Clinical trial NCT02989844
Conditions: Acute Myelogenous Leukemia (AML) Myelodysplastic Syndrome (MDS)
Sponsor: Masonic Cancer Center, University of Minnesota
Start date: 2017-04-12; Completion date: 2022-08-31
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single-arm, multi-center Phase II trial using IL-15 super-agonist complex (N-803 formerly known as Alt-803) maintenance after allogeneic hematopoietic cell transplant (alloHCT) for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS).

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: N-803
Intervention descriptions: intervention 1: N-803 at 6 mcg/kg SQ Day 1 of a 4 week (28 day) cycle with ± 1 week window Continue N-803 every 4 weeks for 10 doses or until relapse, unacceptable toxicity, or patient refusal, whichever comes earlier.

Protocol documents:
Prot_SAP_000.pdf: 
Masonic Cancer Center, University of Minnesota 
Cancer Experimental Therapeutics Initiative (CETI) 
 
 
Relapse Prophylaxis with IL-15 Super Agonist N-803 in Patients with 
Acute Myelogenous Leukemia and Myelodysplastic Syndrome Following 
Reduced Intensity Conditioning (RIC)  
Allogeneic Stem Cell Transplantation 
 
 
MT2016-07 
CPRC #2016LS058 
IND 119578 
 
University of Minnesota 
Principal Investigator/IND Sponsor: 
Jeffrey S. Miller, MD 
 
 
Collaborators:: 
 
Bruce Blazar, MD* 
Daniel J. Weisdorf, MD 
*will not consent patients 
 
 
Biostatistician: 
Ryan Shanley, MS 
 
 
Version Date: 
April 14, 2022 
 
 
 
 
 
Confidential 


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Key Study Personnel Contact Information 
Contact Information 
Role 
Jeffrey S Miller, MD 
Masonic Cancer Center, University of Minnesota 
Medicine - Hematology/Oncology/Transplantation 
420 Delaware Street SE MMC 806 
Minneapolis, MN 55455 
Phone: 612-625-7409 
Fax:  612-626-4915 
Email: mille011@umn.edu 
Study PI 
Roby NIcklow, RN  
Masonic Cancer Center Clinical Trials Office 
925 Delaware St. SE 
Suite 310 Dinnaken MC 2131 
Minneapolis, MN. 55414 
Phone: 612 624-5492 
Email: affilates@umn.edu  
Fax: 612-625-6468 
Multisite Program Manager 
 
Refer to the Procedures Manual for Participating Sites for a complete list of study personnel and 
contact information.  
 
 


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Revision History 
 
 
 
Revision 
# 
Version 
Date 
Revision Details 
Consent 
Revision 
 
08/26/2016 
Original  
n/a 
 
09/07/2016 
In response to CPRC’s initial review  
Updated background and drug administration language as 
provided by Altor and other general edits and formatting 
n/a 
 
12/13/2016 
Edits prior to IRB and FDA submission 
Section 8.1 – add CMV/EBV monitoring and add associated 2nd 
objectives/endpoints (synopsis, Section 1.2, 12.2) 
Section 8.2.3 – delete Nantomics related research samples, delete 
related correlative objective/endpoint 
Synopsis, Section 4.2 – prohibit prior ALT-803 treatment Appendix 
V – add Altor’s patient diary for injection reactions 
Section 6.1 – delete table of suggested pre-meds and update pre-
med language to be on a per patient basis as needed. 
Section 6.5 – add a bullet point to duration of study participation to 
end study follow-up if patient is discharged to hospice or not 
returning to study site but obtain info from other sources as 
available 
Section 7.3 – add management of cytokine release syndrome and 
collection of CRS toxicity (Section 10, Appendix IV) 
Section 8 and 10 – clarify that if a patient is no longer abiding by 
the clinical care calendar that the schedule of research related 
sample collection and toxicity assessments may be adjusted or 
discontinued. 
Cover page and page 2 - Update affiliate institutions 
Minor edits, updates and clarifications through-out 
n/a 
 
03/13/2017 
In response to FDA potential deficiencies and IRB stips: 
Schema – add final treatment visit 30 day (±7 days)  
Section 6.1 – clarify situations where a one-time ALT-803 dose 
decrease is permitted; expand criteria for holding ALT-803 dose 
on the day of a scheduled treatment; clarify missed doses will not 
be made up to maintain the 8 week treatment cycles; add 
language for the management of patients who are unable to 
restart ALT-803 after a 1 week rest. 
Section 7.2 – add a paragraph on management of injection site 
reaction/skin rash to evaluate systemic rashes outside of the 
injection area and rashes lasting more than 7 days to rule out 
GVHD. 
Sections 10.4 and 13.5.2 – add an early study stopping rule for 
Grade 4/5 non-relapse toxicity; add GVHD assessment to Section 
8.1 Required Clinical Care Evaluations 
Insert a new Appendix IV – aGVHD and cGVHD grading; 
renumber other appendices (and update protocol text)  
Insert a new Section 11.5 entitled “Teleconferences – Lead 
Institution and Affiliate Sites” describing planned communications 
yes 


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Revision 
# 
Version 
Date 
Revision Details 
Consent 
Revision 
between the UMN and other sites in response to an IRB 
stipulations 
Other minor edits and clarifications 
 
04/03/2017 
Interim version submitted to FDA only: 
FDA response to non-hold recommendation:  
• Section 8.2 - bank serum samples at the following time points 
for immunogenicity testing: pre cycle 1, 28-30 days after the 
first exposure of ALT-803, pre cycle 2, pre cycle 3, pre cycle 4, 
and 30-45 days after the last exposure of ALT-803, currently 
done at pre cycle 2 and cycle 3 
• Minor edits from study initiation visit (SIV) : 
• Section 4.1.2 – expand definition of sustained blood counts  
• Section 4.2.5 – clarify any prior infection must be under control 
• Section 6.1 – add patient must be assessed by provider 
(specifically for injection site reaction and GVHD) prior to 
administration of that day's ALT-803 injection and to refer to the 
"Dose Hold" section; update pre-meds to acetaminophen 650 
mg prior to each injection.   
• Appendix I – update to reflect changes in Section 4 
Other edits:  
• Add Dr. Weisdorf as co-I on title page 
• Add Dr. Romee as PI at WU 
• Clarify BM aspirate samples are sent to TTL 
• Sections 6.1 and 9.6 – for patients weighing > 100 kg, ALT-803 
dose will be calculated using a capped weight of 100 kg 
• Section 6.2 Supportive Care – suggest management for chills, 
n/v, diarrhea  
• Section 8.1 – clarify baseline EKG will be paid for by research 
as not SOC post-transplant 
yes 
1 
05/05/2017 
Incorporates all April 3, 2017 protocol version revisions plus the 
following: 
Section 6.1 – update criteria of inadequate dosing and clarify 
criteria for previous injection site reaction requirements for 
retreatment 
Section 1.1 – delete definition of evaluable patient from primary 
objective in response to changes to Section 6.1 
Section 13.1 – Analysis Population updated to reflect changes in 
Section 6.1 
no 
2 
10/19/2017 
Clarifications related to acute GVHD: 
Synopsis and Section 4.1.3 – permit enrollment of patients with 
aGVHD that is clinically improving on topical steroids or systemic 
steroids, previously had to be resolved 
Section 6.1 – expand and clarify provider’s pre-dose assessment 
and move dose hold section up to be part of this section for 
continuity, refer to a new Section 6.2 for GVHD management 
guidance; delete number of ALT-803 doses required for 
continuation on to cycle 2 and cycle 3 
Section 6.5 Duration of Treatment – delete develops aGVHD 
requiring treatment and replace with grade IV GVHD 
yes 


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Revision 
# 
Version 
Date 
Revision Details 
Consent 
Revision 
Appendix VI  ALT-803 Injection Reaction Diary – add instructions 
that a new form is to be used for each injection site and the form is 
to be completed until the injection reaction resolves. 
Other edits and clarifications 
Section 8.1 – replace basic metabolic panel with CMP on day 1 
and day 5  
Section 8.2 – create separate research related sample collection 
tables with Section 8.2.1 be for UMN patients and Section 8.2.2 be 
for affiliate sites  
Section 9.6 – delete sentence about dividing dose between 
syringes for larger volumes as not applicable in this study 
Section 10.1 – update definition of major and minor deviations to 
reflect MCC’s updated DSMP 
Section 10.6 – update institutional reporting table to report all 
events meeting the definition of SAE and updated deviation  
Section 10.7 – update MCC’s reporting requirements 
Other edits and clarifications throughout including:  
Remove affiliate names from cover sheet and contact list on page 
2, update Erica Orcholski’s contact info and add Jane Gau as 
Primary Clinical Research Coordinator 
Shorten follow-up for survival only from 2 additional years to 1 
additional year (or 2 years from HSCT) 
Section 6.1 clarify ALT-803 dose calculation based on weight 
change 
Section 11.1 – expand the data management section to detail 
where the data will be stored 
Section 11.3 – update the DSMP section  to include affiliate 
monitoring 
3 
7/31/2018 
Updated change in Principal Investigator (Dr. Claudio Brunstein is 
the new PI) and updated Affiliate Sites Manager contact info. 
Yes 
4 
11/29/2018 
Throughout document 
• Update the ALT-803 product name to N-803 and replace 
references to Altor with Nant due to the recent sale of ALT-803 
to Nant 
• Update the treatment schedule to every 4 week dosing for a 
max of 10 doses based on experience with this study and 
other ALT-803 clinical trials that the proposed 4 weekly 
injections followed by 4 weeks rest was too intense and not 
well tolerated. 
• Move the start period for N-803 from Day 60-100 post-
transplant to Day 42-60 post-transplant to provide immune 
protection earlier 
• Update the primary objective/endpoint to monitor for 2 years 
from alloHCT rather than 1 year 
• Add an early analysis for futility after 40 patients are enrolled 
(without pause in enrollment) to consider discontinuing the trial 
if the cumulative incidence of 2 year relapse is >34% 
• Update overall survival and non-relapse mortality objectives/ 
endpoints from 1 year to 2 years 
• Modify Section 8 Clinical Evaluations and Procedures to reflect 
updated treatment schedule. 
Yes 
 


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Revision 
# 
Version 
Date 
Revision Details 
Consent 
Revision 
Edits based on current protocol template including 
• Add table of key abbreviations 
• Update Section 5 Patient Screening and Enrollment to current 
language 
• Update Section 10.1 to reflect current clinical deviation 
definitions and IRB reporting requirements 
5 
06/14/2019 
Update ALT-803 drug sections based on updated IB – A sufficient 
number of patients have been treated with ALT-803 (also known as 
N-803) that the toxicity profile is no longer based on IL-2. 
• Update Section 2.4 
• Section 7 - Delete hypotension management guidelines as 
hypotension (change in blood pressure) is not included in the 
updated toxicity profile. 
• Section 9 - ALT-803 Formulation, Supply and Potential Toxicity – 
update to reflect updated IB including vial concentration for SC 
administration and updated toxicity profile. 
• Appendix V – N-803 table of risks – Delete as now in Section 9.8. 
Renumber Appendices and update in body of protocol. 
Synopsis, Section 4.1.2 and Appendix I – clarify that anti-cancer 
therapy that is “directed at the diseases under study” 
Edit to inclusion criteria Update Appendix I – Eligibility checklist to 
new format 
Other minor edits and hyperlinks added through-out the document 
to confirm with electronic submission to the FDA. 
yes 
6 
07/06/2020 
• Section 8 - add a Day 8 lab visit for Cycles 3 and 6 – blood work 
and research samples were revised downward when the study 
changed from a weekly injection schedule to an every 4 week 
injection schedule - two time points added back in to allow sufficient 
data collection for study endpoints  
• Section 7 – Delete management of CRS as CRS has been deleted 
from the updated IB as “N-803 did not trigger a broad-based 
cytokine release in vitro by either human or murine immune cells, 
suggesting that N-803 is unlikely to trigger a cytokine storm”  
• Section 9 – Delete CRS event grading and Lee ref. 
• Section 9.7 – add atrial fibrillation as possible risk of N-803, update 
risks of N-803 based on IB dated April 2020 
• Remove Sarah Cooley from the title page as she has left the 
University of Minnesota 
• Update to current participating sites protocol template 
• Delete Appendix I – Eligibility Checklist per updated CTO policy 
and renumber all remaining appendices 
• Update Nant’s name to ImmunityBio, Inc  
• Other edits and updates for consistency and clarity 
yes 
7 
4/14/2022 
• Updated change in Principal Investigator (Dr. Jeffrey Miller is 
the new PI) and updated Affiliate Sites Manager contact info. 
no 


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TABLE OF CONTENTS 
 
Key Study Personnel Contact Information ............................................................................. 2 
Key Abbreviations ................................................................................................................. 9 
Protocol Synopsis ............................................................................................................... 10 
Schema ............................................................................................................................... 12 
1 
Objectives .................................................................................................................... 13 
1.1 Primary Objective ....................................................................................................13 
1.2 Secondary Objectives ..............................................................................................13 
1.3 Correlative Objectives ..............................................................................................13 
2 
Background and Significance ....................................................................................... 13 
2.1 Introduction and Rationale for the Approach ............................................................13 
2.2 rhIL-15 .....................................................................................................................14 
2.3 IL-15/IL-15Rα-Fc (N-803) ........................................................................................15 
2.4 N-803 by Subcutaneous Injection ............................................................................15 
2.5 Study Rationale .......................................................................................................16 
3 
Study Design ................................................................................................................ 18 
4 
Patient Selection .......................................................................................................... 19 
4.1 Inclusion Criteria ......................................................................................................19 
4.2 Exclusion Criteria .....................................................................................................20 
5 
Patient Screening and Enrollment ................................................................................ 21 
5.1 Enrollment with the University of Minnesota Clinical Trials Office ............................21 
5.2 Patient Enrollment to Study Treatment in OnCore ...................................................21 
5.3 Patients Who Do Not Begin Study Treatment ..........................................................22 
6 
Treatment Plan............................................................................................................. 22 
6.1 N-803 Administration ...............................................................................................22 
6.2 GVHD Management Guidance ................................................................................24 
6.3 Supportive Care .......................................................................................................25 
6.4 General Concomitant Medications Guidelines .........................................................25 
6.5 Duration of Treatment ..............................................................................................26 
6.6 Duration of Study Participation.................................................................................26 
7 
Management of Injection Site Reactions/Skin Rash in Association with N-803 ............. 27 
8 
Clinical Evaluations and Procedures ............................................................................ 27 
8.1 Required Clinical Care Evaluations ..........................................................................27 
8.2 Research Related Tests and Procedures ................................................................28 
9 
N-803 Formulation, Supply, and Potential Toxicity ....................................................... 30 
9.1 Structural Formula ...................................................................................................31 
9.2 Formulation..............................................................................................................31 
9.3 Packaging ................................................................................................................31 
9.4 Storage ....................................................................................................................31 
9.5 Study Drug Preparation ...........................................................................................32 
9.6 Agent Inventory Records .........................................................................................32 
9.7 Toxicity ....................................................................................................................32 
9.8 Agent Ordering ........................................................................................................34 


