QUILT-2.021: Randomized Study of Single Course of Intraperitoneal (IP) ALT-803 Followed by Subcutaneous (SQ) Maintenance ALT-803 Versus Subcutaneous (SQ) Maintenance ALT-803 Only After 1st Line Chemotherapy for Advanced Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
Phase: PHASE2
Conditions: FIGO Stage III and IV Ovarian Cancer, FIGO Stage III and IV Fallopian Tube Cancer, FIGO Stage III Primary Peritoneal Cancer
Sponsor: Masonic Cancer Center, University of Minnesota

 
 
Masonic Cancer Center, University of Minnesota  
Cancer Experimental Therapeutics Initiative (CETI) 
 
 
Randomized Study of Single Course of Intraperitoneal (IP) ALT-803 Followed 
by Subcutaneous (SQ) Maintenance ALT-803 Versus Subcutaneous (SQ) 
Maintenance ALT-803 Only after 1st Line Chemotherapy for Advanced Ovarian, 
Fallopian Tube, and Primary Peritoneal Cancer 
 
CPRC #2016LS034 
IND 134220 
 
 
Principal Investigator/IND Sponsor: 
 
Melissa A. Geller, MD  
 
Co-Investigators: 
Department of Medicine: 
Jeffrey S. Miller, MD  
 
Department of Obstetrics and Gynecology:  
Peter A. Argenta, MD 
Deanna G. Teoh, MD 
Sally A. Mullany, MD 
Boris Winterhoff, MD, MS 
Britt Erickson, MD 
Colleen Rivard, MD 
Rahel Ghebre, MD, MPH  
 
 
Biostatistician: 
Todd E. DeFor, MS 
 
 
 
 
 
Version Date: 
May 21, 2019 
 
 
 
Confidential 

 
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Revision History 
Revision 
# 
Version 
Date 
Revision Details 
Consent 
Revision 
 
09/15/2016 
Original to CPRC 
n/a 
 
01/06/2017 
In response to CPRC minor stips and other interim edits including: 
 A new IND will be filed with Dr. Geller as the sponsor 
 Clarify and expand primary objective (triggered in part by CPRC 
review) 
 Update and expand genomic, transcriptomic and proteomic 
correlative testing on archived tumor and fresh blood – add 
available archived tumor to inclusion criteria 
 Add cytokine release syndrome (CRS) as a risk of ALT-803 and 
the planned monitoring/management 
 Update Section 8 based on updated IB for ALT-803 
 Add patient diaries for SQ and IP dosing reactions 
n/a 
 
03/24/2017 
in response to FDA’s initial review: 
 Synopsis, Inclusion Criteria, Appendix I –Patient Eligibility 
Checklist, Appendix II – FIGO Staging, GOG PS and NYHA 
Classification - limit enrollment to FIGO stage III and IV 
 Synopsis ,Exclusion Criteria, Appendix I –Patient Eligibility 
Checklist  - Expand exclusion criteria adding uncontrolled 
hypertension, history of pulmonary disease or abnormal PFTs, 
narcolepsy or any neuro condition which may impair consciousness 
 Inclusion Criteria, Appendix I –Patient Eligibility Checklist: Add 
ANC and ALC requirements for eligibility 
 Duration of Study Participation, Required Clinical Care Tests and 
Procedures: Revise final treatment visit to continue follow-up if 
ongoing treatment related AEs until resolution/stabilization 
 Section 7.2: Incorporate FDA’s recommended following time points 
for immunogenicity testing: pre cycle 1, 28-30 days after the first 
exposure of ALT-803, pre cycle 2, pre cycle 3, pre cycle 4, and 30-
45 days after the last exposure of ALT-803. 
Additional revision to the protocol since original FDA submission: 
 Synopsis, Secondary Objectives, Duration of Study Participation, 
Required Clinical Care Tests and Procedures: Extend follow-up 
through 2 years from 1st dose (previously 1 year) – update 
secondary objectives to survival at 1 and 2 years 
 Intraperitoneal ALT-803 Administration (Arm 2 only): Add pre-
medication and monitoring guidelines to IP infusions  
yes 
1 
08/09/2017 
 Delete optional pre-screening through-out protocol including 
Section 7.1 and Section 7.2 
 Synopsis – delete reference to all treatment will be given as an 
outpatient, correct duration of follow-up to 2 years to match rest of 
protocol 
 Synopsis and Section 4.1 Inclusion Criteria – clarify a minimum of 3 
cycles of IP chemo must be given but patients may continue on IV 
only for additional cycles and study treatment must begin within 3 
weeks (± 1 week) of the final dose of 1st line therapy (previously 
stated final dose of IP/IV therapy) 
 Section 4.1.8 Inclusion criteria – delete “available archived tumor” 
requirement as not a criteria for study treatment 
 Section 4.27 – reword for clarity exclusion criteria for hypertension 
 Section 6.1 – subcutaneous ALT-803 language updated to match 
other ALT-803 protocols requiring provider assessment prior to 
each dose and situations for skipping ALT-803 dosing. 
 Sections 6.1 and 6.2 – clarify place of treatment 
Yes and delete 
pre-screening 
consent 

 
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Revision 
# 
Version 
Date 
Revision Details 
Consent 
Revision 
 Sections 6.2.and 6.3 -delete language pertaining to warming of 
any infusate – fluids for IP washings and drug administration will 
be given at room temperature 
 Section 6.7 – update dosing requirements to receive the next 
treatment course based on changes made to other ALT-803 
protocols 
Minor edits 
Move S/I contact information back to under revision history 
Section 2.5 – correct ALT803 to ALT-803 throughout section and 
replace figure with a better version 
Section 4.1.7 – delete (<1 mg/day) in regards to steroid use as 
nonsensical  
Section 9.1 – update to Cancer Center’s new deviation definitions 
2 
04/27/2018 
 Revise protocol eligibility to permit enrollment within 3 months of 
last dose of chemotherapy rather than 3 weeks 
 Revise Sections 4.1 to delete ALC requirement as goal of ALT-
803 is to increase ALC and update lab value thresholds to ≥ or ≤ 
as applicable for consistency 
 Sections 6.1, 6.2 and 8.6 – clarification ALT-803 dose calculation, 
monitoring, assessment, minimum dosing to match other ALT-803 
protocols 
 Section 7 – clarify patient must return to clinic for each of the 
planned visits whether or not they are receiving ALT-803,  
 Section 7 - add footnote to tables in Section 7.1. and 7.2 that if 
disease reassessment if required specifically for the protocol, that 
the costs will be paid for by research (i.e. CT scan needs to be 
repeated as outside of the study’s 30 day window requirement for 
baseline screening)  
 Section 8.1 – add vial concentration of ALT-803 2 mg/ml to reflect 
current lot release (none shipped to UMN yet) 
 Section 8.6 – cap dose calculation at a max weight of 100 kg, 
replace D5W with normal saline (NS) for ALT-803 IP 
administration 
 Section 8.8 –delete out of date toxicity language from 2016, add 
pain and cramping as side effect of IP administration and IP fluid 
collection just prior to ALT-803 
 Section 12.4 – revise grade 3 abdominal pain to remove > 3 as no 
grade 4, 5 abdominal pain in CTCAE and qualify must no respond 
to pain medication and last more than 72 hours to count as a 
stopping rule event 
 Numerous updates to match other ALT-803 protocols and current 
template 
 Move S/I contact info to end of table of contents, other minor 
updates 
Yes 
3 
05/21/2019 
Update ALT-803 drug sections based on updated IB – A sufficient 
number of patients have been treated with ALT-803 (also known as 
N-803) that the toxicity profile is no longer based on IL-2 
Update document with hyperlinks in preparation for electronic 
submission to FDA 
 Section 6.4 – delete hypotension management guidelines as 
hypotension (change in blood pressure) is not included in the 
updated toxicity profile. 
 Section 8 – ALT-803 Formulation, Supply and Potential Toxicity – 
update to reflect updated IB including vial concentration for SC 
administration and updated toxicity profile. 
Yes 

 
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Revision 
# 
Version 
Date 
Revision Details 
Consent 
Revision 
 Title page - update list of Co-Is by deleting Drs Cooley, Carson 
and Downs, Add Dr. Ghebre 
 
Section 4.2.1, Appendix I  – exclude women with somatic or 
germline BRCA 1/2+ as now are eligible for PARP inhibitors as 
maintenance therapy  
Minor edits and clarifications 
 
Section 6.1 and Section 6.2 - add diphenhydramine to standard 
pre-meds  
 
Section 6.1, 6.2 and 7 – replace dosing window language with 
more flexible dosing language 
 
Section 7.1 – Remove EBV testing, clarify that the anchor for 
follow-up is based on every 3 months from the last disease 
reassessment not the end of treatment visit. 
 
Section 7.2 – add back X’s for green and red tops as accidentally 
deleted with last revision, rearrange columns for clarity 
 
Section 8.1 – update ALT-803 formulation 
 
Appendix I – update to new format 
 
Appendix V – Injection Site Reaction Diary add a 2nd page as 
reactions rarely resolve within 1 week. 
 
Appendix VI  IP Reactions Diary - add “Intraperitoneal (IP) 
Injection” to the header to avoid confusion with the Appendix V 
Injection Site Reactions Diary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S/I Contact Information: 
Melissa Geller, MD 
Department of Obstetrics and Gynecology 
420 Delaware Street SE MMC 395 
Minneapolis, MN 55455 
Phone: 612 626-3111  
Email: gelle005@umn.edu 

 
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TABLE OF CONTENTS 
 
Synopsis ................................................................................................................................................. 7 
Schema ................................................................................................................................................... 8 
1 
Objectives ....................................................................................................................................... 9 
1.1 
Primary Objective ...................................................................................................................... 9 
1.2 
Secondary Objectives ................................................................................................................ 9 
1.3 
Correlative Objectives ............................................................................................................... 9 
2 
Background and Significance ......................................................................................................... 9 
2.1 
Introduction ................................................................................................................................ 9 
2.2 
Interleukin-15 (IL-15) ............................................................................................................... 10 
2.3 
ALT-803 ................................................................................................................................... 10 
2.4 
ALT-803 by Subcutaneous Injection and Intravesical Instillation ............................................ 11 
2.5 
Study Rationale ....................................................................................................................... 12 
3 
Study Design ................................................................................................................................ 14 
4 
Patient Selection ........................................................................................................................... 15 
4.1 
Inclusion Criteria ...................................................................................................................... 15 
4.2 
Exclusion Criteria ..................................................................................................................... 16 
5 
Screening and Study Enrollment .................................................................................................. 17 
5.1 
Consent and Study Screening in OnCore ............................................................................... 17 
5.2 
Study Enrollment and Treatment Arm Assignment ................................................................. 17 
5.3 
Patients Who Are Enrolled and Do Not Receive Study Treatment ......................................... 17 
6 
Treatment Plan ............................................................................................................................. 18 
6.1 
Subcutaneous ALT-803 Administration ................................................................................... 18 
6.2 
Intraperitoneal ALT-803 Administration (Arm 2 only) .............................................................. 20 
6.3 
Intraperitoneal Washing (all patients weekly through Day 29 of Treatment Course 1) ........... 22 
6.4 
Managing of Selected Expected Adverse Events ................................................................... 22 
6.5 
Supportive Care ....................................................................................................................... 23 
6.6 
General Concomitant Medications Guidelines ........................................................................ 23 
6.7 
Duration of Treatment .............................................................................................................. 23 
6.8 
Duration of Study Participation ................................................................................................ 24 
7 
Clinical Evaluations and Procedures ............................................................................................ 24 
7.1 
Required Clinical Care Tests and Procedures ........................................................................ 25 
7.2 
Research Related Tests and Procedures ............................................................................... 26 
8 
ALT-803 Formulation, Supply, and Potential Toxicity .................................................................. 29 
8.1 
Formulation and Composition.................................................................................................. 29 
8.2 
Structural Formula ................................................................................................................... 29 
8.3 
Storage and Handling .............................................................................................................. 30 
8.4 
Study Drug Preparation and Administration ............................................................................ 30 
8.5 
Agent Inventory Records ......................................................................................................... 31 
8.6 
Toxicity ..................................................................................................................................... 31 
9 
Adverse Event Monitoring, Documentation and Reporting .......................................................... 32 
9.1 
Adverse Event Terminology .................................................................................................... 33 
9.2 
AE Documentation and Reporting Requirements ................................................................... 33 
9.3 
SAE Documentation and Reporting Requirements ................................................................. 34 
9.4 
Early Stopping Rule Events Documentation and Reporting Requirements ............................ 34 
9.5 
Documentation of Death and Reporting Requirements .......................................................... 35 
9.6 
Expedited Reporting the UMN IRB, FDA and Altor Bioscience .............................................. 35 
10 
Study Data Collection and Monitoring .......................................................................................... 36 

 
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10.1 Data Management ................................................................................................................... 36 
10.2 Case Report Forms ................................................................................................................. 36 
10.3 Data and Safety Monitoring Plan (DSMP) ............................................................................... 37 
10.4 Record Retention ..................................................................................................................... 37 
11 
Primary and Secondary Endpoints ............................................................................................... 37 
11.1 Primary Endpoint ..................................................................................................................... 37 
11.2 Secondary Endpoints .............................................................................................................. 38 
12 
Statistical Considerations ............................................................................................................. 38 
12.1 Study Design, Objectives and Endpoints ................................................................................ 38 
12.2 Statistical Analyses .................................................................................................................. 39 
12.3 Sample Size............................................................................................................................. 40 
12.4 Stopping Rules ........................................................................................................................ 40 
13 
Conduct of the Study .................................................................................................................... 41 
13.1 Good Clinical Practice ............................................................................................................. 41 
13.2 Ethical Considerations ............................................................................................................. 41 
14 
References ................................................................................................................................... 41 
Appendix I –Patient Eligibility Checklist ................................................................................................ 44 
Appendix II – FIGO Staging, GOG PS and NYHA Classification ......................................................... 46 
Appendix III – RECIST version 1.1 With Updated CA-125 Criteria(27) ............................................... 47 
Appendix IV – ALT-803 Targeted Toxicity Worksheet ......................................................................... 52 
Appendix V – ALT-803 Injection Site Reactions Diary ......................................................................... 53 
Appendix VI – ALT-803 Intraperitoneal (IP) Reactions Diary ............................................................... 56 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Synopsis 
Randomized Study of Single Course of Intraperitoneal (IP) ALT-803 Followed by Subcutaneous (SQ) 
Maintenance ALT-803 Versus Subcutaneous (SQ) Maintenance ALT-803 Only after 1st Line Chemotherapy 
for Advanced Ovarian, Fallopian Tube, and Primary Peritoneal Cancer 
 
Study Design: 
This is a single center, randomized phase II study of an IL-15Rα-Fc super-agonist complex (ALT-
803, more recently known as N-803 ) given as maintenance therapy after the completion of 1st line 
chemotherapy for the treatment of FIGO stage III and IV ovarian, fallopian tube, and primary 
peritoneal cancer.  
 
In this study all patients receive four 8 week cycles of ALT-803 consisting of 4 weekly doses followed 
by a 4 week rest (no treatment). As it is not known how intraperitoneal (IP) administration (a route 
of drug administration frequently used for gynecologic cancers) of ALT-803 compares to 
subcutaneous (SQ) administration, both routes of administration will be tested. The primary 
objective of this trial is to select one method of delivery for further testing.  
 
A 1:1 randomization will apply to the 1st treatment course only:   
Arm 1: ALT-803 SQ only – patient receives ALT-803 10 mcg/kg SQ weekly x 4 followed by 4 weeks 
of no treatment before continuing with treatment courses 2, 3, and 4 as described below 
 
Arm 2:  ALT-803 IP and SQ – patient receives ALT-803 10 mcg/kg IP weekly x 4 weeks followed 
by 4 weeks of no treatment before continuing with treatment courses 2, 3, and 4  
 
All patients, regardless of assignment will have weekly IP peritoneal washings through Day 29. 
 
Treatment courses 2, 3, and 4 are identical for all patients – ALT-803 10 mcg/kg SQ weekly x 4 with 
a 4 week rest (4 weeks on/4 weeks off).  
 
Patients will be followed until disease progression or for a maximum of 2 years from the 1st dose of 
ALT-803. 
   
Primary 
Objective: 
 
The primary objective of this trial is to select a “winner” for future study with the intent to ensure that 
if one method is clearly inferior in terms of the primary endpoint of progression free survival (PFS) 
at 6 months. There is a small probability that the inferior method will be carried forward if the 
difference between IP and SQ administration is small, selection of the method will be allowed to 
include other factors (attraction of lymphocytes to the peritoneal cavity, ease of the methodology 
and safety). 
 
Secondary 
Objectives: 
 To determine one and two year progression free survival (PFS) 
 To determine one and two year overall survival (OS) 
 To document ALT-803 associated toxicity when administered by IP in this patient population 
 To evaluate the safety of ALT-803 when administered by IP on this schedule 
 
Correlative 
Objectives: 
 To evaluate blood and peritoneal washing lymphocyte number, phenotype and function 
 To characterize ALT-803 pharmacokinetics and immunogenicity 
 To determine genomic and proteomic profile of tumors 
 
Key Inclusion 
Criteria: 
 Diagnosis of FIGO stage III or IV epithelial ovarian, fallopian tube or primary peritoneal carcinoma, 
has received at least 3 cycles of first line IV/IP cisplatin and paclitaxel chemotherapy and has 
stable disease or better as defined by measurable/evaluable tumor and/or CA-125 levels 
 Able to begin study therapy within 3 months of final dose of first line chemotherapy 
 GOG performance status ≤ 2  
 Functional IP catheter 
Enrollment: 
28 patients enrolled over 3 years (8-10 patients per year) 

 
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1 Objectives 
1.1 Primary Objective 
The primary objective of this trial is to select a “winner” for future study with 
the intent to ensure that if one method is clearly inferior in terms of the primary 
endpoint of progression free survival (PFS) by 6 months of subcutaneous 
administration against intraperitoneal and subcutaneous administration of 
ALT-803. There is a small probability that the inferior method will be carried 
forward if the difference between IP and SQ administration is small, selection 
of the method will be allowed to include other factors (attraction of lymphocytes 
to the peritoneal cavity, ease of the methodology and safety). 
1.2 Secondary Objectives 
 To determine one and two year progression free survival (PFS) 
 To determine one and two year overall survival (OS) 
 To document ALT-803 associated toxicity when administered by IP in this 
patient population 
 To evaluate the safety of ALT-803 when administered by IP on this schedule 
1.3 Correlative Objectives 
 To evaluate peripheral blood and peritoneal washing lymphocyte number, 
phenotype and function 
 To characterize ALT-803 immunogenicity 
 To determine the genomic, transcriptomic, and proteomic profile of subjects’ 
tumors to identify gene mutations, gene amplifications, RNA-expression 
levels, and protein-expression levels. Correlations between genomic, 
transcriptomic, and proteomic profiles and efficacy outcomes will be 
assessed.   
 
2 Background and Significance  
2.1 Introduction 
Ovarian cancer is the most lethal gynecologic malignancy. The estimated 5-
year survival is 46% for all stages of ovarian cancer, and 28% for distant 
disease. Notably, 62% of women with ovarian cancer present with Stage III or 
IV disease, for which the rate of recurrence is 60-70% (1). Women who recur 
cannot be cured with current therapies (2). Our long term research objective is 
to exploit the innate immune system to treat ovarian cancer and substantially 
improve survival rates.  

 
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Miramar, FL) has developed IL-15/IL-15Rα-Fc super-agonist complexes (ALT-
803), the design of which includes the addition of a sushi domain to inhibit 
complement activation, increased avidity of the molecule to IL-2Rβɣ on NK 
cells, and increased half-life and stability by inclusion of the Fc domain(10, 11, 
12). We have secured a supply of ALT-803 (Altor IL-15/IL-15Rα-Fc) for testing 
in the proposed clinical trial.  
 
ALT-803 is a novel IL-15 immunoconjugate designed to have a prolonged 
serum half-life. The novel IL-15 immunoconjugate, ALT-803 (IL-15N72D:IL-
15RαSu/IgG1 Fc complex) (See Figure 1) was developed by our collaborator, 
Altor BioScience, 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)(13). 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 (CD122) and the 
common -chain (CD132) receptor components. 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 (14). In addition, 
ALT-803 contains a novel IL-15 mutant 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)(15). 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). Soluble IL-15R and IL-15 in solution can form 
stable heterodimeric complexes capable of modulating (ie, either stimulating or 
blocking) immune responses via the IL-2R complex(16,17,18). 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 (16,18). 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 (19). We hypothesize that ALT-803 will require only weekly 
administration to achieve similar benefits to that provided by low-dose 
continuous rhIL15 exposure. 
2.4 ALT-803 by Subcutaneous Injection and Intravesical Instillation 
In August 2016, Altor prepared a Safety Summary of ALT-803 based on several 
ongoing early stage trials for various cancer indications (unverified/unaudited 

 
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data). At the time 107 patients had received at least 1 dose of ALT-803, of 
which 35 were by subcutaneous injection and 26 of those patients treated at 
the University of Minnesota. Dosing ranged from 1 mcg/kg to 20 mcg/kg with 
the majority treated at 6 mcg/kg (n=16) and 10 mcg/kg (n=12). The Altor clinical 
update concurred with our experience that subcutaneous dosing was generally 
well tolerated with an injection site related skin rash as the most notable event, 
often quite widespread; however none were dose limiting. Typically the rash 
resolved by 7 days post-injection. Other effects included fever, fatigue, and 
changes in blood pressure. 
 
In the same Safety Summary, toxicity data was presented on an ongoing Altor-
sponsored multi-center trial of intravesical ALT-803 plus BCG in patients with 
non-invasive bladder cancer (NCT02138734 – University of Minnesota is not a 
participate). During the phase I dose escalation component, weekly ALT-803 
combined with standard BCG was administered in a standard 3+3 design 
testing dose levels 100, 200, and 300 mcg/instillation. The expansion phase is 
currently enrolling using ALT-803 mcg/instillation. The most common adverse 
events (N=9) during dose escalation included hematuria, headache and urinary 
tract pain. 
2.5 Study Rationale 
Rationale for Using ALT-803 
IL-15, in contrast to IL-2, does not support the expansion of regulatory T cells 
(Tregs) (20). Thus, IL-15 administration holds promise to specifically boost NK 
cell alloreactivity without the undesired stimulation of Tregs. ALT-803 is a highly 
potent recombinant IL-15 super-agonist which has an augmented capacity to 
expand NK cells compared with IL15 (21,22). We have chosen the 10 mcg/kg 
subcutaneous dose for this trial based on testing here at the university and Dr. 
Miller’s involvement in national trials through the NCI CITN.  
 
While some studies continue to dose escalate (currently 15 and 20 mcg/kg are 
under study), 10 mcg/kg is safe in other solid tumor cohorts, especially with 
subcutaneous dosing. In addition, we have some immunologic data suggesting 
that 10 mcg/kg induces a stronger proliferative signal in most subjects while the 
6 mcg/kg dose seems more variable. Given the safety profile of both doses and 
the goal of IL-15 in this trial to maintain persistence and possible NK cells in 
vivo (especially in the peritoneal cavity), we have chosen the 10 mcg/kg 
subcutaneous dose for studies proposed here. 
 
 
 

 
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Rationale for Using IP dosing 
Based on our recently published in vivo mouse data(23),  our current platform 
for NK cell therapy in ovarian cancer delivers NK cells IP as we have seen 
significant inhibition of ovarian cancer growth using this delivery. As ovarian 
cancer is an intraperitoneal disease, rarely metastasizing beyond the 
abdominal cavity, therapy delivered directly to the tumor site makes intuitive 
sense. Recent studies done by our collaborators defined the lymphocyte 
population within the peritoneal fluid (PF) of women with high-grade serous 
ovarian cancer (Figure 
2). They found that 
women with ovarian 
cancer 
had 
a 
significantly 
lower 
percentage of NK cells 
in the PF compared to 
women with benign 
disease. Importantly, 
the 
ovarian 
cancer 
patients 
with 
lower 
number of NK cells 
had significantly lower 
survival. 
This 
data 
provides the rationale 
for delivering ALT-803 
IP to increase and 
expand 
NK 
cells 
directly 
within 
the 
peritoneal cavity.  
 
We 
have 
recently 
identified 
that 
subcutaneous dosing 
of ALT-803 is safer 
than IV. In the switch 
from IV to SQ ALT-
803, we have been 
able to show better 
clinical tolerance with 
less constitutional systems related to a lower ALT-803 peak serum 
concentration with SQ administration and less early post injection systemic 
inflammatory cytokines. One interesting and surprising finding serves at the 
 
Figure 2 a) main cell populations in the peritoneal fluid (PF) of benign patients vs. high grade 
serous ovarian ca patients b) the percentage of NK cell in PF is significantly higher in benign 
patients (p<0.0001). A higher percentages of PFNK cells is present in patients surviving longer 
than the median survival rate c) the Kaplan Meier curve of the low NK group (< median) vs. 
patient with high NK cell count in PF (p<0.01). CD3 counts 

 
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primary rationale for testing IP injection of ALT-803. Several patients on SQ 
ALT-803 trials have developed prominent skin rashes, which in some cases 
involved half the abdomen surface area [with an abdominal SQ injection]. 
Biopsy of these lesions shows an inflammatory infiltrate comprised of 
lymphocytes and myeloid cells [macrophage type cells]. The lymphocytes are 
predominantly T cells with less NK cells. Unexpectedly, the T cell infiltrate in 
some patients is predominantly of the CD4 subset. This leads to a new 
hypothesis to be tested here that IP injection of ALT-803 will be safe but will 
better attract lymphocytes to the site of ovarian cancer, in the abdomen. We 
propose that ALT-803 has strong chemotactic activity for T and NK cells and 
will promote an “intratumoral” lymphocyte infiltrate that can be activated locally 
to overcome tumor induced immune suppression and may lead to better anti-
tumor activity.  
 
3 Study Design  
This is a single center, randomized phase II study of an IL-15Rα-Fc super-agonist 
complex (ALT-803) given as maintenance therapy after the completion of 1st line 
cisplatin and paclitaxel chemotherapy for the treatment of advanced ovarian, 
fallopian tube, and primary peritoneal cancer.  
 
In this study all patients receive 4 cycles of ALT-803 consisting of 4 weekly doses 
followed by a 4 week rest (no treatment). As it is not known how intraperitoneal 
(IP) administration (a route of drug administration frequently used for gynecologic 
cancers) of ALT-803 compares to subcutaneous (SQ) administration, both routes 
of administration will be tested. All patients will be required to have a functional IP 
catheter in place at study enrollment to permit weekly IP washings through Day 29 
of the 1st treatment course as attraction of lymphocytes to the peritoneal cavity is 
a critical factor for the primary endpoint.    
 
Randomization will apply to the 1st treatment course only with the following arms:   
Arm 1: ALT-803 10 mcg/kg SQ only – patient receives ALT-803 10 mcg/kg SQ 
weekly x 4 followed by 4 weeks of no treatment before continuing with treatment 
courses 2, 3, and 4 as described below 
Arm 2:  ALT-803 10 mcg/kg IP and SQ – patient receives ALT-803 10 mcg/kg IP 
weekly x 4 weeks followed by 4 weeks of no treatment before continuing with 
treatment courses 2, 3, and 4 as described below 
 
Treatment courses 2, 3, and 4 are identical for all patients – ALT-803 10 mcg/kg 
SQ weekly x 4 with a 4 week rest (4 weeks on/4 weeks off).  
 

 
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Patients will be followed until disease progression, then for survival only for a 
maximum of 2 years from the 1st dose of ALT-803. 
 
 
4 Patient Selection 
Study entry is open to females 18 years and older regardless of race or ethnic 
background. While there will be every effort to seek out and include minority 
patients, enrollment is expected to be similar to other that of other 1st line treatment 
studies at the University and referring community physicians. 
4.1 Inclusion Criteria 
4.1.1 Diagnosis of FIGO stage III or grade IV epithelial ovarian, fallopian tube 
or primary peritoneal carcinoma, has received at least 3 cycles of first 
line IV/IP cisplatin and paclitaxel chemotherapy and has stable disease 
or better – refer to Appendix II for FIGO staging system (Note:  to be 
eligible for this study, the patient must receive a minimum of 3 cycles of 
IP therapy; however, patients may continue on IV only 1st line therapy 
for additional cycles as long as inclusion criteria 4.1.2 is met) 
 
4.1.2 Able to begin study therapy within 3 months of final dose of first line 
chemotherapy 
 
4.1.3 Functioning intraperitoneal catheter 
 
4.1.4 ≥ 18 years of age  
 
4.1.5 GOG performance status ≤ 2 (Appendix II) 
 
4.1.6 Adequate organ function within 14 days of enrollment defined as: 
Hematology:  hemoglobin ≥ 8 g/dl, absolute neutrophil count (ANC) ≥ 
1500/ul, platelets ≥ 50 x 109/L 
Creatinine:  ≤ 2.0 mg/dL  
Hepatic:  SGOT and SGPT ≤ 3 x upper limit of institutional normal (ULN)  
 
4.1.7 Ability to be off prednisone and other immunosuppressive drugs for at 
least 3 days prior to and while receiving ALT-803 
 
4.1.8 Voluntary written consent prior to the performance of any research 
related procedures 
 

 
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4.2 Exclusion Criteria 
4.2.1 Somatic or germline BRCA1 or BRCA2 mutations 
 
4.2.2 Received any investigational agent within the 14 days before the start of 
ALT-803 
 
4.2.3 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) 
 
4.2.4 Marked baseline prolongation of QT/QTc interval (e.g. demonstration of 
a QTc interval greater than 500 milliseconds) 
 
4.2.5 Uncontrolled bacterial, fungal or viral infections including HIV-1/2 or 
active hepatitis C/B – chronic asymptomatic viral hepatitis is allowed  
 
4.2.6 Active autoimmune disease requiring systemic immunosuppressive 
therapy 
 
4.2.7 History of severe asthma and currently on chronic systemic medications 
(mild asthma requiring inhaled steroids only is eligible) 
 
4.2.8 Uncontrolled hypertension: defined as ≥2 readings over 160 mmHg 
systolic or 110 mmHg diastolic within month prior to enrollment despite 
optimal anti-hypertensive medication.  Patients with high readings which 
improve to ≤160/110 after adjustment of medications will be eligible. 
 
4.2.9  History of pulmonary disease or abnormal pulmonary function studies 
 
4.2.10 History of narcolepsy or any neurological condition which may impair 
consciousness  
 
 
 

 
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5 Screening and Study Enrollment 
Written consent must be obtained prior to the performance of any research related 
tests or procedures. Consent is usually obtained before final eligibility is 
determined. 
5.1 Consent and Study Screening in OnCore  
Any patient who has been consented is to be entered in OnCore by the Primary 
Clinical Research Coordinator (PCRC) or designee. If a patient is consented 
but is not enrolled, the patient’s record is updated in OnCore as a screen failure 
and reason for exclusion recorded.  
5.2 Study Enrollment and Treatment Arm Assignment 
To be eligible for this study, the patient must sign the treatment consent and 
meet each inclusion criteria and none of the exclusion criteria listed on the 
eligibility checklist (found in Appendix I) based on the eligibility assessment 
documented in the patient’s medical record. 
 
The Primary Clinical Research Coordinator (PCRC) or designee will complete 
the enrollment process in OnCore by assigning the treatment arm and entering 
the on treatment date. 
 
At the time of enrollment, the patient is randomized to one of the following 
treatment arms: 
 
Arm 1: ALT-803 SQ only – patient receives ALT-803 10 mcg/kg SQ weekly x 
4 followed by 4 weeks of no treatment (rest) before continuing with treatment 
courses 2, 3, and 4 
 
Arm 2:  ALT-803 IP and SQ – patient receives ALT-803 10 mcg/kg IP weekly 
x 4 weeks followed by 4 weeks (rest) of no treatment before continuing with 
treatment courses 2, 3, and 4 
 
Treatment courses 2, 3, and 4 are identical for all patients – ALT-803 at 10 
mcg/kg SQ weekly x 4 with a 4 week rest (4 weeks on/4 weeks off).  
5.3 Patients Who Are Enrolled and Do Not Receive Study Treatment 
If a patient is enrolled to the study, and is later found not able to begin ALT-803 
within the required timeframe, for whatever reason, the patient will be removed 
from study and treated at the physician’s discretion. The study staff will update 
OnCore of the patient’s non-treatment status (off study). The reason for 

 
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removal from study prior to starting study treatment will be clearly indicated in 
OnCore. The patient will be replaced to complete enrollment. 
 
 
6 Treatment Plan 
In order to provide optimal patient care and to account for individual medical 
conditions, investigator discretion may be used in the prescribing of all supportive 
care drug therapy (i.e. acetaminophen, diphenhydramine, antimicrobials, etc.); 
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.  
 
A 1:1 randomization will be done at the time of enrollment for the 1st treatment 
course only with the following arms:   
 
Arm 1: ALT-803 10 mcg/kg SQ only – patient receives ALT-803 10 mcg/kg SQ 
weekly x 4 followed by 4 weeks of no treatment before continuing with treatment 
courses 2, 3, and 4 per Section 6.1. 
Arm 2:  ALT-803 10 mcg/kg IP and SQ – patient receives ALT-803 10 mcg/kg IP 
weekly x 4 weeks followed by 4 weeks of no treatment per Section 6.2 before 
continuing with treatment courses 2, 3, and 4 as described in Section 6.1. 
 
Note: All patients regardless of treatment assignment will have IP washings weekly 
through Day 29 of the 1st treatment course per Section 6.3. 
6.1 Subcutaneous ALT-803 Administration 
The 1st course of ALT-803 is administered on the Phase I unit due to the 
peritoneal washings required on all patients. Treatment courses 2, 3, and 4 
may be administered in the outpatient clinic or the Phase I unit. 
 
ALT-803 10 mcg/kg will be administered subcutaneously once a week on Day 
1, 8, 15 and 22 followed by 4 weeks of no treatment (beginning Day 29). This 
constitutes 1 treatment course. ALT-803 dosing should be weekly (every 7 
days) however; in the event of scheduling issues (i.e. holiday, bad weather, 
etc.), at least 6 days, and no more than 10 days must separate each dose.  
 
A study trained provider must assess the patient prior to administration of each 
day’s ALT-803 injection to ensure no concerns are present. Refer to the 
Provider’s Assessment section below. 
 

 
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ALT-803 dosing will be calculated using a weight obtained within 5 days prior 
to the first dose. For patients > 100 kilograms weight, the ALT-803 dose will be 
calculated using a weight capped at 100 kg. The weight will be re-checked at 
the beginning of each subsequent cycle with the dose re-calculated if ≥ 10% 
change from the weight used for the previous dose calculation. 
 
All injections are given in the abdominal area. Injection sites should be rotated 
per institutional guidelines and each injection site separated by at least 1 inch. 
 
Doses of ALT-803 can be administered on an outpatient basis. 
 
Provider’s Assessment Prior to Each ALT-803: In order to proceed with a 
planned ALT-803 injection, a provider must assess the patient prior to 
administration to rule-out any of the following contraindications for dosing: 
 the previous injection site reaction is not showing signs of resolving 
(improving) based on measurement or intensity 
 signs or symptoms of a new infection 
 fever > 101°F (38.3 °C) 
 
The ALT-803 dose will not be given if one or more of the above conditions are 
present. 
 
In addition, ALT-803 may be held on the day of a planned dose for either of the 
following situations: 
 any grade 3 or greater ongoing ALT-803 treatment related toxicity (injection 
site reaction, neurologic, increased liver function tests) 
 if in the opinion of the treating physician, holding ALT-803 would be of benefit 
to the patient   
 
If after a 1 week rest, the patient meets the provider assessment criteria for 
treatment; the patient may resume treatment. The intent will be to give all 
remaining doses of ALT-803 for the treatment course, but the missed dose will 
not be made up to maintain the 8 week treatment course. 
 
If treatment is not restarted after a 1 week rest, any remaining ALT-803 doses 
within that course will not be given with the 8 week treatment course 
maintained. Patients must return for each planned treatment day visit (i.e. Day 
8, 15 and 22 of the course) and Day 29 in Course 1 only for assessment and 
bloodwork even if ALT-803 has been discontinued for that treatment course.  
 

 
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Dose modification: A one-time dose decrease to 6 mcg/kg is allowed for 
recurrent constitutional symptoms (e.g. fever, fatigue, muscle aches) interfering 
with activities of daily (ADL) related to ALT-803 dosing despite pre-medication. 
Patients unable to tolerate the reduced dose will be discontinued from further 
ALT-803. Re-escalation of the dose is not permitted. 
 
Pre-medications: Administer acetaminophen 650 mg and diphenhydramine 
25 mg PO prior to each injection. Use of additional pre-medications is at the 
discretion of the treating physician on an individual patient basis. 
 
Monitoring:  Patients will be observed for a minimum of 2 hours after the 1st 
SQ dose for immediate adverse events. Vital signs (heart rate, blood pressure, 
respiration, temperature, and oxygen saturation) will be done prior to each ALT-
803 injection and then at 30, 60 and 120 minutes with a ± 20 minute window 
for each time point. 
 
If the 1st SQ dose is well tolerated, subsequent doses may be administered with 
a 30 minute post dosing observation period. Vital signs (heart rate, blood 
pressure, respiration, temperature, and oxygen saturation) will be documented 
prior to each ALT-803 injection and at 30 minutes (+20 minute window). 
 
Inadequate dosing (Treatment Course 1 only): 
If a patient receives only one dose of ALT-803 during treatment course 1, the 
patient will be taken off treatment and followed per Section 7.1. The patient will 
be fully evaluable for safety and toxicity, but replaced in the evaluation of 
efficacy. Patients receiving at least two doses of ALT-803 during treatment 
course 1 will be evaluable and may continue therapy. 
6.2 Intraperitoneal ALT-803 Administration (Arm 2 only) 
As this study is the first to use IP delivery of ALT-803, an overnight stay on the 
Phase I Unit is required for the 1st 2 doses in each of the 1st 3 patients to 
ensure no unacceptable toxicity occurs post-dosing. Based on the toxicity 
observed, a recommendation will be made regarding overnight stays for 
subsequent doses and future patients. 
 
For the 1st treatment course only, ALT-803 is administered intraperitoneally at 
10 mcg/kg once a week on Day 1, 8, 15 and 22 followed by 4 weeks of no 
treatment. ALT-803 dosing should be weekly (every 7 days) however; in the 
event of scheduling issues (i.e. holiday, bad weather, etc.), at least 6 days, and 
no more than 10 days must separate each dose. 
 

 
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ALT-803 dosing will be calculated using a weight obtained within 5 days prior 
to the first dose. For patients > 100 kilograms weight, the ALT-803 dose will be 
calculated using a weight capped at 100 kg. The weight will be re-checked at 
the beginning of each subsequent cycle with the dose re-calculated if ≥ 10% 
change from the weight used for the previous dose calculation. 
 
Treatment course 2, 3, and 4 are administered subcutaneously as detailed in 
Section 6.1. 
 
ALT-803 is administered IP in approximately 50 cc of room temperature Normal 
Saline (NS) via peritoneal catheter. After the ALT-803 infusion and the NS 
flush, the patient will be asked to change position at 15-minute intervals for two 
hours to ensure adequate intra-abdominal distribution. No attempt will be made 
to retrieve the infusate. 
 
Provider’s Assessment Prior to Each ALT-803: In order to proceed with a 
planned ALT-803 infusion, a provider must assess the patient prior to 
administration to rule-out any of the following contraindications for dosing: 
 signs or symptoms of a new infection 
 fever > 101°F (38.3 °C) 
 there are signs or symptoms of disease progression 
 
The ALT-803 dose will not be given if one or more of the above conditions are 
present. 
 
In addition, ALT-803 may be held on the day of a planned dose for either of the 
following situations: 
 any Grade 3 or greater ongoing ALT-803 treatment related toxicity 
(neurologic, increased liver function tests) 
 if in the opinion of the treating physician, holding ALT-803 would be of benefit 
to the patient   
 
Pre-medications: Administer acetaminophen 650 mg and diphenhydramine 
25 mg PO prior to each injection. Use of additional pre-medications is at the 
discretion of the treating physician on an individual patient basis. 
 
Monitoring:  Patients will be observed for immediate adverse events during 
the 2 hour IP process. Vital signs (heart rate, blood pressure, respiration, 
temperature, and oxygen saturation) will be done prior to each ALT-803 IP 

 
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dosing and then at 30, 60 and 120 minutes with a ± 20 minute window for each 
time point. 
 
Dose modification and inadequate dosing as described in Section 6.1 also 
applies to IP dosing.  
 
In the event the patient “loses” the IP catheter, the treatment modality will be 
switched to SQ dosing for the remainder of cycle 1. The patient remains in the 
IP study arm for the purpose of analysis as this study uses the Intent to Treat 
(ITT) principle per Section 12.2. Blood samples for research will continue to be 
collected as planned; however, IP fluid collection would not. 
6.3 Intraperitoneal Washing (all patients weekly through Day 29 of 
Treatment Course 1) 
The presence of a functioning IP catheter is required for study eligibility. All 
patients, including those assigned to the SQ treatment arm, will have 
intraperitoneal washings prior to each ALT-803 administration during treatment 
course 1 and 1 week after the last dose.  
 
For the peritoneal washing a volume of approximately 250cc of room 
temperature NS will be infused into the abdomen. After infusion the patient will 
be asked to change position (right lateral, left lateral, Trendelenburg (feet 
higher than head by 30 degrees), reverse Trendelenburg) at 5-minute intervals 
to ensure adequate intra-abdominal distribution. Fifty (50) cc of infusate will 
then be retrieved through the indwelling catheter. 
 
If a minimum of 50cc of infusate is not retrieved, another 250 cc of NS will be 
infused and the above process repeated. If insufficient infusate can be 
retrieved, the process will be terminated. 
 
The collection(s) regardless of volume, will be sent to TTL.  
 
The IP catheter may be removed after the last IP washing 1 week after the last 
dose of ALT-803 of treatment course 1. 
6.4 Managing of Selected Expected Adverse Events 
6.4.1 Skin Rash in Association with Subcutaneous ALT-803 
Based on current experience, localized skin rashes are common with 
subcutaneous administration. If a rash occurs and the rash area surrounding 
the ALT-803 injection site is > 6 cm and symptomatic (painful and/or itchy), it 

 
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may be treated (at the discretion of the treating physician) with topical 0.05% 
clobetasol propionate (i.e. 0.05% Cormax) or 0.1% triamcinolone (i.e., 
Kenalog) cream. Diphenhydramine may be administered pre- (25-50 mg TID 
orally) and post-dosing (25-50 mg TID orally x 2 days) of ALT-803 at the 
discretion of the treating physician. Diphenhydramine should be eliminated if 
not tolerated. 
6.4.2 Cytokine Release Syndrome (CRS) or CRS-Like Symptoms 
While CRS is a clearly defined syndrome in T cell therapy, it is not known to 
occur to the full extent in NK cell therapies. However, we have seen immune 
activation syndromes that include fever, and rash but without T cell mediated 
vascular collapse. If symptoms occur, CRP, IL-6 and ferritin levels will be 
assessed. If medically indicated by the presence of enormously elevated IL-6 
levels (> 500), steroids are the first line of treatment. 
 
Patients will be monitored for clinical signs and symptoms of CRS. Refer to 
Section 9 for the revised CRS grading system that will be used for this study. 
6.5 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.  
6.6 
General Concomitant Medications Guidelines 
Administration of additional glucocorticoids is discouraged during the ALT-803 
treatment period as the use of systemic steroid medications may result in loss 
of therapeutic effects of the study drug. Sustained use of steroids or steroid use 
to treat related toxicity will be an indication to stop ALT-803. Transient use is 
permitted as needed per standard of care. Topical steroid cream is permitted.  
 
Beta-blockers and other anti-hypertensives may potentiate the hypotension 
and 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.  
6.7 Duration of Treatment 
ALT-803 post-transplant may continue for up to four 8 week cycles (4 weeks 
on/4 weeks/off) unless one of the following occurs: 
 unacceptable toxicity 

 
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 meets the criteria for inadequate dosing during the Course 1 by receiving 
only 1 dose of ALT-803 (refer to Section 6.1) 
 requires new anti-cancer therapy 
 consent is withdrawn or patient is not compliant 
 the treating investigator feels continuing study treatment is not in the best 
interest of the patient 
6.8 Duration of Study Participation 
All patients must be followed for a minimum of 4 weeks after the last dose of 
ALT-803 for any occurrence of ALT-803 treatment related toxicity. Patients who 
have an adverse event or serious adverse event must be followed until 
resolution 
or 
stabilization 
of 
that 
event, 
even 
if 
the 
time 
to 
resolution/stabilization greater than 4 weeks after discontinuation of ALT-803. 
 
Evaluable patients will be followed for overall progression free survival and 
overall survival for 2 years from the 1st dose of ALT-803 unless consent is 
withdrawn.  
 
7 Clinical Evaluations and Procedures 
Scheduled evaluations during the treatment courses may be performed ±2 days 
from the targeted date unless otherwise specify in the x-chart. ALT-803 dosing 
should be weekly (every 7 days) however; in the event of scheduling issues (i.e. 
holiday, bad weather, etc.), at least 6 days, and no more than 10 days must 
separate each dose. 
 
The End of Treatment visit may be done ±7 days of the targeted date.  
 
Follow-up is by record review through 2 years from the 1st dose of ALT-803. 
Response assessments are done according to standard of care (usually every 3 
months in this patient population). Disease status is recorded in OnCore until 
disease progression or start of a new therapy, whichever is earlier. Then the 
patient is followed for survival only until 2 years from the start of ALT-803.  
 
In addition, targeted days may be altered as clinically appropriate.

 
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7.1 Required Clinical Care Tests and Procedures  
 
Screening 
(within 30 
days of 
treatment 
start)1` 
Each Treatment Course = 8 weeks (4 weekly doses 
followed by 4 weeks no treatment for up to 4 courses) 
Course 
1 only 
Day 
29  
Every 3 
months based 
on SOC 
assessment 
schedule 
End of treatment 
visit  
(4 weeks after the 
last ALT-803 dose) 
SOC Follow-up for 
response and survival (for 
2 years from rx start) 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
Day 1 
(-3 
days) 
Course 1 
Day 5  
(- 2 days) 
Day 8 
Day 15 
Day 22 
Consent 
X 
 
 
 
 
 
 
 
 
 
Baseline Screening 
Assessment 
X 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
 
 
 
 
X 
 
X 
 
Provider Assessment 
 
X 
X 
X 
X 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
 
 
 
 
 
 
 
 
Vitals and pulse oximetry 
X 
X 
 
X 
X 
X 
X 
 
X 
 
Weight 
X 
X 
 
 
 
 
X 
 
 
 
GOG Performance Status 
X 
X 
 
 
 
 
 
 
X 
 
Survival Status 
 
 
 
 
 
 
 
 
 
X 
Toxicity Assessment 
 
X 
 
X 
X 
X 
X 
 
X3 
 
Review of Patient Reactions 
Diary from previous ALT-
803 
 
X 
 
 
 
 
X 
 
 
 
Disease Assessment – 
Imaging Studies 
X1 
 
 
 
 
 
 
X 
 
X2 
CA-125 
X1 
 
 
 
 
 
 
X 
 
X2 
CBC, diff, plt 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Comprehensive metabolic 
panel 
X 
X 
 
X 
X 
X 
X 
 
X 
 
Basic metabolic panel 
 
 
X 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
Pulmonary Function Tests4 
X 
 
 
 
 
 
 
 
 
 
1 - within 14 days for labs required for eligibility per Section 4.1, if SOC imaging studies for screening are not within the 30 day window, imaging must be repeated but will be charged to 
research, obtaining the consent is exempt from 30 day limit and may be signed at any time  
2 –per standard of care (usually every 3 months) using 3 months after the last disease assessment while on study as the starting point – follow response until progression or start of new 
treatment (by record review) then for survival only 
3- any ongoing AE or SAE must be followed until resolution/stabilization per Section 6.8  
4 – only required if symptoms or prior impairment   

 
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7.2 Research Related Tests and Procedures  
 
 
Baseline/ 
Screening 
 
During Each Treatment Course 
Course 1 only 
End of 
Treatment 
visit  
(4 weeks after the 
last ALT-803 
dose) 
Day 1  
(-3 days) 
Day 8 
Day 
15 
Day 
22 
Day 5 
(-2 days) 
Day 
29 
Toxicity Notation 
 
Refer to Section 9.2 for documentation requirements 
Monitor for Stopping 
Rule Events 
 
per Section 12.4 
X 
Disease Assessment 
– Imaging Studies 
and CA-125 (only if 
SOC is outside of the 
30 day window) 
X7 
 
 
 
 
 
 
 
50 ml of heparinized 
blood (5 green top 
tubes)  
 
X 
X 
X 
X 
X 
 
X 
10 ml of serum (1 
red top tube) 
 
X 
X 
X 
X 
X 
 
X 
IP washing1 (refer 
to Section 6.3)  
 
X 
X 
X 
X 
 
X2 
 
Immunogenicity 
 5 ml of serum (1 
red top tube)5 
 
X 
 
 
 
 
X 
X 
Exploratory Molecular Profiling (baseline only) – refer to Section 7.2.3  
1 red top and 1 
marble top tube 
(NantOmics Kit) 
X 
 
 
 
 
 
 
 
FFPE tumor tissue 
sample6 
From 
definitive 
surgery 
 
 
 
 
 
 
 
1 Collect prior to ALT-803 dosing, Cycle 1 only – all samples (no matter how small) go to TTL  
2 IP catheter may be removed after IP washing 
3 Collect research blood samples weekly (i.e. prior to dosing including any weeks where dosing is held) 
4 Do not collect any additional research samples once a patient is off treatment for disease progression 
5 To TTL per Section 7.2.2 
6 If available, a minimum tissue surface area of 25 mm2, 75 µm thick, with at least 30% malignant tissue 
7 Charge to research only if patient’s SOC assessments are outside of the 30 day window required for screening 
 
Note: if a patient is not abiding by the required clinical care calendar (Section 7.1), 
the collection schedule of the toxicity (adverse event) data and research related 
samples may be altered or discontinued on an individual patient basis, as 
appropriate. However; in cases where a dose is held, the patient must return for 
each planned treatment day visit (i.e. Day 8, 15, and 22 of the cycle) and for Cycle 
1 only, Day 29, for assessment and bloodwork for that cycle.  
 
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 

 
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reason, up to 3 extra samples for a total of 180 ml of blood may be drawn at 
additional relevant time points, as per the PI’s opinion, and are not specified above.  
7.2.1 Assessment of Immune Activation (TTL) 
Blood and IP wash samples to evaluate lymphocyte number, phenotype and 
function will be collected as detailed above for the Masonic Cancer Center 
Translational Therapy Lab (TTL) along with serum (red top tubes) for measure of 
cytokines that can reflect immune activation. 
 
Flow cytometry analysis of a fraction of the PBMC will detect surface markers that 
define lymphocyte subsets (NK, NKT, B, and T cells, both CD4 and CD8), as well 
as intracellular markers that define regulatory T cells (Foxp3) and proliferating cells 
(Ki67). All remaining PBMC will be cryopreserved in 10% DMSO and stored in 
liquid nitrogen for future testing, if subject agreed to future storage at the time of 
initial consent. 
7.2.2 Immunogenicity (ALTOR) 
Immunogenicity assays will be performed at Altor BioScience Corporation.  
 
The blood sample will be processed (centrifuge at 1000-1500 xg for 10 minutes) 
by TTL and the serum portion will be frozen and shipped to Altor BioScience in 
batches upon request for evaluation using validated ELISA methods.  
 
In these tests, human anti-ALT-803 antibodies are detected in patient serum 
samples using a direct sandwich ELISA method with plates coated with ALT-803. 
After the appropriate wash conditions, biotinylated ALT-803 is used for detection 
with standard HRP-labeled streptavidin reagents. For analysis of clinical samples, 
anti-IL-15 antibody serve as reference standard and serum from ALT-803 
immunized mice serve as a positive control. The level of anti-ALT-803 antibody in 
patient samples is determined based on the anti-IL-15 antibody standard curve. 
7.2.3 Genomic, Transcriptomic, and Proteomic Analysis (NantOmics) 
The objective of this testing is to determine the genomic, transcriptomic, and 
proteomic profile of subjects’ tumors to identify gene mutations, gene 
amplifications, RNA-expression levels, and protein-expression levels. Correlations 
between genomic, transcriptomic, and proteomic profiles and efficacy outcomes 
will be assessed. 
 
Genomic sequencing of tumor cells from tissue relative to non-tumor cells from 
whole blood will be profiled to identify the genomic variances that may contribute 
to response or disease progression and provide an understanding of molecular 

 
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abnormalities. RNA sequencing will be conducted to provide expression data and 
give relevance to DNA mutations; Quantitative proteomics analysis will be 
conducted to determine the exact amounts of specific proteins and to confirm 
expression of genes that are correlative of response and disease progression. All 
genomic, transcriptomic, and proteomic molecular analyses will be retrospective 
and exploratory. 
 
General Information for Collection of Tumor Tissues and Whole Blood 
Tumor tissue and whole blood samples are to be collected according to the 
instruction cards included in the Tissue Specimen Kit and Blood Specimen Kit. The 
kits include the materials necessary to collect and ship FFPE tumor tissue samples 
and whole blood samples.   
 
Consent for these research studies will be embedded in the main treatment 
consent. 
 
The Primary Clinical Research Coordinator (PCRC) or designee is responsible for 
completing the Clinical Trial Requisition Form with the following information: 
- 
Clinical Site Information 
- 
Patient Information  
- 
Specimen Information 
- 
Specimen Collection Information 
The PCRC or designee will return the completed Clinical Trial Requisition Form 
via Fax per the instructions provided on the form. 
 
Detailed specimen requirements and procedural instructions for FFPE tumor 
tissue samples and whole blood samples are provided in the Genomic, 
Transcriptomic, and Proteomic Sample Collection Manual.  
   
A single FFPE tumor tissue block is required for the extraction of tumor DNA, tumor 
RNA, and tumor protein. A whole blood sample is required for the extraction of 
subject normal DNA. Tumor tissue and whole blood will be processed in the 
NantOmics, LLC CAP accredited/CLIA certified laboratories.   
 
Schedule of Collection for Exploratory Molecular Profiling 
Exploratory Molecular Profiling 
Baseline 
Whole blood (normal comparator against tumor) 
per current kita 
 
Formalin-fixed, paraffin-embedded tumor tissue blockb 
A minimum tissue surface area of 25 mm2, 75 µm thick, with 
at least 30% malignant tissue 
 

 
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a Whole blood to be collected at baseline only for genomic sequencing. Tubes are provided in the Blood 
Specimen Kit (see Genomic, Transcriptomic, and Proteomic Sample Collection Manual).  
b FFPE tissue blocks to be obtained at baseline when available for genomic sequencing, RNAseq, and 
proteomic analysis. A single block meeting the minimum requirements for genomics and proteomics is 
required. FFPE tissue blocks to be collected per local pathology laboratory procedures; detailed specimen 
and procedural instructions are provided in the Genomic, Transcriptomic, and Proteomic Sample Collection 
Manual. 
 
The Primary Clinical Research Coordinator or designee will process and 
ship samples directly to NantOmics. Refer to the Lab Manual for the 
NantOmics directed procedures (patient enrollment, ordering of supplies, 
shipping etc.).  
 
 
8 ALT-803 Formulation, Supply, and Potential Toxicity 
 
ALT-803 (now also known as N-803 as Altor BioScience is a wholly owned subsidiary 
of NantCell, Inc.), 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 an anti-cancer and anti-viral 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.  
8.1 Formulation and Composition 
The biological drug product, ALT-803, is formulated in a phosphate buffered saline 
(PBS) solution. The solution appears as a clear and colorless liquid. The drug 
substance is produced by a recombinant mammalian cell line and is manufactured 
using a protein free media. The vialed quantitative composition of ALT-803 is listed 
in the table below. 
 
Quantitative Composition of ALT-803 (N-803) 
Componenta 
Concentration 
Amount/Vial 
N-803 (ALT-803) 
1.0 mg/mL 
0.6 mg 
N-803 (ALT-803) 
2.0 mg/mL 
1.2 mg 
PBSb 
QS 
0.6 mLc 
 
a – N-803 is available in 2 different concentrations. The volume of PBS used is the same for both. 
b- PBS Formulation: Sodium Chloride (USP) 8.18 g/L; Sodium Phosphate Dibasic (USP) 2.68 g/L; Potassium 
Phosphate Monobasic (NF) 1.36 g/L pH 7.4. 
c- Fill volume is 0.6 mL, extractable volume is 0.5mL. 
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 

 
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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 
N-803 is supplied in a 2-mL single-dose/single-use vial containing 0.6 mL of N-803 
(extractable volume is 0.5 mL) at a concentration of 1 mg/mL or 2 mg/mL. 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 Study Drug Preparation and Administration  
ALT-803 dose calculation will be based on actual body weight; however for 
patients > 100 kilograms weight, the ALT-803 dose will be calculated using a 
weight capped at 100 kg. Refer to Section 6.1 and 6.2 for additional details.  
 
The calculated amount of ALT-803 will be drawn into a syringe for subcutaneous 
injection. The current IDS stock concentration is 1 mg/ml. Doses will be drawn 
directly into the syringe for injection. If the total subcutaneous dose is greater than 
1.5 mL, the dose will be divided into 2-3 subcutaneous injections as needed. 
For intraperitoneal administration, the ALT-803 dose is administered IP in 50 cc of 
room temperature Normal Saline via peritoneal catheter. Refer to Section 6.2 for 
full details. 

 
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8.5 Agent Inventory Records 
The investigator, or a responsible party designated by the investigator (e.g. 
institutional investigational pharmacy), must maintain a record of the inventory and 
disposition of study product using the Study Agent Drug Accountability Record.  
8.6 Toxicity 
The most common side effects seen in studies with subcutaneous (under the skin) 
injections have been, fever, chills, hypoalbuminemia, and injection site reaction, 
and skin rash, which at times has been widespread. These localized skins 
reactions are common (occurring in more than 50% of patients).  
 
Very common  
Common  
Rare 
 injection site reactions 
 fever 
 hypoalbuminemia  
 chills 
 
 fatigue 
 decreased lymphocyte count 
 limb edema 
 arthralgia 
 achiness 
 vomiting 
 headache 
 abdominal pain 
 back pain 
• anemia 
• edema 
• anorexia 
• hematuria 
• immunogenicity  
 
 
 
Anti-N-803 antibodies have been detected in subjects receiving N-803. The impact 
of anti-N-803 antibody formation on clinical efficacy and safety of N-803 is 
unknown. 
 
ALT-803 has not been given intraperitoneally, although this route of administration 
is common for other agents in the treatment of gynecological cancers with the most 
common complaints of pain and cramping during and after instillation, often severe 
enough to require pain medication. In a study using intravesical administration of 
ALT-803, the most common side effects have included hypertension, hematuria, 
pollakiuria, and fatigue. 
 
Previous editions of the ALT-803 Investigator’s Brochure relied heavily on clinical 
experience with the related cytokine therapeutic Proleukin® Interleukin-2 to 
anticipate potential risks associated with ALT-803 (N-803) administration. This 
approach was based on the fact that N-803 and IL-2 are both γ chain cytokines 
and thus could reasonably be predicted to have similar immunostimulatory 
properties. However, the substantial accumulated information on N-803 effects in 
humans presented the most recent IB (version 6 dated April 2019) indicates that 
many side effects of IL-2 are not observed in patients treated with N-803 at the 
doses being used clinically. For this reason, side effects observed in subjects 
treated with IL-2 but not N-803, such as capillary leak syndrome, pulmonary 

 
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dysfunction, acidosis, and gastritis, have been removed from the IB and are 
reflected in this protocol and its consent form.   
 
Refer to the current Investigator Brochure (version 6) for additional information. 
 
9 Adverse Event Monitoring, Documentation and Reporting 
Toxicity and adverse events will be classified and graded according to NCI's Common 
Terminology Criteria for Adverse Events V 4.0 (CTCAE) and reported on the schedule 
below. A copy of the CTCAE can be downloaded from the CTEP home page 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 
 
An exception to the use of CTCAE will be for the assessment of cytokine release 
syndrome (CRS). Individual adverse events which are associated with CRS will be 
graded per CTCAE; however the ultimate assessment will be made using a revised 
grading system for CRS as presented by Lee et al (24). 
 
CRS Revised Grading System (replaces CTCAE v4 CRS grading) 
Grade 
Toxicity Description 
Grade 1 
Symptoms are not life threatening and require symptomatic treatment only, e.g., fever, 
nausea, fatigue, headache, myalgias, malaise 
Grade 2 
Symptoms require and respond to moderate intervention - Oxygen requirement < 40% or 
Hypotension responsive to fluids or low dose of one vasopressor or Grade 2 organ toxicity 
Grade 3 
Grade 3 Symptoms require and respond to aggressive intervention - Oxygen requirement 
≥40% or Hypotension requiring high dose  or multiple vasopressors or Grade 3 organ toxicity 
or grade 4 transaminitis 
Grade 4 
Life-threatening symptoms - Requirement for ventilator support or Grade 4 organ toxicity 
(excluding transaminitis) 
Grade 5 
Death 
Grades 2-4 refer to CTCAE v4.0 grading. 
 
The following definitions of adverse events (AEs) and serious adverse events (SAEs) 
will determine whether the event requires expedited reporting via the SAE Report 
Form in addition to routine documentation in the AE case report form (CRF).  
 
The reporting timeframes for SAEs and other reportable events are located in Section 
9.6 
 
Note:  throughout this section the generic term “study drug” refers to the study related 
treatment (ALT-803). 

 
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9.1 Adverse Event Terminology 
Adverse Event:  Any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
 
Serious Adverse Event:  An adverse event is considered “serious” if, in the view 
of either the investigator or sponsor, it results in any of the following outcomes:  
 Death 
 A life-threatening adverse event 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions 
 A congenital anomaly/birth defect 
 Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  
 
Unexpected Event: An adverse event or suspected adverse reaction is 
considered “unexpected” if it is not listed in the investigator brochure or is not 
listed at the specificity or severity that has been observed; or, if an investigator 
brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current 
application, as amended.  
 
The following definitions are from the Masonic Cancer Center’s Standard 
Operating Procedure (SOP) Deviation Reporting: 
 
Major Deviation: A deviation or violation that impacts the risks and benefits of 
the research; may impact subject safety, affect the integrity of research data 
and/or affect a subject’s willingness to participate in the research. Deviations 
that place a subject at risk, but do not result in harm are considered to be major 
deviations. 
 
Minor Deviation: A deviation or violation that does not impact subject safety, 
compromise the integrity of research data and/or affect a subject’s willingness 
to participate in the research. 
9.2 AE Documentation and Reporting Requirements 
Adverse event collection for the purposes of this study will focus on events felt 
to be related to ALT-803 or events that cannot be attributed to other causes (i.e. 

 
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underlying diseases). At each visit through the final treatment visit, a targeted 
toxicity worksheet (Appendix IV) will be completed to document select expected 
toxicities associated with ALT-803.  
 
On days of ALT-803 administration, the worksheet will be completed: 
 prior to ALT-803 administration 
 At the end of dose monitoring period (as described in Section 6.1) with 
±20 minute window for 2 hour monitoring or ±10 minute window for 30 
minute monitoring 
 Day 29 Treatment Course 1 only 
 End of Treatment visit approximately 4 weeks after the last dose of ALT-
803 
 
In addition, the patient will be provided with an Injection Site Reactions Diary to 
be completed daily at home each day for 7 days after the each ALT-803 
subcutaneous injection (Appendix V) or intraperitoneal infusion (Appendix VI). 
Unexpected events and expected events that are not listed in Appendix IV and 
Section 8.8, or the consent form must be documented. 
 
Note: if a patient is not abiding by the standard of care study calendar (Section 
7.1), collection of the corresponding targeted events (and research related 
samples) also may be altered or discontinued on an individual patient basis, as 
appropriate.   
 
After the End of Treatment visit, monitoring for adverse events will become less 
frequent based on the schedule in Section 7.1 and only events that are 
unexpected and at least possibly related to ALT-803 will be documented upon 
knowledge.  
9.3 SAE Documentation and Reporting Requirements 
All SAEs are documented using the MCC OnCore SAE Report Form and 
reported. Any event that is both serious and unexpected and at least possibly 
related to the study treatment must be reported in an expedited manner.  
9.4 Early Stopping Rule Events Documentation and Reporting Requirements 
The following event counts toward an early study stopping rule and must be 
reported to the using the Event Form found OnCore under the reports tab: 
 Grade 3-5 organ toxicity (cardiac, gastrointestinal, hepatic, pulmonary, 
renal/genitourinary, or neurologic) not pre-existing within the 1st two months 
lasting more than 72 hours.  

 
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 Any grade 4 treatment emergent toxicity, grade 3 abdominal pain refractory 
to pain medication and persisting more than 72 hours or grade 3 or greater 
ascites 
 
An event that counts toward an early stopping rule does not necessarily 
constitute a SAE and should be reported as such only if they meet the criteria 
for reporting as defined in Section 9.3. 
9.5 Documentation of Death and Reporting Requirements 
Deaths, including due to disease, will be recorded as an SAE. Deaths due to 
disease should be recorded as a Grade 5 Neoplasm and will be reported to the 
FDA as part of the IND annual report. In addition, the death date and cause 
must be recorded in the patient follow-up tab in OnCore using the comment 
field in the survival status section to record the cause.  
9.6 Expedited Reporting the UMN IRB, FDA and Altor Bioscience 
 
Agency 
Criteria for reporting 
Timeframe 
Form to 
Use 
Submission address/ 
fax numbers 
U of MN 
IRB 
Events requiring prompt reporting including, but not 
limited to unanticipated death of a locally enrolled 
subject(s); new or increased risk; any adverse event  
that requires a change to the protocol or consent 
form or any protocol deviation that resulting in harm  
For a complete list refer to 
http://www.research.umn.edu/irb/guidance/ae.html#.
VC7xraI0-sh  
Within 5 
business 
days of event 
discovery 
 
RNI 
Ethos 
 
Deviation reporting per current IRB reporting 
requirements. 
Per current 
IRB 
requirements 
Deviation 
report  
FDA 
 
Unexpected and fatal or unexpected and  life 
threatening suspected adverse reaction 
no later than 
7 Calendar 
Days 
MCC 
SAE 
Submit to FDA as an 
amendment to IND with 
a copy to 
SAE.Reporting@Nantbi
o.com or Fax: (800) 
853-3497  
1) Serious and unexpected suspected adverse 
reaction or 
2)  increased occurrence of serious suspected 
adverse reactions over that listed in the protocol or 
investigator 
brochure or 
3) findings from other sources (other studies, animal 
or in vitro testing) 
no later than 
15 Calendar-
Days 
Altor 
BioScience 
Any SAE report regardless of attribution or FDA 
reporting requirements 
Within 24 
hours of 
receipt 
MCC 
SAE 
SAE.Reporting@Nantbio
.com or 
Fax: (800) 853-3497  
Masonic 
Cancer 
Center 
SAE 
Coordinator 
Events that count toward the early study stopping 
rule. 
At time of 
reporting 
Event 
Form 
SAE Coordinator 
mcc-saes@umn.edu, 
 
SAE.Reporting@Nantbi
o.com or 
Fax: (800) 853-3497  

 
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10 Study Data Collection and Monitoring 
10.1 Data Management 
This study will collect regulatory and clinical data using University of Minnesota 
CTSI’s 
instance 
of 
OnCore®(Online 
Enterprise 
Research 
Management 
Environment).  
 
The Oncore database resides on dedicated secure and PHI compliant hardware 
located in the University of Minnesota (UMN) datacenter (WBOB). All the data 
servers are managed by the Academic Health Center – Information Systems 
(AHC-IS) virtual servers which utilize clustered infrastructure to provide real-time 
failover of virtual servers. This real-time clustering is physically limited to the UMN 
data center. All relevant AHC IS procedures related for PHI compliant servers (as 
required by the Center of Excellence for HIPAA Data) apply to Oncore databases. 
 
The integrated data will be stored in PHI compliant servers managed by AHC IS 
with access given to those authorized users in the Clinical and Translation Science 
Institute Informatics team (CTSI BPIC and MCC CISS). The data will be integrated 
and extracted to researchers through the CTSI Informatics team and will be 
delivered through secure and compliant mechanisms (e.g. AHC IE data shelter, 
BOX, sftp, etc). If data de-identification is needed, then compliant AHC IE data de-
identification tools will be used. The informatics team will grant the IRB approved 
study team members access to data. 
 
Additional immune monitoring data about correlative laboratory samples 
generated by the Masonic Cancer Center Translational Therapy Laboratory (TTL) 
from the protocol-directed correlative research samples is stored in their 
Laboratory Information Management System (LIMS).The LIMS database 
application is also stored on a production server located in the UMN datacenter 
(WBOB) and is managed by the Academic Health Center 
 
Key study personnel are trained on the use of OnCore and will comply with protocol 
specific instructions embedded within the OnCore. 
10.2 Case Report Forms 
Participant data will be collected using protocol specific electronic case report 
forms (e-CRFs) developed within OnCore based on its library of standardized 
forms. The e-CRF will be approved by the study’s Principal Investigator and the 
Biostatistician prior to release for use. The Clinical Research Coordinator (PCRC) 
or designee will be responsible for registering the patient into OnCore at time of 

 
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study entry, completing e-CRFs based on the patient specific calendar, and 
updating the patient record until patient death or end of required study 
participation.  
10.3 Data and Safety Monitoring Plan (DSMP) 
The study’s Data and Safety Monitoring Plan will be in compliance with the 
University of Minnesota Masonic Cancer Center's Data & Safety Monitoring Plan 
(DSMP), which can be accessed at http://z.umn.edu/dmsp 
 
For the purposes of data and safety monitoring, this study is classified as high risk 
(under a locally held IND). Therefore the following requirements will be fulfilled: 
 
 At least quarterly review of the study’s progress by the Masonic Cancer Center 
Data and Safety Monitoring Council (DSMC)  
 The PI will comply with at least twice yearly monitoring of the project by the 
Masonic Cancer Center monitoring services. 
 The PI will oversee the submission of all reportable events per Section 9.6 to 
the Masonic Cancer Center’s SAE Coordinator, the University of Minnesota 
IRB, and the FDA.  
 
IND Annual Reports 
In accordance with regulation 21 CFR § 312.33, the IND sponsor (Dr. Geller) will 
submit a progress report annually. The report will be submitted within 60 days of 
the anniversary date that the IND went into effect.  
10.4 Record Retention 
The investigator will retain study records including source data, copies of case 
report forms, consent forms, HIPAA authorizations, and all study correspondence 
in a secured facility for at least 6 years after the study file is closed with the IRB 
and FDA.  
 
The Clinical Trials Office (CTO) will keep a master log of all patients participating 
in the study with sufficient information to allow retrieval of the medical records for 
that patient. Please contact the CTO before destroying any study related records. 
 
 
11 Primary and Secondary Endpoints  
11.1 Primary Endpoint 
The primary endpoint of this phase II screening trial is to select a “winner” among 
the two methods of delivery for future study. Progression free survival (PFS) at 6 

 
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months will be used to determine if one method is clearly inferior over the other. 
Other factors will be considered if the differences between the routes are small 
in terms of PFS. 
11.2 Secondary Endpoints 
 Progression free survival by 1 and 2 years is defined as alive at 1 and 2 years 
without disease progression from the start of ALT-803 dosing  
 Overall survival (OS) by 1 year and 2 years is defined as alive at 1 year and 
2 years from the start of ALT-803 dosing 
 ALT-803 associated toxicities when administered by intraperitoneal infusion 
will be documented using CTCAE v4 toxicity classification and grading 
 The safety of ALT-803 will be documented by lack of Grade 3 and greater 
toxicity 
 
 
12 Statistical Considerations   
12.1 Study Design, Objectives and Endpoints 
The primary objective of this phase II screening trial is to select a “winner” among 
the two methods of delivery for future study. The study is not intended to seek 
definite evidence that one method is superior to the other based on progression-
free-survival alone by 6 months for which a properly powered phase III trial would 
be needed. Instead this trial is intended  
 
(1) to ensure that if one of the two delivery methods is clearly inferior to the other 
in terms of the primary endpoint of progression free survival (PFS) by 6 months, 
there is a small probability that the inferior method will be carried forward to a more 
highly powered trial 
(2) if the difference between the methods is small in terms of PFS, the selection of 
the method will be allowed to include other factors (attraction of lymphocytes to 
the peritoneal cavity, ease of the methodology and safety). 
 
This study includes 2 randomized arms using intraperitoneal (IP) administered 
ALT-803 at 10 mcg/kg during the initial course and subcutaneous ALT-803 at 10 
mcg/kg. No arm is expected to be more toxic than the other. At the end of the trial, 
we will need to select a “winner” for any subsequent comparative trials. Hence, we 
adopt the design for selection between multiple screening trials proposed by 
Sargent & Goldberg (25). Following the notations in Sargent & Goldberg, we set 
up the selection rule as follows. Let π1 and π2 denote the true PFS. Define δ = π2 
– π1 and let p1 and p2 denote the observed PFS of the two arms where p2 has 
the highest PFS. In our calculation, if the difference between the two rates is 

 
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greater than a threshold d (i.e. |p2 – p1| > d), the treatment with the higher PFS 
rate will be selected for use in a future trial; otherwise, the method, which has a 
higher attraction of lymphocytes to the peritoneal cavity, easier methodology or 
fewer toxicities may be selected. The goal is to find a sample size n that can ensure 
that “the probability of correct selection” (which is analogous to “power”) exceeds 
a certain threshold (λ), that is 
Pr 𝑝2 −𝑝1 > 𝑑|𝜋1, 𝜋2 = 1 −ϕ  
𝑑−𝛿
  1
𝑛  𝜋1 1−𝜋1 +𝜋2 1−𝜋2  
 > 𝜆. 
 
 
Secondary endpoints include: 
Overall survival (OS) at 1 year 
Progression free survival (PFS) at 1 year 
 
Correlative endpoints include: 
 In both blood and the peritoneal wash 
1. Change in total number of T cells and NK cells, as well as activated 
cells (CD69, HLA-DR, CD25), T cell subsets, and NK cell subsets 
2. Change in NK cell function 
 
Randomization will apply to the 1st treatment course only with the following arms:   
Arm 1: ALT-803 SQ only – patient receives ALT-803 10 mcg/kg SQ weekly x 4 
followed by 4 weeks of no treatment before continuing with treatment courses 2, 
3, and 4 as described below 
Arm 2:  ALT-803 IP and SQ – patient receives ALT-803 10 mcg/kg IP weekly x 4 
weeks followed by 4 weeks of no treatment before continuing with treatment 
courses 2, 3, and 4 as described below 
 
Treatment courses 2, 3, and 4 are identical for all patients - ALT-803 10 mcg/kg 
SQ weekly x 4 with a 4 week rest (4 weeks on/4 weeks off).  
12.2 Statistical Analyses 
Primary analyses will follow the intent-to-treat principle where the effect will be 
measured according to how treatments were randomized. A secondary analysis 
will only include those patients who received at least two treatment courses of the 
assigned regimen. The endpoints of progression-free survival and overall survival 
will be estimated from Kaplan-Meier curves. Descriptive statistics and plots such 
as median, range and interquartile range and box-plots will be used to measure 
the change in the total number of cells. The general-Wilcoxon test will be employed 
across groups. Change in NK cell function will be measure with simple proportions. 

 
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The Chi-square test or Fisher’s exact test will be employed to test NK cell function 
across groups depending on expected cell counts. 
12.3 Sample Size 
We expect that all patients will receive at least 2 treatment courses. But we are 
including enough patients to realize at least 80% power under the secondary 
analysis even if 3 patients in each arm do not receive at last 2 treatment courses. 
If the true PFS is 70% and 90% (i.e. 90% is the best survival and 70% is the 
expected PFS in the other arm) and we choose a selection threshold of d = 15%, 
a sample size of 14 patients in each arm will achieve at least 81% power under 
ITT and 11 patients in each arm will achieve at least 80% power under the non-
ITT analyses. Power calculations are generated from partial code from X. Luo in R 
3.0.2 (R Development Core Team, Vienna, Austria). 
12.4 Stopping Rules     
Stopping rules will be monitored for each arm separately. Stopping rules were 
developed based on an adaptation of the Pocock stopping boundaries (26). 
 
1) Grade 3-5 organ toxicity (cardiac, gastrointestinal, hepatic, pulmonary, 
renal/genitourinary, or neurologic) not pre-existing within the 1st two 
months lasting more than 72 hours  
The goal is to construct a boundary based on excessive toxicity such that the 
probability of early stopping is at most 10% if the rate is equal to 5% and our 
sample size is 14. With these stipulations, the study will be stopped if there is 
excess toxicity in 2 out of 2 patients or 3 events at any time. If the actual 
probability of toxicity is 20% or 30%, the probability of reaching the boundary will 
be 64% and 88% respectively. 
 
2) Any grade 4 treatment emergent toxicity, grade 3 abdominal pain refractory 
to pain medication and persisting more than 72 hours or grade 3 or greater 
ascites 
The goal is to construct a boundary based on excessive toxicity such that the 
probability of early stopping is at most 10% if the rate is equal to 5% and our 
sample size is 14. With these stipulations, the study will be stopped if there is 
excess toxicity in 2 out of 2 patients or 3 events at any time. If the actual 
probability of toxicity is 20% or 30%, the probability of reaching the boundary will 
be 64% and 88% respectively. 
 
 

 
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13 Conduct of the Study 
13.1 
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.  
13.2 Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki. The IRB will review all appropriate study documentation in 
order to safeguard the rights, safety and well-being of the patients. The study will 
only be conducted at sites where IRB approval has been obtained. The protocol, 
consent, written information given to the patients, safety updates, progress reports, 
and any revisions to these documents will be provided to the IRB by the 
Investigator.  
 
14 References  
 
1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin.60(5):277-
300.  
2. The Oncologist October 2002 vol. 7 Supplement 5 20-28. 
3. Cheever MA. Twelve immunotherapy drugs that could cure cancers. Immunological 
reviews. 2008;222:357-68. Epub 2008/03/28.  
4. Cooper MA, Bush JE, Fehniger TA, VanDeusen JB, Waite RE, Liu Y, et al. In vivo 
evidence for a dependence on interleukin 15 for survival of natural killer cells. Blood. 
2002;100(10):3633-8. Epub 2002/10/24. 
5. Bachanova V, Cooley S, Defor TE, Verneris MR, Zhang B, McKenna DH, et al. 
Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved 
using IL-2 diphtheria toxin fusion protein. Blood. 2014. Epub 2014/04/11. 
6. 
Oh S, Perera LP, Burke DS, Waldmann TA, Berzofsky JA. IL-15/IL-15Ralpha-mediated 
avidity maturation of memory CD8+ T cells. Proc Natl Acad Sci U S A. 
2004;101(42):15154-9. Epub 2004/10/13.  
7. 
Kobayashi H, Dubois S, Sato N, Sabzevari H, Sakai Y, Waldmann TA, et al. Role of 
trans-cellular IL-15 presentation in the activation of NK cell-mediated killing, which leads 
to enhanced tumor immunosurveillance. Blood. 2005;105(2):721-7. Epub 2004/09/16. 
doi: 10.1182/blood-2003-12-4187 2003-12-4187 [pii]. PubMed PMID: 15367431. 
8. 
Budagian V, Bulanova E, Orinska Z, Ludwig A, Rose-John S, Saftig P, et al. Natural 
soluble interleukin-15Ralpha is generated by cleavage that involves the tumor necrosis 
factor-alpha-converting enzyme (TACE/ADAM17). J Biol Chem. 2004;279(39):40368-
75. Epub 2004/06/25.  

 
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9. 
Conlon KC, Lugli E, Welles HC, Rosenberg SA, Fojo AT, Morris JC, et al. 
Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and 
cytokine production during first-in-human clinical trial of recombinant human interleukin-
15 in patients with cancer. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology. 2015;33(1):74-82. Epub 2014/11/19.  
10. Xu W, Jones M, Liu B, Zhu X, Johnson CB, Edwards AC, et al. Efficacy and 
mechanism-of-action of a novel superagonist interleukin-15: interleukin-15 receptor 
alphaSu/Fc fusion complex in syngeneic murine models of multiple myeloma. Cancer 
Res. 2013;73(10):3075-86. Epub 2013/05/07.  
11. Wong RL, Liu B, Zhu X, You L, Kong L, Han KP, et al. Interleukin-15:Interleukin-15 
receptor alpha scaffold for creation of multivalent targeted immune molecules. Protein 
Eng Des Sel. 2011;24(4):373-83. Epub 2010/12/24. 
12. Han KP, Zhu X, Liu B, Jeng E, Kong L, Yovandich JL, 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):804-10. Epub 2011/10/25.  
13. Steel JC, Waldmann TA, Morris JC. Interleukin-15 biology and its therapeutic 
implications in cancer. Trends in pharmacological sciences. 2012;33(1):35-41. Epub 
2011/10/29.  
14. 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):588-93. Epub 2007/01/05.  
15. Zhu X, Marcus WD, Xu W, Lee HI, Han K, Egan JO, et al. Novel human interleukin-15 
agonists. J Immunol. 2009;183(6):3598-607. Epub 2009/08/28.  
16. Bergamaschi C, Bear J, Rosati M, Beach RK, Alicea C, Sowder R, et al. Circulating IL-
15 exists as heterodimeric complex with soluble IL-15Ralpha in human and mouse 
serum. Blood. 2012;120(1):e1-8. Epub 2012/04/13.  
17. Rubinstein MP, Kovar M, Purton JF, Cho JH, Boyman O, Surh CD, 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):9166-71. Epub 2006/06/08. 
18. Stoklasek TA, Schluns KS, Lefrancois L. Combined IL-15/IL-15Ralpha immunotherapy 
maximizes IL-15 activity in vivo. J Immunol. 2006;177(9):6072-80. Epub 2006/10/24.  
19. Mortier E, Quemener A, Vusio P, Lorenzen I, Boublik Y, Grotzinger J, et al. Soluble 
interleukin-15 receptor alpha (IL-15R alpha)-sushi as a selective and potent agonist 19 
IL-15 action through IL-15R beta/gamma. Hyperagonist IL-15 x IL-15R alpha fusion 
proteins. J Biol Chem. 2006;281(3):1612-9. Epub 2005/11/15. 
20. Marshall D, Sinclair, C, Tung S, et al. Differential requirement for IL-2 and IL-15 during 
bifurcated development of thymic regulatory T cells. J Immunol. 2014 Dec 
1;193(11):5525-33. 
21. Kim PS, Kwilas AR, Xu W, et al. IL-15 superagonist/IL-15RαSushi-Fc fusion complex 
(IL-15SA/IL-15RαSu-Fc; ALT-803) markedly enhances specific subpopulations of NK 
and memory CD8+ T cells, and mediates potent anti-tumor activity against murine 
breast and colon carcinomas. Oncotarget. 2016 Mar 29;7(13):16130-45. 
22. Wu Z1, Xu Y. IL-15R alpha-IgG1-Fc enhances IL-2 and IL-15 anti-tumor action through 
NK and CD8+ T cells proliferation and activation. J Mol Cell Biol. 2010 Aug;2(4):217-22. 

 
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23. Hermanson DL, Bendzick L, Pribyl L, McCullar V, Vogel RI, Miller JS, et al. Induced 
Pluripotent Stem Cell-Derived Natural Killer Cells for Treatment of Ovarian Cancer. 
Stem Cells. 2016;34(1):93-101. Epub 2015/10/28.  
24. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management 
of cytokine release syndrome. Blood. 2014;124(2):188-195. 
25. Sargent, D. J., & Goldberg, R. M. (2001). A flexible design for multiple armed screening 
trials. Statistics in Medicine, 20: (1051-1060). 
26. Ivanova I, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials in 
Oncology. Biometrics 2005, 61: 540-545. 
27. Rustin G; Vergote I; Eisenhauer E, et al. Definitions for Response and Progression in 
Ovarian Cancer Clinical Trials Incorporating RECIST 1.1 and CA 125 Agreed by the 
Gynecological Cancer Intergroup (GCIG). International Journal of Gynecological 
Cancer & Volume 21, Number 2, February 2011. 
 
 
 

 
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Appendix I –Patient Eligibility Checklist  
Randomized Study of Single Course of Intraperitoneal (IP) ALT-803 Followed by 
Subcutaneous (SQ) Maintenance ALT-803 Versus Subcutaneous (SQ) 
Maintenance ALT-803 Only after 1st Line Chemotherapy for Advanced Ovarian, 
Fallopian Tube, and Primary Peritoneal Cancer (CPRC #2016LS034) 
 
 

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 Appendix II – FIGO Staging, GOG PS and NYHA Classification 
The FIGO staging systems are determined by the International Federation of Gynecology 
and Obstetrics (Fédération Internationale de Gynécologie et d’Obstétrique). In general, 
there are five stages: 
 
stage 0: carcinoma in situ (common in cervical, vaginal, and vulval cancer)  
stage I: confined to the organ of origin  
stage II: invasion of surrounding organs or tissue 
stage III: spread to distant nodes or tissue within the pelvis  
stage IV: distant metastasis(es) 
 
please refer to https://radiopaedia.org/articles/figo-staging-system for detailed primary 
specific staging. 
 
ref: Prat J, FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and 
peritoneum. Int J Gynaecol Obstet. 2014 Jan. 124 (1):1-5. 
 
 
GOG 
Score  
Activity Level  
0  
Fully active, unrestricted activities of daily living  
1  
Ambulatory, but restricted in strenuous activity  
2  
Ambulatory, and capable of self care. Unable to work. Out of 
bed for greater than 50% of waking hours  
3  
Limited self care, or confined to bed or chair 50% of waking 
hours. Needs special assistance  
4  
Completely disabled, and no self care  
5  
Dead  
 
 
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 – RECIST version 1.1 With Updated CA-125 Criteria(27) 
 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 
1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
 
 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 
mm with CT scan, or >10 mm with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 

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recorded at baseline. Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
Methods for Evaluation of Measurable Disease  
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g. for body scans).  
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is 
beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should 
be used and the image acquisition protocol should be followed as closely as possible to prior 
scans. Body scans should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.  
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
 

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Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
 
Tumor markers  This study will use CA-125 response based on International Journal of 
Gynecological Cancer & Volume 21, Number 2, February 2011 (26), published after the current 
version of RECIST. 
 
A CA 125 response is defined as at least a 50% reduction in CA 125 levels from a pretreatment 
sample. The response must be confirmed and maintained for at least 28 days. Patients can be 
evaluated according to CA 125 only if they have a pretreatment sample that is at least twice the 
upper limit of the reference range and within 2 weeks before starting the treatment. 
 
Progression or recurrence based on serum CA 125 levels will be defined on the basis of a 
progressive serial elevation of serum CA 125 according to the following criteria: 
a. Patients with elevated CA-125 pretreatment and normalization of CA-125 must show 
evidence of CA-125 ≥2 times the upper limit of the reference range on 2 occasions at least 1 
week apart or 
b. Patients with elevated CA-125 before treatment, which never normalizes, must show 
evidence of CA-125 ≥ 2 times the nadir value on 2 occasions at least 1 week apart or 
c. Patients with CA-125 in the reference range before treatment must show evidence of CA-125 
≥ 2 times the upper limit of the reference range on 2 occasions at least 1 week apart. 
 
CA 125 progression will be assigned the date of the first measurement that meets the criteria as 
noted. A patient may be declared to have PD on the basis of either the objective RECIST 1.1 
criteria or the CA 125 criteria. The date of progression will be the date of the earlier of the 2 
events if both are documented. 
 
Cytology, Histology  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT  scans are needed to determine if there is truly progression occurring at that 
site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the 
positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in 

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the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
<10 mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note:  the appearance of one or 
more new lesions is also considered progressions). 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while 
on study. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 
mm short axis) 
Note:  If tumor markers are initially above the upper normal limit, they 
must normalize for a patient to be considered in complete clinical 
response. 
 
Non-CR/Non-PD: 
 
Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression 
should not normally trump target lesion status. It must be 
representative of overall disease status change, not a single lesion 
increase.    
Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should prevail in 
such circumstances, and the progression status should be confirmed 
at a later time by the review panel (or Principal Investigator). 
 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
 

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For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
documented at least once >4 wks. 
from baseline** 
PD 
Any 
Yes or 
No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used 
as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised 
 
Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started, including the baseline measurements.  
 
Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 

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Appendix IV – ALT-803 Targeted Toxicity Worksheet 
See Section 9.2 for time points 
 
 
 
 
 
 
based on CTCAE v4 
 Patient Initials:  _______ 
Date of Assessment:  _________     Assessment Time Point:  _________      
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ALT-803 Injection 
site reaction 
None 
Tenderness with or 
without associated 
symptoms (e.g., warmth, 
erythema, itching) 
Pain; lipodystrophy; edema; 
phlebitis 
Ulceration or necrosis; severe 
tissue damage; operative 
intervention indicated 
Life-threatening consequences; 
urgent intervention indicated 
Abdominal Pain 
(IP related) 
None 
Asymptomatic but 
distention 
Moderate pain; limiting 
instrumental ADL 
Severe pain; limiting self care 
ADL 
-------------- 
Dyspnea 
None or 
no change 
Shortness of breath with 
moderate exertion 
Shortness of breath with minimal 
exertion; limiting instrumental ADL 
Shortness of breath at rest; 
limiting self care ADL 
Life-threatening consequences; 
urgent intervention indicated 
Hypoxia 
None 
……………… 
Decreased O2 saturation with 
exercise (e.g., pulse oximeter < 
88%) intermittent supplemental 
oxygen 
Decreased oxygen saturation at 
rest (e.g., pulse oximeter < 88% 
or PaO2 ≤ 55 mm Hg) 
Life-threatening airway 
compromise; urgent 
intervention indicated (e.g., 
tracheotomy or intubation) 
Fever 
None 
38.0 - 39.0◦ C (100.4 -
102.2◦ F) 
> 39.0 - 40.0◦C (102.3 - 104.0◦F) 
> 40.0 ◦ C (>104.0◦ F) for ≤ 24 hrs 
> 40.0 ◦ C (>104.0◦ F) for > 24 
hrs 
Chills 
None 
Mild sensation of cold; 
shivering; chattering of teeth
Moderate tremor of the entire body; 
narcotics indicated 
Severe or prolonged, not 
responsive to narcotics 
……………………… 
Hypertension 
None 
Pre-hypertension (systolic 
BP 120 - 139 mm Hg or 
diastolic BP 80 - 89 mm 
Hg) 
Stage 1 hypertension (systolic BP 
140 - 159 mm Hg or diastolic BP 90 -
99 mm Hg); medical intervention 
indicated; recurrent or persistent ≥ 
24 hrs); symptomatic increase by 
>20 mm Hg (diastolic) or to >140/90 
mm Hg if previously WNL; 
monotherapy indicated. 
Stage 2 hypertension (systolic BP 
≥ 160 mm Hg or diastolic BP ≥ 
100 mm Hg); medical intervention 
indicated; more than one drug or 
more intensive therapy than 
previously used indicated. 
Life-threatening 
consequences (e.g., 
malignant hypertension, 
transient or permanent 
neurologic deficit, 
hypertensive crisis); urgent 
intervention indicated. 
Hypotension 
None 
Asymptomatic, intervention 
not indicated 
Non-urgent medical 
intervention indicated 
Medical intervention or 
hospitalization indicated 
Life-threatening and urgent 
intervention indicated 
Edema 
None 
Localized to dependent 
areas, no disability or 
functional impairment 
Moderate localized edema 
and intervention indicated; 
limiting instrumental ADL 
Severe localized edema and 
intervention indicated; limiting self 
care ADL 
……………………… 
Pneumonitis 
None 
Asymptomatic; clinical or 
diagnostic observations 
only; intervention not 
indicated 
Symptomatic; medical 
intervention indicated; limiting 
instrumental ADL 
Severe symptoms; limiting self 
care ADL; oxygen indicated 
Life-threatening respiratory 
compromise; urgent 
intervention indicated (e.g. 
intubation or tracheotomy) 
Headache 
None 
Mild pain 
Moderate pain; limiting 
instrumental ADL 
Severe pain; limiting self care 
ADL 
……………………… 
Confusion 
(Altered Mental 
Status) 
None 
Mild disorientation 
Moderate disorientation; limiting 
instrumental ADL 
Severe disorientation; limiting self 
care ADL 
Life-threatening  
consequences; urgent 
intervention indicated 
Rash 
None 
Covering < 10% body 
surface area (BSA) 
Covering 10-30% body surface 
area (BSA) 
>30% body surface area (BSA) 
Generalized exfoliative, 
ulcerative, or bullous dermatitis 
Gait Disturbance 
None 
Mild change in gait (eg, 
wide-based, limping or 
hobbling) 
Moderate change in gait (eg, wide-
based, limping or hobbling); 
assistance device indicated;  
limiting instrumental ADL 
Disabling; limiting self care ADL 
……………………… 
 
Person Completing Form:   
 
 
 
 
ADL = activities of daily living 
 
 

Randomized Study of Maintenance ALT-803 Therapy IP Followed by SQ Versus SQ Only 
 
 
 
 
May 21, 2019 
Page 53 of 57 
CPRC #2016LS034 
 
Appendix V – ALT-803 Injection Site Reactions Diary 
 
 
The Diary is to be completed by the patient as a self-assessment after each dose of ALT-803.  
 
A new diary must be started for each ALT-803 injection/IP infusion.  
 
If the previous injection reaction has not resolved, continue to collect information on its diary based on the days from that 
injection. In other words if at Day 6 post-injection, an injection site reaction is still present continue to collect data for items 
1-4 daily until the reaction resolves. 
 
 
  
 
Note: patients assigned to intraperitoneal (IP) ALT-803 during the 1st treatment course will complete the modified Patient 
Diary found in Appendix VI.

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

Randomized Study of Maintenance ALT-803 Therapy IP Followed by SQ Versus SQ Only 
 
 
 
 
May 21, 2019 
Page 55 of 57 
CPRC #2016LS034 
 
Patient Number* 
 
Date of Study Drug Injection* 
________/_________/________ 
*To be completed by the site. 
Complete daily for 7 days or until the injection site has resolved (returned to normal) . Please bring back this completed diary to your next clinic visit. 
 
 
Instructions 
Day 7 
Post Injection 
____/____/_________ 
Day 8 
Post Injection 
____/____/_________ 
Day 9 
Post Injection 
____/____/_________ 
Day 10 
Post Injection 
____/____/_________ 
Day 11 
Post Injection 
____/____/________ 
Day 12 
Post Injection 
___/___/________ 
Day 13 
Post Injection 
____/____/_________ 
 
1. Is there redness at 
the injection site? 
 
Check: 
Yes  or No 
If yes, measure longest 
diameter in cm 
Yes  No 
 
________cm 
Yes  No 
 
________cm 
Yes  No  
 
________cm 
Yes  No 
 
________cm 
Yes  No 
 
________cm 
Yes  No 
 
________cm 
Yes  No 
 
________cm 
 
2. Is there firmness or 
swelling at the 
injection site? 
Check: 
Yes  or No 
 
Yes  No 
 
Yes  No 
 
Yes  No 
 
Yes  No 
 
Yes  No 
 
Yes  No 
 
Yes  No 
 
 
3. Have you 
experienced any pain 
or itching at the 
injection site? 
Check the pain 
and/or itch box if 
present 
And tell us if the pain 
and/or itching is mild, 
moderate or severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe     Severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe     Severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe     Severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe    Severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe     Severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe     Severe 
 Pain   Itch 
Mild          Mild 
Mod          Mod 
Severe     Severe 
 
4. Have you taken or 
applied any 
medication for 
injection site pain or 
itching? 
Check: 
Yes  or No 
Provide name of 
medication(s) 
Yes  No 
Name(s): 
 
Yes  No 
Name(s): 
 
Yes  No 
Name: 
 
Yes  No 
Name: 
 
Yes  No 
Name: 
 
Yes  No 
Name: 
 
Yes  No 
Name: 
 
Grading Injection Site Pain or Itching 
 
 
 
 
 
 
 
Mild – Noticeable, does not interfere with activity 
 
 
 
 
 
 
Moderate – Interferes with activity, limiting activities of daily living 
 
 
 
 
Severe – Severely limiting self-care activities of daily living, incapacitating  
 
 
 
 
 

Randomized Study of Maintenance ALT-803 Therapy IP Followed by SQ Versus SQ Only 
 
 
 
 
May 21, 2019 
Page 56 of 57 
CPRC #2016LS034 
 
Appendix VI – ALT-803 Intraperitoneal (IP) Reactions Diary 
 
 
 

INTRAPERITONEAL (IP) INJECTION 
 
 
Patient Number* 
 
Date of Study Drug IP Infusion* 
________/_________/________ 
*To be completed by the site. 
Please answer all questions below daily for 7 days, beginning with day of treatment. Be sure to bring back this completed diary to your next clinic visit. 
 
 
Instructions 
Day of Study 
Drug IP Infusion 
____/____/_________ 
Day 1 
Post Infusion 
____/____/_________ 
Day 2 
Post Infusion 
____/____/_________ 
Day 3 
Post Infusion 
____/____/_________ 
Day 4 
Post Infusion 
____/____/________ 
Day 5 
Post Infusion 
___/___/________ 
Day 6 
Post Infusion 
____/____/_________ 
1. Have you 
experienced any 
abdominal pain? 
Check: 
Yes or No 
If yes, tell us if the pain 
is mild, moderate or 
severe 
Yes  No  
Mild       
Moderate       
Severe     
Yes  No  
Mild       
Moderate       
Severe     
Yes  No  
Mild       
Moderate       
Severe     
Yes  No  
Mild       
Moderate       
Severe     
Yes  No  
Mild       
Moderate       
Severe     
Yes  No  
Mild       
Moderate       
Severe     
Yes  No  
Mild       
Moderate       
Severe     
1. Have you 
experienced any 
abdominal 
distention? 
Check: 
Yes or No 
If yes, tell us if the 
extent of the 
abdominal distention 
Yes  No 
Asymptomatic 
(visually 
distended but 
not bothersome)   
Symptomatic:  
Severe 
discomfort 
Yes  No 
Asymptomatic 
(visually 
distended but 
not bothersome)   
Symptomatic:  
Severe 
discomfort 
Yes  No 
Asymptomatic 
(visually 
distended but 
not bothersome)   
Symptomatic:  
Severe 
discomfort 
Yes  No 
Asymptomatic 
(visually 
distended but 
not bothersome)   
Symptomatic:  
Severe 
discomfort 
Yes  No 
Asymptomatic 
(visually 
distended but 
not bothersome)   
Symptomatic:  
Severe 
discomfort 
Yes  No 
Asymptomatic 
(visually 
distended but 
not bothersome)   
Symptomatic:  
Severe 
discomfort 
Yes  No 
Asymptomatic 
(visually 
distended but 
not bothersome)   
Symptomatic:  
Severe 
discomfort 
 
4. Have you taken any 
medication for 
abdominal pain? 
Check: 
Yes or No 
Provide name of 
medication(s) 
Yes  No 
Name(s): 
 
Yes  No 
Name(s): 
 
Yes  No 
Name: 
 
Yes  No 
Name: 
 
Yes  No 
Name: 
 
Yes  No 
Name: 
 
Yes  No 
Name: 
 
 
5. Have you 
experienced any 
chills? 
 
Check: 
Yes or No 
If yes, tell us if the 
chills are mild, 
moderate or severe 
Yes  No 
       Mild 
Moderate 
       Severe 
Yes  No 
       Mild 
Moderate 
       Severe 
Yes  No 
       Mild 
Moderate 
       Severe 
Yes  No 
       Mild 
Moderate 
       Severe 
Yes  No 
       Mild 
Moderate 
       Severe 
Yes  No 
       Mild 
Moderate 
       Severe 
Yes  No 
       Mild 
Moderate 
       Severe 
 
6. Record your daily 
temperature upon 
waking 
 (do not drink anything 5 
minutes before taking your 
temperature) 
 
 
Check: 
Yes  or No 
If your temperature is 
101°F for more than 
24 hours notify your 
study doctor or the 
research staff. 
 
Yes  No 
________°F 
 
Time: 
____:____   
AM / PM 
Yes  No 
________°F 
 
Time: 
____:____  
AM / PM 
Yes  No 
________°F 
 
Time: 
____:____  
AM / PM 
Yes  No 
________°F 
 
Time: 
____:____  
AM / PM 
Yes  No 
________°F 
 
Time: 
____:____  
AM / PM 
Yes  No 
________°F 
 
Time: 
____:____  
AM / PM 
Yes  No 
________°F 
 
Time: 
____:____  
AM / PM 
Grading Abdominal Pain  
 
 
 
 
 
Grading Chills 
Mild – Noticeable, does not interfere with activity 
 
 
 
Mild – Mild sensitive of cold, shivering, chattering of teeth 
Moderate – Interferes with activity, limiting activities of daily living 
 
Moderate – Moderate tremor of entire body, medication taken 
Severe – Severely limiting self-care activities of daily living, incapacitating  
Severe – Prolonged or severe, does not respond to medication