B2 at baseline, > 50% increase 
from nadir and at least 5,000 neoplastic cells/μL 
Relapse 
Increase of neoplastic blood lymphocytes to ≥ B1 in those with CR 
Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive 
disease. 
* As determined by absolute number of neoplastic cells/μL 
† If a bone marrow biopsy was performed at baseline and determined to unequivocally be indicative of 
lymphomatous involvement, then to confirm a global CR where blood assessment now meets criteria 
for B0, a repeat bone marrow biopsy must show no residual disease or the response should be 
considered a PR only. 
‡ There is no PR in those with B1 disease at baseline as the difference within the range of neoplastic 
cells that define B1 is not considered significant and should not affect determination of global 
objective response. 
§ Whichever occurs first 
 
 


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Version Date: 11/16/2020 
16.4 APPENDIX D:  IL-15 DILUTION INSTRUCTIONS 
All dose preparations will be performed aseptically in a laminar flow hood in compliance with all 
legal requirements and in accordance with guidelines of recognized organizations.  Vials of IL-15 
do not contain any preservatives. 
0.1% human serum albumin (HSA) in 5% dextrose in water, USP (D5W), should be used for the 
dilutions listed below. 
To prepare an IL-15 dose for Dose Level 1 (2 mcg/kg) OR Dose Level 2 (4 mcg/kg): 
1. Thaw vial(s) of IL-15, 147 mcg/0.3 mL (490 mcg/mL) at room temperature. 
2. Using a 27-gauge needle, slowly draw up the required dose in a 1 mL syringe. Doses should 
be rounded to the nearest 0.01 mL.  
3. Add the calculated volume of diluted IL-15 to 0.1% HSA in D5W in a PVC or polyolefin 
bag. 
4. Label the bag with a 4-hour beyond-use date. The infusion may be started within 4 hours 
at room temperature, or within 24 hours if bag was kept at 2-8°C. The infusion must be 
completed within 24 hours of initiation. 
Administered dose = _______ kg (Patient’s weight) X _______ mcg/kg (DL) = _______ mcg 
Prepared dose = _______ mcg (Administered dose) + 10 mcg (Overfill dose) = _______ mcg 
IL-15 volume = _______ mcg (Prepared dose)  490 mcg/mL (vial concentration) = _______ mL 
Total infusion volume =  
     _______ mcg (Prepared dose)  1 mcg/mL (final infusion concentration) = _______ mL 
Diluent volume =  
     _______ mL (Total infusion volume) - _______ mL (IL-15 volume) = _______ mL 
Please note: The dosing examples listed below are for the 147 mcg/0.3 mL in a 3mL vial size and 
dilution ONLY. The following dosing chart may be used as a reference, but doses should always 
be re-calculated at the time of preparation. In the future, different concentrations of IL-15 may be 
available and doses and dilutions will need to be recalculated. 
Patient’s 
weight 
IL-15 volume 
(490 mcg/ml) 
Diluent volume 
Total infusion volume  
(1 mcg/ml) 
DL1 
DL2 
DL1 
DL2 
DL1 
DL2 
60 kg 
0.27 
0.51 
129.73 
249.49 
130 ml 
250 ml 
75 kg 
0.33 
0.63 
159.67 
309.37 
160 ml 
310 ml 
90 kg 
0.39 
0.76 
189.61 
369.24 
190 ml 
370 ml 
105 kg 
0.45 
0.88 
219.55 
429.12 
220 ml 
430ml 
Dose Level 1 (DL1) = 2 mcg/kg, Dose Level 2 (DL2) = 4 mcg/kg 
Dose calculation for obese patients: 
For patients whose body mass index (BMI) is >30 kg/m2, the factor for body weight used in 
calculating IL-15 doses will be determined as follows: 
Corrected body weight (kg) = 30 x (height [m])2 


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Version Date: 11/16/2020 
16.5 APPENDIX E: ASSAY FOR ANTIBODIES TO RHIL-15 
 
• Plates are coated with human IL-15 for 3 hours at 37°C, washed, blocked with 3% FBS 
and washed again. 
• A standard curve for assay quantitation and quality control is constructed using serial 
dilutions of a commercial affinity purified goat anti-human IL-15 that is diluted in heat-
inactivated normal human serum.  The standard curve samples are incubated for 2 hours at 
37°C and washed. 
• Biotin conjugated IL-15 is added to each well, incubated 2 hours at 37°C, and the plates 
are washed. 
• Alkaline phosphatase–conjugated streptavidin is added to each well for 2 hours at 37°C 
and then washed. 
• The assay is developed with the addition of diethanolamine buffer with p-Nitrophenyl 
Phosphatase for 1 hour at 37°C and then immediately read at 405 nm. 
• To detect antibodies to human IL-15 in test samples, serum from the test subject will be 
assayed in duplicate at dilutions of 1/3 and 1/9 concomitantly with the standard curve 
samples as above and the resultant OD obtained used to quantitate the level of antibody 
present. 
 