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10 Adverse Event Monitoring, Documentation, and Reporting .......................................... 34 
10.1 Adverse Event Terminology .....................................................................................34 
10.2 AE Documentation Requirements ............................................................................35 
10.3 SAE Documentation and Reporting .........................................................................36 
10.4 Early Stopping Rule Event Documentation and Reporting Requirements ................36 
10.5 Documentation of Death and Reporting Requirements ............................................37 
10.6 Institutional Event Reporting Table ..........................................................................38 
10.7 Expedited MCC Reporting Requirements (MCC) .....................................................39 
11 Study Data Collection and Monitoring .......................................................................... 39 
11.1 Data Management ...................................................................................................39 
11.2 Case Report Forms .................................................................................................40 
11.3 Data and Safety Monitoring Plan (DSMP) ................................................................40 
11.4 Participating Site Monitoring ....................................................................................41 
11.5 Teleconferences – Lead Site and Participating Sites ...............................................41 
11.6 Record Retention .....................................................................................................42 
12 Study Endpoints ........................................................................................................... 42 
12.1 Primary Endpoint .....................................................................................................42 
12.2 Secondary Endpoints ...............................................................................................42 
13 Statistical Considerations ............................................................................................. 42 
13.1 Objectives and Study Design ...................................................................................42 
13.2 Statistical Analysis ...................................................................................................43 
13.3 Sample Size and Power...........................................................................................44 
13.4 Stopping Rules ........................................................................................................44 
14 Conduct of the Study .................................................................................................... 45 
14.1 Good Clinical Practice .............................................................................................45 
14.2 Ethical Considerations .............................................................................................45 
15 References ................................................................................................................... 46 
Appendix I – Karnofsky PS and NYHA Classification .......................................................... 48 
Appendix II – Disease Specific Response Criteria ............................................................... 49 
Appendix III– GVHD Grading Scales ................................................................................... 51 
Appendix IV - N-803 Targeted Toxicity Worksheet .............................................................. 54 
Appendix V – N-803 Injection Site Reactions Diary ............................................................. 55 
 
 
 


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Key Abbreviations 
Abbreviation 
Definition 
ABW 
actual body weight 
ADL 
activities of daily living 
AE 
adverse event 
alloHCT 
allogeneic hematopoietic cell transplant 
AML 
acute myelogenous leukemia 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CRS 
cytokine release syndrome 
CTCAE 
Common Terminology Criteria for Adverse Events 
DFS 
disease free survival 
DLCO 
diffusing capacity of the lungs for carbon monoxide 
eCRF 
electronic case report form 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GvHD 
graft-versus-host disease 
HCT 
hematopoietic cell transplantation 
HSCT 
hematopoietic stem cell transplantation 
IB 
Investigator’s Brochure 
IBW 
ideal body weight 
ICH 
International Conference on Harmonisation 
IL-15 
Interleukin-15 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
intravenous 
MDS 
myelodysplastic syndrome 
NC 
nucleated cells 
NCI 
National Cancer Institute 
NK 
natural killer 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
PFS 
progression free survival 
PFT 
pulmonary function test 
PO 
per os; orally 
PTLD 
post-transplant lymphoproliferative disorder 
rhIL-15 
Recombinant human interleukin-15 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RIC 
reduced intensity conditioning 
SOC 
Standard of care 
SAE 
serious adverse event 
SD 
stable disease 
SUSAR 
suspected unexpected serious adverse reaction 
TNC 
total nucleated cells 
TRM  
treatment related mortality 
TTP 
time to progression 
ULN 
upper limit of normal 
 
 


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Protocol Synopsis 
Relapse Prophylaxis with IL-15 Super Agonist N-803 in Patients with Acute 
Myelogenous Leukemia and Myelodysplastic Syndrome Following Reduced Intensity 
Conditioning (RIC) Allogeneic Stem Cell Transplantation 
 
 
Study 
Design: 
This is a single-arm, multi-center Phase II trial using IL-15 super-agonist complex (N-803 formerly 
known as Alt-803) maintenance after allogeneic hematopoietic cell transplant (alloHCT) for acute 
myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). The primary objective is to 
determine if post-transplant N-803 effectively reduces relapse as measured by the cumulative incidence 
of relapse between the 1st dose of N-803 and two years after reduced intensity conditioning (RIC) 
alloHCT. The hypothesis is that N-803 will reduce relapse from a historical estimate of 35% to 20% in 
the study cohort. The rationale is that N-803 will enhance allogeneic immunity through activation and 
expansion of donor-derived NK cells and CD8+ T cells capable of mediating a response to remaining 
leukemia cells (minimal residual disease, MRD); therefore decreasing relapse rates. A secondary aim 
is to achieve this goal without increasing frequency or severity of graft-versus-host disease (GVHD) 
 
In this study N-803 is given at 6 mcg/kg subcutaneously (SQ) once every 4 weeks for a maximum 
of 10 doses. Treatment must begin between Day 42 and Day 60 post-transplant with the goal to 
enroll patients as close to Day 42 as feasible as starting anti-tumor maintenance is a logical goal. 
GVHD prophylaxis will continue per individual institutional standard practice. Follow-up for late 
toxicity, disease status, and survival continues for 2 years from alloHCT. 
 
Sixty patients are planned for enrollment with an analysis for futility after 40 patients are enrolled 
(while enrollment continues). The trial will be discontinued if the cumulative incidence estimate of 
2 year relapse is projected at >34%. Otherwise, enrollment continues to complete the trial in the 
absence of excessive toxicity as monitored by early stopping rules by donor type (sibling, umbilical 
cord blood, unrelated and haploidentical): 
1) 
Grade III-IV acute GVHD by Day 120 post-transplant 
2) 
Grade 4 and 5 non-relapse toxicity by Day 120 post-transplant 
 
Primary 
Objective: 
The primary objective is to determine if post-transplant N-803 effectively reduces relapse from a 
historical estimate of 35% to 20% in the study cohort as measured by cumulative incidence of relapse 
between the 1st dose of N-803 and 2 years after a reduced intensity conditioning (RIC) allogeneic 
hematopoietic cell transplant (alloHCT) for acute myelogenous leukemia (AML) and myelodysplastic 
syndrome (MDS). 
 
Secondary 
Objectives: 
 
• To evaluate the safety and tolerability of every 4 week N-803 administration  
• To determine the incidence of relapse at two years after alloHCT stratified by number of doses 
of N-803 (1-3 or 4-10) 
• To determine the frequency and severity of acute and late acute/chronic graft-versus-host 
disease (GVHD) by graft source 
• To evaluate whether cytogenetic and flow cytometry positive minimal residual disease (MRD) 
post-transplant (before and after N-803)  determine overall survival at 2 years post-transplant 
• To determine the incidence of non-relapse mortality at 2 years post-transplant 
 
Correlative 
Objectives: 
• To monitor the number and function of NK cells, T cells, T regulatory cells and myeloid derived 
suppressor cells pre- and post-N-803 therapy and serum cytokines that could influence 
response 
• To determine the incidence of CMV viremia or disease by Day 100 post-transplant  
• To characterize N-803 immunogenicity 


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Eligible 
Diseases/ 
Donor Cell 
Sources 
Patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) for whom 
a reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplant (alloHCT) is 
planned or has recently been performed. Acceptable donor sources are: sibling donor, a 
haploidentical donor [restricted to post-transplant cyclophosphamide GVHD prophylaxis], an 
unrelated donor, or umbilical cord blood (UCB) as the cell source 
Key 
Inclusion 
Criteria: 
• Able to begin N-803 between Day 42 and Day 60 post-transplant and meet all of the following 
requirements: 
o 
Sustained neutrophil (ANC > 1000/mcL for 3 consecutive days without growth factor) and 
platelet (> 30,000/ mcL without growth factors or transfusions) engraftment 
o 
>50% donor myeloid and lymphoid chimerism in blood or bone marrow on most recent 
BM evaluation 
o 
No morphologic evidence of relapse (<5% bone marrow blasts) on most recent BM 
evaluation (Day 21 or 28 post-transplant is acceptable) 
o 
Being followed in the outpatient setting (not an inpatient) 
o 
No plan of giving other anti-cancer treatment directed at the diseases under study (i.e. 
maintenance therapy [e.g. sorafenib for FLT3m+ AML or hypomethylating therapy], 
additional therapy for MDS)  
• Age 18 years or older 
• Karnofsky performance status ≥ 70% 
• Adequate renal (creatinine ≤ 2 mg/dl) and liver (ALT and AST ≤ 3 x upper limit of normal) 
function 
• If acute GVHD is present it must be clinically improving on topical or low dose steroids (≤ 0.3 
mg/kg/day prednisone equivalent) - GVHD prophylaxis will be continued per individual 
institutional standard practice 
Key 
Exclusion 
Criteria: 
• Prior N-803 (previously known as ALT-803) 
• Pregnancy  
• Marked baseline prolongation of QT/QTc interval (e.g. demonstration of a QTc interval > 500 
millisec) 
• Active untreated bacterial, fungal, or viral infections – all prior infections must be under control 
following therapy and must be afebrile for at least 24 hours at time of enrollment 
• Active autoimmune disease requiring systemic immunosuppressive therapy 
• History of severe asthma and currently on chronic systemic medications (mild asthma 
requiring inhaled steroids only is eligible) 
 Enrollment 
Plan: 
60 patients over 2 years with an early stopping rule for futility once 40 patients are enrolled. 
With up 5 sites participating, it is expected 20-30 patients will be enrolled per year. 


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Schema  
 
 
                                                                          N-803 SQ once every 4 weeks x 10 doses 
 
 
Post HCT 
BM Bx 
screen 
 
 
 
 
 
 
 
 
 
 
Follow-up 
 
                                                       Dose # 1      2      3      4      5       6       7      8     9     10   EOT 
 
 
• 
Begin between Day 42 and Day 60 post-transplant, but as close to Day 42 as feasible  
 
• 
All treatment is administered in the outpatient setting 
 
• 
N-803 at 6 mcg/kg SQ Day 1 of a 4 week (28 day) cycle with ± 1 week window 
 
• 
Continue N-803 every 4 weeks for 10 doses or until relapse, unacceptable toxicity, or patient 
refusal, whichever comes earlier. 
 
• 
An End of Treatment (EOT) visit occurs 30 days (±1 week) after the last dose of N-803 
 
• 
Disease related reassessment and follow-up based on disease specific post-transplant 
standard of care 
 
• 
Follow-up for late toxicity, disease status, and survival will be done for 2 years from alloHCT 
(approximately 22 months after 1st administration of N-803) 
 
HCT timeline: Day 0 
30 
42 
100 
        180  
 
 
365    720 


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1 Objectives 
1.1 Primary Objective 
The primary objective is to determine if post-transplant N-803 effectively 
reduces relapse from a historical estimate of 35% to 20% in the study cohort 
as measured by cumulative incidence of relapse between the 1st dose of N-
803 and 2 years after a reduced intensity conditioning (RIC) allogeneic 
hematopoietic cell transplant (alloHCT) for acute myelogenous leukemia (AML) 
and myelodysplastic syndrome (MDS).  
1.2 Secondary Objectives 
• To evaluate the safety and tolerability of every 4 week N-803 administration  
• To determine the incidence of relapse at two years after alloHCT stratified 
by number of doses of N-803 (1-3 or 4-10) 
• To determine the incidence of acute and late acute/chronic graft-versus-host 
disease (GVHD) 
• To evaluate whether cytogenetic and flow cytometry positive minimal residual 
disease (MRD) post-transplant (before and after N-803) 
• To determine overall survival at 2 years post-transplant 
• To determine the incidence of non-relapse mortality at 2 years post-
transplant 
1.3 Correlative Objectives 
• To monitor the number and function of NK cells, T cells, T regulatory cells and 
myeloid derived suppressor cells pre- and post-N-803 therapy, as well as 
serum cytokines reflecting the immune activation 
• To determine the incidence of CMV viremia or disease by Day 100 post-
transplant 
• To characterize the immunogenicity profile of N-803 
 
 
2 Background and Significance 
2.1 Introduction and Rationale for the Approach  
Acute myeloid leukemia (AML) is the most common acute leukemia in adults 
with 18,860 cases estimated for 2014 and an additional 800 cases in children 
(www.LLS.org). The incidence is increasing, as it develops in patients who 
survive treatment from other cancers or evolves in elderly patients with 
myelodysplastic syndrome (MDS). The main cause of treatment failure for AML 
continues 
to 
be 
relapse. 
Successful 
allogeneic 
hematopoietic 
cell 


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transplantation (HCT) requires the infusion of healthy stem cells, as well as 
lymphocytes capable of participating in a graft-versus-tumor/leukemia (GVL) 
reaction. The importance of the infused lymphocytes has been demonstrated 
in studies showing increased relapse after transplants with lymphocyte-
depleted grafts and by the therapeutic efficacy of donor lymphocyte infusions1-
2. Unfortunately, relapse after allogeneic HCT remains a significant problem 
with rates approaching 35% in patients receiving non-myeloablative 
conditioning (NMAC), and even higher in those with high-risk disease3. Optimal 
strategies to balance immune responses to favor GVL without harmful graft-
versus-host disease (GVHD) are needed.  
 
Profound NK Cell Functional Defects After HCT. Unlike adaptive B and T 
cells, which express a single somatically recombined, clonally expressed 
antigen receptor that recognize specific or cross reactive antigen, NK cell 
activation is controlled by germline-encoded activating and inhibitory receptors. 
With the notable exception of CD16, which binds to the Fc portion of 
immunoglobulin and mediates ADCC, no activating receptor is functionally 
dominant, and each can be counteracted by inhibitory receptor signaling4,5. 
Activating and inhibitory killer cell lectin-like receptors (NKG2C and NKG2A) 
and KIR are encoded by gene complexes, recognize class I molecules, and are 
expressed in a variegated fashion6. These inhibitory receptors are primarily 
responsible for NK cell education, the process by which acquisition of function 
is mediated through engagement of class I MHC. After HCT, NK cells are the 
first cancer fighting defense as NK cells reconstitute in large numbers. 
However, we have identified a profound defect in the function of reconstituting 
NK cells for up to 6 months after HCT. Our approach is to stimulate this function 
as early as possible after transplant in hope of preventing relapse. 
2.2 rhIL-15 
Interleukin-15 (IL-15) is a cytokine and growth factor capable of expanding 
activated T cells and NK cells. By broad consensus, the NCI Immunotherapy 
Workshop (2007) ranked IL-15 as the #1 agent with “high potential for 
immunotherapy7.” Based on preclinical non-human primate and early phase 
clinical trial data, including those at the University of Minnesota, IL-15 regimens 
can unquestionably be designed to prospectively and reproducibly increase T-
cell and NK-cell counts. 
 
