IL-15 Super Agonist ALT-803 to Treat Relapse Of Hematologic Malignancy After Allogeneic Stem Cell Transplantation
Phase: PHASE1
Conditions: Acute Myelogenous Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), Myelodysplastic Syndromes (MDS), Lymphoma, Myeloma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML)
Sponsor: Masonic Cancer Center, University of Minnesota

 
 
Masonic Cancer Center, University of Minnesota  
Cancer Experimental Therapeutics Initiative (CETI) 
 
 
 
 
IL-15 Super Agonist ALT-803 to Treat Relapse Of Hematologic 
Malignancy After Allogeneic Stem Cell Transplantation 
CPRC #2012LS023 
HM2013-12  
IND 119578 
 
University Of Minnesota 
 
Principal Investigator/IND Sponsor: 
Jeffrey S. Miller, MD 
 
Co-Investigators: 
Bruce Blazar, MD 
Sarah A. Cooley, MD 
Celalettin Ustun, MD 
David H. McKenna, Jr., MD 
 
Biostatistician: 
Todd E. De For, MS 
 
 
 
Participating Affiliate Institutions (PI): 
Washington University (Rizwan Romee, MD) 
University of Pennsylvania (David L. Porter, MD) 
 
 
 
 
 
 
Version Date: 
April 12, 2016 
 
 
 
 
 
 
Confidential 
 
 

 
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CPRC #2012LS023 
PI Contact Information 
Site 
Contact Information 
Role 
Masonic Cancer Center, 
University of Minnesota 
Jeff Miller, MD 
Division of Hematology/Oncology/Transplantation 
420 Delaware Street SE  MMC 806 
Minneapolis, MN 55455 
Phone : 612-625-7409 
Email : mille011@umn.edu 
Fax : 612-626-4915 
Study PI/ 
IND Sponsor 
Washington University 
Rizwan Romee, MD 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue 
Campus Box 8007 
St. Louis, MO  63110 
Site PI 
University of 
Pennsylvania 
David L. Porter, MD 
Abramson Cancer Center 
Perelman Center for Advanced Medicine, West Pavilion, 2nd Floor 
3400 Civic Center Boulevard 
Philadelphia, PA 19104 
Site PI 
 
Refer to the study’s Affiliate Manual for a complete list of study personnel contact information. 
 
 

 
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CPRC #2012LS023 
Revision History 
 
Revision 
# 
Version 
Date 
Revision Details 
Consent 
Revision 
 
03/29/2013 
Original  
n/a 
 
04/18/2013 
In response to CPRC stips; original to IRB  
n/a 
 
07/29/2013 
Original to FDA 
n/a 
 
09/23/2013 
In response to FDA review – not submitted to the IRB:   
Section 6.2.1.1 – refine the definition of dose limiting toxicity to 
include grade 3 hypotension that persists for > 4 hours, fever 
that persists > 24 hours (the definition of grade 4), and nausea 
or vomiting that persists for > 24 hours despite medical 
intervention; 
Schema and Section 11.4 – Add an early study stopping rule 
for mortality regardless of cause at day 60 after relapse and 
modify the excessive toxicity stopping rule definition to read 
grade 3 to 4, previously grade 3 to 5 non-hematologic, non-
relapse and non-infectious toxicity (except for fevers alone) 
events; 
Sections 4.9 and 6.2 Monitoring section – further clarify 
monitoring requirements and admission requirement if >20% 
change in baseline vital signs 
Synopsis and Sections 6.2.1 and 11.1 – add that at least 72 
hours must separate the 2nd and subsequent patients in a 
dose level (the 1st patient in a dose level must receive a 
minimum of 2 doses before the 2nd patient is enrolled) 
n/a 
1 
09/25/3013 
In response to FDA review, submitted to IRB: 
Synopsis, Schema, Sections 6.2 and 11.1:  replace “treatment 
related” with ”treatment-emergent” when defining DLT;  
Section 9.1 add definition treatment-emergent adverse event; 
Section 6.2 – require 1st dose to be given as an inpatient 
however; if the first dose is well tolerated subsequent doses 
may be administered in an outpatient setting;  
Section 9.2 – adjust targeted toxicity time points to match 
dose 1 as inpatient; 
Appendix V – add nausea and vomiting 
Change infusion rate of ALT-803 from over 2-5 min to over 5-
10 mins throughout protocol 
n/a 
2 
11/15/2013 
synopsis, sections 4.8 and 6.1, eligibility checklist – change 
time off immunosuppressants before dose of ALT-803 from 30 
days to 14 days; 
section  6.5 – clarify use of hydroxyurea is permitted during 
the study as indicated to control blasts count 
section 7.2 – reduce blood volume for research related 
Immunogenicity test from 10ml to 5 ml per time point   
yes 
3 
12/03/2013 
section 6.2 – increase fever threshold for admission from 
100.5° to 102.3° as a trigger for admission to correspond with 
CTCAE v4 grading categories 
no 

 
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CPRC #2012LS023 
Revision 
# 
Version 
Date 
Revision Details 
Consent 
Revision 
section 6.5 – allow topical steroid cream 
section 7.1 – add a footnote allowing several baseline tests to 
be done within 30 days of study registration in part to be 
consistent with eligibility criteria section 4.7; 
section 7.1 – clarify what is required for the neuro exam 
 other minor edits 
 
01/13/2014 
interim version – emailed to the FDA for preliminary review  
section 6.2.1 –expand dose cohort 1 to six patients total to 
gain further experience before escalating to dose cohort 2 as 
planned 
section 6.2.1 – add a 48 hour timeframe to the definition of 
dose limiting toxicity, eliminate exceptions that are not 
applicable with new definition 
section 6.2 – admission to the inpatient unit will be required if 
any of the criteria occur (grade 3 fever, decreased 02 sat,etc.) 
and are present at the end of the 6 hour observation period 
n/a 
4 
02/10/2014 
Based on FDA’s response to the proposed 01/13/2014 
changes, also incorporates changes from WU’s initial review: 
• schema, section 6.2.1 –expand dose cohort 1 to six 
patients total to gain further experience before escalating to 
dose cohort 2 as planned schema  
• schema, sections 6.2.1.1, 11.1 – revise and simplify 
definition of DLT 
• section 4.15, checklist – insert new exclusion criteria 
prohibiting concurrent chemotherapy (except hydroxyurea) 
or IL-2 therapy or anticipated need during the study 
treatment and for 1 week after the last dose of ALT-803 
• section 6.2 – add the caveat to the criteria for admitting 
patients “and is still present at the end of the 6 hour 
observation” to avoid admissions for isolated events that 
quickly resolve (i.e. fever, hypotension) 
• section 6.2 – clarify treatment breaks 
• section 6.5 – clarify use of beta-blockers during ALT-803 
section 8.4 – clarify stability testing  
yes 
5 
05/13/2014 
synopsis and section 1.2 – clarify acute GVHD by 4 weeks 
after the last dose of ALT-803 and delete late acute/chronic 
GVHD from the study endpoint  
section 7.1 and 6.7 – revise x chart for patients who have no 
benefit from ALT-803 and/or begin a new treatment – in 
general disease evaluations will not be required once no 
benefit is confirmed with follow-up ending at 4 weeks after the 
last dose of ALT-803.    
section 7.2 – add a 3 day post dose 1 research sample 
collection, clarify research samples are drawn while during 
treatment (even weeks with dose delays); add 1 more PK 
sample and adjust times 
section 7.2 – clarify day 5 research samples will only be done 
at UMN (Friday collection) 
yes 

 
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Revision 
# 
Version 
Date 
Revision Details 
Consent 
Revision 
section 4.21 and section 4.22 – add “known” before hepatitis 
and HIV 
section 6.2 – paragraph beginning with “Four to six hours after 
discharge” delete last sentence as it makes no sense. 
Section 11.3 – delete ‘patients whose follow-up ends prior to 
day 42’ from patient replacement criteria 
section 11.4 – update stopping rule calculations 
6 
04/28/2015 
Through-out protocol:  change ALT-803 administration route 
from IV to SQ while retaining other aspects of the study design 
(dose escalation plan, treatment schedule, accrual and 
endpoints). Begin SQ enrollment at the current IV dose level 3 
to ensure safety 
Synopsis/Schema, sections 6.2, 7 and 9:  Allow up to 3 
treatment cycles of ALT-803 (4 weekly treatments followed by 
a minimum of 2 weeks rest) in patients with stable disease 
and no unacceptable toxicity 
Schema, sections 4.24 and 7.1: Permit patients who received 
IV treatment to re-enroll as a “new” enrollment in the SQ 
cohort and allow to receive up to 3 additional cycles of ALT-
803 
Synopsis/Schema, section 7:  shorten follow-up time from 5 
years to 2 years 
Schema, sections 6.2.1.1, and 11: DLT and early stopping rule 
– redefine GVHD timeframe to account for up to 3 treatment 
cycles – previously based on time from last dose, now within 6 
weeks after the 1st dose, updated secondary objective 
Correct section 4.1 and appendix I – MDS was inadvertently 
not included in the list of eligible disease in the inclusion 
criteria 
Section 10 – update to current U of MN IRB reporting 
requirements 
yes 
7 
06/26/2015 
Minor clarifications based on CPRC review: 
Schema page , table footnote for 3a: correct dose level as 
3 and add that 3 to 6 patients will be enrolled at this level 
Synopsis, section 11.3: clarify enrollment numbers for the 
dose finding phase   
Other edit: appendix V – add febrile neutropenia 
Correction of header, Appendix IV (table of contents and 
appendix IV) 
no 
8 
04/12/2016 
Enroll a total of 6 patients in level 4 (ALT-803 10 mcg/kg) 
despite no dose limiting toxicity in the 1st patients treated at 
this dose level in order to collect additional toxicity data. The 
Synopsis/Schema and sections 3, 6, and 11 are updated 
Reduce the ALT-803 given at levels 5 and 6 from 20 and 30 
mcg/kg to 15 and 20 mcg/kg to increase safety as it was 
questioned if doubling the dose with each dose level change 
was excessive 
Change duration of formal follow-up from 2 years to 1 year 
yes 

 
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Revision 
# 
Version 
Date 
Revision Details 
Consent 
Revision 
Delete re-enrollment option for patients treated with IV ALT-
803 as no eligible patients remain  
Revisions related to skin rash seen in association with 
subcutaneous route of administration 
• Section 6.2 – add a proactive skin rash management plan 
initiating oral diphenhydramine 1 day prior to and 
continuing for 2 days after each ALT-803 dose plus a 
histamine given on treatment day  
• 
Section 6.2.2.1 – add “grade 3 skin rash not requiring 
systemic steroid therapy” to the list grade 3 toxicities 
that do not count toward DLT  
• 
Section 6.3.2 – add a skin rash section under 
Management of Selected Toxicity  
• 
Section 8.8 – ALT-803 Toxicity – add information 
regarding skin rash with SQ administration 
Updates to protocol to reflect other ALT-803 protocols (this 
protocol served as 1st in humans when written in 2013 and was 
written very conservatively) 
• 
Section 3 – Study design – remove rationale for outpatient 
treatment except keeping details of required stay during 
cycle 1 – remains mandatory during dose escalation 
• 
Section 4.8 and appendix I – delete dedicated caregiver 
requirement from inclusion criteria, change stay after last 
dose from 48 hours to 24 hours for 1st cycle only 
• 
Sections 6.2 and 8.2 – remove reference to caregiver and 
delete follow-up phone call 4 to 6 hours after discharge 
from clinic on each treatment day 
• 
Section 8.8 – update expected toxicity to match other ALT-
803 studies sponsored by Altor – study was initially written 
as 1st in humans and used expected side effects based on 
IL-2 related toxicity  
Synopsis, Section 11.3 – extend planned enrollment period 
Section 4.7, 7.1, and appendix I – delete normal TSH as 
thyroid dysfunction is not associated with diseases under 
treatment, delete baseline PFTs 
Section 7.2 – revise to clarify which samples are drawn during 
cycle 1 only and those samples drawn during all treatment 
cycles 
Appendix III – add response criteria for MDS (previously 
missing) 
Minor clarifications and edits including: 
• 
Sections 9.2 and 9.4 – edit for clarity and to better define 
toxicity monitoring and documentation 
• 
Section 9.3 – simplify affiliate required expedited reporting  
• 
Section 10.4 – update link to the Cancer Center’s DSMP, 
update language to current template 
• 
Appendix V – delete creatinine PI signature line from TT 
form 
 

 
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TABLE OF CONTENTS 
 
Synopsis ..................................................................................................................................................... 9 
Schema .................................................................................................................................................... 11 
1.0 
Objectives ..................................................................................................................................... 13 
1.1 
Primary .................................................................................................................................... 13 
1.2 
Secondary Objectives ............................................................................................................. 13 
1.3 
Correlative Objectives ............................................................................................................. 13 
2.0 
Background and Significance ....................................................................................................... 13 
2.1 
Introduction ............................................................................................................................. 13 
2.2 
Relapse After Allogeneic Stem Cell Transplantation .............................................................. 13 
2.3 
Donor Lymphocyte Infusion After Relapse ............................................................................. 15 
2.4 
Interleukin-15 (IL-15) ............................................................................................................... 15 
2.4.2 rhIL-15 Experience at the University of Minnesota ................................................................. 16 
2.5 
ALT-803 .................................................................................................................................. 16 
2.6 
ALT-803 by Subcutaneous Injection (effective with the April 2015 protocol revision) ............ 17 
3.0 
Study Rationale ............................................................................................................................ 18 
4.0 
Patient Selection .......................................................................................................................... 20 
5.0 
Registration/Dose Assignment Procedures ................................................................................. 22 
5.1 
Registration and ALT-803 Dose Level Assignment ................................................................ 22 
5.2 
Patients Who Are Registered and Do Not Receive Study Treatment .................................... 23 
6 
Treatment Plan ................................................................................................................................. 23 
6.1 
At the Time of Relapse............................................................................................................ 23 
6.2 
ALT-803 Administration........................................................................................................... 23 
6.3 
Management of Selected, Expected Adverse Events ............................................................. 29 
6.4 
Supportive Care ...................................................................................................................... 30 
6.5 
General Concomitant Medications Guidelines ........................................................................ 30 
6.6 
Duration of Treatment ............................................................................................................. 31 
6.7 
Duration of Study Participation ............................................................................................... 32 
7 
Clinical Evaluations and Procedures ............................................................................................... 32 
7.1 
Standard of Care Clinical Evaluations .................................................................................... 33 
7.2 
Research Related Evaluations ................................................................................................ 34 
8 
ALT-803 Formulation, Supply, and Potential Toxicity ...................................................................... 37 
8.1 
Formulation and Composition ................................................................................................. 37 
8.2 
Structural Formula ................................................................................................................... 38 
8.3 
Storage and Handling ............................................................................................................. 38 
8.4 
Stability .................................................................................................................................... 38 
8.5 
Agent Ordering and Agent Accountability ............................................................................... 38 
8.6 
Study Drug Preparation and Administration ........................................................................... 39 
8.7 
Agent Inventory Records......................................................................................................... 39 
8.8 
Toxicity .................................................................................................................................... 39 
9 
Adverse Event Documentation and Reporting ................................................................................. 40 
9.1 
Definitions ............................................................................................................................... 40 
9.2 
Adverse Event Monitoring and Documentation ...................................................................... 42 
9.3 
Affiliate Event Reporting to the U of MN MCC ........................................................................ 43 
9.4 
Required Reporting by the U of MN to the U of MN IRB, the FDA, and Altor BioScience ..... 45 
10 Study Status Updates, Data Collection, and Monitoring .................................................................. 45 
10.1 Study Status Updates ............................................................................................................. 45 
10.2 Data Management ................................................................................................................... 46 

 
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10.3 Case Report Forms ................................................................................................................. 46 
10.4 Data and Safety Monitoring Plan (DSMP) .............................................................................. 46 
10.5 Monitoring ............................................................................................................................... 47 
10.6 Record Retention .................................................................................................................... 47 
11 Statistical Considerations ................................................................................................................. 47 
11.1 Dose Finding Phase ................................................................................................................ 47 
11.2 The Extended Phase ............................................................................................................... 50 
11.3 Enrollment Plan ....................................................................................................................... 51 
11.4 Stopping Rules ........................................................................................................................ 51 
Because of severity of the diseases, ................................................................................................ 51 
11.5 Statistical Analysis Plan .......................................................................................................... 52 
12 Conduct of the Study ........................................................................................................................ 52 
12.1 Good Clinical Practice ............................................................................................................. 52 
12.2 Ethical Considerations ............................................................................................................ 52 
13 References ....................................................................................................................................... 53 
Appendix I –Patient Eligibility Checklist ................................................................................................... 55 
Appendix II – Karnofsky PS and NYHA Classification ............................................................................. 58 
Appendix III – Disease Specific Response Criteria ................................................................................. 59 
CHRONIC MYELOGENOUS LEUKEMIA (CML) RESPONSE CRITERIA ...................................... 59 
ACUTE MYELOGENOUS LEUKEMIA (AML) RESPONSE CRITERIA ........................................... 60 
ACUTE LYMPHOCYTIC LEUKEMIA (ALL) RESPONSE CRITERIA .............................................. 61 
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) RESPONSE CRITERIA ......................................... 62 
REVISED RESPONSE CRITERIA FOR MALIGNANT LYMPHOMA (Cheson, 2007) .................... 64 
MULTIPLE MYELOMA RESPONSE CRITERIA .............................................................................. 65 
MDS RESPONSE CRITERIA ........................................................................................................... 67 
Appendix IV - GvHD Scoring.................................................................................................................... 68 
Appendix V –Targeted Toxicity Form (CTCAE 4.0) ................................................................................. 69 
 
 
 

 
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Synopsis 
Study 
Design: 
This is a multi-center, phase I/II clinical trial for patients who have relapsed more than 60 
days after allogeneic transplant for a hematologic malignancy.  The study consists of two 
phases.  The dose finding phase is a modified version of a phase I trial and the extended 
phase is a modified version of a phase II trial. 
 
