Clinical trial NCT03665285
Conditions: Advanced or Metastatic Solid Tumors Lung Cancer Breast Cancer Head and Neck Squamous Cell Carcinoma Endometrial Cancer Melanoma CRC Urothelial Carcinoma Cholangiocarcinoma
Keywords: Advanced Cancer Metastatic Cancer NC318 Immunotherapy PD-L1 Dose Escalation Biomarker PK Cohort Expansion Solid Tumor
Sponsor: NextCure, Inc.
Start date: 2018-10-01; Completion date: 2023-04-11
Enrollment: 109 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This research study is studying a new drug, NC318, as a possible treatment for advanced or metastatic solid tumors.

Detailed description:

Arms: arm 1: Phase 1 Dose Escalation (Cohort -1): Subjects received NC318 IV at 8mg Q2W until disease progression, withdraw of consent, or intolerable toxicity (whichever comes first). arm 2: Phase 1 Dose Escalation (Cohort 1): Subjects received NC318 IV at 24mg Q2W until disease progression, withdraw of consent, or intolerable toxicity (whichever comes first). arm 3: Phase 1 Dose Escalation/Safety Expansion (Cohort 2): Subjects received NC318 IV at 80mg Q2W until disease progression, withdraw of consent, or intolerable toxicity (whichever comes first). arm 4: Phase 1 Dose Escalation/Safety Expansion (Cohort 3): Subjects received NC318 IV at 240mg Q2W until disease progression, withdraw of consent, or intolerable toxicity (whichever comes first). arm 5: Phase 1 Dose Escalation/Safety Expansion (Cohort 4): Subjects received NC318 IV at 400mg Q2W until disease progression, withdraw of consent, or intolerable toxicity (whichever comes first). arm 6: Phase 1 Dose Escalation (Cohort 5): Subjects received NC318 IV at 800mg Q2W until disease progression, withdraw of consent, or intolerable toxicity (whichever comes first). arm 7: Phase 1 Dose Escalation (Cohort 6): Subjects received NC318 IV at 1600mg Q2W until disease progression, withdraw of consent, or intolerable toxicity (whichever comes first). arm 8: Phase 2 Dose Expansion (400mg): Subjects received NC318 IV at 400mg Q2W until disease progression, withdraw of consent, or intolerable toxicity (whichever comes first). arm 9: Phase 2 Dose Expansion (800mg): Subjects received NC318 IV at 800mg QW for 8 weeks, then Q2W thereafter until disease progression, withdraw of consent, or intolerable toxicity (whichever comes first).
Interventions: intervention 1: NC318
Intervention descriptions: intervention 1: NC318 is an experimental antibody drug that may make the immune response more active against cancer.

Protocol documents:
Prot_SAP_000.pdf: 
Official Title: A PHASE 1/2, OPEN-LABEL, DOSE-ESCALATION, SAFETY AND TOLERABILITY STUDY OF 
NC318 IN SUBJECTS WITH ADVANCED OR METASTATIC SOLID TUMORS
NCT Number: NCT03665285
Document Date: Protocol Amendment 6 (Version 7.0) dated 03-Mar-2022


A PHASE 1/2, OPEN-LABEL, DOSE-ESCALATION, SAFETY AND
TOLERABILITY STUDY OF NC318 IN SUBJECTS WITH ADVANCED
OR METASTATIC SOLID TUMORS
Sponsor Protocol Number: NC318-01
IND Number:
137910
Investigational Product:
NC318
Humanized, IgG1 Monoclonal Antibody Against Siglec-15 (S15)
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:
03-Mar-2022
Amendment 6 (Version 7.0)


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PROTOCOL SYNOPSIS 
 
TITLE 
A Phase 1/2, Open-Label, Dose-Escalation, Safety and Tolerability Study of NC318 in Subjects with 
Advanced or Metastatic Solid Tumors 
HYPOTHESES 
NC318 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 NC318 
2) Define a maximum tolerated dose (MTD) or pharmacologically active dose (PAD) of NC318 in 
subjects with advanced or metastatic solid tumors 
Secondary Objectives 
1) To evaluate the pharmacokinetic (PK) profile of NC318 
2) To assess preliminary efficacy of NC318 by assessing objective response rate (ORR), duration of 
response (DoR), and disease control rate (DCR) per Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 
3) To evaluate expression of Siglec-15 in tumor tissue and immune cell infiltrates at baseline and 
following NC318 treatment, and correlate expression level with efficacy and changes in tumor 
infiltrating lymphocytes 
Exploratory Objectives 
1) To assess the immunogenicity of NC318 
2) To explore biomarkers that may predict the pharmacologic activity of NC318 
3) To characterize the effect of NC318 on immune markers such as cytokine and immune cell 
phenotypes 
4) To assess soluble S15 level at baseline and changes after NC318 treatment, and correlation with 
efficacy. 
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 
Secondary Endpoints 
1) The endpoints for assessment of PK of NC318 include individual NC318 concentrations in serum 
and PK parameters. 
2) The endpoints for assessment of antitumor activity/efficacy include objective response (OR) and 
disease control (DC) based on RECIST v1.1, DoR, progression-free survival (PFS), and overall 
survival (OS) as per RECIST v1.1 
3) Tumor biopsy analyses to evaluate Siglec-15 (S15) expression in tumor tissue and immune cell 
infiltrates at baseline and following treatment, and correlate expression levels with efficacy and 
changes in tumor infiltrating lymphocytes. 




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The Phase 1a design is summarized below: 
A minimum of 3 evaluable subjects will be enrolled in each cohort beginning with Cohort -1 (8 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 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 Cohort -1 (8 mg; starting dose) exceeds the MTD, the sponsor and investigators will consider dosing 
NC318 at a lower dose, and/or investigate 8 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 NC318 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. 
Phase 1b – Safety Expansion 
The purpose of Phase 1b was to evaluate additional PD activity of NC318 and confirm the preliminary 
safety of the dose escalation cohorts from Phase 1a. Several cohorts from Phase 1a were expanded at doses 
and schedules equivalent to or lower than the highest dose levels determined to be safe and/or doses 
determined to be pharmacologically active. 
The following cohorts were expanded during Phase 1b: Cohort 2 (80mg), Cohort 3 (240mg), and Cohort 4 
(400mg). Phase 1 enrollment of the study is complete. A total of 49 subjects were enrolled across Phase 
1a and Phase 1b. 
The Phase 1b design is summarized below: 
Approximately 36 evaluable subjects will be enrolled in the Phase 1b safety expansion, with each cohort 
enrolling approximately 9 evaluable subjects. 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. 


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Phase 2 
The trial is currently enrolling Phase 2. Phase 2 will evaluate subjects with advanced or metastatic solid 
tumors characterized as Tumor Mutational Burden High (TMB-H) and/or MicroSatellite Instability High 
(MSI-H)/ deficient MisMatch Repair (dMMR). The following tumor types will be enrolled: Lung, Head 
and Neck Squamous Cell Carcinoma (HNSCC, Breast, Endometrial, Melanoma, CRC, Urothelial, 
Cholangiocarcinoma, and other tumors known to be TMB-H and/or MSI-H/dMMR. 
Previously as part of the initial Phase 2 design, a RP2D of 400mg Q2W was tested. 47 subjects were 
treated at the initial RP2D. Based on further ongoing evaluation of the PK/PD studies from Phase 1/2, the 
RP2D was adjusted to 800mg with an alternative administration schedule. To further evaluate the new 
RP2D, a Phase 2 Safety Run-In will be conducted utilizing a 3+3 design (Figure S1). 
Phase 2 - Safety Run-in: 
A minimum of 3 evaluable subjects will be enrolled. The first 3 evaluable subjects will be observed for a 
DLT observation period of 28 days. Only one subject will be dosed on the first day of dosing (additional 
subjects can begin in ≥ 48 hours). If there are no DLTs observed in the first 3 subjects, then Phase 2 Dose 
Expansion may begin at the new RP2D. If 1 of the first 3 evaluable subjects enrolled has a DLT, then the 
cohort will be expanded to include 3 additional evaluable subjects. If there are no DLTs in the additional 
3 subjects, then Phase 2 Dose Expansion may begin at the new RP2D. If a DLT occurs in one third or 
more of the 3 additional subjects then the enrollment will be paused and intermediate dose levels or 
alternative dose schedules may be considered. 
Figure S1:       Phase 2 Safety Run-In Design 
 
Abbreviation: DLT = dose-limiting toxicity 


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Phase 2 - Dose Expansion: 
Phase 2 Dose Expansion will further evaluate the safety, tolerability, preliminary efficacy, and PK/PD 
activity of NC318 at the RP2D utilizing a Simon 2-stage design (Figure S2). Subjects will be stratified 
after enrollment into two main cohorts based on S15 expression and tumor type: 
• 
Cohort 1: Select S15+ Tumors (Lung (adenocarcinoma), HNSCC, Breast) 
• 
Cohort 2: Alternate Tumors (including Other S15+ Tumors and S15- Tumors) 
Figure S2:       Phase 2 Dose Expansion (Simon 2-Stage Design) 
 
Abbreviations: CRC = colorectal cancer; dMMR = deficient DNA mismatch repair; MSI = microsatellite instability 
high; NGS = next generation sequencing; NSCLC = non-small cell lung cancer; ORR = objective response rate; 
TMB-H = Tumor mutational burden high; WES = whole exome sequencing. 
Cohort 1: Select S15+ Tumors 
This cohort will include subjects who are 1) confirmed as TMB-H and/or MSI-H/dMMR, 2) express S15, 
and 3) have one of the following tumor types, separated into tumor-specific subgroup: 
• 
Cohort 1a: NSCLC (adenocarcinoma) 
• 
Cohort 1b: HNSCC 
• 
Cohort 1c: Breast cancer 
Each subgroup will be independently assessed and guided by the Simon 2-stage design and will enroll 
9 evaluable subjects in Stage 1. If no responses are observed within a subgroup, then the subgroup will be 
discontinued. If at least 1 response is observed, Stage 2 will begin and enroll 8 additional evaluable 
subjects, for a total of 17 evaluable subjects in each subgroup (1a, 1b, and 1c). 


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Cohort 2: Alternate Tumors (including Other S15+ Tumors and S15- Tumors) 
This basket cohort will include all other enrolled subjects who are confirmed as TMB-H and/or MSI-
H/dMMR but do not fall under the criteria to be included in Cohort 1. Based on results of S15 expression, 
subjects will be further stratified into two subgroups: 
• 
Cohort 2a: Other S15+ Tumors 
• 
Cohort 2b: S15- Tumors 
Each subgroup will be independently assessed and guided by the Simon 2-stage design and will enroll 
9 evaluable subjects in Stage 1. If no responses are observed within a subgroup, then the sub-group will 
be discontinued. If at least 1 response is observed, Stage 2 will begin and enroll 8 additional evaluable 
subjects, for a total of 17 evaluable subjects in each subgroup (2a and 2b). 
DOSE SELECTION AND ADMINISTRATION SCHEDULE 
During Phase 1 Dose Escalation, various dose levels were evaluated ranging from 8 mg to 1600 mg. 
During the initial Phase 2 design, a RP2D of 400 mg Q2W was tested. Based on further evaluation of the 
PK/PD studies from the original Phase 1/2 design, the RP2D has been adjusted to 800 mg with an 
alternative administration schedule. 
The new RP2D and administration schedule will be as follows: 
• 
Initial Dosing: 800 mg weekly for 8 Cycles 
• 
Subsequent Dosing (Cycle 9 onwards): 800 mg every 2 weeks 
Subjects will have regularly scheduled visits on Day 1 of every cycle. The duration of each cycle is 
dependent on the dosing schedule: 
• 
Initial Dosing: 800 mg weekly for 8 Cycles 
o Cycle Duration: 7 days (+3 days after Cycle 1) 
• 
Subsequent Dosing (Cycle 9 onwards): 800 mg every 2 weeks 
o Cycle Duration: 14 days (±3 days) 
Subjects will begin with the Initial Dosing Schedule on Cycle 1 (Day 1) and continue with weekly dosing 
for 8 Cycles. Beginning with Cycle 9, subjects will follow the Subsequent Dosing Schedule of 800 mg 
every 2 weeks. Note: Cycle 9 should occur two weeks following the last weekly dose of NC318. Subjects 
will remain on the Subsequent Dosing Schedule of 800 mg every two weeks until disease progression, 
withdraw of consent, or intolerable toxicity (whichever comes first). 
TARGET SUBJECT POPULATION 
Men and women, 18 years or older, with advanced solid malignancies that can be evaluable by RECIST 
criteria, that 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. Presence of 
measurable disease based on RECIST v1.1, and consent to have a non-target lesion biopsied before 
treatment. Note: Archival tissue may be submitted in place of fresh biopsy at pre-treatment. 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. Subjects with certain 
serious medical conditions (in addition to the diagnosis of cancer) would be excluded from participation 
in the trial. 