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/16/2020
Page 1 of 25
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:
Milos Miljkovic, M.D. 
STUDY TITLE:
Phase 1 Study of Recombinant Human IL-15 (rhIL-15) and 
Mogamulizumab for Patients with Refractory or Relapsed 
Adult T-Cell Leukemia and Mycosis Fungoides/Sézary 
Syndrome
INSTITUTE/CENTER: 
National Cancer Institute
Cohort: Standard 
Consent Version:  11/16/2020
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator: 
Milos Miljkovic, M.D., MSc
Phone:  301-250-5216
Email:  milos.miljkovic@nih.gov 
KEY INFORMATION ABOUT THIS RESEARCH 
This consent form describes a research study and is designed to help you decide if you would 
like to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
This section provides the information we believe is most helpful and important to you to in 
making your decision about participating in this study. Additional information that may help 
you make a decision can be found in other sections of the document. Taking part in research at 
the NIH is your choice.
You are being asked to take part in this study because you have relapsed adult T-cell 
leukemia/lymphoma (ATLL) or mycosis fungoides/Sézary syndrome (MF/SS), that has not 
responded to standard treatments.
The purpose of this study is to test whether the combination of IL-15 and mogamulizumab can 
be used safely in people with your disease.  Mogamulizamab used by itself is approved to treat 
people with relapsed or refractory mycosis fungoides or Sezary syndrome, but not ATLL.  The 
combination of the 2 drugs has not been used before. We will also look at if they are effective 
in treating your disease.  The goals of this study are to determine the safe dose of IL-15 when 
combined with mogamulizumab to be used in humans, to identify the side effects of the 
combination treatment and its effects on your immune system, and to determine if this treatment 
has activity against your cancer.
Recombinant human interleukin 15 (IL-15) is considered investigational, which means that it 
has not been approved by the U.S. Food and Drug Administration (FDA) to treat ATLL or 
mycosis fungoides/ Sézary syndrome (MF/SS). However, mogamulizumab is approved  for the 
treatment of relapsed and/or refractory mycosis fungoides/ Sézary syndrome after at least 1 prior 
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failed therapy. In clinical trials, up to 50% of patients with MF/SS had improvement in skin 
lesions after treatment with mogamulizumab. It also delayed disease progression by 7 months 
on average but hasn’t been shown to prolong life. We are testing it in this research study to see 
whether giving recombinant human interleukin 15 (IL-15) in combination with mogamulizumab  
will improve outcome of therapy for your disease. Since IL-15 and mogamulizumab have never 
before been given together, this treatment is considered investigational, or experimental. The 
FDA has given us permission to use IL-15 and mogamulizumab together in this study.  
There are other drugs and treatments that may be used for your disease, and these can be 
prescribed by your regular cancer doctor, if you are not in this study. These drugs all work in 
different ways in the body as compared to IL-15 and mogamulizumab, and with different side 
effects. In clinical trials, they were able to shrink tumors in 20-30% of patients, and delayed 
progression of disease in a majority of patients by 2-3 months, but none of the other available 
treatments has been shown to prolong life. If you would prefer other drugs or treatments, you 
should consider not joining this study.  
If you decide to join this study, here are some of the most important things that you should know 
that will happen:

In the first groups of participants enrolled (dose escalation), we want to find out the 
highest dose of IL-15 that is safe to use with mogamulizumab. We will test increasing 
doses of IL-15 in small groups. We also want to find out what kind of side effects IL-15 
and mogamulizumab might cause. After the first part is done, we will enroll additional 
participants in a second portion of the study (dose expansion) to learn more about 
whether IL-15 and mogamulizumab can shrink your tumor(s).

Before you begin the study, we will perform tests to find out whether you are eligible to 
participate (screening) that will include tests such as:  a complete physical examination, 
blood and urine tests, bone marrow testing and imaging.  Some of these may be done on 
a separate screening protocol before signing the informed consent document for this 
study.

If you are eligible to receive treatment, during the study, both drugs will be administered 
as intravenous infusions for up to six cycles of 28 days each. You will receive IL-15 over 
the course of the first five days of each cycle, and mogamulizumab on days 1, 8, 15 and 
22 of cycle 1 and only on days 1 and 15 of all cycles that follow.

You will be required to be hospitalized at the NIH Clinical Center for one week to receive 
the first cycle of IL-15. As long as you are accompanied by a caregiver or unless decided 
otherwise by the doctor, you will have the option of receiving the remaining cycles as 
an outpatient, but will still need to report to the hospital each day for the first five days 
of each cycle.

You may experience side effects from taking part in this study. Some can be mild or very 
serious, temporary, long-lasting, or permanent, and may include death.  Examples of 
some of the side effects that you may have include: changes in blood counts (such as low 
red or white cells), gastrointestinal (such diarrhea, nausea, vomiting), rashes, fatigue, 
and infections. Since this is the first time that IL-15 and mogamulizumab are 
administered together, there may be side effects that we cannot predict.
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
You will be seen regularly during the study.  You will have clinical, laboratory, and 
imaging tests to see how you are doing and to see if the treatment is having any effect 
on your disease. We will also collect required samples from you (including blood, bone 
marrow, and tumor biopsies) for both clinical and research purposes.

After the study treatment has ended, we will need to see you at the NIH Clinical Center 
periodically for up to about four (4) years to assess your health and to determine what 
impact, if any, the study drugs may have had on your disease. After this time, we may 
contact you to see how you are doing for the rest of your life.  
Just as we do not know what side effects you might have, we cannot know if you may benefit 
from taking part in this study. If you do not benefit directly, this study and the results from our 
research may help others in the future.
You are free to stop participating in the trial at any time.  If you decide to stop, the study doctor 
may ask you to agree to certain tests to make sure it is safe for you to stop.
The remaining document will now describe more about the research study.  This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information described in this document. Some people have personal, religious, or ethical 
beliefs that may limit the kinds of medical or research treatments they would want to receive (such 
as blood transfusions). Take the time needed to ask any questions and discuss this study with NIH 
staff, and with your family, friends, and personal health care providers.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
This is a research study. The purpose of this research study is to develop a new treatment for adult 
T-cell leukemia/lymphoma (ATLL) and mycosis fungoides/Sézary syndrome (MF/SS), that is 
more effective than existing therapies. 
We are asking you to join this research study because you have relapsed and/or refractory ATLL 
or mycosis fungoides/ Sézary syndrome for which no standard therapy exists, or standard therapy 
has failed.
IL-15 is a man-made version of a small protein (cytokine) that is naturally produced in your body 
by certain white blood cells and increases the activity and strength of the immune system. Patients 
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with cancer can have a weak immune system. This weakness can be caused by the cancer itself, or 
by treatments such as radiation, chemotherapy or other drugs that work against the immune system. 
It is hoped that IL-15 can “boost” or strengthen your immune system as it fights against cancer. In 
fact, in other clinical trials, all of the patients who received IL-15 showed an increase in the number 
of their immune system cells. In some of the patients, the growth was dramatic. We hope the same 
is true in this study.  
Mogamulizumab is a monoclonal antibody that works by attaching to a protein on your tumor cells 
and marking the tumor cell for destruction by other cells of the immune system. Monoclonal 
antibodies are purified proteins that are specially made to attach to pieces of foreign substances 
(such as cancer cells). Recent evidence shows that IL-15 boosts the number of immune system 
cells which are responsible for destroying tumor cells with antibodies attached.
Recombinant human interleukin 15 (IL-15) is considered investigational, which means that it has 
not been approved by the U.S. Food and Drug Administration (FDA) to treat ATLL and mycosis 
fungoides/ Sézary syndrome (MF/SS). However, mogamulizumab is approved  for the treatment 
of relapsed and/or refractory mycosis fungoides/ Sézary syndrome after at least 1 prior failed 
therapy. In clinical trials, up to 50% of patients with MF/SS had improvement in skin lesions after 
treatment with mogamulizumab. It also delayed disease progression by 7 months on average but 
hasn’t been shown to prolong life.  We are testing it in this research study to see whether giving 
recombinant human interleukin 15 (IL-15) in combination with mogamulizumab will improve 
outcome of therapy for your disease. Since IL-15 and mogamulizumab have never before been 
given together, this treatment is considered investigational, or experimental. The FDA has given 
us permission to use IL-15 and mogamulizumab together in this study
WHAT WILL HAPPEN DURING THE STUDY?
If you decide to take part in this study, you will be asked to: 

