Conditions: Advanced or Metastatic Solid Tumors Ovarian Cancer Gastric Cancer Colo-rectal Cancer
Keywords: Advanced Cancer Metastatic Cancer NC410 Solid Tumor Immunotherapy PK Ovarian Cancer Gastric Cancer Colo-rectal Cancer
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 46
Healthy volunteers: no

Brief summary:
This research study is studying a new drug, NC410, as a possible treatment for advanced or metastatic solid tumors.

Detailed description:

Arms:
arm 1: 3mg of NC410 for IV infusion administered in 14 day dosing cycles arm 2: 6mg of NC410 for IV infusion administered in 14 day dosing cycles arm 3: 15mg of NC410 for IV infusion administered in 14 day dosing cycles arm 4: 30mg of NC410 for IV infusion administered in 14 day dosing cycles arm 5: 60mg of NC410 for IV infusion administered in 14 day dosing cycles arm 6: 100mg of NC410 for IV infusion administered in 14 day dosing cycles arm 7: 200mg of NC410 for IV infusion administered in 14 day dosing cycles

Interventions: intervention 1: NC410
Intervention descriptions: intervention 1: NC410 is an experimental antibody drug that may make the immune response more active against cancer

Protocol document:
Prot_SAP_000.pdf: 
  
 
Title:  
A PHASE 1/2, OPEN-LABEL, DOSE-ESCALATION, SAFETY AND TOLERABILITY 
STUDY OF NC410 IN SUBJECTS WITH ADVANCED OR METASTATIC SOLID TUMORS 
 
NCT Number: NCT04408599 
 
Document Date: 30Aug2021 
 
 


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A PHASE 1/2, OPEN-LABEL, DOSE-ESCALATION, SAFETY AND 
TOLERABILITY STUDY OF NC410 IN SUBJECTS WITH ADVANCED 
OR METASTATIC SOLID TUMORS 
 
Sponsor Protocol Number:  
NC410-01 
IND Number: 
 
141990 
Investigational Product: 
 
NC410 
 
 
LAIR-2 IgG1 Fusion Protein 
 
Phase of Study: 
 
1/2 
Sponsor: 
 
NextCure, Inc. 
9000 Virginia Manor Road, Suite 200 
 
 
Beltsville, MD 20705 USA 
Phone: 240-399-4900 
Email: NCClin@nextcure.com 
 
Medical Monitor: 
 
Han Myint, MD, FACP, FRCP, FRCPath 
Chief Medical Officer 
NextCure, Inc. 
 
 
Phone: 240-399-4900 
 
 
Email: NCClin@nextcure.com 
 
 
Original Protocol (Version 1.0) 
20-DEC-2019 
Amendment 1 (Version 2.0) 
30-JAN-2020 
Amendment 1 (Version 2.1) 
31-JAN-2020 
Amendment 2 (Version 3.0)  
30Aug2021 
 


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Protocol Synopsis 
TITLE 
A Phase 1/2, Open-Label, Dose-Escalation, Safety and Tolerability Study of NC410 in 
Subjects with Advanced or Metastatic Solid Tumors 
HYPOTHESES 
NC410 will be adequately tolerated following administration in multiple ascending doses to 
subjects with refractory solid tumors and that such administration may result in clinical 
benefit. 
OBJECTIVES 
 
Primary Objectives 
1) To evaluate the safety, tolerability, and dose-limiting toxicities (DLTs) of NC410 
2) To define a maximum tolerated dose (MTD) or pharmacologically active dose (PAD) of 
NC410  
 
Secondary Objectives 
1) To evaluate the pharmacokinetic (PK) profile of NC410 
2) To assess preliminary efficacy of NC410  
 
Exploratory Objectives 
1) To assess the immunogenicity of NC410 
2) To explore biomarkers that may predict the pharmacologic activity of NC410 
3) To characterize the effect of NC410 on markers of immunity 
STUDY ENDPOINTS 
 
Primary Endpoints 
1) Safety and tolerability will be assessed by monitoring frequency, duration, and severity of 
adverse events (AEs) Note: Toxicity grading per NCI CTCAE v5.0 
2) The MTD or PAD of NC410 will be defined in subjects with advanced or metastatic solid 
tumors 
 
Secondary Endpoints 
1) Assessment of PK of NC410 will include individual NC410 concentrations in serum and 
identification of PK parameters. 
2) Assessment of antitumor activity/efficacy will include objective response (OR) and 
disease control rate (DCR) based on RECIST v1.1, duration of response (DoR), 


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progression-free survival (PFS), and overall survival (OS) as per RECIST v1.1 and 
mRECIST v1.1 
 
Exploratory Endpoints 
1) Immunogenicity, defined as the occurrence of anti-drug antibodies (ADA) to NC410, will 
be determined. 
2) Biomarker effects of NC410 in peripheral blood and tumor tissue will be assessed, 
including but not limited to the following: 
• Whole blood immune cell population profiling/immune-phenotyping. 
• Serum markers of inflammation or immune modulation (cytokine levels). 
• Tumor biopsy analyses to evaluate the tumor microenvironment in tumor tissue and 
immune cell infiltrates at baseline, following treatment, and correlate expression levels 
with efficacy. The expression of additional biomarkers will also be assessed. 
STUDY DESIGN 
This is an open-label, nonrandomized, Phase 1/2 study to determine the safety and tolerability, 
define the MTD or PAD, and to assess the preliminary efficacy of NC410 in subjects with 
advanced or metastatic solid tumors. Subjects will receive NC410 on Day 1 of each cycle. 
Phase 1 of the study will begin with 14-day cycles; however, alternate dose administration 
schedules may also be explored depending on PK, pharmacodynamic (PD), biomarker, safety 
results, and feedback from investigators. The study will be conducted in 2 parts: 
• 
Phase 1 – Dose Escalation and Safety Expansion will determine the PAD, defined as a 
dose that provides a maximal biologic effect, such as an increase in biomarkers of 
immune activation or reduction of markers associated with immunosuppression, and/or 
the MTD of NC410, including defining the optimal dose administration schedule and 
the maximum number of tolerated doses (MNTD). 
• 
Phase 2 – Dose Expansion will evaluate the recommended dose and administration 
schedule determined in Phase 1 in subjects with Head and Neck squamous cell 
carcinoma, non-small cell lung cancer (NSCLC) (adenocarcinoma), Colo-rectal 
carcinoma (CRC), gastric, and cervical cancers. These proposed indications may 
change based on emerging data. 
 
Phase 1a – Dose Escalation 
In Phase 1a, subjects with advanced or metastatic solid tumors who progressed after treatment 
with therapies known to confer clinical benefit, are intolerant to treatment, or refuse standard 
treatment will be enrolled. A 3 + 3 design will be utilized to determine the MTD of NC410. 
A minimum of 3 evaluable subjects will be enrolled in each cohort beginning with Cohort 1 
(3 mg; starting dose). The first 3 evaluable subjects within a cohort will be observed for a DLT 
observation period of 28 days, before the next cohort begins enrollment. Only one subject will 
be dosed on the first day of dosing for each cohort (additional subjects can begin in ≥48 
hours). The dose will be escalated if 0 of the first 3 evaluable subjects enrolled has a DLT. If 1 
of the first 3 evaluable subjects enrolled has a DLT, then the cohort will be expanded to 
include 3 additional evaluable subjects, and if no DLT occurs in the additional 3 subjects, then 
the dose will be escalated. If a DLT occurs in one-third or more of the expanded cohort, then 


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the MTD will be deemed to be exceeded and the previous dose level will be considered the 
MTD. Intermediate dose levels below the MTD may be explored pending safety review. If 
only 3 subjects were treated at the MTD or PAD, then a minimum of 3 additional evaluable 
subjects will be enrolled at this dose before it is administered in Phase 2 of the study. 
If Cohorts exceed the MTD, the sponsor and investigators will consider dosing NC410 at the 
lower dose cohorts, and/or investigate 3 mg at alternate dose schedules, based on available 
safety, PK, PD, and biomarker data. If an alternate schedule is determined to be safe, re-
escalation of NC410 will proceed according to the table below. 
Throughout the treatment period, if > 33% of subjects (a minimum of 6 subjects) experience a 
≥ Grade 3 toxicity related to study drug after completing ≥ 4 cycles, then dose administration 
will be stopped, and the MNTD will be determined in conjunction with the investigators and 
sponsor based on all available safety data. 
Subjects who drop out for reasons other than a DLT (e.g., events clearly associated with the 
underlying disease, disease progression, concomitant medication, or comorbidity) during the 
28-day DLT observation period will be considered non-evaluable and will be replaced. Dose 
modifications should not be made during the DLT observation period without discussion with 
the medical monitor. Intrasubject dose escalation is not permitted; however, once the 
recommended Phase 2 dose (RP2D) and schedule has been determined, ongoing subjects in 
Phase 1 may be permitted to escalate to the RP2D with approval of the medical monitor 
assuming the subject has not experienced ≥Grade 3 toxicity in previous treatment cycles. The 
cohorts and dose levels are shown in the table below. 
 
Cohort 
Dose of NC410 
1 (Starting dose) 
3.0 mg 
2  
6.0 mg 
3  
15 mg 
4 
30 mg 
5 
60 mg 
6 
100 mg 
7 
200 mg 
8 
400 mg 
 
Phase 1b – Safety Expansion 
To evaluate additional PD activity of NC410 and confirm the preliminary safety of the dose 
escalation cohorts, Phase 1 of the study will include safety expansion cohorts (denoted as 
Phase 1b) evaluating doses and schedules equivalent to or lower than the highest dose levels 
determined to be safe and/or doses determined to be pharmacologically active. All doses and 
schedules explored during the safety expansion will depend on PK, PD, biomarker, and safety 
results. 
Approximately 30 evaluable subjects will be enrolled in the Phase 1b safety expansion, with 
each dose cohort enrolling up to 10 additional subjects. If < 3 of 9 evaluable subjects 


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experience a DLT, the cohort will be deemed safe. If > 1 safety expansion cohort is deemed 
safe, then a recommended dose and schedule will be determined in conjunction with the 
investigators and sponsor based on all available safety, PK, PD, and biomarker results. The 
safety expansion cohorts may be conducted in parallel to Phase 2 and may be limited by the 
sponsor to subjects with specific tumor types to achieve a balance across cohorts. 
 
Phase 2 − Dose Expansion 
Phase 2 of the study will further evaluate the safety, tolerability, preliminary efficacy, PK, and 
pharmacologic activity of the RP2D of NC410 in subjects with advanced or metastatic 
HNSCC, NSCLC (adenocarcinoma), CRC,  gastric, and cervical cancers. A sixth cohort may 
be included and will enroll patients of a tumor type pending outcomes of Phase 1a. A Simon 2-
stage design will be utilized with a stopping rule to allow for early termination of a cohort at 
the end of Stage 1 if there are insufficient responses observed. During Stage 1, 9 evaluable 
subjects will be enrolled in each cohort; if no responses are observed within the cohort then the 
cohort will be discontinued. If at least 1 response is observed, 8 additional evaluable subjects 
will be enrolled in the cohort (Stage 2), for at least 17 evaluable subjects per cohort. 
Subjects will continue to receive NC410 at the RP2D and schedule until protocol-defined 
withdrawal criteria are met. Continuous evaluation of toxicity events will be performed 
throughout enrollment in Phase 2 of the study. If the cumulative incidence of DLTs occurs in 
≥ 33% of subjects after 6 subjects have been observed for at least 28 days, further enrollment 
may be interrupted until the sponsor has determined the appropriate course of action. All AEs, 
regardless of the time of occurrence on study may be considered in determining the 
appropriate dose, schedule, and MNTD. 
Toxicity will continue to be monitored throughout the treatment period. If > 33% of subjects 
(minimum of 6 subjects) experience a ≥ Grade 3 toxicity related to study drug after completing 
≥ 4 cycles, then the MNTD will be determined in conjunction with the investigators and 
sponsor based on all available safety data. 
Study Schema 
 
RR = Response Rate (ORR) per RECIST v1.1 


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TARGET SUBJECT POPULATION 
Men and women, 18 years or older, with advanced solid malignancies who have progressed on 
standard treatment, who have been unable to tolerate standard therapy, who have refused 
standard therapy, or for whom no standard anticancer therapy exists may be enrolled. Subjects 
must provide written informed consent and have adequate organ function. Subjects must 
present with measurable disease based on RECIST v1.1 and consent to have a non-target 
lesion biopsied before and during treatment. Subjects with certain serious medical conditions 
(in addition to the diagnosis of cancer) would be excluded from participation in the trial. 
INVESTIGATIONAL PRODUCT, DOSAGE, AND MODE OF ADMINISTRATION 
NC410 will be administered by intravenous (iv) infusion, over a minimum of 30 minutes on 
Day 1 of each cycle. Subjects will continue to receive NC410 until disease progression, 
withdraw of consent, or intolerable toxicity (whichever comes first). After completing 12 
months of treatment, if the subject is deriving benefit from NC410 and has not met any of the 
protocol-defined conditions for withdrawal or discontinuation, the subject will be followed by 
the PI per standard of care. Subjects approved to continue treatment will remain on the dose 
level assigned at the time of enrollment (unless otherwise approved for dose modification by 
the medical monitor). Safety reporting will continue through end of treatment to completion of 
the safety follow-up period.  
 
STATISTICAL ANALYSIS PLAN 
The sample size for this study will be determined so that sufficient subjects are included to 
assess the safety, tolerability, PK, and PD of repeat doses of NC410. The sample size is not 
fixed and will vary based on emerging safety data at the doses studied. 
 


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TABLE OF CONTENTS 
 
A PHASE 1/2, OPEN-LABEL, DOSE-ESCALATION, SAFETY AND 
TOLERABILITY STUDY OF NC410 IN SUBJECTS WITH 
ADVANCED OR METASTATIC SOLID TUMORS ........................... i 
Protocol Synopsis ............................................................................................... ii 
List of In-text Tables ........................................................................................ xii 
List of Figures .................................................................................................. xiii 
List of Appendices ........................................................................................... xiv 
List of Abbreviations ....................................................................................... xv 
1 
INTRODUCTION......................................................................................1 
1.1 Background .............................................................................................................1 
1.1.1 Role of tumor microenvironment in immune surveillance .........................1 
1.1.2 Current Immunotherapy ..............................................................................2 
1.1.3 LAIR-1/2 and Immunity .............................................................................2 
1.1.4 Development of NC410 ..............................................................................4 
1.2 Overview of NC410 ................................................................................................5 
1.2.1 Pharmacokinetics of NC410 .......................................................................5 
1.2.2 Pharmacology of NC410 ............................................................................6 
1.2.3 Non-Clinical Safety and Potential Risks of NC410 ...................................6 
1.3 Study Rationale .......................................................................................................7 
1.3.1 Rationale for the Safe Starting Dose ..........................................................7 
1.3.2 Rationale for Fixed Dosing .........................................................................8 
1.3.3 Rationale for Subject Population for Phase 2 .............................................8 
1.3.4 Rationale for Efficacy Endpoints..............................................................11 
1.4 Summary of Clinical Experience ..........................................................................13 
1.5 Research Hypotheses ............................................................................................13 
2 
OBJECTIVES AND ENDPOINTS ....................................................... 13 
2.1 Objectives .............................................................................................................13 
2.1.1 Primary Objectives ...................................................................................13 


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2.1.2 Secondary Objectives ...............................................................................13 
2.1.3 Exploratory Objectives .............................................................................13 
2.2 Study Endpoints ....................................................................................................13 
2.2.1 Primary Endpoints ....................................................................................13 
2.2.2 Secondary Endpoints ................................................................................14 
2.2.3 Exploratory Endpoints ..............................................................................14 
3 
STUDY DESIGN ..................................................................................... 14 
3.1 Description of the Study .......................................................................................14 
3.1.1 Phase 1 ......................................................................................................15 
3.1.2 Phase 2 − Dose Expansion ........................................................................17 
3.2 Measures Taken to Avoid Bias .............................................................................17 
3.3 Number of Subjects ..............................................................................................17 
3.3.1 Planned Number of Subjects ....................................................................17 
3.3.2 Replacement of Subjects ...........................................................................18 
3.4 Duration of Treatment and Subject Participation .................................................18 
3.5 Overall Study Duration .........................................................................................18 
3.6 Study Termination ................................................................................................18 
4 
SUBJECT ELIGIBILITY ...................................................................... 19 
4.1 Subject Inclusion Criteria .....................................................................................19 
4.2 Subject Exclusion Criteria ....................................................................................20 
5 
TREATMENT ......................................................................................... 23 
5.1 Treatment Assignment ..........................................................................................23 
5.1.1 Subject Numbering and Treatment Assignment .......................................23 
5.1.2 Randomization and Blinding ....................................................................23 
5.2 Study Drug ............................................................................................................23 
5.2.1 Description and Administration ................................................................23 
5.2.2 Supply Packaging and Labeling ...............................................................23 
5.2.3 Storage ......................................................................................................23 
5.2.4 Accountability ...........................................................................................24 
5.3 Treatment Compliance ..........................................................................................24 
5.4 Treatment Interruptions and Adjustments ............................................................24 
5.4.1 Dose Modifications ...................................................................................24 


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5.4.2 Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose24 
5.4.3 Management of Dose-Limiting Toxicities or Other Urgent Situations ....27 
5.4.4 Follow-Up of Dose-Limiting Toxicities ...................................................27 
5.4.5 Procedures for Cohort Review and Dose Escalation ................................27 
5.4.6 Criteria and Procedures for Dose Interruptions and Adjustments of Study 
Drug ..........................................................................................................27 
5.4.7 Definition, Procedures, and Supportive Care Guidelines for Immune-Related 
Adverse Events .........................................................................................28 
5.4.8 Management of Infusion Reactions ..........................................................29 
5.4.9 Criteria for Permanent Discontinuation of Study Drug ............................32 
5.4.10 Treatment After Initial Evidence of Radiologic Disease Progression ......32 
5.5 Withdrawal of Subjects from Study Drug ............................................................32 
5.5.1 Withdrawal Criteria ..................................................................................32 
5.5.2 Withdrawal Procedures .............................................................................33 
5.6 Concomitant Medications .....................................................................................33 
5.6.1 Permitted Medications ..............................................................................34 
5.6.2 Restricted Medications .............................................................................34 
5.6.3 Prohibited Medications .............................................................................34 
6 
SCHEDULE OF STUDY PROCEDURES ........................................... 36 
6.1 Screening ..............................................................................................................42 
6.2 Treatment ..............................................................................................................42 
6.3 End of Treatment ..................................................................................................43 
6.4 Follow-up ..............................................................................................................43 
6.4.1 Safety Follow-up ......................................................................................43 
6.4.2 Disease Status Follow-up .........................................................................43 
6.5 End of Study .........................................................................................................43 
6.6 Unscheduled Visits ...............................................................................................44 
7 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES ..... 44 
7.1 Administration of Informed Consent Form ..........................................................44 
7.2 Demography and Medical History ........................................................................44 
7.2.1 Demographics and General Medical History ...........................................44 
7.2.2 Disease Characteristics and Treatment History ........................................44 
7.3 Prior and Concomitant Medications and Procedures ............................................45 


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7.4 Poststudy Anticancer Therapy and Survival Status ..............................................45 
7.5 Safety Assessments ...............................................................................................45 
7.5.1 Adverse Events .........................................................................................45 
7.5.2 Physical Examinations ..............................................................................45 
7.5.3 Vital Signs and Weight .............................................................................46 
7.5.4 Electrocardiograms ...................................................................................46 
7.5.5 Laboratory Assessments ...........................................................................47 
7.6 Efficacy Assessments ...........................................................................................48 
7.6.1 Modified RECIST v1.1 Assessment of Disease .......................................48 
7.7 Pharmacokinetic Assessments ..............................................................................51 
7.8 Biomarker and Correlative Assessments ..............................................................51 
7.8.1 Tumor Biopsies .........................................................................................51 
7.8.2 Whole Blood Correlative Assessment ......................................................52 
7.8.3 Serum Pharmacodynamic Assessment .....................................................52 
7.8.4 Timing for Serum and Whole Blood Assessments ...................................52 
7.9 Other Study Procedures ........................................................................................53 
8 
SAFETY MONITORING AND REPORTING ................................... 53 
8.1 Adverse Events .....................................................................................................53 
8.1.1 Definitions ................................................................................................53 
8.1.2 Reporting ..................................................................................................53 
8.2 Laboratory Test Abnormalities .............................................................................55 
8.3 Serious Adverse Events ........................................................................................55 
8.3.1 Definitions ................................................................................................55 
8.3.2 Reporting ..................................................................................................56 
8.3.3 Reporting of an Overdose .........................................................................56 
8.4 Emergency Unblinding of Treatment Assignment ...............................................56 
8.5 Pregnancy .............................................................................................................57 
8.6 Warnings and Precautions ....................................................................................57 
8.7 Data Monitoring Committee .................................................................................58 
8.8 Immune-Related Adverse Events .........................................................................58 
8.9 Reporting Product Complaints .............................................................................58 
9 
STATISTICS ........................................................................................... 58 


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9.1 Study Populations .................................................................................................59 
9.2 Selection of Sample Size ......................................................................................59 
9.2.1 Sample Size for Phase 1 ...........................................................................59 
9.2.2 Sample Size for Phase 2 ...........................................................................59 
9.3 Level of Significance ............................................................................................59 
9.4 Interim Analysis ....................................................................................................60 
9.5 Statistical Analyses ...............................................................................................60 
9.5.1 Safety Analyses ........................................................................................60 
9.5.2 PK Analyses ..............................................................................................61 
9.5.3 Efficacy Analyses .....................................................................................61 
9.5.4 Pharmacodynamic and Biomarkers Analysis ...........................................62 
9.6 Analyses for Data Monitoring Committee ...........................................................62 
10 
STUDY AND DATA MANAGEMENT ................................................ 62 
10.1 Training of Study Site Personnel ..........................................................................62 
10.2 Monitoring of the Study........................................................................................63 
10.2.1 Source Data ...............................................................................................63 
10.2.2 Archiving of Study Documents ................................................................64 
10.3 Study Timetable and End of Study .......................................................................64 
10.4 Data Management .................................................................................................64 
10.5 Medical Monitor Coverage ...................................................................................64 
11 
ETHICAL AND REGULATORY REQUIREMENTS....................... 65 
11.1 Ethical Conduct of the Study ................................................................................65 
11.2 Subject Data Protection ........................................................................................65 
11.3 Ethics and Regulatory Review ..............................................................................65 
11.4 Informed Consent .................................................................................................66 
11.5 Changes to the Protocol and Informed Consent Form ..........................................67 
11.6 Audits and Inspections ..........................................................................................67 
12 
REFERENCES ........................................................................................ 68 
 
 


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List of In-text Tables 
Table 1: NC410 Dose Levels and Cohorts ..............................................................................16 
Table 2: Definition of Dose-Limiting Toxicity .......................................................................25 
Table 3: Rules for Interruption and Restarting of Study Drug ................................................28 
Table 4: Supportive Care Guidelines for Subjects Exhibiting Immune-Related Adverse Events
..............................................................................................................29 
Table 5: Infusion Reaction Treatment Guidelines ...................................................................30 
Table 6: Schedule of Assessments ...........................................................................................36 
Table 7: Schedule of Local Laboratory Assessments ..............................................................38 
Table 8: Local Laboratory Tests: Required Analytes ..............................................................39 
Table 9: Schedule of Pharmacokinetic and Anti-Drug Antibody Sampling............................40 
Table 10: Schedule of Pharmacodynamic (Biomarker) Sampling ..........................................41 
Table 11: Timing of Electrocardiograms .................................................................................47 
Table 12: Imaging and Treatment After First Radiographic Evidence of Progressive Disease48 
Table 13: NCI CTCAE v5.0 Grading Scale .............................................................................54 
Table 14: Criteria for Clinically Notable Vital Sign Abnormalities ........................................60 
Table 15: Criteria for Clinically Notable Electrocardiogram Abnormalities ..........................61 
 
 
 


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List of Figures 
Figure 1: LAIR-2 is Capable of Immune Regulation Through Blockade of Ligand Binding to the 
LAIR-1 Receptor to Relieve Immune Suppression ...............................3 
Figure 2: NC410 Binds to Tumor-Associated Ligands to Block LAIR-1 Inhibition ................5 
Figure 3: Analysis of TCGA Data Sets for Expression of Markers in Tumor (T) and Normal (N) 
Tissues....................................................................................................8 
Figure 4: Analysis of Overall Survival for Multiple Tumor Types Based on LAIR-2 Expression
................................................................................................................9 
Figure 5: IHC staining of stomach adenocarcinoma ................................................................10 
Figure 6: LAIR-1 is expressed on suppressive DCs in a spontaneous model of ovarian cancer11 
Figure 7: Study Design ............................................................................................................15 
 
 
 


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List of Appendices 
Appendix 1: Signatures ..................................................................................................................75 
Appendix 2: Additional Safety Guidance ......................................................................................76 
Appendix 3: National Institute of Allergy and Infectious Disease and Food and Allergy 
Anaphylaxis Network Guidance for Anaphylaxis Diagnosis ....................78 
Appendix 4: Eastern Cooperative Oncology Group Performance Status ......................................79 
Appendix 5: Cockcroft-Gault Formula ..........................................................................................80 
 
 


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List of Abbreviations 
Abbreviation or 
Specialized Term 
Definition 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BSA 
Body Surface Area 
Cmax 
Maximum Concentration of Drug 
CNS 
Central Nervous System 
CR 
Complete Response 
CRC 
Colorectal Cancer 
CRF 
Case Report Form 
CRS 
Cytokine Release Syndrome 
CT 
Computed Tomography 
CTLA-4 
Cytotoxic T-Lymphocyte–Associated Protein 4 
DC 
Dendritic cell 
DCR 
Disease Control Rate 
DLT 
Dose-Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DoR 
Duration of Response 
EC30 
Effective Concentration for 30% of Maximum Effect 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EOT 
End-of-Treatment 
FAAN 
Food and Allergy Anaphylaxis Network 
FAS 
Full Analysis Set 
Fc 
Fragment crystallizable 
FIH 
First-in-Human 
FFPE 
Formalin-Fixed Paraffin-Embedded 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 


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Abbreviation or 
Specialized Term 
Definition 
HBV 
Hepatitis B Virus 
HCC 
Hepatocellular Carcinoma 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HNSCC 
Head and Neck Squamous Cell Carcinoma 
HNSTD 
Highest Non-Severely Toxic Dose 
HPV 
Human Papillomavirus 
IB 
Investigator’s Brochure 
IBW 
Ideal Body Weight 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
INs 
Investigator Notifications 
irAE 
Immune-Related Adverse Event 
IRB 
Institutional Review Board 
iv 
Intravenous 
LAIR 
Leukocyte-Associated Immunoglobulin-like Receptor 
LKA 
Last Known Alive 
LPS 
Lipopolysaccharide 
mAb 
Monoclonal Antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNTD 
Maximum Number of Tolerated Doses 
mRECIST 
Modified Response Evaluation Criteria in Solid Tumors 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NIAID 
National Institute of Allergy and Infectious Disease 
NOAEL 
No Observed Adverse Effect Level 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
ORR 
Objective Response Rate 


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Abbreviation or 
Specialized Term 
Definition 
OR 
Objective Response 
OS 
Overall Survival 
PAD 
Pharmacologically Active Dose 
PAS 
PK Analysis Set 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Pharmacodynamics 
PD-1 
Programmed Cell Death Protein 1 
PD-L1 
Programmed Cell Death Protein Ligand 1 
PEF 
Peak Expiratory Flow 
PFS 
Progression-Free Survival 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PR 
Partial Response 
PT 
Prothrombin Time 
QTcF 
Fridericia Correction 
RCC 
Renal Cell Carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic Acid 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SSD 
Safe Starting Dose 
t½ 
Half-Life 
TEAE 
Treatment-Emergent Adverse Event 
TK 
Toxicokinetic 
TME 
Tumor Microenvironment 
TNBC 
Triple Negative Breast Cancer 
TPS 
Tumor Proportion Score 
Treg 
Regulatory T cell 
ULN 
Upper Limit of Normal 
US FDA 
United States Food and Drug Administration 
USA 
United States of America 


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1 
INTRODUCTION 
This is a Phase 1/2, multicenter, open-label, dose-escalation study. The study will be conducted 
in 2 parts. Phase 1 will utilize a 3 + 3 design to determine the maximum tolerated dose (MTD) or 
pharmacologically active dose (PAD) for NC410 in subjects with advanced or metastatic solid 
tumors. Phase 2 of the study will further evaluate the safety, tolerability, preliminary efficacy, 
pharmacokinetics (PK), and pharmacodynamics (PD) of the recommended Phase 2 dose (RP2D) 
and administration schedule of NC410 in subjects with advanced or metastatic HNSCC, NSCLC 
(adenocarcinoma), CRC, gastric, and cervical cancers or other tumor type as identified with 
emerging data. 
1.1 
Background 
1.1.1 
Role of tumor microenvironment in immune surveillance 
The tumor microenvironment (TME) of solid tumors are a complex heterogeneous mixture of 
matrix components and neoplastic cells along with different non-cancerous cell types such as 
fibroblasts, vascular endothelial cells, and immune cells, including T-cells, macrophages, and 
neutrophils, collectively known as tumor stoma. The interaction of cancer cells with stromal cells 
is a crucial determinant of tumor clearance versus progression, thus shaping tumor evolution. 
Cancer cells are under continuous pressure to thwart immune responses through activation of 
negative costimulatory signaling, impairment of antigen presentation, and secretion of 
immunosuppressive and pro-apoptotic factors. The dynamic state of the TME was demonstrated 
in breast tumor progression by comparing ductal carcinoma in situ (DCIS) and invasive ductal 
carcinomas (IDC) wherein there was fewer activated CD8+ T cells and higher programmed cell 
death protein ligand 1 (PD-L1) expression in IDC (Gil Del Alcazar et al., 2017). The presence of 
regulatory T cells (Tregs) in the TME is also a driver of immunosuppression. A detailed analysis 
of CD8+ T cell along with ratio of CD8+ effector T cell to Tregs show significant correlation to 
improved patient prognosis and long-term survival in many solid tumors (Kirk, 2010; Nosho et 
al., 2010; Liu et al., 2011; Mathai et al., 2012; Yoon et al., 2012; Preston et al., 2013; Chang et 
al., 2014; Kim et al., 2014). Myeloid-derived suppressor cells (MDSCs) within the TME also 
drive tumor growth, angiogenesis, metastasis and immune evasion (Yang et al., 2004; Yang et 
al., 2008; Gabrilovich & Nagaraj, 2009; Khaled et al., 2013). In melanoma patients, circulating 
MDSCs correlate to poor clinical outcome upon treatment with ipilimumab (Meyer et al., 2014). 
Disruption of CXCR2-mediated trafficking of MDSCs to the TME in a murine model of 
rhabdomyosarcoma enhanced efficacy of anti-PD1 therapy, further validating MDSC mediated 
immune suppression (Highfill et al., 2014). Tumor-associated M2-like macrophages (TAMs) 
also play a role in promoting tumor progression in the TME (Lewis & Pollard, 2006). Their 
immunosuppressive effects are supported in several different murine models (Fritz et al., 2014; 
Wu et al., 2014; Zhu et al., 2014; Ruffell & Coussens, 2015). In addition, distinct subsets of 
dendritic cells may also contribute to the immunosuppressive milieu in the TME. 
The matrix of the TME itself also contributes to the pro-tumorigenic environment. For example, 
many tumor types overexpress matrix components such as collagens and complement component 
C1q that play an important role in creating a TME; the resulting TME supports tumor cell 


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survival and metastasis leading to unfavorable clinical outcome. Earlier studies have 
demonstrated that these components also serve as ligands for a collagen-binding inhibitory 
receptor known as Leukocyte-Associated Immunoglobulin-like Receptor (LAIR)-1. LAIR-1 
ligands include several types of collagen such as complement component C1q, mannose binding 
lectin (MBL) and surfactant protein-D (SP-D) (Lebbink et al., 2008; Lebbink et al., 2009; Olde 
Nordkamp et al., 2011; Olde Nordkamp et al., 2014b). Dysregulation of LAIR ligands results in 
excessive production of collagens and complement C1q as well as altered forms of collagens that 
may exert strong inhibitory effects in the TME (Afshar-Kharghan, 2017; Pearce et al., 2018). 
Indeed, published data indicate that tumor expressed collagens inhibit immune function through 
LAIR-1 (Rygiel et al., 2011). Other factors common to dysregulated tumor environments, such 
as damage associated molecular patterns (DAMPs), are likely to play supporting roles in 
mediating the enhanced inhibitory function of LAIR-1 in cancer (Son & Diamond, 2014; Son et 
al., 2016). Furthermore, it is hypothesized that LAIR-1 expression on several subsets of 
leukocytes prevents optimal immune responses by limiting both innate and adaptive immune 
functionality.  Overall, these data suggest that targeting the LAIR pathway in cancer patients 
may be a rational approach in potentiating anti-tumor immunity.   
1.1.2 
Current Immunotherapy  
Targeting the immune system to regulate various pro-tumorigenic pathways in the TME is an 
effective approach for cancer therapy as demonstrated by approved checkpoint inhibitors; these 
immunotherapies have gained substantial attention in cancer treatment due to the durability of 
the responses and increased survival benefit. To date, the U.S. Food and Drug Administration 
(US FDA) has approved seven immune checkpoint inhibitors to date. Approvals includes one 
CTLA-4 inhibitor (ipilimumab), three PD-1 inhibitors (nivolumab, pembrolizumab, and 
cemiplimab) and three PD-L1 inhibitors (atezolizumab, durvalumab, and avelumab). 
Despite these impressive responses, only 20-30% of patients in specific subsets of tumor types 
respond to checkpoint inhibitors and can have caveats relating to success. As an example, the 
prolonged time necessary to achieve a response is not ideal for patients with advanced metastatic 
disease. Recent efforts to improve upon the initial success of checkpoint inhibitors have focused 
on combination-based regimens; however, these regimens can have significant toxicity 
associated with its utilization and are not consistently improving efficacy. Further, it is becoming 
increasingly clear that there are additional mechanisms at play as patients can have varying 
responses. Current immunotherapy trials are increasingly incorporating biomarker studies, such 
as assessing the tumor mutational burden (TMB) and PD-L1 expression. It has been shown that 
prior exposure to chemotherapy alleviates the effect of TMB on immunotherapy (Hendriks et al., 
2018). Taken together, there is a significant gap to bridge towards understanding the modest 
response rates with checkpoint inhibitors as well as stratification of patients who will benefit 
from immunotherapy. Therefore, to address the disparity in the number of patients responding to 
immunotherapy and the degree to which they respond, there is a need to develop 
immunomodulators with new and alternative mechanisms of action.  
1.1.3 
LAIR-1/2 and Immunity 
Leukocyte-Associated Immunoglobulin-like Receptor (LAIR)-1 and LAIR-2 are members of the 
Leukocyte Receptor Complex (LRC) on human chromosome 19 (Trowsdale et al., 2015; An & 
Brodsky, 2016). LAIR-1 is a well-described co-inhibitory receptor expressed on several subsets 


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of immune cells, and functions to delimit immune responses (Meyaard et al., 1997; Meyaard et 
al., 1999; Lebbink et al., 2008). LAIR-2 is a secreted protein with homology to the 
transmembrane protein LAIR-1 (Lebbink et al., 2008). 
In cancer, it is hypothesized that LAIR-1 expression on several subsets of leukocytes prevents 
optimal immune responses by limiting both innate and adaptive immune functionality. LAIR-1 
serves to suppress anti-tumor immunity through the inhibition of stimulatory signaling 
pathways. Specifically, LAIR-1 is a checkpoint and adhesion receptor on T cells that limits T 
cell activation and increases adhesion to collagens (Meyaard, 2008). In addition to its role in T 
cell function, LAIR-1 is also expressed on NK, monocyte, macrophage, dendritic cells and 
neutrophils and functions to delimit immune responses. Further, LAIR-1 expression has been 
shown to be associated with suppressive DC and macrophage subpopulations in both mouse and 
human ovarian cancers (Flies et al., 2016).  Blockade of LAIR-1 in cancer should reduce 
inhibitory mechanisms to redirect myeloid cells toward promoting stimulatory responses, 
including T cell responses, against tumors.   
LAIR-2 is a secreted protein with 77.5% homology in the Ig-like C2 domain of extracellular 
region to the transmembrane protein LAIR-1 and serves as a natural, endogenous, secreted decoy 
for LAIR-1 produced primarily by activated T cells (Meyaard, 2008). LAIR-2 is capable of 
blocking LAIR-1 functional interactions with ligands, resulting in improved immune function on 
multiple immune cell subsets (Figure 1). Of note is the observation in which dysregulation of 
LAIR-1 ligands results in excessive production of collagens and complement C1q as well as 
altered forms of collagens that may exert strong inhibitory effects in the TME (Afshar-Kharghan, 
2017; Pearce et al., 2018). Thus, disrupting the interaction of LAIR-1 ligands with LAIR-1 and 
interrupting the inhibitory effects of the TME utilizing a LAIR-2 based therapy is a novel 
approach to cancer therapy.   
Figure 1: LAIR-2 is Capable of Immune Regulation Through Blockade of Ligand Binding 
to the LAIR-1 Receptor to Relieve Immune Suppression 
 


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LAIR-2 binds to collagen, complement C1q, MBL and SP-D, blocks the ligation of LAIR-1 on immune cell surface 
and relieves the LAIR-1 inhibitory signaling. (figure courtesy of (Olde Nordkamp, 2013)) 
1.1.4 
Development of NC410 
NC410 is a dimeric form of the LAIR-2 protein fused to a human Fc domain of the 
immunoglobulin (Ig) subtype IgG1. The rationale for developing NC410 as a cancer therapeutic 
is based on nonclinical data demonstrating LAIR-1 signaling blockade can improve the immune 
response. Because LAIR-2 binds to ligands shared with LAIR-1 with increased affinity, NC410 
can act as a decoy receptor for LAIR-1 ligands with the intent to release the suppression on 
myeloid cells and T cells. In addition, the collagen binding of NC410 may further facilitate the 
tumor targeting and accumulation of NC410 within the TME. 
NC410 has been studied in a variety of in vitro and in vivo systems to support its use as an 
investigational drug in oncology. These studies have demonstrated enhanced immune activity in 
mechanistic studies and tumor models, as outlined below:  
• Binds to LAIR-1 ligands including collagen, C1q, MBL and SP-D with high avidity and 
block the interaction of LAIR-1 to its ligands.   
• Reverses the inhibitory effects of collagen on the Lipopolysaccharide (LPS)-induced NF-
κB and Interferon signaling, important signaling pathways leading to immune cell 
activation.  
• Promotes primary monocyte activation and differentiation toward a stimulatory 
macrophage phenotype induced by HMGB1, the cancer-relevant immune cell stimulator 
in TME.   
• Enhances human T cell expansion and activation in a dose-dependent manner, which 
correlates to the tumor efficacy in a mouse P815 and human HT29 tumor models and 
CXCL12 cytokine production.   
• Distributes to secondary lymphoid organs and TME  
In summary, these studies specifically utilizing human cells, or “humanized models” have 
demonstrated the most significant increase in immune function and anti-tumor activity in the 
presence of NC410, supporting its mechanism of action.  


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Figure 2: NC410 Binds to Tumor-Associated Ligands to Block LAIR-1 Inhibition 
 
NC410 binds to tumor-associated ligands (collagen and C1q) to block LAIR-1 inhibition and promote adaptive (T 
cells) and innate (dendritic cells) immune responses, as well as to activate macrophages, ultimately resulting in 
tumor cell killing. 
 
1.2 
Overview of NC410 
NC410 is a soluble humanized LAIR-2 protein fused to human IgG1 Fc domain and binds 
several LAIR ligands, including collagens, C1q, MBL and SP-D. It is a novel 
immunotherapeutic protein that was developed to enhance the natural decoy mechanism by 
blocking LAIR-1 mediated immune suppression, thus reversing multiple immune suppressive 
mechanisms and restoring immune function. NC410 is being developed as an immunotherapeutic 
agent to treat human oncological diseases.  
1.2.1 
Pharmacokinetics of NC410 
The pharmacokinetics (PK) of NC410 were characterized in cynomolgus monkeys as part of 
single-dose, dose-range-finding and repeat-dose toxicity studies. Because the toxicokinetic (TK) 
parameters of the cynomolgus monkey studies were determined to be a more pharmacologically 
relevant species, these results are summarized below. For additional information, please refer to 
the NC410 Investigator’s Brochure (IB).  
The pharmacokinetic properties of NC410 were assessed in cynomolgus monkeys in a Good 
Laboratory Practices (GLP) repeat-dose study. The mean terminal half-life was 
approximated 55 hours following one IV infusion of NC410 and approximately 60 
hours following 5 repeated doses. In the GLP repeat-dose study, there was a dose proportional 
relationship between dose level and exposure; no gender differences were observed. ADA was 
detected in animals received multiple doses at 20 mg/kg, which appeared to impact systemic 
exposure. Immunogenicity of human protein therapeutics in non-human species is a common 


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occurrence, and immunogenicity data from animals have little value for predicting the risk of 
immunogenicity in humans, as discussed in International Council for Harmonization (ICH) 
S6(R1) and (Ponce et al., 2009).  
1.2.2 
Pharmacology of NC410 
The pharmacology of NC410 has been studied in a variety of in vitro and in vivo systems to 
support its use as an investigational drug in oncology. This section highlights the results of these 
studies; please consult the NC410 IB for additional information.  
NC410 binds to LAIR-1 ligands including collagen, C1q, MBL and SP-D with high avidity and 
this binding blocks the interaction of soluble and cell surface LAIR-1 to its ligands. Using an 
immune cell line or primary peripheral blood mononuclear cells (PBMCs), NC410 reverses the 
inhibitory effects of collagen on the LPS-induced NF-κB and interferon signaling, important 
signaling pathways leading to immune cell activation. Furthermore, NC410 promotes primary 
monocyte activation and stimulatory macrophage differentiation induced by HMGB1, the 
cancer-relevant immune cell stimulator in TME. Employing conditions that would have 
predicted the high risk of CRS for the anti-CD28 monoclonal antibody (mAb) TGN1412 
(Stebbings et al., 2007; Findlay et al., 2010), NC410 did not promote cytokine release relative to 
a negative control (anti-RSV) (Synagis®). 
The in vivo efficacy of NC410 was tested in humanized mouse models in which human PBMCs 
were transferred to NSG mice. NC410 treatment enhanced human T cell expansion and 
activation in a dose-dependent manner, which correlated with tumor efficacy and CXCL12 
cytokine production in a P815 tumor model. Moreover, NC410 dose-dependently reduced the 
tumor growth of HT-29 human colorectal adenocarcinoma.  
 
A biodistribution study was performed in mice to determine the localization of NC410, as well as 
the ability of NC410 to access the tumor microenvironment when administered at very low 
doses. Briefly, NC410 accumulated in the liver and tumor sites was quantitated at 24, 48 and 72 
hours in comparison to a positive control mAb. Interestingly, NC410 accessed the tumor 
similarly to the positive control, which targeted a tumor antigen.  While the overall amount of 
NC410 reaching the tumor is small in comparison to liver, it is similar to the positive control and 
in line with expectations for a subcutaneous tumor model.  These data confirm that NC410 can 
access the tumor similarly to tumor targeting mAbs, distribute in a non-random fashion to the 
liver, spleen and lymph nodes, and can access and accumulate in the lymph nodes. Full analysis 
of this study is described in the NC410 IB.  
1.2.3 
Non-Clinical Safety and Potential Risks of NC410 
The toxicology of NC410 has been studied in a variety of in vitro and in vivo systems to support 
its use as an investigational drug in oncology. A summary of the GLP toxicity study in which 
cynomolgus monkeys were administered escalating doses of NC410 are provided below; full 
results of this study and prior dose toxicity studies are described in the NC410 IB. 
The most notable effects of NC410 following five weekly intravenous infusions over 30 minutes 
to cynomolgus monkeys include a dose-dependent reduction in NK cells at doses ≥ 2 mg/kg 
(with persistence at 20 mg/kg), a transient dose-dependent activation of complement at doses ≥ 2 


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mg/kg and adverse microscopic findings at doses ≥ 2 mg/kg, which either completely or partially 
resolved by the end of the 6-week recovery period. At the 20 mg/kg, these effects were 
accompanied with secretion of cytokines and chemokines following the first dosing, which 
subsided over time and was not observed following the 5th weekly administration. The cytokine 
secretion was not observed at the 0.2 or 2 mg/kg dose levels. Routine laboratory tests will 
include analysis of NK cell population and complement classical pathway activation throughout 
the conduct of this clinical study.  
 
Based upon the results of the GLP 5-week repeat-dose toxicity study, the highest non-severely 
toxic dose (HNSTD) was determined to be 20 mg/kg, and the No Observed Adverse Effect Level 
(NOAEL) was 0.2 mg/kg. These results were used to identify the safe starting dose for the 
clinical study.  
 
1.3 
Study Rationale 
Immunotherapies have demonstrated an effective anti-tumor immune response and induce 
significant clinical benefit for a subset of patients with cancer. This study will evaluate targeting 
the LAIR pathway which through LAIR-1 has been known to limit T cell activation and suppress 
anti-tumor immunity in the TME. While immunotherapies for cancer have shown great promise, 
there is still an unmet medical need for additional therapies with novel approaches. Therefore, 
NC410 may be an effective immunotherapy for some cancer patients. 
1.3.1 
Rationale for the Safe Starting Dose 
The rationale for the proposed Phase 1 starting dose (SSD) of 0.04 mg/kg is based on the 
collection of preclinical pharmacology and toxicology data, including calculated and 
experimentally assessed dose-responses in human cell-based assays, and anti-tumor responses in 
NSG models (NC410 IB).  The clinical starting dose is 5-fold less than the NOAEL and 500-fold 
less than the HNSTD. The proposed dosing scheme provides a starting dose that is expected to 
minimize safety risks and has the potential to provide clinical benefit, which is ethically 
important in an oncology trial. In the absence of dose-limiting toxicity, the maximum dose that 
may be explored in the first in human trial will be 5 mg/kg, which is four-fold below the highest 
non-severely toxic dose (HNSTD) in the GLP-compliant repeat dose tox (20 mg/kg) study in 
cynomolgus monkeys. Based on the dose dependency of the toxicities identified in the 
toxicology studies and the large safety margins, the chosen clinical doses are expected to provide 
therapeutic benefit with minimal safety risk to the patient.  
A summary of the pharmacology and toxicology data is provided below: 
• NOAEL = 0.2 mg/kg (Study 2823-002, as described in the NC410 IB)   
• HNSTD = 20 mg/kg (Study 2823-002, as described in the NC410 IB)  
• Minimum anticipated biological effect level (MABEL) EC30 dose = 0.16 mg/kg (described 
in section 4.1.4.3 of the NC410 IB)  
• In vivo model in NSG mice, ED50 dose = 0.66 mg/kg (data provided in Figure 16 and 
section 4.1.5.4 of the NC410 IB)   
• Recommended starting dose = 0.04 mg/kg  
• Recommended maximum dose = 5 mg/kg 


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Given the known biology of the LAIR pathway and its relevance in immune function, immune 
related adverse events (irAE) are the most likely class of toxicity. This clinical protocol has been 
written to minimize and manage any potential irAEs and any infusion reactions. Eligibility 
criteria have been established to exclude subjects in the Phase 1 clinical study with a history of 
autoimmune disease or who may have experienced an unresolved irAE to another 
immunotherapy. 
1.3.2 
Rationale for Fixed Dosing 
Fixed dosing has several advantages over weight-based dosing, including convenience of 
preparation and administration, reducing errors in preparation calculation, and minimization of 
drug waste. Body size-based dosing and fixed dosing of mAbs have been evaluated with the 2 
dosing approaches performing similarly, with body size–based dosing not always offering an 
advantage in reducing variability of exposure. The authors of these studies concluded that either 
approach may be used in first-in-human (FIH) studies and that fixed dosing is recommended as 
the preferred approach because of the advantages mentioned above (Wang et al., 2009; Bai et al., 
2012). 
1.3.3 
Rationale for Subject Population for Phase 2 
Preliminary identification of tumor types most likely to benefit from NC410 therapy was based  
on several analyses examining LAIR expression and other factors. Initial selection of relevant 
tumor types was first determined based upon results of an analysis from The Cancer Genome 
Atlas (TCGA). Specifically, thirty tumor types were analyzed for RNA expression of LAIR-1 
expression, macrophage markers CD163, LAIR-1/2 ligands C1Q and various collagens, and 
HMBG1 (due to its described role in interacting with C1Q to promote M2 macrophage 
differentiation through LAIR-1) (Son et al., 2016). These results are summarized in Figure 3.   
 
Figure 3: Analysis of TCGA Data Sets for Expression of Markers in Tumor (T) and 
Normal (N) Tissues 
 


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Normal expression uses GTex data. Yellow indicates low expression and red indicated high expression based on the 
scale on the right side of the figure. Blue boxes highlight eight tumor types that fit criteria as potential indications 
for NC410. 
 
Further investigation revealed improved overall survival (OS) in several tumor types relative to 
increased expression levels of LAIR-2 (Figure 4). These data suggest patients with these tumor 
types may be responsive to NC410 therapy. 
 
Figure 4: Analysis of Overall Survival for Multiple Tumor Types Based on LAIR-2 
Expression 
 
Overall survival was assessed for 33 cancer types from TCGA database. Abbreviations shown are TCGA study 
abbreviations. Analysis of overall survival Settings used for OS analysis are group cutoff: Median (50% high; 50% 
low); Hazards ratio based on Cox PH model, 95% confidence interval shown as dotted line. Number (n) varies 
across tumor types as indicated in each graph. Graphs with green boxes show three tumor types with most 
significant correlation between LAIR-2 high expression and improved overall survival. 
 
In addition to the RNA expression studies, immunohistochemical (IHC) studies were conducted 
to further inform identification of potential tumor types for NC410 therapy; these IHC studies 
were also based on criteria from the earlier in-depth nonclinical analyses of tumor types. 
Selection of tumor types for IHC studies utilized the following criteria:  
 
• 
LAIR-1 expression in the TME  
• 
CD163 M2-like macrophage marker, as assessed for relative increase in cancer vs normal tissues  


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• 
Analysis of several LAIR ligands, as assessed for overexpression in the TME in comparison to 
normal tissues   
• 
Expression of HMGB1, as assessed by increased RNA levels in tumor versus normal tissues. 
To assess these markers, IHC analysis, including hematoxylin and eosin (H&E) and trichrome 
staining, LAIR-1 expression, LAIR-2-Fc (NC410) binding and immune cell infiltration, was 
performed. Example of these results from the analysis of the stomach adenocarcinoma (STAD) 
(Figure 5). 
 
Figure 5: IHC staining of stomach adenocarcinoma 
 
 
The analysis of five representative samples of stomach adenocarcinoma (STAD) is shown above. STAD tissues 
were analyzed by H&E staining, for LAIR-2-Fc (NC410) binding and by immuno staining of LAIR-1, CD45, CD3 
and CD163 positive cells. For LAIR-2-Fc binding, brown staining indicates the binding of LAIR2-Fc, and blue 
staining is hematoxylin counterstaining indicating no binding by LAIR2-Fc. LAIR-2 Fc positive (green) and 
negative areas (red) were quantified as demonstrated in the associated piecharts. Five regions of interest (ROI) with 
a diameter of 600 μm were randomly chosen in the LAIR-2 Fc positive area for immune cell quantification. One of 
the ROIs was magnified to show the LAIR-1 staining. The graph shows the quantification of immune cells. The cell 


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counts of LAIR-1+, CD45+, CD3+ and CD163+ cells within the five ROI were quantified and calculated as 
×103/mm2.   
 
In addition to these described parameters, it is also known that LAIR-1 is highly restricted to the 
hematopoietic compartment and is only expressed on immune cells. Specifically, it has been 
observed that LAIR-1 expression is associated with suppressive immune cell populations in 
some cancers. A suppressive, but not stimulatory dendritic cell (DC) subpopulation, as well as 
suppressive macrophages express LAIR-1 in both mouse and human ovarian cancers (Figure 6), 
indicating that blockade of LAIR-1 in ovarian cancer should reverse immune suppression (Flies 
et al., 2016).  
 
Figure 6: LAIR-1 is expressed on suppressive DCs in a spontaneous model of ovarian 
cancer 
 
 
 
 
 
 
 
In the MISIIR Tg spontaneous model of ovarian cancer, LAIR-1 is expressed on CD11c+CD11b+ suppressive DCs 
at primary and metastatic sites of disease.  LAIR-1 is not expressed on the stimulatory DCs (Flies et al., 2016). 
 
The CLIA validation with IHC staining studies are ongoing, but early data support further 
investigation of tumor types identified in the initial analyses. Therefore, to further elucidate the 
effects of NC410, 5 different tumor types have been selected for investigation in Phase 1b and 2 
and will include HNSCC, NSCLC (adenocarcinoma) , CRC, gastric, and cervical cancers. A 
Simon 2-stage design will be used with a stopping rule to allow early termination of a cohort at 
the end of Stage 1 if insufficient response is observed, and enough subjects will be enrolled to 
predict possible target responses (≥ 25%) worthy of cohort expansion and potential for further 
evaluation in future studies. Finally, additional tumor types may be added (by amendment) based 
on emerging data for clinical investigation. 
1.3.4 
Rationale for Efficacy Endpoints 
Efficacy endpoints of this study are secondary and include objective response rate (ORR), 
duration of response (DoR), disease control rate (DCR), and progression-free survival (PFS) by 
investigator assessment based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
and modified RECIST (mRECIST). 
RECIST v1.1 will be adapted to account for the unique tumor response characteristics seen with 
immunotherapy (Chiou & Burotto, 2015). Immunotherapeutic agents may produce antitumor 


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effects by potentiating endogenous cancer-specific immune responses. The response patterns 
seen with such an approach may extend beyond the typical time course of responses seen with 
cytotoxic agents and can manifest a clinical response after an initial increase in tumor burden or 
even the appearance of new lesions. Standard RECIST may not provide an accurate response 
assessment of immunotherapeutic agents. Therefore, RECIST v1.1 will be used with the 
following adaptations: 
If radiologic imaging shows initial progressive disease, then tumor assessment should be 
repeated at least 4 weeks but no later than 6 weeks later to confirm disease progression with the 
option of continuing treatment while awaiting radiologic confirmation of progression. 
In subjects who have initial evidence of radiological progression but are clinically stable as 
defined below, it is at the discretion of the treating physician whether to continue a subject on 
study drug until repeat imaging is obtained. This clinical judgment decision should be based on 
the subject's overall clinical condition, including performance status, clinical symptoms, and 
laboratory data. Subjects may receive treatment while waiting for confirmation of disease 
progression if they are clinically stable as defined by the following criteria: 
• Absence of clinically significant signs and symptoms indicating disease progression 
• No decline in Eastern Cooperative Oncology Group (ECOG) performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
If repeat imaging shows < 20% tumor burden compared with nadir, stable or improved previous 
new lesion (if identified as cause for initial disease progression), and stable/improved nontarget 
disease (if identified as cause for initial disease progression), then treatment may be continued or 
resumed. If repeat imaging confirms disease progression due to any of the scenarios listed below, 
then subjects will be discontinued from study therapy. However, if a subject has confirmed 
radiographic progression (i.e., 2 scans at least 4 weeks but no later than 6 weeks apart 
demonstrating progression) per mRECIST, but the subject is achieving a clinically meaningful 
benefit, then an exception to continue treatment may be considered after consultation with the 
medical monitor. Clinically stable subjects at the confirmatory scan should also have no further 
increase in the target lesions, no unequivocal increase in nontarget lesions, and no additional new 
lesions develop (non-worsening disease progression) to continue study treatment. 
In determining whether the tumor burden has increased or decreased, site study teams should 
consider all target lesions as well as nontarget lesions (refer to RECIST v1.1 guidelines). 
Scenarios where disease progression is confirmed at repeat imaging include the following: 
• Tumor burden remains ≥ 20% and at least 5 mm absolute increase compared with nadir 
• Nontarget disease resulting in initial disease progression is worse (qualitative) 
• New lesion resulting in initial disease progression is worse (qualitative) 


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• Additional new lesion(s) are found since the last evaluation 
When feasible, subjects should not be discontinued until progression is confirmed. This 
allowance to continue treatment despite initial radiologic progression considers the observation 
that some subjects can have a transient tumor flare in the first few months after the start of 
immunotherapy but with subsequent disease response. Subjects who are deemed clinically 
unstable are not required to have repeat imaging for confirmation of disease progression. 
1.4 
Summary of Clinical Experience 
 The phase 1 study of N410, first in human study, has been initiated since 2020 with a 3+3 dose 
escalation design. Thus far the study has been conducted up to cohort 5 (NC410 at 60mg Q2W 
dosing) with no safety signals. PK, PD and biomarkers data suggested that NC410 is 
pharmacologically active and in addition, there are a few subjects with stable disease control.  
1.5 
Research Hypotheses 
NC410 will be adequately tolerated following administration in multiple ascending doses to 
subjects with refractory solid tumors and that such administration may result in clinical benefit. 
2 
OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 
Primary Objectives 
1) 
To evaluate the safety, tolerability, and dose-limiting toxicities (DLTs) of NC410 
2) 
To define an MTD or PAD of NC410    
2.1.2 
Secondary Objectives 
1) 
To evaluate the PK profile of NC410 
2) 
To assess preliminary efficacy of NC410  
2.1.3 
Exploratory Objectives 
1) 
To assess the immunogenicity of NC410 
2) 
To explore biomarkers that may predict the pharmacologic activity of NC410 
3) 
To characterize the effect of NC410 on markers of immunity  
2.2 
Study Endpoints 
2.2.1 
Primary Endpoints 
1) 
Safety and tolerability will be assessed by monitoring frequency, duration, and severity of 
adverse events (AEs). Note: Toxicity grading per NCI CTCAE v5.0. 
2)  
The MTD or PAD of NC410 will be defined in subjects with advanced or metastatic solid 
 
tumors 


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2.2.2 
Secondary Endpoints 
1) 
Assessment of PK of NC410 include individual NC410 concentrations in serum and 
identification of PK parameters. 
2) 
Assessment of antitumor activity/efficacy include objective response (OR) and DCR 
based on RECIST v1.1, DoR, PFS, and overall survival (OS) as per RECIST v1.1 and 
mRECIST v1.1 
2.2.3 
Exploratory Endpoints 
1) 
Immunogenicity, defined as the occurrence of ADA to NC410 will be determined. 
2) 
Biomarker effects of NC410 in peripheral blood and tumor tissue will be assessed, 
including but not limited to the following: 
• Whole blood immune cell population profiling/immune-phenotyping. 
• Serum markers of inflammation or immune modulation (cytokine levels). 
• Tumor biopsy analyses to evaluate the TME within tumor tissue and characterize immune 
cell infiltrate at baseline and after treatment, to correlate expression levels with efficacy. 
The expression of additional biomarkers will also be assessed. 
3 
STUDY DESIGN 
3.1 
Description of the Study 
This is an open-label, nonrandomized, Phase 1/2 study to determine the safety and tolerability, 
define the MTD or PAD, and to assess the preliminary efficacy of NC410 in subjects with 
advanced or metastatic solid tumors. Subjects will receive NC410 on Day 1 of each cycle. Phase 
1 of the study will begin with 14-day cycles; however, alternate dose administration schedules 
may also be explored depending on PK, PD, biomarker, safety results, and feedback from 
investigators. The study will be conducted in 2 parts: 
• Phase 1 – Dose Escalation (Phase 1a) and Safety Expansion (Phase 1b) will determine the 
MTD and/or the PAD, defined as a dose that provides a maximal biochemical effect, or 
an increase in biomarkers of immune activity. It will also define the optimal dose 
administration schedule and the maximum number of tolerated doses (MNTD). 
• Phase 2 – Dose Expansion will evaluate the recommended dose and administration 
schedule determined in Phase 1 in subjects with advanced or metastatic HNSCC, NSCLC 
(adenocarcinoma), CRC, gastric, and cervical cancers or other tumor type as identified 
with emerging data.  
 
 
 


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Figure 7: Study Design 
 
RR: Response Rate (ORR) per RECIST v1.1 
3.1.1 
Phase 1 
3.1.1.1 
Phase 1a - Dose Escalation 
In Phase 1a, subjects with advanced or metastatic solid tumors who progressed after treatment 
with available therapies that are known to confer clinical benefit, who are intolerant to treatment, 
or refuse standard treatment will be enrolled. A 3 + 3 design will be utilized to determine the 
MTD or PAD of NC410. 
A minimum of 3 evaluable subjects will be enrolled in each cohort beginning with Cohort 1 
(3 mg; starting dose). The first 3 evaluable subjects within a cohort will be observed for a DLT 
observation period of 28 days before the next cohort begins enrollment. Only one subject can be 
dosed on the first day of dosing for each cohort (additional subjects can begin dosing in ≥48 
hours). The dose will be escalated if 0 of the first 3 evaluable subjects enrolled has a DLT. If 1 of 
the first 3 evaluable subjects enrolled has a DLT, then the cohort will be expanded to include 3 
additional evaluable subjects, and if no DLT occurs in the additional 3 subjects, then the dose 
will be escalated. If a DLT occurs in one-third or more of the expanded cohort, then the MTD 
will be deemed to be exceeded and the previous dose level will be considered the MTD. 
Intermediate dose levels below the MTD may be explored pending safety review. If only 3 
subjects were treated at the MTD or PAD, then a minimum of 3 additional evaluable subjects 
will be enrolled at this dose before it is administered in Phase 2 of the study. 
If starting dose exceeds the MTD, the sponsor and investigators will consider dosing NC410 at a 
lower dose, and/or investigate 3 mg at alternate dose schedules, based on available safety, PK, 
PD, and biomarker data. If an alternate schedule is determined to be safe, re-escalation of NC410 
will proceed according to Table 1. 


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Throughout the treatment period, if > 33% of subjects (a minimum of 6 subjects) experience a ≥ 
Grade 3 toxicity related to study drug after completing ≥ 4 cycles, then dose administration will 
be stopped, and the MNTD will be determined in conjunction with the investigators and sponsor 
based on all available safety data. 
Additional subjects will be enrolled in a cohort to achieve the minimum of 3 evaluable subjects. 
Subjects who drop out for reasons other than a DLT (e.g., events clearly associated with the 
underlying disease, disease progression, concomitant medication, or comorbidity) during the 28-
day DLT observation period will be considered non-evaluable and will be replaced. Dose 
modifications should not be made during the DLT observation period without discussion with 
the medical monitor. Intrasubject dose escalation is not permitted; however, once the RP2D and 
schedule has been determined, ongoing subjects in Phase 1 may be permitted to escalate to the 
RP2D only with approval of the medical monitor assuming the subject has not experienced 
≥Grade 3 toxicity in previous treatment cycles. The cohorts and dose levels are shown in Table 
1. 
Table 1: NC410 Dose Levels and Cohorts 
Cohort 
Dose of NC410 
1 (Starting dose) 
3.0 mg 
2  
6.0 mg 
3  
15 mg 
4 
30 mg 
5 
60 mg 
6 
100 mg 
7 
200 mg 
8 
400 mg 
 
3.1.1.2 
Phase 1b – Safety Expansion 
To evaluate additional PD activity of NC410 and confirm the preliminary safety of the dose 
escalation cohorts, Phase 1 of the study will include safety expansion cohorts (denoted as Phase 
1b) evaluating doses and schedules equivalent to or lower than the highest dose levels 
determined to be safe and/or doses determined to be pharmacologically active. Fixed doses of 
NC410 (equivalent to or less than the MTD/PAD determined during dose escalation), may also 
be explored during the safety expansion. All doses and schedules explored during the safety 
expansion will depend on PK, PD, biomarker, and safety results. 
Approximately 30 evaluable subjects will be enrolled in the Phase 1b safety expansion, with 
each cohort enrolling up to 10 additional subjects; screening and on treatment biopsies will be 
required.  


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If < 3 of 9 evaluable subjects experience a DLT, the cohort will be deemed safe. If > 1 safety 
expansion cohort is deemed safe, then a recommended dose and schedule will be determined in 
conjunction with the investigators and sponsor based on all available safety, PK, PD, and 
biomarker results. 
The safety expansion cohorts may be conducted in parallel to Phase 2 and may be limited by the 
sponsor to subjects with specific tumor types to achieve a balance across cohorts. 
3.1.2 
Phase 2 − Dose Expansion 
Phase 2 of the study will further evaluate the safety, tolerability, preliminary efficacy, PK, and 
pharmacologic activity of the RP2D of NC410 in subjects with advanced or metastatic HNSCC,   
NSCLC (adenocarcinoma), CRC, gastric, and cervical cancers or other tumor identified based 
upon emerging data. Each cohort will be comprised of an individual tumor type. Biopsies at 
screening and on treatment will be required of all enrolled Phase 2 subjects.  
A Simon 2-stage design will be utilized with a stopping rule to allow for early termination of a 
particular cohort at the end of Stage 1 if there are insufficient responses observed. During Stage 
1, 9 evaluable subjects will be enrolled in each cohort; if no responses are observed within the 
cohort then the cohort will be discontinued. If at least 1 response is observed, 8 additional 
evaluable subjects will be enrolled in the cohort (Stage 2), for at least 17 evaluable subjects per 
cohort. 
Subjects will continue to receive NC410 at the RP2D and schedule until protocol-defined 
withdrawal criteria are met. Continuous evaluation of toxicity events will be performed 
throughout enrollment in Phase 2 of the study. If the cumulative incidence of DLTs occurs in ≥ 
33% of subjects after 6 subjects have been observed for at least 28 days, further enrollment may 
be interrupted until the sponsor has determined the appropriate course of action. All AEs, 
regardless of the time of occurrence on study may be considered in determining the appropriate 
dose, schedule, and MNTD. 
Toxicity will continue to be monitored throughout the treatment period. If > 33% of subjects 
(minimum of 6 subjects) experience a ≥ Grade 3 toxicity related to study drug after completing ≥ 
4 cycles, then the MNTD will be determined in conjunction with the investigators and sponsor 
based on all available safety data. 
3.2 
Measures Taken to Avoid Bias 
This is an open-label study; no formal comparisons will be made between subjects or against 
historical controls. Measurements of safety and efficacy are objective measurements, and only 
comparisons to pretreatment conditions will be made. 
3.3 
Number of Subjects 
3.3.1 
Planned Number of Subjects 
Up to approximately 163 evaluable subjects may be enrolled in this study. 
• Phase 1a Dose Escalation – Approximately 24–48 evaluable subjects 


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• Phase 1b Safety Expansion – Up to 30 additional evaluable subjects 
• Phase 2 Dose Expansion – Up to 85 evaluable subjects (up to 45 in stage 1) 
3.3.2 
Replacement of Subjects 
Subjects may be replaced for any of the following reasons: 
• In Phase 1, any subject who withdraws from treatment before the completion of the DLT 
period for any reason other than a DLT (e.g., subject is not evaluable for DLTs) 
• In Phase 1b and Phase 2, a subject who has not met the biopsy requirements for the study 
(i.e. pre- and on-treatment samples) may not be eligible to enroll. 
• Subject does not meet the eligibility requirements of the study (accidental enrollment) 
3.4 
Duration of Treatment and Subject Participation 
After signing the informed consent form (ICF), screening assessments may be completed over a 
period of up to 30 days. Subjects will continue to receive NC410 until disease progression, 
withdraw of consent, or intolerable toxicity (whichever comes first).  After completing 12 
months of treatment, if the subject is deriving benefit from NC410 and has not met any of the 
protocol-defined conditions for withdrawal or discontinuation, the subject will be followed by 
the PI per standard of care. Subjects approved to continue treatment will remain on the dose level 
assigned at the time of enrollment (unless otherwise approved for dose modification by the 
medical monitor). Safety reporting will continue through end of treatment to completion of the 
safety follow-up period.  If the subject discontinues treatment with NC410, then the treatment 
period will end, and the subject will enter the follow-up period (see Section 6.4).  
3.5 
Overall Study Duration 
The study begins when the first subject signs the ICF. The end of the study will occur when all 
subjects have completed the last study follow-up visit or have discontinued study drug and have 
completed applicable follow-up assessments. 
The end of the study may be declared when no more than 5 subjects remain on study drug for at 
least 6 months, at which point a database lock of the study may occur to allow for analysis of the 
study data. Any remaining subjects may continue to receive study drug and be seen by the 
investigator per standard of care. The investigator will be expected to monitor for and report any 
serious AEs (SAEs) and pregnancies, as detailed in Sections 8.3 and 8.5. The remaining subjects 
will be considered on study until a discontinuation criterion is met and written notification is 
provided to the sponsor. 
3.6 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract. The investigator is to notify the institutional review board 
(IRB)/independent ethics committee (IEC) in writing of the study's completion or early 
termination, send a copy of the notification to the sponsor or sponsor's designee, and retain one 
copy for the site study regulatory file. 


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The sponsor may terminate the study electively, if required by regulatory decision or upon 
review of emerging data. If the study is terminated prematurely, then the sponsor or designee 
will notify the investigators, the IRBs and IECs, and regulatory bodies of the decision and reason 
for termination of the study. 
4 
SUBJECT ELIGIBILITY 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
4.1 
Subject Inclusion Criteria 
A subject who meets all the following criteria may be included in the study: 
1) 
Men and women aged 18 or older. 
2) 
Willingness to provide written informed consent for the study. 
3) 
ECOG performance status 0 to 1. 
4) 
Locally advanced or metastatic disease; locally advanced disease must not be amenable 
to resection with curative intent. 
a. Phase 1a: Subjects with advanced or metastatic tumors including but not limited to: 
head and neck squamous cell carcinoma, non-small cell lung cancer, ovarian 
cancer, cervical cancer, endometrial cancer, gastric cancer (including stomach, 
esophageal, and gastroesophageal junction), hepatocellular carcinoma (HCC), 
melanoma, pancreatic cancer, Merkel cell carcinoma, colorectal cancer (CRC), 
metastatic castrate resistant prostate cancer (CRPC), renal cell carcinoma (RCC), 
triple negative breast cancer (TNBC), urothelial carcinoma , and other tumors 
considered likely to respond to immune checkpoint inhibitors. 
b. Phase 1b and Phase 2: Subjects with HNSCC, NSCLC (adenocarcinoma), CRC, 
gastric, and cervical  cancers. These proposed indications may change based on 
emerging data and at the discretion of the Sponsor. 
5) 
Subjects who have disease progression after treatment with available therapies that are 
known to confer clinical benefit, or who are intolerant to treatment, or who refuse 
standard treatment.  Note: There is no limit to the number of prior treatment regimens. 
6) 
Presence of measurable disease based on RECIST v1.1.  
Note: Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other locoregional therapy, are not considered measurable unless there has been 
demonstrated progression in the lesion. 
7) 
Willingness to undergo pretreatment and on-treatment tumor biopsies (core or 
excisional).  
Note: For Phase 1a, pretreatment tumor biopsies are optional. Biopsies are required for all 
Phase 1b and Phase 2 subjects. 


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Note: For Phase 1b, archival biopsy sample will be accepted. For Phase 2, fresh biopsy 
sample is preferred.  
Note: An archival biopsy obtained within 6 months of screening for other purposes (i.e., 
not an NC410-01 study procedure) before signing consent may be utilized.  
8) 
Female subjects of childbearing potential (defined as women who have not undergone 
surgical sterilization with a hysterectomy and/or bilateral oophorectomy and are not 
postmenopausal, defined as ≥ 12 months of amenorrhea) and non-sterilized male subjects 
must agree to take appropriate precautions to avoid pregnancy or fathering children (with 
at least 99% certainty) from screening through 90 days after the last dose of study drug. 
Note: Females of child-bearing potential must have a negative serum pregnancy test at 
screening.  
 
4.2 
Subject Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1) 
Inability to comprehend or unwilling to sign the ICF. 
2) 
Laboratory and medical history parameters not within the protocol-defined range.  
a. Absolute neutrophil count < 1.5 × 109/L. 
b. Platelets < 100 × 109/L. 
c. Hemoglobin < 9 g/dL or < 5.6 mmol/L. 
d. Serum creatinine > 1.5 × institutional upper limit of normal (ULN) or calculated 
creatinine clearance < 50 mL/min (using Cockcroft-Gault formula) 
e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥ 2.5 × 
ULN.  
Note: Subjects with documented liver metastases may enroll with ALT, AST, and 
alkaline phosphatase ≤ 5 × ULN. Subjects with documented bone metastases may 
enroll with alkaline phosphatase ≤ 5 ×ULN. 
f. Total bilirubin ≥ 1.5 × ULN 
Note: Subjects with documented Gilbert's syndrome with elevated baseline total 
bilirubin ≤ 3.0 mg/dL may be enrolled. 
g. International normalized ratio (INR)/prothrombin time (PT) > 1.5 × ULN and 
Activated partial thromboplastin time (aPTT) > 1.5 × ULN; applies only to 
subjects who do not receive therapeutic anticoagulation; subjects receiving 
therapeutic anticoagulation should be on a stable dose.  
3) 
Transfusion of blood products (including platelets or red blood cells) or administration of 
colony-stimulating factors (including granulocyte colony–stimulating factor, granulocyte 
macrophage colony–stimulating factor, or recombinant erythropoietin) within 7 days 
before the first administration of study drug. 
 
 


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4) 
Receipt of anticancer medications or investigational drugs within the following intervals 
before the first administration of study drug: 
a. ≤ 14 days for chemotherapy, targeted small molecule therapy, hormonal therapy 
or radiation therapy. Subjects must not have had radiation pneumonitis because of 
a treatment. A 1-week washout is permitted for palliative radiation to non–central 
nervous system (CNS) disease provided recovery is adequate.  
Note: Bisphosphonates and denosumab are permitted medications; continuation 
of hormonal therapy is allowed for CRPC patients. 
b. ≤ 28 days for prior immunotherapy or persistence of active cellular therapy (e.g., 
chimeric antigen receptor T cell therapy; other cellular therapies must be 
discussed with the medical monitor to determine eligibility). 
c. ≤ 28 days for a prior mAb used for anticancer therapy except for denosumab. 
d. ≤ 7 days for immune-suppressive–based treatment for any reason.  
Note: Use of inhaled or topical steroids or corticosteroid use for radiographic 
procedures is permitted.  
Note: The use of corticosteroids equivalent to prednisone ≤ 10mg/day is allowed. 
e. ≤ 28 days or 5 half-lives, t½, (whichever is longer) before the first dose for all 
other investigational study drugs or devices.  
f. ≤ 14 days for a COVID-19 vaccine. Note: For 2-dose COVID-19 vaccines, 
subjects must wait at least 14-days after 2nd dose administration. 
5) 
Has not recovered to ≤ Grade 1 from toxic effects of prior therapy (including prior 
immunotherapy and radiation therapy) and/or complications from prior surgical 
intervention before starting therapy.  
Note: Subjects with stable chronic conditions (≤ Grade 2) not expected to resolve (such 
as neuropathy and alopecia) are exceptions and may enroll.  
Note: Subjects with a history of any grade immune-related ocular AE (e.g., episcleritis, 
scleritis, uveitis) will be excluded.  
Note: Subjects with a history of a Grade 3 or higher irAE from prior immunotherapies 
are excluded from the Phase 1a dose-escalation portion of the study. 
6) 
Receipt of a live vaccine within 30 days of planned start of study therapy.  
Note: Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, chicken pox/zoster, yellow fever, rabies, Bacillus Calmette–Guérin, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are 
live attenuated vaccines and are not allowed. 
7) 
Active autoimmune disease that required systemic treatment in the past (i.e., with use of 
disease-modifying agents, corticosteroids, or immunosuppressive drugs).  
Note: Subjects with hyperthyroidism or hypothyroidism, who have not required systemic 
treatment for an autoimmune disease for at least 2 years and are stable on thyroid 
hormone replacement are allowed to participate in the study. 


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Note: Replacement and symptomatic therapies (e.g. insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) are not considered a form 
of systemic immune suppressive therapy and are allowed. 
8) 
Known active CNS metastases and/or carcinomatous meningitis.  
Note: Subjects with previously treated brain metastases may participate provided they are 
stable (without evidence of progression by imaging for at least 28 days before the first 
dose of study drug and any neurologic symptoms have returned to baseline), have no 
evidence of new or enlarging brain metastases or CNS edema, and have not required 
steroids for at least 7 days before the first dose of study drug. 
9) 
Known concurrent malignancy that is progressing or requires active treatment, or history 
of other malignancy within 2 years of study entry after treatment with curative intent. 
Note: Cured basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, 
prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or 
indolent malignancy, or cancers from which the subject has been disease-free for > 1 year 
are not considered exclusionary.  
10) 
Evidence of active, noninfectious pneumonitis or history of interstitial lung disease. 
11) 
Subjects with screening QTc interval > 470 milliseconds (corrected by Fridericia) are 
excluded.  
12) 
Uncontrolled systemic fungal, bacterial, viral, or other infection despite appropriate anti-
infection treatment.  
13) 
Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV), unless it is considered to 
be cured.   
Note: Subjects with no prior history of hepatitis B infection who have been vaccinated 
against hepatitis B and who have a positive antibody against hepatitis B surface antigen 
test as the only evidence of prior exposure may participate in the study. 
Note: If HCV/HBV antibody or antigen tests are positive, reflex testing (HCV RNA 
and/or HBV DNA tests) should be performed to confirm results prior to assessing subject 
eligibility.  
Note: Subjects with prior hepatitis B virus [HBV] infection must have HBV viral load 
[VL] < 100 IU/mL before study enrollment and must be treated according to local 
standards; hepatitis C virus [HCV] infection must have, before study enrollment, no 
detectable VL and must be treated according to local standards. 
14) 
Known history of HIV (HIV 1 or HIV 2 antibodies). 
15) 
Known allergy or reaction to any component of study drug or formulation components. 
16) 
Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 90 days after the 
last dose of study treatment. 
17) 
Any condition that would, in the investigator's judgment, interfere with full participation 
in the study, including administration of study drug and attending required study visits; 
pose a significant risk to the subject; or interfere with interpretation of study data. 


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5 
TREATMENT 
5.1 
Treatment Assignment 
5.1.1 
Subject Numbering and Treatment Assignment 
All subjects will sign an ICF and be assigned a unique 7-digit subject number with the first 3 
digits serving as the site number. The subject numbering  will be managed by the Sponsor/CRO 
Investigative sites must complete all applicable CRFs for subjects consented to the trial, even if 
the subject is not treated with study drug. 
Dose level and cohort assignment will occur at time of subject enrollment and as indicated by the 
sponsor or designee. Dose level and cohort assignment will be maintained within the CRF per 
the CRF completion guidelines and managed by the Sponsor/CRO 
All subjects will be assigned to a cohort to receive NC410; there is no placebo. 
5.1.2 
Randomization and Blinding 
This is an open-label nonrandomized study; therefore, randomization and blinding do not apply. 
5.2 
Study Drug 
5.2.1 
Description and Administration 
The study drug (NC410) is in frozen liquid form formulated for iv infusion, over a minimum of 
30 minutes on Day 1 of each cycle (if the infusion is interrupted for any non-clinical reason, sites 
must notify the medical monitor). The drug product is provided in two concentrations.  The 
20 mg/mL configuration has 320 mg/vial in 16.0 mLs of deliverable volume whereas the 1 
mg/mL configuration has 1 mg/vial in 16.0 mLs of deliverable volume. The drug can be diluted 
as low as 0.04 mg/mL; additional information can be found in the NC410 IB. The infusion site 
should not be used for blood sampling. 
5.2.2 
Supply Packaging and Labeling 
Study drug will be supplied as 16mL aqueous solution in 20 mL glass vials with either 20 
mg/mL or 1 mg/mL of NC410. Study drug will be packaged as open-labeled supplies, each vial 
will be labeled and placed in a carton. The Pharmacy Manual contains additional information 
regarding supply, packaging, and labeling of study drug. 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study drug in 
accordance with the protocol and any applicable laws and regulations. 
5.2.3 
Storage 
Study drug must be stored in a freezer (-20°C to -50°C), protected from light, in a secure, 
controlled-access location. Receipt and dispensing of study drug must be recorded by an 
authorized person at the study site. Study drug may not be used for any purpose other than that 


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stated in the protocol. The Pharmacy Manual contains additional information regarding storage 
of study drug. 
5.2.4 
Accountability 
Detailed information such as requirements for accountability and disposal of study drug can be 
located within the pharmacy manual, which will be provided separately. 
5.3 
Treatment Compliance 
Compliance with study drug dosing will be calculated by the sponsor based on the drug 
accountability and infusion records documented by the site staff and monitored by the 
sponsor/designee. 
5.4 
Treatment Interruptions and Adjustments 
5.4.1 
Dose Modifications 
Selections and modifications to the study drug are planned for dose-escalation cohorts (after 
consultation with the medical monitor). Dose interruptions and modifications also may occur for 
individual study subjects. The identification of DLTs will define the doses used in planned 
cohorts (see Section 5.4.2). The occurrence of DLTs and other toxicities (related or unrelated to 
study drug) will guide decisions for treatment interruptions and discontinuation for individual 
subjects. Intrasubject dose escalation is not permitted; however, once the RP2D has been 
determined, ongoing subjects in Phase 1 may be permitted to dose escalate to the RP2D only 
with medical monitor approval assuming the subject has not experienced ≥Grade 3 toxicity in 
previous treatment cycles. 
5.4.2 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose 
The evaluation period for DLTs will begin on Cycle 1 Day 1 and will continue up to 28 days. All 
DLTs will be assessed by the investigator using National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) v5.0. A DLT will be defined as the occurrence of any 
toxicity in Table 2, except for events clearly associated with the underlying disease, disease 
progression, a concomitant medication, or comorbidity. 
Individual subject dose reductions may be made based on events observed at any time during 
treatment with study drug; however, for the purposes of dose cohort escalation/de-escalation, 
expanding a dose cohort, and determining the MTD/PAD of study drug, decisions will be made 
based on events that are observed from the first day of study drug administration through and 
including the 28-day DLT period. A lower MTD may subsequently be determined based on 
relevant toxicities that become evident after the 28-day DLT period. 


25 
 
 
Table 2: Definition of Dose-Limiting Toxicity 
Nonhematologic toxicity 
Any ≥ Grade 3 nonhematologic toxicity EXCEPT the following: 
• Transient (≤ 72 hours) abnormal laboratory values without associated clinically significant signs or symptoms. 
• An event clearly associated with the underlying disease, disease progression, a concomitant medication, or comorbidity. 
• Asymptomatic changes in lipid profiles. 
• Asymptomatic changes in amylase and lipase. 
Single or non-fasting elevations in blood glucose Note: Any non-hematologic toxicity ≥ Grade 3  should count as DLTs except 
those that are clearly and incontrovertibly due to disease progression or extraneous causes. 
Hematologic toxicity 
• Grade 3 thrombocytopenia with clinically significant bleeding (i.e., requires hospitalization, transfusion of blood products, or 
other urgent medical intervention). 
• Grade 4 thrombocytopenia. 
• ≥ Grade 3 febrile neutropenia (absolute neutrophil count < 1.0 × 109/L and fever > 38.3°C). 
• Grade 4 neutropenia that does not recover to ≤ Grade 2 in ≤ 3 days after interrupting study drug. 
• Grade 4 anemia not explained by underlying disease or some other concomitant disorder. 
Immune-related toxicity 
• ≥ Grade 2 ocular irAEs 
• Grade 3 irAEs that do not improve to baseline or at least Grade 1 in < 5 days with appropriate care or with corticosteroid therapy  
• Grade 4 irAEs regardless of duration. 
 
 


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General 
• Inability to receive the planned number of doses within the 28-day DLT period due to toxicity, regardless of grade, will be 
considered a DLT. 
• Combined elevations in serum ALT >3 times the upper limit of normal (ULN) and bilirubin >2 ULN in the absence of alkaline 
phosphatase (ALP) elevation (<2 ULN) 
o Abnormal liver function tests as indicated by the criteria above will be considered a DLT if no other reason can be 
found to explain the combination of increased liver markers such as viral hepatitis A, B, or C; preexisting or acute 
liver disease; or another drug capable of causing the observed injury. 
• Any death not clearly due to the underlying disease or extraneous causes. 
MTD 
• In Phase 1 of the study, the MTD will be defined as 1 dose level below that at which ≥ one-third of subjects in a cohort have 
DLTs. 
• In Phase 2 of the study, toxicities will continue to be monitored. If the cumulative incidence of DLTs occurs in > 33% of 
subjects after 6 subjects have been observed for at least 28 days, then further enrollment may be interrupted, and the 
investigators and sponsor will meet and reassess the MTD. All AEs, regardless of the time of occurrence on study, may be 
considered in determining the appropriate dose, schedule, and MNTD. 
MNTD 
• Throughout the treatment period, if > 33% of subjects (minimum of 6 subjects) experience a ≥ Grade 3 toxicity related to study 
drug after completing ≥ 4 cycles, then dose administration will be stopped, and the MNTD will be determined in conjunction 
with the investigators and sponsor based on all available safety data. 
 


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5.4.3 
Management of Dose-Limiting Toxicities or Other Urgent Situations 
In all cases, investigators may employ any measures or concomitant medications, after 
discussion with the medical monitor (whenever possible), necessary to optimally treat the 
subject. 
5.4.4 
Follow-Up of Dose-Limiting Toxicities 
Any DLT should be followed until it resolves to baseline or appears to have stabilized for a 
minimum of 4 weeks (e.g., 28 days). During follow-up, subjects should be seen as often as 
medically indicated to assure safety. 
5.4.5 
Procedures for Cohort Review and Dose Escalation 
Telephone conferences will be scheduled by the sponsor, or sponsor’s delegate, with study 
investigators to review cohort-specific data and overall safety data, to agree on dose escalation, 
adjudicate individual high-grade AEs as potentially dose-limiting, and guide other major study 
decisions. 
5.4.6 
Criteria and Procedures for Dose Interruptions and Adjustments of Study Drug 
Treatment with study drug may be delayed allowing for resolution of toxicity. Subjects may 
resume treatment if no medical condition or other circumstance exists that, in the opinion of the 
investigator, would make the subject unsuitable for further participation in the study. For 
toxicities that occur outside of the 28-day DLT period, the treating investigator should contact 
the medical monitor to discuss the case of any subject whose treatment has been delayed for 
more than 4 weeks (28 days) before restarting treatment with study drug. 
Instructions for dose modifications and interruptions are outlined in Table 3. Individual decisions 
regarding dose interruptions and reductions should be made using appropriate clinical judgment 
in consultation with the medical monitor, considering relatedness of the AE to the study drug and 
the subject's underlying condition. Adverse events that have a clear alternative explanation, or 
transient (≤ 72 hours) abnormal laboratory values without associated clinically significant signs 
or symptoms may be exempt from dose-reduction rules. Dose interruptions/delays are permitted 
in the case of medical/surgical events or logistical reasons not related to study therapy (e.g., 
elective surgery, unrelated medical events, subject vacation, and/or holidays). Subjects should be 
placed back on study therapy within 4 weeks (28 days) of the scheduled interruption/delay, 
unless otherwise discussed with the medical monitor. The reason for interruption/delay should be 
documented in the subject's study record. 


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Table 3: Rules for Interruption and Restarting of Study Drug 
NCI CTCAE 
v.5.0 
Grade/Severity 
Timing for 
Restarting 
Treatment 
Dose Level for 
Restarting 
Treatment 
Treatment 
Discontinuation 
1-2 (mild-
moderate) 
Continue treatment 
at the discretion of 
the investigator. 
N/A 
N/A 
3 (severe) 
Toxicity resolves to 
Grade 0-1. 
Reduce by 1 dose 
level.a 
Toxicity does not resolve 
within 4 weeks (28 days) of 
last dose, except by 
approval of the medical 
monitor. 
or 
Second occurrence of 
previously resolved Grade 
3 AE. 
4 (life-
threatening) 
Permanently 
discontinue. 
N/A 
Permanently discontinue. 
Note: Permanently discontinue for any severe or Grade 3 AE that recurs or any life-threatening event. 
a No more than 2 dose reductions of study drug are permitted (see Table 1). Subjects should be permanently discontinued from 
study drug if they have AEs requiring more than 2 dose reductions of study drug. 
 
5.4.7 
Definition, Procedures, and Supportive Care Guidelines for Immune-Related 
Adverse Events 
NC410 is an immune modulator, and it is possible that irAEs (both nonserious and serious) 
similar to those described with approved immunotherapies may occur. Adverse events of a 
potential immunologic etiology or irAEs may be defined as an AE consistent with an immune 
phenomenon associated with drug exposure after all other etiologies have been ruled out. 
Immune-related AEs may be expected based on the nature of NC410, its mechanism of action, 
and based on reported experience with other immunotherapies. Special attention should be paid 
to AEs that may be suggestive of potential irAEs. An irAE can occur shortly after the first dose 
or several months after the last dose of treatment. Suspected irAEs should be discussed with the 
medical monitor when possible. 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of drug-related 
AEs with potential immunologic etiology are outlined in Table 4. Detailed supportive care 
guidelines for specific irAEs can be in found in Brahmer et al. (Brahmer et al., 2018). For each 
AE, attempts should be made to rule out other causes, including but not limited to metastatic 
disease or bacterial or viral infection, which might require specific supportive care. 


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Table 4: Supportive Care Guidelines for Subjects Exhibiting Immune-Related Adverse 
Events 
NCI CTCAE v.5.0 
Grade/Severity 
Supportive Care 
Grade 1 (mild) 
• Monitor symptoms and provide symptomatic treatment. 
Grade 2 (moderate) 
• Monitor symptoms and provide symptomatic treatment. 
• Consider consultation with specialists as necessary. 
• Consider systemic corticosteroids per institutional standard of care. 
Grade 3-4 
(severe–life-threatening) 
• Monitor symptoms and provide symptomatic treatment. 
• Consider consultation with specialists as necessary. 
• Administer corticosteroids per institutional standard of care. 
• More potent immunosuppressive therapies should be considered 
for events not responding to systemic steroids after discussing with 
the medical monitor. 
• Study drug should be permanently discontinued for clinically 
significant or severe irAEs or for events where steroid course cannot 
be tapered below 7.5 mg/day prednisone or equivalent to manage 
symptoms. 
 
5.4.8 
Management of Infusion Reactions 
Table 5 shows treatment guidelines for subjects who experience an infusion reaction associated 
with administration of study drug. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 


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Table 5: Infusion Reaction Treatment Guidelines 
NCI CTCAE v5.0 
Grade/Severity 
Treatment 
Premedication at Subsequent Dose 
Administration 
Grade 1: 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated. 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically stable 
in the opinion of the investigator. 
None. 
Grade 2: 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, nonsteroidal 
anti-inflammatory drugs 
(NSAIDs), narcotics, IV fluids); 
prophylactic medications 
indicated for ≤ 24 hours. 
Stop infusion and monitor symptoms. 
Additional appropriate medical therapy may include 
but is not limited to the following: 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
 
Increase monitoring of vital signs as medically 
indicated until the subject 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. Otherwise, dose administration 
will be interrupted until symptoms resolve, and the 
subject should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug administration. 
Subject may be premedicated 1.5 h (± 30 
min) prior to infusion with the 
following: 
• Diphenhydramine 50 mg orally (or 
equivalent dose of antihistamine). 
• Acetaminophen 500-1000 mg orally 
(or equivalent dose of antipyretic). 


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NCI CTCAE v5.0 
Grade/Severity 
Treatment 
Premedication at Subsequent Dose 
Administration 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates). 
or 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated. 
Stop infusion. 
Additional appropriate medical therapy may include 
but is not limited to: 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
• Oxygen 
• Pressors 
• Corticosteroids 
• Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically stable 
in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further 
study drug administration. 
No subsequent dose. 
 


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5.4.9 
Criteria for Permanent Discontinuation of Study Drug 
The occurrence of an unacceptable toxicity not caused by the underlying malignancy will be 
presumed to be related to study drug and will require that the study drug be permanently 
discontinued. Unacceptable toxicity is defined as follows: 
• Symptomatic Grade 4 or a life-threatening AE 
• ≥ Grade 2 ocular irAE 
• Occurrence of an AE that is related to treatment with the study drug that, in the judgment 
of the investigator or the sponsor's medical monitor, compromises the subject's ability to 
continue study-specific procedures, or is considered to not be in the subject's best interest. 
• Persistent AE requiring a delay of study drug beyond 4 weeks (28 days), unless the delay 
has been approved by the medical monitor. 
5.4.10 
Treatment After Initial Evidence of Radiologic Disease Progression 
Immunotherapeutic agents may produce antitumor effects by potentiating endogenous cancer-
specific immune responses. The response patterns seen with such an approach may extend 
beyond the typical time course of responses seen with cytotoxic agents and may manifest as a 
clinical response after an initial increase in tumor burden or even the appearance of new lesions. 
As a result, scans showing progressive disease should be repeated within 4-6 weeks to rule out 
pseudoprogression at the discretion of the PI. 
If radiologic imaging shows disease progression, then subjects have the option to continue 
treatment while awaiting radiographic confirmation of progression as outlined in Section 7.6.1. 
5.5 
Withdrawal of Subjects from Study Drug 
5.5.1 
Withdrawal Criteria 
A subject may choose to withdraw from the study at any time or be withdrawn from the study by 
the investigator or sponsor, if the subject is noncompliant with the study requirements. Subjects 
may also be withdrawn at the discretion of the US FDA or health authorities. If a subject is 
withdrawn, then every reasonable effort should be made to determine the reason for withdrawal, 
and this information should be recorded in the electronic case report form (eCRF). 
Subjects must be withdrawn from study drug for the following reasons: 
• The subject becomes pregnant 
• Consent is withdrawn 
• Further participation would be injurious to the subject’s health or well being 
• The subject is lost to follow-up 
• Toxicity (Section 5.4.9). Subjects with unacceptable toxicities must be withdrawn from 
study drug but will continue to be followed during the safety follow-up visits as specified 
in Section 6.4 


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• The study is terminated by the IRB or regulatory authority 
• The study is terminated by the sponsor 
A subject may be discontinued from study drug as follows: 
• Confirmed radiographic progression of disease per mRECIST v1.1. 
• If, during the course of the study, a subject is found not to have met eligibility criteria 
(see Section 4), then the medical monitor, in collaboration with the investigator, will 
determine whether the subject should be withdrawn from the study. 
• If a subject is noncompliant with study procedures or study drug administration in the 
investigator's opinion, then the sponsor should be consulted for instruction on handling 
the subject. 
5.5.2 
Withdrawal Procedures 
If the decision is made to permanently discontinue the study drug, the subject will be withdrawn 
from the study, and the end-of-treatment (EOT) visit should be conducted. Reasonable efforts 
should be made to have the subject  complete the safety follow-up. These visits are described in 
Section 6.4. The last date of the last dose of study drug and the reason for subject withdrawal 
will be recorded in the eCRF. 
If a subject is withdrawn from the study: 
• The study site monitor and medical monitor must be notified. 
• The reason(s) for withdrawal must be documented in the subject's medical record and in 
the eCRF 
• The EOT visit should be performed 
• The date of the EOT visit should be recorded in the eCRF 
• Subjects must be followed for safety until the time of the follow-up visit or until study 
drug–related toxicities resolve, return to baseline, or are deemed irreversible, whichever 
is longest 
If the subject discontinues study drug and actively withdraws consent for collection of follow-up 
data (safety follow-up or disease assessment), then no additional data collection should occur; 
however, subjects will have the option of withdrawing consent for study drug but continuing in 
the follow-up period of the study for safety/efficacy assessments. 
5.6 
Concomitant Medications 
All concomitant medications and treatments must be recorded in the eCRF. Any prior medication 
received up to 30 days before the first dose of study drug and 90 days after the last dose of study 
drug will be recorded in the eCRF. Any addition, deletion, or change in the dose of these 
medications will also be recorded. Concomitant medications administered after 90 days after the 
last dose of study drug should be recorded for SAEs as defined in Section 8.3. Concomitant 
treatments/procedures that are required to manage a subject's medical condition during the study 
will also be recorded in the eCRF. 


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5.6.1 
Permitted Medications 
All treatments that the investigator considers necessary for a subject's welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medications will be recorded on the eCRF, including all 
prescription, over-the-counter, herbal supplements, and iv medications and fluids. If changes 
occur during the study period, documentation of drug regimen, frequency, route, and date may 
also be included on the eCRF. Note: The use of bisphosphonates and denosumab are permitted 
in this study; concurrent hormonal therapy is allowed for CRPC patients. 
5.6.2 
Restricted Medications 
Use of systemic glucocorticoids is restricted to prophylaxis for contrast allergies for radiographic 
procedures, or to modulate symptoms or treat an AE of suspected immunologic etiology. The use 
of physiologic corticosteroid replacement therapy may be approved after consultation with the 
medical monitor. 
Note: Non-systemic steroids are allowed (e.g., inhaled, intraocular, intranasal, transdermal, and 
topical steroids are allowed). A short course of steroids (prednisone or equivalent) ≤ 10 mg/day 
may be permitted with medical monitor approval. 
Acetaminophen and NSAIDs (e.g., ibuprofen) may be used. Due to the risk of liver injury with 
the use of high doses of acetaminophen, subjects should be advised to stay within the 
recommended daily dose of acetaminophen. 
5.6.3 
Prohibited Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria (see Section 4.2) are 
not allowed during the ongoing study. If there is a clinical indication for one of these 
medications or vaccinations specifically prohibited during the study, discontinuation from study 
drug or vaccination may be required. The investigator should discuss any questions regarding 
this with the medical monitor. The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the subject's primary physician. However, the decision to continue 
the subject on study drug or vaccination schedule requires the agreement of the investigator, the 
sponsor, and the subject. 
Subjects are prohibited from receiving the following therapies during the screening and 
treatment periods of this study: 
• Any anticancer medications, including chemotherapy or biologic therapy other than the 
study drug. 
• Any immunological-based treatment for any reason from screening through follow-up 
visit.  
Note: Completed adjuvant therapy (e.g., vaccines) with medical monitor approval. 
Note: Inhaled or topical steroids and systemic steroids at doses ≤ 10 mg/day prednisone 
or equivalents are allowed.  


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Note: Immune suppressants are allowed for treatment of immune toxicities as described 
in Section 5.4.7 and Brahmer et al. (Brahmer et al., 2018).  
Note: Allergy shots may be permitted after consultation with the medical monitor. 
• Investigational agents other than the study drug from screening through the follow-up 
visits. 
• Concomitant radiation therapy.  
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
considered on an exceptional case-by-case basis after consultation with the medical 
monitor. The subject must have clear measurable disease outside the radiated field. 
Administration of palliative radiation therapy will be considered clinical progression for 
the purposes of determining PFS. 
• Live vaccines within 30 days before the first dose of study drug and while participating 
in the study.  
Note: Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette–Guérin, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed. However, intranasal influenza vaccines (e.g., FluMist®) are 
live attenuated vaccines and are not allowed. 
• COVID-19 vaccine within 14 days prior to receiving the first dose of study drug and 
during the 28-day DLT period.  
Note: For 2-dose COVID-19 vaccines, subjects must wait at least 14-days after 2nd 
vaccine dose administration.  
• COVID-19 treatments/interventions including but not limited to: remdesivir, 
dexamethasone, convalescent plasma, supplemental oxygen, etc.  
Note: Sites should manage COVID-19 testing as per institutional policies. In the case 
where the site is notified of a subject testing positive for COVID-19, investigators should 
contact the study Medical Monitor immediately for further guidance. Subjects who have 
mild or asymptomatic COVID-19 infection could stay in the study, however, subjects 
with severe infection needing oxygen, and other interventions including but not limited to 
remdesivir, dexamethasone, and convalescent plasma should discontinue study treatment. 
Subjects who withdraw from study treatment due to COVID-19 should be followed for 
safety monitoring and be encouraged to complete the End of Treatment and Safety 
Follow-up visits per protocol. 
 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study. Subjects may receive 
other medications that the investigator deems to be medically necessary. The exclusion criteria 
describe other medications that are prohibited in this study. 


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6 
SCHEDULE OF STUDY PROCEDURES 
Table 6: Schedule of Assessments 
Visit Day 
Protocol 
Section 
Screening 
 
Treatmenta,c 
Post-Treatmentb 
All Cycles 
 
Cycles 1 & 5 
Every 
8/12 weeks 
EOT 
Safety 
Follow-Up 
1 
Safety 
Follow-Up 
2 
Day 1 
Day 2 
Day 3 
Day 8 
Disease Status 
Evaluation/Window (Range) 
 
Day - 30 
to - 1 
± 3 days 
(after 
Cycle 1) 
 
 
± 1 day 
± 7 days 
 
30 days 
(+ 7 days) 
90 days 
(+ 7 days) 
ADMINISTRATIVE PROCEDURES 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
 
Eligibility (I/E) criteria 
4 
X 
 
 
 
 
 
 
 
 
Demographics 
7.2 
X 
 
 
 
 
 
 
 
 
Cancer History and Diagnosis 
 
7.2 
X 
 
 
 
 
 
 
 
 
Medical Historyd  
7.2 
X 
 
 
 
 
 
 
 
 
Prior/concomitant medse 
7.3 
X 
Poststudy anticancer therapy and Survival 
status 
7.4 
 
 
 
 
 
 
X 
X 
X 
CLINICAL PROCEDURES/ASSESSMENTS 
Administer NC410 
5.2.1 
 
X 
 
 
 
 
 
 
 
Comprehensive PEf 
7.5.2.1 
X 
 
 
 
 
 
X 
 
 
Targeted physical assessmentf 
7.5.2.2 
 
X 
 
 
X 
 
X 
 
 
Vital signs and weight 
7.5.3 
X 
Xg 
 
 
X 
 
X 
 
 
ECOG performance 
7.5.2.1 
X 
X 
 
 
X 
 
X 
 
 
12-lead ECGh (Table 11) 
7.5.4 
Xi 
Xj 
 
 
 
 
Xi 
 
 
AE assessment 
7.5.1 
X 
Laboratory assessmentsk (Table 7 and Table 8) 
7.5.5 
X 
X 
 
 
X 
 
X 
 
 
PK/PD assessments (Table 9 and Table 10) 
7.7 and 7.8 
 
X 
X 
X 
X 
 
X 
 
 
Tumor Biopsyl 
7.8 
X 
X 
 
 
 
 
X 
 
 
EFFICACY MEASUREMENTS 
Radiologic assessments 
7.6.1.1 
Xm 
 
 
 
 
Xn 
Xo 
Xo 
 
 
 


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a Treatment cycles will begin every 14 days (± 3 days after Cycle 1). Alternate dosing schedules may also be explored based on emerging data. 
b Mandatory safety follow-up should be conducted approximately 30 days and 90 days after EOT visit (or after last dose of study drug if EOT was not performed). Safety follow-up should be 
performed before the initiation of a new systemic anticancer treatment, regardless if it occurs before or during the safety follow-up period. Safety follow-up may be performed by phone. 
c Visit at Day 8 is required for all subjects at Cycles 1 and 5. Visits on Days 2 and 3 are applicable for Phase 1 subjects only. 
d Medical history will include relevant medical or surgical treatment within the last 10 years that are considered to be clinically significant by the investigator.  
e Any prior medication received up to 30 days before the first dose of study drug and 90 days after the last dose of study drug will be recorded in the eCRF. Please also refer to sections 5.6.2 
and 5.6.3 for details on prohibited and restricted medications.  
f Comprehensive Physical examinations must be performed by a medically qualified individual such as a licensed physician, physician's assistant, or an advanced registered nurse practitioner, 
as local law permits. The comprehensive physical examination will include assessment(s) of the following organ or body systems: skin; head, eyes, ears, nose, and throat; thyroid; lungs; 
cardiovascular system; abdomen (liver, spleen); extremities; and lymph nodes, as well as a brief neurological examination. The screening physical examination should also include a 
measurement of height. The targeted physical examination will be a symptom-directed evaluation conducted by the investigator or a medically qualified designee. Notable abnormalities that 
are considered clinically significant in the judgment of the investigator are to be reported as AEs or Medical History (if applicable at Screening). 
g During Cycle 1, subjects will be required to stay at the study site for safety observation for 4 hours post-infusion. Vital signs (blood pressure, pulse, respiratory rate, and body temperature) 
will be assessed pre-dose, at the end of infusion, and every 60 minutes ± 10 minutes for 4 hours post end of infusion. For all subsequent cycles (with the exception of Cycle 5), subjects will 
be required to be observed for 1 hour post end of infusion or per PI discretion, if indicated. Vitals signs will be assessed pre-dose, at the end of infusion (+10 minutes), and thereafter at the  
PI’s discretion. Subjects will also be assessed for the onset of acute AEs. 
h All 12-lead ECGs will be performed with the subject in a recumbent or semirecumbent position after 5 minutes of rest and should not be performed within 15 minutes after a blood 
collection.  
i A single 12-lead ECG is required at screening and EOT.  
j A single 12-lead ECG should be performed on Day 1 of Cycles 1 and 5 at the following timepoints: pre-infusion (-30 minutes) and post-infusion (+30 minutes). Additional ECGs should be 
performed per PI discretion if any clinically significant abnormal findings are noted or as indicated. 
k If a central line is used for study drug infusion, collect blood samples via peripheral blood draw to prevent sample contamination. 
l For Phase 1a, tumor biopsies are optional. Biopsies are required for all Phase 1b and Phase 2 subjects. Biopsies will be collected at Screening and at Cycle 3 (prior to Cycle 4 dose). An 
optional EOT biopsy will be collected for subjects who consent for EOT biopsy at time of ICF. 
m The initial tumor imaging will be performed within 30 days before the first dose of study drug. Scans performed as part of routine clinical management are acceptable for use as the 
screening scan if they are of diagnostic quality and performed within 30 days before the first dose of study drug. The same imaging technique should be used for a subject throughout the 
study. Local reading (investigator assessment with site radiology reading) will be used to determine eligibility and for subject management. 
n On-study imaging will be performed at Week 8 and then every 8 weeks (56 days ± 7 days ) for the first 6 months and then every 12 weeks (84 days ± 7 days) thereafter. For subjects who 
continue treatment beyond 12 months, imaging should be performed per standard of care and per PI discretion. Imaging should follow calendar days and should NOT be adjusted for delays 
in cycle starts. If imaging shows disease progression, then another imaging assessment should be performed 4 to 6 weeks later to confirm progression per mRECIST. 
o If scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation (EOT) is not mandatory. For subjects who discontinue study therapy without 
confirmed disease progression, a radiologic evaluation should be repeated at the time of treatment discontinuation (i.e., date of discontinuation ± 4-week window). For subjects who 
discontinue treatment for reasons other than disease progression, every effort should be made to continue monitoring their disease status every 8 weeks (56 days ± 7 days) for the first 6 
months (from first dose) and then every 12 weeks (84 days ± 7 days)  by radiographic imaging until 1) withdrawal of consent, 2) the start of new systemic anticancer therapy, 3) documented 
disease progression, 4) death, or 5) the end of the study, whichever occurs first. 
  


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Table 7: Schedule of Local Laboratory Assessments 
Visit Day 
Protocol 
Section 
Screeninga 
Treatment 
Post-Treatment 
C1,and C5 
All Other Odd 
Numbered Cycles 
(C3,  C7, C9, etc.) 
Even Numbered Cycles 
(C4, C6, C8, C10, etc.) 
EOT 
D1b,c 
D8 
D1c 
D1c 
Evaluation/Window (Range) 
 
Day 
- 30 to - 1 
Pre-
infusion  
± 1 day 
- 3 days 
- 3 days 
 
Comprehensive serum chemistriesd 
7.5.5 
X 
X 
X 
X 
X 
X 
Hematology with differentiale 
7.5.5 
X 
X 
X 
X 
X 
X 
Coagulation panelf 
7.5.5 
X 
X 
X 
X 
 
X 
Total Hemolytic Complement Test 
(CH50) 
7.5.5 
 
X 
 
X 
 
X 
Urinalysisg 
7.5.5 
X 
X 
X 
X 
 
X 
Endocrine function testsh 
7.5.5 
X 
X 
X 
X 
 
X 
Hepatitis B and Ci 
7.5.5.2 
X 
 
 
 
 
 
Serum pregnancy test  
(childbearing females only)j 
7.5.5.1 
Xk 
 
 
 
 
X 
Urine pregnancy test  
(childbearing females only)l 
7.5.5.1 
 
Xm 
 
Xm 
Xm 
 
a Serum chemistry, hematology, coagulation, urinalysis, and endocrine function tests must be performed during screening period.  
b Laboratory samples on Cycle 1 Day 1 must be performed before study drug administration. Safety lab results should be reviewed by the investigator designee and found to be acceptable 
prior to the administration of study drug.  
c After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours before study drug administration.  Safety lab results should be reviewed by the investigator or qualified 
designee and found to be acceptable before a new cycle of treatment is initiated. 
d Chemistry required analytes in Table 8. 
e Hematology required analytes in Table 8. 
f Coagulation panel required analytes in Table 8. Per PI discretion, coagulation panel can be discontinued after Cycle 5 unless directly related to AE/SAE or as indicated. 
g Urinalysis required analytes in Table 8. Urine dipstick – if positive, perform microscopic urinalysis. Per PI discretion, urinalysis can be discontinued after Cycle 5 unless directly related to 
AE/SAE or as indicated. 
h Endocrine function tests required analytes in Table 8.  
i Hepatitis testing required analytes in Table 8. 
j Serum pregnancy testing obtained from females of child bearing potential only. 
k The serum pregnancy test performed at screening must be performed within 72 hours before the first dose of study drug. 
l If positive, confirm results with serum pregnancy test. 
m For women of child-bearing potential only, Day 1 urine pregnancy must be performed and resulted before study drug administration.  


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Table 8: Local Laboratory Tests: Required Analytes 
Serum Chemistries 
Hematology 
Urinalysis 
Hepatitis Screening 
Coagulation 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatinine 
Glucose 
Lactate dehydrogenase 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin (if total bilirubin 
is elevated above ULN) 
Total protein 
Uric acid 
Amylase 
Lipase 
Complete blood count, 
including: 
Hemoglobin 
Hematocrit 
Platelet count 
Red blood cell count 
White blood cell count 
Mean corpuscular volume 
 
Differential count, including: 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
 
Absolute values must be 
provided for the following 
WBC differential 
laboratory results: 
White blood cells 
Lymphocytes 
Neutrophils 
 
Color and appearance 
pH and specific 
gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Urobilinogen 
Hepatitis B surface antigen 
Hepatitis B core antibody 
HBV-DNA* 
HCV antibody 
HCV-RNA* 
 
*Note: If HCV/HBV antibody or 
antigen tests are positive, reflex 
testing (HCV RNA and/or HBV 
DNA tests) should be performed to 
confirm results prior to assessing 
subject eligibility. 
PT 
aPTT 
INR 
Complement Assay 
Endocrine Function Tests 
Pregnancy Testing 
Total Complement 
Test (CH50) 
 
 
 
Thyroid-stimulating hormone 
Free thyroxine (Free T4) 
Total triiodothyronine (Total T3)/ 
Free triiodothyronine (Free T3)b 
Female subjects of 
childbearing potential 
require a serum test at 
screening and EOT. 
Urine pregnancy tests 
will be performed on 
Day 1 of all other cycles.  
 
Pregnancy tests (serum 
or urine) should be 
repeated if required by 
local regulations. 
WBC = white blood cell. 
Note: Additional tests may be required, as agreed by investigator and sponsor, based on emerging safety data. 
a Urine pregnancy tests are only required if medically indicated or a country-specific requirement. 
b Based on site standard  


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Table 9: Schedule of Pharmacokinetic and Anti-Drug Antibody Sampling 
Study Visit 
Phase 1 Phase 2 
Assessment 
Timing of Sample Collection 
Cycle 1 Day 1 
X 
X 
PK and ADA 
• Pre-infusion 
X 
PK 
• Post-infusion (+ 10 min) 
• 2 h (± 30 min) post-infusion 
• 4 h (± 30 min) post-infusion 
Cycle 1 Day 2 
X 
PK  
• 24 h (± 60 min) post-infusion 
Cycle 1 Day 3 
X 
PK 
• 48 h (± 60 min) post-infusion 
Cycle 1 Day 8 
X 
PK 
• Untimed PK sample 
Cycle 2 Day 1 
X 
PK  
 
• Pre-infusion 
 
Cycle 3 Day 1 
X 
X 
PK and ADA 
 
• Pre-infusion 
Cycle 5 Day 1 
X 
X 
PK and ADA 
• Pre-infusion 
X 
PK 
• Post-infusion (+ 10 min) 
• 2 h (± 30 min) post-infusion 
• 4 h (± 30 min) post-infusion 
Cycle 5 Day 2 
X 
PK 
• 24 h (± 60 min) post-infusion 
Cycle 5 Day 3 
X 
PK 
• 48 h (± 60 min) post-infusion 
Cycle 5 Day 8 
X 
PK 
• Untimed PK sample 
Cycle 6 Day 1 
X 
PK 
• Pre-infusion 
Day 1 of Cycles  
7, 9, 11, 17, and 23 
X 
X 
PK and ADA 
 
• Pre-infusion 
End of Treatment 
X 
X 
ADA 
• Untimed ADA sample 
 
 


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Table 10: Schedule of Pharmacodynamic (Biomarker) Sampling  
Biomarker Assessment 
Study Visit 
Phase 1 Phase 2 
Timing of Sample 
Whole blood 
immunophenotyping 
Cycle 1 Day 1 
X 
X 
• 
Pre-infusion 
Cycle 1 Day 3 
 
X 
 
• 
Anytime 
Cycle 3 Day 1 
Cycle 5 Day 1 
Cycle 7 Day 1 
Cycle 11 Day 1 
Cycle 23 Day 1 
X 
X 
• 
Pre-infusion 
Serum correlative sample for 
cytokine levels 
Day 1 of Cycles 
1, 5 
X 
X 
• 
Pre-infusion 
• 
Post-infusion 
o ≤ 60 min post-
infusion 
o With 2h PK 
o With 4h PK 
Day 2 of Cycles 
1 and 5 
X 
 
• 
Anytime  
Day 1 of Cycle 11 
X 
X 
• 
Pre-infusion 
• 
Post-infusion 
Biopsiesa 
Screening 
Cycle 3 b 
EOT  
X 
X 
• 
Anytime 
Plasma ctDNA 
Day 1 of Cycle 1 
X 
X 
• 
Pre-infusion 
a Tumor biopsies are optional for Phase 1a. Screening (pre-treatment) and Cycle 3 (on-treatment) biopsies are mandatory for 
Phase 1b and Phase 2. EOT biopsies are optional for Phase 1 and 2. 
b Cycle 3 (± 1 week). Biopsy must be completed prior to 1st on-treatment scan (~ Cycle 4) and subsequent dose.  


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6.1 
Screening 
Screening is the interval between signing the ICF and the day the subject is enrolled in the study 
(e.g., Cycle 1 Day 1). Screening should not exceed approximately 30 days. Informed consent 
must be obtained before performing any study-specific procedures that are not considered 
standard of care. However, procedures conducted as part of the subject's routine clinical 
management obtained before signing of informed consent may be used for screening or baseline 
purposes with approval of the medical monitor, provided that the procedure meets the protocol-
defined criteria. Assessments that are required to demonstrate eligibility may be performed over 
the course of one or more days during the screening process. 
Results from the screening visit evaluations will be reviewed to confirm subject eligibility before 
enrollment or administration of study drug. Tests with results that fail eligibility requirements 
may be repeated once during screening if the investigator believes the results to be in error. For 
screening assessments that are repeated, the most recent available result before enrollment will 
be used to determine subject eligibility. Additionally, a subject who fails screening may repeat 
the screening process 1 time if the investigator believes there has been a change in eligibility 
status (e.g., after recovery from an infection). Treatment should start as soon as possible after the 
date of enrollment. 
6.2 
Treatment 
The treatment period begins on the day the subject receives the first dose of study drug (Cycle 1 
Day 1) through the point at which the investigator determines that the subject will be 
permanently discontinued from study drug. Cycle 1 Day 1 must take place within approximately 
30 days after the subject has signed the ICF. 
Subjects will have regularly scheduled study visits on Day 1 of every cycle (± 3 days after Cycle 
1). Additional visits will be required on Day 2 and 3 (Phase 1 only) and Day 8 (all subjects) of 
Cycles 1 and 5. During study visits, the subject will have clinical and laboratory assessments as 
outlined in Table 6 and Table 7. At certain study visits as indicated in Section 7.7 and Section 
7.8, subjects will have PK, PD, and biomarker samples obtained (see Table 9 and Table 10). 
Toxicities will be monitored continuously and will be graded using the NCI CTCAE v5.0 
criteria. 
During Cycle 1 subjects will be required to stay at the study site for safety observation for 4 
hours post end of infusion. On Day 1 of all subsequent cycles (with the exception of Cycle 5) 
subjects will be required to be observed for a minimum of 1 hour post end of infusion or per PI 
discretion if indicated. It is recommended that the subject does not leave the site for any reason 
during the safety observation period. During the safety observation period, subjects will be 
assessed for the onset of acute AEs. 
After completing 12 months of treatment, if the subject is deriving benefit from NC410 and has 
not met any of the protocol-defined conditions for withdrawal or discontinuation, the subject will 
be followed by the PI per standard of care. Subjects approved to continue treatment will remain 
on the dose level assigned at the time of enrollment (unless otherwise approved for dose 


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modification by the medical monitor). Safety reporting will continue through end of treatment to 
completion of the safety follow-up period. 
6.3 
End of Treatment 
When the subject permanently discontinues study drug, the EOT visit should be conducted. If the 
EOT visit coincides with a regular study visit, then the EOT evaluations will supersede those of 
that scheduled visit, and the data should be entered in the EOT visit in the eCRF. The subject 
should be encouraged to return for the follow-up visit(s). 
6.4 
Follow-up 
6.4.1 
Safety Follow-up 
The safety follow-up period is the interval between the EOT visit and the scheduled follow-ups, 
which should occur 30 days (+ 7 days) and 90 days (+ 7 days) after the EOT visit (or after the 
last dose of study drug if the EOT visit was not performed). AEs and SAEs must be reported up 
until at least 90 days after the last dose of study drug, the date of the last safety follow-up, or 
until toxicities resolve, return to baseline, or are deemed irreversible, whichever is longer. The 
safety follow-up must be performed before any new systemic anticancer therapy is started 
regardless of whether it occurs before or during the safety follow-up period; it can, in fact, be 
done on the same day provided it is done before the start of the new systemic anticancer therapy 
(e.g. prior to dosing). 
6.4.2 
Disease Status Follow-up 
Subjects who discontinue study drug for a reason other than disease progression will move into 
the disease status follow-up period and should continue to be assessed every 8 weeks (56 days 
± 7 days) for the first 6 months and then every 12 weeks (84 days ± 7 days) thereafter or per 
standard of care, by radiologic imaging to monitor disease status. Every effort should be made to 
collect information regarding disease status until the earliest of the following: 
• Withdrawal of consent 
• The start of a new systemic anticancer therapy 
• Documented disease progression 
• Death 
• End of the study 
6.5 
End of Study 
The end of the study will occur when all subjects have completed the last study follow-up visit or 
have discontinued study drug and have completed applicable follow-up assessments. 
Additionally, subjects will be considered as having completed the study if they meet any of the 
following criteria: 
• Subject dies and a date of death is available 
• Subject is known to have died; however, the date of death cannot be determined 


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• Consent is withdrawn for any further contact to this study (Every reasonable effort should 
be made to determine the reason a subject withdraws prematurely, and this information 
should be recorded) 
• The study is terminated by the sponsor 
• The study is terminated by the IRB or local health authority 
6.6 
Unscheduled Visits 
Unscheduled study visits may occur at any time if medically warranted. Any assessments 
performed at those visits should be recorded in the eCRF. 
7 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
Individual study procedures are described in detail below. It may be necessary to perform these 
procedures at unscheduled timepoints if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary for reasons related to 
subject safety. In some cases, such evaluation/testing may be potentially sensitive in nature (e.g., 
HBV, HCV), and thus local regulations may require that additional informed consent be obtained 
from the subject. In these cases, such evaluations/testing will be performed in accordance with 
those regulations. Subjects of childbearing potential must agree to take appropriate measures to 
avoid pregnancy in order to participate in the study. 
7.1 
Administration of Informed Consent Form 
Valid informed consent must be obtained from the subject before conducting any study-specific 
procedures using an ICF approved by the IRB/IEC. The ICF should contain all elements required 
by ICH E6 and describe the nature, scope, and possible consequences of the study in a manner 
that the subject can understand. Local and institutional guidelines for ICF content and 
administration must be followed; the original signed ICF must be retained by the investigator, 
and a copy of the signed ICF must be provided to the study subject. The informed consent 
process for each subject must be documented in writing within the subject source documentation. 
7.2 
Demography and Medical History 
7.2.1 
Demographics and General Medical History 
Demographic data and a complete medical and medication history will be collected at screening 
by the investigator or qualified designee and will include date of birth, race, ethnicity, medical 
and surgical history, and current illnesses. Medical history will include relevant medical or 
surgical treatment within the last 10 years that are considered to be clinically significant by the 
investigator. 
7.2.2 
Disease Characteristics and Treatment History 
A disease-targeted medical and medication history will be collected at screening. Details 
regarding the subject's malignancy under study including date of diagnosis, initial and current 
cancer stage, primary tumor histology, and prior treatments including systemic, radiation, and 


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surgical procedures will be recorded. For subjects with cancer types commonly-associated with 
Human Papillomavirus (HPV), HPV status will be collected.  
7.3 
Prior and Concomitant Medications and Procedures 
Prior and concomitant medications and procedures will be reviewed to determine subject 
eligibility. All concomitant medications and measures must be recorded in the eCRF, and any 
medication received, or procedure performed within 30days before the first dose of study drug 
and up to the end of the follow-up phase of the study will be recorded in the eCRF. The 
medication record will be maintained after signing the ICF to document concomitant 
medications, including any changes to the dose or regimen. Concomitant medications include 
any prescription, over-the-counter, or natural/herbal preparations taken or administered during 
the study period. Concomitant treatments and/or procedures that are required to manage a 
subject's medical condition during the study will also be recorded in the eCRF. 
7.4 
Poststudy Anticancer Therapy and Survival Status 
The investigator or qualified designee will review all new systemic anticancer therapy initiated 
after the last dose of study drug. The subject’s survival status and death details (if applicable) 
will also be collected.  
Note: If a subject initiates a new systemic anticancer therapy within 30 to 90 days after the last 
dose of study drug, the 30-day or 90-day safety follow-up should occur before the first dose of 
the new systemic anticancer therapy. 
7.5 
Safety Assessments 
7.5.1 
Adverse Events 
Adverse events will be monitored from the time the subject signs the ICF. Subjects will be 
instructed to report all AEs during the study and will be assessed for the occurrence of AEs 
throughout the study. In order to avoid bias in eliciting AEs, subjects will be asked general, 
nonleading questions such as "How are you feeling?" All AEs (serious and nonserious) must be 
recorded on the source documents and eCRFs regardless of the assumption of a causal 
relationship with the study drug. The definition, reporting, and recording requirements for AEs 
are described in Section 8.1. 
7.5.2 
Physical Examinations 
7.5.2.1 
Comprehensive Physical Examination 
Physical examinations must be performed by a medically qualified individual such as a licensed 
physician, physician's assistant, or an advanced registered nurse practitioner, as local law 
permits. ECOG performance status should be assessed. 
The comprehensive physical examination will include assessment(s) of the following organ or 
body systems: skin; head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular system; 
abdomen (liver, spleen); extremities; and lymph nodes, as well as a brief neurological 
examination. The screening physical examination should also include a measurement of height. 


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Clinically notable abnormalities that are considered clinically significant in the judgment of the 
investigator are to be reported as AEs. 
7.5.2.2 
Targeted Physical Examination 
The targeted physical examination will be a symptom-directed evaluation conducted by the 
investigator or a medically qualified designee. The targeted physical examination will include 
assessment(s) of the body systems or organs, as indicated by subject symptoms, AEs, or other 
findings. Clinically notable abnormalities that are considered clinically significant in the 
judgment of the investigator are to be reported as AEs. 
7.5.3 
Vital Signs and Weight 
Vital sign measurements include blood pressure, pulse, respiratory rate, and body temperature. 
Blood pressure and pulse will be taken with the subject in the recumbent or semi recumbent 
position after 5 minutes of rest.  
On Cycle 1, vital signs (blood pressure, pulse, respiratory rate, and body temperature) will be 
collected pre-dose, at end of infusion (+10 minutes), and every 60 minutes (±10 minutes) 
thereafter for 4 hours post end of infusion. 
On Day 1 of all subsequent cycles, vital signs will be assessed pre-dose, at end of infusion (+10 
minutes), and thereafter at the PI’s discretion.   
It is recommended that the subject does not leave the site for any reason during the safety 
observation period. Subjects will also be assessed for the onset of acute AEs 
Weight will also be assessed at each study visit. Clinically notable abnormalities that are 
considered clinically significant in the judgment of the investigator are to be reported as AEs. 
7.5.4 
Electrocardiograms 
All 12-lead ECGs will be performed with the subject in a recumbent or semirecumbent position 
after 5 minutes of rest and should not be performed within 15 minutes of a blood collection. ECG 
assessments will be done as shown in Table 11.  
A single 12-lead ECG should be performed at Screening and EOT for all subjects. 
On Day 1 of Cycles 1 and 5 , ECG’s will be collected at the following timepoints: pre-infusion (-
30 minutes) and post-infusion (+30 minutes). Additional ECGs should be performed per PI 
discretion if any clinically significant abnormal findings are noted or as indicated. 
The automated 12-lead ECGs readings will be interpreted by the investigator, or qualified 
designee at the site to be used for immediate subject management. The decision to include or 
exclude a subject or withdraw a subject from the study based on a locally analyzed ECG flagged 
as "Abnormal, Clinically Significant" is the responsibility of the investigator, in consultation 
with the medical monitor, as appropriate. Clinically significant abnormal findings before signing 
consent should be recorded as medical history. Clinically significant abnormal findings after 
signing consent should be recorded as an AE. For any subjects with clinically significant 


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abnormalities, ECGs may be conducted more frequently than the protocol-required timepoints 
per PI discretion. 
Table 11: Timing of Electrocardiograms 
 
Timing of Sample 
Study Visit 
Any Time 
Pre-infusion (-30 minutes) 
Post-infusion (+30 minutes) 
Screening  
X 
 
 
C1D1  
 
X 
X 
C5D1  
 
X 
X 
EOT 
X 
 
 
 
7.5.5 
Laboratory Assessments 
A laboratory local to the study site and subject will perform all clinical laboratory assessments 
for safety (i.e., blood chemistries, hematology assessments, coagulation tests, endocrine function, 
and urinalysis). The investigative site will enter the laboratory results into the eCRF and select 
the laboratory name so that the laboratory normal ranges will populate. All local laboratory 
assessments should be performed using standard procedures on the days indicated in Table 6 and 
Table 7. Table 8 lists the specific laboratory analytes required for each test. Additional testing 
may be required by the sponsor based on emerging safety data. Additional tests may also be 
performed if clinically indicated. 
Serum chemistry, hematology, coagulation, urinalysis, and endocrine function tests must be 
performed during the screening period.  
Laboratory samples collected on Cycle 1 Day 1 must be performed before study drug 
administration. Cycle 1 Day 1 safety lab results should be reviewed by the investigator or 
qualified designee and found to be acceptable prior to study drug administration.   
After Cycle 1, pre-infusion laboratory procedures can be conducted up to 72 hours before study 
drug administration, and results should be reviewed by the investigator or qualified designee and 
found to be acceptable before a new cycle of treatment is initiated. 
7.5.5.1 
Pregnancy Testing 
A local laboratory serum pregnancy test will be required for all women of childbearing potential 
during screening and at the EOT visit. The serum pregnancy test performed at screening must be 
performed within 72 hours before the first dose of study drug. Urine pregnancy tests will be 
performed locally as outlined in Table 7, as medically indicated, or per country-specific 
requirement. If a urine pregnancy test is positive, then the results should be confirmed with a 
serum pregnancy test. 
If the serum pregnancy test is negative after a urine test was positive, then the investigator will 
assess the potential benefit/risk to the subject and determine whether it is in the subject's best 
interest to resume study drug and continue participation in the study. 


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7.5.5.2 
Hepatitis Screening Tests 
Hepatitis screening assessments will be performed at the screening visit (Table 7) to rule out 
hepatitis infection; required analytes are shown in Table 8. Generally, hepatitis tests should be 
performed early in the screening process due to the length of time needed to obtain the results. 
Additional tests may be performed if clinically indicated. 
7.6 
Efficacy Assessments 
7.6.1 
Modified RECIST v1.1 Assessment of Disease 
Modified RECIST will be applied by the site as the primary measure for assessment of tumor 
response and as a basis for protocol guidelines related to disease status (e.g., discontinuation of 
study therapy). As noted in Section 1.3.4, RECIST v1.1 has been adapted to account for the 
unique tumor responses seen with immunotherapy (Wolchok et al., 2009). 
If radiologic imaging shows progressive disease, then tumor assessments should be repeated at a 
minimum of 4 weeks, but no later than 6 weeks later to confirm progression, with the option of 
continuing treatment while awaiting radiologic confirmation of progression. Table 12 provides 
instructions on how to proceed with treatment based on the subject's clinical status once the 
initial scan showing radiologic evidence of progression is observed. 
Subjects may receive treatment while waiting for confirmation of progression if they are 
clinically stable as defined by the following criteria: 
• Absence of clinically significant signs and symptoms (including worsening of laboratory 
findings) consistent with disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
Absence of progressive tumor at critical anatomic sites (such as spinal cord compression) 
requiring urgent alternative medical intervention 
Table 12: Imaging and Treatment After First Radiographic Evidence of Progressive 
Disease 
 
Clinically Stable 
Clinically Unstable 
Tumor Imaging 
Treatment 
Tumor Imaging 
Treatment 
First radiologic 
evidence of 
progression 
Repeat imaging 
4-6 weeks to confirm 
progression 
May continue study 
treatment at the 
investigator's discretion 
while awaiting 
confirmatory tumor 
imaging  
Repeat tumor 
imaging 4-6 weeks to 
confirm progression 
per physician 
discretion only 
Discontinue treatment 
Repeat scan 
confirms 
progression 
No additional tumor 
imaging required 
Discontinue treatment 
No additional tumor 
imaging required 
N/A 


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Repeat scan 
shows SD, PR, 
or CR 
Continue regularly 
scheduled tumor 
imaging assessments 
Continue study 
treatment at the 
investigator's discretion 
Continue regularly 
scheduled tumor 
imaging assessments 
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
investigator's discretion 
SD = stable disease; PR = partial response; CR = complete response. 
 
As noted above, if disease progression is observed, then the study site may elect to continue 
treatment and repeat imaging at a minimum of 4 weeks, but no later than 6 weeks later, to assess 
tumor response or confirm progression per mRECIST. 
In determining whether or not the tumor burden has increased or decreased, study site 
investigators should consider all target lesions as well as nontarget lesions. Subjects that are 
deemed clinically unstable are not required to have repeat tumor imaging for confirmation.  
If radiologic progression is confirmed by subsequent scan, then the subject should be 
discontinued from study treatment. If radiologic progression is not confirmed, then the subject 
should resume or continue study treatment and have the next tumor imaging according to the 
protocol schedule (see Table 6). If progression is not confirmed and the subject continues on 
treatment, then the date of the next scan that documents disease progression (and is confirmed by 
a second scan at least 4 weeks, but no later than 6 weeks later) will be considered the date of 
disease progression. 
If a subject has confirmed radiographic progression (i.e., 2 scans at least 4 weeks, but no later 
than 6 weeks apart demonstrating progression) per mRECIST, but the subject is achieving a 
clinically meaningful benefit, an exception to continue treatment may be considered after 
consultation with the medical monitor. Clinically stable subjects at the confirmatory scan should 
also have no further increase in the target lesions, no unequivocal increase in nontarget lesions, 
and no additional new lesions develop (non-worsening disease progression) to continue study 
treatment. 
7.6.1.1 
Tumor Imaging 
The same imaging technique should be used for a subject throughout the study. The 
baseline scan must be a contrast computed tomography (CT) or magnetic resonance imaging 
(MRI), except in circumstances where there is a contrast allergy or with medical monitor 
approval. When the CT component of a positron emission tomography/CT uses higher energy 
and thinner slices, it may be acceptable with medical monitor approval. Images of the chest and 
abdomen are required for all subjects. 
7.6.1.1.1 
Tumor Imaging During Screening 
Initial tumor imaging must be performed within 30 days before the first dose of study drug. The 
site study team must review pre-study images to confirm that the subject has measurable disease 
per RECIST v1.1. Tumor lesions that are located in a previously irradiated area or in an area 
subjected to other locoregional therapy should not be selected as target lesions. If a subject only 
has lesions in an area previously irradiated or subjected to locoregional therapy but has had 
shown measurable progression subsequent to the therapy, then the subject will be allowed to 


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enroll. Additionally, it is recommended that tumor lesions selected for biopsy not be selected as 
target lesions. 
CT or MRI scan of the brain will be performed at screening if there are signs or symptoms 
suggesting that the subject has disease involvement in the CNS. An MRI of the brain will also be 
required at screening for all subjects with melanoma. 
Scans performed as part of routine clinical management are acceptable for use as the screening 
scan if they are of diagnostic quality and performed within 30 days before the first dose of study 
drug. 
7.6.1.1.2 
Tumor Imaging During the Study 
The first imaging assessment should be performed 8 weeks after the first dose of study drug and 
then every 8 weeks (56 days ± 7 days) for 6 months and then every 12 weeks (84 days ± 7 days) 
thereafter until disease progression is determined. Subjects who remain on treatment beyond 12 
months will have imaging performed per standard of care and PI discretion.  Imaging 
assessments may be done more frequently if clinically indicated. Imaging should not be 
delayed for delays in cycle starts.  
NOTE: If imaging is delayed, the missed scan should be conducted as soon as possible, and all 
subsequent scans must remain on schedule (every 8/12 weeks relative to the first dose of NC410) 
and should not be adjusted. 
Per mRECIST v1.1, response should be confirmed by a repeat radiographic assessment not less 
than 4 weeks from the date that the response was first documented. The scan for confirmation of 
response may be performed at the earliest 4 weeks after the first indication of response or at the 
next scheduled scan, whichever is clinically indicated. 
Imaging should continue to be performed until documented disease progression, the start of new 
systemic anticancer treatment, withdrawal of consent, death, or the end of the study, whichever 
occurs first. Disease progression should be confirmed at least 4 weeks, but no later than 6 weeks 
after the first scan indicating progression in clinically stable subjects.  
Subjects who have unconfirmed disease progression may continue on treatment until progression 
is confirmed, provided that they have met the conditions detailed in Section 7.6.1. A central 
imaging vendor will not be used in this study. 
7.6.1.1.3 
Imaging During Follow-Up 
If the subject discontinues study drug for reasons other than disease progression, imaging 
assessments should continue at the protocol-specified interval until documented disease 
progression, the start of a new systemic anticancer treatment, withdrawal of consent, death, or 
the end of the study, whichever occurs first. 
If scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment 
discontinuation (EOT) is not mandatory. For subjects who discontinue study therapy without 
confirmed disease progression, a radiologic evaluation should be repeated at the time of 


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treatment discontinuation (i.e., date of discontinuation ± 4-week window). For subjects who 
discontinue treatment for reasons other than disease progression, every effort should be made to 
continue monitoring their disease status every 8 weeks (56 days ± 7 days) for the first 6 months 
(from first dose) and then every 12 weeks (84 days ± 7 days) thereafter until 1) withdrawal of 
consent 2) the start of new systemic anticancer therapy, 3) documented disease progression, 4) 
death, or 5) the end of the study, whichever occurs first. 
7.7 
Pharmacokinetic Assessments 
PK and ADA samples will be obtained at the visits and times indicated in Table 9. PK and ADA 
samples should not be collected through the same line in which the study drug is infused. If a 
central line is used for study drug infusion, collect PK and ADA samples via peripheral blood 
draw to prevent sample contamination. 
Pre-infusion is defined as within 24 hours before administration of study drug. After the pre-dose 
PK sample is drawn, subjects will begin the study drug infusion. Adjustments to the timing of 
blood sampling may be made based on emerging PK data. The exact date and time of each PK 
blood draw will be recorded in the eCRF. Instructions for sample preparation and shipping will 
be provided in the Laboratory Manual. 
7.8 
Biomarker and Correlative Assessments 
Tumor, whole blood, and serum samples will be collected at the visits outlined in Table 10. If a 
central line is used for study drug infusion, collect blood samples via peripheral blood draw to 
prevent sample contamination. Additional biomarker assessments that might be correlated with 
safety, response, or resistance to treatment beyond those listed (e.g., monitoring inflammatory or 
immune markers, measuring specific cell populations, tumor markers, RNA profiles of specific 
cell populations, or measuring cell surface markers by flow cytometry, Western blot, mass 
spectroscopy, or immunoassay) may be evaluated at the discretion of the sponsor using excess 
translational biomarker or PK samples. All analyses will be conducted by NextCure or 
NextCure’s designee. For information regarding handling/shipping of specimens, please refer to 
the Laboratory Manual for the study. 
7.8.1 
Tumor Biopsies 
7.8.1.1 
Tumor Tissue Collection Requirements 
Tumor biopsy samples are optional for the Phase 1a dose escalation portion of the study. 
Tumor biopsy samples are required for subject participation in the Phase 1b safety 
expansion and Phase 2 of the study.  
Mandatory and optional tumor biopsies will be collected as specified below: 
• Screening (mandatory in Phase 1b Safety Expansion and Phase 2): A baseline biopsy 
obtained for other purposes (i.e., not an NC410-01 procedure) may be utilized if the 
subject has not had any intervening systemic therapy from the time of the biopsy to the 
start of treatment (Cycle 1 Day 1). Note: Fresh tumor biopsies should be taken from 
nontarget lesions when possible. 


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• On-treatment (mandatory in Phase 1b Safety Expansion and Phase 2): A second 
mandatory on-treatment biopsy must be obtained anytime during Cycle 3 ± 1 week (prior 
to 1st on-treatment scan (~ Cycle 4) and subsequent dose). Note: On-treatment biopsies 
should be performed at the same site as the screening biopsy whenever possible. 
• At the End of Treatment (optional): A third optional tumor specimen referred to as the 
End of Treatment (EOT) biopsy may be obtained at the time that study treatment has been 
discontinued. 
If a subject is scheduled to have a tumor biopsy for the purposes of this study and it is 
subsequently determined that tumor tissue cannot safely be obtained, then the subject may still 
enroll in the study after consultation with the medical monitor.  
NOTE: Details and methods for obtaining, processing, and shipping the fresh tumor biopsy 
samples will be provided in the Laboratory Manual for the study. 
7.8.1.2 
Tumor Tissue Assessment 
Tumor biopsy samples will be used to investigate molecular signatures associated with response 
or resistance to treatment with the study drug. DNA and/or RNA may be extracted from these 
samples to perform somatic mutation analysis, epigenetic analysis, whole exome sequencing, and 
genetic expression analysis. Tissue may also be examined by histology and 
immunohistochemistry or by exploratory methods to evaluate markers of inflammation and T-
effector cell populations, growth, signaling, apoptosis, etc. that may be associated with safety, 
response, or resistance to treatment with the study drug. 
7.8.2 
Whole Blood Correlative Assessment 
Whole blood samples will be used for immune cell population profiling (which may include T 
lymphocytes, B lymphocytes, myeloid, and natural killer cells). Analysis of T cell receptor 
(TCR) clones may also be analyzed to detect evidence of on therapy clonal expansion. Other 
assays relevant to the objectives of the study, such as flow cytometry analysis of intracellular 
cytokines, may be performed based upon emerging data. 
7.8.3 
Serum Pharmacodynamic Assessment 
Serum samples will be evaluated to assess evidence of NC410 activity. 
Serum samples will be used to examine markers of inflammation, immune modulation, and 
remodeling of the tumor microenvironment (which may include but are not limited to: IFNγ, IL-
2, IL-4, IL-6, and TNFα) pre- and on-treatment with NC410. Other assays relevant to the 
objectives of the study may be performed based on emerging data. 
7.8.4 
Timing for Serum and Whole Blood Assessments 
Biomarkers will be analyzed in serum and whole blood samples collected at baseline and on the 
days and times as outlined in Table 10. Throughout the study, the exact date and time of the 
biomarker blood draws will be recorded in the eCRF along with the date and time study drug 
was administered in the clinic. For information regarding handling/shipping of specimens, please 
refer to the Laboratory Manual for the study. 


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7.9 
Other Study Procedures 
Not applicable. 
8 
SAFETY MONITORING AND REPORTING 
8.1 
Adverse Events 
8.1.1 
Definitions 
For the purposes of this protocol, an AE is defined as any untoward medical occurrence 
associated with the use of a drug in humans, whether considered drug related, that occurs after a 
subject provides informed consent and through the follow-up period. Both nonserious and 
serious AEs (SAEs) will be monitored throughout the study.  
A pre-treatment event (PTE) is one that occurs after the time of informed consent (e.g. during the 
screening process) but prior to study drug administration. AEs directly related to a study test or 
procedure should be reported during the Screening period. Conditions that were already present 
at the time of informed consent should be recorded on the Medical History form in the eCRF. 
A treatment-emergent adverse event (TEAE) is one that occurs from the time of the first dose of 
study drug through 90 days after the last dose of study drug. TEAEs should be monitored until 
they are resolved or are clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es).  
Abnormal laboratory values or test results occurring after informed consent constitute AEs only 
if they induce clinical signs or symptoms, are considered clinically meaningful, require therapy 
(e.g., hematologic abnormality that requires transfusion), or require changes in the study drug(s). 
8.1.2 
Reporting 
AEs that begin or worsen after informed consent should be recorded on the AE form in the 
eCRF. Monitoring for the occurrence of new AEs should be continued for at least 90 days 
after the last dose of study drug.  
AEs (including laboratory abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible rather than by individual underlying signs and symptoms. 
The severity of AEs will be assessed using NCI CTCAE v5.0 Grades 1 through 4. The NCI 
CTCAE v5.0 severity of Grade 5 will not be used; AEs resulting in death will be graded 
accordingly using Grades 1 through 4 and have the outcome noted as fatal. 
If an event is not classified by NCI CTCAE, the severity of the AE will be graded according to 
Table 13 to estimate the grade of severity. 


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Table 13: NCI CTCAE v5.0 Grading Scale 
Grade 
Clinical Characteristics 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate activities of daily living. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
 
The occurrence of AEs should be sought by nondirective questioning of the subject during the 
screening process after signing the ICF and at each visit during the study. Adverse events may 
also be detected when they are volunteered by the subject during the screening process or 
between visits, or through physical examination, laboratory test, or other assessments. To the 
extent possible, each AE should be evaluated to determine: 
• The severity grade (NCI CTCAE v5.0 Grade 1 to 4). 
• Whether there is at least a reasonable possibility that the AE is related to the study 
treatment: suspected (yes) or not suspected (no). 
• The start and end dates, unless unresolved at final follow-up. 
• The action taken with regard to study drug. 
• The event outcome (e.g., not recovered/not resolved, recovered/resolved, 
recovering/resolving, recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per SAE definition provided in Section 8.3.1 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements (see Section 8.3.2). 
All AEs should be treated appropriately. If an AE is treated with a concomitant medication or 
nondrug therapy, this action should be recorded on the AE form in the eCRF and the treatment 
should be specified on the Prior/Concomitant Medications or Procedures and Non-Drug Therapy 
form in the eCRF. 
Once an AE is detected, it should be followed until it has resolved or until it is judged to be 
permanent; assessment should be made at each visit (or more frequently if necessary) of any 
changes in severity, the suspected relationship to the study drug, the interventions required to 
treat the event, and the outcome. 
When the severity of an AE changes over time for a reporting period (e.g., between visits), each 
change in severity will be reported as a separate AE until the event resolves. For example, 2 


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separate AEs will be reported if a subject has Grade 1 diarrhea, meeting the definition of an AE, 
that lasts for 3 days before worsening to a Grade 3 severity. The Grade 1 event will be reported 
as an AE with a start date equal to the day the event met the Grade 1 AE definition and a stop 
date equal to the day that the event increased in severity from Grade 1 to Grade 3. The Grade 3 
event will also be reported as an AE, with the start date equal to the day the event changed in 
intensity from Grade 1 to Grade 3 and a stop date equal to the day that the event either changed 
severity again or resolved. 
8.2 
Laboratory Test Abnormalities 
Laboratory abnormalities that constitute an AE in their own right (considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes 
in study drug) should be recorded on the AE form in the eCRF. Whenever possible, a diagnosis 
rather than a symptom should be provided (e.g., "anemia" instead of "low hemoglobin"). 
Laboratory abnormalities that meet the criteria for AEs should be followed until they have 
returned to normal or an adequate explanation of the abnormality is found. When an abnormal 
laboratory test result corresponds to a sign or symptom of a previously reported AE, it is not 
necessary to separately record the laboratory test result as an additional event. 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs. 
A Grade 3 or 4 (severe) AE does not automatically indicate an SAE unless it meets the definition 
of serious, as defined in Section 8.3.1. A dose modification for the laboratory abnormality may 
be required (see Section 5.4.6) and should not contribute to the designation of a laboratory test 
abnormality as an SAE. 
8.3 
Serious Adverse Events 
8.3.1 
Definitions 
An SAE is defined as an event that meets at least 1 of the following criteria: 
• Is fatal or life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is a result of: 
− A routine treatment or monitoring of the studied indication not associated with 
any deterioration in condition. 
− An elective surgery or preplanned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since signing the 
ICF. 
− A treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE and not resulting in hospital admission. 
− Any social reasons and respite care, in the absence of any deterioration in the 
subject's general condition. 
• Results in persistent or significant disability, incapacity, or a substantial disruption of a 
person's ability to conduct normal life functions. 


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• Constitutes a congenital anomaly or birth defect. 
• Is an important medical event or a medically significant event that may not result in 
death, be immediately life-threatening, or require hospitalization but may be considered 
serious when, based on appropriate medical judgment, the event may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes 
listed above. 
Symptoms and clinical manifestations of disease progression can be classified as an SAE (if it 
meets the above criteria); however, progressive disease is not an SAE. 
8.3.2 
Reporting 
Within 24 hours of identifying an SAE, regardless of the presumed relationship to the 
investigational product, the investigator or qualified designee must complete the SAE 
Report Form and submit it to the Sponsor or its designee.  Instructions for SAE reporting 
will be provided by the CRO. The sponsor is responsible for reporting certain SAEs as 
expedited safety reports to applicable regulatory authorities, ethics committees, and participating 
investigators, in accordance with ICH Guidelines and/or local regulatory requirements. The 
sponsor may be required to report certain SAEs to regulatory authorities within 7 calendar days 
of being notified about the event; therefore, it is important that investigators submit additional 
information requested by the sponsor or delegate as soon as it becomes available. 
Investigators should provide all available information at the time of SAE Report Form 
completion. Investigators should not wait to collect additional information to fully document the 
event before notifying the Sponsor or its designee of an SAE. When additional information 
becomes available, investigators should submit a follow-up SAE Report Form (separate from the 
initial report form) with the new information. Any follow-up information to an SAE also needs 
to be provided the Sponsor or its designee within 24 hours of learning of the new information. 
8.3.3 
Reporting of an Overdose 
An overdose is defined as a subject receiving a dose of investigational product in excess of that 
specified in the NC410 IB, unless otherwise specified in this protocol. 
Any overdose of a study subject with the investigational product, with or without associated 
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to the Sponsor 
or its designee. If the overdose results in an AE, the AE must also be recorded on the AE eCRF. 
Overdose does not automatically make an AE serious, but if the consequences of the overdose 
are serious, for example death or hospitalization, the event is serious and must be reported as an 
SAE. NextCure does not recommend specific treatment for an overdose. The investigator will 
use clinical judgment to treat any overdose. 
8.4 
Emergency Unblinding of Treatment Assignment 
Not applicable. 


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8.5 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method. When a 
pregnancy has been confirmed in a subject (or a male subject’s partner) during maternal or 
paternal exposure to study drug, within 90 days of the last dose of study drug or within 30 days 
after cessation of treatment if the subject initiates new systemic anticancer therapy, the following 
procedures should be followed to ensure subject safety: 
• The study drug must be discontinued immediately (female subjects only). 
• Consent must be obtained from female partners of male subjects. 
• The investigator must complete and submit the Clinical Trial Pregnancy form to the 
sponsor or its designee within 24 hours of learning of the pregnancy. 
• A serum pregnancy test must be performed to confirm the urine pregnancy test result 
(female subjects only). 
If a negative serum test does not confirm the urine pregnancy test result, then: 
− The investigator will use his or her expert judgment, based on an assessment of 
the potential benefit/risk to the subject, to determine whether it is in the subject's 
best interest to resume study drug and continue participation in the study. 
• The EOT visit evaluations must be performed (female subjects only). 
Data on fetal outcome and breastfeeding are collected for regulatory reporting and drug safety 
evaluation. Follow-up should be conducted for each pregnancy to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications, by following 
until the first well-baby visit. Pregnancy should be recorded on a Clinical Trial Pregnancy form 
and reported by the investigator to the sponsor or its designee. Pregnancy follow-up information 
should be recorded on the same form and should include an assessment of the possible causal 
relationship to the sponsor's study drug to any pregnancy outcome. The baby should be evaluated 
for the first 8 weeks or the duration specified in local regulations, whichever is later. 
Any SAE occurring during pregnancy must be recorded on the SAE report form and 
submitted to the sponsor or designee. 
8.6 
Warnings and Precautions 
Special warnings or precautions for the study drug, derived from safety information collected by 
the sponsor or its designee, are presented in the IB. Additional safety information collected 
between IB updates will be communicated in the form of Investigator Notifications (INs). Any 
important new safety information should be discussed with the subject during the study, as 
necessary, and provided to the IRB. If new significant risks are identified, they will be added to 
the ICF. 


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8.7 
Data Monitoring Committee 
A Data Monitoring Committee (DMC) will be established for this open-label study. For Phase 1, the 
sponsor in conjunction with the study medical monitor and CRO will conduct telephone conferences 
with investigators in order to review cohort-specific data, overall safety data from prior cohorts (if 
applicable), and to agree on dose escalation, de-escalation, and cohort expansion decisions on a 
regular basis. For Phase 2, a formal DMC will be organized and comprised of the following members 
including but not limited to: a chairperson, two non-participating physicians specializing in 
oncology, the study medical monitor, a non-voting biostatistician, and representatives of the Sponsor 
and CRO. The committee will meet on a regular basis to review safety and tolerability throughout the 
study. Additional information on the DMC will be detailed in the DMC Charter.   
8.8 
Immune-Related Adverse Events 
Adverse events of a potential immunologic etiology or irAEs may be defined as an AE consistent 
with an immune phenomenon associated with drug exposure after all other etiologies have been 
eliminated. Immune-related AEs may be expected based on the nature of NC410, its mechanism 
of action, and reported experience with other immunotherapies. Special attention should be paid 
to AEs that may be suggestive of potential irAEs. An irAE can occur shortly after the first dose 
or several months after the last dose of treatment. Guidance for the assessment, diagnosis, and 
management of irAEs is provided in Section 5.4.7. Suspected irAEs should be discussed with the 
medical monitor. 
8.9 
Reporting Product Complaints 
Any defects with the investigational products must be reported immediately to NextCure by the 
site with further notification to the site monitor. During the investigation of the product 
complaint, all investigational products must be stored per instructions in pharmacy manual 
unless otherwise instructed. 
NextCure contact information for reporting product complaints: 
Email: NCClin@nextcure.com 
 
Email subject line should include: “NC410-01 Product Complaint” 
Mail: NextCure, Inc. 
 
Attn: Clinical Operations 
 
9000 Virginia Manor Road 
 
Beltsville, MD 20705 USA 
9 
STATISTICS 
Tabular summaries will be presented by dose groups. Categorical data will be summarized by the 
number and percentage of subjects in each category. Continuous variables will be summarized 
by descriptive statistics including mean, standard deviation, median, minimal, and maximal 
values. All analyses, unless specified otherwise, will be based on as-treated population, which 


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includes all subjects who receive any dose of NC410. Additional details of statistical analyses 
will be described in the Statistical Analysis Plan (SAP). 
9.1 
Study Populations 
The full analysis set (FAS) includes all subjects enrolled in the study who received at least one 
full dose of NC410. This population will be used in all the summaries and analyses except for the 
of safety analysis set (SAS) and PK. The SAS will include all the subjects who receive any 
amount of study drug. The summaries and analyses of safety data will be performed on the SAS. 
The PK analysis set (PAS) will include all the subjects whose blood samples are collected for PK 
analysis. The PK data summaries and analyses will be performed on the PAS. 
9.2 
Selection of Sample Size 
A maximum of 163 eligible subjects in Phase 1 and Phase 2 (78 + 85) will be included in this 
study. 
9.2.1 
Sample Size for Phase 1 
The primary objective of the dose escalation part in Phase 1 of the study (Phase 1a) is to 
determine the MTD or PAD of NC410. A 3 + 3 study design will be used for dose escalation. A 
maximum of 8 dose levels will be tested. Therefore, a maximum of 48 subjects, who are 
evaluable for DLTs, will be included in the dose escalation phase. Subjects evaluable for DLTs 
are defined as the subjects who take a full dose of NC410 and then are followed up for 28 days 
for assessment of DLTs. Any subjects who do not meet the criteria will be replaced. 
Phase 1 of the study may also include safety expansion cohorts (Phase 1b) evaluating doses and 
schedules equivalent to or lower than the highest dose levels determined to be safe and/or doses 
determined to be pharmacologically active. Each safety expansion cohort will enroll up to an 
additional 10 evaluable subjects (total of 30 additional subjects in the Phase 1b). If < 3 of 9 
evaluable subjects experience a DLT, the cohort will be deemed safe. If more than 1 safety 
expansion cohort is deemed safe, then the RP2D will be determined in conjunction with the 
investigators and sponsor based on all available safety, PK, PD, and biomarker results. 
9.2.2 
Sample Size for Phase 2 
Phase 2 of the study will further evaluate the safety, tolerability, preliminary efficacy, PK, and 
pharmacologic activity of the recommended dose of NC410. The sample size for each tumor 
type will be guided by the Simon 2-stage design (Simon, 1989). Let 5% be a clinically 
insignificant response rate for all tumor types. During Stage 1, 9 subjects will be enrolled; if no 
responses are observed, then the cohort will be discontinued. If at least 1 response is observed, 
then 8 additional subjects will be enrolled (Stage 2), for a maximum of 17 subjects per tumor 
type in Phase 2. The detailed calculation is based on a 1-sided Type I error of 0.05 and power of 
80% to detect a 25% response rate for each of the tumor types. 
9.3 
Level of Significance 
There is no formal hypothesis test planned for this study. A statistically significant level of 0.05 
is used for calculation of CI. 


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9.4 
Interim Analysis 
No formal interim analysis is planned. However, the safety, PK and efficacy data will be 
regularly reviewed and monitored for decisions involving dose escalation in Phase 1 and 
continuation in Phase 2 of the study. 
9.5 
Statistical Analyses 
9.5.1 
Safety Analyses 
The safety assessments include adverse events, laboratory tests (hematology, clinical chemistry, 
coagulation, and urinalysis), ECG, physical examination, vital signs, ECOG performance status, 
and medical history. All the safety data in the SAS will be summarized and listed by phase, 
treatment group, and cohort. 
9.5.1.1 
Adverse Events 
A treatment-emergent adverse event (TEAE) is any AE either reported for the first time or 
worsening of a pre-existing event after the first dose of study drug. Analysis of AEs will be 
limited to TEAEs, but data listings will include all AEs regardless of their timing to study drug 
administration. Adverse events will be tabulated by the MedDRA preferred term and system 
organ class. Severity of AEs will be based on the NCI CTCAE v5.0 using Grades 1 through 4. 
The subset of AEs considered by the investigator to have a relationship to study drug will be 
considered to be treatment-related AEs. If the investigator does not specify the relationship of the 
AE to study drug, then the AE will be considered treatment-related. The incidence, frequency, 
duration, and severity of all AEs (regardless of causality) will be tabulated. 
9.5.1.2 
Vital Signs 
Descriptive statistics and mean change from baseline will be determined for vital signs (blood 
pressure, pulse, respiratory rate, and body temperature) at each assessment time. Vital sign 
results will be reviewed for clinically notable abnormalities (see Table 14) and subjects 
exhibiting clinically notable vital sign abnormalities will be listed. A value will be considered an 
"alert" value if it is outside the established range and shows a > 25% change from baseline. 
Table 14: Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 40 mmHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38ºC 
< 35.5ºC 
Respiratory rate 
> 24 breaths/min 
< 8 breaths/min 
 


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9.5.1.3 
Electrocardiograms 
Descriptive statistics and mean change from baseline will be determined for each ECG parameter 
at each assessment time. ECG results will be reviewed for clinically notable abnormalities 
according to predefined criteria (see Table 15). Subjects exhibiting clinically notable ECG 
abnormalities will be listed. 
Table 15: Criteria for Clinically Notable Electrocardiogram Abnormalities 
Parameter 
High Threshold 
Low Threshold 
QTcF 
> 460 msec 
< 295 msec 
PR 
> 220 msec 
< 75 msec 
QRS 
> 120 msec 
< 50 msec 
QT 
> 500 msec 
< 300 msec 
RR 
> 1330 msec 
< 600 msec 
QTcF = Fridericia correction. 
 
9.5.2 
PK Analyses 
The PK analyses will be based off the PAS, and PK time-concentration data will be summarized, 
listed, and plotted. PK parameters (AUC0-336, AUC0-∞, Cmax, t½, etc.) derived from time-
concentration data will be summarized. 
9.5.3 
Efficacy Analyses 
The response will be assessed by CT/MRI image during screening and every 8 weeks (56 
± 7 days) post-dosing for 6 months and then every 12 weeks (84 ± 7 days) thereafter (or per 
standard of care). The efficacy study endpoints include ORR, DCR, DoR, PFS, and OS. Tumor 
response will be determined according to RECIST v1.1. Time-to-event data (DoR, PFS, and OS) 
will be analyzed using the Kaplan-Meier method. All the efficacy data will be summarized by 
phase, dose group, and cohort. 
• ORR includes RECIST v1.1 complete and partial response (CR or PR). ORR with 95% 
exact confidence interval (CI) will be summarized by phase, dose group, and cohort. 
• DCR includes RECIST v1.1 complete, partial response, and stable disease (CR, PR or 
stable disease lasting 24 weeks or longer). DCR with 95% exact CI will be summarized 
by phase, dose group, and cohort. 
• DoR is defined as the duration from the first documented ORR to the first documented 
progressive disease or death due to any cause, whichever occurs first. For subjects who 
are alive and progression-free at the time of discontinuation from study, data cutoff for 
analysis, or use of other anticancer drug, DoR will be censored at the last tumor 
assessment date. 
The DoR will only be analyzed for the subgroup of subjects with an objective response. 
DoR = (progressive disease, death, or censored date) – (date of first response + 1) 


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• PFS is defined as from starting study treatment to the first documented progressive 
disease or death due to any cause, whichever occurs first. For subjects who are alive and 
progression-free at the time of discontinuation from study, data cutoff for analysis, or use 
of other anticancer drug, PFS will be censored at the last tumor assessment date. 
PFS = (progressive disease, death, or censored date) – (date of first dose of study drug + 
1) 
• OS is defined as from starting study treatment to death due to any cause. For subjects 
who are alive will be censored at the date of last known alive (LKA). 
OS = (Death or LKA date) – (date of first dose of study drug + 1) 
9.5.4 
Pharmacodynamic and Biomarkers Analysis 
The PD and biomarkers are explorative for this study. These data will be listed only. 
Descriptive statistics will be the primary methods for the exploratory analyses. Among the 
variables to be included in the exploratory analyses are: 
• Correlation analysis between PD biomarkers and the disease response to treatment with 
NC410. 
The immunogenic potential of NC410 will be assessed by summarizing the number and 
percentage of subjects who develop detectable ADAs. The impact of ADAs on PK will be 
assessed if data allow. Samples will be collected for evaluating neutralizing capacity of ADAs in 
the future. 
9.6 
Analyses for Data Monitoring Committee 
Not applicable. 
10 
STUDY AND DATA MANAGEMENT 
10.1 
Training of Study Site Personnel 
Before the first subject is entered into the study, a NextCure representative will review and 
discuss the requirements of this protocol and related documents with the investigational staff and 
train them in any study-specific procedures and system(s) utilized. 
The Principal Investigator (PI) will ensure that appropriate training relevant to the study is given 
to all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The PI will maintain a record of all individuals involved in the study (medical, nursing and other 
staff). 


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10.2 
Monitoring of the Study 
During the study, a NextCure representative will have regular contacts with the study site, 
including visits to: 
• Provide information and support to the investigator(s). 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the NC410-01 Laboratory Manual and that study drug accountability 
checks are being performed. 
• Perform source data verification (a comparison of the data in the eCRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to the 
study) including verification of informed consent of participating subjects. This will 
require direct access to all original records for each subject (e.g., clinic charts). 
• Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject. 
The NextCure representative will be available between visits if the investigator(s) or other staff 
at the center needs information or advice about the study conduct. 
10.2.1 
Source Data 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Data reported in the eCRF derived from source documents should be 
consistent with the source documents. 
The primary source document for this study will be the subject’s medical record. If the 
investigator(s) maintains separate research records, both the medical record and the research 
records will be considered the source documents for the purposes of auditing the study. 
Data recorded on source documents will be entered into eCRFs. The investigator must promptly 
review the completed eCRFs for each subject. A study monitor representing the sponsor will 
review the source documents against the eCRF on a regular basis throughout the study. 
The PI at each/the center should comply with all the terms, conditions, and obligations of the 
Clinical Study Agreement, or equivalent, for this study. In the event of any inconsistency 
between this protocol and the Clinical Study Agreement, the terms of the protocol shall prevail 
with respect to the conduct of the study and the treatment of subjects and in all other respects, 
not relating to study conduct or treatment of subjects, the terms of the Clinical Study Agreement 
shall prevail. 
Agreements between NextCure and the PI must be in place before any study-related procedures 
can take place, or subjects are enrolled. 


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10.2.2 
Archiving of Study Documents 
The Investigator follows the principles outlined in the Clinical Study Agreement and according 
to the ICH-GCP and applicable regulatory requirements. Records will be retained for at least 2 
years after the last marketing application approval or 2 years after the study is discontinued and 
the FDA is notified.  
 
10.3 
Study Timetable and End of Study 
An individual subject will be considered to have completed the study if the subject was followed 
through the last protocol-specified visit/assessment (including telephone contact), regardless of 
the number of doses of investigational product that was received. 
Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up (see Section 5.5.1). 
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last subject in the study. 
10.4 
Data Management 
Data management will be performed according to the study specific Data Management Plan. 
A web based Electronic Data Capture ( EDC) system will be used for data collection and query 
handling. The investigator will ensure that data are recorded on the eCRFs as specified in the 
study protocol and in accordance with the instructions provided. 
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and of 
the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived at 
the study site. 
10.5 
Medical Monitor Coverage 
Each subject will be provided with contact information for the PI and the site coordinator(s). In 
an emergent situation, a subject may present to a medical facility where the treating health care 
provider is not involved with this clinical trial. The treating healthcare provider may require 
additional information on the study drug, and the subject should provide contact information for 
the site coordinator(s) or the PI. 
The PI will then be required to update the medical monitor. 


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11 
ETHICAL AND REGULATORY REQUIREMENTS 
11.1 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice (GCP), and 
applicable regulatory requirements. 
11.2 
Subject Data Protection 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
The anonymity of subjects must be maintained. Subjects will be identified by their initials and an 
assigned subject number on eCRFs and other documents submitted to the sponsor. Documents 
that identify the subject beyond initials and subject number will not be submitted to the sponsor 
(e.g.; the signed ICF) and must be maintained in strict confidence by the investigator, except to 
the extent necessary to allow auditing by the regulatory authorities, site monitor, or sponsor 
representatives. 
NextCure will not provide individual genotype results to subjects, any insurance company, any 
employer, their family members, general physician, or any other third party, unless required to 
do so by law. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject. In exceptional circumstances, however, certain individuals might see 
both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, a NextCure medical monitor or an investigator might know a subject’s 
identity and also have access to his or her genetic data. Also, Regulatory authorities may require 
access to the relevant files, though the subject’s medical information and the genetic files would 
remain physically separate. 
11.3 
Ethics and Regulatory Review 
An IRB/IEC should approve the final study protocol, including the final version of the ICF and 
any other written information and/or materials to be provided to the subjects. The investigator 
will ensure the distribution of these documents to the applicable IRB/IEC, and to the study site 
staff. 
The opinion of the IRB/IEC should be given in writing. The investigator should submit the 
written approval to the sponsor or designee before enrollment of any subject into the study. 
The IRB/IEC should approve all advertising used to recruit subjects for the study. 
The sponsor or designee should approve any modifications to the ICF that are needed to meet 
local requirements. 
If required by local regulations, the protocol should be re-approved by the IRB/IEC annually. 


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Before enrollment of any subject into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations. 
The sponsor or designee will handle the distribution of any of these documents to the national 
regulatory authorities. 
The sponsor or designee will provide Regulatory Authorities, IRB/IEC, and PIs with safety 
updates/reports according to local requirements, including suspected unexpected serious adverse 
reactions (SUSARs), where relevant. 
Each PI must inform the IRB/IEC of: 
• Changes in informed consent 
• Revisions of other documents originally submitted for review 
• Serious and/or unexpected AEs occurring during the study  
• New information that may adversely affect the safety of subjects or the conduct of the 
study 
• Annual update and/or request for re-approval 
• Study completion 
11.4 
Informed Consent 
A copy of the proposed ICF must be submitted to the sponsor for review and comment prior to 
submission to the reviewing IRB/IEC. The ICF must be approved by the IRB/IEC and contain all 
elements required by national, state, local and institutional regulations or requirements. 
The PI at each center will: 
• Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study 
• Ensure each subject is notified that they are free to discontinue from the study at any time 
• Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided 
• Ensure each subject voluntarily provides signed and dated informed consent before 
conducting any procedure specifically for the study 
• Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File 
• Ensure a copy of the signed ICF is given to the subject 
• Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the ICF that is approved by an IRB/IEC 


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11.5 
Changes to the Protocol and Informed Consent Form 
Protocol revisions will be prepared and approved by NextCure and the medical monitor. Minor 
revisions will be submitted as administrative changes. If there are any substantial changes to the 
study protocol, then these changes will be documented in a study protocol amendment and where 
required in a new version of the study protocol. 
All protocol amendments will be signed by the PI and approved by the relevant IRB/IEC and if 
applicable, also the national regulatory authority approval, before implementation. Local 
requirements are to be followed for revised protocols. Documentation of IRB/ IEC approval must 
be forwarded to the sponsor, or sponsor’s delegate. 
The sponsor or designee will distribute any subsequent amendments and new versions of the 
protocol to each PI. For distribution to IRB/IEC see Section 11.3. 
If a protocol amendment alters the study design, increases potential risk to the subject or 
otherwise affects statements in the ICF, the ICF must be revised accordingly and submitted to the 
sponsor or designee and the IRB/IEC for review and approval before the revised ICF is used. 
The approved ICF must be used to obtain informed consent from new subjects prior to 
enrollment and must be used to obtain informed consent from subjects already enrolled if they 
are affected by the amendment. 
If local regulations require, any administrative change will be communicated to or approved by 
each IRB/IEC. 
11.6 
Audits and Inspections 
Authorized representatives of NextCure, a regulatory authority, or an IRB/IEC may perform 
audits or inspections at the clinical sites, including source data verification. The purpose of an 
audit or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, GCP, guidelines of the ICH, and any 
applicable regulatory requirements. The investigator will contact NextCure immediately if 
contacted by a regulatory agency about an inspection at the site. 


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Appendix 1: Signatures 
Sponsor Signature(s) 
A Phase 1/2, Open-Label, Dose-Escalation, Safety and Tolerability Study of 
NC410 in Subjects with Advanced or Metastatic Solid Tumors 
 
I agree to the terms of this protocol. 
 
Signature and date:   
 
 
 
 
 
 
 
 
 
Han Myint, MD 
Chief Medical Officer 
NextCure, Inc. 
9000 Virginia Manor Road, Suite 200, Beltsville, MD 20705 USA 
Telephone number: 240-399-4900 


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Sponsor Signature(s) 
A Phase 1/2, Open-Label, Dose-Escalation, Safety and Tolerability Study of 
NC410 in Subjects with Advanced or Metastatic Solid Tumors 
 
I agree to the terms of this protocol. 
 
Signature and date:   
 
 
 
 
 
 
 
 
 
Stephanie Zeidan 
Associate Director, Clinical Operations 
NextCure, Inc. 
9000 Virginia Manor Road, Suite 200, Beltsville, MD 20705 USA 
Telephone number: 240-763-0535 


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Signature of Principal Investigator 
A Phase 1/2, Open-Label, Dose-Escalation, Safety and Tolerability Study of 
NC410 in Subjects with Advanced or Metastatic Solid Tumors 
I, the undersigned, have reviewed this protocol, and I agree to conduct this protocol in 
accordance with ethical principles that have their origin in the Declaration of Helsinki and are 
consistent with the International Council for Harmonisation (ICH) guidelines on Good Clinical 
Practice (GCP), any applicable laws and requirements, and any conditions required by a 
regulatory authority and/or Institutional Review Board/Independent Ethics Committee 
(IRB/IEC). 
I understand that the protocol may not be modified without written approval of the sponsor. All 
changes to the protocol must be submitted to the applicable regulatory authority and IRB/IEC 
and must be approved by the IRB/IEC prior to implementation except when necessary to 
eliminate immediate hazards to the subjects or when the change(s), as deemed by the sponsor, 
involves only logistical or administrative changes. Documentation of IRB/IEC approval must be 
sent to the sponsor immediately upon receipt. 
Signature and date:   
 
 
 
 
 
 
 
 
 
Name and title:  
 
 
 
 
 
 
 
 
 
 
Address including postal code:  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
Telephone number:   
 
 
 
 
 
 
 
 
 
Site/Center Number (if available) 
 
 
 
 
This document contains confidential information, which should not be copied, referred to, released, or published 
without written approval from NextCure. Investigators are cautioned that the information in this protocol may be 
subject to change and revision. 


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Appendix 2: Additional Safety Guidance 
Assessment of Severity 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
adverse events (AEs) and serious adverse events (SAEs). Severity will be graded according to 
the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
v5.0 as provided below. The determination of severity for all other events not listed in the NCI 
CTCAE should be made by the investigator based upon medical judgment and the severity 
categories of Grade 1 to 4 as defined below. 
Grade 1 (mild) 
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living. 
Grade 2 (moderate) 
An event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities 
of daily living, causing discomfort but poses no significant or 
permanent risk of harm to the subject. 
Grade 3 (severe) 
An event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the 
clinical status of the subject. 
Grade 4 (life threatening) 
An event, and/or its immediate sequelae, that is associated with an 
imminent risk of death or with physical or mental disabilities that 
affect or limit the ability of the subject to perform activities of 
daily living (eating, ambulation, toileting, etc.). 
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 8.3.1. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that persists 
for several hours may not meet the regulatory definition of an SAE and would be considered a 
nonserious event, whereas a Grade 2 seizure resulting in a hospital admission would be 
considered an SAE. 
The NCI CTCAE v5.0 can be downloaded from the Cancer Treatment Evaluation Program 
(CTEP) 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_5x7.pdf). 
Assessment of Relationship 
Relationship to Investigational Product 
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product. 


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An event will be considered “not related” to use of the investigational product if any of the 
following tests are met: 
• An unreasonable temporal relationship between administration of the investigational 
product and the onset of the event (e.g., the event occurred either before, or too long 
after, administration of the investigational product for it to be considered product-related) 
• A causal relationship between the investigational product and the event is biologically 
implausible (e.g., death as a passenger in an automobile accident) 
• A clearly more likely alternative explanation for the event is present (e.g., typical adverse 
reaction to a concomitant drug and/or typical disease-related event) 
Individual AE/SAE reports will be considered “related” to use of the investigational product if 
the “not related” criteria are not met. 
“Related” implies that the event is considered to be “associated with the use of the drug” 
meaning that there is “a reasonable possibility” that the event may have been caused by the 
product under investigation (i.e., there are facts, evidence, or arguments to suggest possible 
causation). 
Relationship to Protocol Procedures 
The investigator is also required to provide an assessment of relationship of SAEs to protocol 
procedures on the SAE Report Form. This includes nontreatment-emergent SAEs (i.e., SAEs that 
occur prior to the administration of investigational product) as well as treatment-emergent SAEs. 
A protocol-related SAE may occur as a result of a procedure or intervention required during the 
study (e.g., blood collection, washout of an existing medication). The following guidelines 
should be used by investigators to assess the relationship of SAEs to the protocol: 
Protocol related: 
The event occurred due to a procedure/intervention that was described in 
the protocol for which there is no alternative etiology present in the 
subject’s medical record. 
Not protocol related: The event is related to an etiology other than the procedure/ intervention 
that was described in the protocol (the alternative etiology must be 
documented in the study subject’s medical record). 


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Appendix 3: National Institute of Allergy and Infectious Disease and Food and 
Allergy Anaphylaxis Network Guidance for Anaphylaxis 
Diagnosis 
National Institute of Allergy and Infectious Disease (NIAID) and Food and Allergy Anaphylaxis 
Network (FAAN) define anaphylaxis as a serious allergic reaction that is rapid in onset and may 
cause death (Sampson et al., 2006). They recognize 3 categories of anaphylaxis, with criteria 
designated to capture from 80% of cases (category 1) to >95% of all cases of anaphylaxis (for all 
3 categories). 
1) 
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-
uvula) 
 
AND AT LEAST ONE OF THE FOLLOWING: 
• Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow (PEF), hypoxemia) 
• Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g., 
hypotonia [collapse], syncope, incontinence) 
2) 
Two or more of the following that occur rapidly after exposure to a likely allergen for 
that subject (minutes to several hours): 
• Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen lips-
tongue-uvula) 
• Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
• Reduced blood pressure or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence) 
• Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
3) 
Reduced blood pressure after exposure to known allergen for that subject (minutes to 
several hours): 
• Infants and children: low systolic blood pressure (age specific) or greater than 30% 
decrease in systolic blood pressure 
• Adults: systolic blood pressure of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline 


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Appendix 4: Eastern Cooperative Oncology Group Performance Status 
Grade 
Eastern Cooperative Oncology Group (ECOG) 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
(Oken et al., 1982) 
 


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Appendix 5: Cockcroft-Gault Formula 
Estimated creatinine clearance or glomerular filtration rate = 
[(140-Age) * Mass (in kg)] \ [72 * Serum creatinine (in mg/dL)] 
If the subject is female, multiply the above by 0.85 
If the subject is obese (>30% over ideal body weight), use ideal body weight in calculation of 
estimated creatinine clearance. 
 
Calculation of Ideal Body Weight (IBW) 
IBW in kg 
Males = 50 + [2.3 x each inch over 5 ft] 
 
or 50 + [2.3 kg x (each cm over 152.4/2.54)] 
Females = 45.5 + [2.3 x each inch over 5 ft] 
 
or 45.5 + [2.3 kg x (each cm over 152.4/2.54)] 
 
Calculation for Obesity 
[(actual wt - IBW)/IBW]*100%. If this value is >30% then the person is obese. 
Example: 
Subject weight = 160. Subject ideal weight = 120 
160-120 = 40 
40 /120 = 0.33 
0.33 x 100% = 33% 
 
(Cockcroft and Gault 1976)