The primary objective of the dose finding phase is to determine the maximum tolerated, 
minimum efficacious dose (MTD/MED) of a interleukin-15 (IL-15) super agonist complex 
(ALT-803) when given once weekly for 4 weeks.  Effective with the April 2015 revision, 
patient may receive up to 3 treatment cycles.  The study will follow a standard 3+3 design 
of dose escalation for toxicity with an added feature of stopping early if biologic activity is 
detected using absolute lymphocyte count as a surrogate marker. Up to six dose levels of 
ALT-803  will be tested to determine the MTD/MED.   
 
The primary goal of the extended phase is to study the potential efficacy of ALT-803 in 
this patient population.  Efficacy will be measured using rates of remission induction.  An 
optimal Simon’s two-stage design will be used in this phase.  Stage 1 will enroll 14 
patients, including the 6 patients treated at the MTD/MED during the dose finding phase.  
If 3 or more of these 14 patients respond to ALT-803, the trial will move to stage 2 and 
enroll an additional 23 patients.  
 
The hypothesis is that ALT-803 will enhance allogeneic immunity through NK cells and 
CD8+ T cells capable of mediating a response without the need for lymphodepleting 
chemotherapy.  A secondary aim is to achieve this goal without being limited by severe 
GVHD side effects. 
 
Follow-up for overall response, toxicity, and survival through 1 year from the 1st dose of 
ALT-803. 
 
Primary 
Objective: 
Dose finding phase:  To determine the maximum tolerated, minimum efficacious dose 
(MTD/MED) of ALT-803 when given weekly for 4 doses in patients with a hematologic 
malignancy who have relapsed after allogeneic transplant 
 
Extended Phase:  To study the potential efficacy of ALT-803 in this patient population as 
measured by the rates of remission induction 
 
Secondary 
Objectives: 
• 
To evaluate the safety of the ALT-803 when administered on this schedule 
• 
To determine the incidence of acute GVHD within 6 weeks after the 1st dose of ALT-803
 
Correlative 
Objectives: 
• 
To monitor the number and function of NK cells, T cells, and T regulatory cells pre- 
and post-therapy 
• 
To quantify serum levels of ALT-803 and ALT-803 antibodies 
 
Eligible 
Diseases: 
• 
Relapse ≥ 60 days post allogeneic stem cell transplantation for one of the following 
hematologic malignancies: 
o 
Acute myelogenous leukemia (AML) 
o 
Acute lymphoblastic leukemia (ALL) 
o 
Myelodysplastic syndromes (MDS) 
o 
Lymphoma 
o 
Myeloma 
o 
Chronic Lymphocytic Leukemia (CLL) 
o 
Chronic myelogenous leukemia (CML) – failed or refused TKI and DLI 
 
 

 
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Inclusion 
Criteria: 
• 
Minimum of 10% donor cell chimerism 
• 
Age ≥ 18 years of age, Karnofsky performance status ≥ 70% 
• 
Adequate renal, hepatic, and cardiac function 
• 
Off prednisone and other systemic immunosuppressants for at least 14 days prior to 
1st dose of study drug 
• 
No indicators of acute or chronic GVDH requiring systemic treatment 
• 
Prior DLI permitted but must be at least 30 days between DLI and 1st dose of ALT-803 
Post-transplant lymphoproliferative diseases are not eligible 
 
Endpoints: 
Dose Finding Phase:  the Maximum Tolerated Dose (MTD) and/or Minimum Efficacious 
Dose (MED) for ALT-803 will be identified based on severity of treatment-emergent 
toxicity using CTCAE version 4 and/or biologic activity using a surrogate marker of 
absolute lymphocyte count (ALC)  
 
Extended Phase:  Potential efficacy will be measured by the rates of remission induction 
based on bone marrow examination 1 and 3 months after the last dose of ALT-803 
 
Sample Size: 
Dose Finding Phase:   16 patients were enrolled in the IV dosing cohort testing dose 
levels 1 through 4.  With the change to SQ injection and enrollment re-starting at dose 
level 3 as required; the minimum additional enrollment during the dose-escalation phase 
will be 6 with a maximum additional 24 patients (6 each at the 4 remaining doses). 
 
Extended Phase:  stage 1 – 14 patients (includes the 6 patients treated at the MTD/MED 
during the dose finding phase), if stage 2 is activated an additional 23 patients will be 
required  
 
Enrollment 
Enrollment to dose level 1 is limited to University of Minnesota patients. 
Affiliate sites may begin enrollment with dose level 2.   
 
Enrollment is expected to take 24-36 months if all study components are completed. 

 
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Schema 
                                1 treatment cycle 
 
 
                                                                                            final                            if no progression               follow all 
                                                                                            treatment 
           follow for 12 months          for survival  
                                                                   bm bx*              visit                            from 1st dose                     for 1 year 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day            1       8       15      22    29    36                 30 days  
              every 3                           at 1 year   
                                                                                                        after last ALT-803      months    
 
    
 
*Patients with stable disease and meet the criteria in section 6.2 may receive up to 3 treatment cycles 
 
Dose Finding Phase (refer to section 6.2.1):  
          ALT-803 at assigned dose SQ on days 1, 8, 15, and 22 of a 6 week cycle – up to 3 treatment cycles 
may be given in absence of disease progression.  Refer to section 6.2 for additional re-treatment 
requirements 
 
Dose escalation will stop for toxicity (MTD) or earlier if the efficacy goal (MED) of an absolute lymphocyte 
count (ALC) of > 25,000 cells/μl in ≥ 2 of 3 patients (or ≥ 4 of 6) within a cohort is achieved. 
Dose Level 
ALT-803  
Weekly Dose 
Route of 
Administration 
Number of 
Patients 
Enrolling 
Institutions 
1 
1 microgram/kg 
IV 
6* 
U of MN 
2 
3 microgram/kg 
IV 
3 to 6 
 
U of MN and 
affiliates 
3 
6 microgram/kg 
IV 
3 to 6 
3a# 
6 microgram/kg 
SQ 
3 to 6 
4 
10 microgram/kg 
SQ 
6& 
5 
15 microgram/kg 
SQ 
3 to 6 
6 
20 microgram/kg 
SQ 
3 to 6 
* with the Feb 10, 2014 protocol version - dose level 1 was expanded to 6 patients total after which 
dose escalation will continue as planned 
# with the April 28, 2015 protocol version ALT-803 dosing was changed from IV to SQ and dose 
level 3 was repeated with an additional 3-6 patients to confirm safety with the new route of 
administration – in the unlikely event of dose de-escalation to level 2 or 1, the route of administration 
will be SQ 
&with the April 2016 protocol version Dose Level 4 (10 mcg/kg) was expanded to enroll 6 patients 
despite the absence of DLT to gain further toxicity information before making the decision to continue 
dose escalation or declare level 4 the optimal dose and proceed to the extended phase. Dosing 
cohorts 5 and 6 were lowered to increase safety. 
Within a dose level, the 1st patient must receive a minimum of 2 doses before additional patients are 
enrolled. The 1st dose for subsequent patients within a dose level must be separated by at least 72 
hours.  Dose escalation to the next level cannot proceed until all patients in the current level have 
received at least 3 out of 4 planned doses of ALT-803. 
 
Dose Limiting Toxicity (DLT) is defined as (during first treatment cycle only): 
• any treatment-emergent grade 3 non-hematologic toxicity lasting more than 48 hours (refer to section 
6.2.1.1 for full definition) 
• any treatment-emergent grade 4 or 5 non-hematologic toxicity of any duration 
• grade III or IV acute GVHD within 6 weeks after the first ALT-803 dose  
 
Maximum Tolerated Dose (MTD) is defined as the dose level where ≤ 1 out of 6 patients has DLT during 
the first treatment cycle 

 
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Minimum Efficacious Dose (MED) as a measure of biologic activity using absolute lymphocyte count 
(ALC) as a surrogate marker is defined as an ALC of > 25,000 cells/μl that is sustained for more than 24 
hours in ≥ 2 of 3 patients (or ≥ 4 of 6) within a dose cohort.   
 
Extended Phase: 
          ALT-803 at MTD/MED from Dose Finding Phase SQ on days 1, 8, 15, and 22 of a 6 week cycle  
       Up to 3 treatment cycles may be given if no disease progression or unacceptable toxicity 
 
Stage 1:  Enroll 8 additional patients at the MTD/MED dose 
Activate Stage 2 if ≥ 3 responses are seen in the 1st 14 patients treated at MTD/MED (includes the 6 
patients treated during the dose finding phase) 
 
Stage 2:  Enroll an additional 23 patients.   
 
Extended Phase Early Study Stopping Rules: 
• excessive toxicity defined as treatment related grade 3-4 non-hematologic, non-relapse, non-
infectious events (except fever alone) 
• overall mortality at day 60 post relapse 
• grade III or IV acute GVHD within 6 weeks of the first dose of ALT-803 
 
 
 
 

 
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1.0 
Objectives 
1.1 Primary 
Dose Finding Phase:  To determine the maximum tolerated, minimum 
efficacious dose (MTD/MED) of ALT-803 when given weekly for 4 doses in 
patients with a hematologic malignancy who have relapsed after 
allogeneic transplant 
 
Extended Phase:  To study the potential efficacy of ALT-803 at the dose 
identified in the dose finding phase in this patient population as measured 
by rates of remission induction 
1.2 Secondary Objectives 
• To evaluate the safety of ALT-803 when administered on this schedule 
• To determine the incidence of acute GVHD within 6 weeks after the 
first dose of ALT-803 
1.3 Correlative Objectives 
• To monitor the number and function of NK cells, T cells, and T 
regulatory cells pre and post therapy 
• To quantify serum levels of ALT-803 and ALT-803 antibodies 
 
 
2.0 
Background and Significance 
2.1 
Introduction 
Allogeneic bone marrow transplantation results in an approximately 40-
60% disease-free survival in patients with acute or chronic leukemias and 
myelodysplastic syndromes.  The effectiveness of allogeneic bone marrow 
transplantation depends in part on ablation of the malignant clone with a 
preparative regimen and reinfusion of benign stem cells to restore normal 
hematopoiesis.  However, it is well established that the success of 
allogeneic transplantation is in part mediated by a graft-versus-leukemia 
effect induced by donor-derived T lymphocytes or NK cells.  This graft-
versus-leukemia effect is usually associated with acute and/or chronic 
graft-versus-host disease which are also mediated by donor-derived 
lymphocytes.  In patients with leukemia and multiple myeloma there is a 
statistically significant correlation between the occurrence of acute graft-
versus-host disease and freedom from relapse (1-4). 
2.2 
Relapse After Allogeneic Stem Cell Transplantation 
The effectiveness of bone marrow transplantation for diseases such as 
CML, AML, MDS and ALL depends on the disease and the disease stage 
at the time of transplant.  Relapse rates in patients undergoing 
transplantation with unmodified allogeneic donor grafts vary and are 

 
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approximately 15% for good risk patients and fully ablative preparative 
regimens and up to 50% for advanced leukemias and reduced intensity 
preparative regimens.  Relapse rates are higher in those patients who 
receive lymphocyte depleted grafts, especially for CML where relapse 
rates are as high as 70% at 3 years (1-3).  CLL numbers are small and 
often are not separated out from other miscellaneous lymphoid 
malignancies in the literature, however there definite long-term survivors 
after allogeneic transplant.  If a patient relapsed after hematopoietic cell 
transplantation, prior to lymphocyte infusions, very few effective therapies 
were available. 
 
In multiple myeloma, in a study of 17 patients with advanced stage 
disease, the rate of complete remission increased to 73% after a dose-
reduced allograft increase from 18% after cytoreductive autografting.  (5) 
For patients with AML and ALL, a second course of reinduction 
chemotherapy can be given with variable results.  Between 12% and 70% 
of patients will achieve a second complete remission.  However, the 
median survival of patients undergoing additional chemotherapy for 
relapse post-transplant in acute leukemia varies between 5.5 and 12 
months.  Long-term disease-free survival is very unlikely. 
 
 
Table 1: Treatment for Relapse Post-Transplant - AML/ALL: Chemotherapy 
Group (reference) 
 
Number 
patients 
CR 
Median 
Survival 
Westminster (ALL/AML) 
88 
7 (12%) 
7 months 
Minnesota (ALL) (6) 
53 
29 (56%) 
5.5 months 
EBMTR (ALL/AML) (7) 
74 
32 (40%) 
12 months 
Seattle (AML) (8) 
62 
20 (30%) 
6 months 
Seattle (ALL) (8) 
94 
52 (65%) 
10.5 months 
 
A second marrow transplant can be performed for AML, ALL, CML, or 
MDS but with significant mortality.  Several studies demonstrate that 
continuous complete remission for greater than one year varies between 
10 and 50%.  A second bone marrow transplant is associated with very 
high early mortality (between 20 and 55%).  IBMTR data evaluating 
second sibling transplants in 114 patients demonstrate that leukemia-free 
survival was 7% if undergoing transplantation within 6 months of first 
transplantation and 28% if second transplantation occurred greater than 6 
months after the first (9).  Hospitalizations for second transplants are 
lengthy, complicated and costly. 
 
Table 2: Treatment for Relapse Post-Transplant - AML/ALL/CML: Second Transplant 
Group (reference) 
Number 
patients 
CCR  
(> 1 year) 
Acute Mortality 
 (< 100 days) 
Minnesota 
23 
38% 
39% 
Seattle (10) 
77 
15% 
30% 
MD Anderson 
17 
12% 
24% 
EBMTR (11) 
90 
12% 
48% 
Hopkins (12) 
23 
39% 
--- 

 
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Group (reference) 
Number 
patients 
CCR  
(> 1 year) 
Acute Mortality 
 (< 100 days) 
Sidney 
9 
11% 
44% 
Duarte 
5 
20% 
20% 
Goldman (13) 
16 
50% 
31% 
2.3 
Donor Lymphocyte Infusion After Relapse 
Donor lymphocyte infusions (DLIs) can produce long lasting remissions 
after relapse for chronic myelogenous leukemia (CML), although it has 
proven less effective in non-CML blood disorders.  As there are few 
treatment options available after relapse in this patient population, donor 
lymphocyte infusion (DLI) using the same donor as transplant or a close 
relative as the cell source is the fallback standard of care.  Based on our 
experience, using a lymphodepleting chemotherapy compared to no 
lymphodepletion improved complete remission rate and improved 1 and 2 
year survival in those who achieved a CR; however the incidence of grade 
3-4 acute GVHD lead to morbidity (14).  By reducing the DLI cell dose, the 
incidence of severe acute GVHD dropped the incidence of severe GVHD 
(25% for the lower cell dose vs 66% for the higher cell dose) while the CR 
rates were similar (45% and 53% respectively) and long term DFS is still 
limited by subsequent relapse (15).  
2.4 
Interleukin-15 (IL-15) 
Interleukin-15 (IL-15) is a cytokine and growth factor capable of expanding 
activated T cells and NK cells. By broad consensus, the NCI 
Immunotherapy Workshop (2007) ranked IL-15 as the #1 agent with “high 
potential for immunotherapy.”(16). Based on preclinical non-human 
primate and early phase clinical trial data, IL-15 regimens can 
unquestionably be designed to prospectively and reproducibly increase T-
cell and NK-cell counts. Increased T-cell and NK-cell counts are likely to 
expand the autochthonous T-cell response present in some patients with 
melanoma (17;18) and to augment the efficacy of other immunotherapy 
modalities. Other immune modalities that might work together with IL-15 
include T-cell therapy, cancer vaccines, monoclonal antibody treatment, 
therapy with other immune response modifiers/T-cell growth factors such 
as IL-7, blockers of the programmed death 1 (PD-1)/programmed death 
ligand-1 axis and cytotoxic T-lymphocyte antigen-4 (CTLA-4), and 
agonistic antibodies to CD40 or OX40 costimulatory molecules. 
 