Receive IL-15 as a continuous intravenous infusion (civ) over 24 hours on days 1-5 of a 
28-day cycle, together with intravenous infusion (IV) of mogamulizumab. 
Mogamulizumab will be given at a set dose on days 1, 8, 15 and 22 of cycle 1 and only on 
days 1 and 15 of all cycles that follow (up to 6 cycles total).  Mogamulizumab will be 
infused over at least 1 hour.

In order to confirm that the doses are safe, participants will be enrolled in groups:
o
Dose escalation group: First, a groups of 3-6 study participants will receive IL-15 
and mogamulizumab. The dose of IL-15 will be escalated (or increased) in a new 
group of participants, as long as it is safe to do so, until the best dose of IL-15 is 
found.  All participants will receive the same dose of mogamulizumab.  Each group 
of participants will be checked closely for side effects for at least 4 weeks before 
enrolling at the next higher dose of IL-15 with mogamulizumab.
o
Dose expansion group: Once the dose of IL-15 with mogamulizumab is determined, 
up to 9 more participants will receive IL-15 dose with mogamulizumab to learn 
more about the drugs and their effect on the types of cancer being studied.
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
All participants will be given treatment on an inpatient basis for the first week of the first 
cycle, and on an outpatient basis for subsequent weeks and cycles unless decided 
otherwise by the physician, based on clinical judgement. Treatment can continue for up 
to 6 (28-day) cycles. You will only be eligible for outpatient treatment if you have a 
caregiver to accompany you and help you manage the ambulatory infusion pump.

If IL-15 needs to be discontinued, you may be able to continue on mogamulizumab alone 
if your doctor thinks this is appropriate. Your study team will discuss this with you.
Another way to find out what will happen to you during the study is to read the chart below.  Start 
reading at the left side and read across to the right, following the lines and arrows:  
 
Screening  
Before you begin the study, you will have several tests performed to check whether the study is 
suitable for you. Some of these will be done before signing the informed consent document for 
this study. This is called screening. Your doctor will review your medical history and the drugs 
that you are currently taking as well as the previous treatments of your disease to determine 
whether you can participate in this study.
A previously collected blood sample or small part of your tumor tissue (depending on your disease) 
that was collected from any previous surgery or biopsy will be tested at NCI to confirm your 
diagnosis. If no sample is available or if additional sample is needed to confirm your diagnosis, a 
fresh blood sample or biopsy will be taken. A biopsy will also be done prior to treatment if there 
is not enough tissue available from your diagnostic biopsy for study purposes (seeing whether the 
target of mogamulizumab can be found on the surface of the tumor cell; the results of this test will 
not affect your eligibility). Any leftover tissue may be stored for future research studies, but a 
biopsy will not be performed solely for these studies. You will be told if this mandatory biopsy is 
needed. 
Some of these tests or procedures are part of regular care and may be done even if you are not 
being considered to join the study. If you have had some of these tests or procedures recently, they 
may or may not have to be repeated. The following tests and procedures will be performed prior 
to starting treatment:
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
Your medical history, including previous cancer treatments, any current or previous 
medications (prescription, supplement, and over-the-counter medicines), will be reviewed. 
If you have medical records from another clinic or hospital, you will be asked to get copies 
of these records, or your study doctor may be able to request them on your behalf.

A complete physical examination will be performed that will include your vital signs 
(blood pressure, pulse, body temperature, and respiratory rate) and recording your height 
and weight, and evaluation of your ability to carry out daily activities.

Blood and urine tests will be collected to:
o
measure your liver, kidney, and thyroid function, red and white blood cells, 
platelets, electrolytes and others;
o
measure how well your blood clots;
o
test for human T-lymphotropic virus (HTLV) and Hepatitis B infection
o
test for human immunodeficiency virus (HIV) infection. This is the virus that 
causes AIDS. If you are infected with HIV you will not be able to participate in this 
study. We will tell you what the results mean, how to find care, how to avoid 
infecting others, how we report HIV infection, and the importance of informing 
your partners at possible risk because of your HIV infection.
o
run routine tests done in people with your type of cancer to confirm your diagnosis 
and the status of your disease.

If you have received a live vaccine within 30 days of starting study treatment, you will not 
be able to immediately participate. Examples of live vaccines include but are not limited 
to: the intranasal influenza vaccine known as Flu-Mist, measles, mumps, rubella, 
varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.

For females of child-bearing potential, a pregnancy test will be done (urine or blood 
sample). You will not be able to participate if you are pregnant or you are breast feeding 
because we don’t know how this medicine would affect your baby or your unborn child.

Pulmonary function test to test how well your lungs function. 

An electrocardiogram (EKG) and echocardiogram (ECHO) to check your heart function.

