QUILT-3.033: Haploidentical Donor Natural Killer (NK) Cell Infusion With Subcutaneous ALT-803 in Adults With Refractory or Relapsed Acute Myelogenous Leukemia
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Sponsor: Masonic Cancer Center, University of Minnesota

 
Masonic Cancer Center, University of Minnesota 
Cancer Experimental Therapeutics Initiative (CETI) 
 
 
 
Haploidentical Donor Natural Killer (NK) Cell Infusion with 
Subcutaneous ALT-803 in Adults with Refractory or Relapsed 
Acute Myelogenous Leukemia (AML)    
MT2016-05 
CPRC # 2016LS056 
IND #14448 
 
University of Minnesota 
Principal Investigator: 
Claudio Brunstein, MD, PhD 
 
Co-Investigators: 
Jeffrey S. Miller, MD (IND Sponsor) 
Daniel J. Weisdorf, MD 
David H. McKenna, Jr., MD* 
Veronika Bachanova, MD 
*Will not consent patients 
 
Biostatistician: 
Todd E. DeFor, MS 
 
 
Participating Affiliate Institution 
Ohio State University (PI - Steven Devine, MD)  
 
 
Version Date: 
January 22, 2019 
 
 
 
 
 
Confidential 
 
 

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Key Study Personnel Contact Information 
 
Site 
Contact Information 
Role 
Masonic Cancer Center, 
University of Minnesota 
Claudio Brunstein, MD, PhD 
Division of Hematology/Oncology/Transplantation 
420 Delaware Street SE MMC 480 
Minneapolis, MN 55455 
Phone: 612-624-3918 
Email: bruns072@umn.edu  
Pager: 612-899-6170 
Study PI 
Julianne Feola 
Clinical Trials Office 
925 Delaware Street SE 
Minneapolis, MN 55414 
Phone: 612 626-5174 
Email: affiliates@umn.edu 
Fax: 612 625-6145 
Affiliate Sites 
Manager 
Ohio State University 
Steven Devine, MD 
Division of Hematology/Department of Medicine 
B316 Starling-Loving Hall 
320 W 10th Ave 
Columbus, OH 43210 
Phone:  614-293-5655 
Email:  devine.54@osu.edu  
Site PI 
 
Refer to the Procedures Manual for Affiliate Sites for a complete list of study personnel and contact 
information.  

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Revision History 
 
Revision 
# 
Version 
Date 
Detail of Changes 
Consent 
change? 
(Y/N) 
 
07/24/2016 
Original version for CPRC 
n/a 
 
08/24/2016 
In response to CPRC stips and Altor’s review 
Other minor edits and clarifications 
n/a 
 
12/21/2016 
Original to IRB and FDA 
Add cytokine release syndrome (CRS) 
• Section 9.3: Add risk of CRS 
• Section 12: Add assessment of CRS with updated 
Targeted toxicity worksheet in appendix V 
• Section 11.2.2: Add PK sampling; CRP/ferritin sample 
collection at 4 time points related to CRS 
Section 12.2: clarify adverse event documentation 
Section 14.4: change stopping rule timeframe from Day 
+100 to Day +42 
Other edits through-out protocol including 
Clarify complete remission refers to CR and CRp 
Clarify disease eligibility  
Minor clarifications to inclusion/exclusion criteria 
Update and clarify study SOC and research activities in 
Section 11 
Update ALT-803 pre-med and monitoring to be consistent 
across protocols 
Add IND number and Jeffrey Miller as IND sponsor 
n/a 
1 
5/15/2017 
In response to FDA comments on other ALT-803 
protocols (for consistency between protocols when 
applicable): 
• Sections 8.5 and 10.6  – for patients > 100 kg in weight, 
ALT-803 dose calculation will be capped at 100 kg 
• Section 9.6 – revise CRS management plan 
• Section 13.4 – add section regarding regular 
teleconferences between lead institution and affiliate 
sites to facilitate communication between sites 
Additional edits/clarifications from SIV and other reviews: 
• Cover page and page 2 – remove Emory as an affiliate 
site 
• Synopsis and Section 5.2 – make disease eligibility 
criteria more clear 
• Sections 6.5 and 11.2 - update donor screen panel to 
current panel (replace RPR with treponema, add NAT) 
• Section 8.3 – for product samples to TTL add a 3rd 
sampling (after depletion but before ALT-803) 
• Section 8.4 – delete statement regarding patient not 
evaluable if requires treatment with steroids 
No 

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Revision 
# 
Version 
Date 
Detail of Changes 
Consent 
change? 
(Y/N) 
• Section 8.5 – clarify that the ALT-803 dose will be 
based on patient weight at admission/pre-chemo, 
update ALT-803 pre meds 
• Sections 11.1and 11.2.2 – Day +14 bm bx is SOC, not 
research 
• Sections 12.1 and 12.6 – align definitions for deviations 
with  updated MCC definitions 
• Section 12.2 – clarify that a new patient injection 
reaction diary (appendix VI) is to be started for each 
injection site and that the diary is to continue to be 
completed for an injection site until it resolves or the 
form is completed. 
• Section 14.4. – update to reflect single stopping rule 
• Update appendices to reflect changes within the 
protocol 
Other minor edits and clarifications 
2 
1/22/2019 
Change in Principal Investigator 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
 
Key Study Personnel Contact Information ............................................................................................. 2 
Protocol Synopsis ................................................................................................................................... 7 
Study Schema ........................................................................................................................................ 8 
1 
Objectives ....................................................................................................................................... 9 
1.1 
Primary Objective ............................................................................................................................... 9 
1.2 
Secondary Objectives ........................................................................................................................ 9 
1.3 
Correlative Objectives........................................................................................................................ 9 
2 
Background and Significance ......................................................................................................... 9 
2.1 
Human Natural Killer (NK) Cells as Mediators of Antitumor Therapy ......................................... 9 
2.2 
NK Cell-Based Immunotherapy for Advanced Malignancies ....................................................... 9 
2.3 
rhIL-15 ................................................................................................................................................ 10 
2.4 
IL-15/IL-15Rα-Fc (ALT-803) ........................................................................................................... 10 
2.5 
ALT-803 by Subcutaneous Injection ............................................................................................. 11 
3 
Study Rationale ............................................................................................................................ 12 
4 
Study Design ................................................................................................................................ 12 
5 
Patient Selection ........................................................................................................................... 13 
6 
Donor Selection ............................................................................................................................ 15 
7 
Patient/Donor Registration ........................................................................................................... 16 
7.1 
Registration with the University of Minnesota Clinical Trials Office .......................................... 16 
7.2 
Patients Who Do Not Begin Study Treatment .............................................................................. 17 
8 
Treatment Plan ............................................................................................................................. 17 
8.1 
Preparative Regimen (Day -5 through Day -2) ............................................................................ 18 
8.2 
Donor Leukapheresis (Day -1) ....................................................................................................... 18 
8.3 
Preparation of Allogeneic NK Cells / Product Release Criteria ................................................. 19 
8.4 
Allogeneic CD3- CD19- Selected NK Cell Infusion (Day 0) ........................................................ 19 
8.5 
ALT803 (Day 0, +5, and +10) ......................................................................................................... 20 
8.6 
Supportive Care ................................................................................................................................ 21 
8.7 
General Concomitant Medication Guidelines ............................................................................... 22 
8.8 
Duration of Study Participation/Opportunity for Allogeneic Transplant .................................... 22 
9 
Management of Selected Expected Toxicities Associated with NK Cell Infusion and ALT-803 .. 23 
9.1 
Tumor Lysis Syndrome.................................................................................................................... 23 
9.2 
Acute Allergic Reaction Secondary to the Infusion of Allogeneic NK Cells ............................. 23 
9.3 
Injection Site Reactions/Skin Rash in Association with ALT-803 .............................................. 23 
9.4 
Hypotension (systolic blood pressure < 90 mm Hg) ................................................................... 23 
9.5 
Vascular Leak Syndrome ................................................................................................................ 24 
9.6 
Cytokine Release Syndrome (CRS) or CRS-Like Symptoms ................................................... 24 
9.7 
Prolonged Marrow Suppression ..................................................................................................... 25 
10 ALT-803 Formulation, Supply, and Potential Toxicity .................................................................. 25 
10.1 
Formulation and Composition ........................................................................................................ 26 
10.2 
Structural Formula ............................................................................................................................ 26 
10.3 
Storage and Handling ...................................................................................................................... 26 
10.4 
Stability .............................................................................................................................................. 27 
10.5 
Agent Ordering and Agent Accountability ..................................................................................... 27 
10.6 
Study Drug Preparation and Administration ................................................................................. 27 
10.7 
Agent Inventory Records ................................................................................................................. 27 
10.8 
Toxicity ............................................................................................................................................... 27 
11 Clinical Evaluations and Procedures ............................................................................................ 29 
11.1 
Required Clinical Care Evaluations ............................................................................................... 30 

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11.2 
Research Related Evaluations ....................................................................................................... 31 
12 Event Monitoring, Documentation, and Reporting ........................................................................ 34 
12.1 
Event Terminology ........................................................................................................................... 35 
12.2 
Event Documentation Requirements ............................................................................................. 36 
12.3 
SAE Documentation and Reporting Requirements ..................................................................... 37 
12.4 
Early Stopping Rule Events Documentation and Reporting Requirements ............................ 37 
12.5 
Other Event Documentation and Reporting Requirements........................................................ 37 
12.6 
Institutional Event Reporting Table ................................................................................................ 38 
12.7 
MCC Reporting Requirements ....................................................................................................... 38 
13 Study Data Collection and Monitoring .......................................................................................... 38 
13.1 
Data Management ............................................................................................................................ 38 
13.2 
Case Report Forms .......................................................................................................................... 39 
13.3 
Data and Safety Monitoring Plan (DSMP) .................................................................................... 39 
13.4 
Teleconferences – Lead Site and Affiliate .................................................................................... 40 
13.5 
Affiliate Site Monitoring .................................................................................................................... 40 
13.6 
Record Retention ............................................................................................................................. 40 
14 Statistical Considerations ............................................................................................................. 41 
14.1 
Study Design, Objectives and Endpoints ..................................................................................... 41 
14.2 
Statistical Analysis ........................................................................................................................... 41 
14.3 
Sample Size ...................................................................................................................................... 42 
14.4 
Stopping Rule for Excessive Toxicity ............................................................................................ 42 
15 Ethical and Regulatory Considerations ........................................................................................ 42 
15.1 
Good Clinical Practice ..................................................................................................................... 42 
15.2 
Ethical Considerations ..................................................................................................................... 42 
15.3 
Informed Consent ............................................................................................................................. 43 
16 References ................................................................................................................................... 43 
Appendix I – Eligibility Checklist – Patient ............................................................................................ 45 
Appendix II – Eligibility Checklist – Donor ............................................................................................ 47 
Appendix III - Performance Status Scale ............................................................................................. 48 
Appendix IV – Expected Toxicities of the Preparative Regimen .......................................................... 49 
Appendix V – Targeted Expected Toxicities Worksheet ...................................................................... 50 
Appendix VI – ALT-803 Injection Site Reactions Diary ........................................................................ 51 
 
 
 

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Protocol Synopsis 
Haploidentical Donor Natural Killer (NK) Cell Infusion with Subcutaneous ALT-803 in 
Adults with Refractory or Relapsed Acute Myelogenous Leukemia (AML)   
 
Study 
Design: 
This is a multi-institutional Simon’s optimal two-stage single arm phase II trial of CD3/CD19 depleted, 
ALT-803 activated, haploidentical donor NK cells and subcutaneous ALT-803 given after 
lymphodepleting chemotherapy (CY/FLU) for the treatment of refractory or relapsed acute 
myelogenous leukemia (AML). 
 
The primary objective is to study the potential efficacy of NK cells and ALT-803 to achieve complete 
remission (CR/CRp) with or without platelet recovery by Day 42 while maintaining safety. CRp is 
defined as leukemia clearance (< 5% marrow blast and no circulating peripheral blasts) and neutrophil 
recovery but with incomplete platelet recovery.  
 
The two stage design will enroll 9 patients in stage 1. If 3 or more of the 9 patients achieve CR/CRp 
by Day 42 post NK cell infusion, an additional 15 patients will be enrolled in stage 2 to obtain a more 
precise estimate of CR/CRp. If 10 or more out of the total 24 patients show clearance, further 
investigation will be considered. 
 
Patients are followed for 1 year from the NK cell infusion to determine disease free survival, treatment 
related mortality, and time to relapse.  
 
Patients achieving a complete remission (CR or CRp) and neutrophil recovery (ANC > 500 cells/μl) 
for at least 4 weeks will be considered for allogeneic transplant, independent of this study, to prolong 
remission.  
 
Primary 
Objective: 
To estimate the rate of complete remission (CR/CRp) by Day 42 after the infusion of CD3/CD19 
depleted, ALT-803 activated, donor NK cells and subcutaneous ALT-803 given after lymphodepleting 
chemotherapy (CY/FLU) for the treatment of refractory or relapsed acute myelogenous leukemia 
(AML)   
 
Secondary 
Objectives: 
• To determine the incidence of in vivo expansion (≥ 100 donor derived NK cells per µL blood) of 
NK cells by Day +14 
• To document ALT-803 associated toxicity when given subcutaneously in this patient population 
• To evaluate the safety of the therapy as measured by rate of treatment related mortality (TRM) at 
6 months 
Correlative 
Objectives 
• To measure the effect of ALT-803 on the function of adoptively transferred NK cells 
• To correlate CR/CRp with in vivo donor derived NK cell expansion 
• To characterize ALT-803 immunogenicity 
   
Eligible 
Diseases: 
Diagnosis of acute myeloid leukemia (AML) and meets one of the following disease criteria: 
Primary induction failure:   
o De novo AML - no CR after 2 or more chemotherapy induction attempts 
o Secondary AML (from MDS or treatment related): no CR after 1 or more chemotherapy induction 
attempts  
Relapse after chemotherapy: not in CR after 1, 2 or 3 re-induction attempts 
o Patients > 60 years of age, the 1 chemotherapy re-induction is not required  
Relapse after hematopoietic stem cell transplant:  
o Relapse must have occurred > 18 months after transplant 
o No re-induction attempts required and no more than 1 re-induction attempt is allowed.  
 
Notes:  
1) For hypomethylating agents (i.e. decitabine, azacititdine) to count as an induction/re-induction attempt, the 
patient must have completed a minimum of 3 monthly cycles 
2) For targeting agents (i.e. sorafenib) to count as an induction/re-induction attempt, the patient must have 
completed a minimum of 1 month without attaining CR 
3) 7+3 followed by 5+2 counts as TWO induction attempts 
4) Use of hydroxyurea is permitted to control blasts until Day -3 per Section 8.7 
5) A history of AML related CNS involvement is allowed if CSF analysis is negative on 2 test dates at least 2 
weeks apart prior to study treatment. The use of ongoing CNS maintenance therapy is allowed while on study  

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Key 
Inclusion 
Criteria: 
• age ≥18, but ≤ 70 years 
• Karnofsky performance status ≥ 60% 
• available HLA-haploidentical donor (aged 12 to 75 years) with donor/recipient match based on 
a minimum of intermediate resolution DNA based Class I typing of the A and B locus (at least 
2/4 class I allele) 
• adequate liver, renal, pulmonary and cardiac function  
• ability to be off prednisone and other immunosuppressive drugs for at least 3 days prior to the 
NK cell infusion  
• voluntary written consent 
 
Key 
Exclusion 
Criteria: 
• acute leukemia of ambiguous lineage 
• pregnant or breastfeeding 
• new or progressive pulmonary infiltrates  
• active autoimmune disease requiring systemic immunosuppressive therapy 
• history of severe asthma currently on chronic systemic medications (mild asthma requiring 
inhaled steroids only is eligible) 
 
Accrual 
Objective: 
Stage 1: 9 patients  Stage 2: 15 patients  
Targeted yearly enrollment - 8 patients  
 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphodepleting Chemotherapy: 
Fludarabine 25 mg/m2 x 5 days start Day -6 
Cyclophosphamide 60 mg/kg x 2 days on Day -5 and -4  
 
ALT-803 Stimulated Donor NK Cells: 
The apheresis product (collected Day -1) will be enriched for NK cells with the large-scale CliniMacs® 
device (Miltenyi) by depletion of CD3+ cells to remove T-lymphocytes and depletion of CD19+ cells to 
remove B-lymphocytes. The NK cell enriched product will be stimulated by overnight incubation with 
36.1 ng/mL ALT-803 under GMP conditions and infused on Day 0. 
 
ALT-803 to Facilitate NK Cell Survival and Expansion: 
ALT-803 at 10 mcg/kg subcutaneously (SC) with the 1st dose administered on Day 0 (no sooner than 
4 hours post NK cells), Day +5 and Day +10 for 3 doses total 
 
 
Fludarabine 
Cyclophosphamide 
Haplo ALT-803 
stimulated NK cells 
Evaluate for CR or CRp - 
-6     -5     -4      -3     -2      -1      0           +5            +10               +14        +28              +42 
Evaluate for Response 
ALT-803 
  
Collect donor cells on Day -1  
rest

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1 Objectives 
1.1 Primary Objective 
To estimate the rate of complete remission with or without platelet recovery 
(CR/CRp) by Day 42 after the infusion of CD3/CD19 depleted, ALT-803 
stimulated, donor NK cells and subcutaneous ALT-803 given after a non-
myeloablative preparative regimen for the treatment of refractory or relapsed 
acute myelogenous leukemia (AML)    
1.2 Secondary Objectives 
• To determine the incidence of in vivo expansion (≥ 100 donor derived NK 
cells per µL blood) of NK cells by Day +14 
• To document ALT-803 associated toxicity when given in this patient 
population 
• To evaluate the safety of the therapy as measured by rate of treatment 
related mortality (TRM) at 6 months 
1.3 Correlative Objectives 
• To measure the effect of ALT-803 on the function of adoptively transferred 
NK cells 
• To correlate CR/CRp with in vivo donor derived NK cell expansion  
• To characterize ALT-803 immunogenicity 
 
2 Background and Significance  
2.1 Human Natural Killer (NK) Cells as Mediators of Antitumor Therapy  
We and others have focused on the role of NK cells in tumor suppression. 
Human NK cells are a subset of peripheral blood lymphocytes defined by the 
expression of CD56 or CD16 and the absence of the T-cell receptor (CD3) 1-10. 
A number of studies suggest that NK cells may have a role in tumor 
surveillance. Cell lines susceptible to NK lysis are designated “NK sensitive” 
targets. The prototype target is the hematopoietic cell line K562. Following 
incubation of NK cells with various cytokines, in particular IL-2, NK cells acquire 
the ability to lyse a broad array of fresh and cultured tumor targets not normally 
sensitive to NK lysis (NK resistant targets) including the Raji and Colo cell lines.  
2.2 NK Cell-Based Immunotherapy for Advanced Malignancies  
In a number of tumor types generally considered unresponsive to 
chemotherapy, a series of well-publicized trials at the National Cancer Institute 
have documented anti-tumor effects in patients using so-called adoptive 

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immunotherapy 11. This approach involves harvesting mononuclear cells from 
patients via lymphapheresis, expansion of the cells ex vivo using high 
concentrations of the lymphokine Interleukin-2 (IL-2), and administration of the 
expanded and IL-2 activated cells (lymphokine-activated killer, or LAK, cells) to 
the patient along with IL-2. This approach produced approximately 20% 
complete and partial responses in initial trials at the NCI, with responses 
occurring primarily in melanoma, renal cell cancers, and NHL 12. The MHC-
unrestricted cytolytic activity of LAK cells is mediated predominantly by cells 
with the NK phenotype 13. A randomized trial performed at the NCI 11 suggests 
that a portion of the antitumor activity is mediated by exogenous LAK cells, and 
a portion by the high-dose IL-2 which is apparently required to maintain high 
levels of cytolytic activity 14. Our recent study demonstrated that adoptively 
transferred NK cells could expand in vivo, and that induction of remission in 5 
of 19 poor-prognosis AML patients was associated with NK expansion and KIR 
ligand-mismatch donors 15.  
2.3 rhIL-15  
Interleukin-15 (IL-15) is a cytokine and growth factor capable of expanding 
activated T cells and NK cells. By broad consensus, the NCI Immunotherapy 
Workshop (2007) ranked IL-15 as the #1 agent with “high potential for 
immunotherapy16.”  Based on preclinical non-human primate and early phase 
clinical trial data, including those at the University of Minnesota, IL-15 regimens 
can unquestionably be designed to prospectively and reproducibly increase T-
cell and NK-cell counts. 
 
The NCI Biological Resource Branch has manufactured E. coli-expressed 
recombinant human IL-15 (rhIL-15), and this is the first IL-15 product tested 
here at the University of Minnesota. Systemic administration of NCI rhIL-15 by 
daily intravenous (IV) bolus has been shown to increase the number of 
circulating CD8+ T and NK cells, but the cytokine has a very short half-life. We 
have established the MTD for NCI-manufactured rhIL-15 using IV and 
subcutaneous dosing. Although safer with subcutaneous administration 
allowing more drug delivery, we identified limitations with the rhIL-15 in clinical 
testing. Specifically, high levels of free rhIL-15 decrease circulating IL-15Rα, 
acting as a negative feedback signal to reduce further IL-15 trans-presentation. 
This is the rationale in this trial for using IL-15/IL-15Rα-Fc (ALT-803), an IL-15 
product that physiologically trans-presents IL-15. 
2.4 IL-15/IL-15Rα-Fc (ALT-803) 
This trial will evaluate an alternative IL-15 construct designed to have a 
prolonged serum half-life. The novel IL-15 immunoconjugate, ALT-803, was 

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developed by our collaborator, Altor BioScience Corporation (Altor, Miramar, 
FL), to overcome some of the biologic, regulatory, and commercial limitations 
of monomeric NCI rhIL-15. Under natural circumstances, IL-15 and IL-15 
Receptor-alpha (IL-15R) are coordinately expressed by antigen-presenting 
cells (i.e., monocytes and dendritic cells) 17. During signaling by the IL-15 
pathway, IL-15 bound to IL-15R is presented in trans to neighboring NK or 
CD8+ T cells expressing only the IL-2R receptor. At the immunologic synapse, 
IL15 trans-presentation appears to be a dominant mechanism for IL-15 action 
in vivo, providing tight physiologic control over the functions of IL-15 under 
homeostatic conditions and in response to immune stimuli 18. ALT-803 is a 
soluble complex consisting of two protein subunits of a human IL-15 variant19 
associated with high affinity to a dimeric human IL-15 receptor α (IL-15Rα) 
sushi domain/human IgG1 Fc fusion protein 20. 
  
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)11. 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. ALT-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) 19.  
2.5 ALT-803 by Subcutaneous Injection  
In August 2016, Altor prepared a Safety Summary of ALT-803 based on several 
ongoing early stage trials for various cancer indications (unverified/unaudited 
data). At the time 107 patients had received at least 1 dose of ALT-803, of 
which 35 were by subcutaneous injection and 26 of those patients treated at 
the University of Minnesota. Dosing ranged from 1 mcg/kg to 20 mcg/kg with 
the majority treated at 6 mcg/kg (n=16) and 10 mcg/kg (n=12). A summary of 
ALT-803 by route and dose is found in Section 10.8. The Altor clinical update 
concurred with our experience 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 effects included fever, fatigue, and changes in 
blood pressure. 
 