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ELIGIBILITY CRITERIA 
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) Willing and able to provide written informed consent for the study. 
3) ECOG performance status 0 to 1. 
4) Subjects with advanced unresectable and/or metastatic solid tumors confirmed to be TMB-H 
and/or MSI-H/dMMR including: Lung, Breast, HNSCC, Endometrial, Melanoma, CRC, 
Urothelial, Cholangiocarcinoma, and other tumors known to be TMB-H and/or MSI-H/dMMR. 
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. 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) Able to provide pretreatment tumor tissue sample (archival ≤ 5 years old) or undergo tumor biopsy 
at Screening (must allow for adequate sample of tissue from appropriate site). 
Note: Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly 
obtained biopsies are preferred to archived tissue. 
8) Subjects of childbearing potential (defined as female subjects who have not undergone surgical 
sterilization with a hysterectomy and/or bilateral oophorectomy and are not postmenopausal, 
defined as ≥ 12 months of amenorrhea not caused by reversible conditions, diseases, or 
medications) 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: Female subjects of childbearing potential must have negative serum pregnancy test at 
screening. 
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 provide informed consent. 
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 measured or 
calculated creatinine clearance < 30 ml/min for subjects with creatinine levels 
<1.5 × institutional ULN. 
e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 2.5 × ULN. 
Note: Subjects with liver metastases are permitted to enroll if AST/ALT is ≤ 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 or activated 
partial thromboplastin time (aPTT) > 1.5 × ULN; applies only to subjects who do not 
receive therapeutic anticoagulation; subjects receiving therapeutic anticoagulation should 
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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 prior to first 
administration of study drug. 
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, 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. 
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 (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/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 any systemic 
treatment for an autoimmune disease for at least 2 years and have normal thyroid function or are 
stable on thyroid hormone replacement are allowed to participate in the study. 


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Note: Replacement and symptomatic therapies (e.g., levothyroxine, 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 additional 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) Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or 
has current pneumonitis / interstitial lung disease. 
11) Documented known activating or driver mutations (i.e. EGFR mutations/amplification, BRAF 
mutations, ALK alterations, etc.) which have not been previously treated with a standard of care 
targeted therapy. 
12) Subjects with screening QTc interval > 470 milliseconds (corrected by Fridericia) are excluded. 
13) Uncontrolled systemic fungal, bacterial, viral, or other infection despite appropriate anti-infection 
treatment. 
14) Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV), unless the hepatitis 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 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. 
15) Known history of HIV (HIV 1 or HIV 2 antibodies). 
16) Known allergy or reaction to any component of study drug or formulation components. 
17) 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. 
18) 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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INVESTIGATIONAL PRODUCT, DOSAGE, AND MODE OF ADMINISTRATION 
NC318 will be administered by intravenous (IV) infusion, over a minimum of 30 minutes on Day 1 of 
each cycle. Subjects will continue to receive NC318 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 NC318 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 dose level assigned at the time of enrollment (unless otherwise approved for dose 
modification by the Sponsor). Safety reporting, documentation of disease assessments, and collection of 
survival status will continue per protocol. 
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 NC318. 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 
TITLE PAGE ................................................................................................................................... I 
PROTOCOL SYNOPSIS ................................................................................................................ II 
TABLE OF CONTENTS ............................................................................................................. XII 
LIST OF TABLES ................................................................................................................... XVIII 
LIST OF FIGURES ................................................................................................................. XVIII 
LIST OF ABBREVIATIONS .................................................................................................... XIX 
1. 
INTRODUCTION ........................................................................................................1 
1.1. 
Background ...................................................................................................................1 
1.1.1. 
The Role of the Immune System in Cancer ..................................................................1 
1.1.2. 
Immune Modulators ......................................................................................................2 
1.1.3. 
Siglec-15 and Immunity ...............................................................................................2 
1.2. 
Overview of NC318 ......................................................................................................3 
1.2.1. 
Pharmacokinetics of NC318: Pre-clinical Data ............................................................3 
1.2.2. 
Pharmacokinetics of NC318: Clinical Data ..................................................................4 
1.2.3. 
Pharmacology of NC318 ..............................................................................................5 
1.2.4. 
Non-Clinical Safety and Potential Risks of NC318......................................................6 
1.3. 
Study Rationale .............................................................................................................7 
1.3.1. 
Rationale for the Safe Starting Dose .............................................................................7 
1.3.2. 
Rationale for Fixed Dosing ...........................................................................................9 
1.3.3. 
Rationale for Phase 2 Dose Selection and Administration Schedule .........................10 
1.3.3.1. 
Phase 2 Safety Run-In Rationale ................................................................................10 
1.3.4. 
Rationale for Subject Population for Phase 2 .............................................................10 
1.3.5. 
Rationale for Efficacy Endpoints ................................................................................11 
1.4. 
Summary of Clinical Experience ................................................................................13 
1.4.1. 
Ongoing Clinical Study NC318-01.............................................................................13 
1.5. 
Research Hypotheses ..................................................................................................13 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................14 
2.1. 
Objectives ...................................................................................................................14 
2.1.1. 
Primary Objectives .....................................................................................................14 
2.1.2. 
Secondary Objectives .................................................................................................14 
2.1.3. 
Exploratory Objectives ...............................................................................................14 


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2.2. 
Study Endpoints ..........................................................................................................14 
2.2.1. 
Primary Endpoints ......................................................................................................14 
2.2.2. 
Secondary Endpoints ..................................................................................................14 
2.2.3. 
Exploratory Endpoints ................................................................................................15 
3. 
STUDY DESIGN .......................................................................................................15 
3.1. 
Description of the Study .............................................................................................15 
3.1.1. 
Phase 1 ........................................................................................................................15 
3.1.1.1. 
Phase 1a - Dose Escalation .........................................................................................15 
3.1.1.2. 
Phase 1b – Safety Expansion ......................................................................................17 
3.1.2. 
Phase 2 ........................................................................................................................17 
3.1.2.1. 
Phase 2 Safety Run-In to Evaluate New RP2D ..........................................................17 
3.1.2.2. 
Phase 2 Dose Expansion at New RP2D ......................................................................18 
3.2. 
Measures Taken to Avoid Bias ...................................................................................20 
3.3. 
Number of Subjects ....................................................................................................20 
3.3.1. 
Planned Number of Subjects.......................................................................................20 
3.3.2. 
Replacement of Subjects .............................................................................................20 
3.4. 
Duration of Treatment and Subject Participation .......................................................20 
3.5. 
Overall Study Duration ...............................................................................................21 
3.6. 
Study Termination ......................................................................................................21 
4. 
SUBJECT ELIGIBILITY ...........................................................................................21 
4.1. 
Subject Inclusion Criteria ...........................................................................................21 
4.2. 
Subject Exclusion Criteria ..........................................................................................22 
5. 
TREATMENT ............................................................................................................25 
5.1. 
Treatment Assignment ................................................................................................25 
5.1.1. 
Subject Numbering and Treatment Assignment .........................................................25 
5.2. 
Study Drug ..................................................................................................................25 
5.2.1. 
Description and Administration ..................................................................................25 
5.2.2. 
Supply Packaging and Labeling .................................................................................26 
5.2.3. 
Storage ........................................................................................................................26 
5.2.4. 
Accountability .............................................................................................................26 
5.3. 
Treatment Compliance ................................................................................................26 
5.4. 
Treatment Interruptions and Adjustments ..................................................................26 
5.4.1. 
Dose Modifications .....................................................................................................26 


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5.4.2. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose ................27 
5.4.3. 
Management of Dose-Limiting Toxicities or Other Urgent Situations ......................30 
5.4.4. 
Follow-Up of Dose-Limiting Toxicities .....................................................................30 
5.4.5. 
Procedures for Cohort Review and Dose Escalation ..................................................30 
5.4.6. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study 
Drug ............................................................................................................................30 
5.4.7. 
Definition, Procedures, and Supportive Care Guidelines for Immune-Related 
Adverse Events ...........................................................................................................31 
5.4.8. 
Management of Infusion Reactions ............................................................................32 
5.4.9. 
Criteria for Permanent Discontinuation of Study Drug ..............................................35 
5.4.10. 
Treatment After Initial Evidence of Radiologic Disease Progression ........................35 
5.5. 
Withdrawal of Subjects from Study Drug ..................................................................35 
5.5.1. 
Withdrawal Criteria ....................................................................................................35 
5.5.2. 
Withdrawal Procedures ...............................................................................................36 
5.6. 
Concomitant Medications ...........................................................................................36 
5.6.1. 
Permitted Medications ................................................................................................37 
5.6.2. 
Restricted Medications ...............................................................................................37 
5.6.3. 
Prohibited Medications ...............................................................................................37 
6. 
SCHEDULE OF STUDY PROCEDURES ................................................................39 
6.1. 
Screening Period .........................................................................................................45 
6.2. 
Treatment Period ........................................................................................................45 
6.3. 
End of Treatment Visit ...............................................................................................46 
6.4. 
Post-Treatment Follow-up ..........................................................................................46 
6.4.1. 
Disease Status Follow-up ...........................................................................................46 
6.4.2. 
Survival Follow-up .....................................................................................................47 
6.4.2.1. 
Survival Status ............................................................................................................47 
6.5. 
End of Study ...............................................................................................................47 
6.6. 
Unscheduled Visits .....................................................................................................47 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES ...........................47 
7.1. 
Administration of Informed Consent Form ................................................................48 
7.2. 
Demography and Medical History ..............................................................................48 
7.2.1. 
Demographics and General Medical History..............................................................48 
7.2.2. 
Disease Characteristics and Treatment History ..........................................................48 


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7.3. 
Prior and Concomitant Medications and Procedures ..................................................48 
7.4. 
Poststudy Anticancer Therapy ....................................................................................48 
7.5. 
Safety Assessments .....................................................................................................49 
7.5.1. 
Adverse Events ...........................................................................................................49 
7.5.2. 
Physical Examinations ................................................................................................49 
7.5.2.1. 
Comprehensive Physical Examination .......................................................................49 
7.5.2.2. 
Targeted Physical Examination ..................................................................................49 
7.5.2.3. 
Vital Signs and Weight ...............................................................................................49 
7.5.3. 
Electrocardiograms .....................................................................................................50 
7.5.4. 
Laboratory Assessments .............................................................................................50 
7.5.4.1. 
Pregnancy Testing.......................................................................................................51 
7.5.4.2. 
Hepatitis Screening Tests............................................................................................51 
7.6. 
Efficacy Assessments .................................................................................................51 
7.6.1. 
Modified RECIST v1.1 Assessment of Disease .........................................................51 
7.6.1.1. 
Tumor Imaging ...........................................................................................................52 
7.6.1.2. 
Tumor Imaging During Screening ..............................................................................53 
7.6.1.3. 
Tumor Imaging During the Study ...............................................................................53 
7.6.1.4. 
Imaging During Follow-Up ........................................................................................53 
7.7. 
Pharmacokinetic Assessments ....................................................................................54 
7.8. 
Biomarker and Correlative Assessments ....................................................................54 
7.8.1. 
Tumor Biopsies ...........................................................................................................54 
7.8.1.1. 
Tumor Tissue Collection Requirements .....................................................................54 
7.8.1.2. 
Tumor Tissue Assessment ..........................................................................................55 
7.8.2. 
Whole Blood Correlative Assessment ........................................................................55 
7.8.3. 
Plasma Pharmacodynamic Assessment ......................................................................55 
7.8.4. 
Timing for Plasma and Whole Blood Assessments ....................................................55 
7.9. 
Other Study Procedures ..............................................................................................55 
8. 
SAFETY MONITORING AND REPORTING .........................................................56 
8.1. 
Adverse Events ...........................................................................................................56 
8.1.1. 
Definitions ..................................................................................................................56 
8.1.2. 
Reporting ....................................................................................................................56 
8.2. 
Laboratory Test Abnormalities ...................................................................................58 
8.3. 
Serious Adverse Events ..............................................................................................58 