Bone marrow testing and imaging will be done to check your disease, as needed.  
o
A bone marrow aspiration and/or biopsy will be done prior to starting treatment if 
not done within the last 3 months since completing the last treatment received to 
confirm the stage and status of your disease. These are done by numbing your 
hipbone using a small needle containing local anesthesia, and then a needle will be 
put into the hipbone, and a small amount of bone marrow will be taken out through 
the needle
o
Imaging will include a CT scan of neck, chest, abdomen and pelvis, and a PET/CT 
scan of the torso. Other body areas may be imaged if clinically indicated. For 
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participants with suspected involvement of disease in the central nervous system, 
an MRI of the brain will be taken.
During the study
If the screening process shows that you are eligible for the study, and you choose to be in it, you 
may need to have a few additional standard tests completed if not done recently. You will also 
have additional samples collected for research tests. 
You will come to the NIH Clinical Center for treatment and procedures. The treatment will be 
given in the inpatient setting for the first week of the first cycle and then in the outpatient setting 
at the Clinical Center for the remainder of the study. You will be given IL-15 as a continuous 
intravenous infusion as described in section “What will happen during the study?”, over a 24-hour 
period. Your dose of IL-15 will be assigned depending on what dose level is open at the time of 
your enrollment (gradually increasing doses during the dose escalation or the maximum tolerated 
dose during the dose expansion portion). Mogamulizumab is also an IV infusion and will be given 
to you over about a 1-hour period.
A midline catheter may need to be inserted for each IL-15 infusion and maintained for the duration 
of the infusion. If you receive part of the treatment as an outpatient, you will get training on how 
to maintain the midline catheter and the ambulatory infusion pump before being discharged from 
the hospital.  For the first five days of each cycle, you will need to report to the day hospital each 
day for an IL-15 bag change. Each IL-15 infusion is expected to start between 8am and 8pm, and 
bags will be replaced at the same time each day; however, if for any reason IL-15 infusion begins 
after hours (8pm-8am), you will need to come into the hospital during the night for nursing staff 
to manage the pump. 
We will give you standard pre-medications before the IL-15 and mogamulizumab infusions. These 
may include acetaminophen (Tylenol), nonsteroidal anti-inflammatory drugs (NSAIDs such as 
ibuprofen) and/or an antihistamine (Benadryl). These are given to help prevent infusion related 
side effects. Your study doctor or a member of the study staff can explain these to you in more 
detail. Because of the unknown side effects, we will ask you to stay at the clinic for an additional 
30 minutes after your mogamulizumab infusion so we may monitor you.
Similar to the tests done at the beginning of the study, the following will be repeated during the 
study to see how you are doing and how the cancer may be responding to treatment:

Review of medical history, and a physical exam (check weight and vitals), including 
obtaining information about how you function in your daily activities, side effects and 
symptoms, and review of medications

Routine blood and urine tests

Bone marrow testing and imaging:
o
Bone marrow testing will be repeated at the end of study treatment if needed to 
confirm response, if and only if other tests show a complete response. 
o
Tumor imaging (such as, CT scan, PET/CT) will be done to assess the sites of your 
disease every 8 weeks during treatment An MRI of the brain and lumbar puncture 
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is only required in participants with neurological symptoms. In participants with 
disease primarily on their skin, clinical photography and evaluation by a 
dermatologist will be used to assess the disease sites present on the skin, Other body 
areas may be imaged if clinically indicated. If your disease does not progress, 
follow-up imaging may be done every 60 days for the first  6 months after treatment, 
then every 90 days for 2 years and then every six months for another 2 years and 
then annually until you start another treatment, your disease progresses or the study 
ends.
Additional research testing
In addition, the following research samples will be collected, and some are optional:

Blood Samples: Blood will be collected for required research studies to learn more about 
how IL-15 and mogamulizumab affect your cancer at the beginning of the study prior to 
starting treatment, during the first cycle of treatment, and at about the same time as each 
imaging assessment. If at any time your doctor thinks you have responded or may have 
progressed during or after treatment, we will again collect samples. Optional blood samples 
may be obtained more frequently throughout the treatment cycles depending upon the days 
that you are seen in the clinic.  You will be told which samples are required and which are 
optional.

Cheek Swab or Saliva Samples: A required cheek swab and/or saliva sample to collect 
normal tissue will be done, likely at the beginning of the study only. To obtain a cheek 
swab, a small brush is rubbed against the inside of the cheek to wipe off some cells. To 
obtain saliva, a special collection tube will be used and it may take a few minutes to collect 
the saliva.

Tumor Biopsies: A biopsy will be mandatory prior to treatment if we do not have sufficient 
material from your prior biopsies to perform some research studies. All other biopsies are 
an optional part of the study and you will only be asked to do so if it is felt to be safe. We 
will ask you to undergo a tumor biopsy during the first Cycle of treatment and again if your 
disease should progress during or after treatment on this study. The tissue is being collected 
for special research tests. Your doctor or the study team will discuss the biopsies with you. 
The biopsies to be performed are exclusively for research purposes and will not benefit 
you. They might help other people in the future. You may agree to biopsies now and change 
your mind later. If at any time you do not want to have a biopsy done, please tell us.
Usually tissue can be obtained safely and comfortably with local anesthesia. If you require 
sedation before undergoing a biopsy, you will be informed of the risks and you will be 
asked to sign an additional consent prior to undergoing the procedure. Biopsies will NOT 
be done on this study if they require general anesthesia. We may ask that you have 
ultrasound to help clearly locate your tumor when doing a biopsy.  
All of your samples collected for research purposes on this study may be used to look for specific 
changes in the DNA in tumors that could be used to develop new ways of diagnosing and treating 
cancer. DNA (also called deoxyribonucleic acid) in the cells carries genetic information and passes 
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it from one generation of cells to the next – like an instruction manual. Normal tissue contains the 
DNA (instructions) that you were born with, DNA in tumor cells has changed – or mutated – and 
we think that change in the DNA is what causes tumors to form and to grow. 
To look at your DNA, we may do what is called “whole genome sequencing.”  This where we will 
do special tests in the lab to look at the entire sequence, or order, of how your DNA is put together.  
This is what makes you unique.  
To determine which parts of the DNA have mutated, we will compare the DNA in your tumor cells 
to DNA from your normal cells. We will then analyze the results from similar tumors to see if 
there are any changes in the DNA that are common to a particular type of tumor. To examine the 
tumor and normal tissue we may use several different techniques depending on the type of tissue 
we collect. These could include growing cell lines (cells which keep dividing and growing in the 
laboratory, sometimes for years allowing us to continually study those cells), xenograft studies 
(placing or growing cells in another animal, such as mice), and looking in detail at the parts of the 
genes that produce specific proteins.
However, you should know that the analyses that we perform in our laboratory are for research 
purposes only; they are not nearly as sensitive as the tests that are performed in a laboratory that 
is certified to perform genetic testing or testing for routine clinical care. For these reasons, we will 
not give you the results of the research tests done on your research samples in most cases.  There 
may be exceptions to what we share with you and this is described later in this consent form in the 
section for “Return of research results”.
When you are finished taking the drugs (treatment)
When you finish taking the experimental therapy, we will ask you to come to the clinic for follow-
up visits and assessments at about the following times after treatment: every 60 days for the first 
6 months, then every 90 days for 2 years and then every six months for another 2 years. After 
almost 5 years we may contact you by phone or by email to see how you are doing until you start 
another treatment, your disease progresses, or the study ends. Only in certain cases, a participant 
may be asked to come in annually indefinitely. These clinic visits will include having required 
blood samples collected for routine analysis and for research, and may include CT or PET/CT 
scans. Visits usually take about 3 hours but should take no longer than 8 hours. 
HOW LONG WILL THE STUDY TAKE?
If you agree to take part in this study, your involvement will last for at least four years.
HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY?
Approximately 20 people will participate in this study at the NIH. 
WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY?
If you choose to take part in this study, there is a risk that the recombinant human IL-15 may not 
be as good as the usual approach for your cancer or condition at shrinking or stabilizing your 
cancer.
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You also may have the following discomforts:

