Clinical trial NCT03417154
Conditions: Acute Myeloid Leukemia Higher Risk Myelodysplastic Syndrome
Keywords: AML MDS
Sponsor: Masonic Cancer Center, University of Minnesota
Start date: 2018-08-13; Completion date: 2022-01-25
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase II trial of nivolumab and low dose cyclophosphamide (CTX) when given in combination to patients with relapsed/refractory acute myeloid leukemia (AML) and higher-risk myelodysplastic syndrome (MDS) who are not eligible for or decline hematopoietic stem cell transplant. It includes a randomized pilot sub-study during stage 1.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Nivolumab intervention 2: Low dose Cyclophosphamide (CTX) Daily intervention 3: Low dose Cyclophosphamide (CTX) Every 7 Days
Intervention descriptions: intervention 1: 3mg/kg IV (or if prior alloHSCT, 1 mg/kg) over 30 minutes every 14 days on Days 1 and 15 for up to four 28-day courses. intervention 2: Oral cyclophosphamide 50mg + nivolumab 3 mg/kg IV every 2 weeks for up to 4 courses of treatment intervention 3: Oral cyclophosphamide 350 mg every 7 days + nivolumab 3mg/kg IV every 2 weeks for up to 4 courses of treatment

Protocol documents:
Prot_SAP_000.pdf: 
HM2017-33:  Nivolumab, Oral CTX and N-803 in Relapsed/Refractory AML and Higher-Risk MDS 
 
Masonic Cancer Center  
University of Minnesota  
  
Nivolumab, Oral Cyclophosphamide, and N-803 for Relapsed/Refractory Acute 
Myeloid Leukemia (AML) and Higher-Risk Myelodysplastic Syndrome (MDS)  
  
HM2017-33  
CPRC # 2017LS116  
IND 138758  
BMS protocol number CA209-9WK  
  
Principal Investigator/IND Sponsor:  
Fiona He, MD  
  
Co-Investigators:  
Mukta Arora, MD  
Veronika Bachanova, MD, PhD  
Claudio Brunstein, MD, PhD  
Craig Eckfeldt, MD, PhD   
Najla El Jurdi, MD  
Michael Linden, MD, PhD*  
Joseph Maakaron, MD  
Jeffrey Miller, MD  
Armin Rashidi MD, PhD   
Zohar Sachs, MD, PhD  
Erica Warlick, MD   
Daniel J. Weisdorf, MD  
  
*will not consent study participants  
  
Biostatistician:  
Qing Cao, MS  
  
  
  
Version Date:  
May 12, 2021  
  
Confidential  
  
Revision History  
  


HM2017-33:  Nivolumab, Oral CTX and N-803 in Relapsed/Refractory AML and Higher-Risk MDS 
  
  
  
  
May 
12, 2021  
Page 2 of 79  
CPRC #2017LS116  
Revision 
#  
Version 
Date  
Detail of Changes  
Consent 
change?  
(Y/N)  
  
10/03/2017  
Original version for CPRC and BMS (earlier version sent)  
n/a  
  
11/01/2017  
In response to CPRC stips:   
Expand nivolumab background information in Section 2.3 and Section 2.4 
(new)    
Add wording to Section 6.2 regarding use of hydroxurea and 
immunosuppression during the study treatment.   
Other edits:   
Cover page - update Co-I’s   
Section 4.2.1 – clarify negative pregnancy test with 7 days of study 
administration   
Section 13 and Section 14.2 – provide more detail pertaining to study 
endpoints   
Section 14.3 – expand definition of evaluable   
Other minor edits and updates  
n/a  
  
02/23/2018  
Original version to the IRB and FDA:  
To align versions approved by CPRC and the older version approved by 
BMS (no changes from BMS affecting the 11/01/2017 version approved by 
the CPRC)   
Update in protocol template language:  
• Update Section 5 Patient Registration/Study Enrollment to current 
template language  
• Section 12.3 – delete wording about submitting copy of IRB continuing 
review to CPRC  
• Replace CTCAE v 4.03 with v 5.0   
• Replace study coordinator with newer designation of Primary Clinical 
Research Coordinator (PCRC)  
• Add co-investigators  
Other minor edits and clarifications throughout.  
n/a  
  
03/20/2018  
In response to FDA’s potential hold and non-hold comments:  
• Synopsis, schema, Section 3 and Section 6.3 – clarify and make 
consistent that an increase in absolute blast count is ≥ 25% in 
peripheral blood or bone marrow from baseline is criteria for stopping 
treatment due to disease progression  
• Synopsis, Section 4.1.2 and Appendix I - Add risk score of >4.5 to the 
definition of higher risk MDS, separate relapsed AML and MDS 
eligibility requirements  
• Synopsis, Section 4.1.4 and Appendix I – add bilirubin ≤ 3 x ULN to 
eligibility and require both AST and ALT results (previously or)  
• Section 3, Section 11.2 and Section 14.4 – add selected Grade 3 
nonhematologic events that result in the permanent discontinuation of 
nivolumab (diarrhea, colitis, pneumonitis, transaminitis, myocarditis, 
adrenal insufficiency)  
• Section 6.1.1 – clarify nivolumab will be administered in the outpatient 
setting, add monitoring language.  
• Add IND number to the title page  
yes  
1  
05/17/2018  
• Per BMS for patient safety - Nivolumab may induce graft versus host 
disease in patients who have had a prior allo-HSCT. To reduce this risk, 
patients who have had a prior alloHSCT will receive a lower dose of 
nivolumab (1 mg/kg instead of 3 mg/kg).  
• Increase research sample blood volume as an insufficient amount was 
originally written into the protocol   
• Minor edits to match current protocol template  
Yes  


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CPRC #2017LS116  
2  
09/13/2018  
• Updated Principal Investigator/IND Sponsor to Fiona He, MD  
Yes  
 
Revision 
#  
Version 
Date  
Detail of Changes  
Consent 
change?  
(Y/N)  
 
 
• Section 4.1.2 & Eligibility checklist: Updated eligibility criteria (disease 
status)  
• Minor clarification of research blood draw procedure  
• Section 14.4 updated sample size  
• Protocol synopsis: Updated for clarification including monthly peripheral 
blood blast count disease evaluation   
• Section 1.3 correlative objectives added neo-antigen identification on 
blasts   
• Section 8.1 bone marrow biopsy evaluations, changed screening bone 
marrow biopsy to within 21 days of study registration, and that bone 
marrow biopsies may be omitted if not medically safe to perform   
 
3  
03/26/2019  
• Removed bone marrow biopsy response assessment from final 
treatment visit  
• Cyclophosphamide will now be provided by BMS  
• Updated study committee to remove Drs Cooley & Ustun  
Yes  
4  
12/04/2019  
• Updated study committee to add Najla El Jurdi and Joseph Maakaron   
• Schema, Synopsis, Section 1, , Section 3, Section 6.1, Section 7.3, 
Section 10.3,Section 14.3, Appendix V, Appendix VI:  Added SC N-803 
once every 3 weeks in treatment schema, changed Nivolumab dosing 
frequency to once every 3 weeks   
• Schema, Section 3, Section 5.2, Section 6, Section 8.1, Section 8.2, 
Section 14.1: Changed total number of cycles from 4 to 5 (each cycle 
defined as 3 weeks instead of 4 weeks)   
• Synopsis, Section 1.1, Section 3, Section 6.4, Section 13, Section 14: 
Changed bone marrow evaluation schedule from D30 and D90 to D21 
and D42   
• Section 2.6, Section 2.8: Added background information for N-803  
• Section 8.2: Added research blood draw at C1D8, C1D15, C2D1, C2D8, 
C2D15, C3D1, C4D1, C5D1, end of treatment visit   
• Synopsis, Section 4.1, Section 8.2: Added disease eligibility criteria of 
extramedullary leukemia that is biopsy-confirmed in absence of bone 
marrow involvement; added CT or PET-scan for disease restaging   
• Section 4.1: Added to inclusion criteria: Ability to be off prednisone and 
other immunosuppressive drugs (>10 mg daily prednisone equivalent) for 
at least 14 days prior to and while receiving N-803. Inhaled or topical 
steroids, and adrenal replacement steroid doses < 10 mg daily 
prednisone equivalent, are permitted in the absence of active 
autoimmune disease  
• Section 4.2: Added prior N-803 administration and cellular therapy 
product within 30 days as exclusion   
• Added Appendix V and Appendix VI  
• Section 6.1, Section 7, Section 11, and Section 14.4 reverted protocol 
back to CTCAE v 4.03 in order to match protocol build in Oncore  
• Section 1.1, Section 14.1: Changed timepoint for primary endpoint of 
ORR to day 42  
Yes  


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5  
06/08/2020  
Per FDA Stipulations:  
• 
Synopsis, Schema, Section 3, Section 5.2, Section 6.1, Section 
14.1: Clarified that original treatments as closed Arms 1 and 2, 
treatment with N803 will be called Arms 3 and 4  
• 
Synopsis, Section 3; Clarified that Day 42 BMBX will be used to 
help determine additional cycles  
• 
Synopsis, Section 1.3: added correlative objective to assess Tcell 
infiltration through immunohistochemical testing in the bone 
marrow  
• 
Synopsis, Section 4.1: clarified eligibility for relapsed MDS  
• 
Synopsis, section 4.2: added exclusion for allo HSCT receiving 
calcineurin inhibitor within 4 weeks  
• 
Section 6.1: updated eligibility for additional cycles (moved 
information previously in section 6.1.5)  
• 
Section 6.1.5: updated dose administration guidelines for N803  
• 
Section 6.2: Updated GVHD management guidelines  
No  
Revision 
#  
Version 
Date  
Detail of Changes  
Consent 
change?  
(Y/N)  
 
 
• 
Section 6.3: updated definition of disease progression  
• 
Section 11.2, section 14.4: updated stopping rule 
events Per IRB Stipulation:  
• 
Section 3 – Added N803 as part of endpoint  Minor 
edits and clarifications:  
• 
Section 7.1, section 8.1 – added “N-803”   
• 
Section 8.2: updated research tests performed on lab 
samples  
• 
Throughout protocol updated internal HTML and 
section links  
 
6  
9/18/2020  
Per FDA Stipulations:  
Synopsis, Section 1.1, Section 3.0, Section 5.2,   Section 14.1 - Removed 
stage II from trial design  
Synopsis, Section 1.2, Section 14.1 - defined response rate in secondary 
objectives  
Synopsis, Section 3.0,  Section 14.1- updated accrual goal  
Section 3.0, Section 11.2, Section 14.4- Updated stopping rules  
Section 6.1 – clarified eligibility to begin additional treatment courses  
Section 6.2 – Updated study management in the case of new onset GVHD  
  
Additional Edits:  
Section 7.1, Section 10.1, Section 10.3.6, Section 10.4 Updated the risk 
language for N-803 and Nivolumab, based information from other trials 
using study product and latest Investigator Brochures  
  
Yes  
7  
04/28/2021  
Synopsis, Schema, Section 3.0, Section 5.2, Section 14.3, Section 14.4, 
number of patients changed from 24 to 20 – Rationale: improve feasibility 
of recruitment while maintaining goals for statistical power  
Synopsis, section 1.3, Section 8.2, added and clarified correlative studies 
Rationale: add immune-related gene expression profiling of bone marrow 
to evaluate other pathways that may confer sensitivity or resistance to 
therapy  
Section 8.2 added bone marrow sample. Rationale: for RNA gene 
expression studies  
Section 13.0, Section 14.1 changed primary endpoint to dose 
determination, moved original primary endpoint to secondary. Rationale: 
prior amendment removed stage II from study design. Primary endpoint 
changed to reflect dose finding rather than efficacy.  
Yes  


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7A  
05/12/2021  
Synopsis, Schema – corrected number of patients. Rationale – error 
correction (number of patients was amended in previous version)  
No  
  
  
PI/IND Sponsor Contact Information: 
Fiona He, MD  
Assistant Professor of Medicine 
Division of Hematology, Oncology 
and Transplantation MMC 480, 420 
Delaware Street S.E.  
Minneapolis, MN 55455  
(612) 624-6982 (phone) 
(612) 625-6919 (fax)  
fionahe@umn.edu Table of 
Contents  
  
Table of Key Abbreviations ........................................................................................................................................ 7 
Protocol Synopsis ........................................................................................................................................................ 8 
Study Schema ............................................................................................................................................................ 11 
1  Objectives .............................................................................................................................................................. 12 
1.1  Primary Objective .......................................................................................................................................... 12 
1.2  Secondary Objectives ..................................................................................................................................... 12 
1.3  Correlative Objectives .................................................................................................................................... 12 
2  Background and Rationale .................................................................................................................................... 12 
2.1  High-risk AML and MDS .............................................................................................................................. 12 
2.2  Defective Leukemic Immunosurveillance in AML and MDS ....................................................................... 13 
2.3  PD-1/PD-L1 Pathway in Malignancies .......................................................................................................... 13 
2.4  PD-1/PD-L1 Pathway in AML and MDS ...................................................................................................... 15 
2.5  Low Dose Cyclophosphamide........................................................................................................................ 16 
2.6  IL-15 ............................................................................................................................................................... 17 
2.7  Areas of Investigation .................................................................................................................................... 18 
2.8  Rationale ........................................................................................................................................................ 19 
3  Study Design ......................................................................................................................................................... 20 
4  Patient Selection .................................................................................................................................................... 21 
4.1  Inclusion Criteria ............................................................................................................................................ 21 
4.2  Exclusion Criteria ........................................................................................................................................... 22 
5  Screening and Study Enrollment ........................................................................................................................... 22 
5.1  Consent and Study Screening in OnCore ....................................................................................................... 22 
5.2  Study Enrollment and Treatment Assignment ............................................................................................... 22 
5.3  Patients Who Do Not Begin Study Treatment................................................................................................ 23 
6  Treatment Plan ...................................................................................................................................................... 23 
6.1  Study Drug Administration ............................................................................................................................ 23 
6.2  GVHD Management Guidance in recipients of allogeneic HSCT ................................................................. 26 
6.3  Supportive Care .............................................................................................................................................. 27 
6.4  Duration of Study Treatment .......................................................................................................................... 27 
6.5  Duration of Study Participation ...................................................................................................................... 27 
7  Management of Selected Toxicity ......................................................................................................................... 28 
7.1  Nivolumab and N-803 .................................................................................................................................... 28 
7.2  Oral Cyclophosphamide ................................................................................................................................. 38 