The NCI Biological Resource Branch has manufactured E. coli-expressed 
recombinant human IL-15 (rhIL-15), and this is the first IL-15 product tested 
here at the University of Minnesota. Systemic administration of NCI rhIL-15 by 
daily intravenous (IV) bolus has been shown to increase the number of 


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circulating CD8+ T and NK cells, but the cytokine has a very short half-life. We 
have established the MTD for NCI-manufactured rhIL-15 using IV and 
subcutaneous dosing. Although safer with subcutaneous administration 
allowing more drug delivery, we identified limitations with the rhIL-15 in clinical 
testing. Specifically, high levels of free rhIL-15 decrease circulating IL-15R, 
acting as a negative feedback signal to reduce further IL-15 trans-presentation. 
This is the rationale in this trial for using IL-15/IL-15R-Fc (N-803), an IL-15 
product that physiologically trans-presents IL-15. 
2.3 IL-15/IL-15R-Fc (N-803) 
This trial will evaluate an alternative IL-15 construct designed to have a 
prolonged serum half-life. The novel IL-15 immunoconjugate, N-803, was 
developed by our collaborator, Altor BioScience Corporation (Altor, Miramar, 
FL), to overcome some of the biologic, regulatory, and commercial limitations 
of monomeric NCI rhIL-15. Under natural circumstances, IL-15 and IL-15 
Receptor-alpha (IL-15R) are coordinately expressed by antigen-presenting 
cells (i.e., monocytes and dendritic cells)8. During signaling by the IL-15 
pathway, IL-15 bound to IL-15R is presented in trans to neighboring NK or 
CD8+ T cells expressing only the IL-2R receptor. At the immunologic synapse, 
IL15 trans-presentation appears to be a dominant mechanism for IL-15 action 
in vivo, providing tight physiologic control over the functions of IL-15 under 
homeostatic conditions and in response to immune stimuli9. N-803 is a soluble 
complex consisting of two protein subunits of a human IL-15 variant10 
associated with high affinity to a dimeric human IL-15 Receptor α (IL-15Rα) 
sushi domain/human IgG1 Fc fusion protein11. 
  
The IL-15 variant is a 114 aa polypeptide comprising the mature human IL-15 
cytokine sequence with an Asn to Asp substitution at position 72 of helix C 
(N72D)12. The human IL-15Rα sushi domain/human IgG1 Fc fusion protein 
comprises the sushi domain of the human IL-15 Receptor α subunit (IL-15Rα) 
(aa 1-65 of the mature human IL-15Rα protein) linked with the human IgG1 
CH2-CH3 region containing the Fc domain (232 amino acids). Aside from the 
N72D substitution, all of the protein sequences are human. N-803 has a 
prolonged serum half-life in preclinical animal models and has a 4-fold increase 
in biologic activity greater than wild-type IL-15 (IL-15 wt)10.  
2.4 N-803 by Subcutaneous Injection  
IV and SC administration of N-803 were compared in early phase 1 studies in 
solid and hematologic tumors (QUILT-3.003, QUILT-3.004, QUILT-3.005). The 
decision to discontinue IV administration was based on the high Cmax 


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observed via this route, which was associated with markedly increased serum 
cytokine levels and high fever, rigors, tachycardia, and relative hypotension.15 
SC administration of N-803 results in an approximately 100-fold lower Cmax 
than IV and allows N-803 serum concentration to be maintained up to 96 hours 
post-dose with still detectable levels at 7 days (while IV N-803 declined below 
detection 48 - 96 hours post-administration). A PK study using SC N-803 in 
healthy volunteers (QUILT-1.004) showed that serum levels of N-803 remained 
elevated over a relatively prolonged period after a single administration of the 
drug; the apparent mean half-life of the complex was 20-21 hours. SC 
administration resulted in significant attenuation of AEs as compared to IV 
administration. Subjects receiving N-803 via SC administration most commonly 
experienced injection site reaction, mild fever, hypoalbuminemia, and chills, 
while those receiving IV N-803 most commonly experienced higher fever, 
rigors, fatigue, nausea, and hypertension. The common localized skin rash 
observed with SC administration of N-803 could be managed with topical 
steroids when necessary. In addition to its favorable tolerability and PK profile, 
SC administration of N-803 is associated with equivalent and possibly 
enhanced efficacy and biological activity. In QUILT-3.004 (hematologic 
malignancies), SC administration of N-803 was associated with a greater 
increase in circulating NK cells than IV administration.15 In QUILT-3.002 
(relapsed or refractory iNHL), the combination of rituximab with N-803 led to 
objective responses in 58% (7 out of 12) of SC-treated subjects and 44% (4 out 
of 9) of IV-treated subjects. In total, these observations show that SC 
administration is well tolerated, yields a lower Cmax yet more sustained serum 
levels of N-803 over time, and has equivalent or greater efficacy and biological 
activity as compared to IV administration. 
 
Refer to the updated Investigator Brochure (dated April 2020) for additional 
details. 
. 
2.5 Study Rationale 
As we perform more transplants in older adults using reduced intensity 
conditioning, relapse rates are unacceptably high irrespective of graft 
source13,14. Currently there is no effective maintenance therapy available for 
this patient population. We also described an NK cell defect early after HCT. 
IL-15 is an optimal cytokine to improve NK and T cell function; potentially 
improving graft versus tumor effect and reducing the relapse risk after RIC 
transplants. We have tested a number of IL-15 products and IL-15/IL-15R-Fc 
(N-803) seems to be the best candidate for use in this setting.  
 


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While some studies continue to dose escalate (currently 15 and 20 mcg/kg are 
under study); we are testing immune activation in a minimal residual setting 
and will use a lower safe dose (N-803 6 mcg/kg SQ). We have chosen to be 
conservative in the dosing here 1) because of the complexity of patients early 
post-transplant and 2) because of the use in the prophylactic setting. In 
addition, we have shown that 6 mcg/kg is safe, especially with subcutaneous 
dosing, where as unlike IV N-803, subcutaneous dosing is associated with less 
severe constitutional symptoms compared to IV dosing. In addition, we have 
immunologic data suggesting that 6 mcg/kg is biologically active.  
 
The cumulative experience with ALT-803 (initially from Altor BioSciences) has 
grown and we published the first-in-human experience in 31 transplant patients 
as the rationale for this trial15. This paper also details the immune activation 
and long half-life of subcutaneous (SQ) dosing, the approach we use here. We 
have treated 8 subjects with weekly SQ dosing in this current trial and learned 
that weekly dosing is simply not feasible because injection site reactions (very 
common in all cohorts tested) take more than one week to resolve. In addition, 
pre-clinical data suggest that higher levels of IL-15 may lead to NK cell 
exhaustion16. During the progress of this trial, BioSciences became a wholly-
owned subsidiary of ImmunityBio, Inc. While there is no change in the drug, 
they now refer to it as N-803, reflecting the business acquisition. ImmunityBio, 
Inc. has also performed additional studies in normal volunteers (unpublished) 
showing that dosing intervals should probably be 3-4 weeks to prevent 
exhaustion and maximize immune activation. Every 4-week dosing was chosen 
to amend this trial based on this new information recognizing the higher risk 
cohort and to maximize patient convenience with this maintenance therapy 
strategy. In addition, the treatment plan was revised to initiate N-803 dosing 
closer post-HCT (from a window of Day 60 - Day 100) to as close to Day 42 as 
feasible, and no later than Day 60 post-transplant. Starting anti-tumor 
maintenance earlier is a logical goal, while continuing GVHD prophylaxis per 
individual institutional practice. This decision is supported by an ongoing clinical 
study (NCT02782546) which administers 4 doses of N-803 subcutaneously 
between on Day +7 and Day +17 after a RIC allo-HCT (Day 0)/haploidentical 
NK cells on Day +7 without an increased incidence of GVHD (Todd Fehniger, 
MD - personal communication). 
 
 
 


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3 Study Design 
This is a single-arm, multi-center Phase II trial using IL-15 super-agonist complex 
(N-803) maintenance after allogeneic hematopoietic cell transplant (alloHCT) for 
acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). The 
primary objective is to determine if post-transplant N-803 effectively reduces 
relapse as measured by the cumulative incidence of relapse between the 1st dose 
of N-803 (Day 42 to Day 60 post-transplant) and two years after RIC alloHCT. The 
rationale is that N-803 will enhance allogeneic immunity through activation and 
expansion of donor-derived NK cells and CD8+ T cells capable of mediating a 
response to remaining leukemia cells (minimal residual disease, MRD); therefore 
decreasing relapse rates. A secondary aim is to achieve this goal without increasing 
frequency or severity of graft-versus-host disease (GVHD). 
 
In this study N-803 is given at 6 mcg/kg subcutaneously (SQ) once every 4 weeks 
to a maximum of 10 doses. Treatment must begin between Day 42 and Day 60 
post-transplant with the goal to enroll patients as close to Day 42 as feasible as 
starting anti-tumor maintenance is a logical goal. GVHD prophylaxis will continue 
per individual institutional standard practice. Follow-up for late toxicity, disease 
status, and survival continues for 2 years from alloHCT. 
 
Sixty patients are planned for enrollment with an analysis for futility after 40 patients 
are enrolled (while enrollment continues). The trial will be discontinued if the 
cumulative incidence estimate of 2 year relapse is projected at >34%. Otherwise, 
enrollment continues to complete the trial in the absence of excessive toxicity as 
monitored by early stopping rules. 
 
We hypothesize that risk of acute graft versus host disease (GVHD) and Grade 4-
5 non-relapse toxicity following N-803 treatment could vary by donor type. 
Therefore, we will count events towards the stopping rules separately for each 
donor type (sibling, umbilical cord blood, unrelated, and haploidentical) as follows: 
1) Grade III-IV acute GVHD by Day 120 post-transplant 
2) Grade 4 and 5 non-relapse toxicity by Day 120 post-transplant 
 
Note: Overall enrollment is irrespective of donor type. If a stopping rule is met for 
one donor type, enrollment will be suspended for that group only. Enrollment for all 
other donor groups may continue until the maximum study size is reached. 
 
 
 


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4 Patient Selection 
Study entry is open to adults 18 years and older regardless of gender, race or ethnic 
background. While there will be every effort to seek out and include females and 
minority patients, the patient population is expected to be no different than other 
transplant studies for AML and MDS at the participating institutions.  
 
Depending on institutional practices, the patient may be presented with the study 
prior to transplant; however, final eligibility cannot be established until post-
transplant. The treatment consent must be signed within 28 days of planned 
treatment start. If the consent is signed during pre-screening, the patient must sign 
a new consent or initial and date the prior consent if it is still the current IRB-
approved consent.   
4.1 Inclusion Criteria 
4.1.1 Diagnosis of acute myelogenous leukemia (AML) or myelodysplastic 
syndrome (MDS) for whom an allogeneic hematopoietic stem cell 
transplant using a reduced intensity conditioning is planned or has been 
performed and patient is prior to Day 60 post-transplant.  
 
4.1.2 Able to begin study treatment between Day 42 and Day 60 after the 
transplant and meets the following transplant related requirements: 
• 
Sustained neutrophil (ANC > 1000/mcL for 3 consecutive days 
without growth factor) and platelet (> 30,000/ mcL without growth 
factors or transfusions) engraftment 
• >50% donor myeloid and lymphoid chimerism in blood or bone 
marrow on most recent bone marrow (BM) evaluation 
• No morphologic evidence of relapse (< 5% bone marrow blasts) on 
most recent BM evaluation (Day 21 or 28 post-transplant is 
acceptable) 
• Being followed in the outpatient setting (not an inpatient) 
• No plan of giving other anti-cancer treatment directed at the 
diseases under study (i.e. maintenance therapy [e.g. sorafenib for 
FLT3m+ AML or hypomethylating therapy], additional therapy for 
MDS) 
 
4.1.3 If acute GVHD is present it must be clinically improving on topical 
steroids and/or on low dose systemic steroids (≤ 0.3 mg/kg/day 
prednisone) and with clinical stability for at least 1 week prior to 
determination of eligibility. GVHD prophylaxis will be continued per 
individual institutional standard practice 
 


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4.1.4 One of the following donor graft sources used for the transplant: 
• sibling donor 
• haploidentical donor [with post-transplant cyclophosphamide] 
• unrelated donor 
• unrelated umbilical cord blood 
 
4.1.5 ≥ 18 years of age  
 
4.1.6 Karnofsky performance status ≥ 70% (Appendix I) 
 
4.1.7 Adequate organ function within 14 days of study enrollment defined as: 
• Renal:  serum creatinine:  ≤ 2.0 mg/dL  
• Hepatic:  SGOT ≤ 3 x upper limit of institutional normal (ULN)  
 
4.1.8 Sexually active females of child-bearing potential and males with 
partners of child bearing potential must agree to use effective 
contraception during therapy and for 4 months after completion of 
therapy 
 
4.1.9 Voluntary written consent prior to the performance of any research 
related procedures 
4.2 Exclusion Criteria 
4.2.1 Prior N-803 (previously known as ALT-803) 
 
4.2.2 Pregnant or breastfeeding – N-803 is an investigational agent. Women 
of child-bearing potential must have a negative pregnancy test at 
screening 
 
4.2.3 Class II or greater New York Heart Association Functional Classification 
criteria (Appendix I) or serious cardiac arrhythmias likely to increase the 
risk of cardiac complications of cytokine therapy (e.g. ventricular 
tachycardia, 
frequent 
ventricular 
ectopy, 
or 
supraventricular 
tachyarrhythmia requiring chronic therapy) 
 
4.2.4 Marked baseline prolongation of QT/QTc interval (e.g. demonstration of 
a QTc interval > 500 milliseconds) 
 


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4.2.5 Active uncontrolled bacterial, fungal, or viral infections – all prior 
infections must be under control following therapy and must be afebrile 
for at least 24 hours at time of enrollment  
 
4.2.6 Active autoimmune disease requiring systemic immunosuppressive 
therapy (GVHD prophylaxis is permitted per institutional practice) 
 
4.2.7 History of severe asthma and currently on chronic systemic medications 
(mild asthma requiring inhaled steroids only is eligible) 
 
4.2.8 Received any investigational agent within the 14 days before the start of 
study treatment (1st dose of N-803) 
 
 
5 Patient Screening and Enrollment 
Depending on institutional practices, the patient may be presented with the study 
consent prior to transplant; however, final eligibility cannot be established until 
post-transplant.  
 
