A Phase 1/2 Study of N-803 in Patients With Relapse/Refractory Indolent B Cell Non-Hodgkin Lymphoma in Conjunction With Rituximab
Phase: PHASE1
Conditions: Relapsed/Refractory Indolent B Cell Non-Hodgkin Lymphoma
Sponsor: Altor BioScience

 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Number: 
CA-ALT-803-02-14 
 
 
Protocol Title: 
A phase 1/2 study of ALT-803 in patients with 
relapse/refractory indolent B cell non-Hodgkin 
lymphoma in conjunction with rituximab 
 
 
Date of Protocol: 
 
Version# 01 
 
September 4, 2014 
 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 
 
 

 
INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
CA-ALT-803-02-14 
 
 
Protocol Title: 
A phase 1/2 study of ALT-803 in patients with 
relapse/refractory indolent B cell non-Hodgkin 
lymphoma in conjunction with rituximab 
 
 
Date of Protocol: 
 
Version# 01 
 
September 4, 2014 
 
 
 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 
By my signature below, I hereby attest that I have read, and that I understand and will abide by all the 
conditions, instructions, and restrictions contained in the attached protocol. 
 
Additionally, I will not initiate this study without approval of the appropriate Institutional Review Board 
(IRB), and I understand that any changes in the protocol must be approved in writing by the sponsor, the 
IRB, and, in certain cases the FDA, before they can be implemented, except where necessary to 
eliminate hazards to subjects. 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Name (Print) 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
SYNOPSIS ................................................................................................................................................................6 
1. 
OBJECTIVES ................................................................................................................................................13 
1.1 
PRIMARY OBJECTIVES .............................................................................................................................13 
1.2 
SECONDARY OBJECTIVES ........................................................................................................................13 
2. 
BACKGROUND ............................................................................................................................................13 
2.1 
ALT-803 – GENERAL INFORMATION.......................................................................................................13 
2.2 
INDOLENT NON-HODGKIN LYMPHOMA (INHL) ......................................................................................14 
2.3 
IMMUNE-BASED THERAPIES FOR INHL ...................................................................................................15 
2.4 
PHARMACOLOGICAL EFFECTS OF ALT-803 IN VITRO AND IN ANIMALS ..................................................16 
 
Development of ALT-803 (IL-15N72D:IL-15RαSu/IgG1 Fc complex) .............................................................. 16 
2.4.1
 
In vitro biological activity of ALT-803 including ADCC enhancement ............................................................. 16 
2.4.2
 
In vivo biological activity of ALT-803 ............................................................................................................... 19 
2.4.3
 
Potent anti-tumor activity of ALT-803 in mouse models in vivo ........................................................................ 20 
2.4.4
2.5 
NON-CLINICAL TOXICOLOGY ..................................................................................................................22 
 
Multi-dose toxicity studies in mice ..................................................................................................................... 22 
2.5.1
 
Multi-dose toxicity studies in cynomolgus monkeys ........................................................................................... 23 
2.5.2
2.6 
PHARMACOKINETICS ...............................................................................................................................25 
 
Non-clinical pharmacokinetics .......................................................................................................................... 25 
2.6.1
 
Clinical pharmacokinetics ................................................................................................................................. 25 
2.6.2
2.7 
RATIONALE FOR HUMAN CLINICAL STARTING DOSE ...............................................................................25 
2.8 
HUMAN EXPERIENCE ...............................................................................................................................26 
3. 
RATIONALE FOR THE CURRENT STUDY ...........................................................................................27 
4. 
OVERALL STUDY DESIGN .......................................................................................................................28 
5. 
STUDY POPULATION ................................................................................................................................30 
5.1 
INCLUSION CRITERIA ...............................................................................................................................30 
5.2 
EXCLUSION CRITERIA ..............................................................................................................................31 
5.3 
INCLUSION OF WOMEN AND MINORITIES .................................................................................................31 
6. 
STUDY DESIGN ...........................................................................................................................................32 
6.1 
SCREENING AND ENROLLMENT ...............................................................................................................32 
6.2 
STUDY TREATMENT .................................................................................................................................32 
 
Treatment setting ............................................................................................................................................... 32 
6.2.1
 
Treatment regimen and study scheme ................................................................................................................ 32 
6.2.2
 
Study treatment preparation .............................................................................................................................. 33 
6.2.3
 
Study treatment administration .......................................................................................................................... 33 
6.2.4
 
Pre and post-therapy intervention guidelines .................................................................................................... 34 
6.2.5
6.3 
DURATION OF PATIENT PARTICIPATION ..................................................................................................35 
6.4 
DOSE ESCALATION PHASE .......................................................................................................................35 
6.5 
EXPANSION PHASE ..................................................................................................................................36 
6.6 
STOPPING RULES .....................................................................................................................................37 
 
During dose escalation phase of the study ......................................................................................................... 37 
6.6.1
 
During expansion phase of the study ................................................................................................................. 38 
6.6.2
 
At any time during the study .............................................................................................................................. 38 
6.6.3
6.7 
PATIENT MONITORING, RESPONSE EVALUATION, DISEASE PROGRESSION & SURVIVAL FOLLOW-UP .....38 
 
Patient monitoring ............................................................................................................................................. 38 
6.7.1
 
Response evaluation ........................................................................................................................................... 38 
6.7.2
 
Disease progression and survival follow-up ...................................................................................................... 39 
6.7.3
6.8 
DOSE LIMITING TOXICITY ........................................................................................................................39 
 
Definition of dose limiting toxicity ..................................................................................................................... 39 
6.8.1

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Definition of maximum tolerated dose (MTD) ................................................................................................... 39 
6.8.2
 
Definition of minimal efficacious dose (MED) .................................................................................................. 40 
6.8.3
6.9 
STUDY TREATMENT DISCONTINUATION ..................................................................................................40 
 
Study treatment discontinuation events .............................................................................................................. 40 
6.9.1
 
Replacement of participants............................................................................................................................... 40 
6.9.2
 
Follow-ups after treatment discontinuation ....................................................................................................... 41 
6.9.3
 
Discontinuation due to SAEs or on-going study drug related AEs .......................................................... 41 
6.9.3.1.
 
Discontinuation due to any other reasons ................................................................................................. 41 
6.9.3.2.
6.10 
STUDY TREATMENT INTERRUPTION ........................................................................................................41 
 
Kidney dysfunction ........................................................................................................................................ 41 
6.10.1
 
Hematological dysfunction ............................................................................................................................ 41 
6.10.2
 
Hypotension .................................................................................................................................................. 41 
6.10.3
 
Allergic reactions and cytokine release syndrome/acute infusion reaction .................................................. 42 
6.10.4
6.11 
GENERAL SUPPORTIVE CARE GUIDELINES AND DRUG INTERACTION ......................................................42 
 
ALT-803 ........................................................................................................................................................ 42 
6.11.1
 
Hypotension and capillary leak syndrome ................................................................................................ 42 
6.11.1.1.
 
Pulmonary dysfunction ............................................................................................................................. 43 
6.11.1.2.
 
Impaired kidney and liver functions ......................................................................................................... 43 
6.11.1.3.
 
Infection ................................................................................................................................................... 43 
6.11.1.4.
 
Fever and chills ........................................................................................................................................ 43 
6.11.1.5.
 
Gastritis .................................................................................................................................................... 43 
6.11.1.6.
 
Diarrhea, nausea and vomiting ................................................................................................................. 43 
6.11.1.7.
 
Pruritus and dermatitis .............................................................................................................................. 43 
6.11.1.8.
 
Acidosis .................................................................................................................................................... 43 
6.11.1.9.
 
Life-threatening toxicities .................................................................................................................... 43 
6.11.1.10.
 
Other supportive care ........................................................................................................................... 43 
6.11.1.11.
 
Drug interaction ................................................................................................................................... 44 
6.11.1.12.
 
Rituximab ...................................................................................................................................................... 45 
6.11.2
7. 
STUDY DRUG: AVAILABILITY, ACCOUNTABILITY, PACKAGING & LABELING ...................45 
7.1 
ALT-803..................................................................................................................................................45 
 
Availability ......................................................................................................................................................... 45 
7.1.1
 
Accountability .................................................................................................................................................... 45 
7.1.2
 
Packaging .......................................................................................................................................................... 45 
7.1.3
 
Labeling ............................................................................................................................................................. 45 
7.1.4
7.2 
RITUXIMAB ..............................................................................................................................................45 
8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS ................................................................46 
8.1 
STUDY CALENDAR ...................................................................................................................................46 
8.2 
PROCEDURE AND TESTS ..........................................................................................................................47 
 
Assays for immune cell number, phenotype, and function ................................................................................. 47 
8.2.1
 
Medical history & prior therapy ........................................................................................................................ 47 
8.2.2
 
Pregnancy test .................................................................................................................................................... 47 
8.2.3
 
Physical examination, PS assessment, B symptom assessment .......................................................................... 47 
8.2.4
 
Vital signs, body weight & height ...................................................................................................................... 47 
8.2.5
 
Cardiac assessment ............................................................................................................................................ 47 
8.2.6
 
Pulmonary function monitoring ......................................................................................................................... 48 
8.2.7
 
Clinical blood tests ............................................................................................................................................ 48 
8.2.8
 
Disease assessment tests and procedures .......................................................................................................... 48 
8.2.9
 
Adverse event assessment .............................................................................................................................. 48 
8.2.10
 
Response assessment ..................................................................................................................................... 48 
8.2.11
 
Disease progression and survival follow-up ................................................................................................. 48 
8.2.12
 
Pharmacokinetic (PK) testing ....................................................................................................................... 49 
8.2.13
 
Biomarker assays for IL-2, IL-4, IL-6, IL-10, IFN-γ and TNF-α .................................................................. 49 
8.2.14
 
Immunogenicity tests - detection of anti-ALT-803 antibodies ....................................................................... 49 
8.2.15
 
Fc receptor polymorphism testing ................................................................................................................. 49 
8.2.16

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Evaluation of recurrent lymphoma mutations ............................................................................................... 50 
8.2.17
9. 
MEASUREMENT OF EFFECT ..................................................................................................................51 
9.1 
MEASURABLE DISEASE ............................................................................................................................51 
9.2 
METHODOLOGY OF RESPONSE EVALUATION ..........................................................................................51 
9.3 
RESPONSE EVALUATION CRITERIA ..........................................................................................................51 
9.4 
DISEASE PROGRESSION EVALUATION CRITERIA ......................................................................................51 
10. 
STATISTICAL ANALYSIS .....................................................................................................................51 
10.1 
SAMPLE SIZE ............................................................................................................................................51 
10.2 
DATA COLLECTION ..................................................................................................................................53 
10.3 
DATA ANALYSIS ......................................................................................................................................53 
 
Analysis of safety ........................................................................................................................................... 53 
10.3.1
 
Analysis of response ...................................................................................................................................... 53 
10.3.2
 
Pharmacokinetics .......................................................................................................................................... 53 
10.3.3
11. 
REGULATORY AND REPORTING REQUIREMENTS ....................................................................55 
11.1 
ADVERSE EVENTS RECORDING, REPORTING AND COMMUNICATION .......................................................55 
11.2 
ADVERSE EVENT TERMINOLOGY AND DEFINITIONS ................................................................................55 
11.3 
ADVERSE EVENT REPORTING PROCEDURES ...........................................................................................56 
11.4 
ADVERSE EVENT EXPEDITED REPORTING GUIDELINES ..........................................................................57 
11.5 
SUBMISSION OF SERIOUS ADVERSE EVENT REPORTING ...........................................................................57 
11.6 
DATA REPORTING FORMS .......................................................................................................................57 
11.7 
REPORT /DATA SUBMISSION ADDRESS & CONTACT ................................................................................58 
11.8 
PATIENT RECORDS, QUALITY ASSURANCE, RECORDS RETENTION ..........................................................58 
11.9 
METHOD OF REVIEW ...............................................................................................................................58 
11.10 
SPECIAL REGULATORY CONSIDERATIONS ...........................................................................................59 
 
HIPAA ........................................................................................................................................................... 59 
11.10.1
 
Protocol amendments, informed consent, and IRB approval ........................................................................ 59 
11.10.2
12. 
CONFIDENTIALITY ...............................................................................................................................59 
13. 
ETHICAL STANDARDS & INVESTIGATOR OBLIGATIONS .......................................................59 
14. 
LIST OF EXPECTED ADVERSE EVENTS ..........................................................................................60 
15. 
CTCAE .......................................................................................................................................................62 
16. 
REFERENCES ..........................................................................................................................................63 
17. 
APPENDIX A: ECOG ..............................................................................................................................67 
18. 
APPENDIX B: NEW YORK HEART ASSOCIATION CLASSIFICATION ....................................67 
19. 
APPENDIX C: ETHICAL STANDARDS ..............................................................................................68 
20. 
APPENDIX D: INVESTIGATOR OBLIGATIONS ..............................................................................69 
21. 
APPENDIX E: CONTACT LIST - ALTOR ...........................................................................................73 
22. 
APPENDIX F: CONTACT LIST – DATA SAFETY MONITORING BOARD (DSMB) ..................74 
23. 
APPENDIX G: CONTACT LIST - LABORATORIES ........................................................................74 

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SYNOPSIS 
Sponsor: 
Altor Bioscience Corporation 
Protocol#: 
CA-ALT-803-02-14 
Study Drug Name: ALT-803 
Study Treatment 
Active agents: 
ALT-803, a “recombinant human super agonist interleukin-15 (IL-15) complex” 
(AKA, IL-15N72D:IL-15RαSu/IgG1 Fc complex) 
Study Type: 
Interventional 
Study Phase: 
1/2 
Protocol Title: 
A phase 1/2 study of ALT-803 in patients with relapse/refractory indolent B cell 
non-Hodgkin lymphoma in conjunction with rituximab 
Objectives: 
To evaluate the safety and tolerability of escalating doses, identify the Maximum 
Tolerated Dose level (MTD) or Minimum Efficacious Dose (MED) and designate 
a dose level for Phase 2 study (RP2D) of ALT-803 in combination with standard-
of-care rituximab therapy in patients with relapsed or refractory (rel/ref) indolent B 
cell non-Hodgkin lymphoma (iNHL). 
To estimate the anti-tumor activity of ALT-803 as measured by response rate, 
overall survival, progression free survival, time to response, duration of response, 
time to treatment failure, and time to subsequent treatment in patients with rel/ref 
iNHL.  
To evaluate the effect of ALT-803 on the peripheral absolute lymphocyte counts 
(ALC) and white blood cell (WBC) counts, the number and phenotype of 
peripheral blood T (total and subsets) and NK cells. 
To characterize the immunogenicity and pharmacokinetic profile, including 
induced serum levels of IL-2, IL-4, IL-6, IL-10, IFN-γ and TNF-α, of ALT-803 in 
rel/ref iNHL patients. 
To correlate clinical outcomes with fcgr3a polymorphisms and recurrent genomic 
mutations in rel/ref iNHL patients. 
Study Design: 
This is a Phase 1/2, open-label, multi-center, competitive enrollment and dose-
escalation study of ALT-803 in patients with rel/ref iNHL in conjunction with 
rituximab. 
The study includes a dose escalation phase to determine the MTD or MED using a 
3+3 dose escalation design and to designate a dose level for the Phase 2 expansion 
phase (RP2D) of ALT-803 and a two-stage expansion phase using a Simon two-
stage design at the ALT-803 RP2D level in combination with rituximab. In Phase 
1, three dose levels will be evaluated. A step-down dose level (level -1) will be 
provided in the event of encountering DLT in two patients at the planned initial 
dose level.  
The study will be conducted in conformity with Good Clinical Practice (GCP).  

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Treatments:  
The study treatment plan for each enrolled patient includes one 4-week induction 
treatment cycle. During induction, patients will receive up to four weekly doses of 
ALT-803 and rituximab (375 mg/m2) by intravenous injection. For the first dose of 
treatment, patients will received rituximab on day 1 followed by ALT-803 on day 
2 in order to avoid simultaneous infusion of both agents and reduce the potential of 
infusion-related adverse events.  Eligible patients will receive the consolidation 
treatment.  Consolidation consists of treatment with ALT-803 at the same dose 
level used in the induction plus rituximab (375 mg/m2) every 8 weeks (1 cycle = 8 
weeks), for a total of 4 consolidation cycles.  
Treated patients will have at least two response evaluation visits. Patients who 
receive at least two study drug doses during the induction treatment period will be 
evaluated for disease response during week 11. Patients who have at least stable 
disease from the first anti-tumor evaluation and who do not experience or have 
sufficiently recovered from toxicities of the induction treatment cycle and who 
meet other criteria to continue study treatment will receive up to four consolidation 
treatment cycles, with a single treatment of ALT-803 plus rituximab, repeated 
every 8 weeks for a total of 4 additional ALT-803 plus rituximab doses.  The 
ALT-803 dose level utilized in the induction cycle will be continued in 
consolidation, with reassessment for continued tumor response performed upon 
completion at week 40. 
The study treatment and response evaluation schema: 
Treatment Phase 
Induction 
REST 
Response 
Evaluation  
Consolidation 
Response 
Evaluation 
Treatment Week 
1 
2 
3 
4 
5-10 
11 
12 20 28 36 
40** 
Treatment Day 
1, 2* 8 15 22 
29-70 
71-77 
78 134 190 246 
274-280 
ALT-803 1 
2 
3 
4 
Rest 
 
5 
6 
7 
8 
 
rituximab 1 
2 
3 
4 
 
5 
6 
7 
8 
 
Consolidation Cycle 
 
 
 
 
 
1 
2 
3 
4 
 
Response Evaluation 
 
 
 
 
X 
 
 
 
 
X 
*For the first week, rituximab is administered on day 1, ALT-803 on day 2 
**Long term follow-up after 40 weeks includes restaging every 6 months for 2 years, and 
then every 12 months for 5 years (until progression). 
Patients will be assessed for response using the 2007 IHP criteria.1  Patients will be 
followed for progression, and at the time of progression there are no restrictions on 
further therapies.  
Enrolled patients will receive the study treatment at qualified cancer treatment 
centers with adequate diagnostic and treatment facilities to provide appropriate 
management of therapy and complications. ALT-803 will be administered by 
intravenous infusion into a central or peripheral vein under the supervision of a 
qualified physician experienced in the use of biologic anti-cancer agents. 
Rituximab will be administered as described in the product package insert 
provided by the manufacturer. 
Dose Escalation 
Phase: 
A 3 + 3 design will be used for identifying a tolerable dose of ALT-803 for Phase 
2 studies by monitoring patients for DLTs to determine the MTD and for 

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identifying an efficacious dose by monitoring patients’ ALC and WBC count to 
determine the MED during the DLT observation period. The dose escalation phase 
is concluded when either the MTD or the MED is determined. An ALT-803 dose 
level (RP2D) will then be designated for Phase 2 study. There are three escalating 
dose levels of ALT-803 and a step-down cohort (-1) with a lower dose level of 
ALT-803 in the event that unexpected toxicity is encountered at the initial dose 
level.   
Below are the planned dose levels of the study drug during the dose escalation 
phase of the study.  
 
 
 
 
 
 
Dose limiting toxicity (DLT) is defined as follows: any toxicity that is not clearly 
unrelated to drug administration that is of Grade 3 and does not resolve to Grade 1 
or lower within a week despite the use of medical intervention or that is of Grade 
4, with exceptions described in the study protocol.  
The DLT Observation Period is defined as the duration of the induction treatment, 
days 1-28. 
Maximum Tolerated Dose level (MTD) is defined as a dose level at which <2 out 
of 6 patients experienced DLT and that is one level below a dose that was not 
tolerated or the maximum planned dose level if designated by the study committee. 
Minimal Efficacious Dose (MED) is defined as a dose level which produces an 
ALC ≥25,000/µL sustained for 14 days or a total WBC ≥35,000/µL sustained for 
14 days among 2/3 or 4/6 of patients. For safety, a dose level is also defined as 
“exceeding MED” with the occurrence of ALC ≥50,000/µL or WBC ≥60,000/µL 
sustained for 14 days.  If patients have circulating malignant lymphocytes in the 
peripheral blood, these lymphoma cells will be excluded from the WBC and ALC 
calculations for MED. 
Expansion 
Phase 
Two expansion arms will be used to investigate indolent NHL patients with 
different expectations regarding response to single agent rituximab: rituximab-
refractory (RR) and rituximab-sensitive (RS).  For each arm, a two-stage 
expansion phase at the MTD or the MED level will be conducted using an optimal 
Simon’s two-stage design. The best objective overall response rate (ORR) is 
defined as complete response (CR) + partial response (PR) assessed at the week 11 
or 40 response assessment, or during the 2 year follow-up period.  For RR patients, 
a lack of efficacy for ORR of 5% will be used, with an ORR > 25% constituting a 
clinically interesting result.  For RS patients, a lack of efficacy for ORR of 40% 
Cohort 
ALT-803 Dose (µg/kg) 
Number of patients 
-1 
0.5 
3 to 6 
1 (initial) 
1 
3 to 6 
2 
3 
3 to 6 
3 
6 
3 to 6 

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will be used, with a clinically interesting ORR > 60%.  Each expansion arm will 
be analyzed independently for preliminary efficacy. 
Stopping Rules: 
Patient enrollment will be temporarily suspended based on occurrence of any of 
the following events, and the study committee, including the sponsor, the Data 
Safety Monitoring Board and principal investigators will meet to discuss how to 
proceed with future patient enrollment in the study. 
During the dose escalation phase of the study,  
• If the maximum planned dose level has been reached, but neither the MTD nor 
MED can be determined. 
• If de-escalation occurs and the step-down dose level cannot be designated as 
the MTD or MED.  
Any time during the expansion phase of the study,  
• More than 33% of patients experience a possible, probable or definite study 
drug related DLT. 
• Favorable anti-tumor response data collected from enrolled patients. 
At any time during the study, 
the study committee may meet to discuss how to proceed with the study and may 
make any or all of the following recommendations for further patient enrollment:  
• Downward adjust the study drug dose. 
• Adjust the study drug dosing schedule. 
• Recommend more effective pre-therapy, intra-therapy and post-therapy side 
effect mitigation interventions. 
• Correct protocol technical errors that caused unnecessary dose omissions or 
premature treatment discontinuations. After correction of protocol errors, the 
DSMB may meet to re-evaluate the safety profile of the study treatment and 
recommend how to proceed with the study, if necessary. 
Evaluations: 
Patients will be evaluated for clinical toxicities during the treatment. The disease 
response will be evaluated at weeks 11 and 40 from the start of study treatment, 
and every 6 months for 2 years thereafter. After this two year period the 
institutional standards for disease assessment will be followed, with at least annual 
disease assessments, for up to 5 years. Prior to and during the treatment period, 
patients’ blood and serum samples will be collected to assess the pharmacokinetic 
profile and immunogenicity of the study drug, as well as for immunomodulation, 
and fcgr3a polymorphisms.  Disease containing biopsies will be used for recurrent 
lymphoma gene mutation analysis.  All patients who receive at least 2 doses of the 
study drug ALT-803 will be included in the anti-tumor response evaluation. 
Population: 
Patients of 18 years of age and above with relapsed or refractory CD20+ indolent 
NHL (follicular lymphoma (FL), marginal zone lymphoma (MZL), small 
lymphocytic lymphoma (SLL), and lymphoplasmacytic lymphoma (LPL)). 
Rituximab-refractory (RR) patients are defined as those that progress on rituximab 

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therapy or within 6 months of their last dose of rituximab.  For RR patients, a 
biopsy to confirm CD20 expression is required.  Patients also need to have 
adequate cardiac, pulmonary, liver and kidney functions and have an Eastern 
Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.   
Sample Size: 
A total of up to 18 assessable patients will be accrued to the dose escalation phase of 
the study (Phase 1). Anticipated enrollment to this phase is 12 patients. For the RS 
patient arm, a total of 16 patients will be enrolled at the MTD/MED dose in the first 
stage, and 30 patients in the second stage of a 2-stage Phase 2 cohort (total for RS 
expansion cohort 46).  For the RR, a total of 9 patients will be enrolled in the first 
stage, and an additional 8 patients in the second stage of a 2 stage Phase 2 study 
(total for RR expansion cohort 17).  Thus, enrollment of evaluable patients on the 
Phase 1 portion, and the first stage of both expansion cohorts (including 6 patients of 
the MTD/MED cohort) is expected to be 31 patients, with the maximum number of 
43 patients.  Assuming a 5% frequency of non-evaluable patients, the phase 1 and 
the first stage of both expansion cohorts is estimated at 33 patients.   
Primary 
Endpoints 
For Phase 1 only 
(1) Determination of the MTD or MED of ALT-803 and designation of the 
recommended dose level (RP2D) for Phase 2 study of ALT-803 in 
conjunction with rituximab in patients with rel/ref iNHL. 
For Phase 1 & 2 
(2) Safety profile of ALT-803 plus rituximab in treated patients. 
 
(3) Overall response rate (CR+PR) of treated patients.  
Secondary  
Endpoints  
 
(1) Evaluate overall survival, progression free survival, time to response, duration 
of response, time to treatment failure, and time to subsequent treatment. 
 
(2) Evaluation of the effect of ALT-803 on the peripheral ALC and WBC counts, 
the number and phenotype of peripheral blood NK cells and T (total and 
subsets), and NK cell function. 
 
(3) Characterization of the immunogenicity and pharmacokinetic profile, 
including serum levels of IL-2, IL-4, IL-6, IL-10, IFN-γ and TNF-α, of ALT-
803 in treated patients. 
 
(4) Correlation of fcgr3a polymorphism status and recurrent lymphoma mutations 
with clinical outcomes of the study. 
Pharmacokinetics 
& Biomarkers: 
Fresh blood samples will be collected to assess immune cell number, phenotype 
and function. Serum samples will be collected for pharmacokinetics (PK) and 
immunogenicity of the study drug ALT-803. The same serum samples collected 
for PK analysis will be used to assess the serum levels of IL-2, IL-4, IL-6, IL-10, 
IFN-γ and TNF-α. Non-compartmental and compartmental analyses will be 
conducted. Baseline peripheral blood will be used for fcgr3a polymorphism 

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testing, and a baseline tumor sample will be used for lymphoma mutation analysis 
using next-generation sequencing. 
Monitoring Tests: Blood samples for standard chemistry and CBC with differential will be obtained 
at screening, on each study treatment infusion day, and at response evaluation 
visits. Blood samples for immunogenicity testing of anti-ALT-803 antibodies will 
be collected prior to dosing on the first and fourth ALT-803 infusion visit, and at 
the response evaluation visit during week 11.  
Response 
Assessment: 
There are at least two response assessments for treated patients: the first 
assessment during week 11 (following induction) and the second assessment 
during week 40 (following consolidation) from the start of study treatment. After 
completion of the induction cycle of study treatment, patients who have received at 
least 2 doses of ALT-803 will have the first response assessment. After completion 
of four additional consolidation study treatments patients will have a second 
response assessment. If patients are unable to continue study therapy for all 4 
consolidation cycles due to an adverse event, disease assessments will be 
performed at the time of going off study.  In non-progressing patients, after 
completion of consolidation, disease assessments will be performed every 6 
months for 2 years, and then per institutional guidelines, at least annually, for up to 
5 years.  If a focused physical examination or patient symptoms raise the concern 
for progression, a complete response assessment should be performed at that time.  
Response assessments will be carried out according to the 2007 IHP criteria for 
response assessment of lymphoma.1 Baseline evaluations (except for baseline 
imaging and bone marrow biopsy) should be performed up to 14 days before study 
treatment start.  
Progression & 
Survival 
Assessment: 
Progression-free survival, overall survival, and duration of response of all treated 
patients will be assessed at least every three months during years 1 and 2, every 4 
months during year 3, and then every 6 months (+/- 2 months) during years 4 and 
5 from the start of study treatment, or through the point designated as the end of 
the study follow up (5 years). 
Adverse Events: 
All patients will be monitored and evaluated for clinical toxicities during the 
treatment period and queried at each follow-up visit for Adverse Events (AEs). 
Patients may volunteer information concerning AEs. All adverse events will be 
graded by using the NCI Common Terminology Criteria for Adverse Events 
version 4.0 (CTCAE v4.0), and logged in the patient Case Report Form. The study 
centers should report all Serious Adverse Events (SAEs) and all events that trigger 
patient’s study treatment discontinuation to the sponsor via phone, fax or email (or 
a combination) no more than 24 hours after learning of the event. The sponsor will 
use the information to manage and coordinate the dose escalation, cohort 
expansion and patient enrollment. The sponsor will then inform all of the 
participating clinical sites of the current dose level and the number of patients to 
be enrolled at that level, or of any patient enrollment suspension via phone, fax or 
email within 24 hours of learning of the event. The study centers should report all 

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Page 12 of 74 
other adverse events to the sponsor following the guidelines defined in the study 
protocol. All study drug related AEs that are both serious and unexpected will be 
reported to the FDA in an expedited manner in accordance with 21 CFR §312.32. 
Statistical Plan: 
For each cohort, all AEs will be tabulated and examined and all safety, 
pharmacokinetic, biomarker and tumor response data will be evaluated. For 
estimation of duration of response and progression free survival, the Kaplan-Meier 
method will be used. P-values of ≤0.05 (two-sided) will be considered to indicate 
statistical significance.  
 
 

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8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS 
8.1 
Study calendar  
 
TESTS & PROCEDURES 
SCREEN/ 
BASELINE1 
INDUCTION 
REST  
RESPONSE 
EVALUATION CONSOLIDATION RESPONSE 
EVALUATION 
DISEASE ASSESSMENT & FOLLOW-UPS 
Study Month  
 
1 
2-3 
3 
3-9 
10 
12 
15 
18 
21 24 
28 
32 
36 
42 
48 
54 
60 
Study Week  
 
1 
2 
3 
4 
5-10 
11 
12 
20 
28 
36 
40 
 
Study Day  
 
1 
2 
3 
5 
8 
15 
22 
23 
25 
29-70 
71-77 
78 134 190 246 
274-280 
 
Tolerance Window 
 
+/- 2 days 
Any day 
Any day 
+/- 7 days 
Any day 
+/- 2 weeks 
Medical history 
X 
 
 
 
 
 
 
 
 
 
R 
 
E 
 
S 
 
T 
 
 
P 
 
E 
 
R 
 
I 
 
O 
 
D 
 
 
 
 
 
 
 
Serum pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam (PE) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Focused PE, ECOG PS, B symptom assessment 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Vital signs, Weight, Height3, Cardiac & Lung 
function monitoring  
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Concurrent medication 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Adverse event assessment4 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
CBC with Differential5 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Blood Chemistry with LDH5  
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFT only when clinically indicated 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Response assessment6 
  
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Contrast CT of NCAP or PET-CT 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Bone marrow biopsy7 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Focused PE, ECOG PS, B symptom & AE 
X17  
X 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Disease and survival follow-up/post therapies8 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X X16 X16 X16 X16 
Immune cell number, phenotype & function9, 14 
X 
 
X10 X 
X X10 
 
X10 X 
X 
 
X11 
 
 
 
 
 
Polymorphism  (SNP) testing14 
  X10 
 
 
 
 
 
 
 
 
 
 
 
 
PK, IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α12,14 
 
X12 X 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity tests13, 14 
 
 
X13 
 
 
 
 
X10 
 
 
X 
 
 
 
 
Recurrent mutation evaluation15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rituximab
 
r1 
 
 
 
r2 r3 r4 
 
 
 
r5 r6 r7 
r8 
Study drug (ALT-803)
 
 
a1 
 
 
a2 a3 a4 
 
 
a5 a6 a7 
a8 
1Screening/baseline evaluations are performed < 14 days prior to start of therapy; baseline CTs or PET-CT are performed ≤ 28 days and baseline bone marrow biopsy performed ≤ 42 days prior to start of therapy. If the 
patient's condition is deteriorating, ECOG status and laboratory evaluations should be repeated within 48 hours prior to initiation of study treatment infusion.  2Pregnancy test is for women with childbearing potential 
only.  3Vital signs (especially blood pressure), clinical status and laboratory tests should be reviewed before start of therapy. Vital signs will be evaluated at 15, 30, 60 and 120 min then hourly post infusion until 
discharge or at completion of dose monitoring. Body weight will be collected before infusion on each drug infusion day for all patients. Height only collected at baseline. 4Patients who have an on-going study drug-
related SAE upon study completion or at discontinuation of study will be contacted by the investigator or his/her designee every week until the event is resolved or determined to be irreversible. 5Safety labs can be 
drawn within 48 hours of scheduled dose.6Disease response and progression assessment will be evaluated using the 2007 IHP criteria for assessment of lymphoma. 7Only performed to confirm a CR if disease present at 
baseline. Once confirmed, only repeat if relapse suspected. 8Information about tumor assessment & other therapies received after completion of study treatment will be collected if available.  9Fresh blood samples (3 
tubes per time point) for immune cell number, phenotype & function testing will be collected. 10Collect before dosing. 11Collect before dosing and 24 hours post-infusion. 12Collect blood samples at Time 0 (before drug 
infusion), at 30 min (+/- 5 min), 2 hour (+/- 15 min), 6 hour (+/- 60 min) or before discharge on dosing day, 24 hour (+/- 6 hour) from Time 0.  IL-2, IL-4, IL-6, IL-10, IFN-γ and TNF-α assays are performed using the 
same samples and at the same schedule as PK.  13Use the sample collected before dosing for PK test. 14Residual samples may be used by Sponsor for research studies of other biomarkers. All attempts will be made to 
collect research samples but missed samples will not be considered a protocol deviation.15Fesh/frozen or FFPE tissue block (or substitute) preferably from biopsy immediately prior to treatment start. If the patient has an 
elevated baseline ALC and concern for peripheral blood involvement with circulating lymphoma cells, an oral rinse will be performed to obtain an additional non-tumor cellular sample.16+/- 2 months. 17Complete PE 
required at screening, not focused PE. 

 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Number: 
CA-ALT-803-02-14 
 
 
Protocol Title: 
A phase 1/2 study of ALT-803 in patients with 
relapse/refractory indolent B cell non-Hodgkin 
lymphoma in conjunction with rituximab 
 
 
Date of Protocol: 
 
Version# 01 
Version# 02 
 
September 4, 2014 
March 18, 2015 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 
 
 

 
INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
CA-ALT-803-02-14 
 
 
Protocol Title: 
A phase 1/2 study of ALT-803 in patients with 
relapse/refractory indolent B cell non-Hodgkin 
lymphoma in conjunction with rituximab 
 
 
Date of Protocol: 
 
Version# 01 
Version# 02 
September 4, 2014 
March 18, 2015 
 
 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 
By my signature below, I hereby attest that I have read, and that I understand and will abide by all the 
conditions, instructions, and restrictions contained in the attached protocol. 
 
Additionally, I will not initiate this study without approval of the appropriate Institutional Review Board 
(IRB), and I understand that any changes in the protocol must be approved in writing by the sponsor, the 
IRB, and, in certain cases the FDA, before they can be implemented, except where necessary to 
eliminate hazards to subjects. 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Name (Print) 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
SYNOPSIS ................................................................................................................................................................6 
1. 
OBJECTIVES ................................................................................................................................................13 
1.1 
PRIMARY OBJECTIVES .............................................................................................................................13 
1.2 
SECONDARY OBJECTIVES ........................................................................................................................13 
2. 
BACKGROUND ............................................................................................................................................13 
2.1 
ALT-803 – GENERAL INFORMATION.......................................................................................................13 
2.2 
INDOLENT NON-HODGKIN LYMPHOMA (INHL) ......................................................................................14 
2.3 
IMMUNE-BASED THERAPIES FOR INHL ...................................................................................................15 
2.4 
PHARMACOLOGICAL EFFECTS OF ALT-803 IN VITRO AND IN ANIMALS ..................................................16 
 
Development of ALT-803 (IL-15N72D:IL-15RαSu/IgG1 Fc complex) .............................................................. 16 
2.4.1
 
In vitro biological activity of ALT-803 including ADCC enhancement ............................................................. 16 
2.4.2
 
In vivo biological activity of ALT-803 ............................................................................................................... 19 
2.4.3
 
Potent anti-tumor activity of ALT-803 in mouse models in vivo ........................................................................ 20 
2.4.4
2.5 
NON-CLINICAL TOXICOLOGY ..................................................................................................................22 
 
Multi-dose toxicity studies in mice ..................................................................................................................... 22 
2.5.1
 
Multi-dose toxicity studies in cynomolgus monkeys ........................................................................................... 23 
2.5.2
2.6 
PHARMACOKINETICS ...............................................................................................................................25 
 
Non-clinical pharmacokinetics .......................................................................................................................... 25 
2.6.1
 
Clinical pharmacokinetics ................................................................................................................................. 25 
2.6.2
2.7 
RATIONALE FOR HUMAN CLINICAL STARTING DOSE ...............................................................................25 
2.8 
HUMAN EXPERIENCE ...............................................................................................................................26 
3. 
RATIONALE FOR THE CURRENT STUDY ...........................................................................................27 
4. 
OVERALL STUDY DESIGN .......................................................................................................................28 
5. 
STUDY POPULATION ................................................................................................................................30 
5.1 
INCLUSION CRITERIA ...............................................................................................................................30 
5.2 
EXCLUSION CRITERIA ..............................................................................................................................31 
5.3 
INCLUSION OF WOMEN AND MINORITIES .................................................................................................31 
6. 
STUDY DESIGN ...........................................................................................................................................32 
6.1 
SCREENING AND ENROLLMENT ...............................................................................................................32 
6.2 
STUDY TREATMENT .................................................................................................................................32 
 
Treatment setting ............................................................................................................................................... 32 
6.2.1
 
Treatment regimen and study scheme ................................................................................................................ 32 
6.2.2
 
Study treatment preparation .............................................................................................................................. 33 
6.2.3
 
Study treatment administration .......................................................................................................................... 33 
6.2.4
 
Pre and post-therapy intervention guidelines .................................................................................................... 34 
6.2.5
6.3 
DURATION OF PATIENT PARTICIPATION ..................................................................................................35 
6.4 
DOSE ESCALATION PHASE .......................................................................................................................35 
6.5 
EXPANSION PHASE ..................................................................................................................................36 
6.6 
STOPPING RULES .....................................................................................................................................37 
 
During dose escalation phase of the study ......................................................................................................... 37 
6.6.1
 
During expansion phase of the study ................................................................................................................. 38 
6.6.2
 
At any time during the study .............................................................................................................................. 38 
6.6.3
6.7 
PATIENT MONITORING, RESPONSE EVALUATION, DISEASE PROGRESSION & SURVIVAL FOLLOW-UP .....38 
 
Patient monitoring ............................................................................................................................................. 38 
6.7.1
 
Response evaluation ........................................................................................................................................... 38 
6.7.2
 
Disease progression and survival follow-up ...................................................................................................... 39 
6.7.3
6.8 
DOSE LIMITING TOXICITY ........................................................................................................................39 
 
Definition of dose limiting toxicity ..................................................................................................................... 39 
6.8.1

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Definition of maximum tolerated dose (MTD) ................................................................................................... 39 
6.8.2
 
Definition of minimal efficacious dose (MED) .................................................................................................. 40 
6.8.3
6.9 
STUDY TREATMENT DISCONTINUATION ..................................................................................................40 
 
Study treatment discontinuation events .............................................................................................................. 40 
6.9.1
 
Replacement of participants............................................................................................................................... 40 
6.9.2
 
Follow-ups after treatment discontinuation ....................................................................................................... 41 
6.9.3
 
Discontinuation due to SAEs or on-going study drug related AEs .......................................................... 41 
6.9.3.1.
 
Discontinuation due to any other reasons ................................................................................................. 41 
6.9.3.2.
6.10 
STUDY TREATMENT INTERRUPTION ........................................................................................................41 
 
Kidney dysfunction ........................................................................................................................................ 41 
6.10.1
 
Hematological dysfunction ............................................................................................................................ 41 
6.10.2
 
Hypotension .................................................................................................................................................. 41 
6.10.3
 
Allergic reactions and cytokine release syndrome/acute infusion reaction .................................................. 42 
6.10.4
6.11 
GENERAL SUPPORTIVE CARE GUIDELINES AND DRUG INTERACTION ......................................................42 
 
ALT-803 ........................................................................................................................................................ 42 
6.11.1
 
Hypotension and capillary leak syndrome ................................................................................................ 42 
6.11.1.1.
 
Pulmonary dysfunction ............................................................................................................................. 43 
6.11.1.2.
 
Impaired kidney and liver functions ......................................................................................................... 43 
6.11.1.3.
 
Infection ................................................................................................................................................... 43 
6.11.1.4.
 
Fever and chills ........................................................................................................................................ 43 
6.11.1.5.
 
Gastritis .................................................................................................................................................... 43 
6.11.1.6.
 
Diarrhea, nausea and vomiting ................................................................................................................. 43 
6.11.1.7.
 
Pruritus and dermatitis .............................................................................................................................. 43 
6.11.1.8.
 
Acidosis .................................................................................................................................................... 43 
6.11.1.9.
 
Life-threatening toxicities .................................................................................................................... 43 
6.11.1.10.
 
Other supportive care ........................................................................................................................... 43 
6.11.1.11.
 
Drug interaction ................................................................................................................................... 44 
6.11.1.12.
 
Rituximab ...................................................................................................................................................... 45 
6.11.2
7. 
STUDY DRUG: AVAILABILITY, ACCOUNTABILITY, PACKAGING & LABELING ...................45 
7.1 
ALT-803..................................................................................................................................................45 
 
Availability ......................................................................................................................................................... 45 
7.1.1
 
Accountability .................................................................................................................................................... 45 
7.1.2
 
Packaging .......................................................................................................................................................... 45 
7.1.3
 
Labeling ............................................................................................................................................................. 45 
7.1.4
7.2 
RITUXIMAB ..............................................................................................................................................45 
8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS ................................................................46 
8.1 
STUDY CALENDAR ...................................................................................................................................46 
8.2 
PROCEDURE AND TESTS ..........................................................................................................................47 
 
Assays for immune cell number, phenotype, and function ................................................................................. 47 
8.2.1
 
Medical history & prior therapy ........................................................................................................................ 47 
8.2.2
 
Pregnancy test .................................................................................................................................................... 47 
8.2.3
 
Physical examination, PS assessment, B symptom assessment .......................................................................... 47 
8.2.4
 
Vital signs, body weight & height ...................................................................................................................... 47 
8.2.5
 
Cardiac assessment ............................................................................................................................................ 47 
8.2.6
 
Pulmonary function monitoring ......................................................................................................................... 48 
8.2.7
 
Clinical blood tests ............................................................................................................................................ 48 
8.2.8
 
Disease assessment tests and procedures .......................................................................................................... 48 
8.2.9
 
Adverse event assessment .............................................................................................................................. 48 
8.2.10
 
Response assessment ..................................................................................................................................... 48 
8.2.11
 
Disease progression and survival follow-up ................................................................................................. 48 
8.2.12
 
Pharmacokinetic (PK) testing ....................................................................................................................... 49 
8.2.13
 
Biomarker assays for IL-2, IL-4, IL-6, IL-10, IFN-γ and TNF-α .................................................................. 49 
8.2.14
 
Immunogenicity tests - detection of anti-ALT-803 antibodies ....................................................................... 49 
8.2.15
 
Fc receptor polymorphism testing ................................................................................................................. 49 
8.2.16

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Evaluation of recurrent lymphoma mutations ............................................................................................... 50 
8.2.17
9. 
MEASUREMENT OF EFFECT ..................................................................................................................51 
9.1 
MEASURABLE DISEASE ............................................................................................................................51 
9.2 
METHODOLOGY OF RESPONSE EVALUATION ..........................................................................................51 
9.3 
RESPONSE EVALUATION CRITERIA ..........................................................................................................51 
9.4 
DISEASE PROGRESSION EVALUATION CRITERIA ......................................................................................51 
10. 
STATISTICAL ANALYSIS .....................................................................................................................51 
10.1 
SAMPLE SIZE ............................................................................................................................................51 
10.2 
DATA COLLECTION ..................................................................................................................................53 
10.3 
DATA ANALYSIS ......................................................................................................................................53 
 
Analysis of safety ........................................................................................................................................... 53 
10.3.1
 
Analysis of response ...................................................................................................................................... 53 
10.3.2
 
Pharmacokinetics .......................................................................................................................................... 53 
10.3.3
11. 
REGULATORY AND REPORTING REQUIREMENTS ....................................................................55 
11.1 
ADVERSE EVENTS RECORDING, REPORTING AND COMMUNICATION .......................................................55 
11.2 
ADVERSE EVENT TERMINOLOGY AND DEFINITIONS ................................................................................55 
11.3 
ADVERSE EVENT REPORTING PROCEDURES ...........................................................................................56 
11.4 
ADVERSE EVENT EXPEDITED REPORTING GUIDELINES ..........................................................................57 
11.5 
SUBMISSION OF SERIOUS ADVERSE EVENT REPORTING ...........................................................................57 
11.6 
DATA REPORTING FORMS .......................................................................................................................57 
11.7 
REPORT /DATA SUBMISSION ADDRESS & CONTACT ................................................................................58 
11.8 
PATIENT RECORDS, QUALITY ASSURANCE, RECORDS RETENTION ..........................................................58 
11.9 
METHOD OF REVIEW ...............................................................................................................................58 
11.10 
SPECIAL REGULATORY CONSIDERATIONS ...........................................................................................59 
 
HIPAA ........................................................................................................................................................... 59 
11.10.1
 
Protocol amendments, informed consent, and IRB approval ........................................................................ 59 
11.10.2
12. 
CONFIDENTIALITY ...............................................................................................................................59 
13. 
ETHICAL STANDARDS & INVESTIGATOR OBLIGATIONS .......................................................59 
14. 
LIST OF EXPECTED ADVERSE EVENTS ..........................................................................................60 
15. 
CTCAE .......................................................................................................................................................62 
16. 
REFERENCES ..........................................................................................................................................63 
17. 
APPENDIX A: ECOG ..............................................................................................................................67 
18. 
APPENDIX B: NEW YORK HEART ASSOCIATION CLASSIFICATION ....................................67 
19. 
APPENDIX C: ETHICAL STANDARDS ..............................................................................................68 
20. 
APPENDIX D: INVESTIGATOR OBLIGATIONS ..............................................................................69 
21. 
APPENDIX E: CONTACT LIST - ALTOR ...........................................................................................73 
22. 
APPENDIX F: CONTACT LIST – DATA SAFETY MONITORING BOARD (DSMB) ..................74 
23. 
APPENDIX G: CONTACT LIST - LABORATORIES ........................................................................74 

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SYNOPSIS 
Sponsor: 
Altor Bioscience Corporation 
Protocol#: 
CA-ALT-803-02-14 
Study Drug Name: ALT-803 
Study Treatment 
Active agents: 
ALT-803, a “recombinant human super agonist interleukin-15 (IL-15) complex” 
(AKA, IL-15N72D:IL-15RαSu/IgG1 Fc complex) 
Study Type: 
Interventional 
Study Phase: 
1/2 
Protocol Title: 
A phase 1/2 study of ALT-803 in patients with relapse/refractory indolent B cell 
non-Hodgkin lymphoma in conjunction with rituximab 
Objectives: 
To evaluate the safety and tolerability of escalating doses, identify the Maximum 
Tolerated Dose level (MTD) or Minimum Efficacious Dose (MED) and designate 
a dose level for Phase 2 study (RP2D) of ALT-803 in combination with standard-
of-care rituximab therapy in patients with relapsed or refractory (rel/ref) indolent B 
cell non-Hodgkin lymphoma (iNHL). 
To estimate the anti-tumor activity of ALT-803 as measured by response rate, 
overall survival, progression free survival, time to response, duration of response, 
time to treatment failure, and time to subsequent treatment in patients with rel/ref 
iNHL.  
To evaluate the effect of ALT-803 on the peripheral absolute lymphocyte counts 
(ALC) and white blood cell (WBC) counts, the number and phenotype of 
peripheral blood T (total and subsets) and NK cells. 
To characterize the immunogenicity and pharmacokinetic profile, including 
induced serum levels of IL-2, IL-4, IL-6, IL-10, IFN-γ and TNF-α, of ALT-803 in 
rel/ref iNHL patients. 
To correlate clinical outcomes with fcgr3a polymorphisms and recurrent genomic 
mutations in rel/ref iNHL patients. 
Study Design: 
This is a Phase 1/2, open-label, multi-center, competitive enrollment and dose-
escalation study of ALT-803 in patients with rel/ref iNHL in conjunction with 
rituximab. 
The study includes a dose escalation phase to determine the MTD or MED using a 
3+3 dose escalation design and to designate a dose level for the Phase 2 expansion 
phase (RP2D) of ALT-803 and a two-stage expansion phase using a Simon two-
stage design at the ALT-803 RP2D level in combination with rituximab. In Phase 
1, three dose levels will be evaluated. A step-down dose level (level -1) will be 
provided in the event of encountering DLT in two patients at the planned initial 
dose level.  
The study will be conducted in conformity with Good Clinical Practice (GCP).  

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Treatments:  
The study treatment plan for each enrolled patient includes one 4-week induction 
treatment cycle. During induction, patients will receive up to four weekly doses of 
ALT-803 and rituximab (375 mg/m2) by intravenous injection. For the first dose of 
treatment, patients will received rituximab on day 1 followed by ALT-803 on day 
2 in order to avoid simultaneous infusion of both agents and reduce the potential of 
infusion-related adverse events.  Eligible patients will receive the consolidation 
treatment.  Consolidation consists of treatment with ALT-803 at the same dose 
level used in the induction plus rituximab (375 mg/m2) every 8 weeks (1 cycle = 8 
weeks), for a total of 4 consolidation cycles.  
Treated patients will have at least two response evaluation visits. Patients who 
receive at least two study drug doses during the induction treatment period will be 
evaluated for disease response during week 11. Patients who have at least stable 
disease from the first anti-tumor evaluation and who do not experience or have 
sufficiently recovered from toxicities of the induction treatment cycle and who 
meet other criteria to continue study treatment will receive up to four consolidation 
treatment cycles, with a single treatment of ALT-803 plus rituximab, repeated 
every 8 weeks for a total of 4 additional ALT-803 plus rituximab doses.  The 
ALT-803 dose level utilized in the induction cycle will be continued in 
consolidation, with reassessment for continued tumor response performed upon 
completion at week 40. 
The study treatment and response evaluation schema: 
Treatment Phase 
Induction 
REST 
Response 
Evaluation  
Consolidation 
Response 
Evaluation 
Treatment Week 
1 
2 
3 
4 
5-10 
11 
12 20 28 36 
40** 
Treatment Day 
1, 2* 8 15 22 
29-70 
71-77 
78 134 190 246 
274-280 
ALT-803 1 
2 
3 
4 
Rest 
 
5 
6 
7 
8 
 
rituximab 1 
2 
3 
4 
 
5 
6 
7 
8 
 
Consolidation Cycle 
 
 
 
 
 
1 
2 
3 
4 
 
Response Evaluation 
 
 
 
 
X 
 
 
 
 
X 
*For the first week, rituximab is administered on day 1, ALT-803 on day 2 
**Long term follow-up after 40 weeks includes restaging every 6 months for 2 years, and 
then every 12 months for 5 years (until progression). 
Patients will be assessed for response using the 2007 IHP criteria.1  Patients will be 
followed for progression, and at the time of progression there are no restrictions on 
further therapies.  
Enrolled patients will receive the study treatment at qualified cancer treatment 
centers with adequate diagnostic and treatment facilities to provide appropriate 
management of therapy and complications. ALT-803 will be administered by 
intravenous infusion into a central or peripheral vein under the supervision of a 
qualified physician experienced in the use of biologic anti-cancer agents. 
Rituximab will be administered as described in the product package insert 
provided by the manufacturer. 
Dose Escalation 
Phase: 
A 3 + 3 design will be used for identifying a tolerable dose of ALT-803 for Phase 
2 studies by monitoring patients for DLTs to determine the MTD and for 

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identifying an efficacious dose by monitoring patients’ ALC and WBC count to 
determine the MED during the DLT observation period. The dose escalation phase 
is concluded when either the MTD or the MED is determined. An ALT-803 dose 
level (RP2D) will then be designated for Phase 2 study. There are three escalating 
dose levels of ALT-803 and a step-down cohort (-1) with a lower dose level of 
ALT-803 in the event that unexpected toxicity is encountered at the initial dose 
level.   
Below are the planned dose levels of the study drug during the dose escalation 
phase of the study.  
 
 
 
 
 
 
Dose limiting toxicity (DLT) is defined as follows: any toxicity that is not clearly 
unrelated to drug administration that is of Grade 3 and does not resolve to Grade 1 
or lower within a week despite the use of medical intervention or that is of Grade 
4, with exceptions described in the study protocol.  
The DLT Observation Period is defined as the duration of the induction treatment, 
days 1-28. 
Maximum Tolerated Dose level (MTD) is defined as a dose level at which <2 out 
of 6 patients experienced DLT and that is one level below a dose that was not 
tolerated or the maximum planned dose level if designated by the study committee. 
Minimal Efficacious Dose (MED) is defined as a dose level which produces an 
ALC ≥25,000/µL sustained for 14 days or a total WBC ≥35,000/µL sustained for 
14 days among 2/3 or 4/6 of patients. For safety, a dose level is also defined as 
“exceeding MED” with the occurrence of ALC ≥50,000/µL or WBC ≥60,000/µL 
sustained for 14 days.  If patients have circulating malignant lymphocytes in the 
peripheral blood, these lymphoma cells will be excluded from the WBC and ALC 
calculations for MED. 
Expansion 
Phase 
Two expansion arms will be used to investigate indolent NHL patients with 
different expectations regarding response to single agent rituximab: rituximab-
refractory (RR) and rituximab-sensitive (RS).  For each arm, a two-stage 
expansion phase at the MTD or the MED level will be conducted using an optimal 
Simon’s two-stage design. The best objective overall response rate (ORR) is 
defined as complete response (CR) + partial response (PR) assessed at the week 11 
or 40 response assessment, or during the 2 year follow-up period.  For RR patients, 
a lack of efficacy for ORR of 5% will be used, with an ORR > 25% constituting a 
clinically interesting result.  For RS patients, a lack of efficacy for ORR of 40% 
Cohort 
ALT-803 Dose (µg/kg) 
Number of patients 
-1 
0.5 
3 to 6 
1 (initial) 
1 
3 to 6 
2 
3 
3 to 6 
3 
6 
3 to 6 

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will be used, with a clinically interesting ORR > 60%.  Each expansion arm will 
be analyzed independently for preliminary efficacy. 
Stopping Rules: 
Patient enrollment will be temporarily suspended based on occurrence of any of 
the following events, and the study committee, including the sponsor, the Data 
Safety Monitoring Board and principal investigators will meet to discuss how to 
proceed with future patient enrollment in the study. 
During the dose escalation phase of the study,  
• If the maximum planned dose level has been reached, but neither the MTD nor 
MED can be determined. 
• If de-escalation occurs and the step-down dose level cannot be designated as 
the MTD or MED.  
Any time during the expansion phase of the study,  
• More than 33% of patients experience a possible, probable or definite study 
drug related DLT. 
• Favorable anti-tumor response data collected from enrolled patients. 
At any time during the study, 
the study committee may meet to discuss how to proceed with the study and may 
make any or all of the following recommendations for further patient enrollment:  
• Downward adjust the study drug dose. 
• Adjust the study drug dosing schedule. 
• Recommend more effective pre-therapy, intra-therapy and post-therapy side 
effect mitigation interventions. 
• Correct protocol technical errors that caused unnecessary dose omissions or 
premature treatment discontinuations. After correction of protocol errors, the 
DSMB may meet to re-evaluate the safety profile of the study treatment and 
recommend how to proceed with the study, if necessary. 
Evaluations: 
Patients will be evaluated for clinical toxicities during the treatment. The disease 
response will be evaluated at weeks 11 and 40 from the start of study treatment, 
and every 6 months for 2 years thereafter. After this two year period the 
institutional standards for disease assessment will be followed, with at least annual 
disease assessments, for up to 5 years. Prior to and during the treatment period, 
patients’ blood and serum samples will be collected to assess the pharmacokinetic 
profile and immunogenicity of the study drug, as well as for immunomodulation, 
and fcgr3a polymorphisms.  Disease containing biopsies and an oral sample will 
be used for recurrent lymphoma gene mutation analysis.  All patients who receive 
at least 2 doses of the study drug ALT-803 will be included in the anti-tumor 
response evaluation. 
Population: 
Patients of 18 years of age and above with relapsed or refractory CD20+ indolent 
NHL (follicular lymphoma (FL), marginal zone lymphoma (MZL), small 
lymphocytic lymphoma (SLL), and lymphoplasmacytic lymphoma (LPL)). 

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Rituximab-refractory (RR) patients are defined as those that progress on rituximab 
therapy or within 6 months of their last dose of rituximab.  For RR patients, a 
biopsy to confirm CD20 expression is required.  Patients also need to have 
adequate cardiac, pulmonary, liver and kidney functions and have an Eastern 
Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.   
Sample Size: 
A total of up to 18 assessable patients will be accrued to the dose escalation phase of 
the study (Phase 1). Anticipated enrollment to this phase is 12 patients. For the RS 
patient arm, a total of 16 patients will be enrolled at the MTD/MED dose in the first 
stage, and 30 patients in the second stage of a 2-stage Phase 2 cohort (total for RS 
expansion cohort 46).  For the RR, a total of 9 patients will be enrolled in the first 
stage, and an additional 8 patients in the second stage of a 2 stage Phase 2 study 
(total for RR expansion cohort 17).  Thus, enrollment of evaluable patients on the 
Phase 1 portion, and the first stage of both expansion cohorts (including 6 patients of 
the MTD/MED cohort) is expected to be 31 patients, with the maximum number of 
43 patients.  Assuming a 5% frequency of non-evaluable patients, the phase 1 and 
the first stage of both expansion cohorts is estimated at 33 patients.   
Primary 
Endpoints 
For Phase 1 only 
(1) Determination of the MTD or MED of ALT-803 and designation of the 
recommended dose level (RP2D) for Phase 2 study of ALT-803 in 
conjunction with rituximab in patients with rel/ref iNHL. 
For Phase 1 & 2 
(2) Safety profile of ALT-803 plus rituximab in treated patients. 
 
(3) Overall response rate (CR+PR) of treated patients.  
Secondary  
Endpoints  
 
(1) Evaluate overall survival, progression free survival, time to response, duration 
of response, time to treatment failure, and time to subsequent treatment. 
 
(2) Evaluation of the effect of ALT-803 on the peripheral ALC and WBC counts, 
the number and phenotype of peripheral blood NK cells and T (total and 
subsets), and NK cell function. 
 
(3) Characterization of the immunogenicity and pharmacokinetic profile, 
including serum levels of IL-2, IL-4, IL-6, IL-10, IFN-γ and TNF-α, of ALT-
803 in treated patients. 
 
(4) Correlation of fcgr3a polymorphism status and recurrent lymphoma mutations 
with clinical outcomes of the study. 
Pharmacokinetics 
& Biomarkers: 
Fresh blood samples will be collected to assess immune cell number, phenotype 
and function. Serum samples will be collected for pharmacokinetics (PK) and 
immunogenicity of the study drug ALT-803. The same serum samples collected 
for PK analysis will be used to assess the serum levels of IL-2, IL-4, IL-6, IL-10, 
IFN-γ and TNF-α. Non-compartmental and compartmental analyses will be 
conducted. Baseline peripheral blood will be used for fcgr3a polymorphism 

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testing, and a baseline tumor sample and oral sample will be used for lymphoma 
mutation analysis using next-generation sequencing. 
Monitoring Tests: Blood samples for standard chemistry and CBC with differential will be obtained 
at screening, on each study treatment infusion day, and at response evaluation 
visits. Blood samples for immunogenicity testing of anti-ALT-803 antibodies will 
be collected prior to dosing on the first and fourth ALT-803 infusion visit, and at 
the response evaluation visit during week 11.  
Response 
Assessment: 
There are at least two response assessments for treated patients: the first 
assessment during week 11 (following induction) and the second assessment 
during week 40 (following consolidation) from the start of study treatment. After 
completion of the induction cycle of study treatment, patients who have received at 
least 2 doses of ALT-803 will have the first response assessment. After completion 
of four additional consolidation study treatments patients will have a second 
response assessment. If patients are unable to continue study therapy for all 4 
consolidation cycles due to an adverse event, disease assessments will be 
performed at the time of going off study.  In non-progressing patients, after 
completion of consolidation, disease assessments will be performed every 6 
months for 2 years, and then per institutional guidelines, at least annually, for up to 
5 years.  If a focused physical examination or patient symptoms raise the concern 
for progression, a complete response assessment should be performed at that time.  
Response assessments will be carried out according to the 2007 IHP criteria for 
response assessment of lymphoma.1 Baseline evaluations (except for baseline 
imaging and bone marrow biopsy) should be performed up to 14 days before study 
treatment start.  
Progression & 
Survival 
Assessment: 
Progression-free survival, overall survival, and duration of response of all treated 
patients will be assessed at least every three months during years 1 and 2, every 4 
months during year 3, and then every 6 months (+/- 2 months) during years 4 and 
5 from the start of study treatment, or through the point designated as the end of 
the study follow up (5 years). 
Adverse Events: 
All patients will be monitored and evaluated for clinical toxicities during the 
treatment period and queried at each follow-up visit for Adverse Events (AEs). 
Patients may volunteer information concerning AEs. All adverse events will be 
graded by using the NCI Common Terminology Criteria for Adverse Events 
version 4.0 (CTCAE v4.0), and logged in the patient Case Report Form. The study 
centers should report all Serious Adverse Events (SAEs) and all events that trigger 
patient’s study treatment discontinuation to the sponsor via phone, fax or email (or 
a combination) no more than 24 hours after learning of the event. The sponsor will 
use the information to manage and coordinate the dose escalation, cohort 
expansion and patient enrollment. The sponsor will then inform all of the 
participating clinical sites of the current dose level and the number of patients to 
be enrolled at that level, or of any patient enrollment suspension via phone, fax or 
email within 24 hours of learning of the event. The study centers should report all 

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other adverse events to the sponsor following the guidelines defined in the study 
protocol. All study drug related AEs that are both serious and unexpected will be 
reported to the FDA in an expedited manner in accordance with 21 CFR §312.32. 
Statistical Plan: 
For each cohort, all AEs will be tabulated and examined and all safety, 
pharmacokinetic, biomarker and tumor response data will be evaluated. For 
estimation of duration of response and progression free survival, the Kaplan-Meier 
method will be used. P-values of ≤0.05 (two-sided) will be considered to indicate 
statistical significance.  
 
 

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8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS 
8.1 
Study calendar  
 
TESTS & PROCEDURES 
SCREEN/ 
BASELINE1 
INDUCTION 
REST  
RESPONSE 
EVALUATION CONSOLIDATION RESPONSE 
EVALUATION 
DISEASE ASSESSMENT & FOLLOW-UPS 
Study Month  
 
1 
2-3 
3 
3-9 
10 
12 
15 
18 
21 24 
28 
32 
36 
42 
48 
54 
60 
Study Week  
 
1 
2 
3 
4 
5-10 
11 
12 
20 
28 
36 
40 
 
Study Day  
 
1 
2 
3 
5 
8 
15 
22 
23 
25 
29-70 
71-77 
78 134 190 246 
274-280 
 
Tolerance Window 
 
+/- 2 days 
Any day 
Any day 
+/- 7 days 
Any day 
+/- 2 weeks 
Medical history 
X 
 
 
 
 
 
 
 
 
 
R 
 
E 
 
S 
 
T 
 
 
P 
 
E 
 
R 
 
I 
 
O 
 
D 
 
 
 
 
 
 
 
Serum pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam (PE) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Focused PE, ECOG PS, B symptom assessment 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Vital signs, Weight, Height3, Cardiac & Lung 
function monitoring  
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Concurrent medication 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Adverse event assessment4 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
CBC with Differential5 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Blood Chemistry with LDH5  
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFT only when clinically indicated 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Response assessment6 
  
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Contrast CT of NCAP or PET-CT 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Bone marrow biopsy7 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Focused PE, ECOG PS, B symptom & AE 
X17  
X 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Disease and survival follow-up/post therapies8 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X X16 X16 X16 X16 
Immune cell number, phenotype & function9, 14 
X 
 
X10 X 
X X10 
 
X10 X 
X 
 
X11 
 
 
 
 
 
Polymorphism  (SNP) testing14 
  X10 
 
 
 
 
 
 
 
 
 
 
 
 
PK, IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α12,14 
 
X12 X 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity tests13, 14 
 
 
X13 
 
 
 
 
X10 
 
 
X 
 
 
 
 
Recurrent mutation evaluation15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rituximab
 
r1 
 
 
 
r2 r3 r4 
 
 
 
r5 r6 r7 
r8 
Study drug (ALT-803)
 
 
a1 
 
 
a2 a3 a4 
 
 
a5 a6 a7 
a8 
1Screening/baseline evaluations are performed < 14 days prior to start of therapy; baseline CTs or PET-CT are performed ≤ 28 days and baseline bone marrow biopsy performed ≤ 42 days prior to start of therapy. If the 
patient's condition is deteriorating, ECOG status and laboratory evaluations should be repeated within 48 hours prior to initiation of study treatment infusion.  2Pregnancy test is for women with childbearing potential 
only.  3Vital signs (especially blood pressure), clinical status and laboratory tests should be reviewed before start of therapy. Vital signs will be evaluated at 15, 30, 60 and 120 min then hourly post infusion until 
discharge or at completion of dose monitoring. Body weight will be collected before infusion on each drug infusion day for all patients. Height only collected at baseline. 4Patients who have an on-going study drug-
related SAE upon study completion or at discontinuation of study will be contacted by the investigator or his/her designee every week until the event is resolved or determined to be irreversible. 5Safety labs can be 
drawn within 48 hours of scheduled dose.6Disease response and progression assessment will be evaluated using the 2007 IHP criteria for assessment of lymphoma. 7Only performed to confirm a CR if disease present at 
baseline. Once confirmed, only repeat if relapse suspected. 8Information about tumor assessment & other therapies received after completion of study treatment will be collected if available.  9Fresh blood samples (6 
tubes per time point) for immune cell number, phenotype & function testing will be collected. 10Collect before dosing. 11Collect before dosing and 24 hours post-infusion. 12Collect blood samples at Time 0 (before drug 
infusion), at 30 min (+/- 5 min), 2 hour (+/- 15 min), 6 hour (+/- 60 min) or before discharge on dosing day, 24 hour (+/- 6 hour) from Time 0.  IL-2, IL-4, IL-6, IL-10, IFN-γ and TNF-α assays are performed using the 
same samples and at the same schedule as PK.  13Use the sample collected before dosing for PK test. 14Residual samples may be used by Sponsor for research studies of other biomarkers. All attempts will be made to 
collect research samples but missed samples will not be considered a protocol deviation.15Fesh/frozen or FFPE tissue block (or substitute) preferably from biopsy immediately prior to treatment start. An oral sample will 
be collected to obtain an additional non-tumor cellular sample.16+/- 2 months. 17Complete PE required at screening, not focused PE. 

 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Number: 
CA-ALT-803-02-14 
 
 
Protocol Title: 
A phase 1/2 study of ALT-803 in patients with 
relapse/refractory indolent B cell non-Hodgkin 
lymphoma in conjunction with rituximab 
 
 
Date of Protocol: 
 
Version# 01 
Version# 02 
Version# 03 
 
September 4, 2014 
March 18, 2015 
December 17, 2015 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 
 
 

 
INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
CA-ALT-803-02-14 
 
 
Protocol Title: 
A phase 1/2 study of ALT-803 in patients with 
relapse/refractory indolent B cell non-Hodgkin 
lymphoma in conjunction with rituximab 
 
 
Date of Protocol: 
 
Version# 01 
Version# 02 
Version# 03 
September 4, 2014 
March 18, 2015 
December 17, 2015 
 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor Bioscience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 
By my signature below, I hereby attest that I have read, and that I understand and will abide by all the 
conditions, instructions, and restrictions contained in the attached protocol. 
 
Additionally, I will not initiate this study without approval of the appropriate Institutional Review Board 
(IRB), and I understand that any changes in the protocol must be approved in writing by the sponsor, the 
IRB, and, in certain cases the FDA, before they can be implemented, except where necessary to 
eliminate hazards to subjects. 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Name (Print) 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
SYNOPSIS ................................................................................................................................................................6 
1. 
OBJECTIVES ................................................................................................................................................13 
1.1 
PRIMARY OBJECTIVES .............................................................................................................................13 
1.2 
SECONDARY OBJECTIVES ........................................................................................................................13 
2. 
BACKGROUND ............................................................................................................................................13 
2.1 
ALT-803 – GENERAL INFORMATION.......................................................................................................13 
2.2 
INDOLENT NON-HODGKIN LYMPHOMA (INHL) ......................................................................................14 
2.3 
IMMUNE-BASED THERAPIES FOR INHL ...................................................................................................15 
2.4 
PHARMACOLOGICAL EFFECTS OF ALT-803 IN VITRO AND IN ANIMALS ..................................................16 
 
Development of ALT-803 (IL-15N72D:IL-15RαSu/IgG1 Fc complex) .............................................................. 16 
2.4.1
 
In vitro biological activity of ALT-803 including ADCC enhancement ............................................................. 16 
2.4.2
 
In vivo biological activity of ALT-803 ............................................................................................................... 19 
2.4.3
 
Potent anti-tumor activity of ALT-803 in mouse models in vivo ........................................................................ 20 
2.4.4
2.5 
NON-CLINICAL TOXICOLOGY ..................................................................................................................22 
 
Multi-dose toxicity studies in mice ..................................................................................................................... 22 
2.5.1
 
Multi-dose toxicity studies in cynomolgus monkeys ........................................................................................... 23 
2.5.2
2.6 
COMPARATIVE STUDIES OF INTRAVENOUS AND SUBCUTANEOUS ALT-803 ...........................................25 
2.7 
PHARMACOKINETICS ...............................................................................................................................26 
 
Non-clinical pharmacokinetics .......................................................................................................................... 26 
2.7.1
2.8 
RATIONALE FOR HUMAN CLINICAL STARTING DOSE ...............................................................................26 
2.9 
HUMAN EXPERIENCE ...............................................................................................................................27 
3. 
RATIONALE FOR THE CURRENT STUDY ...........................................................................................29 
4. 
OVERALL STUDY DESIGN .......................................................................................................................30 
5. 
STUDY POPULATION ................................................................................................................................32 
5.1 
INCLUSION CRITERIA ...............................................................................................................................32 
5.2 
EXCLUSION CRITERIA ..............................................................................................................................33 
5.3 
INCLUSION OF WOMEN AND MINORITIES .................................................................................................33 
6. 
STUDY DESIGN ...........................................................................................................................................34 
6.1 
SCREENING AND ENROLLMENT ...............................................................................................................34 
6.2 
STUDY TREATMENT .................................................................................................................................34 
 
Treatment setting ............................................................................................................................................... 34 
6.2.1
 
Treatment regimen and study scheme ................................................................................................................ 34 
6.2.2
 
Study treatment preparation .............................................................................................................................. 35 
6.2.3
 
Study treatment administration .......................................................................................................................... 35 
6.2.4
 
Pre and post-therapy intervention guidelines .................................................................................................... 36 
6.2.5
6.3 
DURATION OF PATIENT PARTICIPATION ..................................................................................................37 
6.4 
DOSE ESCALATION PHASE .......................................................................................................................37 
6.5 
EXPANSION PHASE ..................................................................................................................................39 
6.6 
STOPPING RULES .....................................................................................................................................40 
 
During dose escalation phase of the study ......................................................................................................... 40 
6.6.1
 
During expansion phase of the study ................................................................................................................. 41 
6.6.2
 
At any time during the study .............................................................................................................................. 41 
6.6.3
6.7 
PATIENT MONITORING, RESPONSE EVALUATION, DISEASE PROGRESSION & SURVIVAL FOLLOW-UP .....41 
 
Patient monitoring ............................................................................................................................................. 41 
6.7.1
 
Response evaluation ........................................................................................................................................... 41 
6.7.2
 
Disease progression and survival follow-up ...................................................................................................... 42 
6.7.3
6.8 
DOSE LIMITING TOXICITY ........................................................................................................................42 
 
Definition of dose limiting toxicity ..................................................................................................................... 42 
6.8.1

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Definition of maximum tolerated dose (MTD) ................................................................................................... 42 
6.8.2
 
Definition of minimal efficacious dose (MED) .................................................................................................. 43 
6.8.3
6.9 
STUDY TREATMENT DISCONTINUATION ..................................................................................................43 
 
Study treatment discontinuation events .............................................................................................................. 43 
6.9.1
 
Replacement of participants............................................................................................................................... 43 
6.9.2
 
Follow-ups after treatment discontinuation ....................................................................................................... 44 
6.9.3
 
Discontinuation due to SAEs or on-going study drug related AEs .......................................................... 44 
6.9.3.1.
 
Discontinuation due to any other reasons ................................................................................................. 44 
6.9.3.2.
6.10 
STUDY TREATMENT INTERRUPTION ........................................................................................................44 
 
Kidney dysfunction ........................................................................................................................................ 44 
6.10.1
 
Hematological dysfunction ............................................................................................................................ 44 
6.10.2
 
Hypotension .................................................................................................................................................. 44 
6.10.3
 
Allergic reactions and cytokine release syndrome/acute infusion reaction .................................................. 45 
6.10.4
6.11 
GENERAL SUPPORTIVE CARE GUIDELINES AND DRUG INTERACTION ......................................................45 
 
ALT-803 ........................................................................................................................................................ 45 
6.11.1
 
Hypotension and capillary leak syndrome ................................................................................................ 45 
6.11.1.1.
 
Pulmonary dysfunction ............................................................................................................................. 46 
6.11.1.2.
 
Impaired kidney and liver functions ......................................................................................................... 46 
6.11.1.3.
 
Infection ................................................................................................................................................... 46 
6.11.1.4.
 
Fever and chills ........................................................................................................................................ 46 
6.11.1.5.
 
Gastritis .................................................................................................................................................... 46 
6.11.1.6.
 
Diarrhea, nausea and vomiting ................................................................................................................. 46 
6.11.1.7.
 
Pruritus and dermatitis .............................................................................................................................. 46 
6.11.1.8.
 
Acidosis .................................................................................................................................................... 46 
6.11.1.9.
 
Life-threatening toxicities .................................................................................................................... 46 
6.11.1.10.
 
Other supportive care ........................................................................................................................... 46 
6.11.1.11.
 
Drug interaction ................................................................................................................................... 47 
6.11.1.12.
 
Rituximab ...................................................................................................................................................... 48 
6.11.2
7. 
STUDY DRUG: AVAILABILITY, ACCOUNTABILITY, PACKAGING & LABELING ...................48 
7.1 
ALT-803..................................................................................................................................................48 
 
Availability ......................................................................................................................................................... 48 
7.1.1
 
Accountability .................................................................................................................................................... 48 
7.1.2
 
Packaging .......................................................................................................................................................... 48 
7.1.3
 
Labeling ............................................................................................................................................................. 48 
7.1.4
7.2 
RITUXIMAB ..............................................................................................................................................48 
8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS ................................................................49 
8.1 
STUDY CALENDAR ...................................................................................................................................49 
8.2 
PROCEDURE AND TESTS ..........................................................................................................................50 
 
Medical history & prior therapy ........................................................................................................................ 50 
8.2.1
 
Pregnancy test .................................................................................................................................................... 50 
8.2.2
 
Physical examination, PS assessment, B symptom assessment .......................................................................... 50 
8.2.3
 
Vital signs, body weight & height ...................................................................................................................... 50 
8.2.4
 
Cardiac assessment ............................................................................................................................................ 50 
8.2.5
 
Pulmonary function monitoring ......................................................................................................................... 50 
8.2.6
 
Clinical blood tests ............................................................................................................................................ 50 
8.2.7
 
Disease assessment tests and procedures .......................................................................................................... 51 
8.2.8
 
Adverse event assessment................................................................................................................................... 51 
8.2.9
 
Response assessment ..................................................................................................................................... 51 
8.2.10
 
Disease progression and survival follow-up ................................................................................................. 51 
8.2.11
 
Pharmacokinetic (PK) testing ....................................................................................................................... 51 
8.2.12
 
Biomarker assays for IL-2, IL-4, IL-6, IL-10, IFN-γ, MCP-1 and TNF-α .................................................... 52 
8.2.13
 
Immunogenicity tests - detection of anti-ALT-803 antibodies ....................................................................... 52 
8.2.14
 
Assays for immune cell number, phenotype, and function ............................................................................ 52 
8.2.15
 
Fc receptor polymorphism testing ................................................................................................................. 53 
8.2.16

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Evaluation of recurrent lymphoma mutations ............................................................................................... 53 
8.2.17
 
Lymph node biopsy evaluation ...................................................................................................................... 53 
8.2.18
9. 
MEASUREMENT OF EFFECT ..................................................................................................................54 
9.1 
MEASURABLE DISEASE ............................................................................................................................54 
9.2 
METHODOLOGY OF RESPONSE EVALUATION ..........................................................................................54 
9.3 
RESPONSE EVALUATION CRITERIA ..........................................................................................................54 
9.4 
DISEASE PROGRESSION EVALUATION CRITERIA ......................................................................................54 
10. 
STATISTICAL ANALYSIS .....................................................................................................................54 
10.1 
SAMPLE SIZE ............................................................................................................................................54 
10.2 
DATA COLLECTION ..................................................................................................................................56 
10.3 
DATA ANALYSIS ......................................................................................................................................56 
 
Analysis of safety ........................................................................................................................................... 56 
10.3.1
 
Analysis of response ...................................................................................................................................... 56 
10.3.2
 
Pharmacokinetics .......................................................................................................................................... 56 
10.3.3
11. 
REGULATORY AND REPORTING REQUIREMENTS ....................................................................58 
11.1 
ADVERSE EVENTS RECORDING, REPORTING AND COMMUNICATION .......................................................58 
11.2 
ADVERSE EVENT TERMINOLOGY AND DEFINITIONS ................................................................................58 
11.3 
ADVERSE EVENT REPORTING PROCEDURES ...........................................................................................59 
11.4 
ADVERSE EVENT EXPEDITED REPORTING GUIDELINES ..........................................................................60 
11.5 
SUBMISSION OF SERIOUS ADVERSE EVENT REPORTING ...........................................................................60 
11.6 
DATA REPORTING FORMS .......................................................................................................................60 
11.7 
REPORT /DATA SUBMISSION ADDRESS & CONTACT ................................................................................61 
11.8 
PATIENT RECORDS, QUALITY ASSURANCE, RECORDS RETENTION ..........................................................61 
11.9 
METHOD OF REVIEW ...............................................................................................................................61 
11.10 
SPECIAL REGULATORY CONSIDERATIONS ...........................................................................................62 
 
HIPAA ........................................................................................................................................................... 62 
11.10.1
 
Protocol amendments, informed consent, and IRB approval ........................................................................ 62 
11.10.2
12. 
CONFIDENTIALITY ...............................................................................................................................62 
13. 
ETHICAL STANDARDS & INVESTIGATOR OBLIGATIONS .......................................................62 
14. 
LIST OF EXPECTED ADVERSE EVENTS ..........................................................................................63 
15. 
CTCAE .......................................................................................................................................................65 
16. 
REFERENCES ..........................................................................................................................................66 
17. 
APPENDIX A: ECOG ..............................................................................................................................70 
18. 
APPENDIX B: NEW YORK HEART ASSOCIATION CLASSIFICATION ....................................70 
19. 
APPENDIX C: ETHICAL STANDARDS ..............................................................................................71 
20. 
APPENDIX D: INVESTIGATOR OBLIGATIONS ..............................................................................72 
21. 
APPENDIX E: CONTACT LIST - ALTOR ...........................................................................................76 
22. 
APPENDIX F: CONTACT LIST – DATA SAFETY MONITORING BOARD (DSMB) ..................77 
23. 
APPENDIX G: CONTACT LIST - LABORATORIES ........................................................................77 

Altor BioScience Corp. 
 
 
 
CONFIDENTIAL 
                      CA-ALT-803-02-14 Version#3 
IND 114006 SERIAL #0008 
 
                                                 
 
                        December 17, 2015 
Page 6 of 77 
SYNOPSIS 
Sponsor: 
Altor Bioscience Corporation 
Protocol#: 
CA-ALT-803-02-14 
Study Drug Name: ALT-803 
Study Treatment 
Active agents: 
ALT-803, a “recombinant human super agonist interleukin-15 (IL-15) complex” 
(AKA, IL-15N72D:IL-15RαSu/IgG1 Fc complex) 
Study Type: 
Interventional 
Study Phase: 
1/2 
Protocol Title: 
A phase 1/2 study of ALT-803 in patients with relapse/refractory indolent B cell 
non-Hodgkin lymphoma in conjunction with rituximab 
Objectives: 
To evaluate the safety and tolerability of escalating doses, identify the Maximum 
Tolerated Dose level (MTD) or Minimum Efficacious Dose (MED) and designate 
a dose level for Phase 2 study (RP2D) of ALT-803 in combination with standard-
of-care rituximab therapy in patients with relapsed or refractory (rel/ref) indolent B 
cell non-Hodgkin lymphoma (iNHL). 
To estimate the anti-tumor activity of ALT-803 as measured by response rate, 
overall survival, progression free survival, time to response, duration of response, 
time to treatment failure, and time to subsequent treatment in patients with rel/ref 
iNHL.  
To evaluate the effect of ALT-803 on the peripheral absolute lymphocyte counts 
(ALC) and white blood cell (WBC) counts, the number, phenotype and repertoire 
of peripheral blood T (total and subsets) and NK cells. In addition, a subset of 
patients will be evaluated for changes in lymph node immune composition. 
To characterize the immunogenicity and pharmacokinetic profile, including 
induced serum levels of IL-2, IL-4, IL-6, IL-10, IFN-γ, MCP-1 and TNF-α of 
ALT-803 in rel/ref iNHL patients. 
To correlate clinical outcomes with fcgr3a polymorphisms and recurrent genomic 
mutations in rel/ref iNHL patients. 
Study Design: 
This is a Phase 1/2, open-label, multi-center, competitive enrollment and dose-
escalation study of ALT-803 in patients with rel/ref iNHL in conjunction with 
rituximab. 
The study includes a dose escalation phase to determine the MTD or MED using a 
3+3 dose escalation design and to designate a dose level for the Phase 2 expansion 
(RP2D) of ALT-803 in combination with rituximab and an expansion phase at the 
ALT-803 RP2D level using a Simon two-stage design. In Phase 1, seven cohorts 
will be evaluated. A step-down dose level (level -1) will be provided in the event 
of encountering DLT in two patients at the planned initial dose level.  
The study will be conducted in conformity with Good Clinical Practice (GCP).  

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                        December 17, 2015 
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Treatments:  
The study treatment plan for each enrolled patient includes one 4-week induction 
treatment cycle. During induction for cohort 1, 2 and 3, patients will receive up to 
four weekly doses of ALT-803 and rituximab (375 mg/m2) by intravenous 
injection (IV). During induction for cohort 4, 5, 6 and 7, patients will receive four 
weekly doses of ALT-803 by subcutaneous (SubQ) injection and rituximab (375 
mg/m2) by IV. For the first dose of treatment in all cohorts, patients will receive 
rituximab on day 1 followed by ALT-803 on day 2 in order to avoid simultaneous 
dosing of both agents and reduce the potential of infusion-related adverse events.  
Eligible patients will receive the consolidation treatment.  Consolidation consists 
of treatment with ALT-803 at the same dose level and route of administration used 
in the induction plus rituximab (375 mg/m2) every 8 weeks (1 cycle = 8 weeks), 
for a total of 4 consolidation cycles.  
Treated patients will have at least two response evaluation visits. Patients who 
receive at least two study drug doses during the induction treatment period will be 
evaluated for disease response during week 11. Patients who have at least stable 
disease from the first anti-tumor evaluation and who do not experience or have 
sufficiently recovered from toxicities of the induction treatment cycle and who 
meet other criteria to continue study treatment will receive up to four consolidation 
treatment cycles, with a single treatment of ALT-803 plus rituximab, repeated 
every 8 weeks for a total of 4 additional ALT-803 plus rituximab doses.  The 
ALT-803 dose level and route of administration utilized in the induction cycle will 
be continued in consolidation, with reassessment for continued tumor response 
performed upon completion at week 40. 
The study treatment and response evaluation visits are illustrated below (refer to 
study calendar for all study visits): 
Treatment Phase 
Induction 
REST 
Response 
Evaluation  
Consolidation 
Response 
Evaluation 
Treatment Week 
1 
2 
3 
4 
5-10 
11 
12 20 28 36 
40** 
Treatment Day 
1, 2* 8 15 22 
29-70 
71-77 
78 134 190 246 
274-280 
ALT-803 1 
2 
3 
4 
Rest 
 
5 
6 
7 
8 
 
rituximab 1 
2 
3 
4 
 
5 
6 
7 
8 
 
Consolidation Cycle 
 
 
 
 
 
1 
2 
3 
4 
 
Response Evaluation 
 
 
 
 
X 
 
 
 
 
X 
*For the first week, rituximab is administered on day 1, ALT-803 on day 2 
**Long term follow-up after 40 weeks includes restaging every 6 months for 2 years, and 
then every 12 months for 5 years (until progression). 
Patients will be assessed for response using the 2007 IHP criteria 1.  Patients will 
be followed for progression, and at the time of progression there are no restrictions 
on further therapies.  
Enrolled patients will receive the study treatment at qualified cancer treatment 
centers with adequate diagnostic and treatment facilities to provide appropriate 
management of therapy and complications. ALT-803 will be administered by 
intravenous infusion for cohort 1, 2 and 3 into a central or peripheral vein under 
the supervision of a qualified physician experienced in the use of biologic anti-
cancer agents. ALT-803 will be administered by subcutaneous injection for cohort 

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                        December 17, 2015 
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4, 5, 6 and 7 under the supervision of a qualified physician experienced in the use 
of biologic anti-cancer agents. Rituximab will be administered as described in the 
product package insert provided by the manufacturer. 
Dose Escalation 
Phase: 
A 3 + 3 design will be used for identifying a tolerable dose of ALT-803 for Phase 
2 studies by monitoring patients for DLTs to determine the MTD and for 
identifying an efficacious dose by monitoring patients’ ALC and WBC count to 
determine the MED during the DLT observation period. The dose escalation phase 
is concluded when either the MTD or the MED is determined. An ALT-803 dose 
level (RP2D) will then be designated for Phase 2 study. There are seven cohorts of 
ALT-803 and a step-down cohort (-1) with a lower dose level of ALT-803 in the 
event that unexpected toxicity is encountered at the initial dose level.   
Below are the planned dose levels and respective route of administration for the 
study drug during the dose escalation phase of the study.  
 
 
 
 
 
 
 
 
 
 
Dose limiting toxicity (DLT) is defined as follows: any toxicity that is not clearly 
unrelated to drug administration that is of Grade 3 and does not resolve to Grade 1 
or lower within a week despite the use of medical intervention or that is of Grade 
4, with exceptions described in the study protocol.  
The DLT Observation Period is defined as the duration of the induction treatment, 
days 1-28. 
Maximum Tolerated Dose level (MTD) is defined as a dose level at which <2 out 
of 6 patients experienced DLT and that is one level below a dose that was not 
tolerated or the maximum planned dose level if designated by the study committee. 
Minimal Efficacious Dose (MED) is defined as a dose level which produces an 
ALC ≥25,000/µL sustained for 14 days or a total WBC ≥35,000/µL sustained for 
14 days among 2/3 or 4/6 of patients. For safety, a dose level is also defined as 
“exceeding MED” with the occurrence of ALC ≥50,000/µL or WBC ≥60,000/µL 
sustained for 14 days.  If patients have circulating malignant lymphocytes in the 
peripheral blood, these lymphoma cells will be excluded from the WBC and ALC 
calculations for MED. 
Cohort 
ALT-803 Dose 
(µg/kg) 
Route 
Number of patients 
-1 
0.5 
IV 
3 to 6 
1 (initial) 
1 
IV 
3 to 6 
2 
3 
IV 
3 to 6 
3 
6 
IV 
3 to 6 
4 
6 
SubQ 
3 to 6 
5 
10 
SubQ 
3 to 6 
6 
15 
SubQ 
3 to 6 
7 
20 
SubQ 
3 to 6 

Altor BioScience Corp. 
 
 
 
CONFIDENTIAL 
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IND 114006 SERIAL #0008 
 
                                                 
 
                        December 17, 2015 
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Expansion 
Phase 
Two expansion arms will be used to investigate indolent NHL patients with 
different expectations regarding response to single agent rituximab: rituximab-
refractory (RR) and rituximab-sensitive (RS).  For each arm, a two-stage 
expansion phase at the MTD or the MED level will be conducted using an optimal 
Simon’s two-stage design. The best objective overall response rate (ORR) is 
defined as complete response (CR) + partial response (PR) assessed at the week 11 
or 40 response assessment, or during the 2 year follow-up period.  For RR patients, 
a lack of efficacy for ORR of 10% will be used, with an ORR > 35% constituting a 
clinically interesting result.  For RS patients, a lack of efficacy for ORR of 40% 
will be used, with a clinically interesting ORR > 60%.  Each expansion arm will 
be analyzed independently for preliminary efficacy. 
Stopping Rules: 
Patient enrollment will be temporarily suspended based on occurrence of any of 
the following events, and the study committee, including the sponsor, the Data 
Safety Monitoring Board and principal investigators will meet to discuss how to 
proceed with future patient enrollment in the study. 
During the dose escalation phase of the study,  
• If the maximum planned dose level has been reached, but neither the MTD nor 
MED can be determined. 
• If de-escalation occurs and the step-down dose level cannot be designated as 
the MTD or MED.  
Any time during the expansion phase of the study,  
• More than 33% of patients experience a possible, probable or definite study 
drug related DLT. 
• Favorable anti-tumor response data collected from enrolled patients. 
At any time during the study, 
the study committee may meet to discuss how to proceed with the study and may 
make any or all of the following recommendations for further patient enrollment:  
• Downward adjust the study drug dose. 
• Adjust the study drug dosing schedule. 
• Recommend more effective pre-therapy, intra-therapy and post-therapy side 
effect mitigation interventions. 
• Correct protocol technical errors that caused unnecessary dose omissions or 
premature treatment discontinuations. After correction of protocol errors, the 
DSMB may meet to re-evaluate the safety profile of the study treatment and 
recommend how to proceed with the study, if necessary. 
Evaluations: 
Patients will be evaluated for clinical toxicities during the treatment. The disease 
response will be evaluated at weeks 11 and 40 from the start of study treatment, 
and every 6 months for 2 years thereafter. After this two year period the 
institutional standards for disease assessment will be followed, with at least annual 

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                        December 17, 2015 
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disease assessments, for up to 5 years. Prior to and during the treatment period, 
patients’ blood and serum samples will be collected to assess the pharmacokinetic 
profile and immunogenicity of the study drug, as well as for immunomodulation, 
and fcgr3a polymorphisms.  Disease containing biopsies and an oral sample will 
be used for recurrent lymphoma gene mutation analysis.  All patients who receive 
at least 2 doses of the study drug ALT-803 will be included in the anti-tumor 
response evaluation. 
Population: 
Patients of 18 years of age and above with relapsed or refractory CD20+ indolent 
NHL (follicular lymphoma (FL), marginal zone lymphoma (MZL), small 
lymphocytic lymphoma (SLL), and lymphoplasmacytic lymphoma (LPL)). 
Rituximab-refractory (RR) patients are defined as those that progress on rituximab 
therapy or within 6 months of their last dose of rituximab.  For RR patients, a 
biopsy to confirm CD20 expression is required.  Patients also need to have 
adequate cardiac, pulmonary, liver and kidney functions and have an Eastern 
Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.   
Sample Size: 
A total of up to 42 assessable patients will be accrued to the dose escalation phase of 
the study (Phase 1). Anticipated enrollment to this phase is 24 patients. For the RS 
patient arm, a total of 16 patients will be enrolled at the MTD/MED dose in the first 
stage and 30 patients in the second stage of a 2-stage Phase 2 cohort (total for RS 
expansion cohort 46).  For the RR, a total of 8 patients will be enrolled in the first 
stage and an additional 14 patients in the second stage of a 2-stage Phase 2 study 
(total for RR expansion cohort 22).  Thus, enrollment of evaluable patients on the 
Phase 1 portion, and the first stage of both expansion cohorts (including 6 patients of 
the MTD/MED cohort) is expected to be 42 patients, with the maximum number of 
60 patients.  Assuming a 5% frequency of non-evaluable patients, the phase 1 and 
the first stage of both expansion cohorts is estimated at 45 patients.   
Primary 
Endpoints 
For Phase 1 only 
(1) Determination of the MTD or MED of ALT-803 and designation of the 
recommended dose level (RP2D) for Phase 2 study of ALT-803 in 
conjunction with rituximab in patients with rel/ref iNHL. 
For Phase 1 & 2 
(2) Safety profile of ALT-803 plus rituximab in treated patients. 
 
(3) Overall response rate (CR+PR) of treated patients.  
Secondary  
Endpoints  
 
(1) Evaluate overall survival, progression free survival, time to response, duration 
of response, time to treatment failure, and time to subsequent treatment. 
 
(2) Evaluation of the effect of ALT-803 on the peripheral ALC and WBC counts, 
the number, phenotype and repertoire of peripheral blood NK cells and T 
(total and subsets), and NK cell function.  In addition, a subset of patients will 
be evaluated for changes in lymph node immune composition. 

Altor BioScience Corp. 
 
 
 
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                        December 17, 2015 
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(3) Characterization of the immunogenicity and pharmacokinetic profile, 
including serum levels of IL-2, IL-4, IL-6, IL-10, IFN-γ, MCP-1 and TNF-α, 
of ALT-803 in treated patients. 
 
(4) Correlation of fcgr3a polymorphism status and recurrent lymphoma mutations 
with clinical outcomes of the study. 
Pharmacokinetics 
& Biomarkers: 
Fresh blood samples will be collected to assess immune cell number, phenotype, 
repertoire and function prior to and during the study treatment. Serum samples will 
be collected for pharmacokinetics (PK) and immunogenicity of the study drug 
ALT-803. The same serum samples collected for PK analysis will be used to 
assess the serum levels of IL-2, IL-4, IL-6, IL-10, IFN-γ, MCP-1 and TNF-α. Non-
compartmental and compartmental PK analyses will be conducted. Baseline 
peripheral blood will be used for fcgr3a polymorphism testing, and a baseline 
tumor sample and oral sample will be used for lymphoma mutation analysis using 
next-generation sequencing. Lymph node biopsies will be performed to determine 
the impact of study treatment on the immune cell composition within the tumor 
microenvironment. 
Monitoring Tests: Blood samples for standard chemistry and CBC with differential will be obtained 
at screening, on each study treatment day, and at response evaluation visits. Blood 
samples for immunogenicity testing of anti-ALT-803 antibodies will be collected 
prior to dosing on the first and fourth ALT-803 treatment visit, and at the response 
evaluation visit during week 11.  
Response 
Assessment: 
There are at least two response assessments for treated patients: the first 
assessment during week 11 (following induction) and the second assessment 
during week 40 (following consolidation) from the start of study treatment. After 
completion of the induction cycle of study treatment, patients who have received at 
least 2 doses of ALT-803 will have the first response assessment. After completion 
of four additional consolidation study treatments patients will have a second 
response assessment. If patients are unable to continue study therapy for all 4 
consolidation cycles due to an adverse event, disease assessments will be 
performed at the time of going off study.  In non-progressing patients, after 
completion of consolidation, disease assessments will be performed every 6 
months for 2 years, and then per institutional guidelines, at least annually, for up to 
5 years.  If a focused physical examination or patient symptoms raise the concern 
for progression, a complete response assessment should be performed at that time.  
Response assessments will be carried out according to the 2007 IHP criteria for 
response assessment of lymphoma 1. Baseline evaluations (except for baseline 
imaging and bone marrow biopsy) should be performed up to 28 days before study 
treatment start unless otherwise specified in the protocol.  
Progression & 
Survival 
Assessment: 
Progression-free survival, overall survival, and duration of response of all treated 
patients will be assessed at least every three months during years 1 and 2, every 4 
months during year 3, and then every 6 months (+/- 2 months) during years 4 and 

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                        December 17, 2015 
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5 from the start of study treatment, or through the point designated as the end of 
the study follow up (5 years). 
Adverse Events: 
All patients will be monitored and evaluated for clinical toxicities during the 
treatment period and queried at each follow-up visit for Adverse Events (AEs). 
Patients may volunteer information concerning AEs. All adverse events will be 
graded by using the NCI Common Terminology Criteria for Adverse Events 
version 4.0 (CTCAE v4.0), and logged in the patient Case Report Form. The study 
centers should report all Serious Adverse Events (SAEs) and all events that trigger 
patient’s study treatment discontinuation to the sponsor via phone, fax or email (or 
a combination) no more than 24 hours after learning of the event. The sponsor will 
use the information to manage and coordinate the dose escalation, cohort 
expansion and patient enrollment. The sponsor will then inform all of the 
participating clinical sites of the current dose level and the number of patients to 
be enrolled at that level, or of any patient enrollment suspension via phone, fax or 
email within 24 hours of learning of the event. The study centers should report all 
other adverse events to the sponsor following the guidelines defined in the study 
protocol. All study drug related AEs that are both serious and unexpected will be 
reported to the FDA in an expedited manner in accordance with 21 CFR §312.32. 
Statistical Plan: 
For each cohort, all AEs will be tabulated and examined and all safety, 
pharmacokinetic, biomarker and tumor response data will be evaluated. For 
estimation of duration of response and progression free survival, the Kaplan-Meier 
method will be used. P-values of ≤0.05 (two-sided) will be considered to indicate 
statistical significance.  
 
 

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             December 17, 2015 
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8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS 
8.1 
Study calendar  
1Screening/baseline evaluations including baseline CTs or PET-CT are performed ≤ 28 days  prior to start of therapy and baseline bone marrow biopsy performed ≤ 42 days prior to start of therapy. If the patient's 
condition is deteriorating, ECOG status and laboratory evaluations should be repeated within 48 hours prior to initiation of study treatment.  2Pregnancy test is for women with childbearing potential only.  3Vital 
signs (especially blood pressure), clinical status and laboratory tests should be reviewed before start of therapy. Vital signs will be evaluated at 15, 30, 60 and 120 min then hourly post treatment  until discharge or 
at completion of dose monitoring. Body weight will be collected before treatment  on each drug treatment day for all patients. Height only collected at baseline. 4Patients who have an on-going study drug-related 
SAE upon study completion or at discontinuation of study will be contacted by the investigator or his/her designee every week until the event is resolved or determined to be irreversible. 5Safety labs can be drawn 
within 72 hours of scheduled dose.6Disease response and progression assessment will be evaluated using the 2007 IHP criteria for assessment of lymphoma. 7Only performed to confirm a CR if disease present at 
baseline. Once confirmed, only repeat if relapse suspected. 8Information about tumor assessment & other therapies received after completion of study treatment will be collected if available.  9Fresh blood samples (6 
tubes per time point) for immune cell number, phenotype & function testing will be collected. 10Collect before dosing. 11Collect before dosing and 24 hours post-treatment. 12Collect blood samples at Time 0 (before  
treatment), at 30 min (+/- 5 min), 2 hour (+/- 15 min), 6 hour (+/- 60 min) or before discharge on dosing day, 24 hour (+/- 6 hour) from Time 0.  IL-2, IL-4, IL-6, IL-10, IFN-γ, MCP-1  and TNF-α assays are 
performed using the same samples as PK.  13Use the sample collected before dosing for PK test. 14Residual samples may be used by Sponsor for research studies of other biomarkers. All attempts will be made to 
collect research samples but missed samples will not be considered a protocol deviation.15Fesh/frozen or FFPE tissue block (or substitute) preferably from biopsy immediately prior to treatment start. An oral sample 
will be collected to obtain an additional non-tumor cellular sample.16+/- 2 months. 17Complete PE required at screening, not focused PE. 18 LN biopsy is optional, and will be performed on consenting patients that 
have lymph nodes appropriate for baseline and repeat week 4 radiology-guided biopsies.19 The Cycle 1 Day 4 visit is optional if patient is not available.
TESTS & PROCEDURES 
SCREEN/ 
BASELINE1 
INDUCTION 
REST  
RESPONSE 
EVALUATION CONSOLIDATION RESPONSE 
EVALUATION 
DISEASE ASSESSMENT & FOLLOW-UPS 
Study Month  
 
1 
2-3 
3 
3-9 
10 
12 
15 
18 
21 24 
28 
32 
36 
42 
48 
54 
60 
Study Week  
 
1 
2 
3 
4 
5-10 
11 
12 
20 
28 
36 
40 
 
Study Day  
 
1 
2 
3 
4 
5 
8 
15 
22 
23 
25 
29-70 
71-77 
78 134 190 246 
274-280 
 
Tolerance Window 
 
+/- 2 days 
 
+/- 7 days 
+/- 7 days 
+/- 7 days 
+/- 2 weeks 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
R 
 
E 
 
S 
 
T 
 
 
P 
 
E 
 
R 
 
I 
 
O 
 
D 
 
 
 
 
 
 
 
Serum pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam (PE) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Focused PE, ECOG PS, B symptom assessment 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Vital signs, Weight, Height3, Cardiac & Lung 
function monitoring  
X 
X 
X 
 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Concurrent medication 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Adverse event assessment4 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
CBC with Differential5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Chemistry with LDH5  
X 
X 
X 
 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFT only when clinically indicated 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Response assessment6 
  
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Contrast CT of NCAP or PET-CT 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Bone marrow biopsy7 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Focused PE, ECOG PS, B symptom & AE 
X17  
X 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Disease and survival follow-up/post therapies8 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X X16 X16 X16 X16 
Lymph node biopsy18 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Immune cell number, phenotype & function9, 14 
X 
 
X10 X X19 X X10 X10 X10 X 
X 
 
X11 
 
 
 
Polymorphism  (SNP) testing14 
  X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK, IL-2, IL-4, IL-6, IL-10, IFN-γ, MCP-1, TNF-
α12,14 
 
X12 X X19 X 
 
 
 
 
 
 
 
 
 
 
Immunogenicity tests13, 14 
 
 
X13 
 
 
 
 
 
X10 
 
 
X 
 
 
 
 
Recurrent mutation evaluation15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rituximab
 
r1 
 
 
 
 
r2 r3 r4 
 
 
 
r5 r6 r7 
r8 
Study drug (ALT-803)
 
 
a1 
 
 
 
a2 a3 a4 
 
 
a5 a6 a7 
a8 

 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Number: 
CA-ALT-803-02-14 
 
 
Protocol Title: 
A phase 1/2 study of ALT-803 in patients with 
relapse/refractory indolent B cell non-Hodgkin 
lymphoma in conjunction with rituximab 
 
 
Date of Protocol: 
 
Version# 01 
Version# 02 
Version# 03 
Version# 04 
 
September 4, 2014 
March 18, 2015 
December 17, 2015 
February 6, 2017 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor BioScience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 
 
 

 
INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
CA-ALT-803-02-14 
 
 
Protocol Title: 
A phase 1/2 study of ALT-803 in patients with 
relapse/refractory indolent B cell non-Hodgkin 
lymphoma in conjunction with rituximab 
 
 
Date of Protocol: 
 
Version# 01 
Version# 02 
Version# 03 
Version# 04 
 
September 4, 2014 
March 18, 2015 
December 17, 2015 
February 6, 2017 
Sponsor Contact: 
 
Hing C. Wong, Ph.D. 
Altor BioScience Corporation. 
Miramar, Florida 33025 
Telephone: 
954-443-8600 
Safety Data Fax: 
954-443-8602 
 
 
 
By my signature below, I hereby attest that I have read, and that I understand and will abide by all the 
conditions, instructions, and restrictions contained in the attached protocol. 
 
Additionally, I will not initiate this study without approval of the appropriate Institutional Review Board 
(IRB), and I understand that any changes in the protocol must be approved in writing by the sponsor, the 
IRB, and, in certain cases the FDA, before they can be implemented, except where necessary to 
eliminate hazards to subjects. 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Name (Print) 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
SYNOPSIS ................................................................................................................................................................6 
1. 
OBJECTIVES ................................................................................................................................................13 
1.1 
PRIMARY OBJECTIVES .............................................................................................................................13 
1.2 
SECONDARY OBJECTIVES ........................................................................................................................13 
2. 
BACKGROUND ............................................................................................................................................13 
2.1 
ALT-803 – GENERAL INFORMATION.......................................................................................................13 
2.2 
INDOLENT NON-HODGKIN LYMPHOMA (INHL) ......................................................................................14 
2.3 
IMMUNE-BASED THERAPIES FOR INHL ...................................................................................................15 
2.4 
PHARMACOLOGICAL EFFECTS OF ALT-803 IN VITRO AND IN ANIMALS .................................................16 
 
Development of ALT-803 (IL-15N72D:IL-15RαSu/IgG1 Fc complex) .............................................................. 16 
 
In vitro biological activity of ALT-803 including ADCC enhancement ............................................................. 16 
 
In vivo biological activity of ALT-803 ............................................................................................................... 19 
 
Potent anti-tumor activity of ALT-803 in mouse models in vivo ........................................................................ 20 
2.5 
NON-CLINICAL TOXICOLOGY ..................................................................................................................22 
 
Multi-dose toxicity studies in mice ..................................................................................................................... 22 
 
Multi-dose toxicity studies in cynomolgus monkeys ........................................................................................... 23 
2.6 
COMPARATIVE STUDIES OF INTRAVENOUS AND SUBCUTANEOUS ALT-803 ...........................................25 
2.7 
PHARMACOKINETICS ...............................................................................................................................26 
 
Non-clinical pharmacokinetics .......................................................................................................................... 26 
2.8 
RATIONALE FOR HUMAN CLINICAL STARTING DOSE ...............................................................................26 
2.9 
HUMAN EXPERIENCE ...............................................................................................................................26 
3. 
RATIONALE FOR THE CURRENT STUDY ...........................................................................................27 
4. 
OVERALL STUDY DESIGN .......................................................................................................................28 
5. 
STUDY POPULATION ................................................................................................................................30 
5.1 
INCLUSION CRITERIA ...............................................................................................................................30 
5.2 
EXCLUSION CRITERIA ..............................................................................................................................31 
5.3 
INCLUSION OF WOMEN AND MINORITIES .................................................................................................31 
6. 
STUDY DESIGN ...........................................................................................................................................32 
6.1 
SCREENING AND ENROLLMENT ...............................................................................................................32 
6.2 
STUDY TREATMENT .................................................................................................................................32 
 
Treatment setting ............................................................................................................................................... 32 
 
Treatment regimen and study scheme ................................................................................................................ 32 
 
Study treatment preparation .............................................................................................................................. 33 
 
Study treatment administration .......................................................................................................................... 33 
 
Pre and post-therapy intervention guidelines .................................................................................................... 34 
6.3 
DURATION OF PATIENT PARTICIPATION ..................................................................................................35 
6.4 
DOSE ESCALATION PHASE .......................................................................................................................35 
6.5 
EXPANSION PHASE ..................................................................................................................................37 
6.6 
STOPPING RULES .....................................................................................................................................38 
 
During dose escalation phase of the study ......................................................................................................... 38 
 
During expansion phase of the study ................................................................................................................. 39 
 
At any time during the study .............................................................................................................................. 39 
6.7 
PATIENT MONITORING, RESPONSE EVALUATION, DISEASE PROGRESSION & SURVIVAL FOLLOW-UP .....39 
 
Patient monitoring ............................................................................................................................................. 39 
 
Response evaluation ........................................................................................................................................... 39 
 
Disease progression and survival follow-up ...................................................................................................... 40 
6.8 
DOSE LIMITING TOXICITY ........................................................................................................................40 
 
Definition of dose limiting toxicity ..................................................................................................................... 40 

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Definition of maximum tolerated dose (MTD) ................................................................................................... 41 
 
Definition of minimal efficacious dose (MED) .................................................................................................. 41 
6.9 
STUDY TREATMENT DISCONTINUATION ..................................................................................................41 
 
Study treatment discontinuation events .............................................................................................................. 41 
 
Replacement of participants............................................................................................................................... 41 
 
Follow-ups after treatment discontinuation ....................................................................................................... 42 
 
Discontinuation due to SAEs or on-going study drug related AEs .......................................................... 42 
 
Discontinuation due to any other reasons ................................................................................................. 42 
6.10 
STUDY TREATMENT INTERRUPTION ........................................................................................................42 
 
Kidney dysfunction ........................................................................................................................................ 42 
 
Hematological dysfunction ............................................................................................................................ 42 
 
Hypotension .................................................................................................................................................. 42 
 
Allergic reactions and cytokine release syndrome ........................................................................................ 43 
 
Skin Rash in Association with Subcutaneous Administration of ALT-803 .................................................... 43 
6.11 
GENERAL SUPPORTIVE CARE GUIDELINES AND DRUG INTERACTION ......................................................43 
 
ALT-803 ........................................................................................................................................................ 43 
 
Hypotension and capillary leak syndrome ................................................................................................ 43 
 
Pulmonary dysfunction ............................................................................................................................. 44 
 
Impaired kidney and liver functions ......................................................................................................... 44 
 
Infection ................................................................................................................................................... 44 
 
Fever and chills ........................................................................................................................................ 44 
 
Gastritis .................................................................................................................................................... 44 
 
Diarrhea, nausea and vomiting ................................................................................................................. 44 
 
Pruritus and dermatitis .............................................................................................................................. 44 
 
Acidosis .................................................................................................................................................... 44 
 
Life-threatening toxicities .................................................................................................................... 45 
 
Other supportive care ........................................................................................................................... 45 
 
Drug interaction ................................................................................................................................... 45 
 
Rituximab ...................................................................................................................................................... 46 
7. 
STUDY DRUG: AVAILABILITY, ACCOUNTABILITY, PACKAGING & LABELING ...................46 
7.1 
ALT-803..................................................................................................................................................46 
 
Availability ......................................................................................................................................................... 46 
 
Accountability .................................................................................................................................................... 46 
 
Packaging .......................................................................................................................................................... 46 
 
Labeling ............................................................................................................................................................. 47 
7.2 
RITUXIMAB ..............................................................................................................................................47 
8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS ................................................................48 
8.1 
STUDY CALENDAR ...................................................................................................................................48 
8.2 
PROCEDURES AND TESTS .........................................................................................................................51 
 
Medical history & prior therapy ........................................................................................................................ 51 
 
Pregnancy test .................................................................................................................................................... 51 
 
Physical examination, PS assessment, B symptom assessment .......................................................................... 51 
 
Vital signs, body weight & height ...................................................................................................................... 51 
 
Cardiac assessment ............................................................................................................................................ 51 
 
Pulmonary function monitoring ......................................................................................................................... 51 
 
Clinical blood tests ............................................................................................................................................ 51 
 
Disease assessment tests and procedures .......................................................................................................... 52 
 
Adverse event assessment................................................................................................................................... 52 
 
Response assessment ..................................................................................................................................... 52 
 
Disease progression and survival follow-up ................................................................................................. 52 
 
Pharmacokinetic (PK) testing ....................................................................................................................... 52 
 
Biomarker assays .......................................................................................................................................... 53 
 
Immunogenicity tests - detection of anti-ALT-803 antibodies ....................................................................... 53 
 
Assays for immune cell number, phenotype, and function ............................................................................ 53 

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Fc receptor polymorphism testing ................................................................................................................. 54 
 
Evaluation of recurrent lymphoma mutations ............................................................................................... 54 
 
Lymph node biopsy evaluation ...................................................................................................................... 54 
9. 
MEASUREMENT OF EFFECT ..................................................................................................................55 
9.1 
MEASURABLE DISEASE ............................................................................................................................55 
9.2 
METHODOLOGY OF RESPONSE EVALUATION ..........................................................................................55 
9.3 
RESPONSE EVALUATION CRITERIA ..........................................................................................................55 
9.4 
DISEASE PROGRESSION EVALUATION CRITERIA ......................................................................................55 
10. 
STATISTICAL ANALYSIS .....................................................................................................................55 
10.1 
SAMPLE SIZE ............................................................................................................................................55 
10.2 
DATA COLLECTION ..................................................................................................................................57 
10.3 
DATA ANALYSIS ......................................................................................................................................57 
 
Analysis of safety ........................................................................................................................................... 57 
 
Analysis of response ...................................................................................................................................... 57 
 
Pharmacokinetics .......................................................................................................................................... 57 
11. 
REGULATORY AND REPORTING REQUIREMENTS ....................................................................59 
11.1 
ADVERSE EVENTS RECORDING, REPORTING AND COMMUNICATION .......................................................59 
11.2 
ADVERSE EVENT TERMINOLOGY AND DEFINITIONS ................................................................................59 
11.3 
ADVERSE EVENT REPORTING PROCEDURES ...........................................................................................60 
11.4 
ADVERSE EVENT EXPEDITED REPORTING GUIDELINES ..........................................................................61 
11.5 
SUBMISSION OF SERIOUS ADVERSE EVENT REPORTING ...........................................................................61 
11.6 
DATA REPORTING FORMS .......................................................................................................................61 
11.7 
REPORT /DATA SUBMISSION ADDRESS & CONTACT ................................................................................62 
11.8 
PATIENT RECORDS, QUALITY ASSURANCE, RECORDS RETENTION ..........................................................62 
11.9 
METHOD OF REVIEW ...............................................................................................................................62 
11.10 
SPECIAL REGULATORY CONSIDERATIONS ...........................................................................................63 
 
HIPAA ........................................................................................................................................................... 63 
 
Protocol amendments, informed consent, and IRB approval ........................................................................ 63 
12. 
CONFIDENTIALITY ...............................................................................................................................63 
13. 
ETHICAL STANDARDS & INVESTIGATOR OBLIGATIONS .......................................................63 
14. 
LIST OF EXPECTED ADVERSE EVENTS ..........................................................................................64 
15. 
CTCAE .......................................................................................................................................................66 
16. 
REFERENCES ..........................................................................................................................................67 
17. 
APPENDIX A: ECOG ..............................................................................................................................70 
18. 
APPENDIX B: NEW YORK HEART ASSOCIATION CLASSIFICATION ....................................70 
19. 
APPENDIX C: INJECTION SITE REACTION SUBJECT DIARY ..................................................71 
20. 
APPENDIX D: ETHICAL STANDARDS ..............................................................................................72 
21. 
APPENDIX E: INVESTIGATOR OBLIGATIONS ..............................................................................73 
22. 
APPENDIX F: CONTACT LIST - ALTOR ...........................................................................................77 
23. 
APPENDIX G: CONTACT LIST – DATA SAFETY MONITORING BOARD (DSMB) .................78 
24. 
APPENDIX H: CONTACT LIST - LABORATORIES ........................................................................78 

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SYNOPSIS 
Sponsor: 
Altor BioScience Corporation 
Protocol#: 
CA-ALT-803-02-14 
Study Drug Name: ALT-803 
Study Treatment 
Active agents: 
ALT-803, a “recombinant human super agonist interleukin-15 (IL-15) complex” 
(AKA, IL-15N72D:IL-15RαSu/IgG1 Fc complex) 
Study Type: 
Interventional 
Study Phase: 
1/2 
Protocol Title: 
A phase 1/2 study of ALT-803 in patients with relapse/refractory indolent B cell 
non-Hodgkin lymphoma in conjunction with rituximab 
Objectives: 
To evaluate the safety and tolerability of escalating doses, identify the Maximum 
Tolerated Dose level (MTD) or Minimum Efficacious Dose (MED) and designate a 
dose level for Phase 2 study (RP2D) of ALT-803 in combination with standard-of-
care rituximab therapy in patients with relapsed or refractory (rel/ref) indolent B cell 
non-Hodgkin lymphoma (iNHL). 
To estimate the anti-tumor activity of ALT-803 as measured by response rate, 
overall survival, progression free survival, time to response, duration of response, 
time to treatment failure, and time to subsequent treatment in patients with rel/ref 
iNHL.  
To evaluate the effect of ALT-803 on the peripheral absolute lymphocyte counts 
(ALC) and white blood cell (WBC) counts, the number, phenotype and repertoire 
of peripheral blood T (total and subsets) and NK cells. In addition, a subset of 
patients will be evaluated for changes in lymph node immune composition. 
To characterize the immunogenicity and pharmacokinetic profile of ALT-803, and 
assess the induced serum levels of chemokines and cytokines in rel/ref iNHL 
patients. 
To correlate clinical outcomes with fcgr3a polymorphisms and recurrent genomic 
mutations in rel/ref iNHL patients. 
Study Design: 
This is a Phase 1/2, open-label, multi-center, competitive enrollment and dose-
escalation study of ALT-803 in patients with rel/ref iNHL in conjunction with 
rituximab. 
The study includes a dose escalation phase to determine the MTD or MED using a 
3+3 dose escalation design and to designate a dose level for the Phase 2 expansion 
(RP2D) of ALT-803 in combination with rituximab and an expansion phase at the 
ALT-803 RP2D level using a Simon two-stage design. In Phase 1, seven cohorts 
will be evaluated. A step-down dose level (level -1) will be provided in the event of 
encountering DLT in two patients at the planned initial dose level.  
The study will be conducted in conformity with Good Clinical Practice (GCP).  

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Treatments:  
The study treatment plan for each enrolled patient includes one 4-week induction 
treatment cycle. During induction for cohort 1, 2 and 3, patients will receive up to 
four weekly doses of ALT-803 and rituximab (375 mg/m2) by intravenous injection 
(IV). During induction for cohort 4, 5, 6 and 7, patients will receive four weekly 
doses of ALT-803 by subcutaneous (SubQ) injection and rituximab (375 mg/m2) by 
IV. For the first dose of treatment in cohorts 1, 2, 3, and 4, patients will receive 
rituximab on day 1 followed by ALT-803 on day 2. For all other treatment days and 
for all treatment visits in cohort 5, 6 and 7, patients will receive ALT-803 and 
rituximab on the same day. Eligible patients will receive the consolidation treatment.  
Consolidation consists of treatment with ALT-803 at the same dose level and route 
of administration used in the induction plus rituximab (375 mg/m2) every 8 weeks 
(1 cycle = 8 weeks), for a total of 4 consolidation cycles.  
Treated patients will have at least two response evaluation visits. Patients who 
receive at least two study drug doses during the induction treatment period will be 
evaluated for disease response during week 11. Patients who have at least stable 
disease from the first anti-tumor evaluation and who do not experience or have 
sufficiently recovered from toxicities of the induction treatment cycle and who meet 
other criteria to continue study treatment will receive up to four consolidation 
treatment cycles, with a single treatment of ALT-803 plus rituximab, repeated every 
8 weeks for a total of 4 additional ALT-803 plus rituximab doses.  The ALT-803 
dose level and route of administration utilized in the induction cycle will be 
continued in consolidation, with reassessment for continued tumor response 
performed upon completion at week 40. 
The study treatment and response evaluation visits for cohorts 5, 6, and 7 are 
illustrated below (refer to study calendar for all study visits): 
Treatment Phase 
Induction 
REST 
Response 
Evaluation  
Consolidation 
Response 
Evaluation 
Treatment Week 
1 
2 
3 
4 
5-10 
11 
12 20 28 36 
40* 
Treatment Day 
1 
8 15 22 
29-70 
71-77 
78 134 190 246 
274-280 
ALT-803 1 
2 
3 
4 
Rest 
 
5 
6 
7 
8 
 
rituximab 1 
2 
3 
4 
 
5 
6 
7 
8 
 
Consolidation Cycle 
 
 
 
 
 
1 
2 
3 
4 
 
Response Evaluation 
 
 
 
 
X 
 
 
 
 
X 
*Long term follow-up after 40 weeks includes restaging every 6 months for 2 years, and 
then every 12 months for 5 years (until progression). 
Patients will be assessed for response using the 2007 IHP criteria 1 with progression 
assessment modifications to incorporate Indeterminate Response (IR) criteria2.  
Patients will be followed for progression, and at the time of progression there are no 
restrictions on further therapies.  
Enrolled patients will receive the study treatment at qualified cancer treatment 
centers with adequate diagnostic and treatment facilities to provide appropriate 
management of therapy and complications. ALT-803 will be administered by 
intravenous infusion for cohort 1, 2 and 3 into a central or peripheral vein under the 
supervision of a qualified physician experienced in the use of biologic anti-cancer 
agents. ALT-803 will be administered by subcutaneous injection for cohort 4, 5, 6 

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and 7 under the supervision of a qualified physician experienced in the use of 
biologic anti-cancer agents. Rituximab will be administered as described in the 
product package insert provided by the manufacturer. 
Dose Escalation 
Phase: 
A 3 + 3 design will be used for identifying a tolerable dose of ALT-803 for Phase 2 
studies by monitoring patients for DLTs to determine the MTD and for identifying 
an efficacious dose by monitoring patients’ ALC and WBC count to determine the 
MED during the DLT observation period. The dose escalation phase is concluded 
when either the MTD or the MED is determined. An ALT-803 dose level (RP2D) 
will then be designated for Phase 2 study. There are seven cohorts of ALT-803 and 
a step-down cohort (-1) with a lower dose level of ALT-803 in the event that 
unexpected toxicity is encountered at the initial dose level.   
Below are the planned dose levels and respective route of administration for the 
study drug during the dose escalation phase of the study.  
 
 
 
 
 
 
 
 
 
 
Dose limiting toxicity (DLT) is defined as follows: any toxicity that is not clearly 
unrelated to drug administration that is of Grade 3 and does not resolve to Grade 1 
or lower (or to Baseline or lower, if a patient enters the study with a toxicity that is 
Grade 2 or higher) within a week despite the use of medical intervention or that is 
of Grade 4, with exceptions described in the study protocol.  
The DLT Observation Period is defined as the duration of the induction treatment, 
days 1-28. 
Maximum Tolerated Dose level (MTD) is defined as a dose level at which <2 out 
of 6 patients experienced DLT and that is one level below a dose that was not 
tolerated or the maximum planned dose level if designated by the study committee. 
Minimal Efficacious Dose (MED) is defined as a dose level which produces an ALC 
≥25,000/µL sustained for 14 days or a total WBC ≥35,000/µL sustained for 14 days 
among 2/3 or 4/6 of patients. For safety, a dose level is also defined as “exceeding 
MED” with the occurrence of ALC ≥50,000/µL or WBC ≥60,000/µL sustained for 
14 days.  If patients have circulating malignant lymphocytes in the peripheral blood, 
Cohort 
ALT-803 Dose 
(µg/kg) 
Route 
Number of patients 
-1 
0.5 
IV 
3 to 6 
1 (initial) 
1 
IV 
3 to 6 
2 
3 
IV 
3 to 6 
3 
6 
IV 
3 to 6 
4 
6 
SubQ 
3 to 6 
5 
10 
SubQ 
3 to 6 
6 
15 
SubQ 
3 to 6 
7 
20 
SubQ 
3 to 6 

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these lymphoma cells will be excluded from the WBC and ALC calculations for 
MED. 
Expansion 
Phase 
Two expansion arms will be used to investigate indolent NHL patients with different 
expectations regarding response to single agent anti-CD20 mAB: anti-CD20 mAB-
refractory (CD20-R) and anti-CD20 mAB- sensitive (CD20-S).  For each arm, a 
two-stage expansion phase at the MTD or the MED level will be conducted using 
an optimal Simon’s two-stage design. The best objective overall response rate 
(ORR) is defined as complete response (CR) + partial response (PR) assessed at the 
week 11 or 40 response assessment, or during the 2 year follow-up period.  For 
CD20-R patients, a lack of efficacy for ORR of 10% will be used, with an ORR > 
35% constituting a clinically interesting result.  For CD20-S patients, a lack of 
efficacy for ORR of 40% will be used, with a clinically interesting ORR > 60%.  
Each expansion arm will be analyzed independently for preliminary efficacy. 
Stopping Rules: 
Patient enrollment will be temporarily suspended based on occurrence of any of the 
following events, and the study committee, including the sponsor, the Data Safety 
Monitoring Board and principal investigators will meet to discuss how to proceed 
with future patient enrollment in the study. 
During the dose escalation phase of the study,  
• If the maximum planned dose level has been reached, but neither the MTD nor 
MED can be determined. 
• If de-escalation occurs and the step-down dose level cannot be designated as the 
MTD or MED.  
Any time during the expansion phase of the study,  
• More than 33% of patients experience a possible, probable or definite study drug 
related DLT. 
• Favorable anti-tumor response data collected from enrolled patients. 
At any time during the study, the study committee may meet to discuss how to 
proceed with the study and may make any or all of the following recommendations 
for further patient enrollment:  
• Downward adjust the study drug dose. 
• Adjust the study drug dosing schedule. 
• Recommend more effective pre-therapy, intra-therapy and post-therapy side 
effect mitigation interventions. 
• Correct protocol technical errors that caused unnecessary dose omissions or 
premature treatment discontinuations. After correction of protocol errors, the 
DSMB may meet to re-evaluate the safety profile of the study treatment and 
recommend how to proceed with the study, if necessary. 
Evaluations: 
Patients will be evaluated for clinical toxicities during the treatment. The disease 
response will be evaluated at weeks 11 and 40 from the start of study treatment, and 

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every 6 months for 2 years thereafter (starting from Month-18). After this two year 
period the institutional standards for disease assessment will be followed, with at 
least annual disease assessments, for up to 5 years. Prior to and during the treatment 
period, patients’ blood and serum samples will be collected to assess the 
pharmacokinetic profile and immunogenicity of the study drug, as well as for 
immunomodulation, and fcgr3a polymorphisms.  Disease containing biopsies and 
an oral sample will be used for recurrent lymphoma gene mutation analysis.  All 
patients who receive at least 2 doses of the study drug ALT-803 will be included in 
the anti-tumor response evaluation. 
Population: 
Patients of 18 years of age and above with relapsed or refractory CD20+ indolent 
NHL (follicular lymphoma (FL), marginal zone lymphoma (MZL), small 
lymphocytic lymphoma (SLL), and lymphoplasmacytic lymphoma (LPL)). Anti-
CD20 mAb-refractory (CD20-R) patients are defined as those that progress on Anti-
CD20 mAb therapy or within 6 months of their last dose of Anti-CD20 mAb.  For 
CD20-R patients, a biopsy to confirm CD20 expression is required.  Patients also 
need to have adequate cardiac, pulmonary, liver and kidney functions and have an 
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.   
Sample Size: 
A total of up to 42 assessable patients will be accrued to the dose escalation phase of 
the study (Phase 1). Anticipated enrollment to this phase is 24 patients. For the CD20-
S patient arm, a total of 16 patients will be enrolled at the MTD/MED dose in the first 
stage and 30 patients in the second stage of a 2-stage Phase 2 cohort (total for CD20-
S expansion cohort 46).  For the CD20-R, a total of 8 patients will be enrolled in the 
first stage and an additional 14 patients in the second stage of a 2-stage Phase 2 study 
(total for CD20-R expansion cohort 22).  Thus, enrollment of evaluable patients on 
the Phase 1 portion, and the first stage of both expansion cohorts (including 6 patients 
of the MTD/MED cohort) is expected to be 42 patients, with the maximum number 
of 60 patients.  Assuming a 5% frequency of non-evaluable patients, the phase 1 and 
the first stage of both expansion cohorts is estimated at 45 patients.   
Primary 
Endpoints 
For Phase 1 only 
(1) Determination of the MTD or MED of ALT-803 and designation of the 
recommended dose level (RP2D) for Phase 2 study of ALT-803 in conjunction 
with rituximab in patients with rel/ref iNHL. 
For Phase 1 & 2 
(2) Safety profile of ALT-803 plus rituximab in treated patients. 
 
(3) Overall response rate (CR+PR) of treated patients.  
Secondary  
Endpoints  
 
(1) Evaluate overall survival, progression free survival, time to response, duration 
of response, time to treatment failure, and time to subsequent treatment. 
 
(2) Evaluation of the effect of ALT-803 on the peripheral ALC and WBC counts, 
the number, phenotype and repertoire of peripheral blood NK cells and T (total 
and subsets), and NK cell function.  In addition, a subset of patients will be 
evaluated for changes in lymph node immune composition. 

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(3) Characterization of the immunogenicity and pharmacokinetic profile of ALT-
803, and assess the serum levels of chemokines and cytokines in treated 
patients. 
 
(4) Correlation of fcgr3a polymorphism status and recurrent lymphoma mutations 
with clinical outcomes of the study. 
Pharmacokinetics 
& Biomarkers: 
Fresh blood samples will be collected to assess immune cell number, phenotype, 
repertoire and function prior to and during the study treatment. Serum samples will 
be collected for pharmacokinetics (PK) and immunogenicity of the study drug ALT-
803. The same serum samples collected for PK analysis will be used to assess the 
serum levels including but not limited to IL-2, IL-4, IL-6, IL-10, IFN-γ, MCP-1 and 
TNF-α. Non-compartmental and compartmental PK analyses will be conducted. 
Baseline peripheral blood will be used for fcgr3a polymorphism testing, and a 
baseline tumor sample and oral sample will be used for lymphoma mutation analysis 
using next-generation sequencing. Lymph node biopsies will be performed to 
determine the impact of study treatment on the immune cell composition within the 
tumor microenvironment. 
Monitoring Tests: Blood samples for standard chemistry and CBC with differential will be obtained at 
screening, on each study treatment day, and at response evaluation visits. Blood 
samples for immunogenicity testing of anti-ALT-803 antibodies will be collected 
prior to dosing on the first and fourth ALT-803 treatment visit, and at the response 
evaluation visit during week 11.  
Response 
Assessment: 
There are at least two response assessments for treated patients: the first assessment 
during week 11 (following induction) and the second assessment during week 40 
(following consolidation) from the start of study treatment. After completion of the 
induction cycle of study treatment, patients who have received at least 2 doses of 
ALT-803 will have the first response assessment. After completion of four 
additional consolidation study treatments patients will have a second response 
assessment. If patients are unable to continue study therapy for all 4 consolidation 
cycles due to an adverse event, disease assessments will be performed at the time of 
going off study.  In non-progressing patients, after completion of consolidation, 
disease assessments will be performed every 6 months for 2 years (starting at 
Month-18), and then per institutional guidelines, at least annually, for up to 5 years.  
If a focused physical examination or patient symptoms raise the concern for 
progression, a complete response assessment should be performed at that time.  
Response assessments will be carried out according to the 2007 IHP criteria for 
response assessment of lymphoma 1 with progression assessment modifications to 
incorporate Indeterminate Response (IR) criteria2. Baseline evaluations (except for 
baseline imaging and bone marrow biopsy) should be performed up to 28 days 
before study treatment start unless otherwise specified in the protocol.  
Progression & 
Survival 
Assessment: 
Progression-free survival, overall survival, and duration of response of all treated 
patients will be assessed at least every three months during years 1 and 2, every 4 

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months during year 3, and then every 6 months (+/- 2 months) during years 4 and 5 
from the start of study treatment, or through the point designated as the end of the 
study follow up (5 years). 
Adverse Events: 
All patients will be monitored and evaluated for clinical toxicities during the 
treatment period and queried at each follow-up visit for Adverse Events (AEs). 
Patients may volunteer information concerning AEs. All adverse events will be 
graded by using the NCI Common Terminology Criteria for Adverse Events version 
4.0 (CTCAE v4.0), and logged in the patient Case Report Form. The study centers 
should report all Serious Adverse Events (SAEs) and all events that trigger patient’s 
study treatment discontinuation to the sponsor via phone, fax or email (or a 
combination) no more than 24 hours after learning of the event. The sponsor will 
use the information to manage and coordinate the dose escalation, cohort expansion 
and patient enrollment. The sponsor will then inform all of the participating clinical 
sites of the current dose level and the number of patients to be enrolled at that level, 
or of any patient enrollment suspension via phone, fax or email within 24 hours of 
learning of the event. The study centers should report all other adverse events to the 
sponsor following the guidelines defined in the study protocol. All study drug 
related AEs that are both serious and unexpected will be reported to the FDA in an 
expedited manner in accordance with 21 CFR §312.32. 
Statistical Plan: 
For each cohort, all AEs will be tabulated and examined and all safety, 
pharmacokinetic, biomarker and tumor response data will be evaluated. For 
estimation of duration of response and progression free survival, the Kaplan-Meier 
method will be used. P-values of ≤0.05 (two-sided) will be considered to indicate 
statistical significance.  
 
 

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     CA-ALT-803-02-14 Version# 04 
IND 114006 SERIAL# 0011 
 
          
 
 
 
        
 
 
 
                  
                               February 6, 2017 
Page 48 of 78 
8. 
STUDY CALENDAR, CLINICAL PROCEDURES & TESTS 
8.1 
Study calendar  
*Note: Refer to the next page for all footers that correlate with this table. 
 
 
TESTS & PROCEDURES 
SCREEN/ 
BASELINE1 
INDUCTION 
REST  
RESPONSE 
EVALUATION 
CONSOLIDATION 
RESPONSE 
EVALUATION 
DISEASE ASSESSMENT & FOLLOW-UPS 
Study Month  
 
1 
2-3 
3 
3-9 
10 
12 15 18 21 24 28 32 36 42 48 54 60 
Study Week  
 
1 
2 
3 
4 
5-10 
11 
12 
20 28 36 
40 
 
Study Day  
 
1 
2 
5 
8 
15 22 23 26 
29-70 
71-77 
78 79 82 134 190 246 
274-280 
 
Tolerance Window 
 
+/- 2 days 
 
+/- 7 days 
+/- 7 days 
+/- 7 days 
+/- 2 weeks 
Medical history 
X 
 
 
 
 
 
 
 
 
R 
 
E 
 
S 
 
T 
 
 
P 
 
E 
 
R 
 
I 
 
O 
 
D 
 
 
 
 
 
 
 
 
 
Serum pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam (PE) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Focused PE, ECOG PS, B symptom assessment 
 
X24 
 
 
 
 
 
 
 
 
X 
 
 
X X X 
 
Vital signs, Weight, Height3, Cardiac & Lung 
function monitoring  
X 
X 
 
 
X X X 
 
 
X 
X 
 
 
X X X 
X 
Concurrent medication 
X 
X 
 
 
X X X 
 
 
X 
X 
 
 
X X X 
X 
Adverse event assessment4, 22 
X 
X 
 
 
X X X 
 
 
X 
X 
 
 
X X X 
X 
Injection Site Reaction Subject Diary25 
 
X 
 
 
X X X 
 
 
 
X 
 
 
X X X 
 
CBC with Differential5 
X 
X X X19 X X X X X20 
X 
X X X21 X X X 
X 
Blood Chemistry with LDH5 , B2M23 
X 
X 
 
 
X X X 
 
 
X 
X 
 
 
X X X 
X 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFT only when clinically indicated 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Response assessment6 
  
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Contrast CT of NCAP or PET-CT 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Bone marrow biopsy7 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Focused PE, ECOG PS, B symptom & AE 
X17  
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Disease and survival follow-up/post therapies8 
 
 
 
X X X X X X X X X16 X16 X16 X16 
Lymph node biopsy18, 26 
X 
 
 
 
 
 
 
 
X20 
 
 
 
 
 
 
 
 
Immune cell number, phenotype & function9, 14, 26 
 
X10 X X19 X10 X10 X10 X X20 
 
X11 X X21  
 
 
Polymorphism  (SNP) testing14, 26 
X10   
 
 
 
 
 
 
 
 
 
 
 
 
 
PK, IL-2, IL-4, IL-6, IL-10, IFN-γ, MCP-1, TNF-
α12,14, 26 
X12 X X19 X10 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity tests13, 14, 26 
 
X13  
 
 
 
X10 
 
 
X 
 
 
 
 
 
 
Recurrent mutation evaluation15, 26 
 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rituximab
 
r1 
 
 
r2 r3 r4 
 
 
 
r5 
 
 
r6 r7 r8 
Study drug (ALT-803)
 
a1 
 
 
a2 a3 a4 
 
 
a5 
 
 
a6 a7 a8