Spend more time in the hospital or doctor’s office.

Be asked sensitive or private questions about things you normally do not discuss.

May not be able to take part in future studies.
The recombinant human IL-15 used in this study may affect how different parts of your body work 
such as your liver, kidneys, heart, and blood.  The study doctor will test your blood and will let 
you know if changes occur that may affect your health.
There is also a risk that you could have side effects from the study drug(s)/study approach.
Here are important things to know about side effects:

The study doctors do not know who will or will not have side effects.

Some side effects may go away soon, some may last a long time, and some may never go 
away.

Some side effects may make it hard for you to have children.

Some side effects may be mild.  Other side effects may be very serious and even result in 
death.
You can ask your study doctor questions about side effects at any time.  Here are important ways 
to make side effects less of a problem:

If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect.

Your study doctor will work with you to treat your side effects.

Your study doctor may adjust the study drugs to try to reduce side effects.
The tables below show the most common and the most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you.
Risks of IL-15
You may have side effects from the IL-15 while on the study. We pay close attention to any side 
effects you have. However, we don’t know all the side effects that may happen. Side effects may 
be mild or very serious. We may give you medicines to help lessen side effects. Many side effects 
go away soon after you stop taking the IL-15. In some cases, side effects can be serious, long 
lasting, or may never go away. It is possible that IL-15 could increase the growth of your leukemic 
cells, that is the IL-15 could make your cancer worse. There also is a risk of death.
Please talk to us about any symptoms you have while you are in the study.   
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In studies with humans, common and not very common risks and side effects related to the IL-15 
included the following:
POSSIBLE, SOME MAY BE SERIOUS

Anemia (low red blood cells) which may require blood transfusion

Abnormal heartbeat

Pain in belly

Diarrhea, nausea, vomiting

Chills, tiredness, fever

Swelling of arms, legs

Swelling and redness at the site of the medication injection

Severe blood infection

Bruising, bleeding

Infection, especially when white blood cell count is low

Muscle weakness

Dizziness, headache

Shortness of breath

Dry skin

Rash

Fluid in the organs which may cause low blood pressure, shortness of breath, swelling of 
ankles

High blood pressure which may cause blurred vision

Low blood pressure which may cause feeling faint

Increases in blood levels of liver function tests, which may indicate damage to the liver.
Other risks seen with IL-15 that are possibly related to the drug include:

Chest pain

bronchopulmonary hemorrhage and diffuse alveolar hemorrhage (bleeding in the lungs)

Confusion, psychosis (i.e., delusions, hallucinations)

Kidney failure - signs of kidney problems may include: decrease in the amount of urine, 
blood in your urine, ankle swelling. Severe kidney failure requiring hemodialysis has 
occurred when IL-15 was given with mogamulizumab, and may have been caused by IL-
15-associated capillary leak syndrome (fluid in the organs which may cause low blood 
pressure, shortness of breath, swelling of ankles).

Papilledema (changes in vision due to increased pressure in the brain)

Uveitis (inflammation of the eye – symptoms may include redness, pain, blurred vision)
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
Pneumonitis (inflammation of the lungs) - symptoms may include new or worsening 
cough, chest pain, shortness of breath.

Inflammation of the lining of the first part of the small intestine symptoms may include 
nausea, vomiting, stomach burning, pain, indigestion

Liver damage which may cause yellowing of eyes and skin, swelling and may result in 
liver failure

Decreases in blood levels of albumin, phosphorus (these are standard blood tests)

Low number of white blood cells, cells that help fight infection (lymphopenia, 
leukopenia, neutropenia) 

Low platelets, cells that help blood to clot (thrombocytopenia)

Low blood oxygen – symptoms may include changes in skin color, confusion, cough, fast 
heartbeat, shortness of breath

Immune related adverse events: hives, hypothyroidism and production of autoantibodies 
– symptoms made include joint pain, tiredness fever, rashes,  allergy-type symptoms, 
muscle weakness
Risk of Mogamulizumab
You may have side effects from the mogamulizumab while on the study. Mogamulizumab may 
cause serious side effects that can be severe or life-threatening including skin problems, infusion 
reactions, infections, autoimmune problems, and complications from stem cell transplant.
Please talk to us about any symptoms you have while you are in the study.   
In studies with humans, common and not very common risks and side effects related to the 
mogamulizumab included the following:
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OCCASIONAL, SOME MAY BE SERIOUS  
In 100 people receiving mogamulizumab, from 4 to 20 may have:

Nausea

Tiredness, fever

Flu-like symptoms including chills, body aches, muscle pain

Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat

Infection, especially when white blood cell count is low

Bruising, bleeding

Pain in joints

Muscle weakness

Damage to organs (lungs, heart, others) which may cause shortness of breath

Rash, skin changes
RARE, AND SERIOUS
In 100 people receiving mogamulizumab, 3 or fewer may have:

Chest pain

Heart attack, heart failure which may cause shortness of breath, swelling of ankles, 
cough or tiredness

Damage to organs in the body when donor cells attack host organs which may cause 
yellowing of eyes and skin, itchy dry skin, diarrhea 

Kidney damage which may require dialysis

Severe skin rash with blisters and peeling which can involve mouth and other parts of 
the body
Other Study Risks

Blood draws: The possible side effects of drawing blood include pain, bleeding, bruising, 
dizziness, light-headedness, fainting and, on rare occasions, local blood clot formation or 
infection with redness and irritation of the vein.

EKG: Some skin irritation can occur where the EKG (also referred to as ECG) electrodes 
are placed. Once the electrodes are placed, the test will begin, is completely painless, and 
generally takes less than a minute to perform. After the test, the electrodes are removed.

Imaging/scans: CT, PET and/or MRI scans are used to monitor your disease while you are 
in this study. CT and PET scans expose you to radiation and the amount depends on the 
number of body areas scanned. In addition, CT, PET and MRI scans may involve use of 
contrast (oral and/or IV) so that the cancer may be seen better on the images. In the small 
group of patients who have a reaction, the most common symptoms are nausea, pain in the 
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vein where the contrast was given, headache, a metallic or bitter taste in the mouth, and a 
warm or flushing feeling that lasts from 1-3 minutes.  Rarely, these symptoms may require 
treatment.  In very rare cases, people have had more severe allergic reactions that result in 
skin rashes, shortness of breath, wheezing, or lowering of the blood pressure.  If you have 
had a reaction in the past, be sure to tell your doctor or nurse about it.  Please ask the study 
doctor if you have questions about the risks of these scans. If done, MRI scans do not 
involve radiation risk. The scans that you will receive during this study are considered 
standard for your type of disease.  

Bone marrow biopsy: A numbing agent that can cause a stinging or burning sensation may 
be injected at the site of your bone marrow biopsy. The biopsy needle will go through the 
skin into the bone and may produce a brief, sharp pain. As the bone marrow liquid is taken 
from the bone, there may be a brief, sharp pain. Since the inside of the bone cannot be 
numbed, this procedure may cause some discomfort, however not all people experience 
discomfort. The possible side effects associated with a bone marrow biopsy include pain, 
bleeding, bruising, and infection, as well as a reaction to the numbing agent.  

Tumor biopsy: The likely side effects include discomfort or pain, redness, swelling, and/or 
bruising at the site of the needle insertion. Bleeding from the site of the needle insertion is 
a less likely risk. Rarely, significant infection or bleeding from this procedure, allergic 
reaction to the anesthetic, or formation of a scar at the site of needle entry occurs. If you 
will have sedation with the procedure, these risks will be discussed with you prior to the 
procedure. You will be asked to sign a separate consent form prior to any biopsy procedure.

Midline Catheter Insertion: A non-tunneled central catheter is a soft tube a doctor puts into 
a vein leading to your heart. It is a way to take blood samples or give you fluids, medicines, 
or nutrients over a long period of time.  Possible side effects include pain, bleeding, 
bruising, and, on rare occasions, swelling in your arm, chest, neck, or face on the same side 
as your catheter or infection.  
Radiation Exposure from Imaging
During your participation in this research study, you will be exposed to radiation from CT of the 
neck, chest, abdomen, and pelvis, and from FDG PET/CT of the torso and the extremities. The 
amount of radiation exposure you will receive from these procedures is equal to approximately 
12.7 rem. A rem is a unit of absorbed radiation. 
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT and FDG PET/CT that you get in this study will expose you to the roughly the same 
amount of radiation as 42 years’ worth of background radiation. Being exposed to too much 
radiation can cause harmful side effects such as an increase in the risk of cancer.  The risk depends 
on how much radiation you are exposed to. Please be aware that about 40 out of 100 people (40%) 
will get cancer during their lifetime, and 20 out of 100 (20%) will die from cancer. The risk of 
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getting cancer from the radiation exposure in this study is 1.3 out of 100 (1.3%) and of getting a 
fatal cancer is 0.6 out of 100 (0.6%).
Radiation Exposure in People Capable of Becoming Pregnant
You may not participate in this study if you are pregnant. If you are able to become pregnant, we 
will perform a pregnancy test before exposing you to radiation. You must tell us if you may have 
become pregnant within the previous 14 days because the pregnancy test is unreliable during that 
time.
MRI Risks
Your doctor may want you to get a magnetic resonance imaging (MRI) scan.  We will obtain 
pictures of your brain for this study. The MRI scanner is a metal cylinder surrounded by a strong 
magnetic field.  During the MRI, you will lie on a table that can slide in and out of the cylinder.  
We will place soft padding or a coil around your head. You will be in the scanner about 45 minutes. 
You may be asked to lie still for up to 15 minutes at a time. While in the scanner you will hear 
loud knocking noises, and you will be fitted with earplugs or earmuffs to muffle the sound. You 
will be able to communicate with the MRI staff at all times during your scan, and you may ask to 
be moved out of the machine at any time.
It is very important for the experiment that you do not move your head or body inside the scanner. 
We will use padding around your head to help keep it in place.
We may place a bar in your mouth to help keep your head still.
People are at risk for injury from the MRI magnet if they have some kinds of metal in their body.  
It may be unsafe for you to have an MRI scan if you have pacemakers or other implanted electrical 
devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall 
of a large artery), metal prostheses (including metal pins and rods, heart valves, and cochlear 
implants), permanent eyeliner, tattoos, an implanted delivery pump, or shrapnel fragments. 
Welders and metal workers may have small metal fragments in the eye. You will be screened for 
these conditions before having any MRI scan.  If you have a question about metal in your body, 
you should inform the staff. You will be asked to complete an MRI screening form before each 
MRI scan you have. 
In addition, all magnetic objects (like watches, coins, jewelry, and credit cards) must be removed 
before entering the MRI scan room.
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner.  The noise from the scanner 
is loud enough to damage hearing, especially in people who already have hearing loss. Everyone 
having a research MRI scan will be fitted with hearing protection. If the hearing protection comes 
loose during the scan, you should let us know right away.
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There are no known long-term risks of MRI scans.
Risks for gadolinium enhanced MRI scans:
Procedure
During part of the MRI you may receive gadolinium, a contrast agent, through an intravenous (IV) 
catheter. It will be done for medical purposes.
Risks
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with 
pain and swelling.  
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and 
usually go away quickly.  Mild symptoms may include coldness in the arm during the injection, a 
metallic taste, headache, and nausea.  In an extremely small number, fewer than one in 300,000 
people, more severe symptoms have been reported including shortness of breath, wheezing, hives, 
and lowering of blood pressure. You should not receive gadolinium if you previously had an 
allergic reaction to it.  You will be asked about such allergic reactions before gadolinium is given.   
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis” which has resulted in a very small number of deaths.  A blood test 
of your kidney function may be done within the month before an MRI scan with gadolinium 
contrast. You will not receive gadolinium for a research MRI scan if your kidney function is not 
normal or if you received gadolinium within the previous month. 
Most of the gadolinium contrast leaves the body in the urine.  However, the FDA recently issued 
a safety alert that indicates small amounts of gadolinium may remain in the body for months to 
years.  The effects of the retained gadolinium are not clear. At this time, retained gadolinium has 
not been linked to health risks in people whose kidneys work well. T
Some types of gadolinium contrast drugs are less likely to remain than others.  In this study, we 
will use the gadolinium contrast drugs that are less likely to remain. 
We will also give you additional information called a “Medication Guide.”  Upon request, we will 
give you individual information about retained gadolinium we see on your studies.
Psychological or Social Risks Associated with Return of Incidental or Secondary Findings
As part of the research study, it is possible that you could learn that you have genetic risks for 
another disease or disability. This may be upsetting and, depending on what you learn, might create 
a need to make challenging decisions about how to respond. 
Although your genomic information is unique to you, you share some genomic similarities with 
your children, parents, brothers, sisters, and other blood relatives. Therefore, learning your 
research results could mean something about your family members and might cause you or your 
family distress. Before joining the study, it may be beneficial to talk with your family members 
about whether and how they want you to share your results with them. 
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Privacy Risks Associated with Return of Incidental or Secondary Findings
Although your genetic information is unique to you, you do share some genetic information with 
your children, parents, brothers, sisters, and other blood relatives. Consequently, it may be possible 
that genetic information from them could be used to help identify you.  Similarly, it may be 
possible that genetic information from you could be used to help identify them.  Patterns of genetic 
variation also can be used by law enforcement agencies to identify a person or his/her blood 
relatives.  
Protections against misuse of genetic information 
This study involves genetic testing on samples.  Some genetic information can help predict future 
health problems of you and your family and this information might be of interest to your employers 
or insurers. The Genetic Information Nondiscrimination Act (GINA) is a federal law that prohibits 
plans and health insurers from requesting genetic information or using genetic information. It also 
prohibits employment discrimination based on your health information. However, GINA does not 
address discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not protect you against discrimination based on an already-diagnosed 
condition or disease that has a genetic component.
What are the risks related to pregnancy? 
If you are capable of becoming pregnant, we will ask you to have a pregnancy test before beginning 
this study.  If you are a woman who is breast feeding or pregnant, you may not take part in the 
study because we don’t know how this medicine would affect your baby or your unborn child. 
There may be long-term effects of the treatment being studied that could increase the risk of harm 
to a fetus.  If you are a woman who can become pregnant or are the partner of a woman who can 
become pregnant, you will need to practice an effective form of birth control before starting study 
treatment, during study treatment, and for six (6) months after you finish study treatment.  You 
must tell the study doctor if your birth control method fails during the restricted period.  If you 
think that you or your partner is pregnant, you should tell your study doctor or nurse at once. Men 
should also not donate sperm during the restricted period.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
You might not benefit from being in this study. 
Because there is not much information about the drug’s effect on your cancer, we do not know if 
you will benefit from taking part in this study. Talk to your doctor about other approved agents 
and treatments that are available to you and that may provide clinical benefit without taking part 
in this study.  
Are there any potential benefits to others that might result from the study?
In the future, other people might benefit from this study because of the knowledge gained from 
the study drug combination or the results of the research studies. 
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WHAT OTHER OPTIONS ARE THERE FOR YOU?
Before you decide whether or not to be in this study, we will discuss the other options that are 
available to you. Instead of being in this study, you could:

Get treatment or care for your cancer without being in a study.  These can be prescribed by 
your regular cancer doctor, even if you are not in this study. Some of the other treatments 
were able to shrink tumors and delay progression of disease in some people, but none has 
been shown to prolong life. Your study doctor can talk to you more about these other 
treatment options, how they are given and their possible side effects.  

Take part in another study

Get comfort care, also called palliative care. This type of care helps reduce pain, tiredness, 
appetite problems and other problems caused by the cancer.  It does not treat the cancer 
directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep you as active 
and comfortable as possible.
DISCUSSION OF FINDINGS
New information about the study
If we find out any new information that may affect your choice to participate in this study, we 
will get in touch with you to explain what we have learned. This may be information we have 
learned while doing this study here at the NIH or information we have learned from other 
scientists doing similar research in other places.
Return of research results
When we are examining your DNA, it is possible that we could identify possible changes in other 
parts of your DNA that are not related to this research. These are known as “incidental medical 
findings”. 
These include: 

Changes in genes that are related to diseases other than cancer 

Changes in genes that are not known to cause any disease. These are known as normal 
variations. 

Changes in genes that are new and of uncertain clinical importance. This means that we do 
not know if they could cause or contribute to a disease or if they are normal variations. 
Since the analyses that we perform in our laboratory are not nearly as sensitive as the tests that are 
performed in a laboratory that is certified to perform genetic testing, the genetic changes that we 
find may or may not be valid.  Therefore, we do not plan to inform you of all of the genetic results 
of testing on your tissue and blood that is performed in our research lab. However, in the unlikely 
event that we discover a finding believed to be clinically important based on medical standards at 
the time we first analyze your results, we will contact you. This could be many years in the future. 
We will ask you to have an additional tube of blood drawn to verify the findings we have seen in 
our lab. If the results are verified, you will be re-contacted and offered a referral to a genetic 
healthcare provider to discuss the results.
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EARLY WITHDRAWAL FROM THE STUDY 
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease worsens or comes back during treatment

if you have side effects from the treatment that your doctor thinks are too severe