Written consent must be obtained prior to the performance of any research related 
tests or procedures. Consent is obtained before eligibility is confirmed. 
5.1 Enrollment with the University of Minnesota Clinical Trials Office 
Any patient who is consented is to be entered in OnCore by the site Study 
Coordinator or designee.  
 
If a patient is consented but is not enrolled in the study treatment (i.e. is found 
to be ineligible), the patient’s record is updated in OnCore as a screen failure 
and reason for exclusion recorded.  
 
Complete enrollment information is found in the study’s Procedures Manual for 
Participating Sites. 
 
In addition, participating institutions are responsible for fulfilling any local study 
registration requirements. 
5.2 Patient Enrollment to Study Treatment in OnCore 
To be eligible for study treatment, the patient must sign the treatment consent 
and meet each inclusion criteria and none of the exclusion criteria on the 
eligibility checklist based on an eligibility assessment documented in the 
patient’s medical record. 


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5.3 Patients Who Do Not Begin Study Treatment 
If a patient is enrolled in the study (i.e. assigned a sequence number) and is 
later found unable to begin N-803 by Day 60, the patient will be removed from 
study and treated at the physician’s discretion. The study staff will update 
OnCore of the patient’s non-treatment status (off study) with the reason for 
removal from study prior to starting study treatment clearly indicated. The 
patient will be replaced to complete enrollment. 
 
 
6 Treatment Plan 
In order to provide optimal patient care and to account for individual medical 
conditions, investigator discretion may be used in the prescribing of all supportive 
care drug therapy (i.e. acetaminophen, diphenhydramine, antimicrobials, etc.).  
 
The use of systemic steroid medications may result in loss of therapeutic effects 
of the study drug and should be avoided. Standard of care GVHD prophylaxis is 
permitted per institutional practice. Topical steroid cream is permitted. 
 
CMV and other viral prophylaxis/management will be per institutional practice. 
6.1 
N-803 Administration 
Treatment is given as an outpatient. 
 
N-803 at 6 mcg/kg is administered subcutaneously on Day 1 of a 28 day cycle 
for a maximum of 10 doses, or until relapse, unacceptable toxicity, or patient 
refusal, whichever comes earlier.  
 
A window of ±1 week is permitted for each “monthly” N-803 injection in the 
event of scheduling issues (i.e. holiday, bad weather or other scheduling 
issues) but the first dose must be given by Day 60. There is no resetting of the 
treatment calendar when a treatment window is used as the recommended 
schedule for N-803, in general is every 3 to 4 weeks. At minimum of 3 weeks 
must separate each injection. 
 
N-803 dosing is calculated using a weight obtained within 7 days prior to the 
first dose. For patients > 100 kilograms weight, the N-803 dose is calculated 
using a weight capped at 100 kg. The patient’s weight is re-checked prior to 
each dose (within 7 days) and the dose re-calculated if ≥ 10% change from the 
weight used for the previous dose calculation. Rounding of a dose is permitted 
per institutional policy. 


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If the total subcutaneous dose is greater than 1.5 mL volume, the dose will be 
divided by the pharmacist into 2-3 subcutaneous injections as needed. 
Injections are given in the abdominal area. The injection site should be rotated 
per institutional guidelines and each injection site separated by at least 1 inch.  
 
Pre-medication 
Use of pre-medications is at the discretion of the treating physician on an 
individual patient basis. Acetaminophen may be given prior to the injection to 
reduce the intensity of the fever that often occurs a few hours later.  
 
Required post N-803 dose monitoring  
Patients will be observed for a minimum of 2 hours after the 1st dose of N-
803 for immediate adverse events. Vital signs (heart rate, blood pressure, 
respiration, temperature, and oxygen saturation) will be documented prior to 
the N-803 injection and then at 30, 60 and 120 minutes with a ± 20 minute 
window for each time point.  
 
If the 1st dose of N-803 is well tolerated, subsequent doses may be 
administered with a 30 minute post dosing observation period. Vital signs 
(heart rate, blood pressure, respiration, temperature, and oxygen saturation) 
will be documented prior to each N-803 injection and then at 30 minutes ± 10 
minutes. 
6.1.1 Provider’s Assessment Prior to Each N-803 
In order to proceed with a planned N-803 injection, a provider must assess the 
patient prior to administration to rule-out any of the following contraindications 
for dosing: 
• the previous injection site reaction is not showing signs of resolving 
(improving) based on measurement or intensity 
• signs or symptoms of a new infection 
• fever > 101°F (38.3 °C) 
• there are signs or symptoms of new acute GVHD as evidenced by new skin 
rash outside of the injection reaction area 
• there is clinical progression of existing acute GVHD 
• there are signs or symptoms of relapse 
 
The N-803 dose will be delayed for 1 week if one or more of the above 
conditions are present. Refer to Section 6.2 GVHD Management Guidance in 
the event of new (or suspected) aGVHD or worsening of existing aGVHD. 
 


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In addition, N-803 may be delayed for 1 week on the day of a planned dose for 
either of the following situations: 
• any Grade 3 or greater ongoing N-803 treatment related toxicity (injection 
site reaction, neurologic, increased liver function tests) 
• if in the opinion of the treating physician, holding N-803 would be of benefit 
to the patient   
 
If after a 1 week rest: 
• The patient meets the criteria for treatment, the patient may receive N-803. 
The patient calendar would not be adjusted (reset)  
• The patient does not meet the criteria for treatment or the investigator feels 
holding treatment would be of benefit to the patient, the dosing may be 
skipped with treatment resumed at the next planned date.  
 
There is no resetting of the treatment calendar in OnCore for either 
scheduling issues or delays due to toxicities. Cycle 1 Day 1 is the anchor 
for all subsequent injections spaced every 4 weeks. A ± 1 week window is 
associated with each injection date; however injections should be no closer 
than 3 weeks apart. 
6.1.2 Dose Reduction 
A one-time dose decrease to 4 mcg/kg is allowed for recurrent N-803 related 
constitutional symptoms (e.g. fever, fatigue, muscle aches) interfering with 
activities of daily living (ADL) despite pre-medication. Patients unable to 
tolerate the reduced dose will be discontinued from further N-803. Re-
escalation of the dose is not permitted. 
6.1.3 Inadequate Dosing 
If a patient receives only one dose of N-803, the patient will be taken off 
treatment and followed per Section 8.1. The patient will be fully evaluable for 
safety and toxicity, but replaced in the evaluation of efficacy.  
6.2 GVHD Management Guidance 
New or worsening skin rash outside of injection site area (whether GVHD 
clinically suspected or previously diagnosed) and other GVHD manifestations 
should be managed as described in this section. Refer to Section 7.1 for 
management of skin rash/injection site reaction within the vicinity of the 
injection. 
 
The following guidance is based on GVHD grading criteria using the University 
of Minnesota aGVHD Grading Scale (Appendix III).  


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If new GVHD Grade I or Grade II is clinically suspected or definitive, hold 
N-803 until the next planned dose. N-803 may resume with the next planned 
dose if GVHD is clinically improving with topical steroids and/or low dose 
systemic steroids (prednisone ≤ 0.3 mg/kg/day or equivalent) with clinical 
stability for at least 1 week prior to the planned N-803 injection (and other 
criteria for treatment in Section 6.1 is met).  
 
If new or worsening GVHD Grade III is clinically suspected or definitive, 
hold N-803 until the next planned dose. If the GVHD flare was in the context of 
tapering immunosuppressive medications, one could consider subsequent 
cycles if GVHD is controlled with systemic steroids (≤ 0.3 mg/kg/day) with 
clinical stability for at least 1 week prior to the planned N-803 injection. If GVHD 
flare was not in the context of tapering immunosuppressive medications, one 
should consider permanently discontinuing N-803. If prednisone > 0.3 
mg/kg/day (or equivalent) is required, N-803 will be permanently discontinued. 
 
If new or worsening GVHD Grade IV, N-803 will be permanently discontinued. 
6.3 Supportive Care 
Supportive care will be provided per institutional guidelines and standard of 
care. Guidelines may be updated based on current data/drugs without requiring 
a protocol amendment or be considered a protocol deviation.  
 
At study enrollment, GVHD prophylaxis will be continued according individual 
institutional standard practice. 
 
Supportive care may be given as needed on an individual patient basis 
including, but not limited to: 
Fever - acetaminophen 
Chills - meperidine or morphine sulfate  
Nausea and vomiting - anti-emetics and IV fluids 
Diarrhea - loperamide and fluids after stool testing 
6.4 General Concomitant Medications Guidelines 
Administration of additional glucocorticoids is discouraged during the N-803 
treatment period as the use of systemic steroid medications may result in loss 
of therapeutic effects of the study drug. Sustained use of steroids at a 
prednisone dose > 0.3 mg/kg/day or equivalent (other than standard GVHD 
prophylaxis per institutional practice) or steroid use to treat related toxicity will 


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be an indication to stop N-803. Transient use is permitted as needed per 
standard of care. Topical steroid cream is permitted.  
 
CMV prophylaxis/management will be per institutional practice. 
 
The use of anti-cancer therapies including maintenance therapy, agents that 
affect immunity, and investigational agents, are prohibited while a patient is 
receiving study treatment. 
 
Refer to Section 6.2 for guidelines in the management of GVHD. 
6.5 Duration of Treatment 
N-803 post-transplant may continue for a maximum of 10 doses unless one of 
the following occurs: 
• unacceptable toxicity 
• development of Grade IV aGVHD (refer to Appendix III) or GVHD requires 
steroid dose > 0.3 mg/kg/day prednisone or equivalent 
• initiation of new anti-cancer therapy or other prohibited therapy (including 
approved therapies, investigational agents, agents that affect immunity)  
• consent is withdrawn or patient is not compliant 
 
An End of Treatment (EOT) visit occurs 4 weeks (± 1 week) after the last dose 
of N-803 to assess for signs of acute GVHD and N-803 related toxicity. 
 
All patients will be followed per Section 8.1 and evaluable per Section 13.1. 
6.6 Duration of Study Participation 
Patients are followed for late toxicity, disease status, and survival for 2 years 
from the date of transplant, unless one of the following occurs: 
• consent is withdrawn  
• patient is discharged to hospice and/or not returning to the study site for 
routine post-transplant follow-up – in these cases, follow-up information 
including date and cause of death may be obtained, as available from other 
sources (i.e. BMT database). 
  
 
 


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7 Management of Injection Site Reactions/Skin Rash in 
Association with N-803 
Based on current experience, localized skin rashes are common with 
subcutaneous administration. If a rash occurs and the rash area surrounding the 
N-803 injection site is > 6 cm or symptomatic (painful and/or itchy), it may be 
treated with topical 0.05% clobetasol propionate (i.e. 0.05% Cormax) or 0.1% 
triamcinolone (i.e., Kenalog) cream. Diphenhydramine may be administered pre- 
and post-dosing (25-50 mg TID orally x 2 days) of N-803 at the discretion of the 
treating physician.  
 
Usually the rash associated with an N-803 starts small at the site of the injection 
and spreads outwardly sometimes covering a large area of the abdomen. It 
generally resolves within 7 days of treatment. Patients will be instructed to contact 
a member of the study team for rashes outside of the injection site area and/or 
lasting more than 7 days. 
 
8 Clinical Evaluations and Procedures 
Scheduled evaluations during the treatment cycles may be performed up to 3 days 
before (-3 days) the targeted date with the additional visits during Cycle 1 having a 
±1 day window.  
 
A window of ±1 week for the N-803 dosing is allowed in the event of scheduling 
issues. Treatment may be delayed for 1 week for toxicity related reasons as detailed 
in Section 6.1.1; however, if treatment cannot be given after a 1 week delay, 
treatment will be held until the next planned dose.  
 
The End of Treatment (EOT) visit (4 weeks after the last dose of N-803) may be 
scheduled using a ±1 week. After the EOT visit, follow-up for this study will coincide 
with the standard of care transplant follow-up schedule through 2 years post-
transplant. In addition, targeted days may be altered as clinically appropriate. 
 
8.1 Required Clinical Care Evaluations 
 
 
Optional 
Pre-
Screening 
(prior to 
transplant or 
later) 
Screening1 
within 30 
days unless 
o/w noted 
Day of N-
803 
dosing 
Day 1  
(-7 days) 
With 1st Dose only 
Cycle 3 
and 6 only  
Day 8 (±1 
day) 
End of 
Treatment 
(EOT) Visit (4 
weeks ±1 week 
after final N-803 
dose) 
Follow-up for 
2 year post 
HCT5 
Day 8 
(±1 day) 
Day 15 
(±1 day) 
 
Initial Presentation 
of Study  
optional 
 
 
 
 
 
 
 
Consent 
optional 
X 
 
 
 
 
 
 


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Screening 
Assessment 
 
X 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
X 
Concomitant 
Medications 
associated with 
treating an injection 
site reaction per 
Section 7.1 
 
 
X 
X 
X 
 
X 
 
Late Toxicity 
Assessment 
 
 
 
 
 
 
X 
X 
Physical Exam  
 
X 
X 
 
 
 
 
X 
Provider 
Assessment per 
Section 6.1.1 
 
X 
X 
X 
X 
 
 
 
Assess for GVHD 
 
X 
X 
 
 
 
X 
 
Weight 
 
X 
X 
 
 
 
X 
 
Vitals, Pulse 
Oximetry 
 
X 
X 
X 
X 
 
X 
 
Performance 
Status 
 
X 
 
X 
 
 
X 
 
CBC, diff, plt 
 
X 
X 
X 
X 
X 
X 
 
CMV surveillance 
 
Weekly through Day 100 
 
EBV and other 
viral monitoring 
 
Per individual institutional usual practice 
 
Comprehensive 
Metabolic Panel 
(CMP) or 
equivalent2 
 
X 
X 
X 
X 
 
X 
 
Pregnancy 
Testing3 
 
X 
 
 
 
 
 
 
Peripheral Blood 
Chimerism 
 
X 
 
 
 
 
 
 
Bone Marrow 
Biopsy 
Day -21 or -28 bx 
acceptable 
At time of post-transplant SOC BM bx (i.e. Day +100, Day +180, 1 year, 2 year)4 
Bone Marrow 
Chimerism 
Day -21 or -28 bx 
acceptable 
At time of post-transplant SOC BM bx (i.e. Day +100, Day +180, 1 year, 2 year)4 
MRD by flow pf 
BM aspirate 
Day -21 or -28 bx 
acceptable 
At time of post-transplant SOC BM bx (i.e. Day +100, Day +180, 1 year, 2 year)4 
Disease Staging 
 
 
 
 
 
 
 
X 
Survival Status 
 
 
 