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7.3  N-803 ............................................................................................................................................................. 39 
8  Schedule of Tests and Procedures ......................................................................................................................... 39 
8.1 Required Clinical Care Evaluations ................................................................................................................ 40 
8.2 Research Related Evaluations ......................................................................................................................... 41 
9  Disease Assessment Criteria ................................................................................................................................. 42 
10  Drug Formulation, Availability and Preparation ................................................................................................. 42 
10.1 Nivolumab ..................................................................................................................................................... 42 
10.2 Low Dose Cyclophosphamide....................................................................................................................... 44 
10.3  N-803 Formulation, Supply, and Potential Toxicity .................................................................................... 44 
10.4  N-803 in Combination with Nivolumab ....................................................................................................... 48 
11  Adverse Event Monitoring, Documentation and Reporting ................................................................................ 48 
11.1 Adverse Event Terminology ......................................................................................................................... 49 
11.2 Adverse Event Documentation ...................................................................................................................... 50 
11.3 Required Reporting FDA, IRB, and Masonic Cancer Center’s SAE Coordinator ........................................ 52 
11.4  Additional BMS Requirements for Nivolumab ............................................................................................ 53 
12  Study Data Collection and Monitoring ............................................................................................................... 53 
12.1  Data Management ........................................................................................................................................ 53 
12.2 Case Report Forms ........................................................................................................................................ 54 
12.3 Data and Safety Monitoring Plan (DSMP) .................................................................................................... 55 
12.4 Monitoring..................................................................................................................................................... 55 
12.5  Record Retention .......................................................................................................................................... 55 
13  Endpoints ............................................................................................................................................................ 56 
14  Statistical Considerations .................................................................................................................................... 56 
14.1  Study Design ................................................................................................................................................ 56 
14.2  Data Analysis Plan ....................................................................................................................................... 57 
14.3  Sample Size Justification ............................................................................................................................. 58 
14.4  Early Study Stopping Rule for Safety .......................................................................................................... 59 
15  Ethical and Regulatory Considerations ............................................................................................................... 59 
15.1  Good Clinical Practice ................................................................................................................................. 59 
15.2  Ethical Considerations .................................................................................................................................. 59 
15.3  Informed Consent ......................................................................................................................................... 60 
16  References ........................................................................................................................................................... 60 
Appendix I – ECOG Performance Status .................................................................................................................. 67 
Appendix II – Revised International Prognostic Scoring System ............................................................................. 68 
Appendix III – Response Criteria For MDS and AML ............................................................................................. 69 
Appendix IV – GVHD Grading Scales ..................................................................................................................... 69 
Appendix V - N-803 Targeted Toxicity Worksheet .................................................................................................. 73 
Appendix VI – N-803 Injection Site Reactions Diary ............................................................................................... 75 
 
  
  
  
  
  
 


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Table of Key Abbreviations  
  
ALT  
alanine aminotransferase (aka SGPT)  
alloHSCT  
allogeneic hematopoietic stem cell transplant  
AML  
acute myeloid leukemia  
AST  
aspartate aminotransferase (aka SGOT)  
BM  
bone marrow  
CNS  
central nervous system  
CR  
complete remission  
CRi  
complete remission with incomplete blood count 
recovery  
CRp  
complete remission with incomplete platelet count 
recovery  
CTCAE  
v4.03  
Common Terminology Criteria for Adverse Events 
version 4.03  
CTX  
cyclophosphamide  
DC  
dendritic cell  
ECOG  
Eastern Cooperative Oncology Group  
FDA  
Food and Drug Administration  
HCT  
hematopoietic cell transplant  
HI  
hematologic improvement   
IDO  
indolamine 2,3 dioxygenase  
IPSS  
International Prognostic Scoring System  
irAE  
immune related adverse event  
IV  
intravenous  
MDS  
myelodysplastic syndrome  
MDSC  
myeloid derived suppressor cells  
NK  
natural killer  
OR  
objective response  
ORR  
overall response rate   
OS  
overall survival  
PO  
per os   
PR  
partial remission  


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PFS  
progression-free survival  
SOC  
standard of care  
WOCBP  
women of childbearing potential  
  
  
Protocol Synopsis  
Nivolumab, Oral Cyclophosphamide and N-803 for Relapsed/Refractory Acute 
Myeloid Leukemia (AML) and Higher-Risk Myelodysplastic Syndrome (MDS)  
  
Study 
Design:  
This is a phase I trial of nivolumab, low dose cyclophosphamide (CTX) 
and 
N-803 
when 
given 
in 
combination 
to 
patients 
with 
relapsed/refractory acute myeloid leukemia (AML) and higher-risk 
myelodysplastic syndrome (MDS) who are not eligible for or decline 
hematopoietic stem cell transplant. It includes a randomized pilot 
substudy during stage 1. Arm 1 and Arm 2 previously randomized 
patients in 1:1 ratio to IV nivolumab 3 mg/kg every 2 weeks and oral 
cyclophosphamide 50 mg daily or IV nivolumab 3 mg/kg every 2 
weeks and oral cyclophosphamide 350 mg weekly. Arms 1 and 2 are 
now closed.    
  
20 patients enrolled in the study are randomized to either Arm 3 (CTX 
50mg PO daily + nivolumab IV and 10 ug/kg SC N-803 every 3 weeks) 
or Arm 4 (CTX 350 mg PO every 7 days + nivolumab IV and 10 ug/kg 
SC N-803 every 3 weeks) with 10 subjects in each arm. Nivolumab 
dosing is 360 mg unless the patient has had a prior allogeneic 
transplant, in which case the nivolumab dose is 180 mg.  
  
Disease will be assessed by bone marrow biopsy at 21 and 42 days 
after initiation of study drugs. If the increase in absolute blast count is 
<25% in peripheral blood or bone marrow from baseline at day 42 or 
later and there is perceived clinical benefit by the treating physician, 
the subject will proceed with further treatment with up to five 21-day 
courses.   
  
Continuous stopping rules are used to monitor excessive toxicity for 
each arm. If one arm is terminated by the toxicity stopping rule, all 
subsequent patients will be assigned to the other arm if it is not 
terminated by the toxicity stopping rule to continue enrollment of up to 
20 patients.   
  
All patients receive nivolumab IV and SC N-803 every 3 weeks and 
oral cyclophosphamide (daily or weekly) as assigned for up to 5 


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treatment courses with each treatment course equal to 21 days. A final 
treatment visit occurs 30 days after the last dose of study drug with 
follow-up for response and survival continuing through 2 years from 
beginning of treatment. For patients with clinical benefit after the 5 
treatment courses, additional therapy with the study drugs or other 
treatment may be offered.  
  
Primary  
To identify the safety, immunological activity, and clinical benefit of  
Objective: combination of nivolumab, N-803 and low-dose oral CTX when given in 
patients with relapsed/refractory AML and higher-risk MDS   
  
Secondary • To estimate objective response rate (ORR) at 42 days from  
Objectives: treatment start. Response is defined as CR + CRi + CRp + PR in AML and 
CR/PR/hematologic improvement (HI) in MDS  
• 
To estimate progression-free survival (PFS) and overall survival 
(OS) at 6 months from treatment start  
Correlative  
•  
To evaluate level of immune activation in blood and bone  
Objectives:  
marrow microenvironment by measuring quantities and 
activation status of T-cells subsets, natural killer (NK) cells, 
myeloid derived suppressor cells (MDSC), and dendritic cells 
(DC) during treatment  
• 
To assess PD1/PD-L1 and TIM-3/galectin-9 interactions through 
quantified expression of PD-L1 and galectin-9 on leukemic 
blasts, galectin-9 in serum, PD-1 and TIM-3 on immune cells as 
biomarkers of response and potential mechanisms of resistance 
to treatment    
• 
To assess T-cell infiltration through immunohistochemical 
testing in the bone marrow   
• 
To evaluate immune and leukemia-related gene expression 
patterns in bone marrow aspirates at baseline and during 
treatment   
  
  
Eligible 
Diseases:  
Primary (de novo) AML or higher-risk MDS with induction failure: No 
CR after 2 or more induction attempts with high dose chemotherapy, 
hypomethylating agents, or other agents; No CR after 1 induction 
attempt and not eligible for a 2nd induction. Higher risk MDS defined 
as risk score > 4.5 based on the by revised International Prognostic 
Scoring System (IPSS) criteria.     
  


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Secondary AML (from antecedent hematologic malignancy or 
treatment-related): Not in CR after 1 or more cycles of chemotherapy   
  
Relapsed AML: Blasts ≥5% in bone marrow or peripheral blood after 
prior attainment of CR or biopsy-proven extramedullary leukemia in 
absence of bone marrow involvement; relapse at any time, but 
currently ≥100 days following allogeneic HCT  
  
Relapsed MDS: morphologic evidence of relapse or increase in blasts 
to ≥5% in bone marrow or peripheral blood after prior attainment of CR 
and not eligible for or decline intensive chemotherapy; relapse at any 
time but currently ≥100 days following allogeneic HCT  
   
Key 
Inclusion 
Criteria:  
• ≥18 years of age  
• ECOG status ≤ 2  
• ineligible for or declines allogenic hematopoietic transplantation  
• voluntary written consent   
• Adequate organ function as defined by ALC > 500 cells/m3, serum 
creatinine ≤2 mg/dL, AST and ALT ≤ 5x ULN, Bilirubin ≤3 x ULN, 
no O2 requirements on room air or requiring ≤2L O2   
  
Key 
Exclusion 
Criteria:  
• acute promyelocytic leukemia   
• pregnant or breastfeeding  
• prior allogeneic hematopoietic stem cell transplantation currently 
within 100 days (note patients with prior alloHSCT receive a 
reduced dose of nivolumab); they are eligible after that date  
• therapeutic immunosuppression within preceding 1 month  
• signs or symptoms of graft versus host disease   
• active pneumonitis or uncontrolled infection  
• active, uncontrolled autoimmune disease  
• chemotherapy within the previous 2 weeks  
• estimated life expectancy less than 28 days   
• Previously treated with N-803 (or “ALT-803”)  
• Cellular therapy product within 30 days   
• Allogeneic HSCT recipient receiving calcineurin inhibitor within 4 
weeks  
  
Accrual  
Objective:  
20 patients randomized (50:50) to 1 of 2 treatment arms  
  
Enrollment: 1-2 patients per month  


HM2017-33:  Nivolumab, Oral CTX and N-803 in Relapsed/Refractory AML and Higher-Risk MDS 
 
Study Schema  
   
Arm 1 and Arm 2 previously randomized patients in 1:1 ratio to nivolumab 3 mg/kg every 2 
weeks and low dose cyclophosphamide 50 mg daily or 350 mg weekly and enrolled 12 
patients. Due to low response rates (no complete responses and only 2 patients with partial 
response) and 4 patients receiving ≤1 cycle of treatment due to rapid disease progression, 
arms 1 and 2 are now closed.  Arms 3 and 4 are open and will add N-803 to the platform of 
nivolumab and low dose cyclophosphamide daily or weekly. All patients without prior history of 
allogeneic stem cell transplantation receive nivolumab 360 mg every 3 weeks, low dose 
cyclophosphamide (CTX) at assigned dose/schedule (daily versus weekly), and N-803 
subcutaneously at 10 ug/kg every 3 weeks for up to 5 treatment courses. Patients with prior 
allogeneic stem cell transplantation will receive reduced dose of 180 mg nivolumab every 3 
weeks.  
  
One treatment course = 3 weeks  
  
Randomized Pilot of 20 patients randomized (1:1) to Arm 3 or Arm 4  
  
  
   
  
*Nivolumab dose is 360 mg unless the patient has had a prior allogeneic hematopoietic 
stem cell transplant (alloHSCT), in which case, the nivolumab dose is  
 
180 mg.  
  


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1 Objectives  
1.1 Primary Objective  
To identify the safety, immunological activity, and clinical benefit of combination 
of nivolumab, N-803 and low-dose oral CTX when given in patients with 
relapsed/refractory AML and higher-risk MDS   
  
  
1.2 Secondary Objectives  
• 
To estimate the overall response rate (ORR) at 42 days from treatment start.  
Response is defined as CR + CRi + CRp + PR in AML and  
CR/PR/hematologic improvement (HI) in MDS  
• 
To estimate progression-free survival (PFS) and overall survival (OS) at 6 
months from treatment start  
 
1.3  Correlative Objectives  
• 
To evaluate level of immune activation in blood and bone marrow 
microenvironment by measuring quantities and activation status of T-cells 
subsets and natural killer (NK) cells during treatment  
• 
To assess PD1/PD-L1 and TIM-3/galectin-9 interactions through quantified 
expression of PD-L1 and galectin-9 on leukemic blasts, PD-1 and TIM-3 on 
immune cells as biomarkers of response and potential mechanisms of 
resistance to treatment    
• 
To assess T-cell and NK cell infiltration through immunohistochemical 
testing in the bone marrow   
• 
To evaluate immune-related gene expression patterns in bone marrow 
aspirates at baseline and during treatment  
2 Background and Rationale  
 
2.1  High-risk AML and MDS   
Acute myeloid leukemia is a disease with high mortality rate that is predominantly 
diagnosed in the elderly with median age of diagnosis of 67. Elderly patients are 
more likely to present with more aggressive disease, as evidenced by higher 
rates of adverse molecular and cytogenetic features compared to younger 
patients.[1] Although 50-60% of patients with good performance status may 
achieve complete remission with cytotoxic chemotherapy (anthracycline and 
cytarabine in “7+3” regimen), 2-year survival is poor at 15-20% due to high rates 
of relapse.[2] Salvage cytotoxic chemotherapy can induce objective response in 
25 to 40% of patients, but these remissions are not durable, likely due to inability 
of chemotherapy to kill leukemic stem cells that persist. [3]   


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Higher-risk MDS, as defined by the revised International Prognostic Scoring 
System (R-IPSS) which evaluates cytogenetic risk, bone marrow blast count, 
hemoglobin, platelet count, and absolute neutrophil count, is associated with 
median overall survival of 0.8 to 1.6 years and 0.7 to 1.4 years for median time 
to 25% AML evolution. [4] Therapies are limited to hypomethylating agents and 
AML induction chemotherapy regimens in most cases.   
Current approved therapies for AML and high-risk MDS include cytotoxic 
chemotherapies, molecularly targeted therapies in a fraction of eligible patients 
with FLT3/ITD or IDH2 mutations, and immunotherapy in the form of allogeneic 
hematopoietic stem cell transplantation (HCT). There is a need for novel 
treatments that not only increase survival, but also can be well tolerated in this 
predominantly elderly population.    
 