if you become pregnant

if the IL-15 or mogamulizumab becomes unavailable

if new information shows that another treatment would be better for you

if you do not follow the study rules

if the study is stopped for any reason
In this case, you will be informed of the reason therapy is being stopped.  
After therapy is stopped we would like to see you for a safety visit 30 days after your last dose.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Division of Cancer Treatment 
and Diagnosis (DCTD) or designated representatives.
WILL YOUR SPECIMENS OR DATA BE SAVED FOR USE IN OTHER RESEARCH 
STUDIES?
As part of this study, we are obtaining specimens and data from you. We plan to use these 
specimens and data for studies going on right now, as well as studies in the future. These studies 
may provide additional information that will be helpful in understanding T-cell leukemias and 
lymphomas or other diseases or conditions. This could include studies to develop other research 
tests, treatments, drugs, or devices, that may lead to the development of a commercial product 
by the NIH and/or its research or commercial partners. There are no plans to provide financial 
compensation to you if this happens. Also, it is unlikely that we will learn anything from these 
studies that may directly benefit you. By agreeing to let us use your specimens and data, you 
give the NIH any rights you may have in the specimens and data. 
We may share your specimens and data with other researchers. They may be doing research in 
areas similar to this research or in other unrelated areas. These researchers may be at NIH, other 
research centers and institutions, or industry sponsors of research:
We may put your research data in a large database for broad sharing with the research 
community. These databases are commonly called data repositories. These data repositories 
might or might not be located at the NIH. The information in this database could include but is 
not limited to genetic information, ethnicity and sex.  If your individual research data is placed 
in one of these repositories, it will not be labeled with your name or other information that could 
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be used to easily identify you, and only qualified researchers will be able to look at your data. 
These researchers must receive prior approval from individuals or committees to access the data.
In addition to the use and sharing of your specimens and data described above, we might remove 
any information from your specimens and data that can identify you such as name, address, or 
medical record number, and then use the specimens and data for additional research studies at 
the NIH or other places. If we do this, we might not contact you to ask your permission or 
otherwise inform you.
If you change your mind and do not want us to store and use your specimens and data for future 
research, you should contact the research team member identified at the top of this document. 
We will do our best to comply with your request but cannot guarantee that we will always be 
able to destroy your specimens. For example, if some research with your specimens and data has 
already been completed, the information from that research may still be used. Also, for example, 
if the specimens and data have been shared already with other researchers, it might not be 
possible to withdraw the specimens and data. 
Please place your initials in the blank next to Yes or No for each of the questions below:
My specimens and data may be stored and used for future research as described above.
_____ Yes
_____ No
Initials
Initials
My specimens and data may be shared with other researchers and used by these researchers for 
future research as described above.
_____ Yes 
_____ No
Initials
Initials
NIH policies require that your clinical and other study data be placed in an internal NIH database 
that is accessible to other NIH researchers for future research. These researchers will not have 
access to any of your identifiers, such as your name, date of birth, address, or medical record 
number; and your data will be labeled with only a code. We cannot offer you a choice of whether 
your data to be placed in this database or not.  If you do not wish to have your data placed in this 
database, you should not enroll in this study.
How Long Will Your Specimens and Data be Stored by the NIH?
Your specimens and data will be stored at NIH as long as the study is open. When this study is 
closed, we may keep the data and any samples that are leftover for future research indefinitely. 
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Risks of Storage and Sharing of Specimens and Data
When we store your specimens and data, we take precautions to protect your information from 
others that should not have access to it. When we share your specimens and data, we will do 
everything we can to protect your identity, for example, when appropriate, we remove information 
that can identify you. Even with the safeguards we put in place, we cannot guarantee that your 
identity will never become known or someone may gain unauthorized access to your information. 
New methods may be created in the future that could make it possible to re-identify your specimens 
and data.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid.  Someone will work 
with you to provide more information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

If some tests and procedures are performed outside the NIH Clinical Center, 
you may have to pay for these costs if they are not covered by your insurance 
company.

Medicines that are not part of the study treatment will not be provided or paid 
for by the NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be 
provided by the NIH Clinical Center.
CONFLICT OF INTEREST(COI) 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a COI Guide.  You may ask your research team for a copy 
of the COI Guide or for more information.  Members of the research team who do not work for 
NIH are expected to follow these guidelines or the guidelines of their home institution, but they 
do not need to report their personal finances to the NIH.
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Clinical Trial Agreements 
The Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis 
(DCTD) is providing IL-15 for this study to NIH without charge. No NIH investigator involved in 
this study receives payments or other benefits from CTEP.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Some of your health information, and/or information about your specimen, from this study will 
be kept in a central database for research. Your name or contact information will not be put in 
the database. Your test results will be identified by a unique code and the list that links the code 
to your name will be kept separate from your sample and health information. Your information 
may be given out if required by law. For example, certain states require doctors to report to health 
boards if they find a disease like tuberculosis. However, the researchers will do their best to 
make sure that any information that is released will not identify you.
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

Qualified representatives from Cancer Therapy Evaluation Program (CTEP), Division of 
Cancer Treatment and Diagnosis (DCTD), NCI, who supplies the rhIL-15.
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any 
information about your research involvement without your written permission.  However, if you 
sign a release of information form, for example, for an insurance company, the NIH will give the 
insurance company information from your medical record.  This information might affect (either 
favorably or unfavorably) the willingness of the insurance company to sell you insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens and data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act.
IRB NUMBER: 20C0011
IRB APPROVAL DATE: 11/19/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/16/2020
Page 23 of 25
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Certificate of Confidentiality 
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances. 
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical information 
that we collect under the authority of the Public Health Service Act.  In some cases, the Privacy 
Act protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy 
Act allows release of information from your record without your permission, for example, if it is 
requested by Congress.  Information may also be released for certain research purposes with due 
consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting,  to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit. However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
IRB NUMBER: 20C0011
IRB APPROVAL DATE: 11/19/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/16/2020
Page 24 of 25
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Milos 
Miljkovic, M.D., milos.miljkovic@nih.gov, Building 10, Room 4N115, Telephone:  301-250-
5216.  You may also call the NIH Clinical Center Patient Representative at 301-496-2626, or the 
NIH Office of IRB Operations at 301-402-3713, if you have a research-related complaint or 
concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 20C0011
IRB APPROVAL DATE: 11/19/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/16/2020
Page 25 of 25
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the 
explanation about this study and have been given the opportunity to discuss it and to ask questions. I am 
legally authorized to make research decisions on behalf of the adult participant unable to consent and have 
the authority to provide consent to this study. As applicable, the information in the above consent was 
described to the adult participant unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: 
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language 
facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may 
not also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language 
facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 20C0011
IRB APPROVAL DATE: 11/19/2020