 
 
 
 
X 
1 –within 14 days for labs required for eligibility per Section 4.1.7, if consent signed during pre-screening, patient must sign a new consent or initial 
and date prior consent if it is still the current IRB approved consent   
2– comprehensive metabolic panel consists of albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), blood urea nitrogen (BUN), calcium, creatinine, glucose, lytes (CO2, Cl, Na, K), total bilirubin, and total protein 
3- women of child bearing potential – urine or serum  
4-for UMN only:  at the time of SOC bm bx collect an additional 30 ml aspirate for TTL 
5–unless unevaluable, withdraws consent, or is discharged to hospice/not returning to study site per Section 6.6; death should be recorded upon 
knowledge per Section 10.5 
 
 
8.2 
Research Related Tests and Procedures 
 
 
Lead Lab Study 
Section 
Baseline 
All Doses 
Cycle 1, 3, 6 
Cycle 1 only 
At the End of 
Treatment 
(EOT) visit 
 
Day 1 (day of planned 
dose)2 before N-803 
is given 
Day 8  
Day 15 
ECG 
 
X 
 
 
 
 


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50 ml of heparinized blood (5 
green top tubes) 1 
Masonic Cancer 
Center TTL 
Section 8.2.1 
 
X 
X 
X 
X 
10 ml of serum (1 red top tube) 1 
 
X 
X 
X 
X 
Immunogenicity: 5 ml of serum 
(1 red top tube)3 
Site batch ships 
to ImmunityBio, 
Inc per, Section 
8.2.2 
 
X 
X 
X 
X 
UMN Only: 30 ml or lesser 
based on the amount of aspirate 
that can be obtained  
 
At time of each BM biopsy and aspirate done for clinical purposes 
Toxicity Notation 
 
Refer to Section 10.2 for documentation requirements 
Targeted Toxicities 
 
Refer to Section 10.2 for documentation requirements 
Completion of the Infection 
CRF 
 
On day of planned dose and EOT visit 
Review of Patient Diary of 
Injection Reactions 
 
 
At each treatment visit and the EOT visit 
1 
Samples, other than for immunogenicity, are shipped the day of collection (Monday-Thursday) for next 
day delivery to the Masonic Cancer Center’s Translational Therapy Lab (TTL). 
2 
Collect research samples as scheduled even if N-803 dose is delayed, but do not collect a 2nd of 
samples if patient is treated 1 week later  
3 
Immunogenicity samples are stored frozen at the study site until the time of batch shipping directly to 
ImmunityBio, Inc’s central laboratory. 
 
Refer to the Laboratory Manual for additional details. 
 
Note: if a patient is not abiding by the required clinical care calendar (Section 8.1), 
the collection schedule of the toxicity (adverse event) data and research related 
samples schedule may be altered or discontinued on an individual patient basis, 
as appropriate. It will not be a protocol deviation if a research related sample 
collection is not done because the patient did not comply with the standard of care 
visit. 
 
It is recognized that with novel therapies as used in this study, the timing of protocol 
directed research samples may miss important patient specific events. For this 
reason, up to 3 extra samples of 60 ml of blood each may be drawn at additional 
relevant time points (i.e. development of GVHD, relapse, change in blood counts 
(lymphocytosis)) as per the PI’s opinion, and are not specified above.  
8.2.1 Assessment of Immune Activation (TTL) 
Samples to evaluate lymphocyte number, phenotype and function will be 
collected as detailed above for the Masonic Cancer Center Translational 
Therapy Lab (TTL) along with serum (red top tubes) for measure of cytokines 
that can reflect immune activation. 
 
Flow cytometry analysis of a fraction of the PBMC will detect surface markers 
that define lymphocyte subsets (NK, NKT, B, and T cells, both CD4 and CD8), 
as well as intracellular markers that define regulatory T cells (Foxp3) and 
proliferating cells (Ki67). All remaining PBMC will be cryopreserved in 10% 


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DMSO and stored in liquid nitrogen for future testing, if subject agreed to future 
storage at the time of initial consent. 
8.2.2 Immunogenicity (ImmunityBio, Inc) 
Immunogenicity assays will be performed at ImmunityBio, Inc. Serum samples 
for immunogenicity testing will be collected for all. The collection schedule is 
specified in the Study Calendar. One 5 mL silicone coated (red top) tube per 
time point will be collected.  
 
The collected blood samples will be processed (centrifuge at 1000-1500 x g for 
10 minutes) at the study site and the serum portion will be frozen and shipped 
to ImmunityBio, Inc in batches upon request for evaluation using validated 
ELISA methods.  
 
In these tests, human anti-N-803 antibodies are detected in patient serum 
samples using a direct sandwich ELISA method with plates coated with N-803. 
After the appropriate wash conditions, biotinylated N-803 is used for detection 
with standard HRP-labeled streptavidin reagents. For analysis of clinical 
samples, anti-IL-15 antibody serve as reference standard and serum from N-
803 immunized mice serve as a positive control. The level of anti-N-803 
antibody in patient samples is determined based on the anti-IL-15 antibody 
standard curve. 
 
9 N-803 Formulation, Supply, and Potential Toxicity 
N-803 (previously known as ALT-803 - Altor BioScience is now a wholly owned 
subsidiary of ImmunityBio, Inc.) is a recombinant human superagonist IL-15 
complex. Its active ingredient is N-803 and its pharmacologic class is an anti-
cancer and anti-viral immunotherapeutic. 
 
N-803 has been referred to as IL-15N72D:IL-15RαSu/IgG1 Fc complex in various 
preclinical study reports, publications, and other related documents.  
 
N-803 is an IL-15-based immunostimulatory protein complex that acts as a growth 
and activation factor for NK cells and effector and memory T cells. Based on the 
results of animal tumor models, N-803 stimulated cellular immune responses 
are expected to exhibit potent activity against human tumor cells. Due to the 
higher affinity single amino acid substituted IL-15 variant and the presentation of 
IL-15 with IL-15RαSu, N-803 is likely to be effective at low concentrations. 
Owning to its longer half-life as a result of fusion with Fc, N-803 is likely to be 
effective using a practical regimen of every 4 week injections in this patient 


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population. It is likely that low concentrations of N-803 will increase the 
peripheral blood T cell and NK cell counts to predictable levels with a safety 
profile appropriate for outpatient use. 
9.1 Structural Formula 
N-803 is a soluble complex consisting of 2 protein subunits of a human IL-15 
variant associated with high affinity to a dimeric IL-15R sushi domain/human 
IgG1 Fc fusion protein. The IL-15 variant is a 114 aa polypeptide comprising 
the mature human IL-15 cytokine sequence with an Asn to Asp substitution at 
position 72 of helix C (N72D).6. The human IL-15R sushi domain/human IgG1 
Fc fusion protein comprises the sushi domain of the IL-15R subunit (aa 1-65 of 
the mature human IL-15Rα protein) linked with the human IgG1 CH2-CH3 
region containing the Fc domain (232 amino acids). Aside from the N72D 
substitution, all of the protein sequences are human. Based on the amino acid 
sequence of the subunits, calculated molecular weight of the complex 
comprising 2 IL-15N72D polypeptides and a disulfide linked homodimeric IL-
15RαSu/IgG1 Fc protein is 92.4 kDa. Each IL-15N72D polypeptide has a 
calculated molecular weight of approximately 12.8 kDa and the IL-
15RαSu/IgG1 Fc fusion protein has a calculated molecular weight of 
approximately 33.4 kDa. Both the IL-15N72D and IL-15RαSu/IgG1 Fc proteins 
are glycosylated resulting in an apparent molecular weight of N-803 as 
approximately 114 kDa by size exclusion chromatography. The isoelectric point 
(pI) determined for N-803 range from approximately 5.6 to 6.5. Thus, the fusion 
protein is negatively charged at pH 7. The calculated molar extinction 
coefficient at A280 for N-803 is 116,540 M-1, or 1.26 OD280 for a 1 mg/mL 
solution of ALT-801, or one OD280 is equivalent to 0.79 mg/mL solution of N-
803. 
9.2 Formulation  
The biological drug product, N-803, is formulated in a phosphate buffered 
saline (PBS) solution. The solution appears as a clear and colorless liquid. The 
drug substance is produced by a recombinant mammalian cell line and is 
manufactured using a protein free media.  
9.3 Packaging 
Vials are packaged in cartons and shipped to the clinical site. 
9.4 Storage 
N-803 is supplied in a 2-mL single-dose/single-use vial containing 0.6 mL of N-
803 (extractable volume is 0.5 mL) at a concentration of 1 mg/mL or 2 mg/mL. 


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N-803 will be stored at the site in a secured area at 2°C to 8°C with limited 
access and protection from excess light and heat. 
9.5 Study Drug Preparation  
N-803 dosing is calculated using a weight obtained within 7 days prior to the 
first dose. For patients > 100 kilograms weight, the N-803 dose is calculated 
using a weight capped at 100 kg. The patient’s weight is re-checked prior to 
each dose (within 7 days) and the dose re-calculated if ≥ 10% change from the 
weight used for the previous dose calculation. Rounding of a dose is permitted 
per institutional policy. 
The appropriate volume of N-803 is withdrawn.  
If the total subcutaneous dose is greater than 1.5 mL, the dose will be divided 
into 2-3 subcutaneous injections as needed. 
N-803 can be stored in a syringe for up to 24 hours at 4°C.  
9.6 Agent Inventory Records 
The investigator, or a responsible party designated by the investigator (e.g. 
institutional investigational pharmacy), must maintain a record of the inventory 
and disposition of all agents received from ImmunityBio, Inc using the Study 
Agent Drug Accountability Record.  
9.7 Toxicity 
The most common side effects seen in studies with subcutaneous (under the 
skin) injections have been fever, chills, hypoalbuminemia, and injection site 
reaction, and skin rash, which at times has been widespread. These localized 
skins reactions are common (occurring in more than 50% of patients).  
 
In June 2020 an SAE was filed on a study participant who developed atrial 
fibrillation (a-fib) with no prior history resulting in a hospitalization. We identified 
a previous case of a patient who developed a-fib while on treatment from a 
different clinical trial that used N-803 weekly to treat relapse. In both cases of 
a-fib, there were other potential explanations that could have triggered the 
arrhythmia. While we cannot directly attribute causality between N-803 and a-
fib, it is at least possible that they are related, directly or indirectly. A-fib may 
be indirectly triggered in susceptible patients by fevers and/or use of diuretics 
for fluid retention that can be observed with some N803 regimens. Based on 
this information, we decided to add the development of a-fib as a possible rare 
side effect from N-803 in the consent form. 


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Risks of N-803 when given as a subcutaneous injection  
Very common (more than 1 
in 10 patients experience) 
Common (between 1 in 30 and 
1 in 10 patients experience) 
Rare (fewer than 1 in 30 patients 
experience) 
• injection site reaction 
(skin rash), which may 
be large (> 2 inches), 
itchy, and/or painful 
• fever 
• chills 
• anemia 
• change in blood 
pressure 
• nausea 
• swelling of hands or 
feet 
• temporary changes in 
routine lab results 
including decreased 
albumin and decreased 
lymphocytes 
• flu-like symptoms, 
including headache, 
muscle, or joint pain 
• fatigue 
• decreased appetite 
• diarrhea, vomiting 
• abdominal pain 
• itchy skin and/or skin 
irritation 
• shortness of breath 
• high blood sugar 
(hyperglycemia) 
• changes in electrolytes on 
routine lab work 
• inflammatory reaction 
• infection including upper respiratory 
infection 
• atrial fibrillation (a-fib) – may be 
asymptomatic, but when symptoms 
do appear they may include irregular 
and often rapid heartbeat, shortness 
of breath, and fatigue 
Tuberculosis is a potential risk of N-803. One instance of tuberculosis has been 
reported in a participant receiving N-803 in combination with BCG (a live, 
attenuated strain of Mycobacterium bovis) administered into the bladder by a 
urinary catheter. A causal relationship between N-803, in combination with 
BCG, and tuberculosis infection cannot be definitely ruled out. 
 
Anti N-803 antibodies have been detected in subjects receiving N-803. The 
impact of anti-N-803 antibody formation on clinical efficacy and safety of N-803 
is unknown. 
 
Previous editions of the ALT-803 Investigator’s Brochure prior to 2019 relied 
heavily on clinical experience with the related cytokine therapeutic Proleukin® 
Interleukin-2 to anticipate potential risks associated with ALT-803 (N-803) 
administration. This approach was based on the fact that N-803 and IL-2 are 
both γ chain cytokines and thus could reasonably be predicted to have similar 
immunostimulatory properties. However, the substantial accumulated 
information on N-803 effects in humans indicates that many side effects of IL-
2 are not observed in patients treated with N-803 at the doses being used 
clinically. For this reason, side effects observed in subjects treated with IL-2 but 
not N-803, such as capillary leak syndrome, pulmonary dysfunction, acidosis, 
and gastritis, have been removed from the IB and are reflected in this protocol 
and its consent form.   
 
Refer to the current Investigator Brochure (April 2020 version 7) for additional 
information. 


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9.8 Agent Ordering 
N-803 will be shipped by cold chain from ImmunityBio, Inc directly to the study 
site. 
 
10 Adverse Event Monitoring, Documentation, and Reporting 
Toxicity and adverse events will be classified and graded according to NCI's 
Common Terminology Criteria for Adverse Events V 4.0 (CTCAE) and reported on 
the schedule below. A copy of the CTCAE can be downloaded from the CTEP 
home page: 
 (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 
 
The following definitions of adverse events (AEs) and serious adverse events 
(SAEs) will determine whether the event requires expedited reporting via the 
OnCore SAE Report Form in addition to routine documentation in the OnCore AE 
case report form (CRF).  
 
The reporting timeframes for SAEs, product related issues, and other reportable 
events are located in Section 10.6. 
 
Note: Throughout this section the generic term “study drug” refers to the study 
related treatment (N-803 injections). 
10.1 Adverse Event Terminology 
Adverse Event:  Any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug related. 
 
Serious Adverse Event:  An adverse event is considered “serious” if, in the 
view of either the investigator or sponsor, it results in any of the following 
outcomes:  
• Death 
• A life-threatening adverse event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions 
• A congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject 


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and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  
 
Unexpected Event: An adverse event or suspected adverse reaction is 
considered “unexpected” if it is not listed in the investigator brochure or is 
not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the 
risk information described in the general investigational plan or elsewhere 
in the current application, as amended.  
 