2.2  Defective Leukemic Immunosurveillance in AML and MDS  
Multiple mechanisms of immune evasion have been implicated in active AML and 
MDS. The tumor microenvironment is permissive towards preventing both innate 
and adaptive anti-leukemic immunity. Increased proportions of regulatory T-cells 
and myeloid-derived suppressor cells (MDSCs) have been identified in both AML 
and MDS patients as poor prognostic markers. [5][6][7] T-cells display aberrant 
gene expression activation patterns and form defective immune synapses in 
vitro.[8] Natural killer (NK) cell cytotoxicity is dampened by increased frequency 
of inhibitory KIR receptors on AML blasts.[9] Other pathways in AML and MDS 
that may contribute to immune dysfunction include PD-1/PD-L1, TIM3/Galectin-
9, and IDO-1.   
 
2.3  PD-1/PD-L1 Pathway in Malignancies     
PD-1 is a member of the B7/CD28 family of 
co-stimulatory receptors that binds its 
ligands programmed death ligand-1 (PD-L1) 
and programmed death ligand-2 (PD-L2). 
PD-1 receptor is most highly expressed on 
activated mature T-cells, but also at low 
levels 
on 
NK 
cells, 
B-cells, 
and 
monocytes.[10] PD-1 binding of its ligand 
PD-L1 along with a co-stimulatory signal of 
T-cell 
receptor 
binding 
of 
the 
major 
histocompatibility complex (MHC) Figure 1. PD-
1/PD-L1 pathway presenting an antigen results in reduced T-cell receptor 
signaling, activation, and cytotoxicity as a physiological termination of the 
immune response (Figure 1). PD-1 overexpression is a phenotype of 
“exhausted,” dysfunctional T-cells in states such as chronic viral infection and 


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malignancy. PD-L1 is constitutively expressed at a low level in professional 
and non-professional antigen presenting cells (APCs), but can be 
overexpressed in malignant cells as a mechanism of immune escape. To 
exploit this overactive immunosuppressive pathway, PD-1 blockade through 
nivolumab, a monoclonal antibody to PD-1, has been used to unleash tumor-
directed cytotoxicity in multiple types of malignancy.   
The safety and efficacy of nivolumab has been established by multiple large trials 
in solid tumors. In melanoma, the randomized Checkmate-066 trial enrolled 
newly diagnosed metastatic melanoma patients to nivolumab or dacarbazine (n 
= 418) and reported higher ORR (34% vs. 9%) and median OS (not reached vs. 
10.8 months, HR 0.42, p<0.0001) in the nivolumab arm.[11] Responses were 
durable with 43 of 63 responding patients achieving ongoing response of 6 
months or longer. In patients with metastatic squamous non-small cell lung 
cancer who had progressed on a platinum-containing regimen, nivolumab was 
compared to docetaxel (n = 272) in the Checkmate-017 trial and was associated 
with significantly increased overall survival (median OS 9.2 months vs. 6 months, 
HR 0.59, p=0.0002).[12] In a similar study of metastatic non-squamous non-small 
cell lung cancer (n = 582) randomized to nivolumab or docetaxel, overall survival 
was 12.2 months for nivolumab vs. 9.2 months for docetaxel (HR 0.73, 
p=0.002).[13] Multiple other studies have solidified the role of PD-1 inhibitors in 
solid tumors including renal cell carcinoma, [14] squamous cell carcinoma of the 
head and neck, [15] and hepatocellular carcinoma. [16] Pooled safety analyses 
in melanoma trials (n=576) reported 71% (95% CI, 67% to 75%) with any-grade 
treatment-related adverse events (AEs) (most commonly fatigue [25%], pruritus 
[17%], diarrhea [13%], and rash [13%]), and 10% (95%CI, 8%to 13%) with grade 
3 to 4 treatment-related AEs. Median time to onset of AEs ranged from 5 weeks 
for skin to 15 weeks for renal AEs. [17]  
Within hematologic malignancies, PD-1 inhibitors have had efficacy in Hodgkin 
lymphoma, largely due to genetic alterations of the 9p24.1 locus leading to 
overexpression of PD-L1 and immune evasion. A phase II study of recurrent 
Hodgkin lymphoma relapsed post-autologous transplantation enrolled 80 
patients and reported ORR of 66% (95% CI 54.8–76.4) with acceptable safety 
profile. In the post-allogeneic transplantation setting of relapsed Hodgkin 
lymphoma, a multicenter retrospective review of 31 patients reported ORR of 
77%, with 55% rate of acute graft-versus-host disease (9 of 17 with grade III-IV 
aGVHD or severe chronic GVHD) using standard 3 mg/kg nivolumab dosing. [18] 
A prospective phase I trial of nivolumab in relapsed hematologic malignancies 
reported dosing of 1 mg/kg (n = 6) and 0.5 mg/kg (n = 2). In the 1 mg/kg cohort, 
1 patient had mild chronic GVHD and 2 patients had immune-related adverse 
events. [19]  


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Nivolumab has been shown to be safe and well tolerated up to a dose level of 10 
mg/kg, and pharmacokinetic studies have not reported relationship between 
nivolumab exposure produced by 3 mg/kg and efficacy. This indicates that the 
safety and efficacy profile of 240 mg nivolumab is similar to that of 3 mg/kg 
nivolumab. Similarly, a flat dose of 360 mg corresponds to a dose of 4.5 mg/kg 
q3w, which is similar to the nivolumab doses evaluated in combination with 
chemotherapy in NCT01454012, ranging from 5-10 mg/kg q3w. The simulated 
steady state concentration at trough (Cminss), peak (Cmaxss), and average (Cavgss) 
with 360 mg are less than 10 mg/kg every 2 weeks. Thus, these regimens are 
expected to be safe and tolerable.  
 
2.4  PD-1/PD-L1 Pathway in AML and MDS  
In AML, the PD-L1/PD-1 pathway is aberrantly upregulated in an estimated 
4257% of AML patients,[20][21] with increased expression of PD-L1 on leukemic 
blasts at time of relapse [22] and increased expression of PD-1 on cytotoxic 
Tcells. Aberrant activity of this inhibitory immune checkpoint pathway is 
associated with defective recognition and cytotoxicity towards leukemic blasts. 
[23]   
The immunosuppressive function of T-regs may be intimately connected to 
aberrant PD-L1/PD-1 pathways. T-regs were unable to suppress CD8+ 
proliferation or cytokine secretion in both a PD-1 knockout AML mouse model 
and PD-1 wild-type AML mouse treated with monoclonal antibody to PD-L1. Treg 
depletion through IL2-diptheria toxin in combination with PD-1/PD-L1 blockade 
showed synergistic activity in reducing AML blast burden. [24] Murine models 
have demonstrated that PD-L1 overexpressing antigen-presenting cells may 
convert naïve T-cells into a T-regulatory phenotype and aid in their expansion 
and proliferation, although this has not been tested in an AML model.[25]  
Clinical trials of PD-1/PD-L1 blockade in AML are currently in early phase. 
CT011, a humanized IgG1 monoclonal PD-1 antibody, showed safety and 
tolerability in a phase 1 trial of advanced hematologic malignancies when given 
as a single dose of 0.2 to 6.0 mg/kg. [26] Seven of 8 patients with AML who were 
enrolled in this study had disease progression. One patient had blast reduction 
from 50% to 5% with two doses of CT-011 5 months apart, with disease control 
for 61 weeks.    
PD-L1 expression has also been widely detected in MDS, but may be more 
commonly expressed in non-leukemic immune cells than leukemic blasts (12% 
of CD34+ myeloid progenitor cells, 36% of CD34- myeloid progenitor cells, 26% 
of lymphocytes).[27] Another study showed increased PD-1 expression in two 
subtypes of T-regs as well as CD4+ effector memory T-cells in MDS patients 
compared to healthy controls.[28] PD-L1 expression may increase after failure of 


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hypomethylating agents (HMA), suggesting PD-L1 upregulation as a mechanism 
of resistance to HMAs.   
Nivolumab has been studied as monotherapy and in combination with 
azacitadine in a phase II study of MDS patients after failure of hypomethylating 
agents. Although efficacy was seen with objective response rate of 69% in the 
combination arm (n = 13), there was no single agent activity noted in the 
Nivolumab monotherapy arm (n = 15). Pembrolizumab monotherapy was studied 
in 28 patients with MDS after HMA failure in the phase 1b KEYNOTE-013 study, 
which showed ORR of 4%, stable disease in 52%, and hematologic improvement 
in 11%. [29]  
 
2.5  Low Dose Cyclophosphamide  
Cyclophosphamide (CTX) is an alkylating agent with differential effects at high 
and low doses. At maximal tolerated dose, it exerts broad anti-proliferative, 
cytotoxic effects in a variety of malignancies. At low, continuous dosing 
(“metronomic”), it has immunomodulatory and anti-angiogenic properties as a 
monotherapy or in combination with other agents.   
Low dose CTX has been reported to decrease number of FOXP3+ regulatory 
Tcells, although this effect has not been sustained in most studies. [41] In vitro 
studies have additionally shown an attenuation of T-reg function and proliferative 
abilities.[42] Other immunomodulating effects of low dose CTX include 
polarization of CD4+ helper T-cells towards a Th1 profile that secrete type-1 IFNs 
and IL-2, favorable for conversion into a memory CD8+ T-cell phenotype,[43] and 
increased Th17+ population that secrete the pro-inflammatory cytokine IL-17.[44] 
In heavily pre-treated metastatic breast cancer patients, daily oral CTX at 50 mg 
daily was noted to increase percentage of tumor-specific T-cells and stabilize 
disease in 7 of 12 patients. Independent of effects on T-regs, studies have shown 
sustained increase in proliferative capacity of CD8+ effector T-cells. [45] Most 
studies of low dose CTX are in breast cancer, but efficacy has also been shown 
in hormone-resistant prostate cancer [46] and metastatic melanoma [47].   
The immunomodulatory properties of cyclophosphamide have been exploited by 
combining it with dendritic cell vaccines to prime the immune system in murine 
models. Preconditioning with low dose CTX in murine models of colon cancer 
and melanoma resulted in enhanced numbers of antigen-specific T-cells and 
increased tumor regression.[48] In addition to enhancing effector T-cells, CTX 
has been shown to increase number and activation status of dendritic cells in a 
murine model of colon cancer. [49] A combination of dendritic cell vaccine, low 
dose CTX, and anti-PD-1 therapy was effective in inducing an antigen-specific 
immune response leading to long-term tumor control in a murine model of glioma. 
[50]  


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Within hematologic malignancies, the use of continuous low dose CTX has been 
limited to non-Hodgkin lymphoma and multiple myeloma in combination with 
other agents. CTX and high-dose Celecoxib in a phase II trial had efficacy in a 
population of relapsed and refractory non-Hodgkin lymphoma patients, with 37% 
ORR and median PFS of 4.7 months.[51] To date, there are no published studies 
of low dose CTX for treatment of MDS or AML.   
Low dose CTX also has known anti-angiogenic effects, promoting normalization 
of the bone marrow vasculature through upregulation of thrombospondin-1 
(TSP1), a glycoprotein with potent endogenous angiogenesis inhibiting 
properties. [52] [53] Endothelial cells have been reported to be very sensitive to 
low doses of CTX. Induction of hypoxia results in disruption of endothelial cell 
ability to form tubes and leads to apoptosis.[54] In-vitro studies suggest a 
synergistic mechanism of CTX with other anti-angiogenic agents. Anti-
angiogenic effects of CTX have been mainly studied in solid tumor models. In 
AML, the role of angiogenesis in the vascular niche of leukemic blasts and stem 
cells has been investigated. Significantly increased microvascular density has 
been observed in the bone marrow of AML patients compared to healthy 
controls,[55] and may be a poor prognostic feature.[56] Induction of TSP-1 can 
directly induce apoptosis in AML cell lines, and is a potential therapeutic 
mechanism of low dose CTX in this setting. [57] While not proposed for direct 
testing, this may be a contributing therapeutic effect of the proposed therapy.  
 
2.6  IL-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 
immunotherapy.”[58] Based on preclinical non-human primate and early phase 
clinical trial data, including those at the University of Minnesota, IL-15-containing 
regimens can 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); daily administration of rhIL-15 intravenously 
(IV) or subcutaneously (SC) has been shown to increase the number and 
activation status of circulating CD8+ T and NK cells, but the cytokine has a very 
short half-life. Furthermore, high levels of free rhIL-15 decrease circulating IL- 
15Rα, acting as a negative feedback signal to reduce further IL-15 
transpresentation. Trans-presentation appears to be a dominant mechanism for 
IL- 15 action in vivo in response to immune stimuli.[59] N-803 (Nantcell Inc, 
Culver City, CA) is a soluble complex consisting of two protein subunits of a 
human IL-15 variant associated with high affinity to a dimeric human IL-15 


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receptor α (IL- 15Rα) sushi domain/human IgG1 Fc fusion protein, that 
physiologically transpresents IL-15.[60][61] 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). [60]  
N-803 has been used in a Phase I study of relapsed AML patients post-alloHSCT 
and found to have good tolerability and some clinical activity. [62] N-803 in 
combination with Nivolumab was safe and had clinical activity in a study of 
advanced non-small cell lung cancer patients with previous progression on single 
agent PD-1 inhibitor.[63] A summary of N-803 by route and dose is found in 
Section 6.1.4. The University of Minnesota’s experience with N-803 was that 
subcutaneous dosing was generally well tolerated with an injection site related 
skin rash as the most notable event, often quite widespread; however none were 
dose limiting. Typically, the rash resolved by 7 days post-injection. Other adverse 
events included fever, fatigue, and changes in blood pressure.  
In phase 1 studies that used weekly dosing of SC N-803, correlative data showed 
that highest level of immune stimulation, as measured by staining intensity of 
Ki67 in NK cells, increased concentration of circulating IFN-gamma was highest 
on day 4, and decreased with subsequent doses. [62] [63] This suggests that 
prolonged continuous treatment leads to immune anergy and reduced biological 
responsive. Thus subsequent studies using this agent have been amended to 
use less frequent dosing schedules for N-803 (NCT02989844). This study will 
use every 3 week dosing at 10 ug/kg given subcutaneously.    
 
2.7  Areas of Investigation    
The somatic mutational profile of AML (Cancer Genome Atlas Project) may be 
simpler than most solid tumors, with an average of only 13 mutations per gene, 
though it may be two-fold greater in secondary AML.[64] Cancers with high 
somatic mutation frequency have shown variable sensitivity to single agent PD1 
blockade, from 50-60% clinical benefit with durable response in melanoma to low 
efficacy in squamous cell carcinoma of the lung, suggesting that other factors 
contribute to predicting response to checkpoint blockade. Within AML, Wilms 
Tumor (WT) has been identified as a potential neo-antigen targetable with a 
WTspecific cytotoxic T-cell response. Subgroups of AML with mutations 
including FLT3/ITD or NPM1 may also have neo-antigen targets and might 


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benefit from PD-1 blockade. The relative importance of neo-antigen burden 
compared to factors such as PD-L1 expression on tumor cells and an immune 
environment that promotes immune activation is unknown.  
At cytotoxic doses, CTX may be able to alter the immunosuppressive 
microenvironment via downregulation of IDO. The effects of low dose continuous 
cyclophosphamide on IDO regulation have not been well studied. Since 
upregulation of IDO has been identified as a pathogenic feature of AML and may 
contribute to tolerogenic immune environment, the interaction of IDO and 
checkpoint blockade is of interest. [39]  
The function and activity of dendritic cells to either induce antigen-directed 
cytotoxicity or anergy in T-cells in AML and MDS is an important variable in 
efficacy of PD-1/PD-L1 directed therapy. Dendritic cells have been classified into 
two groups, myeloid and plasmacytoid, based on expression of CD11c, both 
which can be derived from a malignant clone.[65] AML-derived DCs, particularly 
the plasmacytoid variant, have been reported to express tolerogenic cytokines 
such as IL-10 and secrete IDO, which induces an immunosuppressive 
Tregulatory response.[66] A study of MDS patients reported reduced numbers of 
peripheral blood DCs that were all clonally-derived.[67] In newly diagnosed AML 
patients, a small study showed a range of normal quantitative DC subsets, 
increased DC subsets, or no detectable DC subsets. Functional studies showed 
reduced ability to induce proliferative responses in naïve T-cells in DCs from AML 
patients compared to healthy controls. [68] Further understanding of the role of 
DCs in tumor evasion in the setting of relapsed/refractory AML and MDS may 
enhance delivery of effective immunotherapies.   
 
2.8  Rationale  
Immunotherapy is a highly promising area of investigation in the treatment of 
AML and MDS. The ability of alloHCT to eliminate leukemic blasts and 
leukemiainitiating cells/leukemia stem cells highlights its curative potential. Many 
patients are not eligible for alloHCT due to pre-existing comorbidities, lack of 
donor graft availability, older age, and excessive leukemia burden. Immune 
checkpoint inhibitors of the PD-1/PD-L1 pathway have widespread efficacy 
across multiple cancer types and favorable tolerability. This research 
hypothesizes that PD-1 inhibitors in combination with immunomodulatory agents 
will induce leukemiadirected immune stimulation in AML and higher-risk MDS. 
Low dose cyclophosphamide is an immunomodulator which has not been 
reported to cause severe myelosuppression in a population that commonly has 
neutropenia and increased risk of infection due to active disease. N-803 is a 
promising immunotherapeutic agent that is safe, has known synergistic activity 
with PD-1 inhibitors, and is highly potent for increasing frequency and activation 
of T-cells and NK cells. Immune dysfunction induced by active AML may benefit 


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from additional stimulation with an agent such as N-803 to induce T-cell 
cytotoxicity after PD-1 blockade.   
3 Study Design   
This phase I study consists of a randomized pilot sub-study of two dosage arms of CTX 
in combination with nivolumab and N-803 in stage I.    
  
Arm 1 (CTX 50 mg PO daily + nivolumab IV) and Arm 2 (CTX 350 mg PO every 7 days+ 
nivolumab IV) previously enrolled randomized patients in a 1:1 ratio. Due to low 
response rates (no complete responses and only 2 patients with partial response) and 
4 patients receiving ≤1 cycle of treatment due to rapid disease progression, arms 1 and 
2 are now closed. In the amended protocol, the first 20 patients enrolled in the study 
are randomized to either Arm 3 (CTX 50 mg PO daily + nivolumab IV + SC N-803 every 
3 weeks) or Arm 4 (CTX 350 mg PO every 7 days+ nivolumab IV + SC N-803 every 3 
weeks) with 10 subjects in each arm. Nivolumab is dosed at 360 mg, unless the patient 
has had a prior allogeneic hematopoietic stem cell transplant (alloHSCT), in which case 
nivolumab is given at 180 mg IV every 3 weeks. N-803 is dosed at 10 ug/kg every 3 
weeks and given subcutaneously.  
  
Continuous stopping rules, defined as selected Grade 3 non-hematologic events, 
graftversus-host disease, and any Grade 4 or 5 non-hematologic event, will be used to 
monitor excessive toxicity for each arm.   
  
Efficacy will be assessed with pooled total from both arms 3 and 4 with up to 20 patients 
available for assessment of OR at 42 days.   
  
All patients receive nivolumab IV over 30 minutes every 3 weeks, N-803 SC every 3 
weeks and oral cyclophosphamide as assigned for up to 5 treatment courses with each 
treatment course equal to 21 days. Nivolumab is dosed at 360 mg, unless the patient 
has had a prior allogeneic hematopoietic stem cell transplant (alloHSCT), in which case 
nivolumab is given at 180 mg IV every 3 weeks. N-803 is dosed at 10 ug/kg every 3 
weeks and given subcutaneously.  
  
Disease will be assessed by bone marrow biopsy at 21 and 42 days after initiation of 
study drugs. If the increase in absolute blast count is <25% in peripheral blood or bone 
marrow from baseline at day 42 or later and there is perceived clinical benefit by the 
treating physician, the subject will proceed with further cycles of treatment with up to 5 
courses of treatment on study.  
  
A final treatment visit occurs 30 days after the last dose of study drug with follow-up for 
response and survival continuing through 2 years from beginning of treatment. For 


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patients with clinical benefit after the 5 treatment courses, additional therapy with the 
study drugs or other treatment may be offered.  
4 Patient Selection  
Study entry is open to patients 18 years of age and older regardless of gender, race, or 
ethnic background. While there will be every effort to seek out and include minority 
patients, the patient population is expected to be no different than that of other 
relapsed/refractory acute myeloid leukemia (AML) and high-risk myelodysplastic 
syndrome studies at the University of Minnesota.  
4.1 Inclusion Criteria  
4.1.1 ≥18 years of age   
4.1.2 Meets one of the following disease criteria:  
• 
Primary (de novo) AML or higher-risk MDS with induction failure: No 
CR after 2 or more induction attempts with chemotherapy, 
hypomethylating, agents or other agents; no CR after 1 induction 
attempt and not eligible for a 2nd induction. Higher risk MDS defined 
as risk score > 4.5 based on the revised IPSS criteria (refer to 
Appendix  
II).     
• 
Secondary AML (from antecedent hematologic malignancy or 
treatment-related): Not in CR after 1 or more cycles of chemotherapy.   
• 
Relapsed AML: Blasts ≥5% in bone marrow or peripheral blood after 
prior attainment of CR or biopsy-proven extramedullary leukemia in 
absence of bone marrow involvement; relapse at any time but 
currently ≥100 days following allogeneic HCT.  
• 
Relapsed MDS: Morphologic evidence of relapse or increase in blasts 
to ≥5% in bone marrow or peripheral blood after prior hematologic 
improvement or partial or complete response and not eligible for or 
decline intensive chemotherapy; relapse at any time but currently 
≥100 days following allogeneic HCT.   
4.1.3 ECOG Performance Status ≤ 2 – refer to Appendix I  
4.1.4 Adequate organ function within 14 days of study registration defined as:  
• 
Absolute Lymphocyte Count:  ≥ 500 cells/mm3  
• 
Hepatic:  total bilirubin ≤ 3 x upper limit of institutional normal (ULN); 
ALT and AST ≤ 5 x ULN  
• 
Renal: Serum creatinine ≤ 2 mg/dL   
• 
Pulmonary: No oxygen requirement on room air or requiring ≤ 2L 
supplemental O2  
4.1.5 Ability to be off prednisone and other immunosuppressive drugs (>10 mg 
daily prednisone equivalent) for at least 14 days prior to and while receiving 


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N-803. Inhaled or topical steroids, and adrenal replacement steroid doses 
< 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease  
4.1.6 Sexually active females of child bearing potential and males with partners 
of child bearing potential must agree to use effective contraception during 
therapy and continuing (23 weeks for females, 31 weeks for males) after 
the last dose of nivolumab  
4.1.7 Voluntary written consent   
4.2 Exclusion Criteria  
4.2.1 Pregnant or breastfeeding –The agents used in this study fall under 
Pregnancy Category D - Drugs which have caused, are suspected to have 
caused or may be expected to cause, an increased incidence of human 
fetal malformations or irreversible damage. Women of childbearing 
potential must have a negative pregnancy test (urine or serum) within 7 
days of study drug administration.  
4.2.2 Prior allogeneic hematopoietic stem cell transplantation currently within 
previous 100 days (note patients with a prior alloHSCT receive nivolumab 
at the reduced dose of 180 mg); they are eligible after that date  
4.2.3 Signs or symptoms of active graft versus host disease   
4.2.4 Active pneumonitis or uncontrolled infection  
4.2.5 Received chemotherapy drugs within previous 2 weeks  
4.2.6 Estimated life expectancy <28 days in the opinion of the enrolling 
investigator  
4.2.7 Previously treated with N-803 (or “ALT-803”)  
4.2.8 Received cellular therapy product within 30 days   
4.2.9 Allogeneic HSCT recipient receiving calcineurin inhibitor within 4 weeks  
 5  
Screening and Study Enrollment   
Written consent must be obtained prior to the performance of any research 
related tests or procedures. Consent is usually obtained before final eligibility is 
determined.  
5.1 Consent and Study Screening in OnCore  
Any patient who has been consented is to be entered in OnCore by the Primary 
Clinical Research Coordinator (PCRC) or designee. If a patient is consented, but 
not enrolled, the patient’s record is updated in OnCore as a screen failure and 
reason for exclusion recorded.  
5.2 Study Enrollment and Treatment Assignment  
To be eligible for study enrollment, the patient must sign the treatment consent 
and meet each of the inclusion criteria and none of the exclusion on the eligibility 


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checklist based on the eligibility assessment documented in the patient’s medical 
record.  
  
The Primary Clinical Research Coordinator (PCRC) or designee will complete 
the enrollment process in OnCore by assigning the treatment arm and entering 
the on treatment date.  
  
Up to 20 patients enrolled in the study are randomized via OnCore at the time of 
study registration to either:   
Arm 3: CTX 50 mg PO daily + nivolumab 360 mg (or if prior alloHSCT, 180 mg) 
IV every 3 weeks + SC N-803 10 ug/kg every 3 weeks or   
Arm 4: CTX 350 mg PO every 7 days + nivolumab 360 mg (or if prior alloHSCT, 
180 mg) IV every 3 weeks + SC N-803 10 ug/kg every 3 weeks  
  
No additional patients will be enrolled to Arm 1 or 2 (closed). If Arm 3 or Arm 4 is 
terminated by the toxicity stopping rule, all subsequent patients will be assigned 
to the other arm if it is not terminated by the toxicity stopping rule to continue 
enrollment of up to 20 patients.  
5.3 Patients Who Do Not Begin Study Treatment  
If a patient is enrolled to the study, and is later found not able to begin the first 
dose of study drug, for whatever reason, 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). The reason for removal from study 
prior to starting study treatment will be clearly indicated in OnCore. The patient 
will be replaced to fulfill study enrollment requirements.  
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.).   
6.1 Study Drug Administration  
Participants will receive one of the two following treatment plans based on 
assignment at enrollment:  
  
Arm 3: CTX 50 mg PO daily + nivolumab 360 mg (or if prior alloHSCT, 180 mg) 
IV every 3 weeks + SC N-803 10 ug/kg every 3 weeks or   
Arm 4: CTX 350 mg PO every 7 days + nivolumab 360 mg (or if prior alloHSCT, 
180 mg) IV every 3 weeks + SC N-803 10 ug/kg every 3 weeks  
  


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Each treatment course consists of 3 weeks with up to 5 treatment courses 
permitted. A window of ±3 days is permitted for the nivolumab infusion to 
accommodate scheduling difficulties (i.e. holidays, inclement weather).   
  
To begin a new treatment course (Day 1) the following criteria must be met:  
• 
Cyclophosphamide  
o No grade 3-4 oral mucositis or grade 3-4 
cystitis   o No signs or symptoms of new 
infection   
• 
Nivolumab o No contraindication for continuation based on immune-
related adverse events (see Section 7.1)  
o No signs or symptoms of new infection   o No 
active GVHD  
• 
N-803  o Previous injection site reaction is not showing signs of resolving  
(improving) based on measurement or intensity  o No 
hypotension (systolic blood pressure <90 mmHg) not resolving with 
intravenous fluids   
o No contraindication for continuation based on 
immune-related adverse events (see Section 
7.1)  
o No signs or symptoms of new infection  o No 
active GVHD   
  
Patients who have delay of nivolumab and/or N-803 greater than 3 weeks for 
toxicities that are at least possibly related despite supportive treatment should be 
considered to have study treatment discontinued, unless the treating physician 
considers that the patient may benefit from continued study treatment after 
resolution of AEs.   
If nivolumab is delayed, N-803 and/or cyclophosphamide should continue if no 
contraindication is present.   
If N-803 is delayed, nivolumab and/or cyclophosphamide should continue if no 
contraindication present.   
If cyclophosphamide is delayed, nivolumab and/or N-803 should continue if no 
contraindication present.   
If nivolumab and N-803 are both permanently discontinued, cyclophosphamide 
should be discontinued and patient should be taken off study.   
6.1.1  
Nivolumab (All Participants)  
Nivolumab will be given at a fixed dose of 360 mg (or if prior alloHSCT, 180 mg) 
IV over 30 minutes every 21 days on Days 1 of each cycle for up to five 21-day 
courses.    


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Nivolumab will be administered in the outpatient setting; however, inpatient 
administration is permitted as medically appropriate if a patient is hospitalized. 
No premedication is required. Monitoring will be according to institutional 
guidelines with interruption or slowing of rate of infusion with grade 1 to 2 
infusional toxicities and discontinuation of nivolumab with grade 3 to 4 infusional 
toxicities.   
  
No dose modifications are permitted for nivolumab but dose may be withheld 
based on occurrence of significant immune-related AE Grade 2 or higher based 
on NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.03, as 
described in Section 7.1.  
6.1.2 Oral Cyclophosphamide (CTX) Administered Daily (Arm 3)  
The patient should be instructed to take CTX once a day, every day, by mouth at 
approximately the same time each day. The tablet must be swallowed whole, 
with a full glassful of water. Cyclophosphamide tablets are best taken early in the 
day about an hour before a meal. However, to avoid queasiness, it may be taken 
with food. The patient should be encouraged to drink plenty of liquids.  
  
If a dose is missed and it is more than 12 hours before the next dose is due, the 
patient should take the missed dose and retain the previous schedule. If the next 
dose is due in less than 12 hours, the patient must skip the missed dose, 
recording the dose as missed on the daily drug log.  
6.1.3 Oral Cyclophosphamide (CTX) Administered Weekly (Arm 4)  
The patient should be instructed to take CTX once weekly at approximately the 
same time each week. The tablet must be swallowed whole, with a full glassful 
of water. Cyclophosphamide tablets are best taken early in the day about an hour 
before a meal. However, to avoid queasiness, it may be taken with food. The 
patient should be encouraged to drink plenty of liquids.  
  
If a dose is missed, it may be taken if less than 48 hours from missed dose. If 
greater than 48 hours from missed dose, the patient must skip the missed dose 
and resume at next scheduled dose if clinically appropriate.   
6.1.4 N-803 (All Participants)  
N-803 at 10 ug/kg is administered subcutaneously on D1 of a 21-day cycle for a 
maximum of 5 doses, or until stopping rules are met or patient refusal. A window 
of +/- 1 week if permitted for each N-803 injection in the event of scheduling 
issues (i.e. holiday, bad weather, or other scheduling issues). N-803 will be 
administered in the outpatient setting; however, inpatient administration is 
permitted as medically appropriate if a patient is hospitalized.  


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N-803 dosing is calculated using a weight obtained within 3 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.   
  
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.  
6.1.5 Dose Reduction  
A one-time dose decrease to 6 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.  
6.2 GVHD Management Guidance in recipients of allogeneic HSCT   
New or worsening skin rash outside of injection site area and other GVHD 
manifestations should be managed per institutional guidelines. Refer to Section 
7.3 for management of skin rash/injection site reaction within the vicinity of the 
injection.  
  


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GVHD will be graded using the University of Minnesota aGVHD Grading Scale 
(Appendix IV).   
  
N-803 and Nivolumab will be permanently discontinued with diagnosis of new 
onset of GVHD.   
6.3 Supportive Care  
Concurrent Hydroxyurea use will be permitted for high blast count leukemia for 
up to 1 month after enrollment in study.    
  
Steroids or other immune modulatory medications should be avoided unless 
required for treating a grade 3-4 Nivolumab or N-803-related adverse event.    
  
Supportive Care will be provided per University of Minnesota institutional 
guidelines.   
 6.4  
Duration of Study Treatment  
Patients will receive five 21-day treatment courses unless any one of the 
following occurs:  
• 
Unacceptable toxicity  
• 
Progression as defined by increase in absolute blast count of ≥25% in 
peripheral blood or bone marrow by day 42 or later   
• 
A different anti-cancer treatment is indicated  
• 
Patient is non-compliant or refuses treatment  
• 
In the opinion of the treating investigator, continuation of study therapy is 
not of benefit to the patient   
  
A final treatment visit occurs 30 days after the last dose of study drug (maximum 
of 5 courses).    
  
Any patient unable to receive at least 1 cycle of study therapy will be replaced.  
  
If follow-up ends before Day 42 for a reason other than death or progression, the 
patient will be considered unevaluable and will be replaced per Section 14.  
 6.5  
Duration of Study Participation  
Follow-up for disease status and survival for study end points occurs at 6 months 
by clinic visit, review of the medical record or contact with a local medical doctor 
unless the patient is:  
• 
Unevaluable (e.g. unable to receive at least 1 cycle of study therapy)  
• 
enters hospice care  
• 
refuses follow-up  


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After 6 months, follow-up for survival only by record review will continue until 2 
years from study enrollment.   
  
The date and cause of death should be entered into the follow-up tab in OnCore 
upon knowledge.  
 7  
Management of Selected Toxicity   
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will 
be used to grade adverse events. A copy of the CTCAE v 4.03 can be downloaded: 
(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-
0614_QuickReference_8.5x11.pdf).  
7.1 Nivolumab and N-803  
Immune-Related Adverse Events Management   
Immune-related adverse events (irAEs) from nivolumab and N-803 will be 
managed depending on severity (NCI CTCAE 4.03 grade) as outlined below.   
Grade 1 to 2: Treat symptomatically or with moderate dose steroids, more 
frequent monitoring.  
Grade 1 to 2 (persistent): Manage similar to Grade 3 to 4 irAE  
Grade 3 to 4:  Treat with high dose corticosteroids  
Any Grade 4 irAEs require treatment discontinuation with nivolumab and 
N-803 except for single laboratory values out of normal range that are unlikely 
related to study treatment as assessed by the Investigator, do not have any 
clinical correlate, and resolve within 7 days with adequate medical management  
Any Grade 3 irAEs require withholding nivolumab and N-803 except for any 
of the following: Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which 
is controlled with medical management, transient (≤ 24 hours) Grade 3 fatigue, 
local reactions, headache, nausea, emesis that resolves to Grade ≤ 1 and single 
laboratory values out of normal range (excluding Grade ≥ 3 liver function test 
increase) that are unlikely related to study treatment according to the 
Investigator, do not have any clinical correlate, and resolve to Grade ≤ 1 within 7 
days with adequate medical management  
Any Grade 2 irAEs should be managed as follows:  
If a Grade 2 irAE resolves to Grade ≤ 1 by the next planned cycle, treatment may 
continue.  


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If a Grade 2 irAE does not resolve to Grade ≤ 1 by the next planned cycle, 
treatment should be withheld at next cycle. If at the end of the following cycle the 
event has not resolved to < Grade 1, the subject should permanently discontinue 
treatment with nivolumab and N-803 (except for hormone insufficiencies, that can 
be managed by replacement therapy).   
  
Upon the recurrence of the same Grade 2 irAE (except for hormone 
insufficiencies that can be managed by replacement therapy) in the same 
subject, treatment with nivolumab and N-803 should be permanently 
discontinued. Treatment of gastrointestinal, dermatological, pulmonary, hepatic, 
renal, cardiac, neurological and endocrine irAEs should follow guidelines set forth 
in the table below.  
Gastrointestinal irAEs  
Severity of  
Diarrhea/Colitis  
Management   
Follow-up  
Grade 1  
Diarrhea: < 4 
stools/day over 
baseline  
Colitis: asymptomatic   
Continue nivolumab and N-
803 therapy  
Symptomatic treatment (for 
example, loperamide)  
Close monitoring for worsening  
symptoms  
Educate subject to 
report worsening 
immediately If worsens:  
Treat as Grade 2 or 3/4   
Grade 2  
Diarrhea:  4 to 6 
stools per day over 
baseline; IV fluids 
indicated < 24 hours;  
not interfering with  
ADL  
Colitis: 
 
abdominal 
pain; blood in stool   
Withhold nivolumab and N- 
803   
Symptomatic treatment  
If improves to Grade <1:   
Resume nivolumab and N-803 
therapy  
If persists > 5-7 days or recur  
• 
0.5-1.0 
mg/kg/day 
methylprednisolone 
or 
oral 
equivalent  
• 
When symptoms improve to  
grade 1, taper steroids at least 1 
month, consider prophylactic 
antibiotics for opportunistic 
infections, and resume I-O  
therapy per protocol  
  
If worsens or persists > 3-5 with 
oral steroids, then treat as Grade  
3 to 4  
  


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Grade 3 to 4  
Diarrhea (Grade 3): ≥  
7 stools per day over  
Baseline; 
incontinence; IV fluids 
≥ 24 hrs.; interfering 
with ADL  
Colitis (Grade 3):  
severe abdominal 
pain, medical 
intervention indicated, 
peritoneal signs 
Grade 4: 
lifethreatening, 
perforation  
Permanently discontinue 
nivolumab and N-803 for  
Grade 4   
  
Withhold nivolumab and 
N803 for Grade 3   
  
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or  
equivalent Add 
prophylactic  
antibiotics for opportunistic 
infections   
Consider colonoscopy if  
needed   
If improves, continue steroids 
until Grade < 1, then taper over at 
least 1 month  
If worsens, persists > 3 to 5 days, 
or recurs after improvement, add 
infliximab 5 mg/kg (if no 
contraindication), Note: Infliximab 
should not be used in cases of  
perforation or sepsis   
  
Grade 3:  If improves to Grade  
≤1: Resume nivolumab and N803 
therapy  
  
  
  
Dermatological irAEs  
Grade of Rash  
Management  
Follow-up  
Grade 1 to 2  
Covering ≤ 30% body 
surface area  
Symptomatic therapy (for 
example, antihistamines, 
topical steroids)  
Hold nivolumab and N803, 
may resume if resolving 
after 1 week   
If persists > 1 to 2 weeks or 
recurs:  
Consider skin biopsy  
Delay nivolumab and N-803. 
Consider 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent. Once improving, taper 
steroids over at least 1 month, 
consider prophylactic antibiotics 
for opportunistic infections, and 
resume nivolumab. If worsens. 
treat as Grade 3 or 4  


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Grade 3 to 4  
Covering > 30%  
Grade 4: body surface 
area; life threatening 
consequences   
Withhold nivolumab and N- 
803 for Grade 3  
Permanently discontinue 
nivolumab and N-803 for  
Grade 4 or recurrent  
Grade 3  
Consider skin biopsy,  
Dermatology consult  1.0 
to 2.0 mg/kg/day 
methylprednisolone IV or  
IV equivalent   
If improves to <Grade 1, taper 
steroids over at least 1 month and 
add prophylactic antibiotics for 
opportunistic infections  
Resume nivolumab and N-803 
therapy  
Pulmonary irAEs  
Grade of 
Pneumonitis  
Management  
Follow-up  
Grade 1 Radiographic 
changes only   
Consider delay of 
nivolumab and N-803 
therapy  
Monitor for symptoms 
every 2 to 3 days   
Consider pulmonary and  
Infectious disease consults  
If improves or resolves, continue 
planned therapy.  
Re-image at least every 3 weeks  
If worsens, treat as Grade 2 or 34  
 
Grade 2  
Mild to moderate new 
symptoms   
Delay nivolumab and N- 
803 therapy  
Pulmonary and Infectious  
Disease consults 
Monitor symptoms daily, 
consider hospitalization  
1.0 mg/kg/day 
methylprednisolone IV or 
oral equivalent   
Consider bronchoscopy, 
lung biopsy   
Re-image every 1-3 days  
When symptoms improve to  
Grade < 1, taper steroids over at 
least 1 month and then resume 
nivolumab and consider 
prophylactic antibiotics  
If not improving after 2 weeks or 
worsening, treat as Grade 3 to 4   


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Grade 3 to 4 
Severe new 
symptoms; New / 
worsening hypoxia; 
life-threatening   
Permanently discontinue 
nivolumab and N-803  
Hospitalize   
Pulmonary and Infectious  
Disease consults 
2 to 4 mg/kg/day  
methylprednisolone IV or  
IV equivalent  
Add prophylactic  
antibiotics for opportunistic 
infections   
Consider bronchoscopy, 
lung biopsy   
When symptoms improve to  
Grade < 1, taper steroids over at 
least 6 weeks  
If not improving after 48 hours or 
worsening:, add additional 
immunosuppression (for example, 
infliximab, cyclophosphamide, IV 
immunoglobulin, or  
mycophenolate mofetil)   
  
Hepatic irAEs  
Grade of Liver Test 
Elevation  
Management  
Follow-up  
Grade 1  
Grade 1 AST or ALT 
> ULN to 3.0 x ULN  
and / or total bilirubin  
> ULN to 1.5 x ULN   
Continue nivolumab and 
N-803  
Continue liver function monitoring   
If worsens, treat as Grade 2 or 3 to 
4   
Grade 2  
AST or ALT > 3.0 to ≤ 
5 x ULN and / or total  
bilirubin > 1.5 to ≤ 3 x  
ULN   
Withhold nivolumab and  
N-803  
Increase frequency of 
monitoring to every 3 
days   
If returns Grade < 1,  resume 
routine monitoring, resume 
nivolumab and N-803  
If elevations persist > 5-7 days or 
worsens, 0.5 to 1 mg/kg/day 
methylprednisolone or oral  
equivalent and when LFT returns to 
Grade < 1, taper steroids over at 
least 1 month, consider prophylactic 
antibiotics for  
 
 
opportunistic infections, resume 
nivolumab and N-803  


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Grade 3 to 4  
AST or ALT > 5 x ULN 
and / or total bilirubin 
> 3 x ULN   
Permanently discontinue 
nivolumab and N-803 
Increase frequency of 
monitoring to every 1 to  
2 days   
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or  
IV equivalent Add 
prophylactic 
antibiotics for  
opportunistic infections, 
Consult 
gastroenterologist 
Consider obtaining  
MRI/CT scan of liver and 
liver biopsy if clinically  
warranted   
If returns to Grade < 1, taper 
steroids over at least 1 month  If 
does not improve in >3 - 5 days, 
worsens or rebounds, add 
mycophenolate mofetil 1 gram (g) 
twice daily   
If no response within an additional  
3 to 5 days, consider other 
immunosuppressants per local 
guidelines   
  
 


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Renal irAEs  
Grade of Creatinine 
Elevation  
Management  
Follow-up  
Grade 1  
Creatinine > ULN and  
> than baseline but ≤  
1.5x baseline  
Continue nivolumab and  
N-803  
Monitor creatinine weekly  
If returns to baseline:  
•Resume routine creatinine 
monitoring per protocol If 
worsens:  
•Treat as Grade 2 or 3/4  
Grade 2-3 
Creatinine > 
1.5x baseline to 
≤ 6x ULN  
Delay nivolumab and N- 
803  
Monitor creatinine every  
2-3 days  
0.5 to 1.0 mg/kg/day 
methylprednisolone IV or 
oral equivalent Consider 
renal biopsy with 
nephrology consult  
If returns to Grade 1:  
•Taper steroids over at least 1 
month, consider prophylactic 
antibiotics for opportunistic 
infections, and resume  nivolumab 
and N-803 therapy and routine 
creatinine monitoring per protocol If 
elevations persist > 7 days or 
worsen:  
•Treat as Grade 4  
Grade 4  
Creatinine > 6x ULN  
Permanently discontinue 
nivolumab and N-803  
Monitor creatinine daily  
  
1.0-2.0 mg/kg/day 
methylprednisolone IV or 
IV equivalent  
Consult nephrologist  
Consider renal biopsy  
If returns to Grade 1 : Taper 
steroids over at least 1 month and 
add prophylactic antibiotics for 
opportunistic infections  
  
  
Neurological irAEs  
Grade of  
Neurological 
Toxicity  
Management  
Follow-up  
Grade 1  
Asymptomatic or 
mild symptoms; 
Intervention not 
indicated  
Continue nivolumab and 
N-803  
If returns to baseline:  
•Resume routine monitoring per 
protocol If worsens:  
•Treat as Grade 2 or 3/4  


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Grade 2  
Moderate symptoms; 
Limiting instrumental  
ADL  
Delay nivolumab and N- 
803  
Treat symptoms per local 
guidelines Consider 0.5 
to 1.0 mg/kg/day  
methylprednisolone IV or  
PO equivalent  
If returns to baseline:  
• resume  nivolumab and N-803 
therapy when returned to baseline 
If worsen:  
•Treat as Grade 3-4  
Grade 3-4  
Severe symptoms;  
Limiting self-care  
ADL;  
Life-threatening  
Permanently discontinue 
nivolumab and N-803 
Obtain neurology consult 
Treat symptoms per local 
guidelines  
1.0-2.0 mg/kg/day IV 
methylprednisolone IV or  
IV equivalent Add 
prophylactic antibiotics 
for opportunistic 
infections  
If improves to Grade 2:  
Taper steroids over at least 1  
month  
If worsens or atypical presentation: 
Consider IVIG or other 
immunosuppressive therapies per 
local guidelines  
  
 
Cardiac irAEs  
Myocarditis  
Management  
Follow-up  


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Grade 2  
Symptoms with mild  
to  
moderate activity or 
exertion  
  
Withhold nivolumab and N- 
803  
Hospitalize.  
Urgent Cardiology consult 
to establish etiology and 
rule-out immune-mediated 
myocarditis, consider  
myocardial biopsy;  
management o 
Troponin and BNP o 
ECG +/- continuous 
cardiac monitoring o 
Echocardiogram  
o Cardiac MRI  
  
Prompt initiation of 2 
mg/kg/day  
methylprednisolone IV or 
equivalent  
  
If symptoms improve and 
immune-mediated etiology is 
ruled out, resume nivolumab and 
N-803.   
  
If worsens, intensify treatment 
according to grade  
• 
Upon recovery, taper steroids 
over at least 1 month with 
close monitoring of troponin 
and BNP as well as for new 
symptoms  
• 
Repeat cardiac MRI for post 
treatment assessment and  
cardiology follow-up  
• 
Retreatment may be 
considered after recovery and 
completion of steroid taper  
Grade 3 or Grade 4  
Permanently discontinue 
nivolumab and N-803 
Hospitalize to intensive 
cardiac monitoring 
Cardiac evaluation to 
include:  
• 
Troponin and BNP 
monitoring  
• 
ECG +/- continuous 
cardiac monitoring  
• 
Echocardiogram  
• 
Cardiac MRI  
• 
Myocardial biopsy if 
feasible  
  
• 
Immediate initiation of 
2 mg/kg/day  
methylprednisolone IV or  
1 g IV bolus  
• Consider adding a second  
Once improving, taper steroids 
over at least 1 month  with close 
monitoring of troponin and BNP  
as well as for new symptoms  
  
If no improvement or worsening, 
consider additional 
immunosuppressants (e.g. 
azathioprine, cyclosporine A)  
  
Repeat cardiac MRI for post 
treatment assessments and 
cardiology follow-up  
 




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Suspicion of 
adrenal crisis (e.g. 
severe dehydration, 
hypotension, shock 
out of proportion to 
current illness  
Delay or Permanently 
discontinue nivolumab and N803  
Rule out sepsis  
Stress dose of IV steroids 
with mineralocorticoid activity 
IV fluids  
Consult endocrinologist  
If adrenal crisis ruled out, then 
treat as above for 
symptomatic endocrinopathy  
  
  
  
  
  
  
  
  
  
  
  
Nivolumab may induce graft versus host disease in patients who have had a prior 
allogeneic hematopoietic stem cell transplant. To reduce this risk, patients who 
have undergone a prior alloHSCT will receive a lower dose of nivolumab (180 
mg instead of 360 mg).  
  
Complications of allogeneic hematopoietic stem cell transplantation after 
nivolumab have been seen including severe or refractory graft versus host 
disease, hyper-acute GVHD, steroid requiring febrile syndrome without an 
identified infectious cause, encephalitis, and hepatic veno-occlusive disease. 
The consent contains language instructing the participant to inform the transplant 
team of previous nivolumab treatment if he/she undergoes a HSCT at any time 
in the future.   
 
7.2  
Oral Cyclophosphamide  
Management of toxicities from oral cyclophosphamide will be per the package 
insert and standard institutional guidelines.   
  
For Grade 2 or greater GI toxicities assessed as likely attributable to CTX, drug 
may be held for up to 2 weeks and restarted after improvement of symptoms.  
  
For neutropenic fever with ANC <500 cells/mm3, drug may be held for up to 2 
weeks and restarted as assessed as clinically appropriate by the treating 
physician.   


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7.3  
N-803  
Hypotension (systolic blood pressure < 90 mm Hg)  
N-803 dosing should be held for hypotension (defined as systolic blood pressure 
less than 90 mm Hg) if in the presence of any clinically significant symptoms (in 
the opinion of the treating physician), until the systolic blood pressure reading is 
stable. If mild dehydration is suspected, an IV fluid bolus may be used per 
standard of care.  
  
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 and symptomatic (painful and/or itchy), it may be 
treated (at the discretion of the treating physician) with topical 0.05% clobetasol 
propionate (i.e. 0.05% Cormax) or 0.1% triamcinolone (i.e., Kenalog) cream. 
Diphenhydramine may be administered pre- (25-50 mg TID orally) and 
postdosing (25-50 mg TID orally x 2 days) of N-803 at the discretion of the 
treating physician. Diphenhydramine should be eliminated if not tolerated.  
 8  
Schedule of Tests and Procedures  
Scheduled evaluations through during treatment may be performed ±3 days from the 
targeted date. The end of treatment visit may be performed ±7 days of the targeted 
date. Follow-up for disease status and survival for study end points occurs at 6 months 
by clinic visit, review of the medical record or contact with a local medical doctor. 
Followup for survival only will continue until 2 years from study enrollment. Collection of 
research samples are linked with the standard of care testing as no visit is done solely 
for research. Targeted days may be altered as clinically appropriate.  
  
  
 


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8.1  
Required Clinical Care Evaluations    
  
Evaluations/Tests 
and Procedures  
Baseline (within 
14 days of study 
registration)  
During each treatment cycle (up to 5 cycles)  
Final Treatment  
Visit (30 days post 
treatment)  
 
Follow-up 
from C1D1  
Day 11  
Day 8  
Day 15  
Consent   
X  
  
  
  
  
  
Medical History  
X  
  
  
  
  
  
Physical Exam  
X  
X  
  
  
X  
  
Weight  
X  
X  
  
X  
  
  
Brief Provider  
Assessment1  
  
X  
X  
X  
  
  
ECOG PS  
X  
  
  
  
  
  
Adverse Event 
Assessment  
including targeted 
toxicities  
  
X  
X  
X  
X  
  
CBC, diff, plt  
X  
X  
X  
X  
X  
  
Complete metabolic 
panel (CMP)  
X  
X  
X  
X  
X  
  
Pregnancy test for  
WOCBP2  
X  
  
  
  
  
  
Bone Marrow  
Biopsy and  
Aspirate  
X4  
Prior to cycle 
2 and 3  
  
  
  
  
Response 
assessment in BM  
  
Prior to cycle 
2 and 3  
  
  
  
  
Response 
assessment in 
peripheral blood  
  
Prior to cycle 
2, 3, 4, 5  
  
  
  
  
CT or PET-CT scan 
(extramedullary 
disease only)   
X  
Prior to cycle 
3 and 5  
  
  
  
  
Survival (PFS and 
OS) by record 
review  
  
  
  
  
  
X (through 2 
years)  
Nivolumab IV 
(charge to 
research)  
  
X  
  
  
  
  
Cyclophosphamide 
PO (charge to 
research)3  
  
X  
X  
X  
  
  
Cyclophosphamide 
drug diary and 
reconciliation  
  
X  
  
  
X  
  
N-803 SC (charge 
to research)  
  
X  
  
  
  
  
N-803 Skin Rash  
Diary   
X  
X  
  
  
X  
  
1 – include assessment for infection and bleeding  
2 – women of child bearing potential must have a negative pregnancy test (serum or urine) within 7 days of each cycle day 1 3 
 
-- cyclophosphamide administration per patient’s assigned regimen (daily vs weekly)  
  
  
  
  


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8.2 Research Related Evaluations  
  
  
  
Screen  
Weekly  
Cycle 1   
  
  
Cycle 2   
Cycle 3 
D1  
Cycle 4 
D1  
Cycle 5 
D1  
Final  
Treatment  
Visit  
D1  
D8  
D15  
D1  
D8  
D15  
Assessment of 
immune related 
AEs  
  
X  
  
  
  
  
  
  
  
  
  
X6  
TSH (to FV lab)  
X  
  
  
  
  
X  
  
  
  
  
  
X  
Bone Marrow  
Aspirate (20 
mL 
heparinized 
sample syringe 
or divided into 
4 green top 
tubes, 2 x 2 
mL tubes (4 
mL) in  
Qiagen  
Paxgene  
syringe) at time 
of SOC BM bx5  
  
X  
  
  
  
  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
  
  
  
  
  
  
  
X  
  
  
Peripheral  
Blood (40 mL 
heparinized 
serum divided 
into 3 heparin 
green top 
tubes and 1 
red top tube)  
X  
  
X  
X  
X  
X  
  
  
  
  
  
X  
  
  
  
  
  
X  
  
  
  
  
  
X  
  
  
  
  
  
X  
  
  
  
  
  
X  
X  
  
4 
– Bone Marrow Biopsies may be omitted if not medically safe to perform. If so, peripheral blood counts will be used for 
disease assessment. Baseline bone marrow biopsy may be within 21 days of study registration.   
5 
If additional bone marrow biopsies performed as standard of care, research aspirates may be obtained   
  
6 
– BMS requires SAE reporting for 3 months after last dose of nivolumab per Section 11.4.  
  
All research samples are submitted to TTL unless otherwise noted.  
  
Note: if a patient is not abiding by the required clinical care calendar (Section 
8.1), the collection schedule of the toxicity data and research related samples 
may be altered or discontinued on an individual patient basis, as appropriate.    
  
Research related testing on the bone marrow aspirate includes analysis of 
immune checkpoint receptor expression on T-cell and NK cell subsets by flow 
cytometry and bone marrow infiltration by immunohistochemistry. AML blast 
immune checkpoint ligand expression will be evaluated by flow cytometry.  Gene 
expression analysis of genes will be performed by Nanostring Ncounter to 
evaluate T-cell immune activation  
  


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Research related testing on the peripheral blood includes analysis of T-cell and 
NK cell subsets, and myeloid blast immune checkpoint ligand expression by flow 
cytometry.   
9  
Disease Assessment Criteria  
See Appendix II and Appendix III.   
  
10 Drug Formulation, Availability and Preparation  
Qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and 
safe disposal of chemotherapeutic agents in a self-contained, protective environment. 
Discard unused portions of injectable chemotherapeutic agents that do not contain a 
bacteriostatic agent or are prepared with un-preserved diluents (i.e., Sterile Water for 
Injection USP or 0.9% Sodium Chloride for Injection USP) within eight hours of vial entry 
to minimize the risk of bacterial contamination. The total administered dose of study 
drug may be rounded up or down within a range of 5% of the actual calculated dose. 
Drug dosages need not be changed unless the calculated dose changes by at least 
10%.  
 
10.1  
Nivolumab  
Nivolumab (Opdivo) is a humanized IgG4 monoclonal antibody to PD-1. Its 
mechanism of action is to block an inhibitory signal that decreases cytotoxicity 
towards malignant cells. Nivolumab was initially FDA-approved in 2014 for 
treatment of unresectable or metastatic melanoma, and since has received 
approvals for treatment of metastatic non-small cell lung cancer, metastatic renal 
cell carcinoma, metastatic squamous cell carcinoma of the head and neck, 
relapsed classical Hodgkin lymphoma, and metastatic urothelial carcinoma. 
FDA-approved dosing is 240 mg every 2 weeks or 480 mg every 4 weeks for 
Hodgkin Lymphoma and squamous cell carcinoma of the head and neck. For 
NSCLC, renal cell carcinoma, and urothelial carcinoma, FDA-approved dosing is 
240 mg every 2 weeks or 480 mg every 4 weeks. There have not been any 
observed differences in safety and efficacy between nivolumab dose of 3 mg/kg 
and 240 mg every 2 weeks in patients with melanoma, NSCLC, and RCC.   
Availability   
Cartons containing 5 vials of 100 mg, 10 mg/mL Nivolumab will be provided for 
the study.   
  
Storage and Stability   
Nivolumab must be dispensed only from official study sites and to eligible patients 
under the supervision of the site investigator. Nivolumab should be stored in a 


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secure area according to local regulations. It is the responsibility of the site 
investigator to ensure that study drug is only dispensed to patients on this study.    
Store Nivolumab under refrigeration at 2°C to 8°C (36°F to 46°F). Protect 
nivolumab from light by storing in the original package until time of use. Do not 
freeze.  
  
The product does not contain a preservative. After preparation, store the 
nivolumab infusion either:  
• 
at room temperature for no more than 8 hours from the time of preparation. 
This includes room temperature storage of the infusion in the IV container and 
time for administration of the infusion or  
• 
under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours 
from the time of infusion preparation.  
  
Administration   
Refer to the current Investigator’s Brochure for the most up to date information.  
Nivolumab is to be administered as an intravenous infusion over 30 minutes 
according to institutional practice.   
  
Toxicities  
Refer to the current Investigator’s Brochure for the most up to date information.  
  
The most common (>10%) adverse events reported in patients treated with 
nivolumab are: fatigue, rash, pruritus, diarrhea, nausea, hypothyroidism, loss of 
appetite, constipation, musculoskeletal pain, peripheral neuropathy, and pyrexia. 
Events reported in 5-10% of subjects included pneumonia, vomiting, abdominal 
pain, hyperthyroidism, headache, dyspnea, ventricular arrhythmia, nephritis, 
cough, dry mouth, colitis, autoimmune hypothyroidism, thyroiditis upper 
respiratory tract infection and peripheral edema. Laboratory abnormalities 
reported in >10% of patients include hypertransaminasaemia (including ALT 
increased, AST increased, Transaminases increased), increased alkaline 
phosphatase, increased lipase, increased amylase, hyponatremia, and 
hyperkalemia.  
  
As of the most recent Nivolumab Investigator Brochure, (v19) Fulminant type 1 
diabetes mellitus is included as a SAR based on a comprehensive evaluation. 
Fulminant type 1 diabetes mellitus is characterized by rapid-onset diabetic 
ketoacidosis, low glycated hemoglobin (HbA1c) value, undetectable serum 
Cpeptide, and negative islet-related autoantibodies. Fulminant type 1 diabetes 
mellitus is generally believed to be a sub-type of non-autoimmune diabetes, but 
some reports show evidence of involvement of autoimmune mechanism in the 


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onset of fulminant type 1 diabetes. In cases observed in nivolumab clinical trials, 
most patients received insulin therapy and were able to control the event of 
diabetes mellitus. It has been established that nivolumab and other check point 
inhibitors may cause immune-related endocrinopathies, including diabetes. 
Clinical experts do not alter treatment or management strategies for onset of type 
1 diabetes in patients on immunotherapy and do not recommend discontinuation 
of therapy in response to diabetes-related event.  
 
10.2  
Low Dose Cyclophosphamide  
Cyclophosphamide is a synthetic alkylating agent chemically related to the 
nitrogen mustards. CTX received initial approval by the FDA in 1959. Leukemias 
are among the approved indications. Dosing can be oral or intravenous. CTX is 
activated by cytochrome P450, mainly CYP 2B6 and 3A4, to its active metabolite, 
phosphoramide mustard which forms cross links in DNA. The active dosing for 
malignant diseases is generally 1 mg/kg to 5 mg/kg PO per day for cytotoxic 
effect. For immunomodulatory effect, CTX has been given most commonly at 50 
mg PO daily.[69]   
Refer to the FDA-approved package insert for oral cyclophosphamide for product 
information, extensive instructions, and a comprehensive list of adverse events.  
Availability   
Oral cyclophosphamide in 25 mg and 50 mg tablets will be provided for the study.   
  
Storage and Stability   
Store at room temperature at or below 77 degrees F (25 degrees C) away from 
light and moisture. Brief storage not exceeding 86 degrees F (30 degrees C) is 
permitted.   
Unopened vials of cyclophosphamide are stable until the date indicated on the 
package when stored at or below 25°C (77°F).  
Administration   
Oral, cannot be crushed   
 
10.3  
N-803 Formulation, Supply, and Potential Toxicity  
  
N-803 (previously known as ALT-803), a recombinant human superagonist IL-15 
complex, is the working name of the drug under investigation. Its active ingredient 
is N-803 and its pharmacologic class is an anti-cancer and anti-viral 
immunotherapeutic.  
  


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N-803 has been referred to as IL-15N72D:IL-15RαSu/IgG1 Fc complex in various 
preclinical study reports, publications, and other related documents.   
10.3.1 Formulation and Composition  
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. The vialed quantitative composition of 
N-803 is listed in the table below.  
  
Quantitative Composition of N-803   
Componenta  
Concentration  
Amount/Vial  
N-803   
1.0 mg/mL  
0.6 mg  
N-803  
2.0 mg/mL  
1.2 mg  
PBSb  
QS  
0.6 mLc  
  
a – N-803 is available in 2 different concentrations. The volume of PBS used is the same for both. 
b- PBS Formulation: Sodium Chloride (USP) 8.18 g/L; Sodium Phosphate Dibasic (USP) 2.68 
g/L; Potassium Phosphate Monobasic (NF) 1.36 g/L pH 7.4. c- Fill volume is 0.6 mL, extractable 
volume is 0.5mL.  
10.3.2 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 IL15N72D 
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 N-803, or one OD280 is equivalent to 0.79 mg/mL solution of 
N-803.  


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10.3.3 Storage and Handling  
N-803 is supplied in a 2-mL single-dose/single-use vial containing 0.6 mL of N803 
(extractable volume is 0.5 mL) at a concentration of 1 mg/mL or 2 mg/mL. Vials 
are packaged in cartons and shipped to the clinical site. Study medication must 
be maintained at a temperature between 2°C and 8°C.  
10.3.4 Study Drug Preparation and Administration   
N-803 dose calculation will be based on actual body weight; however for patients 
> 100 kilograms weight, the N-803 dose will be calculated using a weight capped 
at 100 kg. Refer to Section 6.1.4 for additional details.   
  
The calculated amount of N-803 will be drawn into a syringe for subcutaneous 
injection. The current IDS stock concentration is 1 mg/ml. Doses will be drawn 
directly into the syringe for injection. If the total subcutaneous dose is greater 
than 1.5 mL, the dose will be divided into 2-3 subcutaneous injections as needed.  
10.3.5 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 study product using the Study Agent Drug Accountability 
Record.   
10.3.6 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 
afib, 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.  
  
Very common   
Common   
Rare  


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• 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 N-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 (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 presented the most recent IB  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 (version 7) for additional information.  
  


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10.4  
N-803 in Combination with Nivolumab  
The combination of N-803 + nivolumab has been associated with AEs of injection 
site reaction, flu-like symptoms, fever, fatigue, nausea, pain, chills, dizziness, 
hypotension, cough, dyspnea, anorexia, constipation, and vomiting.  
11 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 version 4.03 (CTCAE) and 
reported on the schedule below. A copy of the CTCAE v4.03 can be downloaded 
from the CTEP home page  
(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06- 
14_QuickReference_8.5x11.pdf)  
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).   
  
SAE Email Address: Worldwide.Safety@BMS.com   
SAE Facsimile Number: +1 609-818-3804   
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially 
reported.)   
  
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 
hours to BMS (or designee) using the same procedure used for transmitting the 
initial SAE report.   
  
All SAEs should be followed to resolution or stabilization.   
  
SAEs should be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/. The website will instruct you 
where to send the SAE forms.  
  
The reporting timeframes for SAEs and other reportable events are located in 
Section 11.3.  
  
Note:  throughout this section the generic term “study drug” refers to the study 
related treatment (nivolumab, N-803, and cyclophosphamide). Adverse event 
monitoring will begin with the 1st dose of study drug.  


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11.1  
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 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.   
  
Attribution of Event:  
• 
Definite – The AE is clearly related to the study treatment.  
• 
Probable – The AE is likely related to the study treatment.  
• 
Possible – The AE may be related to the study treatment.  
• 
Unlikely – The AE is doubtfully related to the study treatment.  
• 
Unrelated – The AE is clearly NOT related to the study treatment.  
  
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.    
  


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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.  
11.2 Adverse Event Documentation  
Adverse event monitoring and documentation begins with the 1st dose of the 
study drug through the final treatment visit. For the purposes of this study, 
adverse event documentation will focus on immune related adverse events 
(irAEs). Most commonly affected are the skin (rash/vitiligo/pruritis); the liver 
(hepatitis/rise in liver enzymes); the bowel (diarrhea/colitis), and the endocrine 
system (hypophysitis, thyroiditis, adrenal insufficiency). More rarely, uveitis, 
conjunctivitis, neuropathy, myopathy, and nephritis may occur. In addition, any 
unexpected grade 3 or greater toxicity at least possibility related to study 
treatment will be documented.  
  
Patients self-administering oral cyclophosphamide will complete a drug diary to 
document administration and side effects.  
  
At visits through the End of Treatment visit a targeted toxicity worksheet 
(Appendix V) will be completed to document select expected toxicities associated 
with N-803 as follows:  
• 
Prior to each planned N-803 injection  
• 
At the end of dose monitoring period (as described in Section 6.1.4) with 
±20 minute window for 2 hour monitoring or ±10 minute window for 30 
minute monitoring  
• 
At the End of Treatment visit  
  
Events that count toward an early stopping rule:  
The following events may or may not meet the definition of a reportable event; 
however they will be reported to the University of Minnesota Primary Clinical 
Research Coordinator or designee as counting toward an early study stopping 
rule (refer to Section 14). These will be monitored throughout stage 1 of the study 
by treatment arm.  
• 
Selected Grade 3 non-hematologic events o diarrhea o colitis o pneumonitis 
o transaminitis o myocarditis  o adrenal insufficiency o rash that does 
resolve to grade ≤2 in 1 week   
o cystitis  
• 
Any new onset of graft versus host disease   
• 
Any Grade 4 or 5 non-hematologic adverse event  
• 
Any adverse events requiring discontinuation of any study drug   
  


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11.3 Required Reporting FDA, IRB, and Masonic Cancer Center’s SAE 
Coordinator  
Agency  
Criteria for reporting  
Timeframe  Form to 
Use  
Submission 
address/fax 
numbers  
U of MN 
IRB  
Events requiring prompt reporting including, but not limited to 
unanticipated death of a locally enrolled subject(s); new or 
increased risk; any adverse event  that require a change to the 
protocol or consent form or any protocol deviation that 
resulting in harm. refer to  
http://www.research.umn.edu/irb/guidance/ae.html#.VC7xraI0sh 
Within 5 
business 
days of 
event 
discovery  
Report 
Form  
irb@umn.edu  
  
Protocol or Subject Deviations  
Per current IRB 
reporting requirements  
FDA  
  
Unexpected and fatal or life threatening suspected adverse 
reaction  
As soon as 
possible 
but no later 
than 7 
Calendar- 
Days  
UMCC  
SAE   
Submit as an 
amendment 
to IND with 
copy to BMS  
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)  
As soon as 
possible 
but no later 
than 15 
Calendar- 
Days  
All other events per CFR 312.33  
At time of 
IND annual 
report  
Summary 
format  
Submit as 
part of the 
IND annual 
report  
BMS   
Refer to Section 11.4  
 
 
Cancer  
Center  
SAE  
Coordinator  
Any event that counts toward a stopping rule  
Upon  
reporting  
Event 
Form  
 n/a  
  
In each IND safety report, the sponsor must identify all IND safety reports 
previously submitted to the FDA concerning a similar suspected adverse reaction 
and must analyze the significance of the suspected adverse reaction in light of 
the previous, similar reports or other relevant information.  
  
The SAE Coordinator will provide the Masonic Cancer Center’s Data and Safety 
Monitoring Council (DSMC) with the SAE in an appropriate format depending on 
the individual SAE (as reported or in a summary format).  
  
  


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11.4  
Additional BMS Requirements for Nivolumab  
Non-serious Adverse Event Collection and Reporting  
The collection of non-serious AE (AE that is not an SAE) information should begin 
at initiation of study drug. All non-serious adverse events (not only those deemed 
to be treatment-related) should be collected continuously during the treatment 
period and for a minimum of 30 days following the last dose of study treatment.   
Non-serious AEs should be followed to resolution or stabilization, or reported as 
SAEs if they become serious. Follow-up is also required for non-serious AEs that 
cause interruption or discontinuation of study drug and for those present at the 
end of study treatment as appropriate.   
Laboratory Test Abnormalities  
All laboratory test results captured as part of the study should be recorded 
following institutional procedures. Test results that constitute SAEs should be 
documented and reported as such.  
The following laboratory abnormalities should be documented and reported 
appropriately:  
• any laboratory test result that is clinically significant or meets the definition 
of an SAE  
• any laboratory abnormality that required the subject to have study drug 
discontinued or interrupted  
• any laboratory abnormality that required the subject to receive specific 
corrective therapy.   
Other Safety Considerations  
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether 
or not these procedures are required by the protocol, should also be recorded as 
a non-serious or serious AE, as appropriate, and reported accordingly.  
Serious Adverse Events (SAEs)  
BMS requires monitoring for Serious Adverse Events (SAEs) that occur following 
the subject’s written consent to participate in the study through 100 days of 
discontinuation of dosing.  
12 Study Data Collection and Monitoring  
12.1 Data Management  
This study will collect regulatory and clinical data using University of Minnesota 
CTSI’s instance of OnCore® (Online Enterprise Research Management 
Environment).   


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The Oncore database resides on dedicated secure and PHI compliant hardware 
consisting of 3 physical servers: dev, DR, and production. The dev server is 
located in the University of Minnesota (UMN) datacenter (WBOB) and houses six 
database instances (test, train, sandbox, mcc reports, oncdm, and vendor) that 
are backed up locally because the data is refreshed from Oncore production data. 
The production server is located in the UMN datacenter (WBOB). All the data 
servers are managed by the Academic Health Center – Information Systems 
(AHC-IS) virtual servers which utilize clustered infrastructure to provide real-time 
failover of virtual servers. This real-time clustering is physically limited to the UMN 
data center. All relevant AHC IS procedures related for PHI compliant servers (as 
required by the Center of Excellence for HIPAA Data) apply to Oncore databases.  
  
The integrated data will be stored in PHI compliant servers managed by AHC IS 
with access given to those authorized users in the Clinical and Translation 
Science Institute Informatics team (CTSI BPIC and MCC CISS). The data will be 
integrated and extracted to researchers through the CTSI Informatics team and 
will be delivered through secure and compliant mechanisms (e.g. AHC IE data 
shelter, BOX, sftp, etc). If data de-identification is needed, then compliant AHC 
IE data de-identification tools will be used. The informatics team will grant the 
IRB approved study team members access to data.  
  
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 
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.  
12.2 Case Report Forms  
Participant data will be collected using protocol specific electronic case report 
forms (e-CRF) 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 Primary Clinical Research Coordinator 
or designee will be responsible for registering the patient into OnCore at time of 
study entry, completing e-CRF based on the patient specific calendar, and 
updating the patient record until patient death or end of required study 
participation.   


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12.3  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 can be accessed at http://z.umn.edu/dmsp  
  
For the purposes of data and safety monitoring, this study is classified as high 
risk (investigator initiated). Therefore the following requirements will be fulfilled:  
▪ The Masonic Cancer Center Data and Safety Monitoring Council (DSMC) will 
review the study’s progress at least quarterly.  
▪ The PI will comply with at least twice yearly monitoring of the project by the 
Masonic Cancer Center monitoring services.  
▪ The PI will oversee the submission of all reportable adverse events per the 
definition of reportable in Section 11.3 to the Masonic Cancer Center’s SAE 
Coordinator, the University of Minnesota IRB, and the FDA.   
  
IND Annual Reports  
In accordance with regulation 21 CFR § 312.33, the Sponsor-Investigator will 
submit a progress report annually. The report will be submitted within 60 days of 
the anniversary date that the IND went into effect.   
 
12.4  Monitoring  
The IND sponsor/investigator will permit study-related monitoring, audits, and 
inspections by the Masonic Cancer Center or their designee, IRB, government 
regulatory bodies, and University of Minnesota compliance groups. All study 
related documents (e.g. source documents, regulatory documents, data 
collection instruments, study data, etc.) will be made available. The S/I 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.  
 
12.5  Record Retention  
The investigator will retain study records including source data, copies of case 
report form, 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.   
  
In addition, the Clinical Trials Office (CTO) will keep a master log of all patients 
participating in the study with sufficient information to allow retrieval of the 
medical records for that patient.   
  
Please contact the CTO before destroying any study related records.  


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13 Endpoints   
Primary endpoint:   
Secondary endpoints:   
Overall response rate (ORR) at 42 days from start of treatment defined as:  
• ORR = [# CR/PR/HI for MDS] + [# CR + CRi + CRp + PR for AML] at day 42 
divided by number of evaluable patients enrolled in study (Appendix II – R-IPSS  
Criteria for MDS, Appendix III – Modified Response Criteria for AML)  
  
Progression free survival (PFS) at 6 months  
• PFS is defined as the time (in months) from treatment start date to the date of 
progression or death, whichever occurs first. Patients who do not progress nor 
die will be censored on their last tumor assessment date. Patients who have no 
post-treatment tumor assessment, will be censored on their treatment start 
date.  
6-month PFS rate will be estimated using the Kaplan-Meier method.   
  
Overall survival (OS) at 6 months   
• OS is defined as the time (in months) from treatment start date to death date. 
Patients who do not die will be censored on their last known alive date. 6-month 
OS rate will be estimated using the Kaplan-Meier method.   
14 Statistical Considerations  
14.1 Study Design   
This is a phase I trial which includes a randomized pilot sub-study of two dosing 
arms of cyclophosphamide in combination with Nivolumab and N-803. The 
primary objective is safety and the secondary objective is efficacy, as defined by 
overall response rate. The study will consist of relapsed/refractory AML and 
higher-risk MDS.   
  
The primary endpoint of the trial is to determine the appropriate dosing arm for 
phase 2 study based on safety and toxicity profile. The secondary endpoints 
include ORR at day 42, OS at six months and PFS at six months. Exploratory 
endpoints include correlation of immune checkpoint ligands PD-L1 and TIM-3 on 
leukemic cells with response to treatment, and evaluation of subsets of T-cell,  
NK cell, MDSCs, and DCs in bone marrow and peripheral blood during treatment.    
  
By September 2019, there were 12 patients enrolled on Arm 1 and Arm 2 who 
received treatment with combination of nivolumab and cyclophosphamide daily 
or weekly. The previous treatment Arms 1 and 2 are closed due to no patients 
obtaining complete response and 4 patients receiving <1 cycle of treatment due 


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to disease progression. These 12 subjects in Arms 1 and 2 will be analyzed 
separately for safety and efficacy from Arms 3 and 4.    
  
Arms 3 and 4 will enroll 20 patients with addition of N-803 to treatment plan. 
Patients will be randomized to Arm 3 (CTX 50mg daily + nivolumab 360 mg 
q3week + SC N-803 10 ug/kg q3week) and Arm 4 (CTX 350 mg PO q7 days+ 
nivolumab 360 mg q3week + SC N-803 10 ug/kg q3week) with 10 subjects in 
each arm. Continuous stopping rule will be used to monitor excessive toxicity for 
each arm. If one arm is terminated by the toxicity stopping rule, all subsequent 
patients will be assigned to the other arm if it is not terminated by the toxicity 
stopping rule to continue enrollment of up to 20 patients. If both arms succeed, 
then for future studies, selection of one of the two products will be based on 
evaluation of tolerability, clinical benefit as assessed by hematologic 
improvement and blast reduction, and immunological parameters. Immune 
stimulation will be assessed as decrease in T-regulatory cells and MDSCs, and 
increase in cytotoxic T-cells and differentiated NK cells.   
  
  
1. A randomized comparison of two CTX treatments (CTX 50mg daily + 
nivolumab 360 mg q3week + N-803 10 ug/kg SC q3week vs. CTX 350 mg 
PO q7 days+ nivolumab 360 mg q3week + N-803 10 ug/kg SC q3week) using 
10 patients in each Arm.  
2. 20 patients available for assessment of day 42 overall response for the entire 
study population.   
14.2 Data Analysis Plan  
Only subjects enrolled after addition of N-803 to treatment protocol will be 
included in the data analysis. The endpoints of OR and toxicity rate will be 
estimated by simple proportion with 95% confidence intervals. All toxicity and 
safety assessments will be presented in the data listings and summarized with 
descriptive statistics.  
  
The endpoints of overall survival (OS) and progression-free survival (PFS) at six 
months will be estimated by Kaplan-Meier curves.[70] Other correlative 
endpoints will be described with simple descriptive statistics such as medians, 
ranges, interquartile ranges, proportions, charts and plots. Logistic regression 
will be the primary method to compare the PD-L1 and Galectin-9 expression with 
response.   
  
Groups that will be considered for comparison include: AML vs. MDS, high vs. 
low blast count at time of study enrollment, high, intermediate, or low disease risk 


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by cytogenetic and molecular subtype, high vs. low total peripheral lymphocyte 
count, high vs. low immune cell subsets in blood and bone marrow at time of 
study enrollment, younger vs. older age, number of prior treatments, high vs. low 
PD-L1 expression, and prior transplant vs. no transplant.   
  
P-values for subgroup analyses will be adjusted for multiplicity.   
  
All analyses will be conducted using SAS software 9.4 (SAS Institute Inc., Cary, 
NC). Results will be deemed statistically significant at the 0.05 significance 
level unless otherwise specified.  
14.3 Sample Size Justification  
This phase I study for the secondary endpoint of overall response uses pooled 
efficacy analysis. Based on this design, patients from both arms will be analyzed 
for efficacy analysis. Up to 20 patients will be used which is sufficient to maintain 
an overall type I error of 5% while providing 80% statistical power. The maximum 
number of the patients will be 20 and the minimum number of patients will be 18 
to maintain statistical power of 77% if patients become unevaluable or withdraw 
from study.   
  
Sample Size  
Power  
18  
77%  
20  
80%  
24  
85%  
  
This is based on our null hypothesis of ≤10% ORR versus the alternative 
hypothesis of ORR ≥32%.   
  
The accrual will start after amendment to add N-803 to treatment protocol is 
implemented. The 12 patients enrolled by September 2019 treated without N803 
will be analyzed separately.  A patient will be considered unevaluable for the 
primary endpoint and replaced if unable to complete ≥1 cycle of nivolumab and 
cyclophosphamide. 
If 
patient 
receives 
≥1 
cycle 
of 
nivolumab 
and 
cyclophosphamide and follow up is not discontinued prior to 42 days for reasons 
other than progression or death, they will be considered evaluable.   
  
ORR will be analyzed using the evaluable patient population.   
PFS and OS will be analyzed using the all treated patient population.   


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14.4 Early Study Stopping Rule for Safety  
Continuous stopping rules are in place to stop the study in case there are 
excessive complications. In the case that the boundaries are crossed, the 
Principal Investigator will be notified who will report it to the Masonic Cancer 
Center Data Safety Monitoring Committee and Bristol Myers Squibb. The 
protocol will be reviewed to determine if the protocol should be terminated. 
Stopping rules were developed using Pocock stopping boundaries.[71] The 
stopping rules will be applied separately for each platform.   
  
Early stopping rule for each randomization study arm for subjects 
enrolled after amendment to add N-803 to treatment protocol is 
implemented.  
The goal is to construct a boundary based on selected Grade 3 non-hematologic 
events that result in the permanent discontinuation of study drugs, new onset of 
GVHD, and grade 4-5 non-hematologic toxicities (CTCAE v4.03) such that the 
probability of early stopping is at most 10% if the toxicity rate is equal to 15% and 
our sample size is 10. With these stipulations, the study will be stopped if there 
are events in 2 out of 2, 3 out of 6, 4 at any time within a 60 day follow-up time 
period. If the actual probability of failure is 40% or 50%, the probability of reaching 
the boundary will be 66% or 85%. The stopping rule will be applied to Arm 3 and 
4 separately.   
  
15 Ethical and Regulatory Considerations  
 
15.1  
Good Clinical Practice  
The study will be conducted in accordance with the appropriate regulatory 
requirement(s). Essential clinical documents will be 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.   
 
15.2  
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, informed consent, written information given to the patients, safety 
updates, annual progress reports, and any revisions to these documents will be 
provided to the IRB by the investigator.   


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15.3 Informed Consent  
All potential study participants will be given a copy of the IRB-approved Consent 
to review. The investigator or designee will explain all aspects of the study in lay 
language and answer all questions regarding the study. If the participant decides 
to participate in the study, he/she will be asked to sign and date the consent 
document. Patients who refuse to participate or who withdraw from the study will 
be treated without prejudice.  
  
16 References  
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Working Group (IWG) response criteria in myelodysplasia. Blood 2006;108:419– 
25. doi:10.1182/blood-2005-10-4149.  
  


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Appendix I – ECOG Performance Status  
  
GRADE  
ECOG PERFORMANCE STATUS  
0  
Fully active, able to carry on all pre-disease performance without restriction  
1  
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work  
2  
Ambulatory and capable of all selfcare but unable to carry out any work activities; up and 
about more than 50% of waking hours  
3  
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours  
4  
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair  
5  
Dead  
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group.Am J Clin 
Oncol. 1982;5:649-655.  
  
  
 


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Appendix II – Revised International Prognostic Scoring System   
(R-IPSS) Criteria for MDS  
  
Prognostic 
Variable  
0  
0.5  
1  
1.5  
2  
3  
4  
Cytogenetics  
Very 
good  
-  
Good  
-  
Intermedia 
te  
Poor  
Very 
Poor  
BM blast %  
≤ 2%  
-  
> 2%-< 
5%  
-  
5%-10%  
> 10%  
-  
Hemoglobin  
≥ 10  
-  
8 to 10  
<8  
-  
-  
-  
Platelets  
≥ 
100  
50- 
<100  
< 50  
-  
-  
-  
-  
ANC  
≥ 0.8  < 0.8  
-  
-  
-  
-  
-  
  
  
Cytogenetic Prognostic subgroups   
Very Good  
-Y, del(11q)  
Good  
Normal, del(5q), del(12p), del(20q), double including del(5q)  
Intermediate  
del(7q), +8, +19, i(17q), any other single or double independent clones  
Poor  
-7, inv(3)/t(3q)/del(3q), double including -7/del(7q), complex: 3 
abnormalities  
Very poor  
Complex:  >3 abnormalities  
  
  
Risk category   Risk score   
Very low   
≤ 1.5  
Low   
> 1.5-3  
Intermediate   
> 3-4.5  
High   
> 4.5-6  
Very high   
> 6  
  
  


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Appendix III – Response Criteria For MDS and AML  
  
  
Response to treatment will be defined per modified criteria as outlined below.[72][73]   
  
Complete Remission  
For subjects to be classified as being in CR, they must have bone marrow regenerating normal hematopoietic 
cells and achieve a morphologic leukemia-free state and must have an ANC > 1 x 109/L and platelet count ≥  
100 x 109/L and normal marrow differential with   
< 5% blasts, and they will be RBC and platelet transfusion independent (defined as 1 week without RBC 
transfusion and 1 week without platelet transfusion). There should be no evidence of extramedullary leukemia.  
  
Complete Remission with Incomplete Platelet Recovery (CRp)  
For subjects to be classified as being in CRp, they must achieve CR except for incomplete platelet recovery 
(<100 x 109/L).  
  
Complete Remission with Incomplete Hematologic Recovery (CRi)  
For subjects to be classified as being in CRi, they must fulfill all the criteria for CR except for incomplete 
hematological recovery with residual neutropenia <1 x 109/L with or without complete platelet recovery. RBC 
and platelet transfusion independence is not required.  
  
Partial Remission (PR)  
For subjects to be classified as being in PR, they must have ≥50% bone marrow blast reduction or decrease to 
5 to 25%.   
  
Hematologic Improvement (HR)   
For subjects to be classified as having HI, they must have pre-treatment hemoglobin of <11 g/dL, platelets of 
<100 x 109/L, and absolute neutrophil count < 1000 cells/mm3. They should have improvement in hemoglobin 
by ≥1.5 g/dL, platelets by ≥30 x 109/L, and neutrophil count by 100% or 500 cells/mm3. Responses should be 
sustained for at least 4 weeks.   
  
  
Appendix IV – 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)  








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Appendix V - N-803 Targeted Toxicity Worksheet  
MT2017-33                                                         CTCAE v4            Refer to Section 11.2 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, 
widebased, limping or hobbling); 
assistance device indicated;  limiting 
instrumental ADL  
Disabling; limiting self care ADL  
………………………  
  


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Person Completing Form:    
  
  
  
  
  
ADL = activities of daily living  


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Appendix VI – 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.  
  


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CPRC #2017LS116  
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  
And tell us 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:  
  




HM2017-33:  Nivolumab and Oral CTX in Relapsed/Refractory AML and Higher-Risk MDS  
  
  
  
  
  
May 12, 2021  
Page 78 of 79  CPRC #2017LS116  
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  
And tell us 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   
  
  
  


HM2017-33:  Nivolumab and Oral CTX in Relapsed/Refractory AML and Higher-Risk MDS  
  
  
  
  
  
May 12, 2021  
Page 79 of 79  CPRC #2017LS116  
  
  

ICF_001.pdf: