A First-in-Human Phase 1 Study of NL-201 Monotherapy and in Combination With Pembrolizumab in Patients With Relapsed or Refractory Cancer
Phase: PHASE1
Conditions: Solid Tumor, Advanced Solid Tumor
Sponsor: Neurogene Inc.

Compound: NL-201 
Protocol: NL201-101 
Protocol Date and Version: 08 September 2022; Amendment 6.0 
CONFIDENTIAL 
Page 1 of 151 
TITLE PAGE 
Protocol Title: 
A First-in-Human Phase 1 Study of NL-201 Monotherapy and 
in Combination With Pembrolizumab in Patients With 
Relapsed or Refractory Cancer 
Protocol Number: 
NL201-101 
Compound: 
NL-201 
Study Phase: 
1 
Short Title: 
A Phase 1 Study of NL-201 Monotherapy and Combination 
With Pembrolizumab in Patients With Relapsed or Refractory 
Cancer 
Sponsor  
Sponsor Name: 
Neoleukin Therapeutics, Inc. 
Address: 
188 E. Blaine Street 
Suite 450 
Seattle, WA 98102 
Regulatory Agency 
Identifier Number(s) 
IND: 144891 
NCT: 04659629 
Protocol Date: 
Document Version 
Date 
Original (v 1.0) 
29 July 2020 
Amendment 1 (v 2.0) 
26 August 2020 
Amendment 1.1 (v 2.1) 
04 December 2020 
Amendment 2.0 
23 February 2021 
Amendment 3.0 
26 August 2021 
Amendment 4.0 
03 December 2021 
Amendment 5.0 
26 January 2022 
Amendment 6.0 
08 September 2022 
CONFIDENTIALITY NOTICE 
The information contained in this protocol and all other information relevant to NL-201 are the 
confidential and proprietary information of Neoleukin and, except as may be required by federal, 
state, or local laws or regulation, may not be disclosed to others without the prior written 
permission of Neoleukin. 

Compound: NL-201 
Neoleukin Therapeutics, Inc. 
Protocol: NL201-101 
Protocol Date and Version: 08 September 2022; Amendment 6.0 
 
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SPONSOR SIGNATORY: 
NL201-101: A First-in-Human Phase 1 Study of NL-201 Monotherapy and in Combination With 
Pembrolizumab in Patients With Relapsed or Refractory Cancer 
I, the undersigned, have approved Amendment 6.0 of the clinical study protocol with the date of 
08 September 2022. 
Name and Title 
Signature and Date 
 
  
 
 
 
 
 
 
 
 

Compound: NL-201 
Neoleukin Therapeutics, Inc. 
Protocol: NL201-101 
Protocol Date and Version: 08 September 2022; Amendment 6.0 
 
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INVESTIGATOR AGREEMENT 
NL201-101: A First-in-Human Phase 1 Study of NL-201 Monotherapy and in Combination With 
Pembrolizumab in Patients With Relapsed or Refractory Cancer 
I have read the protocol, including all appendices, and I agree that it contains all the necessary 
information for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein, in compliance with current Good Clinical Practice (GCP) standards as defined 
by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) Guideline for GCP, all applicable national, state, and local laws and 
regulations, and the applicable Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) and other institutional requirements.  
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Neoleukin or specified designees. I will 
discuss the material with them to ensure that they are fully informed about NL-201, understand 
this study, and are able to comply. 
______________________________ 
 
__________________________ 
Principal Investigator Name (printed) 
 
Signature 
______________________________ 
Date 
 
 

Compound: NL-201 
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Protocol: NL201-101 
Protocol Date and Version: 08 September 2022; Amendment 6.0 
 
CONFIDENTIAL 
 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................8 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................9 
1 
PROTOCOL SUMMARY ......................................................................................................14 
1.1 
Synopsis .............................................................................................................................14 
1.2 
Schema ...............................................................................................................................23 
1.3 
Schedule of Events .............................................................................................................27 
2 
INTRODUCTION ..................................................................................................................47 
2.1 
Study Rationale ..................................................................................................................47 
2.2 
Background ........................................................................................................................47 
2.2.1 
Disease Background.....................................................................................................47 
2.2.2 
Neoleukin Investigational Product Background: NL-201 ...........................................48 
2.2.3 
Non-Neoleukin Investigational Product: Pembrolizumab ...........................................49 
2.3 
Benefit/Risk Assessment ...................................................................................................51 
2.3.1 
Risk Assessment ..........................................................................................................52 
2.3.2 
Benefit Assessment ......................................................................................................57 
2.3.3 
Overall Benefit: Risk Conclusion ................................................................................57 
3 
OBJECTIVES AND ENDPOINTS ........................................................................................58 
4 
STUDY DESIGN ...................................................................................................................59 
4.1 
Overall Design ...................................................................................................................59 
4.1.1 
Study Duration for Patients ..........................................................................................63 
4.1.2 
Number of Patients ......................................................................................................63 
4.1.3 
Replacement of Patients ...............................................................................................63 
4.1.4 
Number of Sites ...........................................................................................................63 
4.2 
Scientific Rationale for Study Design ................................................................................64 
4.3 
Justification for Dose .........................................................................................................64 
4.4 
End of Study ......................................................................................................................66 
4.5 
Patient Input on Study Design ...........................................................................................66 
5 
STUDY POPULATION .........................................................................................................66 
5.1 
Inclusion Criteria ...............................................................................................................67 
5.2 
Exclusion Criteria ..............................................................................................................69 
5.3 
Screen Failures ...................................................................................................................71 
6 
STUDY TREATMENT ..........................................................................................................71 
6.1 
Study Drug(s) Administered ..............................................................................................72 
6.1.1 
Investigational Products ...............................................................................................72 
6.1.2 
Preparation/Handling/Storage/Accountability .............................................................74 

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6.1.3 
Other Protocol-Required Intervention .........................................................................74 
6.1.4 
Cytokine Release Syndrome Management Guidance ..................................................75 
6.1.5 
Excluded Treatments, Medical Devices, and/or Procedures During Study 
Period ..........................................................................................................................75 
6.2 
Dose Modification .............................................................................................................76 
6.2.1 
Dose-Cohort Study Escalation, De-Escalation, and Stopping Rules ...........................76 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, Permanent 
Discontinuation ...........................................................................................................83 
6.3 
Measures to Minimize Bias: Randomization and Blinding ...............................................91 
6.3.1 
Randomization .............................................................................................................91 
6.3.2 
Blinding........................................................................................................................92 
6.4 
Study Drug Compliance .....................................................................................................92 
6.5 
Concomitant Therapy.........................................................................................................92 
6.6 
Intervention After the End of the Study .............................................................................93 
7 
DISCONTINUATION OF STUDY TREATMENT AND PATIENT 
DISCONTINUATION/WITHDRAWAL ..............................................................................93 
7.1 
Discontinuation of Study Treatment ..................................................................................93 
7.2 
Discontinuation/Withdrawal From the Study ....................................................................94 
7.3 
Lost to Follow-Up ..............................................................................................................94 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................95 
8.1 
General Study Periods........................................................................................................96 
8.1.1 
Screening and Enrollment ............................................................................................96 
8.1.2 
Treatment Period ..........................................................................................................96 
8.1.3 
End of Treatment .........................................................................................................96 
8.1.4 
Radiological Follow-Up...............................................................................................97 
8.1.5 
Long-Term Follow-Up.................................................................................................97 
8.2 
Efficacy Assessments .........................................................................................................97 
8.2.1 
Assessment of Clinical Outcome: Imaging ..................................................................97 
8.3 
Safety Assessments ............................................................................................................98 
8.3.1 
Physical Examinations .................................................................................................99 
8.3.2 
Vital Signs ....................................................................................................................99 
8.3.3 
Electrocardiograms ......................................................................................................99 
8.3.4 
Clinical Safety Laboratory Assessments .....................................................................99 
8.3.5 
Pregnancy Testing ......................................................................................................100 
8.3.6 
Vital Status .................................................................................................................100 
8.4 
Adverse Events and Serious Adverse Events ..................................................................100 
8.4.1 
Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events Information .....................................................................................100 
8.4.2 
Events of Clinical Interest (ECI)................................................................................101 
8.4.3 
Method of Detecting Adverse Events and Serious Adverse Events ..........................101 

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8.4.4 
Follow-up of Adverse Events and Serious Adverse Events ......................................101 
8.4.5 
Regulatory Reporting Requirements for Serious Adverse Events .............................102 
8.4.6 
Pregnancy ...................................................................................................................102 
8.5 
Reporting and Treatment of Overdose .............................................................................102 
8.6 
Pharmacokinetics .............................................................................................................103 
8.7 
Pharmacodynamics/Biomarkers ......................................................................................103 
8.7.1 
Exploratory Assessment of NL-201-Dependent Effects in Blood .............................103 
8.7.2 
Exploratory Assessment of NL-201-Dependent Effects on the Tumor 
Microenvironment (Patients who Have Consented to Tumor Biopsy 
Collection Part 1, Part 2 and Part 4) .........................................................................103 
8.7.3 
PD-L1 Expression (Part 4 Only) ................................................................................104 
8.7.4 
Tumor Mutational Burden Determination (Part 4 Only) ...........................................104 
8.8 
Immunogenicity Assessments ..........................................................................................104 
9 
STATISTICAL CONSIDERATIONS .................................................................................105 
9.1 
Statistical Hypothesis .......................................................................................................105 
9.2 
Sample Size Determination ..............................................................................................105 
9.3 
Populations for Analyses .................................................................................................106 
9.4 
Statistical Analyses ..........................................................................................................107 
9.4.1 
General Considerations ..............................................................................................107 
9.4.2 
Determination of MTD in Part 1 and Part 3 ..............................................................107 
9.4.3 
Assessment of Preliminary Efficacy in Part 2 and Part 4 ..........................................107 
9.4.4 
Pharmacokinetics .......................................................................................................107 
9.4.5 
Exploratory Evaluations .............................................................................................108 
9.4.6 
Safety Data .................................................................................................................108 
10  SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......109 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ..........................109 
10.1.1 
Regulatory and Ethical Considerations ......................................................................109 
10.1.2 
Financial Disclosure ...................................................................................................109 
10.1.3 
Informed Consent Process .........................................................................................110 
10.1.4 
Data Protection...........................................................................................................110 
10.1.5 
Confidentiality ...........................................................................................................111 
10.1.6 
Retention of Source Data and Samples ......................................................................111 
10.1.7 
Dissemination of Clinical Study Data ........................................................................111 
10.1.8 
Data Quality Assurance .............................................................................................111 
10.1.9 
Source Documents .....................................................................................................112 
10.1.10 
Study and Site Start and Closure ...............................................................................112 
10.1.11 
Publication Policy ......................................................................................................113 
10.2 
Appendix 2: Clinical Laboratory Tests ............................................................................114 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .........................................................................115 

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10.3.1 
Definition of Adverse Event ......................................................................................115 
10.3.2 
Definition of Serious Adverse Event .........................................................................116 
10.3.3 
Recording and Follow-Up of Adverse Events and/or Serious Adverse Events .........117 
10.3.4 
Reporting of Serious Adverse Events ........................................................................119 
10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ...........120 
10.5 
Appendix 5: Liver Safety: Suggested Actions and Follow-Up Assessments and 
Study Drug Rechallenge Guidelines .............................................................................124 
10.6 
Appendix 6: Tumor Assessments ....................................................................................127 
10.6.1 
Methods of Lesion Measurement...............................................................................127 
10.6.2 
Tumor Assessments According to RECIST 1.1 ........................................................127 
10.6.3 
iRECIST Response Assessment ................................................................................132 
11  REFERENCES .....................................................................................................................136 
12  SUMMARY OF CHANGES ................................................................................................139 
 
 
LIST OF TABLES 
Table 1 
Schedule of Events – Schedule A (Q3W Dosing) .................................................28 
Table 2 
Schedule of Events – Schedule B (D1 & D8 Dosing) ...........................................32 
Table 3 
Schedule of Events – Schedule A (Q3W Dosing) if Step-Dosing is Implemented
................................................................................................................................37 
Table 4 
Schedule of Events – Schedule B (D1 & D8 Dosing) if Step-Dosing is 
Implemented ..........................................................................................................42 
Table 5 
Risk Assessment ....................................................................................................52 
Table 6 
Potential Risks for Pembrolizumab .......................................................................56 
Table 7 
Investigational Products: NL-201 and Pembrolizumab .........................................72 
Table 8 
Sample Dose Escalation Scheme for Part 1 IV ......................................................77 
Table 9 
Sample Dose Escalation Scheme for Part 3 ...........................................................79 
Table 10 
Step-Dosing Guidance ...........................................................................................82 
Table 11 
Dose Delaya and Modification Guidance for IV Administration ..........................84 
Table 12 
Dose Modification and Toxicity Management Guidelines for Immune-Related 
Adverse Events Associated with Pembrolizumab .................................................87 
Table 13 
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
................................................................................................................................90 
Table 14 
Observed ORR and 95% Confidence Interval with a Sample Size of 30 ............106 
Table 15 
Populations for Analyses .....................................................................................106 
Table 16 
Protocol-Required Laboratory Assessments ........................................................114 
Table 17 
Assessment of Response According to RECIST 1.1 ...........................................129 
Table 18 
Overall Lesion Response at Each Assessment: Patients With Target Lesions 
(± Non-Target Lesions) ........................................................................................131 

Compound: NL-201 
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Protocol: NL201-101 
Protocol Date and Version: 08 September 2022; Amendment 6.0 
 
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Table 19 
Overall Lesion Response at Each Assessment: Patients With Non-Target Lesions 
Only......................................................................................................................131 
Table 20 
Time Point (TP) iResponse ..................................................................................134 
Table 21 
iRECIST Best Overall Response (iBOR) ............................................................135 
 
 
LIST OF FIGURES 
Figure 1 
Part 1 IV Study Schemaa ........................................................................................23 
Figure 2 
Part 2 Study Schema ..............................................................................................24 
Figure 3 
Part 3 Study Schema (Dose Escalation of NL-201 in Combination with 
Pembrolizumab)a ....................................................................................................25 
Figure 4 
Part 4 Study Schema (Dose Expansion of NL-201 in Combination with 
Pembrolizumab) .....................................................................................................26 
Figure 5 
mTPI Design Matrix for Part 1 ..............................................................................76 
Figure 6 
mTPI Design Matrix for Part 3 ..............................................................................78 
 
 
 
 

Compound: NL-201 
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Protocol: NL201-101 
Protocol Date and Version: 08 September 2022; Amendment 6.0 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
antidrug antibody 
AE 
adverse event 
AIH 
autoimmune hepatitis 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the serum concentration time curve 
AUCinf 
area under the serum concentration time curve from time 0 to 
infinity 
AUCt 
area under the serum concentration time curve from time 0 to time t 
BUN 
blood urea nitrogen 
CAR-T 
chimeric antigen receptor T-cell 
CD 
cluster of differentiation 
CFR 
Code of Federal Regulation 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration  
CL 
clearance 
Cmax 
maximum observed serum concentration 
CNS 
central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
CPI 
checkpoint inhibitor 
CPK 
creatine phosphokinase 
CR 
complete response 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTD 
cohort target dose 
CTFG 
Clinical Trial Facilitation Group 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
D 
day 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 

Compound: NL-201 
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Protocol: NL201-101 
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Abbreviation 
Definition 
DRESS 
drug reaction with eosinophilia and systemic symptoms 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECI 
events of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
eGFR 
estimated glomerular filtration rate 
EOI 
end of infusion 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed, paraffin embedded 
FoxP3 
forkhead box P3 
FSH 
follicle-stimulating hormone  
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLDH 
glutamate dehydrogenase 
GLP 
Good Laboratory Practice 
HIV 
human immunodeficiency virus 
HNSCC 
head and neck squamous cell carcinoma 
HRT 
hormonal replacement therapy  
HTID 
highest tolerated initial dose 
iBOR 
immune best overall response 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
ICI 
immune checkpoint inhibitors 
iCPD 
immune confirmed progressive disease 
iCR 
immune complete response 
ICU 
intensive care unit 
IEC 
Independent Ethics Committee 
IFN- γ 
interferon gamma 
Ig 
immunoglobulin 
IgG4 
immunoglobulin G4 
IHC 
immunohistochemistry 
IL 
interleukin 

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Abbreviation 
Definition 
INR 
international normalized ratio 
iPR 
immune partial response 
irAE 
immune-related Adverse Event 
IRB 
Institutional Review Board 
iRECIST 
Response Evaluation Criteria in Solid Tumors for use in cancer 
immunotherapy trials 
iSD 
immune stable disease 
iUPD 
immune unconfirmed progressive disease 
 
 
IV 
intravenous 
IVF 
intravenous fluids 
LTFU 
long-term follow-up 
mAB 
monoclonal antibody 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MRI 
magnetic resonance imaging 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MTD 
maximum tolerated dose 
mTPI 
modified toxicity probability interval 
MUGA 
multi-gated acquisition 
NE 
not evaluable 
NK 
natural killer 
NL 
new lesion  
NLNT 
new lesion-non-target 
NLT 
new lesion-target 
NOAEL 
no observed adverse effect level 
NSAID 
non-steroidal anti-inflammatory drugs 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PAD 
pharmacologically active dose 
PBMC 
peripheral blood mononuclear cell 
PBPK 
physiologically-based PK 
PD 
progressive disease 

Compound: NL-201 
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Abbreviation 
Definition 
Vd 
volume of distribution 
WBC 
white blood cell 
WNL 
within normal limits 
WOCBP 
woman of childbearing potential 
 

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Protocol: NL201-101 
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OBJECTIVES 
ENDPOINTS 
 Evaluation of exploratory biomarkers including 
pharmacodynamic and potential patient selection 
biomarkers 
 Programmed cell death ligand 1 (PD-L1) 
expression in tumors (as available) 
 Tumor microenvironment (TME) immune score (as 
available) 
 Estimate additional measures of antitumor activity 
of NL-201 in combination with pembrolizumab per 
RECIST 1.1 and/or iRECIST criteria 
 OS 
 Clinical benefit rate 
Overall Design: 
This is a Phase 1 first-in-human, open-label, dose escalation and cohort expansion study of 
NL-201 that will be conducted in 4 parts.  
Parts 1 and 2 (NL-201 Monotherapy) 
Part 1 will be an adaptive modified toxicity probability interval (mTPI) design dose escalation 
study in adult patients with advanced solid tumors to determine the safety profile and the 
recommended phase 2 dose (RP2D) and treatment schedule of NL-201 as monotherapy. Part 1 
will include intravenous (IV) (Schedule A and B), each with up to approximately 50 patients. In 
addition, there will be backfill cohorts (up to approximately 12 patients in total) , at certain 
DMC-cleared dose levels and schedules, to collect, pharmacokinetic, pharmacodynamic and 
response data in certain tumor types or to explore additional pre-medication regimens (eg, 
steroids). The decision to enroll patients into backfill cohorts and to define the patients to be 
enrolled will be made by the Sponsor. Part 1 will enroll up to approximately 115 adult patients in 
total. Part 2 will be a Simon 2-stage dose expansion cohort study in patients in 2 indications (up 
to n = 30 per cohort) with exploratory paired biopsies to estimate the tolerability and antitumor 
activity of NL-201 as monotherapy in these indications. 
Parts 3 and 4 (NL-201 in Combination with Pembrolizumab) 
Part 3 will be an adaptive mTPI design dose escalation study in up to 42 adult patients with 
advanced solid tumors to determine the safety profile, RP2D and treatment schedule of NL-201 
in combination with pembrolizumab. Part 4 will be a dose expansion phase in 3 cohorts (up to 
n = 30 per cohort) to confirm the combination RP2D and obtain additional estimation of 
pharmacokinetics (PK), pharmacodynamics (PDn), and antitumor activity. 
All Parts 
Patients will enter the screening period, up to 28 days prior to Cycle 1 Day 1 of treatment. PK, 
PDn, and exploratory tumor biopsy samples will be obtained per the study Schedule of Events 
(see Section 1.3). Tumor response to treatment will be assessed by radiographic evaluation per 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and RECIST for use in cancer 
immunotherapy trials (iRECIST) every 6 weeks for 12 weeks, and every 12 weeks thereafter 
while on study treatment. Patients may continue on treatment until unacceptable toxicity, disease 
progression per iRECIST with either confirmation or clinical decline, completion of 
35 administrations (approximately 2 years) with pembrolizumab (for Parts 3 and 4), withdrawal 

Compound: NL-201 
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Protocol: NL201-101 
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of consent, patient or physician decision, study termination, or death. Patients with progressive 
disease who are considered to be clinically stable and whose progression is considered to be 
minimal are required to have a confirmatory scan and tumor evaluation after the initial 
determination of progression. Patients with progressive disease per RECIST criteria may 
continue on treatment past progression if, in the opinion of the Investigator, the patient is 
considered to be clinically stable or has experienced clinical benefit from NL-201 alone or in 
combination with pembrolizumab (see Section 6.1.1.1). 
Upon permanent discontinuation of study drug for any reason, an end of treatment visit should be 
scheduled as soon as possible but within 30 days following cessation of study treatment or before 
patient initiates new anti-cancer therapy, whichever is earlier. Adverse events (AEs) and 
concomitant medication will be followed up to 30 days after last dose of NL-201. 
For Parts 3 and 4, all AEs will be followed up to 30 days following cessation of study treatment 
and all SAEs will be followed up to 90 days following cessation of study treatment, or 30 days 
following cessation of study treatment if the participant initiates new anti-cancer therapy, 
whichever is earlier. Patients who discontinue from treatment due to progressive disease based 
on RECIST or iRECIST will enter long-term follow-up to assess survival. Patients in Parts 2 and 
4 will also need to record any subsequent anti-cancer therapies during long-term follow-up.  
For Parts 2 and 4, patients who discontinue from treatment due to reasons other than progressive 
disease based on RECIST or iRECIST will be followed in radiologic follow-up for documented 
progressive disease by RECIST 1.1 and will enter long-term follow-up. If subsequent anti-cancer 
therapies are initiated during the period of time between discontinuation of treatment and 
progressive disease documentation, the patient will no longer be radiologically assessed for 
progression and will enter long-term follow-up. 
Patients in long-term follow-up will be followed until death, withdrawal of consent, lost to 
follow-up, or study closure, whichever occurs first, for a maximum of 2 years after the end of 
treatment. 
Part 1: Intrasubject Dose Escalation 
Intrasubject dose escalation is permitted with Medical Monitor approval. In cases where no 
treatment-related Grade 2 or higher adverse events have been observed, dose escalation to a 
higher dose will be permitted provided that the dose level has been cleared by the DMC.   
Part 1: Optional Tumor Biopsy 
During dose escalation, paired biopsies are optional. For patients who consent to have paired 
biopsies, the same lesion will be sampled within 28 days prior to the first dose of NL-201 (ie, 
pre-treatment biopsy) and on study (ie, post-treatment biopsy). The post-treatment, second 
biopsy will occur between 5 to 9 days after receiving dose at Cycle 2 Day 1 and for Schedule B 
patients, before the dosing at Cycle 2 Day 8 visit. The lesion to be biopsied cannot be the only 
site of measurable disease. 

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Part 1: IV Dose Escalation Study of NL-201 
Dose escalation will follow a mTPI design to guide dose escalation and de-escalation within each 
schedule. NL-201 will be administered as an IV infusion in 21-day cycles in cohorts of n ≥ 3 
patients at a time. Schedule A cohorts will be dosed every 21 days, while Schedule B cohorts 
will be dosed on Days 1 and 8 of every 21-day cycle.  
The Schedule A and Schedule B cohorts will enroll on a rolling basis in parallel and cohorts will 
be managed by a Cohort Management Plan. The first new patient of each new dose level shall be 
observed for 48 hours after their first infusion, prior to enrolling subsequent patients to that dose 
level and schedule. 
In addition, there will be backfill cohorts (up to approximately 12 patients in total) , at certain 
DMC-cleared dose levels and schedules, to collect, pharmacokinetic, pharmacodynamic and 
response data in certain tumor types or to explore additional pre-medication regimens (eg. 
steroids). These patients will not be part of the DLT evaluation but will be included in the safety 
population. 
Refer to Section 6.2.1 for details regarding dose escalation. The final decision in terms of the 
dose to be applied to the next set of n ≥ 3 patients will be made by the DMC based upon the 
mTPI design together with the available safety and laboratory data.  
Based on the totality of data arising in Part 1, the DMC will determine a RP2D. If the RP2D 
requires step-dosing, the step-dosing regimen would be incorporated into dosing for patients in 
Part 2. 
Part 2: Monotherapy Dose Expansion Study of NL-201 
This monotherapy dose expansion cohort study will evaluate safety and estimate antitumor 
activity of NL-201 as monotherapy in diseases that are responsive to IL-2, ie, (1) malignant 
melanoma and (2) RCC. The RP2D (and treatment schedule) for these cohorts will be 
determined in Part 1. 
Expansion cohorts will individually comprise up to 30 patients each, of which a minimum of 
8 patients per cohort will be required to have paired biopsies of the same lesion before and after 
treatment with NL-201. Pre-treatment biopsies will occur up to 28 days prior to the first dose 
(Cycle 1 Day 1), while post-treatment biopsies will occur 7 (± 2) days after the Cycle 2 dose. 
Part 3: Dose Escalation Study of NL-201 in Combination with Pembrolizumab 
Dose escalation will follow a mTPI design to guide dose escalation and de-escalation within each 
schedule. NL-201 will be administered as an IV infusion in 21-day cycles in cohorts of 
n ≥ 3 patients at a time. The starting dose of NL-201 will be at least 1 dose level below the 
highest dose level that has been recommended as safe and tolerable by DMC from Part 1 of the 
study.  

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Schedule A cohorts will be dosed every 21 days, while Schedule B cohorts will be dosed on 
Days 1 and 8 of every 21-day cycle. A fixed dose of 200 mg pembrolizumab will be 
administered on Day 1 of every 21-day cycle, regardless of Schedule. Pembrolizumab will be 
administered before NL-201. NL-201 infusion will start 30-60 minutes after pembrolizumab 
infusion is complete. Refer to Section 6.1.1 for additional details regarding drug administration. 
The DMC may modify the NL-201 and pembrolizumab dosing schedule based on emerging 
safety data. 
Schedule A will open first to enrollment. Schedule B can be started subsequently as determined 
by safety from monotherapy, provided that each dose level must be cleared in Schedule A before 
enrolling to Schedule B at the same dose level. If Schedule A and Schedule B are enrolling 
simultaneously, Schedule A enrollment will be prioritized over Schedule B to ensure no delay to 
study enrollment. The first new patient of each new dose level (for both Schedule A and 
Schedule B) shall be observed for 96 hours after the conclusion of their infusion(s), prior to 
enrolling subsequent patients to that dose level and schedule. 
The final decision in terms of the dose to be applied to the next set of n ≥ 3 patients will be made 
by the DMC based upon the mTPI design together with the available safety and laboratory data. 
Based on the totality of data arising in Part 3, the DMC will determine a RP2D for NL-201 in 
combination with pembrolizumab. If the combination RP2D requires step-dosing, the 
step-dosing regimen would be incorporated into dosing for patients in Part 4.  
Part 4: Dose Expansion Study of NL-201 in Combination with Pembrolizumab 
This combination therapy dose expansion cohort will further evaluate safety and estimate 
antitumor activity of NL-201 in combination with pembrolizumab at the selected RP2D (dose 
and schedule) determined in Part 3 in diseases that are responsive to IL-2, ie, (1) immune 
checkpoint inhibitors (ICI) naïve malignant melanoma and (2) ICI naïve RCC, and (3) patients 
with non-small cell lung cancer (NSCLC), melanoma, or head and neck squamous cell 
carcinoma (HNSCC) who have received prior treatment with pembrolizumab achieving a best 
response of stable disease (SD).  
Expansion cohorts will individually comprise up to 30 patients each, of which a minimum of 
8 patients per cohort will be required to have paired biopsies of the same lesion before and after 
treatment with NL-201. Pre-treatment biopsies will occur up to 28 days prior to the first dose 
(Cycle 1 Day 1), while post-treatment biopsies will occur 7 (± 2) days after the Cycle 2 dose. 
Number of Patients: 
Part 1 will enroll up to approximately 50 patients for each of IV Schedule A and IV Schedule B 
in cohorts of n ≥ 3 for dose escalation, and up to approximately 12 patients in total for backfill 
cohorts at certain dose levels and schedules which have been previously cleared by DMC to 
collect PK, PD and response data in certain tumor types or to explore additional pre-medication 
regimens (eg, steroids). In total, up to approximately 115 adult patients will be enrolled in Part 1.  
Part 2 will enroll up to 30 patients in each cohort, up to a maximum of 60 patients in total. 

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1.2 
Schema 
Figure 1 
Part 1 IV Study Schemaa 
  
 
D = day; DMC = Data Monitoring Committee; PD = progressive disease; Q3W = every 3 weeks  
a 
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Figure 2 
Part 2 Study Schema 
Screening (up to 28 days)
Enrollment (D1)
Treatment with NL‐201
RP2D
Part 2:  
Monotherapy
Long‐term Follow‐up
Radiological 
follow‐up
End of 
Treatment
Treatment discontinued 
due to PD
Treatment discontinued 
prior to PD
 
D = day; PD = progressive disease; RP2D = recommended Phase 2 dose 
 
 
 

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Figure 3 
Part 3 Study Schema (Dose Escalation of NL-201 in Combination with Pembrolizumab)a 
  
 
D = day; DMC = Data Monitoring Committee; IV = intravenous; PD = progressive disease; Q3W = every 3 weeks 
* 
The starting dose of NL-201 will be at least 1 dose level below the dose level that has been recommended as safe and tolerable by DMC from Part 1 of the 
study.  
a 
At the recommendation of the DMC or based on Sponsor’s determination, additional dose levels may be tested and/or cohorts may be expanded. 
 

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Figure 4 
Part 4 Study Schema (Dose Expansion of NL-201 in Combination with Pembrolizumab) 
Screening (up to 28 days)
Enrollment (D1)
Treatment with NL‐201 + 
pembrolizumab 200 mg IV Q3W
RP2D
Part 3:  
Combination
Long‐term Follow‐up
Radiological 
follow‐up
End of 
Treatment
Treatment discontinued 
due to PD
Treatment discontinued 
prior to PD
 
D = day; IV = intravenous; PD = progressive disease; RP2D = recommended Phase 2 dose 

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2 INTRODUCTION 
NL-201 is a novel, potent, and selective long-acting agonist of the beta and gamma receptors of 
the interleukin (IL)-2 receptor that is being developed as cancer immunotherapy. 
2.1 
Study Rationale 
A majority of patients with relapsed or refractory solid tumors, who have failed available 
approved lines of therapies, represent a significant unmet medical need. IL-2 and IL-15 are 
immune agonists that may elicit antitumor responses in T-cells and natural killer (NK) cells. 
NL-201 is a novel therapeutic that triggers signaling in both T-cells and NK cells through the 
IL-2 receptor and may be less toxic than native proteins due to eliminating bias towards off 
target cells. Among the range of solid cancers that may respond to an immune agonist like 
NL-201, renal cell carcinoma (RCC) and melanoma cancer are of special interest because 
recombinant human IL-2 (aldesleukin) has been shown to benefit some patients with these 
malignancies. Standard of care for malignant melanoma and RCC includes immunotherapy with 
checkpoint inhibitors (CPIs). However, most patients progress or do not tolerate these therapies, 
and new modalities for the treatment of relapsed or refractory malignant melanoma and RCC are 
needed.1 Thus, NL-201-101 will evaluate the benefit/risk profile of NL-201 in patients with 
relapsed or refractory solid tumors. 
For the majority of cancer patients, new therapies are urgently needed that can turn cold tumors, 
tumors that have low numbers T-cell infiltrates, hot, leading to infiltration and activation of 
immune cells into the tumor microenvironment (TME). In pre-clinical models, NL-201 has been 
shown to increase T-cell receptor diversity in the TME, and to turn cold tumors hot. The 
combination of NL-201 with CPIs has shown marked additive and/or synergistic activity in 
multiple preclinical models. Thus, it is of interest to test this combination in patients as a 
potential novel regimen. 
2.2 
Background 
2.2.1 
Disease Background 
Relapsed or refractory advanced cancer remains a major health problem worldwide, ranking 
second to cardiovascular disease as an overall cause of mortality according to the World Health 
Organization. Although there has been significant progress over the last few decades, patients 
with relapsed or refractory advanced solid tumors still have a generally poor prognosis. Among 
the range of solid cancers that may respond to an immune agonist like NL-201, RCC and 
melanoma cancer are of special interest, though patients with other tumor types who have 
exhausted available therapies may also participate in the proposed dose escalation study. 
2.2.1.1 
Renal Cell Carcinoma 
RCC are tumors of the epithelium of the kidney, and they represent the most common cancer of 
the kidneys in the United States. Approximately 75% of RCC are classified as clear cell 

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carcinoma, with papillary (15%) and chromophobe (5%) types comprising the bulk of the 
remaining cases. The prognosis of advanced RCC is poor. 
The pathogenesis of RCC includes impairment of host immune function, with an up-regulation 
of regulatory T-cells and myeloid-derived suppressor cells, as well as down-regulation of T-cell 
mediated immunity.2 Immunotherapies that activate T-cell mediated antitumor activity, including 
IL-2, can counteract this pathogenic immune dysregulation, and have been shown to be effective 
in the treatment of malignant RCC. To this end, IL-2 has been used for patients with metastatic 
clear cell RCC. Clinical studies of high-dose IL-2 yielded durable complete responses (CRs) in 
7% to 28% of patients, with a median duration of approximately 19 months,2 and its use is 
warranted in patients with low-volume disease, good performance status, and predominantly 
clear cell carcinoma. Unfortunately, high-dose IL-2 is known to cause significant dose-related 
morbidity. Common serious adverse effects of high-dose IL-2 therapy include hypotension, 
pulmonary edema and capillary leak syndrome, wherein fluid accumulates in the extravascular 
space resulting in hypovolemia, oliguria, ischemia, and confusion. Other toxicities involve the 
heart, lungs, kidneys, and central nervous system (CNS). This toxicity profile has limited the use 
of high-dose IL-2 to specialized medical centers with experienced medical providers, where 
mortality can generally be minimized. Despite these risks, IL-2 can significantly benefit a 
modest number of patients. 
2.2.1.2 
Malignant Melanoma 
Melanoma is 1 of the most common cancers in the United States, and is the most morbid 
malignancy of the skin, accounting for up to 75% of skin cancer-related deaths. While early 
melanoma is a localized disease, and is most often curable by surgical resection before metastatic 
spread, disseminated melanoma is a difficult disease to treat effectively.  
Melanoma is a highly immunogenic tumor due to somatic mutations in the genomes of 
melanoma cells caused by ultraviolet radiation. These somatic mutations cause neoantigens in 
the tumor that can be recognized by the immune system, enabling a T-cell mediated antitumor 
immune response. Thus, immunotherapy can be an effective treatment for melanoma. Recent 
advances with CPIs have increased the 3-year survival rate of advanced melanoma to as high as 
58%,3 but CR rates are generally low, and recurrent and refractory disease remains an unmet 
medical need. High-dose IL-2 can also potentiate T-cell mediated antitumor responses in 
melanoma, with an objective response rate (ORR) of 16%, including a CR rate of 6%.4 As 
described above, the severe toxicity associated with IL-2 therapy has limited its use to patients 
with good organ function who are being closely monitored by experienced clinicians in 
specialized medical centers. 
2.2.2 
Neoleukin Investigational Product Background: NL-201 
NL-201 is a de novo computationally designed protein that is conjugated to a single polyethylene 
glycol (PEG) molecule and is a mimetic of the natural cytokines IL-2 and IL-15. The protein was 
originally designed using canonical amino acids (excluding cysteine).5 Briefly, the 
crystallographic holo-structure of human IL-2 in complex with its receptor was used to derive the 
position and orientation of critical amino acids that mediate binding to IL-2 receptor beta and 

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gamma (but not IL-2 receptor alpha). These structural data were used to design a 
computationally de novo protein that was predicted to recapitulate these critical binding amino 
acids using a novel sequence and structural topology. As this protein was designed de novo, it 
has no significant homology to any protein found in nature. 
After initial computational design, the protein was optimized by selecting high affinity and 
stability variants from a single-site saturation mutagenesis library. Multiple enriching mutations 
from this selection were combined to generate the final protein, named Neoleukin-2/15 
(Neo-2/15). Neo-2/15 was found to have nanomolar binding affinity for both the human and 
murine IL-2 receptor beta and gamma, while having no binding affinity of any kind for human or 
murine IL-2 receptor alpha. The predicted structure of Neo-2/15 in complex with murine IL-2 
receptor was confirmed by X-ray crystallography. 
NL-201 was created by mutating a single amino-acid in the third helical element of Neo-2/15 
(that does not interact with IL-2 receptor) to cysteine, and conjugating a single 40 kDa linear 
PEG molecule to that cysteine using maleimide chemistry. It behaves similarly to Neo-2/15 in 
that it binds the same receptors with similar affinity and triggers signal transducer and activator 
of transcription 5 (STAT5) signaling on human cells with similar potency but is expected to have 
a longer serum half-life (t1/2) due to decreased renal filtration. 
Neo-2/15 triggers phosphorylation of STAT5 with an 50% effective concentration of 
approximately 10-11 M. Ex vivo, it drives proliferation of primary murine derived T-cells as well 
as of murine CTLL-2 cell lines. In vivo, NL-201 causes expansion of multiple lymphoid cell 
lineages, including T-cells, and in murine models is an efficacious treatment for CT-26 colon 
cancer. 
Safety studies of NL-201 involved no unscheduled deaths and no significant macroscopic 
findings and identified a no observed adverse effect level (NOAEL) of 11.44 µg/kg in 
non-human primates. Microscopic findings at terminal necropsy showed moderate 
dose-dependent mixed leukocyte infiltration in multiple tissues, including the choroid plexus of 
the brain, glandular organs, urogenital and reproductive tract, heart, kidneys, injection site, 
gastrointestinal tract and skin. Leukocytic infiltration caused by higher doses of NL-201 led to 
minimal to mild myofiber degradation and necrosis and minimal to mild renal tubular 
degeneration. All changes at 11.44 µg/kg were less severe after 4 weeks of recovery, consistent 
with partial or full reversibility.  
A detailed description of the chemistry, pharmacology, and safety of NL-201 is provided in the 
Investigator’s Brochure. 
2.2.3 
Non-Neoleukin Investigational Product: Pembrolizumab 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting 
its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an IV immunotherapy for advanced malignancies. Keytruda® 

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(pembrolizumab) is indicated for the treatment of patients across a number of indications. For 
more details on specific indications refer to the Investigator’s Brochure. 
Refer to the Investigator’s Brochure/approved labeling for detailed background information on 
pembrolizumab. 
2.2.3.1 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades.6 Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of cluster of differentiation (CD)8+ T-cells and the ratio 
of CD8+ effector T-cells/forkhead box P3 (FoxP3)+ regulatory T-cells (T-regs) correlates with 
improved prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, 
and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and RCC. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma.7,8  
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) 
superfamily member related to CD28 and cytotoxic T-lymphocyte-associated protein 4 
(CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2).9,10  
The structure of murine PD-1 has been resolved.11 PD-1 and its family members are type I 
transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif. Following 
T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the 
immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell 
signaling cascade.10,12–14 The mechanism by which PD-1 down-modulates T-cell responses is 
similar to, but distinct from, that of CTLA-4, because both molecules regulate an overlapping set 
of signaling proteins.15,16 As a consequence, the PD-1/PD-L1 pathway is an attractive target for 
therapeutic intervention in patients with relapsed or refractory cancer. 
2.2.3.2 
Pre-Clinical and Clinical Trials 
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and ultimately 
leads to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities.17–23 Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated antitumor 
responses in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, acute 

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myeloid leukemia and colorectal carcinoma.11,20,22–24 In such studies, tumor infiltration by CD8+ 
T-cells and increased interferon gamma (IFN-γ), granzyme B and perforin expression were 
observed, indicating that the mechanism underlying the antitumor activity of PD-1 checkpoint 
inhibition involved local infiltration and activation of effector T-cell function in vivo.22 
Experiments have confirmed the in vivo efficacy of anti-mouse PD-1 antibody as a monotherapy, 
as well as in combination with chemotherapy, in syngeneic mouse tumor models (see the 
Investigator’s Brochure).  
2.3 
Benefit/Risk Assessment 
Potential risks for the planned NL201-101 first-in-human clinical study comprise cytokine 
release syndrome, flu like symptoms, cardiac toxicity, and auto-immunity. Considering the high 
unmet medical need in the targeted patient population and that patients do not forego any 
established and effective standard therapy, the risk/benefit ratio of applying an engineered IL-2 
mimetic with potential for durable responses that is safer than IL-2 is considered justified by the 
Sponsor. To further lower the safety risks for patients in the NL201-101 study, risk mitigation 
measures have been implemented at multiple levels in the design of the clinical study. These 
include dose escalation/de-escalation, prophylactic measures, steps that allow for early diagnosis 
and/or aggressive clinical management of safety events, and a Data Monitoring Committee 
(DMC). 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of NL-201 may be found in the Investigator’s Brochure.

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2.3.1.1 
Pembrolizumab (Parts 3 and 4 only) 
Among the many immunotherapeutic strategies, immune checkpoint blockade enhances a cancer 
patient’s immune system to fight an array of cancers. By increasing the activity of the immune 
system, immune checkpoint blockade can induce inflammatory side effects known as 
immune-related Adverse Events (irAE). Although any organ system can be affected, irAEs most 
commonly involve the gastrointestinal tract, endocrine glands, skin, and liver. Less often, the 
CNS and cardiovascular, pulmonary, musculoskeletal, and hematologic systems are involved. 
The wide range of potential irAEs requires multidisciplinary, collaborative management by 
providers across the clinical spectrum. 
Immune-related adverse reactions may be mild to moderate in severity but can be severe or fatal 
and can occur in any organ system or tissue in patients receiving pembrolizumab and may also 
occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, 
there should be adequate evaluation to confirm etiology and exclude other causes. 
The key safety risks for pembrolizumab include immune-related toxicities, infusion-related 
reactions, and embryofetal toxicity (Table 6). Refer to Section 6.2.2.2 for specific 
recommendations regarding the mitigation and management of these risks. 
Refer to the pembrolizumab Investigator’s Brochure for additional safety information. 
Table 6 
Potential Risks for Pembrolizumab 
Safety Risk 
Description 
Immune-related toxicities 
Immune-related adverse effects associated with PD-1 blocking agents 
include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and 
renal dysfunction, skin reactions, encephalitis, vasculitis, sclerosing 
cholangitis, and other immune-related adverse reactions.  
Infusion-related reactions 
Signs and symptoms may include pyrexia, chills, rigors, flushing, 
urticaria, hypotension, dyspnea, wheezing, headache, back pain, and 
abdominal pain.  
Embryofetal toxicity 
Blockade of PD-1 signaling has been shown in animal models of 
pregnancy to disrupt tolerance to the fetus and to result in an increase in 
fetal loss; therefore, there is the possibility of fetal harm if administered 
during pregnancy.  
PD-1 = programmed cell death 1 
 
2.3.1.2 
NL-201 Combination With Pembrolizumab (Parts 3 and 4 only) 
Based on biological mechanism of action and initial clinical safety information from the 
monotherapy study with NL-201, the key safety risks described for monotherapy would also be 
expected along with the potential risks described for pembrolizumab. Moreover, with 
combination treatment, AEs may be more severe and occur at different time points and/or dose 
levels in comparison to monotherapy. In particular, target-dependent and target-independent 
synergistic activation of T-cells is expected and may contribute to more severe immune-related 
toxicities. 

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Potential safety risks for the combination of NL-201 and pembrolizumab include: 
 Exacerbated cytokine release syndrome and/or infusion-related reactions  
 Exacerbation of autoimmune/inflammatory disorders 
 Exacerbation of autoimmune AEs 
Patients will be monitored closely in a hospital setting for 24 hours after receiving their first dose 
in the first cycle. The pre-medication requirements are expected to mitigate many of the NL-201 
associated toxicity.   
Dose and schedule of pembrolizumab administration will be according to the approved label 
200 mg every 21 days. Patients will be monitored for 30 minutes following pembrolizumab 
administration before NL-201 infusion is initiated. The starting dose of NL-201 in combination 
with pembrolizumab will be one dose level below the highest cleared dose.  
Refer to the individual Investigator’s Brochures for a more detailed assessment.  
2.3.2 
Benefit Assessment 
NL-201 has been shown to effectively stimulate T-cell and NK-cell mediated antitumor activity 
in multiple animal models of cancer, in some cases more effectively than check-point inhibitors 
or IL-2. The agent is engineered to have no binding affinity for CD25, which is hypothesized to 
improve its safety profile. Indeed, animal safety experiments have demonstrated tolerability of 
NL-201 in multiple species (see Section 2.2.2), and published reports show that the parent 
protein Neo-2/15 is less toxic than natural IL-2.5 An individual patient in the study may see 
benefit from NL-201 by experiencing stable disease (SD) or an objective response. They may 
potentially experience a durable CR, as has been observed with IL-2 therapy in advanced solid 
cancer patients. Clinical benefit in this open-label study will be estimated based on progression-
free survival (PFS), ORR, and response duration.Parts 3 and 4: It is hypothesized that NL-201 in 
combination with pembrolizumab may improve response to pembrolizumab as was demonstrated 
in animal models. NL-201 has been shown to increase PD-1 expression in CD+ T-cells, 
increased the immune infiltration of the TME, and may make tumor cells more sensitive to the 
effects of pembrolizumab. 
Refer to the individual Investigator’s Brochures for a more detailed assessment.  
2.3.3 Overall Benefit: Risk Conclusion 
Patients will have advanced and incurable disease and will have exhausted all approved 
therapies. Under the controlled setting of clinical investigation, NL-201 offers a reasonable 
potential of clinical benefit. The patient will weigh the risk vs potential benefit based on 
informed consent. 

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Parts 3 and 4 (NL-201 in Combination with Pembrolizumab) 
Part 3 will be an adaptive mTPI design dose escalation study in up to 42 adult patients with 
advanced solid tumors to determine the safety profile, RP2D and treatment schedule of NL-201 
in combination with pembrolizumab. Part 4 will be a dose expansion phase in 3 cohorts (up to 
n = 30 per cohort) to confirm the combination RP2D and obtain additional estimation of 
pharmacokinetics (PK),pharmacodynamics (PDn), and antitumor activity. 
All Parts 
Patients will enter the screening period, up to 28 days prior to Cycle 1 Day 1 of treatment. PK, 
PDn, and exploratory tumor biopsy samples will be obtained per the study Schedule of Events 
(see Section 1.3). Tumor response to treatment will be assessed by radiographic evaluation per 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and RECIST for use in cancer 
immunotherapy trials (iRECIST) every 6 weeks for 12 weeks, and every 12 weeks thereafter 
while on treatment. Patients may continue on treatment until unacceptable toxicity, disease 
progression per iRECIST with either confirmation or clinical decline, completion of 
35 administrations (approximately 2 years) with pembrolizumab (for Parts 3 and 4), withdrawal 
of consent, patient or physician decision, study termination, or death. Patients with progressive 
disease who are considered to be clinically stable and whose progression is considered to be 
minimal are required to have a confirmatory scan and tumor evaluation after the initial 
determination of progression. Patients with progressive disease per RECIST criteria may 
continue on treatment past progression if, in the opinion of the Investigator, the patient is 
considered to be clinically stable or has experienced clinical benefit from NL-201 alone or in 
combination with pembrolizumab (see Section 6.1.1.1). 
Upon permanent discontinuation of study drug for any reason, an end of treatment visit should be 
scheduled as soon as possible, but within 30 days following cessation of study treatment or 
before patient initiates new anti-cancer therapy, whichever is earlier. All AEs and concomitant 
medication will be followed up to 30 days after last dose of NL-201. 
For Parts 3 and 4, all adverse events will be followed up to 30 days following cessation of study 
treatment and all serious adverse events will be followed up to 90 days following cessation of 
study treatment, or 30 days following cessation of study treatment if the participant initiates new 
anti-cancer therapy, whichever is earlier. Patients who discontinue from treatment due to 
progressive disease based on RECIST or iRECIST will enter long-term follow-up to assess 
survival and subsequent anti-cancer therapies. Patients in Parts 2 and 4 will also need to record 
any subsequent anti-cancer therapies during long-term follow-up.  
For Parts 2 and 4, patients who discontinue from treatment due to reasons other than progressive 
disease based on RECIST or iRECIST will be followed in radiologic follow-up for documented 
progressive disease by RECIST 1.1 and will enter long-term follow-up. If subsequent anti-cancer 
therapies are initiated during the period of time between discontinuation of treatment and 
progressive disease documentation, the patient will no longer be radiologically assessed for 
progression and will enter long-term follow-up. 

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Patients in long-term follow-up will be followed until death, withdrawal of consent, lost to 
follow-up, or study closure, whichever occurs first, for a maximum of 2 years after the end of 
treatment. 
Part 1: Intrasubject Dose Escalation 
Intrasubject dose escalation is permitted with Medical Monitor approval. In cases where no 
treatment-related Grade 2 or higher adverse events have been observed, dose escalation to a 
higher dose will be permitted provided that the dose level has been cleared by the DMC.   
Part 1: Optional Tumor Biopsy 
During dose escalation, paired biopsies are optional. For patients who consent to have paired 
biopsies, the same lesion will be sampled within 28 days prior to the first dose of NL-201 (ie, 
pre-treatment biopsy) and on study (ie, post-treatment biopsy). The post-treatment, second 
biopsy will occur between 5 to 9 days after receiving dose at Cycle 2 Day 1 and for Schedule B 
patients, before the dosing at Cycle 2 Day 8 visit. The lesion to be biopsied cannot be the only 
site of measurable disease.  
Part 1: IV Dose Escalation Study of NL-201 
Dose escalation will follow a mTPI design25 to guide dose escalation and de-escalation within 
each schedule. NL-201 will be administered as an IV infusion in 21-day cycles in cohorts of 
n ≥ 3 patients at a time. Schedule A cohorts will be dosed every 21 days, while Schedule B 
cohorts will be dosed on Days 1 and 8 of every 21-day cycle.  
The Schedule A and Schedule B cohorts will enroll on a rolling basis in parallel and cohorts will 
be managed by a Cohort Management Plan. The first new patient of each new dose level (for 
both Schedule A and Schedule B) shall be observed for 48 hours after their first infusion prior to 
enrolling subsequent patients to that dose level and schedule. 
In addition, there will be backfill cohorts (up to approximately 12 patients in total) , at certain 
DMC-cleared dose levels and schedules, to collect, pharmacokinetic, pharmacodynamic and 
response data in certain tumor types or to explore additional pre-medication regimens (eg. 
steroids). These patients will not be part of the DLT evaluation but will be included in the safety 
population. 
Refer to Section 6.2.1 for details regarding dose escalation. The final decision in terms of the 
dose to be applied to the next set of n ≥ 3 patients will be made by the DMC based upon the 
mTPI design together with the available safety and laboratory data.  
Based on the totality of data arising in Part 1, the DMC will determine a RP2D. If the RP2D 
requires step-dosing, the step-dosing regimen would be incorporated into dosing for patients in 
Part 2. 

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Part 2: Monotherapy Dose Expansion Study of NL-201 
This monotherapy dose expansion cohort study will evaluate safety and estimate antitumor 
activity of NL-201 as monotherapy in diseases that are responsive to IL-2, ie, (1) malignant 
melanoma and (2) RCC. The RP2D (and treatment schedule) for these cohorts will be 
determined in Part 1. 
Expansion cohorts will individually comprise up to 30 patients each, of which a minimum of 
8 patients per cohort will be required to have paired biopsies of the same lesion before and after 
treatment with NL-201. Pre-treatment biopsies will occur up to 28 days prior to the first dose 
(Cycle 1 Day 1), while post-treatment biopsies will occur 7 (± 2) days after the Cycle 2 dose. 
Part 3: Dose Escalation Study of NL-201 in Combination with Pembrolizumab 
Dose escalation will follow a mTPI design to guide dose escalation and de-escalation within each 
schedule. NL-201 will be administered as an IV infusion in 21-day cycles in cohorts of 
n ≥ 3 patients at a time. The starting dose of NL-201 will be at least 1 dose level below the 
highest dose level that has been recommended as safe and tolerable by DMC from Part 1 of the 
study.  
Schedule A cohorts will be dosed every 21 days, while Schedule B cohorts will be dosed on 
Days 1 and 8 of every 21-day cycle. A fixed dose of 200 mg pembrolizumab will be 
administered on Day 1 of every 21-day cycle, regardless of Schedule. Pembrolizumab will be 
administered before NL-201. NL-201 infusion will start 30-60 minutes after pembrolizumab 
infusion is complete. Refer to Section 6.1.1 for additional details regarding drug administration. 
The DMC may modify the NL-201 and pembrolizumab dosing schedule based on emerging 
safety data. 
Schedule A will open first to enrollment. Schedule B can be started subsequently as determined 
by safety from monotherapy, provided that each dose level must be cleared in Schedule A before 
enrolling to Schedule B at the same dose level. If Schedule A and Schedule B are enrolling 
simultaneously, Schedule A enrollment will be prioritized over Schedule B to ensure no delay to 
study enrollment. The first new patient of each new dose level (for both Schedule A and 
Schedule B) shall be observed for 96 hours after the conclusion of their infusion(s), prior to 
enrolling subsequent patients to that dose level and schedule. 
The final decision in terms of the dose to be applied to the next set of n ≥ 3 patients will be made 
by the DMC based upon the mTPI design together with the available safety and laboratory data. 
Based on the totality of data arising in Part 3, the DMC will determine a RP2D for NL-201 in 
combination with pembrolizumab. If the combination RP2D requires step-dosing, the 
step-dosing regimen would be incorporated into dosing for patients in Part 4.  
Part 4: Dose Expansion Study of NL-201 in Combination with Pembrolizumab 
This combination therapy dose expansion cohort will further evaluate safety and estimate 
antitumor activity of NL-201 in combination with pembrolizumab at the selected RP2D (dose 

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and schedule) determined in Part 3 in diseases that are responsive to IL-2, ie, (1) immune 
checkpoint inhibitors (ICI) naïve malignant melanoma, (2) ICI naïve RCC, and (3) patients with 
non-small cell lung cancer (NSCLC), melanoma, or head and neck squamous cell carcinoma 
(HNSCC) who have been treated with pembrolizumab achieving a best response of SD.  
Expansion cohorts will individually comprise up to 30 patients each, of which a minimum of 
8 patients per cohort will be required to have paired biopsies of the same lesion before and after 
treatment with NL-201. Pre-treatment biopsies will occur up to 28 days prior to the first dose 
(Cycle 1 Day 1), while post-treatment biopsies will occur 7 (± 2) days after the Cycle 2 dose. 
4.1.1 
Study Duration for Patients 
The duration of screening is up to 28 days prior to Cycle 1 Day 1 and the duration of treatment 
for an individual patient is anticipated to be a median of 3 months. For Parts 2 and 4 only, this 
will be followed by radiology follow-up visits until disease progression or initiation of new 
therapy. Upon disease progression or initiation of new therapy, patients enter long term 
follow-up (every 6 months ± 1 month) until death, lost to follow-up, withdrawal of consent or 
study closure, whichever occurs first, for a maximum of 2 years after end of treatment. Long 
term follow-up visits may occur over the telephone. 
The total study duration for an individual patient is estimated to be approximately 12 months. 
4.1.2 
Number of Patients 
Part 1 will enroll up to approximately 50 patients for each of IV Schedule A, IV Schedule B in 
cohorts of n ≥ 3 for dose escalation, and up to approximately 12 patients in total for backfill 
cohorts at certain dose levels and schedules which have been previously cleared by DMC In 
total, up to approximately 115 patients will be enrolled in Part 1.  
Part 2 will enroll up to 30 patients in each cohort, up to a maximum of 60 patients in total. Part 3 
will enroll up to 21 patients for each of Schedule A and Schedule B in cohorts of n ≥ 3 for a 
maximum of 42 patients in total. Part 4 will enroll up to 30 patients in each cohort, up to a 
maximum of 90 patients in total. 
Combined enrollment for all parts of the study is up to an approximately 310 patients. 
4.1.3 
Replacement of Patients 
In Parts 1 and 3, patients who are unable to be evaluated for toxicity during the DLT window due 
to discontinuation for unrelated AEs or disease progression will be replaced. In Parts 2 and 4, 
patients who are withdrawn or removed from treatment or the study will not be replaced.  
4.1.4 
Number of Sites 
Approximately 10 sites in North America and Australia will participate in Parts 1 and 3, and 
approximately 20 sites in North America and Australia will participate in Parts 2 and 4 of this 

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global study. During the conduct of the study, additional sites and countries within these regions 
may be added as necessary. 
4.2 
Scientific Rationale for Study Design 
Aldesleukin is a recombinant human IL-2 protein that has monotherapeutic efficacy in malignant 
melanoma and RCC. It activates T-cell-mediated tumor inhibition by heterodimerizing the beta 
and gamma subunits of the IL-2 receptor, leading to phosphorylation of STAT5. However, 
serious toxicity has limited the clinical utility of IL-2.26 The cause of this toxicity is related to its 
high binding affinity for CD25+ cells: preferential activation of CD25+ cells, such as endothelial 
cells and regulatory T-cells, leads to vascular leak and immunosuppression.27,28 NL-201 is a 
novel immunotherapeutic based on a de novo designed mimic of IL-2 that acts through the same 
mechanism of action as IL-2 but has no affinity for CD25. The parental protein of NL-201 binds 
with high affinity and in the correct orientation to the beta and gamma subunits of the IL-2 
receptor without any affinity for CD25, and leads to significantly less toxicity than recombinant 
IL-2 in animal models.5 NL-201 triggers STAT5 phosphorylation with high potency, and leads to 
inflammatory cytokine signaling, tumor inhibition and prolonged survival in animal models. 
These studies suggest that NL-201 may provide antitumor benefit with an improved safety 
profile. 
4.3 
Justification for Dose 
Part 1: NL-201 IV Monotherapy Dose Escalation 
The FIH starting dose was selected based on evaluation of the totality of the nonclinical data 
including in vitro evaluation of PDn effects in human peripheral blood mononuclear cells 
(PBMCs), the most sensitive assay, and in vivo toxicity data in monkeys, the most sensitive 
species. The proposed starting dose of 0.1 µg/kg is predicted to result in an in vivo Cmax in 
patients of approximately 2 ng/mL. The proposed dose is anticipated to approximate the lowest 
pharmacologically active dose (PAD) based on in vitro PDn evaluations and is 150- to 300-fold 
below the Cmax achieved in monkeys given 11.44 µg/kg NL-201; a dose considered to be the 
NOAEL (see Table 8 for dose escalation scheme). 
Part 2: NL-201 Monotherapy Dose Expansion 
The recommended monotherapy dose and schedule of NL-201 that is determined during dose 
escalation will be used during monotherapy dose expansion (Part 1). The DMC will determine 
this dose and schedule by considering the PK, PDn, tolerability, antitumor activity, and the 
occurrence of  any cumulative toxicities over multiple cycles of NL-201. No randomization or 
dose escalation will occur, though dose reduction or delay for toxicity will be allowed.  
Part 3: NL-201 in Combination with Pembrolizumab Dose Escalation 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is an 
appropriate dose of pembrolizumab for adults across all indications. As outlined below, this dose 
is justified by: 

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 Clinical data from 8 randomized studies in melanoma and NSCLC indications demonstrating 
flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks 
(Q2W) representing an approximate 5- to 7.5-fold exposure range (refer to the Investigator’s 
Brochure)  
 Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of exposures, 
supporting suitability of 200 mg Q3W 
 Clinical data showing meaningful improvement in benefit-risk including overall survival 
(OS) at 200 mg Q3W across multiple indications, and 
 Pharmacology data showing full target saturation in both systemic circulation (inferred from 
PK data) and tumor (inferred from physiologically-based PK [PBPK] analysis) at 200 mg 
Q3W. 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment naïve, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W 
(KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies compared 
10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All 
of these studies demonstrated flat dose- and exposure-response relationships across the doses 
studied representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 
200 mg fixed-dose) Q3W provided similar responses to the highest doses studied. Subsequently, 
flat dose-exposure-response relationships were also observed in other tumor types including head 
and neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 
200 mg Q3W as the appropriate dose independent of the tumor type. These findings are 
consistent with the mechanism of action of pembrolizumab, which acts by interaction with 
immune cells, and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression. This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported 
by these PK characteristics and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for 
evaluation across all pembrolizumab protocols. 

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Part 4: NL-201 in Combination with Pembrolizumab Dose Expansion 
The recommended dose and schedule of NL-201 in combination with pembrolizumab that is 
determined during dose escalation (Part 3) will be used during combination dose expansion. 
Supported by the mTPI design, the DMC will determine this dose and schedule by considering 
the PK, PDn, and any cumulative toxicities over multiple cycles of NL-201 in combination with 
pembrolizumab. No randomization or dose escalation will occur, though dose reduction or delay 
for toxicity will be allowed. 
4.4 
End of Study 
End of Study (Individual Patient): A patient is considered to have completed the study if 
he/she has completed all phases of the study including the last visit shown in the Schedule of 
Events (Section 1.3; eg, last long-term follow up visit as described in Section 0). 
Primary Completion: The primary completion date is defined as the date when the last patient 
is assessed or receives an intervention for the final collection of data to support the primary 
endpoint(s) for the purposes of conducting the primary analysis. This date is defined to be up to 
30 days after the last patient has completed the last treatment. 
End of Study: The end of the study is defined as the date of the last visit of the last patient in the 
study or last scheduled procedure shown in the Schedule of Events (Section 1.3) for the last 
patient in the study globally. The total study duration, including all follow-up, is expected to be 
approximately 5 years. 
4.5 
Patient Input on Study Design 
Patient input was not obtained for this study. 
5 STUDY POPULATION 
Before any study-specific activities/procedures, the appropriate written informed consent must 
be obtained (see Section 10.1.3). Patients must meet all enrollment criteria to be eligible for this 
study. 
Part 1 target population: Adult patients with measurable advanced and incurable solid tumors 
who have failed all lines of treatment, including CPIs if indicated. 
Part 2 target population: Adult patients with pathologically proven diagnosis of the target disease 
indications, (1) malignant melanoma and (2) RCC, who have advanced and incurable disease and 
have failed at least 1 line of treatment, including CPIs. 
Part 3 target population: Adult patients with histologically-confirmed solid tumors who have 
received ≥ 1 prior line of therapy for advanced or metastatic disease. 
Part 4 target population: Adult patients with pathologically proven diagnosis of the target disease 
indications, (1) ICI naïve malignant melanoma and (2) ICI naïve RCC, and (3) patients with 

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NSCLC, melanoma, or HNSCC who have received prior treatment with pembrolizumab 
achieving a best response of SD. 
5.1 
Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply at the 
time of screening: 
1. Patients ≥ 18 years of age inclusive, at the time of signing the informed consent. 
2. Capable of giving informed consent as described in Section 10.1.3, which includes 
compliance with the requirements and restrictions listed in the informed consent form (ICF) 
and in this protocol. 
3. Patients with measurable disease per RECIST 1.1 as assessed by the local site 
investigator/radiology. Lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions. 
4. Patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
5. Patients with adequate organ function, defined as: 
a. Hematologic function laboratory values (specimens must be collected within 10 days 
prior to the start of study treatment): 
i. Platelets ≥ 100,000/mm3 
ii. Absolute neutrophil count (ANC) > 1500/mm3 
iii. Hemoglobin: Parts 1 and 2: ≥ 8.0 g/dL; Parts 3 and 4: ≥ 9.0 g/dL (NOTE: Criteria 
must be met without packed red blood cell transfusion within the prior 2 weeks. 
Participants can be on stable dose of erythropoietin (≥ approximately 3 months). 
iv. Lymphocyte count ≥ 500/mm3 
v. Eosinophils < 1000/mm3 
b. Renal function (specimens must be collected within 10 days prior to the start of study 
treatment): estimated glomerular filtration rate (eGFR) ≥ 50 mL/min/1.73 m2 as 
determined by 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation,29 or creatinine within normal limits (WNL) 
c. Hepatic function (specimens must be collected within 10 days prior to the start of study 
treatment): 
i. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): Parts 1 and 2: 
≤ 3 x upper limit of normal (ULN), or ≤ 5 x ULN if known liver malignancy or 
metastasis; Parts 3 and 4: AST/ALT ≤ 2.5 x ULN, or ≤ 5 x ULN if known liver 
malignancy or metastasis 
ii. Total bilirubin (TBL) WNL, or ≤ 3 x ULN if known Gilbert’s syndrome 
d. Adequate cardiovascular and respiratory function with transthoracic echocardiogram 
(ECHO) and pulmonary function testing showing no clinically significant findings. If 
ECHO is not available or appropriate according to the institutional standard, then 
multi-gated acquisition (MUGA) scan is permitted. 

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e. Coagulation (specimens must be collected within 10 days prior to the start of study 
treatment): international normalized ratio (INR) OR prothrombin time (PT) ≤ 1.5 x ULN 
unless participant is receiving anticoagulant therapy as long as PT or partial 
thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants 
6. At least 6 weeks from any prior nitrosurea or mitomycin C therapy; at least 4 weeks from any 
other prior chemotherapy or CPI; at least 2 weeks from any kinase inhibitor. 
7. Women are not pregnant or breastfeeding and 1 of the following conditions applies: 
a. Is a woman of non-childbearing potential as defined in Section 10.4 
b. Is a woman of childbearing potential (WOCBP) and using a contraceptive method that is 
highly effective, with a failure rate of < 1% (as described in Section 10.4) during the 
study treatment period and for at least 60 days after the last dose of NL-201 (Parts 3 and 
4 only: 120 days after the last dose of study treatment). The Investigator should evaluate 
the potential for contraceptive method failure (eg, noncompliance, recently initiated) in 
relationship to the first dose of study drug. 
8. A WOCBP must have a negative highly sensitive pregnancy test (serum or urine) at 
screening.  
9. Men are eligible to participate if they agree to the following during the study drug period and 
for at least 90 days after the last dose of NL-201 (Parts 3 and 4 only: 120 days after the last 
dose of pembrolizumab): 
a. Refrain from donating sperm 
b. For men with partners of childbearing potential or partners who are pregnant or 
breastfeeding: Use a male condom and should also be advised of the benefit for a female 
partner to use a highly effective method of contraception as a condom may break or leak 
when having sexual intercourse with a woman of childbearing potential who is not 
currently pregnant. 
Part 1 Only 
10. Patients with any relapsed or refractory advanced solid tumor, other than prostate cancer, 
who have progressed, not tolerated or are ineligible for all approved non-IL-2-based lines of 
therapy. 
Parts 2 and 4 Only 
11. Patients with a diagnosed target disease indication that has failed at least 1 line of systemic 
therapy. 
Parts 3 and 4 Only 
12. Part 3 only: Patients with histologically-confirmed solid tumors who have received ≥ 1 prior 
line of therapy for advanced or metastatic disease. 
13. Part 4 only: Patients with a diagnosed target disease indication OR have received prior 
treatment with pembrolizumab achieving a best response of SD. 
14. Part 4 only: Have archival tumor tissue sample available or newly obtained core/excisional 
biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded 
(FFPE) tissue blocks are preferred to slides. If archival tissue is not available, and there is not 
a readily accessible lesion for biopsy, the biopsy may be waived with Sponsor approval. 

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Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing 
laboratory within 14 days from the date slides are cut (details pertaining to tumor tissue 
submission can be found in the Procedures Manual). 
Note: Archival biopsy should be within 5 years of screen date for PD-L1 analysis.  
5.2 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Known active CNS metastases and/or carcinomatous meningitis. Participants with previously 
treated brain metastases may participate provided they are radiologically stable, ie, without 
evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging 
should be performed during study screening), clinically stable and without requirement of 
steroid treatment for at least 14 days prior to first dose of study treatment. 
2. Development of clinically severe non-endocrine autoimmune disorder leading to 
discontinuation of prior immunotherapy (eg, pneumonitis, myocarditis, neuropathy, or 
nephritis). 
3. Active autoimmune disease that has required systemic treatment in past 2 years (ie, with use 
of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement 
therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal 
or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. 
4. History of solid organ transplant or bone marrow transplant. 
5. Myocardial infarction in the 6 months prior to initiating therapy. 
6. Class II or greater heart failure per New York Heart Association Classification. 
7. Clinically significant bleeding, such as gastrointestinal or intracranial bleeding, or deep vein 
thrombosis or pulmonary embolism in the 3 months prior to initiating therapy. Thrombus 
prophylaxis is acceptable. 
8. Evidence or clinical suspicion of ongoing serious active infection requiring systemic 
treatment.  
9. Known history of human immunodeficiency virus (HIV) or positive for HIV at screening. 
10. Known chronic or active viral hepatitis. 
11. Known or suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
infection, unless patient tests negative for SARS-CoV-2 within the screening period. 
12. Parts 3 and 4 only: Has a history of (non-infectious) pneumonitis/interstitial lung disease that 
required steroids or has current pneumonitis/interstitial lung disease. 
13. Parts 3 and 4 only: Has a known additional malignancy that is progressing or has required 
active treatment within the past 2 years.  
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, 
or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone 
potentially curative therapy are not excluded. 

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Prior/Concomitant Therapy 
14. Live or live-attenuated vaccine(s) within 30 days prior to screening or plans to receive such 
vaccines during the study. Note: Administration of killed vaccines are allowed. 
15. Prior chimeric antigen receptor T-cell (CAR-T) or allogeneic cellular therapy. 
16. Prior IL-2-based cancer immunotherapy. 
17. Diagnosis of immunodeficiency or is receiving ongoing systemic immunosuppressive 
therapy (stable replacement doses of systemic prednisone ≤ 10 mg/day or equivalent will be 
allowed) or any other form of immunosuppressive therapy within 7 days prior the first dose 
of study treatment. 
18. History of hypersensitivity to PEG or PEGylated drugs. 
19. Parts 3 and 4 only: Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of 
its excipients. 
20. Parts 3 and 4 only: Patients on a prior PD-1 or PD-L1 inhibitor who experienced a Grade 3 or 
higher irAEs. 
21. Parts 3 and 4 only: Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 
agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor 
(eg, CTLA-4, OX 40, CD137), and was discontinued from that treatment due to a Grade 3 or 
higher irAE. 
22. Parts 3 and 4 only: Has received prior systemic anti-cancer therapy including investigational 
agents within 4 weeks (could consider shorter interval for kinase inhibitors or other short 
half-life drugs) prior to treatment. 
Note: Participants must have recovered from all AEs due to previous therapies to ≤ Grade 1 
or baseline. Participants with ≤ Grade 2 neuropathy may be eligible. Participants with 
endocrine-related AEs Grade ≤ 2 requiring treatment or hormone replacement may be 
eligible. 
Note: If the participant had major surgery, the participant must have recovered adequately 
from the procedure and/or any complications from the surgery prior to starting study 
intervention. 
23. Parts 3 and 4 only: Has received prior radiotherapy within 2 weeks of start of study 
treatment. Participants must have recovered from all radiation-related toxicities, not require 
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for 
palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease. 
24. History of drug-induced Stevens Johnson syndrome, drug reaction with eosinophilia and 
systemic symptoms (DRESS syndrome) or drug induced toxic epidermal necrolysis. 
25. Anticoagulation, unless patient has been on a stable dose of their anticoagulant for ≥ 4 weeks 
without new thrombotic or clinically significant bleeding events. 
26. Concurrent therapy with any other investigational agent, vaccine, or device. Concomitant 
participation in observational studies is acceptable after Sponsor approval. 

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Prior/Concurrent Clinical Study Experience 
27. Current enrollment or past participation within the last 28 days before first planned dose 
(Cycle 1 Day 1) in any other clinical study involving an investigational study treatment or 
any other type of medical research. 
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous investigational 
agent. 
Diagnostic Assessments 
28. Diabetes mellitus with hemoglobin A1c ≥ 8.5% at screening. 
29. Corrected QT interval (QTc) > 470 milliseconds or known history of familial long QT 
syndrome. 
Other Exclusions 
30. Major surgery in the 8 weeks prior to initiating therapy. 
31. Any serious medical condition (including preexisting autoimmune disease or inflammatory 
disorder), laboratory abnormality, psychiatric condition, or any other significant or unstable 
concurrent medical illness that in the opinion of the Investigator would preclude protocol 
adherence or would make the safety of the study drug difficult to assess. 
5.3 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but do not 
meet inclusion/exclusion criteria for study treatment. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure patients to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened 1 time. Informed consent is required before patients can be rescreened if outside the 
original 28-day screening window. See Section 10.1.3 for Informed Consent Process details. 
6 STUDY TREATMENT 
Study drug is defined as any investigational intervention(s), non-investigational product(s), 
marketed product(s), placebo, or medical device(s) intended to be administered to a study patient 
according to the study protocol. 
Refer to the Pharmacy Instructions for more detailed information regarding the storage, 
preparation, destruction, and administration of each treatment. 

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6.1 
Study Drug(s) Administered 
6.1.1 
Investigational Products 
Table 7 
Investigational Products: NL-201 and Pembrolizumab 
Intervention 
Name 
NL-201  
Pembrolizumab (Parts 3 and 4 only) 
Type  
Biologic 
 
Dose 
Formulation 
Solution for infusion 
Solution for infusion 
Unit Dose 
Strength(s) 
See Table 8 and Table 9 
100 mg/vial 
Dosage 
Level(s) 
200 mg Q3W 
Route of 
Administration 
IV infusion 
IV infusion 
Dosing 
Instructions 
NL-201 will be dosed as per the 
Pharmacy Instructions. IV dosing will 
occur either every 21 days (for 
Schedule A) or on Days 1 and 8 of 
every 21-day cycle (for Schedule B). 
For IV:  patients that weigh ≥ 100 kg, 
the dose is capped as to not allow 
more than 100 times the current dose 
level to be administered to a patient at 
1 time (see Table 8 and Table 9). 
Parts 3 and 4 only: NL-201 to be 
administered 30-60 minutes post 
administration of pembrolizumab.  
Pembrolizumab will be administered using IV 
infusion on Day 1 of each 21-day cycle after all 
procedures and assessments have been completed. 
Pembrolizumab will be administered as a dose of 
200 mg using a 30-minute IV infusion. Sites should 
make every effort to target infusion timing to be as 
close to 30 minutes as possible. However, given the 
variability of infusion pumps from site to site, a 
window between -5 minutes and +10 minutes is 
permitted (ie, infusion time is 30 minutes 
(-5 min/+10 min). 
After Cycle 1 trial treatment of pembrolizumab may 
be administered up to 3 days before or after the 
scheduled Day 1 of each cycle due to administrative 
reasons, however, pembrolizumab must always be 
administered on the same day as NL-201 when used 
in combination. 
The Pharmacy Manual contains specific instructions 
for the preparation of the pembrolizumab infusion 
and administration of infusion solution.  
Hospitalization 
Guidance 
Patients will remain in a hospital setting for the first 24 hours after completion of their first 
dose (IV) on study (may be extended per Investigator discretion), and for 8 hours after 
receiving subsequent doses. This period of hospital observation will be reduced to 2 hours for 
patients that have tolerated 3 consecutive doses. 
Required monitoring times may be adjusted by Neoleukin and/or per DMC recommendation 
pending review of safety data. 
Patients should also be advised to stay within a reasonable distance of the clinical site for the 
first week after the first dose. 
Use 
Investigational 
Sourcing 
Provided centrally by the Sponsor. 
Packaging and 
Labeling 
Study drug will be provided in glass 
vials. Each glass vial will be labeled 
as required per country requirement. 
 
DMC = Data Monitoring Committee; IV = intravenous; Q3W = every 3 weeks 

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NOTE: Refer to the Pharmacy Instructions for further details. 
NL-201 will be administered until unacceptable toxicity, disease progression, withdrawal of 
consent, patient or physician decision, or study termination. Patients with progressive disease 
who have experienced clinical benefit from NL-201 will have the option to continue on therapy 
past progression. 
6.1.1.1 
Treatment Beyond Disease Progression 
Because of the possibility of an initial increase in tumor burden caused by immune cell 
infiltration in the setting of a T-cell response (termed pseudoprogression), radiographic 
progression per RECIST 1.1 may not be indicative of true disease progression. The iRECIST 
criteria allows for continued treatment beyond apparent progression of disease in order to 
confirm response. In patients who have initial evidence of radiological disease progression per 
RECIST 1.1, it is at the discretion of the treating physician whether to continue a patient on 
study treatment until repeat imaging is obtained. This clinical judgement decision should be 
based on the patient's overall clinical condition, including performance status, clinical symptoms, 
and laboratory data. Patient may receive study treatment while waiting for confirmation of 
disease progression if they are clinically stable as defined by the following: 
 Evidence of clinical benefit as assessed by the Investigator (without any rapid disease 
progression) 
 Tolerance of NL-201 
 No decline in ECOG performance status that can be attributed to disease progression 
 Absence of tumor progression at critical anatomical sites (eg, leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions 
 Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, no evidence that disease progression may result in 
impending organ impairment) 
When feasible, patient should not be discontinued until progression is confirmed. This allowance 
to continue treatment despite initial radiologic progression takes into account the observation that 
some patients can have a transient tumor flare in the first few months after the start of 
immunotherapy, but with subsequent disease response. Patients that are deemed clinically 
unstable are not required to have repeat imaging for confirmation of disease progression. 
Patients who continue treatment beyond radiographic disease progression per RECIST 1.1 
should be closely monitored clinically and with a follow-up scan in 4 weeks or sooner at the 
Investigator’s discretion. Treatment should be discontinued if clinical deterioration due to 
disease progression occurs at any time, or if persistent disease growth is confirmed in a follow-
up scan. In addition, patients should be discontinued for unacceptable toxicity or for any other 
signs or symptoms of deterioration attributed to disease progression as determined by the 
Investigator after an integrated assessment of radiographic data and clinical status. 

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6.1.2 
Preparation/Handling/Storage/Accountability 
 The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit and storage for all study drug received and any discrepancies are 
reported and resolved before use of the study drug. 
 Only patients enrolled in the study may receive study drug and only authorized site staff may 
supply or administer study drug. All study drug must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the Investigator and authorized site staff. 
 The same lot should be used intra-patient. 
 The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study drug accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
 Further guidance and information for the final disposition of unused study drugs are provided 
in the Pharmacy Instructions. 
6.1.3 
Other Protocol-Required Intervention 
To mitigate potential NL-201-related, cytokine associated toxicities, pre-treatment is required to 
be administered before the start of each NL-201 dose for: 
 NL-201 IV doses ≥ 0.6 µg/kg monotherapy,  
 NL-201 doses in combination with pembrolizumab  
Required Pre-Medication Protocol for NL-201:  
1) Pre-medication Requirement: Administration of an agent from each of the following two 
therapeutic classes must have been completed within 30 to 60 minutes before the start of 
NL-201 administration:  
a) Anti-pyretic agent (325-1000 mg acetaminophen [or equivalent]) and to follow NL-201 
administration with ongoing anti-pyretic as needed to control fever. 
b) Histamine receptor antagonist (50-100 mg diphenhydramine [or equivalent]).  
The specific drugs discussed above should be selected according to the institutional guidelines. 
Cases where a patient has a medical condition that precludes pretreatment should be discussed 
with the Medical Monitor.  
 Hydration Requirement: Unless medically contraindicated, infusion of at least 1 liter of 
normal saline completed on the day of each NL-201 dose administration.   
a) It is recommended that patients be instructed to orally hydrate with at least 1 liter of 
appropriate fluids per day for at least 2 days after each NL-201 dose.  
 Patients should hold all antihypertensive medications for 12 to 48 hours prior to the 
administration of NL-201 unless medically contraindicated. 

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Although continued pre-medication is recommended for all NL-201 administrations, after Cycle 
2, the investigator may adjust the dosage and/or avoid using certain pre-medication agents during 
the treatment, if supported by the investigator’s assessment of the risk from cytokine release 
syndrome, capillary leak syndrome or other infusion-related reactions. 
Pre-medication is also permitted if a patient experiences signs or symptoms of cytokine release 
syndrome, capillary leak syndrome or other infusion-related reaction at lower doses. The DMC 
may recommend further exploration with additional toxicity mitigations, such as steroids. 
For patients that require pre-treatment with antihistamine and/or IV fluids for pembrolizumab, 
dosing of antihistamine should not be repeated before NL-201 and IV fluids should only be 
given prior to pembrolizumab, but as close to the start of pembrolizumab infusion as possible. 
6.1.4 
Cytokine Release Syndrome Management Guidance 
In the event symptoms of cytokine release syndrome occur, (fever, chills, nausea, vomiting and 
hypotension), despite pre-treatment, consider non-steroidal anti-inflammatory drugs (NSAIDs), 
repeat acetaminophen treatment, and repeat anti-pyretic or histamine receptor antagonist 
treatment. IVF boluses should also be considered to support symptomatic hypotension.  
For symptoms of cytokine release syndrome (including hypotension and hypoxia) that persists 
and is unresponsive to above treatment, corticosteroid treatment with short biological half-life as 
per guidance in Table 11 should be considered. Additionally, vasopressor support and/or 
tocilizumab per institutional guidelines should be considered.  
6.1.5 
Excluded Treatments, Medical Devices, and/or Procedures During Study Period 
The following treatments and/or procedures are excluded during the treatment period of the 
study: 
 Antineoplastic systemic chemotherapy or biological therapy 
 Immunotherapy not specified in the protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than NL-201 
 Radiation therapy with the following exceptions: 
o Radiation therapy to a symptomatic, non-target lesion or to the brain may be considered 
after consultation with the Sponsor and medical monitor approval 
o The patient must have clear measurable disease outside of the radiated field 
 Live or live-attenuated vaccines (Note: Killed vaccines are allowed.) 
 Systemic immunosuppressive therapy, with the following exceptions will be allowed: 
o  Stable replacement doses of prednisone ≤ 10 mg/day [or equivalent]   
o Stress dosing treatment of patients with adrenal insufficiency 
o Study drug pre-medications for prophylaxis of study drug-related toxicities 

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o For treatment of any AE (see Table 11 for guidance), provided that the steroid dose is 
tapered to ≤ 10 mg/day prednisone (or equivalent) prior to receiving the next dose of 
NL-201  
 Any other investigational agent, vaccine, or device 
 Any major surgery, unless approved by Medical Monitor 
If the Investigator determines that a participant requires any of the aforementioned treatments for 
any reason, study intervention (NL-201 and for Parts 3 and 4, pembrolizumab) must be 
discontinued. 
6.2 
Dose Modification 
6.2.1 
Dose-Cohort Study Escalation, De-Escalation, and Stopping Rules 
6.2.1.1 
Part 1: Dose Escalation Study of NL-201 Monotherapy 
In Part 1, an mTPI25 will be used to guide dose escalation and de-escalation within each schedule 
(ie, IV Schedule A, IV Schedule B), with the final decision regarding dose assignment being 
made by the DMC. In IV Schedule A, patients will be dosed every 21 days, while in IV Schedule 
B patients will be dosed on Days 1 and 8 of every 21-day cycle. The mTPI design matrix is 
shown in Figure 5. 
Figure 5 
mTPI Design Matrix for Part 1 
 

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Based on review of DLTs, the DMC may initiate step-dosing to improve the tolerability of 
NL-201, wherein 1 or more step-doses below the target dose would be provided prior to reaching 
the target dose (see Section 6.2.1.4). If step-dosing is used, the DLT window would extend from 
the first dose to 21 days after receiving the target dose (ie, would include the initial reduced-dose 
cycles in addition to the first target-dose cycle). Once a patient receives the intended target dose 
for their cohort, subsequent doses for that patient will continue at that dose level unless a delay in 
dosing of > 6 weeks causes washout of the drug, in which case the step-dosing regimen would be 
repeated if the patient is to resume dosing. 
Supported by the mTPI design, the DMC will determine the RP2D and treatment schedule (IV 
Schedule A, IV Schedule  B) for Part 2 by considering the PK, PDn, tolerability, antitumor 
activity, and the occurrence of any cumulative toxicities over multiple cycles of NL-201. 
6.2.1.2 
Part 3: Dose Escalation Study of NL-201 in Combination with 
Pembrolizumab 
In Part 3, an mTPI25 will be used to guide dose escalation and de-escalation for NL-201 within 
each schedule, with the final decision regarding dose assignment being made by the DMC. In 
Schedule A, patients will be dosed every 21 days, while in Schedule B patients will be dosed on 
Days 1 and 8 of every 21day cycle. The mTPI design matrix is shown in Figure 6. 
Figure 6 
mTPI Design Matrix for Part 3 
 

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Based on review of DLTs, the DMC may initiate step-dosing to improve the tolerability of 
NL-201, wherein 1 or more step-doses below the target dose would be provided prior to reaching 
the target dose (see Section 6.2.1.4). If step-dosing is used, the DLT window would extend from 
the first dose to 21 days after receiving the target dose (ie, would include the initial reduced-dose 
cycles in addition to the first target-dose cycle). Once a patient receives the intended target dose 
for their cohort, subsequent doses for that patient will continue at that dose level unless a delay in 
dosing of > 6 weeks causes washout of the drug, in which case the step-dosing regimen would be 
repeated if the patient is to resume dosing. 
Supported by the mTPI design, the DMC will determine the RP2D for NL-201 in combination 
with pembrolizumab and treatment schedule (either A or B) for Part 4 by considering the PK, 
PDn, and any cumulative toxicities over multiple cycles of NL-201 in combination with 
pembrolizumab. 
6.2.1.3 
Dose-Limiting Toxicity 
Part 1 
DLT must occur within Cycle 1 (< 21 days from first dose), or prior to completion of 21 days 
after first administration of NL-201 or after reaching the cohort target dose (CTD) in patients 
receiving step-dosing (see Appendix 1 [Section 10.1]). DLT is defined by the following: 
 Any death not clearly due to the underlying disease or extraneous causes  
 Hy’s law: 
o AST/ALT > 3 × ULN, and 
o TBL > 2 × ULN, and 
o Alkaline phosphatase < 2 × ULN without alternative etiology 
o No other reason can be found to explain the combination of increased ALT/AST and 
TBL, such as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug 
capable of causing the observed hepatocellular injury 
 Neutropenic fever 
 ≥ Grade 4 neutropenia or thrombocytopenia > 5 days  
 ≥ Grade 3 thrombocytopenia with bleeding  
 ≥ Grade 4 vomiting/diarrhea of any duration 
 ≥ Grade 3 autoimmune disorder. Examples include, but are not limited to, 
treatment-emergent myasthenia gravis, toxic thyroiditis, bullous pemphigoid, and 
Stevens-Johnson Syndrome 
 ≥ Grade 3 fatigue ≥ 1 week  
 ≥ Grade 3 electrolyte abnormalities that lasts > 72 hours or are symptomatic 
 ≥ Grade 3 lipase and amylase if associated with symptoms of pancreatitis 
 ≥ Grade 3 AST or ALT elevation lasting ≥ 14 days 
 Any other ≥ Grade 3 non-hematologic toxicity that is at least possibly related to the study 
drug 

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 Recurrent Grade 3 infusion-related reaction despite pre-medication, or Grade 4 
infusion-related reaction on the first occurrence 
 Dose delay of > 14 days for the study drug due to an AE 
All AEs of the specified grades will be considered DLTs except those that are clearly and 
incontrovertibly due to disease progression or extraneous causes. 
Part 3 
All toxicities will be graded using Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0 based on the investigator assessment. The DLT window of observation will be during 
Cycle 1.  
The occurrence of any of the following toxicities during Cycle 1 will be considered a DLT, if 
assessed by the investigator to be possibly, probably, or definitely related to study treatment 
administration.  
 Grade 4 nonhematologic toxicity (not laboratory). 
 Grade 4 hematologic toxicity lasting ≥ 7 days, except thrombocytopenia: 
o Grade 4 thrombocytopenia of any duration 
o Grade 3 thrombocytopenia associated with clinically significant bleeding 
 Any nonhematologic AE ≥ Grade 3 in severity should be considered a DLT, with the 
following exceptions: Grade 3 fatigue lasting ≤ 3 days; Grade 3 diarrhea, nausea, or vomiting 
without use of anti-emetics or anti-diarrheals per standard of care; Grade 3 rash without use 
of corticosteroids or anti-inflammatory agents per standard of care. 
 Any Grade 3 or Grade 4 non-hematologic laboratory value if: 
o Clinically significant medical intervention is required to treat the participant or 
o The abnormality leads to hospitalization, or 
o The abnormality persists for > 1 week. 
o The abnormality results in a drug-induced liver injury (DILI)   
o Exceptions: Clinically nonsignificant, treatable, or reversible laboratory abnormalities 
including liver function tests, uric acid, etc. 
 Febrile neutropenia Grade 3 or Grade 4: 
o Grade 3 is defined as ANC < 1000/mm3 with a single temperature of > 38.3°C 
(101°F) or a sustained temperature of ≥ 38°C (100.4°F) for more than 1 hour 
o Grade 4 is defined as ANC < 1000/mm3 with a single temperature of > 38.3°C 
(101°F) or a sustained temperature of ≥ 38°C (100.4°F) for more than 1 hour, with 
life-threatening consequences and urgent intervention indicated. 
 Prolonged delay (> 2 weeks) in initiating Cycle 2 due to treatment-related toxicity. 
 Any treatment-related toxicity that causes the participant to discontinue treatment during 
Cycle 1. 
 Missing > 25% of NL-201 doses as a result of drug-related AE(s) during the first cycle. 
 Grade 5 toxicity. 

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6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, Permanent 
Discontinuation 
6.2.2.1 
NL-201 Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Patients that experience a DLT may be dose-reduced or withdrawn from the study after 
discussion with the medical monitor. The reason for dose change of NL-201 is to be recorded on 
each patient’s case report form (CRF). Dose escalation patients and expansion patients may also 
experience delays, reductions and other dose adjustments. Dose may be delayed up to 21 days; 
any delay beyond 21 days must be approved by the medical monitor. If Cycle 2 is skipped, then 
PK, antitumor activity, cytokines, and PDn samples should still be collected at the next cycle 
according to the Cycle 2 schedule and documented as unscheduled visits. 
Refer to Table 11 for guidance on toxicity management and dose modifications. 
For Parts 3 and 4, refer to Section 6.2.2.2 for guidance on withholding NL-201 when given in 
combination with pembrolizumab. 

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6.2.2.2 
Pembrolizumab Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation  
6.2.2.2.1 
Dose Modification and Toxicity Management for Immune-Related AEs 
Associated with Pembrolizumab 
AEs associated with pembrolizumab combination exposure, including coadministration with 
additional compounds may represent an immune-related response. These irAEs may occur 
shortly after the first dose or several months after the last dose of pembrolizumab combination 
treatment and may affect more than one body system simultaneously. Therefore, early 
recognition and initiation of treatment is critical to reduce complications. Based on existing 
clinical study data, most irAEs were reversible and could be managed with interruptions of 
pembrolizumab combination treatment, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. Dose modification and toxicity management guidelines for 
irAEs associated with pembrolizumab are provided in Table 12. 
Attribution of Toxicity:  
When study interventions are administered in combination, attribution of an AE to a single 
component is likely to be difficult. Therefore, while the investigator may attribute a toxicity 
event to the combination, to NL-201 alone, or to pembrolizumab alone, for AEs listed in Table 
12, both interventions must be held according to the criteria in Table 12.  
Holding Study Interventions:  
When study interventions are administered in combination, if the AE is considered 
immune-related, both interventions should be held according to recommended dose 
modifications. 
Restarting Study Interventions:  
Participants may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab in this study, as described in Table 12.  
If the toxicity does not resolve or the criteria for resuming treatment are not met, the participant 
must be discontinued from all study interventions.  
If the toxicities do resolve and conditions are aligned with what is defined in Table 12, the 
combination of NL-201 and pembrolizumab may be restarted at the discretion of the investigator. 
In these cases where the toxicity is attributed to the combination or to NL-201 alone, re-initiation 
of pembrolizumab as a monotherapy may be considered after communication with and 
agreement by the Sponsor. 

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Table 13 
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines 
CTCAE Grade 
Treatment 
Pre-medication at Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the participant 
is deemed medically stable in the 
opinion of the investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤ 24 hrs. 
 
Stop Infusion. 
 
Additional appropriate medical 
therapy may include but is not 
limited to: 
o 
IV fluids 
o 
Antihistamines 
o 
NSAIDs 
o 
Acetaminophen 
o 
Narcotics 
 
Increase monitoring of vital signs as 
medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator. 
 
If symptoms resolve within 1 hour 
of stopping drug infusion, the 
infusion may be restarted at 50% of 
the original infusion rate (eg, from 
100 mL/hr. to 50 mL/hr.). 
Otherwise dosing will be held until 
symptoms resolve and the 
participant should be pre-medicated 
for the next scheduled dose. 
 
Participants who develop Grade 2 
toxicity despite adequate 
pre-medication should be 
permanently discontinued from 
further study drug treatment 
Participant may be pre-medicated 1.5h 
(± 30 minutes) prior to infusion of 
study intervention with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic). 

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CTCAE Grade 
Treatment 
Pre-medication at Subsequent 
Dosing 
Grades 3 or 4 
 
Grade 3: 
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilator support indicated 
 
Stop Infusion. 
 
Additional appropriate medical 
therapy may include but is not 
limited to: 
o 
Epinephrine** 
o 
IV fluids 
o 
Antihistamines 
o 
NSAIDs 
o 
Acetaminophen 
o 
Narcotics 
o 
Oxygen 
o 
Pressors 
o 
Corticosteroids 
 
Increase monitoring of vital signs as 
medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator. 
 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine 
should be used immediately. 
Participant is permanently discontinued 
from further study drug treatment. 
No subsequent dosing 
IV = intravenous; CTCAE = Common Terminology Criteria for Adverse Events; NSAID = non-steroidal 
anti-inflammatory drug 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration. For further information, please refer to the CTCAE V5.0 at 
http://ctep.cancer.gov. 
6.2.2.2.3 
Other Allowed Dose Interruption for Pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical or surgical events and/or unforeseen circumstances not related to study intervention. 
However, study intervention is to be restarted within 3 weeks or 21 days of the originally 
scheduled dose and within 42 days of the previously administered dose, unless otherwise 
discussed with the Sponsor. The reason for interruption is to be documented in the patient's study 
record. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1 
Randomization 
This is an open-label, dose escalation/dose expansion study; patients will not be randomized. 

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6.3.2 
Blinding 
This is an open-label study. 
6.4 
Study Drug Compliance 
When patients are dosed at the site, they will receive study drug directly from the Investigator or 
designee, under medical supervision. The date and time of each dose administered in the clinic 
will be recorded in the source documents and recorded in the CRF. The dose of study drug and 
study patient identification will be confirmed at the time of dosing by a member of the study site 
staff other than the person administering the study drug. 
6.5 
Concomitant Therapy 
Necessary supportive care, including antibiotics, blood products, IV fluids, anti-diarrheals, 
anti-emetics will be allowed per local standard of care. All treatments that the investigator 
considers necessary for a participant’s welfare may be administered at the discretion of the 
investigator in keeping with the community standards of medical care. 
Any medication or vaccine (including over-the-counter or prescription medicines, and/or herbal 
supplements) that the patient is receiving at the time of enrollment or receives during the study 
must be recorded along with: 
 Reason for use 
 Dates of administration including start and end dates (if known) 
 Concomitant therapies of interest only and if available during the course of the study: dosage 
information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
All concomitant medications received within 28 days prior to the first dose of study treatment 
and up to 30 days after the last dose of study treatment will be recorded. All concomitant 
medications administered during SAEs or ECIs are to be recorded. SAEs and events of clinical 
interest (ECIs) are defined in Section 8.4. 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 6.2.2.2.1.  
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, the 
investigator does not need to follow the treatment guidance. Refer to Table 12 in 
Section 6.2.2.2.1 for guidelines regarding dose modification and supportive care.  

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It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
6.6 
Intervention After the End of the Study 
Neoleukin reserves the unilateral right, at its sole discretion, to determine whether to supply 
NL-201 and by what mechanism, after termination of the study and before the product(s) is/are 
available commercially. 
Parts 3 and 4 only: Participants who are still on study intervention at the time of study 
completion/termination may continue to receive study intervention if they are experiencing 
clinical benefit. The continued access to study intervention will end when a criterion for 
discontinuation is met or 35 doses of pembrolizumab have been administered. 
7 DISCONTINUATION OF STUDY TREATMENT AND PATIENT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Treatment 
Patients can decline to continue receiving investigational product and/or other protocol-required 
therapies or procedures at any time during the study but continue participation in the study. If 
this occurs, the Investigator is to discuss with the patient the appropriate processes for 
discontinuation from investigational product or other protocol-required therapies and must 
discuss with the patient the possibilities for continuation of the Schedule of Events (see 
Section 1.3) including different options of follow-up (eg, in person, by phone/mail, through 
family/friends, in correspondence/communication with other treating physicians, from the review 
of medical records) and collection of data, including endpoints and AEs, as applicable and must 
document this decision in the patient’s source documentation. Patients who have discontinued 
investigational product and/or other protocol-required therapies or procedures should not be 
automatically removed from the study. Whenever safe and feasible, it is imperative that patients 
remain on-study to ensure safety surveillance and/or collection of outcome data. 
Reasons for removal from study drug may include any of the following: 
 AEs (including any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 6.2.2) 
 Pregnancy (see Section 8.3.5 and Section 10.4) 
 Disease-state criteria (eg, progressive disease that requires discontinuation of the study drug) 
 Protocol deviation 
 Requires alternative therapy 
 Sponsor decision 
 Patient request to discontinue study drug 

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 Parts 3 and 4 only: Discontinuation of treatment may be considered for participants who have 
attained a confirmed CR and have been treated for at least 8 cycles (at least 24 weeks), 
receiving 2 cycles of the combination including 2 doses of pembrolizumab and at least 
2 doses of NL-201 (if still being treated with combination therapy) beyond the date when the 
initial CR was declared. 
 Parts 3 and 4 only: Completion of 35 administrations (approximately 2 years) with 
pembrolizumab 
Note: The number of administrations is calculated starting with the first dose of 
pembrolizumab. 
See the Schedule of Events (Section 1.3) for data to be collected at the end of treatment visit and 
follow-up and for any further evaluations that need to be completed. 
7.2 
Discontinuation/Withdrawal From the Study 
An Investigator may discontinue or withdraw a patient from the study for the following reasons: 
 Sponsor decision 
 Withdrawal of consent from study 
 Death 
 Lost to follow-up 
 Other 
At the time of discontinuing from the study, if possible, an end of treatment visit should be 
conducted, as shown in the Schedule of Events (Section 1.3). See Schedule of Events for data to 
be collected at the time of study discontinuation and follow-up and for any further evaluations 
that need to be completed. 
The patient will be permanently discontinued both from the study drug and from the study at that 
time. 
If the patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site study records. Any samples 
untested at withdrawal will be retained and tested if the patient does not request destruction of 
samples. 
7.3 
Lost to Follow-Up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 

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The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
 The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit schedule 
and ascertain whether or not the patient wishes to and/or should continue in the study. 
 Before a patient is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the patient (where possible, 3 telephone calls and, if necessary, a 
certified letter to the patient’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the patient’s source documentation. 
 Should the patient continue to be unreachable, he/she will be considered to have withdrawn 
from the study.  
 For patients who are lost to follow-up, the Investigator can search publicly available records 
(where permitted) to ascertain survival status. This ensures that the data set(s) produced as an 
outcome of the study is/are as comprehensive as possible. 
Discontinuation of specific sites or of the study as a whole are handled in Section 10.1.10. 
8 STUDY ASSESSMENTS AND PROCEDURES 
 Only patients who meet all inclusion and exclusion criteria specified in Section 5 will be 
enrolled in this study. 
 Study procedures and their timing are summarized in the Schedule of Events (Section 1.3). 
 Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
drug. 
 Adherence to the study design requirements, including those specified in the Schedule of 
Events, is essential and required for study conduct. 
 All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable. ECOG and laboratory evaluations required for Cycle 1 Day 1 (within 
48 hours prior to dosing) must conform to the following criteria prior to first dose of 
study drug on Cycle 1 Day 1:  
1. Patients with ECOG performance status of 0 or 1  
2. Platelets ≥ 100,000/mm3 
3. ANC > 1500/mm3 
4. Hemoglobin: Parts 1 and 2: ≥ 8.0 g/dL; Parts 3 and 4: ≥ 9.0 g/dL (NOTE: Criteria must be 
met without packed red blood cell transfusion within the prior 2 weeks. Participants can be 
on stable dose of erythropoietin [≥ approximately 3 months]). 
5. Lymphocyte count ≥ 500/mm3 
6. Eosinophils < 1000/mm3 

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7. Renal function: eGFR ≥ 50 mL/min/1.73 m2 as determined by 2009 CKD-EPI equation,29 
or creatinine WNL 
8. AST and ALT: Parts 1 and 2: ≤ 3x ULN, or ≤ 5x ULN if known liver malignancy or 
metastasis; Parts 3 and 4: ≤ 2.5x ULN, or ≤ 5x ULN if known liver malignancy or metastasis 
9. TBL WNL, or ≤ 3x ULN if known Gilbert’s syndrome 
10. Coagulation: INR OR PT ≤ 1.5 x ULN 
11. Highly sensitive pregnancy test (serum or urine) confirming no pregnancy 
 Procedures conducted as part of the patient’s routine clinical management (eg, blood count) 
and obtained before signing of the ICF may be utilized for screening or baseline purposes, 
provided the procedures met the protocol-specified criteria and were performed within the 
time frame defined in the Schedule of Events. 
8.1 
General Study Periods 
8.1.1 
Screening and Enrollment 
Informed consent must be obtained before completing any screening procedure, discontinuation 
of standard therapy for any disallowed therapy, or obtaining sensitive medical or social 
information (eg, HIV-positivity status). After the patient has signed the ICF, the study staff 
registers the patient in screening log or CRF in order to assess eligibility for participation. 
Patients who meet all inclusion criteria and none of the exclusion criteria are eligible for 
enrollment into this study. All screening evaluations must be performed within 28 days prior 
to Cycle 1 Day 1. 
8.1.2 
Treatment Period 
Visits will occur per the Schedule of Events (Section 1.3). The date of the first dose of 
protocol-required therapies is defined as Day 1. All subsequent doses and study visits will be 
scheduled based on the Day 1 date. Administration of protocol-required therapies is to be 
administered last during each visit that it is required, unless otherwise indicated in the Schedule 
of Events. 
After discontinuation from study treatment, patients in Parts 2 and 4, who do not have confirmed 
disease progression are required to continue disease response assessments and report new 
anti-cancer treatment per the Schedule of Events (Section 1.3) and Section 8.1.5. Frequency of 
these disease response assessments will continue per the Schedule of Events until first 
subsequent anti-cancer treatment, death, lost to follow-up, withdrawal of consent, or confirmed 
disease progression, whichever comes first. Following confirmed disease progression, all 
patients enter long-term follow-up and will be assessed as per the Schedule of Events 
(Section 1.3) and Section 8.1.5. 
8.1.3 
End of Treatment 
Upon permanent discontinuation of study drug for any reason, an end of treatment visit should be 
scheduled as soon as possible, but within 30 days following cessation of study treatment or 

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before patient initiates new anti-cancer therapy, whichever is earlier. For Parts 1 and 3 (dose 
escalation), if study treatment is discontinued for reasons other than death, withdrawal of 
consent, lost to follow-up, or study closure, a CT scan should be performed at EOT visit (within 
+ 2 weeks) if a post-baseline CT scan has not been performed within 5 weeks prior to the EOT 
visit. Adverse events and concomitant medication will be followed up to 30 days after last dose 
of NL-201. 
For Parts 3 and 4, all AEs will be followed up to 30 days following cessation of study treatment 
and all SAEs will be followed up to 90 days following cessation of study treatment, or 30 days 
following cessation of study treatment if the participant initiates new anti-cancer therapy, 
whichever is earlier. 
Patients who discontinue from treatment due to progressive diseased based on RECIST or 
iRECIST or initiation of new anti-cancer therapy will enter long-term follow-up and will be 
followed per the Schedule of Events (Section 1.3) and Section 8.1.5. 
8.1.4 
Radiological Follow-Up 
For Parts 2 and 4 (expansion cohorts), patients who discontinue from treatment due to reasons 
other than progressive disease based on RECIST or iRECIST will be followed in radiologic 
follow-up for documented progressive disease by RECIST and will enter long-term follow-up. If 
subsequent anti-cancer therapies are initiated during the period of time between discontinuation 
of treatment and progressive disease documentation, the patient will no longer be radiologically 
assessed for progression and will enter long-term follow-up.  
8.1.5 
Long-Term Follow-Up 
Once confirmed disease progression (by RECIST 1.1 or iRECIST) or initiation of new 
anti-cancer therapy beyond NL-201, patients enter long-term follow-up. The site will call 
patients every 6 months (± 1 month) to assess survival. Patients in Parts 2 and 4 will also have 
any subsequent anti-cancer therapies recorded during long-term follow-up. Long-term follow-up 
will continue until death, withdrawal of consent, lost to follow-up, or study closure, whichever 
occurs first, for a maximum of 2 years after end of treatment. The total study duration, including 
all follow-up, is expected to be approximately 5 years. 
8.2 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the Schedule of Events 
(Section 1.3). 
8.2.1 
Assessment of Clinical Outcome: Imaging 
Clinical outcome is measured with tumor assessment/response related endpoints as assessed 
according to RECIST 1.1,30 and additionally, as assessed according to RECIST for use in cancer 
immunotherapy trials (iRECIST).31 

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At each tumor assessment visit, all images (as scheduled by the study protocol and additionally, 
all images as medically indicated) will be interpreted (assessment of response) by a radiologist 
according to RECIST 1.1 and additionally according to iRECIST. In Part 1, assessments will be 
performed locally. In Part 2, images must be sent to the central lab for assessment. 
It is at the discretion of the treating Investigator whether to withdraw the patient from the study 
based on disease progression as determined by tumor assessment according to RECIST 1.1 or 
iRECIST or, in exceptional cases, based on clinical signs of progression. 
Imaging for tumor response assessment is performed as indicated in the Schedule of Events 
(Section 1.3). During screening, baseline imaging by computed tomography (CT) of at least the 
chest, abdomen, and pelvis must be performed within 28 days prior to Cycle 1 Day 1. Radiologic 
evaluation of the brain is required for patients with history of CNS metastasis, or neurologic 
abnormality that suggests possible CNS metastasis or malignancy. Depending on the tumor 
entity, and if clinically indicated, imaging of further areas (eg, bone) should be conducted. 
During the treatment period (and long-term follow-up in Parts 2 and 4 if study treatment was 
discontinued for reasons other than disease progression), CT of at least chest, abdomen, pelvis, 
and all areas affected with tumor lesions according to baseline imaging is performed. If clinically 
indicated, imaging of the brain and further areas should be conducted. Radiological imaging can 
also be done at additional times, if clinically indicated. All radiological images should be 
considered for tumor response assessment. If the patient cannot tolerate CT-contrast agents, 
assessments may be performed using magnetic resonance imaging (MRI). In a given patient, the 
same imaging modality and technique (eg, slice thickness, field of view) should be used for all 
scans during the study (if unable to use the same imaging modality and technique, the 
corresponding data will be excluded from the efficacy analysis). 
For Parts 2 and 4 radiologic follow-up should continue until radiologic disease progression, start 
of a new anti-cancer treatment, loss to follow-up, or death. 
CR and PR require confirmation by a repeat assessment no earlier than 4 weeks after the imaging 
criteria for response is first met. 
Tumor images to determine tumor assessment/response rates and PFS will be evaluated based on 
RECIST 1.1 and additionally on iRECIST. For more detailed guidance on RECIST 1.1 please 
refer to the original publication30 and 2 further publications should be considered in case of need 
for further definitions.32,33 
For details regarding methods of lesion measurement and tumor response, see Section 10.6. 
8.3 
Safety Assessments 
Planned time points for all safety assessments are provided in the Schedule of Events 
(Section 1.3). 

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8.3.1 
Physical Examinations 
 Screening and end of treatment visits: A complete physical examination will include, at a 
minimum, assessments of the following body parts/systems: skin, abdomen, extremities, 
head, neck, heart, lungs, lymph nodes (if palpable) and neurological systems. 
 All other time points: A brief physical examination will include, at a minimum, assessments 
of the skin, lungs, abdomen, and cardiovascular system. 
8.3.2 
Vital Signs 
 Temperature, pulse rate, oxygen saturation, blood pressure, and respiration rate will be 
assessed. 
 Vital signs will be measured in a semi-supine position after 5 minutes rest. Blood pressure 
will include both systolic and diastolic blood pressures. 
8.3.3 
Electrocardiograms 
 12-lead ECG will be obtained as outlined in the Schedule of Events (see Section 1.3) using 
an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and 
QTc intervals. 
8.3.4 
Clinical Safety Laboratory Assessments 
 See Section 10.2 for the list of clinical laboratory tests to be performed and to the Schedule 
of Events (Section 1.3) for the timing and frequency. 
 The Investigator must review the laboratory report, document this review, and record in the 
AE section of the CRF any clinically relevant changes occurring during the study. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those that are not associated with the underlying disease, unless 
judged by the Investigator to be more severe than expected for the patient's condition. 
 All laboratory tests with values considered clinically significantly abnormal during 
participation in the study (Cycle 1 Day 1 through 30 days after the last dose of NL-201) 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator or medical monitor. 
o If such values do not return to normal/baseline within a period of time judged reasonable 
by the Investigator, the etiology should be identified and the Sponsor notified. 
o All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Events. 
o If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in patient management or are considered 
clinically significant by the Investigator (eg, SAE, or AE, or dose modification), then the 
results must be recorded. 

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8.3.5 
Pregnancy Testing 
 Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria. 
 Highly sensitive pregnancy testing should be conducted before dosing on Day 1 of every 
cycle and other time points per the Schedule of Events. 
 Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
Investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the patient's participation in the study. 
8.3.6 
Vital Status 
Vital status must be obtained for all patients within the limits of local law. This includes patients 
who may have discontinued study visits with or without withdrawing consent and should include 
interrogation of public databases, if necessary. If deceased, the date and reported cause of death 
should be obtained. 
8.4 
Adverse Events and Serious Adverse Events 
The definitions of an AE and SAE can be found in Section 10.3. 
Adverse event(s) will be reported by the patient (or, when appropriate, by a caregiver, or 
surrogate). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study drug or study procedures, or that caused 
the patient to discontinue the study drug or study (see Section 7). 
8.4.1 
Time Period and Frequency for Collecting Adverse Events and Serious Adverse 
Events Information 
Adverse events related to study-required procedures will be collected from signing of the ICF 
until the first dose of study drug. All AEs will be collected during the treatment period and 
followed for 30 days after the final dose of NL-201. In Parts 3 and 4, SAEs will be collected for 
90 days following cessation of study treatment, or 30 days following cessation of study treatment 
if the participant initiates new anti-cancer therapy, whichever is earlier. 
Medical occurrences not related to study-required procedures that begin before the start of study 
drug but after obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the CRF not the AE section. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 

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Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a patient has been discharged from the study, and he/she considers the event to be reasonably 
related to the study drug or study participation, the Investigator must promptly notify the 
Sponsor. 
In general, an abnormal laboratory value should not be recorded as an AE unless it is associated 
with clinical sign or symptoms, requires intervention, results in a SAE, or results in study 
termination or interruption, delay or discontinuation of study treatment. 
8.4.2 
Events of Clinical Interest (ECI) 
Selected non-serious and SAEs are also known as ECI and must be reported to the Sponsor 
within 24 hours of awareness.  
Events of clinical interest for this trial include:  
 An elevated AST or ALT lab value that is greater than or equal to 3 x the ULN and an 
elevated TBL lab value that is greater than or equal to 2 x the ULN and, at the same time, an 
alkaline phosphatase lab value that is less than 2 x the ULN, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing. 
Note: These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. The trial site guidance for assessment and follow up of 
these criteria can be made available. It may also be appropriate to conduct additional 
evaluation for an underlying etiology in the setting of abnormalities of liver blood tests 
including AST, ALT, bilirubin, and alkaline phosphatase that do not meet the criteria noted 
above. In these cases, the decision to proceed with additional evaluation will be made 
through consultation between the study investigators and the Sponsor Clinical Director. 
However, abnormalities of liver blood tests that do not meet the criteria noted above are not 
ECIs for this trial. 
8.4.3 
Method of Detecting Adverse Events and Serious Adverse Events 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences. 
8.4.4 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the patient is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is given in Section 10.3. 

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8.4.5 
Regulatory Reporting Requirements for Serious Adverse Events 
 All SAEs must be reported within 24 hours of site awareness by the Investigator to the 
Sponsor so that legal obligations and ethical responsibilities towards the safety of patients 
and the safety of a study drug under clinical investigation are met. 
 The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study drug under clinical investigation. The Sponsor 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and Investigators. 
 Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. 
 An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
8.4.6 
Pregnancy  
 Details of all pregnancies in female patients and female partners of male patients and 
exposure during breastfeeding will be collected after the start of study drug and until 60 days 
after the last dose of NL-201 and 120 days after the last dose of pembrolizumab, or 30 days 
following cessation of study treatment if the patient initiates new anti-cancer therapy must be 
reported by the investigator. 
o If a participant inadvertently becomes pregnant while on study treatment the 
participant will be immediately discontinued from study treatment. 
 If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 10.4. 
 Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.5 
Reporting and Treatment of Overdose 
Any overdose of the Sponsor's product, as defined below, should be reported to the Sponsor 
within 24 hours of awareness, regardless if associated with clinical symptoms or abnormal 
laboratory results. 
For this study, any dose of NL-201 greater than 20% of target dose within a 24-hour time period 
will be considered an overdose. 
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 

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2. Consider standard supportive therapy including, if necessary, hospitalization for observation 
and monitoring. 
3. Closely monitor the patient for any AE/SAE and laboratory abnormalities. 
4. Obtain a serum sample for PK analysis if requested by the Medical Monitor (determined on a 
case-by-case basis). 
5. Document the quantity of the excess dose as well as the duration of the overdose in the CRF. 
Decisions regarding dose modifications will be made by the Investigator in consultation with the 
Medical Monitor based on the clinical evaluation of the patient. 
Parts 3 and 4 only: For this study, an overdose of pembrolizumab will be defined as any dose of 
1000 mg or greater.  
No specific information is available on the treatment of overdose of pembrolizumab. In the event 
of overdose, the participant should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated. 
8.6 
Pharmacokinetics 
Serial serum samples for PK analysis of NL-201 will be collected during Cycles 1 and 2 for IV 
Schedule A, IV Schedule B. In addition, trough samples (ie, pre-dose) and peak samples 
(ie, 1 hour after dosing) will be collected at prespecified time points as described in the Schedule 
of Events (Section 1.3). The primary purpose of collecting these samples is to measure the serum 
concentrations of NL-201 to characterize the PK of NL-201 after single- and multiple-dose 
administration. This information will also further inform the building of PK models to describe 
NL-201 PK and such models will be used to predict NL-201 serum levels under different dosing 
scenarios to help select an appropriate dose/schedule of NL-201. The dates and exact times of 
NL-201 administration before collecting PK samples and the dates and exact times of post-dose 
PK sample collections will be recorded. PK characterization will assess both NL-201 and the 
free protein.  
8.7 
Pharmacodynamics/Biomarkers 
8.7.1 
Exploratory Assessment of NL-201-Dependent Effects in Blood 
Blood samples will be collected as indicated in the Schedule of Events (Section 1.3) to assess the 
PDn effect of NL-201 during therapy. Planned assays include flow-cytometric analysis on 
PBMCs as well as serum measurements of inflammatory cytokines. 
8.7.2 
Exploratory Assessment of NL-201-Dependent Effects on the Tumor 
Microenvironment (Patients who Have Consented to Tumor Biopsy Collection Part 1, 
Part 2 and Part 4) 
To understand the relationship between the biological characteristics of tumors before treatment 
and patient outcomes, tissue from pre-treatment (archival or freshly obtained specimens) and 
on-treatment tumor biopsies will be examined. Biopsies will be assessed for specific PD, 

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predictive, and prognostic biomarkers in the tumor. To characterize the malignancy and response 
to study treatment, biomarker assessments in tumor biospecimens may include measurements of 
NL-201 potential metabolites, PD-L1, as well as characterization of the TME, drug target(s), 
tumor subtyping, and/or gene expression. Assays may include immunohistochemistry (IHC) and 
next generation sequencing of ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). 
Tumor biopsies should be performed as indicated in the Schedule of Events (Section 1.3). 
Biopsies should be collected by appropriately trained clinical site personnel (eg, an 
interventional radiologist for internal tumor biopsies; trained personnel such as a dermatologist 
for cutaneous tumor biopsies). It is strongly recommended that a pathologist be present during 
biopsies when feasible to ensure sufficient tumor content of the biopsy location, and to confirm 
that biopsy acquisition and processing techniques are optimal.34 
Tumor biopsies will be collected for the assessment of NL-201-mediated effects on the tumor 
microenvironment (TME), including paired pre- and post-treatment biopsies. Biopsy tissues for 
exploratory analysis should be in FFPE blocks when possible, and secondarily as slides. 
Analyses will include, but will not necessarily be limited to, transcriptional profiling and 
multiplex immunohistochemistry and to assess treatment-related changes in immune cell 
populations, phenotypes and spatial organization within the TME. 
8.7.3 
PD-L1 Expression (Part 4 Only) 
Tumor tissue (archival or fresh biopsy) will be collected at screening to assess PD-L1 
expression. 
8.7.4 
Tumor Mutational Burden Determination (Part 4 Only) 
Tumor tissue (archival or fresh biopsy, as available) will be collected at screening to assess 
tumor mutational burden (TMB). 
8.8 
Immunogenicity Assessments 
Antibodies to NL-201 will be evaluated in blood samples collected from all patients according to 
the Schedule of Events. These samples will be tested by the Sponsor's designee. 
Blood samples will be screened for antibodies binding to NL-201 and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to NL-201 and/or further characterize the immunogenicity of NL-201. 
The detection and characterization of antibodies to NL-201 will be performed using a validated 
assay method under the supervision of the Sponsor. All samples collected for detection of 
antibodies to study drug will also be evaluated for NL-201 serum concentration to enable 
interpretation of the antibody data. Antibodies may be further characterized and/or evaluated for 
their ability to neutralize the activity of the study drug(s). 

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9 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypothesis 
For NL-201 monotherapy (Parts 1 and 2), no statistical hypothesis will be tested during dose 
escalation in Part 1. In Part 2, the null hypothesis that the response rate to NL-201 is ≤ 2.5% in 
each cohort will be tested against the alternative hypothesis that the response rate is ≥ 15%. 
For NL-201 in combination with pembrolizumab (Parts 3 and 4), no statistical hypothesis will be 
tested during dose escalation in Part 3 and dose expansion in Part 4. 
9.2 
Sample Size Determination 
In Part 1, 2 NL-201 monotherapy dosing schedules (IV Schedule A, IV Schedule B) will be 
evaluated with the goal being to determine the MTD of each schedule. The MTD is defined as 
the highest dose for which the probability of a patient experiencing a DLT with NL-201 is ≤ 
33%. Based on the totality of data arising in Part 1, the DMC will determine a RP2D and 
treatment schedule of NL-201 for Part 2 that will not exceed the MTD. 
Dose escalation in Part 1 will be guided by an mTPI design with up to approximately 50 enrolled 
per schedule as depicted in Figure 5. This design and number of patients per schedule provides a 
high likelihood of correctly identifying the MTD with approximately one half of the patients 
(ie, approximately n = 15) being exposed to the MTD, very few being exposed to lower, less 
effective doses and relatively few being exposed to the MTD+1 dose. 
In addition, there will be backfill cohorts (up to approximately 12 patients in total) , at certain 
DMC-cleared dose levels and schedules, to collect, pharmacokinetic, pharmacodynamic and 
response data in certain tumor types or to explore additional pre-medication regimens (eg. 
steroids). The decision to enroll patients into backfill cohorts and to define the patients to be 
enrolled will be made by the Sponsor.  
Note: “Enrolled” means any patient that has met all of the study inclusion and exclusion criteria 
and is eligible to receive study drug.  
In Part 2, an expansion cohort study will evaluate safety and estimate antitumor activity of 
NL-201 as a monotherapy at the RP2D in 2 cohorts of patients: (1) melanoma and (2) RCC. 
A Simon’s 2-stage design will be used for each cohort independently to test the null hypothesis 
that the true monotherapy response rate is ≤ 2.5% vs the alternative that the true response rate is 
≥ 15%. In the first stage, 18 patients will be evaluated. If 0/18 objective responses are seen, 
recruitment to the cohort will be stopped for futility. Otherwise, a further 12 patients will be 
evaluated for a total of 30 patients. This design provides 80% power and a Type I error rate of 
0.031 under the stated null and alternative hypotheses.  
In Part 3, with the mTPI study design, the exact number of patients needed to complete the dose 
escalation is unknown because it depends on the number of cohorts required to reach MTD and 
the number of patients in each cohort. Dose escalation will be conducted in up to 42 adult 

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patients (21 patients in each schedule) with advanced solid tumors to determine the safety 
profile, RP2D and treatment schedule of NL-201 in combination with pembrolizumab.  
No formal hypothesis test is planned for Part 4 (dose expansion). The sample size of 30 is 
considered appropriate and sufficient to confirm the combination RP2D. The sample size for 
each cohort was based on the consideration of precision of estimates of ORR. For a sample size 
of 30, below is the summary of expected precision of ORR estimates. For example, if there is 
6 responders observed among 30 patients treated, the observed ORR will be 20%, with 95% 
confidence interval of (7.7%, 38.6%). 
Table 14 
Observed ORR and 95% Confidence Interval with a Sample Size of 30 
Number of Responders 
Observed ORR 
95% Confidence Interval* 
6 
20% 
(7.7%, 38.6%) 
9 
30% 
(14.7%, 49.4%) 
12 
40% 
(22.7%, 59.4%) 
ORR = objective response rate 
* Based on Clopper-Pearson method (1934) 
9.3 
Populations for Analyses 
For purposes of analysis, the following populations are defined in Table 15. 
Table 15 
Populations for Analyses 
Population 
Description 
Safety Evaluable Population 
For Parts 1 and 2, all patients who receive any amount of study drug (NL-201) 
will be considered evaluable for safety regardless of the duration of NL-201 
treatment. This population is defined for Part 1, and Part 2.  
For Parts 3 and 4, all patients who receive any amount of study drug (NL-201 
or pembrolizumab) will be considered evaluable for safety regardless of the 
duration of treatment. 
This population is defined for Part 1 and Part 3, and Part 2 and Part 4, 
expansion cohorts. This population will be used to summarize safety 
parameters. 
Efficacy Evaluable Population 
For Parts 1 and 2, all patients with measurable disease by RECIST, who 
receive any amount of study drug (NL-201) or who discontinue study drug 
early due to disease progression and/or death will be considered evaluable for 
efficacy.  
For Parts 3 and 4, all patients with measurable disease by RECIST, who 
receive any amount of study drug (NL-201 or pembrolizumab) or who 
discontinue study drug early due to disease progression and/or death will be 
considered evaluable for efficacy. 
This population is defined for Part 1 and Part 3,  and Part 2 and Part 4. 
DLT-Evaluable Population 
Patients enrolled into Part 1 or Part 3 who either complete the first 21 days of 
study or who experience a DLT. 
DLT = dose limiting toxicity; RECIST = Response Evaluation Criteria in Solid Tumors 

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9.4 
Statistical Analyses 
9.4.1 
General Considerations 
Demographic data and disease-related characteristics will be summarized separately for Part 1, 
by schedule (eg, IV Schedule A, IV Schedule B), and Part 2, by expansion cohort. Descriptive 
statistics (count and percent, mean, median, standard deviation, minimum, maximum) will be 
used. All patient data, efficacy and safety data will be summarized. Data from Parts 3 and 4 
(NL-201 in combination with pembrolizumab) will be summarized in a similar manner. 
A full Statistical Analysis Plan will be prepared to describe in full the statistical methods and 
analyses to be applied to the data arising in this study. 
9.4.2 
Determination of MTD in Part 1 and Part 3 
For each schedule (IV Schedule A, IV Schedule B ) in Part 1 (NL-201 monotherapy), the 
determination of MTD will be the highest dose for which the probability of a patient 
experiencing a DLT with NL-201 during Cycle 1 is ≤ 33%. Refer to Section 9.2 for more details. 
Similarly, for each schedule separately in Part 3 (NL-201 in combination with pembrolizumab), 
the determination of MTD will be the highest dose for which the probability of a patient 
experiencing a DLT with NL-201 during Cycle 1 is ≤ 33%. Refer to Section 9.2 for more details. 
9.4.3 
Assessment of Preliminary Efficacy in Part 2 and Part 4 
For NL-201 monotherapy, while tumor response data based on both RECIST 1.1 and iRECIST 
will be collected from all patients in dose escalation and expansion, formal analysis of tumor 
response will only be performed for the expansion cohorts in Part 2 based on iRECIST. Results 
will be presented and summarized using an exact 95% binomial confidence interval. 
Other response-related efficacy parameters including time to response, duration of response, and 
clinical benefit rate will be also summarized by Part 2 expansion cohort. 
In expansion cohorts in Part 2, OS and progression free survival (defined as the time from study 
entry to the time of disease progression or death from any cause) will be displayed graphically 
using Kaplan-Meier plots. Median PFS and OS will be extracted from the Kaplan-Meier plots 
along with their associated 95% confidence intervals. PFS and OS rates at 3 monthly intervals 
will also be extracted. Patients who do not experience progression or death will be censored at 
their last clinic visit contact for the assessment of disease progression. 
For NL-201 in combination with pembrolizumab, data from Part 4 dose expansion cohort will be 
summarized and analyzed in a similar manner. 
9.4.4 
Pharmacokinetics 
The PK concentrations and summary parameters of NL-201 will be listed, summarized and 
displayed graphically by schedules in Part 1 and the 2 expansion cohorts in Part 2. 

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Individual and mean serum concentration data will be plotted over time. Descriptive statistics 
will be presented for serum PK parameters including (but not limited to) Cmax, tmax, AUCt, 
AUCinf, t1/2, CL, volume of distribution (Vd), etc. 
PK data collected in this study are intended to additionally contribute to population PK 
modeling. These models may be used to predict NL-201 PK in different dosing scenarios to 
further support the selection of a RP2D of NL-201. The population PK analyses may include 
data collected in additional NL-201 clinical studies. The analysis plan for population PK 
modeling will be separately developed and the results of such modeling will not be presented in 
the clinical study report for this study but will be presented in a separate report. 
The PK data from Parts 3 and 4 will be summarized similarly. 
9.4.5 
Exploratory Evaluations 
The relationship between tumor response and markers of immune cell activation and exhaustion, 
and also inflammatory cytokine levels and/or other biomarkers of interest will be explored via 
logistic regression. Data from Part 1, by schedules, and the 2 expansion cohorts in Part 2 will be 
included. 
Similar exploratory analyses may be performed for data from Parts 3 and 4, as appropriate. 
9.4.6 
Safety Data 
Safety data will be summarized for the safety evaluable population for Part 1 by schedule (eg, IV 
Schedule A, IV Schedule B), and Part 2; a summary will also be made by dose/schedule 
combining safety data from all parts of the study as appropriate. These data will include AEs and 
laboratory parameters. Adverse event terms will be coded using the Medical Dictionary for Drug 
Regulatory Activities (MedDRA®, version 23.0 or later). Adverse events will be summarized by 
body system, preferred term, severity, and relationship to treatment, with procedure-related 
events from Screening summarized separately from treatment-emergent AE. Serious adverse 
events, deaths, and AEs leading to early discontinuation of study drug will be summarized. 
Laboratory parameters will be summarized by maximum National Cancer Institute CTCAE 
severity grade and also by change from study entry to scheduled time points using descriptive 
statistics. Laboratory parameter listings will include the normal ranges for each parameter. Each 
value will be classified as falling above, below, or within the normal range. 
Safety data from Parts 3 and 4 will be summarized similarly, with further details to be provided 
in Statistical Analysis Plan. 

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences International 
Ethical Guidelines 
 Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines 
 Applicable laws and regulations 
The protocol, protocol amendments, informed consent form (ICF), Investigator’s Brochure, and 
other relevant documents (eg, patient recruitment advertisements) must be submitted to an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients. 
The Investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC 
 Notifying the IRB/IEC of serious adverse events (SAEs) or other significant safety findings 
as required by IRB/IEC procedures 
 Providing oversight of the conduct of the study at the site and adherence to requirements of 
21 Code of Federal Regulation (CFR), ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations 
10.1.2 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information, as requested, to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 

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10.1.3 
Informed Consent Process 
 An initial sample ICF is provided for the Investigator to prepare the informed consent 
document to be used at his or her site. Updates to the sample ICF are to be communicated 
formally in writing from the Neoleukin Study Manager to the Investigator. The written ICF is 
to be prepared in the language(s) of the potential patient population. The ICF to be used at 
each site, and any changes to a site’s ICF, must be approved by the Sponsor before use. 
 The Investigator or his/her representative is responsible for presenting the nature of the study 
to the patient in lay language, as well as risks and alternate therapies, and answer all 
questions regarding the study, using the IRB/IEC approved informed consent document. 
 Patients must be informed that their participation is voluntary. Patients will be required to 
sign a statement of informed consent that meets the requirements of Food and Drug 
Administration (FDA) CFR (21 CFR 50, 56, 312), Declaration of Helsinki (Brazil, 2015), 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center. 
 Source documentation must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
 If informed consent is obtained from a legally authorized representative for a patient who is 
unable to provide informed consent at study entry (if applicable), but the patient is later able 
to provide informed consent, the Investigator or his/her representative must obtain written 
informed consent from the patient. 
 Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
 The original signed ICF must be retained in accordance with institutional policy, and a copy 
of the ICF(s) must be provided to the patient. 
A patient who is rescreened is not required to sign another ICF if the rescreening occurs within 
28 days from the previous ICF signature date. 
10.1.4 
Data Protection 
 Patients will be assigned a unique identifier by the Sponsor. Any patient records or datasets 
that are transferred to the Sponsor will contain the identifier only; patient names or any 
information that would make the patient identifiable will not be transferred. 
 The patient must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the patient who will be required to give consent for their data to be used as 
described in the informed consent. 
 The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
 The Investigator must ensure that the patient’s confidentiality is maintained for documents 
submitted to Neoleukin. 

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 For SAEs reported to Neoleukin, patients are to be identified by their unique patient 
identification number, initials (for faxed reports, in accordance with local laws and 
regulations), and age (in accordance with local laws and regulations). 
 In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the patient’s original medical 
records for verification of study related procedures and data. Direct access includes 
examining, analyzing, verifying, and reproducing any records and reports that are important 
to the evaluation of the study.  
10.1.5 
Confidentiality 
All information provided by the Sponsor and all data and information generated by the site as 
part of the study (other than a patient’s medical records) will be kept confidential by the 
Investigator and other site staff. This information and data will not be used by the Investigator or 
other site personnel for any purpose other than conducting the study. These restrictions do not 
apply to: (1) information that becomes publicly available through no fault of the Investigator or 
site staff; (2) information that it is necessary to disclose in confidence to an IRB/IEC or other 
personnel as provided in this protocol; or (3) information that it is necessary to disclose in order 
to provide appropriate medical care to a study patient. If a written contract with a site for the 
conduct of the study that includes confidentiality provisions inconsistent with this statement is 
executed, that contract’s confidentiality provisions shall apply for that site rather than this 
statement. 
10.1.6 
Retention of Source Data and Samples 
Study data for all parts of this study must be retained until ≥ 25 years or per local agency 
requirements after the last marketing approval in an ICH region or ≥ 25 years or as per local 
agency requirements have elapsed since the formal discontinuation of clinical development of 
the investigational product (eg, via notification of the FDA or local regulatory authority). The 
Investigator/institution may not destroy records without written authorization from the Sponsor. 
If an Investigator leaves the institution at which the study was conducted, arrangements must be 
made to ensure another responsible party is designated to maintain the records. 
Normally, these records will be held in the Investigator’s archives. If the Investigator is unable to 
meet this obligation, he or she must ask the Sponsor for permission to make alternative 
arrangements. Details of these arrangements must be documented in writing to the Sponsor. 
10.1.7 
Dissemination of Clinical Study Data 
The Sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by local laws and regulations. 
10.1.8 
Data Quality Assurance 
 All patient data relating to the study will be recorded on printed or electronic case report 
forms (CRFs) unless transmitted to the Sponsor or designee electronically (eg, laboratory 

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data). The Investigator is responsible for verifying that data entries are accurate and correct 
by physically or electronically signing the CRF. 
 The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
 The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections, and provide direct access to source data documents. 
 Monitoring details describing strategy (eg, risk-based initiatives in operations and quality, 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan. 
 The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
 The Sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations). 
 Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
 CRFs must be completed in English. TRADENAMES® (if used) for concomitant 
medications may be entered in the local language. Consult the country-specific language 
requirements. 
10.1.9 
Source Documents 
 Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
 Data reported on the CRF or entered in the electronic CRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available. 
10.1.10 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
patients. 
The first act of recruitment is the first site activated and will be the study start date. 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 

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The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
 Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
 Inadequate recruitment of patients by the Investigator 
 Discontinuation of further study drug development 
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator will promptly inform the patient and must 
ensure appropriate patient therapy and/or follow-up. 
10.1.11 
Publication Policy 
 The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows the Sponsor to protect proprietary information and to provide 
comments. 
 The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In this 
case, a coordinating Investigator will be designated by mutual agreement. 
 Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
 If a written contract with a site for the conduct of the study that includes publication 
provisions inconsistent with this statement is executed, that contract’s publication provisions 
shall apply for that site rather than this statement. 
 
 
 

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10.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting 
10.3.1 
Definition of Adverse Event 
Adverse Event Definition: 
 An adverse event (AE) is any untoward medical occurrence in a clinical study patient, 
temporally associated with the use of the study drug, whether or not considered related to the 
study drug. 
o When recording an AE resulting from a laboratory abnormality, the resulting medical 
condition rather than the abnormality itself should be recorded (eg, record “anemia” 
rather than “low hemoglobin”). 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of the study drug. 
Events Meeting the Adverse Event Definition: 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, electrocardiogram [ECG], radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the Investigator (ie, not related to progression of 
underlying disease). 
 Exacerbation of a chronic or intermittent preexisting condition including either an increase in 
frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study drug administration even though it may 
have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 “Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, the 
signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as 
an AE or SAE if they fulfil the definition of an AE or SAE. 

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Events Not Meeting the Adverse Event Definition: 
 Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
that are associated with the underlying disease or preexisting condition, unless judged by the 
Investigator to be more severe than expected. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the patient’s condition. 
 Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2 
Definition of Serious Adverse Event 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
Serious Adverse Event Definition: 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at immediate risk of death at the time of the event. It does not refer to an event 
that hypothetically might have caused death if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the patient has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE. 
d. Results in refractory disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (eg, sprained ankle) that may interfere with or prevent everyday life functions but do 
not constitute a substantial disruption. 

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e. Is a congenital anomaly/birth defect 
f. Other medically significant serious event: 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may 
require medical or surgical intervention to prevent 1 of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse. 
10.3.3 
Recording and Follow-Up of Adverse Events and/or Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording: 
 When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
 The Investigator will then record all relevant AE/SAE information in the AE/SAE Report 
Form and supporting case report forms (CRFs) (eg, Medical History, and Concomitant 
Medications). 
 It is not acceptable for the Investigator to send photocopies of the patient’s medical records 
to the Sponsor or designee in lieu of completion of the AE/SAE Report Form. 
 There may be instances when copies of medical records for certain cases are requested by the 
Sponsor or designee. In this case, all patient identifiers, with the exception of the patient 
number, will be redacted on the copies of the medical records before submission. 
 The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
 The Investigator must assign the following AE attributes: 
o AE diagnosis or syndrome(s), if known (if not known, signs or symptoms) 
o Dates of onset and resolution (if resolved) 
o Intensity (or toxicity defined below) 
o Assessment of relatedness to study drug or other protocol-required therapies 
o Action taken 
 If AE severity changes, record each change as a single event. 
 The following should be considered when recording SAEs: 
o Death is an outcome of an event. The event that results in the death should be recorded 
and reported on both the SAE Report Form and CRF. Deaths due to disease progression 
will not be classified as an AE and should be recorded in the CRF on the Death Form. 
o For hospitalizations, surgical, or diagnostic procedures, the illness leading to the surgical 
or diagnostic procedure should be recorded as the SAE, not the procedure itself. 

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 There are special instructions for reporting of cytokine release syndrome. For any events of 
cytokine release syndrome, instead of reporting a general term of cytokine release syndrome, 
please report all signs and symptoms of cytokine release syndrome (eg, fever, chills/rigors, 
vomiting, tachycardia, headache, rash, arthralgia, myalgia, chest discomfort, angioedema, 
hypotension, dyspnea) as separate events and indicate on the CRF that they are associated 
with cytokine release syndrome. 
Assessment of Severity: 
The Investigator will make an assessment of severity for each AE and SAE reported during the 
study and assign it using the Common Terminology Criteria for Adverse Events (CTCAE) V5.0, 
which is available at the following location: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf. 
An event is defined as ‘serious’ when it meets ≥ 1 of the predefined outcomes as described in the 
definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality: 
 The Investigator is obligated to assess the relationship between study drug and each 
occurrence of each AE/SAE. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled out. 
 The Investigator will use clinical judgment to determine the relationship. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study drug administration, will be 
considered and investigated. 
 The Investigator will also consult the Investigator’s Brochure in his/her assessment. 
 For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to 
 
However, the Investigator should always make an assessment of causality for every event 
before the initial transmission of the SAE data to 
 
 The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
 The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. 
 All SAEs have to be reported within 24 hours of study site awareness, whether or not 
considered causally related to the study drug or to a study procedure(s). 

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Follow-Up of Adverse Events and Serious Adverse Events: 
 The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated to fully elucidate the nature and/or 
causality of the AE or SAE. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
 If a patient dies during participation in the study or during a recognized Follow-up Period, 
the Investigator will provide 
 with a copy of any postmortem findings including 
histopathology. 
 New or updated information will be recorded in the originally completed CRF. 
 The Investigator will submit any updated SAE data to
 within 24 hours of receipt of new 
information. 
 If a non-SAE becomes serious, this event will be classified as an SAE and the 24-hour 
reporting clock begins. 
10.3.4 
Reporting of Serious Adverse Events  
Serious Adverse Events Reporting via an Electronic Data Collection Tool: 
 The primary mechanism for reporting an SAE will be the electronic data collection tool. 
 If the electronic system is unavailable, then the study site will use the paper SAE data 
collection tool in order to report the event within 24 hours. 
 The study site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 After the study is completed at a given study site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a study site receives a report of a new SAE from a study patient or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-line, 
then the study site can report this information on a paper SAE form or by telephone. 
 (Pharmacovigilance Department) Contact Information: 
Location:  
United States 
 
 
 
Australia 
24-hour hotline:  
 
 
 
 
Fax Number:  
 
 
 
 
 
 
 
 
 

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10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study drug, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(eg, mullerian agenesis, androgen insensitivity), Investigator discretion should be applied to 
determining study entry. 
Note: Documentation can come from the site personnel’s: review of the patient’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
o A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than 1 FSH measurement is required.  
o Females on HRT and whose menopausal status is in doubt will be required to use 1 of the 
non-estrogen hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment. 

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Contraception Guidance: 
NL-201 and pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not 
known if pembrolizumab has transient adverse effects on the composition of sperm. 
Participants should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the 
study, participants of childbearing potential must adhere to the contraception requirement from 
the day of study medication initiation (or 14 days prior to the initiation of study medication for 
oral contraception) throughout the study period up to 60 days after the last dose of NL-201 or 
120 days after the last dose of pembrolizumab for WOCBP and up to 90 days after the last dose 
of NL-201 or 120 days after the last dose of pembrolizumab for men. If there is any question that 
a participant of childbearing potential will not reliably comply with the requirements for 
contraception, that participant should not be entered into the study. 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing infant, 
participants who are breastfeeding are not eligible for enrollment. 
 Contraceptivesa allowed during the study include: 
o Highly effective methodsb that have low user dependency 
Failure rate of < 1% per year when used consistently and correctly. 
 Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc 
 Intrauterine device 
 Intrauterine hormone-releasing systemc 
 Bilateral tubal occlusion 
 Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is 
the sole sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male patient can come from the study site 
personnel’s review of the patient’s medical records, medical examination, or medical 
history interview. 
o Highly effective methodsb that are user dependent 
Failure rate of < 1% per year when used consistently and correctly. 
 Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulationc 
 oral 
 intravaginal 
 transdermal 
 injectable 

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 Progestogen-only hormone contraception associated with inhibition of ovulationc 
 oral 
 injectable 
 Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
patient. 
a. 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b. Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c. 
Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with 
Clinical Trial Facilitation Group guidelines, acceptable contraceptive methods are limited to those which inhibit 
ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, and post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method are not acceptable methods of contraception. Male condom 
and female condom should not be used together due to risk of failure from friction. 
Collection of Pregnancy Information 
Male patients with partners who become pregnant 
 The Investigator will attempt to collect pregnancy information on any male patient’s female 
partner who becomes pregnant while the male patient is in this study. This applies only to 
male patients who receive NL-201. 
 After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the Sponsor. Generally, the follow-up will 
be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure.  
Female patients who become pregnant 
 The Investigator will collect pregnancy information on any female patient who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of a patient's pregnancy.  
 The patient will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the patient and the neonate and the information will be 
forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date. Any termination of pregnancy will be reported, 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 

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 A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth (occurring 
at > 22 weeks gestational age) is always considered to be an serious adverse event (SAE) and 
will be reported as such.  
 Any post-study pregnancy-related SAE considered reasonably related to the study drug by 
the Investigator will be reported to the Sponsor as described in Section 8.4.5 and 
Section 8.4.6. While the Investigator is not obligated to actively seek this information in 
former study patients, he or she may learn of an SAE through spontaneous reporting. 
 Any female patient who becomes pregnant while participating in the study will discontinue 
study drug or be withdrawn from the study. 
 
 

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b 
All events of ALT or AST  3 x ULN and total bilirubin  2 x ULN (> 35% direct bilirubin) or ALT or 
AST  3 x ULN and INR >1.5 may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported to 
Sponsor in an expedited manner and as an SAE if SAE criteria met (excluding studies of hepatic impairment or 
cirrhosis). The INR stated threshold value will not apply to patients receiving anticoagulants. 
c 
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia). d 
PK 
sample may not be required for patients known to be receiving placebo or non-comparator interventions. Record 
the date/time of the PK blood sample draw and the date/time of the last dose of study drug prior to the PK blood 
sample draw on the CRF. If the date or time of the last dose is unclear, provide the patient’s best approximation. 
If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the time period 
indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in the Laboratory 
Manual. 
 
 

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10.6 Appendix 6: Tumor Assessments 
10.6.1 
Methods of Lesion Measurement 
The following considerations are to be made when evaluating the tumor (applicable for Response 
Evaluation Criteria in Solid Tumors [RECIST] 1.1 and RECIST for use in cancer 
immunotherapy trials [iRECIST]): 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
Computed tomography (CT) is the best currently available and reproducible method to measure 
lesions selected for response assessment. Magnetic resonance imaging (MRI) is also acceptable 
in certain situations. Therefore, imaging of chest, abdomen, pelvis and brain will be performed 
by CT or MRI in this study. 
Bone metastases will be assessed by X-ray or CT or MRI or bone scan in this study.  
Cytology, histology: the cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment can be considered if the measurable tumor has met criteria 
for response or stable disease (SD) in order to differentiate between response (or SD) and 
progressive disease.  
10.6.2 
Tumor Assessments According to RECIST 1.1 
Categorization of tumor lesions 
Measurable disease is defined as the presence of at least 1 measurable lesion. A measurable 
lesion is a lesion that can be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of 10 mm by CT/MRI scan. 
Measurability of lesions on CT/MRI scan is defined based on the assumption that CT/MRI slice 
thickness is 5 mm or less. However, when CT/MRI scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness. 
Note: methods of tumor assessments as outlined in RECIST 1.1 are slightly modified in this 
study in order to achieve a better standardization: images of chest, abdomen, pelvis and brain 
should be performed by CT or MRI and bone lesions will be assessed by X-ray or CT or MRI or 
bone scan. Clinical exam or chest X-ray is not regarded as appropriate methods for tumor 
assessment in this study. 
Non-measurable lesions are all other lesions, including small lesions (longest diameter < 10 mm 
or pathological lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 

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Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT/MRI scan (CT/MRI scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short 
axis will be measured and followed. 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability described 
above.  
Blastic bone lesions are non-measurable. Bone scan, positron emission tomography (PET) scan 
or plain films are not considered adequate imaging techniques to measure bone lesions. 
However, these techniques can be used to confirm the presence or disappearance of bone lesions. 
Cystic lesions: lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions neither measurable nor non-measurable since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
Lesions that are situated in a previously irradiated area, or in an area patient to other 
loco-regional therapy, should be considered non-measurable lesions and will be evaluated only 
qualitatively as non-target lesions.  
Baseline documentation of target and non-target lesions  
When more than 1 measurable lesion is present at baseline all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where patients have only 1 or 2 organ sites involved a maximum of 2 and 4 lesions 
respectively will be recorded).  
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. As mentioned above pathological nodes which 
are defined as measurable and may be identified as target lesions must meet the criterion of a 
short axis of ≥ 15 mm by CT/MRI scan. Only the short axis of these nodes will contribute to the 
baseline sum. All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should 
be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes will be 

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included in the sum, only the short axis is added into the sum. The baseline sum diameters will 
be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes with short axis 
≥ 10 mm but < 15 mm should be identified as non-target lesions and should also be recorded at 
baseline. Measurements are not required and these lesions should be followed as ‘present’, 
‘absent’, or in rare cases ‘unequivocal progression’ (more details to follow). In addition, it is 
possible to record multiple non-target lesions involving the same organ as a single item on the 
case record form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
Evaluation of target, non-target and new lesions according to RECIST 1.1 
All images will be interpreted (assessment of response) by the radiologist according to 
RECIST 1.1. At each tumor assessment visit, response is assessed first separately for target, 
non-target lesions (see Table 17) and new lesions (see below “appearance of new lesions”). 
These evaluations are then used to calculate the overall lesion response considering target 
lesions, non-target lesions and new lesions for patients with measurable disease (see Table 18) 
and non-target lesions and new lesions for patients with non-measurable disease only at baseline 
(see Table 19). 
Table 17 
Assessment of Response According to RECIST 1.1 
Response Category for Target Lesions  
CR 
Disappearance of all target lesions. Any pathological lymph nodes (whether target 
or non-target) must have reduction in short axis to < 10 mm. 
PR 
At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters of the diameters of target lesions. 
SD 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
PD 
At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  
Response Category for Non-Target Lesions 
CR 
Disappearance of all non-target lesions. All lymph nodes must be non-pathological 
in size (< 10 mm short axis). 
Non-CR/Non-PD 
Persistence of 1 or more non-target lesions 
PD 
Unequivocal progression (see comments below) of existing non-target lesions.  
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease 
Appearance of new lesions 
The appearance of any new lesions is considered progression. There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 

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bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the patient’s baseline lesions show partial or CR. For example, necrosis of a 
liver lesion may be reported on a CT/MRI scan report as a ‘new’ cystic lesion, which it is not. A 
lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of disease 
progression even if he/she did not have brain imaging at baseline. If a new lesion is equivocal, 
for example because of its small size, continued therapy and follow-up evaluation will clarify if 
it represents truly new disease. If repeat scans confirm there is definitely a new lesion, then 
progression should be declared using the date of the initial scan. 
Special notes on assessment of progression of non-target disease 
When the patient also has measurable disease: In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
‘increase’ in the size of 1 or more non-target lesions is usually not sufficient to quality for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
When the patient has only non-measurable disease: The same general concepts apply here as 
noted above, however, in this instance there is no measurable disease assessment to factor into 
the interpretation of an increase in non-measurable disease burden. Because worsening in 
non-target disease cannot be easily quantified (by definition: if all lesions are truly 
non-measurable) a useful test that can be applied when assessing patients for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be required to 
declare disease progression for measurable disease: ie, an increase in tumor burden representing 
an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from localized to widespread, or may be described as ‘sufficient 
to require a change in therapy’. If ‘unequivocal progression’ is seen, the patient should be 
considered to have had overall disease progression at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore, the increase must be substantial. 
Evaluation of overall lesion response according to RECIST 1.1 
Only patients with at least 1 measurable lesion or non-measurable disease only at baseline 
(enrollment not allowed according to protocol) will be included in the tumor assessment 
according to RECIST 1.1. For patients with measurable disease at baseline the evaluation of 
overall response at each assessment is a composite of the target lesion response, non-target lesion 
response and presence of new lesions as shown below in Table 18 (ie, target lesions with/without 

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or “NE” (not evaluable) in case criteria for disease progression are not met. However, the 
Investigator should take into consideration the reason for the on-study intervention 
(eg, progression of a lesion or shrinkage of a lesion) when providing the overall assessment. 
10.6.3 
iRECIST Response Assessment 
Overall response will also be assessed using iRECIST. Immunotherapeutics may result in 
infiltration of immune cells leading to transient increase in the size in malignant lesions, or 
undetectable lesions becoming detectable. The criteria are identical to those of RECIST 1.1 in 
many respects but have been adapted to account for instances where an increase in tumor burden, 
or the appearance of new lesions, does not reflect true tumor progression.  
Key differences are described below. All responses defined using iRECIST criteria are 
designated with a prefix. iRECIST time-point and best overall responses will be recorded 
separately. 
Confirming Progression 
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the terms 
immune unconfirmed progressive disease (iUPD) (unconfirmed progression) and immune 
confirmed progressive disease (iCPD) (confirmed progression). Confirmatory scans should be 
performed at least 4 weeks, but no longer than 8 weeks after iUPD. 
iCPD is confirmed if further increase in tumor burden, compared to the last assessment, is seen 
as evidenced by 1 or more of the following: 
 Continued increase in tumor burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, non-target disease or new lesions 
o Progression in target disease worsens with an increase of at least 5 mm in the absolute 
value of the sum 
o Continued unequivocal progression in non-target disease with an increase in tumor 
burden 
o Increase in size of previously identified new lesion (s) (an increase of at least 5 mm in the 
absolute value of the sum of those considered to be target new lesions) or additional new 
lesions. 
 RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) where 
progression was not previously identified, including the appearance of additional new 
lesions. 
If iUPD is not confirmed at the next assessment, then the appropriate response will be assigned 
(iUPD if the criteria are still met, but no worsening, or immune stable disease [iSD], immune 
partial response [iPR] or immune complete response [iCR] if those criteria are met compared to 
baseline). As can be seen in Table 20, the prior documentation of iUPD does not preclude 
assigning iCR, iPR, or iSD in subsequent time-point assessments or as best overall response 
(BOR) providing that iCPD is not documented at the next assessment after iUPD. 

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New Lesions 
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria 
(maximum of 5 lesions, no more than 2 per site, at least 10 mm in long axis (or 15 mm in short 
axis for nodal lesions), and recorded as New Lesions-Target (NLT) and New Lesion-Non-Target 
(NLNT) to allow clear differentiation from baseline target and non-target lesions. 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). However, 
the measurements of target lesions should NOT be included in the sum of measures of original 
target lesions identified at baseline. Rather, these measurements will be collected on a separate 
table in the case record form. 
PD is confirmed in the New Lesion category if the next imaging assessment, conducted at least 
4 weeks (but not more than 8 weeks) after iUPD confirms further progression from iUPD with 
either an increase of at least 5 mm in the absolute value of the sum of NLT OR an increase (but 
not necessarily unequivocal increase) in the size of NLNT lesions OR the appearance of 
additional new lesions. 

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doi:10.1128/MCB.25.21.9543-9553.2005 
16.  
Francisco LM, Sage PT, Sharpe AH. The PD‐1 pathway in tolerance and autoimmunity. 
Immunological Reviews. 2010;236(1):219-242. doi:10.1111/j.1600-065X.2010.00923.x 

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17.  
Hirano F, Kaneko K, Tamura H, et al. Blockade of B7-H1 and PD-1 by Monoclonal 
Antibodies Potentiates Cancer Therapeutic Immunity. Cancer Res. 2005;65(3):1089-1096. 
doi:10.1158/0008-5472.1089.65.3 
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Blank C, Brown I, Peterson AC, et al. PD-L1/B7H-1 Inhibits the Effector Phase of 
Tumor Rejection by T Cell Receptor (TCR) Transgenic CD8+ T Cells. Cancer Res. 
2004;64(3):1140-1145. doi:10.1158/0008-5472.CAN-03-3259 
19.  
Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer--
preclinical background: CTLA-4 and PD-1 blockade. Semin Oncol. 2010;37(5):430-439. 
doi:10.1053/j.seminoncol.2010.09.005 
20.  
Strome SE, Dong H, Tamura H, et al. B7-H1 blockade augments adoptive T-cell 
immunotherapy for squamous cell carcinoma. Cancer Res. 2003;63(19):6501-6505. 
21.  
Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of 
tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored 
IL-2 production and proliferation of CD8+ T cells directly within the tumor 
microenvironment. J Immunother Cancer. 2014;2(1):3. doi:10.1186/2051-1426-2-3 
22.  
Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination 
blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 
melanoma tumors. Proc Natl Acad Sci U S A. 2010;107(9):4275-4280. 
doi:10.1073/pnas.0915174107 
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Pilon-Thomas S, Mackay A, Vohra N, Mul JJ. Blockade of Programmed Death Ligand 1 
Enhances the Therapeutic Efficacy of Combination Immunotherapy against Melanoma. J 
Immunol. 2010;184(7):3442-3449. doi:10.4049/jimmunol.0904114 
24.  
Nomi T, Sho M, Akahori T, et al. Clinical Significance and Therapeutic Potential of the 
Programmed Death-1 Ligand/Programmed Death-1 Pathway in Human Pancreatic Cancer. 
Clin Cancer Res. 2007;13(7):2151-2157. doi:10.1158/1078-0432.CCR-06-2746 
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Ji Y, Wang S-J. Modified Toxicity Probability Interval Design: A Safer and More 
Reliable Method Than the 3 + 3 Design for Practical Phase I Trials. J Clin Oncol. 
2013;31(14):1785-1791. doi:10.1200/JCO.2012.45.7903 
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Choudhry H, Helmi N, Abdulaal WH, et al. Prospects of IL-2 in Cancer Immunotherapy. 
BioMed Research International. 2018;2018:1-7. doi:10.1155/2018/9056173 
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Epstein AL. Identification of a Protein Fragment of Interleukin 2 Responsible for 
Vasopermeability. J Natl Cancer Inst. 2003;95(10):741-749. doi:10.1093/jnci/95.10.741 
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Ahmadzadeh, Rosenberg. IL-2 administration increases CD4+CD25hi Foxp3+ regulatory 
T cells in cancer patients. Blood. 2006;107(6):2409-2414. doi:10.1182/blood-2005-06-2399 
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Levey AS, Stevens LA, Schmid CH, et al. A New Equation to Estimate Glomerular 
Filtration Rate. Ann Intern Med. 2009;150(9):604-612. doi:10.7326/0003-4819-150-9-
200905050-00006 
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Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
doi:10.1016/j.ejca.2008.10.026 
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Seymour, Bogaerts, Perrone, et al. iRECIST: guidelines for response criteria for use in 
trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):E143-E152. doi:10.1016/S1470-
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Schwartz, Litière, de Vries, et al. RECIST 1.1—Update and clarification: From the 
RECIST committee. Eur J Cancer. 2016;62:132-137. doi:10.1016/j.ejca.2016.03.081 
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adaptations: Perspectives from the RECIST Working Group. Eur J Cancer. 2016;62:138-
145. doi:10.1016/j.ejca.2016.03.082 
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Ferry-Galow KV, Datta V, Makhlouf HR, et al. What Can Be Done to Improve Research 
Biopsy Quality in Oncology Clinical Trials? Journal of Oncology Practice. 
2018;14(11):E722-E728. doi:10.1200/JOP.18.00092 
 

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12 SUMMARY OF CHANGES 
Version 2.0 (26 August 2020) replaces Version 1.0 (29 July 2020) 
Description and rationale for changes: 
 The starting dose has been changed from 0.3 to 0.1 µg/kg. 
A first-in-human starting dose of 0.1 µg/kg for NL-201 is anticipated to approximate the 
lowest pharmacologically active dose (PAD). This dose is based on the minimum anticipated 
biologic effect level approach using results from the most sensitive in vitro assays. In 
addition, a starting dose of 0.1 µg/kg for NL-201 is 150-fold lower than the no observed 
adverse effect level (NOAEL) of 15 µg/kg (50-fold lower than the human equivalent dose of 
5 µg/kg) in monkeys when administered weekly for 5 consecutive weeks. 
 In Section 9.3 (Population for Analyses), the “DLT-Evaluable Population” has been added. 
This population was defined in body of protocol but was missing from statistical 
considerations. 
 Administrative changes have been throughout the protocol (version number and approval 
date). 
 
Amendment 1.1, Version 2.1 (04 December 2020) replaces version 2.0 (26 August 2020) 
 
Description and rationale for changes: 
 The first-in-human starting dose rationale has been updated. 
 Administrative changes have been throughout the protocol (version number and approval 
date). 
 
 
 

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Amendment 2.0 (23 February 2021) replaces Amendment 1.1, version 2.1 (04 December 2020) 
Description and rationale for changes: 
Description of Change 
Rationale for Change 
Location(s) for Change 
Sponsor Address 
The Sponsor’s address was updated to: 
188 E Blaine Street 
Suite 450 
Seattle, WA 98102 
Title page 
The Regulatory Agency Identifier Number was added. 
NCT: 04659629 was previously not available, and was added 
to this amendment. 
Title page 
Respiration rate was added to vital signs (Section 8.2). 
This is a standard measurement of vital signs. 
Section 8.3.2 
The schedule of events and overall design sections have been 
updated with additional descriptions that biopsy samples will be 
collected from a minimum of 8 patients. 
The changes were made to make the protocol consistent. 
Tables 1 through 4, and 
Section 4.1 
The timing of pregnancy testing has been updated in the 
schedule of events (Table 1 Schedule A [Q3W Dosing]; Table 2 
Schedule B [D1 & D8 Dosing]; Table 3 Schedule A [Q3W 
Dosing if Step-dosing is Implemented]; and Table 4 Schedule B 
[D1 & D8 if Step-dosing is Implemented]), and in inclusion 
criterion #8. Both serum and urine pregnancy testing is 
acceptable. 
The timing of pregnancy testing and appropriates samples 
were clarified. 
Tables 1 through 4, and 
inclusion criterion #8 
Pharmacodynamic blood sampling is not required at the End of 
Treatment visit for Schedule B (Table 2) and was removed. 
This change corrected a transcription error. 
Table 2 
Hematology and chemistry samples were not collected on 
Schedule B (step dosing, Table 4) at the radiologic follow-up 
visit 
This change was made to remove unnecessary samples. 
Table 4 
Exclusion Criterion # 20 
‘signing of consent’ was replaced with ‘first planned dose’ 
The updated wording clarifies prior/concurrent clinical study 
experience. 
Section 5.2 
Wording for administration in Section 6.1.1 (in-text table) was 
updated to cross-reference the Pharmacy Instructions 
The updated wording provides the correct reference to the 
resource that describes the process for preparing the drug 
substance. 
Section 6.1.1 

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Description of Change 
Rationale for Change 
Location(s) for Change 
The dose and frequency of concomitant medications will be 
collected for concomitant medications of interest only 
(Section 6.5), but only when they become available. 
Additional information regarding concomitant medications of 
interest will better inform the Sponsor. 
Section 6.5 
ECOG Performance Status will be collected at Screening, Day 1 
of all cycles, and the End of Treatment visit for all schedules 
(Tables 1 through 4) 
This change was made to capture the data collected in 
inclusion criterion #4. 
Tables 1 through 4 
The CT scanning was updated to match the occurrence in per 
Table 1, Schedule A (Q3W Dosing) 
The change was made to resolve a transcription error. 
Table 2 
Viral serology (Table 2 Schedule B [D1 & D8 Dosing]) was 
updated to match the wording in Schedule A (Table 2) 
This change was made to resolve a transcription error. 
Table 2 
NOAEL was updated to match Section 4.4. 
The NOAEL was updated to 11.44 µg/kg to make with 
consistent throughout the document. 
Section 2.2.2 
For screen failures, medical history and prior therapies were 
removed (Section 5.3) 
This data is not necessary to collect on screen failures. 
Section 5.3 
‘Biopsy-related adverse events’ were removed from the first 
sentence. 
The change was made to clarify the risks. 
Section 2.3 
The risk table (Section 2.3.1) was updated: 
The row ‘Biopsy related adverse event’ was removed. 
This is no longer needed. 
Section 2.3.1 
The row ‘Public health related exposures during global 
pandemics’ was updated with additional wording to clarify the 
timing of SARS-CoV-2 immunization(s) relative to the timing of 
the first dose of study drug on Cycle 1 Day 1 of any schedule. 
The first bullet point was removed (‘Non-dosing days beyond 
C1D2 requiring sample collection can be performed by home 
healthcare provider as an alternative to a site visit.’). 
The previously fifth bullet point was reworded (‘Vaccination 
approved for the prevention of infection are allowed’): 
‘Vaccination approved for the prevention of infection are 
allowed if completed at least 14 days before Cycle 1 Day 1 or 
any time after Cycle 2 Day 1.’ 
A new fifth bullet point was added (‘Severe acute respiratory 
coronavirus 2 (SARS-CoV-2) testing will be required as per 
local regulations’). 
Additional wording was included to inform patients on when 
to consider receiving a SARS-CoV-2 vaccine while on study. 
 
Section 2.3.1 

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Description of Change 
Rationale for Change 
Location(s) for Change 
A new sixth bullet point was added (‘An enrolled patient may 
have a study drug (NL-201) dosing delay of up to 14 days, if the 
patient received an approved SARS-CoV-2 immunization or 
treatment before receiving their first dose of study drug on C1D1 
in any schedule.’). 
The number of patients was updated to ‘up to approximately 
n = 60’ in Part 1 and ‘n=60’ for Part 2 of Figure 1-1 (Overall 
Study Design). 
In the previous protocol amendment, the maximum number of 
patients was absent from this figure for Part 1. Part 1 was 
updated to enroll 60 patients for each Schedule A and 
Schedule B in cohorts of n ≥ 3 patients for a maximum of 
60 patients in total. 
In the previous protocol amendment, the maximum number of 
patients was 30. Part 2 was updated to enroll 30 patients in 
each cohort, up to a maximum of 60 patients in total. 
Combined enrollment in Part 1 and Part 2 will be 120 patients. 
Figure 1 
The last bullet point was updated to remove the following 
wording; ‘in the CRF’. 
The change was made to clarify that laboratory values will be 
recorded, but not in the CRF. 
Section 8.3.4 
Several instances of ‘Pharmacy Manual’ were changed to 
‘Pharmacy Instructions’ 
The change was made to clarify that the Pharmacy Instructions 
should be referred to. 
Sections 6, 6.1.1, and 
6.1.2 
‘Pharmacy Manual’ was changed to ‘Laboratory Manual’ in the 
footnote c in the table pertaining to liver chemistry stopping 
criteria. 
The change was made to clarify that the Laboratory Manual 
should be referred to. 
Appendix 10.5 
The definition of dose limiting toxicities was updated with the 
addition of 2 definitions, which are: 
‘recurrent Grade 3 infusion-related reaction despite pre-
medication. Grade 4 infusion-related reaction on the first 
occurrence.’ 
‘dose delay of > 14 days for study drug due to an adverse event’ 
The DLT definition was updated to align with current practice 
and to align with FDA comments on 17 December 2020. 
Section 6.2.1.2 
The last bullet point was updated to: 
‘Concomitant therapies of interest only and if available during 
the course of the study: dosage information including dose and 
frequency.’ 
The updated wording clarifies concomitant therapies of 
interest. 
Section 6.5 
The addition of ‘PK characterization will assess both the NL-201 
and the free protein’ 
Additional wording clarifies the PK characterization of 
NL-201 and aligns with FDA comments on 07 January 2020. 
Section 8.6 

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Description of Change 
Rationale for Change 
Location(s) for Change 
The addition of ‘start of new anti-cancer therapy, withdrawal of 
consent, study closure, or death, whichever occurs first’ was 
added to the overall design. 
The wording was updated for additional consistency. 
Synopsis, Tables 1 
through 4, and 
Section 4.1 
The minimum number of biopsies has been changed from 10 to 
16 patients. 
The change was made to reflect the updated number of 
biopsies to be conducted in Part 2. 
Sections 1.1 and 4.1 
In the second sentence of the last paragraph, ‘≤ 5%’ was 
replaced with ‘≤ 2.5%’. 
In the fourth sentence of the last paragraph, ‘≤’ was removed and 
‘objective responses’ was added after ‘0/18’. 
This change was made to resolve a transcription error. 
Section 9.2 
‘(screening only)’ was added to Hemoglobin A1c. 
The updated wording clarifies the timing of this test. 
Table 10 
The 6th bullet under ‘The Investigator must assign the following 
AE attributes’ was updated. 
‘Action taken. If adverse event severity changes, record each 
change as a single event.’ 
The wording clarifies the recording of an adverse event. 
Section 10.3.3 
 
 

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Amendment 3.0 (26 August 2021) replaces Amendment 2.0, version 2.1 (23 February 2021) 
Description and Rationale for Changes: 
Description of Change 
Rationale for Change 
Location(s) for Change 
Updates to the Schedule of Events tables 
 
Clarified timing for Eastern Cooperative Oncology Group (ECOG) 
performance status 
 
Clarified timing of Pregnancy test 
 
Clarified timing of safety laboratory tests  
 
Clarified timing of Day 8 for collection of PK samples 
Schedule of Events, Tables 1 
through 4 
Updates to the Inclusion and Exclusion 
Criteria 
 
Broaden autoimmune disease eligibility requirements. 
 
Lowering hemoglobin from 9.0 to 8.0 g/dL and remove transfusion 
window.  
 
Changing steroid limit from ≤ 7.5 to ≤ 10 mg. 
 
Calculation for renal function set to Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI). 
 
Clarified timing if pregnancy test.  
Sections 5.1 and 5.2 
Risk assessment table updated  
 
Clarification of management of cytokine release syndrome and capillary 
leak syndrome per investigators discretions and according to institutional 
guidelines.  
 
Summary of Data/Rationale for Risk for Auto-immunity updated. 
Table 5 
Capillary leak syndrome added to the Dose 
Delay and Modification Guideline table  
 
Capillary leak syndrome added as a new potential toxicity. 
Table 9 
Requirement to re-confirm eligibility on 
Cycle 1 Day 1 
 
Enrollment language in protocol has been clarified to specify the safety 
laboratory tests will be reconfirmed before dosing.  
Schedule of Events, Tables 1 
through 4, and Section 8 
Definition of “enrolled” updated. 
 
Definition updated to include patients that have met eligibility criteria and 
to receive drug.  
Section 9.2 
Retention of source data and samples 
updated to ≥ 25 years or per local agency 
requirements 
 
Updated to align with Health Canada requirement 
Section 10.1.6 
Add albumin to the list of clinical 
laboratory tests 
 
Albumin is followed because it can change with the development of 
vascular leak syndrome. 
Table 11 

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Description of Change 
Rationale for Change 
Location(s) for Change 
Clarification and typographical errors 
 
Bioassays collection of serum, rather than plasma 
 
Formatting of document to align with Style Guide including paragraphs, 
tables and figures etc. 
General 
 

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Amendment 4.0 (03 December 2021) replaces Amendment 3.0 (26 August 2021) 
Description and Rationale for Changes: 
Description of Change 
Rationale for Change 
Location(s) for Change 
Signatory updates 
 
Change of signatories  
Sponsor Signatory page 
Addition of Intermediate Doses  
 
At the recommendation of the DMC, predetermined intermediate dose 
levels may be tested. 
Synopsis, Schema, 
Section 6.2.1.1, and Table 7 
Risk Assessment table updated 
 
Inclusion of “infusion-related reaction” to the first Potential Risk of 
Clinical Significance. In addition to the specific risks described below, 
unknown risks may be associated with a first in human application (eg, 
allergic reactions). 
 
Specific PTs have been added to clarify the constellation of symptoms 
which are expected as part of the general PTs. 
Table 5 
mTPI design updated 
 
Updated to align with presentation style in literature. 
Figure 3 
Determination of MTD in Part 1 updated  
 
Updated to clarify the MTD and RP2D determination. 
Section 9.4.2 
Formatting 
 
Formatting of document to align with Style Guide. 
General 

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Amendment 5.0 (26 January 2022) replaces Amendment 4.0 (03 December 2021) 
Description and Rationale for Changes: 
Description of Change 
Rationale for Change 
Location(s) for Change 
Addition of Parts 3 and 4 - NL-201 
in combination with pembrolizumab 
 
It is hypothesized that NL-201 in combination with pembrolizumab may 
improve response to pembrolizumab as was demonstrated in animal models. 
NL-201 has been shown to increase PD-1 expression in CD+ T-cells, increased 
the immune infiltration of the TME, and may make tumor cells more sensitive 
to the effects of pembrolizumab. 
Synopsis, Schema, Schedule of 
Events, Sections 2.2.3, 2.3.1.1, 
2.3.1.2, 2.3.2, 3, 4.1, 4.3, 5, 
6.1.1, 6.1.4, 6.2.1.2, 6.2.1.3, 
6.2.2, 6.5, 6.6, 7.1, 8.1.3, 8.4.2, 
8.4.6, 8.5, 8.7.3, 9, Appendix 2, 
Appendix 4 
Note for AE review and Concomitant 
medication review updated  
 
Note updated to clarify SAEs related to standard laboratory tests  
Schedule of Events,  
CT Scan clarification  
 
Clarification of 4-week CT scan to confirm PR or CR as per RECIST criteria 
Schedule of Events, 
Section 8.2.1 
Risk Assessment table updated 
 
Required updates as a result of changes in Table 11 
Table 5 
Pre-Medication modifications  
 
Addition of pre-medication requirement at C1D1 for dose levels > 1 µg/kg of 
NL-201 
Section 6.1.3 
Dose Modification table updated 
 
To modify guidance for specific potential toxicities that are manageable with 
supportive measures by the investigator, eg, cytokine release syndrome 
Table 11 
Publication policy updated 
 
Clarification that site’s publication contract provisions supersedes the protocol 
publication policy 
Section 10.1.11 
Formatting 
 
Formatting of document to align with Style Guide.  
General 
 

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Amendment 6.0 (08 September 2022) replaces Amendment 5.0 (26 January 2022) 
Description and Rationale for Changes: 
Description of Change 
Rationale for Change 
Location(s) for Change 
Protocol Title updated to include combination 
therapy with pembrolizumab 
Requested by HREC 
Throughout protocol 
Part 3 cohort number corrected  
 
Correction of typographical error 
Synopsis, Table 9 
Removing NL-201 dose levels 18 and 24 µg/kg 
 
Not likely to achieve higher end of the initial 
dose range. 
Synopsis, Table 8 and 9, Figure 1 and 3 
Addition of language for intrasubject dose 
escalation upon clearance of each dose level for 
Part 1 
 
To allow patients to benefit from higher doses 
(safely cleared by the DMC) 
Synopsis, Section 4.1, Section 6.2.1 
Study Schema Part 1 and Part 3 updated 
 
Updated to reflect changes made in the 
protocol 
Figure 1  
Included language to allow for steroid 
medication 
 
Allow for circumstances where steroid 
medication is needed  
Section 6.1.4 
Hematology and chemistry sampling added on 
Schedule B (step dosing, Table 4) 
 
Inadvertently left out of protocol for 
hematology and chemistry at end of treatment 
(EOT) 
Schedule of Events (Table 4) 
De-couple Schedule A and Schedule B dose 
escalation for Part 1 
 
Schedule B dose escalation no longer gated 
on clearance of dose level in Schedule A 
 
Synopsis and Section 4.1 
Note on concomitant medication review 
updated  
 
Note updated to clarify collection of 
concomitant medications   
Schedule of Events  
Clarification added to weight assessment note in 
Schedule of Events for weight adjustment and 
dose calculation 
 
Updated to reflect the protocol 
Schedule of Events 
Addition to backfill cleared dose levels in Part 1 
 
 
To collect additional data for the evaluation 
of including, but not limited to, pre-
medications, biopsy and antitumor activity. 
Synopsis, Sections 4.1, Section 4.1.2, 
Section 4.1.3, Section 9.2 

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Description of Change 
Rationale for Change 
Location(s) for Change 
Addition of optional biopsies in Part 1 
 
Generate anecdotal data on impact to tumor 
microenvironment 
 
Synopsis, Schedule of Events (Table 1 and 
2), Section 4.1  
Addition of language around risk of 
pembrolizumab administration 
 
Requested by HREC 
Section 2.3.1.2 
Addition toxicity mitigations, such as steroids 
 
Based on Administrative Letters 2 through 5 
Section 6.1.3 
Updated Part 2 target population 
 
Incomplete sentence 
Section 5 
Updated observation time after first new patient 
of each new dose level to 48 hours 
 
Most of the adverse events are recorded 
within first 48 hours 
Synopsis, Section 4.1,  
Included thrombus prophylaxis as acceptable to 
exclusion criteria # 7 
 
For thrombosis that is ongoing and being 
treated, these patients are suitable to come 
onto study. 
Section 5.2 
Under Section 10.3.1, Definition of Adverse 
Event, Events Meeting the Adverse Event 
Definition:  
Removed - “For situations when an AE or SAE 
is due to the primary tumor type being studied, 
all known signs and symptoms should be 
reported. Death due to disease progression in 
the absence of signs and symptoms should be 
reported as the primary tumor type (eg, RCC). 
Note: The term “disease progression” should 
not be used to describe the AE”. 
 
Clarification on classification of signs, 
symptoms or deaths related to disease 
progression 
 
Natural progression or deterioration of the 
patient’s malignancy/disorder under study 
(including new sites of metastasis and death 
due to disease progression) will be recorded 
as part of the efficacy evaluation and should 
not be reported as an AE or as an SAE; 
unless, signs or symptoms of the primary 
tumor type are considered more severe than 
expected for the patient’s condition. 
Section 10.3.1 
Addition that death due to disease progression 
will not be recorded as a SAE 
 
Updated to align with Administration Letter 5 
Section 10.3.3 

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Description of Change 
Rationale for Change 
Location(s) for Change 
Interventions for NL-201 monotherapy and 
pembrolizumab combination therapy  
 
Instituting interventions to mitigate the risks 
for hypotension and cytokine-related 
symptoms that have been observed in patients 
on the monotherapy arm of NL-201-101 
Schedule of Events and Section 6.1.3 
Footnote updated for dosing table to clarify 
dose expansion and cohort expansion  
 
Updated to reflect protocol 
Synopsis, Table 8 and 9 
Number of patients for Part 1 and overall 
number of patients for study 
 
Updated to reflect protocol 
Synopsis, Section 4.1, Section 4.1.2, 
Section 9.2 
Dosing instructions for pembrolizumab 
 
Updated to clarify that pembrolizumab must 
always be administered on the same day as 
NL-201 
Table 7 
Collection of PK and cytokines timepoints 
clarified 
 
Clarification to the SOE regarding collection 
for PK and cytokines (not relevant to other 
sample draws) to state that the collection 
timepoints on D1 (eg, pre and post EOI) 
should be anchored to the infusion of NL-201 
and NOT to the infusion of pembrolizumab.    
Schedule of Events 
Language added for pembrolizumab risks 
 
Requested by HREC 
Section 2.3.1 
Update to number of sites 
 
Current estimation 
Section 4.1.4 
Clarification added for when scans after disease 
progression can be performed 
 
Updated to reflect protocol 
Section 6.1.1.1 
Clarification added to delays and doses skipped 
with regard to Cycle number 
 
To clarify that Cycle 2 sampling is still 
required if Cycle 2 is skipped 
Section 6.2.2.1 
Language added to the assessment of NL-201 
dependent effects on tumor microenvironment 
 
To understand the relationship between the 
biological characteristics of tumors before 
treatment and patient outcomes 
Section 8.7.2 

Compound: NL-201 
Neoleukin Therapeutics, Inc. 
Protocol: NL201-101 
Protocol Date and Version: 08 September 2022; Amendment 6.0 
 
CONFIDENTIAL 
 
Page 151 of 151 
Description of Change 
Rationale for Change 
Location(s) for Change 
Clarification on timing of tumor biopsies for 
Schedule A and Schedule B   
 
Updated to reflect protocol 
Schedule of Events, Synopsis, Section 4.1 
Clarification on end of treatment visit 
 
Updated to reflect protocol 
Synopsis, Section 4.1, Section 8.1.3 
Updated men’s contraceptive inclusion criteria 
#9 
 
To align per CTFG contraception guidance 
Section 5.1, Section 10.4 
Updated overdose reporting language 
 
Updated to reflect protocol 
Section 8.5 
Updated adverse events and serious adverse 
event section with instructions for reporting 
cytokine release syndrome 
 
Updated to reflect protocol 
Section 10.3.3 
Removal of subsequent dosing for outpatient 
setting in Part 3 
 
Subsequent dosing guidance is described in 
Section 6.2.2 
Synopsis, Section 4.1, Section 6.2.2 
Update of radiologic follow up language 
 
During dose escalation to be less burdensome 
to patients.  
Synopsis, Schedule of Events, Section 4.1, 
Section 8.1.2, Section 8.1.4, Section 8.2.1 
Update on long term follow-up 
 
Adequate data can be collected to assess 
endpoints with less the frequent assessments 
Synopsis, Schedule of Events, Section 4.1, 
Section 8.1.2, Section 8.1.5, Section 8.2.1 
Addition of language for cytokine release 
syndrome treatment guidance 
 
Additional guidance for a known toxicity 
Section 6.1.4 
Signatory updates 
 
Change in signatories 
Sponsor Signature page 
Formatting 
 
Formatting of document to align with Style 
Guide.  
General