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3 Study Rationale  
Patients with poor prognosis acute myelogenous leukemia (AML) cannot be cured 
with standard therapy. This protocol is based on previous University of Minnesota 
protocols testing adoptive transfer of NK cells to treat patients with advanced 
leukemia who failed standard therapies. Allogeneic NK cells, which are not 
suppressed through inhibitory receptor recognition of “self” class I MHC molecules 
expressed on cancer cells, may effectively treat these leukemias. We have 
extensive experience using adoptive transfer of haploidentical NK cells and IL-2 
following lymphodepleting chemotherapy (cyclophosphamide and fludarabine) and 
find that 30-50% can achieve a remission and proceed to best donor transplant. 
IL-2 was administered to the patient after NK cell infusion in an attempt to expand 
them in vivo.  
 
Although these results are an improvement over standard salvage therapy for 
patients with refractory leukemia (expected CR rate of 10%), they suggest that 
adoptive cell therapy in its current form requires additional anti-tumor activity 21. 
The limitations of our prior approaches include the lack of in vivo NK cell expansion 
in most possibly due to the stimulation of Treg by IL-2. IL-15 in contrast to IL-2, 
does not support the expansion of regulatory T cells (Tregs). We now know that 
IL-15 will overcome these limitations and successfully expand NK cells in vivo 
perhaps leading to safer preparative regimens and greater clinical efficacy. Thus 
we will test adoptive transfer of haploidentical NK cells with the IL-15 super-agonist 
ALT-803 in patients with refractory AML.  
 
4 Study Design 
This is a multi-institutional, Simon’s optimal two-stage single arm phase II trial of 
CD3/CD19 depleted, ALT-803 activated, donor NK cells and subcutaneous ALT-
803 given after lymphodepleting chemotherapy (CY/FLU) for the treatment of 
refractory or relapsed acute myelogenous leukemia (AML). The primary objective 
is to study the potential efficacy of NK cells and subsequent ALT-803 dosing to 
achieve complete remission (CR) with or without platelet recovery (CRp) by Day 
42 while maintaining safety. CR is defined as ≤5% blasts in the bone marrow with 
recovery of neutrophils and platelets. CRp is defined as leukemia clearance (< 5% 
marrow blast and no circulating peripheral blasts) and neutrophil recovery but with 
incomplete platelet recovery.  
 
The two stage design will enroll 9 patients in stage 1. If 3 or more of the 9 patients 
show leukemic clearance by Day 42 post NK cell infusion, an additional 15 patients 
will be enrolled in stage 2 to obtain a more precise estimate of CR/CRp. If 10 or 

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more out of the total 24 patients show clearance, further investigation will be 
considered. 
 
The CD3/CD19 depleted, ALT-803 stimulated donor NK cells are infused on Day 
0, 
after 
a 
non-myeloablative 
preparative 
regimen 
of 
fludarabine/ 
cyclophosphamide. Subcutaneous ALT-803 is given on Day 0 (no sooner than 4 
hours after the NK cell infusion), Day +5 and Day +10 for a total of 3 doses.  
 
Patients are followed for 1 year from the NK cell infusion for disease free survival 
(DFS), treatment related mortality (TRM), and incidence of relapse. 
 
Patients achieving a complete remission (CR or CRp) with neutrophil recovery 
(ANC > 500 cells/μl) for at least 4 weeks will be considered for allogeneic 
transplant, independent of this study, to prolong remission. Follow-up will continue 
for 1 year from the NK cell infusion. 
 
5 Patient Selection 
Study entry is open to patients 18 - 70 years of age 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 high 
risk acute myeloid leukemia studies at the University of Minnesota and the other 
participating institutions. 
 
Inclusion Criteria: 
5.1 ≥18 but ≤ 70 years of age  
 
5.2 Diagnosis of acute myeloid leukemia (AML) and meets one of the 
following disease criteria: 
 Primary induction failure:   
o De novo AML - no CR after 2 or more chemotherapy induction attempts 
o Secondary AML (from MDS or treatment related) - no CR after 1 or 
more chemotherapy induction attempts  
 Relapse after chemotherapy: not in CR after 1, 2, or 3 re-induction 
attempts 
o Patients > 60 years of age, the 1 cycle of chemotherapy is not required  
 Relapse after hematopoietic stem cell transplant:  
o Relapse must have occurred > 18 months after transplant 
o No re-induction required and no more than 1 re-induction attempt is 
allowed.  

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Notes:  
1) For hypomethylating agents (i.e. decitabine, azacititdine) to count as 
an induction/re-induction attempt, the patient must have completed a 
minimum of 3 monthly cycles 
2) For targeting agents (i.e. sorafenib) to count as an induction/re-
induction attempt, the patient must have completed a minimum of 1 
month without attaining CR 
3) 7+3 followed by 5+2 counts as TWO induction attempts 
4) Use of hydroxyurea is permitted to control blasts until Day -3 per 
Section 8.7 
5) A history of AML related CNS involvement is allowed if CSF analysis 
is negative on 2 test dates at least 2 weeks apart prior to study 
treatment. The use of ongoing CNS maintenance therapy is allowed 
while on study. 
 
5.3 HLA-haploidentical related donor (aged 12 to 75 years) with donor/recipient 
match based on a minimum of intermediate resolution DNA based Class I 
typing of the A and B locus (at least 2/4 class I allele) 
 
5.4 Karnofsky Performance Status ≥ 60% (appendix III) 
 
5.5 Adequate organ function within 14 days of study registration (28 days for 
pulmonary and cardiac) defined as: 
• Creatinine:  ≤ 2.0 mg/dL  
• Hepatic:  AST and ALT < 3 x upper limit of institutional normal 
• Pulmonary Function:  oxygen saturation ≥ 90% on room air; PFT’s 
required only if symptomatic or prior known impairment - must have 
pulmonary function >50% corrected DLCO and FEV1.   
• Cardiac Function: LVEF ≥ 40% by echocardiography, MUGA or cardiac 
MRI, no uncontrolled angina, severe uncontrolled ventricular arrhythmias, 
or electrocardiographic evidence of acute ischemia or active conduction 
system abnormalities 
 
5.6 Able to be off prednisone or other systemic immunosuppressive medications 
for at least 3 days prior to NK cell infusion (excluding preparative regimen 
pre-medications) 
 
5.7 Sexually active females of child bearing potential and males with partners of 
child bearing potential must agree to use effective contraception during 
therapy and for 4 months after completion of therapy 

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5.8 
Voluntary written consent prior to the performance of any research related 
procedures 
 
Exclusion Criteria: 
5.9 
Acute leukemias of ambiguous lineage 
 
5.10 Pregnant or breastfeeding - The agents used in this study include those that 
fall under Pregnancy Category D - have known teratogenic potential. Women 
of child bearing potential must have a negative pregnancy test at screening 
 
5.11 Active autoimmune disease requiring systemic immunosuppressive therapy 
 
5.12 History of severe asthma and currently on systemic chronic medications 
(mild asthma requiring inhaled steroids only is eligible) 
 
5.13 New or progressive pulmonary infiltrates on screening chest X-ray or chest 
CT scan unless cleared for study by Pulmonary. Infiltrates attributed to 
infection must be stable/improving (with associated clinical improvement) 
after 1 week of appropriate therapy (4 weeks for presumed or documented 
fungal infections).  
 
5.14 Uncontrolled bacterial, fungal or viral infections including HIV-1/2 or active 
hepatitis C/B - chronic asymptomatic viral hepatitis is allowed 
 
5.15 Received any investigational agent within the 14 days before the start of study 
treatment (1st dose of fludarabine) 
 
5.16 Prior ALT-803 
 
 
6 Donor Selection 
Donor selection will be in compliance with 21 CFR 1271. Donor assessment and 
consent process will occur in the apheresis center or similar donor facility. 
 
6.1 
HLA-haploidentical related donor (aged 12 to 75 years) with donor/recipient 
match based on a minimum of intermediate resolution DNA based Class I 
typing of the A and B locus (at least 2/4 class I allele) - It is recognized 
individual institutions may have differing donor age guidelines. This is 

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acceptable as long as no donor is younger than 12 years or older than 75 
years. 
6.2 
Body weight of at least 40 kilograms  
6.3 
In general good health as determined by the medical provider 
6.4 
Adequate organ function defined as: 
• Hematologic: hemoglobin, WBC, platelet within 10% of upper and lower limit 
of normal range of test (gender based for hemoglobin) 
 Hepatic:  ALT < 2 x upper limit of normal,  
 Renal:  serum creatinine < 1.8 mg/dl 
6.5 Performance of a donor infectious disease screen panel including CMV 
Antibody, Hepatitis B Surface Antigen, Hepatitis B Core Antibody, Hepatitis 
C Antibody, HIV 1/2 Antibody, HTLVA 1/2 Antibody, Treponema and 
Trypanosoma Cruzi (T. Cruzi) plus HBV, HCV, WNV, HIV by nucleic acid 
testing (NAT);or per current standard institutional donor screen – must be 
negative for HIV and active hepatitis B  
6.6 
Not pregnant - females of childbearing potential must have a negative 
pregnancy test within 7 days of apheresis 
6.7 
Voluntary written consent (and assent if donor < 18 years of age) prior to 
the performance of any research related procedure 
 
7 Patient/Donor Registration  
To be eligible for registration to this study, the patient must meet each inclusion 
criteria listed and none of the exclusion on the eligibility checklist based on the 
eligibility assessment documented in the patient’s medical record.  
 
The eligibility checklist for both the patient and donor will be completed at the time 
of study registration. 
7.1 Registration with the University of Minnesota Clinical Trials Office 
Upon completion of the screening evaluation, eligibility checklist and obtaining 
consent, the site study coordinator or designee will register the patient. The 
donor also is registered in OnCore. Complete registration information is found 
in the study’s Procedures Manual for Affiliate Sites. 

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Affiliate sites only: At the time of registration, the signed consent will be 
uploaded into OnCore as an attachment under the appropriate record (patient 
or donor).  
 
Affiliates are responsible for fulfilling any local registration requirements. 
7.2 Patients Who Do Not Begin Study Treatment 
If a patient is registered to the study and is later found not able to begin study 
treatment (beginning with the 1st dose of fludarabine), 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 complete enrollment. 
 
8 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.).  
 
Patients are to receive allopurinol 300 mg PO daily, unless known allergy, 
beginning prior to chemotherapy start and continuing until Day +14 or as clinically 
indicated. 
 
 
 
Study 
Day 
Therapy 
Protocol 
Section  
-6 
Fludarabine 25 mg/m2: 1 hour infusion 
8.1 
-5 
Fludarabine 25 mg/m2: 1 hour infusion 
Cyclophosphamide 60 mg/kg: 2 hour infusion 
8.1 
-4 
Fludarabine 25 mg/m2: 1 hour infusion  
Cyclophosphamide 60 mg/kg: 2 hour infusion 
8.1 
-3 
Fludarabine 25 mg/m2: 1 hour infusion  
8.1 
-2 
Fludarabine 25 mg/m2: 1 hour infusion 
8.1 
-1 
Rest day for patient 
Donor apheresis and cell product processing 
8.1 
8.2, 8.3 
0 
NK cell infusion   
ALT-803 10 mcg/kg SQ no sooner than 4 hours after the 
NK cell infusion 
8.4 
8.5 
+5 
ALT-803 10 mcg/kg SQ 
8.5 
+10 
ALT-803 10 mcg/kg SQ 
8.5 

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8.1 Preparative Regimen (Day -5 through Day -2) 
The administration of the preparative regimen will follow the institutional dosing 
guidelines. Dose and/or schedule adjustments consistent with the standard of 
care may be made on an individual patient basis as needed for safety.  
 
 
Patients are to receive allopurinol 300 mg PO daily, unless known allergy, 
beginning prior to chemotherapy start and continuing until Day +14 or as 
clinically indicated. 
 
Fludarabine is administered as a 1 hour intravenous infusion per institutional 
guidelines once a day for 5 doses beginning on Day -6. 
 
Cyclophosphamide 60 mg/kg will be administered as a 2 hour intravenous 
infusion on Day –5 and Day -4.  
 
Cyclophosphamide dosing is calculated based on ABW (Actual Body Weight) 
unless ABW is >150% of the IBW (Ideal Body Weight). Then the dose should 
be computed using adjusted body weight.  
 
Ideal body weight is calculated using 50kg + [2.3kg x (height in inches – 60)] 
for men; 45.5kg + [2.3kg x (height in inches – 60)] for women.  
 
Adjusted body weight = IBW + 0.5(ABW-IBW). 
 
Cyclophosphamide associated hydration will be given according to 
recommended institutional standards (recommend starting 12 hours prior to 
cyclophosphamide). 
 
Mesna is given as five divided doses (totaling the daily cyclophosphamide dose 
in mg) with the 1st dose prior to the cyclophosphamide infusion, then at 3, 6, 9, 
and 12 hours later.  
8.2 Donor Leukapheresis (Day -1) 
The donor will be scheduled for the morning before the day of the planned NK 
cell infusion to undergo leukapheresis. Peripheral blood mononuclear cells 
(PBMCs) will be collected by a single apheresis over 5 hours as described by 
McKenna, et al22. At the time of the apheresis, three 9 or 10 ml green top tubes 
will be collected for research per Section 11.2.1. 

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8.3 Preparation of Allogeneic NK Cells / Product Release Criteria 
The apheresis product will be T cell-depleted (CD3-) and B cell-depleted 
(CD19-) using the Miltenyi Biotec CliniMACS® Cell Selection System and CD3 
and CD19 MicroBeads and reagent (Miltenyi Biotec, Auburn, CA). The NK cell 
enriched product will be activated by overnight stimulation with 36.1 ng/mL 
ALT-803 under GMP conditions in the treating institution cell processing facility. 
ALT-803 at 36.1 ng/mL is the equivalent of NCI IL-15 at 10 ng/ml based on the 
chemical conversions. ALT-803 is a bigger molecule requiring and as a result 
a 3.6 fold more is needed to give the same amount of IL-15 tested previously. 
 
Refer to the chemistry, manufacturing and control (CMC) section of the 
Investigational New Drug (IND) application for additional preparation 
information and lot release criteria. 
 
Cell Product Samples to MCC Translational Therapy Lab  
Samples of the cell product from enrolling sites will be sent to the Masonic 
Cancer Center’s Translational Therapy Lab (TTL) for cell function and 
phenotype studies being performed under a separate protocol. The following 
samples will be collected: 
1) the apheresis unit before processing (100 x 106 cells)  
2) the product after depletion, but prior to addition of ALT-803 (10 x 106 
cells) 
3) the final NK cell product (50 x 106 cells) pulled prior to calculating lot 
release 
 
Both samples will be sent as a single shipment on Day 0 for overnight delivery 
to the Masonic Cancer Center’s Translational Therapy Lab (TTL). Refer to the 
Laboratory Manual for shipping information. 
8.4 
Allogeneic CD3- CD19- Selected NK Cell Infusion (Day 0) 
Pre-medications:  Patients should be pre-medicated with acetaminophen 650 
mg PO and/or diphenhydramine 25 mg PO before and 4 hours after the NK cell 
infusion. Corticosteroids should not be used. 
 
Infusion guidelines:  The NK cells will be infused without a filter or pump, 
slowly by gravity over at least 15 minutes, but no more than one hour.    
 
If less than 1.5 x 107 MNC/kg are available, then all cells (after quality control 
testing) should be given and the therapy plan will remain the same. Outcomes 

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will not be included in the primary analysis for these patients and they will be 
replaced. 
 
Monitoring:  Patients will be monitored for adverse effects of the NK cell 
infusion such as rash, acute allergic reaction, bronchospasm, respiratory 
distress, and acute vascular leak syndrome. If severe acute reactions occur 
(defined as CTCAE v 4.0 grade 4 - life-threatening consequences; urgent 
intervention indicated), the infusion will be stopped.  
 
Hydration will be administered per institutional guidelines. Any elevation of 
daily metabolic monitoring will be treated with more aggressive hydration, while 
being attentive to fluid overload.  
 
Corticosteroids are to be avoided Day -3 through Day +14 (during the period 
of in vivo NK cell expansion) except for pre-medications for the preparative 
regimen. If absolutely necessary, steroids may be given as clinically indicated 
but aiming for a cumulative dose of systemic steroids ≤ 100 mg of 
hydrocortisone per day during this window.  
8.5 ALT803 (Day 0, +5, and +10) 
ALT-803 10 mcg/kg will be administered subcutaneously on Day 0 (no sooner 
than 4 hours after the NK cell infusion), Day +5 and Day +10.  
 
ALT-803 dosing will be based on a weight obtained at admission/pre-
chemotherapy.. For patients > 100 kilograms weight, the ALT-803 dose will be 
calculated using a weight capped at 100 kg. The dose will be re-calculated in 
subsequent doses in the event of a 10% or greater weight change from the 
baseline weight.  
 
Injection sites should be rotated per institutional guidelines and each injection 
site separated by at least 1 inch. 
 
The 1st dose of ALT-803 will be given no sooner than 4 hours after the NK cell 
infusion in the absence of a grade 4 NK cell infusion related toxicity. If the 
patient experiences grade 4 infusion related toxicity during the NK cell infusion 
and it resolves to grade 2 or better within the 48 hours, ALT-803 may be started 
late with all planned doses to be given; however the administration of remaining 
2 doses will be shifted to maintain a minimum of 4 days between dosing.  
 
If ALT-803 cannot be started within 48 hours after the NK cell infusion, no ALT-
803 will be given and the patient will be replaced. 

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A window of +2 days for ALT-803 dosing is allowed in the event of scheduling 
issues or patient status; however all injections must be separated by a 
minimum of 4 days rest and be completed by Day +14. Refer to “Dose Hold” 
below.  
 
Monitoring:  Patients will be observed for a minimum of 2 hours after the 1st 
dose for immediate adverse events. Vital signs (heart rate, blood pressure, 
respiration, temperature, and oxygen saturation) will be documented prior to 
each ALT-803 injection and then at 30, 60, and 120 minutes with a ± 20 minute 
window for each time point. If the first dose is well tolerated after 2 hours of 
monitoring, subsequent doses may be administered with 30 minute post-dose 
monitoring. 
 
Pre medications: Give acetaminophen 650 mg PO and diphenhydramine 25 
mg PO prior to and 4 hours after each ALT-803 dose. On Day 0, if 
acetaminophen post dose for NK cell infusion was given within the last 4 hours, 
do not give an additional dose prior to the 1st dose of ALT-803.  
 
Dose modification:  A one-time dose decrease to 6 mcg/kg is allowed if 
recurrent constitutional symptoms seem related to ALT-803 dosing. Patients 
unable to tolerate the reduced dose will be discontinued from further ALT-803. 
Re-escalation of the dose is not permitted. 
 
Dose hold:  A 48 hour window is permitted for the 1st dose as described above. 
The 2nd or 3rd dose of ALT-803 may be held on the day of a planned dose for 
either of the following situations: 
• the patient has a fever of > 101°F (38.3 °C) 
• if in the opinion of the treating physician, holding would be of benefit to the 
patient 
 
The following guidelines must be followed: 1) A minimum 4 day rest period is 
required between doses and 2) any dose not given by Day +14 will be skipped. 
8.6 Supportive Care 
Throughout the study, the investigator may prescribe any concomitant 
medications or treatment deemed necessary to provide adequate supportive 
care. Supportive care may include antibiotics, anti-fungals, analgesics, 
transfusions, growth factors.  

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8.7 
General Concomitant Medication Guidelines 
Concurrent chemotherapies (except hydroxyurea) with ALT-803 are prohibited. 
Hydroxyurea may be used to control blast count until Day -3. 
 
Administration of glucocorticoids is discouraged during the ALT-803 treatment 
period as the use of systemic steroid medications may result in loss of 
therapeutic effects of the study drug. Sustained use of steroids or steroid use 
to treat related toxicity will be an indication to stop ALT-803. Transient use is 
permitted as needed per standard of care. Topical steroid cream is permitted.  
 
Beta-blockers and other anti-hypertensives may potentiate the hypotension 
and extra caution should be used during ALT-803 regimen treatment period. It 
is recognized, that ALT-803 treatment, like IL-2 and IL-15, may be associated 
with low blood pressure especially if the patient is not well hydrated.  
8.8 Duration of Study Participation/Opportunity for Allogeneic Transplant 
Patients will be followed for disease response (including those who go to 
transplant) until disease progression/relapse, then for survival only to a 
maximum of 12 months from the NK cell infusion unless: 
• consent is withdrawn 
• patient is discharged to hospice and/or not returning to the study site for 
follow-up – in these cases, follow-up information including date and cause 
of death may be obtained, as available from other sources   
• the patient is unevaluable - if a patient is not evaluable, he/she will be 
followed only until the resolution or stabilization of treatment related toxicity 
• new anti-cancer treatment is started 
 
Formal follow-up ends at 12 months; however for the purposes of IND annual 
reporting, the date and cause of death will be recorded in OnCore upon 
knowledge in the follow-up tab. 
 
Patients achieving a complete remission (CR or CRp) may be eligible for 
subsequent allogeneic transplant. The transplant will be done independent of 
this study. Patients would continue to be followed for survival through 12 
months from the NK cell infusion.   
 

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9 Management of Selected Expected Toxicities Associated with NK 
Cell Infusion and ALT-803 
See appendix IV for expected toxicities of the preparative regimen and Section 
10.8 for the expected toxicities of ALT-803. 
9.1 Tumor Lysis Syndrome 
Tumor lysis syndrome is a possible risk associated with therapy of active 
leukemia. All patients (except those with known allergy) are to receive 
allopurinol 300 mg every day beginning before chemotherapy and continuing 
until Day +14 or as clinically appropriate. 
9.2 Acute Allergic Reaction Secondary to the Infusion of Allogeneic NK Cells 
Although infusion of donor lymphocytes has not been associated with acute 
allergic reactions, patients will be closely watched for the occurrence of 
hypotension, dyspnea and angioedema during and immediately after the 
infusion.  
 
The NK cell infusion will be stopped if severe acute reactions occurs (defined 
as CTCAE grade 4 - life-threatening consequences; urgent intervention 
indicated). Refer to NCI Common Terminology Criteria for Adverse Events v4.0 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#
ctc_40).  
9.3 Injection Site Reactions/Skin Rash in Association with ALT-803 
Based on current experience, localized skin rashes are common with 
subcutaneous administration. If a rash occurs and the rash area surrounding 
the ALT-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 post-dosing (25-50 mg TID orally x 2 days) of ALT-803 at the 
discretion of the treating physician. Diphenhydramine should be eliminated if 
not tolerated. 
9.4 Hypotension (systolic blood pressure < 90 mm Hg)  
ALT-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. 

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9.5 Vascular Leak Syndrome 
Neither administration of allogeneic NK cells nor autologous IL-2 activated NK 
infusions have been associated with vascular leak syndrome in our previous 
experience. Nevertheless, patients will be monitored for weight gain (by 
weights at least 3 times per week) and pulmonary edema during and after the 
ALT-803 administration. 
9.6 Cytokine Release Syndrome (CRS) or CRS-Like Symptoms 
Patients will be monitored for clinical signs and symptoms of CRS through 
routine daily patient assessments and via the Targeted Expected Toxicities 
Worksheet (appendix V). Refer to Section 12 for the revised CRS grading 
system that will be used for this study. 
 
While CRS is a clearly defined syndrome in T cell therapy, it is not known to 
occur to the same extent in NK cell therapies and may have other 
manifestations or may evolve differently. We have seen immune activation 
syndromes with other IL-15 products that include fever, CNS toxicities, and 
rash. CRS will be graded using the revised grading system by Lee et al.23 
 
CRS Revised Grading System (replaces CTCAE v4 CRS grading) 
Grade 
Toxicity Description 
Grade 1 
Symptoms are not life threatening and require symptomatic treatment only, e.g., fever, 
nausea, fatigue, headache, myalgias, malaise 
Grade 2 
Symptoms require and respond to moderate intervention - Oxygen requirement < 40% 
or Hypotension responsive to fluids or low dose of one vasopressor or Grade 2 organ 
toxicity 
Grade 3 
Grade 3 Symptoms require and respond to aggressive intervention - Oxygen 
requirement ≥40% or Hypotension requiring high dose  or multiple vasopressors or 
Grade 3 organ toxicity or grade 4 transaminitis 
Grade 4 
Life-threatening symptoms - Requirement for ventilator support or Grade 4 organ toxicity 
(excluding transaminitis) 
Grade 5 
Death 
Grades 2-4 refer to CTCAE v4.0 grading. 
 
The above will be used for CRS grading in conjunction with CTCAE v 4 for 
other toxicity grading.  
 
Most patients will already be in the hospital. However, if CRS is suspected after 
ALT-803 is completed and within 30 days of NK cell infusion, management will 
be as follows below.  
 
If symptoms occur, CRP, IL-6 and ferritin levels will be assessed. In our 
experience, having at least 2 of 3 elevations of CPR > 150, IL-6 > 150, or ferritin 
> 5000 could be consistent with CRS if in the context of persistent grade >2 

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fever and other associated symptoms (CRS or neurologic). Of the few patients 
we have suspected of CRS during treatment with NK cells and IL-15 in the past, 
all had this degree of fever. 
 
1) CRS grade 1, continue current setting management 
2) CRS grade 1 for > 24 hours or CRS grade >2, admit to hospital (if not 
already inpatient) 
3) Start methylprednisolone at 100 mg/kg (or equivalent) IV per day for grade 
1-2 CRS for 72 hours or earlier if grade >2 neuro symptoms. 
4) Tocilizumab should be administered if grade ≥3 CRS or grade 1-2 
symptoms not responding to steroids after 72 hours (and without other 
cause of fever identified) or if any upgrade in severity (grade ≥3 CRS or 
neurologic or other per CTCAE v4). 
 
Participating centers must have emergency access (same day) to tocilizumab 
to take part in this trial. 
9.7 Prolonged Marrow Suppression 
Pancytopenia will occur with this regimen and should be treated as follows: 
 
Anemia and Thrombocytopenia are expected in all patients, and they will 
receive standard supportive transfusion care according to transfusion 
committee guidelines or as modified based on clinical parameters. Prolonged 
anemia or thrombocytopenia are not unexpected will not count towards toxicity.  
 
Neutropenia:   
• Days –7 to +14:  In the absence of severe, uncontrolled infection, G-CSF or 
granulocytes should be avoided. If the clinical situation warrants growth 
factor use, ALT-803 administration will be stopped and the patient replaced. 
• At Day +14:  If the ANC is <500/mm3, G-CSF will be initiated  
 
10 
ALT-803 Formulation, Supply, and Potential Toxicity 
ALT-803, a recombinant human superagonist IL-15 complex, is the working name 
of the drug under investigation. Its active ingredient is ALT-803 and its 
pharmacologic class is as a targeted anticancer immunotherapeutic. 
 
ALT-803 has been referred to as IL-15N72D:IL-15RαSu/IgG1 Fc complex in 
various preclinical study reports, publications, and other related documents. No 
other names exist for this product, as it is a novel investigational biologic. 

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10.1 Formulation and Composition 
The biological drug product, ALT-803, is formulated in a phosphate buffered 
saline solution. The drug substance is produced by a recombinant mammalian 
cell line and is manufactured without the use of animal derived components. 
The vialed quantitative composition of ALT-803 is listed in the table below. 
 
Quantitative Composition of ALT-803 
Component 
Concentration 
Amount/Vial 
ALT-803 
1 mg/mL 
1.2 mg 
Phosphate 
Buffered 
Saline 
(PBS) 
QS 
1.2 mL 
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. 
10.2 Structural Formula   
ALT-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). The human IL-15R sushi domain/human IgG1 
Fc fusion protein comprises the sushi domain of the IL-15R subunit (aa 1-65 of 
the mature human IL-15Rα protein) linked with the human IgG1 CH2-CH3 
region containing the Fc domain (232 amino acids). Aside from the N72D 
substitution, all of the protein sequences are human. Based on the amino acid 
sequence of the subunits, calculated molecular weight of the complex 
comprising 2 IL-15N72D polypeptides and a disulfide linked homodimeric IL-
15RαSu/IgG1 Fc protein is 92.4 kDa. Each IL-15N72D polypeptide has a 
calculated molecular weight of approximately 12.8 kDa and the IL-
15RαSu/IgG1 Fc fusion protein has a calculated molecular weight of 
approximately 33.4 kDa. Both the IL-15N72D and IL-15RαSu/IgG1 Fc proteins 
are glycosylated resulting in an apparent molecular weight of ALT-803 as 
approximately 114 kDa by size exclusion chromatography. The isoelectric point 
(pI) determined for ALT-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 ALT-803 is 116,540 M-1, or 1.26 OD280 for a 1 mg/mL 
solution of ALT-803, or one OD280 is equivalent to 0.79 mg/mL solution of ALT-
803. 
10.3 Storage and Handling 
Study medication is provided in a 2 mL vial containing 1.2 mL of ALT-803 at a 
concentration of 1 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. 

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10.4 Stability 
Stability studies are ongoing and will be continued throughout the clinical study. 
Based on previous lots, the study drug is expected to be stable for over 2 years. 
The site will be periodically updated on the stability of the drug and will be 
immediately informed if there is evidence that the drug no longer meets its 
stability specifications.  
10.5 Agent Ordering and Agent Accountability 
ALT-803 is produced in the USA for Altor BioScience Corporation, Miramar, 
FL. After manufacturing, the product is stored at Altor BioScience Corporation 
for clinical supply, packaging, and labeling. The label indicates the product 
name, strength, manufacturing date, and the study requirement information. 
ALT-803 will be shipped by cold chain from Altor BioScience Corporation to 
each participating site. (See the Procedures Manual for Affiliate Sites for 
instructions on how to order ALT-803.) 
10.6 Study Drug Preparation and Administration  
ALT-803 dose calculation will be based on actual body weight. For patients > 
100 kilograms weight, the ALT-803 dose will be calculated using a weight 
capped at 100 kg. The calculated amount of ALT-803 will be drawn into a 
syringe for subcutaneous injection. The 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. 
 
10.7 Agent Inventory Records 
The investigator, or a responsible party designated by the investigator (e.g. 
institutional investigational pharmacy), must maintain a record of the inventory 
and disposition of all agents received from Altor BioScience Corporation using 
the Study Agent Drug Accountability Record. (See the Study Procedures 
Manual for the form to use and instructions on how to complete it.) 
10.8 Toxicity 
As of August 2016, 107 patients were treated with ALT-803. A summary of 
exposure by route and dose level is presented below. 
 
 
 

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Summary of Exposure, by route and dose level 
Intravenous:  
 
Subcutaneous:  
 
Intravesical:  
Dose  
N   
Dose  
N  
 
Dose  
N  
< 1 μg/kg IV  
17   
1 μg/kg SQ  
2   
100 μg  
3  
3 μg/kg IV  
12   
3 μg/kg SQ  
0   
200 μg  
3  
6 μg/kg IV  
13   
6 μg/kg SQ  
16   
400 μg  
18  
10 μg/kg IV  
6   
10 μg/kg SQ  
12   
Total  
24  
Total  
48   
15 μg/kg SQ 
4 
 
 
 
 
20 μg/kg SQ 
1  
 
 
Total 
35  
 
The most common side effects seen in studies with subcutaneous (under the 
skin) injections have been change in blood pressure (increase or decrease), 
fever, fatigue 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).  
 
The study drug ALT-803 can cause many side effects which may be similar to 
the side effects of interleukin-2 (IL-2), which has been used for more than 20 
years.  
 
Risks of ALT-803 
Most likely  (greater than 
10% - 1 in 10 patients) 
Less likely  (3% to 10% - 1 in 
30 to 1 in 10 patients) 
Rarely (< 3% - 1 in 30 
patients) 
• pain and redness at the 
injection site 
• weight gain with swelling of 
hands and feet due to fluid 
retention  
• feeling tired or short of 
breath due to a low red blood 
count (anemia) 
• increase or decrease in 
blood pressure  
• flu-like symptoms such as 
fever, chills, shaking, 
headache, stiffness, aching 
muscles and joints 
• increased risk of infection 
due to a low white blood 
count 
• increased risk of bruising and 
bleeding due to a low platelet 
count 
• skin rash 
• heart problems - causing low 
blood pressure, dizziness, 
chest pain or changes in 
heart rhythm (heart beat) 
• changes in liver and kidney 
function as detected on 
routine blood tests 
• cough and shortness of 
breath 
• mouth sores 
• confusion, sleepiness and 
depression especially in older 
persons or persons with a 
history of depression 
• allergic reaction  
• temporary thinning of hair 

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Risks of ALT-803 
Most likely  (greater than 
10% - 1 in 10 patients) 
Less likely  (3% to 10% - 1 in 
30 to 1 in 10 patients) 
Rarely (< 3% - 1 in 30 
patients) 
• weakness, headache, 
dizziness 
• vomiting, nausea, loss of 
appetite 
• reduced levels of electrolytes 
as detected by routine blood 
tests 
 
 
11 Clinical Evaluations and Procedures  
Scheduled evaluations up to Day 28 may be performed +/-3 days from the 
targeted date; assessments to be performed after Day 28 may be done +/-7 
days of the targeted date. In addition, targeted days may be altered as clinically 
appropriate. 
 
 

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11.1  Required Clinical Care Evaluations   
 
Screening 
Within 30 days 
of study 
registration1 
During 
preparative 
regimen until 
ANC> 5002 
Day 
0 
Day 
+5 
Day 
+7 
Day 
+10 
Day 
+14 
Day 
+21 
Day 
+28 
Day 
+42 
Day 
+60 
Day 
+100 
6 and 12 
months8 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
daily 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Weight 
X 
3 x week 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vitals and pulse 
oximetry 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
 
Performance Status 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
Toxicity Assessment 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HLA typing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Recipient viral panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC, diff, plt 
X 
daily 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Basic metabolic panel 
(BMP) or equivalent3 
 
daily  
(unless CMP is 
done) 
 
 
 
 
 
 
 
 
 
 
 
Comprehensive 
metabolic panel (CMP) 
or equiivalent4 
X 
weekly 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Urine or serum 
pregnancy test for 
WOCBP5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
BM biopsy and 
aspirate6 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
X 
Disease staging 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
X 
CXR or chest CT scan  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function 
Tests7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram, 
MUGA, or Cardiac MRI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
1 –within 14 days for labs required for eligibility per Section 5.5, consent and HLA typing exempt from 30 day limit  
2 – or as clinically indicated 
3 –basic metabolic panel consists of BUN, creatinine, calcium, glucose, lytes (CO2, Cl, Na, K)  
4 – comprehensive metabolic panel consists of albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), blood urea nitrogen (BUN), calcium, creatinine, glucose, lytes (CO2, Cl, Na,, K), total bilirubin, and 
total protein 
5- women of child bearing potential  
6- collect 30 ml heparinized bone marrow for research at time of all bone marrow biopsies for clinical care (refer to Section 11.2) 
7 -testing only required if symptomatic or prior known impairment 
8 –formal follow-up ends 12 months after the NK cell infusion unless unevaluable, withdraws consent, discharged to hospice/not 
returning to study site or starts new anticancer therapy; however deaths should be recorded upon knowledge per Section 8.8  
 
 
 

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11.2  Research Related Evaluations  
 11.2.1 
Donor Research Related  
 
Screen 
Day of  
apheresis 
Consent 
X 
 
HLA Typing  
X 
 
Type and Screen (ABO/RH 
/Indirect Antiglobulin) 
X 
 
BMT Donor Infectious Disease 
Panel plus NAT testing (HCV, 
WNV, HIV) 
X 
X2 
Donor chimerism (affiliate only to 
TTL) 
X 
 
Medical History 
X 
 
Physical Exam 
X 
X 
CBC, diff, platelet  
X 
X 
ALT, creatinine 
X 
 
Pregnancy test, if applicable 
X 
X2 
Three 9 or 10 ml green top tubes 
(research related) to TTL 
 
X 
1- including CMV Antibody, Hepatitis B Surface Antigen, Hepatitis B Core Antibody, Hepatitis C Antibody, HIV 
1/2 Antibody, HTLVA 1/2 Antibody, Treponema, and Trypanosoma Cruzi (T. Cruzi) plus HBV, HCV, WNV, 
HIV by nucleic acid testing (NAT); or per current standard institutional donor screen – must be negative for 
HIV and active hepatitis B 
2- repeat if more than 7 days since previous testing 
 
 
The research related donor samples are shipped the day of collection (Monday-
Thursday) for next day delivery to the Masonic Cancer Center’s Translational 
Therapy Lab (TTL). 
 
Refer to the Laboratory Manual for additional details. 

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11.2.2 Patient Research Related Evaluations 
Day: 
  
Before 
chemo 
start 
 
Day 0 
Day 0 at least 4 hours 
after the NK cell infusion 
Day +1, 
Day +2, 
Day+3, 
Day+4 
Day +5  
Day 
+7 
Day 
+9 
Day +10 
Days in Reference to the NK Cell infusion 
Prior to NK 
cells 
ALT-803 
injection 
Post ALT-803 
dose 1 
Day 
+14 
Day 
+21 
Day 
+28 
Day 
+42 
Day 
+60 
Month 
3 
ALT-803 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Toxicity notation 3 
X 
X (pre + 
1 hr post) 
X  
(pre) 
X  
(2 hour) 
 
X  
(pre ALT-803 
and 30 min 
post) 
X 
 
X  
(pre ALT-803 
and 30 min 
post) 
X 
 
 
 
 
X 
Skin Reaction Diary – 
start day of ALT-803 
injection and continue until 
next injection or for 6 days 
 
 
X 
 
 
X 
X 
 
X 
 
 
 
 
 
 
Monitoring for Stopping 
Rule Events 
 
 
Through Day 42 
 
 
Chimerism – PB 
unseperated 
X 
 
 
 
 
 
X 
 
 
X1 
X1 
X1 
X1 
X1 
 
Calculation of NK cell 
expansion (by study PI) 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
 
 
CRP, ferritin4 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Six 9 or 10 ml green 
top tubes   
X 
X 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
One 9 or 10 ml of red 
top tube 
X 
X 
 
 
 
X (pre ALT-
803) 
X 
 
X (pre ALT-
803) 
X 
X 
X 
X 
X 
X 
Pharmacokinetics 
(PKs)  5 ml red top (a 
minimum of 2 ml blood 
needed) per time point 
 
 
X  
(pre ALT-
803) 
 
X 
X (pre ALT-
803) 
X 
X 
 
 
 
 
 
 
 
Immunogenicity  5 ml of 
serum (1 red top tube) 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
30 ml heparinized bone 
marrow at time of each 
BM biopsy 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
1- if donor cells are present at Day 14, chimerism monitoring will recheck Day 21. If present Day 21, check Day 28, If present, then Day 42 and Day 60 or until gone 
2 - In the event of a CTCAE grade 4 infusion related toxicity (non-hematologic, excluding fever alone) a sample of banked blood will be tested for HADA 
3 – per Section 12.2  
4 – CRP and ferritin testing at these time points are research related to better understand the development (or not) of cytokine release syndrome. CPR and ferritin testing at other time 
points in association with CRS will be SOC as part of clinical care per Section 9.6 

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Note: if a patient is not abiding by the required clinical care calendar (Section 
11.1), the collection schedule of the toxicity data and research related samples 
may be altered or discontinued on an individual patient basis, as appropriate.   
 
It is recognized that with novel therapies as used in this study, the timing of 
protocol directed research samples may miss important patient specific events. 
For this reason, up to 3 extra samples for a total of 180 ml of blood may be 
drawn at additional time points that are not specified above.  
 
Samples, other than for immunogenicity and pharmacokinetics (PK), are 
shipped the day of collection (Monday-Thursday) for next day delivery to the 
Masonic Cancer Center’s Translational Therapy Lab (TTL). Immunogenicity 
and PK samples are stored frozen at the study site until the time of batch 
shipping directly to Altor Bioscience’s central laboratory. 
 
Refer to the Laboratory Manual for additional details. 
11.2.1 
Assessment of Immune Activation (TTL) 
Samples to evaluate lymphocyte number and phenotype will be collected as 
detailed above for the Masonic Cancer Center Translational Therapy Lab (TTL) 
along with serum (red top tubes) for measure of cytokines that can reflect 
immune activation. Donor immune cells (green top tubes) and the donor 
apheresis product will used to understand how donor cells interact with patient 
cancer and patient immune system. 
 
Flow cytometry analysis of a fraction of the PBMC will detect surface markers 
that define lymphocyte subsets (NK, NKT, B, and T cells, both CD4 and CD8), 
as well as intracellular markers that define regulatory T cells (Foxp3) and 
proliferating cells (Ki67). All remaining PBMC will be cryopreserved in 10% 
DMSO and stored in liquid nitrogen for future testing, if subject agreed to future 
storage at the time of initial consent. 
11.2.2 
Pharmacokinetics (ALTOR)  
PK analysis will be performed at Altor BioScience Corporation. Serum samples 
for PK testing will be collected on all patients. The collection schedule is 
specified in the Study Calendar. One 5 mL silicone coated (red top) tube per 
time point will be collected.  
 
The collected blood samples will be processed (centrifuge at 1000-1500 xg for 
10 minutes) at the study site and the serum portion will be frozen and shipped 
to Altor BioScience in batches upon request.  

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11.2.3 
Immunogenicity (ALTOR) 
Immunogenicity assays will be performed at Altor BioScience Corporation. 
Serum samples for immunogenicity testing will be collected on all patients. The 
collection schedule is specified in the Study Calendar. One 5 mL silicone 
coated (red top) tube per time point will be collected.  
 
The collected blood samples will be processed (centrifuge at 1000-1500 xg for 
10 minutes) at the study site and the serum portion will be frozen and shipped 
to Altor BioScience in batches upon request for evaluation using validated 
ELISA methods.  
 
12 Event Monitoring, Documentation, and Reporting 
Toxicity and adverse events will be classified and graded according to NCI's 
Common Terminology Criteria for Adverse Events V 4.0 (CTCAE) and reported 
on the schedule below. A copy of the CTCAE can be downloaded from the 
CTEP 
home 
page 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#
ctc_40). 
 
An exception to the use of CTCAE will be for the assessment of cytokine 
release syndrome (CRS). Individual adverse events which are associated with 
CRS will be graded per CTCAE; however the ultimate assessment will be made 
using a revised grading system for CRS as presented by Lee et al23 
 
CRS Revised Grading System (replaces CTCAE v4 CRS grading) 
Grade 
Toxicity Description 
Grade 1 
Symptoms are not life threatening and require symptomatic treatment only, e.g., 
fever, nausea, fatigue, headache, myalgias, malaise 
Grade 2 
Symptoms require and respond to moderate intervention - Oxygen requirement < 
40% or Hypotension responsive to fluids or low dose of one vasopressor or Grade 2 
organ toxicity 
Grade 3 
Grade 3 Symptoms require and respond to aggressive intervention - Oxygen 
requirement ≥40% or Hypotension requiring high dose  or multiple vasopressors or 
Grade 3 organ toxicity or grade 4 transaminitis 
Grade 4 
Life-threatening symptoms - Requirement for ventilator support or Grade 4 organ 
toxicity (excluding transaminitis) 
Grade 5 
Death 
Grades 2-4 refer to CTCAE v4.0 grading. 
 
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).  

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The reporting timeframes for SAEs and other reportable events are located in 
Section 12.6. 
 
Note:  throughout this section the generic term “study drug” refers to the study 
related treatment (the preparative regimen, NK cell infusion, ALT-803 
injections). 
12.1 
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.  
 
Major Deviation as defined by the Masonic Cancer Center: 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 as defined by the Masonic Cancer Center: 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. 
12.2 Event Documentation Requirements 
Due to the intentional clearing of the marrow with chemotherapy as 
preparation for the NK cell infusion, it is expected that all patients will 
experience severe depression of their blood counts and other related 
toxicities as detailed in appendix IV. Therefore, adverse event 
documentation for the purposes of this study will focus on: 
• targeted expected toxicities felt to be related to the NK cell 
infusion and/or ALT-803 – refer to worksheet in appendix V 
o Prior to chemotherapy start 
o Prior to NK cell infusion 
o 1 hour (+/- 10 min) post NK cell infusion 
o Prior to ALT-803 dose 1 
o 2 hours (± 30 min) post ALT-803 dose 1 
o 24 hours after the NK cell infusion 
o Prior to ALT-803 dose 2 
o 2 hours (± 30 min) post ALT-803 dose 2 
o Day 7 
o Prior to ALT-803 dose 3 
o 2 hours (± 30 min) post ALT-803 dose 3 
o Day 14 
• skin reactions as documented in the patient skin reaction diary 
(Appendix VI) – This form is to be completed by a member of the 
research staff while the patient is an inpatient. Each skin reaction 
diary focuses on a single injection site. That said, in this study on 
Day +5, a new skin reaction diary form is started for the most 
recent injection; however, if the Day 0 injection site reaction has 
not resolved its form continues to be completed until resolution. 
Refer to instructions in Appendix VI.  
• other adverse events not on the targeted event worksheet felt to 
be related to the NK cell infusion and/or ALT-803 
• unexpected adverse events that cannot be attributed to the 
preparative regimen or other causes (i.e. underlying disease, co-
morbidities) 
 

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After Day 14, monitoring for adverse events will become less frequent 
based on the schedule in Section 11 and only events that are unexpected 
and at least possibly related to either the NK cell infusion and/or ALT-803 
will be documented.  
 
Note: if a patient is not abiding by the standard of care study calendar 
(Section 11.1), collection of the corresponding targeted events (and 
research related samples) also may be altered or discontinued on an 
individual patient basis, as appropriate.   
12.3 SAE Documentation and Reporting Requirements 
Any event meeting the definition of a serious adverse event (SAE) 
requires documentation using the MCC SAE Report Form in OnCore. 
 
Any event that is both serious and unexpected, and at least possibly 
related to the study treatment must be reported to Masonic Cancer 
Center Affiliate Sites Manager and to Altor BioScience within 24 hours of 
knowledge. All others must be reported within 5 working days of 
knowledge. Refer to Section 12.6. 
12.4 Early Stopping Rule Events Documentation and Reporting 
Requirements 
Excessive toxicity defined as grade 4-5 non-hematologic, non-relapse 
and non-infectious toxicity (except for fevers alone) by Day 42 is 
considered an early study stopping rule event and must be reported per 
Section 12.6 using the Event Form found OnCore under the reports tab. 
 
An event that counts toward an early stopping rule does not necessarily 
constitute a SAE and should be reported as such only if they meet the 
criteria for reporting as defined in Section 12.3. 
12.5 Other Event Documentation and Reporting Requirements 
Deaths, including due to disease, will be recorded as an SAE and 
reported per Section 12.6. Deaths due to disease should be recorded as 
a Grade 5 “Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) – Other (Progressive Disease). In addition, the death date and 
cause must be reported in the patient follow-up tab in OnCore using the 
comment field in the survival status section to record the cause.  
 

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12.6 Institutional Event Reporting Table 
Individual institutional sites will be responsible for reporting any event 
meeting local reporting requirements to their institutional IRB and/or 
other research oversight committees. 
 
Event Type 
Reporting Timeframe 
Form in OnCore 
to Use 
Report to 
SAEs Requiring Expedited 
Reporting (serious, 
unexpected and at least 
possibly related to ALT-
803) 
Within 24 hours of 
knowledge 
SAE Report 
Form 
For Affiliate Sites: 
Masonic Cancer Center (MCC) 
Affiliate Sites Manager  
eorchols@umn.edu 
 
Altor BioScience at 
cancer_trial@altorbioscience.com 
 
Local institutional IRB or other 
entities per institutional policies 
and guidelines 
 
For UMN MCC: Report to the 
study’s regulatory specialist 
All other SAEs 
Not required  
n/a 
Stopping Rule Events 
Within 24 hours of 
knowledge 
Event Form 
Major Deviations 
Within 5 working days 
of knowledge 
Deviation Report 
Form 
 
12.7 MCC Reporting Requirements 
As the study sponsor, the Masonic Cancer Center has the following 
expedited reporting responsibilities for events reported in Section 12.6: 
 
 
13 Study Data Collection and Monitoring 
13.1 Data Management 
This study will report clinical data using The Online Enterprise Research 
Management Environment (OnCore®), a web based Oracle® database 
utilizing study specific electronic case report forms. Key study personnel are 
trained on the use of OnCore and will comply with protocol specific 
Agency 
Criteria for reporting 
Timeframe 
Form to 
Use 
Submission 
address/ fax 
numbers 
FDA 
 
Unexpected and fatal or unexpected and  life 
threatening suspected adverse reaction 
no later than 
7 Calendar 
Days 
MCC SAE 
Submit to FDA as 
an amendment to 
IND with a copy to 
Altor Bioscience  
at 
cancer_trial@altor
bioscience.com 
And each affiliate 
institution 
 
1) Serious and unexpected suspected adverse 
reaction or 
2)  increased occurrence of serious suspected adverse 
reactions over that listed in the protocol or investigator 
brochure or 
3) findings from other sources (other studies, animal 
or in vitro testing) 
no later than 
15 Calendar-
Days 
Masonic 
Cancer Center 
SAE 
Coordinator 
Events that count toward the early study stopping rule. 
At time of 
reporting 
Event 
Form 
mcc-
saes@umn.edu 

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instructions embedded within the OnCore. Patient demographics, patient 
specific study treatment calendars, targeted expected toxicities and other 
information required for IND annual reporting will be placed in OnCore and 
other research databases maintained by MCC IT. 
13.2 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 Study 
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.  
13.3 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 (under a locally held IND). Therefore the following requirements 
will be fulfilled: 
 
 At least quarterly review of the study’s progress by the Masonic Cancer 
Center Data and Safety Monitoring Council (DSMC). 
 The PI at each site will comply with at least twice yearly monitoring of 
the project by the Masonic Cancer Center monitoring services. 
 The Masonic Cancer Center PI will oversee the submission of all 
reportable adverse events per Section 12.7 to the Masonic Cancer 
Center’s SAE Coordinator, the University of Minnesota IRB, and the 
FDA.  
 The PI with the CTO has oversight responsibility for trial monitoring at 
affiliate sites 
 
In addition, at the time of the continuing review with the University of 
Minnesota IRB, a copy of the report with any attachments will be submitted 
to the Cancer Protocol Review Committee (CPRC). 
 
 
 

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

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CPRC #2016LS056 
correspondence in a secured facility for at least 6 years after the study file is 
closed with the IRB and FDA.  
 
Please contact the CTO before destroying any study related records. 
 
 
14 Statistical Considerations  
14.1 Study Design, Objectives and Endpoints  
The primary objective of this phase II trial is to study the potential efficacy 
of NK cells and ALT-803 to achieve a complete remission (CR or CRp) by 
Day 42 while maintaining safety. The primary endpoint, CRp is defined as 
leukemia clearance (< 5% marrow blast and no circulating peripheral blasts) 
and neutrophil recovery without platelet recovery. CR is defined as ≤5% 
blasts in the bone marrow with recovery of neutrophils and platelets.  
 
Secondary endpoints include:  
• The incidence of in vivo expansion (≥ 100 donor derived NK cells per uL 
blood) of NK cells by Day +14 
• ALT-803 associated toxicity 
• Treatment related mortality (TRM) by 6 months post-therapy 
 
The two stage design will enroll 9 patients in stage 1. If 3 or more patients 
show clearance out of 9, an additional 15 patients will be enrolled to obtain 
a more precise estimate of CR/CRp. If 10 or more out of the total 24 patients 
show clearance, this method will be considered for further investigation. 
14.2 Statistical Analysis  
The primary endpoint of clearance will be estimated by simple proportions 
with confidence intervals calculated from asymptotic standard errors. 
Secondary endpoints of in vivo expansion and various safety/toxicity 
measures will similarly be estimated with simple proportions. Cumulative 
incidence will be used to estimate the probability of treatment related 
mortality treating relapse as a competing event. 24 
 
The correlation of CR/CRp with in vivo NK cell expansion will be evaluated 
with a chi-square test. The function of adoptively transferred NK cells will 
be measured descriptively with non-parametric statistics such as median, 
range and interquartile range. 

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14.3 Sample Size 
The overall sample size of 24 patients is based on Simon’s optimal two-
stage design assuming a type-I error of 5% and 80% power.25 The null 
hypothesis or the rate considered unworthy of further investigation is 25% 
clearance. The alternative hypothesis or the rate considered worthy of 
further investigation is 50%.  
 
If we reach the second stage, the study will go on to enroll an additional 15 
patients for a total sample size of 24 patients. Based on prior enrollment in 
a similar phase I trial, we expect to accrue at least 8 patients per year. 
Therefore, we anticipate completion of enrollment within 3 years. 
14.4 Stopping Rule for Excessive Toxicity  
Excess toxicity will be monitored using an early stopping rule. The stopping 
rule was developed using Pocock stopping boundaries.26 
 
Patients with refractory AML are expected to die. Therefore, excess toxicity 
needs to be carefully evaluated. Based on current experience, grade 4-5 
non-hematologic, non-relapse and non-infectious toxicity (except for fevers 
alone) as defined by the NCI’s CTCAE version 4 is expected to be about 
10%. The goal is to construct a boundary based on excessive toxicity by 
Day 42 such that the probability of early stopping is at most 10% if the rate 
is equal to 10% and our sample size is 24. With these stipulations, the study 
will be stopped if there is excess toxicity in 2 out 3 patients, 3 out of 8 
patients, 4 out of 14 patients, 5 out of 21 patients or 6 patients at any time. 
If the actual probability of toxicity is 30% or 40%, the probability of reaching 
the boundary will be 86% and 98% respectively. 
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 

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Page 43 of 52 
CPRC #2016LS056 
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.  
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  
1. Miller JS, Oelkers S, Verfaillie C, McGlave P. Role of monocytes in the expansion of 
human activated natural killer cells. Blood. 1992;80:2221-2229. 
2. Miller JS, Verfaillie C, McGlave P. The generation of human natural killer cells from 
CD34+/DR- primitive progenitors in long-term bone marrow culture. Blood. 
1992;80:2182-2187. 
3. Pierson B, Miller J, Verfaillie B, McGlave P, Hu W-S. Population dynamics of human 
activated killer cells in culture. Biotechnology and Bioengineering. 1994;43:685-692. 
4. Miller JS, Alley KA, McGlave P. Differentiation of natural killer (NK) cells from human 
primitive marrow progenitors in a stroma-based long-term culture system: identification 
of a CD34+7+ NK progenitor. Blood. 1994;83:2594-2601. 
5. Miller JS, Klingsporn S, Lund J, Perry EH, Verfaillie C, McGlave P. Large scale ex vivo 
expansion and activation of human natural killer cells for autologous therapy. Bone 
Marrow Transplant. 1994;14:555-562. 
6. Pierson BA, McGlave PB, Hu WS, Miller JS. Natural killer cell proliferation is 
dependent on human serum and markedly increased utilizing an enriched 
supplemented basal medium. J Hematother. 1995;4:149-158. 
7. Pierson BA, Gupta K, Hu WS, Miller JS. Human natural killer cell expansion is 
regulated by thrombospondin-mediated activation of transforming growth factor-beta 
1 and independent accessory cell-derived contact and soluble factors. Blood. 
1996;87:180-189. 
8. Cervantes F, Pierson BA, McGlave PB, Verfaillie CM, Miller JS. Autologous activated 
natural killer cells suppress primitive chronic myelogenous leukemia progenitors in 
long-term culture. Blood. 1996;87:2476-2485. 
9. Pierson BA, Europa AF, Hu WS, Miller JS. Production of human natural killer cells for 
adoptive immunotherapy using a computer-controlled stirred-tank bioreactor. J 
Hematother. 1996;5:475-483. 

MT2016-05:  Haploidentical NK Cells and ALT-803 In Adults with Refractory or Relapsed AML 
 
 
 
 
 
January 22, 2019 
Page 44 of 52 
CPRC #2016LS056 
10. Pierson BA, Miller JS. CD56+bright and CD56+dim natural killer cells in patients with 
chronic myelogenous leukemia progressively decrease in number, respond less to 
stimuli that recruit clonogenic natural killer cells, and exhibit decreased proliferation on 
a per cell basis. Blood. 1996;88:2279-2287. 
11. Rosenberg SA. Karnofsky Memorial Lecture. The immunotherapy and gene therapy 
of cancer. J Clin Oncol. 1992;10:180-199. 
12. Rosenberg SA, Lotze MT, Muul LM, et al. A progress report on the treatment of 157 
patients with advanced cancer using lymphokine-activated killer cells and interleukin-
2 or high-dose interleukin-2 alone. N Engl J Med. 1987;316:889-897. 
13. Herberman R, Balch C, Bolhuis R. Lymphokine-activated killer cell activity:  
characteristics of effector cells and their progenitors in blood and spleen. Immunology 
Today. 1987;8:178-181. 
14. Maghazachi AA, Herberman RB, Vujanovic NL, Hiserodt JC. In vivo distribution and 
tissue localization of highly purified rat lymphokine-activated killer (LAK) cells. Cell 
Immunol. 1988;115:179-194. 
15. Miller J, Soignier Y, Panoskaltsis-Mortari A, et al. Successful adoptive transfer and in 
vivo expansion of human haploidentical NK cells in patients with cancer. Blood. 
2005;105:3051-3057. 
16. Cheever MA. Twelve immunotherapy drugs that could cure cancers. Immunol Rev. 
2008;222:357-368. 
17. Steel JC, Waldmann TA, Morris JC. Interleukin-15 biology and its therapeutic 
implications in cancer. Trends Pharmacol Sci. 2012;33(1):35-41.  
18. Sato N, Patel HJ, Waldmann TA, Tagaya Y. The IL-15/IL-15Ralpha on cell surfaces 
enables sustained IL-15 activity and contributes to the long survival of CD8 memory T 
cells. Proc Natl Acad Sci U S A. 2007;104(2):588-593. 
19. Zhu X, Marcus W, Xu W, et al. Novel Human Interleukin-15 Agonists. J of Immunology, 
2009, 183(6): 3598–3607. 
20. Han KP, Zhu X, Liu B, et al. IL-15:IL-15 receptor alpha superagonist complex: High-
level co-expression in recombinant mammalian cells, purification and characterization. 
Cytokine. 2011;56(3):804-810. 
21. Bachanova V, Cooley S, Defor TE, et al. Clearance of acute myeloid leukemia by 
haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein. 
Blood 2014. 
22. McKenna DH, Jr., Sumstad D, Bostrom N, et al. Good manufacturing practices 
production of natural killer cells for immunotherapy: a six-year single-institution 
experience. Transfusion. 2007;47(3):520-528. 
23. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and 
management of cytokine release syndrome. Blood. 2014;124(2):188-195.Lin DY.  
24. Lin DY.Non-parametric inference for cumulative incidence functions in competing risks 
studies. Stat Med 1997;16(8):901-10. 
25. Simon, Richard. 'Optimal Two-Stage Designs for Phase II Clinical Trials', Controlled 
Clinical Trials, 1989, Volume 10, pages 1-10. 
26. Ivanova A, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials in 
oncology. Biometrics. 2005;61:540-545. 

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CPRC #2016LS056 
Appendix I – Eligibility Checklist – Patient  
Haploidentical Donor Natural Killer (NK) Cell Infusion with Subcutaneous ALT-803 in Adults with 
Refractory or Relapsed Acute Myelogenous Leukemia (AML)  
Patient Eligibility Checklist – page 1 of 2 
Patient initials   
     
 
 
Patient ID 
-
 
 
(site code – seq #) 
 
INCLUSION CRITERIA  
A "NO" response to any of the following disqualifies the patient from study entry. 
 
 
Yes      No 
1. 
≥18 but ≤ 70 years of age 
    
 
2. 
Diagnosis of acute myeloid leukemia (AML) and meets one of the following disease criteria: 
 
Primary induction failure:   
o De novo AML - no CR after 2 or more chemotherapy induction attempts 
o Secondary AML (from MDS or treatment related): no CR after 1 or more chemotherapy induction 
attempts 
 
Relapse after chemotherapy: not in CR after 1, 2, or 3 re-induction attempts 
o Patients > 60 years of age, the 1 chemotherapy re-induction is not required  
 
Relapse after hematopoietic stem cell transplant:  
o Relapse must have occurred > 18 months after transplant 
o No re-induction required and no more than 1 re-induction attempt is allowed.  
Notes:  
1) For hypomethylating agents (i.e. decitabine, azacititdine) to count as an induction/re-induction attempt, the patient must 
have completed a minimum of 3 monthly cycles 
2) For targeting agents (i.e. sorafenib) to count as an induction/re-induction attempt, the patient must have completed a 
minimum of 1 month without attaining CR 
3) 7+3 followed by 5+2 counts as TWO induction attempts 
4) Use of hydroxyurea is permitted to control blasts until Day -3 per Section 8.7 
5) A history of AML related CNS involvement is allowed if CSF analysis is negative on 2 test dates at least 2 weeks apart 
prior to study treatment. The use of ongoing CNS maintenance therapy is allowed while on study 
 
    
 
3. 
HLA-haploidentical related donor (aged 12 to 75 years) with donor/recipient match based on a 
minimum of intermediate resolution DNA based Class I typing of the A and B locus  (at least 2/4 class 
I allele) 
    
 
4. 
Karnofsky Performance Status ≥ 60%                                         PS - 
       
    
 
5. 
Adequate organ function within 14 days of study registration (28 days for pulmonary and cardiac) 
defined as: 
Test 
Required Value 
Patient’s Value 
Date of Test Result 
serum creatinine 
≤ 2.0 mg/d 
.
  mg/d 
/
/
AST  
< 3 x upper limit of institutional normal 
value:
 u/L 
  u/L 
/
/
ALT 
< 3 x upper limit of institutional normal 
value:
 u/L 
  u/L 
/
/
oxygen saturation 
≥ 90% on room air 
 
/
/
pulmonary function (only if 
sxs or know impairment) 
>50% corrected DLCO and FEV1 
.
% 
/
/
cardiac 
LVEF ≥ 40% by echo, MUGA or MRI, 
no uncontrolled angina, severe uncontrolled 
ventricular arrhythmias, or ECG evidence of 
acute ischemia or active conduction system 
abnormalities 
.
% 
/
/
    
 

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CPRC #2016LS056 
 
Haploidentical Donor Natural Killer (NK) Cell Infusion with Subcutaneous ALT-803 in Adults with 
Refractory or Relapsed Acute Myelogenous Leukemia (AML)  
Patient Eligibility Checklist – page 2 of 2 
Patient initials   
     
 
 
INCLUSION CRITERIA  
A "NO" response to any of the following disqualifies the patient from study entry. 
 
 
 
Yes      No 
6. 
 Able to be off prednisone or other systemic immunosuppressive medications for at least 3 days 
prior to NK cell infusion (excluding preparative regimen pre-medications) 
    
 
7. 
 
Sexually active females of child bearing potential and males with partners of child bearing 
potential must agree to use effective contraception during therapy and for 4 months after 
completion of therapy 
    
 
8. 
 Voluntary written consent prior to the performance of any research related procedures 
    
 
 
EXCLUSION CRITERIA 
A "YES" response to any of the following disqualifies the patient from study entry. 
 
 
Yes      No 
9. 
 Acute leukemias of ambiguous lineage 
    
 
10.  Pregnant or breastfeeding 
    
 
11.  Active autoimmune disease requiring systemic immunosuppressive therapy  
    
 
12.  History of severe asthma and currently on systemic chronic medications (mild asthma requiring 
inhaled steroids only is eligible) 
    
 
13.  
New or progressive pulmonary infiltrates on screening chest x-ray or chest CT scan unless 
cleared for study by Pulmonary. Infiltrates attributed to infection must be stable/improving (with 
associated clinical improvement) after 1 week of appropriate therapy (4 weeks for presumed or 
documented fungal infections) 
    
 
14.  Uncontrolled bacterial, fungal or viral infections including HIV-1/2 or active hepatitis C/B - chronic 
asymptomatic viral hepatitis is allowed. 
    
 
15.  Received any investigational agent within the 14 days before the start of study treatment (1st 
dose of fludarabine)  
    
 
16.  Prior ALT-803 
    
 
 
Having obtained consent and reviewed each of the inclusion/exclusion criteria, I verify that this patient is eligible. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of enrolling investigator 
 
 
 
 
Date 
 
 
 

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CPRC #2016LS056 
Appendix II – Eligibility Checklist – Donor  
Haploidentical Donor Natural Killer (NK) Cell Infusion with Subcutaneous ALT-803 in Adults with 
Refractory or Relapsed Acute Myelogenous Leukemia (AML)  
 
Donor Eligibility Checklist – page 1 of 1 
Donor initials   
     
 
 
 
 
INCLUSION CRITERIA  
A "NO" response to any of the following disqualifies the donor from study entry. 
 
 
Yes   No 
1. 
HLA-haploidentical related donor (aged 12 to 75 years) with donor/recipient match 
based on a minimum of intermediate resolution DNA based Class I typing of the A and 
B locus (at least 2/4 class I allele).  
    
 
2. 
Body weight of at least 40 kilograms 
    
 
3. 
In general good health as determined by the medical provider 
    
 
4. 
Adequate organ function defined as: 
• 
Hematologic: hemoglobin, WBC, platelet within 10% of upper and lower limit of 
normal range of test (gender based for hemoglobin) 
 
Hepatic:  ALT < 2 x upper limit of normal, 
 
 Renal:  serum creatinine < 1.8 mg/dl 
    
 
5. 
Performance of a donor infectious disease screen panel including CMV Antibody, 
Hepatitis B Surface Antigen, Hepatitis B Core Antibody, Hepatitis C Antibody, HIV 1/2 
Antibody, HTLVA 1/2 Antibody, Treponema and Trypanosoma Cruzi (T. Cruzi) plus 
HBV, HCV, WNV, HIV by nucleic acid testing (NAT); or per current standard 
institutional donor screen – must be negative for HIV and active hepatitis B 
    
 
6. 
Not pregnant - females of childbearing potential must have a negative pregnancy test 
within 7 days of apheresis 
    
 
7. 
Voluntary written consent (and assent if donor < 18 years of age) prior to the 
performance of any research related procedure 
    
 
 
 
 
 
 
 
 
 
 
 
 
Signature of person completing eligibility checklist 
 
 
 

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Appendix III - Performance Status Scale 
 
KARNOFSKY PERFORMANCE STATUS SCALE 
Percentage 
 
100 
Normal, no complaints, no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
80 
Normal activity with effort; some signs or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or do active work 
60 
Requires occasional assistance, but is able to care for most of his/her needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled, hospitalization indicated. Death not imminent 
20 
Very sick, hospitalization necessary, active supportive treatment necessary 
10 
Moribund, fatal processes, progressing rapidly 
0 
Dead 
 
REFERENCE 
  
Karnofsky DA:  Meaningful clinical classification of therapeutic responses to anti-cancer drugs. Editorial:  Clin Pharmacol Ther 
2:709-712, 1961. 
 
 

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Appendix IV – Expected Toxicities of the Preparative Regimen 
 
Cyclophosphamide – 
Common 
Less Common 
Rare, but may be serious 
• low white blood cell count with 
increased risk of infection  
• hair loss or thinning, including face 
and body hair (usually grows back 
after treatment)  
• nausea  
• vomiting  
• loss of appetite  
• sores in mouth or on lips  
• bleeding from bladder, with blood 
in urine  
• diarrhea  
• long-term or short-term infertility 
(inability to have children) in 
women and men 
• low platelet count (mild) 
with increased risk of 
bleeding  
• darkening of nail beds  
• acne  
• tiredness  
• infection 
• fetal changes if you 
become pregnant while 
taking 
cyclophosphamide  
 
• heart problems with high doses, with chest pain, 
shortness of breath, or swollen feet 
• severe allergic reactions 
• skin rash  
• scarring of bladder 
• kidney damage (renal tubular necrosis) which can 
lead to kidney failure 
• heart damage, with trouble getting your breath, 
swelling of feet, rapid weight gain 
• scarring of lung tissue, with cough and shortness 
of breath 
• second cancer, which can happen years after 
taking this drug 
• death from infection, bleeding, heart failure, 
allergic reaction, or other causes 
 
Fludarabine - 
Common 
Less Common 
Rare, but may be serious 
• low white blood cell count with 
increased risk of infection  
• low platelet count with increased 
risk of bleeding  
• low red blood cell count (anemia) 
with tiredness and weakness 
• tiredness (fatigue)  
• nausea  
• vomiting  
• fever and chills 
• infection 
• pneumonia  
• diarrhea  
• loss of appetite 
• weakness 
• pain 
 
• numbness and tingling in hands and/or feet 
related to irritation of nerves  
• changes in vision  
• agitation  
• confusion 
• clumsiness 
• seizures 
• coma  
• cough  
• trouble breathing  
• intestinal bleeding 
• weakness  
• death due to effects on the brain, infection, 
bleeding, severe anemia, skin blistering, or other 
causes 
 
 
 
 

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Appendix V – Targeted Expected Toxicities Worksheet 
MT2016-05                                                       
 
 
CTCAE v4            Refer to Section 12.2 for time points  
 Patient Initials:  _______ Date of Assessment:  _________     Assessment Time point:  _________      
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Infusion related 
reaction (NK 
cells) 
None 
Mild transient reaction; 
infusion interruption not 
indicated; intervention not 
indicated 
Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, narcotics, 
IV fluids); prophylactic medications 
indicated for ≤ 24 hrs 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of symptoms
following initial improvement; 
hospitalization indicated for clinical 
sequelae 
Life-threatening consequences; 
urgent intervention indicated 
ALT-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 
None 
Covering < 10% body 
surface area (BSA) 
Covering 10-30% body surface 
area (BSA) 
>30% body surface area (BSA) 
Generalized exfoliative, 
ulcerative, or bullous dermatitis 
Gait Disturbance 
None 
Mild change in gait (eg, 
wide-based, limping or 
hobbling) 
Moderate change in gait (eg, wide-
based, limping or hobbling); 
assistance device indicated;  
limiting instrumental ADL 
Disabling; limiting self care ADL 
……………………… 
 
 
Person Completing Form:  
 
 
 
 
 
 
ADL = activities of daily living 
 
 

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Appendix VI – ALT-803 Injection Site Reactions Diary 
 
 
The Diary is to be completed by the patient as a self-assessment in association with each dose of ALT-803.  
 
A new diary must be started for each ALT-803 injection. If the previous injection reaction has not resolved, continue to 
collect information on its diary based on the days from that injection. In this study, the Day 5 post-injection for the Day 0 
injection will be the same date as date of injection for the Day +5 injection and both forms will be completed assessing the 
form’s targeted injection site. If at Day 6 post-injection, an injection site reaction is still present continue to collect data for 
items 1-4 daily until the reaction resolves.. 
 
 
For inpatients, the diary is completed by study personnel. 
 

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