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8.3.1. 
Definitions ..................................................................................................................58 
8.3.2. 
Reporting ....................................................................................................................59 
8.3.3. 
Reporting of an Overdose ...........................................................................................59 
8.4. 
Emergency Unblinding of Treatment Assignment .....................................................59 
8.5. 
Pregnancy ...................................................................................................................59 
8.6. 
Warnings and Precautions ..........................................................................................60 
8.7. 
Data Monitoring Committee .......................................................................................60 
8.8. 
Immune-Related Adverse Events ...............................................................................61 
8.9. 
Reporting Product Complaints ...................................................................................61 
9. 
STATISTICS ..............................................................................................................61 
9.1. 
Study Populations .......................................................................................................62 
9.2. 
Selection of Sample Size ............................................................................................62 
9.2.1. 
Sample Size for Phase 1..............................................................................................62 
9.2.2. 
Sample Size for Phase 2..............................................................................................62 
9.2.2.1. 
Cohort 1: Select S15+ Tumors (Lung (adenocarcinoma), HNSCC, and 
Breast) .........................................................................................................................62 
9.2.2.2. 
Cohort 2: Alternate Tumors (Other S15+ Tumors/S15- Tumors) ..............................63 
9.3. 
Level of Significance ..................................................................................................63 
9.4. 
Interim Analysis ..........................................................................................................63 
9.5. 
Statistical Analyses .....................................................................................................63 
9.5.1. 
Summary of Baseline Characteristics, Demographics and Other Analyses ...............63 
9.5.2. 
Safety Analyses...........................................................................................................63 
9.5.2.1. 
Adverse Events ...........................................................................................................63 
9.5.3. 
PK Analyses ................................................................................................................64 
9.5.4. 
Efficacy Analyses .......................................................................................................64 
9.5.5. 
Pharmacodynamic and Biomarkers Analysis .............................................................65 
9.6. 
Analyses for Data Monitoring Committee ..................................................................65 
10. 
STUDY AND DATA MANAGEMENT ...................................................................65 
10.1. 
Training of Study Site Personnel ................................................................................65 
10.2. 
Monitoring of the Study ..............................................................................................65 
10.2.1. 
Source Data .................................................................................................................66 
10.2.2. 
Archiving of Study Documents ..................................................................................66 
10.3. 
Study Timetable and End of Study .............................................................................66 


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10.4. 
Data Management .......................................................................................................66 
10.5. 
Medical Monitor Coverage .........................................................................................67 
11. 
ETHICAL AND REGULATORY REQUIREMENTS ..............................................67 
11.1. 
Ethical Conduct of the Study ......................................................................................67 
11.2. 
Subject Data Protection ..............................................................................................67 
11.3. 
Ethics and Regulatory Review ....................................................................................68 
11.4. 
Informed Consent .......................................................................................................68 
11.5. 
Changes to the Protocol and Informed Consent Form ................................................69 
11.6. 
Audits and Inspections ................................................................................................69 
12. 
REFERENCES ...........................................................................................................70 
APPENDIX 1. SIGNATURES ...................................................................................................73 
APPENDIX 2. ADDITIONAL SAFETY GUIDANCE .............................................................76 
APPENDIX 3. NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS 
DISEASE AND FOOD AND ALLERGY ANAPHYLAXIS GUIDANCE 
FOR ANAPHYLAXIS DIAGNOSIS .........................................................................78 
APPENDIX 4. EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS .....................................................................................................................79 
APPENDIX 5. SUMMARY OF CHANGES .............................................................................80 


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LIST OF TABLES 
Table 1: 
Human-Equivalent Dose of EC30 from a Co-Stimulation PBMC Assay of 
NC318 ...........................................................................................................................9 
Table 2: 
NC318 Dose Levels and Cohorts ...............................................................................16 
Table 3: 
Definition of Dose-Limiting Toxicity (NCI CTCAE v5.0) ........................................28 
Table 4: 
Rules for Interruption and Restarting of Study Drug..................................................31 
Table 5: 
Supportive Care Guidelines for Subjects Exhibiting Immune-Related 
Adverse Events ...........................................................................................................32 
Table 6: 
Infusion Reaction Treatment Guidelines ....................................................................33 
Table 7: 
Schedule of Assessments ............................................................................................39 
Table 8: 
Schedule of Local Laboratory Assessments ...............................................................41 
Table 9: 
Local Laboratory Tests: Required Analytes ...............................................................42 
Table 10: Schedule of Pharmacokinetic and Anti-Drug Antibody Sampling .............................43 
Table 11: Schedule of Pharmacodynamic (Biomarker) Sampling..............................................44 
Table 12: Imaging and Treatment After First Radiographic Evidence of Progressive 
Disease ........................................................................................................................52 
Table 13: NCI CTCAE v5.0 Grading Scale ................................................................................57 
 
 
 
LIST OF FIGURES 
Figure 1: 
Soluble Siglec-15 Increases at 24 hours and Reduces to Lower Levels on 
Day 8 .............................................................................................................................4 
Figure 2: 
NC318 Area Under the Curve (AUC) by Dosing Schedule .........................................5 
Figure 3: 
Pharmacology Data Set .................................................................................................8 
Figure 4: 
S15 Expression in Breast, Lung, and Head and Neck Tumors ...................................11 
Figure 5: 
Phase 2 Safety Run-In Design (3+3) ..........................................................................18 
Figure 6: 
Phase 2 Dose Expansion Design (Simon 2-Stage) .....................................................19 


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LIST OF ABBREVIATIONS 
 
Abbreviation or 
Specialized Term 
Definition 
ADA 
Anti-Drug Antibody 
ADCC 
Antibody Dependent Cellular Cytotoxicity 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALK 
Anaplastic lymphoma kinase 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BRAF 
v-Raf murine sarcoma viral oncogene homologue B1 
BSA 
Body Surface Area 
CDC 
Complement Dependent Cytotoxicity 
CI 
Confidence Interval 
CL 
Clearance 
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 
Disease Control 
DCR 
Disease Control Rate 
DLT 
Dose-Limiting Toxicity 
dMMR 
Deficient DNA Mismatch Repair 
DNA 
Deoxyribonucleic Acid 
DoR 
Duration of Response 
EC30 
Effective Concentration for 30% of Maximum Effect 
EC50 
Effective Concentration for 50% of Maximum Effect 
ECG 
Electrocardiogram 
ECL 
Electrochemiluminescence 
ECOG 
Eastern Cooperative Oncology Group 


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Abbreviation or 
Specialized Term 
Definition 
eCRF 
Electronic Case Report Form 
ED30 
Effective Dose for 30% of Maximum Effect 
EGFR 
Epidermal growth factor receptor 
EOT 
End-of-Treatment 
FAAN 
Food and Allergy Anaphylaxis Network 
FAS 
Full Analysis Set 
FIH 
First-in-Human 
FFPE 
Formalin-Fixed Paraffin-Embedded 
FoxP3 
Forkhead Box P3 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
HBV 
Hepatitis B Virus 
HCC 
Hepatocellular Carcinoma 
HCV 
Hepatitis C Virus 
HED 
Human-Equivalent Dose 
HIV 
Human Immunodeficiency Virus 
HNSCC 
Head and Neck Squamous Cell Carcinoma 
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 
IP 
Intraperitoneal 
irAE 
Immune-Related Adverse Event 
IRB 
Institutional Review Board 
IV 
Intravenous 
KO 
Knock Out 
LKA 
Last Known Alive 
LPS 
Lipopolysaccharide 


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Abbreviation or 
Specialized Term 
Definition 
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 
MSI-H 
Microsatellite Instability-High 
MTD 
Maximum Tolerated Dose 
NAb 
Neutralizing Antibody 
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 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
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 


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Abbreviation or 
Specialized Term 
Definition 
S15 
Siglec-15 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SC 
Subcutaneous 
SD 
Study Day 
Siglec 
Sialic acid-binding Immunoglobulin Lectins 
SSD 
Safe Starting Dose 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t½ 
Half-Life 
TEAE 
Treatment-Emergent Adverse Event 
TIL 
Tumor Infiltrating Lymphocyte 
TK 
Toxicokinetic 
TMB 
Tumor mutational burden 
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 
Vd 
Volume of Distribution 
WBDC 
Web Based Data Capture 


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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 NC318 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) 
of NC318. The study is currently enrolling Phase 2. 
1.1. 
Background 
1.1.1. 
The Role of the Immune System in Cancer 
The immune system is comprised of diverse sets of cells designed to protect a host from pathogens 
while distinguishing from host and foreign antigens. This immune response is controlled by a 
series of checks and balances to allow for robust immune responses to pathogens while preventing 
either an excessive inflammatory event or an autoimmune response. Through immune 
surveillance, the immune system has been shown to recognize, attack, and destroy tumor cells 
(Wolchok 2008). The presence of tumor infiltrating lymphocytes (TIL) in cancer tissue among 
various malignancies has been shown to confer a more favorable prognosis (Uppaluri 2008; Bellati 
2009; Oble 2009; Nosho 2010; Shirabe 2010; Bremnes 2011; Gooden 2011; Schreiber 2011; 
Talmadge 2011; Mei 2014; Salgado 2015). Detailed analysis of CD8+ T cells and the ratio of CD8+ 
effector T cells/forkhead box P3 (FoxP3)+ regulatory T cells (Tregs) seem to correlate with 
improved prognosis and long-term survival in many solid tumors (Salgado 2015). Although the 
immune system has been shown to recognize and reject a tumor, many tumors evade immune 
surveillance or develop mechanisms of resistance. 
Histologic evaluation of multiple human cancers shows extensive infiltration by pro-inflammatory 
immune cells (Galon 2006), that are immune-suppressive leading to tumor progression. In some 
cases, as tumors grow, an "equilibrium" may be reached where tumor growth is matched by 
immune-mediated tumor destruction. However, malignant cells may accumulate certain mutations, 
making them nonimmunogenic, and/or immunosuppressive pathways become activated, allowing 
the tumor to escape immune recognition (Dunn 2002; Schreiber 2011; DuPage 2012; Matsushita 
2012). The accumulation of suppressive cells and an inhibitory cytokine milieu in and around a 
tumor can form an immunosuppressive environment that prevents successful T cell–mediated 
destruction of malignant cells (Schaer 2011). This balance of immune control is not limited to 
lymphocytes. For example, although M1 macrophages secrete pro-inflammatory cytokines that 
stimulate immunity (including anti-tumor immune responses), the M2 macrophages have been 
described as promotors of immunosuppression and tumor progression (Sica 2006). Overcoming 
tumor resistance to immune surveillance either through stimulating the immune response or 
preventing inhibition is the basic rationale for the development of immunotherapies. 
Targeting the immune system is a proven and effective approach for cancer therapies. United 
States Food and Drug Administration (US FDA)–approved checkpoint inhibitors, such as 
ipilimumab, nivolumab, and pembrolizumab, allow for the immune response to continue to 
proliferate by preventing inhibitory signals. Preventing Siglec-15 (S15) mediated immune 


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suppression through M2 Macrophages and S15+ tumors is another promising treatment approach 
and is the focus of this clinical trial. 
 
1.1.2. 
Immune Modulators 
Immune cell receptors known as checkpoint modulators (collectively known as immune 
modulators) provide a critical mechanism for the regulation of an immune response. Checkpoint 
modulation can either diminish an immunosuppressive process or stimulate T cell responses to 
enhance the overall immune response and prevent or reverse tumor progression. Modulation of 
coinhibitory and costimulatory receptors of the immune system has become a proven approach for 
the immunotherapy of cancer (Chen 2013). 
The development of fully human antibodies that target and modulate immunomodulatory proteins 
in humans have led to the discovery of multiple validated targets for the immunotherapy of cancer 
(Leach 1996; Chen 2013). Antibodies that engage the various checkpoint modulators can broadly 
be classified into two categories based on mechanism of action: antagonists (blocking the 
interaction between receptor and cognate ligand[s]), and agonists (inducing or facilitating receptor- 
mediated signaling pathways). Clinical testing of therapeutic antibodies has demonstrated their 
ability to influence the direction and magnitude of the immune responses, leading to tumor 
eradication (Yao 2013). The blocking of coinhibitory receptors such as cytotoxic T-lymphocyte– 
associated protein 4 (CTLA-4) or programmed cell death protein 1 (PD-1) blockade are the basis 
of US FDA approved therapies to augment an antitumor immune response. Preclinical research 
has demonstrated a rationale for targeting the inhibitory receptor S15 found on tumor cells and 
myeloid cells (Wang 2019). 
1.1.3. 
Siglec-15 and Immunity 
S15 is a member of the Siglec family (Sialic acid-binding Immunoglobulin Lectins), a distinct 
subgroup of immunoglobulin (Ig) superfamily proteins involved in the discrimination between self 
and non-self-immune regulation (Macauley 2014). It is a type-I transmembrane protein consisting 
of two Ig-like domains (IgV and IgC) and a short cytoplasmic tail. It has been implicated in playing 
a role in immune suppression. 
Studies of S15 knock out (KO) mice led to mice developing without physical abnormalities other 
than slightly increased trabecular bone mass and mild osteopetrosis (Hiruma 2013). Like the 
findings by Hiruma et al., KO mice generated in the Chen lab did not exhibit any noticeable 
phenotype (Wang 2019). However, follow-on functional studies demonstrated that mice with S15 
deficiency have enhanced pro-inflammatory cytokine production upon lipopolysaccharide (LPS) 
stimulation and enhanced antigen-specific T cell responses in vivo, suggesting a role for S15 in 
mediating immunosuppression. Subsequent studies demonstrated a key role for S15-positive 
(S15+) myeloid cells in mediating immunosuppression. The S15 KO mice demonstrate that 
absence of S15+ expression results in a decrease in tumor progression and an increase in survival 
for the glioma GL261 and B16.GMCSF melanoma murine tumor models. Taken together these 
findings suggest a tumor immune-escape mechanism and opportunity to target S15 as a means of 
enhancing immune function and antitumor responses in the tumor microenvironment (TME). 
The interaction of S15 with its receptor mediates immunosuppression. NC318 blocks the 
interactions between S15 and its receptor which is expressed on myeloid cells and the T cells of 
the TME thereby relieving inhibitory signaling and blocking immunosuppression. The rationale 


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for developing NC318 for cancer is based on nonclinical models that demonstrate that the targeting 
of S15 can improve the immune response and provide benefit in multiple oncology indications. 
 
1.2. 
Overview of NC318 
NC318 is a humanized modified IgG1κ monoclonal antibody (mAb) that binds to the extracellular 
domain of the human S15 receptor. Blocking S15 with NC318 may prevent immune suppression 
and result in augmented immune responses including some anti-tumor immune responses. NC318 
is being developed for the treatment of advanced malignancies. 
 
1.2.1. 
Pharmacokinetics of NC318: Pre-clinical Data 
Single-dose and repeat-dose PK of NC318 were characterized in both Sprague Dawley rats and 
cynomolgus monkeys. Concentrations of NC318 in serum were analyzed using a quantitative 
electrochemiluminescence (ECL) method developed by Meso Scale Discovery (MSD, Rockville, 
MD). Immunogenicity testing was also conducted in conjunction with these studies. Serum 
samples were screened for the presence of anti-drug antibodies (ADA) and confirmed by immune- 
competition with free NC318. 
Repeat-dose PK of NC318 was first investigated in a Good Laboratory Practices (GLP)-compliant 
repeat-dose study in Sprague Dawley rats. Animals received 3, 30, or 100 mg/kg NC318 
(N=9/sex/group; 3/sex/timepoint) by IV tail vein injection on SD 1, 8, 15, 22 and 29. PK analysis 
(excluding ADA-positive animals) showed that exposure (Cmax, and AUC) of NC318 was linearly 
proportional to dose level, across the range of doses that were tested. Accumulation of NC318 was 
observed with every week dosing. Mean volume of distribution ranged from 51.0 to 80.2 ml/kg on 
SD 1 and from 24.8 to 54 ml/kg on SD 29, indicating limited distribution outside of the vasculature. 
Mean CL on SD 29 ranged from 0.08 to 0.19 ml/h/kg. PK parameters were generally equivalent 
in both genders. The overall mean terminal t½ was 6 to 10 days following the fifth dose. 
Repeat-dose PK of NC318 was next examined in a GLP-compliant repeat-dose study in 
cynomolgus monkeys. Animals were administered with 0, 3, or 30 mg/kg NC318 (N=5/ sex/group; 
3/sex Main Group and 2/sex Recovery Group) on SD 1, 8, 15, 22, and 29 by 30-minute IV infusion. 
Animals at the highest dose level received 100 mg/kg NC318 (N=5/sex) on SD 1 and 60 
mg/kg/dose on SD 8, 15, 22, and 29. The dose level for the highest dose was lowered beginning 
with the second dose due to periorbital swelling observation in male animals and severe toxicity 
in 2 female monkeys that required early sacrifice following the 100 mg/kg dose on SD 1. ADA 
were observed in 6 of the NC318-treated animals, which was associated with accelerated CL after 
the fifth dose. PK analysis showed that exposure (Cmax and AUC) of NC318 was linearly 
proportional to dose level, across the range of doses that were tested. Slight accumulations were 
observed with every week dosing. The mean volume of distribution (Vd) and mean CL) were 
generally comparable for males and females at all dose levels on SD 1 and SD 29. Mean Vd ranged 
from 60 to 80 ml/kg on SD 1 and from 38.8 to 117 ml/kg on SD 29. Mean CL on SD 29 ranged 
from 0.12 to 0.71 ml/h/kg. PK parameters were generally equivalent in both genders. The overall 
mean terminal t½ was 5 - 9 days following the fifth dose. 
The presence of ADA in dosed rats and cynomolgus monkeys correlated with more rapid CL. 
Immunogenicity of human protein therapeutics in non-human species is a common 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 






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NC318 has been tested in cell-based assays using human peripheral blood mononuclear cells 
(PBMC). Expression of S15 in healthy human PBMC is limited. Assays using exogenous S15 
fusion protein have been established to assess the activity of NC318. NC318 blocks S15 fusion 
protein mediated effects on primary human myeloid cells and T cells. THP-1, a human myeloid 
cell line, was stably transduced with S15 to further test NC318. The THP-1.hS15 cells highly 
express S15. NC318 demonstrated blocking of the immunosuppressive effect mediated by S15 
expressed in these myeloid cells. NC318 was tested in a co-stimulation assay with healthy human 
PBMC. NC318 dose dependently increased IL-2 secretion in the presence of anti-CD3/SEB co- 
stimulation of PBMC from approximately 50% of the tested donors screened. 
In vivo, mouse NC318 was effective as a monotherapy in three subcutaneous (SC) tumor models 
and one lung metastasis model. These models may be relevant to the subset of human cancers with 
S15+ tumor cells or S15+ M2 macrophages. Mouse NC318 treatment increased CD8 T cell and 
tumor specific CD8 T cell infiltration into the tumors and reduced the number of macrophages in 
the TME. Mouse NC318 combined with PD-1 blockade showed enhanced anti-tumor activity in a 
SC tumor model. Mouse NC318 can enhance an LPS-mediated immune response in wild type 
mice that is line with the outcome from LPS challenged S15 KO mice. 
 
1.2.4. 
Non-Clinical Safety and Potential Risks of NC318 
The toxicology of NC318 has been studied in a variety of in vitro and in vivo systems to support 
its use as an investigational drug in oncology. 
In a GLP-compliant repeat-dose toxicology study of NC318 in Sprague Dawley rats, 178 animals 
(87/sex) were randomly assigned to four groups. Each main study group that received 0, 3, 30 and 
100 mg/kg of NC318 included 15/sex/group; 10/sex/group were sacrificed 4 days (SD 33) after 
the last dose and 5/sex/group were sacrificed following a 6-week recovery period (SD 75). Animals 
were subjected to a full gross necropsy on SD 33 (terminal) or SD 75 (recovery). The toxicokinetic 
(TK) satellite group included 9/sex/group with 3, 30 or 100 mg/kg of NC318 treatment; 
3/sex/group were evaluated at each timepoint. Eight animals developed ADA against NC318 in 
the main & recovery animals that received NC318. Treatment with NC318 at doses up to 100 
mg/kg had no effect on mortality, physical examinations, cage-side and post dose observations, 
body weights, body weight changes, food consumption, clinical pathology (clinical chemistry, 
hematology, coagulation, and urinalysis), gross pathology, absolute and relative organ weights, or 
histopathology. The NOAEL for NC318 following 5 weekly IV doses was 100 mg/kg in Sprague 
Dawley rats. 
In a GLP-compliant repeat-dose toxicology study in cynomolgus monkeys, animals were 
administered with 0, 3, or 30 mg/kg NC318 (N=5/sex/group; 3/sex Main Group and 2/sex 
Recovery Group) on SD 1, 8, 15, 22, and 29 by 30-min IV infusion. Animals at the highest dose 
level received 100 mg/kg NC318 (N=5/sex) on SD 1 and 60 mg/kg/dose on SD 8, 15, 22, and 29. 
The dose level for the highest dose was lowered beginning with the second dose due to periorbital 
swelling observation in male animals and 2 female monkeys with severe toxicity following the 
first dose on SD 1. Animals were subjected to a full gross necropsy and histopathology analysis 
on SD 31 (terminal) or 71 (recovery). Three NC318 treated recovery monkeys developed 
neutralized antibody (nAb), which was associated with accelerated CL, and they were removed 
from the mean TK profiling. No adverse findings were associated with ADA positivity. At terminal 
necropsy, 1 out of 6 animals at 30 mg/kg dose and 2 out of 5 animals at 100/60 mg/kg/dose showed 


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microscopic changes in the kidneys that consisted of minimal degeneration/necrosis of renal 
tubular cells with intratubular neutrophilic inflammation and intratubular and/or tubular 
hemorrhage. Evidence of kidney injury was present at the end of the recovery period (6 weeks 
after the fifth dose) in 1 out of 3 animals at 100/60 mg/kg/dose; no animals (0 out of 4) at 
30 mg/kg/dose displayed renal injury suggesting that glomerular findings at 30 mg/kg/dose was 
reversible. The cause of severe adverse effects of the 2 female animals on SD 1 after 100 mg/kg 
dose was undetermined but the same microscopic changes in the kidneys were observed. There 
was no evidence of any microscopic changes at the lowest dose (3 mg/kg). The microscopic 
changes in the kidney were in a dose dependent manner; however, they were not accompanied by 
any evident clinical findings. The NOAEL of NC318 was 3 mg/kg when administered five times 
over a four-week interval to male and female cynomolgus monkeys by 30-minute IV infusion. The 
MTD was 30 mg/kg. 
 
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 a novel 
target, S15, which has been shown to mitigate immunosuppressive macrophages in the TME. 
Immunotherapies for cancer have shown great promise, however, there is still an unmet medical 
need for additional therapies. NC318 may be an effective immunotherapy for some cancer patients. 
1.3.1. 
Rationale for the Safe Starting Dose 
The safe starting dose (SSD) for NC318 is 8 mg (correlates to 0.1 mg/kg), and this was determined 
based on all relevant preclinical pharmacology and toxicology data, including dose-response in 
human cell-based assays, and anti-tumor effects in mouse tumor models. 
NC318 has been well-tolerated and repeated administration of dosages 100-fold higher (on a 
mg/kg basis) than the planned clinical starting dose were not associated with any adverse toxicities. 
A risk assessment for NC318 was performed to support dose selection. Relevant factors for NC318 
are discussed below: 
• Mechanism of action: NC318 does not directly activate T cells. NC318 did not promote 
cytokine release from PBMC, using assays that would have predicted the TGN1412 
cytokine storms. NC318 may help to promote an effective anti-tumor immune response by 
two mechanisms. NC318 blocks the interactions between S15 and its binding partner on 
T cells or myeloid cells and releases S15-mediated suppression. NC318 may also bind to 
cells expressing high levels of S15 and mediate direct tumor killing. 
• Nature of the target: S15 is not a master regulator of the immune system such as CD28 or 
CTLA-4. While CTLA-4 KO mice die 3-4 weeks after birth from lymphoproliferative 
disease affecting multiple organs, S15 KO mice developed without physical abnormalities 
other than slightly increased trabecular bone mass and mild osteopetrosis (Hiruma 2013). 
• Relevance of animal models: S15 is conserved across mammals and NC318’s parent, 5G12, 
is active in multiple species including rodents. 
The rationale for the proposed Phase 1 SSD of 8 mg (0.1 mg/kg) is based on the collection of 
preclinical pharmacology and toxicology data, including calculated and experimentally assessed 




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Abbreviations: EC30 = effective concentration for 30% of maximum effect; IL = interleukin. 




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1.3.3. 
Rationale for Phase 2 Dose Selection and Administration Schedule 
During Phase 1 Dose Escalation, various dose levels were evaluated ranging from 8mg to 1600mg. 
During the initial Phase 2 design, a RP2D of 400mg Q2W was tested. As stated in Section 1.2.2, 
PK/PD modeling shows initial weekly dosing of 800 mg will achieve adequate exposure of NC318. 
Upon further review of ongoing Phase 1/2 study, soluble S15 levels that increased within 24 hours 
of NC318 infusion during Cycle 1 seemed to normalize after cycle 4 (~8 weeks). Furthermore, T 
cell activation appears critical only for the first 8 weeks of immune checkpoint therapies. Rizvi 
has shown that a patient responded for months after tumor-specific T cells decreased after 9 weeks 
(Rizvi 2015). Taken together, a new RP2D and administration schedule have been chosen for 
NC318. The new RP2D and administration schedule will be as follows: 
• Initial Dosing: 800 mg weekly for 8 Cycles 
• Subsequent Dosing (Cycle 9 onwards): 800 mg every 2 weeks 
Subjects will remain on the Subsequent Dosing Schedule of 800 mg every two weeks until disease 
progression, withdraw of consent, or intolerable toxicity (whichever comes first). 
 
1.3.3.1.     Phase 2 Safety Run-In Rationale 
Based on PK/PD modeling and normalization of soluble S15, NC318 will be given at 800 mg Q1W 
for 8 cycles and subsequent cycles will be given at 800mg Q2W. During Phase 1 Dose Escalation 
(n=49), various dose levels were evaluated ranging from 8 mg to 1600 mg. There were no DLTs at 
800 mg Q2W. However, there was one DLT at 1600 mg Q2W as previously reported during annual 
reporting amongst the 4 patients treated in that dose escalation cohort. At 800 mg Q2W (n=4), only 
non-serious adverse events ≤ Grade 2 were reported. 
In accordance with the PK/PD data from the ongoing Phase 1/2, the RP2D has been adjusted to 
800 mg with an alternative administration schedule. To evaluate the new RP2D and administration 
schedule, a Phase 2 Safety Run-In will be conducted utilizing a 3+3 design. 
 
1.3.4. 
Rationale for Subject Population for Phase 2 
To further elucidate the effects of NC318, 6 different tumor types were initially selected for 
investigation in Phase 2. HNSCC and NSCLC will be evaluated, because they are both 
immunogenic histologies that have been proven to respond to checkpoint inhibitors (CTLA-4 and 
PD-1). Included in the Investigational New Drug (IND) enabling studies, experiments looked at 
the expression of S15 on tumor samples from patients with a variety of tumor histologies including, 
but not limited to, NSCLC, TNBC, and ovarian cancer. 
Previously the study was designed to enroll patients with low PD-L1 (<50% TPS) based on the 
notion of mutually exclusive expression of PD-L1 and siglec-15 as stated above due to the lack of 
standardized siglec-15 staining. However, the most recent CLIA validation study has validated 
adenocarcinoma of the lung, squamous cell carcinoma of head and neck, and breast cancers for 
siglec-15 staining in tumors and immune cell infiltrates in the stroma (Figure 4). Therefore, to 
elucidate the effects of NC318, 3 tumor types with CLIA validated siglec-15 positive staining, 
namely adenocarcinoma of the lung, squamous carcinoma of head and neck, and breast cancer, 
were selected. 


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Figure 4:       S15 Expression in Breast, Lung, and Head and Neck Tumors 
 
In addition, the following observations have been made based on the data obtained from the 
ongoing Phase 1/2 trial thus far: 
1. Of the 4 responders (1 CR and 1 PR in NSCLC, 1 PR in HNSCC, and 1 PR in TNBC) of 
96 evaluable subjects enrolled in Phase 1/2, 2 had TMB-H, and 1 had MSI/dMMR. 
Therefore, it is likely that either TMB-H and/or MSI/dMMR status is driving the T cell 
infiltration in the TME of those subjects to respond to NC318. Since all of those subjects 
were refractory to ICI therapies, we hypothesize that NC318 might have alleviated the 
immunosuppressive environment of the TME in those patients for the reactivation of T 
cells. Therefore, in cohort 1, we will include TMB-H and/or MSI/dMMR positive NSCLC, 
HNSCC, or Breast cancer, followed by selection of S15 expression in the TME. 
a. The basis for evaluating subjects based on S15 expression came from the data 
obtained in the ongoing Phase 1/2 study (Shum 2021). S15 expression confirmed 
by CLIA validated IHC staining was associated with 40% disease control (stable 
disease) compared to only 12% disease control in the S15- group. 
2. Since TMB-H and MSI-H have been widely accepted predictors for immunotherapies, a 
separate cohort of TMB-H and/or MSI-H/dMMR tumors that do not fall under the criteria 
to be included in Cohort 1 has been added to the study. Upon enrollment, subjects will be 
stratified into two subgroups based on S15 expression (S15+ Cohort 2a and S15- Cohort 
2b) to explore how vital S15 expression is in the TME. 
 
1.3.5. 
Rationale for Efficacy Endpoints 
Efficacy endpoints of this study are secondary and include objective response rate (ORR), duration 
of response (DoR), duration of disease control (DC), 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 2015). 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 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: 


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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 (Oken 
1982) 
• 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) 
• 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. 


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1.4. 
Summary of Clinical Experience 
The Phase 1 component demonstrated that NC318 is safe and tolerable when administered as a 
monotherapy at doses ranging from 8 mg to 800 mg. In order to seek optimal benefit for potential 
patients, a revised dosage and administration schedule will be explored using an updated Phase 2 
design. Based on the results of the amended design, the optimal dosing strategy will be used for 
subsequent clinical trials. During the ongoing Phase 2 component of the study, analysis of PK and 
PD has revealed that doses ranging from 240 mg to 1600 mg every 2 weeks are pharmacologically 
active. 
 
1.4.1. 
Ongoing Clinical Study NC318-01 
The FIH clinical trial, Study NC318-01 completed Phase 1 enrollment with 49 subjects dosed in 
15 tumor types. Subjects received NC318 every two weeks at doses of 8, 24, 80, 240, 400, 800, 
and 1600 mg. NC318 was well tolerated at doses up to 800 mg every two weeks and expanded 
cohorts of subjects were further evaluated at the 80, 240, and 400 mg dose levels. One Phase 1a 
subject enrolled in Cohort 6 (1600 mg) with Grade 3 pneumonitis died of respiratory failure due 
to healthcare acquired pneumonia on 28-SEP-2019 and no further subjects were enrolled in the 
1600mg cohort (n=4). As such, 400 mg every 2 weeks was determined as the original 
recommended Phase 2 dose. 
As of the data cutoff date of 29-SEP-2021, the treatment-related adverse events (TRAEs) of any 
grades experienced by more than 5% of patients in Phase 1 (n=49) were pruritis (16.3%), diarrhea 
(16.3%), were infusion related reactions (10.2%), fatigue (8.2%),  elevated  amylase (8.2%), 
elevated lipase (8.2%), muscular weakness (8.2%), and headaches (6.1%). In Phase 1, there was 1 
case of Grade 3 increased amylase, 3 cases of increased lipase {Grade 3 (n=2), Grade 4 (n=1)}, 
and 1 case of Grade 3 Muscle Weakness. TRAEs of any grade experienced by more than 5% of 
patients in Phase 2 (n=47) were infusion reaction (19.1%), pruritis (8,5%), chills (8.5%), influenza- 
like illness (6.4%), and nausea (6.4%). In Phase 2, there was 1 Grade 3 Infusion reaction. 
From clinical benefit aspect from Phase 1 and 2 studies of NC318, there were 1 CR in NSCLC, 
3 PR (1 each in NSCLC, HNSCC and TNBC) and 28 SD (stable disease), with total disease control 
rate of 37% and median progression free survival of 5.0 months (Shum, 2021). One subject with 
NSCLC in CR remains on study more than 3 years. One other subject with NSCLC in PR elected 
to discontinue study treatment after nearly 3 years on study. Furthermore, of the 4 responders, 1 
had MSI, and 2 had TMB-H, but no tumor abnormality data is available from the CR subject. 
Additional details regarding clinical experience with NC318 are available in the Investigator’s 
Brochure. 
 
1.5. 
Research Hypotheses 
NC318 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. 


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2. 
OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objectives 
1) To evaluate the safety, tolerability, and dose-limiting toxicities (DLTs) of NC318 
2) Define an MTD or PAD of NC318 in subjects with advanced or metastatic solid tumors 
 
2.1.2. 
Secondary Objectives 
1) To evaluate the PK profile of NC318 
2) To assess preliminary efficacy of NC318 by assessing ORR, DoR, and disease control 
rate (DCR) per RECIST v1.1 
3) To evaluate expression of Siglec-15 in tumor tissue and immune cell infiltrates at 
baseline and following NC318 treatment, and correlate expression level with efficacy and 
changes in tumor infiltrating lymphocytes 
 
2.1.3. 
Exploratory Objectives 
1) To assess the immunogenicity of NC318 
2) To explore biomarkers that may predict the pharmacologic activity of NC318 
3) To characterize the effect of NC318 on immune markers such as cytokine and immune 
cell phenotypes 
4) Soluble S15 level at baseline and changes after NC318 treatment, and correlation with 
efficacy. 
 
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) Define an MTD or PAD of NC318 in subjects with advanced or metastatic solid tumors 
 
2.2.2. 
Secondary Endpoints 
1) The endpoints for assessment of PK of NC318 include individual NC318 concentrations 
in serum and PK parameters. 
2) The endpoints for assessment of antitumor activity/efficacy include objective response 
(OR) and DC based on RECIST v1.1, DoR, PFS, and overall survival (OS) as per 
RECIST v1.1 
3) To evaluate expression of Siglec-15 in tumor tissue and immune cell infiltrates at base 
line and following NC318 treatment, and correlate expression level with efficacy and 
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2.2.3. 
Exploratory Endpoints 
1) Immunogenicity, defined as the occurrence of ADA to NC318 will be determined. 
2) Biomarker effects of NC318 in peripheral blood and tumor tissue will be assessed, 
including but not limited to the following: 
• Whole blood immune cell population profiling/immune-phenotyping. 
• Plasma markers of inflammation or immune modulation (cytokine levels). 
• Soluble S15 level at baseline and changes after NC318 treatment, and correlation 
with efficacy. 
• The expression of additional biomarkers may 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 NC318 in subjects with 
advanced or metastatic solid tumors. Subjects will receive NC318 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 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 
NC318, including defining the optimal dose administration schedule and the maximum 
number of tolerated doses (MNTD). Phase 1 enrollment of the study is complete. 
• Phase 2 – Safety Run-In and Dose Expansion will further evaluate the safety, tolerability, 
preliminary efficacy, and PK/PD activity of NC318. The study is currently enrolling 
Phase 2. 
 
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 were enrolled. A 3 + 3 design with escalating dose levels were explored 
to determine the MTD and PAD of NC318. The cohorts and dose levels evaluated during Phase 1 
are shown in Table 2. 




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3.1.1.2. 
Phase 1b – Safety Expansion 
The purpose of Phase 1b was to evaluate additional PD activity of NC318 and confirm the 
preliminary safety of the dose escalation cohorts from Phase 1a. Several cohorts from Phase 1a 
were expanded at 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. 
The following cohorts were expanded during Phase 1b: Cohort 2 (80 mg), Cohort 3 (240 mg), and 
Cohort 4 (400 mg). Phase 1 enrollment of the study is complete. A total of 49 subjects were 
enrolled across Phase 1a and Phase 1b. 
 
The Phase 1a design is summarized below: 
Approximately 36 evaluable subjects will be enrolled in the Phase 1b safety expansion, with each 
cohort enrolling approximately 9 evaluable subjects. 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 
The trial is currently enrolling Phase 2. Phase 2 will evaluate subjects with advanced or 
metastatic solid tumors characterized as Tumor Mutational Burden High (TMB-H) and/or 
MicroSatellite Instability High (MSI-H)/ deficient MisMatch Repair (dMMR). The following 
tumor types will be enrolled: Lung, HNSCC, Breast, Endometrial, Melanoma, CRC, Urothelial, 
Cholangiocarcinoma, and other tumors known to be TMB-H and/or MSI-H/dMMR. 
Previously as part of the initial Phase 2 design, a RP2D of 400 mg Q2W was tested. 47 subjects 
were treated at the initial RP2D. Based on further evaluation of the PK/PD studies from the original 
Phase 1/2, the RP2D was adjusted to 800 mg with an alternative administration schedule. To 
further evaluate the new RP2D, a Phase 2 Safety Run-In will be conducted utilizing a 3+3 design 
(Figure 5). 
 
3.1.2.1. 
Phase 2 Safety Run-In to Evaluate New RP2D 
The first 3 evaluable subjects will be observed for a DLT observation period of 28 days. Only one 
subject will be dosed on the first day of dosing (additional subjects can begin in ≥ 48 hours). If 
there are no DLTs observed in the first 3 subjects, then Phase 2 Dose Expansion may begin at the 
new RP2D. If 1 of the first 3 evaluable subjects enrolled has a DLT, then the cohort will be 
expanded to include 3 additional evaluable subjects. If there are no DLTs in the additional 
3 subjects, then Phase 2 Dose Expansion can begin at the new RP2D. If a DLT occurs in one-third 
or more of the expanded cohort, then enrollment will be paused and intermediate dose levels or 
alternative dose schedules may be considered. 


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Figure 5:       Phase 2 Safety Run-In Design (3+3) 
 
Abbreviation: DLT = dose-limiting toxicity 
 
3.1.2.2. 
Phase 2 Dose Expansion at New RP2D 
Phase 2 Dose Expansion will further evaluate the safety, tolerability, preliminary efficacy, and 
PK/PD activity of NC318 at the RP2D utilizing a Simon 2-stage design (Figure 6: Phase 2 Dose 
Expansion Design (Simon 2-Stage) 
). Subjects will be stratified after enrollment into two main cohorts based on S15 expression and 
tumor type: 
• Cohort 1: Select S15+ Tumors (Lung (adenocarcinoma), HNSCC, Breast) 
• Cohort 2: Alternate Tumors (including Other S15+ Tumors and S15- Tumors) 


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Figure 6: 
Phase 2 Dose Expansion Design (Simon 2-Stage) 
 
Abbreviations: CRC = colorectal cancer; dMMR = deficient DNA mismatch repair; MSI = microsatellite instability 
high; NGS = next generation sequencing; NSCLC = non-small cell lung cancer; ORR = objective response rate; TMB-
H = Tumor mutational burden high; WES = whole exome sequencing. 
 
 
Cohort 1: Select S15+ Tumors 
This cohort will include subjects who are 1) confirmed as TMB-H and/or MSI-H/dMMR, 2) 
express S15, and 3) have one of the following tumor types, separated into tumor-specific subgroup: 
• Cohort 1a: NSCLC (adenocarcinoma) 
• Cohort 1b: HNSCC 
• Cohort 1c: Breast cancer 
Each subgroup will be independently assessed, guided by the Simon 2-stage design, and will enroll 
9 evaluable subjects in Stage 1. If no responses are observed within a subgroup, then the sub-group 
will be discontinued. If 1 or more response are observed, Stage 2 will begin and enroll 8 additional 
evaluable subjects, for a total of 17 evaluable subjects within each subgroup (1a, 1b, and 1c). 
Cohort 2: Alternate Tumors (including Other S15+ Tumors and S15- Tumors) 
This basket cohort will include all other enrolled subjects who are confirmed as TMB-H and/or 
MSI-H/dMMR but do not fall under the criteria to be included in Cohort 1. Based on results of 
S15 expression, subjects will be further stratified into two subgroups: 
• Cohort 2a: Other S15+ Tumors 
• Cohort 2b: S15- Tumors 


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Each subgroup will be independently assessed, guided by the Simon 2-stage design, and will enroll 
9 evaluable subjects in Stage 1. If no responses are observed within a subgroup, then the sub-group 
will be discontinued. If 1 or more response are observed, Stage 2 will begin and enroll 8 additional 
evaluable subjects, for a total of 17 evaluable subjects within each subgroup (2a and 2b). 
 
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 187 evaluable subjects may be enrolled in this study. 
• Phase 1a Dose Escalation and Phase 1b Safety Expansion – 49 subjects enrolled 
• Previous Phase 2 Design – 47 subjects enrolled 
• New RP2D Phase 2 Safety Run-in – Up to 6 evaluable subjects 
• New RP2D Phase 2 Dose Expansion – Up to 85 evaluable subjects 
Note: Number of planned subjects includes actual enrollment to date under previous 
protocol versions/amendments (during Phase 1 and previous Phase 2) and expected 
enrollment under revised Phase 2 design. 
 
3.3.2. 
Replacement of Subjects 
Subjects may be replaced for any of the following reasons: 
• In Phase 1 and Phase 2, any subject who withdraws from treatment before the completion 
of the DLT period for any reason other than a DLT (is not evaluable for DLTs) 
• A subject who is scheduled to have a biopsy for the purpose of this study and it is 
subsequently determined that tumor tissue cannot safely be obtained 
• Subject does not meet the eligibility requirements of the study (accidental enrollment) 
3.4. 
Duration of Treatment and Subject Participation 
After signing the main informed consent form (ICF), screening assessments may be completed 
over a period of approximately 30 days. 
Subjects will continue to receive NC318 until disease progression, withdrawal of consent, or 
intolerable toxicity (whichever comes first). After completing 12 months of treatment, if the 
subject is deriving benefit from NC318 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 dose level assigned at the time of enrollment (unless 
otherwise approved for dose modification by the Sponsor). Safety reporting, documentation of 
disease assessments, and collection of survival status will continue per protocol. 


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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 1 copy 
for the site study regulatory file. 
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) Willing and able to provide written informed consent for the study. 
3) ECOG performance status 0 to 1. 
4) Subjects with advanced unresectable and/or metastatic solid tumors confirmed to be TMB- 
H and/or MSI-H/dMMR including: Lung, Breast, HNSCC, Endometrial, Melanoma, CRC, 
Urothelial, Cholangiocarcinoma, and other tumors known to be TMB-H or MSI-H/dMMR. 
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. 


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6) Presence of measurable disease based on RECIST v1.1. 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) Able to provide pretreatment tumor tissue sample (archival ≤ 5 years old) or undergo tumor 
biopsy at Screening (must allow for adequate sample of tissue from appropriate site). 
Note: Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. 
Newly obtained biopsies are preferred to archived tissue. 
8) Female subjects of childbearing potential (defined as female subjects who have not 
undergone surgical sterilization with a hysterectomy and/or bilateral oophorectomy and are 
not postmenopausal, defined as ≥ 12 months of amenorrhea not caused by reversible 
conditions, diseases, or medications) 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 subjects of childbearing potential must have 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 provide informed consent. 
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 measured 
or calculated creatinine clearance < 30 ml/min for subjects with creatinine levels 
<1.5 x institutional ULN. 
e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
> 2.5 × ULN with the following exceptions: Subjects with documented liver 
metastases: ALT, AST, and alkaline phosphatase ≤ 5 × ULN. Subjects with 
documented bone metastases: 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 or 
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. 


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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 prior 
to first administration of study drug. 
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, 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. 
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 (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/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. 


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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 any 
systemic treatment for an autoimmune disease for at least 2 years and have normal thyroid 
function or are stable on thyroid hormone replacement are allowed to participate in the 
study. 
Note: Replacement and symptomatic therapies (e.g., levothyroxine, 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 additional 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) Has a history of (non-infectious) pneumonitis / interstitial lung disease that required 
steroids or has current pneumonitis / interstitial lung disease. 
11) Documented known activating or driver mutations (i.e. EGFR mutations/amplification, 
BRAF mutations, ALK alterations, etc.) which have not been previously treated with a 
standard of care targeted therapy. 
12) Subjects with screening QTc interval > 470 milliseconds (corrected by Fridericia) are 
excluded. 
13) Uncontrolled systemic fungal, bacterial, viral, or other infection despite appropriate anti-
infection treatment. 
14) Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV), unless the hepatitis 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 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; 


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hepatitis C virus [HCV] infection must have, before study enrollment, no detectable VL 
and must be treated according to local standards. 
15) Known history of HIV (HIV 1 or HIV 2 antibodies). 
16) Known allergy or reaction to any component of study drug or formulation components. 
17) 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. 
18) 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. 
 
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 4-digit subject number within the case report 
form (CRF). The subject numbering process is defined in the CRF completion guidelines. 
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. Dose level and cohort assignment will be maintained within the CRF per the CRF 
completion guidelines. 
All subjects will be assigned to a cohort to receive NC318; there is no placebo. 
NC318 must be administered the same day the investigational product is assigned. If there is a 
delay in the administration of investigational product such that it will not be administered within 
the specified timeframe, the sponsor must be notified immediately. 
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 (NC318) is available in sterile frozen liquid or sterile lyophilized formulations 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 will be 
provided in 10 ml vials. Each vial will have 400 mg NC318. The concentration of the NC318 
frozen liquid formulation is 60mg/mL; total deliverable volume is 6.7 ml. When reconstituted with 
sterile water, the concentration of the NC318 lyophilized product is 100mg/mL; total deliverable 
volume is 4.0 mL. For preparation of the study drug for infusion, NC318-01 should be diluted with 


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normal saline to a concentration no less than 0.2 mg/ml. The infusion site should not be used for 
blood sampling. 
 
5.2.2. 
Supply Packaging and Labeling 
Study drug is supplied in a tamper evident patient kit box containing frozen liquid drug (400 mg, 
60 mg/mL) or refrigerated lyophilized NC318 vials (400 mg). For the frozen liquid formulation, 
the study drug name (NC318), lot number, concentration, amount of drug in vial, volume, and 
storage conditions appear on the vial. For the lyophilized formulation, the study drug name 
(NC318), lot number, amount of drug in vial, and storage conditions appear on the vial. 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) if liquid or a refrigerator (2°C to 8°C) if 
lyophilized, 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 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 with medical monitor 
approval. 


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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 and including 
Study Day (SD) 28. 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 3, except for events clearly associated with the underlying 
disease, disease progression, a concomitant medication, or comorbidity. 






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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). 
Instructions for dose modifications and interruptions are outlined in Table 4. Individual decisions 
regarding dose interruptions and reductions should be made using appropriate clinical judgment 
in consultation with the medical monitor, considering the 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 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 unless otherwise discussed 
with the medical monitor. The reason for interruption should be documented in the subject's study 
record. 


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Table 4:        Rules for Interruption and Restarting of Study Drug 
 
NCI CTCAE 
v5.0 
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. 
Abbreviation: N/A = not applicable. 
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 . 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 
NC318 is an immune modulator, and although no significant toxicities were identified in 
preclinical models, 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 eliminated. Immune-related AEs may be expected 
based on the nature of NC318, 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. If there 
is any suspicion of potential cytokine-release syndrome (CRS), subjects should be treated per 
institutional policy. 
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 5. Detailed supportive care guidelines for 
specific irAEs can be in found in Brahmer et al. (Brahmer 2018). For each AE, attempts should be 
made to rule out other causes, including but not limited to metastatic disease or bacterial or viral 
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Table 5: 
Supportive Care Guidelines for Subjects Exhibiting Immune-Related 
Adverse Events 
 
NCI CTCAE v5.0 
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. 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; irAE = immune-related adverse 
event; NCI = National Cancer Institute. 
 
5.4.8. 
Management of Infusion Reactions 
Table 6 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. As of 
29-SEP-2021 data cutoff, there were 4 with infusion reactions (two grade 1 [n=2] and two grade 2 
[n=2]) amongst subjects from Phase 1 study (n=49) and 7 had infusion reactions (Grade 1 [n= 1], 
Grade 2 [n=5], and Grade 3 [n=1]) amongst subjects from Phase 2 study (n=43). 


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Table 6: 
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 therapy or infusion interruption but 
responds promptly to symptomatic treatment (e.g., 
antihistamines, 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: 
Stop infusion. 
No subsequent dose. 
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). 
Additional appropriate medical therapy may include but 
is not limited to: 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDs 
OR 
Grade 4: 
Life-threatening; pressor or ventilatory support 
indicated. 
• 
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. 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute. 


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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: 
• 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 treatment related AE requiring a delay of study drug beyond 4 weeks (28 days) 
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 withdraw consent at any time for any reason or be removed from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the trial 
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 eCRF. 
Discontinuation of study treatment does not represent withdrawal from the study. A subject may 
discontinue from treatment but agree to remain on-study, as long as the subject does not withdraw 
consent. 
Subjects must be withdrawn from the trial for any of the following reasons: 
• The subject is lost to follow-up 
• Consent is withdrawn for study (does not agree to follow-up); no additional data collection 
should occur 


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Subjects must discontinue from the study treatment but can continue to be monitored for any of 
the following reasons: 
• The subject becomes pregnant 
• Consent is withdrawn for further treatment (agrees to follow-up) 
• Further participation would be injurious to the subject’s health or well being 
• Unacceptable 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 
• The study is terminated by the local IRB or regulatory authority 
• The study is terminated by the sponsor 
• Confirmed radiographic progression of disease per RECIST v1.1. (except if Sponsor 
approves treatment continuation) 
• Investigator decision to withdraw subject 
• If, during the course of the study, a subject is found not to have met eligibility criteria, then 
the medical monitor in collaboration with the investigator, will determine whether the 
subject should be withdrawn from the study 
• If the subject is noncompliant with study procedure or study drug administration in the 
investigators opinion then the Sponsor should be consulted for instruction on handling the 
subject. 
Subjects who discontinue study treatment but agree to remain on-study should continue to be 
followed according to the applicable Post-Treatment Follow-up schedule. 
 
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 participate in the follow-up period. The date on which the 
decision was made to discontinue study treatment and the reason for treatment discontinuation will 
be recorded in the eCRF. 
If a subject discontinues study treatment, the site monitor and Sponsor must be notified. 
 
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 will be recorded. Upon discontinuation 
of study treatment, only post-anticancer treatments and concomitant medications and procedures 
related to adverse events should be recorded. Any addition, deletion, or change in the dose of these 
medications will also be recorded. 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, 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. 
 
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, 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 nonsteroidal anti-inflammatory drugs (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 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 safety 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. 
Note: Immune suppressants are allowed for treatment of immune toxicities as described in 
Section 5.4.7 and Brahmer et al. (Brahmer 2018). 
Note: Allergy shots may be permitted after consultation with the medical monitor. 


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• 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. 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 the 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. 
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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a Subjects will begin with the Initial Dosing Schedule of 800mg weekly (Cycle Duration: 7 days (+3 day window after Cycle 1)) and continue with weekly dosing for 8 cycles. 
Beginning with Cycle 9, subjects will follow the Subsequent Dosing Schedule of 800mg every 2 weeks (Cycle Duration: 14 days (±3 day window). Note: Cycle 9 should occur 
two weeks following the last weekly dose of NC318. Subjects will remain on the Subsequent Dosing Schedule of 800 mg every two weeks until disease progression, withdraw of 
consent, or intolerable toxicity (whichever comes first). Alternate dosing schedules may also be explored based on emerging data. For Phase 2 Safety Run-In Only: The first 4 
cycles should be administered every 7 days during the DLT period. 
b Subjects who discontinue study therapy for reasons other than disease progression will move to Disease Status Follow-up and will continue to have radiologic imaging performed 
until 1) withdrawal of consent, 2) documented disease progression, 3) start of new anticancer treatment, 4) death, or 5) the end of the study, whichever occurs first. 
c. Subjects that experience site assessed PD or start a new anti-cancer therapy should be followed approximately every 3 months to assess for survival status until death, withdrawal 
of consent, or the end of the study, whichever occurs first. Updated survival status may be requested by the Sponsor at any time during the course of the study. Survival follow-up 
may be performed by phone. 
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 will be recorded. Upon discontinuation of study treatment, only post-anticancer treatments and 
concomitant medications and procedures related to adverse events should be recorded. 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. 
g 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). 
h During Cycle 1 subjects will be required to stay at the study site for safety observation for 4 hours post end of infusion. At Cycle 1, vital signs (blood pressure, pulse, respiratory 
rate, and body temperature) will be assessed pre-dose, at the end of infusion (+10 minutes), and every 60 minutes (± 10 minutes) for 4 hours post end of infusion. On Day 1 of all 
subsequent cycles subjects will be required to be observed for up 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. 
i A single 12-lead electrocardiogram (ECG) will be performed at screening, using local standard procedures. Clinically significant abnormal findings should be recorded as medical 
history. Additional ECGs should be performed per PI discretion if any clinically significant abnormal findings are noted or as indicated. All 12-lead ECGs will be performed with 
the subject in a recumbent or semi-recumbent position after 5 minutes of rest and should generally not be performed within 15 minutes after a blood collection.. 
j All AEs and SAEs that occur after the consent form is signed but before first study treatment must be reported by the investigator if they are the result of a protocol-specified 
intervention. From the time of first study treatment through 30 days following end of treatment, all adverse events must be reported by the investigator. SAEs will be collected for 
90 days after the end of treatment or 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier. 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. 
k If a central line is used for study drug infusion, collect blood samples via peripheral blood draw to prevent sample contamination. 
l On Day 1 of Cycles 1 and 5, subjects will be required to stay on-site for 4 hours post-dose for collection of PK samples. 
m At Screening, archival tumor tissue ≤ 5 years will be acceptable, however a fresh biopsy is preferred. Optional on-treatment tumor biopsy may be performed at Week 7, prior to 
the first on-study radiologic assessment for subjects who consent at time of informed consent. A second optional biopsy may be performed at EOT for subjects who consent at time 
of informed consent. 
n 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. 
o 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. After 
completing 12 months of treatment, subjects will have imaging performed per standard of care and 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. 
p For subjects who discontinue for reasons other than disease progression, radiologic evaluation should be repeated at the time of treatment discontinuation (i.e., date of 
discontinuation ± 4-week window). If scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation (EOT) is not mandatory. 


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Table 8: 
Schedule of Local Laboratory Assessments 
 
Visit Day (Range) 
Protocol Section 
Screeninga 
Treatment 
Post-Treatment 
Day 1 of All Cycles 
EOT 
D1b,c 
Evaluation/Window 
Day 
- 30 to - 1 
Predose 
Comprehensive Metabolic Panel (CMP)d – serum 
7.5.5 
X 
X 
X 
Complete Blood Count (CBC) with differentiale 
7.5.5 
X 
X 
X 
Coagulation panelf 
7.5.5 
X 
X 
Urinalysisg 
7.5.5 
X 
X 
Endocrine function testsh 
7.5.5 
X 
X 
X 
Hepatitis B and Ci 
7.5.5.2 
X 
Serum pregnancy testj 
(childbearing females only) 
7.5.5.1 
Xj 
X 
Urine pregnancy testk 
(childbearing females only) 
7.5.5.1 
Xl 
Abbreviations; CBC = complete blood count; CMP = comprehensive metabolic panel; D = day; EOT = end-of-treatment. 
a Lab tests must be performed during screening period (within 30 day window). 
b Cycle 1 Day 1 laboratory samples must be collected prior to study drug administration. Results should be reviewed by the investigator or qualified designee and found to be 
acceptable prior to the start of study drug treatment. Note: If screening labs were preformed within 7 days of Cycle 1 Day 1, results from screening can be used as indicator to 
begin study treatment. 
c For all subsequent cycles after Cycle 1, pre-dose laboratory procedures may be performed up to 72 hours prior to study drug administration. Results should be reviewed by the 
investigator or qualified designee and found to be acceptable before the subsequent 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. 
g Urinalysis required analytes in Table 8. Urine dipstick – if positive, perform microscopic urinalysis. 
h Endocrine function tests required analytes in Table 8. 
i Hepatitis testing required analytes in Table 8. 
j Pregnancy testing is required for females of child-bearing potential. A serum pregnancy test must be performed at screening. 
k If positive, confirm results with serum pregnancy test. 
l 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 11: 
Schedule of Pharmacodynamic (Biomarker) Sampling 
 
Biomarker Assessment 
Study Visit 
Timing of Sample 
Anytime 
Pre- 
Infusion 
Post-infusion 
(+ 10 minutes) 
PBMC’s 
Cycle 1 Day 1 
X 
Cycle 1 Day 2 
X 
Day 1 of Cycles 3, 5, 9, 13, 
17, 21 
X 
Serum correlative sample for 
cytokine levels 
Cycle 1 Day 1 
X 
X 
Cycle 1 Day 2 
X 
Cycle 1 Day 3 
X 
Cycle 5 Day 1 
X 
X 
Cycle 5 Day 2 
X 
Cycle 5 Day 3 
X 
Cycle 9 Day 1 
X 
X 
Plasma ctDNA 
Day 1 of Cycle 1 
X 
Biopsies 
Screening 
Week 7 (optional) 
EOT (optional) 
X 
Abbreviations: ctDNA = circulating tumor deoxyribonucleic acid; EOT = end-of-treatment; PBMC = peripheral 
blood mononuclear cells. 


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6.1. 
Screening Period 
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 assessments may be completed over a period of 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 1 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 Period 
The treatment period begins on the day the subject receives the first dose of study drug (Cycle 1 
Day 1). Cycle 1 Day 1 should 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. The duration of each 
cycle is dependent on the dosing schedule: 
• Initial Dosing: 800 mg weekly for 8 Cycles 
o Cycle Duration: 7 days (+3 days after Cycle 1) 
• Subsequent Dosing (Cycle 9 onwards): 800 mg every 2 weeks 
o Cycle Duration: 14 days (±3 days) 
For Phase 2 Safety Run-In Only: The first 4 cycles should be administered every 7 days during 
the DLT period. 
Subjects will begin with the Initial Dosing Schedule on Cycle 1 (Day 1) and continue with weekly 
dosing for 8 Cycles. Beginning with Cycle 9, subjects will follow the Subsequent Dosing Schedule 
of 800 mg every 2 weeks. Note: Cycle 9 should occur two weeks following the last weekly dose 
of NC318. Subjects will remain on the Subsequent Dosing Schedule of 800 mg every two weeks 
until disease progression, withdraw of consent, or intolerable toxicity (whichever comes first). 
Additional visits will be required on Days 2 and 3 of Cycles 1 and 5. During study visits, the 
subject will have clinical and laboratory assessments as outlined in Table 7 and Table 8. At certain 
study visits, subjects will have PK, PD, and biomarker samples obtained (see Table 10 and 


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Table 11). 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. For all other cycles (with the exception of Cycle 5), subjects will 
be required to stay at study site for 1 hour post end of infusion for observation 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. 
Subjects will continue to receive NC318 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 NC318 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 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. 
 
6.3. 
End of Treatment Visit 
When the subject permanently discontinues (i.e. stops receiving) 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. 
Post-Treatment Follow-up 
6.4.1. 
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 by radiologic imaging to 
monitor disease status. 
Information regarding post-study anticancer treatment will be collected if new treatment is 
initiated. 
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 anti-cancer therapy 
• Documented disease progression 
• Pregnancy 
• Death 
• End of the study 


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6.4.2. 
Survival Follow-up 
Subjects who experience confirmed disease progression or start a new anticancer therapy will 
move into Survival Follow-up. Survival Follow-up will occur approximately every 3 months after 
the end of treatment and will continue until death, withdrawal of consent, or the end of the study, 
whichever occurs first. 
Subjects will be contacted by phone to collect post-study anticancer therapy and survival status. 
AEs will be collected through 30 days following end of treatment. SAEs will be collected for 
90 days after the end of treatment or 30 days after the end of treatment if the subject initiates new 
anticancer therapy, whichever is earlier. 
 
6.4.2.1.     Survival Status 
To ensure current and complete survival data is available at the time of database lock, updated 
survival status may be requested during the study by the Sponsor. Upon Sponsor notification, all 
subjects who do not/will not have a scheduled study visit or study contact during the sponsor 
defined time period will be contacted for their survival status (excluding subject that have a 
previously recorded death event in the eCRF). 
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 (i.e. stopped receiving) 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 
• 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 local 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 


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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 local 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, smoking 
history, 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 surgical 
procedures will be recorded. 
 
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 30 days 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. Use of GnRH agonists or antagonists and COVID-19 
vaccines should also be recorded in the eCRF. 
 
7.4. 
Poststudy Anticancer Therapy 
The investigator or qualified designee will review all new anticancer therapy initiated after the last 
dose of study drug, including but not limited to systemic therapy, radiotherapy, and surgery. 


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7.5. 
Safety Assessments 
7.5.1. 
Adverse Events 
Adverse events monitoring will begin at the time the subject signs the ICF. All AEs and SAEs that 
occur after the consent form is signed but before first study treatment must be reported by the 
investigator if they are the result of a protocol-specified intervention. 
From the time of first study treatment through 30 days following end of treatment, all adverse 
events must be reported by the investigator. SAEs will be collected for 90 days after the end of 
treatment or 30 days after the end of treatment if the subject initiates new anticancer therapy, 
whichever is earlier. 
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. Clinically 
notable abnormalities that are considered clinically significant in the judgment of the investigator 
are to be reported as AEs or medical history. 
 
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. 
 
7.5.2.3. 
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, semi recumbent, or 
sitting position after 5 minutes of rest. 


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During Cycle 1 Day 1, vital signs (blood pressure, pulse, respiratory rate, and body temperature) 
will be assessed pre-dose, at the end of infusion (+10 minutes) and every 60 minutes (± 10 minutes) 
for 4 hours post end of infusion. 
On Day 1 of all subsequent cycles, vitals signs will be assessed pre-dose and at the 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. 
Note: 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. 
 
7.5.3. 
Electrocardiograms 
All 12-lead ECGs will be performed with the subject in a recumbent or semi-recumbent position 
after 5 minutes of rest and should generally not be performed within 15 minutes of a blood 
collection. 
A single 12-lead ECG should be performed at screening using local standard procedures. Clinical 
significant abnormal findings should be recorded as medical history. Additional ECGs should be 
performed per PI discretion if any clinically significant abnormal findings are noted or as indicated. 
The 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. 
 
7.5.4. 
Laboratory Assessments 
A laboratory local to the study site and subject will perform all clinical laboratory assessments for 
safety (i.e., blood chemistries, complete blood count (w/ differential), coagulation tests, endocrine 
function, and urinalysis). The investigative site will enter the laboratory results and laboratory 
normal ranges into the eCRF. All local laboratory assessments should be performed using standard 
procedures on the days indicated in Table 7 and Table 8. Table 9 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. 
Safety Lab tests must be performed during screening period (within 30-day window). 
Cycle 1 Day 1 laboratory samples must be collected prior to study drug administration. Results 
should be reviewed by the investigator or qualified designee and found to be acceptable prior to 
the start of study drug treatment. Note: If screening labs were preformed within 7 days of Cycle 1 
Day 1, results from screening can be used as indicator to begin study treatment. 
For all subsequent cycles after Cycle 1, pre-dose laboratory procedures may be performed up to 
72 hours prior to study drug administration. Results should be reviewed by the investigator or 
qualified designee and found to be acceptable before treatment is initiated. 


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7.5.4.1. 
Pregnancy Testing 
A local laboratory serum pregnancy test will be required for all women of childbearing potential 
during screening and at the EOT visit. Urine pregnancy tests will be performed locally on Day 1 
of each cycle as outlined in Table 7, as medically indicated, or per country-specific requirement. 
Urine pregnancy tests on Day 1 of each Cycle must be performed and resulted before study drug 
administration. 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. 
 
7.5.4.2. 
Hepatitis Screening Tests 
Hepatitis screening assessments will be performed during the screening period (Table 8) to rule 
out hepatitis infection; required analytes are shown in Table 9. 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 (mRECIST) 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 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 


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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 
Repeat scan 
shows stable 
disease, 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 
Abbreviation: N/A = not applicable. 
As noted above, if disease progression is observed, then the study site may elect to continue 
treatment, repeat imaging at a minimum of 4 weeks, but no later than 6 weeks later, and assess 
tumor response or confirmed 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 7). 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 


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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. 
 
7.6.1.2. 
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, then the subject 
will be allowed to 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. 
 
7.6.1.3. 
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. Imaging assessments may be done more 
frequently if clinically indicated. After completing 12 months of treatment, subjects will have 
imaging performed per standard of care and PI discretion. Imaging should not be delayed for 
delays in cycle starts. 
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 
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. 
7.6.1.4. 
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 new anticancer treatment, withdrawal of consent, death, or the end of the 
study, whichever occurs first. 


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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 until 1) withdrawal of consent 2) the start of new anti-cancer 
therapy, 3) documented disease progression, 4) death, or 5) the end of the study, whichever occurs 
first. 
7.7. 
Pharmacokinetic Assessments 
Timing of PK and ADA assessments are outlined in Table 10. After the pre-dose PK sample is 
drawn, subjects will begin the study drug infusion. Predose is defined as within 24 hours before 
administration of study drug. 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 plasma samples will be collected at the visits outlined in Table 11. 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 biopsies will be collected as specified below: 
• Screening: A fresh biopsy or collection of archival tumor tissue (≤ 5 years) from a previous 
biopsy is required at Screening. 
o An archival baseline biopsy obtained within 5 years for other purposes (i.e., not an 
NC318-01 procedure) may be utilized 
o Fresh tumor biopsies should be taken from nontarget lesions when possible. 
o 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. 
• On-treatment (optional): An on-treatment biopsy may be obtained anytime during Week 
7 (before the first radiographic assessment) for subjects who consent for on- treatment 
biopsy at time of informed consent. 


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o On-treatment biopsies should be performed at the same site as the screening biopsy 
whenever possible. 
• At the End of Treatment (optional): An End of Treatment (EOT) biopsy may be obtained 
at the time that study treatment has been discontinued for subjects who consent for EOT 
biopsy at time of informed consent. 
Details and methods for obtaining, processing, and shipping the fresh tumor biopsy samples will 
be provided in the Biopsy Collection 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). 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. 
Plasma Pharmacodynamic Assessment 
Plasma samples will be evaluated to assess evidence of NC318 activity. 
Plasma samples will be used to examine markers of inflammation or immune modulation (which 
may include, but are not limited to: IFNγ, IL-2, IL-4, IL-6, and TNFα) pre- and on-treatment with 
NC318. Other assays relevant to the objectives of the study may be performed based on emerging 
data. 
 
7.8.4. 
Timing for Plasma and Whole Blood Assessments 
Biomarkers will be analyzed in plasma and whole blood samples collected at baseline and on the 
days and times outlined in Table 11. Timing for biomarker samples is outlined in Table 11. 
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. 
7.9. 
Other Study Procedures 
Not applicable. 


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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. PTEs 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 
Adverse events monitoring will begin at the time the subject signs the ICF. All AEs and SAEs that 
occur after the consent form is signed but before first study treatment must be reported by the 
investigator if they are the result of a protocol-specified intervention. 
From the time of first study treatment through 30 days following end of treatment, all adverse 
events must be reported by the investigator. SAEs will be collected for 90 days after the end of 
treatment or 30 days after the end of treatment if the subject initiates a new anticancer therapy. 
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 v5.0, 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 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 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 


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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 
A serious adverse event (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: 
o A routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 
o 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. 
o 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. 
o 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. 
• 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. 


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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 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 to 
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 Investigator’s Brochure (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 Sponsor or its 
designee (see Section 8.3.2 for contact information). 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. 
 
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 anticancer therapy, the following procedures should be 
followed to ensure subject safety: 
• The study drug must be discontinued immediately (female subjects only). 


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• Consent must be obtained from female partners of male subjects. 
• The investigator must complete and submit the NextCure 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: 
o 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. 
8.7. 
Data Monitoring Committee 
For Phase 1, the sponsor will conduct telephone conferences with investigators in order to review 
cohort-specific data, to review 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. 


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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 NC318, 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. 
Based on the known biology of the S15 pathway and its importance in immune function, as well 
as clinical experience with other immunotherapies in oncology, immune-related adverse events 
(irAEs) are the most likely class of toxicity. 
 
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: ClinicalSupply@nextcure.com 
Email subject line should include: “NC318-01 Product Complaint” 
Mail:   NextCure, Inc. 
Attn: Clinical Operations 
9000 Virginia Manor Road 
Beltsville, MD 20705 USA 
 
9. 
STATISTICS 
This section outlines the statistical analysis strategy and procedures for the study. If, after the study 
has begun, but prior to any final database lock, changes are made to primary and/or key secondary 
hypotheses, or the statistical methods related to those hypotheses, then the protocol will be 
amended (consistent with ICH Guideline E-9). Changes to exploratory or other non-confirmatory 
analyses made after the protocol has been finalized, but prior to final database lock, will be 
documented in a supplemental SAP (sSAP) and referenced in the Clinical Study Report (CSR) for 
the study. Post hoc exploratory analyses will be clearly identified in the CSR. 
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 includes all 
subjects who receive any dose of NC318. Additional details of statistical analyses will be described 
in the SAP. 


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9.1. 
Study Populations 
The full analysis set (FAS) includes all subjects enrolled in the study who received at least one full 
dose of NC318. This population will be used in all the summaries and analyses except for those 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 187 eligible subjects in Phase 1 and Phase 2 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 is to determine the MTD 
or PAD of NC318. A 3 + 3 study design will be used for dose escalation. A maximum of 7 dose 
levels will be tested. Therefore, a maximum of 42 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 NC318 and then are followed up for 28 days for assessment of DLTs. Any 
subjects who don’t 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 a total of 
9 evaluable subjects (up to 24 additional subjects). 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. 
Phase 1 enrollment of the study is complete. A total of 49 subjects were enrolled across Phase 1a 
and Phase 1b. The following cohorts were expanded during Phase 1b: Cohort 2 (80 mg), Cohort 3 
(240 mg), and Cohort 4 (400 mg). 
 
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 NC318. In Phase 2, subjects will be stratified 
after enrollment into cohorts based on S15 expression and tumor type. 
 
9.2.2.1. 
Cohort 1: Select S15+ Tumors (Lung (adenocarcinoma), HNSCC, and Breast) 
This cohort will include subjects who are 1) confirmed as TMB-H and/or MSI-H/dMMR, 2) upon 
enrollment are confirmed to express S15, and 3) have one of the following tumor types, separated 
into tumor-specific subgroup: 1a) Lung (adenocarcinoma), 1b) HNSCC, and 1c) Breast cancer. 
The sample size of each subgroup will be guided by the Simon 2-stage design (Simon 1989). Let 
5% be a clinically insignificant response rate for all tumor cohorts. During Stage 1, each tumor-
specific subgroup will enroll 9 evaluable subjects; if no responses are observed within a sub-group, 
then the sub-group will be discontinued. If 1 or more response is observed within a sub-group, 
then Stage 2 will begin and 8 additional subjects will be enrolled, for a maximum of 


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17 subjects within the sub-group. Each tumor-specific sub-group (1a, 1b, and 1c) will be 
independently assessed. 
 
9.2.2.2. 
Cohort 2: Alternate Tumors (Other S15+ Tumors/S15- Tumors) 
This basket cohort will include all other enrolled subjects who are confirmed as TMB-H and/or 
MSI-H/dMMR but do not fall under the criteria to be included in Cohort 1. Based on the result of 
S15 expression, subjects will be stratified after enrollment into two groups within the cohort: 2a) 
Other S15+ Tumors and 2b) Select 15- Tumors. Each group in the cohort 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 into each group; if no response is observed within 
a group, then the group will be discontinued. If 1 or more responses is observed within a group, 
then Stage 2 will begin and 8 additional subjects will be enrolled, for a maximum of 17 subjects 
per group. Each group (2a and 2b) will be assessed independently. 
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. 
 
9.4. 
Interim Analysis 
No formal interim analysis is planned. However, the safety, PK and efficacy data will be regularly 
reviewed and monitored for deciding on dose escalation in Phase 1 and continuation in Phase 2 of 
the study. 
 
9.5. 
Statistical Analyses 
9.5.1. 
Summary of Baseline Characteristics, Demographics and Other Analyses 
The number and percentage of subjects screened, treated, and the primary reason for 
discontinuation will be displayed. Demographic variables (e.g., age, gender), baseline 
characteristics, cancer history and diagnosis, and prior and concomitant therapies will be 
summarized either by descriptive statistics or categorical tables. 
 
9.5.2. 
Safety Analyses 
The safety assessments include adverse events, laboratory tests, and vital signs. All the safety data 
in the SAS will be summarized and listed by phase, treatment group, and cohort. Count and 
percentage of AE will be provided. 
 
9.5.2.1.     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. 


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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. 
 
 
9.5.3. 
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. 
 
9.5.4. 
Efficacy Analyses 
The response will be assessed by CT/MRI image during screening and every 8 weeks (± 7 days) 
post-dosing for 6 months and then every 12 weeks (± 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 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). 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 anti-cancer 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) 
• 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 anti-cancer drug, DOR 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 at the time of discontinuation from study or data cutoff for analysis, OS will be 
censored at the date of last known alive (LKA). 
OS = (Death or LKA date) – (date of first dose of study drug + 1) 


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9.5.5. 
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 
NC318. 
The immunogenic potential of NC318 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 
No formal analysis will be performed for Data Monitoring Committee purposes. 
 
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 the Clinical Study 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). 
 
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 NC318-01 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). 


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• 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 Clinical Study Protocol and the Clinical Study Agreement, the terms of Clinical Study 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. 
 
10.2.2. 
Archiving of Study Documents 
The Investigator follows the principles outlined in the Clinical Study Agreement. 
 
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 by Syneos Health, on behalf of NextCure, according to the 
study specific Data Management Plan. 


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A Web Based Data Capture (WBDC) 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. 
 
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. 


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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 NextCure before enrollment of any subject into the study. 
The IRB/IEC should approve all advertising used to recruit subjects for the study. 
NextCure 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. 
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. 
NextCure will handle the distribution of any of these documents to the national regulatory 
authorities. 
NextCure 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 


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• 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 
 
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. 
NextCure 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 NextCure 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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12. 
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Matsushita H, Vesely MD, Koboldt DC, et al. Cancer exome analysis reveals a T-cell-dependent 
mechanism of cancer immunoediting. Nature. 2012;482:400-4. 
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Nosho K, Baba Y, Tanaka N, et al. Tumour-infiltrating T-cell subsets, molecular changes in 
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Oble DA, Loewe R, Yu P, Mihm MC, Jr. Focus on TILs: prognostic significance of tumor 
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Sponsor Signature(s) 
A Phase 1/2, Open-Label, Dose-Escalation, Safety and Tolerability Study of NC318 in 
Subjects with Advanced or Metastatic Solid Tumors 
 
I agree to the terms of this protocol. 
 
   
 
 
 
 
 
 


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Signature of Principal Investigator 
A Phase 1/2, Open-Label, Dose-Escalation, Safety and Tolerability Study of NC318 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 
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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 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 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 
Source: Oken 1982. 


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APPENDIX 5. SUMMARY OF CHANGES 
 
Original Protocol (Version 1.0) 
26-JUL-2018 
Amendment 1 (Version 2.0) 
20-SEP-2018 
Amendment 2 (Version 3.0) 
17-JUN-2019 
Amendment 3 (Version 4.0) 
27-AUG-2019 
Amendment 3.1 (Version 4.1) 
16-MAR-2020 
Amendment 4 (Version 5.0) 
24-MAY-2021 
Amendment 5 (Version 6.0) 
18-AUG-2021