2.4.1 rhIL-15 
The NCI Biological Resource Branch has manufactured E. coli-
expressed recombinant human IL-15 (rhIL-15), and testing is currently 
underway. 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. In non-
human primates, NCI rhIL-15 was most effective when administered by 
continuous IV infusion. To a lesser extent, daily subcutaneous injection 

 
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of NCI rhIL-15 was also effective at expanding the number of 
peripheral blood activated T cells and NK cells. These data strongly 
imply that low-dose continued presence of IL-15 in serum will be most 
effective at expanding T cells and NK cells.  
2.4.2 rhIL-15 Experience at the University of Minnesota 
To date 10 patients have treated on our investigator initiated, dose 
escalation, single institution clinical trial of intravenous rhIL-15 given 
daily for 12 days beginning the morning after the administration of 
haploidentical donor NK cells in adults with relapsed or refractory AML. 
This is after high dose cyclophosphamide and fludarabine but in a non-
transplant setting.  Initially 5 dose levels were proposed (0.25 mcg/kg 
to 3 mcg/kg daily for 12 doses); however; after one dose limiting 
toxicity (DLT - diffuse alveolar hemorrhage leading to respiratory 
compromise) and prolonged neutropenia experienced in 2 out of 4 
patients at dose level 3 (1 mcg/kg/day), and after discussion with the 
FDA, dosing was dropped down to half way between dose level 2 and 
3 (0.75 mcg/kg/day).  This decision was based on no DLTs at dose 
level 2 and NK cell expansion at dose level 3. Enrollment continues at 
the 0.75 mcg/kg/day dose level with chills, febrile neutropenia and 
hypertension the most frequent side effects. 
2.5 
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 developed by our collaborator, Altor BioScience Corporation (Altor, 
Miramar, FL), to overcome some of the biologic, regulatory, and 
commercial limitations of unmodified E. coli-derived 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) 
(19). 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 (20). ALT-803 is a novel 
recombinant human superagonist IL-15 complex (ie, IL-15N72D:IL-
15RαSu/IgG1 Fc complex) with a prolonged serum half-life in preclinical 
animal models. In addition, ALT-803 contains a novel IL-15 mutein with a 
single substituted amino acid (rhIL-15N72D) that has a 4-fold increase in 
biologic activity greater than wild-type IL-15 (IL-15 wt) (21).  
 
Normal soluble IL-15R fragments, containing the “sushi” domain (Su) at 
the N terminus, have been shown to contain most of the structural 
elements responsible for cytokine binding, and IL-15R binds IL-15 with 
high affinity (Kd 100 pM). In addition, soluble IL-15R and IL-15 in solution 

 
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can form stable heterodimeric complexes capable of modulating (ie, either 
stimulating or blocking) immune responses via the IL-2R complex (22, 23, 
24)). Previous studies have shown that the biologic activity of IL-15 could 
be increased 50-fold by administering preformed complexes of IL-15 and 
soluble IL-15R, which has a longer half-life than rhIL-15 (22, 24). The IL-
15:IL-15R complex increases activity at lower concentrations, and the 
fusion with Ig-G1 Fc increases serum half-life, providing more ideal 
pharmacokinetics with prolonged cytokine function (25).   
 
We hypothesize that ALT-803 will likely require only weekly or twice 
weekly injections to achieve a similar benefits to that provided by low-dose 
continuous rhIL15 exposure. This will allow a less complex administration 
schedule that should be preferred by patients and clinicians. Data from 
preclinical studies in mice and non-human primates support this 
hypothesis (26). Moreover, ALT-803 will provide a safe and effective 
method for increasing activated antigen-specific T cells and NK cells to 
benefit patients with hematologic malignancy who have relapsed after an 
allogeneic stem cell transplant. 
 
ALT-803 has undergone good laboratory practice (GLP) pharmacology 
and toxicity studies in non-human primate models, to complete the 
investigational new drug (IND) requirements for the planned first time in 
humans testing. The preliminary results from the GLP toxicity study in 
non-human primates indicate that 4 weekly doses of ALT-803 are well 
tolerated at 0.1 mg/kg (100 mcg/kg), well above the highest dose level 
proposed in this study.  
2.6 
ALT-803 by Subcutaneous Injection (effective with the April 2015 
protocol revision) 
Emerging data from ongoing trials using the NCI’s recombinant human IL-
15 (rhIL-15) product and preclinical reports from Altor suggests that 
intravenous dosing likely is not optimal for IL-15 because it induces a high 
Cmax and secondary cytokine release (IL-6 and IFNγ) that affects its 
tolerability therefore limiting.  Alternately, based on pre-clinical studies, 
other studies using rHIL-15, and published studies with IL-2, 
subcutaneous dosing is safer and provides much better tolerability.  The 
increased tolerance of subcutaneous dosing is likely a result of a 
decreased Cmax compared with the same dose level administered 
intravenously and more sustained levels of the rIL-15 product in 
circulation.  Lowering the Cmax allows for more drug delivery overall. 
 
Waldmann and colleagues conducted the first in human solid tumor trial of 
rhIL-15 using daily intravenous bolus infusion for 12 consecutive days. 
(27)  Dose limiting toxicities observed at the 3.0 and 1.0 mcg/kg per day 
cohort were grade 3 hypotension, thrombocytopenia, and elevations of 
ALT and AST.  The maximum tolerated dose was declared at 0.3mcg/kg 

 
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per day.  In contrast, the ongoing subcutaneous trial using the same rhIL-
15 product being conducted through the Cancer Immunotherapy Trials 
Network ([Protocol CITN11-02: A Phase 1 Study of Recombinant IL15 
(rhIL15) in Adults with Advanced Solid Tumors: Melanoma, Renal Cell, 
Non-Small Cell Lung and Head and Neck Cancer – Dr. Jeffrey Miller - PI] 
has successfully completed dose cohorts of 0.25, 0.5, 1.0, and 2.0 mcg/kg 
of rhIL-15 given as 10 daily doses out of 12 days (no dosing on days 6 
and 7).  The study is currently enrolling at 3 mcg/kg with no dose limiting 
toxicity.  The major conclusion from this experience is that going from IV to 
subcutaneous dosing increases safety and allows for an MTD ≥ 6 times 
higher. In addition, research lab correlates show an increase in in vivo NK 
cell counts with this subcutaneous dose of rhIL-15 compared to what is 
reported with IV dosing. 
Altor BioScience has also conducted pre-clinical studies to compare the 
pharmacokinetics, pharmacodynamics and antitumor efficacy of ALT-803 
intravenous versus subcutaneous administration in mice.  The results of 
these studies indicated that going to subcutaneous dosing decreases the 
Cmax compared to IV dosing, retains the immunostimulatory and 
antitumor efficacy without exaggerating toxicity.  The main summary of the 
mice data (as no humor data) is that: when comparing IV to SQ, the peak 
concentration decreased by nearly 3-fold.  We believe that peak 
concentration correlates with secondary cytokine release, such as IFNy 
and IL-6, which may be linked to fevers and low blood pressure, both of 
which are frequent and often treatment limiting side effects in this current 
clinical trial. 
To date, potential efficacy was seen in two patients who received IV 
dosing.  One subject had relapsed acute myeloid leukemia (AML) and had 
a pericardial chloroma (but no BM involvement) that decreased in size two 
months after treatment on CT scan. A second subject had 10% blasts 
associated with thrombocytopenia late after transplant. During treatment, 
his platelet count increased and two months later, his marrow blast count 
was still 10%. Although still with disease, stable disease is unusual in AML 
and untreated progression is usually rapid.  Encouragement is seen with 
these two patients and switching to a SQ route of administration may allow 
more effective dosing with fewer limiting side effects. 
3.0 
Study Rationale 
Relapse after allogeneic stem cell transplantation remains a clinical challenge. 
Donor Lymphocyte infusion (DLI) has been documented to induce varying levels 
of response depending on the underlying hematologic malignancy. CML remains 
the most clinically responsive with lymphoma, AML/MDS, CLL, and ALL showing 
decreasing levels of response and long term disease free survival. These studies 
establish proofs of concept that allogeneic immune responses can have direct 
anti-tumor responses but, how often these responses are inadequate.  

 
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A study is ongoing with r IL-15 at the University of Minnesota building on an 
ongoing trial at the NIH for melanoma and renal cell; however only a dosing 
schedule of 12 daily infusions is being tested.  This current schedule requires 
either inpatient administration or daily visits (including weekends) by the patient 
imposing greatly on quality of life, as well as resulting in considerable expense in 
terms of resources and money.   
 
ALT-803 is a recombinant human super agonist IL-15 complex with IL-15 
presented with IL-15Rα and with the complex fused with Fc. Due to the higher 
affinity single amino acid substituted IL-15 and the presentation of IL-15 with IL-
15Rα, ALT-803 is likely to be effective at low concentrations. Due to its longer 
half-life as a result of fusion with Fc, ALT-803 is likely to be effective using a 
practical regimen of weekly or biweekly injections. It is likely that low 
concentrations of ALT-803 will enhance allogeneic immunity through NK cells 
and CD8+ T cells capable of mediating a response without the need for 
lymphodepleting chemotherapy and with a safety profile appropriate for 
outpatient use.  
 
If the first dose of ALT-803 as an inpatient is well tolerated, subsequent treatment 
may be offered in the outpatient clinic setting with the understanding that the 
patient will be admitted to the hospital if medically indicated. Given that relapse 
after transplant often leads to death, many patients prefer the opportunity of 
treatment/medical management in a full service outpatient setting over 
hospitalization to maximize quality of life.  Patients who require admission for 
medical reasons will receive treatment in the hospital. 
 
To be eligible for this study, the patient must agree to stay within a reasonable 
distance (i.e. 30 minutes travel time) of the study center for the duration of the 
first treatment cycle through 24 hours after the last dose.  Patients enrolled in the 
dose escalation component will be required to remain in the area.  Patients 
enrolled in the extension may have this requirement waived on an individual 
basis at the discretion of the treating physician.   
 
Up to six dose levels of ALT-803 will be tested using a standard 3+3 design of 
dose escalation for toxicity with an added feature of stopping early if efficacy is 
confirmed using absolute lymphocyte count as a surrogate biomarker.  The 
starting dose level of ALT-803 will be 1 mcg/kg.  This dose is equivalent to the 
starting dose of a CITN trial under development for metastatic melanoma and   
based on allometric scaling to an equivalent human dose of pre-clinical mouse 
and cynomolgus monkey data (personal communication with Altor).    
 
In April 2015 the protocol was revised to replace intravenous (IV) administration 
of ALT-803 with a subcutaneous (SQ) injection while maintaining the current 
dose escalation/enrollment plan.  To ensure safety with the SQ dosing, a 
minimum of 3 patients will be enrolled in the highest dose level tested during 

 
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intravenous administration (dose level 3 - 6 mcg/kg).  Enrollment will continue 
until the MTD/MED is identified or until dose level 6 (30 mcg/kg) is completed.  
The extended phase will be activated to complete study enrollment. 
 
In addition in April 2015 the protocol was amended to provide additional 
treatment opportunities:    
• With the change to SQ administration, the treatment plan was changed to 
permit the administration of up to 3 treatment cycles in patients with stable 
disease who meet the criteria found in section 6.2. 
• patients who were previously treated with intravenous ALT-803 will be 
eligible to re-enroll in the protocol at the current ALT-803 dose level under 
the subcutaneous treatment plan provided they received at least 3 doses 
of IV ALT-803 without dose limiting toxicity and they meet the 
inclusion/exclusion criteria per section 4.  (re-enrollment details deleted in 
the April 2016 version as there were no eligible patients remaining) 
 
In April 2016 the protocol was amended to enroll a total of 6 patients in dose 
level 4 (ALT-803 at 10 mcg/kg) despite no dose limiting toxicity in the 1st 2 
patients.  As clinical activity has been observed in the dosing cohorts tested so 
far (at least one complete response and several subjects with stable disease) in 
the absence of unacceptable toxicity, this dose may prove to be the optimal level 
for the extended phase.  The decision whether to continue dose escalation, or 
more likely, to declare ALT 803 at 10 mcg/kg the optimal dose for additional 
testing will be made after 6 patients are treated at dose level 4.  If we decide to 
dose escalate further, dosing cohorts 5 and 6 have also been lowered to 
increase safety. 
 
 
4.0 
Patient Selection 
Study entry is open to adults 18 years and older regardless of gender, race or 
ethnic background.  While there will be every effort to seek out and include 
females and minority patients, the patient population is expected to be no 
different than that of allogeneic stem cell transplant studies at the University of 
Minnesota and other participating institutions. 
 
Inclusion Criteria 
4.1 
Relapse after previous allogeneic stem cell transplant for one of the 
following hematologic malignancies - acute myelogenous leukemia, acute 
lymphoblastic leukemia, myelodysplastic syndromes (MDS), lymphoma, 
myeloma, chronic lymphocytic leukemia, chronic myelogenous leukemia 
meeting the following: 
• For non-CML, relapse will be defined based on disease specific 
morphologic criteria from a bone marrow biopsy and aspirate or 
recurrence of disease specific cytogenetics.  For disease specific 
definition of relapse, see appendix III.  Relapse can be determined 
morphologically. Equivocal results for relapse should result in a 

 
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repeated test after an appropriate time interval (suggested 1 month) to 
determine eligibility. 
• For CML, relapse will be defined as any cytogenetic evidence of a 
Philadelphia chromosome or persistence of BCR/ABL rearrangements 
by molecular testing on at least two measurements over a 6 month 
interval.  If cytogenetics are normal and there is PCR evidence of a 
BCR/ABL fusion, patients will be eligible if they have evidence of a 
quantitative increase in CML measured either by quantitative PCR or 
by fluorescent in situ hybridization (FISH).  
For Chronic Phase CML patients only: 
• must have failed (no response in 3 months or incomplete response 
at 6 months) or refused treatment with a tyrosine-kinase inhibitor 
(TKI) 
• must have failed (defined as incomplete response or relapse) or 
refused DLI  
4.2 
Relapse must have occurred ≥ 60 days after transplant 
4.3 
Prior DLI is allowed, however not within the 30 days before the 1st dose of 
ALT-803 
4.4 
Minimum donor chimerism of 10% 
4.5 
≥ 18 years of age  
4.6 
Karnofsky performance status ≥ 70% (appendix II) 
4.7 
Adequate organ function within 14 days (30 days for cardiac) of enrollment 
defined as: 
o Creatinine:  ≤ 2.0 mg/dL  
o Hepatic:  SGOT/SGPT < 5 x upper limit of institutional normal (ULN)  
o Cardiac: LVEF by ECHO or MUGA > 40%  
4.8 
Ability to be off prednisone and other immunosuppressive drugs for at 
least 14 days before first dose of study drug 
4.9 
Patient agrees to stay within a reasonable distance (i.e. 30 minutes travel 
time) of the study site for the duration of the first treatment cycle through 
24 hours after the last dose  
4.10 Women of child bearing potential and men with partners of child bearing 
potential must agree to use effective contraception during therapy and for 
4 months after completion of therapy 
4.11 Voluntary written consent 
 
Exclusion Criteria 
4.12 Post-transplant lymphoproliferative diseases (often referred to as EBV-
associated lymphomas)  
4.13 Known active CNS leukemia or lymphoma – patients with previously 
treated CNS disease is permitted if neurologically stable with no ongoing 
or anticipated need for steroid therapy are eligible 
4.14 Ongoing active acute or chronic GVHD requiring immunosuppressive 
therapy or signs of aGVHD or cGVHD requiring treatment 
4.15 Concurrent chemotherapy (except hydroxyurea) or IL-2 therapy or 
anticipated need during the study treatment and for 1 week after the last 

 
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dose of ALT-803 – hydroxyurea is permitted at any time to control blast 
count  
4.16 Pregnant or lactating – Women of child bearing potential must have a 
negative pregnancy test within 14 days of study treatment start 
4.17 Class II or greater New York Heart Association Functional Classification 
criteria (appendix II) or serious cardiac arrhythmias likely to increase the 
risk of cardiac complications of cytokine therapy (e.g. ventricular 
tachycardia, frequent ventricular ectopy, or supraventricular 
tachyarrhythmia requiring chronic therapy) 
4.18 Marked baseline prolongation of QT/QTc interval (e.g. demonstration of a 
QTc interval greater than 500 milliseconds) 
4.19 New progressive pulmonary infiltrates on screening chest x-ray or chest 
CT scan for which evaluation with bronchoscopy is not feasible.  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). 
4.20 Active bacterial, fungal, or viral infections – all prior infections must have 
resolved following optimal therapy  
4.21 Known positive hepatitis C serology or active hepatitis B infection because 
of the risk of hepatic inflammation and the possible confounding of drug 
toxicity assessment  – chronic asymptomatic viral hepatitis is allowed 
4.22 Known HIV positive because the effect of IL-15 viral loads, HIV immunity, 
and infectivity of proliferating T cells is unknown 
4.23 History of severe asthma, presently on chronic medications (a history of 
mild asthma not requiring therapy is eligible) 
 
 
5.0 
Registration/Dose Assignment Procedures 
Registration will occur after the patient has signed the subject consent and 
eligibility is confirmed, but before any study related procedures are performed.   
 
To be eligible for registration to this study, the patient must meet each of the 
criteria listed on the eligibility checklist based on the eligibility assessment 
documented in the patient’s medical record.   
 
A copy of the eligibility checklist is in appendix I and under attachments within 
this study in OnCore. 
5.1 
Registration and ALT-803 Dose Level Assignment 
Upon completion of the screening evaluation, eligibility confirmation and 
obtaining written consent, study site coordinator or designee will enroll the 
patient into OnCore.  
 
OnCore will automatically generate an email alerting key study personnel 
of the registration.  The Masonic Cancer Center (MCC) Study Coordinator 
or designee will assign the ALT-803 dose level in OnCore to complete the 

 
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registration.  An email with the dose level assignment will be sent to 
relevant study personnel.   
 
Affiliate sites only:  At the time of registration, a copy of the signed consent 
and completed eligibility checklist will be uploaded as an attachment into 
OnCore under the patient’s record.  Affiliates are responsible for fulfilling 
any local patient registration requirements.  
5.2 
Patients Who Are Registered and Do Not Receive Study Treatment 
If a patient is registered to the study and is later found not able to begin 
ALT-803, for whatever reason, the patient will be removed from study and 
treated at the physician’s discretion.  Study staff will update OnCore of the 
patient’s non-treatment status.  Study data will be collected until the time 
the patient is taken off study.  The reason for removal from study will be 
clearly indicated in OnCore.  The patient will be considered unevaluable 
and replaced per section 11.3. 
 
