A Phase 1, Open-Label, Safety, Tolerability, And Efficacy Study of NC525 in Subjects With Advanced Myeloid Neoplasms
Phase: PHASE1
Conditions: Relapsed or Refractory Acute Myeloid Leukemia, Relapsed or Refractory Chronic Myelomonocytic Leukemia, Relapsed or Refractory Myelodysplastic Syndrome
Sponsor: NextCure, Inc.

Oﬃcial Title: A PHASE 1, OPEN-LABEL, SAFETY, TOLERABILITY, AND EFFICACY STUDY OF  
NC525 IN SUBJECTS WITH ADVANCED MYELOID NEOPLASMS 
 
NCT Number: NCT05787496 
 
Document Date: Protocol (Version 4.0) dated 16-Oct-2023 

 
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A PHASE 1, OPEN-LABEL, SAFETY, TOLERABILITY, AND EFFICACY STUDY OF 
NC525 IN SUBJECTS WITH ADVANCED MYELOID NEOPLASMS 
 
Sponsor Protocol Number:  
NC525-01 
IND Number: 
 
157274 
Investigation Product:  
      NC525 [LAIR-1 IgG1 Humanized Monoclonal Antibody] 
 
Phase of Study: 
      1 
 
Sponsor: 
      NextCure, Inc. 
                                                      9000 Virginia Manor Road, Suite 200 
      Beltsville, MD 20705 USA 
Phone: 240-399-4900 
Email: NCClin@nextcure.com 
 
Medical Monitor 
      
 
 
      
 
 
      
 
      
 
 
 
      
 
 
 
Protocol Amendment (Version 4.0) 
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PROTOCOL SYNOPSIS 
HYPOTHESIS 
Treatment with NC525, a humanized immunoglobulin gamma 1, kappa (IgG1κ) monoclonal antibody 
specific for LAIR-1, will, specifically kill leukemic cells while sparing healthy cells in both the bone-
marrow and the periphery, ameliorating disease with minimal toxicity, and resulting in clinical benefit for 
subjects with advanced myeloid neoplasms.  
STUDY OBJECTIVES  
Primary Objectives 
1) To evaluate the safety, tolerability, and dose-limiting toxicities (DLTs) of NC525 
2) The recommended Phase 2 dose (RP2D) of NC525 will be defined in subjects with advanced myeloid 
neoplasms 
3) Define a minimally active dose (MAD), pharmacologically active dose (PAD), and maximum tolerated 
dose (MTD) of NC525 in subjects with advanced myeloid neoplasms 
Secondary Objectives 
1)  To evaluate the clinical benefit of NC525 
2) To evaluate the time to achieve an objective response (OR) 
3) To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of NC525 
Exploratory Objectives 
1) To assess the immunogenicity of NC525 
2) To explore biomarkers that may predict the pharmacologic activity of NC525 
 
STUDY ENDPOINTS  
Primary Endpoints 
1) Safety and tolerability will be assessed by monitoring the frequency, duration, and severity of adverse 
events (AEs). Note: Toxicity grading per NCI CTCAE v5.0 
2) The recommended Phase 2 dose (RP2D) of NC525 in subjects with advanced myeloid neoplasms. 
3) The MAD, PAD, and MTD of NC525 will be defined in subjects with advanced myeloid neoplasms. 
Secondary Endpoints 
1) Assessment of anti-leukemia activity/efficacy will be used to evaluate the clinical benefit of NC525, 
including:  
a. Objective Response (OR)  
i. CR, CRi, or CRh and MLFS 
b. Event-free survival (EFS), and  

 
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c. Overall survival (OS)  
2) Assessment of time to achieve response, defined as CR, CRi, or CRh 
a. To evaluate the time to achieve an objective response from Cycle 1 Day 1 to day remission is 
achieved as defined per protocol  
3) Assessment of PK of NC525 concentration(s) in serum, as well as assessment of the PK/PD profile 
Exploratory Endpoints 
1) Immunogenicity, defined as the occurrence of anti-drug antibodies (ADA) to NC525 will be determined 
2) Biomarker effects of NC525 in peripheral blood and bone marrow will be assessed, including but not 
limited to the following: 
a. Percentage and/or expression level of LAIR-1 blast cells and/or Leukemic Stem Cells (LSC) or 
Hematopoietic Stem Cells (HSC) 
b. Any relation to response (clearing of blast cells to achieving CR) 
c. Serum markers of inflammation or immune modulation (cytokine & chemokine levels) 
STUDY DESIGN 
Description 
This is an open-label, non-randomized, Phase 1 study to determine the safety and tolerability of NC525. This 
study will also assess the clinical benefit in subjects with advanced myeloid neoplasms. The study includes a 
dose escalation phase to determine MTD followed by expansion cohorts to further evaluate the safety and 
tolerability of the MTD (Figure S1). 
Figure S1: Phase 1 Study Design 
 

 
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The safety and tolerability of NC525 will be evaluated by escalating dose levels of NC525. In addition, the 
minimally active dose (MAD), pharmacologically active dose (PAD), and maximum tolerated dose (MTD), 
of NC525 will be determined. 
The PAD will be defined as a dose that provides a maximal biologic effect, such as achieving a complete 
remission (CR) and other variants of complete remission (CRh, CRi), and/or the MTD of NC525. 
Once the biologically-effective dose(s) deemed to be safe have been identified,  safety and tolerability will 
be further assessed through expansion of  two dose levels to determine an optimal biologically active 
Recommended Phase 2 Dose (RP2D) and administration schedule of NC525. 
A Bayesian Optimal Interval (BOIN) design (Figure S2) for Phase I clinical trials (Liu 2015) with a target 
dose-limiting toxicity (DLT) rate of approximately 25% will be applied for dose escalation and confirmation 
to determine a recommended Phase 2 dose (RP2D) for NC525. 
Figure S2: Dose-Finding Rules per BOIN 
 
 

 
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Study Phase and Cohorts 
A BOIN design will be utilized to determine the MTD of NC525, where a minimum of 3 evaluable subjects 
will be enrolled in each dose level from Cohort 2 onwards. In the case of the starting dose level (2mg/kg), a 
minimum of 1 evaluable subject may be enrolled (in the absence of severe toxicity) prior to determining 
escalation to the next dose level given the dose is an approximation of the minimally active dose (PD30). 
All dose escalation and de-escalation decisions will be based on the occurrence of DLTs at a given dose during 
the first 56-day period (i.e., first 2 cycles), also referred to as the DLT observation period (Figure S3), and will 
be made jointly by the Clinical Study Team comprised of the Sponsor (Chief Medical Officer and Medical 
Monitor), CRO Medical Monitor and Investigators once the minimum number of evaluable subjects (n=3) 
have completed the DLT observation period. 
Figure S3: Phase 1 Study Schema 
a. Cohort 1 
 

 
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b. Cohort 2 and Above 
 
A subject is considered evaluable if they have received at least four doses of NC525 and completed the 56-
day DLT observation period or discontinued earlier due to an adverse event. Only one subject will be dosed 
on the first day of dosing for each cohort (additional subjects can begin in ≥ 48 hours). If there are multiple 
subjects in the screening process at the time the third subject within a cohort begins treatment, additional 
subjects may be enrolled with approval of the Sponsor using the BOIN design and based on the number of 
subjects evaluable at the current dose level. 
The Escalation/De-escalation Rules per BOIN (Table S1) can be used to help inform decisions during the 
safety review meetings. Dosing decisions include escalate to the next higher dose, stay at the current dose, de-
escalate to the next lower dose, or eliminate the dose level (i.e., unacceptably toxic dose). Dose escalation and 
de-escalation will be based on the cohort size of 3. That is, no dose escalation will be made before 3 patients 
are treated at the current dose, except the first dose where the accelerated titration may be performed and a 
minimum of 1 subject may be enrolled. 
To reference the dose finding rules, one can use the number of evaluable subjects in a cohort that have been 
treated to determine the appropriate action based on the number of subjects who have experienced a DLT as 
indicated by the column. For example, at a given dose level, if 6 subjects have been enrolled but only 5 
evaluable subjects have passed the 56-day DLT observation period, a decision could be made to escalate to 
the next dose cohort as long as there is ≤ 1 DLT in any of the 5 subjects. 
 
 
 
 

 
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*Cohort 1: Biweekly (Q2W) for Cycles 1 through 6 followed by every 4 weeks (Q4W) thereafter. For Cohort 
2 and Above: Weekly (QW) dosing for Cycles 1 and 2. Subjects may continue weekly (QW) dosing until 
overall response (e.g., CR, CRh, or CRi) is achieved, at which time they may switch to biweekly (Q2W) 
dosing. For subjects who maintain a weekly dosing schedule, local bone marrow biopsies and aspirates should 
continue to be collected every 28-days.  
The planned dose levels for Dose Escalation include a maximum dose increment of less than a half-log (233%) 
between each dose level.  Using the Escalation/De-escalation Rules governed by the BOIN design, if criteria 
is met allowing dose escalation, the subsequent dose level will first be evaluated against the Dose Increment 
Modification Rules For Dose Escalation (Table S2) taking into consideration the number of adverse events 
(Grade ≥ 2) and dose limiting toxicities which occurred at the current dose level prior to selecting the next 
dose. 
In the event a dose increment modification is indicated during the Dose Escalation phase of the study, an ad-
hoc safety meeting will occur with the Clinical Study Team to review the adverse event(s) against the 
qualifying criteria before any dose modifications are made. 
All Adverse Events (excluding AEs unequivocally due to the underlying disease or an extraneous cause) 
occurring during the DLT Observation Period will be evaluated against the Dose Increment Modification rules, 
as follows: 
• 
Limit the maximum dose increment to 100% if patients of a given cohort experience one Grade ≥ 2 AE during 
the DLT period. 
o Example: If one ≥ Grade 2 AE occurs in Dose Cohort 1 (2mg/kg), the subsequent dose level will be 
increased by 100% (4mg/kg) instead of the originally planned dose of 4.5mg/kg. 
 
• 
Limit the maximum dose increment to 50% if patients of a given cohort experience two or more Grade ≥ 2 
AEs during the DLT period. 
o Example: If two or more ≥ Grade 2 AE occurs in Dose Cohort 1 (2mg/kg), the subsequent dose level 
will be increased by 50% (3mg/kg) instead of the originally planned dose of 4.5mg/kg. 
 
• 
Limit the maximum dose increment to 50% if patients of a given cohort experience one DLT during the DLT 
period. 
o Example: If one DLT occurs in Dose Cohort 1 (2mg/kg), the subsequent dose level will be increased 
by 50% (3mg/kg) instead of the originally planned dose of 4.5mg/kg. 
 
• 
Limit the maximum dose increment to 30% if patients of a given cohort experience two DLTs during the DLT 
period. 
o Example: If two DLTs occur in Dose Cohort 1 (2mg/kg), the subsequent dose level will be increased 
by 30% (2.6mg/kg) instead of the originally planned dose of 4.5mg/kg. 
 
 
 
 
 

 
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ELIGIBILITY CRITERIA 
Inclusion Criteria: 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1) The subject is willing to provide written informed consent for the trial. 
2) Be ≥ 18 years of age on the day of signing informed consent. 
3) Subject has one of the following Myeloid Neoplasms determined by pathology review at the 
treating institution: 
• Relapsed or Refractory AML, 
Note: Active, relapsed, or refractory AML is defined as any one of the following:  
▪ Primary induction failure, or (PIF) after 2 or more cycles of therapy, 
▪ First early relapse after a remission duration of fewer than 6 months, 
▪ Relapse refractory to salvage combination chemotherapy second or subsequent 
relapse, or  
▪ Relapsed or refractory AML with at least 5% blasts by bone marrow biopsy or 
aspirate, or at least 1% blasts in peripheral blood. 
• Relapsed or Refractory Myelodysplastic syndrome (MDS) after prior hypomethylating 
agents. 
Note: Subject must have sub-type MDS-EB2 with 10-19% blasts by bone marrow biopsy or 
aspirate. 
• Relapsed or Refractory Chronic myelomonocytic leukemia (CMML) with progressive 
disease or lack of response to hypomethylating agents. 
4) A male subject must agree to use approved contraception (based on institutional guidelines) and 
refrain from sperm donation or expecting to father a child, from Screening through the treatment 
period and for at least 90 days after the last dose of study treatment.  
5) A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least 
one of the following conditions applies: 
a. Not a woman of childbearing potential (WOCBP); 
b. A WOCBP agrees to follow approved contraceptive guidance (based on institutional 
guidelines) from Screening through the treatment period and for at least 90 days after the 
last dose of study treatment. 
6) Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 
7) Life expectancy greater than or equal to 12 weeks as judged by the Investigator. 
8) Have adequate organ function as defined in the following table (Table S3).  
 
 
 

 
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Table S3: Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematology  
 
Peripheral white blood cell (WBC) 
≤ 25,000/μL1 
Renal 
 
Measured or calculated2 creatinine 
clearance 
Creatinine clearance > 60 mL/min  
Hepatic 
 
Total bilirubin 
<1.5 × ULN OR direct bilirubin ≤ ULN for subjects 
with total bilirubin levels >1.5 × ULN.  
Note: Subjects with documented Gilbert's syndrome 
with elevated baseline total bilirubin ≤ 3.0 mg/dL or 
indirect hyperbilirubinemia suspected to be result of 
hemolysis may be enrolled. 
AST (SGOT) and ALT (SGPT) 
≤ 3.0 × ULN 
ALT (SGPT) =alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) =aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal. 
1 Hydroxyurea or cytarabine therapy is allowed to reduce white blood cells to meet this inclusion criterion. White 
blood cells should be determined ≥ 24 hours after the last leukoreduction therapy administration. Final leukoreduction 
therapy administration should not be administered ≤ 3 days prior to the first dose of NC525 without medical monitor 
approval. 
2 Creatinine clearance (CrCl) should be calculated per institutional standard. GFR can also be used in place of 
creatinine or CrCl. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of specific 
chemotherapies. 
Note: Screening labs must be collected within 7 days prior to the start of study treatment. 
 
Exclusion Criteria: 
Participants are excluded from the study if any of the following criteria apply: 
1) Has a diagnosis of acute promyelocytic leukemia (M3, APL), accelerated phase or blast crisis of 
chronic myeloid leukemia. 
2) History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult 
seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar 
disease, organic brain syndrome, or psychosis. 

 
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3) Patients with active Central Nervous System (CNS) involvement (such as leukemic infiltration, 
blast in the spinal fluid, or subjects with extramedullary disease). 
4) A WOCBP who has a positive pregnancy test (within 72 hours) prior to treatment.  
5) History or evidence of any other clinically significant disorder, condition or disease (e.g., 
symptomatic congestive heart failure, unstable angina pectoris, symptomatic myocardial 
infection, uncontrolled cardiac arrhythmia, pericardial disease or heart failure New York Heart 
Association Class III or IV), or severe debilitating pulmonary disease, that would potentially 
increase patients' risk for toxicity and in the opinion of the Investigator, would pose a risk to 
patient safety or interfere with the study evaluation, procedures or completion. 
6) Chronic respiratory disease or any other medical condition that requires continuous oxygen that 
in the opinion of the Investigator, would adversely affect his/her participation in this study. 
7) Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study 
intervention. 
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. 
8) Is currently participating in or has participated in a study of the following prior to the first dose 
of study treatment: 
a. An investigational biologic or an investigational device within 4 weeks or 5 half-lives 
(whichever is longer); 
b. An investigational oral agent within 2 weeks or 5 half-lives (whichever is shorter). 
Note: Subjects who have entered the follow-up phase of an investigational study may participate 
as long as the specified washout period has been completed.  
9) Has not recovered to ≤ Grade 1 from toxic effects of prior therapy (including prior chemotherapy, 
immunotherapy and radiation therapy) and/or complications from interventions before starting 
therapy.  
Note: Subjects with stable chronic conditions (≤ Grade 2) not expected to resolve (such as 
neuropathy and alopecia) are exceptions and may still enroll. 
10) Has previously had an allogeneic solid organ transplant. 
11) Autologous HSCT within 6 weeks before the start of study treatment. 
12) Allogeneic HSCT within 6 months before the start of study treatment.  
13) Any active acute or chronic graft-versus-host disease (GvHD), grade 2-4, or active chronic GvHD 
requiring systemic treatment. 
14) Any systemic therapy (e.g. calcineurin inhibitors (CNI), steroids, etc.) against GvHD within 4 
weeks before the start of study treatment. 

 
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15) Any Grade ≥ 2 persistent non-hematological toxicity related to allogeneic transplant, such as 
those requiring systemic immunosuppressive therapy. 
16) Previous CAR-T therapy. 
17) Known concurrent malignancy that is progressing or requires active treatment, or history of other 
malignancy within 2 years of study entry after treatment with curative intent.  
Note: Cured basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, 
prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent 
malignancy, or cancers from which the subject has been disease-free for > 1 year are not 
considered exclusionary. 
18) Has severe hypersensitivity (≥ Grade 3), known allergy or reaction to Immunoglobulins or 
NC525, and/or any of their excipients. 
19) Uncontrolled systemic fungal, bacterial, viral, or other infection despite appropriate anti-
infection treatment at the time of eligibility confirmation. 
20) Has a known history of HIV infection. Note: No HIV testing is required unless mandated by the 
local health authority.  
21) Has a known active chronic hepatitis B infection or chronic hepatitis C infection with the 
exception of those with an undetectable viral load within 3 months.  
22) Has a history or current evidence of any condition, therapy, or laboratory abnormality, or other 
circumstance that might confound the results of the study or interfere with the subject's 
participation for the full duration of the study, such that it is not in the best interest of the subject 
to participate, in the opinion of the treating investigator. 
23) Has a known psychiatric or substance abuse disorder that would interfere with the subject’s 
ability to cooperate with the requirements of the study. 
STUDY DRUG ADMINISTRATION AND TREATMENT SCHEDULE 
For Cohort 1, NC525 is given by Intravenous (IV) infusion every two weeks (on Days 1 and 15 of each 
cycle) for the first 6 cycles. For subjects who continue on treatment beyond Cycle 6, NC525 will be 
administered every 4 weeks (on Day 1 of each cycle only). 
For Cohort 2 and above, NC525 will be administered every week on Days 1, 8, 15 and 22 during Cycles 
1 and 2. Subjects may continue weekly dosing until overall response (e.g., CR, CRh, or CRi) is achieved, 
at which time they may switch to biweekly dosing. For biweekly dosing, NC525 will be administered 
every two weeks on Days 1 and 15 of each cycle. Subjects who derive clinical benefit may continue to 
receive NC525 for a total of 2 years or until the criteria for discontinuation of treatment are met 
(whichever comes first).  
Each cycle will be 28-days in duration. A detailed description of the treatment schedule is included below 
(Table S4): 
 

 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ........................................................................................................... II 
TABLE OF CONTENTS ............................................................................................................ 1 
LIST OF TABLES ...................................................................................................................... 7 
LIST OF FIGURES .................................................................................................................... 8 
LIST OF ABBREVIATIONS...................................................................................................... 9 
1. 
INTRODUCTION .................................................................................................. 14 
1.1. 
Background ............................................................................................................ 14 
1.1.1. 
Pharmaceutical and Therapeutic Background .......................................................... 14 
1.1.2. 
Pharmacokinetics of NC525 ................................................................................... 16 
1.1.3. 
Pharmacology of NC525......................................................................................... 17 
1.1.4. 
Non-Clinical Safety and Potential Risks of NC525 ................................................. 17 
1.2. 
Study Rationale ...................................................................................................... 18 
1.2.1. 
Rationale for the Safe Starting Dose ....................................................................... 18 
1.2.2. 
Rationale of Disease Selection for Phase 1 Study .................................................... 20 
1.2.3. 
Rationale for Efficacy Endpoints ............................................................................ 20 
1.2.3.1. 
Response Criteria for Disease Assessment .............................................................. 20 
1.3. 
Research Hypotheses .............................................................................................. 21 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................... 22 
2.1. 
STUDY OBJECTIVES........................................................................................... 22 
2.1.1. 
Primary Objectives ................................................................................................. 22 
2.1.2. 
Secondary Objectives ............................................................................................. 22 
2.1.3. 
Exploratory Objectives ........................................................................................... 22 
2.2. 
STUDY ENDPOINTS ............................................................................................ 22 
2.2.1. 
Primary Endpoints .................................................................................................. 22 
2.2.2. 
Secondary Endpoints .............................................................................................. 22 
2.2.3. 
Exploratory Endpoints ............................................................................................ 23 
3. 
STUDY DESIGN ................................................................................................... 24 
3.1. 
Description of the Study ......................................................................................... 24 
3.2. 
Study Phase and Cohorts ........................................................................................ 25 
3.2.1. 
Phase 1 Design ....................................................................................................... 25 

 
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3.2.2. 
Dose Levels and Cohorts ........................................................................................ 28 
3.3. 
Measures Taken to Avoid Bias ............................................................................... 29 
3.4. 
Number of Subjects ................................................................................................ 30 
3.4.1. 
Planned Number of Subjects ................................................................................... 30 
3.4.2. 
Replacement of Subjects ......................................................................................... 30 
3.5. 
Duration of Treatment and Participation ................................................................. 30 
3.6. 
Overall Study Duration ........................................................................................... 30 
3.7. 
Continued Access ................................................................................................... 30 
3.8. 
Study Termination .................................................................................................. 30 
4. 
SUBJECT ELIGIBILITY ....................................................................................... 32 
4.1. 
Subject Inclusion Criteria ....................................................................................... 32 
4.2. 
Exclusion Criteria: .................................................................................................. 34 
5. 
TREATMENT ........................................................................................................ 36 
5.1. 
Treatment Assignment ............................................................................................ 36 
5.1.1. 
Subject Numbering and Treatment Assignment ...................................................... 36 
5.1.2. 
Randomization and Blinding................................................................................... 36 
5.2. 
Description and Administration .............................................................................. 36 
5.2.1. 
NC525 Description ................................................................................................. 36 
5.2.2. 
Study Drug Administration ..................................................................................... 36 
5.3. 
Supply Packaging and Labeling .............................................................................. 37 
5.4. 
Storage ................................................................................................................... 37 
5.5. 
Accountability ........................................................................................................ 37 
5.6. 
Treatment Compliance ............................................................................................ 37 
5.7. 
Reporting Product Complaints ................................................................................ 37 
5.8. 
Dose Modifications................................................................................................. 37 
5.8.1. 
Criteria and Procedures for Modifications, Dose Interruptions and 
Adjustments of Study Treatments ........................................................................... 37 
5.8.2. 
Instructions for Dose Modifications for Adverse Events ......................................... 38 
5.8.3. 
Prophylaxis and Monitoring for Tumor Lysis Syndrome (TLS) .............................. 40 
5.8.4. 
Toxicity Management of Infusion-Reactions Related to NC525 .............................. 41 
5.9. 
Dose Limiting Toxicities (DLTs) ............................................................................ 43 
5.9.1. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose ............... 43 
5.9.2. 
Management of Dose-Limiting Toxicities or Other Urgent Situations ..................... 45 

 
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5.9.3. 
Follow-Up of Dose-Limiting Toxicities .................................................................. 45 
5.10. 
Withdrawal/Discontinuation of Subjects from Study Treatment .............................. 45 
5.10.1. 
Withdrawal/Discontinuation Criteria....................................................................... 45 
5.10.2. 
Withdrawal Procedures ........................................................................................... 46 
5.11. 
Concomitant Therapy During Study Treatment ....................................................... 46 
5.11.1. 
Prohibited Concomitant Medications ...................................................................... 46 
6. 
SCHEDULE OF STUDY PROCEDURES ............................................................. 47 
7. 
STUDY VISIT SCHEDULE .................................................................................. 59 
7.1. 
Screening Period ..................................................................................................... 59 
7.2. 
Treatment Period .................................................................................................... 59 
7.3. 
Treatment Schedule ................................................................................................ 59 
7.3.1. 
Treatment Discontinuation ...................................................................................... 60 
7.4. 
End of Treatment Visit ........................................................................................... 60 
7.5. 
Post-Treatment Follow-up ...................................................................................... 61 
7.5.1. 
30 Day Safety Follow-Up Visit ............................................................................... 61 
7.5.2. 
Survival Follow-Up ................................................................................................ 61 
7.6. 
Unscheduled Visits ................................................................................................. 61 
8. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES .......................... 62 
8.1. 
Administration of Informed Consent Form ............................................................. 62 
8.2. 
Subject Identification Card ..................................................................................... 62 
8.3. 
Demography and Medical History .......................................................................... 62 
8.3.1. 
Demographics and General Medical History ........................................................... 62 
8.3.2. 
Disease Characteristics and Prior Anticancer Treatment History ............................. 62 
8.4. 
Prior and Concomitant Medications and Procedures ............................................... 63 
8.5. 
Post-Treatment Cancer Therapy .............................................................................. 63 
8.6. 
Clinical Assessments and Procedures ...................................................................... 63 
8.6.1. 
Adverse Event Monitoring ...................................................................................... 63 
8.6.2. 
Physical Examinations ............................................................................................ 63 
8.6.2.1. 
Comprehensive Physical Examination .................................................................... 63 
8.6.2.2. 
Targeted Physical Examination ............................................................................... 63 
8.6.3. 
Eastern Cooperative Oncology Group Performance Status ...................................... 64 
8.6.4. 
Height, Weight, and Vital Signs .............................................................................. 64 

 
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8.6.5. 
Tumor Lysis Syndrome (TLS) Prophylaxis ............................................................. 64 
8.6.6. 
Safety Observation ................................................................................................. 64 
8.6.7. 
12-Lead Electrocardiogram ..................................................................................... 64 
8.6.8. 
Local Safety Laboratory Assessments ..................................................................... 65 
8.6.9. 
Pregnancy Testing .................................................................................................. 65 
8.6.10. 
Hepatitis Screening Tests ........................................................................................ 65 
8.6.11. 
Central Laboratory Assessments ............................................................................. 66 
8.7. 
Pharmacokinetic Assessments................................................................................. 66 
8.8. 
Biomarker and Correlative Assessments ................................................................. 66 
8.9. 
Bone Marrow Biopsies ........................................................................................... 66 
8.9.1. 
Bone Marrow Biopsy Collection Requirements ...................................................... 66 
8.9.2. 
Bone Marrow Aspirate and Biopsy for Disease Assessment .................................... 67 
9. 
SAFETY MONITORING AND REPORTING ....................................................... 68 
9.1. 
Adverse Events (AEs) ............................................................................................. 68 
9.1.1. 
Adverse Event Definition ....................................................................................... 68 
9.1.2. 
Serious Adverse Event Definition ........................................................................... 68 
9.1.3. 
Events of Clinical Interest (ECI) ............................................................................. 69 
9.1.4. 
Management of Myelosuppression Related to Disease ............................................ 70 
9.1.5. 
Reporting of an Overdose ....................................................................................... 70 
9.1.6. 
Reporting of AEs .................................................................................................... 70 
9.1.7. 
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information ........................................................................................ 71 
9.1.8. 
Reporting of SAEs or ECIs ..................................................................................... 72 
9.2. 
Laboratory Test Abnormalities ............................................................................... 72 
9.3. 
Pregnancy ............................................................................................................... 73 
9.4. 
Warnings and Precautions ....................................................................................... 74 
9.5. 
Procedures for Cohort Safety Review and Dose Escalation Meetings ...................... 74 
10. 
STATISTICS .......................................................................................................... 75 
10.1. 
Statistical Analysis Overview ................................................................................. 75 
10.2. 
Selection of Sample Size ........................................................................................ 76 
10.2.1. 
Sample Size for Dose Escalation ............................................................................. 77 
10.2.2. 
Sample Size for Safety Expansion .......................................................................... 78 
10.3. 
Statistical Analyses ................................................................................................. 80 

 
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10.3.1. 
Safety Analyses ...................................................................................................... 80 
10.3.1.1. 
Adverse Events ....................................................................................................... 80 
10.3.2. 
PK Analyses ........................................................................................................... 80 
10.3.3. 
Pharmacodynamic and Biomarkers Analysis........................................................... 80 
11. 
STUDY AND DATA MANAGEMENT................................................................. 82 
11.1. 
Training of Study Site Personnel ............................................................................. 82 
11.2. 
Monitoring of the Study .......................................................................................... 82 
11.2.1. 
Source Data ............................................................................................................ 82 
11.2.2. 
Archiving of Study Documents ............................................................................... 83 
11.3. 
Study Timetable and End of Study .......................................................................... 83 
11.4. 
Data Management ................................................................................................... 83 
11.5. 
Medical Monitor Coverage ..................................................................................... 83 
12. 
ETHICAL AND REGULATORY REQUIREMENTS ............................................ 84 
12.1. 
Ethical Conduct of the Study .................................................................................. 84 
12.2. 
Subject Data Protection .......................................................................................... 84 
12.3. 
Regulatory Review ................................................................................................. 84 
12.4. 
Informed Consent ................................................................................................... 85 
12.5. 
Changes to the Protocol and Informed Consent Form ............................................. 85 
12.6. 
Audits and Inspections ............................................................................................ 86 
13. 
REFERENCES ....................................................................................................... 87 
SIGNATURES.......................................................................................................................... 89 
APPENDIX 1: ADDITIONAL SAFETY GUIDANCE ............................................................. 92 
APPENDIX 2: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS 
DISEASE AND FOOD AND ALLERGY ANAPHYLAXIS NETWORK 
GUIDANCE FOR ANAPHYLAXIS DIAGNOSIS ................................................ 93 
APPENDIX 3: EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS ................................................................................................................ 94 
APPENDIX 4. TUMOR LYSIS SYNDROME CLASSIFICATION ......................................... 95 
APPENDIX 5. RECOMMENDATIONS FOR INITIAL MANAGEMENT OF 
ELECTROLYTE IMBALANCES AND PREVENTION OF TUMOR 
LYSIS SYNDROME (TLS) ................................................................................... 96 
APPENDIX 6: OUTCOME MEASURES (EUROPEAN LEUKEMIA NET (ELN) 2022, 
BLOOD JULY 2022 (ONLINE VERSION) ........................................................... 98 
APPENDIX 7: NC525 STUDY DRUG ADMINISTRATION GUIDANCE ............................. 99 

 
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APPENDIX 8: WEIGHT-BASED DOSING CALCULATION CONSIDERATIONS ............ 100 
SUMMARY OF CHANGES ................................................................................................... 101 

 
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LIST OF TABLES 
Table 1: Dose escalation/de-escalation rule for the BOIN Design .............................................. 27 
Table 2: Dose Increment Modification Rules for Dose Escalation ............................................. 29 
Table 3: Adequate Organ Function Laboratory Values .............................................................. 33 
Table 4: Dose Modifications for Adverse Events ....................................................................... 38 
Table 5: Infusion Reaction Dose Modification and Treatment Guidelines (NC525) ................... 41 
Table 6: Definition of Dose-Limiting Toxicity National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 ................................ 44 
Table 7: Schedule of Study Procedures...................................................................................... 47 
Table 8: Clinical Laboratory Test .............................................................................................. 56 
Table 9: Schedule of Pharmacokinetic (PK), Pharmacodynamic (PD) and Biomarker 
Sample Collection .................................................................................................. 57 
Table 10: Schedule of Bone Marrow Biopsies and Bone Marrow Immunophenotyping ............. 58 
Table 11: NC525 Dosing Schedule ............................................................................................ 60 
Table 12: NCI CTCAE v5.0 Grading Scale ............................................................................... 70 
Table 13: Key Elements of the Statistical Analysis Plan (SAP) ................................................. 75 
Table 14: Operating characteristics of the BOIN design ............................................................ 78 
Table 15: Futility Stopping Rule ............................................................................................... 79 
Table 16: Optimized Stopping Boundaries ................................................................................ 79 
Table 17: Operating Characteristics ........................................................................................... 80 
 

 
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LIST OF FIGURES 
Figure 1: Phase 1 Study Design ................................................................................................. 24 
Figure 2: Dose Finding Rules Per BOIN.................................................................................... 25 
Figure 3: Phase 1 Study Schema ................................................................................................ 26 
 
 

 
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LIST OF ABBREVIATIONS 
Abbreviation or 
Specialized Term 
Definition 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase (also called SGPT) 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute Neutrophil Count 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase (also called SGOT) 
AUC 
Area Under the Curve 
BM 
Bone Marrow  
bpm 
Beats per Minute 
BSA 
Body Surface Area 
CLL 
Chronic Lymphocytic Leukemia 
Cmax 
Maximum Concentration of Drug 
CMML 
Chronic myelomonocytic leukemia 
CNS 
Central Nervous System 
ctDNA 
Circulating Tumor Deoxyribonucleic Acid 
CR 
Complete Response 
CRh 
Complete Remission with partial hematologic recovery 
CRi 
Complete Remission with Incomplete Blood Count Recovery 
CRF 
Case Report Form 
CRS 
Cytokine Release Syndrome 
CS 
Clinically Significant  
CTACE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trial Facilitation Group 
CTLA-4 
Cytotoxic T-Lymphocyte–Associated Protein 4 
DC 
Dendritic cell 
DCR 
Disease Control Rate 
DLT 
Dose-Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
EC30 
Effective Concentration for 30% of Maximum Effect 

 
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Abbreviation or 
Specialized Term 
Definition 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EFS 
Event-Free Survival 
EOT 
End-of-Treatment 
ESA 
Erythropoietin-Stimulating Agent 
FAAN 
Food and Allergy Anaphylaxis Network 
FAS 
Full Analysis Set 
Fc 
Fragment crystallizable 
FDA 
Food and Drug Administration 
FIH 
First-in-Human 
FFPE 
Formalin-Fixed Paraffin-Embedded 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
GLP 
Good Laboratory Practices 
GM-CSF 
Granulocyte Macrophage Colony Stimulating Factor 
HBV 
Hepatitis B Virus 
HCC 
Hepatocellular Carcinoma 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HMA 
Hypomethylating agent 
HNSTD 
Highest Non-Severely Toxic Dose 
HPV 
Human Papillomavirus 
HR 
Hematologic Response 
hr 
Hours 
HSCT 
Hematopoietic Stem Cell Transplantation 
IB 
Investigator’s Brochure 
IBW 
Ideal Body Weight 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IDMC 
Independent Data Monitoring Committee 

 
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Abbreviation or 
Specialized Term 
Definition 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
INs 
Investigator Notifications 
irAE 
Immune-Related Adverse Event 
IRC 
Independent Review Committee 
IRB 
Institutional Review Board 
iv 
Intravenous 
LAIR 
Leukocyte-Associated Immunoglobulin-like Receptor 
LDH 
Lactate Dehydrogenase 
LTLS 
Laboratory Tumor Lysis Syndrome 
LKA 
Last Known Alive 
LPS 
Lipopolysaccharide 
mAb 
Monoclonal Antibody 
MDS 
Myelodysplastic syndromes 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minutes 
MLFS 
Morphologic Leukemia-free State 
MNTD 
Maximum Number of Tolerated Doses 
MR 
Morphologic Relapse 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NCS 
Not clinically significant 
NIAID 
National Institute of Allergy and Infectious Disease 
NOAEL 
No Observed Adverse Effect Level 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
ORR 
Overall Response Rate 
OR 
Objective Response 
OS 
Overall Survival 

 
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Abbreviation or 
Specialized Term 
Definition 
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 Remission 
PT 
Prothrombin Time 
QTcF 
QT interval measurement corrected by Fridericia's formula. 
RBC 
Red Blood Cell  
RNA 
Ribonucleic Acid 
RP2D 
Recommended Phase 2 Dose 
R/R 
Relapse/Refractory 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SSD 
Safe Starting Dose 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t½ 
Half-Life 
TEAE 
Treatment-Emergent Adverse Event 
TK 
Toxicokinetic 
TLS 
Tumor Lysis Syndrome 
TTP 
Time to Progression  
TME 
Tumor Microenvironment 
TPS 
Tumor Proportion Score 
Treg 
Regulatory T cell 
ULN 
Upper Limit of Normal 

 
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Abbreviation or 
Specialized Term 
Definition 
US FDA 
United States Food and Drug Administration 
USA 
United States of America 
WBC 
White Blood Cell  
WHO  
World Health Organization  

 
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1. 
INTRODUCTION 
This is an open-label, non-randomized, Phase 1 study to determine the safety and tolerability of 
NC525. This study will also assess the clinical benefit in subjects with advanced myeloid 
neoplasms. The study will be conducted in 2 parts, Dose Escalation and Safety Expansion. The 
safety and tolerability of NC525 will be evaluated by exploring escalating dose levels of NC525. 
In addition, the pharmacologically active dose (PAD), maximum tolerated dose (MTD), and 
minimally active dose (MAD) of NC525 will be determined. Once the MTD is achieved or the 
highest dose cohort is completed without the MTD, the safety and tolerability will be further 
assessed through expansion of a few dose levels to determine an optimal Recommended Phase 2 
Dose (RP2D) and administration schedule of NC525.  
1.1. 
Background 
1.1.1. 
Pharmaceutical and Therapeutic Background 
NC525 is a humanized immunoglobulin gamma 1, kappa (IgG1κ) monoclonal antibody specific 
for Leukocyte Associated Immunoglobulin Like Receptor 1 (LAIR-1) protein that is being 
developed for the treatment of acute myeloid leukemia (AML). LAIR-1 is a member of both the 
immunoglobulin superfamily and the leukocyte-associated inhibitory receptor family. Its genetic 
locus maps to a region of 19q13.4 called the leukocyte receptor cluster, which contains at least 29 
genes encoding leukocyte-expressed receptors of the immunoglobulin superfamily. LAIR-1 has 
been identified as an anchor for tyrosine phosphatase SHP-1. While LAIR-1 is exclusively 
expressed on immune cells, its expression is aberrantly elevated on AML cells. High LAIR-1 
expression on leukemic stem cells from AML patients and its absence on normal hematopoietic 
stem cells (HSCs) make it a unique and attractive target for a novel AML therapy.  
LAIR-1 regulates the immune system by binding to extracellular ligands that possess collagenous 
structures and delivering a signal to immune cells via a cytoplasmic tail containing two 
immunoreceptor tyrosine-based inhibition motifs (ITIMs). Endogenous LAIR-1 ligands identified 
to date include collagen, complement protein C1q, Surfactant Protein-D (SP-D), Mannose Binding 
Lectin (MBL), and Colec12. When LAIR-1 is activated by binding to its ligand, both ITIMs are 
phosphorylated, and SHP-1 phosphatases are recruited and phosphorylated to trigger immune-
inhibitory signaling in healthy immune cells. In AML, LAIR-1 functions to promote leukemia cell 
stemness and disease progression via the recruitment of SHP-1 but signaling occurs through a 
phosphatase independent SHP-1 pathway. NC525 binds to LAIR-1 with higher affinity than 
natural ligands and induces LAIR-1 ligation dependent cell death of AML cells.     
NC525 binds human LAIR-1 with an affinity of 2.27 nM and causes AML cell death primarily by 
inducing LAIR-1 receptor mediated signaling pathways in AML cells. NC525 restricted leukemic 
tumor growth of human MV4-11, and THP-1 AML in cell line-derived xenograft (CDX) models. 
In patient-derived xenograft (PDX) models, the disease progression and tumor burden of the 
patient-derived AML PBMCs implanted in NSG-SGM3 mice were decreased by NC525 
treatment. This anti-tumor activity was observed in multiple experiments utilizing patient-derived 
blasts from AML patients. NC525 also inhibited colony formation of patient-derived leukemic 
stem cells in an in vitro assay but did not affect colony formation of normal HSCs.  
NC525 does not function as a check point inhibitor. NC525 did not affect normal immune cells 
from CD34+ cord blood cells reconstituted in an NSG-SGM3 murine model. In a human 

 
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lymphocyte-replete CDX model NC525 treatment effectively reduced disease progression 
compared to animals treated with isotype, but NC525 had no effect on total numbers of T cells or 
B cells in the spleen, bone marrow, or blood, nor did NC525 alter T-cell activation status as 
measured by CD25 expression, suggesting NC525 does not function as a checkpoint inhibitor.  
Leukemias are malignant blood disorders characterized by uncontrolled overproduction of 
hematopoietic progenitors in acute leukemias or terminally differentiated leukocytes in chronic 
leukemias. Acute myeloid leukemia (AML) is the most common adult acute leukemia, whereas 
acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Extensive 
research has led to the recent approval of novel therapies in AML. However, the mainstay of 
treatment in AML has remained unchanged since the 1970s. Therefore, there is a significant unmet 
need for AML patients that fail to respond to or relapse after standard-of-care (SOC) treatments, 
including allogeneic stem cell transplantation and targeting actionable mutations. In addition, a 
significant fraction of SOC patients relapses due to the persistence of chemotherapy-resistant 
leukemia stem cells (LSCs) or immune evasion. Therefore, identifying unique therapies that target 
elusive LSCs and promote immune responses to AML to prevent relapse is highly sought after. 
Furthermore, since AML progenitors and normal myeloid progenitors share similar expression of 
cluster of differentiation (CD) markers, it is crucial to differentiate LSCs from HSCs and their 
normal progenitors to lessen or prevent cytopenia and other adverse side effects.  
LAIR-1 has been reported as a cell surface marker of acute lymphoblastic leukemia (ALL), and 
higher expression of LAIR-1 correlates with worse clinical outcomes (Yousef Alrayes et al. 
2019). Deletion of LAIR-1 in mouse BCR-ABL1 B cell leukemia cells led to cell death in vitro 
and disease remission within a leukemia transplant mouse model (Chen et al. 2015). Taken 
together, these data suggest that LAIR-1 may play a similar role in promoting ALL development 
through dominant oncogenic signaling pathways. 
In myeloid neoplasms, LAIR-1 expression is aberrantly high on AML blasts and LSCs, 
Myelodysplastic Syndrome (MDS) blasts and monocytes, and myelo-monoblasts of Chronic 
Myelomonocytic Leukemia.  
Our analyses have shown that LAIR-1 is preferentially expressed in LSCs and leukemic 
progenitors compared to HSCs and progenitors. Furthermore, Galen et al. have shown from a 
combination of transcriptomics and mutational analyses in single cells from AML patients, the 
existence of distinct functional subsets and their associated drivers (van Galen et al. 2019). This 
difference may explain the preferential killing of leukemic blasts and LSCs by NC525 with sparing 
of normal hematopoietic cells in preclinical studies, including in vitro CFU assays and in vivo in 
both CDX and PDX models.  
It has been reported that LAIR-1 functions to promote leukemia cell stemness and disease 
development via recruitment of Src Homology Region-1 (SHP-1) (Kang et al. 2015). Ligands 
containing collagen-like domains activate LAIR-1 to subsequently trigger downstream signaling 
molecules CAMK1 and CREB (Kang et al. 2015) which have been implicated in sustaining AML 
stem cell activity (Kang et al. 2015; Kang et al. 2016). LAIR-1 knockdown increases the cell death 
of leukemia cells (Kang et al. 2015). Interestingly, our data support a model in which enhanced 
LAIR-1 signaling by NC525 receptor ligation drives apoptotic signaling and cell death in AML 
cells.  
In summary, NC525, a LAIR-1 specific mAb being developed as a treatment for AML, has 
demonstrated potent activity against AML in several CDX and PDX models of disease. In addition, 

 
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these studies support the unique ability to spare normal stem cells and immune cells while 
simultaneously targeting and killing AML blast and leukemia stem cells through LAIR-1 ligation-
mediated cell death. The FIH study, NC525-01, will evaluate NC525 among patients with 
advanced myeloid neoplasms. 
1.1.2. 
Pharmacokinetics of NC525 
The pharmacokinetics (PK) of NC525 were studied in a single dose, dose-range finding (DRF) 
study, and a repeat dose Good Laboratory Practice (GLP) study.  
In the DRF study, NC525 serum concentration-time data following a single 0.5 h intravenous (IV) 
infusion was evaluated in four dose cohorts that ranged from 0.5 to 85 mg/kg in male and female 
cynomolgus monkeys. Two female monkeys dosed in the two lowest dose cohorts developed anti-
drug antibodies (ADA,) which resulted in a rapid clearance of NC525 from the system. Since only 
partial toxicokinetic (TK) was useful for these animals, they were excluded from TK analyses. In 
animals which did not develop ADA, NC525 remained quantifiable until the end of the study (504 
h) following dosing. The concentration-time profiles of serum NC525 were characterized by a bi-
phasic decline with time. Serum concentrations and TK parameters of NC525 within and between 
genders were generally comparable and within the expected biological variation. Serum maximum 
concentration (Cmax) of NC525 was observed at the end of infusion (tmax =0.5 h) except for animals 
dosed with 27.5 mg/kg NC525, which was 2 h. Serum Cmax and the area under the curve (AUC) 
of NC525 remained mostly dose proportional across doses and genders. Most of the circulating 
NC525 found in serum at Cmax disappeared during the rapid phase of elimination within 96 h; the 
rest was cleared afterward, during the terminal phase of elimination. The initial and terminal half-
life (T½) of NC525 ranged between 3.4-11.5 and 151-248 h, respectively, except for 0.5 mg/kg 
male, which was 341 h. Two apparent volumes of distribution of the two compartments, central 
(serum) and the tissue compartments (Vc,compt and Vt,compt), were 0.13-0.20 and 0.08-0.12 
mL/kg. Vc,compt and Vt,compt) were 0.13-0.20 and 0.08-0.12 mL/kg. The apparent volume of 
distribution at steady state (Vss) were 0.22-0.29 mL/kg. The combined Vss were 0.22-0.29 mL/kg. 
The combined clearance (Cl) of NC525 was 0.004-0.013 mL/h/ kg. The mean residence time 
(MRT) of NC525 was between 211 and 480 h in male and 205 and 337 h in female monkeys. 
A weekly dosing regimen was selected for the GLP repeat dose study to enable a weekly or bi-
weekly dosing regimen in the Phase I clinical trial. NC525 serum concentration-time data 
following a weekly dosing of 0, 2, 20, and 100 mg/kg over 0.5 h by IV infusion in male and female 
cynomolgus monkeys were determined after the first (Day 1) and last dose (Day 29). NC525 serum 
concentrations were below the lower limit of quantitation (LLOQ = 1500 ng/mL) in all pre-dose 
samples obtained from treated animals on Day 1 and from all 0.5-hour post start of infusion (SOI) 
samples analyzed from control animals on Day 29. 
Systemic exposure to NC525 appeared to be independent of sex. There were no consistent 
differences in individual serum concentrations, Cmax, and AUC values between males and females; 
therefore, the following discussion is based on combined data for males and females. NC525 was 
quantifiable up to 168 hours post SOI on Day 1 and up to 24 hours post SOI (the last timepoint for 
main study animals) or 240, 504, 672, and 840 hours post SOI at 2 mg/kg and up to 24 hours post 
SOI (the last timepoint for main study animals) or 1176 hours post SOI at 20 and 100 mg/kg on 
Day 29. Median NC525 Tmax values were observed by 0.5 hours post SOI on Days 1 and 29 
(median values could not be reported at 2 mg/kg on Day 29 or at 20 mg/kg on Day 1 due to not 
being an actual collection time point). Individual NC525 Tmax values ranged from 0.5 to 2.33 hours 

 
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post SOI at 2 mg/kg, 0.5 to 8 hours post SOI at 20 mg/kg, and from 0.5 to 2 hours post SOI at 100 
mg/kg. Following once weekly IV infusion administration of NC525, mean Cmax, AUC0-24hr, and 
AUC0-168hr values for NC525 increased with increasing dose in an approximately dose proportional 
manner on Days 1 and 29.  
Systemic exposure (AUC0-24hr and AUC0-168hr) to NC525 appeared to generally increase (~2-fold) 
following repeated administration of NC525. On Day 29, mean T1/2 values were 133, 262, and 255 
hours at 2, 20, and 100 mg/kg and mean Cl values were 0.410, 0.255, and 0.256 mL/hr/kg at 2, 20, 
and 100 mg/kg. 
All animals that were evaluated for ADA were negative at pretest, pre-dose on Days 15 and 29, 
and at recovery, with the exception of 1 male and 1 female at 20 mg/kg, which were confirmed 
positive at recovery (titers of 1:8 and 1:80, respectively). These animals were not excluded from 
the TK analysis. 
1.1.3. 
Pharmacology of NC525 
The pharmacology of NC525 has been studied in a variety of in vitro, ex vivo, and in vivo systems 
to support its use as an investigational drug in oncology.  
LAIR-1 regulates the immune system by binding to extracellular ligands and delivering a signal 
to immune cells via a cytoplasmic tail containing two ITIMs. When LAIR-1 is activated by binding 
to its ligand, both ITIMs are phosphorylated to trigger immune signaling, which, in AML, 
functions to promote leukemia cell stemness and disease progression. NC525 binds to LAIR-1 
with a much higher affinity than its natural ligands and induces LAIR-1 ligation dependent cell 
death of AML cells. The ability of NC525 and its parent molecule 11B3.IgG1 to inhibit AML cell 
growth and survival was tested in a series of non-clinical studies summarized below. 
NC525 binds human LAIR-1 with an affinity of 2.27 nM and causes AML cell death primarily by 
inducing LAIR-1 receptor mediated signaling pathways in AML cells. In multiple CDX and PDX 
mouse models, NC525 exhibited potent anti-leukemic activity. NC525 restricted leukemic tumor 
growth of human MV4-11 and THP-1 cells in CDX models. In PDX models, the disease 
progression and tumor burden caused by patient-derived leukemic stem cells implanted into NSG-
SGM3 mice was significantly decreased by NC525 treatment. This anti-tumor activity was 
observed in multiple independent experiments utilizing bone marrow derived from different AML 
patients. NC525 also inhibited colony formation of patient-derived leukemic stem cells ex vivo but 
did not affect colony formation of normal HSCs. Likewise, NC525 did not affect normal immune 
cells from CD34+ cord blood cells reconstituted in an NSG-SGM3 murine model. Finally, in a 
secondary transplant model, recipient mice engrafted with bone m arrow from NC525-treated PDX 
mice did not develop disease, unlike mice engrafted with bone marrow from control-treated PDX 
mice, indicating that NC525 targets and kills leukemic stem cells within the bone marrow.   
In summary, these collective data suggest that NC525 may be a promising agent to treat AML 
malignancy with the advantage of specifically destroying leukemic stem cells and sparing the 
normal HSCs. 
1.1.4. 
Non-Clinical Safety and Potential Risks of NC525 
The toxicology of NC525 has been studied in a variety of in vitro and in vivo systems to support 
its use as an investigational drug in leukemia. 

 
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NC525 treatment of healthy blood leukocytes did not elicit cell death nor cytokine release in vitro, 
nor did administration of NC525 in humanized mice impact leukocyte retention, T cell 
proliferation, or anti-leukemic activity. These data are described in the NC525 Investigator 
Brochure (IB). 
A GLP toxicity study in which cynomolgus monkeys were administered escalating doses of 
NC525 revealed no adverse effects. The most notable findings were a moderate to a marked 
reduction in NK cell counts in male monkeys at the highest dose cohort, 100 mg/kg, and an 
inflammatory response in one male animal in the high dose group, which could not be directly 
attributed to NC525. No clinical or veterinary findings were associated with the decrease in NK 
cells. The highest dose administered, 100 mg/kg, was identified as the NOAEL and HNSTD. 
Complete results of this study and dose-finding studies are described in the NC525 IB. 
1.2. 
Study Rationale 
1.2.1. 
Rationale for the Safe Starting Dose 
The safety of NC525 was assessed in two studies, a single dose range finding study and a repeat 
dose 28-day GLP-compliant study (5 doses, weekly). In the DRF study, NC525 was administered 
at four different dose levels ranging from 0.5 to 85 mg/kg and in the GLP study at, 2, 20, and 100 
mg/kg. There were no test article-related effects on body weight, food consumption, coagulation, 
or urinalysis in either the DRF or the repeat dose GLP study.  
Test article-related effects on hematology parameters in the DRF study were limited to minimally 
decreased red blood cell (RBC) count, hemoglobin, and hematocrit in the 85 mg/kg group female 
at Day 3 with complete reversibility at Day 22. In the GLP study, mild reduction in RBCs in males 
administered 100 mg/kg was also observed at Day 31. The changes in RBC mass parameters were 
not accompanied by alterations in other erythrocyte parameters in either study. A mild reduction 
in neutrophils was also noted in one female dosed at 100 mg/kg in the GLP study. This individual 
also had a lower neutrophil count at second pretreatment, and a similar magnitude of decreased 
neutrophil count was observed in a control male on Day 31. Therefore, the decrease in the 
neutrophil count was considered not likely related to NC525 treatment. 
In the GLP study, cynomolgus male monkeys that received 100 mg/kg/dose, had NC525-related 
decreases in CD45+CD159a+ cell counts (NK cells) evaluated by immunophenotyping, that 
persisted through the recovery period. Additionally, one male at 100 mg/kg/dose had evidence of 
an inflammatory response (minimal to mild increases in Döhle bodies, fibrinogen, and globulin 
with mild decreases in albumin and albumin/globulin ratio) and mild decreases in RBC mass 
parameters (erythrocyte count, hemoglobin concentration, and hematocrit) at the end of the dosing 
period, which had resolved following the recovery period. Due to the unique occurrence (1 out of 
10 monkeys) in this animal at the highest dose level, with a resolution during the non-dosing 
recovery period, these changes were of uncertain relation to NC525 administration. 
Test article-related effects on clinical chemistry parameters were limited to minimally decreased 
glucose concentration in the 27.5 and 85 mg/kg group males at Day 22 of the DRF study. No dose 
dependent changes in glucose were observed in the repeat dose study.  
In conclusion, administration of NC525 by intravenous infusion to cynomolgus monkeys was well 
tolerated at all doses up to 100 mg/kg.  

 
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The no observed adverse effect level (NOAEL) in monkeys was defined as 100 mg/kg. The peak 
plasma levels observed after 5 doses of 100 mg/kg every week were used as the safety threshold.  
Serum concentration profiles in monkeys were fit to a population PK model, which was scaled to 
predict human concentrations. Single species allometric scaling was applied for an average healthy 
adult weight of 80 kg as published (Wang et al. 2016) where 0.85 was applied as an exponent for 
the human to monkey weight ratio on clearance and no exponent was applied to the weight ratio 
on other parameters. The simulated peak serum concentrations were compared to the safety 
threshold, and a factor of 0.85 was estimated to define the Human Equivalent Dose (HED). 
Therefore, 100 mg/kg correspond to a HED of 85 mg/kg, and this is considered the NOAEL in 
human for the purposes of dose definition. 
The rationale for the proposed Phase 1 starting dose has considered all relevant preclinical 
pharmacology, toxicology data, and anti-leukemic effects in murine AML models.  
NC525 is well-tolerated, and repeated administration of dosages 50-fold higher (on a mg/kg basis) 
than the planned clinical starting dose were not associated with any adverse toxicities. 
A risk assessment for NC525 was performed to support dose selection. Relevant factors for NC525 
are discussed below. 
The rationale for the proposed Phase 1 safe starting dose (SSD) of 2 mg/kg is based on combined 
preclinical pharmacology and toxicology data, including anti-leukemic responses in murine AML 
models. The FDA Guidance for Industry Estimating the Maximum Safe Starting Dose (SSD) in 
Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers was used.  
The effectiveness results from CDX murine models were integrated to calculate the doses that lead 
to 30% (PD30 0.72 mg/kg), 50% (PD50 1.7 mg/kg) and 90% (PD90 15.3 mg/kg) of the maximum 
effect. Serum concentrations in mice were fit to a PK model, which was used to simulate the 
exposures in mice after multiple dosing. Simulations of 6 doses administered once weekly in 20 
gram (healthy) mice were performed to predict the exposures in CDX murine models under the 
assumption of equivalence in PK with healthy mice. The median simulated trough concentrations 
(minimum concentration at the end of the dosing interval) at the 3 dose levels were used to 
approximate efficacy thresholds.  
Single species allometric scaling was used to derive human pharmacokinetic parameters from 
Cynomolgus monkeys’ pharmacokinetics. The human PK model was used to simulate serum 
concentrations at different doses administered every two weeks, and the 95% CI of the simulated 
human trough values were compared to the simulated efficacy thresholds in mice. The comparison 
led to the conclusion that 2 mg/kg every two weeks in humans would lead to the majority of 
subjects with trough levels slightly above the median CDX mouse PD30 trough levels and a 5 
mg/kg dose would lead to the majority of subjects with a trough levels above the determined PD50. 
A dose of 30 mg/kg is predicted to result trough levels comparable to the PD90 identified from the 
CDX murine model. 
Therefore, the proposed planned dosing rationale is summarized, incorporating dose increment to 
less than a half-log (233%) between each dose level, as follows: 
• Dose Level 1: 2 mg/kg as an approximation of the minimally active dose (PD30) 
• Dose Level 2: 4.5 mg/kg as an approximation of PD50 
• Dose Level 3: 10 mg/kg to support the characterization of the dose effect curve 

 
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• Dose Level 4: 20 mg/kg to support the characterization of the dose effect curve 
• Dose Level 5: 30 mg/kg as an approximation of PD90 
The proposed dosing scheme provides a starting dose that is expected to minimize safety risks and 
has the potential to provide clinical benefit, which is ethically important in an oncology trial, 
especially in myeloid neoplasms including relapsed refractory AML, MDS, and CMML. In the 
absence of dose-limiting toxicity, the maximum dose that may be explored in the first in human 
trial will be 30 mg/kg, which is approximately 3-fold lower than the HED of the NOAEL (100 
mg/kg) determined by the 5-week GLP-compliant repeat-dose tox study in cynomolgus monkeys. 
Overall, the dose levels proposed should allow the initial characterization of a dose response curve 
in patients.  
1.2.2. 
Rationale of Disease Selection for Phase 1 Study 
NC525 has been extensively studied in AML and shows promising pre-clinical results, notably 
targeting LSCs while sparing HSCs. Therefore, it is naturally appropriate to start the FIH dosing 
in AML. 
NC525 has no effects on solid tumors based on pre-clinical models. Therefore, it is not feasible to 
do a FIH dose escalation study in solid tumors to define a recommended dose for AML. In addition, 
relapsed refractory Chronic myelomonocytic leukemia (CMML) and MDS were chosen for FIH 
dosing since CMML and MDS are relatively slowly progressing myeloid malignancies. 
1.2.3. 
Rationale for Efficacy Endpoints   
The goal of AML treatment is to control and, ideally, to eradicate disease. Being a Phase 1 study, 
the primary endpoint is safety and tolerability. Because of its sparing effect on normal HSCs, the 
aim is also to decrease the incidence of cytopenia-related complications. 
Efficacy will be assessed as a secondary endpoint and will include Objective Response (OR), 
Event-free survival (EFS), and Overall survival (OS). 
Efficacy measures for AML have been well established. The European Leukemia Net (ELN) has 
recently updated the guidelines on response criteria in AML (See Section 1.2.3.1 Response 
Criteria). Ideally, the purpose of an induction therapy is to achieve complete remission (CR). Once 
the CR is achieved, further therapies are given as consolidation and/or maintenance to deepen the 
remission and maximize response duration. However, since NC525 has not been tested in humans, 
despite its potential to eradicate leukemic stem cells from pre-clinical studies, there is 
understanding that transplant eligible patients will likely undergo allogeneic stem cell transplant 
at the discretion of the treating investigator. Assessing optimal value of the study drug will come 
from observing treatment effect of NC525 in patients who are ineligible for allogeneic stem cell 
transplant (SCT). 
1.2.3.1. 
Response Criteria for Disease Assessment  
Disease Assessments will be performed using the European Leukemia Net (ELN) Guidelines 
(Döhner et al. 2022) as outlined in the Schedule of Study Procedures (Table 7) and Appendix 6 for 
the ELN Outcome Measures.  
Criteria for Efficacy Measures evaluation are as follows (Döhner et al. 2022): 

 
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• Complete Remission (CR): Absolute neutrophil count > 1,000/μL , platelets ≥ 100,000/μL, 
red cell transfusion independence, and bone marrow with < 5% blasts. 
• CR with partial hematologic recovery (CRh): Absolute neutrophil count > 500/μL, platelets 
≥ 50,000/μL, otherwise all other CR criteria are met. 
• Complete Remission with Incomplete Blood Count Recovery (Cri): Bone marrow with less 
than 5% blasts, and absolute neutrophils of < 1,000/μL or platelets < 100,000/μL. 
• Partial Remission (PR): All of the hematologic values for a CR but with a decrease of at 
least 50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate. 
• Morphologic Leukemia-free State (MLFS): Less than 5% blasts in an aspirate sample with 
marrow spicules and with a count of at least 200 nucleated cells, absence of blasts with 
Auer rods, absence of circulating blasts, absence of extramedullary disease, no hematologic 
recovery required. 
• No Response: Patients evaluable for response but not meeting the criteria for CR, CRh, 
CRi, MLFS or PR are categorized as having no response prior to the response landmark. 
Patients failing to achieve response by the designated landmark are designated as having 
refractory disease. 
• Non-evaluable Response: Non-evaluable for response will include patients lacking an 
adequate bone marrow response evaluation. This category will include patients with early 
death, withdrawal prior to response assessment, or a technically suboptimal bone marrow 
sample precluding assessment  
Response should be based on the most recent bone marrow and hematology panel values. For 
subjects who require a delay in study treatment for peripheral blood count recovery after a bone 
marrow evaluation, hematology panel values for 2 weeks from the bone marrow analysis can be 
used to determine the ELN response. As a significant number of the subjects in this study may 
have antecedent hematologic illnesses, hematologic response will also be evaluated. 
1.3. 
Research Hypotheses 
Treatment with NC525, a humanized immunoglobulin gamma 1, kappa (IgG1κ) monoclonal 
antibody specific for LAIR-1, will, specifically kill leukemic cells while sparing healthy cells in 
both the bone-marrow and the periphery, ameliorating disease with minimal toxicity, and resulting 
in clinical benefit for subjects with advanced myeloid neoplasms. 

 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
STUDY OBJECTIVES  
2.1.1. 
Primary Objectives 
1) To evaluate the safety, tolerability, and dose-limiting toxicities (DLTs) of NC525 
2) The recommended Phase 2 dose (RP2D) of NC525 will be defined in subjects with 
advanced myeloid neoplasms 
3) Define a minimally active dose (MAD), pharmacologically active dose (PAD), and 
maximum tolerated dose (MTD) of NC525 in subjects with advanced myeloid neoplasms 
2.1.2. 
Secondary Objectives 
1) To evaluate the clinical benefit of NC525 
2) To evaluate the time to achieve an objective response (OR) 
3) To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of NC525 
2.1.3. 
Exploratory Objectives 
1) To assess the immunogenicity of NC525 
2) To explore biomarkers that may predict the pharmacologic activity of NC525 
2.2. 
STUDY ENDPOINTS  
2.2.1. 
Primary Endpoints 
1) Safety and tolerability will be assessed by monitoring the frequency, duration, and severity 
of adverse events (AEs). Note: Toxicity grading per NCI CTCAE v5.0 
2) The recommended Phase 2 dose (RP2D) of NC525 in subjects with advanced myeloid 
neoplasms. 
3) The MAD, PAD, and MTD of NC525 will be defined in subjects with advanced myeloid 
neoplasms. 
2.2.2. 
Secondary Endpoints 
1) Assessment of anti-leukemia activity/efficacy will be used to evaluate the clinical benefit 
of NC525, including:  
a. Objective Response (OR)  
▪ CR, CRi, or CRh and MLFS 
b. Event-free survival (EFS), and  
c. Overall survival (OS)  
2) Assessment of time to achieve response, defined as CR, CRi, or CRh 

 
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a. To evaluate the time to achieve an objective response from Cycle 1 Day 1 to day 
remission is achieved as defined per protocol  
3) Assessment of PK of NC525 concentration(s) in serum, as well as assessment of the PK/PD 
profile 
2.2.3. 
Exploratory Endpoints 
1) Immunogenicity, defined as the occurrence of anti-drug antibodies (ADA) to NC525, will 
be determined 
2) Biomarker effects of NC525 in peripheral blood and bone marrow will be assessed, 
including but not limited to the following: 
a. Percentage and/or expression level of LAIR-1 blast cells and/or Leukemic Stem 
Cells (LSC) or Hematopoietic Stem Cells (HSC) 
b. Any relation to response (clearing of blast cells to achieving CR) 
c. Serum markers of inflammation or immune modulation (cytokine & chemokine 
levels) 

 
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3. 
STUDY DESIGN 
3.1. 
Description of the Study  
This is an open-label, non-randomized, Phase 1 study to determine the safety and tolerability of 
NC525. This study will also assess the clinical benefit in subjects with advanced myeloid 
neoplasms. The study includes a dose escalation phase to determine MTD followed by expansion 
cohorts to further evaluate the safety and tolerability of the MTD (Figure 1). 
Figure 1: Phase 1 Study Design 
 
The safety and tolerability of NC525 will be evaluated by escalating dose levels of NC525. In 
addition, the minimally active dose (MAD), pharmacologically active dose (PAD), and maximum 
tolerated dose (MTD), of NC525 will be determined. 
The PAD will be defined as a dose that provides a maximal biologic effect, such as achieving a 
complete remission (CR) and other variants of complete remission (CRh, CRi), and/or the MTD 
 of NC525. 
Once the biologically-effective dose(s) deemed to be safe have been identified, the safety and 
tolerability will be further assessed through expansion of two dose levels to determine an optimal 
Recommended Phase 2 Dose (RP2D) and administration schedule of NC525.  
A Bayesian Optimal Interval (BOIN) design (Figure 2) with conventional 3+3 escalation rule 
fully nested for Phase I clinical trials (Liu S, Yuan Y, 2015) with a target dose-limiting toxicity 
(DLT) rate of approximately 25% will be applied for dose escalation and confirmation to 
determine a recommended Phase 2 dose (RP2D) for NC525.  

 
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Figure 2: Dose Finding Rules Per BOIN 
 
 
3.2. 
Study Phase and Cohorts 
3.2.1. 
Phase 1 Design 
A BOIN design will be utilized to determine the MTD of NC525, where a minimum of 3 evaluable 
subjects will be enrolled at each level from Cohort 2 onwards. In the case of the starting dose level 
(2mg/kg), a minimum of 1 evaluable subject may be enrolled (in the absence of severe toxicity) 
prior to determining escalation to the next dose level given the dose is an approximation of the 
minimally active dose (PD30). 
All dose escalation decisions will be based on the occurrence of DLTs at a given dose during the 
first 56-day period (i.e., first 2 cycles), also referred to as the DLT observation period (Figure 3). 
Dose escalation decisions will be made jointly by the Clinical Study Team comprised of the 

 
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Sponsor Medical Monitor, CRO Medical Monitor and Investigators once the minimum number of 
evaluable subjects (n=3) have completed the DLT observation period. 
Figure 3: Phase 1 Study Schema 
a. Cohort 1 
 
b. Cohort 2 and Above 
 
A subject is considered evaluable if they have received at least four doses of NC525 and completed 
the 56-day DLT observation period or discontinued earlier due to an adverse event. Only one 
subject will be dosed on the first day of dosing for each cohort (additional subjects can begin in ≥ 
48 hours). If there are multiple subjects in the screening process at the time the third subject within 
a cohort begins treatment, additional subjects may be enrolled with approval of the Sponsor using 
the BOIN design and based on the number of subjects evaluable at the current dose level.  

 
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expansion up to 14 subjects per dose (including subjects treated at that dose level in the dose 
escalation phase) will be performed.  
The doses for safety expansion are required to be no higher than the MTD and show sufficient 
PK/PD and anti-leukemic activities. The RP2D will be chosen based on an overall assessment of 
DLTs, safety profile, subject tolerance, biological activities and clinical efficacy signals collected 
at all different doses tested. The RP2D is required to be no higher than the MTD. A Bayesian 
toxicity monitoring rule will be used to ensure safety during safety expansion. Refer to Section 
10.2.2 for details. 
3.2.2. 
Dose Levels and Cohorts  
The Dose Escalation part of the study will begin the following planned dose levels and cohorts:  
• Dose Level 1: 2 mg/kg biweekly** 
• Dose Level 2: 2.5 mg/kg* weekly** 
• Dose Level 3: 4.5 mg/kg weekly** 
• Dose Level 4: 10 mg/kg weekly** 
• Dose Level 5: 20 mg/kg weekly** 
• Dose Level 6: 30 mg/kg weekly** 
** Cohort 1: Biweekly (Q2W) for Cycles 1 through 6 followed by every 4 weeks (Q4W) thereafter. 
Cohort 2 and above: Weekly (QW) dosing for Cycles 1 and 2. Subjects may continue QW dosing 
until overall response (e.g., CR, CRh, or CRi) is achieved, at which time they may switch to Q2W 
dosing.  
The planned dose levels for Dose Escalation include a maximum dose increment of less than a 
half-log (233%) between each dose level.  Using the Escalation/De-escalation Rules governed by 
the BOIN design, if criteria is met allowing dose escalation, the subsequent dose level will first be 
evaluated against the Dose Increment Modification Rules For Dose Escalation (Table 2) taking 
into consideration the number of adverse events (Grade ≥ 2) and dose limiting toxicities which 
occurred at the current dose level prior to selecting the next dose. 
In the event a dose increment modification is indicated during the Dose Escalation phase of the 
study, an ad-hoc safety meeting will occur with the Clinical Study Team to review the adverse 
event(s) against the qualifying criteria before any dose modifications are made.  
All Adverse Events (excluding AEs unequivocally due to the underlying disease or an extraneous 
cause) occurring during the DLT Observation Period will be evaluated against the Dose Increment 
Modification rules, as follows: 
• Limit the maximum dose increment to 100% if patients of a given cohort experience one 
Grade ≥ 2 AE (except for AEs unequivocally due to the underlying disease or an extraneous 
cause) during the DLT period. 
o Example: If one ≥ Grade 2 AE occurs in Dose Cohort 1 (2mg/kg), the subsequent 
dose level will be increased by 100% (4mg/kg) instead of the originally planned 
dose of 4.5mg/kg. 
 

 
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3.4. 
Number of Subjects 
3.4.1. 
Planned Number of Subjects 
Approximately 63 evaluable subjects may be enrolled in this study.  
Phase 1 Dose Escalation – Up to 30 evaluable subjects. 
Phase 1 Safety Expansion – Up to an additional 33 evaluable subjects may be enrolled. 
3.4.2. 
Replacement of Subjects 
Subjects may be replaced for any of the following reasons: 
• If a subject withdraws from treatment before the completion of the DLT period for any 
reason other than a DLT (e.g., subject is not evaluable for DLTs) 
• Subject does not meet the eligibility requirements of the study (accidental enrollment) 
3.5. 
Duration of Treatment and Participation 
After signing the informed consent form (ICF), screening assessments may be completed over a 
period of approximately 21 days. Subjects will continue for up to 2 years of treatment or until 
progressive disease, unacceptable adverse events (AEs), intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw the subject, subject withdraws 
consent, pregnancy of the subject, noncompliance with trial treatment or procedure requirements, 
or administrative reasons requiring cessation of treatment.  
3.6. 
Overall Study Duration 
The study begins when the first subject signs the ICF. Subjects may be eligible to receive study 
treatment for up to 2 years or until the criteria for discontinuation of treatment are met (whichever 
comes first).  
The end of the study may be declared when no more than 5 subjects remain on study treatment 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 treatment and be seen by the 
investigator per standard of care until withdrawal criteria is met (Section 5.10). The investigator 
will be expected to monitor for and report any serious AEs (SAEs), ECI, overdoses, and 
pregnancies, as detailed in Sections 9.1, 9.1.3, and 9.33. The remaining subjects will be considered 
on study until a discontinuation criterion is met and written notification is provided to the sponsor. 
3.7. 
Continued Access 
Subjects who are still on study intervention at the time of study completion/termination may 
continue to receive study intervention if they are experiencing clinical benefit after one year. The 
continued access to study intervention will end when a criterion for discontinuation is met.  
3.8. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract. The IRB must be notified in writing of the study's completion 

 
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or early termination, send a copy of the notification to the sponsor or sponsor's designee, and retain 
one copy for the site study regulatory file. 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 regulatory 
bodies of the decision and reason for termination of the study. 

 
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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 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
1) The subject is willing to provide written informed consent for the trial. 
2) Be ≥ 18 years of age on the day of signing informed consent. 
3) Subject has one of the following Myeloid Neoplasms determined by pathology review at the 
treating institution: 
• Relapsed or Refractory AML, 
Note: Active, relapsed, or refractory AML is defined as any one of the following:  
▪ Primary induction failure, or (PIF) after 2 or more cycles of therapy, 
▪ First early relapse after a remission duration of fewer than 6 months, 
▪ Relapse refractory to salvage combination chemotherapy second or 
subsequent relapse, or  
▪ Relapsed or refractory AML with at least 5% blasts by bone marrow biopsy 
or aspirate, or at least 1% blasts in peripheral blood 
• Relapsed or Refractory Myelodysplastic syndrome (MDS) after prior hypomethylating 
agents 
Note: Subject must have sub-type MDS-EB2 with 10-19% blasts by bone marrow biopsy 
or aspirate. 
• Relapsed or Refractory Chronic myelomonocytic leukemia (CMML) with progressive 
disease or lack of response to hypomethylating agents 
4) A male subject must agree to use approved contraception (based on institutional guidelines) 
and refrain from sperm donation or expecting to father a child, from Screening through the 
treatment period and for at least 90 days after the last dose of study treatment.  
5) A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least 
one of the following conditions applies: 
a) Not a woman of childbearing potential (WOCBP) 
b) A WOCBP agrees to follow approved contraceptive guidance (based on institutional 
guidelines) from Screening through the treatment period and for at least 90 days after the 
last dose of study treatment. 
6) Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 
7) Life expectancy greater than or equal to 12 weeks as judged by the Investigator. 
8) Have adequate organ function as defined in the following table (Table 3)  

 
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Table 3: Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematology  
 
Peripheral white blood cell (WBC) 
≤ 25,000/μL1 
Renal 
 
Measured or calculated2 creatinine 
clearance 
Creatinine clearance > 60 mL/min  
Hepatic 
 
Total bilirubin 
<1.5 × ULN OR direct bilirubin ≤ ULN for subjects 
with total bilirubin levels >1.5 × ULN.  
Note: Subjects with documented Gilbert's syndrome 
with elevated baseline total bilirubin ≤ 3.0 mg/dL or 
indirect hyperbilirubinemia suspected to be result of 
hemolysis may be enrolled. 
AST (SGOT) and ALT (SGPT) 
≤ 3.0 × ULN 
ALT (SGPT) =alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) =aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal. 
1 Hydroxyurea or cytarabine therapy is allowed to reduce white blood cells to meet this inclusion criterion. White 
blood cells should be determined ≥ 24 hours after the last leukoreduction therapy administration. Final leukoreduction 
therapy administration should not be administered ≤ 3 days prior to the first dose of NC525 without medical monitor 
approval. 
2 Creatinine clearance (CrCl) should be calculated per institutional standard. GFR can also be used in place of 
creatinine or CrCl. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies. 
Note: Screening labs must be collected within 7 days prior to the start of study treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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4.2. 
Exclusion Criteria: 
Subjects are excluded from the study if any of the following criteria apply: 
1) Has a diagnosis of acute promyelocytic leukemia (M3, APL), accelerated phase or blast crisis 
of chronic myeloid leukemia. 
2) History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult 
seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar 
disease, organic brain syndrome, or psychosis. 
3) Subjects with active Central Nervous System (CNS) involvement (such as leukemic 
infiltration, blast in the spinal fluid, or subjects with extramedullary disease). 
4) A WOCBP who has a positive pregnancy test (within 72 hours) prior to treatment.  
5) History or evidence of any other clinically significant disorder, condition or disease (e.g., 
symptomatic congestive heart failure, unstable angina pectoris, symptomatic myocardial 
infection, uncontrolled cardiac arrhythmia, pericardial disease or heart failure New York Heart 
Association Class III or IV), or severe debilitating pulmonary disease, that would potentially 
increase subjects' risk for toxicity and in the opinion of the Investigator, would pose a risk to 
subject safety or interfere with the study evaluation, procedures or completion. 
6) Chronic respiratory disease or any other medical condition that requires continuous oxygen 
that in the opinion of the Investigator, would adversely affect his/her participation in this study. 
7) Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study 
intervention. 
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. 
8) Is currently participating in or has participated in a study of the following prior to the first dose 
of study treatment: 
a. An investigational biologic or an investigational device within 4 weeks or 5 half-lives 
(whichever is longer); 
b. An investigational oral agent within 2 weeks or 5 half-lives (whichever is shorter). 
Note: Subjects who have entered the follow-up phase of an investigational study may 
participate as long as the specified washout period has been completed. 
9) Has not recovered to ≤ Grade 1 from toxic effects of prior therapy (including prior 
chemotherapy, targeted therapies, immunotherapy and radiation therapy) and/or complications 
from prior interventions before starting therapy.  
Note: Subjects with stable chronic conditions (≤ Grade 2) not expected to resolve (such as 
neuropathy and alopecia) are exceptions and may still enroll.  

 
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10) Has previously had an allogeneic solid organ transplant. 
11) Autologous HSCT within 6 weeks before the start of study treatment. 
12) Allogeneic HSCT within 6 months before the start of study treatment. 
13) Any active acute or chronic graft-versus-host disease (GvHD), Grade 2-4, or active chronic 
GvHD requiring systemic treatment.  
14) Any systemic therapy (e.g. calcineurin inhibitors (CNI), steroids, etc.) against GvHD within 4 
weeks before the start of study treatment.  
15) Any Grade ≥ 2 persistent non-hematological toxicity related to allogeneic transplant, such as 
those requiring systemic immunosuppressive therapy. 
16) Previous CAR-T therapy. 
17) Known concurrent malignancy that is progressing or requires active treatment, or history of 
other malignancy within 2 years of study entry after treatment with curative intent.  
Note: Cured basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, 
prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or 
indolent malignancy, or cancers from which the subject has been disease-free for > 1 year are 
not considered exclusionary. 
18) Has severe hypersensitivity (≥ Grade 3), known allergy or reaction to Immunoglobulins or 
NC525, and/or any of their excipients. 
19) Uncontrolled systemic fungal, bacterial, viral, or other infection despite appropriate anti-
infection treatment at the time of eligibility confirmation. 
20) Has a known history of HIV infection. Note: No HIV testing is required unless mandated by 
the local health authority.  
21) Has a known active chronic hepatitis B infection or chronic hepatitis C infection with the 
exception of those with an undetectable viral load within 3 months.  
22) Has a history or current evidence of any condition, therapy, or laboratory abnormality, or other 
circumstance that might confound the results of the study or interfere with the subject's 
participation for the full duration of the study, such that it is not in the best interest of the 
subject to participate, in the opinion of the treating investigator. 
23) Has a known psychiatric or substance abuse disorder that would interfere with the subject’s 
ability to cooperate with the requirements of the study. 

 
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5. 
TREATMENT 
5.1. 
Treatment Assignment 
5.1.1. 
Subject Numbering and Treatment Assignment 
All eligible subjects, after signing the ICF, will be allocated by non-random assignment, and will 
receive a unique subject number with the first 4 digits serving as the site number.  
Dose level and cohort assignment will occur at time of subject enrollment and as indicated by the 
sponsor or designee.  
All subjects will be assigned to a cohort to receive NC525; there is no placebo. 
5.1.2. 
Randomization and Blinding 
This is an open-label nonrandomized study; therefore, randomization and blinding do not apply. 
5.2. 
Description and Administration 
5.2.1. 
NC525 Description  
NC525 is in frozen liquid form formulated for IV infusion. NC525 is formulated at a nominal 
concentration of 60 mg/mL in 20 mM Histidine, 8% (w/w) sucrose, 0.03% (w/w) Polysorbate 80 
pH 5.5. Additional information can be found in the NC525 IB.  
5.2.2. 
Study Drug Administration  
The subject dose (in mg/kg) is determined by cohort enrollment. Dosing will be based on subject’s 
actual weight (or ideal body weight if considered obese) in kilograms. The site should determine 
and evaluate obesity based on institutional guidelines. 
NC525 will be prepared by adding the drug product directly to a bag containing 0.9% sodium 
chloride injection USP (normal saline) and delivered through an IV administration set. Final 
infusion concentration must be at or above 0.4 mg/mL and no more than 20 mg/mL. (Refer to 
Appendix 7).  
The use of 0.2 μm in-line filter is required for study drug administration.  
Storage of study drug after preparation is limited to room temperature. Total in-use storage time 
from the dilution of NC525 in the dilution bag/container to the completion of the study drug 
infusion should not exceed 4 hours at room temperature. If the in-use storage time exceeds these 
limits, a new dose must be prepared from new vials.  
NC525 must be administered by qualified personnel via IV infusion over a minimum of 30 minutes 
(subject to change depending on subject’s assigned dose level). See Appendix 7 for further infusion 
instructions. The minimum infusion rate must be at least 6 ml/hour and not more than 1600 
mg/hour. The NC525 Pharmacy Manual contains more specific instructions for the preparation 
and administration of NC525. 

 
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5.3. 
Supply Packaging and Labeling 
Study drug will be packaged as open-labeled supplies, each vial will be labeled and placed in a 
carton. The Pharmacy Manual contains additional information regarding supply, packaging, and 
labeling of NC525. 
5.4. 
Storage 
NC525 must be stored in a -20°C freezer, 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 
NC525 Pharmacy Manual contains additional information regarding storage of study drug. 
5.5. 
Accountability 
The investigator shall take responsibility for and take all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution, usage, and return or destruction of study 
drug in accordance with the protocol and any applicable laws and regulations. 
Detailed information such as requirements for accountability can be located within the NC525 
pharmacy manual, which will be provided separately. 
5.6. 
Treatment Compliance 
Compliance with NC525 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.  
5.7. 
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: “NC525-01 Product Complaint” 
5.8. 
Dose Modifications  
5.8.1. 
Criteria and Procedures for Modifications, Dose Interruptions and Adjustments 
of Study Treatments 
Treatment with NC525 may be delayed allowing for resolution of toxicities. 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 Cohort 1, NC525 is given by Intravenous (IV) infusion every two weeks (on Days 1 and 15 of 
each cycle) for the first 6 cycles. For subjects who continue on treatment beyond Cycle 6, NC525 
will be administered every 4 weeks (on Day 1 of each cycle only). 

 
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For Cohort 2 and above, there are four doses per cycle when following the weekly (QW) dosing 
schedule. Cycles begin with the first dose of each cycle and no sooner than 7 days from the last 
dose of the prior cycle. Subjects may continue weekly (QW) dosing until overall response (e.g., 
CR, CRh, or CRi) is achieved, at which time they may switch to biweekly (Q2W) dosing. For 
subjects who achieve overall response and switch to a biweekly (Q2W) dosing schedule, there are 
two doses per cycle, cycles begin with the first dose of each cycle and no sooner than 14 days from 
the last dose of the prior cycle. Patients will be taken off study therapy if there is greater than a 14-
day delay in scheduled treatment.  
Cycles must be administered in consecutive order, and a cycle is never skipped even in the event 
of a delayed dose.  
Study Treatment may be interrupted for situations other than treatment-related AEs such as 
medical or surgical events and/or unforeseen circumstances not related to study intervention. 
However, study intervention is to be restarted within 2 weeks or 14 days unless otherwise discussed 
with the Sponsor.  
Individual decisions regarding dose interruptions should be made using appropriate clinical 
judgment in consultation with the medical monitor, considering relatedness of the AE to the study 
treatments and the subject 's underlying condition. The Sponsor should be notified if a delay in 
study treatment is anticipated or occurs.  
If study treatment is interrupted, the reason for interruption is to be documented in the subject's 
study record. 
5.8.2. 
Instructions for Dose Modifications for Adverse Events  
Given that this is a FIH study, it is difficult to determine suspected adverse events however, based 
on established product class effects certain adverse events and their recommended management 
are detailed below. The following guidance may used in addition to institutional guidelines to 
manage dose modifications for such adverse events (Table 4). 
Table 4: Dose Modifications for Adverse Events 
AE Toxicity grade (CTCAE V5.0) 
Action with NC525 
Grade 3 Immune-related AE (e.g. 
pneumonitis, colitis, elevated LFTs 
(in absence of active disease), etc.) 
Interrupt Treatment,  
Restart treatment at one dose level lower when the 
specific immune-related AE resolves to no more than 
Grade 1 in severity. 
If immune-related AE does not resolve in 14 days, or 
if the Grade 3 immune-related AE recurs, the subject 
must permanently discontinue.  
Grade 4 Immune-related AE (e.g. 
pneumonitis, colitis, elevated LFTs 
(in absence of active disease), etc.) 
Permanently Discontinue 

 
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AE Toxicity grade (CTCAE V5.0) 
Action with NC525 
Grade 3 or Grade 4 Tumor Lysis 
Syndrome (TLS) 
Interrupt Treatment, Restart treatment at the same 
dose when the TLS is resolved to no more than Grade 
1 in severity within 2 weeks or 14 days, 
For Management of TLS, see Appendix 5 
Any Grade Infusion Reaction 
See Table 5 for management of infusion reaction.  
Differentiation Syndrome (DS)a  
(Grading based on reporting of 
individual symptoms) 
Interrupt Treatment, Administer corticosteroids per 
standard of care. Restart treatment at the same dose 
level with the DS is resolved within 2 weeks or 14 
days. 
New Onset Grade 4 Neutrophil Count 
Decrease lasting > 1 weekb  
Interrupt Treatment, Restart treatment at the same 
dose when the ANC is ≥ 500/μL within 2 weeks or 14 
days. 
If Grade 4 neutropenia recurs, interrupt again but 
restart at one dose level lower when the ANC is ≥ 
500/μL within 2 weeks or 14 days. 
New Onset Grade 4 Platelet Count 
Decrease lasting > 1 weekb 
Interrupt Treatment, Restart treatment at the same 
dose when the platelet count ≥ 25,000/μL within 2 
weeks or 14 days. 
If Grade 4 thrombocytopenia recurs, interrupt again 
but restart at one dose level lower when the platelet 
count is ≥ 25,000/μL  within 2 weeks or 14 days. 
Any other non-hematological Grade 
3 (other than TLS) adverse reaction  
Interrupt Treatment, Restart treatment at the same 
dose if the adverse reaction resolved to no more than 
Grade 1 in severity within 2 weeks or 14 days. 
If the adverse reaction recurs at Grade 4, the subject 
must permanently discontinue.  
If the adverse reaction recurs a second time at Grade 
3, interrupt again, and the subject must permanently 
discontinue.  
Any other non-hematological Grade 
4 (other than TLS) adverse reaction 
Permanently Discontinue 
a Differentiation Syndrome as determined per PI based on institutional guidelines and in the absence of active 
infection, infusion reaction, heart failure, etc., with any of the following potential signs and symptoms: unexplained 
fever, weight gain, peripheral edema, dyspnea with interstitial pulmonary infiltrates, pleural and/or pericardial 
effusion, hypotension, acute renal failure, with or without increasing total WBC. 
b In the absence of active myeloid neoplasms. 

 
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Note: For subjects who have not recovered ANC ≥ 500/μL or platelet count ≥ 25,000/μL within 
14 days of drug interruption, a repeat bone marrow biopsy and aspirate may be performed to rule 
out active myeloid neoplasms at the investigator discretion before resuming the next cycle of study 
treatment. 
5.8.3. 
Prophylaxis and Monitoring for Tumor Lysis Syndrome (TLS) 
Since NC525 has never been tested in humans, a potential risk for TLS in subjects with advanced 
myeloid neoplasms cannot be discounted, especially in those with elevated leukocyte count, 
circulating blasts, elevated pretreatment LDH levels, renal dysfunction, and dehydration. To 
mitigate the risk for TLS all subjects enrolled into the study will need TLS prophylaxis and 
monitoring. Prophylactic reductions of potassium, inorganic phosphorus or uric acid above normal 
range are recommended prior to beginning study treatment and continue based on the ongoing risk 
of TLS. 
Below are the minimum requirements for TLS prophylaxis and monitoring for subjects enrolled 
into the study. All other prophylaxis and monitoring procedures for TLS will be implemented as 
per regional guidelines/institutional standards: 
• Administration of uric acid reducing agent, adequate oral, and IV hydration while 
monitoring the fluid status of the subject beginning on Day -1 of Cycle 1. 
• For Cycle 1 Day 1 all subjects will be admitted to the hospital for the first 48 hours after 
study treatment or until the investigator deems the subject safe for continued outpatient 
monitoring.  
• Administration of uric acid reducing agent, adequate oral, and IV hydration while 
monitoring the fluid status of the subject beginning on Day -1 of Cycle 1. 
• TLS chemistry tests to be drawn (calcium, inorganic phosphorus, potassium, uric acid, and 
creatinine) within 24 hours prior to NC525 dosing on C1D1 and 6 – 8 hours post dose. TLS 
chemistry will also be drawn 24 hours and 48 hours post-dose on C1D1. TLS Chemistry 
tests should also be drawn within 24 hours pre-dose on C1D8, C1D15 and C1D22, and 24 
hours post-dose and 48 hours post-dose on C1D15.  
• Additional laboratory assessments may be performed, per investigator discretion if 
clinically indicated. 
• Abnormal chemistry tests should be treated promptly. 
• If a subject meets criteria for clinically significant laboratory or clinical TLS (see Appendix 
4), no additional NC525 dose should be administered until resolution. 
 
For continued dosing of NC525, monitor for evidence of TLS during treatment, and manage 
abnormalities of serum creatinine, uric acid, and electrolytes promptly. For subjects at higher risk 
(i.e., circulating blasts), more intensive measures should be considered.

 
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5.8.4. 
Toxicity Management of Infusion-Reactions Related to NC525 
Table 5 shows treatment guidelines for subjects who experience an infusion reaction associated 
with the 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. Adverse 
events that may be manifestations of infusion reactions may include but are not limited to: 
• Fever 
• Chills/Rigors 
• Flushing 
• Nausea/Vomiting 
• Bronchospasms 
• Hypotension/Hypertension 
To prevent infusion reactions from occurring all subjects must be premedicated prior to 
administration of NC525. Suggested premedication within 1.0 hour (± 30 minutes) prior to 
infusion of NC525 is detailed below, however subjects may be premedicated based on institutional 
guidelines: 
• Diphenhydramine 25 – 50 mg po or IV (or equivalent dose of antihistamine) 
• Acetaminophen 500 – 1000 mg po or IV (or equivalent dose of analgesic) 
• Ranitidine 150mg po (or equivalent dose of H2 antagonist) 
• Solu-Cortef 100mg IV (or equivalent corticosteroid) 
 
Table 5: Infusion Reaction Dose Modification and Treatment Guidelines (NC525) 
NCI CTCAE v5.0 Grade of 
Sign or Symptom of 
Infusion-Related Reaction 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction  
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  
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
• 
IV fluids 
• 
Antihistamines 
• 
Acetaminophen 
• 
NSAIDs 
• 
Narcotics 
• 
Prophylactic medications indicated for 
≤24 hrs 
Subject may be 
premedicated 1.5 h our 
(± 30 minutes) prior to 
infusion of study 
intervention with: 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 
mg po (or equivalent dose 
of analgesic). 

 
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NCI CTCAE v5.0 Grade of 
Sign or Symptom of 
Infusion-Related Reaction 
Treatment 
Premedication at 
Subsequent Dosing 
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 (e.g., from 100 
mL/hr. to 50 mL/hr.). Otherwise, dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Discontinue study treatment permanently for 
subjects who develop a Grade 2 or higher 
hypersensitivity reaction despite adequate 
premedication. 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening 
 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
• 
IV fluids 
• 
Antihistamines 
• 
Acetaminophen 
• 
Oxygen 
• 
Corticosteroids 
• 
Epinephrine** 
• 
NSAIDs 
• 
Narcotics 
• 
Pressors 
• 
Ventilator 
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. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Subject is permanently discontinued from 
further study drug treatment. 
No subsequent dosing 
Abbreviations: IV = intravenous; NSAID = nonsteroidal anti-inflammatory drugs; po = orally. 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration. For further information, please refer to the Common Terminology Criteria for 
Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov. 
 

 
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The above table is the recommended guidance, however subjects should be managed per 
institutional guidelines.  
 
5.9. 
Dose Limiting Toxicities (DLTs)  
5.9.1. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose 
During Dose Escalation, the evaluation period for DLTs will begin on Cycle 1 Day 1 and will 
continue up to 56 days. All DLTs will be assessed by the investigator using National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. A DLT will be 
defined as the occurrence of any toxicity in Table 6, except for events clearly associated with the 
underlying disease or an extraneous cause (e.g., car accident). 
Individual subject dose reductions may be made based on events observed at any time during 
treatment with NC525; however, for the purposes of dose cohort escalation/de-escalation, and 
expanding a dose cohort, the decisions will be made based on events that are observed from the 
first day of study treatment through and including the 56-day DLT period. Alternative dose levels 
may subsequently be determined based on relevant toxicities that become evident after the 56-day 
DLT period. 

 
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5.9.2. 
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. 
5.9.3. 
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. 
5.10. 
Withdrawal/Discontinuation of Subjects from Study Treatment 
5.10.1. 
Withdrawal/Discontinuation Criteria 
Subjects 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 
plan is violated, or for administrative and/or other safety reasons. 
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.  
If a subject is withdrawn, then every reasonable effort should be made to determine the reason for 
withdrawal, and this information should be recorded in the electronic case report form (eCRF). 
Subjects must be withdrawn from 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 
Subjects must discontinue from the study treatment but can continue to be monitored for any of 
the following reasons: 
• Consent is withdrawn for treatment (agrees to follow-up) 
• The subject becomes pregnant 
• Confirmed progressive disease (except if Sponsor approves treatment continuation) 
• Unacceptable adverse experiences 
• Investigator’s decision to withdraw subject 
• Subjects proceed to stem cell transplantation 
• Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR, CRh, or CRi and have been treated for two years with NC525  
• Any study intervention-related toxicity specified as a reason for permanent discontinuation 
as defined in the guidelines for dose modification due to AEs in Section 5.8. 
• The study is terminated by the IRB, regulatory authority, or Sponsor 

 
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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. All subjects will be 
followed for overall survival (OS) until death, withdrawal of consent, or the end of the study. 
5.10.2. 
Withdrawal Procedures 
If the decision is made to permanently discontinue the study treatment, an end-of-treatment (EOT) 
visit should be conducted. 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.  
5.11. 
Concomitant Therapy During Study Treatment  
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.  
Certain medications or vaccinations are specifically prohibited prior to and during the study. If 
there is a clinical indication for one of these medications or vaccinations specifically prohibited 
during the study, discontinuation from study drug or vaccination may be required. The investigator 
should discuss any questions regarding this with the medical monitor. The final decision on any 
supportive therapy or vaccination rests with the investigator and/or the subject's primary physician. 
However, the decision to continue the subject on study drug or vaccination schedule requires the 
agreement of the investigator, the sponsor, and the subject. 
5.11.1. 
Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the treatment period 
of this study: 
• Antileukemic systemic chemotherapy or biological therapy  
• Investigational agents other than NC525 
• Live or live attenuated vaccines  
• Hematopoietic growth factors (G-CSF, GM-CSF, ESA) 
• Steroid therapy during study participation should be limited to a lower dose and short 
duration if medically indicated. Exceptions can be inhalational steroids for the treatment 
of asthma or COPD, topical steroids and for prevention and/or treatment of transfusion-
related reactions. 
• Receipt of calcineurin inhibitors (CNI) while participating in the study 
If the investigator determines that a subject requires any of the aforementioned treatments for any 
reason, all study treatments of NC525 must be discontinued.  

 
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a. 
Written consent must be obtained prior to performing any protocol-specific procedure. Results of a test performed prior to the subjects signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 7 days prior to the first dose of trial treatment). 
b. 
Treatment cycles will begin every 28 days (+ 1 day window for weekly dosing schedule and + 7-day visit window for biweekly dosing schedule). 
c. 
NC525 will be administered every week during Cycles 1 and 2 on Day 1, Day 8,  Day 15, and Day 22. Subjects, may continue weekly (QW) dosing until overall response is achieved 
(e.g., CR, CRi, CRh), at which time they may switch to biweekly (Q2W) dosing. For biweekly dosing, NC525 will be administered every two weeks on Days 1 and 15 of each cycle.  
d. 
All subjects will be required to receive prophylaxis for TLS beginning on Day -1 of Cycle 1. Refer to Section 5.8.3 for more details on TLS Prophylaxis and APPENDIX 5– 
Recommendations for Initial Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome (TLS) for further information. 
e. 
Medical history will include relevant medical or surgical treatment within the last 10 years considered to be clinically significant by the investigator. 
f. 
Any prior medication received up to 21 days before the first dose of study drug should be recorded. All concomitant medications received up to 30 days after the last dose of study 
intervention should be recorded. Upon discontinuation of study treatment, only post-anticancer treatments and concomitant medications and procedures related to adverse events 
(including SAEs and ECIs) should be recorded. Please also refer to Sections 5.11.1  for details on prohibited and restricted medications.  
g. 
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 should 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.  
h. 
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. 
i. 
During Cycle 1, vital signs (blood pressure, pulse, respiratory rate, and body temperature) will be assessed pre-dose, at the end of infusion of study treatment (+10 minutes), and 
every 60 minutes ± 10 minutes thereafter for 2 hours or per PI discretion. At subsequent cycles, vital signs will be assessed pre-dose and at the end of infusion (+10 minutes) of study 
treatment. Additional vital signs may be collected per PI’s discretion if indicated.  
j. 
A standard 12-lead electrocardiogram (ECG) will be performed one time during screening using local standard procedures. Clinically significant abnormal findings should be 
recorded as medical history. Additional time points may be performed as clinically necessary at the discretion of PI.  
k. 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed but before first study treatment must be reported by the investigator if they cause the 
subject to be excluded from the study or are the result of a protocol-specified intervention, including but not limited to washout or discontinuation of usual therapy, or a procedure. 
From the time of first study treatment through 30 days following cessation of treatment, all adverse events must be reported by the investigator. SAEs and ECIs will be collected for 
90 days after the end of treatment or 30 days after the end of treatment if the subject initiates new post-treatment cancer therapy, whichever is earlier. . 
l. 
Laboratory tests for screening are to be performed within 7 days prior to the first dose of study treatment. 
m. Local Laboratory samples on Cycle 1 Day 1 must be performed before the administration of any study treatment and should be reviewed by the investigator or designee and found to 
be acceptable prior to the administration of study drug.  
n. 
On the day of study drug administration for all subsequent study treatments, pre-dose laboratory procedures can be conducted up to 72 hours before administration of study 
treatment. Local lab results should be reviewed by the investigator or qualified designee and found to be acceptable before treatment is initiated.  
o. 
Urinalysis to be performed at Screening. Urine dipstick – if abnormal, perform microscopic urinalysis. Additional time points may be performed as clinically necessary at the 
discretion of PI.  
p. 
Bone Marrow aspirate (smear, touch prep, or FFPE) will be sent to the Central Lab for retrospective central lab response analysis. Please refer to the Central Lab Manual for 
processing instructions.  
q. 
The serum pregnancy test performed at screening must be performed within 72 hours before the first dose of study drug. Serum pregnancy will also be performed at EOT. 
r. 
For women of child-bearing potential only, urine pregnancy must be performed within 72 hours prior to study treatment and resulted before study drug administration.  If positive, 
confirm results with serum pregnancy test.  
s. 
During Cycle 1 Day 1, subjects will be required to stay at the study site for safety observation for 48 hours after administration of NC525 infusion. For all subsequent doses subjects 
will be required to be observed for 1 hour post NC525 infusion or per PI discretion. After Cycle 1 Day 1, NC525 may be administered in an outpatient setting per investigator 
discretion. 
t. 
Refer to Table 9 for PK collection timepoints throughout the study.  
u. 
Refer to Table 9 for ADA collection timepoints throughout the study. 
v. 
Immunophenotyping (Bone Marrow) will be performed per Table 10. Please refer to the Central Lab Manual for instructions. 
w. Refer to Table 9 for Cytokine collection timepoints throughout the study.  

 
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x. 
Historical bone marrow aspirates at screening will not be accepted, a bone marrow aspirate and biopsy must be performed for study entry to collect mandatory biomarker 
assessments. 
y. 
Bone marrow aspirate and biopsy at Cycle 1 Day 14 is optional. If it is performed, immunophenotyping sample should also be collected.  
z. 
Bone marrow aspirate and biopsy at the end of Cycle 1 must be performed prior to administration of Cycle 2. Bone marrow aspirate and biopsy at the end of Cycle 2 must be 
completed within 3 days prior to Cycle 3 Day 1. Local Disease Assessments must be reviewed by the investigator or qualified designee and found to be acceptable prior to the 
administration of study drug for Cycle 3. Bone marrow aspirate and biopsies should continue to be collected every 28 days during QW dosing schedule.  
aa. All other subsequent bone marrow aspirate and biopsy collections during Q2W dosing, must be performed every 3 cycles (± 7 days)  and upon concern for progressive disease.  
bb. A Safety Follow-Up Visit should be performed for all subjects approximately 30 days following discontinuation of study drug and then as clinically appropriate for safety 
assessment. The subject should be followed until a satisfactory clinical resolution of any adverse event is achieved. The Safety Follow-up may be performed by phone. 
cc. Following the 30-day Safety Follow-up Visit, subjects should be followed approximately every 2 months to assess for survival status. For subjects who discontinue study drug for 
reasons other than disease progression, hematology and disease assessment data (per standard of care) will continue to be collected until PD or initiation of a new post-treatment 
cancer therapy. Updated survival status may be requested by the Sponsor at any time during the course of the study. 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 subjects that have a death event previously 
recorded). 
dd. Collect only if no bone marrow has been collected within last 6 – 8 weeks, or if relapse of disease has already been confirmed. 
ee. If Bone Marrow is collected per SOC, results should be recorded during the survival follow-up period until the subject discontinues the study. 

 
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Table 9: Schedule of Pharmacokinetic (PK), Pharmacodynamic (PD) and Biomarker 
Sample Collection 
Study Visit 
Assessment  
PK 
ADA 
Serum 
Cytokine 
Timing of Sample Collection 
Cycle 1 Day 1 
X 
X 
X 
Pre-infusion 
X 
 
X 
Post-infusion (+10 min) 
X 
 
 
4 h (± 30 min) post-infusion 
Cycle 1 Day 2 
X 
 
 
Anytime (24hrs post infusion)* 
Cycle 1 Day 3 
X 
 
 
Anytime (48hrs post infusion)* 
Cycle 1 Day 4 
X 
 
 
Anytime (72hrs post infusion)* 
Cycle 1 Day 8 
X 
 
X 
Pre-infusion 
Cycle 1 Day 15 
X 
X 
X 
Pre-infusion 
X 
 
X 
Post-infusion (+10 min) 
X 
 
 
4 h (± 30 min) post-infusion 
Cycle 1 Day 16 
X 
 
 
Anytime (24hrs post infusion)* 
Cycle 1 Day 17 
X 
 
 
Anytime (48hrs post infusion)* 
Cycle 1 Day 18 
X 
 
 
Anytime (72hrs post infusion)* 
Cycle 1 Day 22 
X 
 
X 
Pre-infusion 
Cycle 2 Day 1 
X 
X 
X 
Pre-infusion 
X 
 
X 
Post-infusion (+10 min) 
X 
 
 
4 h (± 30 min) post-infusion 
Cycle 2 Day 2 
X 
 
 
Anytime (24hrs post infusion)* 
Cycle 2 Day 3 
X 
 
 
Anytime (48hrs post infusion)* 
Cycle 2 Day 4 
X 
 
 
Anytime (72hrs post infusion)* 
Cycle 2 Day 8 
X 
 
X 
Pre-infusion 
Cycle 2 Day 15 
X 
X 
X 
Pre-infusion 
X 
 
X 
Post-infusion (+10 min) 
X 
 
 
4 h (± 30 min) post-infusion 
Cycle 2 Day 16  
X 
 
 
Anytime (24hrs post infusion)* 
Cycle 2 Day 17 
X 
 
 
Anytime (48hrs post infusion)* 
Cycle 2 Day 18 
X 
 
 
Anytime (72hrs post infusion)* 
Cycle 2 Day 22 
X 
 
X 
Pre-infusion 
Cycle 3 Day 1 
X 
X 
X 
Pre-infusion 
X 
 
 
Post-infusion (+10 min) 
X 
 
 
4 h (± 30 min) post-infusion 
Cycle 3 Day 2 
X 
 
 
Anytime (24hrs post infusion)* 
Cycle 3 Day 3 
X 
 
 
Anytime (48hrs post infusion)* 
Day 1 of Cycle 5, 
7, 11 
X 
X 
X 
Pre-infusion 
EOT  
 
X 
 
Anytime  
Abbreviations: ADA = anti-drug antibody; h = hours; min = minutes; PK = pharmacokinetics; EOT = End of 
Treatment  
*PK sample(s) is expected to be collected as close to the planned time as operationally feasible and the exact PK 
collection date and time should be recorded. 
 

 
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7. 
STUDY VISIT SCHEDULE  
7.1. 
Screening Period 
Screening is the interval between signing the ICF and the day the subject is enrolled (treated). 
Screening should be completed over approximately 21 days. Informed consent must be obtained 
before performing any study-specific procedures that are not considered standard of care. 
However, procedures conducted as part of the subject 's routine clinical management obtained 
before signing of informed consent may be used for screening or baseline purposes with approval 
of the medical monitor, provided that the procedure meets the protocol-defined criteria. 
Assessments that are required to demonstrate eligibility may be performed over the course of one 
or more days during the screening process. 
Results from the screening visit evaluations will be reviewed to confirm subject eligibility before 
enrollment or administration of study drug. Tests with results that fail eligibility requirements may 
be repeated once during screening if the investigator believes the results to be in error. For 
screening assessments that are repeated, the most recent available result before enrollment will be 
used to determine subject eligibility. Additionally, a subject who fails screening may repeat the 
screening process 1 time if the investigator believes there has been a change in eligibility status 
(e.g., after recovery from an infection). Treatment should start as soon as possible after the date of 
enrollment. 
7.2. 
Treatment Period 
The treatment period begins on Day -1 prior to the first dose of study treatment through the point 
at which the investigator determines that the subject will be permanently discontinued from study 
treatment.  
7.3. 
Treatment Schedule 
For Cohort 1, NC525 is given by Intravenous (IV) infusion every two weeks (on Days 1 and 15 of 
each cycle) for the first 6 cycles. For subjects who continue on treatment beyond Cycle 6, NC525 
will be administered every 4 weeks (on Day 1 of each cycle only). 
For Cohort 2 and above, NC525 will be administered every week on Days 1, 8, 15 and 22 during 
Cycles 1 and 2. Subjects may continue weekly dosing until overall response (e.g., CR, CRh, or 
CRi) is achieved, at which time they may switch to biweekly dosing. For biweekly dosing, NC525 
will be administered every two weeks on Days 1 and 15 of each cycle. Subjects who derive clinical 
benefit may continue to receive NC525 for a total of 2 years or until the criteria for discontinuation 
of treatment are met (whichever comes first). A detailed description of the dosing schedule is 
included below (Table 11): 
 
 

 
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7.5. 
Post-Treatment Follow-up 
7.5.1. 
30 Day Safety Follow-Up Visit 
A Safety Follow-Up Visit should be performed for all subjects approximately 30 days following 
discontinuation of study drug and then as clinically appropriate for safety assessment. If the subject 
has an AE which is ongoing at the time of the visit, the subject will be followed until a satisfactory 
clinical resolution of the adverse event is achieved. Safety Follow-up may be performed by phone. 
If the subject refuses or is unable to attend the Safety Follow-Up Visit, this should be noted in the 
subject's source documentation. 
7.5.2. 
Survival Follow-Up 
Following the 30-Day Safety Follow-Up Visit, overall survival and post treatment information 
(i.e., the date and cause of death, all post treatment cancer therapies including stem cell 
transplantation, regimens, dates of treatment initiation and completion, etc.) will be collected via 
telephone follow-up approximately every 2 months until death, withdrawal of consent, or the end 
of the study, whichever occurs first.  
For subjects who discontinue study drug for reasons other than disease progression, hematology, 
and disease assessment data (per standard of care) will continue to be collected until PD or 
initiation of a new post-treatment cancer therapy.  
7.6. 
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. 

 
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8. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
Individual study procedures are described in detail below. It may be necessary to perform these 
procedures at unscheduled timepoints if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary for reasons related to subject 
safety. In some cases, such evaluation/testing may be potentially sensitive in nature (e.g., HBV, 
HCV), and thus local regulations may require that additional informed consent be obtained from 
the subject. In these cases, such evaluations/testing will be performed in accordance with those 
regulations.  
8.1. 
Administration of Informed Consent Form 
Valid informed consent must be obtained from the subject before conducting any study-specific 
procedures using an ICF approved by the IRB and/or other regulatory authorities (as required per 
local laws and regulations). 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. 
8.2. 
Subject Identification Card 
All subjects will be given a Subject Identification Card identifying them as subjects in a research 
trial. The card will contain trial site contact information (including direct telephone numbers) to 
be utilized in the event of an emergency. The investigator or qualified designee will provide the 
subject with a Subject Identification Card immediately after the subject provides written informed 
consent. 
8.3. 
Demography and Medical History 
8.3.1. 
Demographics and General Medical History 
Demographic data and a complete medical and medication history will be collected at screening 
by the investigator or qualified designee and will include date of birth, race, ethnicity, medical and 
surgical history, and current illnesses. Medical history will include all active conditions, and any 
condition diagnosed within the prior 10 years that are considered to be clinically significant by the 
investigator. Disease details will be recorded separately and not listed as medical history. 
Please note that if the subject has lost at least 15 lbs. (6.8 kg.) over the three months prior to 
screening, “weight loss” should be entered as an active condition on the Medical History. As well, 
any autoimmune disorders, regardless of onset date, should be recorded. 
8.3.2. 
Disease Characteristics and Prior Anticancer Treatment History 
A disease-targeted medical and medication history will be collected at screening. Details regarding 
the subject 's malignancy under study including but not limited to date of diagnosis and subtype, 
antecedent hematologic disorder histology, and prior treatments, and surgical procedures will be 
recorded.  

 
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8.4. 
Prior and Concomitant Medications and Procedures 
Prior and concomitant medications and procedures will be reviewed to determine subject 
eligibility. All concomitant medications and procedures must be recorded in the eCRF, and any 
medication received, or procedure performed within 21 days before the first dose of study drug.  
All concomitant medications administered during the study will be recorded on the eCRF, 
including all prescription, over the counter, vaccines, herbal supplements, and iv medications and 
fluids. Any addition, deletion, or change in the dose of these medications should also be recorded. 
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.  
Upon discontinuation of study treatment, only post-anticancer treatments and concomitant 
medications and procedures related to adverse events (including SAEs and ECIs) should be 
recorded.  
8.5. 
Post-Treatment Cancer Therapy  
The investigator or qualified designee will review all new post treatment cancer therapy initiated 
after the last dose of study drug, including all post treatment cancer therapies including stem cell 
transplantation, regimens, dates of treatment initiation and completion, etc. Once new anti-
leukemic therapy has been initiated the subject will move into survival follow-up.  
8.6. 
Clinical Assessments and Procedures 
8.6.1. 
Adverse Event Monitoring 
Subjects will be instructed to report all AEs during the study and will be assessed for the 
occurrence of new or worsening 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 9.1. 
8.6.2. 
Physical Examinations 
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. 
8.6.2.1. 
Comprehensive Physical Examination 
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. 
Clinically notable abnormalities that are considered clinically significant in the judgment of the 
investigator are to be reported as AEs. 
8.6.2.2. 
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 

 
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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. 
8.6.3. 
Eastern Cooperative Oncology Group Performance Status 
The investigator will assess Eastern Cooperative Oncology Group (ECOG) performance status at 
Screening, and on Days 1, 8, 15, and 22 during QW dosing. ECOG will also be performed at Days 
1 and 15 during Q2W dosing. More information on assessing performance status using ECOG can 
be found in 03. 
8.6.4. 
Height, Weight, and Vital Signs  
Weight will 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. 
Height will be recorded at Screening only. 
Vital sign measurements include blood pressure, pulse, respiratory rate, and body temperature. 
Blood pressure and pulse should be taken with the subject in the recumbent or semi recumbent 
position after 5 minutes of rest.  
During Cycle 1, vital signs will be assessed pre-dose, at the end of infusion (+10 minutes), and 
every 60 minutes ± 10 minutes thereafter for 2 hours and for longer timepoints per PI discretion.  
At subsequent cycles, vital signs will be assessed pre-dose and at the end of infusion (+10 minutes). 
Additional vital signs may be collected per PI’s discretion if indicated.  
8.6.5. 
Tumor Lysis Syndrome (TLS) Prophylaxis 
All subjects will be required to receive prophylaxis for TLS beginning on Day -1 of Cycle 1. 
Refer to Section 5.8.3 for more details on TLS Prophylaxis and Monitoring.  
8.6.6. 
Safety Observation  
NC525 may be administered in an outpatient setting. However, for Cycle 1 Day 1 all subjects will 
be admitted to the hospital for the first 48 hours after study treatment or until the investigator 
deems the subject safe for continued outpatient monitoring.  
During subsequent doses, subjects will be required to stay at the study site for safety observation 
for 1 hour post NC525 infusion or per PI discretion.  
At the Investigators discretion, further treatment can be delivered in an inpatient setting for 
subjects with disease characteristics that, in the Investigators clinical judgment, put the subject at 
higher risk of complications (e.g., TLS). 
8.6.7. 
12-Lead Electrocardiogram 
All 12-lead ECGs should be performed with the subject in a recumbent or semi recumbent position 
after 5 minutes of rest. A single 12-lead ECG will be performed at Screening. Additional ECGs 
should be performed per PI discretion if any clinically significant abnormal findings are noted or 
as indicated. 

 
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8.6.8. 
Local Safety Laboratory Assessments 
A laboratory, local to the study site and subject, will perform all clinical laboratory assessments 
for safety (e.g., blood chemistries, hematology assessments, inflammatory markers, coagulation 
tests, and urinalysis). All local laboratory assessments should be performed using standard 
procedures on the days indicated in the Schedule of Study Procedures in Table 7. Additional 
information regarding the specific laboratory analytes required for each test are detailed in Table 
8. Additional testing may be required by the sponsor based on emerging safety data. Additional 
tests may also be performed if clinically indicated. 
Laboratory tests for screening are to be performed within 7 days prior to the first dose of study 
treatment on Cycle 1 Day 1. 
On Day 1 of all cycles, pre-dose laboratory procedures should be collected within 72 hours and 
results should be reviewed by the investigator or qualified designee and found to be acceptable 
prior to administration of study treatment.  
For any laboratory test value outside the reference range that the investigator considers to be 
clinically significant: 
• The investigator may repeat the test to verify the out-of-range value. 
• The investigator will follow the out-of-range value to a satisfactory clinical resolution. 
• A laboratory test value that requires a subject to be discontinued from the study, requires a 
subject to receive treatment, meets protocol specific criteria (see Section 5.9 regarding 
toxicity management) and/or the investigator considers clinically significant will be 
recorded as an adverse event. 
8.6.9. 
Pregnancy Testing 
A local laboratory serum pregnancy test will be required for all women of childbearing potential 
during screening and at the EOT visit. The serum pregnancy test performed at screening must be 
performed within 72 hours before the first dose of study drug. Urine pregnancy tests will be 
performed locally as outlined in Table 8. 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. 
8.6.10. 
Hepatitis Screening Tests 
Hepatitis screening assessments will be performed at the screening visit to rule out hepatitis 
infection; required analytes are shown in Table 8. Generally, hepatitis tests should be performed 
early in the screening process due to the length of time needed to obtain the results.  

 
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8.6.11. 
Central Laboratory Assessments  
Sample collection, processing, storage, and shipment instructions for the Central Laboratory 
assessments will be provided in the laboratory manual. 
8.7. 
Pharmacokinetic Assessments 
PK and ADA samples should not be collected through the same line in which the study drug is 
infused. If a central line is used for study drug infusion, collect PK and ADA samples via peripheral 
blood draw to prevent sample contamination. 
Pre-infusion is defined as within 24 hours before administration of any study treatment. 
Adjustments to the timing of blood sampling may be made based on emerging PK data. The exact 
date and time of each PK and ADA blood draw will be recorded in the eCRF. Instructions for 
sample preparation and shipping will be provided in the Laboratory Manual. 
8.8. 
Biomarker and Correlative Assessments 
Serum cytokine and biomarker samples will be collected at the visits outlined in the Schedule of 
Study Procedures. 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 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 Central Laboratory Manual for the study. 
8.9. 
Bone Marrow Biopsies 
8.9.1. 
Bone Marrow Biopsy Collection Requirements 
Bone Marrow Biopsy samples are required for participation in the study. Mandatory biopsies will 
be collected as specified below: 
Screening: Bone marrow aspirate and biopsy are required at screening to confirm diagnosis.  
On-treatment: On-treatment bone marrow aspirate and biopsy are required on Cycle 1 Day 28 
and at the end of Cycle 2. Cycle 1 Day 14 bone marrow aspirate and biopsy is optional per PI 
discretion. Bone marrow aspirates and biopsies will continue to be collected every 28 days during 
QW dosing. 
All other subsequent bone marrow aspirate and biopsy collections during Q2W dosing must be 
performed every 3 cycles and upon concern for progressive disease. 
At the End of Treatment (optional), The End of Treatment (EOT) bone marrow aspirate and 
biopsy may be obtained at the time that study treatment has been discontinued. (If no bone marrow 
collected within the last 6 – 8 weeks, or if relapse of disease has already been confirmed). 
NOTE: Details and methods for obtaining, processing, and shipping bone marrow biopsy samples 
will be provided in the Central Laboratory Manual for the study. 

 
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8.9.2. 
Bone Marrow Aspirate and Biopsy for Disease Assessment 
Historical bone marrow aspirates and biopsies at screening will not be accepted; a bone marrow 
aspirate and biopsy must be performed for study entry to collect mandatory biomarker 
assessments. The bone marrow aspirate and/or biopsy should be performed after all other 
eligibility criteria have been met. Bone marrow aspirates and/or biopsies performed as standard of 
care throughout the study should also be captured on the appropriate eCRF. 
A sufficient bone marrow aspirate and bone marrow core biopsy must be collected for all subjects 
at each of the disease assessments for local pathology assessment, mandatory biomarker 
assessments and retrospective central lab response analysis. 

 
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9. 
SAFETY MONITORING AND REPORTING 
9.1. 
Adverse Events (AEs) 
9.1.1. 
Adverse Event Definition 
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. 
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). 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
Hospitalization of a subject to allow for observation and management (e.g., IV hydration) for the 
purpose of TLS prophylaxis will not be captured as an SAE unless there is an additional reason 
for hospitalization or an additional criterion for seriousness other than hospitalization is met.  
9.1.2. 
Serious Adverse Event Definition 
An SAE is defined as an event that meets at least 1 of the following criteria: 
• Death of Subject 
o An event that results in the death of a subject. 
• Life-Threatening 
o An event that, in the investigator’s opinion, would have resulted in immediate 
fatality if the medical intervention had not been taken. This does not include an 
event that would have been fatal if it had occurred in a more severe form. 
• Hospitalization or Prolongation of Hospitalization 
o An event that results in an admission to the hospital for any length of time or 
prolongs the subject's hospital stay. This does not include an emergency room visit 
or admission to an outpatient facility. 
• Congenital Anomaly 
o An anomaly detected at or after birth, or any anomaly that results in fetal loss. 
• Persistent or Significant Disability/Incapacity 

 
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o An event that results in a condition that substantially interferes with the activities 
of daily living of a study subject. Disability is not intended to include experiences 
of relatively minor medical significance such as headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained ankle). 
• Important Medical Event Requiring Medical or Surgical Intervention to Prevent 
Serious Outcome 
o An important medical event that may not be immediately life-threatening or result 
in death or hospitalization, but based on medical judgment, may jeopardize the 
subject and may require medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of the subject, life-threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or significant 
disability/incapacity). Additionally, any elective or spontaneous abortion or 
stillbirth is considered an important medical event. Examples of such events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. 
 
For serious adverse events with the outcome of death, the date and cause of death will be recorded 
on the appropriate case report form.  
 
Progressive disease is not considered a serious adverse event, unless symptoms and clinical 
manifestations of disease progression meet any of the SAE criteria noted above.  
 
9.1.3. 
Events of Clinical Interest (ECI) 
Since NC525 has never been used in clinical trials, selected non-serious and serious adverse 
events are listed below as Events of Clinical Interest (ECI) and must be reported to the Sponsor 
within 24 hours of awareness by the Investigator. Since NC525 is a humanized monoclonal 
antibody, infusion reactions may occur. Furthermore, treatment of advanced myeloid neoplasms 
may cause differentiation syndrome and tumor lysis syndrome. Therefore, ECI are listed as 
precautionary for safety of subjects participating in NC525 study.  
For the time period beginning with initiation of study treatment, any ECI, or follow up to an ECI, 
that occurs to any subject must be reported within 24 hours to the Sponsor. 
Events of clinical interest for this trial include:  
• Infusion Reaction 
• Tumor Lysis Syndrome 
• Differentiation Syndrome 
• An adverse event meeting definition of a DLT as defined in Section 5.9.1. 

 
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9.1.4. 
Management of Myelosuppression Related to Disease 
Myelosuppression and the related adverse events (thrombocytopenia, anemia, neutropenia, and 
febrile neutropenia) are common in subjects with myeloid neoplasms. Subjects with baseline 
neutropenia might be particularly at high risk. 
Anti-infective prophylaxis should be implemented per regional guidelines or institutional 
standards including appropriate prophylaxis for bacterial, viral, and fungal infections. Treatment 
of sepsis and other infections (e.g. viral, other infections) should be managed per institutional 
guidelines.  
Red blood cell transfusion and platelet transfusion should be given per institutional guidelines. 
Erythropoietin-stimulating agent (ESA), Granulocyte Colony Stimulating Factor (G-CSF), and 
Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) are not permitted.  
9.1.5. 
Reporting of an Overdose 
For NC525, a definitive “overdose” level is unknown at this time. For the purpose of this trial, an 
overdose of NC525 will be defined as a subject receiving a dose of NC525 in excess of that 
assigned to them at the time of enrollment unless the alternative dose level was otherwise 
authorized by the Sponsor prior to administration.  
Any overdose of a study subject with NC525 with or without associated AEs/SAEs, is 
required to be reported within 24 hours of knowledge of the event to the Sponsor or its 
designee. If the overdose results in an AE, the AE must also be recorded on the AE eCRF. 
Overdose does not automatically make an AE serious, but if the consequences of the overdose are 
serious, for example death or hospitalization, the event is serious and must be reported as an SAE.  
9.1.6. 
Reporting of AEs 
AEs (including laboratory abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible rather than by individual underlying signs and symptoms. The investigator, 
who is a qualified physician, and any designees are responsible for detecting, assessing, 
documenting, and reporting events that meet the definition of an AE or SAE as well as other 
reportable safety events. Investigators remain responsible for following up AE, SAEs, and other 
reportable safety events for outcome. 
The severity of AEs will be assessed using NCI CTCAE v5.0 Grades 1 through 5.  
If an event is not classified by NCI CTCAE, the severity of the AE will be graded according to 
Table 12 to estimate the grade of severity. 
Table 12: 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. 

 
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Grade 
Clinical Characteristics 
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. 
Grade 5 
Death 
The occurrence of AEs should be sought by nondirective questioning of the subject during the 
screening process after signing the ICF and at each visit during the study. Adverse events may also 
be detected when they are volunteered by the subject during the screening process or between 
visits, or through physical examination, laboratory test, or other assessments. To the extent 
possible, each AE should be evaluated to determine: 
• The severity grade (NCI CTCAE v5.0 Grade 1 to 5). 
• Relationship to study drug: unrelated, unlikely related, possibly related, probably related, 
and definitely related. See Appendix 1. 
• The start and end dates, unless unresolved at final follow-up. 
• The action taken with 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 9.1.2.  
All AEs should be treated appropriately. If an AE is treated with a concomitant medication or 
nondrug therapy (e.g., procedure), this action should be recorded on the AE eCRF and the event 
should be correlated as the indication on the appropriate eCRFs as applicable. 
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 
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. 
9.1.7. 
Time Period and Frequency for Collecting AE, SAE, and Other Reportable Safety 
Event Information 
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed but 
before first study treatment must be reported by the investigator if they cause the subject to be 
excluded from the study or are the result of a protocol-specified intervention, including but not 

 
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limited to washout or discontinuation of usual therapy, diet, or a procedure. SAEs and ECIs will 
be collected for 90 days after the end of treatment or 30 days after the end of treatment if the 
subject initiates new post treatment cancer therapy, whichever is earlier.  
All AEs from the time of first study treatment through 30 days following cessation of study 
treatment must be reported by the investigator.  
All SAEs or ECIs, from the time of first study treatment through 90 days following cessation of 
study treatment, or 30 days following cessation of study treatment if the subject initiates new post-
treatment cancer therapy, whichever is earlier must be reported by the investigator.  
All pregnancies and exposure during breastfeeding, from the time of first study treatment through 
90 days following cessation of study treatment, or 30 days following cessation of study treatment 
if the subject initiates new post-treatment cancer therapy must be reported by the investigator.  
Additionally, any SAE brought to the attention of an investigator at any time outside of the time 
period specified above must be reported immediately to the Sponsor if the event is considered to 
be study drug related. 
9.1.8. 
Reporting of SAEs or ECIs 
Within 24 hours of identifying an SAE/ECI, 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/ECI reporting will be provided 
by the CRO. The sponsor is responsible for reporting certain SAEs as expedited safety reports to 
applicable regulatory authorities, ethics committees, and participating investigators, in accordance 
with ICH Guidelines and/or local regulatory requirements. The sponsor may be required to report 
certain SAEs to regulatory authorities within 7 calendar days of being notified about the event; 
therefore, it is important that investigators submit additional information requested by the sponsor 
or delegate as soon as it becomes available. 
Investigators should provide all available information at the time of SAE Report Form completion. 
Investigators should not wait to collect additional information to fully document the event before 
notifying the Sponsor or its designee of an SAE/ECI. 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/ECI also needs to 
be provided the Sponsor or its designee within 24 hours of learning of the new information. 
9.2. 
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 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. 

 
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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 9.1.2.  
9.3. 
Pregnancy  
If a subject inadvertently becomes pregnant while on study treatment with NC525 the subject will 
be immediately discontinued study treatment. The site will contact the subject at least monthly and 
document the subject’s status until the pregnancy has been completed or terminated. The outcome 
of the pregnancy will be reported to the Sponsor without delay and within 24 hours if the outcome 
is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or 
life-threatening complication to the mother or newborn). The study investigator will make every 
effort to obtain permission to follow the outcome of the pregnancy and report the condition of the 
fetus or newborn to the Sponsor.  
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 treatment or 30 days if 
a new post treatment cancer therapy is initiated, the following procedures should be followed to 
ensure subject safety: 
• The study drug must be discontinued immediately (female subjects only). 
• Consent must be obtained from female partners of male subjects. 
• The investigator must complete and submit the Clinical Trial Pregnancy form to the 
sponsor or its designee within 24 hours of learning of the pregnancy. 
• A serum pregnancy test must be performed to confirm the urine pregnancy test result 
(female subjects only). 
If a negative serum test does not confirm the urine pregnancy test result, then: 
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). 
Pregnancy should be recorded on a Clinical Trial Pregnancy form and reported by the investigator 
to the sponsor or its designee. Pregnancy outcomes of spontaneous abortion missed abortion, 
benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and 
stillbirth must be reported as serious events (Important Medical Events). If the pregnancy 
continues to term, the outcome (health of infant) must also be reported. Pregnancy follow-up 
information should be recorded on the same form and should include an assessment of the possible 
causal relationship to the study treatment to any pregnancy outcome.  
Any SAE occurring during pregnancy must be recorded on the SAE report form and 
submitted to the sponsor or designee. 

 
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9.4. 
Warnings and Precautions 
Special warnings or precautions for the study treatment, derived from safety information collected 
by the sponsor or its designee, are presented in the NC525 IB. Additional safety information 
collected between IB updates will be communicated to Investigators as it becomes available. 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. 
9.5. 
Procedures for Cohort Safety Review and Dose Escalation Meetings 
Telephone conferences will be scheduled by the sponsor, or sponsor’s delegate, with the Clinical 
Study Team to review cohort-specific data and overall safety data, make dose escalation/de-
escalation decisions, evaluate dose increment modifications, agree on dose finding, adjudicate 
individual high-grade AEs as potentially dose-limiting, and guide other major study decisions. 
 

 
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10. 
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 (SAP) 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 NC525. Additional details of statistical analyses will be described 
in a supplemental SAP. 
10.1. 
Statistical Analysis Overview 
Key elements of the statistical analysis plan are summarized in Table 13.  
Table 13: Key Elements of the Statistical Analysis Plan (SAP) 
Element 
Plan for analysis 
Study Design 
Overview 
This is an open-label, non-randomized, Phase 1 study to determine the safety 
and tolerability of NC525. This study will also assess the clinical benefit in 
subjects with advanced myeloid neoplasms. 
Analysis 
Populations 
Safety Analysis Set (SAS): The SAS will include all the subjects who receive 
any amount of NC525 and will be used for summaries and analyses of safety 
data. 
PK Analysis Set (PAS): The PAS will include all the subjects whose blood 
samples are collected for PK analysis and will be used for PK data summaries 
and analyses.  
Full Analysis Set (FAS): The FAS includes all subjects enrolled in the study 
who received at least one full dose of NC525. The FAS will be used for 
summaries and analyses of all data that are not safety or PK 
Primary 
Endpoint(s) 
1) Safety and tolerability will be assessed by monitoring the frequency, 
duration, and severity of adverse events (AEs). Note: Toxicity grading 
per NCI CTCAE v5.0 
2) The recommended Phase 2 dose (RP2D) of NC525 in subjects with 
advanced myeloid neoplasms. 
3) The MAD, PAD, and MTD of NC525 will be defined in subjects with 
advanced myeloid neoplasms. 

 
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Secondary 
Endpoints 
1) Assessment of anti-leukemia activity/efficacy will be used to evaluate the 
clinical benefit of NC525, including:  
a. Objective Response (OR)  
i. CR, CRi, or CRh and MLFS 
b. Event-free survival (EFS), and  
c. Overall survival (OS)  
2) 
Assessment of time to achieve response, defined as CR, CRi, or CRh 
a. To evaluate the time to achieve an objective response from Cycle 1 
Day 1 to day remission is achieved as defined per protocol 
3) 
Assessment of PK of NC525 concentration(s) in serum, as well as 
assessment of the PK/PD profile 
Statistical Methods 
for Efficacy/ 
Immunogenicity/ 
Pharmacokinetic 
Analyses 
Using the FAS, all the efficacy data will be summarized by dose level and 
cohort. 
The PK analyses will be based off the PAS, and PK time-concentration data 
will be summarized, listed, and plotted. PK parameters (AUC0-168, AUC0-∞, 
Cmax, t½, etc.) derived from time-concentration data will be summarized. 
Treatment 
Assignment 
This is an open-label study. 
Statistical Methods 
for Safety Analyses 
All the safety data in the SAS will be summarized and listed by dose level and 
cohort.  
Interim Analyses 
No formal interim analysis is planned. However, the safety, PK and efficacy 
data will be regularly reviewed and monitored for decisions involving the dose 
escalation and safety expansion parts of the study.  
Multiplicity 
Individual cohorts will be evaluated independently. 
Sample Size and 
Power  
The overall study sample size is approximately 63. 
Dose Escalation: The planned sample size is up to 30 subjects. 
Safety Expansion: The planned sample size is up to 33 subjects 
Abbreviations: AE = adverse event; AUC = area under the curve; Cmax = maximum concentration of drug; 
CR = complete response; CTCAE = Common Terminology Criteria for Adverse Events; FAS = Full Analysis Set; 
NCI = National Cancer Institute; OR = objective response; PAS = Pharmacokinetics Analysis Set; 
PD = pharmacodynamics; PK = pharmacokinetics; PR = partial response; RP2D = recommended Phase 2 dose; 
SAS = Safety Analysis Set; t1/2 = half-life. 
10.2. 
Selection of Sample Size 
Approximately 63 eligible subjects (Up 30 in Dose Escalation and up to 33 in Safety Expansion) 
in Phase 1 will be included in this study. 

 
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10.2.1. 
Sample Size for Dose Escalation 
We will employ the Bayesian optimal interval (BOIN) design (Liu 2015; Yuan et al. 2016) to guide 
dose escalation and establish the MTD or the optimal biologically active recommended Phase 2 
dose (RP2D) for NC525.  
The target toxicity rate for the MTD is ϕ= 0.25 and the maximum sample size per cohort is 12. We 
will enroll and treat subjects in cohorts of size 3. DLTs are defined in Section 5.9. The steps to 
implement the BOIN design are described as follows: 
1. To minimize the chance of exposing subjects to potentially subtherapeutic doses, perform 
the accelerated titration at dose level 1 (DL1) as follows: treat the first subject at DL1, if a 
DLT or two or more grade 2 toxicities are observed, treat 2 additional subjects at DL1; 
otherwise escalate to DL2 and hereafter treat subjects in cohort size of 3. 
2. To assign a dose to the next cohort of subjects, conduct dose escalation/de-escalation 
according to the rule displayed in Table 1 (or equivalently Figure 2). When using Table 
1/Figure 3, please note the following: 
• If the criteria is met to escalate the dose, dose escalation will be evaluated against the 
Dose Increment Modification Rule (Table 2). 
• “Eliminate” means eliminate the current and higher doses from the trial to prevent 
treating any future subjects at these doses because they are overly toxic. 
• When we eliminate a dose, automatically de-escalate the dose to the next lower level. 
When the lowest dose is eliminated, stop the trial for safety. In this case, no dose should 
be selected as the MTD. 
• If none of the actions (i.e., escalation, de-escalation or elimination) is triggered, treat 
the new subjects at the current dose. 
• If the current dose is the lowest dose and the rule indicates dose de-escalation, treat the 
new subjects at the lowest dose unless the number of DLTs reaches the elimination 
boundary, at which point terminate the trial for safety. 
• If the current dose is the highest dose and the rule indicates dose escalation, treat the 
new subjects at the highest dose. 
3. Repeat step 2 until the maximum sample size of 30 is reached or stop the trial if the number 
of evaluable subjects treated at the current dose reaches 9 and the decision according to the 
rules described in Step 2 is to stay at the current dose. 
The sample size of dose escalation is not based on conventional power calculation, but chosen to 
be consistent with typical phase I oncology trials and calibrated using simulation. Below provides 
the operating characteristics of the trial design based on 1000 simulations of the trial using shiny 
app "BOIN" (BOIN V2.7.6.0), showing that the design selects the true MTD, if any, with high 
probability and allocates more patients to the dose levels with the DLT rate closest to the target of 
0.25. 
 
 

 
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Table 14: Operating characteristics of the BOIN design 
 
Dose Level 
Number of 
Patients 
% Early 
Stopping 
 
1 
2 
3 
4 
5 
Scenario 1 
 
 
 
 
 
 
 
True DLT Rate 
0.25 
0.41 
0.45 
0.49 
0.53 
 
 
Selection % 
67.6 
16.9 
6 
1.4 
0.2 
 
7.9 
% Pts Treated 
43.5 
34.3 
17.6 
3.9 
0.7 
18.4 
 
Scenario 2 
 
 
 
 
 
 
 
True DLT Rate 
0.12 
0.25 
0.42 
0.49 
0.55 
 
 
Selection % 
25.9 
53.5 
16.9 
2.8 
0.2 
 
0.7 
% Pts Treated 
24.2 
41.1 
27.1 
6.4 
1.1 
21.2 
 
Scenario 3 
 
 
 
 
 
 
 
True DLT Rate 
0.04 
0.12 
0.25 
0.43 
0.63 
 
 
Selection % 
1.8 
23.8 
60.5 
13.5 
0.4 
 
0 
% Pts Treated 
8.4 
25.7 
41.8 
20.6 
3.4 
22.1 
 
Scenario 4 
 
 
 
 
 
 
 
True DLT Rate 
0.02 
0.06 
0.1 
0.25 
0.4 
 
 
Selection % 
0.3 
2.3 
21.4 
58.3 
17.7 
 
0 
% Pts Treated 
5.3 
8.6 
30.3 
37.3 
18.5 
22.9 
 
Scenario 5 
 
 
 
 
 
 
 
True DLT Rate 
0.02 
0.05 
0.08 
0.11 
0.25 
 
 
Selection % 
0.5 
0.9 
7.3 
22.1 
69.2 
 
0 
% Pts Treated 
5.2 
7.5 
20.6 
30.4 
36.4 
21.6 
 
Note: "% Early Stopping"" refers to early stopping due to excessive DLT. 
10.2.2. 
Sample Size for Safety Expansion 
After the dose escalation is completed, select the MTD based on isotonic regression as specified 
(Liu 2015).  
To better characterize and optimize RP2D, depending on the toxicity and PK/PD data, backfill (up 
to 6 additional subjects per dose) could start during the dose escalation given the dose has been 
deemed tolerable by the design, and could be performed at more than two doses.  
After Dose Escalation has been completed, safety expansion up to 14 subjects per dose (including 
subjects treated at that dose level in the dose escalation phase) will be performed. 
The doses for safety expansion are required to be no higher than the MTD and show sufficient 
PK/PD and anti-leukemic activities. The RP2D will be chosen based on an overall assessment of 
DLTs, safety profile, subject tolerance, biological activities and clinical efficacy signals collected 
at all different doses tested. The RP2D is required to be no higher than the MTD. A Bayesian 
toxicity monitoring rule will be used to ensure safety during safety expansion. At the RP2D, if 3 
or more responses are observed, up to an additional 14 subjects may be enrolled to further evaluate 
its antitumor activities, safety and tolerability. Among the total of 28 subjects at the RP2D, if 9 or 
more responses are observed, the treatment is regarded as promising. 

 
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At the RP2D, the futility stopping rule (i.e., the safety expansion is subject to potential termination 
if 2 or fewer responses are observed among the first 14 subjects) yields the operating characteristics 
listed in Table 15 based on simulation.  
Table 15: Futility Stopping Rule 
Scenario Response Rate Early Stopping (%) Claim Promising (%) Average Sample Size 
1 
0.2 
44.81 
8.67 
21.7 
2 
0.4 
3.98 
84.06 
27.4 
3 
0.5 
0.65 
97.84 
27.9 
During safety expansion, we monitor toxicity using the Bayesian optimal phase 2 (BOP2) design 
(Zhou, Lee, and Yuan 2017). Table 16 below provides the stopping boundaries of the BOP2 
design. 
Table 16: Optimized Stopping Boundaries 
No. of subjects treated Stop if no. of toxicity >= 
6 
2 
12 
4 
18 
5 
28 
7 
If the stopping boundaries are crossed, the subject accrual to that dose will be halted and the totality 
of safety data will be reviewed for potential termination of that dose.  
Let 𝒑𝒕𝒐𝒙 denote the true toxicity rate, the above stopping rule is obtained by maximizing Pr (claim 
that the treatment is safe | 𝒑𝒕𝒐𝒙= 𝟎. 𝟏𝟓), while controlling Pr(claim that the treatment is safe | 
𝒑𝒕𝒐𝒙= 𝟎. 𝟐𝟓) ≤ 0.3, based on the following Bayesian stopping rule: the treatment is deemed 
unacceptably toxic if 
𝑷𝒓(𝒑𝒕𝒐𝒙≤𝟎. 𝟐𝟓|𝒅𝒂𝒕𝒂) < 𝝀(𝒏
𝑵)
𝜶/𝟑
, 
where, 𝑛 is the interim sample size, 𝑁 is the maximum sample size, and 𝜆=0.55 and 𝛼=0.07 are 
design parameters optimized, assuming a vague prior Beta(0.25, 0.75) for 𝑝𝑡𝑜𝑥 to make “go/no-
go” decision. Note that the original publication of the design used the probability cutoff 𝜆(𝑛/𝑁)𝛼, 
here the attenuation factor 3 is added (i.e., 𝛼/3) to obtain stricter interim stopping boundaries to 
enhance safety. 
Below in Table 17 are the operating characteristics of the design based on 10,000 
simulations. 
 

 
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Table 17: Operating Characteristics 
Scenario Toxicity Rate Early Stopping (%) Claim Acceptable (%) Average Sample Size 
1 
0.33 
84.03 
7.99 
11.3 
2 
0.25 
62.85 
27.97 
15.7 
3 
0.15 
27.64 
69.63 
22.4 
4 
0.05 
3.38 
96.61 
27.3 
Note: Since NC525 is a humanized monoclonal antibody, infusion reactions may occur. 
Furthermore, treatment of advanced myeloid neoplasms may cause differentiation syndrome and 
tumor lysis syndrome. Therefore, such events will be categorized as ECIs. Although these events 
may contribute to Dose Limiting Toxicities, they will be excluded when calculating the toxicity 
rate for evaluation of the stopping rule, except for Grade ≥ 3 differentiation syndrome that has not 
resolved within 7 days. All other events as defined in the DLT Table (Table 6) will be used as the 
criteria to evaluate the severe toxicity rate in the calculation of the stopping rule. 
10.3. 
Statistical Analyses 
10.3.1. 
Safety Analyses 
All the safety data in the SAS will be summarized and listed by dose level and cohort. 
10.3.1.1. Adverse Events 
A treatment-emergent adverse event (TEAE) is any AE either reported for the first time or 
worsening of a pre-existing event after the first dose of study drug. Analysis of AEs will be limited 
to TEAEs, but data listings will include all AEs regardless of their timing to study drug 
administration. Adverse events will be tabulated by the MedDRA preferred term and system organ 
class. Severity of AEs will be based on the NCI CTCAE v5.0 using Grades 1 through 5. 
The subset of AEs considered by the investigator to have a relationship to study drug will be 
considered treatment-related AEs (TRAEs). 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. 
10.3.2. 
PK Analyses 
The PK analyses will be based off the PAS, and PK time-concentration data will be summarized, 
listed, and plotted. PK parameters (AUC0-168, AUC0-∞, Cmax, t½, etc.) derived from time-
concentration data will be summarized. 
10.3.3. 
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: 

 
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• Correlation analysis between PD biomarkers and the disease response to treatment with 
NC525. 
The immunogenic potential of NC525 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. 

 
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11. 
STUDY AND DATA MANAGEMENT 
11.1. 
Training of Study Site Personnel 
Before the first subject is entered into the study, a NextCure representative will review and discuss 
the requirements of this protocol and related documents with the investigational staff and train 
them in any study-specific procedures and system(s) utilized. 
The Principal Investigator (PI) will ensure that appropriate training relevant to the study is given 
to all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The PI will maintain a record of all individuals involved in the study (medical, nursing, and other 
staff). 
11.2. 
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, and that biological samples are handled in 
accordance with the Central Laboratory Manual  
• That study drug accountability checks are being performed. 
• Perform source data verification (a comparison of the data in the eCRFs with the subject’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating subjects. This will require direct 
access to all original records for each subject (e.g., clinic charts). 
• Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject. 
The NextCure representative will be available between visits if the investigator(s) or other staff at 
the center needs information or advice about the study conduct. 
11.2.1. 
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. 

 
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Data recorded on source documents will be entered into eCRFs. The investigator must promptly 
review the completed eCRFs for each subject. A study monitor representing the sponsor will 
review the source documents against the eCRF on a regular basis throughout the study. 
The PI at each/the center should comply with all the terms, conditions, and obligations of the 
Clinical Study Agreement, or equivalent, for this study. In the event of any inconsistency between 
this protocol and the Clinical Study Agreement, the terms of the protocol shall prevail with respect 
to the conduct of the study and the treatment of subjects and in all other respects, not relating to 
study conduct or treatment of subjects, the terms of the Clinical Study Agreement shall prevail. 
Agreements between NextCure and the PI must be in place before any study-related procedures 
can take place, or subjects are enrolled. 
11.2.2. 
Archiving of Study Documents 
The Investigator follows the principles outlined in the Clinical Study Agreement and according to 
the ICH-GCP and applicable regulatory requirements. Records will be retained for at least 2 years 
after the last marketing application approval or 2 years after the study is discontinued and the FDA 
is notified.  
11.3. 
Study Timetable and End of Study 
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. 
11.4. 
Data Management 
Data management will be performed according to the study specific supplemental Data 
Management Plan. 
A web based Electronic Data Capture (EDC) system will be used for data collection and query 
handling. The investigator will ensure that data are recorded on the eCRFs as specified in the study 
protocol and in accordance with the instructions provided. 
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and of 
the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived at 
the study site. 
11.5. 
Medical Monitor Coverage 
Each subject will be provided with contact information for the PI and the site coordinator(s). In an 
emergent situation, a subject may present to a medical facility where the treating health care 
provider is not involved with this clinical trial. The treating healthcare provider may require 
additional information on the study drug, and the subject should provide contact information for 
the site coordinator(s) or the PI. 
The PI will then be required to update the medical monitor. 

 
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12. 
ETHICAL AND REGULATORY REQUIREMENTS 
12.1. 
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. 
12.2. 
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  any genetic data being linked 
to the identity of the subject (if applicable). 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. 
12.3. 
Regulatory Review 
An IRB 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 opinion of the IRB should be given in writing. Written approval must be received by the 
sponsor or designee before enrollment of any subject into the study. 
The IRB should approve all advertising used to recruit subjects for the study. 
The sponsor or designee should approve any modifications to the ICF that are needed to meet local 
requirements. 
If required by local regulations, the protocol should be re-approved by the IRB 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. 
The sponsor or designee will handle the distribution of any of these documents to the national 
regulatory authorities. 

 
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The sponsor or designee will provide Regulatory Authorities, IRB, and PIs with safety 
updates/reports according to local requirements, including suspected unexpected serious adverse 
reactions (SUSARs), where relevant. 
IRBs must be informed 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 termination or completion 
12.4. 
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. The ICF must be approved by the IRB and contain all elements 
required by national, state, local and institutional regulations, or requirements. 
The PI at each center will: 
• Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk, and benefit of the study 
• Ensure each subject is notified that they are free to discontinue from the study at any time 
• Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided 
• Ensure each subject voluntarily provides signed and dated informed consent before 
conducting any procedure specifically for the study 
• Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File 
• Ensure a copy of the signed ICF is given to the subject  
• Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in the 
ICF that is approved by an IRB 
12.5. 
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 and if 
applicable, also the national regulatory authority approval, before implementation. Local 

 
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requirements are to be followed for revised protocols. Documentation of IRB/ IEC approval must 
be forwarded to the sponsor, or sponsor’s delegate. 
The sponsor or designee will distribute any subsequent amendments and new versions of the 
protocol to each PI. For distribution to IRB see Section 12.3. 
If a protocol amendment alters the study design, increases potential risk to the subject or otherwise 
affects statements in the ICF, the ICF must be revised accordingly and submitted to the sponsor or 
designee and the IRB 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. 
12.6. 
Audits and Inspections 
Authorized representatives of NextCure, a regulatory authority, or an IRB may perform audits or 
inspections at the clinical sites, including source data verification. The purpose of an audit or 
inspection is to examine all study-related activities and documents systematically and 
independently, 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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13. 
REFERENCES 
Chen, Z., S. Shojaee, M. Buchner, H. Geng, J. W. Lee, L. Klemm, B. Titz, T. G. Graeber, E. 
Park, Y. X. Tan, A. Satterthwaite, E. Paietta, S. P. Hunger, C. L. Willman, A. Melnick, 
M. L. Loh, J. U. Jung, J. E. Coligan, S. Bolland, T. W. Mak, A. Limnander, H. Jumaa, M. 
Reth, A. Weiss, C. A. Lowell, and M. Muschen. 2015. 'Signalling thresholds and 
negative B-cell selection in acute lymphoblastic leukaemia', Nature, 521: 357-61. 
Döhner, Hartmut, Andrew H. Wei, Frederick R Appelbaum, Charles Craddock, Courtney D. 
DiNardo, Hervé Dombret, Benjamin L. Ebert, Pierre Fenaux, Lucy A. Godley, Robert P. 
Hasserjian, Richard A. Larson, Ross L. Levine, Yasushi Miyazaki, Dietger Niederwieser, 
Gert J Ossenkoppele, Christoph Röllig, Jorge Sierra, Eytan M. Stein, Martin S. Tallman, 
Hwei-Fang Tien, Jianxiang Wang, Agnieszka Wierzbowska, and Bob Löwenberg. 2022. 
'Diagnosis and Management of AML in Adults: 2022 ELN Recommendations from an 
International Expert Panel', Blood. 
Kang, X., J. Kim, M. Deng, S. John, H. Chen, G. Wu, H. Phan, and C. C. Zhang. 2016. 
'Inhibitory leukocyte immunoglobulin-like receptors: Immune checkpoint proteins and 
tumor sustaining factors', Cell Cycle, 15: 25-40. 
Kang, X., Z. Lu, C. Cui, M. Deng, Y. Fan, B. Dong, X. Han, F. Xie, J. W. Tyner, J. E. Coligan, 
R. H. Collins, X. Xiao, M. J. You, and C. C. Zhang. 2015. 'The ITIM-containing receptor 
LAIR1 is essential for acute myeloid leukaemia development', Nat Cell Biol, 17: 665-77. 
Liu, S., & Yuan, Y. 2015. 'Bayesian optimal interval designs for phase I clinical trials'. 
Oken, M. M., R. H. Creech, D. C. Tormey, J. Horton, T. E. Davis, E. T. McFadden, and P. P. 
Carbone. 1982. 'Toxicity and response criteria of the Eastern Cooperative Oncology 
Group', Am J Clin Oncol, 5: 649-55. 
Sampson, H. A., A. Munoz-Furlong, R. L. Campbell, N. F. Adkinson, Jr., S. A. Bock, A. 
Branum, S. G. Brown, C. A. Camargo, Jr., R. Cydulka, S. J. Galli, J. Gidudu, R. S. 
Gruchalla, A. D. Harlor, Jr., D. L. Hepner, L. M. Lewis, P. L. Lieberman, D. D. Metcalfe, 
R. O'Connor, A. Muraro, A. Rudman, C. Schmitt, D. Scherrer, F. E. Simons, S. Thomas, 
J. P. Wood, and W. W. Decker. 2006. 'Second symposium on the definition and 
management of anaphylaxis: summary report--second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium', Ann Emerg 
Med, 47: 373-80. 
van Galen, P., V. Hovestadt, M. H. Wadsworth Ii, T. K. Hughes, G. K. Griffin, S. Battaglia, J. A. 
Verga, J. Stephansky, T. J. Pastika, J. Lombardi Story, G. S. Pinkus, O. Pozdnyakova, I. 
Galinsky, R. M. Stone, T. A. Graubert, A. K. Shalek, J. C. Aster, A. A. Lane, and B. E. 
Bernstein. 2019. 'Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease 
Progression and Immunity', Cell, 176: 1265-81 e24. 
Wang, J., S. Iyer, P. J. Fielder, J. D. Davis, and R. Deng. 2016. 'Projecting human 
pharmacokinetics of monoclonal antibodies from nonclinical data: comparative 
evaluation of prediction approaches in early drug development', Biopharm Drug Dispos, 
37: 51-65. 
Yousef Alrayes, Mona Hilmy, Reham Hammad Mahmoud Hammad, Botheina Ahmed Thabet 
Farweez, Nayera Hazaa Khalil Elsherif, and Doaa Aly Abd El-fattah Aly. 2019. 'Clinical 

 
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Significance of Leukocyte-Associated Immunoglobulin-Like Receptor-1, T-Cell 
Leukemia/Lymphoma Protein 1 and Nuclear Factor-ҡB in Childhood Acute 
Lymphoblastic Leukemia', Clinical Lymphoma Myeloma and Leukemia, 19. 
Yuan, Y., K. R. Hess, S. G. Hilsenbeck, and M. R. Gilbert. 2016. 'Bayesian Optimal Interval 
Design: A Simple and Well-Performing Design for Phase I Oncology Trials', Clin Cancer 
Res, 22: 4291-301. 
Zhou, H., J. J. Lee, and Y. Yuan. 2017. 'BOP2: Bayesian optimal design for phase II clinical 
trials with simple and complex endpoints', Stat Med, 36: 3302-14. 
 

 
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SIGNATURES 
 
Sponsor Signature(s) 
A PHASE 1, OPEN-LABEL, SAFETY, TOLERABILITY, AND EFFICACY STUDY OF NC525 
IN SUBJECTS WITH ADVANCED MYELOID NEOPLASMS 
I agree to the terms of this protocol. 
 
 
 
 
 
_______
Signature and date 
 
 
 
 
 
 

 
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Sponsor Signature(s) 
A PHASE 1, OPEN-LABEL, SAFETY, TOLERABILITY, AND EFFICACY STUDY OF NC525 
IN SUBJECTS WITH ADVANCED MYELOID NEOPLASMS 
I agree to the terms of this protocol. 
 
 
 
 
 
_______
 
Signature and date 
 
 
 
 
 
 

 
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Signature of Principal Investigator 
A PHASE 1, OPEN-LABEL, SAFETY, TOLERABILITY, AND EFFICACY STUDY OF 
NC525 IN SUBJECTS WITH ADVANCED MYELOID NEOPLASMS 
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 (IRB). 
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 and must 
be approved by the IRB 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 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 1: ADDITIONAL SAFETY GUIDANCE 
Assessment of Relationship 
Relationship to Investigational Product 
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product. 
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 2: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS 
DISEASE AND FOOD AND ALLERGY ANAPHYLAXIS NETWORK 
GUIDANCE FOR ANAPHYLAXIS DIAGNOSIS 
National Institute of Allergy and Infectious Disease (NIAID) and Food and Allergy Anaphylaxis 
Network (FAAN) define anaphylaxis as a serious allergic reaction that is rapid in onset and may 
cause death (Sampson et al. 2006). They recognize 3 categories of anaphylaxis, with criteria 
designated to capture from 80% of cases (category 1) to >95% of all cases of anaphylaxis (for all 
3 categories). 
1) Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
 
AND AT LEAST ONE OF THE FOLLOWING: 
• Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow (PEF), hypoxemia) 
• Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g., 
hypotonia [collapse], syncope, incontinence) 
2) Two or more of the following that occur rapidly after exposure to a likely allergen for that 
subject (minutes to several hours): 
• Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen lips-
tongue-uvula) 
• Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
• Reduced blood pressure or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence) 
• Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
3) Reduced blood pressure after exposure to known allergen for that subject (minutes to several 
hours): 
• Infants and children: low systolic blood pressure (age specific) or greater than 30% 
decrease in systolic blood pressure 
• Adults: systolic blood pressure of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline 

 
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APPENDIX 3: 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 housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
(Oken et al. 1982) 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX 4. TUMOR LYSIS SYNDROME CLASSIFICATION 
Metabolic 
Abnormality 
Criteria for Classification of 
Laboratory Tumor Lysis Syndrome* 
Criteria for Classification of Clinical 
Tumor Lysis Syndrome** 
Hyperuricemia 
Uric acid > 8 mg/dL (475.8 μmol/liter) 
N/A 
Hyperphosphatemia 
Phosphorus > 4.5 mg/dL 
(1.5 mmol/liter) 
N/A 
Hyperkalemia 
Potassium > 6 mmol/liter 
Cardiac dysrhythmia or sudden death 
probably or definitely caused by 
hyperkalemia 
Hypocalcemia 
Corrected calcium < 7.0 mg/dL 
(1.75 mmol/liter) or ionized calcium 
< 1.12 mg/dL (0.3 mmol/liter)# 
Cardiac dysrhythmia, sudden death, 
seizure, neuromuscular irritability 
(Tetany, paresthesia’s, muscle 
twitching, carpopedal spasm, 
Trousseau's sign, Chvostek's sign, 
laryngospasm, or bronchospasm), 
hypotension, or heart failure 
probably or definitely caused by 
hypocalcemia 
Acute Kidney Injury! N/A 
Increase in the serum creatinine level 
of 0.3 mg/dL (26.5 μmol/liter) or the 
presence of oliguria (average urine 
output of < 0.5 mL/kg/hr over a 6-hour 
period) 
* Laboratory TLS requires two or more metabolic abnormalities must be present during the same 24-hour period 
within 3 days before the start of therapy or up to 7 days afterward. 
** Clinical TLS requires the presence of Laboratory TLS plus one or more findings from the Clinical TLS column. 
# Corrected calcium = measured calcium level in mg/dL + 0.8 × (4 – albumin in gm/dL). 
! Acute kidney injury, unless attributable to another cause, represents clinical TLS even if criteria for laboratory TLS 
are not satisfied. 
* Not directly or probably attributable to therapeutic agent. 
† If no institutional ULN is specified, age/sex ULN creatinine may be defined as follows: > 1 to < 12 years of age, 
both male and female, 61.6 μmol/L; ≥ 12 to < 16 years, both male and female, 88 μmol/L; ≥ 16 years, female 
105.6 μmol/L, male 114.4 μmol/L. 
Note: Laboratory tumor lysis syndrome and at least one clinical complication. 
Cross reference: Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 2011;364(19):1844-54. 
 
 
 

 
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APPENDIX 5. RECOMMENDATIONS FOR INITIAL MANAGEMENT OF 
ELECTROLYTE IMBALANCES AND PREVENTION OF TUMOR LYSIS 
SYNDROME (TLS) 
Abnormality  
Management Recommendations  
Hyperkalemia (including rapidly rising potassium) 
Potassium ≥ 0.5 mmol/L 
increase from prior value 
(even if potassium within 
normal limits [WNL]) 
• 
Recheck potassium, phosphorus, uric acid, calcium, and creatinine in 1 
hour STAT. If further ≥ 0.2 mmol/L increase in potassium, but still < 
upper limit of normal (ULN), manage as per potassium ≥ ULN. 
Otherwise recheck in 1 hour 
• 
Resume per protocol testing if change in potassium is < 0.2 mmol/L, 
and potassium < ULN, and no other evidence of tumor lysis. 
• 
At discretion of investigator, may recheck prior to hospitalization. If 
stable or decreased, and still WNL, hospitalization is at the discretion of 
the investigator. Potassium, phosphorus, uric acid, calcium, and 
creatinine must be rechecked within 24 hours. 
Potassium > upper limit 
of normal 
• 
Perform STAT ECG and commence telemetry. 
• 
Nephrology (or other acute dialysis service) notification with 
consideration of initiating dialysis. 
• 
Administer Kayexalate 60 g (or Resonium A 60 g). 
• 
Administer furosemide 20 mg IV × 1. 
• 
Administer calcium gluconate 100 – 200 mg/kg IV slowly if there is 
ECG/telemetry evidence of life-threatening arrhythmias. 
• 
Recheck potassium, phosphorus, uric acid, calcium, and creatinine in 1 
hour STAT. 
• 
If potassium < ULN 1 hour later, repeat potassium, phosphorus, uric acid, 
calcium, and creatinine 1, 2 and 4 hours, if no other evidence of tumor 
lysis. 
Potassium ≥ 6.0 mmol/L 
(6.0 mEq/L) and/or 
symptomatic 
(e.g., muscle cramps, 
weakness, paresthesia’s, 
nausea, vomiting, 
diarrhea) 
• 
Perform STAT ECG and commence telemetry. 
• 
Nephrology (or other acute dialysis service) assessment with 
consideration of initiating dialysis. 
• 
Administer Kayexalate 60 g (or Resonium A 60 g). 
• 
Administer furosemide 20 mg IV × 1. 
• 
Administer insulin 0.1 U/kg IV + D25 2 mL/kg IV. 
• 
Administer sodium bicarbonate 1 – 2 mEq/kg IV push. 
• 
If sodium bicarbonate is used, rasburicase should not be used as this may 
exacerbate calcium phosphate precipitation. 
• 
Administer calcium gluconate 100 – 200 mg/kg IV slowly if there is 
ECG/telemetry evidence of life-threatening arrhythmias. Do not 
administer in same IV line as sodium bicarbonate. 
• 
Recheck potassium, phosphorus, uric acid, calcium, and creatinine every 
hour STAT. 
Abnormality  
Management Recommendations  

 
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Hyperuricemia 
Uric acid ≥ 8.0 mg/dL 
(476 μmol/L) 
• 
Consider rasburicase (dose per institutional guidelines). 
• 
If rasburicase is used, sodium bicarbonate should not be used as this may 
exacerbate calcium phosphate precipitation. 
• 
Recheck potassium, phosphorus, uric acid, calcium, and creatinine in 1 
hour STAT. 
Uric acid ≥ 10 mg/dL 
(595 μmol/L) 
OR 
Uric acid ≥ 8.0 mg/dL 
(476 μmol/L) with 25% 
increase and creatinine 
increase ≥ 0.3 mg/dL 
(≥ 0.027 mmol/L) from 
pre-dose level 
• 
Administer rasburicase (dose per institutional guidelines). 
• 
If rasburicase is used, sodium bicarbonate should not be used as this may 
exacerbate calcium phosphate precipitation. 
• 
Notify nephrology (or other acute dialysis service). 
• 
Recheck potassium, phosphorus, uric acid, calcium, and creatinine in 1 
hour STAT. 
• 
If uric acid < 8.0 mg/dL 1 hour later, repeat potassium, phosphorus, uric 
acid, calcium, and creatinine 2 and 4 hours later if no other evidence of 
tumor lysis. 
Hypocalcemia 
Calcium ≤ 7.0 mg/dL 
(1.75 mmol/L) 
AND 
Patient symptomatic 
e.g., muscle cramps, 
hypotension, tetany, 
cardiac arrhythmias) 
• 
Administer calcium gluconate 50 – 100 mg/kg IV slowly with ECG 
monitoring. 
• 
Telemetry. 
• 
Recheck potassium, phosphorus, uric acid, calcium, and creatinine 
in 1 hour STAT. 
• 
If calcium normalized 1 hour later, repeat potassium, phosphorus, 
uric acid, calcium, and creatinine 2 and 4 hours later if no other 
evidence of tumor lysis. 
• 
Calculate corrected calcium and check ionized calcium if albumin 
low. 
Hyperphosphatemia 
Phosphorus ≥ 5.0 mg/dL 
(1.615 mmol/L) with 
≥ 0.5 mg/dL 
(0.16 mol/L) increase 
• 
Administer a phosphate binder (e.g., aluminum hydroxide, calcium 
carbonate, sevelamer hydroxide, or lanthanum carbonate). 
• 
Nephrology (or other acute dialysis service) notification (dialysis 
required for phosphorus ≥ 10 mg/dL). 
• 
Recheck potassium, phosphorus, uric acid, calcium, and creatinine in 1 
hour STAT. 
• 
If phosphorus < 5.0 mg/dL 1 hour later, repeat potassium, phosphorus, 
uric acid, calcium, and creatinine 2 and 4 hours later, if no other evidence 
of tumor lysis 
Abnormality  
Management Recommendations  
Creatinine 
Increase ≥ 25% from 
baseline 
• 
Start or increase rate of IV fluids. 
• 
Recheck potassium, phosphorus, uric acid, calcium, and creatinine in  
1 – 2 hours STAT. 

 
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APPENDIX 8: WEIGHT-BASED DOSING CALCULATION 
CONSIDERATIONS 
 
Dosing will be based on subject’s actual weight (or ideal body weight if considered obese) in 
kilograms. For the purpose of dose calculations for NC525, the site should determine and evaluate 
obesity based on institutional guidelines.  
 
Below provides a general reference for Calculation of Ideal Body Weight (IBW) and Obesity 
Calculation if needed.  
 
Calculation of Ideal Body Weight (IBW) 
IBW in kg 
Males = 50 + [2.3 x each inch over 5 ft] 
or 50 + [2.3 kg x (each cm over 152.4/2.54)] 
Females = 45.5 + [2.3 x each inch over 5 ft] 
or 45.5 + [2.3 kg x (each cm over 152.4/2.54)] 
 
Calculation for Obesity 
[(actual wt - IBW)/IBW]*100%.  
If this value is >30% then the person is obese and ideal body weight should be used for 
weight-based dosing calculations instead of actual body weight. 
 

 
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SUMMARY OF CHANGES 
Summary of Protocol Changes 
Protocol Version 
 
Date 
Version 1.0 (Original) 
 
15-Sep-2022 
Version 1.1  
25-Oct-2022 
Version 1.2 
27-Oct-2022 
Version 1.3 
28-Oct-2022 
Version 2.0 
26-Apr-2023 
Version 3.0 
19-Jul-2023 
Version 4.0 
16-Oct-2023