The categories for AE attribution to study treatment are as follows:  
• Definite – clearly related 
• Probable – likely related 
• Possible – may be related 
• Unlikely – doubtfully related 
• Unrelated – clearly not related 
 
The following definitions are from the Masonic Cancer Center’s Standard 
Operating Procedure (SOP) Deviation Reporting: 
 
Major Deviation: A deviation or violation that impacts the risks and benefits 
of the research; may impact subject safety, affect the integrity of research 
data and/or affect a subject’s willingness to participate in the research. 
Deviations that place a subject at risk, but do not result in harm are 
considered to be major deviations. 
 
Minor Deviation: A deviation or violation that does not impact subject safety, 
compromise the integrity of research data and/or affect a subject’s 
willingness to participate in the research. 
10.2 AE Documentation Requirements 
Adverse event collection for the purposes of this study will focus on events 
felt to be related to N-803 or events that cannot be attributed to other causes 
(i.e. transplant-related, co-morbidities).  
 
At visits through the End of Treatment visit a targeted toxicity worksheet 
(Appendix IV) will be completed to document select expected toxicities 
associated with N-803 as follows: 
• Prior to each planned N-803 injection 


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• At the end of dose monitoring period (as described in Section 6.1) 
with ±20 minute window for 2 hour monitoring or ±10 minute window 
for 30 minute monitoring 
• Day 8 and Day 15 visits after 1st dose only 
• At the End of Treatment visit 
 
In addition, unexpected events and expected events that are not listed in 
Section 9.7 or the consent form or the IB must also be documented. 
 
Note: if a patient is not abiding by the standard of care study calendar 
(Section 8.1), collection of the corresponding targeted events also may be 
altered or discontinued on an individual patient basis, as appropriate.  
 
After the End of Treatment visit, monitoring for adverse events will become 
less frequent based on the schedule in Section 8.1 and only events that are 
unexpected and at least possibly related to N-803 will be documented upon 
knowledge.  
10.3 SAE Documentation and Reporting 
Any event meeting the definition of an SAE must be documented using the 
paper MCC SAE Report Form. 
 
Any event meeting the definition of serious must be reported to Masonic 
Cancer Center Multisite Program Manager within 24 hours of knowledge. 
Refer to Section 10.6. 
10.4 Early Stopping Rule Event Documentation and Reporting Requirements 
The following event counts toward an early study stopping rule and must be 
reported to the MCC Multisite Program Manager using the Event Form 
found OnCore under the reports tab: 
• Grade III or IV acute GVHD from the day of first dose of N-803 through 
Day 120 after alloHCT (refer to Appendix III for grading) 
• Grade 4 and 5 non-relapse toxicity from the day of first dose of N-803 
through Day 120 after alloHCT 
 
An event that counts toward an early stopping rule does not necessarily 
constitute a SAE and should be reported as such only if it meets the criteria 
for reporting as defined in Section 10.3. 


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10.5 Documentation of Death and Reporting Requirements 
Deaths during the treatment and follow-up period, including due to disease, 
will be recorded as an SAE and reported per Section 10.6. Deaths due to 
disease should be recorded as a Grade 5 Neoplasm.  
 
In addition, the death date and cause must be documented in the patient 
follow-up tab in OnCore upon knowledge using the comment field in the 
survival status section to record the cause. 
 
 


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10.6 Institutional Event Reporting Table 
 
Event Type 
Reporting Timeframe 
Form in OnCore 
to Use 
Report to 
Any event meeting the 
definition of serious and all 
patient deaths 
Within 24 hours of 
knowledge 
SAE Report 
Form 
 
For Participating Sites: 
Masonic Cancer Center (MCC) 
Multisite Program Manager  
affilates@umn.edu. 
 
Local institutional IRB or other 
entities per institutional policies 
and guidelines 
 
 
Stopping Rule Events 
Within 24 hours of 
knowledge 
Stopping Rule 
Event Form 
Major Deviations, as 
defined in Section 10.1. 
Within 5 working days 
of knowledge 
Deviation Report 
Form 
Minor Deviations, as 
defined in Section 10.1. 
Per Institutional Policy 
n/a (record in 
Deviations Tab) 
For UMN MCC: Report to the 
study’s regulatory specialist 
 
For Participating Sites: minor 
deviations are not reportable to 
the MCC Multisite Program 
Manager. Report to local 
institutional IRB or other entities 
per institutional policies and 
guidelines. 
*events occurring at the University of Minnesota are reported to the study’s Regulatory Specialist and 
to the MCC Multisite Program Manager, who will submit to ImmunityBio, Inc and other entities as usual 
 
Individual institutional sites are responsible for reporting any event meeting 
local reporting requirements to their institutional IRB and/or other research 
oversight committees. 
 
 


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10.7 Expedited MCC Reporting Requirements (MCC) 
As the study sponsor, the Masonic Cancer Center has the following expedited 
reporting responsibilities for select events reported in Section 10.6: 
 
11 Study Data Collection and Monitoring 
11.1 Data Management 
This study will collect regulatory and clinical data using University of Minnesota 
CTSI’s instance of OnCore® (Online Enterprise Research Management 
Environment).  
 
The OnCore database resides on dedicated secure and PHI compliant servers. 
All relevant AHC IS procedures related for PHI compliant servers (as required 
by the Center of Excellence for HIPAA Data) apply to OnCore databases. 
 
Additional immune monitoring data about correlative laboratory samples 
generated by the Masonic Cancer Center Translational Therapy Laboratory 
(TTL) from the protocol-directed correlative research samples is stored in their 
Agency 
reporting to 
Criteria for reporting 
Timeframe 
Form to Use 
Submission 
address/email 
address 
U of MN IRB 
(for UMN 
patients only) 
Unanticipated death of a locally enrolled 
subject(s); New or increased risk; Any 
adverse event that requires a change to the 
protocol or consent form – refer to the IRB 
website for complete details  
5 Business 
Days 
RNI 
 
ETHOS 
Deviations that occur at MCC as defined in 
Section 10.1.  
Per current IRB 
requirements 
OnCore Deviation 
Form and IRB 
Report Form 
FDA 
Unexpected and fatal or unexpected and life 
threatening suspected adverse reaction 
no later than 
7 Calendar 
Days 
MCC SAE Report 
Form 
Submit to FDA as 
an amendment to 
IND  
with a copy to 
ImmunityBio, Inc  
and each 
participating site 
 
1) Serious and unexpected suspected 
adverse reaction or 
2)  increased occurrence of serious suspected 
adverse reactions over that listed in the 
protocol or investigator 
brochure or 
3) findings from other sources (other studies, 
animal or in vitro testing) 
no later than 
15 Calendar-
Days 
All other events per CFR 312.33 
At time of 
annual 
report 
Annual report 
Masonic 
Cancer Center 
SAE 
Coordinator 
Events that meet the definition of an early 
study stopping rule event 
At time of 
reporting 
Stopping Rule 
Event Form 
mccsaes@umn.edu 
Nant Inc. 
Any event meeting the definition of an SAE 
Within 24 
hours of 
study team 
knowledge 
MCC SAE Report 
Form 
SAE.Reporting@Na
ntBio.com 
Cc: 
Dawn.Camden@Im
munitybio.com. 


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Laboratory Information Management System (LIMS). The LIMS database 
application is also stored on a production server located in the UMN datacenter 
(WBOB) and is managed by the Academic Health Center 
 
Key study personnel are trained on the use of OnCore and will comply with 
protocol specific instructions embedded within the OnCore. 
11.2 Case Report Forms 
Participant data will be collected using protocol specific electronic case report 
forms (e-CRFs) developed within OnCore based on its library of standardized 
forms. The e-CRF will be approved by the study’s Principal Investigator and the 
Biostatistician prior to release for use. The Study Coordinator or designee will 
be responsible for registering the patient into OnCore at time of study entry, 
completing e-CRFs based on the patient specific calendar, and updating the 
patient record until patient death or end of required study participation.  
11.3 Data and Safety Monitoring Plan (DSMP) 
The study’s Data and Safety Monitoring Plan will be in compliance with the 
University of Minnesota Masonic Cancer Center's Data & Safety Monitoring 
Plan (DSMP), which may be accessed at http://z.umn.edu/dmsp.  
 
For the purposes of data and safety monitoring, this study is classified as high 
risk (under a locally held IND). Therefore, the following requirements will be 
fulfilled at the University of Minnesota and at participating sites: 
▪ At least quarterly review of the study’s progress by the Masonic Cancer 
Center Data and Safety Monitoring Council (DSMC). 
▪ The University of Minnesota (lead site) Principal Investigator will comply 
with at least twice yearly monitoring of the project by the Masonic Cancer 
Center monitoring services. 
▪ The local site PIs will comply with at least twice yearly monitoring of the 
project by each site’s internal monitoring staff. 
▪ The University of Minnesota (lead site) Principal Investigator will oversee 
the submission of all reportable adverse events per Section 10.7 to the 
Masonic Cancer Center’s SAE Coordinator, the University of Minnesota 
IRB; and oversee the submission of all reportable adverse events to the 
FDA and to ImmunityBio, Inc. 
▪ The University of Minnesota (Sponsor) and the MCC CTO have oversight 
responsibility for trial monitoring at participating sites. 
 
 
 


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IND Annual Reports 
In accordance with regulation 21 CFR § 312.33, the IND sponsor (Dr. Miller) 
will submit a progress report annually. The report is submitted within 60 days 
of the anniversary date that the IND went into effect. A copy of the report will 
be provided to ImmunityBio, Inc. 
11.4 Participating Site Monitoring 
The PI (Dr. Miller) with the CTO has oversight responsibility for trial monitoring 
at participating sites.  
 
Participating sites must self-monitor following the University of Minnesota 
Masonic Cancer Center Data and Safety Monitoring Plan (DSMP - 
http://z.umn.edu/dmsp).  
 
The investigator will permit study-related monitoring, audits, and inspections by 
the study’s Principal Investigator and/or IND sponsor and/or any designees, the 
local IRB, government regulatory bodies, and University of Minnesota 
compliance groups. The investigator will make available all study related 
documents (e.g. source documents, regulatory documents, data collection 
instruments, study data, etc.). The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.) will be available for trial related monitoring, audits, or regulatory 
inspections. 
11.5 Teleconferences – Lead Site and Participating Sites  
Regular teleconferences will be held to facilitate communication between 
participating sites regarding the study’s progress, patient updates, summary of 
safety reports, case report form completion, and other issues for discussion. 
The University of Minnesota Multisite Program Manager is responsible for 
arranging these teleconferences and preparing the agenda. Meetings will occur 
every 2 weeks; however, these may be scheduled more or less frequently at 
the discretion of the lead institution. Participation of a minimum of one 
representative from each participating site is expected. These teleconferences 
are in addition to other previously described site interactions including 
centralized patient registration, institutional and MCC required reporting of 
safety related issues, case report form completion in the study’s central 
database (OnCore) and participating site oversight through self-monitoring in 
compliance with the Masonic Cancer Center’s Data and Safety Monitoring plan.  


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11.6 Record Retention 
The investigator will retain study records including source data, copies of case 
report forms, consent forms, HIPAA authorizations, and all study 
correspondence in a secured facility for at least 6 years after the study file is 
closed with the IRB and FDA.  
 
Please contact the CTO before destroying any study related records. 
 
 
12 Study Endpoints  
12.1 Primary Endpoint 
The primary endpoint will be cumulative incidence of relapse evaluated 
between the day of the first dose of N-803 (approximately 42 days after 
alloHCT, but as late as 60 days) and two years after alloHCT. 
12.2 Secondary Endpoints 
Secondary endpoints include safety and efficacy outcomes listed below. 
• Frequency of adverse and serious adverse events 
• Description of N-803 dose intensity based on the number of doses given 
out of the number planned (10 doses) 
• Incidence of relapse at two years after alloHCT stratified by number of 
doses of N-803 (1-3 or 4-10). 
• Incidence of Grade II-IV and Grade III-IV acute/late acute graft-versus-host-
disease (GVHD) at 100 and 180 days after alloHCT 
• Incidence of chronic graft-versus-host disease (GVHD) at one year after 
alloHCT 
• Incidence of cytogenetic and flow cytometry positive minimal residual 
disease (MRD) post-transplant (before and after N-803) 
• Overall survival at two years after alloHCT 
• Incidence of non-relapse mortality at two years after alloHCT 
 
 
13 Statistical Considerations  
13.1 Objectives and Study Design 
This is a single-arm, open-label, multi-center phase II trial with discontinuation 
for futility using IL-15 super-agonist complex (N-803) maintenance after 
alloHCT for AML and MDS. The primary objective is to determine if post-
transplant N-803 effectively reduces relapse from a historical estimate of 35% 
to 20% in the study cohort as measured by cumulative incidence of relapse 


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between the 1st dose of N-803 and 2 years after alloHCT. A total of 60 
subjects will be enrolled if the trial reaches conclusion. An analysis for futility 
will be carried out after 40 patients have been enrolled (without pause in 
enrollment). A secondary aim is to achieve this goal without increasing the 
frequency or severity of graft-versus-host disease (GVHD). 
 
Follow-up for disease status, toxicity, and survival will be done for 2 years 
from alloHCT (i.e., 22 months after 1st administration of N-803). Patients are 
considered evaluable if they receive the first dose of N-803.  
13.2 Statistical Analysis 
Analysis Population 
The primary analysis will be intent-to-treat in that all patients receiving the first 
dose of study drug will be evaluable for relapse. This single arm study will 
compare the cumulative incidence of relapse of N-803 treated patients to an 
historical controls estimate of 35% at 2 years. This estimate is based on data 
of AML or MDS patients from the University of Minnesota as well as data from 
the Center for International Blood and Marrow Transplant Research 
(CIBMTR). 
 
Analysis of the Primary Endpoint 
Relapse and non-relapse mortality at 2 years and their respective 95% 
confidence intervals will be calculated using the cumulative incidence 
function, considering the other event as a competing risk18. For the final test, 
the incidence of relapse will be compared to the historical estimate of 35% 
using a one sample log-rank test with an assumed exponential distribution for 
the null hypothesis with one-sided alpha = 0.05. Interim analysis for futility will 
be carried out after 40 patients have been enrolled (without pause in 
enrollment). If the cumulative incidence of relapse is projected to be greater 
than 34%, enrollment will be suspended, otherwise enrollment will continue 
until 60 subjects have been accrued. 
 
Secondary Analysis 
Adverse events, tolerability, immunogenicity and MRD will be tabulated with 
frequencies and percentages. The function of NK cells, T cells, T regulatory 
cells and myeloid derived suppressor cells pre- and post N-803 therapy and 
cytokines will be correlated with response using the Wilcoxon rank-sum test. 
Overall survival at 2 years and its 95% confidence interval will be estimated 
by the Kaplan-Meier curve19. GVHD and their 95% confidence intervals will 
be calculated using the cumulative incidence function, with death as a 
competing risk20.  


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Cumulative incidence of relapse at 2 years and 95% confidence intervals will 
be described for the following subgroups: patients who receive 1-3 doses of 
N-803, and patients who receive 4-10 doses of N-803. 
 
All primary and secondary outcomes will be described overall and for each 
donor type. Comparison of relapse versus historical controls will be made for 
the pooled cohort only. 
13.3 Sample Size and Power 
This study is designed as a Phase II trial to estimate relapse from 42 days to 
2 years post-transplant. We will potentially enroll a total of 60 patients with 
one interim analysis (without pause in enrollment) at 40 subjects to test for 
futility. Since the goal is to estimate the relapse at a long-term time-point (2 
years), we ran a simulated exponential model 10,000 times based on 
complete follow-up and a one-sided log-rank test through 2 years with interim 
analysis based on accrual of 40 subjects with incomplete follow-up to 
generate sample size and power estimates. 
 
Based on interim analysis of the first 40 patients, we will discontinue the trial 
if the projected cumulative incidence curve has an estimated 2 year relapse 
of >34%. Assuming the null hypothesis of 35% relapse is true, we have a 25-
50% chance of stopping the trial early due to futility depending on the rate of 
initial accrual. Assuming the alternative hypothesis of 20% relapse from 42 
days to 2 years, we have an overall power of approximately 80%.  
 
Accrual 
We expect to complete the study after 2 years of enrollment plus 2 years 
follow up after the last enrolled patient. The study was suspended in October 
2018 to rewrite the protocol using every 4 week N-803 dosing. The study re-
opened to accrual in May 2019, but was suspended in March 2020 due to 
COVID-19.  
13.4 Stopping Rules 
We hypothesize that risk of acute graft versus host disease (GVHD) and 
Grade 4-5 non-relapse toxicity following N-803 treatment could vary by donor 
type. Therefore, there will be separate stopping rules for each donor type 
(sibling, umbilical cord blood, unrelated, and haploidentical)21. If a stopping 
rule is met for one donor type, enrollment will be suspended for that group 
only. Enrollment for all other donor groups may continue until the maximum 
study size is reached. Note: overall enrollment is irrespective of donor type. 


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13.4.1 Grade III-IV acute GVHD 
Grade III-IV acute GVHD between Day 42 and Day 60 has been near 10% 
in adult alloHCT for AML and MDS. We will stop for unacceptably high 
Grade III-IV acute GVHD when 2/4, 3/9, 4/14, or 5 patients at any time are 
diagnosed in a donor group, from the day of first dose of N-803 through Day 
120 after allo-HCT. If the true acute GVHD incidence is 10% (expected), 
there is a 9% probability of stopping in a given group. If the true acute GVHD 
incidence is 30% (unacceptable), there is a 71% probability of stopping, with 
an expected number of 9 patients treated in that group. These expectations 
are based on an assumed group size of 15, but the group sizes will not be 
fixed. 
13.4.2 Grade 4 and 5 Non-Relapse Toxicity  
Grade 4 and 5 non-relapse toxicity between Day 42 and Day 60 is expected 
to be near 10% in adult alloHCT for AML and MDS. We will stop for 
unacceptably high Grade 4 and 5 non-relapse toxicity when 2/4, 3/9, 4/14, 
or 5 patients at any time have toxicity in a donor group, from the day of first 
dose of N-803 through Day 60 after alloHCT. If the true incidence of toxicity 
is 10% (expected), there is a 9% probability of stopping in a given group. If 
the true incidence is 30% (unacceptable), there is a 71% probability of 
stopping, with an expected number of 9 patients treated in that group. These 
expectations are based on an assumed group size of 15, but the group sizes 
will not be fixed. 
 
 
14 Conduct of the Study 
14.1 Good Clinical Practice 
The study will be conducted in accordance the appropriate regulatory 
requirement(s). Essential clinical documents are maintained to demonstrate 
the validity of the study and the integrity of the data collected. Master files 
should be established at the beginning of the study, maintained for the duration 
of the study and retained according to the appropriate regulations.  
14.2 Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in 
the Declaration of Helsinki. The IRB will review all appropriate study 
documentation in order to safeguard the rights, safety and well-being of the 
patients. The study will only be conducted at sites where IRB approval has 
been obtained. The protocol, consent, written information given to the patients, 


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safety updates, progress reports, and any revisions to these documents will be 
provided to the IRB by the Investigator.  
 
 
15 References 
 
1. Chiorean EG, DeFor TE, Weisdorf, DJ, et al. Donor Chimerism Does Not Predict Resonse to 
Donor Lymphocyte Infusion for Relapsed Chronic Myelogenous Leukemia After Allogeneic 
Hematopoetic Cell Transplantation. Biol Blood Marrow Transplant 2004 Mar 10 (3) 171-7. 
 
2. Warlick ED, Defor T, Blazar BR, et al. Successful remission rates and survival after 
lymphodepleting chemotherapy and donor lymphocyte infusion for relapsed hematologic 
malignancies postallogeneic hematopoietic cell transplantation. Biol Blood Marrow 
Transplant. 2012 Mar; 18(3): 480–486. 
 
3. Miller JS, Warren EH, van den Brink MR, et al. NCI First International Workshop on The 
Biology, Prevention, and Treatment of Relapse After Allogeneic Hematopoietic Stem Cell 
Transplantation:  Report from the Committee on the Biology Underlying Recurrence of 
Malignant Disease following Allogeneic HSCT:  Graft-versus-Tumor/Leukemia Reaction. Biol 
Blood Marrow Transplant. 2010 16(5) 565-86. 
 
4. Bryceson, YT, March ME, Ljunggren HG, et al. Activation, coactivation, and costimulation of 
resting human natural killer cells. Immunol Rev. 2006 Dec;214:73-91. 
 
5. Koh CY, Blazar BR, George T, et al. Augmentation of antitumor effects by NK cell inhibitory 
receptor blockade in vitro and in vivo, Blood 2001 May 15;97(10):3132-7. 
 
6. Lanier LL. NK cell recognition. Annu Rev Immunol 2005;23:225-74. 
 
7. Cheever MA. Twelve immunotherapy drugs that could cure cancers. Immunol Rev. 
2008;222:357-368. 
 
8. Steel JC, Waldmann TA, Morris JC. Interleukin-15 biology and its therapeutic implications in 
cancer. Trends Pharmacol Sci. 2012;33(1):35-41.  
 
9. Sato N, Patel HJ, Waldmann TA, Tagaya Y. The IL-15/IL-15Ralpha on cell surfaces enables 
sustained IL-15 activity and contributes to the long survival of CD8 memory T cells. Proc Natl 
Acad Sci U S A. 2007;104(2):588-593. 
 
10. Zhu X, Marcus W, Xu W, et al. Novel Human Interleukin-15 Agonists. J of Immunology, 2009, 
183(6): 3598–3607. 
 
11. Han KP, Zhu X, Liu B, et al. IL-15:IL-15 receptor alpha superagonist complex: High-level co-
expression in recombinant mammalian cells, purification and characterization. Cytokine. 
2011;56(3):804-810. 
 
12. Devine SM, Owzar K, Blum W, et al. Phase II Study of Allogeneic Transplantation for Older 
Patients With Acute Myeloid Leukemia in First Complete Remission Using a Reduced-
Intensity Conditioning Regimen: Results From Cancer and Leukemia Group B. Clin Oncol. 
2015 Dec 10; 33(35):4167-75. 
 


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13. Scott BL, Pasquini MC, Logan BR et al. Myeloablative Versus Reduced-Intensity 
Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic 
Syndromes. J Clin Oncol. 2017 Apr 10;35(11):1154-1161.  
 
14. Sengsayadeth S, Savani BN, Blaise D, et al. Reduced intensity conditioning allogeneic 
hematopoietic cell transplantation for adult acute myeloid leukemia in complete remission - a 
review from the Acute Leukemia Working Party of the EBMT. Haematologica. 2015 
Jul;100(7):859-69. 
 
15. Romee R, Cooley S, Berrien-Elliott MM, et al. First-in-human phase 1 clinical study of the IL-
15 superagonist complex ALT-803 to treat relapse after transplantation. Blood. 2018 Jun 
7;131(23):2515-2527. 
 
16. Felices M, Lenvik AJ, McElmurry R, et al. Continuous treatment with IL-15 exhausts human NK 
cells via a metabolic defect. JCI Insight. 2018;3(3):e96219. 
 
17. Deleted with the July 2020 revision - Lee DW, Gardner R, Porter DL, et al. Current concepts in 
the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-195. 
 
18. Lin DY. Non-parametric inference for cumulative incidence functions in competing risks studies. 
Stat Med 1997;16(8):901-10. 
 
19. Kaplan EL, Meier P. Nonparametric Estimation from Incomplete Observations. Journal of the 
American Statistical Association. 1958;53(282):457-81. 
 
20. Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. Hoboken, NJ, USA: 
John Wiley and Sons; 1980. 
 
21. Ivanova I, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials in Oncology. 
Biometrics 2005, 61: 540-545. 
 
 


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Appendix I – Karnofsky PS and NYHA Classification 
Karnofsky Performance Status Scale 
Able to carry on normal activity and to work; 
no special care needed. 
  100   Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs 
or symptoms of disease.  
Unable to work; able to live at home and 
care for most personal needs; varying 
amount of assistance needed. 
70 
Cares for self; unable to carry on 
normal activity or to do active work. 
60 
Requires occasional assistance, but is 
able to care for most of his personal 
needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires equivalent 
of institutional or hospital care; disease may 
be progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
20 
Very sick; hospital admission 
necessary; active supportive treatment 
necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
Ref:  Karnofsky DA, Burchenal JH. (1949). "The Clinical Evaluation of Chemotherapeutic Agents in Cancer." 
In: MacLeod CM (Ed), Evaluation of Chemotherapeutic Agents. Columbia Univ Press. Page 196. 
 
New York Heart Association Functional Classification 
NYHA 
Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity, e.g. 
shortness of breath when walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during 
ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, 
e.g. walking short distances (20–100 m). 
Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients. 
Ref:   The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256. 
 
 
 


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Appendix II – Disease Specific Response Criteria  
 
ACUTE MYELOGENOUS LEUKEMIA (AML) RESPONSE CRITERIA 
 
Modified RECIST 
Complete Remission (CR) 
CR requires that all of the following be present. 
• Peripheral Blood Counts 
o ANC count > 1,000/mm3 
o Platelet count > 100,000/ mm3 
o Reduced hemoglobin concentration or hematocrit has no bearing on remission status. 
o Leukemic blasts must not be present in the peripheral blood  
• Marrow Aspirate and Biopsy 
o Bone marrow biopsy must demonstrate trilineage hematopoiesis with maturation of all 
cell lines. 
o < 5% blasts 
• Extramedullary leukemia, such as CNS or soft tissue involvement, must not be present. 
 
Morphological Remission (MR) 
MR requires that the following be present: 
• Patient meets all peripheral blood and bone marrow criteria for CR, except that platelet 
count is < 100,000/mm3 but > 50,000/mm3. 
 
Relapse 
Relapse following CR is defined as: 
• Peripheral Blood Counts 
Presence of peripheral blasts. A bone marrow examination must be performed to confirm 
relapse. However, please note that the date of relapse is the first date at which the 
relapsed patient had: leukemic blasts in the peripheral blood smear, or >5% blasts in the 
bone marrow. 
• Bone Marrow Aspirate or Biopsy 
Presence of more than 5% blasts, not attributable to another cause (e.g., bone marrow 
regeneration). 
 
 
 
 


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MYELODYSPLASTIC SYNDROMES (MDS) RESPONSE CRITERIA 
 
Based on International Working Group 2006 Modified Criteria 
 
• 
Complete Remission (CR): < 5% myeloblasts with normal maturation of all cell lines 
o 
Persistent dysplasia will be noted 
o 
Peripheral Blood: 
▪ 
Hgb > 11g/dl 
▪ 
Platelets > 100 X 109 /L 
▪ 
Neutrophils > 1000 
▪ 
Blasts = 0% 
• 
Partial Remission (PR): all CR criteria if abnormal before except: 
o 
BM blasts decreased by > 50% over pre-treatment but still >5% 
• 
Marrow CR: Bone marrow with < 5% myeloblasts and decrease by >50% over pretreatment 
with incomplete peripheral blood count normalization 
• 
Hematologic Improvement (HI): 
o 
Hgb: Increase by > 1.5g/dl or decreased PRBC transfusions by at least 4/8 week 
period (only PRBC given for Hgb<9.0g/dl) 
o 
Platelet Response: Absolute increase of > 30 X 109/L for those starting at >20 X 109/L 
For those < 20 X 109/L at baseline increase by 100%. 
o 
Neutrophil Response: at least 100% increase and an absolute increase of >0.5 X 
109/L 
• 
Stable Disease:  Failure to achieve at least a PR but no evidence of disease progression for 
>8 weeks 
• 
Failure: Death during treatment or disease progression characterized by worsening 
cytopenias, increase percentage of marrow blasts, or progression to a more advanced MDS 
FAB subtype 
• 
Cytogenetic Response:  
o 
Complete: Disappearance of any pre-treatment chromosomal abnormalities without 
the appearance of new ones 
o 
Partial: At least 50% reduction of chromosomal abnormality 
• 
Disease Progression: Compared to pre-treatment values 
o 
Less than 5% blasts: greater than 50% increase to >5% blasts 
o 
5-10% blasts: greater than 50% increase to >10% blasts 
o 
10-20% blasts: greater than 50% increase to >20% blasts 
 


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Appendix III– GVHD Grading Scales 
Acute GVHD: 
 
Consensus Clinical Stage and Grade of Acute GVHD (Glucksberg et al, 1974; Thomas et al, 1975, Przepiorka et al, 1995) 
Stage 
Skin 
Liver 
Lower Gastrointestinal 
Tract 
Upper 
Gastrointestinal 
Tract 
1 
Maculopapular rash 
<25% of body surface 
Bilirubin 2.0 – 3.0 
mg/dl 
Diarrhea 500 – 1000 
mL/day or 280 – 555 
mL/m2 
No protracted nausea 
and vomiting 
2 
Maculopapular rash 
25-50% body surface 
Bilirubin 3.1 – 6.0 
mg/dl 
Diarrhea 1000 – 1500 
mL/day or 556 – 833 
mL/m2 
Persistent nausea, 
vomiting or anorexia 
3 
Generalized 
erythroderma 
Bilirubin 6.1 – 15.0 
mg/dl 
Diarrhea >1500 mL/day 
or >833 mL/m2 
 
4 
Generalized 
erythroderma with 
bullous formation and 
desquamation 
Bilirubin > 15 mg/dl 
Severe abdominal pain, 
with or without ileus, or 
stool with frank blood or 
melena 
 
 
 
University Of Minnesota Acute GVHD Grading 
Acute GVHD Grade 
Skin Stage 
Liver Stage 
Lower GI Stage 
Upper GI Stage 
   I 
1-2 
0 
0 
0 
   II 
3 
1 
1 
1 
   III 
- 
2-4 
2-3 
 
   IV 
4 
- 
4 
 
•  Each column identifies minimum criteria for organ grade.  
•  Each grade is based on maximum stage for each individual organ involved 
e.g. Grade II = skin stage 3 and/or liver stage 1 and/or gut stage 1 and/or UGI stage 1 
 
 
 


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Late Acute and Chronic GVHD: 
Late acute and chronic GVHD will be assessed using the National Institutes of Health (NIH) Consensus Criteria. 
 
Patient ID:   
 
 
 
Date of late acute or chronic GVHD diagnosis (mm/dd/yyyy)  
/
/
 
Onset of chronic GVHD was: 
 Progressive (acute GVHD progressed directly to chronic GVHD) 
 Interrupted (acute GVHD resolved, then chronic GVHD developed) 
 De novo (acute GVHD never developed) 
 Chronic GVHD flare (symptoms reactivated within 30 days of drug tapering or discontinuation) 
 
Karnofsky Performance status: 
 100 Normal, no complaints; no evidence of disease 
 90 Able to carry on normal activity, minor signs or symptoms of disease 
 80 Normal activity with effort; some signs or symptoms of disease 
 70 Cares for self; unable to carry on normal activity or do active work 
 60 Requires occasional assistance, but is able to care for most of his/her needs 
 50 Requires considerable assistance and frequent medical care 
 40 Disabled; requires special care and assistance 
 30 Severely disabled; hospitalization is indicated. Death not imminent 
 20 Very Sick, hospitalization necessary, active supportive treatment necessary 
 10 Moribund, fatal processes, progressing rapidly 
 0 Dead 
 
Diagnosis was based on: 
 Histologic evidence / biopsy proven 
 Clinical evidence 
 Both 
 Unknown 
 
Maximum grade of chronic GVHD 
 Limited 
 Extensive 
 
Overall severity of chronic GVHD 
 Mild 
 Moderate 
 Severe 
 
Organ/System Involvement (check if yes) 
Sclerosis of skin 
Other skin or hair involvement (rash, ulcers, pruritus or itching, dyspigmentation, alopecia, lichenoid 
skin changes, etc) 
Eyes (xerophthalmia (dry eyes), abnormal Schirmer's test, abnormal slit lamp, corneal erosion / 
conjunctivitis, etc) 
Mouth (lichenoid changes, mucositis / ulcers, erythema, etc) 


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Bronchiolitis obliterans 
Other lung involvement 
Organ/System Involvement (check if yes) 
Gastrointestinal tract (esophageal involvement, chronic nausea / vomiting, chronic diarrhea, 
malabsorption, abdominal pain / cramps, etc) 
Liver 
Genitourinary tract (vaginitis / stricture, etc) 
Musculoskeletal (arthritis, contractures, myositis, myasthenia, etc) 
Thrombocytopenia (< 100 x 10^9/L) 
Eosinophilia 
Autoantibodies 
Other hematologic involvement 
Serositis 
Weight loss 
Other organ involvement from chronic GVHD 
Specify other organ:  
 
 
 
Ref: Jagasia MH, Greinix HT, Arora M. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in 
Chronic Graft-versus-Host Disease: The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant. 2015 
March; 21(3): 389– 


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Appendix IV - N-803 Targeted Toxicity Worksheet 
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CTCAE v4            Refer to Section 10.2 for time points  
 Patient Initials:  _______ Date of Assessment:  _________     Assessment Time point:  _________      
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
N-803 Injection 
site reaction 
None 
Tenderness with or 
without associated 
symptoms (e.g., warmth, 
erythema, itching) 
Pain; lipodystrophy; edema; 
phlebitis 
Ulceration or necrosis; severe 
tissue damage; operative 
intervention indicated 
Life-threatening consequences; 
urgent intervention indicated 
Dyspnea 
None or 
no change 
Shortness of breath with 
moderate exertion 
Shortness of breath with minimal 
exertion; limiting instrumental ADL 
Shortness of breath at rest; 
limiting self care ADL 
Life-threatening consequences; 
urgent intervention indicated 
Hypoxia 
None 
……………… 
Decreased O2 saturation with 
exercise (e.g., pulse oximeter < 
88%) intermittent supplemental 
oxygen 
Decreased oxygen saturation at 
rest (e.g., pulse oximeter < 88% 
or PaO2 ≤ 55 mm Hg) 
Life-threatening airway 
compromise; urgent 
intervention indicated (e.g., 
tracheotomy or intubation) 
Fever 
None 
38.0 - 39.0◦ C (100.4 -
102.2◦ F) 
> 39.0 - 40.0◦C (102.3 - 104.0◦F) 
> 40.0 ◦ C (>104.0◦ F) for ≤ 24 hrs 
> 40.0 ◦ C (>104.0◦ F) for > 24 
hrs 
Chills 
None 
Mild sensation of cold; 
shivering; chattering of teeth
Moderate tremor of the entire body; 
narcotics indicated 
Severe or prolonged, not 
responsive to narcotics 
……………………… 
Hypertension 
None 
Pre-hypertension (systolic 
BP 120 - 139 mm Hg or 
diastolic BP 80 - 89 mm 
Hg) 
Stage 1 hypertension (systolic BP 
140 - 159 mm Hg or diastolic BP 90 -
99 mm Hg); medical intervention 
indicated; recurrent or persistent ≥ 
24 hrs); symptomatic increase by 
>20 mm Hg (diastolic) or to >140/90 
mm Hg if previously WNL; 
monotherapy indicated. 
Stage 2 hypertension (systolic BP 
≥ 160 mm Hg or diastolic BP ≥ 
100 mm Hg); medical intervention 
indicated; more than one drug or 
more intensive therapy than 
previously used indicated. 
Life-threatening 
consequences (e.g., 
malignant hypertension, 
transient or permanent 
neurologic deficit, 
hypertensive crisis); urgent 
intervention indicated. 
Hypotension 
None 
Asymptomatic, intervention 
not indicated 
Non-urgent medical 
intervention indicated 
Medical intervention or 
hospitalization indicated 
Life-threatening and urgent 
intervention indicated 
Edema 
None 
Localized to dependent 
areas, no disability or 
functional impairment 
Moderate localized edema 
and intervention indicated; 
limiting instrumental ADL 
Severe localized edema and 
intervention indicated; limiting self 
care ADL 
……………………… 
Pneumonitis 
None 
Asymptomatic; clinical or 
diagnostic observations 
only; intervention not 
indicated 
Symptomatic; medical 
intervention indicated; limiting 
instrumental ADL 
Severe symptoms; limiting self 
care ADL; oxygen indicated 
Life-threatening respiratory 
compromise; urgent 
intervention indicated (e.g. 
intubation or tracheotomy) 
Headache 
None 
Mild pain 
Moderate pain; limiting 
instrumental ADL 
Severe pain; limiting self care 
ADL 
……………………… 
Confusion 
(Altered Mental 
Status) 
None 
Mild disorientation 
Moderate disorientation; limiting 
instrumental ADL 
Severe disorientation; limiting self 
care ADL 
Life-threatening  
consequences; urgent 
intervention indicated 
Rash (outside of 
the injection site 
reaction) 
None 
Covering < 10% body 
surface area (BSA) 
Covering 10-30% body surface 
area (BSA) 
>30% body surface area (BSA) 
Generalized exfoliative, 
ulcerative, or bullous dermatitis 
Gait Disturbance 
None 
Mild change in gait (eg, 
wide-based, limping or 
hobbling) 
Moderate change in gait (eg, wide-
based, limping or hobbling); 
assistance device indicated;  
limiting instrumental ADL 
Disabling; limiting self care ADL 
……………………… 
 
 
Person Completing Form:  
 
 
 
 
 
 
ADL = activities of daily living 
 
 


MT2016-07:  Relapse Prophylaxis with N-803 Following RIC Allogeneic Stem Cell for AML and MDS 
 
 
 
 
 
 
 
April 14, 2022 
Page 55 of 57 
CPRC #2016LS058 
 
Appendix V – N-803 Injection Site Reactions Diary 
 
 
The Diary is to be completed by the patient as a self-assessment in association with each dose of N-803.  
 
A new diary must be started for each N-803 injection.  
 
If the injection reaction has not resolved by Day 6 post-injection, continue to collect information on page 2 based on the 
days from that injection.  
 
 
For inpatients, the diary is completed by study personnel. 
 


Patient Number* 
 
Date of Study Drug Injection* 
________/_________/________ 
*To be completed by the site. 
Please answer all questions below daily for 7 days, beginning with day of treatment. Be sure to bring back this completed diary to your next clinic visit. 
 
 
Instructions 
Day of Study 
Drug Injection 
____/____/_________ 
Day 1 
Post Injection 
____/____/_________ 
Day 2 
Post Injection 
____/____/_________ 
Day 3 
Post Injection 
____/____/_________ 
Day 4 
Post Injection 
____/____/________ 
Day 5 
Post Injection 
___/___/________ 
Day 6 
Post Injection 
____/____/_________ 
 
1. Is there redness at 
the injection site? 
 
Check: 
Yes  or No 
If yes, measure longest 
diameter in cm 
Yes  No 
 
________cm 
Yes  No 
 
________cm 
Yes  No  
 
________cm 
Yes  No 
 
________cm 
Yes  No 
 
________cm 
Yes  No 
 
________cm 
Yes  No 
 
________cm 
 
2. Is there firmness or 
swelling at the 
injection site? 
Check: 
Yes  or No 
 
Yes  No 
 
Yes  No 
 
Yes  No 
 
Yes  No 
 
Yes  No 
 
Yes  No 
 
Yes  No 
 
 
3. Have you 
experienced any pain 
or itching at the 
injection site? 
Check the pain 
and/or itch box if 
present 
Indicate if the pain 
and/or itching is mild, 
moderate or severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe     Severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe     Severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe     Severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe    Severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe     Severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe     Severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe     Severe 
 
4. Have you taken or 
applied any 
medication for 
injection site pain or 
itching? 
Check: 
Yes  or No 
Provide name of 
medication(s) 
Yes  No 
Name(s): 
 
Yes  No 
Name(s): 
 
Yes  No 
Name: 
 
Yes  No 
Name: 
 
Yes  No 
Name: 
 
Yes  No 
Name: 
 
Yes  No 
Name: 
 
 
5. Have you 
experienced any 
chills? 
 
Check: 
Yes  or No 
If yes, circle the worse 
severity of the chills: 
mild, moderate or severe 
Yes  No 
       Mild 
Moderate 
       Severe 
Yes  No 
       Mild 
Moderate 
       Severe 
Yes  No 
       Mild 
Moderate 
       Severe 
Yes  No 
       Mild 
Moderate 
       Severe 
Yes  No 
       Mild 
Moderate 
       Severe 
Yes  No 
       Mild 
Moderate 
       Severe 
Yes  No 
       Mild 
Moderate 
       Severe 
 
6. Record your daily 
temperature upon 
waking 
 (do not drink anything 5 
minutes before taking your 
temperature) 
 
 
Check: 
Yes  or No 
If your temperature is 
101°F for more than 24 
hours notify your study 
doctor or research staff. 
Yes  No 
________°F 
 
Time: 
____:____   
AM / PM 
Yes  No 
________°F 
 
Time: 
____:____  
AM / PM 
Yes  No 
________°F 
 
Time: 
____:____  
AM / PM 
Yes  No 
________°F 
 
Time: 
____:____  
AM / PM 
Yes  No 
________°F 
 
Time: 
____:____  
AM / PM 
Yes  No 
________°F 
 
Time: 
____:____  
AM / PM 
Yes  No 
________°F 
 
Time: 
____:____  
AM / PM 
Grading Injection Site Pain or Itching 
 
 
 
 
 
 
Grading Chills 
Mild – Noticeable, does not interfere with activity 
 
 
 
 
 
Mild – Mild sensitive of cold, shivering, chattering of teeth 
Moderate – Interferes with activity, limiting activities of daily living 
 
 
 
Moderate – Moderate tremor of entire body, medication taken 
Severe – Severely limiting self-care activities of daily living, incapacitating  
 
 
Severe – Prolonged or severe, does not respond to medication 


 
 
 
Page 2 – Please continue to complete for Injection Site Reaction if ongoing after page 1 has been filled out. 
Patient Number* 
 
Date of Study Drug Injection* 
________/_________/________ 
*To be completed by the site. 
Complete daily for 7 days or until the injection site has resolved (returned to normal) . Please bring back this completed diary to your next clinic visit. 
 
 
Instructions 
Day 7 
Post Injection 
____/____/_________ 
Day 8 
Post Injection 
____/____/_________ 
Day 9 
Post Injection 
____/____/_________ 
Day 10 
Post Injection 
____/____/_________ 
Day 11 
Post Injection 
____/____/________ 
Day 12 
Post Injection 
___/___/________ 
Day 13 
Post Injection 
____/____/_________ 
 
1. Is there redness at 
the injection site? 
 
Check: 
Yes  or No 
If yes, measure longest 
diameter in cm 
Yes  No 
 
________cm 
Yes  No 
 
________cm 
Yes  No  
 
________cm 
Yes  No 
 
________cm 
Yes  No 
 
________cm 
Yes  No 
 
________cm 
Yes  No 
 
________cm 
 
2. Is there firmness or 
swelling at the 
injection site? 
Check: 
Yes  or No 
 
Yes  No 
 
Yes  No 
 
Yes  No 
 
Yes  No 
 
Yes  No 
 
Yes  No 
 
Yes  No 
 
 
3. Have you 
experienced any pain 
or itching at the 
injection site? 
Check the pain 
and/or itch box if 
present 
Indicate if the pain 
and/or itching is mild, 
moderate or severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe     Severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe     Severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe     Severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe    Severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe     Severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe     Severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe     Severe 
 
4. Have you taken or 
applied any 
medication for 
injection site pain or 
itching? 
Check: 
Yes  or No 
Provide name of 
medication(s) 
Yes  No 
Name(s): 
 
Yes  No 
Name(s): 
 
Yes  No 
Name: 
 
Yes  No 
Name: 
 
Yes  No 
Name: 
 
Yes  No 
Name: 
 
Yes  No 
Name: 
 
Grading Injection Site Pain or Itching 
 
 
 
 
 
 
 
Mild – Noticeable, does not interfere with activity 
 
 
 
 
 
 
Moderate – Interferes with activity, limiting activities of daily living 
 
 
 
 
Severe – Severely limiting self-care activities of daily living, incapacitating  
 
 
 
 

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