 
6 Treatment Plan 
In order to provide optimal patient care and to account for individual medical 
conditions, investigator discretion may be used in the prescribing of all supportive 
care drug therapy (i.e. acetaminophen, diphenhydramine, antimicrobials, etc.); 
however the use of systemic steroid medications may result in loss of therapeutic 
effects of the study drug and should be avoided.  Topical steroid cream is 
permitted.   
6.1 At the Time of Relapse 
At the time of relapse, patients should be tapered off immunosuppressive 
medications as soon as possible.  To be eligible for this study, patients 
must be off prednisone and other immunosuppressive agents for at least 
14 days before the first dose of ALT-803. 
6.2 
ALT-803 Administration 
ALT-803 will be administered subcutaneously at the assigned dose level 
once a week (on day 1, 8, 15 and 22).  Injection sites should be rotated 
per institutional guidelines and each injection site separated by at least 1 
inch. 
 
The first dose of ALT-803 of the 1st cycle will be given as an inpatient; 
however if the first dose is well tolerated, subsequent doses may be 
administered in an outpatient setting. 
 
A window of +/- 2 days for the weekly ALT-803 dosing is allowed in the 
event of scheduling issues (i.e. holiday).  All other tests and evaluations 
associated with that week’s dose will be adjusted accordingly. 
 

 
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Recommended Skin Rash Management Plan (begins day before ALT-
803 dose): 
With the April 2016 protocol revision a skin rash management plan was 
added.  Since the change to subcutaneous administration, an increase in 
the frequency and severity of skin rash has been noted.    
  
The following is recommended for all patients with every dose of ALT-803.  
Adjustments to the plan are permitted without being a deviation.  Refer to 
section 6.3.2 for management of skin rash despite these preventive 
measures.   
 
• One day prior to each ALT-803 dose:  Diphenhydramine 25-50 mg 
TID orally  
• One hour prior to each ALT-803 dose:  Diphenhydramine 25-50 mg  
orally with one of the following: 
Ranitidine 300 mg orally 
Cimetidine 300 mg orally 
Famotidine 20 mg orally 
• After each ALT-803 dose:  Continue Diphenhydramine 25-50 mg 
TID orally x 2 days 
 
Pre-medication:  Acetaminophen 650 mg PO and diphenhydramine 25 
mg PO/IV thirty minutes before and 4 hours after each dose of ALT-803 is 
recommended.  (adjust as needed if using skin rash prophylaxis) 
 
Non-steroidal anti-inflammatory medication including acetaminophen, 
ibuprofen, or naproxen may be given per physician discretion following the 
recommended dosing thresholds: 
Acetaminophen: not to exceed 3000 mg (3 grams) in 24 hours 
Ibuprofen: not to exceed 2400 mg in 24 hours 
Naproxen: not to exceed 1100 mg in 24 hours 
 
The use of systemic steroid medications may result in loss of therapeutic 
effects of the study drug and should be avoided; however in the event of a 
life-threatening inflammatory reaction to ALT-803, the IV administration of 
dexamethasone or other steroid-based medication is warranted.   
 
Monitoring:   
During the Dose Finding Phase:  Patients will be observed for a minimum 
of 6 hours after each dose of ALT-803 for immediate adverse events.  
 
During the Extended Phase:  Patients will be observed for a minimum of 6 
hours after dose 1 of cycle 1 and a minimum of 2 hours after subsequent 
doses are the care team’s discretion.   
 

 
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Vital signs (heart rate, blood pressure, respiration, temperature, and 
oxygen saturation) for all patients will be documented prior to each ALT-
803 dose and then at 15, 30, 60 and 120 minutes then hourly until 
discharge from clinic (minimum of 6 hours for Dose Finding Phase, 
minimum of 2 hours for Extended Phase).    
 
For inpatients:  continue vitals hourly (+/- 15 minutes) until 6 hours post 
dosing, then every 3 hours, or more often if indicated, beyond the first 6 
hours until 24 hours post dosing. 
 
For outpatients:  Admission to the inpatient unit (or continued outpatient 
monitoring) should be considered if any of the following occurs and is still 
present at the end of required observation period:  
• a new fever >102.3°F (39.0°C) develops or  
• an oxygen saturation drops below 90% or 
• there is a sustained changes in baseline vital signs by 20% for more 
than 1 hour or 
• if there is any change in symptoms of concern 
 
If vital signs remain within baseline and none of the changes above are 
present at the end of the observation period, the patient is eligible for 
continued outpatient monitoring: 
 
Upon discharge from the outpatient infusion area on the day of each 
injection, it will be reiterated the need to contact the study staff or BMT 
physician on call with any questions or concerns.  The patient will be given 
emergency access phone numbers and access to immediate hospital 
admission should be a clinical status change. 
 
 
During week 1 of the first cycle, the patient will be discharged from the 
hospital after the 24 hour post injection assessment and lab work is done 
with a return to clinic at approximately 48, 72, and 96 hours post injection 
for a brief assessment and lab work, if scheduled. 
 
During weeks 2, 3, and 4 of the first cycle and all doses of subsequent 
cycles, the patient will return to clinic approximately 24 hours post injection 
for a brief assessment and lab work.  If ALT-803 is administered in the 
inpatient setting, the 24 hour post injection assessment and lab work will 
be done prior to discharge. 
 
Refer to section 3 regarding requirements for staying close to the study 
site during the 1st treatment cycle. 
 
Targeted toxicities (appendix VI) and unexpected adverse events will be 
collected at the time points listed in section 9.2. 

 
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Dose modification:  No dose modifications are allowed.  If a patient 
experiences toxicity that meets the definition used for dose limiting toxicity 
(DLT) at any time, ALT-803 will be permanently discontinued. 
 
Dose delay:  ALT-803 administration may be delayed by 1 week if on the 
day of the planned injection for any of the following situations: 
• Grade 2 or greater acute GVHD is questioned (documented grade 
3-4 GVHD will require discontinuing ALT-803) 
• the patient has a fever of > 101°F (38.3 °C)  
• treatment related side effects (except skin rash) have not resolved 
to grade 1 or better  
• if in the opinion of the treating physician, a 1 week delay would be 
of benefit to the patient   
 
If after a 1 week rest, the patient no longer meets any of the above criteria 
for dose delay, the patient may resume treatment with the intent of giving 
all 4 doses of ALT-803.   
 
If after 1 week, the patient is still unable to be treated, the patient will be 
taken off treatment and followed per section 6.7. 
 
Up to two separate 1 week delays will be permitted within a cycle 
potentially extending the treatment cycle to a maximum of 6 weeks.   
 
If a delay is required in association with more than 2 of the injections 
within a treatment cycle, the patient will be taken off treatment and 
followed per section 6.7. 
  
Patients who do not receive at least 3 out of 4 doses for reasons other 
than toxicity will be unevaluable and will be replaced in that dose level 
cohort per section 11.3. 
 
Additional treatment cycles:  A disease re-assessment will be done 
approximately 2 weeks after the 4th dose of ALT-803.  Patients with stable 
disease may be considered for an additional treatment cycle (up to 2 
additional cycles) at the same dose of ALT-803 if all of the following 
criteria are met: 
• received all 4 doses in previous cycle (exceptions may be made on an 
individual patient basis if no more than one dose was missed for 
reasons other than toxicity) 
• patient had no unacceptable toxicity during previous cycle (i.e. did not 
experience the equivalence of dose limiting toxicity) 
• treatment related side effects (except skin rash) have resolved to grade 
1 or better 
• no evidence of > grade 1 GVHD   

 
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Day 1 of each subsequent treatment cycle must be at least 2 weeks, but 
not more than 4 weeks after the last dose of the previous cycle.    
 
6.2.1 ALT-803 Dose Level Assignment – Dose Finding Phase 
ALT-803 dose level assignment will occur at the time of study 
registration based on the following Dose Level cohorts: 
Dose Level 
ALT-803  
Weekly 
Dose 
Route of 
Administration 
Number of 
Patients 
Enrolling 
Institutions 
1 
1 microgram/kg 
IV 
6* 
U of MN 
2 
3 microgram/kg 
IV 
3 to 6 
 
U of MN and 
affiliates 
3 
6 microgram/kg 
IV 
3 to 6 
3a# 
6 microgram/kg 
SQ 
 
4 
10 microgram/kg 
SQ 
6& 
5 
15 microgram/kg 
SQ 
3 to 6 
6 
20 microgram/kg 
SQ 
3 to 6 
* with the Feb 10, 2014 dose level 1 was expanded to 6 patients total after which dose escalation 
will continue as planned 
# with the April 28, 2015 protocol version ALT-803 dosing was changed from IV to SQ and dose 
level 3 (6 mcg/kg)  was repeated to confirm safety with the new route of administration – in the 
unlikely event of dose de-escalation to level 2 or 1, the route of administration will be SQ 
&with the April 2016 protocol version Dose Level 4 (10 mcg/kg) was expanded to enroll 6 patients 
despite the absence of DLT to gain further toxicity data before making the decision to continue 
dose escalation or declare level 4 the optimal dose and proceed to the extended phase. Dosing 
cohorts 5 and 6 were lowered to increase safety. 
 
Within a dose level, the 1st patient must receive a minimum of 2 
doses before additional patients are enrolled.  The 1st dose for 
subsequent patients within a dose level must be separated by at 
least 72 hours.  Dose escalation to the next level cannot proceed 
until the following conditions are met: 
• All patients at the current dose level have completed at least 3 
of the 4 planned ALT-803 doses  
• The maximum tolerated dose (MTD) has not been exceeded   
• The minimum efficacious dose (MED) of ALT-803 dose has not 
been reached 
 
In February 2014 dose level 1 was expanded to enroll 6 patients 
total.  This was done to confirm the findings in the 1st 3 patients of 
possible immune activation (evidenced by a fever between 2 to 3 
hours after each dose) and to gain additional experience before 
continuing the dose escalation plan described in section 11.1.   
 
In April 2015, the protocol was revised to replace intravenous (IV) 
administration of ALT-803 with a subcutaneous (SQ) injection while 
maintaining the current dose escalation/enrollment plan.  To ensure 

 
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safety with the SQ dosing, a minimum of 3 patients will be enrolled 
in the highest dose level tested during intravenous administration 
(dose level 3 - 6 mcg/kg).   
 
In April 2016, dose level 4 (10 mcg/kg) was expanded to enroll 6 
patients despite no dose limiting toxicity and dose levels 5 and 6 
were reduced to 15 mcg/kg and 20 mcg/kg. 
 
Intra-patient dose escalation is not allowed. 
 
 
6.2.1.1 Definition of Dose Limiting Toxicity (DLT) 
Toxicity and adverse events will be classified according to NCI’s 
Common Terminology Criteria for Adverse Events V 4.0 (CTCAE).  
 
Dose limiting toxicity (DLT) is defined as (during first treatment 
cycle only): 
• any grade 3 treatment-emergent, non-hematologic toxicity 
lasting more than 48 hours with exception to the following 
events which will not count toward DLT: 
o Grade 3 fatigue and/or anorexia 
o Grade 3 hypertension 
o Grade 3 fever without evidence of infection  
o Grade 3 diarrhea despite the use of adequate/maximal 
medical intervention and/or prophylaxis 
o Grade 3 skin rash not requiring systemic steroid therapy 
• any grade 4 or 5 treatment-emergent, non-hematologic toxicity  
• grade III or IV acute GVHD within 6 weeks of the 1st dose of 
ALT-803 
 
Dose escalation will be done based on the schema found in section 
11.  DLT’s will be counted based on the number of patients with 
DLT at a given dose level, not the absolute number of DLTs.  No 
single patient can trigger more than one DLT event.  No further 
treatment will be given to a patient experiencing a DLT. 
 
6.2.1.2 
Definition of Maximum Tolerated Dose (MTD) 
The maximum tolerated dose is that level where no more than 1 out 
of 6 patients experience dose limiting toxicity during the first 
treatment cycle. 
 
6.2.1.3 
Definition of Minimal Efficacious Dose (MED) 
Since the ultimate goal is to use ALT-803 as a component of a 
more complex therapy, it will be critical to “leave room” for 
additional agents by keeping toxicity to a minimum.  With that 
respect and although the exact threshold for MED is unknown, 

 
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given the action of IL-15 to stimulate homeostatic expansion CD8+ 
T cells and NK cells, we will use the absolute lymphocyte count 
(readily available on a clinical CBC) as a surrogate biomarker of 
biologic activity to define the MED.   
 
MED is defined as an absolute lymphocyte count (ALC) of > 25,000 
cells/μl that is sustained for > 24 hours in ≥ 2 of 3 patients (or ≥ 4 of 
6) within a cohort.   
 
6.2.2 ALT-803 Dose Level Assignment – Extended Phase 
All patients will be treated at the ALT-803 MTD/MED declared 
during the Dose Finding Phase while adhering to the study early 
stopping rules per section 11.4. 
6.3 
Management of Selected, Expected Adverse Events 
6.3.1 Hypotension (systolic blood pressure < 90 mm Hg)  
For hypotension with systolic blood pressure less than 90 mm Hg, 
AND greater than 20 mm Hg below baseline, AND clinically 
significant per investigator, ALT-803 should be held until the 
systolic blood pressure reading rises above 90 mm Hg OR to 
baseline OR is no longer clinically significant.   
 
Since the regimen is intended for outpatient administration, the 
need for fluid support will be considered on a patient-by-patient 
basis and not count toward dose limiting toxicity (if phase I, cycle 
1). 
 
However, if urgent medical intervention, such as IV hydration in the 
emergency room or hospital admission for drug toxicities, is 
indicated, tALT-803 will be permanently stopped.  If the patient is 
enrolled in the Dose Finding Phase and the event occurs during 
cycle 1, a DLT will be reported. 
 
6.3.2 Skin Rash 
Due to the increase in frequency and severity of skin rash with 
subcutaneous injection a proactive skin rash management plan was 
added to section 6.2 in April 2016.   
 
If the skin rash area surrounding the ALT-803 injection site is > 6 
cm, it should be treated with topical 0.05% clobetasol propionate 
(i.e. 0.05% Cormax) or 0.1% triamcinolone (i.e., Kenalog) cream. 
 
A biopsy of skin rash should be considered to confirm or rule-out 
graft versus host disease (GVHD). 
If systemic steroids are required, ALT-803 should be discontinued 
per section 6.5.  If the patient is enrolled in the Dose Finding Phase 

 
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and the rash occurs in association with the 1st cycle, a DLT must be 
reported. 
 
6.3.3 Pulmonary Changes 
Pulmonary function will be monitored at each visit by clinical 
examination, assessment of vital signs and pulse oximetry.  
Patients with dyspnea or clinical signs of respiratory impairment 
(tachypnea or rales) must be further assessed if clinically indicated, 
including the need for hospitalization. 
 
6.3.4 Cardiac Changes 
Cardiac function should be monitored at each visit by clinical 
examination and assessment of vital signs.  In addition, an EKG 
and troponin level will be done at study entry and, for patients 
enrolled in the Dose Finding Phase only before the 1st dose and at 
6 and 24 hours post.  Patients with signs or symptoms of chest 
pain, murmurs, gallops, irregular rhythm, or palpitations must be 
further assessed if clinically indicated, including the need for 
hospitalization.  If there is evidence of cardiac ischemia or 
congestive heart failure, ALT-803 will be permanently discontinued. 
6.4 
Supportive Care 
Supportive care will be provided per institutional guidelines.  Guidelines 
may be updated based on current data/drugs without requiring a protocol 
amendment or be considered a protocol deviation.  
 
Due to the similarity of this agent to IL-2, which can inhibit neutrophil 
chemotaxis and increase the risk of complications from bacterial 
infections, patients who require or who have a pre-existing venous access 
device will receive prophylactic antibiotics (i.e. levofloxacin 250 mg daily or 
other appropriate prophylaxis) for the duration of the study treatment. 
 
Patients with a diagnosis of multiple myeloma may receive additional 
therapy (e.g. lenalidomide, bortezomib) at the discretion of the treating 
physician after a minimum of 14 days have passed from the last dose of 
ALT-803. 
6.5 
General Concomitant Medications Guidelines 
Concurrent chemotherapies (except hydroxyurea) and interferon-alfa 
treatment with ALT-803 are prohibited.  Hydroxyurea may be used to 
control blasts count. 
 
Administration of glucocorticoids is prohibited during the ALT-803 
treatment period as the use of systemic steroid medications may result in 
loss of therapeutic effects of the study drug.  They should be avoided 
except in the event of a severe toxicity or unrelated condition requiring 

 
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steroid and there use will be an indication to stop ALT-803.  Topical 
steroid cream is permitted.   
 
Beta-blockers and other antihypertensives 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.   
 
Due to the similarity to IL-2 the potential drug interactions associated with 
IL-2 listed below may occur with ALT-803 treatment: 
• 
Central nervous function: interactions could occur with concomitant 
administration of psychotropic drugs (e.g., narcotics, analgesics, 
antiemetics, sedatives, tranquilizers). 
• 
Kidney and liver function: concomitant nephrotoxic (e.g., 
aminoglycosides, indomethacin), myelotoxic (e.g., cytotoxic 
chemotherapy), cardiotoxic (e.g., doxorubicin), or hepatotoxic (e.g., 
methotrexate, asparaginase) medications should be avoided during 
ALT-803 regimen treatment period. 
• 
Hypersensitivity reactions: reported in some patients receiving 
combination regimens of sequential high dose Proleukin and 
antineoplastic agents, specifically, dacarbazine, cisplatin, tamoxifen 
and interferon-alfa. Reactions including erythema, pruritus, and 
hypotension occurred within hours of administration of chemotherapy. 
• 
Autoimmune and inflammatory disorders: exacerbation or initial 
presentation of crescentic IgA glomerulonephritis, oculo-bulbar 
myasthenia gravis, inflammatory arthritis, thyroiditis, bullous 
pemphigoid, and Stevens-Johnson syndrome has been observed 
following concurrent use of interferon-alfa and Proleukin. 
• 
Delayed Adverse Reactions to Iodinated Contrast Media: 11–28% of 
patients treated with various Proleukin containing regimens and 
subsequently administered radiographic iodinated contrast media 
experienced acute, atypical adverse reactions. The onset of 
symptoms usually occurred within 1 to 4 hours following the 
administration of contrast media. Most events occurred when contrast 
media was given within 4 weeks after the last dose of Proleukin, but 
reactions were also reported when contrast media was given several 
months after Proleukin treatment. Reactions included fever, chills, 
nausea, vomiting, pruritus, rash, diarrhea, hypotension, edema, and 
oliguria. Similar conditions may occur with ALT-803 treatment. 
6.6 
Duration of Treatment 
Patients may receive up to 3 treatment cycles (4 weekly injections of ALT-
803 followed by at least 2 weeks, but not more than 4 weeks of no 
treatment) unless one or more of the following occurs:  
• consent is withdrawn or patient is noncompliant  

 
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• patient requires a change in therapy 
• patient experiences dose limiting toxicity (DLT) or other 
unacceptable toxicity 
• patient requires more than a 1 week delay in the administration of 
an ALT-803 dose 
• patient requires more than two separate 1 week delays from the 
planned ALT-803 administration day 
• patient requires GVHD therapy 
6.7 
Duration of Study Participation 
Evaluable patients will be followed for overall remission response, toxicity, 
and survival for 12 months from the 1st injection unless one of the 
following occurs: 
• consent is withdrawn  
• the patient is unevaluable per section 11.3 – if a patient is not 
evaluable, he/she will be followed only until the resolution or 
stabilization of treatment related toxicity.  Unevaluable patients will 
be replaced to complete enrollment. 
• the patient has no benefit from ALT-803 and/or begins other 
treatment in attempt to control the disease 
• the patient enters hospice care – is this case date and cause of 
death will be recorded upon knowledge 
• data collection on the study ends  
 
All patients, regardless of circumstances, must be followed for a minimum 
of 4 weeks after the last dose of ALT-803 for incidence of acute GVHD 
(DLT event/early study stopping rule event and study endpoint) and any 
ongoing ALT-803 treatment related toxicity.  If a clinic visit is not 
reasonable, follow-up may be done by an alternate means including via 
communication with the patient, family and/or local medical provider. 
 
 
 
7 Clinical Evaluations and Procedures 
 
Scheduled evaluations during the treatment cycles may be performed +/-2 day 
from the targeted date.  The final treatment visit may be done +/-7 days of the 
targeted date.  During follow-up, schedule assessments may be done +/- 30 days 
of the targeted date.  In addition, targeted days may be altered as clinically 
appropriate. 
 
The 24, 48, 72, and 96 hour follow-ups post dosing may be performed +/- 2 
hours. 

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7.1 
Standard of Care Clinical Evaluations 
 
Screening 
Within 14 
days of 
enrollment 
unless o/w 
indicated 
Each Treatment Cycle (up to a maximum of 3 cycles) 
Final 
Treatment 
visit 4 
weeks 
after final 
dose 
 Follow-up every 
3 months from 
1st dose until PD 
then survival 
only until 1 year 
Dose #1 
Dose #2 
Dose #3 
Dose #4 
Day 29 
or 1 
week 
after 
last 
dose 
After each 
treatment 
cycle (~2 
weeks 
after last 
dose) 
Day1 
Day 2 
(~24 
hours 
post) 
Cycle 1 only 
Day 
8 
Day 9  
(~24 
hours 
post) 
Day 
15 
Day 16 
(~24 
hours 
post) 
Day 
22 
Day 23 
(~24 
hours 
post) 
Day 3  
(~48 
hours 
post)  
Day 4 
(~72 
hours 
post) 
Day 5 
(~96 
hours 
post) 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam  
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X4 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X4 
Vitals  and pulse oximetry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X4 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performance Status 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X4 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Assessment/query for  
reportable event(s)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X4 
GvHD Surveillance refer to 
appendix IV for scoring 
X 
 
 
 
 
 
 
 
 
 
 
 
X5 
X5 
X5  
X4  
CBC, diff, plt 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X4 
BUN, creat, glucose, Na, K, Cl  
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X4 
AST, ALT, bili, alk phos 
X 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X4 
Troponin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM biopsy and aspirate 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X4 
BM chimerism 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X4 
CXR or chest CT scan 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ejection Fraction 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 – Neurological assessment at baseline only including basic motor (gait), coordination (steadiness) and cognitive function (alert and oriented) - any abnormalities should be followed up with a detailed neurologic exam.  
2 - serum or urine, women of childbearing potential  
3 - within 30 days of enrollment  
4 – perform only if ongoing stable disease or benefit from ALT-803 (not required if disease progression  after ALT-803 was previously documented or suspected).   
5- grade III or IV acute  GVHD within 6 weeks of the first dose of ALT-803 is a DLT event or early study stopping rule event based on which component the patient is enrolled 

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7.2 
Research Related Evaluations  
 
protocol 
section 
All Cycles 
Cycle 1 Only (in addition to samples under “all cycles”) 
4 weeks 
after final 
dose5 at 
final 
treatment 
visit 
Week 1 (Dose 1) 
Pre-
dose 
3 
1 week 
post 
final 
dose 
Before 
or on 
Dose 1 
Weekly 
during 
dosing 
period4 
1 week after 
final dose 
within a 
cycle5 
Day 1 
(inpatient) 
Day 2 
Day 3 
(+/- 1 
day) 
Day 5 
(+/- 1 
day) 
(U of MN 
only) 
pre-
dose 
time after 
dose 
Toxicity Notation 
9.2 
Refer to section 9.2 for time points and documentation requirements 
EKG (Dose Finding 
Phase only) 
n/a 
 
 
 
X 
6 hours 
X 
 
 
 
 
 
Troponin (Dose 
Finding Phase only) 
n/a 
 
 
 
X 
6 hours 
X 
 
 
 
 
 
50 ml of heparinized 
blood (5 green top 
tubes) 1  
7.2.1 
X 
X 
X 
 
 
 
X 
X 
 
 
X 
10 ml of serum (1 red 
top tube) 1 
7.2.1 
X 
X 
X 
 
 
 
X 
X 
 
 
X 
Immunogenicity of 
ALT-803 
5 ml red top tube 
7.2.2 
 
 
 
X2 
 
 
 
 
X 
X 
 
Pharmacokinetics 
(PKs)  
5 ml red top (a 
minimum of 2 ml blood 
needed) per time point 
7.2.2 
 
 
 
X2 
30 min, 
2, 4,and 
8 hours 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1 
Collect prior to day’s ALT-803 dosing, if applicable 
2 
For cycle 1, the baseline PK and immunogenicity sample can be collected into the same tube 
3 
Final PK sample 24 hours (+/- 2 hours) post dose 1 
4 
Collect research blood samples weekly (i.e. prior to doses 2, 3, and 4, and on any weeks where dosing is delayed per protocol section 6.2) 
5 
Do not collect any additional research samples once a patient is off treatment for disease progression 
 
 
 
 

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7.2.1 Assessment of Immune Activation (TTL) 
Samples to evaluate lymphocyte number, phenotype and function will 
be collected as detailed above for the Masonic Cancer Center 
Translational Therapy Lab (TTL). 
 
Samples are shipped the day of collection to the University of 
Minnesota Masonic Cancer Center’s Translational Therapy Lab (TTL) 
by overnight delivery in an insulated container with a frozen gel pack 
Monday-Thursday.  Refer to the Affiliate Manual for additional details. 
 
Translational Therapy Core Facility 
University Of Minnesota 
420 Delaware St. SE 
Room A410 Mayo Building 
Minneapolis, MN 55455 
Phone: 612-625-6165 
Fax: 612-625-9631 
 
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. 
 
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 may be 
drawn at additional time points that are not specified above.  
7.2.2 Pharmacokinetics and Antibodies (ALTOR) 
The pharmacokinetics profile of ALT-803 levels will be assessed by 
ELISA using blood collected at the following time points: 
 
ALT-803 
dose 
Pharmacokinetic Time Points for ALT-803  
All cohorts 
Immediate Pre-dose ALT-803 
All cohorts 
30 minutes after (± 5 minutes) ALT-803 injection is completed 
All cohorts 
2 hours after (± 15 minutes) ALT-803 injection is completed 
All cohorts 
4 hours after (± 60 minutes) ALT-803 injection is completed 
All cohorts 
8 hours after (± 60 minutes) ALT-803 injection is completed (omit if 
outpatient) 
All cohorts 
24 hours after (± 2 hours) ALT-803 injection is completed 
NOTE: The precise ALT-803 administration time and the precise pharmacokinetic draw time must 
be recorded on the pharmacokinetic flow sheet. 

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Whole blood will be collected into 5 ml red top tubes (collect a 
minimum of 2 ml blood ) to obtain serum for assays for quantifying 
serum levels of ALT-803.   
 
Patients will be monitored for the presence and development of auto-
antibodies to ALT-803 on day 1 pre-treatment (the baseline PK sample 
can be taken from this sample) and 1 week after the second dose (day 
15) and 1 week after the final dose.     
 
The tubes will be allowed to clot at room temperature and clinical sites 
will separate serum from cells within 4 hours of blood draw. Serum 
aliquots will be stored frozen at -20°C.  Samples (ideally every 2 
patients) will be batched and shipped overnight directly from the 
clinical site on dry ice to the Altor Bioscience’s central laboratory.   
 
Assays for quantifying serum levels of ALT-803 and ALT-803 
antibodies will be conducted in the laboratory at Altor Bioscience, 
Miramar, FL.   
 
 
8 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. 
8.1 
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. 

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8.2 
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).6. The human 
IL-15R sushi domain/human IgG1 Fc fusion protein comprises the sushi 
domain of the IL-15R subunit (aa 1-65 of the mature human IL-15Rα 
protein) linked with the human IgG1 CH2-CH3 region containing the Fc 
domain (232 amino acids). Aside from the N72D substitution, all of the 
protein sequences are human. Based on the amino acid sequence of the 
subunits, calculated molecular weight of the complex comprising 2 IL-
15N72D polypeptides and a disulfide linked homodimeric IL-15RαSu/IgG1 
Fc protein is 92.4 kDa. Each IL-15N72D polypeptide has a calculated 
molecular weight of approximately 12.8 kDa and the IL-15RαSu/IgG1 Fc 
fusion protein has a calculated molecular weight of approximately 33.4 
kDa. Both the IL-15N72D and IL-15RαSu/IgG1 Fc proteins are 
glycosylated resulting in an apparent molecular weight of 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-801, or one OD280 is equivalent to 
0.79 mg/mL solution of ALT-803. 
8.3 
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. 
8.4 
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 
at least 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.  
8.5 
Agent Ordering and Agent Accountability 
ALT-803 is produced in the USA by Altor Biosciences Corporation, 
Miramar, FL. After manufacturing, the product is stored at Altor 
Biosciences 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 from Altor 
Biosciences Corporation to each participating site. (See the Study 
Procedures Manual for instructions on how to order ALT-803.) 

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8.6 
Study Drug Preparation and Administration  
ALT-803 dose calculation will be based on actual body weight.  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.  Each injection site should be 
separated by at least 1 inch. 
8.7 
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 Biosciences 
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.) 
8.8 
Toxicity 
There is no previous safety and effectiveness experience of ALT-803 in 
humans.  The ALT-803 protein complex comprises a variant of iL-15, a 
common γ chain cytokine that may have similar immunostimulatory 
properties as IL-2.   
 
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) 
• 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 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 
• heart problems - causing low 
blood pressure, dizziness, 
chest pain or changes in 
heart rhythm (heart beat) 
• pain and redness at the 
injection site 
• 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) 
platelet count 
• skin rash 
• weakness, headache, 
dizziness 
• vomiting, nausea, loss of 
appetite 
• lower the levels of 
electrolytes as detected by 
routine blood tests 
 
To prevent or reduce the severity of the anticipated fever and chills, all 
patients will receive medications before and after each dose of ALT-803. 
 
The most common side effects seen on this study with subcutaneous 
(under the skin) injections have been change in blood pressure (increase 
or decrease), a reaction at the injection site, and skin rash, which at times 
has been widespread.  These localized skins reactions are expected to be 
common (up to 20% [one in 5 patients]). A biopsy of skin rash should be 
considered to confirm or rule-out graft versus host disease (GVHD).  
Refer to the ALT-803 Investigator Brochure for additional details. 
 
9 Adverse Event Documentation and Reporting 
 
Toxicity and adverse events will be classified 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 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_
40 
 
Note:  throughout this section the generic term “study drug” refers to ALT-803. 
9.1 
Definitions 
The following definitions are based on the Code of Federal Regulations 
Title 21 Part 312.32 (21CFR312.32(a)). 
 
 
Adverse Event:  Any untoward medical occurrence associated with the 
use of a drug in humans, whether or not considered drug related.  
 
Suspected Adverse Reaction:  Any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event.  
 
Treatment-Emergent Adverse Event:  Any event not present prior to the 
initiation of the treatment or any event already present that worsens in 
either intensity or frequency following exposure to the treatment.  A 

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treatment emergent AE refers to an event temporally related to the study 
treatment regardless of the causality assessment by the investigator. 
 
Life-Threatening Adverse Event Or Life-Threatening Suspected 
Adverse Reaction: An adverse event or suspected adverse reaction is 
considered “life-threatening” if, in the view of either the investigator or 
sponsor, its occurrence places the patient or subject at immediate risk of 
death. 
   
Serious Adverse Event Or Serious Suspected Adverse Reaction:  An 
adverse event or suspected adverse reaction 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.  
 
Event Attribution Categories: 
CTCAE does not define an AE as necessarily ‘caused by a therapeutic 
intervention.’ The clinical investigator must assign attribution for an 
adverse event after naming and grading of the event. 
 
Attribution with 
2 Options 
Attribution 
with 5 Options 
Description 
Not related 
Unrelated 
The AE is clearly NOT related to the intervention 
Unlikely 
The AE is doubtfully related to the intervention 
Related 
Possible 
The AE may be related to the intervention 
Probable 
The AE is likely related to the intervention 
Definite 
The AE is clearly related to the intervention   
 
Unexpected adverse event or unexpected suspected adverse 
reaction: An adverse event or suspected adverse reaction is considered 
“unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or, if an investigator 
brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in 
the current application, as amended.  Thus, as defined by the FDA 

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adverse events that occur as part of the disease process or underlying 
medical conditions are considered unexpected; however, for the purposes 
of this study they will not be documented or reported. 
9.2 
Adverse Event Monitoring and Documentation 
9.2.1 Monitoring Period 
Patients will be monitored for toxicity beginning with the 1st dose of ALT-
803 through the final treatment visit approximately 4 weeks after the last 
dose of study drug.  After the final treatment visit, only those events that 
meet the definition of serious, are felt to be at least possibly related to 
ALT-803,and are unexpected will be documented upon knowledge and, if 
applicable, reported in an expedited manner.  Affiliate sites follow section 
9.3 for expedited reporting requirements. 
9.2.2 Event Documentation 
As this study enrolls a medically complicated patient population adverse 
event documentation will be limited to ALT-803 “targeted” toxicities (side 
effects expected with this treatment to document the frequency and 
severity) and unexpected suspected adverse events (reactions).   
 
Targeted adverse events and unexpected suspected adverse reactions 
will be documented using the form in appendix V at the following time 
points:   
 
First cycle only: 
• Before the 1st dose of ALT-803 
• After the 1st dose (cycle 1 only) 
o 1-4 hours post  
o 6 hours +/- 1 hour  
o 24 hours +/- 2 hours  
o 48 hours +/- 2 hours  
o 96 hours +/- 2 hours 
• Before the 2nd, 3rd, and 4th doses of ALT-803 
• After the 2nd, 3rd, and 4th doses of ALT-803 
o At time of discharge from clinic (or 6 hours +/- 1 hour post dose if 
inpatient)  
o 24 hours +/- 2 hours  
• 1 week after the last dose of ALT-803  
 
Subsequent cycles: 
• Before each dose 
• At time of discharge from clinic (or 6 hours +/- 1 hour post dose if 
inpatient) 
• 24 hours +/- 2 hours 
• 1 week after the last dose of ALT-803 of each treatment cycle 

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Final Treatment Visit 
• 4 weeks after the last dose of ALT-803 (final treatment visit)  
 
At each of these time points the worst grade of the targeted toxicity since 
the previous assessment will be recorded in addition to any unexpected 
toxicities felt at least possibly related to ALT-803.  If it has been greater 
than 24 hours since the last assessment (i.e. before each dose, 1 week 
after 4th dose) toxicities will be assessed for the previous 24 hours. 
 
After the final treatment visit, monitoring for adverse events will become 
less frequent based on the follow-up schedule in section 7.1 and only 
events that meet the definition of serious, are at least possibly related to 
ALT-803, and are unexpected will be documented in OnCore and, if 
occurring at an affiliate site, reported to the MCC Study Coordinator per 
section 9.3.  
 
In addition, although not always a reportable event, date and cause of 
death will be recorded in OnCore upon knowledge in the follow-up tab. 
 
9.3 
Affiliate Event Reporting to the U of MN MCC 
Serious events:   
 
Study Time 
Point 
Beginning with the first 
dose of ALT-803 through 
the final treatment visit 
 
After the final 
treatment visit 
Reporting 
Requirements 
any event meeting the 
definition of serious, 
regardless of attribution 
or expectedness 
 
any event that is 
serious, 
unexpected and 
felt to be at least 
possibly related 
to ALT-803 
 
Reports are to be submitted to the Study Coordinator at the University of 
Minnesota Masonic Cancer Center (MCC) within 24 hours of knowledge 
using the SAE reporting form found in OnCore.  The MCC Study 
Coordinator will facilitate reporting to the University Of Minnesota IRB, 
Altor Bioscience, and the FDA as required.   
 
Dose Limiting Toxicity (DLT) – Dose Finding Phase cycle 1 only: 
Events counting toward dose limiting toxicity (DLT) as defined in section 
6.2.1.1 must be reported to the MCC Study Coordinator within 24 hours of 
knowledge using the Event Form found OnCore under the reports tab. 
 
Stopping Rule Events – Extended Phase only:   

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Events counting toward a study early stopping rule per section 11.4 must 
be reported to the MCC Study Coordinator within 24 hours of knowledge 
using the Event Form found OnCore under the reports tab. 
 
Events that count toward a DLT or an early stopping rule do not 
necessarily constitute an adverse event requiring expedited reporting and 
should be reported as such only if they meet the criteria for expedited 
reporting as defined in section 9.1. 
 
Affiliate institutions will be responsible for submitting adverse events to 
their institutional IRB and any other required local regulatory entities. 
 
 

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9.4 
Required Reporting by the U of MN to the U of MN IRB, the FDA, and 
Altor BioScience 
Note:  Affiliate sites report adverse events to the Study Coordinator at the 
University of Minnesota per section 9.3.  The Study Coordinator and 
personnel at the University of Minnesota are responsible for reporting to 
the entities in the below table. 
 
 
 
10 
Study Status Updates, Data Collection, and Monitoring 
 
10.1 
Study Status Updates 
At least monthly teleconferences will be held between the PI (Dr. Miller) 
and key representatives of the affiliate sites to discuss enrollment, 
treatment tolerability and toxicity, disease response, and sample 
collection, as well as other relevant issues.   Depending on the speed of 
enrollment and the level of patient issues, these teleconferences may be 
held more frequently or cancelled if there are no issues to discuss. 
Agency 
Criteria for reporting 
Timeframe 
Form to 
Use 
Submission 
address/ fax 
numbers 
Copy AE to: 
U of MN 
IRB 
Events requiring prompt reporting including, but not 
limited to unanticipated death of a locally enrolled 
subject(s); new or increased risk; any adverse event  
that require a change to the protocol or consent form or 
any protocol deviation that resulting in harm.  refer to 
http://www.research.umn.edu/irb/guidance/ae.html#.VC
7xraI0-sh 
Within 5 
business 
days of 
event 
discovery 
 
 Report 
Form 
irb@umn.edu 
 with a copy to 
Altor 
BioScience 
and each 
institutional PI 
 
SAE Coordinator 
mcc-
saes@umn.edu 
FDA 
 
Unexpected and fatal or life threatening suspected adverse 
reaction 
 
As soon as 
possible 
but no later 
than 7 
Calendar-
Days 
UMCC 
SAE 
form  
Submit as an 
amendment to 
IND with a 
copy to Altor 
BioScience 
and each 
institutional PI 
1) Serious and unexpected suspected adverse reaction or 
2)  increased occurrence of serious suspected adverse 
reactions over that listed in the protocol or investigator 
brochure or 
3) findings from other sources (other studies, animal or in vitro 
testing) 
As soon as 
possible 
but no later 
than 15 
Calendar-
Days 
All other events per CFR 312.33 
At time of 
IND annual 
report 
Summary 
format 
Submit as part 
of the IND 
annual report 
Altor BioScience 
Note:  Events due to the disease under treatment or an underlying medical condition will not require expedited reporting 
to the FDA for the purposes of this study 
Cancer 
Center 
SAE 
Coordinator 
Any event that counts toward a DLT (cycle 1 dose finding 
phase) or stopping rule (extended phase) 
Upon 
reporting 
 Event 
Form 
SAE 
Coordinator 
mcc-
saes@umn.ed
u 
Altor Bioscience 

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10.2 Data Management 
This study will report clinical data using The Online Enterprise Research 
Management Environment (OnCoreTM), a web based Oracle® database 
utilizing study specific electronic case report forms.  Key study personnel 
will be trained on the use of OnCore and will comply with protocol specific 
instructions embedded within the OnCore forms.  Patient demographics, 
patient specific study treatment calendars, targeted adverse events, 
reporting of deaths, and other information required for IND annual 
reporting will be placed in OnCore and other research databases 
maintained by MCC IT.   
10.3 
Case Report Forms 
Participant data will be collected using protocol specific electronic case 
report forms (e-CRFs) developed within OnCore based on its library of 
standardized forms.  The e-CRF will be approved by the study’s Principal 
Investigator and the Biostatistician prior to release for use.  The Study 
Coordinator or designee will be responsible for completing e-CRFs based 
on the patient specific calendar, and updating the patient record until 
patient death or end of required study participation. 
10.4 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://www.cancer.umn.edu/prod/groups/ahc/@pub/ 
@ahc/@mcc/documents/content/ ahc_content_487799.pdf 
 
 
For the purposes of data and safety monitoring, this study is classified as 
high risk (investigator initiated protocol under an IND).  Therefore the 
following requirements will be fulfilled: 
 The Masonic Cancer Center Data and Safety Monitoring Council 
(DSMC) will review the study’s progress at least quarterly (a copy pf 
the Progress Report will be provided to each affiliate site). 
 The PI will comply with at least twice yearly monitoring of the clinical 
protocol by the Masonic Cancer Center monitoring services.   
 The PI with the MCC CTO has oversight responsibility for trial 
monitoring at affiliate sites 
 The PI will oversee the submission of all reportable adverse events per 
the definition of reportable in section 9.4 to the Masonic Cancer 
Center’s SAE Coordinator, the University of Minnesota IRB, FDA, and 
Altor BioScience.   
 
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 (Dr. 
Miller) will submit a progress report annually.  The report will be submitted 
within 60 days of the anniversary date that the IND went into effect.  A 
copy of the IND annual report will be provided to Altor BioScience and 
each affiliate institution. 
10.5 
Monitoring 
The PI (Dr. Miller) with the MCC 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 
(http://www.cancer.umn.edu/prod/groups/ahc/@pub/@ahc/@mcc/docume
nts/content/ahc_content_487799.pdf) and the CTO Affiliate and Satellite 
Site Monitoring SOPs.   
10.6 
Record Retention 
The investigator will retain study records including source data, copies of 
case report form, consent forms, HIPAA authorizations, and all study 
correspondence in a secured facility for at least 6 years after the study file 
is closed with the IRB and FDA.   
 
In addition, the University of Minnesota Clinical Trials Office (CTO) will 
keep a master log of all patients participating in the study with sufficient 
information to allow retrieval of the medical records for that patient.  
 
Please contact the U of MN CTO before destroying any study related 
records. 
 
 
 
11 
Statistical Considerations 
This phase I/II clinical trial includes two phases. The dose finding phase is a 
modified version of a phase I trial and the extended phase is a modified version 
of phase II trial. 
11.1 
Dose Finding Phase 
The primary objective of this phase is to define the “maximum tolerated, 
minimum efficacious dose” (MTD/MED) of interleukin-15 (IL-15) super 
agonist complex (ALT-803) when given once weekly for 4 weeks in 
patients with hematologic malignancy who have relapsed after allogeneic 
transplant. The study will follow a standard 3+3 design of dose escalation 
for toxicity with an added feature of stopping early if efficacy is confirmed. 
The reason for using this modified 3+3 design is because it is possible for 
the MED to be below the MTD. Although the exact threshold for MED is 
unknown, given the action of IL-15 to stimulate homeostatic expansion 

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CD8+ T cells and NK cells, we will use the absolute lymphocyte count 
(readily available on a clinical CBC) as a surrogate biomarker of biologic 
activity to define the MED. We would like to identify MTD or MED 
whichever is encountered first at the dose finding phase and start the 
extended stage with the identified MTD or MED. 
 
There are six dose levels of ALT-803 to determine the MTD/MED: 1, 3, 6, 
10, 20, and 30 mcg/kg (in April 2016, the two highest dose levels were 
reduced to 15 and 20 mcg/kg as it was questioned if doubling the dose 
with each dose level change was excessive).  Within a dose level, the 1st 
patient must receive a minimum of 2 doses before additional patients are 
enrolled.  The 1st dose for subsequent patients within a dose level must be 
separated by at least 72 hours.  Dose escalation to the next level cannot 
proceed until the following conditions are met: 
• All patients at the current dose level have completed at least 3 of the 4 
planned ALT-803 doses  
• The maximum tolerated dose (MTD) has not been exceeded   
• The minimum efficacious dose (MED) of ALT-803 dose has not been 
reached 
 
Intra-patient dose escalation is not allowed. 
 
Dose limiting toxicity (DLT) is generally defined as  
• any treatment-emergent non-hematologic grade 3 toxicity lasting 
more than 48 hours with the exceptions detailed in section 6.2.1.1 
• any treatment-emergent non-hematologic grade 4 or 5 toxicity  
• grade III or IV acute GVHD within 6 weeks of the 1st dose of ALT-
803  
 
Efficacy is defined as an absolute lymphocyte count (ALC) of > 2500 
cells/μl sustained for more than 24 hours in ≥ 2 of 3 patients (or ≥ 4 of 6) 
within a cohort.   
 
The specific dose finding procedure based on traditional 3+3 design to 
determine MTD or MED is listed in the following table. The basic idea is 
that: 
• If the current dose level is neither too toxic nor very effective, 
escalate to the next higher dose level;  
• If the current dose level is toxic to a certain degree, further evaluate 
the current dose level for both toxicity and efficacy. If it turns out the 
current dose is neither too toxic nor very effective, escalate to the 
next higher dose level; if the current dose is very effective, stop and 
declare the current dose the MED (below MTD); if the current dose 
is too toxic, regardless of its efficacy, de-escalate to the next lower 
dose level.  

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• If the current dose level is too toxic, regardless of its efficacy, de-
escalate to the next lower dose level.   
 
The number of patients required in this dose finding phase would range 
from 6 patients at minimum to 36 patients at maximum.   
 
Note:  In February 2014 dose level 1 was expanded to 6 patients total to 
gain additional experience before continuing with the dose escalation plan 
(refer to section 6.2.1 for rationale). 
 
Note:  with the April 28, 2015 version of the protocol the administration 
route was changed from intravenous to subcutaneous and dose level 3 (6 
mcg/kg) was repeated to ensure safety. 
 
Note:  with the April 2016 version of the protocol, dose level 4 was 
expanded to enroll 6 patients despite the absence of dose limiting toxicity 
in the 1st couple of patients treated at this dose level.  Clinical benefit (at 
least 1 complete response and several patients with stable disease) has 
been noted in the absence of unacceptable toxicity.  Therefore rather than 
continuing the dose escalation plan and moving to dose level 5 (ALT-803 
at 20 mcg/kg), it was decided to enroll 6 at dose level 4 to gain additional 
toxicity data.  Once 6 evaluable patients are treated at the ALT-803 10 
mcg/kg level a decision will be made to either continue dose escalation, or 
more likely, proceed to the extended phase using dose level 4. 
 
 
Dose-finding procedure of 3+3 design for determining MTD or MED, whichever 
is encountered first    
 
# of patients 
with DLT at 
current dose 
level  
Step 1 Decision 
Rule 
# of patients 
with efficacy 
at current 
dose level 
Step 2 Decision Rule 
0/3 with DLT  
 check  efficacy   
≤ 1/3 with 
efficacy  
Escalate to current dose level+1 for the next 3 
new patients. 
≥ 2/3 with 
efficacy  
• 
When 6 patients have been treated at 
current dose level, if ≥ 4/6 patients with 
efficacy, declare current dose level the 
MED; otherwise, escalate to current dose 
level +1. 
• 
When only 3 patients have been treated at 
dose level i, enter 3 new patients at dose 
level i. If ≥ 4/6 patients with efficacy, declare 
dose i the MED; otherwise, escalate to dose 
level i+1.  
1/3 with DLT 
Add 3 new patients 
at current dose level. 
If 0/3 with DLT ( i.e. 
1/6 with DLT)  
≤ 1/3 with 
efficacy  
Escalate to current dose level +1 for the next 3 
new patients. 
≥ 2/3 with 
efficacy  
6 patients have been treated at current dose 
level. If ≥ 4/6 with efficacy, declare current dose 
level the MED; otherwise, escalate to current 

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# of patients 
with DLT at 
current dose 
level  
Step 1 Decision 
Rule 
# of patients 
with efficacy 
at current 
dose level 
Step 2 Decision Rule 
dose level +1. 
Add 3 new patients 
at current dose level.  
If ≥ 1/3 with DLT (i.e. 
≥ 2/6 with DLT)  
Regardless of 
efficacy  
Current dose level is above the MTD. De-
escalation starts: 
• 
If 6 patients have been treated at current 
dose level -1, declare current dose level -1 
the MTD; 
• 
If only 3 patients have been treated at 
current dose level -1, add 3 new patients at 
this dose level. If ≤ 1/6 with DLT and ≥ 4/6 
with efficacy, declare current dose level -1 
both the MTD and MED; if ≤ 1/6 with DLT 
and ≤ 3/6 with efficacy, declare current dose 
level -1 the MTD; if ≥ 2/6 with DLT, 
regardless of efficacy, dose de-escalation 
continues according to the same scheme. 
≥ 2/3 with DLT 
 
Regardless of 
efficacy  
Current dose level is above the MTD. De-
escalation starts: 
• 
If 6 patients have been treated at current 
dose level -1, declare current dose level -1 
the MTD; 
• 
If only 3 patients have been treated at 
current dose level -1, add 3 new patients at 
this dose level. If ≤ 1/6 with DLT and ≥ 4/6 
with efficacy, declare current dose level -1 
both the MTD and MED; if ≤ 1/6 with DLT 
and ≤ 3/6 with efficacy, declare current dose 
level -1 the MTD; if ≥ 2/6 with DLT, 
regardless of efficacy, dose de-escalation 
continues according to the same scheme. 
11.2 
The Extended Phase  
The primary objective of this phase is to study the potential efficacy of 
IL-15 super agonist complex, ALT-803, in patients with hematologic 
malignancy who have relapsed after allogeneic transplant.  The ALT-803 
MTD/MED identified during dose finding will be the dose used during this 
enrollment.  Efficacy of ALT-803 will be measured using rates of 
remission induction.  
 
An optimal Simon’s two-stage design will be used in this phase to test 
the null hypothesis of ≤ 10% remission induction versus the alternative 
hypothesis of ≥ 30% remission induction.  For sample size estimation, we 
set the power (the probability of concluding efficacy of ALT-803 given it is 
truly effective) at 80%, and significance level (the probability of concluding 
efficacy of ALT-803 given it is actually not effective) at 0.05.  If 2 or fewer 
of the first 14 patients (including the 6 patients treated at the same dose 
level from the dose finding phase) respond to ALT-803, we will conclude 
ALT-803 is unworthy of further study and terminate the trial early. 

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Otherwise, the trial goes on to the second stage, and an additional 23 
patients will be studied. If the total number of patients responding to ALT-
803 is ≤ 5, we will conclude ALT-803 is not effective.   
 
11.3 
Enrollment Plan 
With the change in April 2016 and enrollment of 2 additional patients at 
dose level 4, the minimum additional enrollment during the dose-
escalation phase will be 2 with a maximum additional 14 patients (2 at 
dose level 4 and 6 each at the 2 remaining doses).  After completion of the 
dose escalation phase, a minimum of 8 additional patients with a 
maximum of 31 additional patients will be required to complete the trial. 
The maximum total additional patients with both phases will be 45 with 37 
evaluable at the end of the phase II trial. 
 
Based on enrollment in this protocol over the past year (N=17), our goal is 
to complete this study in 24 to 36 months. 
 
A patient will be replaced and the ALT-803 dose level cohort reassigned if: 
• the patient does not start ALT-803 
• if more than 1 dose of ALT-803 is missed for a reason other than 
DLT 
• patient requires more than two separate 1 week delays from the 
planned ALT-803 administration day  
11.4 
Stopping Rules  
Excessive Toxicity  
Because of severity of the diseases, toxicity of ALT-803 needs to be 
evaluated carefully. The hypothesized rate of having grade 3-4 non-
hematologic, non-relapse and non-infectious toxicity (except for fevers 
alone) based on the NCI’s CTCAE version 4 is encountered is 5%.  
 
