A Phase 1/2 Study of NM21-1480 (Anti-PDL-1/Anti-4-1BB/Anti-HSA Tri-Specific Antibody) in Adult Patients With Advanced Solid Tumors
Phase: PHASE1
Conditions: Advanced Solid Tumor, Non-small Cell Lung Cancer, Colorectal Cancer, Squamous Cell Carcinoma, Ovarian Carcinoma, Peritoneal Carcinoma, Fallopian Tube Cancer, Head and Neck Squamous Cell Carcinoma, Triple Negative Breast Cancer
Sponsor: Numab Therapeutics AG

 
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TITLE PAGE 
CLINICAL STUDY PROTOCOL TITLE: 
A Phase 1/2 Study of NM21-1480 (Anti-PDL-1/Anti-4-1BB/Anti-HSA Tri-Specific 
Antibody) in Adult Patients with Advanced Solid Tumors 
Protocol Number: 
NB-ND021 (NM21-1480)-101 
Test Product: 
NM21-1480 
Indication: 
Advanced solid tumors 
Development Phase: 
Phase 1/2 
Sponsor: 
Numab Therapeutics AG 
Legal Registered Address: 
Bachtobelstrasse 5, CH-8810 Horgen 
  
Switzerland 
Approval Date: 
17 Nov 2022 (Version 9.0)  
Previous Version(s): 
11 Jul 2022 (Version 8.0)  
 
28 Feb 2022 (Version 7.0) 
 
29 Oct 2021 (Version 6.0) 
 
01 Sep 2021 (Version 5.0) 
 
17 May 2021 (Version 4.0) 
 
15 Jan 2021 (Version 3.0) 
 
04 Jun 2020 (Version 2.0) 
 
27 Apr 2020 (Version 1.2) 
 
20 Apr 2020 (Version 1.1) 
 
07 Feb 2020 (Version 1.0) 
 
The confidential information in this document is provided to you as an Investigator, potential 
Investigator or consultant for review by you, your staff and applicable Independent Ethics 
Committee and/or Institutional Review Board.  It is understood that the information will not be 
disclosed to others without written authorization from Numab Therapeutics AG except to the 
extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. 

 
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2 
STUDY SYNOPSIS 
Name of Sponsor/Company: 
Numab Therapeutics AG 
Name of Product: 
NM21-1480 
Title of Study: 
A Phase 1/2 study of NM21-1480 (anti-PDL-1/anti-4-1BB/anti-HSA tri-specific antibody) in adult patients with 
advanced solid tumors. 
Study Center(s): 
Part A of the study has been conducted at 7 sites in the United States (US) and Taiwan.  Part A was formally 
completed on 23 May 2022 by a Meeting of the Safety Monitoring Committee (SMC) at which the SMC determined 
that Part A of the study did not technically identify a maximum tolerated dose (MTD) as the highest dose assessed 
(800mg flat dose) was considered a tolerable dose. An optional Part A-2 of the study may now be conducted at Part 
A sites and additional selected Part B sites in the US, Spain, the United Kingdom (UK), Germany, and/or the 
Netherlands given formal conclusion on the 28-day dose-limiting toxicity (DLT) assessment period data, and 
resulting determination of a presumptive Recommended Phase 2 Dose (RP2D) based on Part A data has occurred. 
Part A-2 may be conducted to further explore different dose levels and/or dosing intervals in parallel to Part B to 
complement the pharmacokinetics (PK), immunogenicity and PD data to be provided by Part B. Additional sites will 
be added for Part B of the study; Part B will be conducted as up to 8 separate cohorts: B1-B8. Cohorts B1, B2, and 
B7 will be conducted in up to 86 sites in the US, Spain, UK, the Netherlands, Germany, and Taiwan.  Cohort B3 will 
be conducted in up to 30 sites in Turkey, Georgia, Ukraine, and Taiwan. Cohort B4 will be conducted in up to 92 
sites in the US, Spain, UK, the Netherlands, Germany, Taiwan, Turkey, Georgia, and Ukraine. Cohorts B5 and B6 
will be conducted in up to 75 sites in the US, Spain, UK, the Netherlands, and Taiwan. Cohort B8 will be conducted 
in up to 83 sites in the US, Spain, UK, the Netherlands and Germany. 
Development Phase: 
Phase 1/2 
Disclosure Statement: 
With the exception of Cohort B5 (i.e., Part A, optional Part A-2, and Cohorts B1-B4 and B6-B8), this is a single arm 
study with different cohorts. Cohort B5 is a randomized, open-label, active-control study cohort comparing NM21-
1480 plus standard-of-care vs. standard-of-care alone. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Part A 
Primary 
• To assess the safety and tolerability of 
NM21-1480 
• To determine the MTD of NM21-1480 
• To determine up to four (4) safe dose 
levels for further evaluation of PD and 
clinical activity in the optional Part 
A-2 and Part B of the study 
• Incidence and nature of dose-limiting toxicities 
(DLTs) 
• Incidence and severity of treatment-emergent 
adverse events (TEAEs) with specific focus on 
incidence and severity of immune-related 
adverse events (irAEs) 
Secondary 
• To characterize the pharmacokinetic 
(PK) profile of NM21-1480  
• PK parameters 
o 
AUCtau 
o 
AUC (0-infinity) (first dose only) 
o 
Cmax 
o 
Cmin 
o 
t½ 
o 
Tmax 

 
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o 
λz 
o 
CL 
o 
Vd 
• To evaluate the immunogenicity of 
NM21-1480 
• Frequency of specific anti-drug antibodies to 
NM21-1480 
Exploratory 
• To determine the anti-tumor activity 
of NM21-1480 according to Response 
Evaluation Criteria in Solid Tumors 
(RECIST) 1.1  
• To 
determine 
safe 
dose 
levels 
associated 
with 
meaningful 
PD 
response to inform dose selection for 
optional Part A-2 and Part B. This is in 
support of nominating up to four (4) 
safe dose levels to be further studied in 
Part B of the study 
• Best overall response (BOR) 
• Objective response rate (ORR) 
• Time-to-response (TTR) 
• Duration of response (DOR) 
• Progression-free survival (PFS) 
• Overall survival (OS) 
• Characterization of exposure-dependent PD 
markers of target and pathway engagement. 
Potential PD markers are summarized in detail in 
the below list of exploratory markers applicable 
to all Parts A, A-2 and B 
Part A-2 (OPTIONAL) 
Primary 
• To assess the safety and tolerability of 
NM21-1480 at a dose level beyond 
what has been assessed in Part A (i.e. 
at 1400mg) 
• To 
further 
explore 
drug-
exposure/PK/PD 
relationships 
in 
order to complement respective Part B 
data when conducted in parallel to Part 
B 
• Incidence and severity of TEAEs with specific 
focus on incidence and severity of irAEs 
• Characterization of exposure-dependent PD 
markers of target and pathway engagement. 
Potential PD markers are included in the below 
list of exploratory markers applicable to all 
Parts A, A-2, and B 
Secondary 
• To characterize the PK profile of 
NM21-1480 
• To evaluate the immunogenicity of 
NM21-1480 
• PK parameters: 
o 
AUCtau 
o 
AUC (0-infinity) (first dose only) 
o 
Cmax 
o 
Cmin 
o 
t½ 
o 
Tmax 
o 
λz 
o 
CL 
o 
Vd 
• Frequency of specific anti-drug antibodies to 
NM21-1480 
Exploratory 
• To determine the anti-tumor activity 
of 
NM21-1480 
according 
to 
RECIST1.1 
• BOR 
• ORR 
• TTR 
• DOR 
• PFS 
• OS 
Part B 

 
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Primary 
• To determine the anti-tumor activity 
of 
NM21-1480 
according 
to 
RECIST 1.1 
• BOR (Primary endpoint for Cohort B1-4, 6-8) 
• ORR (Primary endpoint for Cohort B5) 
• Incidence and severity of TEAEs with specific 
focus on incidence and severity of irAEs 
• Characterization of exposure-dependent PD 
markers of target and pathway engagement. 
Potential PD markers are included in the below 
list of exploratory markers applicable to all 
Parts A, A-2, and B 
• To assess the safety and tolerability of 
NM21-1480 in patients with selected 
advanced cancers treated at or around 
the 
recommended 
Phase 2 
dose 
(RP2D) 
• To determine the RP2D 
• To determine the safety (including the 
MTD) and efficacy of NM21-1480 in 
combination with standard-of-care 
anti-PD1 therapy in patients with head 
and neck squamous cell cancer 
(Cohort B5) 
 
Secondary 
• To further evaluate the preliminary 
anti-tumor activity of NM21-1480 
• Disease Control Rate (DCR) 
• DOR 
• TTR 
• PFS 
• OS 
• BOR, DCR, ORR, DOR, PFS as per iRECIST 
• To characterize the PK profile of 
NM21-1480  
• PK parameters 
o 
AUCtau 
o 
AUC (0-infinity) (first dose only) 
o 
Cmax 
o 
Cmin 
o 
t½ 
o 
Tmax 
o 
λz 
o 
CL 
o 
Vd 
• To evaluate the immunogenicity of 
NM21-1480 
• Frequency of specific anti-drug antibodies to 
NM21-1480 
Part A, Part A-2 (OPTIONAL), and Part B 
Exploratory 
• To characterize the PD profile of 
NM21-1480 
Change 
from 
baseline 
in 
the 
following 
biomarkers/PD parameters: 
• Change 
from 
baseline 
in 
levels 
of 
cytokines/chemokines 
including 
interleukin 
(IL)-1b, IL-6, tumor necrosis factor (TNF)α 
interferon gamma (IFNϒ), IL2, IL8, CXCL9, 
CXCL10, CXCL11, IL18, and other selected 
markers; soluble PD-L1 (Programmed death-
ligand 1); soluble 4-1BB 
• Phenotypic characterization of peripheral blood 
cells (cellular populations include resting and 
activated 
B-cells, 
T-cell 
subpopulations 
[T-helper cells {Th}, cytotoxic T lymphocytes 
{CTLs}, regulatory T-cells {Treg}], natural 

 
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killer cells {NK cells}, and natural killer T-cells 
{NKT cells}), and cellular receptor occupancy 
(PD-L1; 4-1BB)a  
• In cohort B8: Carcinoembryonic Antigen (CEA); 
circulating tumor DNA (ctDNA) 
• To evaluate biomarkers potentially 
capable of predicting a clinical 
response to NM21-1480 
• Change in RNA expression from baseline and 
after-treatment in tumor tissues 
• Change in PD-L1 expression and presence of 
PD1/CD8/4-1BB triple positive T-cells in 
baseline and after-treatment tumor tissues 
• Change in level of inflammatory infiltrate 
(e.g., CD3 and CD8 density; CD8/Treg ratio; 
CD8/CD4 ratio) in baseline and after-treatment 
tumor tissue 
• Assessment of tumor mutational burden (TMB) 
and microsatellite instability – high/deficient 
mismatch repair (MSI-H/dMMR) status in 
baseline tumor tissues  
• Correlation of PD-L1 expression status in the 
tumor microenvironment (TME) with PD and 
clinical activity 
• Assessment of T-cell Receptor clonality in tumor 
tissue 
• In cohort B8: MHC-I expression on tumor cells; 
specific mutational analysis including e.g., 
BRAF, KRAS, NRAS, POLE, PIK3CA, PTEN. 
APC, p53 
a 
Pending availability of validated assay 
Abbreviations: 
APC = Adenomatous Polyposis Coli; AUC = Area under the serum concentration-time curve, 
AUC(0-infinity) = Area under the serum concentration-time curve extrapolated from the last 
quantifiable concentration to infinity; AUCtau = area under the serum concentration-time curve 
over dosing interval, B-cells = B lymphocytes; BRAF = B-raf proto-oncogene; CD3 = Cluster 
of differentiation 3;  CD4 = Cluster of differentiation 4; CD8 = Cluster of differentiation 8; CEA 
= Carcinoembryonic Antigen; CL = Clearance, Cmax = The maximum observed serum 
concentration determined by direct inspection of the concentration versus time data, Cmin = 
The minimum observed serum concentration determined by direct inspection of the 
concentration versus time data; CTL = Cytotoxic T lymphocytes, CXCL = Chemokine (C-X-C 
motif) ligand, λz = Terminal phase (apparent elimination) rate constant; KRAS = Kirsten Rat 
Sarcoma oncogene;  MHC-I = Major Histocompatibility Complex – I; Microsatellite instability-
high (MIS-H), NK cells = Natural killer cells, NKT = Natural killer T-cells; NRAS = 
Neuroblastoma ras viral oncogene homolog; PD-1 = Programmed cell death protein-1, PD-L1 
= Programmed death-ligand 1; PIK3CA = Phosphaytidylinositol 3-kinase CA; POLE = 
Polymerase Epsilon Catalytic Subunit;  PTEN = Phosphatase and Tensin Homologue; 
RNA = Ribonucleic acid, t½ = Elimination half-life, Tmax = The time from dosing at which 
Cmax is apparent determined by direct inspection of the concentration versus time data, 
Vd = Volume of distribution 
Methodology: 
This is a first-in-human (FIH), open-label, multi-center, Phase 1/2, dose-escalation study with dose expansion 
cohorts in specific tumor types to evaluate NM21-1480 for safety and immunogenicity, to determine the MTD and 
Recommended Phase 2 Dose (RP2D), define the PK, to explore the pharmacodynamics (PD), and to obtain 
preliminary evidence of the clinical activity in adult patients with selected advanced solid tumors. 
NM21-1480 is a recombinant protein consisting of 3 stabilized antibody Fv fragments directed against the molecular 
targets Programmed death-ligand 1 (PD-L1), 4-1BB, and serum albumin (SA).  It is designed for avoidance of 

 
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systemic 4-1BB activation and preferential 4-1BB activation in the TME to avoid the dose-limiting toxicities (DLT) 
of systemically active 4-1BB agonists. 
This is an open-label study and includes an ascending-dose cohort component (Part A) to be optionally followed by 
an additional cohort (optional Part A-2) to further explore different dose levels and/or dosing intervals in parallel to 
Part B to complement the PK, immunogenicity and PD data to be provided by Part B.  Part B may be initiated without 
the conduct of the optional A-2 Cohort.  For patients in all cohorts, the study will consist of 3 periods: Screening (up 
to 28 days), treatment (until confirmed progression or meeting any other reason for discontinuation specified by the 
protocol), and Follow-up (up to 12 weeks). In Part A of the study, NM21-1480 will be administered as a single 
intravenous (IV) infusion approximately every 14 days for a total of 2 infusions per treatment cycle.  A treatment 
cycle is thus defined as 28 days (4 weeks).  In Part A, response assessments are done every 8 weeks, thus one 
assessment cycle is defined as 8 weeks.  Any dose level to be studied in Part B will be below or at the MTD 
determined upon decision by the Safety Monitoring Committee (SMC) once all patients enrolled to Part A have 
completed their 28-day DLT evaluation period.  Part A was formally completed on 23 May 2022 by a Meeting of 
the SMC which determined that Part A of the study did not technically identify an MTD as the highest dose assessed 
(800mg flat dose) was considered a tolerable dose. In Part B of the study, NM21-1480 will thus be administered as 
a single IV infusion approximately every 14 days at the 800mg flat dose, based on Part A PK data which do not 
indicate substantial NM21-1480 accumulation over time with this dosing interval; the 800mg dose of NM21-1480 
thus represents the presumptive RP2D to be further studied in Part B (Cohorts B1- B8) with the aim to confirm this 
dose as the R2PD for the compound. Based on Part A identifying the 800mg dose of NM21-1480 to represent a 
tolerable and fully active dose, optional Part A-2 of the study will explore one additional higher dose level (1400mg 
flat dose with approximately 14-day dosing interval) than was studied in Part A. Such 1400mg dose level is explored 
in Part A-2 applying strict stopping criteria and respecting a 28-day DLT evaluation period before more than 6 
subjects are exposed to it. PK data for this 1400mg dose level in Part A-2 will be closely followed and in case of 
observation of relevant drug accumulation over time, the dosing interval for this dose may be adjusted to 
approximately 21 days. The Sponsor, together with the SMC will determine whether further exploration of this 
1400mg dose in Part B may be clinically meaningful once data are available. The optional Part A-2 of the study is 
conducted in parallel to Part B, and its resulting exposure/PK/PD data will be used to complement Part B data to 
guide later stage clinical development.  Any dose level to be assessed in Part B as by SMC recommendation must 
not exceed the MTD determined in Part A (or Part A-2 when applicable).  In optional Part A-2 and Part B, a treatment 
cycle, dependent on the dosing interval selected by the SMC for a given dose level (i.e., 2-week dosing interval for 
the 800mg dose and 2-week or eventually 3-week dosing interval for the 1400mg dose in Part A-2), is thus defined 
as 28 days (4 weeks) or 42 days (6 weeks), respectively.  Response assessments in the optional Part A-2 and in Part 
B will be done every 6 weeks during the first 24 weeks patients are on treatment and every 8 weeks beyond 24 weeks 
on treatment. 
Part A 
In Part A, a Bayesian optimal interval (BOIN) design was used to assess the safety and tolerability of NM21-1480.  
This part of the study consists of 7 planned escalating flat dose levels; 0.15 mg (dose level 1), 1.5 mg (dose level 2), 
8 mg (dose level 3), 24 mg (dose level 4), 80 mg (dose level 5), 240 mg (dose level 6), and 800 mg (dose level 7).  
Enrollment of patients into dose level 1 took place first and subsequent dose levels were only opened after the 
previous dose level was deemed tolerable.  The first dose level was to enroll a minimum of one patient at 0.15 mg 
(corresponding to approximately 0.002 mg/kg).  Following the detailed rules described in Section 10.3.1 of this 
protocol, as soon as a Grade 2 or higher, treatment-related adverse event (TRAE) was observed during the 28-day 
DLT evaluation period, or when dose level 5 (80 mg dose corresponding to approximately 1 mg/kg) was reached, a 
minimum of 3 patients were to be enrolled at the current dose level as well as at potential additional dose levels 
planned in accordance with the BOIN design dosing rules.  
Part A of the study was formally completed on 23 May 2022 by a Meeting of the SMC at which the SMC determined 
that Part A of the study did not technically identify a MTD as the highest dose assessed (800mg flat dose) was 
considered a tolerable dose. Part A dose-escalation was based on the number of DLTs experienced during the DLT 
evaluation interval as determined by the Investigators, Medical Monitor, and Sponsor.  The DLT evaluation interval 
begins on the first day of treatment and continues for 28 days.  Patients who received at least one dose of 
investigational product in Cycle 1 (i.e., one of the 2 doses intended to be administered in Cycle 1), and either meet 
the minimum exposure criterion and have sufficient safety evaluations or discontinued due to DLT, were considered 
evaluable for DLT determination.  Dose-escalation continued until the stopping rules of the BOIN design were 
reached. 
The MTD was defined as the highest dose associated with DLTs in ≤30% of patients receiving NM21-1480 
administered during the DLT period.  This was the highest dose to be potentially recommended for further evaluation 
in the subsequent part(s) of the study.  At the end of Part A, the SMC concluded on 23 May 2022 that none of the 7 

 
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dose levels, including the highest dose (800mg flat) dose assessed in Part A was to be considered intolerable and 
thus Part A did not technically identify a MTD. Due to the specific pharmacological mechanism of action of NM21-
1480, the SMC, supported by the Sponsor, besides determining the MTD, was also to consider the selection of 
additional (lower) dose levels to be further studied in Part A-2 (optional) and/or Part B, based on review of Part A 
safety, PK, and PD (as far as available) data.  This was based on the assumption that indeed, it may only be possible 
to determine an optimal RP2D in Part B of the study, as binding of NM21-1480 to PD-L1 is a pre-requisite for 
activation of the 4-1BB pathway by the compound. This is likely only possible in a tumor patient population with 
well-documented PD-L1 expression in the TME.  In addition, in a situation with substantial excess of NM21-1480 
over PD-L1 and 4-1BB on target cells in the tumor tissue, a decline in 4-1BB activity (due to a bell-shaped dose 
response curve for the 4-1BB agonistic activity of the compound) cannot be formally excluded to occur within the 
dose range explored in Part A of the study. Such bell-shaped dose response may occur because in such situation of 
substantial excess of NM21-1480, molecules over available PD-L1 and 4-1BB binding sites, an immediate saturation 
of PD-L1 and 4-1BB binding sites by different NM21-1480 molecules may occur.  As such, concomitant binding of 
a single NM21-1480 molecule to both antigens may no longer be possible and consequently the immunological 
synapse between tumor cells and immune cells that is required to trigger 4-1BB signaling, could no longer be 
established.  This important aspect of dose finding was considered based on thorough review of the entirety of non-
clinical and clinical data available at the end of the 28-day DLT evaluation period of the last patient enrolled to Part 
A (i.e. at the 23 May 2022 SMC meeting).  At this point, the SMC, together with the Sponsor, considered the 
nomination of up to 4 different dose levels of NM21-1480 and determined the optimal dosing interval (i.e., dosing 
approximately every 14 or 21 days) for administration of a given NM21-1480 dose for Part B with the goal to 
determine a final RP2D and dosing interval with an optimized activity and safety profile for future development 
within Part B. Part A study data discussed with SMC on 23 May 2022 demonstrated the development of treatment-
emergent anti-drug-antibodies (ADAs) in a relevant fraction of patients dosed at 24mg-240mg. These ADAs were 
typically associated with rapid elimination of NM21-1480 from the circulation and loss of exposure. However, PK, 
PD, receptor occupancy and clinical activity data available for the 800mg dose level indicated that at this higher dose 
level, no relevant loss of exposure was observed and full pharmacodynamic activity of the compound was preserved, 
a phenomenon described for other checkpoint inhibitors (i.e. atezolizumab) at higher doses as well. As such, the 
SMC agreed with the Sponsor to consider the 800mg to represent the presumptive RP2D and further study this dose, 
applying a biweekly dosing interval in Part B of the study. The SMC, together with the Sponsor, also considered at 
this point (i.e., at the end of the 28-day DLT evaluation period of the last patient enrolled to Part A) to enroll 
additional patients into an optional additional Cohort A-2in parallel to Part B to complement the PK, immunogenicity 
and PD data to be provided by Part B.  The Sponsor, following formal completion of Part A on 23 May 2022, is 
therefore exploring within this optional Part A-2 and under continuous review of emerging safety data by the SMC, 
the safety, PK/PD and clinical activity profile of one higher dose level of NM21-1480 (1400mg flat dose) in up to 
10 patients to complement Part B data and thus further inform development of NM21-1480 beyond initial Part B. As 
this dose level to be studied in in Cohort A-2 is above the maximum dose level characterized in Part A, exploration 
of this 1400mg dose level will be conducted under the continuous safety data review and guidance by the SMC, 
applying similar rules as in Part A. 
In summary, Part A was considered completed on 23 May 2022, when the maximal number of patients to be treated 
overall, as per BOIN design rules, was reached, and the SMC, upon documented review of all clinical safety, PK, 
and clinical activity data up to and including the 4-week visit from all patients dosed in Part A determined that even 
the highest dose assessed in Part A (800mg flat) was considered a tolerable dose.  For nomination of dose levels to 
be further evaluated in Part B (and/or optional Cohort A-2), the SMC, together with the Sponsor, considered all 
available non-clinical and clinical data and information (i.e., including all available clinical data beyond 28 days of 
treatment with NM21-1480) at the time the final patient enrolled into Part A according to the BOIN design had 28-
day data available. The 800mg flat dose was nominated as presumptive RP2D to be studied in Part B and a dose of 
1400mg was nominated for additional exploration within optional Part A-2 by the Sponsor.  
Part A-2 (OPTIONAL) 
Part A-2 is an optional part of the study.  It might be initiated after determination of the MTD based on Part A data. 
On 23 May 2022 the SMC determined that Part A did not technically identify a MTD and the highest dose level 
assessed (800mg flat) was considered a tolerated dose.  The rationale behind the potential conduction of Part A-2 
was to cover situations in which the SMC, together with the Sponsor, upon comprehensive review of all available 
data at the time of MTD determination (i.e. at the formal end of Part A on 23 May 2022), came to the conclusion that 
either additional exposure-dependent PD data at dose levels at or below the MTD were needed to allow for selection 
of up to 4 dose levels to be further studied in Part B, or it may be desirable to explore different dose levels and/or 
dosing intervals in parallel to Part B to complement the PK, immunogenicity and PD data to be provided by Part B 
to inform development of NM21-1480 beyond Part B. Indeed, based on the finding that some patients dosed at 24-
240mg in Part A developed treatment-emergent ADAs leading to loss of exposure, while this was not observed at 

 
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the 800mg dose level, a decision was taken to explore one additional higher dose level (1400mg flat dose) in up to 
10 patients within Part A-2 in parallel to studying the 800mg dose level in Part B. The primary intention of exploring 
this 1400mg dose level in Part A-2 is to further study the overall PK/PD relationship of NM21-1480 over a broad 
range of doses. Further dose levels or dosing intervals may in the future be studied within Part A-2 as well if emerging 
data from the ongoing study provides a rationale to do so.  Patients to be enrolled into this optional cohort will need 
to fulfill Part A eligibility criteria but in addition will need to have documented minimal PD-L1 expression on at 
least 1% of tumor and/or immune cells in the TME, as detected by local testing with a Food and Drug Administration 
(FDA)-cleared or any PD-L1 assay approved for use by local competent authority. As the 1400mg flat dose level to 
be explored in Part A-2 is above the maximum dose level characterized in in Part A, exploration of this 1400mg dose 
level will be conducted under the continuous safety data review and guidance by the SMC. 
In this setting in which Part A-2 will be conducted in parallel to Part B, its resulting data will be used to complement 
Part B data in regards of getting to a comprehensive understanding on the PK/PD relationship of different dosing 
regimens for NM21-1480 before engaging into subsequent clinical development steps beyond Part B.  
Part B 
To further characterize the safety and clinical activity of NM21-1480, Part B, Cohorts B1-B4 and B6-B8 will employ 
a Bayesian Optimal Phase II (BOP2) design to enroll patients with selected advanced solid tumors with locally 
advanced or metastatic, non-resectable disease, which has progressed despite treatment with standard first-line, or 
first- and second-line, a maximum of 3 previous cytotoxic treatment regimens, or a defined set of previous standard-
of-care therapies for Cohorts B1-B4 and B6-B8, as described per specific cohort.  Based on the results of Part A of 
the study and as per SMC recommendation, patients in these cohorts will be dosed at the 800mg flat dose level, 
considered the presumptive RP2D of NM21-1480, applying a biweekly dosing interval. Cohort B5 will be a 
randomized, open-label, active-control, Bayesian study cohort in which the combination of NM21-1480 plus 
standard-of-care anti-PD1 therapy will be compared to standard-of-care anti-PD1 monotherapy in patients with head 
and neck squamous cell cancer.  For Cohort B5, patients randomized to the NM21-1480/PD1 checkpoint inhibitor 
arm will be treated with 800mg NM21-1480, administered in a biweekly dosing interval. However, a safety run-in 
for this dose in Cohort B5 will be applied: an enrollment stop will be made once  6 patients have been enrolled to 
the NM21-1480 plus standard of care arm with remaining patients only to be enrolled once the SMC has reviewed 
the 28-day safety data for all these 6 patients in comparison to the anti-PD1 treatment arm and has confirmed the 
tolerability of the 800mg dose in this combination therapy setting.  If the 800mg dose of NM21-1480 was not 
considered to represent a tolerable dose in this combination setting as per SMC decision, the Sponsor may either stop 
Cohort B5 or together with the SMC or select a lower dose level for continued exploration within Cohort B5. In this 
latter case a safety run-in with 6 patients would be applied again at such lower dose before remaining patients were 
to be enrolled to the combination therapy arm. Once an MTD for NM21-1480 in this Cohort B5 combination setting 
has been determined by the SMC, remaining patients may only be assigned to NM21-1480 dose levels at or below 
this combination therapy MTD for NM21-1480.  
Enrollment in Part B (Cohorts B1 through B8) may begin when the SMC has completed its review of the Part A data 
and has recommended the dose levels to be initially studied in Part B. Part A was formally completed on 23 May 
2022 and the SMC determined that the 800mg flat dose level was a tolerable dose to be further studied as the 
presumptive RP2D in Part B of the study. 
Cohort B1:  
This Cohort will be conducted in the US, Spain, UK, the Netherlands, Germany, and Taiwan. 
Cohort B1 will include non-small cell lung cancer (NSCLC) patients with documented previous 
(i.e., prior to initiation of first-line therapy) PD-L1 expression on ≥50% of tumor cells who have 
progressed after first-line treatment with either anti-PD-(L)1 monotherapy, anti-PD-
(L)1/chemotherapy or chemotherapy regimen, or who have progressed after-treatment with up to 
3 previous lines of therapy, including at least one line of anti-PD-(L)1 checkpoint inhibitor therapy. 
It should be noted that, specifically for patients to be enrolled to Cohort B1 in Germany, they 
must have previously received anti-PD-(L)1 therapy and a platinum-based chemotherapy (i.e., at 
least 2 prior lines of treatment) in order to be eligible for enrollment into this cohort. 
Cohort B2:  
This cohort will be conducted in the US, Spain, UK, the Netherlands, Germany, and Taiwan. 
Cohort B2 will include patients with human papillomavirus positive (HPV+) squamous cell 
carcinoma (SCC) of the anus, cervix, vulva, vagina, penis, or oropharynx, who have progressed on 
a first-line standard-of-care anti-PD1 monotherapy, anti-PD-1/chemotherapy, or chemotherapy 
regimen.  Inclusion of patients, who have progressed after receiving 2 previous lines of therapy, 
e.g., one line of anti-PD-1 checkpoint inhibitor therapy and one line of chemotherapy regimen is 
also acceptable; patients must have documented PD-L1 expression in the TME with PD-L1 

 
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expressed on at least 1% of tumor and/or immune cells, as detected by local testing with an 
FDA-cleared or any PD-L1 assay approved for use by local competent authority. 
Cohort B3:  
This Cohort will be conducted in Turkey, Georgia, Ukraine, and Taiwan. Cohort B3 will include 
patients with NSCLC with PD-L1 expression on ≥50% of tumor cells who have progressed on first-
line local standard-of-care chemotherapy. 
Cohort B4:  
This Cohort will be conducted in the US, Spain, UK, the Netherlands, Germany, Taiwan, 
Turkey, Georgia, and Ukraine.  Cohort B4 will include patients with recurrent or persistent 
ovarian, primary peritoneal, or fallopian tumor carcinoma of all histologic types except mucinous 
adenocarcinoma and carcinosarcoma with a history of primary platinum-based chemotherapy with 
a maximum of 3 prior cytotoxic regimens with at least one regimen for recurrent disease containing 
a platinum or a taxane for those with 3 prior regimens: last platinum-free interval must be 
maximally 12 months. 
Cohort B5:  
This Cohort will be conducted in the US, Spain, UK, the Netherlands, and Taiwan.  Cohort B5 
will include patients to be treated in-label with an approved PD-1 checkpoint inhibitor 
(pembrolizumab) as a single agent for the first-line treatment of metastatic or unresectable, 
recurrent head and neck squamous cell cancer whose tumors express PD-L1 (Combined Positive 
Score (CPS)≥1) as standard-of-care treatment with doses not to exceed those approved in local 
product labels.  Patients fulfilling this criterion will be randomized 2:1 to either such 
standard-of-care PD-1 checkpoint inhibitor plus NM21-1480 or the standard-of-care PD-1 
checkpoint inhibitor therapy only. 
Cohort B6:  
This Cohort will be conducted in the US, Spain, UK, the Netherlands, and Taiwan. Cohort B6 
will include patients with metastatic or unresectable, locally advanced triple-negative breast cancer 
(TNBC) that is measurable according to RECIST1.1 criteria.  Tumors need to be Estrogen receptor 
(ER), Progesterone receptor (PR) and HER2 negative as per current American Society of Clinical 
Oncology/College of American Pathologists (ASCO/CAP) Guidelines and patients need to have 
progressed on at least one but no more than 3 previous lines of cytotoxic chemotherapy.  Two 
subgroups of 20 patients each will be enrolled and analysed, based on having received a prior line 
of checkpoint inhibitor therapy or not. 
Cohort B7:  
This Cohort will be conducted in the US, Spain, UK, the Netherlands, Germany, and Taiwan.  
Cohort B7 will include NSCLC patients with documented previous (i.e., prior to initiation of 
previous-line therapies) PD-L1 expression on ≥1%-49% of tumor cells who have progressed after 
first-line treatment with either anti-PD-(L)1 monotherapy, anti-PD-(L)1/chemotherapy or 
chemotherapy regimen, or who have progressed after-treatment with up to 3 previous lines of 
therapy, at least one including an anti-PD-(L)1 checkpoint inhibitor. It should be noted that, 
specifically for patients to be enrolled to Cohort B7 in Germany, they must have previously 
received anti-PD-(L)1 therapy and a platinum-based chemotherapy (i.e., at least 2 prior lines of 
treatment) in order to be eligible for enrollment into this cohort. 
Cohort B8: 
This Cohort will be conducted in the US, Spain, UK, the Netherlands, and Germany. Cohort B8 
will include patients with metastatic colorectal cancer (mCRC) that are MSS or MSI low and who 
have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based 
chemotherapy, and if RAS wild-type, an anti-EGFR therapy, if eligible. Patients previously treated 
with an additional anti-VEGF biological therapy are also eligible. Patients must have documented 
PD-L1 expression in the TME with PD-L1 expressed on at least 1% of tumor and/or immune cells, 
as detected by local testing with an FDA-cleared or any PD-L1 assay approved for use by local 
competent authority. 
Stratification factors will be applied for Part B Cohort enrollment. 
Number of Patients: 
Part A: As guided by the BOIN design, patient recruitment in Part A occurs until a maximum sample size of 25 is 
reached.  Stop Part A if the number of patients treated at the current dose reaches 12. The optional Part A-2 will 
potentially enroll up to 40 patients. Part A was formally completed on 23 May 2022 by means of a formal SMC 
meeting, and based on availability of all required data for 25 patients evaluable for safety evaluation according to the 

 
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BOIN rules. The 800mg flat dose level was determined by the SMC to represent a tolerable dose to be further studied 
as presumptive RP2D in Part B of the trial. 
Part B (Cohorts B1 through B8): As guided by the BOP2 design, up to 40 patients per cohort will be enrolled initially 
into Cohorts B1-B4 and B6-B8.  In Cohorts B1-B4 and B6-B8, patients will be treated with 800mg NM21-1480 to 
be administered approximately every 14 days.  For Cohort B5, initial patients randomized to the NM21-1480/PD1 
checkpoint inhibitor (pembrolizumab) arm will be administered the 800mg flat dose of NM21-1480 approximately 
every 14 days. There will be an enrolment stop after 6 patients have been enrolled to the NM21-1480/anti-PD1 
combination arm. Only upon safety data review and clearance of this NM21-1480 dose level as a tolerable dose in 
the combination therapy setting by the SMC, the remaining patients are to be enrolled to Cohort B5.  Once an MTD 
has been determined for NM21-1480 in this Cohort B5 combination setting, remaining patients may only be assigned 
to NM21-1480 dose levels at or below this combination therapy MTD for NM21-1480.   
For the primary goal of assessing clinical response in Part B, depending on recruitment and availability of primary 
efficacy data, an interim futility analysis will be conducted for each cohort after 25 patients have response data 
following completion of 2 assessment cycles (i.e., 12 weeks). No such interim analysis will be done for Cohort B5 
though. Dose groups may be pooled within cohorts for analysis if the response is deemed independent of dose from 
a PD/clinical perspective. 
For Cohort B5, a total of approximately 200 patients with head and neck squamous cell cancer may ultimately be 
randomized 2:1 to either NM21-1480 plus a PD-1 standard-of-care first-line checkpoint inhibitor or to the 
standard-of-care PD-1 checkpoint inhibitor monotherapy.  Randomization will be stratified by combined positive 
score (CPS ≥1; CPS ≥20), as determined by an FDA-cleared or any PD-L1 test approved for use by local competent 
authority.  An interim analysis will be performed after 60 patients (40 patients in the NM21-1480 arm) have been 
enrolled.  At this point, recruitment will be paused, the accumulated data analysed and regulatory authorities 
consulted.  As with the other cohorts, decisions at this interim point will be taken based on clinical and regulatory 
input and not formal statistical testing. 
Key Inclusion Criteria: 
1. Parts A & A-2: Patients with any previously treated solid tumor-type other than hepatocellular carcinoma or 
intrahepatic cholangiocarcinoma, confirmed by available pathology records and/or current biopsy, that is 
advanced (non-resectable or metastatic), or recurrent and progressing since last anti-tumor therapy, and for 
which no alternative, standard therapy exists.  
2. Part B (all cohorts):  
• 
Cohorts B1 and B7  
o 
Patients with locally advanced or metastatic, non-resectable NSCLC and documented PD-L1 
expression on ≥50% of tumor cells# (Cohort B1) or documented PD-L1 expression on ≥1%-49% of 
tumor cells # (Cohort B7)  
o 
Cohort B1 and B7 will be conducted in the US, Spain, UK, the Netherlands, Germany, and Taiwan. 
Patients must have received at least 1, and a maximum of 3, previous lines of therapy, including at least 
1 previous line containing a PD-(L)1 checkpoint inhibitor. For patients enrolled to Cohorts B1 and 
B7 in Germany, they must have received both an anti-PD-(L)1 therapy and a platinum-based 
chemotherapy (i.e., at least 2 prior lines of treatment) to be eligible for study entry. 
o 
Patients must have disease that is resistant (i.e., primary resistant&) or refractory (i.e., secondary 
resistant&) to anti-PD-(L)1 therapy as defined by: 
a) Has received at least 2 doses of an approved anti-PD-(L)1 monoclonal antibody. 
b) Has demonstrated progressive disease after anti-PD-(L)1 therapy as defined by RECIST 1.1, which 
was subsequently confirmed by a second assessment no less than 4 weeks from the date of the first 
documented progressive disease to rule out pseudo-progression, if the latter could not be excluded 
by the investigator based on the initial imaging demonstrating disease progression. 
# Prospective testing is not done for Cohort B1 and B7, i.e., inclusion relies on documented previous 
testing leading to initiation of anti-PD-(L)1 therapy. 
& Primary vs. secondary resistance will be determined based on documented progression of patients 
following less than or at least 24 weeks on previous anti-PD-(L)1 therapy. 
• 
Cohort B2  
o 
Patients with locally advanced or metastatic, non-resectable HPV-associated (i.e., HPV+ tumor) SCC 
of the anus, cervix, vulva, vagina, penis or oropharynx with documented PD-L1 expression on at least 
1% of tumor and/or immune cells in the TME, as detected by a locally-assayed, FDA-cleared PD-L1 
test or any PD-L1 test approved for use by local competent authority 

 
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o 
Cohort B2 will be conducted in the US, Spain, UK, the Netherlands, Germany, and Taiwan. For Cohort 
B2, disease progression must have been documented following a first-line standard-of-care anti-PD-1 
monotherapy, anti-PD-1/chemotherapy or chemotherapy regimen. Inclusion of patients with 
progression on or after 2 previous lines of therapy, including one line of anti-PD-1 checkpoint inhibitor 
therapy and one line of chemotherapy is also acceptable. Patients must: 
a) Either have documented previous testing results indicating HPV positivity for the current tumor 
or, in absence of a positive previous HPV test result, the current tumor must be tested positive for 
HPV applying the local standard testing approach. 
b) Have demonstrated progressive disease after standard first-line, or first- and second-line, therapy 
as defined by RECIST 1.1 or in the view of the Investigator be ineligible or unwilling to be treated 
with standard first- or second-line therapy. 
NOTE: A maximum of 10 patients with oropharyngeal SCC and a minimum of 15 patients with cervical 
SCC and 15 patients with anal SCC, respectively, will be enrolled within the total of 40 patients in the 
cohort. 
• 
Cohort B3  
o 
Patients with locally advanced or metastatic, non-resectable NSCLC and documented PD-L1 
expression on ≥50% of tumor cells 
o 
Cohort B3 will be conducted in Turkey, Georgia, Ukraine, and Taiwan. For Cohort B3, standard-of-
care first-line treatment is defined as: standard local first-line chemotherapy. Patients must have 
demonstrated progressive disease after standard-of-care local first-line therapy as defined by 
RECIST 1.1. PD-L1 expression on tumor cells is determined centrally by a Sponsor-approved PD-L1 
assay. 
• 
Cohort B4  
o 
Patients with recurrent, persistent or metastatic ovarian, primary peritoneal or fallopian tumor 
carcinoma of all histologic types, except mucinous adenocarcinoma and carcinosarcoma, with 
documented disease progression (disease not amenable to curative therapy) and a history of primary 
platinum-based chemotherapy 
o 
Cohort B4 will be conducted in the US, Spain, UK, the Netherlands, Germany, Taiwan, Turkey, 
Georgia, and Ukraine.  For Cohort B4, patients must have a history of primary platinum-based 
chemotherapy with a maximum of 3 prior cytotoxic regimens and with at least one regimen for recurrent 
disease containing a platinum or a taxane for those with 3 prior regimens; the last platinum-free interval 
must be ≤12 months.  Histologic confirmation of the original primary tumor is required via the 
pathology report.  NOTE: Patients with mucinous or carcinosarcoma histology are not eligible. 
o 
Patients are allowed to have received up to 3 prior cytotoxic regimens for treatment of their epithelial 
ovarian, fallopian tube, or primary peritoneal cancer;  
 
they must have had one prior platinum-based chemotherapeutic regimen for management of 
primary disease, possibly including intra-peritoneal therapy, consolidation, biologic/targeted (non-
cytotoxic) agents or extended therapy (maintenance/consolidation) administered after surgical or 
non-surgical assessment;  
 
patients are allowed to have received, but are not required to have received, one to 2 cytotoxic 
regimens for management of recurrent or persistent disease;  
 
poly-adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors given for recurrent or 
progressive disease will be considered cytotoxic;  
 
PARP inhibitors given as maintenance therapy in continuation with management of primary 
disease will not be considered as separate cytotoxic regimen;  
 
if 2 cytotoxic regimens had been received for management of recurrent or persistent disease, one 
of these regimens would have had to contain either a platinum or a taxane agent 
o 
Platinum-free interval (PFI) – patients must have progressed ≤12 months after completion of their last 
platinum-based chemotherapy; the date (PFI) should be calculated from the last administered dose of 
platinum therapy to documentation of progression 
• 
Cohort B5  
o 
Patients with head and neck squamous cell cancer with documented CPS ≥1 in the TME and as 
determined by an FDA-cleared* or any PD-L1 test approved for use by competent authority 
o 
Cohort B5 will be conducted in the US, Spain, UK, the Netherlands, and Taiwan. For Cohort B5, 
patients must have metastatic or unresectable, recurrent disease considered incurable by local therapies 

 
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. Patients must qualify for in-label first-line, single agent treatment with an approved anti-PD-1 
checkpoint inhibitor and as per investigator judgement would also be put on such treatment as part of 
standard-of-care, i.e., irrespective of clinical trial participation, at doses not exceeding those approved 
in local product labels 
*FDA-cleared tests include: PD-L1 IHC 22C3 (Dako; preferred assay), VENTANAPD-L1 (SP142; 
Ventana/Roche), and PD-L1 IHC 28-8 (Dako, VENTANA PD-L1 (SP263; Ventana/Roche), or any 
other companion /complementary diagnostic PD-L1 assay that may receive FDA approval during the 
conduct of this study. 
• 
Cohort B6  
o 
Patients with TNBC according to current ASCO/CAP guidelines that is measurable according to 
RECIST1.1 criteria 
o 
Cohort B6 will be conducted in the US, Spain, UK, the Netherlands, and Taiwan. For Cohort B6, 
patients must have metastatic disease or locally advanced breast cancer (beyond curative management) 
o 
TNBC must be characterized as having ≤1% cellular expression of ER and PR as determined by 
immunohistochemistry (IHC) and having HER2 expression of 0 to 2+ by IHC as per current 
ASCO/CAP Guidelines. If IHC 2+, a negative in situ hybridization test (preferably fluorescence in situ 
hybridization (FISH); chromogenic or silver-enhanced in situ hybridization (CISH; SISH) acceptable) 
is required by local laboratory testing 
o 
Patients must have received at least one line of previous systemic therapy for advanced breast cancer 
(chemotherapy or targeted therapy allowed); however, patients must not have received more than 3 
previous lines of cytotoxic chemotherapy (i.e., targeted agents not counting as previous line in this 
context) 
o 
20 patients in the cohort must have received prior therapy with an immune checkpoint inhibitor (i.e., an 
approved PD-1 or PD-L1 antibody), while the other 20 patients must not have received prior therapy 
with an immune checkpoint inhibitor (as per stratification) 
• 
Cohort B8 
o 
Cohort B8 will be conducted in the US, Spain, UK, the Netherlands, and Germany. Patients with 
metastatic, non-resectable colorectal cancer (mCRC) that is MSS or MSI low*, previously treated with 
all of the following: 
 
fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy,  
 
and, if RAS wild-type, an anti-EGFR therapy, if eligible.  
 
Patients previously treated with an additional anti-VEGF biological therapy are also eligible 
o 
Patient agrees to paired biopsies and is judged by the Investigator as safe for paired biopsies. 
o 
Patients must have documented PD-L1 expression in the TME with PD-L1 expressed on at least 1% of 
tumor and/or immune cells, as detected by local testing with an FDA-cleared or any PD-L1 assay 
approved for use by local competent authority*. 
*Eligibility determination can be done based on documented previous testing results. If no previous testing result 
is available eligibility determination will be done based on archival tissue or fresh biopsy taken during screening 
3. 
Parts A & A-2: Prior chemotherapy or systemic radiotherapy (for immunotherapy see exclusion criteria) must 
have been completed at least 4 weeks prior to the administration of the first dose of study drug, and patient has 
recovered to Common Terminology Criteria for Adverse Events (CTCAE) V5.0 Grade 1 or better from all AEs 
associated with prior therapy or surgery (however, sensory neuropathy ≤Grade 2, alopecia and endocrine 
disorder treated with hormone replacement is acceptable).  
4. Part B: For Cohorts B1, B2, B6 (subgroup with required previous checkpoint inhibitor therapy) and B7: Last 
dose of therapy with anti-PD-1 antibody must have been received at least 2 weeks prior to the administration of 
the first dose of the study drug.  All cohorts (while not applicable to Cohort B5): Prior chemotherapy must have 
been completed at least 4 weeks prior to the administration of the first dose of study drug.  Exceptions: Hormone 
(e.g., thyroid hormone) replacement therapy.   
5. Part A-2: Documented minimal PD-L1 expression on at least 1% of tumor and/or immune cells in the TME, as 
detected by local testing with an FDA-cleared or any PD-L1assay approved for use by local competent authority. 
Key Exclusion Criteria: 
Patient previously had known immediate or delayed hypersensitivity reaction or idiosyncrasy to the excipients (refer 
to Appendix I) of investigational product (IP) or has experienced ≥Grade 3 irAEs with previous checkpoint inhibitor 
therapy. 

 
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1.     Parts A & A-2: Treatment with any antibody targeting PD-1, CTLA-4, 4-1BB or PD-L1 or other investigational 
biological drugs within 5 half-lives of that antibody prior to the administration of the first dose of study drug (or 
within 8 weeks if the half-life is not known). Part B: 
• 
Cohorts B1 and B7 – NSCLC and documented PD-L1 expression on ≥50% of tumor cells (Cohort B1) or 
documented PD-L1 expression on ≥1%-49% of tumor cells (Cohort B7): 
o 
Treatment with PD-1 antibody within 2 weeks prior to first dose of study drug 
o 
Treatment with any PD-L1-directed therapy within 5 (five) half-lives of the respective drug; if the half-
life of the respective PD-L1 antibody is unknown, treatment with such a PD-L1 antibody within 12 
weeks prior to the first dose of study drug is exclusionary 
o 
Previous treatment with a PD-(L)1x4-1BB bispecific antibody or any other treatment targeting 4-1BB 
o 
Patients who, for the treatment of the current cancer, has received any other treatment than anti-PD-(L)1 
or chemotherapy within 28 days prior to initiation of the study drug or who has not recovered to CTCAE 
V5.0 Grade 1 or better from the AE due to anti-PD-(L)1 administered earlier; in addition, patients with 
any ongoing Grade 1 or higher AE of colitis, hepatitis, nephritis, or pneumonitis considered to be related 
to previous anti-PD-(L)1 therapy is exclusionary.  However, sensory neuropathy ≤Grade 2, alopecia 
and endocrine disorder treated with hormone replacement are acceptable 
• 
Cohort B2 – HPV-associated (i.e. HPV+ tumor) SCCs: 
o 
Patients who, for the treatment of the current cancer, has received any treatment other than anti-PD-1 
or a platinum-based chemotherapy regimen recommended as first-line or second-line treatment by 
current National Comprehensive Cancer Network (NCCN) treatment guidelines or who has not 
recovered to CTCAE V5.0 Grade 1 or better from the AE due first- or second-line treatment; in addition, 
patients with any ongoing Grade 1 or higher AE of colitis, hepatitis, nephritis or pneumonitis considered 
to be related to previous anti-PD-1 therapy is exclusionary. However, sensory neuropathy ≤Grade 2, 
alopecia and endocrine disorders treated with hormone replacement are acceptable 
o 
Treatment with PD-1 antibody within 2 weeks prior to first dose of study drug 
• 
Cohort B3 – NSCLC and documented PD-L1 expression on ≥50% of tumor cells: 
o 
Patients who, for the treatment of the current cancer, has received any treatment other than a local 
standard-of-care first-line chemotherapy regimen or who has not recovered to CTCAE V5.0 Grade 1 
or better from the AE due first-line treatment. However, sensory neuropathy ≤ Grade 2, alopecia and 
endocrine disorders treated with hormone replacement are acceptable 
o 
Patient has received a PD-1, PD-L1, 4-1BB or CTLA-4 antibody or any other investigational biological 
drugs for treatment of the current cancer 
o 
Patients with epithelial growth factor receptor (EGFR) tyrosine kinase activating mutations or 
anaplastic lymphoma kinase (ALK) gene rearrangements. Patients with EGFR inactivating mutations 
(e.g., exon 20) may be eligible 
• 
Cohort B4 – ovarian, primary peritoneal or fallopian tumor carcinoma: 
o 
Patients who have had prior therapy with anti-PD-1, anti-PD-L1, anti-4-1BB or anti-CTLA-4 
antibodies or any other antibody or drug specifically targeting T-cell co-stimulation or immune check 
point pathways 
o 
Patients who have received prior chemotherapy for any abdominal or pelvic tumor other than for 
treatment of ovarian, fallopian tube, or primary peritoneal cancer within the last 3 years; patients may 
have received prior adjuvant chemotherapy and radiotherapy for localized breast cancer, provided that 
it was completed more than 2 years prior to consenting to this study, and the patient remains free of 
recurrent or metastatic disease and hormonal therapy has been discontinued; patients who have received 
prior radiotherapy to any portion of the abdominal cavity or pelvis or thoracic cavity within the last 3 
years are excluded; prior radiation for localized cancer of the head and neck or skin is permitted, 
provided that it was completed more than 3 years prior to consenting to this study, and the patient 
remains free of recurrent or metastatic disease 
• 
Cohort B5 – head and neck squamous cell cancer with documented CPS ≥1: 
o 
Patients who have previously received a checkpoint inhibitor for their disease 
• 
Cohort B6 – TNBC: 
o 
For patients in the subgroup in which previous therapy with a checkpoint inhibitor is required: 
 
Treatment with PD-1 antibody within 2 weeks prior to the first dose of study drug 

 
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 
Treatment with PD-L1 antibody within 5 half-lives prior to first dose of study drug. If the half-
life of a previously used anti-PD-L1 antibody is unknown, the Medical Monitor must be 
contacted. 
 
Patient who has not recovered to CTCAE V5.0 Grade 1 or better from the AE due to anti-PD-
1 or anti-PD-1 antibody administered earlier; in addition, patient with any ongoing Grade 1 or 
higher AE of colitis, hepatitis, nephritis, or pneumonitis considered to be related to previous 
anti-PD1 or anti-PD-L1 therapy is exclusionary. However, sensory neuropathy ≤Grade 2, 
alopecia and endocrine disorder treated with hormone replacement are acceptable 
 
Previous treatment with anti-CTLA-4 or anti-4-1BB antibody or drug specifically targeting T 
cell co-stimulation or immune checkpoint pathways other than the PD-1/PD-L1 pathway 
o 
For patients in the subgroup in which previous therapy with a checkpoint inhibitor is prohibited 
 
Patients who had prior therapy with anti-PD-1, anti-PD-L1, anti-4-1BB or anti CTLA 4 
antibodies or any other antibody or drug specifically targeting T-cell co-stimulation or immune 
check point pathways  
• 
Cohort B8 – mCRC: 
o 
Patients who have previously been treated with trifluridine/tipiracil or regorafenib 
o 
Patients who have previously been treated with T-cell bispecifics, 4-1BB agonists, or immune 
checkpoint blockade therapies, including anti-CTLA-4, anti-PD1 and anti-PD-L1 unless discussed with 
the Medical Monitor and agreed by the Sponsor 
o 
Patients who have received treatment with systemic immunostimulatory agents (including, but not 
limited to, interferon and IL-2) within 4 weeks or 5-half lives, whatever is longer, prior to initiation of 
NM21-1480 treatment 
o 
Patients who have received treatment with systemic immunosuppressive medication (including, but not 
limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-
TNFalpha medications) within 2 weeks prior to initiation of NM21-1480 treatment, or anticipation of 
need for systemic immunosuppressive medication during NM21-1480 treatment  
o 
Presence of ascites that required two or more therapeutic paracenteses in the last 30 days  
2. Parts A & A-2: Use of other biological investigational drugs (drugs not marketed for any indication), including 
use of investigational antibodies targeting CD137/4-1BB, PD-1 or PD-L1 within at least 5 half-lives (or within 
8 weeks if half-life of that investigational drug is not known) prior to the administration of the first dose of study 
drug.  
3. Patient has an active autoimmune disease or a documented history of autoimmune disease.  Patients with vitiligo, 
autoimmune thyroiditis, or psoriasis (not requiring systemic treatment within the past 2 years), type I diabetes 
on stable insulin therapy or – in the view of the Investigator – resolved childhood asthma/atopy would be an 
exception to this rule.  Patients that require intermittent use of bronchodilators, inhaled steroids or local steroid 
injections including intra-articular injections will not be excluded from the study.  Patients with hypothyroidism 
stable on hormone replacement will not be excluded from the study.  Patients with celiac disease adequately 
controlled by diet alone will not be excluded from the study. 
Duration of Treatment: 
There is no pre-specified maximal treatment duration.  Treatment for a given patient shall be continued until there is 
confirmed disease progression by the Investigator or the patient meets any of the pre-specified conditions for 
discontinuation. 
Statistical Methods: 
Sample Size Determination 
No formal group size calculation has been applied as the sample size during dose-escalation cannot be precisely 
determined but depends on the observed toxicity. 
For Part A dose-escalation, a BOIN design with a pre-specified maximal patient number of 25 will be applied. For 
Part A-2 (OPTIONAL), a maximum number of 40 patients will be treated to provide additional PD data in support 
of dose selection for Part B, or in order to complement the PK, immunogenicity, and PD data provided by Part B.  
The sample size is based on clinical rather than statistical considerations. 
For Part B dose expansion (Cohorts B1 through B4 and B6-B8), a BOP2 design will be applied with a maximum of 
40 patients per cohort. An interim futility analysis will be conducted for each Part B cohort (other than Cohort B5) 
after 25 patients have response data following completion of 2 assessment cycles (i.e., 12 weeks).  For Cohort B8, 
the Sponsor will hold enrollment to the Cohort after 25 patients have received at least one dose of NM21-1480 

 
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treatment until all relevant safety, efficacy, PK, immunogenicity and most prominently all relevant PD data that has 
accrued until then has been reviewed by the SMC and the Sponsor. After this interim review, the Sponsor may decide 
to stop the cohort, to continue with full enrollment of the cohort or revise eligibility criteria before the remaining 15 
patients in the cohort are enrolled.  Patients in Part B will be treated at the 800mg flat dose of NM21-1480; for Cohort 
B5, patients in the combination treatment arm will be administered the 800mg flat dose of NM21-1480 approximately 
every 14 days. There will be an enrolment stop after 6 patients have been enrolled to the NM21-1480/anti-PD1 
combination arm. Only upon safety data review and clearance of this NM21-1480 dose level as a tolerable dose in 
the combination therapy setting by the SMC, the remaining patients are to be enrolled to Cohort B5. For any of the 
Part B cohorts, PD data may be analysed during Part B and used to drop dose groups within cohorts based on review 
by the SMC and the Sponsor.  Decisions will be based on clinical considerations, not formal statistical arguments.  
For final response assessment, dose groups may be pooled within cohorts for analyses if the response is deemed to 
be independent of dose from a clinical perspective. 
For Cohort B5, a total of approximately 200 patients with head and neck squamous cell cancer will be randomized 
2:1 to either NM21-1480 plus a PD-1 standard-of-care first-line checkpoint inhibitor or to the standard-of-care PD1 
checkpoint inhibitor monotherapy.  Based on 10,000 trial simulations performed in R, a sample size of 180 patients 
in a 2:1 randomization provides approximately 90% power to detect a difference of 15% between the treatment 
groups with an estimated two-sided Type 1 error rate <0.05 of 0.0391.  Allowing for 10% losses to follow-up, at 
least 200 subjects will be randomized in Cohort B5. An interim analysis will be performed after a minimum of 
60 patients (40 patients in the NM21-1480 arm) have been enrolled.  At this point recruitment will be paused, the 
accumulated data analyzed and regulatory authorities consulted.  Cohort B5 will be regarded as futile (non-binding) 
if the probability of observing a difference in estimated effects between control and treatment of at least 15% is less 
than 0.1.  However, as with the other cohorts, decisions at the interim point will be taken based on clinical and 
regulatory input and not formal statistical testing. 
 
Safety Analyses 
All recorded TEAEs will be listed and tabulated by system organ class, preferred term, and dose and coded according 
to the most current version of Medical Dictionary for Regulatory Activities (MedDRA).  The incidence of Aes will 
be tabulated.  A separate listing and summary of all irAEs will be provided.  Adverse events will be summarized for 
all reported data and by study part as well as study period, i.e., up to and including 70 days post last dose of study 
treatment. Safety data for Part B may be pooled across dose groups to mirror the efficacy analysis decisions to 
facilitate an appropriate risk benefit assessment per cohort. 
Efficacy Analyses 
Summary statistics will be presented for data collected during Part A and Part A-2, and separately for Part B within 
cohorts and pooled across dose groups as appropriate.  If sufficient data are available for the selected dose levels, the 
PD/dose response relationship may be formally modelled. 
In order to perform preliminary evaluation of anti-tumor activity, best overall response (BOR) outcomes, objective 
response rate (ORR) and Disease Control Rate (DCR) according to RECIST 1.1 will be tabulated by frequency 
distribution overall, and 6 weeks and 12 weeks following the start of study treatment in Part A-2 (if applicable) and 
Part B.  For Part B only, these clinical activity assessments will also be done according to iRECIST criteria. Similar 
exploratory analyses will be done for Part A (if applicable) overall and 8 and 16 weeks following Day 1, in 
accordance with the respective imaging visit frequency. Median time-to-response (TTR) and duration of response 
(DOR) will be summarized for those patients with responses, using the Kaplan-Meier method, i.e., by generation of 
Kaplan-Meier curves for time-to-event variables; PFS and OS will be similarly summarized.  Exploratory clinical 
anti-tumor analysis to assess the overall survival (OS) will be provided by Kaplan-Meier method.  Dose groups may 
be pooled within cohorts for interim and final analyses in Part B if the response is deemed to be independent of dose 
from a clinical perspective. 
For Cohort B5, the primary efficacy endpoint will be ORR. The primary analysis will be performed in the Efficacy 
Analysis Set using a Bayesian logistic regression model with treatment and (CPS ≥1; CPS ≥20) as covariates: 
 
끫롾끫롾끫롾끫롾끫롾 ( 끫뢺끫뢬) = 끫뷺0 + 끫뷺1 × 𝑡𝑡끫룂끫룂끫룂𝑡𝑡끫룂끫룂끫룂𝑡𝑡 + 끫뷺2 × 끫롬끫롬끫롬20 
 
The following prior distributions have been assumed: 
β0 ~ N (-1.45, 0.162), equivalent to a control response rate of 20 (±4)% observed in the KEYNOTE-048 study with 
pembrolizumab; 

 
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β1 ~ N (0,1), vague prior on treatment equivalent to expected treatment difference of 0% (95% confidence interval: 
-16% to +43%, which corresponds to a N(0,1) prior on logistic scale) 
β2 ~ N (0, 0.12), vague prior on CPS effect, based on KEYNOTE-048 study with pembrolizumab, where a 0%-3% 
difference in response was observed across CPS levels. 
 
The Bernoulli likelihood is not conjugate to the normal priors on the regression coefficients and so the posterior 
distribution of regression coefficients is not known. Let 끫뷺= (끫뷺0, 끫뷺1, 끫뷺2). 
 
끫븖(끫뷺|끫뢢𝑑𝑑𝑑𝑑𝑑𝑑) ∝끫븖(끫뢢𝑑𝑑𝑑𝑑𝑑𝑑|끫뷺)끫븖(끫뷺) 
 
In order to avoid the use of Monte Carlo methods for inference on parameters (and the requirement of large 
simulations to estimate posteriors with sufficient precision) we fit Laplace approximations to posterior distributions.  
We approximate 끫븖(끫뷺|끫뢢𝑑𝑑𝑑𝑑𝑑𝑑) ≈끫뢂 (끫뷺′, 끫뢒𝑉𝑉𝑉𝑉(끫뷺′)) where 끫뷺′ is the mode of the posterior distribution of 끫븖(끫뷺|끫뢢𝑑𝑑𝑑𝑑𝑑𝑑) with 
끫뢒𝑉𝑉𝑉𝑉(끫뷺′) the posterior covariance matrix estimated at this mode.   
At the interim analysis, Cohort B5 will be regarded as futile (non-binding) if the probability of observing a difference 
in estimated effects between control and treatment of at least 15% is less than 0.1. However, as with the other cohorts, 
decisions at the interim point will be taken based on clinical and regulatory input and not formal statistical testing. 
Statistical superiority of the treatment in the final analysis will be concluded if  𝑃𝑃𝑃𝑃(끫뷺1 > 0 | 끫뢢𝑑𝑑𝑑𝑑𝑑𝑑) is > 0.95.Analysis 
of Pharmacokinetics Endpoints and Anti-Drug Antibody 
Pharmacokinetics parameters such as the maximum observed serum concentration (Cmax), the minimum observed 
serum concentration (Cmin), the time from dosing at which Cmax is apparent (Tmax), terminal phase (apparent 
elimination) rate constant (λz), elimination half-life (t½), area under the serum concentration-time curve extrapolated 
from the last quantifiable concentration to infinity (AUC[0-infinity]), area under serum concentration-time curve 
over dosing interval (AUCtau), clearance (CL), apparent volume of distribution (Vd), and accumulation index will 
be derived from serum concentration versus time data for patients with serial PK samples.  Data obtained from 
patients with serial sampling and limited sampling will eventually be combined with data from other studies for 
population PK analysis but reported separately. 
A listing will be generated of all available immunogenicity data, comprising all numeric titer values.  Additionally, 
a listing of immunogenicity data from those patients with at least 1 positive anti-drug antibody (ADA) assessment 
(titer value greater than 2-fold of baseline titer) at any time point will be provided by dose regimen.  The frequency 
of patients with at least 1 positive ADA assessment (titer value greater than 2-fold of baseline titer), and frequency 
of patients who develop ADA after a negative baseline assessment (i.e., titer value equal to 1), and frequency of 
patients who develop ADA after a baseline titer assessment greater than 1, will be provided by dose. In addition, the 
frequency of patients who do not develop ADAs after treatment following either a negative baseline assessment (i.e., 
titer value equal to 1), or a baseline titer greater than 1 will be provided by dose. Treatment-induced, treatment-
enhanced and treatment-unaffected ADA patients will be summarized. In addition, to examine the potential 
relationship between immunogenicity and safety, the frequency and type of AEs may be examined by overall 
immunogenicity status. 
Pharmacodynamic Characteristics and Exploratory Biomarkers 
Key PD parameters for determination of dose levels to be selected for Part B will comprise all exposure-dependent 
PD markers of target and pathway engagement including but not limited to characterization of peripheral PD (IFNɣ; 
CXCL10; soluble 4-1BB; proliferating CD8+ and effector memory CD8+ cells) and receptor occupancy: this may 
be supplemented by other exploratory biomarker data, for example assessment of T-cell receptor clonality in tumor 
tissue. Summary statistics for blood- and tissue-based PD markers, including but not limited to flow cytometry 
outcomes, cytokines, and their changes (or fold changes) from baseline will be tabulated by cycle, visit, and dose to 
assess PD effects and potential association with PK exposure.  Associations of status of exploratory biomarkers 
(baseline value or change from baseline) with clinical outcome (e.g., tumor response) may be explored based on data 
availability, using response-evaluable patients, to explore potential predictive markers (e.g., PD-L1) expression in 
tumors. Additional tissue biopsy-based exploratory analysis for biomarkers may be applied for mCRC patients 
possibly enrolled to Cohort B8, given there is a mandatory requirement to provide matched fresh biopsies for this 
cohort. 
Administrative interim analyses on safety and clinical activity or on PK, immunogenicity, and selected biomarkers 
may be provided at several times prior to completion of the study in order to facilitate program decisions and to 
support study presentations or publications. 
Date of the protocol: 17 Nov 2022 

 
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3 
TABLE OF CONTENTS 
1 
GENERAL INFORMATION ................................................................................ 3 
2 
STUDY SYNOPSIS .............................................................................................. 4 
3 
TABLE OF CONTENTS .................................................................................... 19 
3.1 
List of Tables .......................................................................................... 23 
3.2 
List of Figures......................................................................................... 23 
4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................ 25 
5 
INTRODUCTION ............................................................................................... 29 
5.1 
Background............................................................................................. 29 
5.1.1 
NM21-1480 ........................................................................................ 31 
5.1.2 
Non-Clinical Summary ...................................................................... 32 
5.1.3 
Clinical ............................................................................................... 37 
5.2 
Study Rationale ...................................................................................... 37 
5.2.1 
Rationale for the NM21-1480 Starting Dose ..................................... 39 
5.3 
Benefit – Risk Assessment ..................................................................... 40 
5.3.1 
Benefit Assessment ............................................................................ 40 
5.3.2 
Risk Assessment ................................................................................ 41 
5.3.3 
Overall Benefit Risk Assessment ...................................................... 41 
6 
STUDY OBJECTIVES AND ENDPOINTS....................................................... 43 
7 
OVERALL STUDY DESIGN AND PLAN........................................................ 47 
7.1 
Study Design Description ....................................................................... 47 
7.1.1 
Estimated Number of Enrolled Patients ............................................. 54 
7.1.1.1 
Part A (Dose-Escalation) .................................................... 54 
7.1.1.2 
Part A-2 (Optional) ............................................................. 55 
7.1.1.3 
Part B (Dose Expansion) .................................................... 55 
7.1.2 
Estimated Number of Screened Patients ............................................ 55 
7.1.3 
Duration of Participation ................................................................... 55 
7.1.4 
Treatment Beyond Disease Progression ............................................ 56 
7.1.5 
Duration of Treatment ....................................................................... 57 
7.1.6 
Schedule of Assessments ................................................................... 58 
7.1.7 
Blood Sampling Schedule (APPLIES TO ALL PARTS [A, A-2 AND 
B] OF THE STUDY) ......................................................................... 69 
7.2 
Study Population .................................................................................... 77 
7.2.1 
Inclusion Criteria (Part A and Part B) ............................................... 77 
7.2.2 
Exclusion Criteria (Part A and Part B) .............................................. 86 
7.2.3 
Strategies for Recruitment and Retention .......................................... 91 
7.2.4 
Screen Failures ................................................................................... 91 

 
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7.2.5 
Stopping Rules and Decision-Making Procedure .............................. 91 
7.2.5.1 
Dose-Limiting Toxicity ...................................................... 93 
7.2.5.2 
Stopping Rules for Delayed AEs During Dose-Escalation 95 
7.2.5.3 
Safety Stopping Rules in the Expansion Cohorts ............... 95 
7.2.5.4 
Stopping Rules for Futility in the Expansion Cohorts ........ 97 
7.2.6 
Withdrawal of Participants ................................................................ 98 
7.2.7 
Lost to Follow-up .............................................................................. 99 
7.2.8 
End of Study Definition ..................................................................... 99 
7.2.9 
Discontinuation of Study Drug .......................................................... 99 
7.2.10 
Discontinuation of Study Sites ........................................................ 101 
7.2.11 
Discontinuation of Study ................................................................. 101 
7.2.12 
Follow-up ......................................................................................... 101 
8 
STUDY TREATMENT ..................................................................................... 102 
8.1 
Administration of Study Treatment(s) .................................................. 102 
8.1.1 
Duration of Treatment with Study Drug .......................................... 103 
8.1.2 
8-Week Assessment ......................................................................... 103 
8.1.3 
Radiological Assessment in the Follow-up Period .......................... 103 
8.1.4 
Re-initiation of Study Therapy for Patients in Follow-up Period .... 104 
8.1.5 
Dose Modification ........................................................................... 104 
8.1.5.1 
Dose Reduction ................................................................ 104 
8.1.5.2 
Dose Withheld .................................................................. 104 
8.1.6 
Dose Resumption ............................................................................. 105 
8.1.7 
Management of Infusion-Related Reactions .................................... 107 
8.2 
Study Treatment Packaging and Labelling........................................... 108 
8.2.1 
Packaging ......................................................................................... 108 
8.2.2 
Storage ............................................................................................. 109 
8.3 
Patient Compliance ............................................................................... 109 
8.4 
Study Treatment Accountability ........................................................... 109 
8.5 
Concomitant Therapy ........................................................................... 109 
8.5.1 
Permitted Medications ..................................................................... 109 
8.5.2 
Prohibited Medications .................................................................... 110 
9 
STUDY ASSESSMENTS AND PROCEDURES............................................. 111 
9.1 
Clinical Activity Assessments .............................................................. 111 
9.1.1 
Tumor Response .............................................................................. 111 
9.2 
Safety Assessments .............................................................................. 112 
9.2.1 
Definitions ....................................................................................... 112 
9.2.1.1 
Adverse Events ................................................................. 112 

 
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9.2.1.2 
Events Meeting the AE Definition ................................... 112 
9.2.1.3 
Events NOT Meeting the AE Definition .......................... 113 
9.2.1.4 
Serious Adverse Event ..................................................... 113 
9.2.1.5 
Treatment-Emergent Adverse Event ................................ 116 
9.2.1.6 
Adverse Event of Special Interest .................................... 116 
9.2.1.7 
Pregnancy ......................................................................... 116 
9.2.2 
Time Period and Frequency for Collecting AE and SAE Information
 ......................................................................................................... 117 
9.2.3 
Method of Detecting AEs and SAEs ............................................... 117 
9.2.4 
Recording of AEs and SAEs ............................................................ 117 
9.2.4.1 
Assessment of Intensity .................................................... 118 
9.2.4.2 
Assessment of Causality ................................................... 118 
9.2.4.3 
Action Taken with Study Drug Due to AE ...................... 121 
9.2.4.4 
Other Action Taken .......................................................... 121 
9.2.4.5 
AE Outcome ..................................................................... 121 
9.2.5 
Follow-up of AEs/SAEs .................................................................. 121 
9.2.6 
Reporting of SAEs ........................................................................... 122 
9.2.6.1 
Safety Reporting to Sponsor ............................................. 122 
9.2.6.2 
Safety Reporting to Health Authorities, Independent Ethics 
Committees/Institutional Review Boards and Investigators
 .......................................................................................... 122 
9.2.7 
Laboratory Assessments .................................................................. 123 
9.2.7.1 
Potential Hy’s Law and Hy’s Law ................................... 124 
9.2.8 
Electrocardiogram Assessments ...................................................... 124 
9.2.9 
Physical Examination ...................................................................... 124 
9.2.10 
Vital Signs ....................................................................................... 125 
9.3 
Pharmacokinetics and Immunogenicity Assessments .......................... 125 
9.4 
Pharmacodynamic Assessments and Biomarker Analysis ................... 126 
10 
STATISTICAL METHOD AND SAMPLE SIZE CALCULATION .............. 126 
10.1 
General Considerations ........................................................................ 126 
10.2 
Sample Size Estimate Calculation ........................................................ 126 
10.3 
Statistical Design .................................................................................. 128 
10.3.1 
Part A - Determining MTD Using Bayesian Optimal Interval Design
 ......................................................................................................... 128 
10.3.2 
Part A-2 (Optional): PD Expansion ................................................. 133 
10.3.3 
Part B - Clinical Activity Monitoring Using BOP2 Design ............ 133 
10.4 
Statistical Analyses Sets ....................................................................... 134 
10.4.1 
Safety Set ......................................................................................... 134 

 
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10.4.2 
Dose-Determining Set...................................................................... 134 
10.4.3 
Pharmacokinetic Set ........................................................................ 135 
10.4.4 
Efficacy Analysis Set ....................................................................... 135 
10.5 
Stratification Factors ............................................................................ 135 
10.6 
Statistical Analyses and Methods ......................................................... 135 
10.6.1 
Patient Characteristics...................................................................... 135 
10.6.2 
Efficacy Analyses ............................................................................ 135 
10.6.2.1 Primary Efficacy Analysis, Cohort B5 ............................. 136 
10.6.2.2 Best Overall Response ...................................................... 137 
10.6.2.3 Objective Response Rate .................................................. 138 
10.6.2.4 Duration of Response ....................................................... 138 
10.6.2.5 Overall Survival ............................................................... 138 
10.6.2.6 Progression-Free Survival ................................................ 138 
10.6.3 
Safety Analyses ............................................................................... 139 
10.6.4 
Study Drug Exposure ....................................................................... 139 
10.6.5 
Concomitant Medications ................................................................ 139 
10.6.6 
Adverse Events ................................................................................ 140 
10.6.7 
Laboratory Parameters ..................................................................... 140 
10.6.8 
Electrocardiograms .......................................................................... 140 
10.6.9 
Other Safety Data ............................................................................ 140 
10.6.10 Analysis of Pharmacokinetics Endpoints and Anti-Drug Antibody 141 
10.6.11 Pharmacodynamic Characteristics and Exploratory Biomarkers ..... 141 
10.7 
Safety Monitoring and Data Monitoring Committee ........................... 141 
11 
ETHICS ............................................................................................................. 143 
11.1 
Independent Ethics Committee/Institutional Review Board ................ 143 
11.2 
Written Informed Consent .................................................................... 143 
12 
QUALITY CONTROL AND QUALITY ASSURANCE ................................ 144 
12.1 
Conduct of the Study ............................................................................ 144 
12.2 
Study Monitoring.................................................................................. 144 
13 
DATA HANDLING AND RECORD KEEPING ............................................. 145 
13.1 
Case Report Forms/Source Data Handling........................................... 145 
13.2 
Data Protection ..................................................................................... 145 
13.3 
Dissemination of Clinical Study Data .................................................. 146 
13.4 
Retention of Essential Documents ........................................................ 146 

 
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14 
PUBLICATION POLICY ................................................................................. 146 
15 
CONFLICT OF INTEREST POLICY .............................................................. 147 
16 
SIGNATURE OF INVESTIGATOR ................................................................ 148 
17 
REFERENCE LIST ........................................................................................... 149 
18 
APPENDICES ................................................................................................... 152 
18.1 
Appendix I: List of NM21-1480 Formulation Excipients .................... 152 
18.2 
Appendix II: Liver Safety Monitoring and Assessment ....................... 153 
18.3 
Appendix III: Response Evaluation Criteria in Solid Tumors Version 1.1
 .............................................................................................................. 157 
18.4 
Appendix IV: Eastern Cooperative Oncology Group Performance Status 
Scale ..................................................................................................... 160 
18.5 
Appendix V: Women of Child-Bearing Potential Definitions and Methods 
of Contraception ................................................................................... 161 
18.6 
Appendix VI Immune-Related Adverse Event Management Guidance for 
Investigators ......................................................................................... 165 
18.7 
Appendix VII Required Laboratory Assessments by Panel ................. 172 
3.1 
List of Tables 
Table 7-1 
Schedule of Assessments (2-week Dosing Interval; APPLIES TO ALL 
PARTS [A, A-2 AND B] OF THE STUDY) ............................................. 58 
Table 7-2 
Backup Schedule of Assessments (3-week Dosing Interval; APPLIES TO 
PART A-2 AND B ONLY IN CASE OF A POTENTIAL FUTURE SMC 
DECISION TO PROLONG DOSING INTERVAL#)............................... 64 
Table 7-3 
Pharmacokinetics, Anti-Drug Antibody, and Pharmacodynamic Blood 
Sampling Schedule (2-week Dosing Interval) ........................................... 69 
Table 7-4 
Backup Pharmacokinetics, Anti-Drug Antibody, and Pharmacodynamic 
Blood Sampling Schedule (3-week Dosing Interval: APPLICABLE TO 
PART A-2 AND B ONLY IN CASE OF A POTENTIAL FUTURE SMC 
DECISION TO PROLONG DOSING INTERVAL#)............................... 73 
Table 8-1 
Management of Infusion-related Reactions ............................................. 107 
Table 9-1 
Assessment of Causality........................................................................... 119 
Table 10-1 
Sample size, power and Type 1 error ....................................................... 128 
Table 10-2 
Dose-Escalation/De-Escalation Decision Rules for the BOIN Design .... 131 
Table 10-3 
Observed Data as of October 29, 2021. ................................................... 131 
Table 10-4 
Operating Characteristics of the BOIN Design ........................................ 132 
3.2 
List of Figures 
Figure 5–1 
NM21-1480 (scMATCH™ 3) Tumor-Localized Agonism of 4-1BB ....... 32 
Figure 5–2 
NM21-1480 Potency to Block A) The PD-L1/PD-1 Interaction, B) The 
PD-L1/B7.1 Interaction in a Competition ELISA, and C) The Potency of 
PD-L1/PD-1 Signaling Blockade in a Transgenic NFAT-Luciferase 
Reporter Jurkat Cell-Line ........................................................................... 33 
Figure 5–3 
ND021 (NM21-1480) Provides Stronger T-cell Activation than Benchmark 
Combo Therapies –IFNϒ ............................................................................ 34 
Figure 5–4 
NM21-1480 In Vitro Proof-of-Mechanism ................................................ 34 

 
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Figure 5–5 
4-1BB Activation by NM21-1480 in NF-κB Reporter Gene Assay in 
Presence of PD L1 Expressing Cancer Cells ............................................. 36 
Figure 10–1 BOIN Design ............................................................................................ 130 

 
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4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ACTH 
Adrenocorticotrophic hormone 
ADA 
ADP 
Anti-drug antibody 
Adenosine Disphosphate 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
ANC 
APC 
ASCO 
Absolute neutrophil count 
Adenomatous Polyposis Coli 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
AUC(0-infinity) 
Area under the serum concentration-time curve extrapolated from 
the last quantifiable concentration to infinity 
AUCtau 
Area under serum concentration-time curve over dosing interval 
AT 
Aminotransferase 
BOIN 
Bayesian optimal interval 
BOP2 
Bayesian optimal phase II 
BOR 
BRAF 
CAP 
Best overall response 
B-raf protooncogene 
College of American Pathologists 
CBD 
CEA 
Cannabidiol 
Carcinembryonic Antigen 
CEC 
Central Ethics Committee 
Cmax 
The maximum observed serum concentration determined by direct 
inspection of the concentration versus time data 
Cmin 
The minimum observed serum concentration determined by direct 
inspection of the concentration versus time data 
CL 
Clearance 
CPI 
CPS 
Checkpoint inhibitor 
Combined Positive Score 
CR 
Complete response 
CSF 
Colony-stimulating factor 
CT 
Computed tomography 
CTCAE 
ctDNA 
Common terminology criteria for adverse events 
Circulating tumor Deoxyribonucleic Acid 
CTLA 
Cytotoxic T-lymphocyte associated protein 
CTL 
Cytotoxic T-lymphocyte 
CYP 
Cytochrome P (450) 
DCR 
Disease Control Rate 

 
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DLT 
Dose-limiting toxicity 
DMC 
Data monitoring committee 
dMMR 
Deficient mismatch repair 
DNA 
DOR 
DSUR 
Deoxyribonucleic acid 
Duration of Response 
Development Safety Update Report 
ECG 
Electrocardiogram 
ECOG 
Eastern cooperative oncology group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGFR 
Epithelial growth factor receptor 
ELISA 
Enzyme-linked immunosorbent assay 
ER 
Estrogen Receptor 
FDA 
Food and drug administration 
FIH 
First-in-human 
FSH 
Follicle stimulating hormone 
GCP 
Good clinical practice 
GGT 
Gamma glutamyl transferase 
HCV 
Hepatitis C virus 
HER2 
Human Epithelial Growth Factor Receptor-2 
HIV 
Human immunodeficiency viruses 
HPV(+) 
Human papillomavirus (positive) 
HSA 
Human serum albumin 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
iCPD 
International council for harmonization 
iRECIST Confirmed Progressive Disease 
IEC 
Independent ethics committee 
IFNϒ 
IHC 
Interferon gamma 
Immuno-Histochemistry 
IL 
Interleukin 
IND 
Investigational new drug 
IP 
Investigational product 
IRAE 
Immune-related adverse event 
IRB 
Institutional review board 
IV 
KRAS 
mCRC 
Intravenous 
Kirsten rat sarcoma oncogene 
Metastatic colorectal cancer 
MedDRA 
MHC 
Medical dictionary for regulatory activities 
Major Histocompatibility complex 

 
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MRI 
Magnetic resonance imaging 
MSI-H 
Microsatellite instability-high 
MTD 
Maximal tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NK 
Natural Killer cells 
NKT 
NRAS 
Natural killer T cells 
Neuroblastoma rat viral oncogene homolog 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
PARP 
PBMC 
Poly-Adenosine Disphosphate (ADP) Ribose Polymerase 
Peripheral blood mononuclear cell 
PD 
Pharmacodynamics 
PD-1 
Programmed cell death protein 1 
PD-L1 
PFI 
Programmed death-ligand 1 
Platinum-Free Interval 
PFS 
PIK3CA 
Progression-free survival 
Phosphatidyl 3-kinase CA 
PK 
POLE 
PR 
Pharmacokinetics 
Polymerase Epsilon Catalytic subunit 
Progesterone Receptor 
PT 
PTEN 
Prothrombin time 
Phosphatase and Tensin homolog 
PTT 
Partial thromboplastin time 
RT 
Radiotherapy 
RECIST 1.1 
Response evaluation criteria in solid tumors version 1.1 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 dose 
SA 
Serum albumin 
SAE 
Serious adverse event 
SCC 
Squamous cell carcinoma  
SMC 
Safety monitoring committee 
SMP 
Safety management plan 
SOP 
Standard operating procedure 
SS 
SUSAR 
Safety set 
Suspected Unexpected Serious Adverse Reaction 
TBL 
Total bilirubin level 
Th 
T-helper cells 
TEAE 
TIL 
TNBC 
Treatment-emergent adverse event 
Tumor-Infiltrating Lymphocyes 
Triple-Negative Breast Cancer 
Treg 
Regulatory T-cells 

 
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TRAE 
Treatment-related adverse event 
Tmax 
The time from dosing at which Cmax is apparent determined by 
direct inspection of the concentration vs time data 
TME 
Tumor microenvironment 
TNF 
Tumor necrosis factor 
TSH 
Thyroid stimulating hormone 
TTR 
Time-to-response 
T½ 
Elimination half-life 
UK 
United Kingdom 
ULN 
Upper limit of normal 
US 
United States 
Vd 
VEGF 
Volume of distribution 
Vascular Endothelial Growth Factor 
WBC 
White blood cell 
WOCBP 
Women of child-bearing potential 
λz 
Terminal phase (apparent elimination) rate constant 

 
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5 
INTRODUCTION 
5.1 
Background 
Immune checkpoint blockade has revolutionized cancer treatment.  Monoclonal antibodies 
targeting programmed cell death protein 1 (PD-1) and its major ligand Programmed 
death-ligand 1 (PD-L1) have demonstrated sustained clinical benefit in diverse cancer types 
including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, bladder 
cancer, head and neck squamous cell carcinoma, microsatellite instability-high (MSI-H) 
colorectal carcinoma, Merkel cell carcinoma, and Hodgkin lymphoma, where they have 
quickly changed the practice of medical oncology (Bartkowiak and Curran, 2015; Chester, et 
al. 2018).  Most recently, approval was even granted for a tumor-type agnostic indication, based 
on presence of certain tumor deoxyribonucleic acid (DNA) biomarkers (MSI-H/DNA 
mismatch repair deficiency).  However, anti-PD-1/PD-L1 therapy exhibits an almost 
dichotomous initial response pattern: some patients experience rapid and durable tumor 
regression (typically 10-30% of patients), while a majority of patients derive minimal or no 
appreciable benefit (i.e., patients with innate/primary resistance).  Furthermore, with longer 
follow-up of patients, a third population of patients has emerged, namely those that respond 
initially but eventually develop disease progression (i.e., patients with acquired/secondary 
resistance) (Jenkins, et al. 2018).  Specifically in melanoma treatment, combination 
immunotherapy or dual immune-checkpoint blockade [anti-PD-1+ anti-cytotoxic T-
lymphocyte-associated protein (anti-cytotoxic T-lymphocyte associated protein [CTLA]-4] has 
recently shown dramatic response rates in patients with metastatic melanoma (response rate 
[RR]: 58% [Jenkins, et al. 2018]); however, half of patients experienced significant toxicity 
from the treatment regimen and furthermore an efficacy advantage of this immune-checkpoint 
inhibitor (CPI) combination in other tumor types remains to be demonstrated at this point.  
From a mechanistic point of view, there are 3 major reasons for failure of immune-checkpoint 
blockade (Jenkins, et al. 2018): 
• Insufficient tumor T-cell generation, due to low mutational burden and/or 
low/insufficient neo-antigen formation, presentation, and/or processing, resulting in 
primary resistance. 
• Inadequate tumor T-cell effector function due to functional exhaustion of CD8+ T-cells, 
similarly resulting in primary resistance. 
• Impaired formation of T-cell memory, resulting in secondary resistance. 
Thus, the next wave of immunomodulatory approaches in oncology aims at increasing the 
fraction of patients that respond and continue to respond to anti-PD-1/PD-L1 immunotherapy, 
however combined with a substantially better tolerability profile than typically observed with 
the anti-PD-1/CTLA-4 combination approach.  A main therapeutic strategy to achieve that goal 
is to agonistically act on immuno-stimulatory receptors to induce immune cell activation.  Such 
“co-stim” strategies have provided the mechanistic foundation for multiple agents in clinical 
development, including antibodies targeting OX40, CD27, CD40, GITR, and 4-1BB 
(Mahoney, et al. 2015; Chester, et al. 2018). 

 
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4-1BB (CD137), a surface glycoprotein and member of the tumor necrosis factor receptor 
superfamily 9, is a uniquely compelling therapeutic target in this context.  Indeed, 4-1BB 
possesses an unequaled capacity for both activation and pro-inflammatory polarization of anti-
tumor lymphocytes (Chester, et al. 2018).  While functional studies of 4-1BB have focused on 
its prominent role in augmenting cytotoxic CD8 T-cells, 4-1BB can also modulate the activity 
of cluster of differentiation 4 T-cells (CD4 T-cells), B-cells, natural killer cells, monocytes, 
macrophages, and dendritic cells.  4-1BB’s expression on both T-cells and antigen presenting 
cells, coupled with its capacity to promote survival, expansion, and enhanced effector function 
of activated T-cells, has made it an alluring target for tumor immunotherapy. 
As such, based on the biological mechanism of action following stimulation of 4-1BB 
signaling, an efficient co-stimulatory activation of this receptor is suggested to play an 
important role in T-cell activation, persistence, and T-cell memory. 
Based on the biological rationale for targeting of 4-1BB to activate the immune system in 
cancer patients, 2 anti-4-1BB therapeutic antibodies have entered clinical development.  The 
agonistic anti-human 4-1BB human immunoglobulin G4 (IgG4) antibody (anti–hu4-1BB 
huIgG4) urelumab (BMS-663513) caused dose-dependent hepatitis in patients, most likely due 
to 4-1BB cross-linking via FcγRIIb-expressing liver-resident cells such as hepatic myeloid and 
sinusoidal endothelial cells (Bartkowiak, et al. 2018; Chester, et al. 2018).  Subsequent studies 
revealed that urelumab could be administered at a safe dose of 0.1 mg/kg, however at this dose 
it only mediated limited efficacy (Chester, et al. 2018).  A second anti-4-1BB antibody, 
anti-hu4-1BB huIgG2 utomilumab (PF-05082566), displayed a better safety profile but lower 
agonistic potency than urelumab (Chester, et al. 2018).  These early clinical data show promise 
for the approach of targeting 4-1BB, however the safety to efficacy balance is not optimal in 
these initial therapeutic molecules. 
Taken together these data indicate that a therapeutic approach which can safely but effectively 
stimulate 4-1BB signaling, in addition to inhibition of the PD-L1/PD-1 axis, has major potential 
to address at least 2 of the major resistance mechanisms for CPIs, i.e., overcoming severe T-cell 
exhaustion and improving T-cell memory.  Furthermore, there is further potential of the 
approach for boosting antigen presentation, while this may require combinations with 
chemotherapy, radiation therapy, or tumor vaccination. 
Overall, there are a number of differences between urelumab and utomilumab (i.e., the known 
differences between the monoclonal antibodies (mAbs) including: intrinsic agonistic activity, 
immunoglobulin subclass, Fc receptor binding profile, targeted epitope on 4-1BB, and 4-1BBL 
blockade capacity) (Chin, et al. 2018; Chester, et al. 2018).  While the impact of these 
individual factors on the respective benefit-to-risk profile of the 2 mAbs is not entirely clear, 
the following conclusion on their clinical impact seems to be justified for standard (bivalent) 
mAbs targeting 4-1BB: 
Conventional monoclonal antibodies, due to their bivalent binding mode to 41BB, lead to 
clustering of 4-1BB on the surface of the target cell, and consequently activation of 4-1BB 

 
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signaling, based on simple bivalent binding to the target – if an optimally active epitope is 
targeted by the antibody (i.e., urelumab) 
Targeting of epitopes that allow for optimal activation of 4-1BB signaling (and thus full 
exploitation of the beneficial co-stimulatory activity of the receptor) by bivalent antibodies will 
necessarily be associated with systemic toxicity. 
It is possible to reduce the toxicity potential of 4-1BB agonistic, bivalently binding antibodies 
by targeting a different epitope on 4-1BB (i.e., using an epitope that competes with binding of 
the natural 4-1BB ligand, such as in the case of utomilumab).  However, this will lead to 
reduced potency, i.e., reduced activation of 4-1BB signaling and thus reduced to absent clinical 
efficacy.  As a consequence, less systemic activity/toxicity but also less activity in the tumor 
microenvironment (TME) is observed with utomilumab in comparison to urelumab. 
Numab has designed ND021 (NM21-1480), in order to resolve the 4-1BB-targeting dilemma, 
i.e., in order to maximize the benefit to-risk profile of targeting this co-stimulatory receptor in 
combination with inhibiting the PD-L1/PD-1 pathway. 
5.1.1 
NM21-1480 
NM21-1480 is a recombinant protein consisting of 3 stabilized antibody Fv fragments directed 
against the molecular targets PD-L1, 4-1BB, and serum albumin (SA).  It is designed for 
avoidance of systemic 4-1BB activation and preferential 4-1BB activation in the TME to avoid 
the dose-limiting toxicities (DLTs) of systemically active 4-1BB agonists.  NM21-1480 is a 
tri-specific antibody targeting the clinically validated inhibition of immunosuppressive PD-L1 
combined with co-stimulation of cancer-specific T-cells via the co-stimulatory receptor 4-1BB.  
This dual action provides the perspective of broader and more sustained treatment response in 
tumor indications known to be responsive to inhibition of the PD1-PD-L1 axis.  Importantly, 
the molecule has been designed to vastly restrict its activities to the TME only, thus avoiding 
the type of DLTs observed with antibodies providing systemic 4-1BB agonism, such as 
urelumab. 
One essential component of the design of a molecule to achieve this goal is to generate an 
antibody (i.e., binding domains within the multi-specific antibody) that binds in a monovalent 
manner to its molecular targets.  Conventional antibodies (such as, e.g., urelumab) bind to 
4-1BB in a bivalent manner and activate the 4-1BB signaling pathway by simple binding on 
4-1BB expressing cells.  In contrast, the monovalent binding of ND021 (NM21-1480) to 
4-1BB-expressing cells does not trigger activation of the 4-1BB signaling pathway as no 
clustering of 4-1BB is triggered on the surface of these cells.  Instead, for ND021 (NM21-1480) 
to induce 4-1BB signaling upon target binding, additional binding to PD-L1 on cancer cells is 
necessary.  Only upon concomitant binding of ND021 (NM21-1480) to 4-1BB on immune cells 
and PD-L1 on tumor cells, an immunological synapse is formed which triggers hyperclustering 
of 4-1BB on T-cells in the proximity of tumor cells. 
Numab has designed a PD-L1/4-1BB/human serum albumin (HSA) tri-specific scMATCH™ 
3 immunomodulatory drug candidate (NM21-1480) that agonizes 4-1BB conditionally upon 

 
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mice engrafted with human umbilical cord blood HUCB-derived CD34+ stem cells – 
efficiently reconstituting the human T-cell repertoire in the mice, were injected with HCC827 
NSCLC cells (a PD-L1 expressing human cancer cell-line).  NM21-1480 surrogate therapy 
resulted 
in 
stronger 
reduction 
of 
tumor 
growth 
than 
therapy 
with 
PD-L1 
immunoglobulin G (IgG) s, 4-1BB IgGs, or the combination thereof.  This correlated with 
higher frequency of cytotoxic T-cells in the TME.  Further, NM21-1480 therapy led to higher 
response rates (shrinking tumors/complete response [CR]) in mice and was generally better 
tolerated than single-agent PD-L1 IgG and combination therapies with PD-L1 IgG and 4-1BB 
IgGs.  In a second model, NOG mice were engrafted with human PBMCs after implantation of 
PD-L1+ HCC827 cells.  Similar to the first model, the NM21-1480 surrogate therapy resulted 
in stronger reduction of tumor growth and led to higher response rates (details are provided in 
the Investigator’s Brochure (IB)).  This clinical response pattern correlated with higher 
frequency of cytotoxic T-cells in the tumor tissue. 
Pre-clinical assessment of the activity of NM21-1480 has demonstrated that the stimulation of 
T-cells via the 4-1BB pathway following PD-L1 dependent clustering results in a bell-shaped 
dose response (see Figure 5–5).  The decrease in activity seen for 4-1BB stimulation at high 
concentrations is most likely driven by the saturation of PD-L1 on tumors cells and the 
concomitant saturation of 4-1BB on T-cells, thus leading to a loss in synapse formation across 
these 2 cell types. Of note is the lack of bell-shaped dose response for PD-L1 antagonism (see 
Figure 5–2).  Since antagonism of PD-L1 is solely dependent on PD-L1 saturation, the activity 
of this mechanism by NM21-1480 reaches maximal inhibition and maintains this maximum 
despite increasing concentrations of drug.  Therefore, a careful assessment is required of the 
dose of NM21-1480 needed to achieve maximal 4-1BB stimulation and concomitant maximal 
PD-L1 stimulation, without overdosing and a resultant decrease in 4-1BB stimulation.  
Importantly, it has also been demonstrated that the concentration required to achieve 50% 
4-1BB stimulation is independent of the level of PD-L1 expression on tumor cells, therefore 
an optimal dose level is predicted to be similar across patients, independent of the level of 
PD-L1 tumor expression.  The maximal level of 4-1BB stimulation does however increase with 
increasing PD-L1 expression on tumor cells, with no stimulation seen in the absence of PD-L1. 

 
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in the blood of these monkeys no significant expansion of proliferating effector memory and 
central memory cytotoxic T-cells could be detected – a cell population that has been reported 
to expand following non-TME restricted stimulation of 4-1BB signaling, e.g., by agonistic 
IgGs. 
5.1.3 
Clinical 
Part A of the study has been formally completed as per discussion of all enrolled patient’s data 
up to and including at least completion of the 28-day DLT evaluation period for all patients 
enrolled to Part A with the SMC on 23 May 2022. At this SMC meeting, the SMC determined 
that Part A of the study did not technically identify a MTD and that the highest dose assessed 
in Part A (800mg) is considered a tolerable dose of NM21-1480. Upon comprehensive review 
of safety, clinical activity, PK, RO and PD data from Part A, the SMC supported further 
assessment of safety and efficacy of the 800mg dose of NM21-1480 as presumptive RP2D in 
Part B of the study. Part A has been conducted at 7 active sites in the US and Taiwan and as  
of November 2022, all enrolled patients have completed treatment in Part A. A summary of 
Part A study results can be found in below sections and the IB (Version 3.0, 15 June 2022), to 
which reference is made for more details (Luke, et al. 2022. SITC poster #732). Based on the 
results of Part A of the study, as supported by the SMC, the Sponsor will study the 800mg dose 
of NM21-1480 in Part B of the study with the aim to confirm this dose as the RP2D for the 
compound. Selection of this dose level for Part B is primarily based on the fact that some 
patients dosed at 24-240mg in Part A experienced the development of treatment-emergent 
ADAs that were associated with loss of exposure to the study drug, while such phenomenon 
was not observed at the 800mg dose level. Full pharmacodynamic activity of NM21-1480 was 
preserved at the 800mg dose in Part A. The Sponsor thus further decided to explore one more 
higher dose level (1400mg flat dose with approximately 14-day dosing interval) in up to 10 
patients within the optional Part A-2 of the study in order to further study the PK/PD 
relationship over a broad range of doses. Exploration of this 1400mg dose within Part A-2 will 
be conducted in parallel to Part B and under application of strict stopping criteria respecting a 
28-day DLT evaluation period before more than 6 patients are exposed to this dose level. PK 
data for this dose level in Part A-2 will be closely followed and in case of observation of 
relevant drug accumulation over time, the dosing interval for this dose may be adjusted to 
approximately 21 days. 
5.2 
Study Rationale 
The combined immunomodulation of PD-L1/PD-1 blockade and 4-1BB activation is 
considered a promising strategy to increase response rates among cancer patients who are 
eligible to receive PD-L1/PD-1 inhibitors.  Unfortunately, encouraging pre-clinical results 
achieved with such regimens have not yet translated into durable clinical success; due to co-
administration of 4-1BB-agonistic antibodies targeting different epitopes on 4-1BB being 
either intolerable at effective doses or ineffective at all evaluated doses.  To eliminate this 
safety/efficacy trade off, Numab has designed a PD-L1/4-1BB/HSA tri-specific scMATCH™ 

 
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3 immuno-modulatory drug candidate (NM21-1480) that agonizes 4-1BB conditionally upon 
PD-L1-binding/-blockade. 
This study will evaluate the safety, tolerability, PK and pharmacodynamic (PD) profile of 
NM21-1480 as well as explore the clinical activity of NM21-1480 in selected tumor types.  
Through analysis of safety, PK and PD, the maximal tolerated dose (MTD) for NM21-1480 in 
adults with selected advanced solid tumors will be determined in Part A of the study.  If 
conducted, the optional Part A-2, in addition to providing additional safety and PK data, will 
aim at further exploring different dose levels and/or dosing intervals in parallel to Part B to 
complement the PK, immunogenicity, and PD data to be provided by Part B to inform later 
clinical development of NM21-1480. Part B of the study aims at assessing the clinical activity 
of the 800mg dose of the compound as presumptive RP2D.  Binding of NM21-1480 to PD-L1 
in the TME is a pre-requisite for not only blocking the PD1/PD-L1 axis but also for additional 
activation of the co-stimulatory 4-1BB pathway by the compound.  Thus, a minimal PD-L1 
expression in the TME of Part B patients is needed from a mechanistic point of view to explore 
the therapeutic potential of NM21-1480 in patients that have the highest likelihood to benefit 
from treatment.  A clinically meaningful benefit for patients with NSCLC and PD-L1 
expression on ≥50% and ≥1%-49% of tumor cells is suggested based on the fact that clinical 
response of NSCLC patients to conventional checkpoint inhibitors correlates with PD-L1 
expression, animal NSCLC models suggesting added benefit of NM21-1480 (see IB for details) 
and another bispecific anti-PD-L1x4-1BB antibody (GEN1046) has recently demonstrated 
clinically relevant response rates in NSCLC patients resistant to PD1/PD-L1 antibodies 
(Garralda, et al. 2020. SITC poster #412). A clinically meaningful benefit for patients with 
HPV+ SCC of different origin and documented PD-L1 expression in the TME is suggested by 
modest clinical activity of conventional checkpoint inhibitors in these tumors, increased PD-
L1 expression in HPV+ tumors (Hong, et al. 2019) and most interestingly, a proposed unique 
therapeutic potential of activating the 4-1BB pathway in HPV+ tumors (Bartkowiak, et al. 
2015). A clinically meaningful benefit for patients with recurrent or persistent ovarian, primary 
peritoneal or fallopian tumor carcinoma is suggested by recent clinical data demonstrating that 
the combination of PD1/PD-1 pathway inhibitors with additional immune-modulatory agents 
substantially increased ORRs over single-agent checkpoint inhibitors (Zamarin, et al. 2020). 
Most importantly, the combination of PD1/PD-L1 pathway inhibition with agonistic 4-1BB 
antibodies is highly effective in animal models of ovarian cancer (Wei, et al. 2013). In addition, 
4-1BB expressing tumor-infiltrating lympohocytes (TILs) in primary and metastatic sites of 
ovarian cancer patients appear to be tumor-specific and 4-1BB-agonistic antibodies further 
enhances anti-PD1-mediated reinvigoration of exhausted CD8+ TILs at both sites (Leem, et al. 
2020). Finally, administration of another bispecific anti-PD-L1x4-1BB antibody (GEN1046) 
resulted in a clinical response in a heavily pretreated ovarian cancer patient 
(Garralda, et al. 2020. SITC poster #412). Similar to ovarian cancer, clinically meaningful 
benefit for patients is also suggested for patients with metastatic or advanced local TNBC. 
Recent data demonstrate specific expansion and activation of TILs from human tumors by an 
agonistic 4-1BB antibody (Harao, et al. 2017) and superior efficacy of combination therapy 
including 4-1BB-agonistic antibodies over PD-1 inhibition alone in mouse TNBC models 

 
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(Dushyanthen, et al. 2017). Finally, early clinical data combining PD-L1 blockade and 
activation of the 4-1BB pathway from 2 independent programs resulted in clinical responses 
of patients with heavily pretreated TNBC (Garralda, et al. 2020. SITC poster #412; Melero, et 
al. 2020. ESMO abstract #1025MO). Monotherapy with anti-PD1 antibodies in patients 
expressing PD-L1 in at least 1% of tumor and/or immune cells has become the standard-of-care 
first-line treatment in patients with metastatic or unresectable, recurrent head and neck 
squamous cell carcinoma (Keytruda Prescribing Information 2021). However, while patients 
responding to anti-PD1 monotherapy benefit from a substantially longer duration of response 
compared to alternative therapy, the ORR observed with anti-PD1 monotherapy remains 
modest in this setting. The combination of anti-PD1 standard-of-care with an anti-PD-L1 
antibody as well as with an agonistic 4-1BB antibody provide the perspective of addressing 
this shortcoming of current therapy. This approach is anticipated to allow for broader anti-
tumoral activity, as proposed by recent scientific and clinical data suggesting differential 
(additive) effects of PD-L1 vs. PD1 blockade and additional benefit by activation of the 4-1BB 
pathway (Bar, et al. 2020; Srivastava, et al. 2017). Based on the  clinical data from Part A of 
this clinical study it is suggested that NM21-1480 may provide substantial clinical benefit to 
MSS mCRC patients, a population that demonstrates notoriously poor response to conventional 
anti-PD1/PD-L1 checkpoint inhibitors (Ciardiello, et al. 2019). In fact, all 3 CRC patients 
enrolled to dose levels 4-7 (i.e., 24mg, 80mg and 800mg) in Part A of the current trial have 
demonstrated at least stabilization of disease with one patient even demonstrating unconfirmed 
partial response at study week 16, associated with reduction of liver metastases diameters in 
the range of 50% or more. Unfortunately, after being on treatment for 4 months at the 24mg 
dose, this patient developed treatment-emergent ADAs that were associated with loss of 
exposure to study drug and subsequent progression of disease at study week 24 (month 6). 
Interestingly, early clinical data with GEN1046 also showed stabilization of mCRC in the 
majority of patients treated in the respective Phase 1 dose escalation of that compound 
(Garralda, et al. 2020. SITC poster #412), suggesting that activation of the 4-1BB pathway may 
have a clinically relevant role in MSS mCRC. As such, this clinical trial will further explore 
the effect of a NM21-1480 treatment in MSS mCRC.  
5.2.1 
Rationale for the NM21-1480 Starting Dose 
NM21-1480 targets immune-modulating receptors (i.e., PD-L1 and 4-1BB, respectively) that 
have already been targeted in patients with various approved and clinical stage monoclonal 
antibodies.  Also, the mechanism of action of NM21-1480, whereby T-cells are activated via 
4-1BB agonism in a tumor-restricted manner, has precedence for testing in clinical stage multi-
specific antibodies. 
Nevertheless, with a novel molecule for clinical investigation, we have used state-of-the-art 
methods for determining a suitable starting dose for NM21-1480.  The starting dose is based 
upon a modelling approach taking into consideration the available pre-clinical data describing 
the PK and PD properties of the molecule.  Through the understanding of the pharmacology of 
the molecule in cell-based assays using primary human T-cells and tumor-derived cell lines 
expressing varying levels of PD-L1, we can derive a concentration to which a minimal 

 
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pharmacological effect level can be seen for NM21-1480.  By combining these data with an 
understanding of the PK of the molecule in the blood of mice and cynomolgus monkeys, as 
well as the bio-distribution of the molecule in mice bearing PD-L1-positive human tumors, we 
have made conservative predictions to a first-in-human (FIH) dose.  Numab is of the opinion 
that this dose provides a highly reasonable compromise between remaining (theoretical) safety 
concerns on the molecule’s systemic 4-1BB activation capacity and yet still retaining a dosing 
level from which there is a potential to provide clinical benefit to enrolled patients. 
5.3 
Benefit – Risk Assessment 
5.3.1 
Benefit Assessment 
In various in vitro and in-vivo experiments, Numab has demonstrated that in contrast to 
bivalently binding urelumab, ND021 (NM21-1480) only triggers 4-1BB activation on T-cells 
in the presence of PD-L1 expressing tumor cells.  In addition, ND021 (NM21-1480) when 
assessed for its T-cell activation potential in cellular assays, was demonstrated to be more 
potent (as measured by interleukin (IL)-2 and IFNϒ release) in the tumor cell proximity in 
comparison to any combination of PD-1/PD-L1 and 4-1BB monoclonal antibodies evaluated 
in clinical trials. 
Efficacy and tolerability of ND021 (NM21-1480) was studied in in-vivo mouse tumor models.  
These studies demonstrated superior efficacy over CPI standard-of-care and even over the 
combination of anti-PD-L1 (avelumab) and anti 4-1BB (urelumab) in suitable PD-L1 
inhibitor-sensitive mouse models.  Animal studies also confirmed the superior safety profile of 
ND021 (NM21-1480) versus avelumab and urelumab in (multiple-dose) mouse and (single- 
and repeat-dose) non-human primate studies (for details see IB). 
The PK profile of ND021 (NM21-1480) assessed in a single-dose non-GLP PK/tolerability 
study conducted in cynomolgus monkeys, resulted in a half-life of approximately 5 days, which 
when applying standard allometric scaling predicts a half-life of ND021 (NM21-1480) of 
approximately 2 weeks in man.  Thus, ND021 (NM21-1480) is expected to allow for a 
clinically convenient 2-week dosing interval in the clinical setting.  As per July 2022, Part A 
of the ongoing FiH study has formally been completed by means of an SMC meeting that 
determined that Part A did not technically identify a MTD and the highest dose assessed 
(800mg) was considered a tolerable dose. Clear evidence of pharmacodynamic activity 
correlating with early signs of clinical activity has been observed in this part of the study. In 
the dose range considered relevant based on exposure, peripheral receptor occupancy and 
pharmacodynamic data (24mg-800mg range), a disease control rate of 62% was observed. 
Within those patients in whom disease control has been observed, 62% had previously been 
treated with and were progressive on such checkpoint inhibitor therapy. In one patient suffering 
from MSS metastatic colorectal cancer, a type of cancer notoriously unresponsive to standard 
checkpoint inhibitor therapy, an unconfirmed partial response associated with pronounced 
reduction of liver metastases diameters was observed. These promising early clinical data in a 
heavily pre-treated patient population suggest NM21-1480 to provide therapeutic benefit 

 
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aligned with the initial development hypothesis of the compound that warrants further clinical 
investigation. For details, reference is made to the IB, Version 3.0 dated 15 June 2022. 
5.3.2 
Risk Assessment 
The tolerability profile and PK of NM21-1480 have been studied in a single-dose, non-GLP 
PK/tolerability study and a formal repeat-dose toxicology study conducted in cynomolgus 
monkeys.  The single-dose study confirmed that NM21-1480 administered at single doses of 
0.2, 2, and 20 mg/kg was well tolerated.  Further, no signs of hepatotoxicity were observed 
even at the highest applied dose (20 mg/kg) as demonstrated by the lack of any clinically 
relevant increase of ALT, AST, and GGT.  Similarly, there was no impact on neutrophil or 
thrombocyte counts, another frequent adverse effect observed with the 4-1BB agonist 
urelumab.  As such, none of the most prominent adverse drug reactions clinically observed 
under urelumab treatment were seen in this monkey study with NM21-1480 even at the highest 
dose applied.  Similar data was generated from the formal repeat-dose toxicology study in 
which NM21-1480 was well tolerated at doses of 20, 60 and 140 mg/kg given over a weekly 
dosing schedule for 5 doses.  NM21-1480 may impact Cytochrome P (CYP) enzyme 
production and activity via cytokine modulation.  For this reason, there may be a risk of drug 
interactions and concomitant medications that are narrow therapeutic index substrates for CYP 
enzymes should be used with caution and appropriate monitoring. As per July 2022, Part A 
(the dose escalation part) of the NM21-1480 FiH study has been completed with at least 28-
day safety data available for all of the 26 patients exposed in this part of the study by 23 May 
2022. Patients received between 1 and 19 infusions of NM21-1480 at one of the 7 dose levels 
to be assessed in Part A of the protocol (0.15 mg, 1.5 mg, 8 mg, 24 mg, 80 mg, 240mg, 800mg). 
Only two Grade 3 TRAEs (one event of hyponatremia/adrenal insufficiency and one event of 
transaminase elevation, according to CTCAE V5.0) were observed and no TRAE was assessed 
as higher than Grade 3 by investigators. Most importantly, only a single TRAE of Grade 3 
transaminase elevation was reported during this study which compares very well to other 
compounds with a similar mechanism of action (Garralda, et al. 2020. SITC poster #412). The 
most frequently observed TRAEs, were Grade 2 infusion-related reactions which in some 
instances have led to discontinuation of patients as despite pre-medication and reduction of 
infusion rate, it was not possible to fully prevent re-occurrence of the IRR.  Development of 
these IRRs was typically observed in patients who developed treatment-emergent ADAs and 
was typically associated with loss of exposure to study drug over time in affected patientsFor 
details, reference is made to the IB, Version 3.0 dated 15 June 2022. 
5.3.3 
Overall Benefit Risk Assessment 
ND021 (NM21-1480) was designed to overcome the clinical limitations of standard CPIs 
targeting the PD-L1/PD-1 axis.  Indeed, based on currently available data, Numab perceives 
ND021 (NM21-1480) to have the potential to become the preferred (i.e., first-line) treatment 
option for various tumors for which PD-1/PD-L1 CPIs (i.e., nivolumab, pembrolizumab, 
avelumab, and durvalumab, etc.) are approved due to its concomitant immune cell activation 
provided by the molecule’s 4-1BB pathway activation in the TME.  ND021 (NM21-1480) 

 
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requires (possibly minimal) expression of PD-L1 on target tumor cells in order to ignite its 
anti-tumoral effects and its therapeutic effects may possibly increase over time due generation 
of a “positive feedback loop” in the TME, induced by activation of the 4-1BB pathway in 
immune cells, leading, e.g., to IFNϒ release resulting in additional subsequent IFNϒ-induced 
PD-L1 expression on tumor cells.  Based on the available pre-clinical data, it is suggested that 
ND021 (NM21-1480) may thus demonstrate a substantially higher overall response rate and 
prolonged overall mean survival time as compared to standard-of-care treatment in various 
tumor types in the clinic.  As such, the basic clinical target product profile for ND021 
(NM21-1480) aims at clinical demonstration of superior efficacy combined with a non-inferior 
safety profile (and thus an improved overall benefit-to-risk profile) as compared with single 
anti-PD-L1 or PD-1 CPIs in suitable patient populations.  For this reason, in principle, all tumor 
types for which PD-L1/PD-1-inhibitors are approved and/or for which clinical efficacy has 
been demonstrated, represent target indications for ND021 (NM21-1480).  In addition, based 
on its mechanism of action, ND021 (NM21-1480) may be able to demonstrate substantial 
incremental clinical benefit in tumor types in which conventional CPIs demonstrate 
comparably poor efficacy (i.e., PD-L1 “negative” tumors).  With Part A of the FiH study for 
NM21-1480 completed, the overall benefit-to-risk assessment remains positive at this point of 
time when considering the totality of available clinical safety, activity, pharmacokinetic and 
pharmacodynamic data and further clinical assessment of NM21-1480 in selected cancer 
population as remains warranted. Full maintenance of exposure combined with fully 
maintained pharmacodynamic and clinical activity was observed at the 800mg dose level which 
has also been determined to represent a tolerable dose by the study SMC. However, careful 
continued evaluation of the impact of treatment-emergent ADAs on patient’s long-term 
exposure to NM21-1480 during further development is warranted. For details, reference is 
made to the IB, Version 3.0 dated 15 June 2022. 

 
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6 
STUDY OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Part A 
Primary 
• To assess the safety and tolerability of 
NM21-1480 
• To determine the MTD of NM21-1480 
• To determine up to four (4) safe dose 
levels for further evaluation of PD and 
clinical activity in the optional Part A-
2 and Part B of the study 
• Incidence and nature of dose-limiting toxicities 
(DLTs) 
• Incidence and severity of treatment-emergent 
adverse events (TEAEs) with specific focus on 
incidence and severity of immune-related adverse 
events (irAEs) 
Secondary 
• To characterize the PK profile of 
NM21-1480  
• PK parameters 
o 
AUCtau 
o 
AUC (0-infinity) (first dose only) 
o 
Cmax 
o 
Cmin 
o 
t½ 
o 
Tmax 
o 
λz 
o 
CL 
o 
Vd 
• To evaluate the immunogenicity of 
NM21-1480 
• Frequency of specific anti-drug antibodies to 
NM21-1480 
Exploratory 
• To determine the anti-tumor activity 
of NM21-1480 according to Response 
Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 
• To 
determine 
safe 
dose 
levels 
associated 
with 
meaningful 
PD 
response to inform dose selection for 
optional Part A-2 and Part B. This is in 
support of nominating up to four (4) 
safe dose levels to be further studied in 
Part B of the study 
• Best overall response (BOR) 
• Objective response rate (ORR) 
• Time-to-response (TTR) 
• Duration of response (DOR) 
• Progression-free survival (PFS) 
• Overall survival (OS) 
• Characterization of exposure-dependent PD 
markers of target and pathway engagement. 
Potential PD markers are summarized in detail in 
the below list of exploratory markers applicable 
to all Parts A, A-2 and B 
Part A-2 (OPTIONAL) 
Primary 
• To assess the safety and tolerability of 
NM21-1480 at a dose level beyond 
what has been assessed in Part A (i.e. 
at 1400mg) 
• To 
further 
explore 
PK/PD 
relationships in order to complement 
respective Part B data when conducted 
in parallel to Part B 
• Incidence and severity of treatment-emergent 
adverse events (TEAEs) with specific focus on 
incidence and severity of immune-related adverse 
events (irAEs) 
• Characterization of exposure-dependent PD 
markers of target and pathway engagement. 
Potential PD markers are included in the below 
list of exploratory markers applicable to all 
Parts A, A-2 and B 
Secondary 
• To characterize the PK profile of 
NM21-1480 
• PK parameters: 
o 
AUCtau 

 
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Objectives 
Endpoints 
• To evaluate the immunogenicity of 
NM21-1480 
o 
AUC (0-infinity) (first dose only) 
o 
Cmax 
o 
Cmin 
o 
t½ 
o 
Tmax 
o 
Λz 
o 
CL 
o 
Vd 
• Frequency of specific anti-drug antibodies to 
NM21-1480 
Exploratory 
• To determine the anti-tumor activity 
of 
NM21-1480 
according 
to 
RECIST 1.1 
• BOR 
• ORR 
• TTR 
• DOR 
• PFS 
• OS 
Part B 
Primary 
• To determine the anti-tumor activity 
of 
NM21-1480 
according 
to 
RECIST 1.1 
• BOR (Primary endpoint for Cohort B1-4, 6-7) 
• ORR (Primary endpoint for Cohort B5) 
• Incidence and severity of TEAEs with specific 
focus on incidence and severity of irAEs 
• Characterization of exposure-dependent PD 
markers of target and pathway engagement. 
Potential PD markers are included in the below 
list of exploratory markers applicable to all 
Parts A, A-2, and B 
• To assess the safety and tolerability of 
NM21-1480 in patients with selected 
advanced cancers 
• To determine the RP2D 
• To determine the safety (including the 
MTD) and efficacy of NM21-1480 in 
combination with standard-of-care 
anti-PD1 therapy in patients with head 
and neck squamous cell cancer 
(Cohort B5) 
 
Secondary 
• To further evaluate the preliminary 
anti-tumor activity of NM21-1480 
• Disease Control Rate (DCR) 
• DOR 
• TTR 
• PFS 
• OS 
• BOR, DCR, ORR, DOR, PFS as per iRECIST 
• To characterize the PK profile of 
NM21-1480  
• PK parameters 
o 
AUCtau 
o 
AUC (0-infinity) (first dose only) 
o 
Cmax 
o 
Cmin 
o 
t½ 
o 
Tmax 
o 
λz 

 
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Objectives 
Endpoints 
o 
CL 
o 
Vd 
• To evaluate the immunogenicity of 
NM21-1480 
• Frequency of specific anti-drug antibodies to 
NM21-1480 
Part A, Part A-2 (OPTIONAL), and Part B 
Exploratory 
• To characterize the pharmacodynamic 
(PD) profile of NM21-1480 
Change 
from 
baseline 
in 
the 
following 
biomarkers/PD parameters: 
• Change 
from 
baseline 
in 
levels 
of 
cytokines/chemokines 
including 
interleukin 
(IL)-1b, IL-6, tumor necrosis factor (TNF)α 
interferon gamma (IFNϒ), IL2, IL8, CXCL9, 
CXCL10, CXCL11, IL18, and other selected 
markers; soluble PD-L1 (Programmed death-
ligand 1); soluble 4-1BB 
• Phenotypic characterization of peripheral blood 
cells (cellular populations include resting and 
activated B-cells, T-cell subpopulations [T-helper 
cells {Th}, cytotoxic T lymphocytes {CTLs}, 
regulatory T-cells {Treg}], NK cells, and NKT 
cells), and cellular receptor occupancy (PD-L1; 
4-1BB)a  
• In Cohort B8: Carcinoembryonic Antigen (CEA); 
circulating tumor DNA (ctDNA) 
• To evaluate biomarkers potentially 
capable of predicting a clinical 
response to NM21-1480 
• Change in RNA expression from baseline and 
after-treatment in tumor tissues 
• Change in PD-L1 expression and presence of 
PD1/CD8/4-1BB triple positive T-cells in 
baseline and after-treatment tumor tissues 
• Change in level of inflammatory infiltrate (e.g., 
CD3 and CD8 density; CD8/Treg ratio; 
CD8/CD4 ratio) in baseline and after-treatment 
tumor tissue 
• Assessment of tumor mutational burden (TMB) 
and microsatellite instability – high/deficient 
mismatch repair (MSI-H/dMMR) status in 
baseline tumor tissues 
• Correlation of PD-L1 expression status in the 
TME with PD and clinical activity 
• Assessment of T-cell Receptor clonality in tumor 
tissue 
• In Cohort B8: MHC-I expression on tumor cells; 
specific mutational analysis including e.g., 
BRAF, KRAS, NRAS, POLE, PIK3CA, PTEN, 
APC, p53 

 
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Objectives 
Endpoints 
a 
Pending availability of validated assay 
Abbreviations: 
APC = Adenomatous Polyposis Coli; AUC = Area under the serum concentration-time curve; 
AUC(0-infinity) = Area under the serum concentration-time curve extrapolated from the last 
quantifiable concentration to infinity; AUCtau = Area under the serum concentration-time curve 
over dosing interval; B-cells = B lymphocytes; BRAF = B-raf proto-oncogene; CD3 = Cluster 
of differentiation 3; CD4 = Cluster of differentiation 4; CD8 = Cluster of differentiation 8; CEA 
= Carcinoembryonic Antigen; CL = Clearance; Cmax = The maximum observed serum 
concentration determined by direct inspection of the concentration versus time data; Cmin = The 
minimum observed serum concentration determined by direct inspection of the concentration 
versus time data; CTL = Cytotoxic T lymphocytes; CXCL = Chemokine (C-X-C motif) ligand; 
KRAS = Kirsten rat sarcoma oncogene; λz = Terminal phase (apparent elimination) rate 
constant; NK cells = Natural killer cells; NKT = Natural killer T-cells; NRAS = Neuroblastoma 
ras viral oncogene homolog; PD-1 = Programmed cell death protein-1; PD-L1 = Programmed 
death-ligand 1; PIK3CA = Phosphatidylinositol 3-kinase CA; POLE = Polymerase Epsilon 
Catalytic Subunit; PTEN = Phosphatase and Tensin Homolog; RNA = Ribonucleic acid; 
t½ = Elimination half-life; Tmax = Time to maximum concentration; Vd = Volume of 
distribution 

 
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7 
OVERALL STUDY DESIGN AND PLAN 
7.1 
Study Design Description 
This is a FIH, open-label, multi-center, Phase 1/2, dose-escalation study with dose expansion 
cohorts in specific tumor types to evaluate NM21-1480 for safety and immunogenicity, to 
determine the MTD and RP2D, define the PK, to explore the PD, and to obtain preliminary 
evidence of the clinical activity in adult patients with selected advanced solid tumors. 
This is an open-label study and includes an ascending-dose cohort component (Part A) to be 
optionally followed by an additional cohort (optional Cohort A-2) to further explore different 
dose levels and/or dosing intervals in parallel to Part B to complement the PK, 
immunogenicity, and PD data to be provided by Part B.  Part B may be initiated without the 
conduct of the optional Part A-2 Cohort. For patients in all cohorts, the study will consist of 3 
periods: Screening (up to 28 days), treatment (until confirmed progression or meeting any other 
reason for discontinuation specified by the protocol), and Follow-up (up to 12 weeks). 
In Part A of the study, NM21-1480 will be administered as a single intravenous (IV) infusion 
approximately every 14 days for a total of 2 infusions per treatment cycle.  A treatment cycle 
is thus defined as 28 days (4 weeks).  In Part A, response assessments are done every 8 weeks, 
thus one assessment cycle is defined as 8 weeks.  Any dose level to be studied in Part B will 
be below or at the MTD determined upon decision by the SMC once all patients enrolled to 
Part A have completed their 28-day DLT evaluation period. Part A was formally completed on 
23 May 2022 by a meeting of the SMC which determined that this part of the study did not 
technically identify a MTD as the highest dose assessed (800mg) was considered a tolerable 
dose. In Part B of the study, NM21-1480 will be thus be administered as a single IV infusion 
approximately every 14 days at the 800mg flat dose, based on Part A PK data which do not 
indicate substantial drug accumulation over time with this dosing interval while full 
pharmacodynamic activity of NM21-1480 is maintained.The 800mg dose of NM21-1480 thus 
represents the presumptive RP2D to be further studied in Part B with the aim to confirm this 
dose as the RP2D for the compound. Optional Part A-2 of the study will explore one more 
higher dose level (1400mg flat dose with approximately 14-day dosing interval) than was 
studied in Part A. Such 1400mg dose level will be explored in order to further study the PK/PD 
relationship over a broad range of doses, applying strict stopping criteria and respecting a 28-
day DLT evaluation period before more than 6 subjects are exposed. PK data for this 1400mg 
dose level in Part A-2 will be closely followed and in case of observation of relevant drug 
accumulation over time, the dosing interval for this dose may be adjusted to approximately 21 
days. The optional Part A-2 of the study is conducted in parallel to Part B, and its resulting 
exposure/PK/PD data will be used to complement Part B data to guide later stage clinical 
development. Any dose level to be assessed in Part B as by the SMC recommendation must 
not exceed the MTD determined in Part A (or Part A-2 if applicable). In optional Part A-2 and 
Part B, a treatment cycle, dependent on the dosing interval selected by the SMC for a given 
dose level (i.e., 2-week dosing interval for the 800mg dose and 2-weekor 3-week dosing 
interval for the 1400mg dose in Part A-2), is thus defined as 28 days (4 weeks) or 42 days (6 
weeks), respectively. Response assessments in the optional Part A-2 and in Part B will be done 

 
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every 6 weeks during the first 24 weeks patients are on treatment and every 8 weeks beyond 
24 weeks on treatment. Sections 7.1.6 and 7.1.7 provide separate tables summarizing schedule 
of assessments and blood sampling schedules, respectively, for 14-day and 21-day dosing 
intervals which may apply for given dose levels in the optional Part A-2 and Part B.  
Part A 
Part A followed a Bayesian optimal interval (BOIN) design.  This part of the study consisted 
of 7 planned escalating flat dose levels; 0.15 mg (dose level 1), 1.5 mg (dose level 2), 8 mg 
(dose level 3), 24 mg (dose level 4), 80 mg (dose level 5), 240 mg (dose level 6), and 800 mg 
(dose level 7).  Enrollment of patients into dose level 1 took place first and subsequent dose 
levels were only to be opened if the previous dose level was deemed tolerable.  The first dose 
level enrolled a minimum of one patient at 0.15 mg (corresponding to approximately 
0.002 mg/kg).  Following the detailed rules described in Section 10.3.1 of this protocol, as soon 
as a Grade 2 or higher treatment-related adverse event (TRAE) is observed during the 28-day 
DLT evaluation period or when dose level 5 (80 mg dose corresponding to approximately 
1 mg/kg) is reached, a minimum of 3 patients were to be enrolled at the current dose level as 
well as at potential additional dose levels in accordance with the BOIN design dosing rules. 
In the event a DLT was observed in the first patient treated at dose level 1 (0.15 mg), the study 
was to be halted and the SMC must be consulted.  Upon thorough evaluation of all available 
data, the SMC was to determine to terminate the study or recommend that 2 more patients were 
to be enrolled at this dose level.  In the latter case, if after completion of the DLT evaluation 
period of this total of 3 patients enrolled at the starting dose level, the BOIN design would 
demand de-escalation of the dose level from the starting dose, the study was to be terminated. 
Part A of the study was formally completed on 23 May 2022 by a Meeting of the SMC at which 
the SMC determined that Part A of the study did not technically identify a MTD as the highest 
dose assessed (800mg flat dose) was considered a tolerable dose. Dose-escalation was based 
on the number of DLTs experienced during the DLT evaluation interval as determined by the 
Investigators, Medical Monitor, and Sponsor.  The DLT evaluation interval begins on the first 
day of treatment and continues for 28 days.  Patients who received at least one dose of 
investigational product in Cycle 1 (i.e., one of the 2 doses intended to be administered in Cycle 
1), and either meet the minimum exposure criterion and have sufficient safety evaluations, or 
discontinued due to DLT, were considered evaluable for DLT determination.  Dose-escalation 
continued until the stopping rules of the BOIN design were reached. The MTD was defined as 
the highest dose associated with DLTs in ≤30% of patients receiving NM21-1480 administered 
during the DLT period.  This was the highest dose to be potentially recommended for further 
evaluation in the subsequent part(s) of the study. At the end of Part A, a formal SMC meeting 
on 23 May 2022 concluded that none of the 7 dose levels, including the highest dose (800mg 
flat) dose assessed in Part A was to be considered intolerable and thus Part A did not technically 
identify a MTD. Due to the specific pharmacological mechanism of action of NM21-1480, the 
SMC, supported by the Sponsor, besides determining the MTD, was also to consider selection 
of additional (lower) dose levels to be further studied in Part A-2 (optional) and/or Part B, 
based on review of Part A safety, PK, and PD (as far as available) data.  This was based on the 

 
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assumption that indeed, it may only be possible to determine an optimal RP2D in Part B of the 
study, as binding of NM21-1480 to PD-L1 is a pre-requisite for activation of the 4-1BB 
pathway by the compound.  This is likely only possible in a tumor patient population with well-
documented PD-L1 expression in the TME and since PD-L1 positivity was not an inclusion 
criterion for Part A, the likelihood of PD activity of the drug in Part A is reduced compared to 
Part B.  In addition, in a situation with substantial excess of NM21-1480 over PD-L1 and 4-
1BB on target cells in the tumor tissue, a decline in 4-1BB activity (due to a bell-shaped dose 
response curve for the 4-1BB agonistic activity of the compound) cannot be formally excluded 
to occur within the dose range explored in Part A of the study.  Such bell-shaped dose response 
curve may occur because in such situation of substantial excess of NM21-1480, molecules over 
available PD-L1 and 4-1BB binding sites, an immediate saturation of PD-L1 and 4-1BB 
binding sites by different NM21-1480 molecules may occur.  As such, concomitant binding of 
a single NM21-1480 molecule to both antigens may no longer be possible and consequently 
the immunological synapse between tumor cells and immune cells that is required to trigger 4-
1BB signaling could no longer be established.  This important aspect of dose finding was 
considered based on thorough review of the entirety of non-clinical and clinical data available 
at the end of the 28-day DLT evaluation period of the last patient enrolled to Part A.  At this 
point (at the end of Part A SMC meeting on 23 May 2022), the SMC, together with the Sponsor, 
considered the nomination of up to 4 different dose levels of NM21-1480 and determine the 
optimal dosing interval (i.e., dosing approximately every 14 or 21 days) for administration of 
a given NM21-1480 dose for the optional Part A-2 and Part B with the goal to determine a final 
RP2D and dosing interval with an optimized activity and safety profile for future development 
within Part B.  Part A study data discussed with SMC on 23 May 2022 demonstrated the 
development of treatment-emergent anti-drug-antibodies (ADAs) in a relevant fraction of 
patients dosed at 24mg-240mg. These ADAs were typically associated with rapid elimination 
of NM21-1480 from the circulation and loss of exposure. However, PK, PD, receptor 
occupancy and clinical activity data available for the 800mg dose level indicated that at this 
dose, the issue of loss of exposure was no longer present while full pharmacodynamic activity 
was maintained, a phenomenon described for other checkpoint inhibitors (i.e. atezolizumab) at 
higher doses as well. As such, the SMC agreed with the Sponsor to consider the 800mg dose 
to represent the presumptive RP2D and further study this dose, applying a biweekly dosing 
interval in Part B of the study. The SMC, together with the Sponsor, also considered at this 
point (i.e., at the end of the 28-day DLT evaluation period of the last patient enrolled to Part 
A) to enroll additional patients into an optional additional Cohort A-2 in parallel to Part B to 
complement the PK, immunogenicity and PD data to be provided by Part B. The Sponsor, 
following formal completion of Part A on 23 May 2022 is therefore exploring within this 
optional Cohort A-2 and under continuous review of emerging safety data by the SMC the 
safety, PK/PD and clinical activity profile of one higher dose level of NM21-1480 (1400mg 
flat dose) in up to 10 patients to complement Part B data and thus further inform development 
of NM21-1480 beyond initial Part B.  As this dose level to be studied in Cohort A-2 is above 
the maximal dose level characterized in Part A, exploration of the 1400mg dose will be 

 
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conducted under the continuous safety data review and guidance by the SMC, applying similar 
rules as in Part A. 
A DLT is defined as a treatment-emergent adverse event (TEAE) occurring during the first 
28 days of dosing that meets the DLT criteria specified in Section 7.2.5.1 of the protocol. 
In summary, Part A was considered completed on 23 May 2022, when the maximal number of 
patients to be treated per overall as per BOIN design rules was reached, and the SMC, upon 
documented review of all clinical safety, PK, and clinical activity data up to and including the 
4-week visit from all patients dosed in Part A determined that even the highest dose assessed 
in Part A (800mg flat) was considered a tolerable dose.  For nomination of dose levels to be 
further evaluated in Part B (or optionally in Cohort A-2), the SMC, together with the Sponsor, 
considered all available non-clinical and clinical data and information (i.e., including all 
available clinical data beyond 28 days of treatment with NM21-1480) at the time the final 
patient enrolled into Part A according to BOIN design had 28-day data available. The 800mg 
flat dose was nominated as the dose level to be studied as presumptive RP2D in Part B and a 
dose of 1400mg was nominated for further exploration within optional Part A-2).  
Part A-2 (OPTIONAL) 
Part A-2 is an optional part of the study.  It might be initiated after determination of the MTD 
based on Part A data. On 23 May 2022, the SMC determined that Part A did not technically 
identify a MTD and the highest dose level assessed (800mg) was considered a tolerated dose. 
The rationale behind the potential conduction of Part A-2 was to cover situations in which the 
SMC, together with the Sponsor, upon comprehensive review of all available data at the time 
of MTD determination (i.e. at the formal end of Part A on 23 May 2022), came to the 
conclusion that either additional exposure-dependent PD data at dose levels at or below the 
MTD were needed to allow for selection of the up to 4 dose levels to be further studied in Part 
B, or it may be desirable to explore different dose levels and/or dosing intervals in parallel to 
Part B to complement the PK, immunogenicity, and PD data to be provided by Part B to inform 
development of NM21-1480 beyond Part B.  Based on the finding that some patients dosed at 
24-240mg in Part A developed treatment-emergent ADAs leading to loss of exposure, while 
this was not observed at the 800mg dose level, a decision was taken to explore one additional 
higher dose level (1400mg flat dose) in up to 10 patients within Part A-2 in parallel to studying 
the 800mg dose level in Part B.  The primary intention of exploring this 1400mg dose level in 
Part A-2 is to further characterize the overall PK/PD relationship of NM21-1480 over a broad 
range of doses. Further dose levels or dosing intervals may in the future be studied within Part 
A-2 as well if emerging data from the ongoing study provide a rationale to do so. Patients to 
be enrolled into this optional cohort will need to fulfill Part A eligibility criteria but in addition 
will need to have documented minimal PD-L1 expression on at least 1% of tumor and/or 
immune cells in the TME, as detected by local testing with a Food and Drug Administration 
(FDA)-cleared or any PD-L1 assay approved for use by local competent authority. As the 
1400mg flat dose level to be explored in Part A-2 is above the maximal dose level characterized 
in Part A, exploration of the 1400mg dose level will be conducted under the continuous safety 
data review and guidance by the SMC. In this setting in which Part A-2 will be conducted in 

 
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parallel to Part B, its resulting data will be used to complement Part B data in regards of getting 
to a comprehensive understanding on the PK/PD relationship of different dosing regimens for 
NM21-1480 before engaging into subsequent clinical development steps beyond Part B.  
Part B 
To further characterize the safety and clinical activity of NM21-1480, Part B will employ a 
Bayesian Optimal Phase II (BOP2) design (Cohorts B1-B4 and B6-B8) or a randomized, open-
label, active-control Bayesian design (Cohort B5) to enroll patients in up to 8 expansion cohorts 
(Cohorts B1 through B8) with selected advanced solid tumors.  Enrollment in Part B will begin 
when the SMC has completed its review of the Part A  data and has recommended dose levels 
to be initially studied in Part B. Part A of the study was formally completed on 23 May 2022 
and the SMC determined that the 800mg flat dose level was a tolerable dose to be further 
studied as the presumptive RP2D in Part B of the study.   
Cohort B1: 
This Cohort will be conducted in the US, Spain, United Kingdom (UK), the 
Netherlands, Germany, and Taiwan. Cohort B1 will include NSCLC patients 
with documented previous (i.e., prior to initiation of first-line therapy) PD-L1 
expression on ≥50% of tumor cells who have progressed after first-line 
treatment with either anti-PD-(L)1 monotherapy, anti-PD-(L)1/chemotherapy 
or chemotherapy regimen or who have progressed after-treatment with up to 3 
previous lines of therapy including at least one line of anti-PD-(L)1 checkpoint 
inhibitor therapy and one or more lines of a chemotherapy regimen. It should 
be noted that, specifically for patients to be enrolled to Cohort B1 in 
Germany, they must have previously received, anti-PD-(L)1 therapy and a 
platinum-based chemotherapy (i.e., at least 2 prior lines of treatment) in order 
to be eligible for enrollment into this cohort. 
Cohort B2: 
This Cohort will be conducted in the US, Spain, UK, the Netherlands, 
Germany, and Taiwan. Cohort B2 will include patients with HPV+ SCC of the 
anus, cervix, vulva, vagina, penis, or oropharynx, who have progressed on a 
first-line standard-of-care anti-PD-1 monotherapy, anti-PD-1/chemotherapy or 
chemotherapy regimen. Inclusion of patients who have progressed after 
receiving 2 previous lines of therapy, e.g., one line of anti-PD-1 checkpoint 
inhibitor therapy and one line of chemotherapy regimen is also acceptable; 
patients must have documented PD-L1 expression in the TME with PD-L1 
expressed on at least 1% of tumor and/or immune cells, as detected by local 
testing with an FDA-cleared or any PD-L1 assay approved for use by local 
competent authority. 
Cohort B3: 
This Cohort will be conducted in Turkey, Georgia, Ukraine, and Taiwan. 
Cohort B3 will include patients with NSCLC with PD-L1 expression on ≥50% 
of tumor cells who have progressed on first-line local standard-of-care 
chemotherapy.  

 
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Cohort B4: 
This Cohort will be conducted in the US, Spain, UK, the Netherlands, 
Germany, Taiwan, Turkey. Georgia, and Ukraine. Cohort B4 will include 
patients with recurrent or persistent ovarian, primary peritoneal, or fallopian 
tumor carcinoma of all histologic types except mucinous adenocarcinoma and 
carcinosarcoma with a history of primary platinum-based chemotherapy with a 
maximum of 3 prior cytotoxic regimens with at least one regimen for recurrent 
disease containing a platinum or a taxane for those with 3 prior regimens: last 
platinum-free interval must be maximally 12 months. 
Cohort B5: 
This Cohort will be conducted in the US, Spain, UK, the Netherlands, and 
Taiwan. Cohort B5 will include patients to be treated in-label with an approved 
PD-1 checkpoint inhibitor (pembrolizumab) as a single agent for the first-line 
treatment of metastatic or unresectable, recurrent head and neck squamous cell 
cancer whose tumors express PD-L1 (CPS≥1) as standard-of-care treatment 
with doses not to exceed those approved in local product labels. Patients 
fulfilling this criterion will be randomized 2:1 to either such standard-of-care 
PD-1 checkpoint inhibitor plus NM21-1480 or the standard-of-care PD-1 
checkpoint inhibitor therapy only. 
Cohort B6: 
This Cohort will be conducted in the US, Spain, UK, the Netherlands, and 
Taiwan. Cohort B6 will include patients with metastatic or unresectable, locally 
advanced TNBC that is measurable according to RECIST1.1 criteria. Tumors 
need to be ER, PR and HER2 negative as per current ASCO/CAP Guidelines 
and patients need to have progressed on at least one but no more than 3 previous 
lines of cytotoxic chemotherapy. Two subgroups of 20 patients each will be 
enrolled and analysed, based on having received a prior line of checkpoint 
inhibitor therapy or not. 
Cohort B7:  
This Cohort will be conducted in the US, Spain, UK, the Netherlands, 
Germany, and Taiwan. Cohort B7 will include NSCLC patients with 
documented previous (i.e., prior to initiation of previous-line therapies) PD-L1 
expression on ≥1% - 49% of tumor cells who have progressed after first-line 
treatment with either anti-PD-(L)1 monotherapy, anti-PD-(L)1/chemotherapy 
or chemotherapy regimen or who have progressed after-treatment with up to 
3 previous lines of therapy, at least one including an anti-PD-(L)1 checkpoint 
inhibitor. It should be noted that, specifically for patients to be enrolled to 
Cohort B7 in Germany, they must have previously received, as per established 
treatment guidelines of the AWMF, anti-PD-(L)1 therapy and a platinum-based 
chemotherapy (i.e., at least 2 prior lines of treatment) in order to be eligible for 
enrollment into this cohort. 
Cohort B8: 
This Cohort will be conducted in the US, Spain, UK, the Netherlands, and 
Germany. Cohort B8 will include patients with metastatic colorectal cancer 
(mCRC) that are MSS or MSI low and who have been previously treated with 
fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and if RAS 

 
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wild-type, an anti-EGFR therapy, if eligible Patients previously treated with an 
anti-VEGF biological therapy are also eligible. Patients must have documented 
PD-L1 expression in the TME with PD-L1 expressed on at least 1% of tumor 
and/or immune cells, as detected by local testing with an FDA-cleared or an PD-
L1 assay approved for use by local competent authority. 
 
Stratification factors will be applied for Part B enrollment (see Section 10.4.4 for details). 
Intra-patient dose-escalation is generally not allowed; upon discussion between Investigators, 
Medical Monitor and Sponsor, exceptions to this rule may be granted for Part B Cohort 
patients. 
In Part A, NM21-1480 (dose levels 1 through 7 in the escalation phase) will be administered 
as a single IV infusion every 14 days for a total of 2 infusions per treatment cycle (4 weeks).  
Each treatment cycle comprises 2 doses of study drug administered on Days 1 and 15. 
Treatment for the second cycle is administered on Days 29 and 43, with a response assessment 
between Days 52 and 56 after the first dose of every other treatment cycle in Part A (i.e., every 
8 weeks at the “8-Week Assessment”, see Table 7-1 for details).  In Part A, response 
assessment between Days 52 and 56 and between Days 108 and 112, respectively, is conducted 
for all patients still in the study, independent of the number of study drug administrations 
received during the previous 8-week/2-treatment cycles.  Following each treatment cycle, the 
decision to treat a patient with additional cycles of NM21-1480 will be based on tolerability of 
the study drug and tumor response evaluation performed every 8 weeks i.e., in the week prior 
to administration of NM21-1480 in all odd number treatment cycles (e.g., Cycles 3, 5, 7, etc.).  
For optional Part A-2 and Part B, depending on SMC decision on dose levels and dosing 
intervals to be chosen for this expansion cohort phase, treatment cycles and dosing intervals 
may remain the same as described above for Part A (i.e., dosing intervals of approximately 14 
days). In Part B of the study, NM21-1480 will thus be administered as a single IV infusion 
approximately every 14 days at the 800mg flat dose, based on Part A PK data which do not 
indicate substantial accumulation over time with this dosing interval; the 800mg dose of 
NM21-1480 thus represents presumptive RP2D to be further studied in Part B Optional Part 
A-2 of the study will explore one more higher dose level (1400mg flat dose with approximately 
14-day dosing interval) than was studied in Part A. Such 1400mg dose level will be explored 
applying strict stopping criteria and respecting a 28-day DLT evaluation period before more 
than 6 subjects are exposed. PK data for this 1400mg dose level in Part A-2 will be closely 
followed and in case of observation of relevant drug accumulation over time, the dosing 
interval for this dose may be adjusted to approximately every 21 days, resulting in treatment 
cycles of 6 weeks in such case. In optional Part A-2 and Part B of the study, response 
assessment is done every 6 weeks for the first 24 weeks patients are on active treatment, before 
switching to a response assessment every 8 weeks thereafter.  Following each response 
assessment in optional Part A-2 and Part B, the decision to treat a patient with additional dose 
administrations of NM21-1480 will be based on tolerability of the study drug, perceived 
clinical benefit and tumor response evaluation performed every 6 weeks (first 24 weeks) or 8 

 
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weeks (beyond 24 weeks) as per discontinuation criteria described in Section 7.2.9.  Unless the 
patient develops a treatment-related adverse event (TRAE) qualifying for permanent 
discontinuation and precluding further treatment, patients will be treated until progressive 
disease is confirmed by the Investigator (for details on study drug discontinuation see Section 
7.2.9). Sections 7.1.6 and 7.1.7 provide separate tables summarizing schedule of assessments 
and blood sampling schedules, respectively, for 14-day and 21-day dosing intervals which may 
apply for given dose levels in optional Part A-2 and Part B. Prior to enrollment of the first 
patient to optional Part A-2 and/or  Part B, sites will receive a written notification of the SMC 
decision on the selection of dose levels and dosing intervals for Part B by means of a letter of 
amendment, to be followed by a full protocol amendment. 
All patients will be followed for survival until death after discontinuation of the Treatment 
and/or completion of Follow-up periods (Section 7.2.12). 
Part A of the study is planned to be conducted at up to 8 sites in the United States (US) and 
Taiwan; optional Part A-2 may be conducted at Part A sites and additional selected Part B sites 
in the US, Spain, the UK, Germany, and/or the Netherlands. Part B will be conducted as up to 
8 separate cohorts B1-B8. Cohort B1, B2 and B7 will be conducted in the US, Spain, UK, the 
Netherlands, Germany, and Taiwan. Cohort B3 will be conducted in Turkey, Georgia, 
Ukraine, and Taiwan. Cohort B4 will be conducted in the US, Spain, UK, the Netherlands, 
Germany, Taiwan, Turkey, Georgia, and Ukraine. Cohorts B5 and B6 will be conducted in 
the US, Spain, UK, the Netherlands, and Taiwan. Cohort B8 will be conducted in the US, 
Spain, UK, the Netherlands and Germany. 
A SMC (consisting of study Investigators and an independent clinical expert as Chairperson, 
with Medical Monitor and Sponsor attending SMC meetings as observers) has been established 
to review cumulative and emerging safety data during study conduct (Part A and B).  The 
Safety Monitoring Committee’s major responsibilities comprise evaluation of DLTs, 
dose-escalation decisions and continuous safety monitoring in Part A.  Safety monitoring 
committee meetings will also be held according to the SMC charter to evaluate the safety data 
emerging in (optional) Part A-2 and Part B (expansion cohorts). Finally, the SMC has an 
additional major responsibility for DLT evaluation and dose escalation decision in the 
evaluation of NM21-1480 safety data in the combinatorial treatment approach with a PD1 
checkpoint inhibitor in Cohort B5. The SMC, based on Part A data, has also supported the 
Sponsor in the determination of dose levels and dosing intervals to be evaluated in Part B. Part 
A of the study was formally completed on 23 May 2022 as a per a regular SMC meeting. 
7.1.1 
Estimated Number of Enrolled Patients 
7.1.1.1 
Part A (Dose-Escalation) 
The number of patients is guided by the BOIN design.  The design recommends recruitment in 
Part A until a maximum sample size of 25 is reached.  Stop Part A if the number of patients 
treated at the current dose reaches 12. 

 
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7.1.1.2 
Part A-2 (Optional) 
The optional Cohort A-2 will enroll up to 40 patients.  
7.1.1.3 
Part B (Dose Expansion) 
For Cohorts B1-B4 and B6-B8, up to 40 patients per Part B cohort will be enrolled.  A BOP2 
design will be applied.  Up to 40 patients per cohort will be enrolled initially.  An interim 
analysis for futility will be conducted after enrollment and treatment of 25 patients per cohort 
according to the BOP2 design in order to stop cohorts for futility and limit exposure of 
additional patients in that cohort in case of lack sufficient clinical activity is observed.  This 
futility analysis will be conducted based on availability of response data following completion 
of 2 assessment cycles (i.e., 12 weeks) for the 25 patients (See Section 10.2). For Cohort B8, 
the Sponsor will hold enrollment to the cohort after 25 patients have received at least one dose 
of NM21-1480 treatment until all relevant safety, efficacy, PK, immunogenicity and most 
prominently all relevant PD data that has accrued until then has been reviewed by the Sponsor 
in consultation with the SMC. After this interim review, the Sponsor may decide to stop the 
cohort, to continue with full enrollment of the cohort or revise eligibility criteria before the 
remaining 15 patients in that cohort are enrolled. 
For Cohort B5, a total of approximately 200 patients with head and neck squamous cell cancer 
may ultimately be randomized 2:1 to either NM21-1480 plus a PD-1 standard-of-care first-line 
checkpoint inhibitor or to the standard-of-care PD1 checkpoint inhibitor monotherapy. 
Randomization will be stratified by combined positive score (CPS ≥1; CPS ≥20), as determined 
by a FDA-cleared or any PD-L1 test approved for use by local competent authority. An interim 
analysis will be performed after a minimum of 60 patients (40 patients in the NM21-1480 arm) 
have been enrolled. At this point recruitment will be paused, the accumulated data analysed 
and regulatory authorities consulted. As with the other cohorts, decisions at the interim point 
will be taken based on clinical and regulatory input and not formal statistical testing. 
7.1.2 
Estimated Number of Screened Patients 
Approximately 42 patients for Part A, up to approximately 67 patients for the optional Part A-
2 and approximately 560 patients for Part B (assuming full enrollment of all Part B Cohorts B1 
through B8) based on an assumed screen-failure rate of 40% for Cohort A, 40% for Cohort A-
2, 25% for Cohorts B1-B2, and B4-B8, and screen-failure rate of 75% for Cohort B3. Patients 
who received <80% of both of the total intended Cycle 1 doses for reasons other than DLT and 
patients who may require discontinuation of NM21-1480 before the end of the DLT evaluation 
period for reasons other than the occurrence of a DLT, can be replaced. 
7.1.3 
Duration of Participation 
All patients may continue to receive NM21-1480 until precluded by toxicity, non-compliance, 
withdrawal of consent, Investigator’s decision, progressive disease, death, or closure of the 
study by the Sponsor (see Sections 7.2.9 and 7.2.11). 

 
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Patients with documented progression in tumor burden or the appearance of new lesions in the 
absence of significant clinical deterioration (decline in performance status and/or laboratory 
values), suspected by the Investigator as pseudo-progression, are permitted to continue with 
treatment until confirmation of disease progression with repeat imaging at least 4 weeks later, 
while the next imaging to confirm disease progression must not exceed 12 weeks from initial 
documentation of disease progression.  Patients continuing on therapy despite suspected 
pseudo-progression need to fulfill the following criteria: 
• Investigator-assessed clinical benefit, such as absence of clinical symptoms and 
signs of disease progression (including worsening laboratory values) 
• Tolerance of study treatment 
• Stable Eastern Cooperative Oncology Group (ECOG) performance status 
• Absence of progression of disease or of progressive tumor at critical anatomical sites 
(e.g., cord compression) that necessitates urgent alternative medical intervention 
Following completion of the Treatment and Follow-up periods, all patients will be followed 
for survival. 
7.1.4 
Treatment Beyond Disease Progression 
In Part A and optional Part A-2 of the study, patients treated with NM21-1480 will be permitted 
to continue NM21-1480 treatment beyond initial Response Evaluation Criteria in Solid Tumors 
1.1 (RECIST 1.1) defined progressive disease until the maximum of 12 months from the first 
treatment, assessed by the Investigator, as long as they meet the following criteria: 
• Investigator-assessed clinical benefit 
• Tolerance of study drug 
• Continues to meet relevant eligibility criteria and criteria for administration of study 
drug 
• Stable performance status 
• Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (e.g., central nervous system 
metastases) 
• Patient provides written informed consent prior to receiving additional NM21-1480 
treatment.  All other elements of the main consent including description of 
reasonably foreseeable risks or discomforts, or other alternative treatment options 
will still apply 
The decision to continue treatment beyond initial Investigator-assessed progression should be 
discussed with the study Medical Monitor (or designee) and documented in the study records.  
A radiographic assessment/scan should be performed at the next scheduled imaging evaluation 
6 weeks (during the first 24 weeks of optional Part A-2 and Part B) or 8 weeks (but no less than 
4 weeks) later to determine whether there has been a decrease in the tumor size or continued 

 
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progressive disease.  The assessment of clinical benefit should be balanced by clinical 
judgement as to whether the patient is clinically deteriorating and unlikely to receive any 
benefit from continued treatment with NM21-1480. 
If the Investigator believes the patient would continue to receive clinical benefit by continuing 
NM21-1480 treatment after scans showing disease progression from continued treatment, the 
patient may continue to receive NM21-1480 treatment, remain on the study, and continue to 
receive monitoring according to the Schedule of Assessments in Section 7.1.6, Table 7-1 and 
Table 7-2.  
For patients who continue NM21-1480 therapy beyond initial RECIST 1.1-defined disease 
progression, further progression is defined as an additional 10% increase in tumor burden from 
the time of the initial progressive disease assessment.  This includes an increase in the sum of 
diameters of all target lesions and/or the diameters of new measurable lesions compared to the 
initial progressive disease evaluation. NM21-1480 treatment should be discontinued 
permanently upon determination of further progression.  Study therapy should be discontinued 
in any patient for whom these criteria are met and should be documented. 
New lesions are considered measurable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm).  Any new lesion considered non-measurable at the time of initial progression may 
become measurable and therefore included in the tumor burden if the longest diameter 
increases to at least 10 mm (except for pathological lymph nodes which must have a short axis 
of at least 15 mm).  In situations where the relative increase in total tumor burden by 10% is 
solely due to inclusion of new lesions which become measurable, these new lesions must 
demonstrate an absolute increase of at least 5 mm. 
While for Part B of the study the criteria for treatment beyond progression described above 
shall be considered, decisions related to potential treatment beyond progression shall follow 
the principles of iRECIST (Seymour, et al. 2017). Any patient that has confirmed iCPD should 
be discontinued. 
7.1.5 
Duration of Treatment 
There is no pre-specified maximal treatment duration.  Treatment for a given patient shall be 
continued until there is confirmed disease progression by the Investigator or the patient meets 
any of the pre-specified conditions for discontinuation (see Section 7.2.9). 

 
 
 
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7.1.6 
Schedule of Assessments 
Table 7-1 
Schedule of Assessments (2-week Dosing Interval; APPLIES TO ALL PARTS [A, A-2 AND B] OF THE STUDY) 
Period 
Screening Period* 
Treatment Period d (2-week Dosing Interval/4-Week Treatment Cycles) 
Follow-up Perioda 
Survival 
Follow-upb 
Visit Name 
Pre-Screen  
(Cohorts B2, 
B3, B5 and B8 
only) bb,dd,ee 
Screening 
 
Cycle Day 1 
Treatment Visite 
Cycle Day 15 
Treatment Visite 
Cycle 1 
Day 21± 
3gg 
(Biopsy 
Visit) 
Imaging and Treatment Response 
Assessment Visits c 
Follow-up (FU) 1, 
FU2, and FU3 Visits 
 
Time point (Day / Week) 
Day -42 to -29 
Day -28 to -1 
C1: Day 1 / Week 1 
C2: Day 29 ± 2 / Week 5 
C3: Day 57 ± 3 / Week 9 
C4: Day 85 ± 3 / Week 13 
C5: Day 113 ± 3 / Week 17 
C6: Day 141 ± 3 / Week 21 
C7: Day 169 ± 3 / Week 25 
C8: Day 197 ± 3 / Week 29 
C1: Day 15 ± 2 / Week 3 
C2: Day 43 ± 2 / Week 7 
C3: Day 71 ± 3 / Week 11 
C4: Day 99 ± 3 / Week 15 
C5: Day 127 ± 3 / Week 19 
C6: Day 155 ± 3 / Week 23 
C7: Day 183 ± 3 / Week 27 
C8: Day 211 ± 3 / Week 31e 
 
Day 39-43 / Week 6 (Pt A-2 and B only) 
Day 52-56 / Week 8 (Pt A only) 
Day 79-85 / Week 12 (Pt  A-2 and B 
only) 
Day 108-112 / Week 16 (Pt A only) 
Day 120-127 / Week 18 (Pt A-2 and B 
only) 
Day 164-168 / Week 24 (Pts A, A-2 and 
B) 
Day 220-224 / Week 32 (Pts A, A-2 and 
B) e 
FU1: 0 to 30 days post 
discontinuation 
FU2: 60 days ± 7 post 
discontinuation 
FU3: 90 days ± 7 post 
discontinuation 
Every 3 months 
±  
7 days  
ICF/ 
HIPAAf 
xbb 
x 
 
 
 
 
 
 
Eligibility Criteria 
 
x 
 
 
 
 
 
 
Demographics & medical 
historyg,h 
 
x 
 
 
 
 
 
 
Diagnosis & confirmation 
stage 
 
x 
 
 
 
 
 
 
Tumor-specific therapy 
historyff 
 
x 
 
 
 
 
 
 
Hepatitis B and C, & HIV 
testing i 
 
x 
 
 
 
 
 
 
CD4 T-cell countj 
 
x 
 
 
 
 
 
 
Covid-19 vaccination 
confirmation or negative 
Covid-19 polymerase chain 
reaction (PCR) test 
 
x 
 
 
 
 
 
 
NM21-1480 infusione 
 
 
x 
x 
 
 
 
 
Vital signsk 
 
x 
x 
x 
 
 
x 
 
Height 
 
x 
 
 
 
 
 
 
Weight 
 
x 
x (Odd-numbered cycles only) 
 
 
 
x (FU1 only) 
 
Physical examl 
 
x 
x 
x 
 
 
x 
 
Oxygen saturationm 
 
 
x 
x 
 
 
 
 
ECOG performance 
 
x 
x 
x 
 
 
x 
 

 
 
 
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Period 
Screening Period* 
Treatment Period d (2-week Dosing Interval/4-Week Treatment Cycles) 
Follow-up Perioda 
Survival 
Follow-upb 
Visit Name 
Pre-Screen  
(Cohorts B2, 
B3, B5 and B8 
only) bb,dd,ee 
Screening 
 
Cycle Day 1 
Treatment Visite 
Cycle Day 15 
Treatment Visite 
Cycle 1 
Day 21± 
3gg 
(Biopsy 
Visit) 
Imaging and Treatment Response 
Assessment Visits c 
Follow-up (FU) 1, 
FU2, and FU3 Visits 
 
Time point (Day / Week) 
Day -42 to -29 
Day -28 to -1 
C1: Day 1 / Week 1 
C2: Day 29 ± 2 / Week 5 
C3: Day 57 ± 3 / Week 9 
C4: Day 85 ± 3 / Week 13 
C5: Day 113 ± 3 / Week 17 
C6: Day 141 ± 3 / Week 21 
C7: Day 169 ± 3 / Week 25 
C8: Day 197 ± 3 / Week 29 
C1: Day 15 ± 2 / Week 3 
C2: Day 43 ± 2 / Week 7 
C3: Day 71 ± 3 / Week 11 
C4: Day 99 ± 3 / Week 15 
C5: Day 127 ± 3 / Week 19 
C6: Day 155 ± 3 / Week 23 
C7: Day 183 ± 3 / Week 27 
C8: Day 211 ± 3 / Week 31e 
 
Day 39-43 / Week 6 (Pt A-2 and B only) 
Day 52-56 / Week 8 (Pt A only) 
Day 79-85 / Week 12 (Pt  A-2 and B 
only) 
Day 108-112 / Week 16 (Pt A only) 
Day 120-127 / Week 18 (Pt A-2 and B 
only) 
Day 164-168 / Week 24 (Pts A, A-2 and 
B) 
Day 220-224 / Week 32 (Pts A, A-2 and 
B) e 
FU1: 0 to 30 days post 
discontinuation 
FU2: 60 days ± 7 post 
discontinuation 
FU3: 90 days ± 7 post 
discontinuation 
Every 3 months 
±  
7 days  
Hematology, Serum Chemistry, 
and Coagulation Parametersn 
 
x 
x 
x 
 
 
x 
 
Urinalysisn 
 
x 
x (Odd-numbered cycles only) 
 
 
 
x 
 
Thyroid functionn 
 
x 
x (Odd-numbered cycles only) 
 
 
 
x 
 
Pregnancy test and FSHo 
 
x 
x (Odd-numbered cycles only) 
 
 
 
x 
 
CEAhh 
 
xhh 
xhh 
xhh 
 
 
x 
 
ECG (12-lead) 
 
xp 
xq (Odd-numbered cycles 
only) 
 
 
 
x (FU1 only) 
 
Serum sample for PKii 
 
 
See PK serum collection schedule in Table 7-3 
 
 
x (FU1 only) 
 
Serum sample for 
immunogenicity assessmentii 
 
 
See ADA serum collection schedule in Table 7-3 
 
 
x (FU1 only) 
 
Blood for PD analysis 
 
 
See PD blood sample collection schedule in Table 7-3 
 
 
 
 
ctDNAhh 
 
xhh 
xhh 
xhh 
 
 
xhh 
 
HPV Testing 
xdd 
 
 
 
 
 
 
 
Tumor or other biopsyr 
(regular) 
xbb,ee 
x 
xr 
xr 
 
 
 
 
Fresh tumor biopsy 
 (Cohort B8)gg 
 
xgg 
 
 
xgg 
 
 
 
CTI or MRI brains, t 
 
xp 
 
 
 
xc,u 
xu,v 
 
CTI or MRI (chest, abdomen, 
pelvis)t 
 
xp 
 
 
 
xc 
xv 
 
Bone scanw 
 
x 
 
 
 
xc 
xv 
 
Tumor-specific blood testsn,x 
 
x 
x (Odd-numbered cycles only) 
 
 
 
xv 
 
Tumor response assessment 
 
 
 
 
 
xc,y 
xv 
 
Concomitant medications 
 
x 
x 
x 
 
 
x 
 
Adverse eventsz 
 
xh 
x 
xcc 
x 
 
xaa 
 
Survival status 
 
 
 
 
 
 
 
x 

 
 
 
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Abbreviations: 
ADA = Anti-drug antibody; AE = Adverse event; BRCA1 = Breast cancer type 1; C = cycle; CA = Carbohydrate antigen; CEA = Carcinoembryonic antigen; CD4 T-
cell = cluster of differentiation 4 T-cell; CRF = Case report form; ctDNA = circulating tumor DNA; CTI = Computed tomography imaging; dMMR = Deficient mismatch repair; 
DLT = Dose-limiting toxicity; ECG = Electrocardiogram; ECOG = Eastern cooperative oncology group; FFPE = Formalin-fixed paraffin-embedded; FSH = Follicule-stimulating 
hormone; FU = Follow-up; HCG = Human chorionic gonadotropin; HCV = Hepatitis C virus; HIPAA = Health insurance portability and accountability act of 1996; HIV = 
Human immunodeficiency virus; HPV = Human papillomavirus; ICF = Informed consent form; irAE = Immune-related adverse event; MRI = Magnetic resonance imaging; 
MSI-H = Microsatellite instability-high; PD = Pharmacodynamics; PK = Pharmacokinetics; PD-L1 = Programmed death-ligand 1; RNA = Ribonucleic acid; SAE = Serious 
adverse event; T4 = Free thyroxine; TMB = Tumor mutational burden; TRAE = Treatment-related adverse event; TSH = Thyroid stimulating hormone. 
* Screening assessments will be used for determination of study eligibility.  
a. 
When a patient will discontinue study drug treatment, the date and reason for study drug discontinuation should be documented on the CRF, all remaining visits of that treatment 
cycle should be completed (without infusions and with only a single PK sample taken at applicable visits), and the patient should enter the Follow-up period.  When a patient will 
be withdrawn from the study (during the treatment or Follow-up period), all evaluations associated with that study visit should be performed and the date and reason for study 
discontinuation should be documented on the CRF. 
b. Following completion or discontinuation of the Treatment and/or Follow-up phases of the study, all patients will be followed (by phone) every 3 months to assess their survival 
status until patient death. 
c. 
These visits are NOT clinic visits. The purpose of these visits are for radiologic assessment and subsequent evaluation of results by the Investigator (tumor response assessment).  
However, should radiologic and clinic visit (comprising a study drug dosing event) be scheduled for the same day, the radiologic procedures and assessments shall occur BEFORE 
the clinic visit/administration of study drug. 
d. In the case that an infusion cannot be administered at a scheduled visit, it has to be administered as soon as possible. If the delay is between 1 and 7 days, the procedures at the 
original scheduled visit should be performed.  If the delay is more than 7 days, the procedures at the next visit should be performed, and subsequent visits will follow every 2 weeks 
(the infusion at the original scheduled visit will be considered a missed dose).  Patients with infusion delays >35 days (i.e., 2 missed doses + 7 days) should normally discontinue 
treatment and enter the Follow-up period with the exception of delays related to prophylactic vaccinations in special cases needed after specific consultation and agreement between 
the Investigator, and the Medical Monitor or in settings where benefit/risk may justify continued study therapy (e.g., patient deriving clinical benefit who requires prolonged steroid 
taper for management of non-DLT irAEs; again upon agreement with the Medical Monitor).   
e. 
Treatment and imaging/tumor assessments will continue until discontinuation criteria have been met. 
f. 
ICF and HIPAA – or any locally applicable – authorization are to be provided before initiation of any Screening assessments and may be obtained before Day 28. 
g. To include collection of prior medication and prior/concurrent medical conditions.  Also to include collecting prior local test results on tumor genetic alterations such as MSI-H, 
dMMR, BRCA1, Kras, PD-L1 status, TMB, etc. (if available). 
h. Aes occurring after signing informed consent/HIPAA authorization, but before study drug administration are to be recorded as Aes (though non-treatment-emergent). 
i. 
Hepatitis B surface antigen (HBVs Ag), Anti-Hepatitis B surface antibody (HBVs Ab), Anti-Hepatitis B core antibody (HBVc Ab), a Hepatitis B panel, and anti-hepatitis C antibody 
(HCV ab) (with reflex viral load assessment by quantitative polymerase chain reaction (PCR) hepatitis C RNA if antibody test is positive) testing.  To be done by local site laboratory 
or its contract laboratory. 
j. 
CD4 T-cell count should only be performed if a patient is HIV positive at Screening. 
k. Vital sign measurements to include temperature, pulse, and resting systolic and diastolic blood pressure.  On the day of each infusion, vital signs will be obtained pre-infusion, every 
15 minutes during the infusion, at the end of the infusion, and 15, 30, and 60 minutes after completion of the infusion.  When slowing or re-starting an infusion due to an infusion 

 
 
 
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reaction/AE, vital signs should be monitored every 15 minutes or as directed by the Investigator until the infusion is completed, and 15, 30, and 60 minutes after completion of the 
infusion and/or until the patient is stabilized.  Vital signs should be collected ± 5 minutes from the scheduled times noted above. 
l. 
Complete physical exam to be performed at Screening, Follow-up 1, and on Day 1 of all odd-numbered cycles from Cycle 3 onward. Limited physical exam to be performed at all 
other clinic visits. Ideally, physical examinations should be performed prior to dose administration on days when both procedures are scheduled to occur. Complete physical 
examination includes assessment of the skin, head, eyes, nose, throat, neck, joints, lungs, heart, abdomen (including liver and spleen), lymph nodes, and extremities.  A brief 
neurological examination should also be performed.  Limited physical examination includes assessment of the lungs, heart, abdomen, and skin.  All abnormal findings noted at the 
Screening and pre-treatment physical examinations should be recorded on the medical history CRF. Abnormal findings of clinical significance that occur after the Cycle 1/Day 1 
evaluation (or new AEs) should be explicitly documented on the AE CRF. 
m. To be done at rest and after mild exertion.  On treatment days, to be completed prior to infusion. 
n. During the study Treatment Period, hematology, coagulation parameters (as per inclusion criterion 14, Section 7.2.1), serum chemistries, urinalysis, thyroid function (free 
triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) [See Section 18.7, Appendix VII for full list of required laboratory tests]. If FT3 and FT4 tests 
are not available, total T3/T4 is acceptable), pregnancy tests and tumor-specific blood tests (if applicable, see footnote x) will be evaluated only by local study site or its contract 
laboratory at these time points.  The hematology and clinical chemistry laboratories must be performed and reviewed before dosing.  If practicable, laboratory samples may be 
drawn up to 72 hours prior to infusions for pre-infusion safety review; in such case it is not necessary to repeat tests on the day of dosing.  Any new ≥Grade 3 laboratory abnormality 
or change consistent with a possible irAE (as opposed to disease progression), such as liver function test elevations, electrolyte fluctuation, or hematologic deterioration should be 
assessed for potential risk to continued dosing.  In the event of uncertainty, the Medical Monitor should be contacted. 
o. Serum β-HCG pregnancy test to be performed at Screening (in case of a positive serum pregnancy test, the site is allowed to apply standard site procedures to rule out false positive 
test results; enrollment of the patient may be considered only in case false positivity of the serum pregnancy test has been confirmed). Urine pregnancy test to be performed at all 
other time points for women of child-bearing potential.  Urine pregnancy tests on days of study drug administration must be performed at the visits indicated and negative before 
study drug administration. FSH to be tested at Screening only, and only if applicable, i.e., if needed to confirm non-childbearing potential in accordance with inclusion criterion 15. 
p. Baseline imaging and 12-lead ECG done as part of the patient’s previous routine care before signing the ICF and completed within 28 days before the administration of ND021 
(NM21-1480) need not be repeated.  Whenever possible, baseline imaging should be done at the same institution/facility and with the same modality which will be used to measure 
response during the patient’s participation in the study. 
q. Not required at Cycle 1 Day 1 visit. 
r. 
Patient must provide baseline tumor tissues at Screening (archival or freshly acquired) for exploratory biomarker analysis.  Archival tumor tissue can be FFPE blocks or slides. 
Whenever clinically feasible, additional tumor or other biopsies (e.g., inflamed tissue at anatomical sites that are readily accessible without the need for general anesthesia) may be 
performed at other times but preferably at or around the time of the first dose administration in Treatment Cycle 2 or Treatment Cycle 3 (i.e., approximately 4 and 8 weeks following 
treatment initiation).  Part A (and optional Part A-2): Additional tumor or other biopsy requires specific agreement by the patient in the informed consent. Part B: Whenever 
considered clinically feasible by the investigator, one additional post-treatment tumor biopsy is mandatory for patients presenting with at least stable disease (i.e., stable disease, 
partial response or complete response) according to RECIST1.1 or suspected pseudo-progression at the Week 6 imaging. 
s. 
Brain scan (MRI preferred) required only if applicable (see inclusion criterion 10, Section 7.2.1) 
t. 
The same technique (CTI/MRI) used at baseline should be utilized throughout the study for a given patient.  CTI is the imaging modality of choice for chest/abdomen/pelvis. 
u. Brain scans during Treatment and Follow-up periods are required only if there is a prior history of lesions present at Screening, or as clinically indicated.  If required, subsequent 
brain CTI scans/MRI should be repeated at each Imaging and Treatment Response Assessment Visit, and at Follow-up Visits in accordance with footnote “v”. 

 
 
 
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v. Only if applicable and only needed for patients who were taken off NM21-1480 therapy due to AE, i.e., without progressive disease or patients with a global deterioration of health 
status requiring discontinuation of treatment without objective evidence of disease progression at that time. Only a single scan during the follow-up period is to be performed (i.e., 
at Follow-up Visit 2 or 3) and should only be performed if at least 4 weeks have passed since the most recent prior assessment.   
w. Bone scans at baseline or subsequent visits will be performed only if clinically indicated. If required, subsequent bone scans should ONLY be repeated every other assessment cycle 
(i.e., at Weeks 16, 32, etc., in Part A; and at Weeks 12, 24, 40, etc., for Part B) and a single scan at Follow-up Visit in accordance with footnote “v” unless the investigator suspects 
progression of disease in bone or in case complete response is identified in target disease.   
x. Blood tests are to be tumor-specific (e.g., CEA and CA 19-9 for colorectal and pancreatic cancer, respectively).  In case of uncertainty, use of a blood test should be discussed with 
the Medical Monitor. 
y. Tumor response status will be assessed by the Investigators using RECIST 1.1 only (Parts A and A-2), or RECIST1.1 and iRECIST (Part B). Response assessments must be 
performed by the Investigator every 8 weeks (Parts A), or every 6 weeks during the first 24 weeks the patient is on treatment and every 8 weeks thereafter (Part A-2 and Part B), to 
document eligibility to remain on treatment with study drug (see also footnote c).   
z. 
All patients who discontinue from the study within 70 days after the administration of the last dose of study drug should be followed until resolution and/or stabilization of any 
study TRAE and of those AE(s) that led to the discontinuation, and should be monitored for 70 days following the last dose of NM21-1480 for the occurrence of study TRAE.  
These patients should complete Follow-up Visits 1 and 2 unless the patient begins a new therapy. 
aa. For all Follow-up periods beyond 70 days from the last dose of study drug, only study treatment-related SAEs or late-occurring irAEs should be reported. 
bb. For Cohort B3 only: The screening process is to be conducted in 2 subsequent steps. Following signature of the ICF, PD-L1 expression scoring on tumor cells needs to be conducted 
either based on archival or fresh biopsy material from the TME and conducted centrally using a Sponsor-approved PD-L1 assay prior to entering the formal 28-day screening period. 
Only upon determination of a PD-L1 tumor cell expression score qualifying for study inclusion, the remaining eligibility criteria will be assessed. 
cc. For Part A (Cycle 1 only), the site is encouraged to call the patient approximately one week after the Day 15 / Week 3 dosing event in order to learn about any AEs that may have 
occurred.  
dd. For Cohort B2 and Cohort B5 only: Pre-screening visit only required if HPV positivity has not previously been determined for the current tumor (or if criteria described in footnote 
ee are met). In case HPV positivity has previously been confirmed, no new HPV testing is required for eligibility. If HPV status is unknown, HPV positivity must be confirmed for 
eligibility by local testing, applying the standard local testing approach for the given tumor, while use of the CINtec p16 histology assay, another p16 immunohistochemistry assay, 
or a locally established RT-PCR or PCR test is recommended. 
ee. For Cohort B2, Cohort B5, and Cohort B8 only: Pre-screening visit only required if PD-L1 expression status has not previously been determined for the current tumor (or if criteria 
described in footnote dd are met). In case PD-L1 expression in at least 1% of tumor and/or immune cells has previously been confirmed, no new PD-L1 testing is required for 
eligibility. If PD-L1 expression status is unknown, PD-L1 expression in at least 1% of tumor and/or immune cells must be confirmed for eligibility by local testing, using any PD-
L1 test approved or cleared for use by the local competent authority. 
ff. Sites are requested to attempt gathering and submitting the last pre-baseline scans for a patient as part of the tumor-specific therapy history; unavailability of these pre-baseline 
scans do not, however, make a patient ineligible for the study. 
gg. Mandatory fresh, paired biopsy to be taken during screening period and at Day 21±3. This only applies to patients with mCRC enrolled to Cohort B8. The on-treatment biopsy 
can be delayed to the next clinically feasible day closest to Day 21 in situations in which as per investigator judgement taking the biopsy is not clinically feasible at the scheduled 
day. In any case, on-treatment biopsies should not be taken at days of dosing with NM21-1480. Both baseline as well as matched on-treatment biopsies. Fresh biopsies can be taken 
from primary tumor or metastases. At least 3 biopsy cores, but preferably more if considered safe by the radiologist, shall be taken at each biopsy event and touch preparation as 
per site standard approach shall be applied to ensure specimen adequacy (i.e., confirm tumor content). Further details are described in the laboratory manual. In addition to these 

 
 
 
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fresh biopsies, for patients for whom there is archival primary tumor tissue available, this archival tissue, as per inclusion criterion 3 requirements shall also be provided for 
biomarker analysis. 
hh. Only applicable for mCRC patients enrolled to Cohort B8. 
ii. Not applicable to patients in Cohort B5 randomized to standard-of-care anti-PD1 therapy only.  

 
 
 
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Table 7-2 
Backup Schedule of Assessments (3-week Dosing Interval; APPLIES TO PART A-2 AND B ONLY IN CASE OF A POTENTIAL 
FUTURE SMC DECISION TO PROLONG DOSING INTERVAL#) 
Period 
Screening Period* 
Treatment Period d (3-week Dosing Interval/6-Week Treatment Cycles) 
Follow-up Perioda 
Survival Follow-upb 
Visit Name 
Pre-Screen  
(Cohorts B2, B3, 
B5 and B8 only) 
bb,cc,dd 
Screening 
 
Cycle Day 1 
Treatment Visite 
Cycle Day 22 
Treatment Visite 
Cycle 1 Day 
28± 3ff 
(Biopsy 
Visit) 
Imaging and Treatment 
Response Assessment Visits c 
Follow-up (FU) 1, 
FU2, and FU3 Visits 
 
Time point (Day / Week) 
Day -42 to -29 
Day -28 to -1 
C1: Day 1 / Week 1 
C2: Day 43 ± 2 / Week 7 
C3: Day 85 ± 3 / Week 13 
C4: Day 127 ± 3 / Week 19 
C5: Day 169 ± 3 / Week 25 
C6: Day 211 ± 3 / Week 31  
 
C1: Day 22 ± 2 / Week 4 
C2: Day 64 ± 2 / Week 10 
C3: Day 106 ± 3 / Week 16 
C4: Day 148 ± 3 / Week 22 
C5: Day 190 ± 3 / Week 28 
C6: Day 232 ± 3 / Week 34e 
 
 
Day 39-43 / Week 6 
Day 79-85 / Week 12 
Day 120-127 / Week 18 
Day 164-168 / Week 24 
Day 220-224 / Week 32 
Day 256-260 / Week 40 e 
FU1: 0 to 30 days post 
discontinuation 
FU2: 60 days ± 7 post 
discontinuation 
FU3: 90 days ± 7 post 
discontinuation 
Every 3 months ±  
7 days  
ICF/ 
HIPAAf 
xbb 
x 
 
 
 
 
 
 
Eligibility Criteria 
 
x 
 
 
 
 
 
 
Demographics & medical 
historyg,h 
 
x 
 
 
 
 
 
 
Diagnosis & confirmation 
stage 
 
x 
 
 
 
 
 
 
Tumor-specific therapy 
historyee 
 
x 
 
 
 
 
 
 
Hepatitis B and C, & HIV 
testingi 
 
x 
 
 
 
 
 
 
CD4 T-cell countj 
 
x 
 
 
 
 
 
 
Covid-19 vaccination 
confirmation or negative 
Covid-19 PCR test 
 
x 
 
 
 
 
 
 
NM21-1480 infusione 
 
 
x 
x 
 
 
 
 
Vital signsk 
 
x 
x 
x 
 
 
x 
 
Height 
 
x 
 
 
 
 
 
 
Weight 
 
x 
x (Odd-numbered cycles only) 
 
 
 
x (FU1 only) 
 
Physical examl 
 
x 
x 
x 
 
 
x 
 
Oxygen saturationm 
 
 
x 
x 
 
 
 
 
ECOG performance 
 
x 
x 
x 
 
 
x 
 
Hematology, Serum 
Chemistry, and Coagulation 
Parametersn 
 
x 
x 
x 
 
 
x 
 
Urinalysisn 
 
x 
x (Odd-numbered cycles only) 
 
 
 
x 
 
Thyroid functionn 
 
x 
x (Odd-numbered cycles only) 
 
 
 
x 
 
Pregnancy test and FSHo 
 
x 
x (Odd-numbered cycles only) 
 
 
 
x 
 
CEAgg 
 
x 
x 
x 
 
 
x 
 
ECG (12-lead) 
 
xp 
xq (Odd-numbered cycles only) 
 
 
 
x (FU1 only) 
 

 
 
 
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Period 
Screening Period* 
Treatment Period d (3-week Dosing Interval/6-Week Treatment Cycles) 
Follow-up Perioda 
Survival Follow-upb 
Visit Name 
Pre-Screen  
(Cohorts B2, B3, 
B5 and B8 only) 
bb,cc,dd 
Screening 
 
Cycle Day 1 
Treatment Visite 
Cycle Day 22 
Treatment Visite 
Cycle 1 Day 
28± 3ff 
(Biopsy 
Visit) 
Imaging and Treatment 
Response Assessment Visits c 
Follow-up (FU) 1, 
FU2, and FU3 Visits 
 
Time point (Day / Week) 
Day -42 to -29 
Day -28 to -1 
C1: Day 1 / Week 1 
C2: Day 43 ± 2 / Week 7 
C3: Day 85 ± 3 / Week 13 
C4: Day 127 ± 3 / Week 19 
C5: Day 169 ± 3 / Week 25 
C6: Day 211 ± 3 / Week 31  
 
C1: Day 22 ± 2 / Week 4 
C2: Day 64 ± 2 / Week 10 
C3: Day 106 ± 3 / Week 16 
C4: Day 148 ± 3 / Week 22 
C5: Day 190 ± 3 / Week 28 
C6: Day 232 ± 3 / Week 34e 
 
 
Day 39-43 / Week 6 
Day 79-85 / Week 12 
Day 120-127 / Week 18 
Day 164-168 / Week 24 
Day 220-224 / Week 32 
Day 256-260 / Week 40 e 
FU1: 0 to 30 days post 
discontinuation 
FU2: 60 days ± 7 post 
discontinuation 
FU3: 90 days ± 7 post 
discontinuation 
Every 3 months ±  
7 days  
Serum sample for PKhh 
 
 
See PK serum collection schedule in Table 7-4 
 
 
x (FU1 only) 
 
Serum sample for 
immunogenicity 
assessmenthh 
 
 
See ADA serum collection schedule in Table 7-4 
 
 
x (FU1 only) 
 
Blood for PD analysis 
 
 
See PD blood sample collection schedule in Table 7-4 
 
 
 
 
ctDNAgg 
 
xgg 
xgg 
xgg 
 
 
xgg 
 
HPV Testing 
xcc 
 
 
 
 
 
 
 
Tumor or other biopsyr  
(regular) 
xbb,dd 
x 
xr 
xr 
 
 
 
 
Fresh tumor biopsy 
 (Cohort B8)ff 
 
xff 
 
 
xff 
 
 
 
CTI or MRI brains, t 
 
xp 
 
 
 
xc,u 
xu,v 
 
CTI or MRI (chest, 
abdomen, pelvis)t 
 
xp 
 
 
 
xc 
xv 
 
Bone scanw 
 
x 
 
 
 
xc 
xv 
 
Tumor-specific blood testsn,x 
 
x 
x (Odd-numbered cycles only) 
 
 
 
xv 
 
Tumor response assessment 
 
 
 
 
 
xc,y 
xv 
 
Concomitant medications 
 
x 
x 
x 
 
 
x 
 
Adverse eventsz 
 
xh 
x 
x 
x 
 
xaa 
 
Survival status 
 
 
 
 
 
 
 
x 
Abbreviations: 
ADA = Anti-drug antibody; AE = Adverse event; BRCA1 = Breast cancer type 1; C = cycle; CA = Carbohydrate antigen; CEA = Carcinoembryonic antigen; CD4 T-
cell = cluster of differentiation 4 T-cell; CRF = Case report form; CTI = Computed tomography imaging; dMMR = Deficient mismatch repair; DLT = Dose-limiting toxicity; 
ECG = Electrocardiogram; ECOG = Eastern cooperative oncology group; FFPE = Formalin-fixed paraffin-embedded; FSH = Follicule-stimulating hormone; FU = Follow-up; 
HCG = Human chorionic gonadotropin; HCV = Hepatitis C virus; HIPAA = Health insurance portability and accountability act of 1996; HIV = Human immunodeficiency 
virus; HPV = Human papillomavirus; ICF = Informed consent form; irAE = Immune-related adverse event; MRI = Magnetic resonance imaging; MSI-H = Microsatellite 
instability-high; PD = Pharmacodynamics; PK = Pharmacokinetics; PDL1 = Programmed death-ligand 1; RNA = Ribonucleic acid; SAE = Serious adverse event; 
T4 = Free thyroxine; TMB = Tumor mutational burden; TRAE = Treatment-related adverse event; TSH = Thyroid stimulating hormone. 
# As per 23 May 2022 SMC call, the 800mg flat dose level shall be further studied in Part B by infusion approximately every 14 days (i.e. following Table 7-1 Schedule of 
Assessments), based on Part A PK data which do not indicate substantial accumulation at this dose level over time with this dosing interval. Optional Part A-2 of the study 
will explore one more higher dose level (1400mg flat dose with approximately 14-day dosing interval, i.e. following Table 7-1 Schedule of Assessments) than was studied in 

 
 
 
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Part A. Such 1400mg dose level will be explored applying strict stopping criteria and respecting a 28-day DLT evaluation period before more than 6 subjects are exposed. PK 
data for this 1400mg dose level in Part A-2 will be closely followed and in case of observation of relevant drug accumulation over time, the dosing interval for this dose may 
be adjusted to approximately every 21 days, in which case Table 7-2 Schedule of Assessments applies. Such change from a 2-week to a 3-week dosing interval would only be 
applicable if communicated separately to sites by a written notification of the SMC decision on such change of dosing interval by means of a letter of amendment, to be 
followed by a full protocol amendment. 
* Screening assessments will be used for determination of study eligibility. 
a. 
When a patient will discontinue study drug treatment, the date and reason for study drug discontinuation should be documented on the CRF, all remaining visits of that treatment 
cycle should be completed (without infusions and with only a single PK sample taken at applicable visits), and the patient should enter the Follow-up period.  When a patient will 
be withdrawn from the study (during the treatment or Follow-up period), all evaluations associated with that study visit should be performed and the date and reason for study 
discontinuation should be documented on the CRF. 
b. Following completion or discontinuation of the Treatment and/or Follow-up phases of the study, all patients will be followed (by phone) every 3 months to assess their survival 
status until patient death. 
c. 
These visits are NOT clinic visits.  The purpose of these visits are for radiologic assessment and subsequent evaluation of results by the Investigator (tumor response assessment).  
However, should radiologic and clinic visit (comprising a study drug dosing event) be scheduled for the same day, the radiologic procedures and assessments shall occur BEFORE 
the clinic visit/administration of study drug.  
d. In the case that an infusion cannot be administered at a scheduled visit, it has to be administered as soon as possible.  If the delay is between 1 and 7 days, the procedures at the 
original scheduled visit should be performed.  If the delay is more than 7 days, the procedures at the next visit should be performed, and subsequent visits will follow every 3 weeks 
(the infusion at the original scheduled visit will be considered a missed dose).  Patients with infusion delays >49 days (i.e., 2 missed doses + 7 days) should normally discontinue 
treatment and enter the Follow-up period with the exception of delays related to prophylactic vaccinations in special cases needed after specific consultation and agreement between 
the Investigator, and the Medical Monitor or in settings where benefit/risk may justify continued study therapy (e.g., patient deriving clinical benefit who requires prolonged steroid 
taper for management of non-DLT irAEs; again upon agreement with the Medical Monitor).  
e. 
Treatment and imaging/tumor assessments will continue until discontinuation criteria have been met. 
f. 
ICF and HIPAA - or any locally applicable - authorization are to be provided before initiation of any Screening assessments and may be obtained before Day 28. 
g. To include collection of prior medication and prior/concurrent medical conditions.  Also to include collecting prior local test results on tumor genetic alterations such as MSI-H, 
dMMR, BRCA1, Kras, PD-L1 status, TMB, etc. (if available). 
h. AEs occurring after signing informed consent/HIPAA authorization, but before study drug administration are to be recorded as AEs (though non-treatment-emergent). 
i. 
Hepatitis B surface antigen (HBVs Ag), Anti-Hepatitis B surface antibody (HBVs Ab), Anti-Hepatitis B core antibody (HBVc Ab), a Hepatitis B panel, and anti-hepatitis C antibody 
(HCV ab) (with reflex viral load assessment by quantitative polymerase chain reaction (PCR) hepatitis C RNA if antibody test is positive) testing.  To be done by local site laboratory 
or its contract laboratory. 
j. 
CD4 T-cell count should only be performed if a patient is HIV positive at Screening. 
k. Vital sign measurements to include temperature, pulse, and resting systolic and diastolic blood pressure.  On the day of each infusion, vital signs will be obtained pre-infusion, every 
15 minutes during the infusion, at the end of the infusion, and 15, 30, and 60 minutes after completion of the infusion.  When slowing or re-starting an infusion due to an infusion 
reaction/AE, vital signs should be monitored every 15 minutes or as directed by the Investigator until the infusion is completed, and 15, 30, and 60 minutes after completion of the 
infusion and/or until the patient is stabilized.  Vital signs should be collected ± 5 minutes from the scheduled times noted above. 

 
 
 
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l. 
Complete physical exam to be performed at Screening, Follow-up 1, and on Day 1 of all odd-numbered cycles from Cycle 3 onward. Limited physical exam to be performed at all 
other clinic visits. Ideally, physical examinations should be performed prior to dose administration on days when both procedures are scheduled to occur. Complete physical 
examination includes assessment of the skin, head, eyes, nose, throat, neck, joints, lungs, heart, abdomen (including liver and spleen), lymph nodes, and extremities.  A brief 
neurological examination should also be performed.  Limited physical examination includes assessment of the lungs, heart, abdomen, and skin.  All abnormal findings noted at the 
Screening and pre-treatment physical examinations should be recorded on the medical history CRF. Abnormal findings of clinical significance that occur after the Cycle 1/Day 1 
evaluation (or new AEs) should be explicitly documented on the AE CRF. 
m. To be done at rest and after mild exertion.  On treatment days, to be completed prior to infusion. 
n. During the study Treatment Period, hematology, coagulation parameters (as per inclusion criterion 14, Section 7.2.1), serum chemistries, urinalysis, thyroid function (free 
triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) [See Section 18.7, Appendix VII for full list of required laboratory tests]. If FT3 and FT4 tests 
are not available, total T3/T4 is acceptable), pregnancy tests and tumor-specific blood tests (if applicable, see footnote x) will be evaluated only by local study site or its contract 
laboratory at these time points.  The hematology and clinical chemistry laboratories must be performed and reviewed before dosing.  If practicable, laboratory samples may be 
drawn up to 72 hours prior to infusions for pre-infusion safety review; in such case it is not necessary to repeat tests on the day of dosing.  Any new ≥Grade 3 laboratory abnormality 
or change consistent with a possible irAE (as opposed to disease progression), such as liver function test elevations, electrolyte fluctuation, or hematologic deterioration should be 
assessed for potential risk to continued dosing.  In the event of uncertainty, the Medical Monitor should be contacted. 
o. Serum β-HCG pregnancy test to be performed at Screening (in case of a positive serum pregnancy test, the site is allowed to apply standard site procedures to rule out false positive 
test results; enrollment of the patient may be considered only in case false positivity of the serum pregnancy test has been confirmed). Urine pregnancy test to be performed at all 
other time points for women of child-bearing potential.  Urine pregnancy tests on days of study drug administration must be performed at the visits indicated and negative before 
study drug administration. FSH to be tested at Screening only, and only if applicable, i.e., if needed to confirm non-childbearing potential in accordance with inclusion criterion 15. 
p. Baseline imaging and 12-lead ECG done as part of the patient’s previous routine care before signing the ICF and completed within 28 days before the administration of ND021 
(NM21-1480) need not be repeated.  Whenever possible, baseline imaging should be done at the same institution/facility and with the same modality which will be used to measure 
response during the patient’s participation in the study. 
q. Not required at Cycle 1 Day 1 visit. 
r. 
Patient must provide baseline tumor tissues at Screening (archival or freshly acquired) for exploratory biomarker analysis.  Archival tumor tissue can be FFPE blocks or slides. 
Whenever clinically feasible, additional tumor or other biopsies (e.g., inflamed tissue at anatomical sites that are readily accessible without the need for general anesthesia) may be 
performed at other times but preferably at or around the time of the first dose administration in Treatment Cycle 2 or Treatment Cycle 3 (i.e., approximately 6 and 12 weeks 
following treatment initiation).  Whenever considered clinically feasible by the investigator, an additional tumor biopsy is mandatory for patients presenting with at least stable 
disease (i.e., stable disease, partial response or complete response) according to RECIST1.1 or suspected pseudo-progression at the Week 6 imaging. 
s. 
Brain scan (MRI preferred) required only if applicable (see inclusion criterion 10, Section 7.2.1) 
t. 
The same technique (CTI/MRI) used at baseline should be utilized throughout the study for a given patient.  CTI is the imaging modality of choice for chest/abdomen/pelvis. 
u. Brain scans during Treatment and Follow-up periods are required only if there is a prior history of lesions present at Screening, or as clinically indicated.  If required, subsequent 
brain CTI scans/MRI should be repeated at each Imaging and Treatment Response Assessment Visit, and at Follow-up Visits in accordance with footnote “v”. 
v. Only if applicable and only needed for patients who were taken off NM21-1480 therapy due to AE, i.e., without progressive disease or patients with a global deterioration of health 
status requiring discontinuation of treatment without objective evidence of disease progression at that time. Only a single scan during the follow-up period is to be performed (i.e., 
at Follow-up Visit 2 or 3) and should only be performed if at least 4 weeks have passed since the most recent prior assessment. 

 
 
 
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w. Bone scans at baseline or subsequent visits will be performed only if clinically indicated. If required, subsequent bone scans should ONLY be repeated every other assessment cycle 
(i.e., at Weeks 12, 24, 40, etc.) and a single scan at Follow-up Visits in accordance with footnote “v” unless the investigator suspects progression of disease in bone or in case 
complete response is identified in target disease. 
x. Blood tests are to be tumor-specific (e.g., CEA and CA 19-9 for colorectal and pancreatic cancer, respectively).  In case of uncertainty, use of a blood test should be discussed with 
the Medical Monitor. 
y. Tumor response status will be assessed by the Investigators using RECIST 1.1 (Part A-2) and RECIST1.1 and iRECIST (Part B).  Response assessments must be performed by the 
Investigator every 6 weeks during the first 24 weeks the patient is on treatment and every 8 weeks thereafter (Part A-2 and B) to document eligibility to remain on treatment with 
study drug (see also footnote c).   
z. 
All patients who discontinue from the study within 70 days after the administration of the last dose of study drug should be followed until resolution and/or stabilization of any 
study TRAE and of those AE(s) that led to the discontinuation, and should be monitored for 70 days following the last dose of NM21-1480 for the occurrence of study TRAE.  
These patients should complete Follow-up Visits 1 and 2 unless the patient begins a new therapy. 
aa. For all Follow-up periods beyond 70 days from the last dose of study drug, only study treatment-related SAEs or late-occurring irAEs should be reported. 
bb. For Cohort B3 only: The screening process is to be conducted in 2 subsequent steps. Following signature of the ICF, PD-L1 expression scoring on tumor cells needs to be conducted 
either based on archival or fresh biopsy material from the TME and conducted centrally using a Sponsor-approved PD-L1 assay prior to entering the formal 28-day screening period. 
Only upon determination of a PD-L1 tumor cell expression score qualifying for study inclusion, the remaining eligibility criteria will be assessed. 
cc. For Cohort B2 and Cohort B5 only: Pre-screening visit only required if HPV positivity has not previously been determined for the current tumor (or if criteria described in footnote 
dd are met). In case HPV positivity has previously been confirmed, no new HPV testing is required for eligibility. If HPV status is unknown, HPV positivity must be confirmed for 
eligibility by local testing, applying the standard local testing approach for the given tumor, while use of the CINtec p16 histology assay, another p16 immunohistochemistry assay, 
or a locally established RT-PCR or PCR test is recommended. 
dd. For Cohort B2, Cohort B5, and Cohort B8 only: Pre-screening visit only required if PD-L1 expression status has not previously been determined for the current tumor (or if criteria 
described in footnote cc are met). In case PD-L1 expression in at least 1% of tumor and/or immune cells has previously been confirmed, no new PD-L1 testing is required for 
eligibility. If PD-L1 expression status is unknown, PD-L1 expression in at least 1% of tumor and/or immune cells must be confirmed for eligibility by local testing, using any PD-
L1 test approved or cleared for use by the local competent authority. 
ee. Sites are requested to attempt gathering and submitting the last pre-baseline scans for a patient as part of the tumor-specific therapy history; unavailability of these pre-baseline 
scans do not, however, make a patient ineligible for the study. 
ff. Mandatory fresh, paired biopsy to be taken during screening period and at Day 28±3. This only applies to patients with mCRC enrolled to Cohort B8. The on-treatment biopsy 
can be delayed to the next clinically feasible day closest to Day 28 in situations in which as per investigator judgement taking the biopsy is not clinically feasible at the scheduled 
day. In any case, on-treatment biopsies should not be taken at days of dosing with NM21-1480. Both baseline as well as matched on-treatment biopsies. Fresh biopsies can be taken 
from primary tumor or metastases. At least 3 biopsy cores, but preferably more if considered safe by the radiologist, shall be taken at each biopsy event and touch preparation as 
per site standard approach shall be applied to ensure specimen adequacy (i.e., confirm tumor content). Further details are described in the laboratory manual. In addition to these 
fresh biopsies, for patients for whom there is archival primary tumor tissue available, this archival tissue, as per inclusion criterion 3 requirements shall also be provided for 
biomarker analysis. 
gg. Only applicable for mCRC patients enrolled to Cohort B8. 
hh. Not applicable to patients in Cohort B5 randomized to standard-of-care anti-PD1 therapy only. 

 
 
 
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7.1.7 
Blood Sampling Schedule (APPLIES TO ALL PARTS [A, A-2 AND B] OF THE STUDY) 
Table 7-3 
Pharmacokinetics, Anti-Drug Antibody, and Pharmacodynamic Blood Sampling Schedule (2-week Dosing Interval) 
PKa,b, j 
ADAj 
IPT 
sPD-L1/ 
sCD137 
Cytokines  
RO 
ctDNAk 
PD-L1 
IHC 
TMB, 
TCRseq, 
& MSI 
by DNA 
Analysis 
mRNA/ 
IF 
DNA, 
mRNA, 
IHCh 
Visit name /  
Study day 
Time Point 
Serum 
Serum 
Whole 
Blood 
Serum 
Serum 
Whole 
Blood 
Whole 
Blood 
Biopsy 
(FFPE) 
Biopsy 
(FFPE)  
Biopsy 
(FFPE)c 
Mandato
ry 
Biopsyh 
Screening /  
Day -28 to -1 
 
-- 
 
 
 
 
 
 
xk 
x 
x 
x 
x 
 
Cycle 1, Day 1 / 
Study Day 1 
  
  
  
Pre-dose 
xg 
xg 
xg 
xg 
xg 
xg 
xk 
 
EOIf ± 
5 min 
xg 
xg 
xg 
xg 
 
 
4 h ± 10 min 
xd 
 
 
8 h ± 1 h 
xd 
 
 
Cycle 1, Day 2 / 
Study Day 2 
24 h ± 2 h 
xd 
xd 
xd 
xd 
 
 
Cycle 1, Day 3 / 
Study Day 3 
48 h ± 4 h 
xd 
 
 
Cycle 1, Day 5 / 
Study Day 5 
96 h ± 12 h 
xd 
xd 
xd 
 
 
Cycle 1, Day 8 / 
Study Day 8 
168 h ± 24 h 
xg 
xg 
xg 
xg 
xg 
xg 
 
 
Cycle 1, Day 15 / 
Study Day 15 ± 2 
Pre-dose 
xg 
xg 
xg 
xg 
xg 
xg 
xk 
 
Cycle 1, Day 21 / 
Study Day 21 ± 3 
-- 
 
 
 
 
 
 
 
 
 
 
xi 

 
 
 
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PKa,b, j 
ADAj 
IPT 
sPD-L1/ 
sCD137 
Cytokines  
RO 
ctDNAk 
PD-L1 
IHC 
TMB, 
TCRseq, 
& MSI 
by DNA 
Analysis 
mRNA/ 
IF 
DNA, 
mRNA, 
IHCh 
Visit name /  
Study day 
Time Point 
Serum 
Serum 
Whole 
Blood 
Serum 
Serum 
Whole 
Blood 
Whole 
Blood 
Biopsy 
(FFPE) 
Biopsy 
(FFPE)  
Biopsy 
(FFPE)c 
Mandato
ry 
Biopsyh 
 
Cycle 2, Day 1 / 
Study Day 29 ± 2 
Pre-dose 
xg 
xg 
xg 
xg 
xg 
xg 
xk 
x 
 
Cycle 2, Day 8 / 
Study Day 36 ± 2 
168 h ± 48 h 
xg 
xg 
xg 
xg 
xg 
xg 
 
 
 
 
 
Cycle 2, Day 15 / 
Study Day 43 ± 2 
Pre-dose 
xg 
xg 
xg 
xg 
xk 
 
 
Cycle 3, Day 1 / 
Study Day 57 ± 3 
  
  
  
Pre-dose 
xg 
xg 
xg 
xg 
xg 
xg 
xk 
 
 
x 
 
EOIf ±  
5 min 
xg 
 
 
 
4 h ± 10 min 
xd 
 
 
8 h ± 1 h 
xd 
 
 
 
 
 
 
 
 
 
 
Cycle 3, Day 2 / 
Study Day 58 
24 h ± 2 h 
xd 
xd 
 
 
Cycle 3, Day 3 / 
Study Day 59 
48 h ± 4 h 
xd 
 
 
Cycle 3, Day 5 /  
Study Day 61 
96 h ± 12 h 
xd 
 
 
 
 
 
 
 
 
 
 
Cycle 3, Day 8 / 
Study Day 64 
168 h ± 24 h 
xg 
 
 
 
xg 
 
 
 
 
 
 
Cycle 3, Day 15 / 
Study Day 71 ± 3 
336 h ± 48 h 
xd 
 
 
 
 
 
xk 
 
 
 
 
 

 
 
 
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17 November 2022 
Protocol NM21-1480 
 
 
 
Final V9.0 
 
Page 71 of 172 
 
 
 
PKa,b, j 
ADAj 
IPT 
sPD-L1/ 
sCD137 
Cytokines  
RO 
ctDNAk 
PD-L1 
IHC 
TMB, 
TCRseq, 
& MSI 
by DNA 
Analysis 
mRNA/ 
IF 
DNA, 
mRNA, 
IHCh 
Visit name /  
Study day 
Time Point 
Serum 
Serum 
Whole 
Blood 
Serum 
Serum 
Whole 
Blood 
Whole 
Blood 
Biopsy 
(FFPE) 
Biopsy 
(FFPE)  
Biopsy 
(FFPE)c 
Mandato
ry 
Biopsyh 
All subsequent even-
numbered cycles, 
Days 1 and 15 / 
Study Days e.g., 85 ± 
3, 99 ± 3, 141 ± 3, 
155 ± 3, etc. 
 
 
 
 
 
 
 
xk 
 
 
 
 
All subsequent even- 
numbered cycles,Day 
8 / Study Days e.g., 
92 ± 3, 148 ± 3, 204 
± 3, etc. 
168 h ± 48 h 
xg 
xg 
xg 
xg 
xg 
xg 
 
 
 
 
 
All subsequent odd- 
numbered cycles, 
Day 1 / Study Days 
113 ± 3, 169 ± 
3, etc. 
Pre-dose 
xg 
xg 
xd 
xd 
xd 
xd 
xk 
 
 
x 
 
All subsequent odd-
numbered cycles, 
Day 15 / Study Days 
e.g., 127 ± 3, 183 ± 
3, etc. 
 
 
 
 
 
 
 
xk 
 
 
 
 
 
Follow-up Period 
-- 
x  
(FU1 
only) 
x  
(FU1 
only) 
 
 
 
 
xk (FU1, 
FU2, and 
FU3) 
 
 
 
 
Abbreviations: 
ADA = Anti-drug antibodies; D = Dose (study drug administration); DNA = Deoxyribonucleic acid; EOI = End of infusion; FFPE = Formalin-fixed paraffin-embedded; 
h = Hour; IHC = Immunohistochemistry; IPT = Immunophenotyping; TMB = Tumor mutational burden; MSI = Microsatellite instability; IF = Immunofluorescence; 

 
 
 
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PK = Pharmacokinetics; PD-L1 = Programmed death-ligand 1; mRNA = Messenger Ribonucleic acid; RO = Receptor occupancy; TCRseq = T-cell receptor 
sequencing; TMB = Tumor mutational burden 
*Assessment of IPT, sPD-L1, sCD137, cytokine panel, RO, PD-L1 IHC, TMB, TCRseq, MSI and mRNA/IF may be adjusted for Part B, following availability of Part A data; conduct 
of RO assay (for Part A and B) will be dependent on availability of a suitable assay. 
a. 
Serial PK samples will be collected from all the patients enrolled in Part A and A-2.  For the patients in Part B serial PK is optional except for the mandatory pre-dose, EOI and 168 
± 24 h sampling timepoints (see footnote “g”). 
b. If a patient permanently discontinues study drug treatment, or is not receiving an infusion at a given visit, a single PK sample will be taken at that visit. 
c. 
Optional biopsy material for patients enrolled in Part A and A-2 from as many cycles as possible, and Follow-up period. For patients in Part B, a single post treatment biopsy 
material collection is considered mandatory per footnote “r” in Table 7-1, i.e., for patients presenting with at least stable disease during treatment with NM21-1480. 
d. Optional sampling point for Part B. Sites are not required to collect these optional PK samples in Part B. These sampling timepoints are however mandatory in Part A and Part A-2. 
For sampling timepoints considered mandatory in Part B at all sites, see also footnote ”g”. 
e. 
EOI: End of Infusion.  This sample should be taken immediately prior to stopping the infusion from the counter arm of the site of injection.   All subsequent timepoints indicated 
for PK blood draws refer to hours after EOI. 
f. 
For FU visits: PK and ADA sample will be taken at Follow-up Visit 1 only. 
g.  Mandatory sample for all patients in Part A, Part A-2 and Part B (unless drawing is not considered clinically feasible due to the condition of the patient).  
h.  Only applicable for mCRC patients enrolled to CohortB8. For specifics on sample acquisition please refer to specialty lab manual. 
i. 
Reference is made to footnote gg in Table 7-1 for timing of these mandatory on-treatment biopsies for mCRC patients enrolled to Cohort B8. 
j. 
Not applicable to patients in Cohort B5 randomized to standard-of-care anti-PD1 therapy only. 
k. Only applicable for mCRC patients enrolled to Cohort B8.    
 

 
 
 
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Table 7-4 
Backup Pharmacokinetics, Anti-Drug Antibody, and Pharmacodynamic Blood Sampling Schedule (3-week Dosing Interval: 
APPLICABLE TO PART A-2 AND B ONLY IN CASE OF A POTENTIAL FUTURE SMC DECISION TO PROLONG DOSING 
INTERVAL#) 
PKa,b,j 
ADAj 
IPT 
sPD-L1/ 
sCD137 
Cytokines  
RO 
ctDNAk 
PD-L1 
IHC 
TMB, 
TCRseq, 
& MSI by 
DNA 
Analysis 
mRNA/IF 
DNA, 
mRNA, 
IHCh 
Visit name /  
Study day 
Time 
Point 
Serum 
Serum 
Whole 
Blood 
Serum 
Serum 
Whole 
Blood 
Whole 
Blood 
Biopsy 
(FFPE) 
Biopsy 
(FFPE)  
Biopsy 
(FFPE)c 
Mandat
ory 
Biopsyh 
Screening /  
Day -28 to -1  
-- 
 
 
 
 
 
 
xk 
x 
x 
x 
x 
 
Cycle 1, Day 1 / 
Study Day 1 
  
  
  
Pre-dose 
xg 
xg 
xg 
xg 
xg 
xg 
xk 
 
 
EOIf ± 
5 min 
xg 
 
 
xg 
xg 
xg 
 
 
 
 
 
4 h ± 10 
min 
xd 
 
 
8 h ± 1 h 
xd 
 
 
 
 
 
 
 
 
 
 
Cycle 1, Day 2 / 
Study Day 2 
24 h ± 2 h 
xd 
xd 
xd 
xd 
 
 
Cycle 1, Day 3 / 
Study Day 3 
48 h ± 4 h 
xd 
 
 
 
 
 
 
 
 
 
 
Cycle 1, Day 5 / 
Study Day 5 
96 h ± 12 h 
xd 
xd 
xd 
 
 
Cycle 1, Day 8 / 
Study Day 8 
168 h ± 24 
h 
xg 
xg 
xg 
xg 
xg 
xg 
 
 
Cycle 1, Day 22 / 
Study Day 22 ± 2 
Pre-dose 
xg 
xg 
xg 
xg 
xg 
xg 
xk 
 
 

 
 
 
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PKa,b,j 
ADAj 
IPT 
sPD-L1/ 
sCD137 
Cytokines  
RO 
ctDNAk 
PD-L1 
IHC 
TMB, 
TCRseq, 
& MSI by 
DNA 
Analysis 
mRNA/IF 
DNA, 
mRNA, 
IHCh 
Visit name /  
Study day 
Time 
Point 
Serum 
Serum 
Whole 
Blood 
Serum 
Serum 
Whole 
Blood 
Whole 
Blood 
Biopsy 
(FFPE) 
Biopsy 
(FFPE)  
Biopsy 
(FFPE)c 
Mandat
ory 
Biopsyh 
Cycle 1, Day 28 / 
Study Day 28 ± 3 
-- 
 
 
 
 
 
 
 
 
 
 
xi 
 
Cycle 2, Day 1 / 
Study Day 43 ± 2 
Pre-dose 
xg 
xg 
xg 
xg 
xg 
xg 
xk 
 
x 
 
Cycle 2, Day 8 
Study Day 50 ± 2 
168 h ± 48 
h 
xg 
xg 
xg 
xg 
xg 
xg 
 
 
 
 
 
Cycle 2, Day 22 / 
Study Day 64 ± 2 
Pre-dose 
xg 
xg 
 
xg 
xg 
 
xk 
 
 
 
 
 
Cycle 3, Day 1 / 
Study Day 85 ± 3 
  
  
  
Pre-dose 
xg 
xg 
xg 
xg 
xg 
xg 
xk 
 
x 
 
EOIf ±  
5 min 
xg 
 
 
 
 
 
 
 
 
 
 
4 h ± 10 
min 
xd 
 
 
8 h ± 1 h 
xd 
 
 
 
 
 
 
 
 
 
 
Cycle 3, Day 2 / 
Study Day 86 
24 h ± 2 h 
xd 
xd 
 
 
Cycle 3, Day 3 / 
Study Day 87 
48 h ± 4 h 
xd 
 
 
 
 
 
 
 
 
 
 
Cycle 3, Day 5 / 
Study Day 89 
96 h ± 12 h 
xd 
 
 
Cycle 3, Day 8 / 
Study Day 92 
168 h ± 24 
h 
xg 
xg 
 
 

 
 
 
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PKa,b,j 
ADAj 
IPT 
sPD-L1/ 
sCD137 
Cytokines  
RO 
ctDNAk 
PD-L1 
IHC 
TMB, 
TCRseq, 
& MSI by 
DNA 
Analysis 
mRNA/IF 
DNA, 
mRNA, 
IHCh 
Visit name /  
Study day 
Time 
Point 
Serum 
Serum 
Whole 
Blood 
Serum 
Serum 
Whole 
Blood 
Whole 
Blood 
Biopsy 
(FFPE) 
Biopsy 
(FFPE)  
Biopsy 
(FFPE)c 
Mandat
ory 
Biopsyh 
 
All subsequent 
even-numbered 
cycles, Days 1 and 
22 / Study Days 
e.g., 127 ± 3, 148 ± 
3, etc. 
 
 
 
 
 
 
 
xk 
 
 
 
 
All subsequent 
even-numbered 
cycles Day 8 / 
Study Days, e.g., 
134 ± 3, 218 ± 3 
etc. 
168 h ± 48 
h 
xg 
xg 
xg 
xg 
xg 
xg 
 
 
 
 
 
All subsequent odd-
numbered cycles, 
Day 1 / 
Study Day 169 ± 3, 
etc. 
Pre-dose 
xg 
xg 
xd 
xd 
xd 
xd 
xk 
 
x 
 
All subsequent odd-
numbered cycles, 
Day 22 / Study 
Days e.g., 190 ± 3, 
etc. 
 
 
 
 
 
 
 
xk 
 
 
 
 
 
Follow-up Period 
-- 
x  
(FU1 
only) 
x  
(FU1 
only) 
 
 
 
 
xk (FU1, 
FU2, and 
FU3) 
 
 
 
 

 
 
 
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Abbreviations: ADA = Anti-drug antibodies; D = Dose (study drug administration); DNA = Deoxyribonucleic acid; EOI = End of infusion; FFPE = Formalin-fixed paraffin-
embedded; h = Hour; IHC = Immunohistochemistry; IPT = Immunophenotyping; TMB = Tumor mutational burden; MSI = Microsatellite instability; IF = 
Immunofluorescence; PK = Pharmacokinetics; PD-L1 = Programmed death-ligand 1; mRNA = Messenger Ribonucleic acid; RO = Receptor occupancy; TCRseq 
= T-cell receptor sequencing; TMB = Tumor mutational burden 
*Assessment of IPT, sPD-L1, sCD137, cytokine panel, RO, PD-L1 IHC, TMB, TCRseq, MSI and mRNA/IF may be adjusted for Part B, following availability of Part A data; conduct 
of RO assay will be dependent on availability of a suitable assay. 
# As per 23 May 2022 SMC call, the 800mg flat dose level shall be further studied in Part B by infusion approximately every 14 days (i.e. following Table 7-1 Schedule of 
Assessments and applying Table 7-3 for PK, ADA and PD sampling), based on Part A PK data which do not indicate substantial accumulation at this dose level over time 
with this dosing interval. Optional Part A-2 of the study may explore one more higher dose level (1400mg flat dose with approximately 14-day dosing interval , i.e. following 
Table 7-1 Schedule of Assessments and applying Table 7-3 for PK, ADA and PD sampling) than was studied in Part A. Such 1400mg dose level will be explored applying strict 
stopping criteria and respecting a 28-day DLT evaluation period before more than 6 subjects are exposed. PK data for this 1400mg dose level in Part A-2 will be closely 
followed and in case of observation of relevant drug accumulation over time, the dosing interval for this dose may be adjusted to approximately every 21 days, in which case 
Table 7-2 Schedule of Assessments applies and consequently Table 7-4 would become applicable for PK, ADA and PD sampling. Such change from a 2-week to a 3-week 
dosing interval would only be applicable if communicated separately to sites by a written notification of the SMC decision on such change of dosing interval by means of a 
letter of amendment, to be followed by a full protocol amendment. 
a. 
Serial PK is optional except for the mandatory pre-dose, EOI and 168 ± 24 h sampling timepoints (see footnote “g”). 
b. If a patient permanently discontinues study drug treatment, or is not receiving an infusion at a given visit, a single PK sample will be taken at that visit. 
c. 
Optional biopsy material for patients enrolled in Part A and A-2 from as many cycles as possible, and Follow-up period. For patients in Part B a single post treatment biopsy material 
collection is considered mandatory per footnote “r” in Table 7-2, i.e., for patients presenting with at least stable disease during treatment with NM21-1480. 
d. Optional sampling point for Part B. Sites are not required to collect these optional PK samples in Part B. These sampling timepoints are, however, mandatory in Part A and Part A-
2. For sampling timepoints considered mandatory in Part B at all sites, see also footnote “g”. 
e. 
EOI: End of Infusion.  This sample should be taken immediately prior to stopping the infusion from the counter arm of the site of injection.  All subsequent timepoints indicated for 
PK blood draws refer to hours after EOI. 
f. 
For FU visits: PK and ADA sample will be taken at Follow-up Visit 1 only. 
g. Mandatory sample for all patients in Part B (unless drawing is not considered clinically feasible due to the condition of the patient). 
h. Only applicable for mCRC patients enrolled to Cohort B8. For specifics on sample acquisition please refer to specialty lab manual. 
i. 
Reference is made to footnote ff in Table 7-2 for timing of these mandatory on-treatment biopsies for mCRC patients enrolled to Cohort B8. 
j. 
Not applicable to patients in Cohort B5 randomized to standard-of-care anti-PD1 therapy only. 
k. Only applicable for mCRC patients enrolled to Cohort B8.    

 
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7.2 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
7.2.1 
Inclusion Criteria (Part A and Part B) 
Patients are eligible to be included in this study only if all of the following criteria apply: 
1. 
Patients aged 18 years or older or above minimum legal age to attend a clinical study on the 
day written informed consent is given. 
2. 
In Part A & A-2: Patients with any previously treated solid tumor-type other than 
hepatocellular carcinoma or intrahepatic cholangiocarcinoma, confirmed by available 
pathology records and/or current biopsy, that is advanced (non-resectable or metastatic), or 
recurrent and progressing since last anti-tumor therapy, and for which no alternative, standard 
therapy exists.  
In Part B (all cohorts):  
• Cohorts B1 and B7: 
o Patients with locally advanced or metastatic, non-resectable NSCLC and 
documented PD-L1 expression on ≥50% of tumor cells# (Cohort B1), or 
documented PD-L1 expression on ≥1%-49% of tumor cells# (Cohort B7) 
o Cohort B1 and B7 will be conducted in the US, Spain, UK, the Netherlands, 
Germany, and Taiwan. Patients must have received at least 1, and a maximum 
of 3, previous lines of therapy, including at least 1 previous line containing a 
PD-(L)1 checkpoint inhibitor. For patients enrolled to Cohorts B1 and B7 
in Germany, they must have received both an anti-PD-(L)1 therapy and a 
platinum-based chemotherapy (i.e., at least 2 prior lines of treatment) to 
be eligible for study entry. 
o Patients must have disease that is resistant (i.e., primary resistant&) or 
refractory (i.e., secondary resistant&) to anti-PD-(L)1 therapy as defined by: 
a) 
Has received at least 2 doses of an approved anti-PD-(L)1 monoclonal 
antibody. 
b) Has demonstrated progressive disease after anti-PD-(L)1 therapy as 
defined by RECIST 1.1, which was subsequently confirmed by a second 
assessment no less than 4 weeks from the date of the first documented 
progressive disease to rule out pseudo-progression, if the latter could not 
be excluded by the investigator based on the initial imaging demonstrating 
disease progression. 

 
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# Prospective testing is not done for Cohort B1 and B7, i.e., inclusion relies on 
documented previous testing leading to initiation of anti-PD-(L)1 therapy.  
& Primary vs. secondary resistance will be determined based on documented 
progression of patients following less than or at least 24 weeks on previous anti-
PD-(L)1 therapy. 
• Cohort B2: 
o Patients with locally advanced or metastatic, non-resectable HPV-associated 
(i.e., HPV+ tumor) SCC of the anus, cervix, vulva, vagina, penis or oropharynx 
with documented PD-L1 expression on at least 1% of tumor and/or immune 
cells in the TME, as detected by a locally-assayed, FDA-cleared PD-L1 test or 
any PD-L1 test approved for use by local competent authority 
o Cohort B2 will be conducted in the US, Spain, UK, the Netherlands, Germany, 
and Taiwan. For Cohort B2, disease progression must have been documented 
following 
a 
first-line 
standard-of-care 
anti-PD-1 
monotherapy, 
anti-PD-1/chemotherapy or chemotherapy regimen or 2 previous lines of 
therapy including one line of anti-PD-1 checkpoint inhibitor therapy and one 
line of chemotherapy. Patients must: 
a) 
Either have documented previous testing results indicating HPV positivity 
for the current tumor or, in absence of a positive previous HPV test result, 
the current tumor must be tested positive for HPV applying the local 
standard testing approach. 
b) Have demonstrated progressive disease after standard first-line, or first- 
and second-line therapy, as defined by RECIST 1.1, or in the view of the 
Investigator be ineligible or unwilling to be treated with standard first- or 
second-line therapy. 
NOTE: A maximum of 10 patients with oropharyngeal SCC and a minimum of 
15 patients with cervical SCC and 15 patients with anal SCC, respectively, will 
be enrolled within the total of 40 patients in this cohort. 
• Cohort B3: 
o Patients with locally advanced or metastatic, non-resectable NSCLC and 
documented PD-L1 expression on ≥50% of tumor cells 
o  Cohort B3: will be conducted in Turkey, Georgia, Ukraine, and Taiwan. For 
Cohort B3, standard-of-care first-line treatment is defined as: standard local 
first-line chemotherapy. Patients must have demonstrated progressive disease 
after standard-of-care local first-line therapy, as defined by RECIST 1.1. PD-

 
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L1 expression on tumor cells is determined centrally by a Sponsor-approved 
PD-L1 assay 
• Cohort B4: 
o Patients with recurrent, persistent or metastatic ovarian, primary peritoneal or 
fallopian tumor carcinoma of all histologic types, except mucinous 
adenocarcinoma and carcinosarcoma, with documented disease progression 
(disease not amenable to curative therapy) and a history of primary platinum-
based chemotherapy 
o Cohort B4 will be conducted in the US, Spain, UK, the Netherlands, Germany, 
Taiwan, Turkey, Georgia, and Ukraine. For Cohort B4, patients must have a 
history of primary platinum-based chemotherapy with a maximum of 3 prior 
cytotoxic regimens and with at least one regimen for recurrent disease 
containing a platinum or a taxane for those with 3 prior regimens; the last 
platinum-free interval must be ≤12 months. Histologic confirmation of the 
original primary tumor is required via the pathology report. NOTE: Patients 
with mucinous or carcinosarcoma history are not eligible. 
o Patients are allowed to have received up to 3 prior cytotoxic regimens for 
treatment of their epithelial ovarian, fallopian tube, or primary peritoneal 
cancer;  
 they must have had one prior platinum-based chemotherapeutic 
regimen for management of primary disease, which could 
include 
intra-peritoneal 
therapy, 
consolidation, 
biological/targeted (non-cytotoxic) agents or extended therapy 
(maintenance/consolidation) administered after surgical or non-
surgical assessment;  
 patients are allowed to have received, but are not required to 
have received, one to 2 cytotoxic regimens for management of 
recurrent or persistent disease;  
 PARP inhibitors given for recurrent or progressive disease will 
be considered cytotoxic;  
 PARP inhibitors given as maintenance therapy in continuation 
with management of primary disease will not be considered as 
separate cytotoxic regimen;  
 if 2 cytotoxic regimens had been received for management of 
recurrent or persistent disease, one of these regimens would have 
had to contain either a platinum or a taxane agent 

 
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o Platinum-free interval (PFI) – patients must have progressed ≤12 months after 
completion of their last platinum-based chemotherapy; the date (PFI) should 
be calculated from the last administered dose of platinum therapy to 
documentation of progression 
• Cohort B5: 
o Patients with head and neck squamous cell cancer with documented CPS ≥1 in 
the TME and as determined by an FDA-cleared* or any PD-L1 test approved 
for use by competent authority 
o Cohort B5 will be conducted in the US, Spain, UK, the Netherlands, and 
Taiwan. For Cohort B5, patients must have metastatic or unresectable, 
recurrent disease considered incurable by local therapies. Patients must qualify 
for in-label first-line, single-agent treatment with an approved anti-PD1 
checkpoint inhibitor and as per investigator judgement would also be put on 
such treatment as part of standard-of-care, i.e., irrespective of clinical trial 
participation, at doses not exceeding those approved in local product labels. 
* FDA-cleared tests include: PD-L1 IHC 22C3 (Dako; preferred assay), 
VENTANAPD-L1 (SP142; Ventana/Roche), and PD-L1 IHC 28-8 (Dako, 
VENTANA PD-L1 (SP263; Ventana/Roche), or any other companion 
/complementary diagnostic PD-L1 assay that may receive FDA approval 
during the conduct of this study. 
• Cohort B6: 
o Patients with TNBC according to current ASCO/CAP guidelines that is 
measurable according to RECIST1.1 criteria 
o Cohort B6 will be conducted in the US, Spain, UK, the Netherlands, and 
Taiwan. For Cohort B6, patients must have metastatic disease or locally 
advanced breast cancer (beyond curative management). 
o TNBC must be characterized as having ≤1% cellular expression of ER and PR 
as determined by IHC and having HER2 expression of 0 to 2+ by IHC as per 
current ASCO/CAP Guidelines. If IHC 2+, a negative in situ hybridization test 
(preferably FISH; CISH or SISH acceptable) is required by local laboratory 
testing 
o Patients must have received at least one line of previous systemic therapy for 
advanced breast cancer (chemotherapy or targeted therapy allowed); however, 
patients must not have received mor than 3 previous lines of cytotoxic 
chemotherapy (i.e., targeted agents not counting as previous line in this 
context) 

 
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o 20 patients in the cohort must have received prior therapy with an immune 
checkpoint inhibitor (i.e., an approved PD-1 or PD-L1 antibody), while the 
other 20 patients must not have received prior therapy with an immune 
checkpoint inhibitor (as per stratification) 
• Cohort B8: 
o Cohort B8 will be conducted in the US, Spain, UK, the Netherlands, and 
Germany. Patients with metastatic, non-resectable colorectal cancer (mCRC) 
that is MSS or MSI low*, previously treated with all of the following: 
 fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, 
 and, if RAS wild-type, an anti-EGFR therapy, if eligible 
 Patients previously treated with an additional anti-VEGF biological 
therapy are also eligible 
o Patient agrees to paired biopsies and is judged by the investigator as safe for 
paired biopsies 
o Patients must have documented PD-L1 expression in the TME with PD-L1 
expressed on at least 1% of tumor and/or immune cells, as detected by local 
testing with an FDA-cleared or any PD-L1 assay approved for use by local 
competent authority*. 
*Eligibility determination can be done based on documented previous testing results. If no 
previous testing result is available eligibility determination will be done based on archival 
tissue or fresh biopsy taken during screening 
3. 
Patients must provide tumor tissue (archival or fresh acquisition) at Screening for biomarker 
and PD evaluation.  Archival tissue sample can be formalin-fixed paraffin-embedded (FFPE) 
tissue block(s) obtained within 5 years (for B cohorts: 2 years) before Screening (preferably 
within 12 months) or (at least 20) freshly sectioned unstained slides with tumor tissue present 
as per pathologist confirmation. Availability of tissue blocks is preferred over slides. 
Acceptable tissue sample include core needle punctured, resected or incisional biopsy, or 
surgical sample. (Note, fine needle aspirate (FNA) sample and tumor tissue from bone 
metastasis are not acceptable). Fresh biopsy should not be obtained from RECIST-defined 
target lesions if possible. Consult the Medical Monitor when no other lesions are suitable for 
biopsy, or in cases where archival tissue was obtained outside the above-specified timeframes, 
as exceptions may be approved on a case-by-case basis.  
4. 
Cohort B8: For biomarker and PD evaluation, MSS or MSI low mCRC patients enrolled must 
mandatorily provide freshly acquired tumor tissue (primary tumor or metastases) at Screening 
and – whenever considered clinically feasible as per investigator judgement – at least once 

 
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while on treatment. Acceptable tissue sample include core needle punctured, resected or 
incisional biopsy, or surgical sample. (Note, FNA sample and tumor tissue from bone 
metastasis are not acceptable). Fresh biopsy should not be obtained from RECIST-defined 
target lesions if possible. Consult the Medical Monitor when no other lesions are suitable for 
biopsy. At least 3 biopsy cores, but preferably more if considered safe by the radiologist, shall 
be taken at each biopsy event and touch preparation as per site standard approach shall be 
applied to ensure specimen adequacy (i.e., confirm tumor content). In addition to these fresh 
biopsies, for patients for whom there is archival primary tumor tissue available, this archival 
tissue, as per inclusion criterion #3 requirements, shall also be provided for biomarker 
analysis. 
5. 
Part A: Patients with liver metastases may be enrolled provided that less than 50% of the 
liver is involved according to the judgement of the Investigator. 
6. 
ECOG performance status 0 or 1. 
7. 
Life expectancy ≥12 weeks. 
8. 
Must have at least 1 measurable lesion per RECIST 1.1 that is progressing or new since last 
anti-tumor therapy.  The measurable lesion(s) can be inside the field of prior radiotherapy 
(RT) provided that the lesion has documented progression post RT as per RECIST 1.1. 
9. 
Part A & A-2: Prior chemotherapy or systemic radiotherapy (for immunotherapy see 
exclusion criteria) must have been completed at least 4 weeks prior to the administration of 
the first dose of study drug, and patient has recovered to Common Terminology Criteria for 
Adverse Events (CTCAE) V5.0 Grade 1 or better from all AEs associated with prior therapy 
or surgery (however, sensory neuropathy, alopecia and endocrine disorder treated with 
hormone replacement ≤Grade 2 is acceptable). 
Part B: For Cohort B1, B2, B6 (subgroup with required previous checkpoint inhibitor 
therapy) and B7: Last dose of therapy with anti-PD-1 monotherapy must have been received 
at least 2 weeks prior to the administration of the first dose of the study drug. All Part B 
Cohorts (while not applicable to Cohort B5): Prior chemotherapy must have been completed 
at least 4 weeks prior to the administration of the first dose of study drug.  Exceptions: 
Hormone (e.g., thyroid hormone) replacement therapy.   
10. Prior treated brain or meningeal metastases must be without magnetic resonance imaging 
(MRI) evidence of progression for at least 8 weeks and off immunosuppressive doses of 
systemic steroids (>10 mg/day prednisone or equivalent) for at least 2 weeks prior to the 
administration of the first dose of study drug; patients must be without neurologic dysfunction 
that would confound the evaluation of neurologic and other AEs (patients with a history of 
carcinomatous meningitis are not eligible). 

 
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11. Part A & A-2: Breast cancer patients who are receiving adjuvant hormonal therapy are 
eligible. 
12. Prior systemic RT must have been completed at least 4 weeks prior to the administration of 
the first dose of study drug.  Prior focal radiotherapy must have been completed at least 2 
weeks before first study drug administration. No radiopharmaceuticals (strontium, samarium) 
must have been used within 8 weeks prior to the administration of the first dose of study drug. 
13. Immunosuppressive medication including immunosuppressive doses of systemic steroids or 
absorbed topical steroids (doses >10 mg/day prednisone or equivalent) must be discontinued 
at least 2 weeks prior to the administration of the first dose of study drug. 
14. Prior major surgery that required general anesthesia must be completed at least 2 weeks prior 
to the administration of the first dose of study drug; minor surgical procedures (such as e.g. 
laparoscopy, endoscopy, port insertion etc.) conducted under general anesthesia or surgery 
requiring regional/epidural anesthesia must be completed at least 72 hours prior to the 
administration of the first dose of study drug and patients should be recovered.  Cutaneous 
biopsies with only local anesthesia should be completed at least 1 hour prior to the 
administration of the first dose of study drug. 
15. Screening laboratory values must meet the following criteria: 
• Hematological: 
o White blood cell (WBC) ≥2.0×109/L 
o Absolute neutrophil count (ANC) ≥1.5×109/L 
o Lymphocyte count ≥0.5×109/L 
o Platelets ≥100×109/L 
o Hemoglobin ≥9 g/dL 
• Renal: serum creatinine ≤1.5 × upper limit of normal (ULN) or calculated using the 
Cockcroft-Gault formula or measured creatinine clearance >50 mL/min. 
끫롲𝐹𝐹𝐹𝐹𝐹𝐹끫롲𝐹𝐹 끫뢠𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 끫뢠𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐끫뢠𝑐𝑐
=
(140 −𝑎𝑎𝑎𝑎𝑎𝑎 𝑖𝑖𝑖𝑖 끫료𝑦𝑦𝑦𝑦𝑦𝑦끫료) ×  weight (kg) ×  0.85
72 ×  serum creatinine in mg/끫뢢𝑑𝑑
 
 
끫뢀𝑀𝑀𝑀𝑀𝑀𝑀 끫뢠𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 끫뢠𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐끫뢠𝑐𝑐
= (140 −𝑎𝑎𝑎𝑎𝑎𝑎 𝑖𝑖𝑖𝑖 끫료𝑦𝑦𝑦𝑦𝑦𝑦끫료) ×  weight (kg) ×  1.00
72 ×  serum creatinine in mg/끫뢢𝑑𝑑
 
• Hepatic: 

 
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o Total bilirubin ≤1.5×ULN (except patients with Gilbert’s syndrome, who must have 
total bilirubin ≤3.0×ULN) 
o AST and ALT ≤2.0×ULN 
o Cohort B8:  
 Serum albumin ≥30 g/L (3.0 g/dL) 
 Lactate dehydrogenase ≤2.5xULN  
• Coagulation: 
o International Normalized Ratio or Prothrombin time (PT) ≤1.5×ULN unless patient is 
receiving anticoagulant therapy as long as PT or Partial Thromboplastin Time (PTT) 
is within therapeutic range of intended use of anticoagulants based on the institutional 
standard-of-care  
o Activated Partial Thromboplastin Time ≤1.5×ULN unless patient is receiving 
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants based on the institutional standard-of-care 
• Thyroid stimulating hormone (TSH) is required to be within normal limits at baseline; 
however, if TSH is not within normal limits at baseline, the patient may still be eligible if 
total triiodothyronine (T3) or free T3 and free thyroxine (T4) are within the normal limits. 
16. Female patients must have a negative serum pregnancy test within 72 hours prior to the 
administration of the first dose of study drug if of child-bearing potential or be of 
non-child-bearing potential.  In case of a positive serum pregnancy test, the site is allowed to 
apply standard site procedures to rule out false positive test results; enrollment of the patient 
may be considered only in case of false positivity of the serum pregnancy test has been 
confirmed. A urine pregnancy test is to be done prior to dosing at all other time points and 
must be negative prior to the administration of the first dose of study drug.  
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required.  The serum pregnancy test must be negative for the patient to be eligible for 
continued treatment with the study medication.  Non-child-bearing potential is defined as (by 
other than medical reasons): 
• ≥45 years of age with continuous amenorrhea for >2 years and a follicle stimulating 
hormone (FSH) of >40 IU/L upon pre-study (Screening) evaluation. 
• Women who were surgically sterilized, i.e., had a hysterectomy and bilateral 
oophorectomy, or have a documented permanent female sterilization procedure including 
tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with 
medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation 

 
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must be confirmed with medical records of the actual procedure otherwise the patient must 
be willing to utilize a reliable form of contraception (either medication – oral, implant or 
injection – or a barrier method). In general, the decision for appropriate methods to prevent 
pregnancy should be determined by discussions between the Investigator and the study 
patient. A FSH level can be used to confirm post-menopausal status in amenorrheic 
patients not on hormonal therapy. 
• Women of child-bearing potential (WOCBP) must agree to use a highly effective method 
of contraception (i.e. pregnancy rate of less than 1% per year) during the study Treatment 
Period and for 180 days following the last dose of study drug. 
17. Men who have female partners of child-bearing potential must agree to the use of 
contraception during the study Treatment Period and for at least 180 days after the last dose 
of study drug (see Appendix V, Section 18.5). 
18. No active bleeding. 
19. Able to understand and give written informed consent and comply with study procedures. 
20. Part A-2: Documented minimal PD-L1 expression on at least 1% of tumor and/or immune 
cells in the TME, as detected by a local testing with an FDA-cleared or any PD-L1 assay 
approved for use by local competent authority. 
21. Part B: Must have received complete Covid-19 vaccination within the timeframe considered 
to provide protection at the time of study enrollment according to current local guidelines, or 
must have a negative Covid-19 test polymerase chain reaction (PCR) test result. 

 
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7.2.2 
Exclusion Criteria (Part A and Part B) 
Patients are excluded from the study if any of the following criteria apply: 
1. 
Patient previously had known immediate or delayed hypersensitivity reaction or idiosyncrasy 
to the excipients (refer to Appendix I, Section 18.1) of IP or has experienced ≥Grade 3 
immune-related adverse events (irAEs) with previous CPI therapy. 
2. 
Prior (other) malignancy active within the previous 2 years (any prior malignancy for which 
there were detectable lesions [solid tumors] or for which the patient was not considered to be 
in complete remission [liquid tumors] or for which there was ongoing curative treatment) 
except for locally curable cancers that have been apparently cured, such as basal or squamous 
cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast.  
3. 
In Part A & A-2: Treatment with any antibody targeting PD-1, CTLA-4, 4-1BB or PD-L1 or 
other investigational biological drugs within 5 half-lives of that antibody prior to the 
administration of the first dose of study drug (or within 8 weeks if the half-life is not known).  
In Part B: 
• Cohorts B1 and B7 −  NSCLC and documented PD-L1 expression on ≥50% of tumor cells 
(Cohort B1) or documented PD-L1 expression  on ≥1%-49% of tumor cells (Cohort B7): 
o Treatment with any PD-1 antibody within 2 weeks prior to first dose of study drug 
o Treatment with any PD-L1-directed therapy within 5 (five) half-lives of the respective 
drug; if the half-life of the respective PD-L1 antibody is unknown, treatment with such 
a PD-L1 antibody within 12 weeks prior to the first dose of study drug is exclusionary. 
o Previous treatment with a PD-(L1)x4-1BB specific antibody or any other treatment 
targeting 4-1BB 
o Patient who for the treatment of the current cancer has received any other treatment 
than anti-PD-(L)1 or chemotherapy within 28 days prior to initiation of the study drug 
or who has not recovered to CTCAE V5.0 Grade 1 or better from the AE due to anti-
PD-(L)1 administered earlier; in addition, patients with any ongoing Grade 1 or higher 
AE of colitis, hepatitis, nephritis, or pneumonitis considered to be related to previous 
anti-PD-(L)1 therapy is exclusionary. However, sensory neuropathy ≤Grade 2, 
alopecia and endocrine disorder treated with hormone replacement is acceptable. 
• Cohort B2 −  HPV-associated (i.e. HPV+ tumor) SCCs: 
o Patients who, for the treatment of the current cancer, has received any treatment other 
than anti-PD-1 or a platinum-based chemotherapy regimen recommended as first-line 
or second-line treatment by current National Comprehensive Cancer Network 
(NCCN) treatment guidelines or who has not recovered to CTCAE V5.0 Grade 1 or 

 
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better from the AE due first-line or second-line treatment; in addition, patients with 
ongoing Grade 1 or higher AE of colitis, hepatitis, nephritis, or pneumonitis 
considered to be related to previous anti-PD-1 therapy is exclusionary. However, 
sensory neuropathy ≤Grade 2, alopecia and endocrine disorders treated with hormonal 
replacement are acceptable. 
o Treatment with PD-1 antibody within 2 weeks prior to first dose of study drug 
• Cohort B3 −  NSCLC and documented PD-L1 expression on ≥50% of tumor cells:  
o Patients who, for the treatment of the current cancer, has received any treatment other 
than a local standard-of-care first-line chemotherapy regimen or who has not 
recovered to CTCAE V5.0 Grade 1 or better from the AE due first-line treatment. 
However, sensory neuropathy ≤Grade 2, alopecia and endocrine disorders treated with 
hormonal replacement are acceptable. 
o Patient has received a PD-1, PD-L1, 4-1BB or CTLA-4 antibody or any other 
investigational biological drugs for treatment of the current cancer. 
o Patients with epithelial growth factor receptor (EGFR) tyrosine kinase activating 
mutations or anaplastic lymphoma kinase (ALK) rearrangements. Patients with EGFR 
inactivating mutations (e.g., exon 20) may be eligible. 
• Cohort B4 − ovarian, primary peritoneal or fallopian tumor carcinoma: 
o Patients who have had prior therapy with anti-PD1, anti-PD-L1, anti-4-1BB or 
anti-CTLA-4 antibodies or any other antibody or drug specifically targeting T-cell 
co-stimulation or immune checkpoint pathways. 
o Patients who have received prior chemotherapy for any abdominal or pelvic tumor 
other than for treatment of ovarian, fallopian tube, or primary peritoneal cancer within 
the last 3 years; patients may have received prior adjuvant chemotherapy and 
radiotherapy for localized breast cancer, provided that it was completed more than 
2 years prior to consenting to this study, the patient remains free of recurrent or 
metastatic disease and hormonal therapy has been discontinued; patients who have 
received prior radiotherapy to any portion of the abdominal cavity or pelvis or thoracic 
cavity within the last 3 years are excluded; prior radiation for localized cancer of the 
head and neck or skin is permitted, provided that it was completed more than 3 years 
prior to consenting to this study, and the patient remains free of recurrence or 
metastatic disease.  
• 
Cohort B5 − head and neck squamous cell cancer with documented CPS≥1: 
o Patients who have previously received a checkpoint inhibitor for their disease 
• 
Cohort B6 − TNBC: 

 
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o For patients in the subgroup in which previous therapy with a checkpoint inhibitor is 
required: 
 Treatment with PD-1 antibody within 2 weeks prior to the first dose of 
study drug 
 Treatment with PD-L1 antibody within 5 half-lives prior to first dose of 
the study drug. If the half-life of a previously used anti-PD-L1 antibody is 
unknown, the Medical Monitor must be contacted. 
 Patient who has not recovered to CTCAE V5.0 Grade 1 or better from the 
AE due to anti-PD-1 or anti-PD-L1 antibody administered earlier; in 
addition, patient with any ongoing Grade 1 or higher AE of colitis, 
hepatitis, nephritis, or pneumonitis considered to be related to previous 
anti-PD-1 or anti-PD-L1 therapy is exclusionary. However, sensory 
neuropathy ≤Grade 2, alopecia and endocrine disorder treated with 
hormone replacement are acceptable 
 Previous treatment with anti-CTLA-4 or anti-4-1BB antibody or drug 
specifically targeting T-cell co-stimulation or immune checkpoint 
pathways other than the PD-1/PD-L1 pathway 
o For patients in the subgroup in which previous therapy with a checkpoint inhibitor is 
prohibited: 
 Patients who had prior therapy with anti-PD-1, anti-PD-L1, anti-4-1BB or 
anti-CTLA-4 antibodies or any other antibody or drug specifically 
targeting T-cell co-stimulation or immune checkpoint pathways 
• Cohort B8 − mCRC: 
o Patients who have previously been treated with trifluridine/tipiracil or regorafenib 
o Patients who have previously been treated with T-cell bispecifics, 4-1BB agonists, or 
immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD1 and anti-
PD-L1 unless discussed with the Medical Monitor and agreed by the Sponsor 
o Patients who have received treatment with systemic immunostimulatory agents 
(including, but not limited to, interferon and IL-2) within 4 weeks or 5-half lives, 
whatever is longer, prior to initiation of NM21-1480 treatment 
o Patients who have received treatment with systemic immunosuppressive medication 
(including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, 
methotrexate, thalidomide, and anti-TNFalpha medications) within 2 weeks prior to 
initiation of NM21-1480 treatment, or anticipation of need for systemic 
immunosuppressive medication* during NM21-1480 treatment  

 
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o Presence of ascites that required two or more therapeutic paracenteses in the last 30 
days 
4. 
Patient is currently participating in a study of an investigational agent or using an 
investigational device within 4 weeks prior to the administration of the first dose of study 
drug (see further specification in exclusion criterion 5 and 6). 
5. 
Use of small molecule-based therapy within at least 5 half-lives based on last dose of the small 
molecule therapy or 4 weeks (if half-life of the small molecule drug is not known) prior to the 
administration of the first dose of study drug. 
6. 
In Part A & A-2: Use of other biological investigational drugs (drugs not marketed for any 
indication), including use of investigational drugs targeting CD137/4-1BB, PD-1 or PD-L1 
within at least 5 half-lives (or within 8 weeks, if half-life of that investigational drug is not 
known) prior to the administration of the first dose of study drug.  
7. 
Patient is expected to require any other form of systemic or localized antineoplastic therapy 
(i.e., chemotherapy, hormonal therapy, immunotherapy, extensive, non-palliative RT, or 
standard or investigational agents for treatment of malignancy) while on study. 
8. 
Concurrent medical condition requiring the use of systemic immunosuppressive medications. 
9. 
Any botanical preparation (e.g., herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study or provide supportive care.  Use of marijuana and its 
derivatives for treatment of symptoms related to cancer or cancer treatment are permitted if 
obtained by medical prescription or if its use (even without a medical prescription) has been 
legalized locally (also refer to exclusion criterion 23). 
10. Patient has an active autoimmune disease or a documented history of autoimmune disease that 
required systemic therapy within 5 years prior to screening. Patients with documented history 
of autoimmune disease who required therapies other than dietary modification for disease 
control within 5 years prior to screening must be discussed with the Medical Monitor to 
determine eligibility status, except for the following cases which are not exclusionary: 
a) Patients with vitiligo, autoimmune thyroiditis, or psoriasis (not requiring systemic 
treatment within the past 2 years); b) Type I diabetes controlled with stable insulin therapy; 
c) Childhood asthma/atopy which, in the view of the investigator, has resolved; d) Patients 
that require intermittent use of bronchodilators, inhaled steroids or local steroid injections 
including intra-articular injections; e) Patients with hypothyroidism stable on hormone 
replacement.   
11. In Part A & A-2: Patients with active or known history of hepatitis (viral or non-viral) or 
liver cirrhosis, colitis, non-infectious pneumonitis or interstitial lung disease; patient with 
hepatocellular carcinoma or intrahepatic cholangiocarcinoma. 

 
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In Part B: Patients with active or known history of hepatitis (viral or non-viral) or liver 
cirrhosis, colitis, non-infectious pneumonitis or interstitial lung disease. Patients who have 
received curative anti-viral treatment for hepatitis C may be eligible but must be discussed 
with and approved by the Medical Monitor prior to inclusion into the study. 
12. Patient with an active infection requiring systemic therapy (antibiotics, antivirals or 
antifungals) or for whom based on screening results initiation of systemic anti-infective 
therapy is indicated in the opinion of the Investigator. 
13. Patient who are seropositive for human immunodeficiency viruses (HIV) and have CD4 T-cell 
counts below 350 cells/mcL or with a history of AIDS-defining opportunistic infections. 
14. Patients who have a known history of or are seropositive for hepatitis B or hepatitis C. Patients 
who have received curative anti-viral treatment for hepatitis C may be eligible but must be 
discussed with and approved by the Medical Monitor prior to inclusion into the study. 
15. Patient with active or known latent tuberculosis. 
16. At time of Screening, patient has an uncontrolled cardiovascular, liver or lung disease, 
myelodysplastic syndrome, neurologic or psychiatric disorder, laboratory abnormality, acute 
infectious disease, or other systemic disease, which the Investigator determines will make the 
administration of study drug hazardous or obscure the interpretation of toxicities or AEs. 
17. Grade >1 QTc prolongation at baseline (>480 msec by Bazett formula) confirmed by a repeat 
electrocardiogram (ECG). 
18. Patients with a history of venous thrombosis within the past 6 months prior to the 
administration of the first dose of study drug. 
19. Patients with a diagnosis of acute coronary syndrome including myocardial infarction or 
unstable angina pectoris, other arterial thrombotic event including cerebrovascular accident 
or transient ischemic attack or stroke within the past 12 months prior to the administration of 
the first dose of study drug. 
20. Patients with congestive heart failure with New York Heart Association Class II or greater 
diagnosis, serious cardiac arrhythmia requiring medication, or uncontrolled hypertension 
(≥160 mmHg systolic and/or ≥100 mmHg diastolic, despite appropriate antihypertensive 
medication). 
21. Patients with a history of hypertensive crisis/hypertensive encephalopathy within the past 
12 months prior to the administration of the first dose of study drug. 
22. Patient has known psychiatric or substance (including alcohol) abuse disorders that would 
interfere with cooperation with the requirements of the study per the determination of the 
Investigator. 

 
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23. Patient is not willing to refrain from or cannot discontinue concomitant intake of medications 
or substances known to cause elevation of liver enzymes, including e.g., acetaminophen 
(a daily dose of up to 2 g/day is allowed to manage acute pain), or systemically active 
cannabidiol (CBD); topical CBD is allowed. 
24. Patient is pregnant or breast feeding or expecting to conceive or father children within the 
projected duration of the study or for 180 days after discontinuing study drug. 
25. Patient has received a live vaccine within 30 days prior to the administration of the first dose 
of study drug. 
26. Receipt of an allogeneic stem cell transplantation or organ allograft. 
27. In Part B: Treatment with systemically active antibiotics within 14 days prior to the 
administration of the first dose of study drug. 
7.2.3 
Strategies for Recruitment and Retention 
All recruitment material will be approved by an Independent Ethics Committee (IEC) or 
Institutional Review Board (IRB) prior to implementation. 
Regular study monitoring will enable identification of any potential issues related to participant 
retention. 
7.2.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but who 
do not subsequently receive a minimum of one dose of study drug.  A minimal set of screen-failure 
information is required to ensure transparent reporting of screen-failure participants to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to queries 
from regulatory authorities.  Minimal information includes demography, screen-failure details, 
eligibility criteria, and any serious adverse event (SAE). 
7.2.5 
Stopping Rules and Decision-Making Procedure 
A BOIN design is applied in Part A.  The DLT evaluation period consists of one full treatment 
cycle, i.e., ends 28 days following the first dose administration.  The target toxicity rate for the 
MTD for the BOIN design applied is ɸ = 0.3 and the maximum sample size is 25.  The design is 
described as follows: 
1. Perform accelerated titration as follows: treat the first patient at dose level 1.  If no ≥Grade 2 
toxicity (as assessed by the Investigator to be related, probably related, or possibly related to 
the drug at any dose level) is observed, escalate the dose to the next higher level.  Continue 
this 1-patient-per-dose dose-escalation process until the first ≥Grade 2 toxicity during the DLT 
evaluation period is observed or dose level 5 (80 mg dose level) is reached.  Treat an additional 

 
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2 patients at the dose at which the first ≥Grade 2 toxicity is observed.  Hereafter, patients are 
treated in cohorts of 3 as described in steps 2 and 3. 
2. To assign a dose to the next cohort of patients, conduct dose-escalation/de-escalation according 
to the BOIN rule, which minimizes the probability of incorrect dose assignment.  Please note 
the following: 
a. 
“Eliminate” means eliminate the current and higher doses from the study to prevent 
treating any future patients at these doses because they are overly toxic. 
b. When a dose is eliminated, automatically de-escalate the dose to the next lower level.  
When the lowest dose is eliminated, stop the study for safety.  In this case, no dose should 
be selected as the MTD. 
c. 
If none of the actions (i.e., escalation, de-escalation or elimination) is triggered, treat the 
new patients at the current dose. 
d. If the current dose is the lowest dose and the rule indicates dose de-escalation, treat the 
new patients at the lowest dose unless the number of DLTs reaches the elimination 
boundary, at which point terminate the study for safety. 
e. 
If the current dose is the highest dose and the rule indicates dose-escalation, treat the new 
patients at the highest dose. 
3. Repeat step 2 until the maximum sample size of 25 is reached or stop Part A of the study if the 
number of patients treated at the current dose reaches 12. 
The first patient treated with each dose level will be observed for 48 hours after dosing for the 
occurrence of DLT before treatment of potential additional patients at this dose level can occur. 
Part A of the study was formally completed on 23 May 2022 at which occasion, based on 
availability of at least 28-day safety data for all 25 patients evaluable for BOIN in Part A, the SMC 
determined that Part A did not technically identify a MTD and that even the highest dose level 
assessed in Part A (800mg flat dose) was considered a tolerated dose. However, based on the 
finding that some patients dosed at 24-240mg in Part A developed treatment-emergent ADAs 
leading to loss of exposure, while this was not observed at the 800mg dose level, a decision was 
taken to explore one higher dose level (1400mg flat dose) in up to 10 patients within Part A-2 in 
parallel to studying the 800mg dose level in Part B. For safety evaluation of this single additional 
dose level, the target toxicity rate applied for BOIN in Part A (ɸ = 0.3) will be applied. Initially, 6 
patients will be dosed with 1400mg of NM21-1480 in Part A-2 and upon completion of the 28-
day DLT evaluation period for these six patients, as per SMC call, an additional up to 4 patients 
may be enrolled at this dose level (to end up with a maximum of 10 patients to be exposed to 
1400mg in Part A-2), applying the decision rules defined for BOIN as detailed in Table 10-2. 
Whenever after 6 patients have completed the 28-day DLT evaluation period at the 1400mg dose 
level, according to the BOIN decision rules, de-escalation from the 1400mg dose or elimination of 

 
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the 1400mg dose would be required, further enrollment into the dose level will be stopped. In such 
situation, ongoing patients who are tolerating the dose level may be continued at 1400mg flat dose 
unless the safety review mandates dose reduction in which case the dose may be reduced to 800mg 
or the patient may be discontinued from treatment based on discussion between the investigator 
and the Medical Monitor. If tolerability of the 1400mg dose allows for completion of the 28-day 
DLT evaluation period for 6-10 patients, the SMC will determine based on the BOIN decision rule 
guidance provided in Table 10-2 whether: 
• The 1400mg dose level is considered a tolerable dose and technically not considered to 
represent the MTD because BOIN would recommend further dose escalation at this point 
(i.e. ɸ ≤ 0.236) 
• The 1400mg dose level is considered a tolerable dose and to represent the MTD if ɸ > 
0.236 and ɸ≤0.3 
• The 1400mg dose level is not considered a tolerable dose (i.e. ɸ>0.3) 
However, the SMC is free to apply a more stringent definition of the MTD for ruling of the 1400mg 
dose level if deemed necessary. 
7.2.5.1 
Dose-Limiting Toxicity 
A DLT is defined as a TEAE (using CTCAE V5.0) occurring during the first 28 days of dosing, 
as follows: 
• Any death not clearly due to the underlying disease or extraneous causes 
• Hematologic AEs: 
o Febrile neutropenia, defined as ANC <1000 mm3 with a single temperature of ≥38.3°C 
or a sustained temperature of; ≥38°C for more than 1 hour; 
o Neutropenia, Grade 4 that does not resolve to Grade 1 with granulocyte macrophage-
colony-stimulating factor (CSF) or granulocyte-CSF treatment within 7 days; 
o Neutropenia or thrombocytopenia Grade 4 or higher present for >7 days, neutropenic 
infection, Grade 3; 
o Thrombocytopenia with clinically significant bleeding, Grade 3; 
o (Life-threatening) anemia, Grade 4. 
• Non-hematologic AEs: 
o Any Grade ≥3 toxicities including maximally treated (with adequate antiemetic and 
other supportive care) Grade ≥3 nausea, vomiting, or diarrhea of >72 hours duration; 
o Grade ≥3 increased AST or ALT, or satisfying Hy’s Law (i.e., AST/ALT >3× ULN 
with concomitant total bilirubin >2× ULN with no evidence of hemolysis and 

 
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alkaline phosphatase (ALP) >2 × ULN or not available), for patients with hepatic 
metastases: AST or ALT >8 × ULN or AST or ALT >5 × ULN for ≥14 days; 
o Grade ≥3 non-hematologic laboratory abnormality requiring medical treatment or 
hospitalization, Grade ≥3 fatigue present for ≥1 week; 
o Grade ≥3 electrolyte abnormality that lasts for >72 hours, unless the patient has clinical 
symptoms, in which case all Grade 3+ electrolyte abnormality regardless of duration 
counts as a DLT; 
o Grade 4 laboratory abnormalities irrespective of duration; 
o Grade 3+ irAEs except for those listed below. 
In addition, any grade drug-related toxicity (with the exception of infusion-related reactions) which 
in the judgement of the Investigator or Sponsor requires removal of the patient from the study. 
Patients who received <80% of both of the total intended Cycle 1 doses for reasons other than DLT 
will not be taken into account in the assessment of the overall DLT rate for the particular dose 
level cohort and can be replaced. 
Resumption of NM21-1480 administration for patients experiencing DLTs may be permitted 
according to the criteria described under Section “Dose Resumption”, if clinically appropriate, 
contingent on the return of the DLT to ≤Grade 0-1 severity or to baseline, and interruption or delay 
of treatment for no more than 35 days (i.e., 2 missed doses + 7 days) from the scheduled dosing 
and upon discussion with and approval by the Medical Monitor. 
The following events shall not be regarded as a DLT: 
• Grade 3 AE of tumor flare (defined as local pain, irritation, or rash localized at sites of known 
or suspected tumor) present for less than 7 continuous days 
• Grade 3 Infusion-related reaction resolving within 6 hours and controlled with medical 
management 
• Transient (≤6 hours) Grade 3 influenza-like symptoms or pyrexia controlled with medical 
management 
• Grade 3 local reaction or headache that resolves to a maximal severity of Grade 1 within 
24 hours 
• Grade 3 skin toxicity, or increase liver enzyme (AST, ALT) that resolves to a maximum 
severity of Grade 1 within 7 days after initiation of medical management 
(e.g., immunosuppressant treatment) 
• Grade 3 skin toxicity that improves to Grade 0 to 2 within 3 days 

 
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• Grade 3+ amylase or lipase elevation not associated with symptoms or clinical manifestations 
of pancreatitis does not represent a DLT 
• Grade 
3 
treatment-related 
endocrinopathy 
AEs, 
such 
as 
adrenal 
insufficiency, 
adrenocorticotrophic hormone (ACTH) deficiency, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone replacement 
(corticosteroids, thyroid hormones) or glucose-controlling agents, respectively 
• Grade 3 laboratory abnormalities that improve to ≤Grade 2 within 3 days only if asymptomatic 
and if medical intervention was not required 
Elevations of ALT/AST that are >3-fold above baseline are to be considered adverse events of 
special interest (AESI) and to be reported with SAE timelines.  The details on how to handle this 
situation are described in Appendix VI, Section “Hepatitis”.  In case of Grade 3+ hepatotoxicity, 
an initial ultrasound or image needs to be done to visualize the biliary tree and to rule out disease 
progression or occurrence of gall stones. 
DLTs must be confirmed by a SMC (consisting of study Investigators, Medical Monitor, and 
Sponsor observers) as related or relevant to treatment with NM21-1480.  Patients with occurrence 
(with the exception of those listed above) of any Grade 3 or worse AE as defined above should be 
permanently discontinued from the study.  All AEs (with the exception of those listed above) of 
the specified grades should count as DLTs except those that are clearly and incontrovertibly due 
to disease progression or extraneous causes. 
A DLT will be considered related to study drug unless there is a clear, well-documented, 
alternative explanation for the toxicity. 
All AEs that meet DLT criteria, as well as any Grade 3 or 4 infusion reactions whether or not the 
event is a DLT, must be reported as AESI within 24 hours using rapid notification procedures. 
7.2.5.2 
Stopping Rules for Delayed AEs During Dose-Escalation 
Delayed AEs fulling criteria of DLTs (i.e., occurring after the 4-week DLT evaluation period) will 
be evaluated on a case-by-case basis.  Delayed DLTs will not be used to estimate the MTD for 
dose-escalation.  However, if 2 or more delayed DLTs are noted within a dose-escalation cohort, 
further accrual in that cohort will be held pending safety analysis of the AEs. 
7.2.5.3 
Safety Stopping Rules in the Expansion Cohorts 
Safety Monitoring Committee (SMC) meetings will be held according to the SMC charter to 
evaluate the safety data in Part A-2 (optional) and Part B.  Within Part A-2, the SMC will meet 
and evaluate the DLT rate and re-consider dosing/dosing intervals whenever a patient experiences 
a DLT as well as when six patients have completed the 28-day DLT evaluation period for patients 
dosed at 1400mg flat dose in the optional Part A-2. The SMC will also meet and evaluate the DLT 
rate within Part B, whenever in a given Part B dose expansion cohort (Part B; expansion cohorts 

 
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B1-B4 and B6-B8) two patients have experienced a DLT and when a minimum of 20 patients have 
been dosed across all Part B expansion cohorts and the DLT evaluation period for all these dose 
expansion patients has been completed.  If the incidence of DLT in Cycle 1 in any Part B cohort 
is greater than 30%, the SMC may pause enrollment of that or all cohorts and re-assess the 
dose/regimen of the study drug. For Cohort B5, the SMC will also follow the same DLT evaluation 
approach for patients enrolled to the combinatorial treatment arm of Cohort B5 as described for 
Cohort A-2 above: The SMC will meet and evaluate the DLT rate and re-consider dosing/dosing 
intervals whenever a patient experiences a DLT as well as when six patients have completed the 
28-day DLT evaluation period for patients dosed at the 800mg NM21-1480 flat dose in the NM21-
1480/PD-1 checkpoint inhibitor arm. 
Enrollment into Part B may be held either if the rate of DLTs is ≥30% across all the expansion 
cohorts or if the rate of DLTs is ≥30% for a specific expansion cohort with more than 6 patients 
enrolled.  New enrollment should be held in the dose level where a ≥30% DLT rate occurs (in such 
cases, however, lower dose level expansion may continue).  Patients who are tolerating a study 
drug dose level that is being reviewed due to DLTs that occurred in other patients will not be 
automatically precluded from continued dosing during this safety review, and will be allowed to 
continue dosing for as long as it is tolerated unless the safety review mandates dose reduction.  
After safety analysis by the Investigators and the Sponsor, a decision will be made by the SMC 
whether to resume enrollment into Part B cohorts and continue dosing at the current dose or 
continue the expansion cohort at a lower NM21-1480 dose.  The SMC will also periodically (at 
least every 6 months, with details described in the SMC charter) review delayed DLTs, while 
enrollment will be held and/or restarted using the same rules as that for DLTs (i.e., based on a 
≥30% DLT rate). 
For expansion Cohort B5, patients randomized to the NM21-1480/PD-1 checkpoint inhibitor arm 
will be treated with the 800mg flat dose of NM21-1480. Once 6 patients have been enrolled to the 
combination treatment arm, enrollment to the cohort will be put on hold until the safety data for 
the 28-day DLT evaluation period for these six patients have been reviewed by the SMC. At this 
point, the SMC will determine whether the 800mg NM21-1480 represents a tolerable dose in the 
combinatorial setting applied in Cohort B5, following the below guiding BOIN principles provided 
in Table 10-2: 
• The 800mg dose level is considered a tolerable dose and technically not considered to 
represent the MTD in this combinatorial setting because BOIN would recommend further 
dose escalation at this point (i.e. ɸ ≤ 0.236) 
• The 800mg dose level is considered a tolerable dose and to represent the MTD in this 
combinatorial setting if ɸ > 0.236 and ɸ≤0.3 
• The 800mg dose level is not considered a tolerable dose (i.e. ɸ>0.3) 

 
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However, the SMC is free to apply a more stringent definition of the MTD for ruling of the 800mg 
dose level of NM21-1480 in the combinatorial setting applied in Cohort B5 if deemed necessary. 
Should the SMC, upon review of the 28-day safety data for the first six patients enrolled to the 
combinatorial arm of Cohort B5 conclude that the 800mg dose is not considered tolerable in this 
setting, Cohort B5 will be stopped. However, if the SMC concludes at this point that the 800mg 
dose of NM21-1480 represents a tolerable dose, enrollment into Cohort B5 may be resumed. 
Following SMC review of the 28-day safety data for the first six patients enrolled to the 
combinatorial arm of Cohort B5, the same safety stopping rules will apply as described for Cohorts 
B1-B4 and B6-B8 above. 
7.2.5.4 
Stopping Rules for Futility in the Expansion Cohorts 
A BOP2 design is applied for Part B, Cohorts B1 through B4, and B6 through B8 which includes 
an interim futility analysis conducted after 25 patients have been enrolled and treated in the 
respective cohort(s).  This futility analysis will be conducted based on availability of response data 
following completion of the first 2 RECIST 1.1 and iRECIST assessments (i.e., when 12 weeks of 
imaging data is available) for the 25 patients.  The Sponsor in consultation with the SMC will 
determine at this point whether the cohort shall be stopped or continued.  Go/no-go criteria based 
on posterior probability will be applied as specified in Table 10-6. For Cohort B8, the Sponsor will 
hold enrollment to the Cohort after 25 patients have received at least one dose of NM21-1480 
treatment until all relevant safety, efficacy, PK, immunogenicity and most prominently all relevant 
PD data that has accrued until then has been reviewed by the Sponsor and the SMC. After this 
interim review, the Sponsor may decide to stop the cohort, to continue with full enrollment of the 
cohort or revise eligibility criteria before the remaining 15 patients in the cohort are enrolled. 
The go/no-go criteria of the BOP2 are non-binding though, in particular as an ORR of 10% in the 
patient population assessed may already be considered a clinically meaningful result by the 
Sponsor e.g., based on clinical subgroup and/or biomarker data.  Futility analyses will be done 
based on availability of 12 weeks data.  The data monitoring committee (DMC), consisting of 
Sponsor representatives will determine whether a cohort shall be stopped or continued after the 
interim analysis. 
In case (a) cohort is not stopped for futility after the interim analysis, enrollment continues until 
40 patients per cohort have been enrolled and treated.  A final analysis will then be conducted after 
initial response data (i.e., based on availability of 12-week data) for the total (maximum) of 
40 patients for a given cohort is available. Part A study data discussed with SMC on 23 May 2022 
demonstrated the development of treatment-emergent anti-drug-antibodies (ADAs) in a relevant 
fraction of patients dosed at 24mg-240mg. These ADAs were typically associated with rapid 
elimination of NM21-1480 from the circulation and loss of exposure. However, PK, PD, receptor 
occupancy and clinical activity data available for the 800mg dose level indicated that at this dose, 
the issue of loss of exposure was no longer present while full pharmacodynamic activity was 

 
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maintained, a phenomenon described for other checkpoint inhibitors (i.e. atezolizumab) at higher 
doses as well. As such, the SMC agreed with the Sponsor to further study the 800mg dose level as 
the presumptive RP2D, applying a biweekly dosing interval in Part B of the study. 
For Cohort B5, an interim analysis will be performed after a minimum of 60 patients have been 
enrolled. At this point recruitment will be paused, the accumulated data analysed and regulatory 
authorities consulted. At the interim analysis the cohort will be regarded as futile (non-binding) if 
the probability of observing a difference in estimated effects between control and treatment of at 
least 15% is less than 0.1. However, as with the other cohorts, decisions at the interim point will 
be taken based on clinical and regulatory input and not formal statistical testing. 
7.2.6 
Withdrawal of Participants 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time or may be withdrawn at the discretion of the Investigator for safety, behavioral, compliance, 
or administrative reasons. 
Withdrawal of consent occurs when a participant does not want to participate in the study anymore 
and does not want to attend any further visits or assessments, have further study-related contact, 
or allow analysis of already obtained biologic material.  If a participant withdraws from the study, 
they may request destruction of any samples taken and not tested, and the Investigator must 
document this in the site study records.  If the participant withdraws consent for disclosure of 
future information, the Sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 
If a patient is withdrawn from the study (during the Treatment or Follow-up period), all evaluations 
associated with that study visit should be performed and the date and reason for study 
discontinuation should be documented on the electronic case report form (eCRF).  For patients 
that are withdrawn while in the treatment period for reasons other than disease progression, every 
effort should be made to continue monitoring their disease status by radiologic imaging at FU2 or 
FU3 or until (1) the start of new anticancer treatment, (2) disease progression, (3) death, or (4) the 
end of the study, whichever occurs first. If a participant withdraws consent, the Investigator must 
make every effort to determine the primary reason for this decision, should obtain written notice 
of the decision from the patient, if possible, should document the decision in source and 
additionally record this information on the treatment disposition eCRF page.  If the participant 
decides to completely withdraw from the study (refuses any further study participation or contact), 
all study participation for that participant will cease and data to be collected at subsequent visits 
will be considered missing.  Investigational treatments must be discontinued and no further 
assessments conducted.  Further attempts to contact the participant are not allowed unless safety 
findings require communication or follow-up. 

 
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However, for safety reasons, visit should be conducted as far as possible if the withdrawn 
participant is willing to undergo the assessments. 
The Investigator must also contact the interactive web response system service to register the 
participant’s discontinuation from investigational treatment. 
7.2.7 
Lost to Follow-up 
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the participant.  Lost to follow-up is 
defined by the inability to reach the participant after a minimum of 3 documented phone calls, 
faxes or emails (not performed on the same day), as well as a lack of response by the participant 
to one registered mail letter.  All attempts should be documented in the participant’s medical 
records.  If it is determined that the participant has died, the site will use permissible local methods 
to obtain the date and cause of death and as much other information as can be obtained, including 
post-mortem reports. 
Data to be collected at subsequent visits will be considered missing. 
7.2.8 
End of Study Definition 
A patient will have completed the study if the patient dies while on Treatment or in Follow-up.  
The cause of death will be documented in the eCRF. 
Patients no longer required to be followed for survival are considered as having completed the 
study if 1 of the following events occurs: disease progression or death. Following the completion 
of the treatment and Safety Follow-up phases of the study, every effort should be made to follow-
up all patients for their survival status until patient death or termination by the Sponsor. 
The end of the study is defined as the date once all patients have completed the Follow-up period 
(i.e., 12 weeks after discontinuation). 
7.2.9 
Discontinuation of Study Drug 
When a patient will discontinue study drug treatment, the date and reason for study drug 
discontinuation should be documented on the CRF, all remaining visits of that treatment cycle 
should be completed (without infusions and with only a single PK sample taken at applicable 
visits), and the patient should enter the Follow-up period.  When a patient will be withdrawn from 
the study (during the Treatment or Follow-up period), all evaluations associated with that study 
visit should be performed and the date and reason for study discontinuation should be documented 
on the CRF.  In addition, if more than 4 weeks since the last imaging-based response assessment 
have passed at the time of discontinuation, a final response assessment shall be done if feasible. 

 
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Following completion or discontinuation of the Treatment and/or Follow-up phases of the study, 
all patients will be followed (by phone) every 3 months to assess their survival status until patient 
death. 
Continued treatment should occur for patients with a best overall response (BOR) of CR (patients 
with confirmed CR may be discontinued from treatment upon discussion between the Investigator, 
Medical Monitor, and Sponsor), partial response (PR), or stable disease until the first occurrence 
of either: 
• Documented progressive disease by RECIST 1.1 – while reference is made to Section 7.1.4 
for treatment beyond progression considering the principles of iRECIST (Seymour et al., 
2017) 
• Clinical deterioration suggesting that no further benefit from treatment is likely 
• Patient meets permanent discontinuation criteria for study therapy due to meeting respective 
tolerability criteria 
• Other intolerability to therapy requiring discontinuation according to the Investigator’s 
opinion 
• Requirement for another form of antineoplastic therapy as determined by the Investigator or 
• Discontinuation resulting from protocol violation, withdrawal of consent, or lost to follow-up 
• Termination of the study by the Sponsor 
• Pregnancy 
• Need for prohibited medication 
• Lack of compliance with the study and/or study procedures (e.g., administration instructions, 
study visits) 
• Patient is lost to follow-up 
If any of the above situations apply, the patient is withdrawn from treatment and enters the 
Follow-up period.  Consequently, the reason for discontinuation of NM21-1480 will be recorded 
in the eCRF.  These reasons include: 
• Radiographic disease progression 
• Any progression or recurrence of any malignancy, or any occurrence of another malignancy 
that requires active treatment 
• Any significant AE that compromises the patient’s ability to participate in the study 
• Patient’s decision to discontinue the study treatment (A patient who discontinues treatment is 
normally expected to continue to participate in the study unless they specifically withdraw 
their consent to further participation in any study procedures and assessments) 

 
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• The Investigator or Sponsor determines it is in the best interest of the patient 
• Death 
7.2.10 
Discontinuation of Study Sites 
Study site participation may be discontinued if Sponsor or designee, the Investigator or IEC/IRB 
of the study site judges it necessary for medical or safety reasons consistent with applicable laws, 
regulations and GCP. 
7.2.11 
Discontinuation of Study 
The study will be discontinued if Sponsor or designee, including through SMC recommendation, 
judges it necessary for medical, safety, or business reasons consistent with applicable laws, 
regulation and GCP. 
7.2.12 
Follow-up 
All patients will be followed for survival until death after discontinuation of the Treatment and/or 
completion of Follow-up periods.  
• Follow-up 1 to be scheduled within 30 days of the last visit. 
• Safety Follow-up Visit 2 and Visit 3 are to be scheduled 60 days and 90 days after 
discontinuation, respectively after discontinuation. 
• Following completion or discontinuation of the Treatment and/or Follow-up phases of the 
study, all patients will be followed (by phone) every 3 months to assess their survival status 
until patient death. 
 
 

 
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8 
STUDY TREATMENT 
Study treatment is defined as the investigational intervention intended to be administered to the 
study participant according to the study protocol. 
8.1 
Administration of Study Treatment(s) 
Part A (Dose-Escalation) 
NM21-1480 will generally be administered over approximately 60-90 minutes as a single IV 
infusion every 14 days for a total of 2 infusions per treatment cycle (4 weeks).  Details on study 
drug administration can be found in the study Pharmacy Manual.  The following escalating flat 
dose levels will be administered according to the BOIN design: 
IV Administration of NM21-1480 
Dose 1: 0.15 mg 
Dose 2: 1.5 mg 
Dose 3: 8 mg 
Dose 4: 24 mg 
Dose 5: 80 mg 
Dose 6: 240 mg 
Dose 7: 800 mg 
Radiological (response) assessments are done every 8 weeks, i.e., 1 assessment cycle (at 8-Week 
Assessment, see Table 7-1). 
Part A-2 (optional) 
Part A of the study was formally completed on 23 May 2022 at which occasion, based on 
availability of at least 28-day safety data for all 25 patients evaluable for BOIN in Part A, the SMC 
determined that Part A did not technically identify a MTD and that even the highest dose level 
assessed in Part A (800mg flat dose) was considered a tolerated dose. However, based on the 
finding that some patients dosed at 24-240mg in Part A developed treatment-emergent ADAs 
leading to loss of exposure, while this was not observed at the 800mg dose level, a decision was 
taken to explore one higher dose level (1400mg flat dose, applying an approximately 14-day 
dosing interval) in up to 10 patients within Part A-2 in parallel to studying the 800mg dose level 
in Part B.  The SMC, together with the Sponsor, may also choose to evaluate different (i.e., longer 
than 2-week) dosing intervals if supported by emerging Part A-2 data.  Additional dose levels (i.e. 
doses other than 1400mg) or dosing intervals (i.e. other than biweekly) may in the future be studied 
within Part A-2 as well if emerging data from the ongoing study provide a rationale to do so.   

 
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Part B (Dose Expansion): 
Based on the comprehensive review of Part A data on 23 May 2022, the SMC determined that the 
800mg flat dose of NM21-1480 shall be further studied as the presumptive RP2D in Part B of the 
study. As such, this dose level will be assessed in Part B, Cohorts B1-B4 and B6-B8 in order to 
confirm the RP2D for NM21-1480 monotherapy. For Cohort B5, the SMC will initially evaluate 
the tolerability of the 800mg NM21-1480 doe in the combinatorial treatment setting with a PD-1 
antibody in six patients enrolled to this treatment arm (see Section 7.2.5.3 for detailed decision 
rules). As no relevant accumulation of NM21-1480 was observed in Part A, the 800mg dose of 
NM21-1480 to be administered in all Part B cohorts will be administered as a single IV infusion 
approximately every 14 days for a total of 2 infusions per treatment cycle (4 weeks). However, PK 
data will be closely followed and in case of observation of relevant drug accumulation over time, 
the dosing interval for may be adjusted to approximately every 21 days, for a total of 2 infusions 
per treatment cycle (or 6 weeks).  Radiological (response) assessments are done every 6 weeks 
during the first 24 weeks on treatment and every 8 weeks, i.e., at 8-Week Assessments thereafter, 
see Table 7-1 and Table 7-2. 
Tumor response will be evaluated by the Investigator using RECIST 1.1 and iRECIST.  Tumor 
response assessments should be completed as instructed in Table 7-1 and Table 7-2 footnotes c 
and v, respectively. 
8.1.1 
Duration of Treatment with Study Drug 
There is no pre-specified maximal treatment duration.  Treatment for a given patient shall be 
continued until there is confirmed disease progression by the Investigator or the patient meets any 
of the pre-specified conditions for discontinuation. 
8.1.2 
8-Week Assessment 
In Part A, radiological assessments are conducted every 8 weeks, this period defines 1 assessment 
cycle (i.e., in the week prior to administration of NM21-1480 in all odd number treatment cycles 
[e.g., Cycles 3, 5, 7]).  In the optional Part A-2 and in Part B, radiological assessments are 
conducted every 6 weeks for the first 24 weeks on treatment and every 8 weeks thereafter. 
8.1.3 
Radiological Assessment in the Follow-up Period 
All patients who discontinue study treatment without radiologically documented disease 
progression will continue to receive radiological assessments until disease progression, patient 
withdraws informed consent, initiation of new anti-cancer treatment, lost to follow-up, death, or 
end of this study, whichever occurs first. 

 
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8.1.4 
Re-initiation of Study Therapy for Patients in Follow-up Period 
Patients that have been discontinued from treatment will not be allowed to be re-initiated with the 
IP.  The only exceptions are treatment re-initiations in patients who were discontinued due to 
confirmed CR and thereafter recurrence or in patients following elective surgery provided that 
patients still meet the eligibility criteria.  Re-initiation of treatment in this situation may be allowed 
following discussion between Investigator, Medical Monitor and Sponsor. 
8.1.5 
Dose Modification 
In the case that an infusion cannot be administered at a scheduled visit, every attempt should be 
made to administer the infusion as soon as possible.  Patients with infusion delays >35 days 
(i.e., 2 missed doses + 7 days in settings with intended biweekly dosing events) or >49 days 
(i.e., 2 missed doses + 7 days in settings with intended dosing events every three weeks) from the 
scheduled dosing should normally discontinue treatment and enter the Follow-up period with the 
exception of delays related to prophylactic vaccinations or after specific consultation and 
agreement between the Investigator and the Medical Monitor in settings where benefit/risk may 
justify continued study therapy (e.g., patient deriving clinical benefit who requires prolonged 
steroid taper for management of non-DLT irAEs).  For more details of dose modification relevant 
to irAEs, please refer to Appendix VI, (irAE management guidance for Investigators). 
8.1.5.1 
Dose Reduction 
In Part A, dose may be reduced to the next lower pre-specified dose level of the BOIN design due 
to toxicity if deemed necessary by the Investigator after consultation with the Medical Monitor, 
specifically after occurrence of a DLT. 
Only one dose reduction is allowed. 
In general, tolerability issues in both Part A and Part B are to be addressed by dose withholding; 
however, dose reduction may be considered upon discussion with the Medical Monitor if deemed 
necessary as per the Investigator’s assessment. 
8.1.5.2 
Dose Withheld 
NM21-1480 will be withheld for any of the following treatment-emergent adverse events 
(TEAEs): 
• Any Grade ≥2 TRAE, with the following exceptions: 
− Grade 2 TRAE fatigue, alopecia, skin rash or laboratory abnormalities do not require a 
treatment delay 
• Any Grade 3 skin, TRAE 
• Any Grade 3 TRAE laboratory abnormality, with the following exceptions for lymphopenia, 
AST, ALT, or total bilirubin or asymptomatic amylase or lipase: 

 
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− Grade 3 lymphopenia does not require dose delay 
− If a patient has a baseline AST, ALT or total bilirubin that is within normal limits, delay 
dosing for treatment-related Grade ≥2 toxicity 
− If a patient has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for treatment-related Grade ≥3 toxicity 
− Any Grade ≥3 treatment-related amylase or lipase abnormality that is not associated 
with symptoms or clinical manifestations of pancreatitis does not require dose delay.  
The Medical Monitor should be consulted for such Grade ≥3 amylase or lipase 
abnormalities 
• Any AE, laboratory abnormality, or intercurrent illness which, in the judgement of the 
Investigator, warrants delaying the dose of study medication. 
•  Grade 2 TRAEs that recur shall be managed by dose modifications (changes in the infusion 
rate) and dose delays, and those that do not resolve to Grade 1 or less by the end of the next 
treatment cycle shall lead to permanent discontinuation of NM21-1480.  Pre-planned dose level 
reductions are not allowed; however, interruptions in delivering the planned dose that results 
in an actual dose that is less than 90% of the planned dose is defined as dose reduction. 
8.1.6 
Dose Resumption 
Patients may resume treatment with NM21-1480 when the TRAEs resolve(s) to Grade ≤1 or 
baseline within 35 days (i.e., 2 missed doses + 7 days in settings with intended biweekly dosing 
events) or within 49 days (i.e., 2 missed doses + 7 days in settings with intended dosing events 
every three weeks) from the scheduled dosing, with the following exceptions: 
• Patients may resume treatment in the presence of Grade 2 fatigue, alopecia, skin rash. 
• Patients who have not experienced a Grade 3 treatment-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity. 
• Patients with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for reasons 
other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the presence 
of Grade 1 AST/ALT or total bilirubin. 
• Patients with combined Grade 2 AST/ALT and total bilirubin values meeting discontinuation 
parameters should have treatment permanently discontinued. 
• Treatment-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed.  Patients with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for re-treatment if discussed with and 
approved by the Medical Monitor. 

 
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• Treatment-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment. 
Two dosing delays due to toxicity will be permitted.  
In the event of a third occurrence of a toxicity which would require dosing delay, study therapy 
may be discontinued permanently after consultation with the Sponsor monitor. 

 
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8.1.7 
Management of Infusion-Related Reactions 
Infusion-related reactions may occur during or after administration of NM21-1480.  Dose 
reductions, other than a decrease in the infusion rate, are not allowed.  Management guidelines for 
infusion reactions are displayed in Table 8-1. 
Table 8-1 
Management of Infusion-related Reactions 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically 
indicated until the symptoms have resolved. 
The infusion rate of study drug/study regimen may be 
decreased by 50% or temporarily interrupted until 
resolution of the event. 
Patient may be pre-
medicated at the discretion 
of the Investigator as per 
institutional norm or 
consider premedication 1.5 
hours (± 30 minutes) prior to 
infusion of NM21-1480 
with: 
• Diphenhydramine 
50 mg orally (or equivalent 
dose of antihistamine) 
• Acetaminophen 
(Paracetamol) 
500-1000 mg orally (or 
equivalent dose of 
antipyretic) 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hours 
Stop infusion and monitor symptoms. 
Additional appropriate medical therapy may include 
but is not limited to: IV fluids, antihistamines, 
NSAIDs, acetaminophen, and narcotics. 
Increase monitoring of vital signs as medically 
indicated until the symptoms have resolved. 
If symptoms resolve within 1 hour of stopping IP 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (e.g., from 100 to 50 mL/hour).  
Otherwise, dosing will be held until symptoms 
resolve and the participant should be pre-medicated 
for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further IP administration. 
Patient should be pre-
medicated as per institutional 
norm or consider 
premedication 1.5 hours 
(± 30 minutes) prior to 
infusion of NM21-1480 with: 
• Diphenhydramine 
50 mg orally (or equivalent 
dose of antihistamine) 
 
• Acetaminophen 
(Paracetamol) 
500-1000 mg orally (or 
equivalent dose of 
antipyretic) 

 
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NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 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; 
pressor or ventilatory 
support indicated 
Stop infusion immediately. 
Begin an IV infusion of normal saline and treat the 
patient as per institutional norms or consider treating 
the patient as follows: Recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 1:1,000 solution for 
subcutaneous administration or 0.1 to 0.25 mg of a 
1:10,000 solution injected slowly for IV 
administration, and/or diphenhydramine 50 mg IV 
with methylprednisolone 100 mg IV (or equivalent), 
as needed.  Patient should be monitored until the 
Investigator is comfortable that the symptoms will not 
recur. 
Additional appropriate medical therapy may include 
but is not limited to: IV fluids, antihistamines, 
NSAIDs, acetaminophen, narcotics, oxygen, pressors, 
corticosteroids, and epinephrine. 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the Investigator. 
Hospitalization may be indicated. 
Participant is permanently discontinued from further 
IP administration. 
Permanently discontinue 
dosing 
Abbreviations: IP = Investigational product; IV = Intravenous; NCI CTCAE = National Cancer Institute Common 
Terminology Criteria for Adverse Events, NSAID = Nonsteroidal anti-inflammatory drug 
8.2 
Study Treatment Packaging and Labelling 
8.2.1 
Packaging 
Prior to addition of the IP, 0.02% poloxamer 188 will be added to the diluent sodium chloride for 
injection, USP (0.45% or 0.9% dependent on the dose level).  Ten (10) mL of the product will be 
filled into 20R type I glass vials from which the required dose volume will be injected into suitable 
infusion bags or administered by perfusion syringes, dependent on dose level.  The intended 
clinical dosing frequency is once every other week, or every third week (if applicable) in optional 
Part A-2 and Part B, over 60-90 minutes through an IV line containing a sterile, non-pyrogenic, 
low protein-binding inline filter (pore size of 0.2 micron).  Additional details can be found in the 
study Pharmacy Manual. 

 
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8.2.2 
Storage 
All IP supplies for this study must be stored under refrigerated conditions (2°C to 8°C) per storage 
conditions stated on the IP label.  Until dispensed for administration to patients, the study drug 
will be stored in a securely locked area, accessible to authorized personnel only.  Details can be 
found in the study Pharmacy Manual. 
8.3 
Patient Compliance 
The dosage, timing and mode of administration of study medication may not be changed.  Any 
departures from the intended regimen must be recorded in the eCRF.  Study medication 
accountability and patient compliance will be documented throughout the study/treatment periods 
using study-specific medication administration record forms.  If a participant does not receive the 
scheduled dose, every effort should be made to administer the dose as soon as possible.  Deviations 
from the intended regimen include: 
• receiving unscheduled dose of study drug 
• missing a dose 
• receiving the incorrect dose 
8.4 
Study Treatment Accountability 
Records shall be maintained of the delivery of study treatment(s) to the study site(s), the inventory 
at the study site(s), the use of each participant and the return to the Sponsor. 
These records shall include dates, quantities, batch numbers, expiry dates and the unique code 
numbers assigned to the study medication and to the study participants. 
The Investigator shall be responsible for ensuring that the records adequately document that the 
participants were provided the doses specified in the protocol and that all study medication 
received from the Sponsor is reconciled. 
8.5 
Concomitant Therapy 
8.5.1 
Permitted Medications 
Patients are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption).  Steroid doses <10 mg daily prednisone or 
equivalent (e.g. for adrenal replacement) are permitted.  A course of corticosteroids for 
prophylaxis for contrast dye allergy is allowed.  
Bone modifying agents, including bisphosphonates and denosumab, should be used in 
accordance with label indications as appropriate for patients with bone metastases.   
 

 
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Colony stimulating factors (G-CSF, GM-CSF, erythropoietin stimulating agents, etc.) should 
not be administered prophylactically.  Interventional use of these agents is permitted for the 
treatment of adverse events. 
Palliative and supportive care measures should be administered at the discretion of the 
Investigator in accord with standards of care. 
NM21-1480 may impact CYP enzyme production and activity via cytokine modulation. For this 
reason, there may be a risk of drug interactions and concomitant medications that are narrow 
therapeutic index substrates for CYP enzymes should be used with caution and appropriate 
monitoring. 
8.5.2 
Prohibited Medications 
The following medications and therapies are not permitted during the study from signature of 
informed consent: 
• Other investigational agents or investigational device. 
• Any other systemic or localized antineoplastic therapy. Palliative radiation therapy may be 
permitted for pain or severe symptom control (i.e., radiation for pain control of bony 
metastases) after discussion with the study Medical Monitor. Radiation will be limited to 
non-target lesions only.  
• Any botanical preparation (e.g., herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study or provide supportive care.  Use of marijuana and 
its derivatives for treatment of symptoms related to cancer or cancer treatment are 
permitted if obtained by medical prescription or if its use (even without a medical 
prescription) has been legalized locally  
• Medications or substances known to cause elevation of liver enzymes, including e.g., 
acetaminophen (a daily dose of up to 2 g/day is allowed to manage acute pain), or 
systemically active cannabidiol (CBD); topical CBD is allowed  
• Immunosuppressive medication including immunosuppressive doses of systemic steroids 
or absorbed topical steroids (doses >10 mg/day prednisone or equivalent). However, 
continued treatment with NM21-1480 of a patient on doses ≤10 mg/day prednisone or 
equivalent that were initiated for treatment of an AE/irAE within the study is allowable if 
that AE/irAE has improved to ≤ Grade 1 in severity or baseline and continued NM21-1480 
treatment is considered in the best interest of the patient as per investigator judgement and 
following consultation with the Medical Monitor.  

 
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9 
STUDY ASSESSMENTS AND PROCEDURES 
9.1 
Clinical Activity Assessments 
9.1.1 
Tumor Response 
Tumor response will be evaluated by the Investigator according to RECIST 1.1 using measurement 
such as computed tomography (CTI) scan (with IV contrast, chest, abdomen, and pelvis) or MRI 
in case of IV contrast contraindication.  In Part B, tumor response will also be evaluated by the 
investigator according to iRECIST and response assessment for RECIST1.1 and iRECIST will be 
independently determined by central reading of images, while decisions on continuation of 
treatment will be based on the investigator’s RECIST1.1 and iRECIST assessment. Response 
assessments will be performed by the Investigators at the end of each assessment cycle to 
document eligibility for entry into the next treatment cycle.  Also, if applicable (see Table 7-1 and 
Table 7-2, footnote v.), response assessment will be performed at Follow-up Visit 1 (0 to 30 days 
after discontinuation), Visit 2 (60±7 days after discontinuation), and/or Visit 3 (90±7 days after 
discontinuation). 
Copies of scans will be collected and stored at Medpace in Part A and optional Part A-2. In part 
B, copies of scans will also be sent to Medpace for independent determination of RECIST1.1 and 
iRECIST assessments. A detailed description of the central read process can be found in the 
imaging charter.   
Sites are also requested to attempt gathering and submitting the last pre-baseline scans for a patient 
as part of the tumor-specific therapy history; inavailability of these pre-baseline scans do however 
not make a patient ineligible for the study. 
The same technique (CTI/MRI) used at baseline will be utilized throughout the study for a given 
patient.  Computed tomography is the imaging modality of choice for chest/abdomen/pelvis.  Brain 
scans during Treatment and Follow-up periods are required only if there is a prior history of lesions 
present at Screening, or as clinically indicated.  If required, subsequent brain CTI scans/MRI 
should be repeated at assessment cycles 1, 2, etc., and at Follow-up Visit 2.  Bone scans at baseline 
or subsequent visits will be performed only if clinically indicated.  If required, subsequent bone 
scans should be repeated every other assessment cycle (end of assessment cycles 2, 4, 6, etc.) and 
a single scan at Follow-up Visit 2 or 3. 
The timing and frequency of clinical activity assessments are described in Table 7-1 and Table 7-2. 
Additional assessments of overall survival (OS) and progression-free survival (PFS) will be 
assessed by the Kaplan-Meier method (described in Section 10.6.2). 
While conducting the study, tumor response assessment will be done locally, CTI/MRI scans will 
also be stored centrally.  During the study, i.e., on an ongoing basis while enrollment into Part B 
is ongoing and/or at the end of Part B, the Sponsor will re-confirm response assessment by a central 

 
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reader blinded to assigned NM21-1480 dose levels (all B cohorts) and treatment assignment 
(Cohort B5). 
9.2 
Safety Assessments 
At Screening, a medical history will be obtained to capture relevant underlying conditions and 
prior medications will be collected.  The Screening examinations will include hepatitis B and C 
test, HIV tests, CD4 T-cell count (only for patients who are HIV positive at Screening), and height 
within 28 days prior to the administration of the first dose of study drug. 
Safety assessments including weight, ECOG performance status, ECG (12-lead), vital signs, 
complete physical examination, limited physical examination, oxygen saturation, concomitant 
medications, AEs, hematology, serum chemistry, urinalysis, TSH and T4, and pregnancy tests, 
will be performed as noted in the Schedule of Assessments. 
The timing and frequency of safety assessments are described in Table 7-1 and Table 7-2. 
9.2.1 
Definitions 
The definition of AEs, TEAEs, and SAEs is given below.  The Investigator and any qualified 
designees are responsible for detecting, documenting, and recording events that meet the definition 
of and AE or SAE and remain responsible for following up AEs that are serious, considered related 
to the study drug or study procedures, or that causes the participant to discontinue the study 
drug/study. 
9.2.1.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a participant, or clinical investigation 
participant administered a pharmaceutical product, and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign, 
symptom or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product. 
9.2.1.2 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgement of the Investigator (i.e., not related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study drug administration even though it may have 
been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 

 
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• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or a 
concomitant medication.  Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent.  Such overdoses should 
be reported regardless of sequelae. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported 
as an AE or SAE.  Such instances will be captured in the efficacy assessments.  However, the 
signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as 
AE or SAE if they fulfill the definition of an AE or SAE. 
9.2.1.3 
Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety assessments, 
which are associated with the underlying disease, unless judged by the Investigator to be more 
severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
9.2.1.4 
Serious Adverse Event 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that: 
• Results in death.  The cause of death is the AE, death is an outcome. 
• Is life-threatening.  The term ‘life-threatening’ in the definition of ‘serious’ refers to an event 
in which the participant was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
• Requires in-patient hospitalization or prolongs existing hospitalization.  In general, 
hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting.  Complications that 

 
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occur during hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious.  When in doubt as to whether ‘hospitalization’ 
occurred or was necessary, the AE should be considered serious.  
• Results in persistent or significant disability/incapacity.  The term disability means a 
substantial disruption of a person’s ability to conduct normal life functions.  This definition is 
not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event.  Important medical events that my not result in death, be 
life-threatening or require hospitalization may be considered a serious adverse drug 
experience, when based on appropriate medical judgement, they may jeopardize the participant 
or the participant may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  Examples of such events include invasive or malignant cancers, 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. Patients will be required to permanently discontinue NM21-1480 
for the following TRAEs: 
o Any Grade 2 TRAE uveitis, eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment 
period OR requires systemic treatment. 
o Any Grade 3 non-skin, TRAE lasting >7 days, with the following exceptions: 
1. Grade 3 TRAE uveitis, pneumonitis, bronchospasm, hypersensitivity reaction, 
or infusion reaction of any duration requires discontinuation. 
2. Grade 3 TRAE endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation. 
3. Grade 3 TRAE laboratory abnormalities not requiring medical treatment or 
hospitalization do not require treatment discontinuation except: 
a. Grade 3 TRAE thrombocytopenia >7 days or associated with clinically 
significant bleeding requires discontinuation. 
b. Any TRAE liver function test abnormality that meets the following criteria 
requires discontinuation: 
i. AST or ALT >5-10 × ULN for >2 weeks or AST or ALT >10 × ULN. 

 
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ii. Total bilirubin >5 × ULN. 
iii. Concurrent AST or ALT >3 × ULN and total bilirubin >2 × ULN 
without initial finding of cholestasis (elevation of alkaline phosphatase 
[ALP]). 
iv. For patients with hepatic metastases: AST or ALT >8 × ULN or AST or 
ALT >5 × ULN for ≥14 days. 
o Any patient experiencing a Grade 4 toxicity or laboratory abnormality must be 
permanently discontinued. 
o Any event that leads to delay in dosing lasting >35 days (i.e., 2 missed doses + 7 
days in settings with intended biweekly dosing events) or >49 days (i.e., 2 missed 
doses + 7 days in settings with intended dosing events every three weeks) from the 
scheduled dosing requires discontinuation, with the following exceptions: 
1. Dosing delays to allow for prolonged steroid tapers to manage TRAEs may be 
allowed if approved by the Medical Monitor.  Prior to re-initiating treatment in 
a patient with a dosing delay lasting >35 days (i.e., 2 missed doses + 7 days in 
settings with intended biweekly dosing events) or >49 days (i.e., 2 missed doses 
+ 7 days in settings with intended dosing events every three weeks) from the 
scheduled dosing, the Medical Monitor must be consulted.  Tumor assessments 
should continue as per-protocol even if dosing is delayed.  Periodic study visits 
to assess safety and laboratory studies should also continue every 2 weeks or 
more frequently if clinically indicated during such dosing delays. 
2. Dosing delays lasting >35 days (i.e., 2 missed doses + 7 days in settings with 
intended biweekly dosing events) or >49 days (i.e., 2 missed doses + 7 days in 
settings with intended dosing events every three weeks) from the scheduled 
dosing that occur for non-drug-related reasons may be allowed if approved by 
the Medical Monitor.  Prior to re-initiating treatment in a patient with a dosing 
delay lasting 35 days (i.e., 2 missed doses + 7 days in settings with intended 
biweekly dosing events) or 49 days (i.e., 2 missed doses + 7 days in settings 
with intended dosing events every three weeks), the Medical Monitor must be 
consulted.  Tumor assessments should continue as per-protocol even if dosing 
is delayed.  Periodic study visits to assess safety and laboratory studies should 
also continue every 2 weeks or more frequently if clinically indicated during 
such dosing delays. 
Patients who meet toxicity related discontinuation criteria discussed above or presented in 
Appendix VI, (management of irAEs) may be permitted to remain on therapy if the benefits are 

 
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considered to outweigh the risks of continued treatment after discussion between the Sponsor and 
Investigator and between the Investigator and the patient. 
In case of development of a ≥Grade 3 (CTCAE V5.0) intolerability or AE related to NM21-1480 
that precludes further treatment with the study drug, but patient does not have worsening 
progression: Patients will complete the remaining visits of their current treatment cycle (without 
infusions) if possible.  Patients will then enter the Follow-up period. 
9.2.1.5 
Treatment-Emergent Adverse Event 
TEAEs are defined as any AE occurring or worsening on or after the first dose of study drug. 
9.2.1.6 
Adverse Event of Special Interest 
An AESI must be reported as if it were an SAE (Section 9.2.6). 
Elevations of ALT/AST that are >3-fold above baseline are to be considered AESI and to be 
reported with SAE timelines.  The details on how to handle such situations are provided in 
Appendix VI, “Hepatitis”).  In case of Grade 3+ hepatotoxicity, an initial ultrasound or image 
needs to be done to visualize the biliary tree and to rule out disease progression or occurrence of 
gall stones. 
The following types of AESIs will be examined: 
• AEs falling under the system order class (SOC) of hepatobiliary disorders (i.e., to cover any 
potential liver toxicity) Grade 3 or higher 
• SOC of immune system disorders (i.e., to cover cytokine release syndrome and irAEs) Grade 
3 or higher 
• Any AE of CTCAE V5.0 Grade 3 or higher 
• Any CTCAE V5.0 Grade 3 or 4 infusion reaction whether or not the event is a DLT or delayed 
DLT 
• Any AE considered by the Investigator to represent a DLT or delayed DLT 
9.2.1.7 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study drug may have 
interfered with the effectiveness of a contraceptive medication.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, normal birth or congenital 
abnormality) must be followed up and documented even after the participant has been withdrawn 
from the study. 
All reports of congenital abnormalities/birth defects are SAEs.  Spontaneous miscarriages should 
also be reported and handled as SAEs.  Elective abortions without complications should not be 

 
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handled as SAEs, but should be reported as a follow-up report for the pregnancy.  All outcomes of 
pregnancy must be reported to the Sponsor on a Pregnancy Outcomes Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study drug 
in the study.  Consent to report information regarding these pregnancy outcomes should be 
obtained from the female partner. 
Pregnancies must be reported to Arriello within 24 hours of awareness, using the reporting details 
provided in Section 9.2.6. 
9.2.2 
Time Period and Frequency for Collecting AE and SAE Information 
Adverse Events occurring after signing informed consent/HIPAA authorization, but before study 
drug administration are to be recorded as AEs (though unrelated to study drug).  All AEs will be 
collected at the time points specified in the Schedule of Assessments (Table 7-1 and Table 7-2).  
All patients who intend to discontinue the study within 70 days after the administration of the last 
dose of study drug should be followed until resolution and/or stabilization of any study TRAEs 
and AEs that led to the discontinuation, and should be monitored for 70 days following the last 
dose of ND021 (NM21-1480) for the occurrence of study TRAEs.  These patients should complete 
Follow-up visits 1 and 2 unless the patient begins a new therapy. 
For all Follow-up periods beyond 70 days from the last dose of study drug, only study treatment-
related SAEs or late-occurring irAEs should be reported. 
At any time after completion of the Follow-up visit, if an Investigator learns of an SAE that can 
be reasonably related to study drug, they should promptly notify the Sponsor. 
9.2.3 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and SAEs.  Open-ended and 
non-leading verbal questioning of the participant is the preferred method to enquire about AE 
occurrences. 
9.2.4 
Recording of AEs and SAEs 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(e.g., hospital progress notes, laboratory reports, and diagnostics reports) related to the event.  The 
Investigator will then record all relevant AE/SAE information in the eCRF.  It is not acceptable 
for the Investigator to send photocopies of the participant’s medical records in lieu of completion 
of the AE/SAE eCRF page.  There may be instances when copies of medical records for certain 
cases are requested.  In this case, all participant identifiers, except for the participant number, will 
be redacted on the copies of the medical records before submission.  The Investigator will attempt 
to establish a diagnosis of the event based on signs, symptoms, and/or other clinical information.  
Whenever possible, the diagnosis (not the individual signs/symptoms) will be documented as the 
AE/SAE. 

 
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The following variables will be recorded for each AE: verbatim/AE description and date for AE 
start and stop, severity (refer to Section 9.2.4.1), seriousness (Section 9.2.1.4), causality rating 
(Section 9.2.4.2), whether or not the AE caused the participant to discontinue (Section 9.2.4.3), 
any other action (Section 9.2.4.4), and the outcome (Section 9.2.4.5).  A new AE must be recorded 
if the severity of the AE changes. 
Should an SAE have an outcome of death, the report should contain a comment regarding the 
co-involvement of progression of disease, if appropriate, and should assign main and contributory 
causes of death. 
9.2.4.1 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study. AEs and SAEs should be assessed and graded based upon NCI CTCAE Version 5.0.  It is 
important to distinguish between serious and severe AEs.  Severity is a measure of intensity and 
both AEs and SAEs can be assessed as severe.  An event is defined as ‘serious’ when it meets at 
least one of the criteria listed in Section 9.2.1.4. 
An AE of severe intensity need not necessarily be considered serious.  For example, nausea that 
persists for several hours may be considered severe nausea, but not an SAE.  On the other hand, a 
stroke that results in only a limited degree of disability may be considered a mild stroke but would 
be an SAE. 
9.2.4.2 
Assessment of Causality 
The Investigator must assess the relationship between study drug and each occurrence of each 
AE/SAE using their clinical judgement.  A reasonable possibility of a causal relationship requires 
that there are facts, evidence, and/or arguments to suggest a relationship, rather than that a 
relationship cannot be ruled out.  Alternative causes, such as underlying disease(s), concomitant 
therapy, and other risk factors, as well as a temporal relationship of the event to study drug 
administration will be considered and investigated.  The Investigator will also consult the IB and/or 
Product Information (for marketed products) as part of their assessment. 
For each AE/SAE, the Investigator must document in the medical notes that they have reviewed 
the AE/SAE and have provided an assessment of causality.  There may be situations in which an 
SAE has occurred and the Investigator has minimal information to include in the initial report.  
However, it is very important that the Investigator always makes an assessment of causality for 
every event before the initial transmission of the SAE data.  The Investigator may change their 
opinion of causality in light of follow-up information and send a SAE follow-up report with the 
updated causality assessment.  The causality assessment is one of the criteria used when 
determining regulatory reporting requirements (Table 9-1). 

 
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Table 9-1 
Assessment of Causality 
Term 
Definition 
Clarification 
Unrelated 
Those AEs, which, after careful consideration, are clearly due to extraneous causes (disease, 
environment, etc.) 
Unlikely 
A clinical event, including 
laboratory test abnormality, with a 
temporal relationship to drug 
administration which makes a 
causal relationship improbable, 
and in which other drugs, 
chemicals or underlying disease 
provide plausible explanations. 
1.  It does not follow a reasonable temporal sequence 
(improbable temporal relationship) from study drug 
administration. 
2.  It could also be explained by participant's concurrent 
disease, environmental factors, medical history and other 
concomitant drugs or chemicals including food-drug 
interactions. 
Possibly 
A clinical event, including 
laboratory test abnormality, with a 
reasonable time sequence to drug 
administration but which could 
also be explained by concurrent 
disease or other drugs or 
chemicals.  Information on drug 
withdrawal may be lacking or 
unclear. 
1.  It follows a reasonable temporal sequence from study 
drug administration. 
2.  It could also be explained by participant's concurrent 
disease, environmental factors, medical history and other 
concomitant drugs or chemicals (including food-drug 
interactions). 
3.  There is no information or uncertainty with regard to 
what has happened after stopping the drug. 
At least 
possibly 
A TEAE is an AE with onset after administration of first study dose and is independent of any 
assessment of causality. 
Any TEAE that is considered at least possibly related to study drug is considered a TRAE. 
Probably 
A clinical event, including 
laboratory test abnormality, with a 
reasonable time sequence to drug 
administration, unlikely to be 
attributed to concurrent disease or 
other drugs or chemicals, and 
which follows a clinically 
reasonable response on 
withdrawal (de-challenge).  
Re-challenge information is not 
required to fulfill this definition. 
1.  It follows a reasonable temporal sequence from study 
drug administration. 
2.  It could not be readily explained (unlikely) by the 
participant's concurrent disease, environmental factors, 
medical history and other concomitant drugs or chemicals 
including food-drug interactions. 
3.  It disappears or decreases in severity on cessation or 
reduction in dose or on administration of a specific 
antagonist wherever possible.  There are important 
exceptions when an AE does not disappear upon 
discontinuation of the drug, yet drug-relatedness clearly 
exists. 
4.  No re-challenge information is available or possible. 
Certain 
A clinical event, including 
laboratory test abnormality, 
occurring in a plausible time 
relationship to administration of 
study drug, and which cannot be 
explained by concurrent disease or 
other drugs or chemicals.  The 
response to withdrawal of the drug 
(de-challenge) should be clinically 
plausible.  The event must be 
definitive pharmacologically or 
phenomenologically, using a 
1.  It follows a plausible time sequence to drug intake; this 
means that there is a positive argument in sufficient detail to 
support the view that the drug is causally involved, 
pharmacologically or pathologically e.g., PK and type of 
reaction. 
2.  It could not be explained by the participant's concurrent 
disease, environmental factors, medical history and other 

 
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Term 
Definition 
Clarification 
satisfactory re-challenge 
procedure if necessary. 
concomitant drugs or chemicals including food-drug 
interactions (i.e., no alternative causes). 
3.  It disappears or decreases in severity on cessation or 
reduction in dose or on administration of a specific 
antagonist wherever possible. 
4.  It is an objective and specific medical disorder or a 
recognized pharmacological phenomenon for instance ‘grey 
baby syndrome’ and chloramphenicol or anaphylaxis 
immediately after the administration of a drug that had been 
given previously.  This means that any other event is 
automatically excluded and can never qualify for ‘Certain’ 
(even in the case of a positive re-challenge observation). 
5.  It reappears on re-administration of the drug (only if 
ethically correct i.e., in case of non-serious, and easily 
treatable AEs). 
Abbreviations: 
AE = Adverse event; PK = pharmacokinetics; TEAE = Treatment-emergent adverse event; 
TRAE = Treatment-related adverse event. 
 
When conducting the causality assessment of an AE, the Investigator should consider the 
following factors: 
• Time relationship between study drug intake and event’s onset 
• De-challenge 
• Re-challenge 
• Medical history 
• Study treatment 
• Mechanism of action of study drug 
• Class effect 
• Concomitant treatments in use 
• Withdrawal of study treatment 
• Lack of efficacy/worsening of existing condition 
• Erroneous treatment with study medication or concomitant medication 
• Protocol-related process. 

 
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9.2.4.3 
Action Taken with Study Drug Due to AE 
The action taken with study drug should be recorded using one of the following: 
• None 
• Study drug temporarily discontinued 
• Study drug permanently discontinued 
• Unknown/not applicable 
9.2.4.4 
Other Action Taken 
Details of any other actions taken should be specified: 
• Specific therapy/medication 
• Surgical medical procedure 
• Prolonged hospitalization 
9.2.4.5 
AE Outcome 
Each AE should be rated according to one of the following outcomes: 
• Recovered/resolved 
• Recovering/resolving 
• Not recovered/not resolved 
• Recovered with sequelae/resolved with sequelae 
• Fatal 
• Unknown 
9.2.5 
Follow-up of AEs/SAEs 
All patients who intend to discontinue the study within 70 days after the administration of the last 
dose of study drug should be followed until resolution and/or stabilization of any study TRAEs 
and AEs that lead to the discontinuation, and should be monitored for 70 days following the last 
dose of ND021 (NM21-1480) for the occurrence of study TRAEs.  These patients should complete 
Follow-up Visits 1 and 2 unless the patient begins a new therapy. 
For all Follow-up periods beyond 70 days from the last dose of study drug, only fatal SAEs, study 
treatment-related SAEs or late-occurring irAEs should be reported to Sponsor/designee and 
Arriello initially, and then followed by report to Arriello according to the Safety Management Plan 
(SMP) for the study according to Section 9.2.6. 

 
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periodic reporting, as delineated in the SMP, to specified Health Authorities according to national 
requirements and to applicable Central Ethics Committees (CECs).  Procedure and timelines for 
safety reporting are provided in the SMP as agreed by Arriello, Medpace, and the Sponsor.  The 
Investigator must comply with any applicable site-specific requirements related to the reporting of 
SAEs (particularly deaths and suspected unexpected serious adverse reactions [SUSARs]) to the 
IEC/IRB that approved the study.  Investigators should provide written documentation of IEC/IRB 
notification for each report to Arriello. In addition, all SAEs will be reported through the yearly 
Development Safety Update Report (DSUR). 
In accordance with ICH GCP, Arriello will inform the Investigators of findings that could 
adversely affect the safety of participant, impact the conduct of the study, or alter the IEC’s/IRB’s 
approval/favorable opinion to continue the study, as assessed by the Sponsor. In particular, and in 
line with respective regulations, Arriello will inform the Investigators of SUSARs.  The 
Investigator should place copies of Safety Reports in the Investigator Site File.  National 
regulations with regards to Safety Report notifications to Investigators will be taken into account.  
When specifically required by regulations and guidelines, Arriello or Medpace (as specified in the 
SMP) will provide appropriate Safety Reports directly to the concerned lead IEC/IRB and will 
maintain records of these notifications. When direct reporting is not clearly defined by national or 
site-specific regulations, the Investigator will be responsible for promptly notifying the concerned 
IEC/IRB of any Safety Reports provided by Arriello and of filing copies of all related 
correspondence in the Investigator Site File. 
9.2.7 
Laboratory Assessments 
The Screening examinations will include hepatitis B and C, HIV, CD4 T-cell count (only for 
patients who are HIV positive at Screening), hematology, serum chemistries, urinalysis, TSH&T4, 
and pregnancy.   
During the study hematology, serum chemistries, urinalysis, thyroid function and pregnancy tests 
will be evaluated only by local study site or its contract laboratory at the time points detailed in 
the Schedule of Assessments (Table 7-1 and Table 7-2).  The hematology and clinical chemistry 
laboratories must be performed and reviewed before dosing.  If practicable, laboratory samples 
may be drawn up to 72 hours prior to infusions for pre-infusion safety review; in such case it is 
not necessary to repeat tests on the day of dosing.  Any new ≥Grade 3 laboratory abnormality or 
change consistent with a possible irAE (as opposed to disease progression), such as liver function 
test elevations, electrolyte fluctuation, or hematologic deterioration should be assessed for 
potential risk to continued dosing.  In the event of uncertainty, the Medical Monitor should be 
contacted. 
A full list of required laboratory tests is included in Section 18.7, Appendix VII. 

 
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9.2.7.1 
Potential Hy’s Law and Hy’s Law 
Cases where a patient shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN without evidence 
of intra- or extra-hepatic bilirubin obstruction (elevated at least ALP) or Gilbert’s syndrome will 
need to be reported as SAEs.  Please refer to Appendix II, Section 18.2 for further instruction on 
cases of increases in liver biochemistry and evaluation of Hy’s Law. 
9.2.8 
Electrocardiogram Assessments 
Computerized 12-lead ECG recordings will be obtained at scheduled study visits (as specified in 
the Schedule of Assessments [Table 7-1 and Table 7-2]) after the participant has rested for at least 
5 minutes in the supine position.  The Investigator will document the occurrence of any clinically 
significant 12-lead ECG abnormalities within the eCRF based on correlation between the 
Investigator reading and clinical findings.  Repeat measurements will be performed if needed. 
The following ECG parameters will be obtained directly from the computerized 12-lead ECG 
recordings: rhythm, ventricular rate, P-R interval (the portion of the ECG between the onset of the 
P wave and the QRS complex), QRS duration and QT/QTcF where, according to the Fridericia 
formula, (QTcF) is the observed QT interval (the time from the beginning of the Q wave to the 
end of the T wave) divided by the cubed root of the R-R interval (interval from the peak of 1 QRS 
complex to the peak of the next) in seconds: 
QTcF = QT 
3√RR 
QTcB (QTc corrected according to Bazett’s formula) will also be recorded, where: 
QTcB = QT 
√RR 
Baseline imaging and 12-lead ECG done as part of the patient’s previous routine care before 
signing the informed consent form (ICF) and completed within 28 days before the administration 
of ND021 (NM21-1480) need not be repeated.  Whenever possible, baseline imaging should be 
done at the same institution/facility and with the same modality which will be used to measure 
response during the patient’s participation in the study. 
9.2.9 
Physical Examination 
A standard complete physical examination will be performed at the weeks specified in the 
Schedule of Assessments (Table 7-1 and Table 7-2).  Complete physical examination includes 
assessment of the skin, head, eyes, nose, throat, neck, joints, lungs, heart, abdomen (including liver 
and spleen), lymph nodes, and extremities.  A brief neurological examination should also be 
performed.  All abnormal findings noted at the Screening physical examination should be recorded 

 
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on the medical history CRF, and any new or worsening signs or symptoms are to be recorded on 
the AE CRF. 
Limited physical examination includes assessment of the lungs, heart, abdomen, and skin.  All 
abnormal findings noted at the Cycle 1/Day 1 evaluation should be recorded on the medical history 
CRF.  Abnormal findings of clinical significance that occur after the Cycle 1/Day 1 evaluation (or 
new AEs) should be explicitly documented on the AE CRF. 
9.2.10 
Vital Signs 
Body temperature, resting systolic and diastolic blood pressure, and pulse will be recorded 
according to the Schedule of Assessments (Table 7-1 and Table 7-2).  Automatic or manual 
devices may be used, but the same device will be used for any given participant throughout the 
study.  The same arm will be used for all blood pressure measurements.  All devices must hold 
valid calibration documentation at the time of use. 
On the day of each infusion, vital signs will be obtained pre-infusion, every 15 minutes during the 
infusion, at the end of the infusion, and 15, 30, and 60 minutes after completion of the infusion.  
When slowing or re-starting an infusion due to an infusion reaction/AE, vital signs should be 
monitored every 15 minutes or as directed by the Investigator until the infusion is completed, and 
15, 30, and 60 minutes after completion of the infusion and/or until the patient is stabilized.  Vital 
signs should be collected ± 5 minutes from the scheduled times noted in the Schedule of 
Assessments (Table 7-1 and Table 7-2). 
9.3 
Pharmacokinetics and Immunogenicity Assessments 
Pharmacokinetic (PK) parameters such as the maximum observed serum concentration determined 
by direct inspection of the concentration versus time data (Cmax), the minimum observed serum 
concentration determined by direct inspection of the concentration versus time data (Cmin), the 
time from dosing at which Cmax is apparent determined by direct inspection of the concentration 
versus time data (Tmax), terminal phase (apparent elimination) rate constant (λz), elimination 
half-life (t½), area under the serum concentration-time curve extrapolated from the last 
quantifiable concentration to infinity (AUC[0-infinity]), area under serum concentration-time 
curve over dosing interval (AUCtau), clearance (CL), volume of distribution (Vd), and 
accumulation index will be derived from serum concentration versus time data for patients with 
serial PK samples. 
Serum samples will be collected to assess the ADAs to NM21-1480.  Pharmacokinetics and 
immunogenicity sampling time points are detailed in the Blood Sampling Schedule (Table 7-3 and 
Table 7-4). 

 
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9.4 
Pharmacodynamic Assessments and Biomarker Analysis 
Whole blood samples will be drawn and biopsy material will be collected for assessment of PD 
and biomarker analysis at the time points indicated in the Blood Sampling Schedule (Table 7-3 
and Table 7-4).  Blood samples will be processed to collect serum. 
Assessment of immunophenotyping, soluble PD-L1, soluble 4-1BB, cytokine efficacy panel, 
receptor occupancy (RO), PD-L1 immunohistochemistry (IHC), tumor mutational burden (TMB), 
TCR clonality sequencing, microsatellite instability (MSI) and mRNA/IF may be adjusted for Part 
B, following availability of Part A data.  Conduct of RO assay (for Part A and B) will be dependent 
on availability of a suitable assay.  
Characterization of exposure-dependent PD markers of target and pathway engagement assessed 
in Part A and the optional Part A-2 (if applicable) will be core elements of selecting up to 4 dose 
levels of NM21-1480 that are at or below the MTD for determination of the RP2D in Part B. In 
mCRC patients enrolled to Cohort B8, additional biomarker/PD marker, including, e.g., 
assessment of ctDNA levels, determination of MHC-I expression on tumor cells; or specific 
mutational analysis including e.g., BRAF, KRAS, NRAS, POLE, PIK3CA, PTEN. APC, p53 may 
be conducted. 
10 
STATISTICAL METHOD AND SAMPLE SIZE CALCULATION 
10.1 
General Considerations 
A detailed statistical analysis plan (SAP) will be prepared by the Sponsor or designee.  This plan 
may modify the statistical methods outlined in the protocol; however, any major modifications of 
the primary endpoint definition or analysis will also be described in a protocol amendment. 
10.2 
Sample Size Estimate Calculation 
No formal group size calculation has been applied as the sample size during dose-escalation cannot 
be precisely determined but depends on the observed toxicity.  
For Part A, dose-escalation cohorts, a BOIN design with a pre-specified maximal patient number 
of 25 will be applied.  
The optional Part A-2 may only be initiated after Part A is complete (i.e., the MTD for Part A has 
been determined).  Up to 40 patients across dose levels may be enrolled to further study the 
exposure-dependent PD response relationship for NM21-1480 to further explore different dose 
levels and/or dosing intervals in parallel to Part B to complement the PK, immunogenicity and PD 
data to be provided by Part B. 
For Part B, Cohorts B1 through B4 and B6 through B8 a BOP2 design will be applied (see 
Section 10.3.2) and a maximum of 40 patients will be enrolled to each cohort to assess clinical 
response.  For Part B, Cohorts B1 through B4 and B6 through B8, an interim analysis for futility 

 
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is planned, depending on recruitment and availability of data.  The interim analysis is planned after 
enrollment and treatment of 25 patients in a given cohort according to the BOP2 design.  This 
futility analysis will be conducted based on availability of response data following completion of 
the first 2 RECIST 1.1 (and iRECIST) assessments (i.e., after 12 weeks) for the 25 patients.  The 
800mg flat dose of NM21-1480 will be further studied as sole dose level in Part B based on results 
of Part A and as per recommendation by the SMC. The Sponsor in consultation with the SMC will 
determine at this point of futility analysis whether the cohort shall be stopped or continued.  If (a) 
cohort will not be stopped due to futility after the interim analysis, the study will continue with an 
estimated total of 40 patients to be enrolled by cohort; a final futility/clinical activity analysis based 
on pre-specified criteria will be conducted at this point and the Sponsor will consider continued 
development of NM21-1480 in a given indication. For Cohort B8, the Sponsor will hold 
enrollment to the cohort after 25 patients have received at least one dose of NM21-1480 treatment 
until all relevant safety, efficacy, PK, immunogenicity and most prominently all relevant PD data 
that has accrued until then has been reviewed by the Sponsor and the SMC. After this interim 
review, the Sponsor may decide to stop the cohort, to continue with full enrollment of the cohort 
or revise eligibility criteria before the remaining 15 patients in that cohort are enrolled. 
For Cohort B5, a total of approximately 200 patients with head and neck squamous cell cancer 
may ultimately be randomized 2:1 to either NM21-1480 plus a PD-1 standard-of-care first-line 
checkpoint inhibitor or to the standard-of-care PD1 checkpoint inhibitor monotherapy. Based on 
10,000 trial simulations performed in R, a sample size of 180 patients in a 2:1 randomization 
provides approximately 90% power to detect a difference of 15% between the treatment groups 
with an estimated two-sided Type 1 error rate <0.05 of 0.0391 (Table 10-1). Based on 
10,000 simulations, the margin of error is approximately ±0.4% for the Type 1 error calculations. 
Allowing for 10% losses to follow-up, at least 200 subjects will be randomized in Cohort B5. 
 
 

 
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Table 10-1 
Sample size, power and Type 1 error 
Sample Size 
Power 
Type 1 error  
60 
72.16% 
5.3% 
72 
77.96% 
5.42% 
84 
82.01% 
5.14% 
96 
84.33% 
4.84% 
108 
86.27% 
4.78% 
120 
87.57% 
4.68% 
132 
88.06% 
4.38% 
144 
88.58% 
4.2% 
156 
89.46% 
4.38% 
168 
89.72% 
4.07% 
180 
90.07% 
3.91% 
192 
90.36% 
3.62% 
204 
90.43% 
3.69% 
 
An interim analysis will be performed after a minimum of 60 patients (40 patients in the NM21-
1480 arm) have been enrolled. At this point recruitment will be paused, the accumulated data 
analysed and regulatory authorities consulted. Cohort B5 will be regarded as futile (non-binding) 
if the probability of observing a difference in estimated effects between control and treatment of 
at least 15% is less than 0.1. However, as with the other cohorts, decisions at the interim point will 
be taken based on clinical and regulatory input and not formal statistical testing. 
10.3 
Statistical Design 
10.3.1 
Part A - Determining MTD Using Bayesian Optimal Interval Design 
For dose-escalation, the BOIN design (Liu and Yuan, 2015; Yuan et al, 2016) is employed to find 
the MTD.  The BOIN design is implemented in a simple way similar to the traditional 3+3 design, 

 
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but is more flexible and possesses superior operating characteristics that are comparable to those 
of the more complex model-based designs, such as the continual reassessment method (CRM) 
(Zhou et al, 2018).  
The target toxicity rate for the MTD is 끫븲= 0.3 and the maximum sample size is 25 (below steps 
describe the process in detail).  To guide dose-escalation decisions, if the observed DLT rate at the 
current dose is ≤0.236, the next cohort of patients will be treated at the next higher dose level; if 
it is ≥0.359, the next cohort of patients will be treated at the next lower dose level.  For the purpose 
of overdose control, doses 끫뢮 and higher levels will be eliminated from further examination if 
Pr(끫뢺끫뢮>0.3 | data) >0.95, where 끫뢺끫뢮 is the true DLT rate of dose level 끫뢮, 끫뢮= 1, 8.  When the lowest 
dose is eliminated, stop the study for safety.  
The study design is illustrated in Figure 10–1 below and described through the following 3 steps: 
a) Perform accelerated titration as follows: treat the first patient at dose level 1.  If no ≥Grade 2 
toxicity (as assessed by the Investigator to be related, probably related, or possibly related to 
the drug at any dose level) is observed, escalate the dose to the next higher level.  Continue 
this 1-patient-per-dose dose-escalation process until the first ≥Grade 2 toxicity is observed or 
dose level 5 (80 mg dose level) is reached.  Treat an additional 2 patients at the dose at which 
the first ≥Grade 2 toxicity is observed.  Hereafter, patients are treated in cohorts of 3 as 
described in steps 2 and 3. 
b) To assign a dose to the next cohort of patients, conduct dose-escalation/de-escalation according 
to the rule displayed in Table 10-2.  When using Table 10-2, please note the following: 
c) 
“Eliminate” means that we eliminate the current and higher doses from the study to 
prevent treating any future patients at these doses because they are overly toxic. 
d) When dose is eliminated, automatically de-escalate the dose to the next lower level.  
When the lowest dose is eliminated, stop the study for safety.  In this case, no dose 
should be selected as the MTD. 
e) 
If none of the actions (i.e., escalation, de-escalation or elimination) is triggered, treat 
the new patients at the current dose. 
f) 
If the current dose is the lowest dose and the rule indicates dose de-escalation, treat 
the new patients at the lowest dose unless the number of DLTs reaches the elimination 
boundary, at which point terminate the study for safety. 
g) If the current dose is the highest dose and the rule indicates dose-escalation, treat the 
new patients at the highest dose. 
h) Repeat step 2 until the maximum sample size of 25 is reached or stop Part A of the study if the 
number of patients treated at the current dose reaches 12. 

 
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After the study is completed, the MTD based on isotonic regression as specified in 
Liu and Yuan, 2015 is selected (the MTD for which the isotonic estimate of the toxicity rate is 
closest to the target toxicity rate.  If there are ties, the higher dose level is selected when the isotonic 
estimate is lower than the target toxicity rate and the lower dose level is selected when the isotonic 
estimate is greater than or equal to the target toxicity rate).  Table 10-2 below provides the decision 
rules to be utilized during the dose-escalation period. 
Table 10-2 
Dose-Escalation/De-Escalation Decision Rules for the BOIN Design 
Actions 
The number of patients treated at the current dose 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Escalate if number of DLT ≤0.236 
0 
0 
0 
0 
1 
1 
1 
1 
2 
2 
2 
2 
De-escalate if number of DLT ≥0.359 
1 
1 
2 
2 
2 
3 
3 
3 
4 
4 
4 
5 
Eliminate if number of DLT 
NA 
NA 
3 
3 
4 
4 
5 
5 
5 
6 
6 
7 
Abbreviations: 
BOIN = Bayesian optimal interval; DLT = Dose-limiting toxicity; NA = Not applicable 
 
As of October 29, 2021, 13 evaluable patients have been treated at DL1 to DL5, as shown in 
Table 10-3 below. PK and PD data show that DL5 has reached the range of therapeutically 
effective dose. To reduce the chance of exposing patients to higher doses that may yield no 
additional benefit, amendment is made in Protocol V6.0 to remove DL8 from dose escalation. 
Accordingly, the maximum sample size in the BOIN is adjusted from 27 to 25.   
Table 10-3 
Observed Data as of October 29, 2021. 
Dose level (DL) 
DL1 
DL2 
DL3 
DL4 
DL5 
DL6 
DL7 
DL8 
Number of evaluable patients 
1 
1 
3 
3 
5 
0 
0 
0 
Number of patients with DLT 
0 
0 
0 
0 
1 
0 
0 
0 
 
Table 10-4 below shows the updated operating characteristics of the study design based on 
1000 simulations, given the observed data (Table 10-3).  The results show that the amended design 
(i.e., reducing the number of dose levels to be assessed in Part A from previously 8 to 7 in Protocol 
V6.0) yields higher probabilities of identifying the MTD than the original design. Of note, 
Table 10-4 does not consider the scenarios with the MTD lower than DL5 because the observed 
data show that is unlikely, and Scenarios 1 to 3 correspond to Scenarios 2-4 in operating 
characteristics of the original design with 8 dose levels. 
 
 

 
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Table 10-4 
Operating Characteristics of the BOIN Design 
Scenarios 
DL1 
DL2 
DL3 
DL4 
DL5 
DL6 
DL7 
Number 
of 
Patients 
% Early 
Stopping 
Scenario 1 
 
 
 
 
 
 
 
 
 
True DLT rate 
0.04 
0.08 
0.12 
0.16 
0.3 
0.47 
0.54 
 
 
Selection % 
0 
0 
0 
3.4 
62.6 
26.8 
7.2 
 
0 
Number of 
patients 
treated 
1 
1 
3 
3.6 
9.1 
6.1 
1.3 
25 
 
Scenario 2 
 
 
 
 
 
 
 
 
 
True DLT rate 
0.04 
0.07 
0.1 
0.12 
0.15 
0.3 
0.48 
 
 
Selection % 
0 
0 
0 
0.3 
23.0 
52.2 
24.5 
 
0 
Number of 
patients 
treated 
1 
1 
3 
3.1 
6.7 
7.1 
3.2 
25 
 
Scenario 3 
 
 
 
 
 
 
 
 
 
True DLT rate 
0.02 
0.04 
0.06 
0.08 
0.1 
0.12 
0.3 
 
 
Selection % 
0 
0 
0 
0 
1.9 
22.9 
75.2 
 
0 
Number of 
patients 
treated 
1 
1 
3 
3 
5.2 
5.1 
6.7 
25 
 
Abbreviations: BOIN = Bayesian optimal interval; DL = Dose Level; DLT = Dose-limiting toxicity 
 
On 16 May 2022 the final (25th BOIN-evaluable) patient, dosed at dose level 7 (800mg), 
completed the 28-day DLT evaluation period. Consequently, a formal SMC meeting was held on 
23 May 2022 to review all Part A clinical data with a primary focus on DLT rate and safety data. 
The below DLT data were observed in Part A (Table 10-5) and consequently the SMC determined 
that Part A of the study did not technically identify a MTD and the highest dose assessed (800mg) 
was considered a tolerable dose. 
Table 10-5 
Observed Data as of May 23, 2022. 
Dose level (DL) 
DL1 
DL2 
DL3 
DL4 
DL5 
DL6 
DL7 
Dose (mg) 
0.15mg 
1.5mg 
8mg 
24mg 
80mg 
240mg 
800mg 
Number of evaluable 
patients 
1 
1 
3 
3 
5 
3 
9 
Number of patients with 
DLT 
0 
0 
0 
0 
1 
0 
0 

 
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10.3.2 
Part A-2 (Optional): PD Expansion 
The primary objective of the optional Part A-2 is to better understand the exposure-dependent 
PD/dose response relationship.  PD data will be combined across Part A and Part A-2 and 
summarized using descriptive statistics.  If appropriate, the PD/dose relationship may be modelled.  
The shape of the dose response curve will be identified after plotting the data. 
10.3.3 
Part B - Clinical Activity Monitoring Using BOP2 Design 
The efficacy endpoint is monitored using the BOP2 design (Zhou et al., 2017) in all Part B cohorts 
except for Cohort B5 (Section 10.6.2.1).  Specifically, let n denote the interim sample size and N 
denote the maximum sample size.  Let 끫뢺끫뢤끫뢤끫뢤 denote the probability of clinical activity (response 
rate) and define the null hypothesis 끫롶0: 끫뢺끫뢤끫뢤끫뢤≤0.05, representing that the treatment is 
inefficacious.  The patient enrollment will be stopped and claimed that the treatment is not 
promising if: 
𝑃𝑃𝑃𝑃(끫뢺끫뢤끫뢤끫뢤> 0.05|끫뢢𝑑𝑑𝑑𝑑𝑑𝑑) < 끫브(𝑛𝑛
끫뢂)끫뷸 
Where λ=0.87 and α=0.62 are design parameters optimized to minimize the chance of incorrectly 
claiming that an efficacious treatment is not promising (i.e., type II error) under the alternative 
hypothesis 끫롶1: 끫뢺끫뢤끫뢤끫뢤= 0.2, while controlling the type I error rate at 0.1 (i.e., the chance of 
incorrectly claiming that an inefficacious treatment is promising is no more than 10%).  Assuming 
a β(0.05, 0.95) prior distribution for 끫뢺끫뢤끫뢤끫뢤, and a maximum of 40 patients per cohort, the above 
decision rule corresponds to the following stopping boundaries and yields a statistical power of 
0.9152 under H1: 
Table 10-6 
Optimized Stopping Boundaries for BOP2 Design 
Number of patients treated 
Stop if # ORR ≤ 
25 
1 
40 
4 
Abbreviations: BOP2 = Bayesian optimal phase II; ORR = Objective response rate. 
The interim analysis will be performed when the number of enrolled patients reaches 25.  In this 
situation, the null hypothesis will be rejected if the number of responses is greater than 1; otherwise 
it is concluded that the treatment is not promising (Table 10-6).  The go/no-go criteria are non-
binding though, in particular as an ORR of 10% in the patient population assessed may already be 
considered a clinically meaningful result by the Sponsor.  Futility analyses will be done based on 
availability of 12 weeks data.  The data monitoring committee (DMC), consisting of Sponsor 
representatives will determine whether a cohort shall be stopped or continued after the interim 
analysis. 

 
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The operating characteristics of the design based on 10,000 simulations using shiny app “BOP2” 
published by MD Anderson Software are presented in Table 10-7. 
Stratification factors will be applied to Part B enrollment. 
Table 10-7 
Operating Characteristics 
Response rate 
Early stopping (%) 
Claim promising (%) 
Sample size 
0.01 
97.42 
0 
25.4 
0.05 
64.24 
4.50 
30.4 
0.10 
27.12 
35.90 
35.9 
0.15 
9.31 
72.22 
36.6 
0.20 
2.74 
91.52 
39.6 
0.25 
0.7 
99.03 
39.9 
0.30 
0.16 
99.64 
40 
0.35 
0.03 
99.94 
40 
0.40 
0.01 
99.99 
40 
0.45 
0 
100 
40 
10.4 
Statistical Analyses Sets 
10.4.1 
Safety Set 
The safety set (SS) consists of all patients who receive at least 1 dose of study drug.  Unless 
otherwise specified, the SS will be the default analysis set used for all analyses. 
10.4.2 
Dose-Determining Set 
The dose-determining set includes all Safety Run-in patients from the SS of Part A who either 
completed the minimum exposure requirement and have sufficient safety evaluations or 
experienced a DLT.  Patients will be considered to have met the minimum exposure requirement 
if they received at least 80% of either originally-assigned dose within the first cycle of dosing (i.e., 
80% of either the dose administered for Cycle 1/Day 1 [C1D1] or Cycle 1/Day 15 [C1D15]).  The 
length of the DLT evaluation period is 28 days. 
Patients who do not experience a DLT during the first cycle will be considered to have sufficient 
safety evaluations if they have been observed for ≥28 days following the first dose, and are 
considered by both the Sponsor and Investigators to have enough safety data to conclude that a 
DLT did not occur. 

 
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10.4.3 
Pharmacokinetic Set 
The PK set will consist of all patients who receive at least 1 dose of NM21-1480 and have at least 
1 post-dose PK blood collection with associated bioanalytical results.  The PK set will be used for 
summaries and listings of PK data. 
10.4.4 
Efficacy Analysis Set 
Consists of all patients who received at least one dose of study drug and have measurable baseline 
disease. The Efficacy Analysis Set will be the primary analysis set for efficacy in this study.   
For Part B, patients who are still on treatment at the time of data cut-off, but have not yet reached 
the first post-baseline tumor assessment, will be excluded. 
10.5 
Stratification Factors 
Stratification factors are applied for Part B cohorts as follows: 
1. Primary vs. secondary resistance (Cohorts B1 and B7) 
2. Number of previous lines of therapy; one vs. 2 lines (Cohort B2) 
3. Duration of last platinum-free interval: ≤6 months vs. >6 months to ≤12 months  
(Cohort B4) 
4.  CPS of ≥1 to<20 vs. ≥20 (Cohort B5) 
5.  Checkpoint inhibitor naïve vs. Checkpoint inhibitor pretreated (Cohort B6) 
No stratification factor is applied for Cohort B3 and for Cohort B8. 
 
10.6 
Statistical Analyses and Methods 
10.6.1 
Patient Characteristics 
The following baseline patient characteristics will be summarized descriptively: demographics 
(age, gender, and race); prior anticancer agents (chemotherapy, biologics, targeted small 
molecules); best response and best response duration to prior anticancer therapy; prior RT, prior 
surgery; primary site of disease; medical history; ECOG performance status; concomitant 
medication usage. 
10.6.2 
Efficacy Analyses 
In order to perform preliminary evaluation of anti-tumor activity, BOR outcomes, ORR, and 
disease control rate (DCR) according to RECIST 1.1 and iRECIST will be tabulated by frequency 
distribution overall, and 6 and 12 weeks following the start of study treatment for Part B cohorts 
as determined by central and institutional reads.  Similar exploratory analyses as determined by 
institutional reads (but for RECIST1.1 only) will be done for Part A and A-2 (if applicable) overall, 
and 8 and 16 weeks following Day 1, in accordance with the respective imaging visit frequency.  

 
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Median TTR and duration of response (DOR) will be summarized for those patients with 
responses, using the Kaplan-Meier method, i.e., by generation of Kaplan-Meier curves for time-
to-event variables; PFS and OS will be similarly summarized.  Individual tumor measurements, 
tumor burden and % changes in tumor burden will be listed.  Changes in tumor burden will be 
presented graphically for each tumor-type.  All primary clinical activity analyses will be based on 
the Efficacy Analysis Set, ongoing patients who have not reached the first post-baseline tumor 
assessment will be excluded from response analyses. Exploratory analysis to assess the OS will be 
provided by a Kaplan-Meier method.  Summary statistics and plots of measures of tumor-specific 
antigen levels may be provided if applicable. 
Efficacy data will be presented in tabular and/or graphical format and summarized descriptively 
by dose level in Part A, Part A-2 and Part A/A-2 combined, and by cohort in Part B.  Dose groups 
in Part B may be pooled within cohorts for final analyses if the response is deemed to be 
independent of dose from a clinical perspective. 
10.6.2.1 
Primary Efficacy Analysis, Cohort B5 
For Cohort B5, the primary efficacy endpoint will be central RECIST 1.1 read of ORR. The 
primary analysis will be performed in the Efficacy Analysis Set using a Bayesian logistic 
regression model with treatment and (CPS ≥1; CPS ≥20) as a covariates: 
끫롾끫롾끫롾끫롾끫롾 ( 끫뢺끫뢬) = 끫뷺0 + 끫뷺1 × 𝑡𝑡끫룂끫룂끫룂𝑡𝑡끫룂끫룂끫룂𝑡𝑡 + 끫뷺2 × 끫롬끫롬끫롬20 
The following prior distributions have been assumed: 
β0 ~ N (-1.45, 0.162), equivalent to a control response rate of 20 (±4)% observed in the KEYNOTE-
048 study with pembrolizumab; 
β1 ~ N (0,1), vague prior on treatment equivalent to expected treatment difference of 0% 
(95% confidence interval: -16% to +43%, which corresponds to a N(0,1) prior on logistic scale) 
β2 ~ N (0, 0.12), vague prior on CPS effect, based on KEYNOTE-048 study with pembrolizumab, 
where a 0%-3% difference in response was observed across CPS levels. 
The Bernoulli likelihood is not conjugate to the normal priors on the regression coefficients and 
so the posterior distribution of regression coefficients is not known. Let 끫뷺= (끫뷺0, 끫뷺1, 끫뷺2). 
끫븖(끫뷺|끫뢢𝑑𝑑𝑑𝑑𝑑𝑑) ∝끫븖(끫뢢𝑑𝑑𝑑𝑑𝑑𝑑|끫뷺)끫븖(끫뷺) 
In order to avoid the use of Monte Carlo methods for inference on parameters (and the requirement 
of large simulations to estimate posteriors with sufficient precision) we fit Laplace approximations 
to posterior distributions.  We approximate 끫븖(끫뷺|끫뢢𝑑𝑑𝑑𝑑𝑑𝑑) ≈끫뢂 (끫뷺′, 끫뢒𝑉𝑉𝑉𝑉(끫뷺′)) where 끫뷺′ is the mode 
of the posterior distribution of 끫븖(끫뷺|끫뢢𝑑𝑑𝑑𝑑𝑑𝑑) with 끫뢒𝑉𝑉𝑉𝑉(끫뷺′) the posterior covariance matrix estimated 
at this mode.   
At the interim analysis, Cohort B5 will be regarded as futile (non-binding) if the probability of 
observing a difference in estimated effects between control and treatment of at least 15% is less 

 
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than 0.1. However, as with the other cohorts, decisions at the interim point will be taken based on 
clinical and regulatory input and not formal statistical testing. Statistical superiority of the 
treatment in the final analysis will be concluded if  𝑃𝑃𝑃𝑃(끫뷺1 > 0 | 끫뢢𝑑𝑑𝑑𝑑𝑑𝑑) is > 0.95. 
10.6.2.2 
Best Overall Response 
Best overall response (BOR) is defined as the best response obtained among all tumor assessment 
visits after the date of first dose of study drug until documented disease progression, taking into 
account the rules as detailed below.  The tumor response will be determined according to 
RECIST 1.1 and also according to iRECIST in Part B.  Only tumor assessments performed before 
the start of any subsequent anticancer therapies and not later than 30 days after last dose will be 
considered in the assessment of BOR.  Clinical deterioration or clinical progression noted on the 
completion eCRF will not be considered as documented disease progression.  
Two sets of BOR will be summarized in a single table by treatment phase, 1 for confirmed and 
1 for confirmed + unconfirmed responses.  Best overall response is determined from the sequence 
of overall (lesion) responses according to the following rules: 
• CR = at least 2 determinations of CR at least 4 weeks apart before disease progression, where 
confirmation required, or 1 determination of CR prior to disease progression, where 
confirmation is not required. 
• PR = at least 2 determinations of PR or better at least 4 weeks apart before disease progression 
(and not qualifying for a CR), where confirmation required, or 1 determination of PR prior to 
disease progression, where confirmation is not required. 
• Stable Disease (applicable only to patient with measurable disease at baseline) = at least 
1 stable disease assessment (or better) ≥6 weeks after start of treatment (and not qualifying for 
CR or PR). 
• Non-CR/non-progressive disease (applicable only to patients with non-measurable disease at 
baseline) = at least 1 non-CR/non-progressive disease assessment (or better) after start of 
treatment and before progression (and not qualifying for CR or PR). 
• Progressive Disease = disease progression ≤12 weeks after first dose of study drug (and not 
qualifying for CR, PR, or stable disease).  
• Not Evaluable = all other cases (i.e., not qualifying for CR or PR and without stable disease 
after at least 6 weeks or early progression within the first 12 weeks).  
Patients with BOR ‘Not Evaluable’ will be summarized by reason for having unknown status.  The 
following reasons will be used: 
• No baseline assessment 
• No adequate post-baseline assessment 

 
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• All post-baseline assessments have overall response of “NE” 
• New anticancer therapy started before first post-baseline assessment 
• Stable disease occurred <6 weeks after date of first dose of study drug 
• Progression >12 weeks after date of first dose of study drug.  
Special (and rare) cases where BOR is ‘Not evaluable’ due to both stable disease occurring 
<6 weeks after first dose of study drug and progression >12 weeks after first dose of study drug 
will be classified as “stable disease occurred <6 weeks after first dose of study drug”.  
10.6.2.3 
Objective Response Rate 
Objective response rate (ORR) is defined as the number of patients achieving an overall best 
response of CR or PR divided by the total number of patients.  Two sets of ORR will be 
summarized, 1 for confirmed and 1 for confirmed + unconfirmed responses.  A 2-sided exact 
95% confidence interval based on the Clopper-Pearson method will be provided for ORR 
(Clopper and Pearson, 1934). 
10.6.2.4 
Duration of Response 
Duration of response is defined as the time from first radiographic evidence of response to the 
earliest documented disease progression or death and is calculated for responders only.  
Responders who do not have a disease progression or death date by the data cut-off date will be 
censored for DOR at their last adequate radiological assessment (i.e., at the date of last tumor 
assessment of CR, PR, or stable disease) prior to cut-off date or date a subsequent anticancer 
therapy is started.  Duration of response will be summarized using the Kaplan-Meier method. 
10.6.2.5 
Overall Survival 
Overall survival is defined as the time from start of study treatment to death due to any cause.  The 
survival follow-up (as defined in Table 7-1 and Table 7-2) is for up to 1 year following treatment 
discontinuation.  Patients alive at the data cut-off date will be censored for survival at their last 
contact date.  One-year survival rate will be estimated using the Kaplan-Meier method. 
10.6.2.6 
Progression-Free Survival 
Progression-free survival is defined as the time from start of study treatment to the earliest 
documented date of disease progression, per RECIST 1.1 (and iRECIST in Part B) and as 
determined by Investigator, or death due to any cause.  Progression-free survival will be calculated 
for all patients and summarized using the Kaplan-Meier method.  Progressive disease and death 
(from any cause) will be considered as events.  If death or disease progression is not observed, the 
PFS will be censored at the date of last adequate tumor assessment (i.e., at the date of last tumor 
assessment of CR, PR, or stable disease) prior to cut-off date or date a subsequent anticancer 
therapy is started (e.g., systemic therapy, non-palliative RT).  However, if a PFS event is observed 

 
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after more than 1 missing or inadequate tumor assessment, PFS will be censored at the last 
adequate tumor assessment.  If a PFS event is observed after a single missing or non-adequate 
tumor assessment, the actual date of event will be used. 
When a patient discontinues treatment for “disease progression” but without documentation of 
radiological and/or pathological evidence of progression based on RECIST it will not be counted 
as a PFS event.  The patient will continue to be followed for PFS until disease progression, 
withdrawal of consent/assent, initiation of subsequent anticancer therapy, the patient is lost to 
follow-up or until death.  If a PFS event occurs during this follow-up, the date of the event will be 
included in the analysis.  If the patient does not have a PFS event during this time, the patient will 
be censored at the last assessment date. 
Handling of missing assessments and censoring rules for PFS are summarized in the SAP. 
10.6.3 
Safety Analyses 
All recorded TEAEs will be listed and tabulated by system organ class, preferred term, and dose 
and coded according to the most current version of Medical Dictionary for Regulatory Affairs 
(MedDRA).  Besides TEAEs, TRAEs (i.e., assessed as at least possibly related to study drug by 
the Investigator) will be separately listed and tabulated.  The incidence of AEs will be tabulated.  
Vital signs and clinical laboratory test results will be listed and summarized by dose level.  Any 
significant physical examination findings and results of clinical laboratory tests will be listed.  
ECG listings will be evaluated by the Investigator and abnormalities, if present, will be listed.  A 
separate listing and summary of all irAEs will be provided.  Adverse events will be summarized 
for all reported data and by study part as well as study period, i.e., up to and including 70 days post 
last dose of study treatment. 
Safety data will be presented in tabular and/or graphical format and summarized descriptively by 
dose cohort and study day, where appropriate.  Safety data for Part B may be pooled across dose 
groups to mirror the efficacy analysis decisions to facilitate an appropriate risk benefit assessment 
per cohort. 
10.6.4 
Study Drug Exposure 
Duration of study treatment exposure, actual cumulative dose and relative dose intensity will be 
summarized.  The number of patients with dose modifications/interruptions will be presented, 
along with reasons for the dose modification.  The actual daily doses and reasons for dose 
modification will be listed. 
10.6.5 
Concomitant Medications 
Concomitant medications will be listed and summarized by Anatomical Therapeutic Chemical 
Classification System term, preferred term.  These summaries will include medications starting on 

 
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or after the start of study treatment or medications starting prior to the start of study treatment and 
continuing after the start of study treatment. 
10.6.6 
Adverse Events 
Adverse events will be coded using the most current version of the MedDRA.  Incidence tables 
will be presented for all AEs by maximum grade according to CTCAE v5.0.  Adverse events, 
SAEs, TEAEs, TRAEs (i.e., assessed as at least possibly related to study drug by the Investigator), 
and AEs resulting in dose reduction, interruption, or discontinuation of study drug will be 
tabulated, as well as AEs leading to additional therapy.  Dose-limiting toxicity will also be 
tabulated.  Summaries for deaths on study will be provided by system organ class and preferred 
term.  Adverse event of special interest for NM21-1480 will be identified according to the most 
recent case retrieval strategy prior to database lock.  Such categories consist of 1 or more well 
defined safety events which are similar in nature and for which there is a specific clinical interest 
in connection with the study treatment.  For each specific category, number and percentage of 
patients with at least 1 event will be reported.  Additional analyses (including time to onset and 
duration) may also be performed for these events. 
Adverse event of special interest do not require expedited reporting to the Sponsor unless the 
event(s) meets SAE reporting criteria (Section 9.2.6). 
10.6.7 
Laboratory Parameters 
Hematology and chemistry laboratory parameters will be presented in shift tables of baseline grade 
versus maximum grade on study as per CTCAE v5.0.  For laboratory parameters that are not 
gradable by CTCAE, shift tables of normal-abnormal will be provided.  Laboratory measurements 
will be summarized descriptively, and plots of measurements over time will be generated for 
selected parameters (liver toxicity parameters, and WBC subpopulation cell counts).  Calcium 
phosphate product values will be calculated using measurement of plasma total calcium and serum 
ionized calcium and will be summarized descriptively. 
10.6.8 
Electrocardiograms 
Electrocardiogram values will be summarized descriptively and/or with shift tables. 
10.6.9 
Other Safety Data 
Vital signs, body weight, and ECOG performance status data will be summarized descriptively by 
visit and/or with shift tables.  Summaries of clinically notable measurements may also be provided.  
Definitions of “clinically notable” will be provided in the SAP. 
A more detailed description of study analyses will be presented in the SAP. 

 
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10.6.10 
Analysis of Pharmacokinetics Endpoints and Anti-Drug Antibody 
Pharmacokinetic parameters such as Cmax, Cmin, Tmax, λz, t½, Tmax, AUCtau, CL, apparent 
Vd, and accumulation index will be derived from serum concentration versus time data for patients 
with serial PK samples.  Data obtained from patients with serial sampling and limited sampling 
will eventually be combined with data from other studies for population PK analysis but reported 
separately. 
A listing will be generated of all available immunogenicity data, comprising all numeric titer 
values.  Additionally, a listing of immunogenicity data from those patients with at least 1 positive 
ADA assessment (titer value greater than 2-fold of baseline titer) at any time point will be provided 
by dose regimen.  The frequency of patients with at least 1 positive ADA assessment (titer value 
greater than 2-fold of baseline titer), and frequency of patients who develop ADA after a negative 
baseline assessment (i.e., titer value equal to 1), and frequency of patients who develop ADAs 
after a baseline titer assessment greater than 1, will be provided by dose.  In addition, the frequency 
of patients who do not develop ADAs after treatment following either a negative baseline 
assessment (i.e., titer value equal to 1), or a baseline titer greater than 1 will be provided by dose. 
Treatment-induced, treatment-enhanced and treatment-unaffected ADA patients will be 
summarized. In addition, to examine the potential relationship between immunogenicity and 
safety, the frequency and type of AEs may be examined by overall immunogenicity status. 
Serum concentrations of NM21-1480 will be determined using validated bioanalytical methods.  
Serum concentration-time profiles for NM21-1480 will be generated.  Descriptive summaries for 
NM21-1480 concentrations will be presented by dose and formulation. 
10.6.11 
Pharmacodynamic Characteristics and Exploratory Biomarkers 
Summary statistics for blood- and tissue-based PD markers, including but not limited to flow 
cytometry outcomes, cytokines, and their changes (or percent changes) from baseline will be 
tabulated by cycle, visit, and dose to assess PD effects and potential association with PK exposure.  
Associations of status of exploratory biomarkers (baseline value or change from baseline) with 
clinical outcome (e.g., tumor response) may be explored based on data availability, using response-
evaluable patients, to explore potential predictive markers (e.g., PD-L1) expression in tumors. 
Administrative interim analyses on safety and clinical activity or on PK, immunogenicity, and 
selected biomarkers may be provided at several times prior to completion of the study in order to 
facilitate program decisions and to support study presentations or publications. 
10.7 
Safety Monitoring and Data Monitoring Committee 
A Safety Monitoring Committee (SMC) (consisting of study Investigators, Medical Monitor and 
Sponsor observers) is formed that will review cumulative and emerging safety data during study 
conduct (Part A, optional Part A-2, and B).  The SMC’s major responsibilities comprise evaluation 
of DLTs, dose-escalation decisions and continuous safety monitoring in Part A.  SMC meetings 

 
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will also be held according to the SMC charter to evaluate the safety data emerging in Part A-2 
and Part B (expansion cohorts).  For Part B, a separate Data Monitoring Committee (DMC), 
consisting of Sponsor representatives, will be established to review PD data and the interim clinical 
activity results.  Based on continuous clinical activity reviews and the results of the Part B interim 
analyses, the DMC will determine whether expansion cohorts are to be continued until the full 
sample size of 40 patients per B cohort is reached or stopped early for futility.  The Investigators 
will only be informed by the Sponsor in case of stopping the study or specific expansion cohorts 
for futility.  
A DMC charter outlines DMC membership, the data that will be reviewed, and the timing and 
frequency of reviews. 

 
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11 
ETHICS 
11.1 
Independent Ethics Committee/Institutional Review Board 
Prior to the start of the study, the Investigator is responsible for ensuring that the protocol and 
consent form have been reviewed and approved by a relevant IEC/IRB.  The IEC/IRB shall be 
appropriately constituted and perform its functions in accordance with FDA, ICH GCP and local 
requirements as applicable. 
The IEC/IRB shall approve all protocol amendments (except for logistical or administrative 
changes), written informed consent documents and document updates, participant recruitment 
procedures (e.g., advertisements), written information to be provided to the participants, IB, 
available safety information, information about payment and compensation available to 
participants, the Investigator's curriculum vitae and/or other evidence of qualifications and any 
other documents requested by the IEC/IRB and Regulatory Authority (Competent Authority) as 
applicable. 
11.2 
Written Informed Consent 
The nature and purpose of the study shall be fully explained to each participant (or their legally 
responsible guardian).  They must be informed that participation is voluntary. 
Written informed consent must be obtained from each participant (or authorized representative) 
prior to any study procedures being performed.  The process of obtaining informed consent must 
be documented in the participant’s source documents.  The authorized person obtaining the 
informed consent must also sign the ICF, and a copy of the ICF must be provided to the participant 
or the participant’s legally authorized representative.  Participants must be re-consented to the most 
current version of the ICF during their participation in the study. 
The consent documents to be used for the study shall include all the elements of informed consent 
as outlined in accordance with FDA, ICH GCP and local requirements as applicable and be 
reviewed and approved by the appropriate IEC/IRB prior to use. 

 
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12 
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 
Conduct of the Study 
The Sponsor shall implement and maintain quality control and quality assurance procedures with 
written standard operating procedure (SOP) to ensure that the study is conducted, and data are 
generated, documented and reported, in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements. 
This study shall be conducted in accordance with the provisions of the Declaration of Helsinki 
(October 2013), FDA (CFR, Sections 312.50 and 312.56), EU (536/2014) and UK regulations 
(The Medicines for Human Use [Clinical Trials] Regulations 2004 [no.1031]), and with ICH GCP 
(CPMP 135/95).  The study also will be carried out in compliance with local legal requirements. 
The Investigator will be responsible for the following: 
1. Providing written summaries of the status of the study to the IEC/IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IEC/IRB 
2. Notifying the IEC/IRB of SAEs or other significant safety findings as required by IEC/IRB 
procedures 
The Investigator may not deviate from the protocol without a formal protocol amendment having 
been established and approved by an appropriate IEC/IRB, except when necessary to eliminate 
immediate hazards to the participant or when the change(s) involve(s) only logistical or 
administrative aspects of the study.  Any deviations may result in the participant having to be 
withdrawn from the study and render that participant non-evaluable. 
The identification and reporting of serious breaches of ICH GCP or the protocol to the Regulatory 
Authorities and Ethics Committees will be conducted according to local SOPs and regulations. 
12.2 
Study Monitoring 
Study monitors will perform ongoing source data verification to confirm that data entered into the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being conducted 
in accordance with the currently approved protocol and any other study agreements, ICH GCP, 
and all applicable regulatory requirements.  The Investigator shall permit the Sponsor Site monitor 
to review study data as frequently as deemed necessary to ensure that data are being recorded in 
an adequate manner and that protocol adherence is satisfactory. 
The Investigator shall access medical records for the monitor in order that entries in the eCRF may 
be verified.  The Investigator, as part of his/her responsibilities, is expected to co-operate with 
Medpace in ensuring that the study adheres to GCP requirements. 

 
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The Investigator may not recruit participants into the study until such time that a visit, or with the 
agreement of the Sponsor, attendance at an Investigator meeting, has been made by a 
Sponsor/Medpace monitor to conduct a detailed review of the protocol and CRF. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of non-compliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the study monitoring plan. 
13 
DATA HANDLING AND RECORD KEEPING 
13.1 
Case Report Forms/Source Data Handling 
All required study data must be entered in the eCRF created for the study.  This data collection 
tool is a validated electronic data capture (EDC) system that contains a system generated audit 
trail.  Data required according to this protocol are recorded by investigational site personnel via 
data entry into the internet-based EDC software system.  The Investigator shall ensure that all data 
from participant visits are promptly entered into the eCRFs in accordance with the specific 
instructions given.  The Investigator must sign each eCRF to verify the integrity of the data 
recorded.  All internal Medpace and external investigational site personnel seeking access to the 
eCRF are supported by a Service Desk (if applicable).  At the end of the study all data captured 
electronically will be provided to the Investigator on CD-ROM for archiving at the investigational 
site. 
A list of the normal ranges for all laboratory tests to be undertaken forms part of the documentation 
to be collated prior to study start.  If a central laboratory has been selected to conduct any or all 
tests, it is essential that all samples be analysed at that laboratory. 
The Investigator must maintain source documents, such as laboratory reports, X-rays, ECGs, 
consultation reports, and complete medical history and physical examination reports.  All 
information in the eCRF must be traceable to the source documents in the participant’s file. 
The Investigator/institution shall provide direct access to source data/documents for study-related 
monitoring, audits, IEC/IRB review and regulatory inspection. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
13.2 
Data Protection 
Participants will be assigned a unique identifier by clinical research organization.  Any participant 
records or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be transferred.  
The participant must be informed that their personal study-related data will be used by the Sponsor 
in accordance with local data protection law.  The level of disclosure must also be explained to the 

 
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participant.  The participant must be informed that their medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IEC/IRB members, and by inspectors from regulatory authorities. 
13.3 
Dissemination of Clinical Study Data 
The study will be registered and post-study results will be posted in accordance with the applicable 
laws and regulations.  The results of this study may be published or presented at conferences/in 
journals. 
13.4 
Retention of Essential Documents 
The Investigator/institution should maintain the study documents as specified in the ICH 
guidelines on GCP and as required by the applicable regulatory requirements.  The 
Investigator/institution should take measures to prevent accidental or premature destruction of 
these documents. 
Essential documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the IP.  These documents should be retained for a longer period, however, if 
required by the applicable regulatory requirements or by an agreement with the Sponsor.  It is the 
responsibility of the Sponsor to inform the Investigator/institution as to when these documents no 
longer need to be retained. 
14 
PUBLICATION POLICY 
The Sponsor shall retain the ownership of all data.  When the study is complete Medpace shall 
arrange the analysis and tabulation of data.  A clinical study report shall then be prepared, which 
may be used for publication, presentation at scientific meetings or submission to regulatory 
authorities.  The Sponsor will generally support publication of multi-center studies only in their 
entirety and not as individual site data.  In this case, a coordinating Investigator will be designated 
by mutual agreement.  Authorship will be determined by mutual agreement and in line with the 
International Committee of Medical Journal Editors authorship agreements.  All proposed 
publications based on this study must be participant to the Sponsor's approval requirements. 
The Sponsor assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov.  In addition, upon study completion and finalization 
of the study report, the results of this study will be submitted for publication and/or posted in a 
publicly accessible database of clinical trial results. 

 
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15 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this study will be disclosed 
and managed.  Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the study.  The 
study leadership in conjunction with the Sponsor has established policies and procedures for all 
study group members to disclose all conflicts of interest and will establish a mechanism for the 
management of all reported dualities of interest. 
 

 
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16 
SIGNATURE OF INVESTIGATOR 
I agree to conduct the study outlined above in accordance with the terms and conditions of the 
protocol, ICH guidelines on GCP and with applicable regulatory requirements.  All information 
pertaining to the study shall be treated in a confidential manner. 
 
 
 
 
 
 
((Type name and job title))   
 
 
 
 
 
Date (day/month/year) 

 
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17 
REFERENCE LIST 
Bar N, Costa F, Das R, Duffy A, Samur M, McCachren S, et al. Differential effects of PD-L1 versus 
PD-1 blockade on myeloid inflammation in human cancer. JCI Insight.2020;5(12):e129353. 
Bartkowiak T and Curran MA. 4-1BB Agonists: multi-potent potentiators of tumor immunity. Front 
Oncol. 2015;8;5:117. 
Bartkowiak T, Singh S, Yang G, Galvan G, Dhwani H, Midan A, et al. Unique potential of 4-1BB 
agonist antibody to promote durable regression of HPV+ tumors when combined with an E6/E7 
peptide vaccine. Proc Natl Acad Sci USA 2015;112(38):E5290-5299. 
Bartkowiak T, Jaiswal AR, Ager CR, Chin R, Chen CH, Budhani P, et al. Activation of 4-1BB on liver 
myeloid cells triggers hepatitis via an interleukin-27-dependent pathway. Clin Cancer Res. 
2018;24(5):1138-1151. 
Chin SM, Kimberlin CR, Roe-Zurz Z, Zhang P, Xu A, Liao-Chan S, et al. Structure of the 4-1BB/4-
1BBL complex and distinct binding and functional properties of utomilumab and urelumab. Nat 
Commun. 2018;9(1):4679. 
Ciardiello D, Vitiello PP, Cardone C, Martini G, Trioani T, et al. Immunotherapy of colorectal cancer: 
Challenges for therapeutic efficacy. Cancer Treat Rev 2019;76:22-32. 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. 
Biometrika. 1934;26(4): 404-413. 
Chester C, Sanmamed MF, Wang J, Melero I. Immunotherapy targeting 4-1BB: mechanistic rationale, 
clinical results and future strategies. Blood. 2018;131(1):49-57. 
Davda J, Declerck P, Hu-Lieskovan S, Hickling TP, Jacobs IA et al. Immunogenicity of 
immunomodulatory, antibody-based, oncology therapeutics. J Immunother Cancer 2019;7(1):105. 
Dushyanthen S, Teo ZL, Caramia F, Svas P, Mintoff CP, Virassamy B, et al. Agonist immunotherapy 
restores T cell function following MEK inhibition improving efficacy in breast cancer. Nature 
Communications. 2017;8:606. 
Garralda E, Geva R, Ben-Ami E, Maurice-Dror C, Calvo E, LoRusso P, et al. First-in-human, Phase 
I/IIa trial to evaluate the safety and initial clinical activity of DuoBody PD-L1x4-1BB (GEN1046) in 
patients with advanced solid tumors. SITC, 2020 Poster #412. 
Harao M, Forget MA, Roszik J, Gao H, Babiera GV, Krishnamurthy S, et al. 4-1BB-enhanced 
expansion of CD8+ TIL from triple-negative breast cancer unveils mutation-specific CD8+ T cells. 
Cancer Immunol Res. 2017;5(6):439-445. 
Hong AM, Ferguson P, Dodds T, Jones D, Li M, Yang J, et al. Significant association of PD-L1 
expression with human papillomavirus positivity and its prognostic impact on oropharyngeal cancer. 
Oral Oncol 2019;92:33-39. 

 
Numab 
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Page 150 of 172 
 
 
Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br 
J Cancer. 2018;118(1):9-16. 
Keytruda Prescribing Information 2021. keytruda_pi.pdf (merck.com). Accessed 21 June 2021. 
Leem G, Park j, Jeon M, Kim ES, Kim SW, Lee YJ, et al. 4-1BB co-stimulation further enhances anti-
PD-1-mediated reinvigoration of exhausted CD39+ CD8 T-cells from primary and metastatic sites of 
epithelial ovarian cancers. J Immunother Cancer. 2020;8:e001650. 
Liu S, Yuan Y.  Bayesian optimal interval designs for phase I clinical trials.  Journal of the Royal 
Statistical Society: Series C (Applied Statistics). 2015;64(3):507-523. 
Luke J, Johnson M, Gadgeel S, Spira A, Yang JCH, Johnson J, et al. First-in-human trial to evaluate 
safety, PK/PD and initial clinical activity of NM21-1480, an affinity-balanced PD-L1x4-1BBxHSA 
trispecific antibody: Results of Phase 1 dose escalation. SITC, 2022 Poster #732. 
Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new 
immunomodulatory targets. Nat Rev Drug Discov. 2015;14(8):561-584. 
Melero I, Sanmamed MF, Calvo E, Moreno I, Moreno Garcia V, Rodriguez-Vida A, et al. First-in-
Human (FIH) phase I study of RO7122290 RO), a novel FAP-targeted 4-1BB agonist, administered 
as single-agent and in combination with atezolizumab (ATZ) to patients with advanced solid tumors. 
Annals of Oncology (2020) 31 (suppl_4): S645-S671. 10.1016/annonc/annonc279. Accessed 21 June 
2021; commented in: RO7122290 Active in First-in-Human Trial for Patients With Select Solid 
Tumors (targetedonc.com). Accessed 21 June 2021. 
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S et al. iRECIST: guidelines for 
response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):e143-e152. 
Srivastava RM, Trivedi S, Concha-Benavente F, Giboson SP, Reeder C, Ferrone S, and Ferris RL. 
CD137 stimulation enhances cetuximab induced natural killer (NK): dendritic cell (DC) priming of 
anti-tumor T cell immunity in head and neck cancer patients. Clin Cancer Res. 2017;23(3):707-716. 
Wei H, Zhao L, Li W, Fan K, Qian W, Hou S, et al. Combinatorial PD1 blockade and CD137 activation 
has therapeutic efficacy in murine cancer models and synergizes with cisplatin. PLOS One. 
2013;8(12):e84927. 
Yuan Y, Hess KR, Hilsenbeck SG, Gilbert MR. Bayesian optimal interval design: a simple and well-
performing design for phase I oncology trials.  Clin Cancer Res. 2016;22(17):4291-4301. 
Zamarin D, Burger RA, Sill MW, Powell DJ, Lankes HA, Feldman MD, et al. Randomized Phase II 
trial of nivolumab and ipilimumab for recurrent or persistent ovarian cancer: An NRG Oncology Study. 
J Clin Oncol. 2020;38(16):1814-1823. 
Zhou, H., Yuan, Y., Nie, L. Accuracy, safety, and reliability of novel phase I trial designs. Clin Cancer 
Res. 2018;24(18),4357-4364 

 
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Zhou H, Lee JJ, Yuan Y.  BOP2: Bayesian optimal design for phase II clinical trials with simple and 
complex endpoints.  Stat med. 2017;36(21):3302-3314. 

 
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18.2 
Appendix II: Liver Safety Monitoring and Assessment 
Introduction 
The purpose of this appendix is to provide guidance for the monitoring of drug-induced liver injury 
(DILI) during the course of the study.  It should be noted that this section does not specify the end 
of study analyses of liver enzymes.  The end of study liver enzymes analyses will be described in 
the SAP.  Any patient enrolled in a study with active drug therapy and who reveals an increase of 
serum aminotransferases (AT) to >3 × ULN (to >5 × ULN in patients with liver metastases) or 
total bilirubin level (TBL) >2 × ULN should undergo detailed testing for liver enzymes (including 
at least ALP, ALT, AST and TBL).  Testing should be repeated within 72 hours of notification of 
the test results.  Patients should be asked if they have any symptoms. 
Definition of Liver Abnormalities 
Confirmed abnormalities will be characterized as moderate and severe where ULN is as shown in 
below table: 
ALT or AST 
 
Total Bilirubin 
Moderate 
>3 × ULN (in patients without liver metastases), 
>5 × ULN (in patients with liver metastases) 
 
or 
 
>2 × ULN 
Severe 
>3 × ULN 
and* 
>2 × ULN 
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal 
*Samples taken simultaneously or within a maximum of 24 hours. 
In addition, the patient should be considered to have severe hepatic abnormalities for any of the 
following: 
• AST or ALT >5-10 × ULN for >2 weeks or AST or ALT >10 × ULN 
• Total bilirubin >5 × ULN 
• Concurrent AST or ALT >3 × ULN and total bilirubin >2 × ULN without initial finding of 
cholestasis (elevation of ALP) 
• For patients with hepatic metastases: AST or ALT >8 × ULN or AST or ALT >5 × ULN for 
≥14 daysThe Investigator may determine that abnormal liver function results, other than those 
described above, may qualify as moderate or severe abnormalities and require additional 
monitoring and follow-up 
 

 
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Follow-up Procedures 
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, physical 
examination and clinical laboratory tests.  The study site personnel are to complete the eCRF.  
Patients with confirmed abnormal liver function tests (LFT) should be followed as described 
below: 
Confirmed moderately or severely abnormal LFTs should be repeated 2 to 3 times weekly then 
weekly or less if abnormalities stabilize or the IP has been discontinued and the patient is 
asymptomatic. 
Severe hepatic liver function abnormalities as defined above, in the absence of another etiology 
may be considered an important medical event and may be reported as an SAE.  The Sponsor 
should be contacted and informed of all patients for whom severe hepatic liver function 
abnormalities possibly attributable to IP are observed. 
To further assess abnormal hepatic laboratory findings, the Investigator is expected to: 
• Obtain a more detailed history of symptoms and prior or concurrent diseases.  Symptoms and 
new-onset diseases are to be recorded as “AEs” in the eCRF.  Illnesses and conditions such as 
hypotensive events and decompensated cardiac disease that may lead to secondary liver 
abnormalities should be noted.  Nonalcoholic steatohepatitis is seen in obese 
hyperlipoproteinemic and/or diabetic patients and may be associated with fluctuating AT 
levels.  The Investigator should ensure that the medical history form captures any illness that 
predates study enrollment that may be relevant in assessing hepatic function; 
• Obtain a history of concomitant drug use (including nonprescription medication, 
complementary and alternative medications), alcohol use, recreational drug use and special 
diets.  Medications, including dose, are to be entered in the eCRF.  Information on alcohol, 
other substance use and diet should be entered on the eCRF or an appropriate document; 
• Obtain a history of exposure to environmental chemical agents; 
• Based on the patient’s history, other testing may be appropriate including: 
− Acute viral hepatitis (A, B, C, D, E or other infectious agents) 
− Ultrasound or other imaging to assess biliary tract disease 
− Other clinical laboratory tests including international normalized ratio and direct 
bilirubin; 
• Consider gastroenterology or hepatology consultations; and 
• Submit results for any additional testing and possible etiology on the eCRF or an appropriate 
document. 

 
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Study Treatment Discontinuation 
In the absence of an explanation for increased LFTs, such as viral hepatitis, pre-existing or acute 
liver disease, presence of liver metastases, or exposure to other agents associated with liver injury, 
the patient may be discontinued from study treatment.  The Investigator may determine that it is 
not in the patient’s best interest to continue study treatment.  Discontinuation of study treatment 
should be considered if: 
• AST or ALT >5-10 × ULN for >2 weeks or AST or ALT >10 × ULN 
• Total bilirubin >5 × ULN 
• Concurrent AST or ALT >3 × ULN and total bilirubin >2 × ULN without initial finding of 
cholestasis (elevation of ALP) 
• For patients with hepatic metastases: AST or ALT >8 × ULN or AST or ALT >5 × ULN for 
≥14 days 
* Samples taken simultaneously or within a maximum of 24 hours. 
In addition, if close monitoring for a patient with moderate or severe hepatic laboratory tests is not 
possible, study treatment should be discontinued. 
Hy’s Law Definition 
1. Evidence that a drug can cause hepatocellular-type injury, generally shown by a higher rate 
than control of people with 3 × AT elevations over the ULN (2 × elevations are too common 
in treated and untreated patients to be discriminating). 
2. Cases of increased bilirubin (to at least 2 × ULN) in people with concomitant AT elevation to 
at least 3 × ULN (but it is almost invariably higher) and no evidence of intra-or extra-hepatic 
bilirubin obstruction (elevated ALP) or Gilbert’s syndrome [Reference: Temple R.  Hy’s Law: 
Predicting Serious Hepatotoxicity.  Pharmacoepidemiol Drug Saf.2006; 15(4):241-3]. 
FDA Guidance for Industry titled “DILI: Premarketing Clinical 
Evaluation” issued by the FDA on July 2009. 
 
FDA Guidance for Industry: 
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control drug or 
placebo. 
2. Among patients showing such AT elevations, often with AT levels much greater than 3 × ULN, 
1 or more also show elevation of serum TBL to >2 × ULN, without initial findings of 
cholestasis (elevated serum ALP). 

 
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3. No other reason can be found to explain the combination of increased AT and TBL, such as 
viral Hepatitis A, B or C; pre-existing or acute liver disease; or another drug capable of causing 
the observed injury. 

 
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18.3 
Appendix III: Response Evaluation Criteria in Solid Tumors Version 1.1 
Tumor lesions will be categorized as follows: 
• Measurable Lesions: Must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of: 
− 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice 
thickness and a minimum of 10 mm) 
− 10 mm caliper measurement by clinical examination (when superficial) 
− Malignant lymph nodes are considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm) 
• Non-measurable Lesions: Non-measurable lesions are defined as all other lesions (or sites of 
disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with 
≥10 to <15 mm short axis).  Lesions considered truly non-measurable include the following: 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, and abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques. 
• Target Lesions: At baseline, all lesions up to a maximum of 5 lesions total (and a maximum 
of 2 lesions per organ) representative of all involved organs should be identified as target 
lesions.  It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. 
• Non-target Lesions: It is possible to record multiple non-target lesions involving the same 
organ as a single item (e.g., “multiple enlarged pelvic lymph nodes” or “multiple liver 
metastases”).  
• New Lesions: Though only certain new lesion measurements will be included in the tumor 
burden, all new lesions that can be accurately measured should be recorded.  Up to 5 additional 
target lesions (maximum of 2 additional lesions per organ) may be added to the tumor burden 
at each post-baseline assessment to facilitate the exploratory RECIST analysis.  Other new 
lesions will be included into the non-tumor burden. 
 

 
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RECIST 1.1 Response Criteria 
Evaluation of Target Lesions 
• CR - Disappearance of all target lesions.  Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to <10 mm (the sum may not be “0” if there are 
target nodes).  
• PR - At least a 30% decrease in the sum of the diameters of target lesions, taking as reference 
the baseline sum diameters. 
• Progressive Disease - At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study).  In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note: the appearance of one or more new lesions is also considered 
disease progression.) 
• Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for disease progression, taking as reference the smallest sum of diameters while on study. 
Evaluation of Non-target Lesions 
• CR - Disappearance of all non-target lesions and normalization of tumor marker level.  All 
lymph nodes must be non-pathological in size (<10 mm short axis).  
• Non-CR/Non-progressive disease - Persistence of 1 or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
• Progressive Disease - Unequivocal progression of existing non-target lesions will be defined 
as the overall level of substantial worsening in non-target disease such that, even in presence 
of stable disease or PR in target disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy (see Section 7.2.9).  In the absence of measurable disease, 
change in non-measurable disease comparable in magnitude to the increase would be required 
to declare disease progression for measurable disease.  Examples include an increase in a 
pleural effusion from ‘trace’ to ‘large,’ an increase in lymphangitic disease from localized to 
widespread. 
Appearance of New Lesions 
The appearance of new lesions is considered disease progression according to RECIST 1.1.  
Considering the unique response kinetics that have been observed with immunotherapy, new 
lesions can nonetheless derive clinical benefit. 
Evaluation of Overall Response 
For the overall response based on RECIST 1.1, confirmation of CR and PR is required by a repeat, 
consecutive assessment no less than 4 weeks from the date of first documentation.  If a patient 
discontinues the study due to disease progression and begins another treatment, a confirmatory 
scan is not required. 

 
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Below table provides overall responses for all possible combinations of tumor responses in target 
and non-target lesions with or without the appearance of new lesions. 
Evaluation of Overall Response Using RECIST 1.1 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
Complete response 
Complete response (or no non-
target lesion) 
No 
Complete response 
No target lesion a  
Complete response 
No 
Complete response 
Complete response 
Not evaluable b 
No 
Partial response 
Complete response 
Non-complete response/ 
non-progressive disease 
No 
Partial response 
Partial response 
Non-progressive disease and 
not evaluable (or no non-target 
lesion) b 
No 
Partial response 
Stable disease 
Non-progressive disease and 
not evaluable (or no non-target 
lesion) b 
No 
Stable disease 
Not all evaluated 
Non-progressive disease 
No 
Not evaluable 
No target lesion a 
Not all evaluated 
No 
Not evaluable 
No target lesion a 
Non-complete response/ 
non-progressive disease 
No 
Non-complete response/ 
non-progressive disease 
Progressive disease 
Any 
Yes/No 
Progressive disease 
Any 
Progressive disease 
Yes/No 
Progressive disease 
Any 
Any 
Yes 
Progressive disease 
No target lesion a 
Unequivocal progressive disease 
Yes/No 
Progressive disease 
No target lesion a 
Any 
Yes 
Progressive disease 
RECIST 1.1 = Response Evaluated Criteria in Solid Tumors version 1.1. 
a 
Defined as no target lesion at baseline. 
b 
Not evaluable is defined as either when no or only a subset of lesion measurements are made at an assessment. 
Reference: Eisenhauer, et al. New response evaluation criteria in solid tumors: Revised RECIST guideline 
(version 1.1), European Journal of Cancer, 2009, Vol.  45, p 228-247 
 

 
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18.4 
Appendix IV: Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
 
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. 
Reference: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group.  Am J Clin Oncol 5:649-655, 1982 

 
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18.5 
Appendix V: Women of Child-Bearing Potential Definitions and Methods of 
Contraception 
Definitions 
Woman of Child-bearing Potential (WOCBP): A woman is considered fertile following menarche 
and until becoming post-menopausal unless permanently sterile.  Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
Women in the following categories are not considered WOCBP: 
• Premenarchal 
• Premenopausal female with 1 of the following: 
1. Documented hysterectomy 
2. Documented bilateral salpingectomy 
3. Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
Post-menopausal female: A post-menopausal state is defined as 12 months of amenorrhea in a 
woman over age 45 years in the absence of other biological or physiological causes.  In addition, 
females under the age of 55 years must have a serum FSH level >40 mIU/mL to confirm 
menopause. 
Contraception Guidance for Female Participants of Child-Bearing Potential 
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 180 days after the end of study 
treatment (local laws and regulations may require use of alternative and/or additional 
contraception methods). 
 
 

 
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Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulationb 
− oral 
− 
injectable 
Highly Effective Methods That Are User Independent 
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb 
• Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants and 
intrauterine hormone-releasing system (IUS)c 
• Intrauterine device (IUD)c 
• Bilateral tubal occlusion 
• Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed.  If not, an additional 
highly effective method of contraception should be used. 
• Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug.  The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant. 
• It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
• WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 7.1.6. 
• Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence. 

 
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a 
Typical use failure rates may differ from those when used consistently and correctly.  Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the investigational medicinal product and other study medications will not alter hormonal exposures such that 
contraception would be ineffective or result in increased exposures that could be potentially hazardous.  In this 
case, alternative methods of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone-releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness 
 
Unacceptable Methods of Contraception* 
• Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously 
• Diaphragm with spermicide 
• Cervical cap with spermicide 
• Vaginal Sponge with spermicide 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action 
• Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• Withdrawal (coitus interruptus) 
• Spermicide only 
• Lactation amenorrhea method (LAM) 
*Local laws and regulations may require use of alternative and/or additional contraception methods. 
 
Contraception Guidance for Male Participants with Partner(s) of Child-Bearing 
Potential 
Male participants with female partners of child-bearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure. 
• Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the Investigator. 
• Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 180 days after the end of study treatment. 

 
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• Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 6 months after the end of 
treatment in the male participant. 
• Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 6 months after the end of study treatment. 
• Refrain from donating sperm for the duration of the study treatment and until 6 months after 
the end of study treatment. 

 
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18.6 
Appendix VI Immune-Related Adverse Event Management Guidance for 
Investigators 
Identification, Diagnosis, Management and Dose Modification for irAEs 
irAE 
Potential signs and 
symptoms 
Diagnosis and 
differential 
diagnosis 
Recommended 
management 
Dose modification 
Pneumonitis 
Symptomatic: 
dyspnea, cough, 
pleuritic chest pain, 
hypoxia 
Asymptomatic: lung 
infiltrates that mimic 
severe bacterial 
pneumonia 
Radiographic 
imaging of chest 
Tissue and lavage 
samples from 
bronchoscopy to rule 
out infectious 
pathogens and 
pathologic 
evaluation 
Grade 2: 
administration of 
corticosteroids at a 
dose of 
1-2 mg/kg/day 
prednisone 
equivalents 
Withhold NM21-
1480 until resolved 
to ≤Grade 1 
 
≥Grade 3: high-dose 
corticosteroids (2-4 
mg/kg/day IV 
methylprednisolone) 
along with 
antibiotics; in-patient 
hospitalization; 
consultation with a 
respiratory 
physician; additional 
immunosuppression 
with infliximab can 
be considered 
Permanent 
discontinuation from 
the study 
Colitis 
Watery diarrhea, 
mucus or blood in 
stool, abdominal 
pain, 
nausea/vomiting, 
dehydration, 
peritoneal signs, 
bowel perforation 
Stool cultures 
Endoscopy or 
colonoscopy to rule 
out infection 
Biopsy to rule out 
alternative etiology 
≤Grade 2 diarrhea: 
antidiarrheal 
medication, oral 
hydration, electrolyte 
supplement 
Continue dosing 
Persistent Grade 2 
diarrhea: 
administration of 
corticosteroids at a 
dose of 1-2 
mg/kg/day 
prednisone 
equivalents 
Withhold NM21-
1480 until resolved 
to ≤Grade 1 

 
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irAE 
Potential signs and 
symptoms 
Diagnosis and 
differential 
diagnosis 
Recommended 
management 
Dose modification 
Grade 3 diarrhea: 
high-dose 
corticosteroids (2-4 
mg/kg/day IV 
methylprednisolone) 
along with 
antibiotics; 
infliximab can be 
considered for 
steroid refractory 
diarrhea 
Withhold NM21-
1480 until resolved 
to ≤Grade 1 
Recurrent Grade 3 or 
Grade 4: high-dose 
corticosteroids (2-4 
mg/kg/day IV 
methylprednisolone) 
along with 
antibiotics; 
infliximab can be 
considered for 
steroid refractory 
diarrhea; in-patient 
hospitalization 
Permanent 
discontinuation from 
the study 
If bowel perforation 
is suspected, steroid 
should be withheld 
and surgical opinion 
should be explored; 
in-patient 
hospitalization; 
Infliximab should 
not be administered 
Permanent 
discontinuation from 
the study 
Hepatitis 
Symptomatic: fever, 
fatigue, nausea, 
abdominal pain, 
jaundice, 
hepatomegaly, 
Asymptomatic: 
elevation of LFT 
(hepatic 
transaminases, 
bilirubin)  
Chemistry: elevated 
levels of hepatic 
transaminases 
Serologic testing: 
should be performed 
to rule out viral 
hepatitis (including 
hepatitis A and B), 
cytomegalovirus, and 
Epstein-Barr virus 
Ultrasonograms of 
the liver 
Biopsy or radiologic 
imaging to 
distinguish from 
Grade 2: 
administration of 
corticosteroids at a 
dose of 1-2 
mg/kg/day 
prednisone 
equivalents 
For patients with 
liver metastasis 
(note: patients with 
HCC are excluded 
from this study) who 
entered the study 
with Grade 2 
elevation of 
AST/ALT, NM21-
Withhold NM21-
1480 until resolved 
to ≤Grade 1 

 
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irAE 
Potential signs and 
symptoms 
Diagnosis and 
differential 
diagnosis 
Recommended 
management 
Dose modification 
other etiologies of 
hepatic injury, such 
as neoplastic disease 
progression in the 
liver, infections, and 
effects of other 
medications or 
alcohol intake 
1480 will be 
withheld if 
AST/ALT increase 
≥50% relative to 
baseline 
≥Grade 3: 
administration of 
high-dose 
corticosteroids (2-4 
mg/kg/day IV 
methylprednisolone); 
if not improved after 
48-72 hours, 
alternative 
immunosuppression 
agents 
(mycophenolate 
mofetil) should be 
considered; in-
patient 
hospitalization; 
consultation with a 
hepatologist 
For patients with 
liver metastasis or 
HCC (note: patients 
with HCC are 
excluded from this 
study) who entered 
the study with Grade 
2 elevation of 
AST/ALT, NM21-
1480 will be 
permanently 
discontinued if 
AST/ALT increase 
≥50% relative to 
baseline and lasting 
≥1 week 
Permanent 
discontinuation from 
the study 

 
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irAE 
Potential signs and 
symptoms 
Diagnosis and 
differential 
diagnosis 
Recommended 
management 
Dose modification 
Total serum bilirubin 
>3 times upper limit 
of normal 
Hypophysitis  
Headache refractory 
to nonsteroidal anti-
inflammatory drugs 
or other analgesics; 
weakness; fatigue, 
weight gain or 
weight loss; changes 
in mood or behavior; 
hypotension; 
electrolyte 
disturbances; 
abdominal pain; loss 
of libido; adrenal 
crisis; hypogonadism 
Clinical chemistry 
tests 
Endocrinologic 
laboratory test, 
ACTH, thyroid 
function test, 
MRI of the brain: 
enlargement of the 
pituitary with 
variable contrast 
enhancement 
characteristics 
Grade 2 without 
adrenal crisis: high-
dose corticosteroids 
(methylprednisolone 
1 to 2 mg/kg/day or 
the equivalent); 
initiate appropriate 
hormone 
replacement therapy; 
consultation with an 
endocrinologist 
Withhold NM21-
1480 until resolved 
to ≤Grade 1 
 
 
 
 
≥Grade 3 or adrenal 
crisis: high-dose 
corticosteroids 
(methylprednisolone 
1 to 2 mg/kg/day or 
the equivalent); 
consultation with an 
endocrinologist 
Permanent 
discontinuation from 
the study 
Nephritis  
Hematuria, 
peripheral edema, 
elevated serum 
creatinine 
Clinical chemistry 
tests 
Urine test 
Biopsy if necessary 
Grade 2: 
administration of 
corticosteroids at a 
dose of 1-2 
mg/kg/day 
prednisone 
equivalents 
Withhold NM21-
1480 until resolved 
to ≤Grade 1 
≥Grade 3: 
administration of 
corticosteroids at a 
dose of 1-2 
mg/kg/day 
prednisone 
equivalents 
Permanent 
discontinuation from 
the study 

 
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irAE 
Potential signs and 
symptoms 
Diagnosis and 
differential 
diagnosis 
Recommended 
management 
Dose modification 
Hypothyroidism/ 
hyperthyroidism 
Typically 
asymptomatic and is 
identified by lab tests 
T3, T4, TSH test 
results 
Asymptomatic 
≤Grade 2 
hypothyroidism: 
thyroxine 
replacement therapy 
Continue dosing 
Asymptomatic 
≤Grade 2 
hyperthyroidism: 
consider beta 
blockade 
Continue dosing 
≥Grade 3 
hypothyroidism: 
replacement therapy 
Withhold NM21-
1480 until resolved 
to ≤Grade 1 or 
baseline 
Grade 3 
hyperthyroidism 
lasting ≥6 weeks 
despite active 
management via 
administration of 
corticosteroids at a 
dose of 1-2 
mg/kg/day 
prednisone 
equivalents 
Withhold NM21-
1480 until resolved 
to ≤Grade 1 
Grade 4 
hyperthyroidism 
Permanent 
discontinuation from 
the study 

 
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irAE 
Potential signs and 
symptoms 
Diagnosis and 
differential 
diagnosis 
Recommended 
management 
Dose modification 
Dermatitis 
Maculopapular rash 
or erythroderma, 
pruritus, skin 
ulceration, bullous 
dermatitis, Stevens-
Johnson syndrome 
Unless an alternative 
etiology is identified, 
it should be 
considered immune-
related 
Pathologic 
evaluation of skin 
biopsy can be 
performed to rule out 
alternative etiology 
≤Grade 2 (up to 30% 
of body surface 
area): topical 
corticosteroids and 
oral over-the-counter 
antihistamines and 
systemic 
corticosteroids if no 
improvement within 
7 days 
Continue dosing 
Grade 3 (>30% of 
body surface area): 
administration of 
corticosteroids at a 
dose of 1-2 
mg/kg/day 
prednisone 
equivalents 
Withhold NM21-
1480 until resolved 
to ≤Grade 2 
Grade 4 (Stevens-
Johnson syndrome, 
toxic epidermal 
necrosis, full-
thickness dermal 
ulceration, necrosis 
or hemorrhage): 
high-dose 
corticosteroids (2-4 
mg/kg/day IV 
methylprednisolone); 
in-patient 
hospitalization; 
consultation with a 
dermatologist 
Permanent 
discontinuation from 
the study 
Neuromuscular 
toxicity 
Peripheral sensory 
neuropathy, muscle 
weakness, Guillain-
Barre syndrome, 
transverse myelitis, 
myasthenia gravis 
Physical exam of 
sensory change, loss 
of deep-tendon 
reflexes 
Neuroimaging, nerve 
conduction exam, 
≤Grade 2: 
administration of 
corticosteroids at a 
dose of 1-2 
mg/kg/day 
prednisone 
equivalents 
Withhold NM21-
1480 until resolved 
to ≤Grade 1 

 
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irAE 
Potential signs and 
symptoms 
Diagnosis and 
differential 
diagnosis 
Recommended 
management 
Dose modification 
Nerve/muscle biopsy  
≥Grade 3: high-dose 
corticosteroids (2-4 
mg/kg/day IV 
methylprednisolone) 
Permanent 
discontinuation from 
the study 
Ocular toxicity 
Photosensitivity, 
pain or dryness of 
the eyes, blurred 
vision, uveitis, iritis, 
episcleritis 
ophthalmic exam  
≤Grade 2: topical 
steroids (1% 
prednisolone) 
Withhold NM21-
1480 until resolved 
to ≤Grade 1; if not 
resolved ≤Grade 1 
within 14 days with 
topical steroids or 
initiation of systemic 
treatment, permanent 
discontinuation from 
the study 
≥Grade 3: high-dose 
systemic 
corticosteroids (2-4 
mg/kg/day IV 
methylprednisolone) 
Permanent 
discontinuation from 
the study 
Other irAEs, 
such as arthritis, 
pancreatitis, 
hemolytic 
anemia, adrenal 
insufficiency, 
myasthenic 
syndrome, and 
rhabdomyolysis 
 
 
Grade 2 
Withhold NM21-
1480 until resolved 
to ≤Grade 1 
≥Grade 3 
Permanent 
discontinuation from 
the study 
Abbreviations: 
ACTH = Adrenocorticotrophic hormone; ALT = Alanine aminotransferase; AST = Aspartate 
aminotransferase; HCC = Hepatocellular carcinoma; irAE = immune-related adverse event; 
IV = intravenous; LFT = Liver function tests; MRI = Magnetic resonance imaging; T4 = Free 
thyroxine; TSH = Thyroid stimulating hormone. 

 
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18.7 
Appendix VII Required Laboratory Assessments by Panel 
Chemistry 
Hematology 
Coagulation 
Thyroid 
Urinalysis 
Hepatitis B, 
Hepatitis C, and 
HIV 
Other 
• AST 
• ALT 
• Alkaline 
Phosphatase 
• Amylase 
• Lipase 
• Creatinine 
• Creatinine 
Clearance 
• Total Bilirubin 
• Direct Bilirubin 
• Albumin 
• Calcium 
• Glucose 
• LDH 
• Total Protein 
• BUN 
• Uric Acid 
• Sodium 
• Phosphorus 
• Potassium 
• Chloride 
• Bicarbonate 
• CRP (if indicated) 
• Hemoglobin 
• Erythrocytes/Red 
Blood Cells 
(RBC) 
• Hematocrit 
• WBC 
• Platelets (direct 
platelet count) 
• Complete Blood 
Count with 
Differential: 
Neutrophils, 
Lymphocyte, 
Eosinophils, 
Basophils, 
Monocytes 
• CD4+ 
lymphocyte count 
(if applicable) 
• PT 
• INR 
• PTT 
• Activated PTT (if 
applicable) 
• TSH 
• T4 (free) 
• T3 (total and free) 
• Gross 
examination 
including specific 
gravity, protein, 
glucose, and 
blood 
• Microscopic 
examination 
including 
WBC/HPF, 
RBC/HPF, and 
any additional 
findings 
• Hepatitis B 
Surface Ag 
• Hepatitis B 
Surface Ab 
• Hepatitis B core 
Ab 
• Hepatitis C Ab 
• HCV RNA 
(Reflex) 
• HIV 
• CD4, Absolute 
and Percentage (if 
patient is HIV 
positive at 
screening) 
• Pregnancy 
(Serum/Urine) 
• FSH  
• Local test results 
on tumor genetic 
alterations such as 
MSI-H, dMMR, 
BRCA1, Kras, 
PD-L1 status, 
TMB, etc. (if 
available at 
medical history) 
• Tumor-specific 
blood tests (as 
applicable), e.g.: 
o CEA for 
colorectal 
cancero 
o CA 19-9 for 
pancreatic 
cancer 
o PSA for 
prostate cancer 
o CA145 for 
ovarian cancer