The goal is to construct a boundary based on toxicity such that the 
probability of early stopping is at most 10% if the true toxicity is equal 
to 5% and our sample size is at most 31 patients. This means 
enrollment will be stopped and the study re-evaluated if there are 2 
patients with a grade 3-4 non-hematologic, non-relapse and non-
infectious toxicity (except for fevers alone) occurring out of the first 7 
patients, 3 out of 16, 4 out of 29, or 5 at any time.   
 
Overall Mortality At Day 60 Post Relapse 
The hypothesized rate of overall mortality at day 60 is 20%.  
 
The goal is to construct a boundary based on mortality such that the 
probability of early stopping is at most 10% if the true mortality rate is 
equal to 20% and our sample size is at most 31 patients. This means 

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enrollment will be stopped and the study re-evaluated if there are 3 
patients with an event out of the first 4 patients, 4 out of 6, 5 out of 10, 
6 out 13, 7 out of 16, 8 out of 20, 9 out of 23, 10 out of 27 or 11 at any 
time.    
 
Grade III-IV Acute GvHD 
The hypothesized rate of having grade III-IV Acute GvHD is 5%.  
 
The goal is to construct a boundary based on toxicity such that the 
probability of early stopping is at most 10% if the true toxicity is equal 
to 5% and our sample size is at most 31patients. This means 
enrollment will be stopped and the study re-evaluated if there are 2 
patients with GVHD occurring within 6 weeks of the 1st dose of ALT-
803 out of the first 7 patients, 3 out of 16, 4 out of 29 or 5 at any time.  
The stopping rules were developed using Pocock stopping 
boundaries.(28) 
 
Note: these stopping rules are based on a per patient count, not the 
absolute number of events experienced by an individual patient.  No single 
patient can count more than once toward these stopping rules. 
11.5 Statistical Analysis Plan 
Descriptive statistics will be calculated for correlative outcomes such as 
number and function of NK cells, T cells, and T regulatory cells.  The 
changes in these correlates pre and post therapy will be evaluated using 
either nonparametric Wilcoxon signed rank test or parametric paired t test. 
For time-to-event data, Kaplan-Meier curves will be generated if no 
competing risk is presented for the event, otherwise cumulative incidence 
will be calculated for the event. 
 
12 
Conduct of the Study 
12.1 Good Clinical Practice 
The study will be conducted in accordance 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.   
12.2 Ethical Considerations 
The study will be conducted in accordance with ethical principles founded 
in the Declaration of Helsinki.  The IRB will review all appropriate study 
documentation in order to safeguard the rights, safety and well-being of 
the patients.  The study will only be conducted at sites where IRB approval 
has been obtained.  The protocol, consent, written information given to the 

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patients, safety updates, progress reports, and any revisions to these 
documents will be provided to the IRB by the Investigator.   
 
13 
References 
 
1. Marmont AM, Horowitz MM, Gale RP et al.: T-Cell Depletion of HLA-Identical Transplants in 
Leukemia. Blood 78:2120-2130, 1991. 
2. Sullivan KM, Weiden PL, Storb R, et al. Influence of acute and chronic graft-versus-host disease 
on relapse and survival after bone marrow transplantation from HLA-identical siblings as 
treatment of acute and chronic leukemia. Blood. 1989;73(6):1720-1728. 
3. Wagner JE, Zahurak M, Piantodosi S et al.: Bone Marrow Transplantation of Chronic 
Myelogenous Leukemia in Chronic Phase: Evaluation of Risks and Benefits. J Clin Oncol 10:779, 
1992. 
4. Luft T, Goldschmidt H, Ho AD, et al: Dissociation of Putative Graft-Versus-Haematopoiesis and 
Graft-Versus-Myeloma Effects in Patients With Rapidly Progressive Multiple Myeloma.  Brit. J of 
Haematology.  123(4):  646-53, Nov 2003. 
5. Kroger N, Schwerdtfeger R, Kiehl M, et al.:  Autologous Stem Cell Transplantation Followed by a 
Dose-Reduced Allograft Induces High Complete Remission Rate in Multiple Myeloma.  Blood 
100(3):  755-60, 2002 Aug 1. 
6. Bostrom B, Woods WG, Nesbit ME et al.: Successful Reinduction of Patients with Acute 
Lymphoblastic Leukemia who Relapse Following Bone Marrow Transplantation. J Clin Oncol 
5:376, 1987. 
7. Frassoni F, Barrett AJ, Granena A et al.: Relapse After Allogeneic Bone Marrow Transplantation 
for Acute Leukaemia: A Survey by the E.B.M.T. of 117 Cases. Br J Haematol 70:317, 1988. 
8. Mortimer J, Blinder MA, Schulman S et al.: Relapse of Acute Leukemia After Marrow 
Transplantation: Natural History and Results of Subsequent Therapy. 7:50, 1989. 
9. Mrsic M, Horowitz MM, Atkinson K, et al. Second HLA-identical sibling transplants for leukemia 
recurrence. Bone Marrow Transplant. 1992;9(4):269-275. 
10. Radich JP, Sanders JE, Buckner CD et al.: Second Allogeneic Marrow Transplantation for 
Patients with Recurrent Leukemia After Initial Transplant with Total-Body Irradiation-Containing 
Regimens. J Clin Oncol 11, 2, 304-313, 1993. 
11. Barrett AJ, Locatelli F, Treleaven JG, Gratwohl A, Szydlo R, Zwaan FE: Second Transplants for 
Leukaemic Relapse After Bone Marrow Transplantation: High Early Mortality but Favourable 
Effect of Chronic GVHD on Continued Remission. Br J Haematol 79:567, 1991. 
12. Wagner JE, Vogelsang GB, Zehnbauer BA, Griffin CA, Shah N, Santos GW. Relapse of leukemia 
after bone marrow transplantation: Effect of second myeloablative therapy. Bone Marrow 
Transplant. 1992;9(3):205-209. 
13. Cullis JO, Schwarer AP, Hughes TP et al.: Second Transplants for Patients With Chronic Myeloid 
Leukaemia in Relapse After Original Transplant with T-Depleted Donor Marrow: Feasibility of 
Using Busulphan Alone for Re-Conditioning. Br J Haematol 80:33, 1992. 
14. Miller JS, Weisdorf DJ, Burns LJ, et al. Lymphodepletion followed by donor lymphocyte infusion 
(DLI) causes significantly more acute graft-versus-host disease than DLI alone. Blood. 
2007;110(7):2761-2763.  
15. Warlick ED, DeFor T, Blazar BR, et al. Successful remission rates and survival after 
lymphodepleting chemotherapy and donor lymphocyte infusion for relapsed hematologic 
malignancies postallogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 
2012;18(3):480-486.  
16. Cheever MA. Twelve immunotherapy drugs that could cure cancers. Immunol Rev. 
2008;222:357-368. 
17. Waldmann, T. A. The biology of interleukin-2 and interleukin-15: implications for cancer therapy 
and vaccine design. Nat Rev Immunol, 2006;6(8), 595-601. 
 

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18. Germeau C, Ma W, Schiavetti F, et al. High frequency of antitumor T cells in the blood of 
melanoma patients before and after vaccination with tumor antigens. J Exp Med. 
2005;201(2):241-248.  
19. Steel JC, Waldmann TA, Morris JC. Interleukin-15 biology and its therapeutic implications in 
cancer. Trends Pharmacol Sci. 2012;33(1):35-41.  
20. 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. 
21. Zhu X, Marcus W, Xu W, et al.  Novel Human Interleukin-15 Agonists.  J of Immunology, 2009, 
183(6): 3598–3607. 
22. Bergamaschi C, Bear J, Rosati M, et al. Circulating IL-15 exists as heterodimeric complex with 
soluble IL-15Ralpha in human and mouse serum. Blood. 2012;120(1):e1-8.  
23. Rubinstein MP, Kovar M, Purton JF, et al. Converting IL-15 to a superagonist by binding to 
soluble IL-15R{alpha}. Proc Natl Acad Sci U S A. 2006;103(24):9166-9171.  
24. Stoklasek TA, Schluns KS, Lefrancois L. Combined IL-15/IL-15Ralpha immunotherapy maximizes 
IL-15 activity in vivo. J Immunol. 2006;177(9):6072-6080. 
25. Mortier E, Quemener A, Vusio P, et al. Soluble interleukin-15 receptor alpha (IL-15R alpha)-sushi 
as a selective and potent agonist of IL-15 action through IL-15R beta/gamma. hyperagonist IL-15 
x IL-15R alpha fusion proteins. J Biol Chem. 2006;281(3):1612-1619. 
26. 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. 
27. Conlon KC, Lugli E, Welles HC, et al. T Redistribution, Hyperproliferation, Activation of Natural 
Killer Cells and CD8 T Cells, and Cytokine Production During First-in-Human Clinical Trial of 
Recombinant Human Interleukin-15 in Patients With Cancer.  J Clin Oncol 33:74-82. 
28. Ivanova I, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials in Oncology. 
Biometrics 2005, 61: 540-545 
 
 
 

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Appendix I –Patient Eligibility Checklist  
IL-15 Super Agonist ALT-803 to Treat Relapse Of Hematologic Malignancy After 
Allogeneic Stem Cell Transplantation (HM2013-12) 
Eligibility Checklist – page 1 of 2 
Patient initials   
     
 
 
Patient ID
-
  
 
 
1st 2 initials of first name + 1st 2 initials of last name 
        3 letter site code – Seq # (i.e. 01, 02, 03, etc.) 
 
INCLUSION CRITERIA  
A "NO" response to any of the following disqualifies the patient from study entry. 
 
 
 
 
Yes      No 
1. 
Relapse after previous allogeneic stem cell transplant for one of the following hematologic malignancies 
- acute myelogenous leukemia, acute lymphoblastic leukemia, lymphoma, myelodysplastic syndrome, 
myeloma, chronic lymphocytic leukemia, chronic myelogenous leukemia meeting the following: 
o For non-CML, relapse will be defined based on disease specific morphologic criteria from a bone 
marrow biopsy and aspirate or recurrence of disease specific cytogenetics.  For disease specific 
definition of relapse, see appendix III.  Relapse can be determined morphologically with < 5 percent 
blasts if definitive relapse can be determined.  Equivocal results for relapse should result in a 
repeated test after an appropriate time interval (suggested 1 month) to determine eligibility. 
o For CML, relapse will be defined as any cytogenetic evidence of a Philadelphia chromosome or 
persistence of BCR/ABL rearrangements by molecular testing on at least two measurements over a 
6 month interval.  If cytogenetics are normal and there is PCR evidence of a BCR/ABL fusion, 
patients will be eligible if they have evidence of a quantitative increase in CML measured either by 
quantitative PCR or by fluorescent in situ hybridization (FISH).  
o For Chronic Phase CML patients only: 
• must have failed (no response in 3 months or incomplete response at 6 months) or refused 
treatment with TKI therapy 
• must have failed (defined as incomplete response or relapse) or refused DLI 
 
 
2. Relapse must be ≥ 60 days after transplant 
 
 
3. Prior DLI is allowed, however not within the 30 days before the 1st dose of ALT-803 
 
 
4. Minimum donor chimerism of 10%  
 
 
5. ≥ 18 years of age 
 
 
6. Karnofsky performance status ≥ 70%   PS = 
% 
 
 
7. 
Adequate organ function within 14 days (30 days for cardiac) of enrollment defined as: 
AST (SGOT) 
< 5 x UNL 
 
/
/
 
ALT (SGPT) 
< 5 x UNL 
 
/
/
 
creatinine 
≤ 2.0 mg/dl 
.
 
/
/
 
 
 
 
 
 
 
 
 
Cardiac 
LVEF > 40% 
% 
/
/
 
 
 
 

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Yes      
No 
 
 
 
8.  Ability to be off prednisone and other immunosuppressive drugs for at least 14 days before first 
dose of study drug 
 
 
9.  Patient agrees to stay within a reasonable distance (i.e. 30 minutes travel time) of the study site for 
the duration of the first treatment cycle through 24 hours after the last dose  
 
 
10.  Women of child bearing potential and men with partners of child bearing potential must agree to use 
effective contraception during therapy and for 4 months after completion of therapy 
 
 
11.  Voluntary written consent 
 
 

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IL-15 Super Agonist ALT-803 to Treat Relapse Of Hematologic Malignancy After 
Allogeneic Stem Cell Transplantation (HM2013-12) 
 
Eligibility Checklist – page 2 of 2 
Patient initials   
     
 
 
EXCLUSION CRITERIA 
A "YES" response to any of the following disqualifies the patient from study entry. 
 
 
Yes      No 
12.  Post-transplant lymphoproliferative diseases (often referred to as EBV-associated lymphomas)  
 
 
13.  
Known active CNS leukemia or lymphoma – patients with previously treated CNS disease is 
permitted if neurologically stable with no ongoing or anticipated need for steroid therapy are 
eligible 
 
 
14.  Ongoing active acute or chronic GVHD requiring immunosuppressive therapy or signs of aGVHD 
or cGVHD requiring treatment 
 
 
15.  Concurrent chemotherapy (except hydroxyurea) or IL-2 therapy or anticipated need during the 
study treatment and for 1 week after the last dose of ALT-803  
 
 
16.  Pregnant or lactating – Women of child bearing potential must have a negative pregnancy test 
within 14 days of study treatment start 
 
 
17.  
Class II or greater New York Heart Association Functional Classification criteria (appendix II) or 
serious cardiac arrhythmias likely to increase the risk of cardiac complications of cytokine 
therapy (e.g. ventricular tachycardia, frequent ventricular ectopy, or supraventricular 
tachyarrhythmia requiring chronic therapy 
 
 
18.  Marked baseline prolongation of QT/QTc interval (e.g. demonstration of a QTc interval greater 
than 500 milliseconds) 
 
 
19.  
New progressive pulmonary infiltrates on screening chest x-ray or chest CT scan for which 
evaluation with bronchoscopy is not feasible.  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). 
 
 
20.  Active bacterial, fungal, or viral infections – all prior infections must have resolved following 
optimal therapy  
 
 
21.  
Known positive hepatitis C serology or active hepatitis B infection because of the risk of hepatic 
inflammation and the possible confounding of drug toxicity assessment  – chronic asymptomatic 
viral hepatitis is allowed 
 
 
22.  Known HIV positive because the effect of IL-15 viral loads, HIV immunity, and infectivity of 
proliferating T cells is unknown 
 
 
23.  History of severe asthma, presently on chronic medications (a history of mild asthma not 
requiring therapy is eligible) 
 
 
 
 
Date consent form signed: 
 
 
 
 
 
Having obtained consent and reviewed each of the inclusion/exclusion criteria, I verify that this patient is:  
 
  Eligible 
  Ineligible    Date registered  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of person verifying eligibility 
 
 
 
Date 
 
 

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

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Appendix III – Disease Specific Response Criteria  
 
CHRONIC MYELOGENOUS LEUKEMIA (CML) RESPONSE CRITERIA 
 
In chronic phase CML, a hematologic response was defined as a 50% reduction in WBC counts from baseline sustained 
for at least 2 weeks. A Complete Hematologic Response (CHR) was defined as WBC < 10,000 per mm3 and platelet 
count < 450,000 per mm3 maintained for at least 4 weeks.  
 
In blast crisis CML, a hematologic response is defined as a decrease in bone marrow blast count to < 5%, the 
disappearance of blasts in the peripheral blood, an absolute neutrophil count > 1000 cells/mm3 and platelet count > 
100,000 cells/mm3.  Patients who did not meet the criteria for a complete hematologic response may be categorized 
according to marrow response.  
A marrow response is defined as either a decrease in the blast count to < 5% or between 5-15% regardless of peripheral 
blood cell counts.  
• 
Disease progression is defined as an increase in marrow blasts > 15%, increase in peripheral blood blasts > 5% 
or WBC > 20,000 cells/mm3.  
• 
A relapse is defined as evidence of disease progression or death.  
 
Cytogenetic Response 
Cytogenetic responses (CR) were defined in terms of percentage of cells in metaphase existing within the bone marrow 
that were Philadelphia (Ph) chromosome positive. These responses were based upon a sample size of twenty cells in 
metaphase.  
• 
A Complete Cytogenetic Response (CCR) was defined as no Ph(+) cells.  
• 
A partial CR was defined as < 35% cells that were Ph(+).  
• 
A minor CR was defined as 35-65% cells that were Ph(+).  
• 
A lack of CR was identified when >65% cells were Ph(+).  
• 
A major cytogenetic response (MCR) is comprised of complete and partial responses.  
Molecular response 
Standardization studies are ongoing and definition of molecular response currently varies. 
• 
Complete molecular response: no detectable bcr-abl transcripts by RT-PCR.  
• 
Major molecular response: ≥ 3-log reduction in the level of bcr-abl transcripts or bcr-abl/abl ratio ≤ 0.05%.  
 
 
 
 

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

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ACUTE LYMPHOCYTIC LEUKEMIA (ALL) RESPONSE CRITERIA 
 
Bone Marrow: 
A1.Maturation of all cell lines: and <5% blasts and no Auer rods. 
A2. Same as A1, except blasts ≥ 5% and < 25%. 
A3. Failure to meet the criteria for A1 or A2. 
 
Peripheral Blood:  
B1. Neutrophils > 1,000/mcl; and platelets > 100,000/mcl; and no leukemia blasts in the peripheral blood. 
B2. Failure to meet the criteria for B1. 
 
Extramedullary Disease: 
C1. None 
C2. Any  
 
CR 
Attainment of A1 marrow status and B1 peripheral blood status and C1 extramedullary disease 
status for a period of at least 28 days. 
CRi 
CR with incomplete blood count recovery: Same as CR but platelets ≤ 100,000/mcl and/or 
neutrophils ≤ 1,000/mcl. 
PR 
Partial Response: All of the above criteria for CR must be met, except that the bone marrow may 
contain ≥ 5% but less than 25% blasts,  
or 
≤ 5% blasts in the presence of Auer rods or abnormal morphology 
Failure – 
resistant 
disease 
Resistant Disease: Patient survives ≥ 7 days following completion of initial treatment course with 
persistent leukemia in the last peripheral blood smear or bone marrow, or with persistent 
extramedullary disease. 
Failure – 
aplasia 
Aplasia: Patient survives ≥ 7 days following completion of initial treatment course then dies while 
cytopenic, with the last post-induction bone marrow aplastic or hypoplastic (i.e. < 20% cellularity) 
and without leukemia blasts. 
Failure - 
indeterminate 
Indeterminate:  
(a) Patient survives < 7 days after completion of initial treatment course;  
or 
(b) patient survives ≥ 7 days following completion of initial treatment course then dies with no 
persistent leukemia in the peripheral smear but no post-induction bone marrow examination. 
relapse from 
CR 
Relapse:  Reappearance of leukemia blasts in the peripheral blood; or > 5% blasts in the bone 
marrow not attributable to another cause (e.g., recovery of normal cells following chemotherapy-
induced aplasia); or appearance or reappearance of extra-medullary disease. 
 
 
 
 
 

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CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) RESPONSE CRITERIA 
 
Complete Remission 
CR requires all of the following criteria as assessed at least 3 months after completion of therapy: 
• 
Absence of clonal lymphocytes in the peripheral blood. 
• 
Absence of significant lymphadenopathy (e.g., lymph nodes > 1.5 cm in diameter) by physical examination or CT 
scan. 
• 
No hepatomegaly or splenomegaly by physical examination or by CT scan. 
• 
Absence of constitutional symptoms. 
• 
Blood counts above the following values: 
o 
Polymorphonuclear leukocytes 1.5 x 109/L or more. 
o 
Platelets more than 100 x 109/L 
o 
Hemoglobin more than 11.0 g/dL; untransfused. 
A bone marrow aspirate and biopsy should be performed at least 3 months after the last treatment if clinical and 
laboratory results demonstrate a CR. The marrow should be analyzed by flow cytometry and/or immunohistochemistry 
to demonstrate that the marrow is free of clonal B-CLL cells. Cases with residual CLL cells by conventional flow 
cytometry or immunohistochemistry are defined as partial remission (PR). 
 
In some cases, lymphoid nodules can be found (formerly used to define nodular PR), which often reflect residual 
disease. Therefore, these nodules should be assessed by immunohistochemistry to define whether they are 
comprised of CLL cells. 
 
CR with Incomplete Bone Marrow Recovery (CRi) 
For the definition of this category, CRi, the marrow evaluation should be performed with scrutiny and not show any 
clonal infiltrate. 
 
Partial Remission 
PR is defined by at least one of these parameters and needs to be documented for a minimal duration of 2 months: 
• A decrease in the number of blood lymphocytes by less than 50% or more from the value before therapy. 
• A decreased lymph node size by 50% or more in the sum products of up to 6 lymph nodes, or in one lymph node 
diameter if only a single lymph node was present before therapy, as assessed by CT scan. 
• No increase in any lymph node, and no new enlarged lymph node. In small lymph nodes (<2 cm), an increase of 
less than 25% is not considered to be significant. 
• A decrease in the size of the liver and/or spleen by 50% or more as defined by CT scan. 
• The blood count should show one of the following results: 
• 
Polymorphonuclear leukocytes at 1.5 x 109/L or more or 50% improvement over baseline without 
granulocyte colony-stimulating factor (G-CSF) support. 
• 
Platelet counts greater than 100 x 109/L or 50% improvement over baseline. 
• 
Hemoglobin greater than 11.0 g/dL or 50% improvement over baseline without red blood cell transfusions or 
erythropoietin support. 
 
 
Progressive Disease 
Progressive disease is characterized by at least one of the following: 
• 
Constitutional symptoms persisting for more than 1 month. 
• 
Progression of lymphadenopathy. 
• 
Appearance of any new lesion, such as enlarged lymph nodes (>1.5 cm), splenomegaly, hepatomegaly or 
other organ infiltrates. 
• 
An increase by 50% or more in greatest determined diameter of any previous site. 
• 
A lymph node of 1 to 1.5 cm must increase by 50% or more to a size greater than cm in the longest axis. A 
lymph node of more than 1.5 cm must increase to more than 2.0 cm in the longest axis. 
• 
An increase of 50% or more in the sum of the product of diameters of multiple nodes. 
• 
An increase in the liver or spleen size by 50% or more or the de novo appearance of hepatomegaly or 
splenomegaly. 
• 
An increase in the number of blood lymphocytes by 50% or more with at least 5000 B lymphocytes per 
microliter. 
• 
Transformation to a more aggressive histology (e.g., Richter syndrome). 

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Whenever possible, this diagnosis should be established by lymph node biopsy. 
After treatment: The progression of any cytopenia (unrelated to autoimmune cytopenia), as documented by a 
decrease of Hb levels by more than 2 g/dL or to less than 10 g/dL, or by a decrease of platelet counts by more than 
50% or to less than 100 x 109/L, which occurs at least 3 months after treatment, defines disease progression, if the 
marrow biopsy demonstrates an infiltrate of clonal CLL cells. 
 
Stable Disease 
Patients who have not achieved a CR or a PR, and who have not exhibited progressive disease, will be considered to 
have stable disease. 
 
 
 
 

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REVISED RESPONSE CRITERIA FOR MALIGNANT LYMPHOMA (Cheson, 2007) 
 
Response 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance of 
all evidence of 
disease 
(a) FDG-avid or PET positive 
prior to therapy; mass of any size 
permitted if PET negative (b) 
Variably FDG-avid or PET 
negative; regression to normal 
size on CT  
Not palpable, nodules 
disappeared 
Infiltrate cleared on repeat 
biopsy; if indeterminate by 
morphology, 
immunohistochemistry should 
be negative 
PR 
Regression of 
measuable disease 
and no new sites 
≥ 50% decrease in SPD of up to 
6 largest dominant masses; no 
increase in size of other nodes 
(a) FDG-avid or PET positive 
prior to therapy; one or more 
PET positive at previously 
involved site (b) Variably FDG-
avid or PET negative; regression 
on CT  
≥ 50% decrease in 
SPD of nodules (for 
single nodule in 
greatest transverse 
diameter); no 
increase in size of 
liver or spleen 
Irrelevant if positive prior to 
therapy; cell type should be 
specified 
SD 
Failure to attain 
CR/PR or PD 
(a) FDG-avid or PET positive 
prior to therapy; PET positive at 
prior sites of disease and no new 
sites on CT or PET 
 
 
 
 
(b) Variably FDG-avid or PET 
negative; no change in size of 
previous lesions on CT 
 
 
Relapsed 
disease or 
PD 
Any new lesion or 
increase by ≥ 50% 
of previously 
involved sites from 
nadir 
Appearance of a new lesion(s) > 
1.5 cm in any axis, ≥ 50% 
increase in SPD of more than 
one node, or ≥ 50% increase in 
longest diameter of a previously 
identifed node > 1 cm in short 
axis  
> 50% increase from 
nadir in the SPD of 
any previous lesions 
New or recurrent involvement 
 
 
Lesions PET positive if FDG-avid 
lymphoma or PET positive prior 
to therapy 
 
 
Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron emission tomography; CT, 
computed tomography; PR, partial remission; SPD, sum of the product of the diameters; SD, stable disease; PD, 
progressive disease.  
Cheson B, Pfistner B, Juweid, ME, et al.  Revised Response Criteria for Malignant Lymphoma.  JCO February 10, 
2007 vol. 25 no. 5 579-586. 
 

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MULTIPLE MYELOMA RESPONSE CRITERIA 
 
International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma (BGM Durie 2006) 
 
Response 
IMWG Criteria 
sCR 
CR as defined below plus normal FLC ratio and absence of clonal cells in bone marrow2 
by immunohistochemistry or immunofluorescence3 
CR 
Negative immunofixation on the serum and urine and disappearance of any soft tissue 
plasmacytomas and < 5% plasma cells in bone marrow2 
VGPR 
Serum and urine M-protein detectable by immunofixation but not on electrophoresis or > 
90% reduction in serum M-protein plus urine M-protein level < 100 mg/24 hour 
PR 
> 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by 
>90% or to < 200 mg/24 hour 
 
If the serum and urine M-protein are unmeasurable,4 a > 50% decrease in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein criteria 
 
If serum and urine M-protein are not measurable, and serum free light assay is also not 
measureable, > 50% reduction in plasma cells is required in place of M-protein, provided 
baseline bone marrow plasma cell percentage was > 30% 
 
In addition to the above listed criteria, if present at baseline, a > 50% reduction in the 
size of soft tissue plasmacytomas is also required 
MR 
Not applicable 
No change/Stable 
disease 
Not meeting criteria for CR, VGPR, PR, or progressive disease 
Plateau 
Increase of > 25% from lowest response value in any one or more of the following: 
 
•Serum M-component and/or (the absolute increase must be > 0.5 g/dL)5 
•Urine M-component and/or (the absolute increase must be > 200 mg/24 h) 
•Only in patients without measurable serum and urine M-protein levels; the difference 
between involved and uninvolved FLC levels. The absolute increase must be > 10 
mg/dL 
•Bone marrow plasma cell percentage; the absolute percentage must be > 10%6  
•Definite development of new bone lesions or soft tissue plasmacytomas or definite 
increase in the size of existing bone lesions or soft tissue plasmacytomas 
•Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL or 2.65 
mmol/L) that can be attributed solely to the plasma cell proliferative disorder 
Relapse from CR4 
(To be used only if 
the end point 
studied is DFS)7 
Any one or more of the following: 
•Reappearance of serum or urine M-protein by immunofixation or electrophoresis 
•Development of > 5% plasma cells in the bone marrow6 
•Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone lesion, 
or hypercalcaemia) 
BGM Durie et al. International uniform response criteria for multiple myeloma. Leukemia (2006) 1-7.  Adapted from Durie BGM, et al. 
Leukemia 2006; 20: 1467-1473; and Kyle RA, Rajkumar SV. Leukemia 2008;23:3-9.  
Note: A clarification to IMWG criteria for coding CR and VGPR in patients in whom the only measurable disease is by serum FLC 
levels: CR in such patients is defined as a normal FLC ratio of 0.26–1.65 in addition to CR criteria listed above. VGPR in such 
patients is defined as a >90% decrease in the difference between involved and uninvolved free light chain (FLC) levels.  
1. 
Confirmation with repeat bone marrow biopsy not needed. 
2. 
Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio 
reflecting presence of an abnormal clone is kappa/lambda of > 4:1 or < 1:2. 
3. 
All relapse categories require two consecutive assessments made at any time before classification as relapse or disease 
progression and/or the institution of any new therapy. In the IMWG criteria, CR patients must also meet the criteria for progressive 
disease shown here to be classified as progressive disease for the purposes of calculating time to progression and progression-
free survival. The definitions of relapse, clinical relapse and relapse from CR are not to be used in calculation of time to 
progression or progression-free survival.  

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4. 
For progressive disease, serum M-component increases of >1 gm/dL are sufficient to define relapse if starting M-component is >5 
g/dL. 
5. 
Relapse from CR has the 5% cut-off versus 10% for other categories of relapse. 
6. 
For purposes of calculating time to progression and progression-free survival, CR patients should also be evaluated using criteria 
listed above for progressive disease. 
 
 
 
 

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MDS RESPONSE CRITERIA 
 
Based on International Working Group 2006 Modified Criteria (BLOOD, 15 JULY 2006  VOLUME 108, NUMBER 2) 
 
• 
Complete Remission (CR): < 5% myeloblasts with normal maturation of all cell lines 
o 
Persistent dysplasia will be noted 
o 
Peripheral Blood: 
 
Hgb > 11g/dl 
 
Platelets > 100 X 109 /L 
 
Neutrophils > 1000 
 
Blasts = 0% 
• 
Partial Remission (PR): all CR criteria if abnormal before except: 
o 
BM blasts decreased by > 50% over pre-treatment but still >5% 
• 
Marrow CR: Bone marrow with < 5% myeloblasts and decrease by >50% over pretreatment with incomplete 
peripheral blood count normalization 
• 
Hematologic Improvement (HI): 
o 
Hgb: Increase by > 1.5g/dl or decreased PRBC transfusions by at least 4/8 week period (only PRBC 
given for Hgb<9.0g/dl) 
o 
Platelet Response: Absolute increase of > 30 X 109/L for those starting at >20 X 109/L For those < 20 X 
109/L at baseline increase by 100%. 
o 
Neutrophil Response: at least 100% increase and an absolute increase of >0.5 X 109/L 
• 
Stable Disease:  Failure to achieve at least a PR but no evidence of disease progression for >8 weeks 
• 
Failure: Death during treatment or disease progression characterized by worsening cytopenias, increase 
percentage of marrow blasts, or progression to a more advanced MDS FAB subtype 
• 
Cytogenetic Response:  
o 
Complete: Disappearance of any pre-treatment chromosomal abnormalities without the appearance of 
new ones 
o 
Partial: At least 50% reduction of chromosomal abnormality 
• 
Disease Progression: Compared to pre-treatment values 
o 
Less than 5% blasts: greater than 50% increase to >5% blasts 
o 
5-10% blasts: greater than 50% increase to >10% blasts 
o 
10-20% blasts: greater than 50% increase to >20% blasts 
 
 
 

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Appendix IV - GvHD Scoring 
 
Acute GVHD 
Organ involvement will be staged using the criteria outlined in the table below.  Biopsy of each organ site at diagnosis or 
major change in disease activity will be performed unless clinical circumstances make it impossible. 
 
Consensus Clinical Stage and Grade of Acute GVHD (Przepiorka et al, 1995) 
Stage 
Skin 
Liver 
Lower Gastrointestinal 
Tract 
Upper 
Gastrointestinal 
Tract 
1 
Maculopapular rash 
<25% of body surface 
Bilirubin 2.0 – 3.0 
mg/dl 
Diarrhea 500 – 1000 
mL/day or 280 – 555 
mL/m2 
No protracted nausea 
and vomiting 
2 
Maculopapular rash 
25-50% body surface 
Bilirubin 3.1 – 6.0 
mg/dl 
Diarrhea 1000 – 1500 
mL/day or 556 – 833 
mL/m2 
Persistent nausea, 
vomiting or anorexia 
3 
Generalized 
erythroderma 
Bilirubin 6.1 – 15.0 
mg/dl 
Diarrhea >1500 mL/day 
or    >833 mL/m2 
 
4 
Generalized 
erythroderma with 
bullous formation and 
desquamation 
Bilirubin > 15 mg/dl 
Severe abdominal pain, 
with or without ileus, or 
stool with frank blood or 
melena 
 
 
Grading for Treatment Criteria: 
 
Mild GVHD  
 
Skin stage I-II only (Equivalent to Seattle Grade I). 
 
Moderate GVHD 
Skin stage I-III and/or liver I-IV and/or Gastrointestinal tract (GI) I-III and/or Upper GI (UGI).  
(Equivalent to Seattle Grade II, III). 
 
Severe GVHD Any stage IV along with severe clinical illness. 
 
 
Late Acute and Chronic GVHD 
Late acute and chronic GVHD will be assessed using the National Institutes of Health (NIH) Consensus Criteria. 

 
 
Appendix V –Targeted Toxicity Form (CTCAE 4.0)  
See section 9.2 for time points HM2013-12 
 
 
 
(shade events may meet definition of DLT) 
 Patient Initials:  _______ Date of Assessment:  _________     Assessment Time Point:  _________      
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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 
degrees F) for ≤ 24 hours 
> 40.0 °C (>104.0°F) for > 
24 hours 
Febrile neutropenia 
None 
……………… 
……………… 
ANC <1000/mm with a single 
temperature of >38.3°C (101 °F) 
or sustained temp ≥38 °C 
(100.4°F) for > 1 hour 
Life-threatening 
consequences; urgent 
intervention indicated 
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) 
Injection Site 
Reaction 
None 
Tenderness with or 
without associated 
symptoms 
Pain; lipodystrophy; edema; phlebitis 
Ulceration or necrosis; severe 
tissue damage; operative 
intervention indicated 
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 
Weight Gain 
None 
5 - <10% from baseline  10 - <20% from baseline  
≥20% from baseline 
……………………… 
Nausea 
None 
Loss of appetite without 
alteration in eating habits 
Oral intake decreased without 
significant weight loss, dehydration or 
malnutrition 
Inadequate oral caloric or fluid 
intake; tube feeding, TPN, or 
hospitalization indicated 
……………………… 
Vomiting 
None 
1 - 2 episodes (separated 
by 5 minutes) in 24 hours 
3 -5 episodes (separated by 5 minutes) 
in 24 hours 
≥6 episodes (separated by 5 
minutes) in 24 hours; tube feeding, 
TPN or hospitalization  
Life-threatening 
consequences; 
urgent intervention indicated 
Other record on AE 
log CRF in Oncore 
  
Mild 
Moderate 
Severe 
Life- threatening 
Person Completing Form:  
 
 
 
 
 
 
 
ADL = activities of daily living 
 All Events are Expected and Attributable Except: