An Open-Label, Phase 1 Clinical Study to Evaluate the Safety, Tolerability, PK/PD and Preliminary Efficacy of HBM4003 in Combination With Toripalimab/ Tislelizumab in Patients With Advanced NEN and Other Solid Tumors
Phase: PHASE1
Conditions: Solid Tumors, Neuroendocrine Tumors, CRC
Sponsor: Harbour BioMed (Guangzhou) Co. Ltd.

Harbour BioMed                                                                                                                                        Study Number: 4003.6  
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CLINICAL TRIAL PROTOCOL SYNOPSIS  
HBM4003  
Version No ./date: 1.0/May 14, 2021  
Study No.: 4003.6  
Protocol title:  
An Open-Label, Phase 1 Clinical Study to Evaluate the Safety, Tolerability, PK/PD and 
Preliminary Efficacy of HBM4003 in Combination With Toripalimab in Patients With 
Advanced NEN and Other Solid Tumors 
Period: Phase 1  
Country and Site: China, multicenter  
Rationale:  
CTLA-4 (CD 152) is an inhibitory immune checkpoint receptor that attenuates T-cell 
receptor signaling by impeding the CD28-B7 costimulatory pathway, which is essential for full 
T-cell activation during the priming phase (Linsley et al., 1994; Krummel and Allison, 1995; 
van der Merwe et al., 1997). Treg cells also significantly express CTLA-4, the strongest 
suppressor of anti-tumor immunity, which mediates the down-regulation of CD80 and CD86 
expression in antigen-presenting cells (Ni L and Dong C, 2017). Therefore, CTLA-4 plays a 
key role in immune tolerance and negative regulation of immune response (Gibson et al., 2007).  
Immune checkpoint blocking drugs for CTLA-4, PD-1, and PD-L1 have become an 
important part of cancer therapy (Pardoll, 2012). Ipilimumab is the only CTLA-4 blocking 
antibody currently approved by the US Food and Drug Administration (FDA) for marketing for 
the treatment of advanced melanoma. CTLA-4 inhibits the early activation of T cells (mainly 
in lymph nodes), while PD-1 regulates the killing activity of T cells (mainly in tumors), and 
combination therapy against both has a synergistic effect (Galon and Bruni, 2019). Nivolumab 
(nivolumab), a PD-1 monoclonal antibody, has been used in the treatment of patients with 
hepatocellular carcinoma, melanoma, renal cell carcinoma, hepatocellular carcinoma, and 
metastatic colorectal cancer with microsatellite instability-high/mismatch repair deficiency 
(Yervoy 2020 and Opdivo 2019). The clinical efficacy of ipilimumab increases with increasing 
dose; however, the toxicity of ipilimumab is also dose-dependent, and its use can be limited by 
potentially life-threatening adverse effects (Haanen et al 2017). As a PD-1 monoclonal antibody 
developed by China itself, teripilumab has demonstrated its controllable safety and preliminary 
clinical response rate in Chinese patients with inoperable locally advanced or metastatic 
melanoma, recurrent/metastatic nasopharyngeal carcinoma who have failed two or more 
previous systemic therapies, and locally advanced or metastatic urothelial carcinoma who have 
progressed within 12 months after failure of platinum-based chemotherapy including 

Harbour BioMed                                                                                                                                        Study Number: 4003.6  
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neoadjuvant or adjuvant chemotherapy, and has obtained the conditional approval for marketing 
by China Food and Drug Administration.  
Over the past few years, multiple studies have reassessed CTLA-4 checkpoint blockade 
strategies in cancer immunotherapy. Complete CTLA-4 occupancy, systemic T cell activation, 
and significant autoreactive T cell proliferation are not necessary for tumor rejection, but are 
associated with immune-related adverse effects (Du et al 2018). In different human tumors, the 
clinically effective anti-CTLA-4 monoclonal antibody increased the density of CD4 and CD8 
positive T cells in the tumor, but did not significantly clear FOXP3 positive Treg (Sharma A et 
al., 2019).  
The results represent a new method for the development of second-generation anti-CTLA-
4 monoclonal antibodies in cancer immunotherapy by selectively enhancing local Tregs 
clearance. The new generation of anti-CTLA-4 monoclonal antibody is designed to improve 
clinical safety by reducing systemic exposure and to provide better clinical efficacy by 
enhancing the clearance of intratumoral Treg cells through antibody-dependent cell-mediated 
cytotoxicity (ADCC) effect.  
The recombinant fully human monoclonal heavy chain antibody HBM4003 immediately 
used the above design idea to enhance Treg clearance effect by blocking the CTLA-4 pathway 
and enhancing ADCC. In the MC38 tumor-bearing model in hCTLA-4 KI mice, HBM4003 
showed better efficacy than the ipilimumab analogue in preclinical in vivo trials, mainly by 
virtue of its potent TIL-Treg clearance effect (not by ipilimumab) and bioactivity comparable 
to that of ipilimumab (in vitro CTLA-4 binding and blockade). In the GLP toxicity study, 
HBM4003 was well tolerated, with the highest nonseverely toxic dose (HNSTD) of 3 mg/kg. 
Given the improved efficacy of HBM4003 in vivo, HBM4003 has a better benefit/risk profile 
than ipilimumab.  
The proposed 4003.6 study is a sub-study of the approved and ongoing 4003.2 study, which 
is mainly a clinical trial of the combination of HBM4003 and Tipilimumab in patients with 
advanced neuroendocrine tumors and other solid tumors to explore the clinical evidence of dual 
immunotherapy and to further focus on studying and improving the unmet clinical treatment 
needs of patients with advanced neuroendocrine tumors. If 4003.2 has completed the dose 
escalation part and determined the RP2D at the time of 4003.6 study initiation, 4003.6 can 
directly use this RP2D to enter the Part 2 - Dose Expansion Stage after discussion and 
confirmation by SRC.  
Objectives:  
Part 1: Dose Escalation Phase to Determine the Highest Tolerated Dose (MTD) and/or 
Recommended Phase 2 Dose (RP2D) of HBM4003 in Combination with Tiprilimumab in 
Patients with Advanced Neuroendocrine Tumors and Other Solid Tumors  
Study objectives  
Study Endpoints  
Primary objective  
Primary endpoint  

Harbour BioMed                                                                                                                                        Study Number: 4003.6  
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1. To evaluate the safety and 
tolerability of HBM4003 
in 
combination 
with 
teriprilumab in patients 
with 
advanced 
neuroendocrine 
tumors 
and other solid tumors;  
• MTD and/or RP2D of HBM4003 in combination 
with Toripalimab;  
• Number of Subjects with DLTs During the First 
Treatment Cycle (21 Days) at Each Dose .  

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Secondary objectives  
1. To evaluate the preliminary 
efficacy of HBM4003 in 
combination with teriprilumab 
in patients with advanced 
neuroendocrine tumors and 
other solid tumors;  
2. To 
evaluate 
the 
pharmacokinetics 
(PK) 
of 
HBM4003 in patients with 
advanced 
neuroendocrine 
tumors and other solid tumors;  
3. To 
evaluate 
the 
immunogenicity of HBM4003 
in 
combination 
with 
Toripalimab in patients with 
advanced 
neuroendocrine 
tumors and other solid tumors;  
4. To exploratively characterize 
the population PK profile of 
HBM4003 
in 
combination 
with Toripalimab in patients 
with advanced neuroendocrine 
tumors and other solid tumors 
based on a population PK 
analysis approach;  
5. To assess the relationship 
between 
exposure 
to 
HBM4003 and efficacy and 
adverse events, if available. 
The 
relationship 
between 
exposure to Toripalimab and 
efficacy and adverse events 
(AEs) will also be assessed.  
6. To 
explore 
the 
pharmacodynamic 
(PD) 
parameters and biomarkers of 
HBM4003 
in 
combination 
with Toripalimab in patients 
Secondary endpoints  
• Objective response rate (ORR): including the 
proportion of patients with complete response 
(CR) and partial response (PR);  
• Disease control rate (DCR): including the 
proportion of patients with complete response 
(CR), partial response (PR) and stable disease 
(SD);  
• Duration of response (DOR) [calculated from the 
first occurrence of confirmed CR or PR until the 
date of disease progression or (due to any cause) 
death];  
• Duration of Disease Control (DDC) [for subjects 
with CR, PR, or SD, duration is calculated from 
the time of initial dose until the date of disease 
progression or death due to any cause];  
• PK parameters of HBM4003 (Cmax, Tmax, 
AUC0-last, AUC0-tau, if applicable, AUC0-inf, 
t1/2, Vd, CL, etc.);  
• Immunogenicity, including the incidence of 
positive anti-drug antibodies (ADAs), of 
HBM4003 and teriprilumab. For those with 
positive anti-drug antibodies, the incidence of 
neutralizing antibodies (Nab) was detected.  
• All the plasma concentration data of HBM4003 
obtained in this study will be used for population 
PK analysis, and a PK model will be established 
to characterize the PK characteristics of 
HBM4003;  
• Dose-response 
assessment: 
to 
explore 
correlation between PK/efficacy and PK/safety, 
if applicable  
• 
Descriptive 
statistics 
for 
biomarker 
assessment, 
such 
as 
cell 
biomarkers, 
cytokines, 
PD-L1 
expression, 
tumor 
microenvironment markers, etc.  

Harbour BioMed                                                                                                                                        Study Number: 4003.6  
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with advanced neuroendocrine 
tumors and other solid tumors.  
• Other possible endpoints [such as tumor 
mutation burden (TMB)] will not be presented in 
the final report of this trial.  

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Part 2: Dose expansion phase to assess the preliminary efficacy and safety of the combination 
of HBM4003 and teriprilumab in patients with advanced neuroendocrine tumors at the RP2D 
dose.  
Study objectives  
Study Endpoints  
Primary objective  
1. To 
evaluate 
the 
preliminary efficacy of 
HBM4003 in combination 
with 
teriprilumab 
in 
patients with advanced 
neuroendocrine tumors;  
Primary endpoint  
• ORR per RECIST 1.1: includes the proportion of 
patients with CR and PR.  
Secondary objectives  
1. To evaluate the safety of 
HBM4003 in combination 
with 
Toripalimab 
in 
patients with advanced 
neuroendocrine tumors;  
2. To evaluate the long-term 
efficacy of HBM4003 in 
combination 
with 
teriprilumab in patients 
with 
advanced 
neuroendocrine tumors;  
3. To 
evaluate 
the 
immunogenicity 
of 
HBM4003 in combination 
with 
teriprilumab 
in 
patients with advanced 
neuroendocrine tumors;  
4. To 
characterize 
the 
population 
PK 
of 
HBM4003 in combination 
with 
Toripalimab 
in 
patients with advanced 
neuroendocrine 
tumors 
who have failed standard 
therapy 
based 
on 
a 
population PK analysis 
approach;  
Secondary endpoints  
• Number of patients with at least one treatment-
related AE;  
• Proportion of patients with DCR per RECIST 
1.1;  
• DOR per RECIST 1.1 [calculated as the duration 
from the first occurrence of confirmed CR or PR 
until the date of disease progression or (due to 
any cause) death];  
• DDC per RECIST 1.1 [for subjects with CR, PR, 
or SD, duration is calculated from time of initial 
dose until date of disease progression or death 
due to any cause];  
• Overall survival (OS): the length of time from 
the start of treatment to the time a subject dies 
(from any cause);  
• Progression-free survival (PFS) per RECIST 
1.1: length of time from start of treatment until 
disease progression or death from any cause;  
• Immunogenicity of HBM4003 and Toripalimab, 
including the incidence of positive ADAs. For 
those with positive anti-drug antibodies, the 
incidence of Nab was tested.  
• All the plasma concentration data of HBM4003 
obtained in this study will be used for population 
PK analysis, and a PK model will be established 

Harbour BioMed                                                                                                                                        Study Number: 4003.6  
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5. To assess the relationship 
between 
exposure 
to 
HBM4003 and efficacy 
and AEs, if available. The 
relationship 
between 
exposure to Toripalimab 
and efficacy and AEs will 
also be assessed.  
6. To evaluate PD parameters 
and 
biomarkers 
of 
HBM4003 in combination 
with 
Toripalimab 
in 
patients with advanced 
neuroendocrine tumors.  
to characterize the PK characteristics of 
HBM4003;  
• Dose-response assessment: to investigate the 
relationship between PK/efficacy and PK/safety, 
if applicable;  
• Descriptive statistics for biomarker assessment, 
such as cell biomarkers, cytokines, PD-L1 
expression, tumor microenvironment markers, 
etc.  
• Other possible endpoints (such as TMB) will not 
be presented in the final report of this trial.  
Study Design:  
Part 1 - Dose Escalation Phase to determine the MTD and/or RP2D of HBM4003 in 
combination with teriprilumab in patients with advanced neuroendocrine tumors and 
other solid tumors.  
Screening Period  
After signing the informed consent form, patients will be screened for eligibility within 28 
days before starting study medication. Subject eligibility will be assessed after all screening 
procedures have been completed.  
Treatment period  
A 21-day treatment cycle. HBM4003 will be administered once on Day 1 of each treatment 
cycle. One dose of fixed dose mg each time is administered on Day 1 of each treatment cycle 
of teriprilumab.  
The DLT observation period was defined as 21 days of the first treatment cycle. After the 
end of DLT observation period, if no DLT event occurs, the subjects will continue to receive 
treatment with HBM4003 in combination with Toripalimab for a maximum treatment period of 
2 years, or withdraw from the trial until confirmed disease progression, intolerance, or 
withdrawal of informed consent, whichever occurs first. Subjects may permanently discontinue 
HBM4003 during the study due to an adverse event, while only treatment with Toripalimab is 
administered in subsequent treatment cycles (see 14.4 Appendix: Management of 
Immunotherapy-related Toxicities for details).  
In the 4003.1 study, the starting dose of HBM4003 was 0.3 mg/kg QW. As of April 13, 
2021, a total of 20 subjects were treated in the dose escalation phase of 4003.1 study, of which 
7 subjects were treated with 0.3 mg/kg weekly HBM4003, 7 subjects were treated with 0.45 
mg/kg every 3 weeks HBM4003, and 6 subjects were treated with 0.6 mg/kg every 3 weeks 

Harbour BioMed                                                                                                                                        Study Number: 4003.6  
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HBM4003. The maximum tolerated dose (MTD) has not been reached. Except for 1 patient in 
the 0.3 mg/kg dose group and 2 patients (1 in the 0.45 mg/kg and 1 in the 0.6 mg/kg dose groups) 
who could not be evaluated, no other patients had DLT. In the 4003.2 study, a dose escalation 
study was conducted using HBM4003 0.03 mg/kg Q3W as the starting dose in combination 
with terpilimumab fixed dose mg Q3W. In the accelerated titration phase of the trial HBM4003 
0.03 mg/kg, only one subject will be enrolled, and if no DLT occurs in this subject, the dose 
can be escalated to the 0.1 mg/kg dose group; from the 0.1 mg/kg dose group, dose escalation 
will be guided by the i3 + 3 principle. As of April 21, 2021, one patient in HBM4003 0.03 
mg/kg group had no DLT, and two patients in HBM4003 0.1 mg/kg group had completed the 
administration once, without DLT. In this study, considering the potential safety risks of the 
combination in combination with the dose escalation results of 4003.1 and 4003.2, 0.03 mg/kg 
was selected as the initial dose of the combination in this study to ensure the safety of subjects. 
This starting dose will be reasonably changed after discussion by SRC if necessary, based on 
the clinical safety, tolerability and PK data of this product in 4003.1 and 2021.2 studies.  
Dose Escalation Schedule  
Group  
1  
(n = 1)  
2 (i3 + 3)  
3 (i3 + 3)  4 (i3 + 3)  
5 (i3 + 3)  
6 (i3 + 3)  
HBM4003 
(mg/kg)  
0.03  
0.1  
0.3  
0.6  
1.0  
1.5  
TERPRELIMAB 
(mg)  
fixed 
dose  
fixed dose  fixed dose  fixed dose  fixed dose  fixed dose  
During the dose escalation process, adjustments may be made to the preset escalating dose 
levels, dosing frequency, total number of HBM4003 doses, and PK blood sampling points based 
on safety, efficacy, and human PK data, as discussed by the SRC.  
Dose escalation and de-escalation principles  
One subject was enrolled in the first cohort. If the subject had DLT, two more subjects 
were enrolled in this cohort. The principle of dose escalation and de-escalation was changed to 
i3 + 3 as below. Beginning with Group 2, 3 subjects were enrolled in each cohort. From Group 
2 onwards, after each cohort completes the DLT observation period, the i3 + 3 algorithm is used 
to guide dose escalation or de-escalation based on the number of all subjects with DLT at the 
current dose level. In this experiment, the target DLT probability of MTD is set as 25%, the 
equivalence interval of DLT probability is 20% ~ 30%, and the maximum sample size is 31. 
Details of the statistical algorithm are provided in the statistical methods section. The following 
table shows possible scenarios for up to 12 subjects at a dose level.  
 
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
11  
12  
0  
E  
E  
E  
E  
E  
E  
E  
E  
E  
E  
E  
E  

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1  
S  
S  
S  
S  
S  
E  
E  
E  
E  
E  
E  
E  
2  
 
DU  
D  
D  
D  
S  
S  
S  
S  
S  
E  
E  
3  
 
 
DU  
DU  
DU  
D  
D  
D  
D  
S  
S  
S  
4  
 
 
 
DU  
DU  
DU  
DU  
DU  
D  
D  
D  
D  
5  
 
 
 
 
DU  
DU  
DU  
DU  
DU  
DU  
D  
D  
6  
 
 
 
 
 
DU  
DU  
DU  
DU  
DU  
DU  
DU  
7  
 
 
 
 
 
 
DU  
DU  
DU  
DU  
DU  
DU  
8  
 
 
 
 
 
 
 
DU  
DU  
DU  
DU  
DU  
9  
 
 
 
 
 
 
 
 
DU  
DU  
DU  
DU  
10  
 
 
 
 
 
 
 
 
 
DU  
DU  
DU  
11  
 
 
 
 
 
 
 
 
 
 
DU  
DU  
12  
 
 
 
 
 
 
 
 
 
 
 
DU  
* Column shows the number of patients treated. Rows represent the number of patients 
with DLT.  
* E: Upgrade to the next higher dose; S: Keep the same dose; D: Downgrade to the previous 
lower dose, keep the same dose if the current dose is the lowest dose; DU: Downgrade to the 
previous lower dose, the current dose will not be used in this trial.  
 
The specific steps are as follows:  
1. start the trial and enroll one subject at the starting dose. If no DLT occurred in this subject, 3 
subjects were enrolled in each cohort starting from Group 2. After DLT evaluation results 
are observed for each subject, dose escalation, reduction or maintenance will be 
performed according to the above table.  
2. dose escalation will end when any of the following conditions are met:  
a. 31 subjects have completed the study;  
b. 9 subjects have been studied at the next dose level to be decided;  
c. At the lowest dose level, Assessment by DLT Is "DU".  
Definition of DLT  
The DLT observation period was defined as 21 days of the first treatment cycle. A DLT 
was defined as any of the following AEs at least possibly related to study drug (IP) that met the 
protocol-defined CTCAE 5.0 severity criteria and occurred during the DLT observation period.  
─ One or more of the following hematological toxicities (only toxicities clearly 
related to the underlying disease or concurrent illness can exclude DLTs):  
o Grade 4 anemia;  

Harbour BioMed                                                                                                                                        Study Number: 4003.6  
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o Grade 4 leukopenia;  
o Grade 4 leukocytosis or grade 3 leukocytosis lasting ≥ 7 days;  
o Grade 4 neutropenia;  
o ≥ Grade 3 febrile neutropenia;  
o Grade 4 thrombocytopenia.  
─ Any grade 3 or higher non-hematological toxicity (DLT can be excluded only 
for toxicities significantly related to the underlying disease or concomitant 
diseases), except:  
o Alopecia of any grade;  
o Grade 3 fatigue, and recovered to ≤ Grade 2 at Grade 2;  
o Grade 3 insomnia, diarrhea, and vomiting that resolved to ≤ Grade 2 in 
72 hours.  
─ Any serious life-threatening complication or abnormality observed during the 
first treatment cycle that was not defined in CTCAE version 5.0 and could be 
attributed to the study medication.  
─ Any other AE not mentioned above that, in the opinion of the investigator, poses 
a safety hazard to the subject may also be assessed and considered a DLT, e.g.:  
o Permanent discontinuation of HBM4003 due to treatment-related 
toxicity;  
o AEs requiring treatment with systemic corticosteroids equivalent to 
prednisone ≥ 10 mg/kg, including but not limited to Grade 1 and higher 
neurologic toxicities (eg, aseptic meningitis, encephalitis, and transverse 
myelitis), 
hematologic 
toxicities 
(eg, 
acquired 
thrombotic 
thrombocytopenic purpura, aplastic anemia, and acquired hemophilia), 
and cardiac toxicities (eg, myocarditis, pericarditis, arrhythmias, 
ventricular compromise with heart failure, and vasculitis).  
Determination of MTD and RP2D  
1. MTD: After the end of the trial, isotonic (isotonic) regression was applied to select the 
MTD (i.e. Guo et al., 2017 ). I.e. selected toxicity Profile The isotonic estimate of the 
rate is closest to Target Probability of Toxicity Of the dose as the MTD. If the isotonic 
estimates of the two toxicity probabilities are equally close to the target toxicity 
probability, the isotonic estimate of the low toxicity probability is selected. If the 
isotonic estimate of the probability of two doses of toxicity is consistent, the higher dose 
is selected as the MTD if the estimate is less than the target toxicity probability, and the 
lower dose is selected as the MTD if the estimate is greater than or equal to the target 
toxicity probability.  

Harbour BioMed                                                                                                                                        Study Number: 4003.6  
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2. RP2D: Conventional guidelines for assessing MTD may not be applicable for 
immunotherapeutic agents. After consultation with the SRC, the sponsor may choose to 
determine the RP2D in combination with other relevant data. The RP2D may be less 
than or equal to the MTD.  
Part 2 - Dose expansion phase to assess the preliminary efficacy and safety of HBM4003 
in combination with teriprilumab at the RP2D in patients with advanced neuroendocrine 
tumors.  
In part 1, after the dose escalation study of HBM4003 in combination with 
TERPRELIZUMAB was reviewed and recommended by SRC and approved by the Ethics 
Committee, and the MTD (or RP2D) was jointly confirmed by the principal investigator (PI) 
and the sponsor, part 2 was conducted to evaluate the preliminary efficacy and safety of 
HBM4003 in combination with TERPRELIZUMAB at the RP2D of HBM4003 in patients with 
advanced neuroendocrine tumors. If at the time of 4003.6 study initiation, the RP2D has been 
determined in 4003.2 study, it can be used directly after discussion and confirmation by SRC. 
Subjects in the dose expansion phase will be treated with HBM4003 at the RP2D dose in 
combination with Toripalimab until 1 year after the last study drug intake, or initiation of new 
antineoplastic therapy, or confirmation of disease progression, whichever occurs first. Subjects 
may permanently discontinue HBM4003 during the study due to an adverse event, while 
treatment with only Toripalimab is administered in subsequent treatment cycles (see Appendix 
14.5: Management of Immunotherapy Related Toxicities for details).  
Inclusion/exclusion criteria  
Primary Inclusion criteria: 
1. Males or females aged ≥ 18 years at the time of signing the informed consent form. 
For Part 1 of this study, the subjects should be ≤ 75 years of age. 
2. Patients for Part 1: patients histopathologically diagnosed with advanced or recurrent 
solid tumors. 
3. For Part 2 of the study, Patients with non- functional metastatic neuroendocrine tumor 
confirmed by histopathology. 
4. Patients must be able to provide archived tumor tissues after latest treatment or fresh 
tumor tissues and relevant pathology report. 
5. Patients whose estimated survival time is more than 3 months. 
6. Patients with at least one measurable lesion at baseline according to RECIST (Version 
1.1). The lesion had not previously received surgery, radiotherapy and/or local 
treatment. 
7. Patients with Eastern Cooperative Oncology Group(ECOG) performance status score 
≤1. 
8. Every woman or man with potential fertility needs to use an effective contraceptive 
method during the study, up to within 3 months after last drug administration. 
9. Willing and able to comply with study-specified visits schedule, treatment plan, 
laboratory examination and other study procedures.  

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Primary Exclusion criteria:  
1. Patients who are simultaneously participating in another clinical study. 
2. Patients with a history of severe allergic diseases, a history of severe drug allergies, 
and known or suspected allergy to macromolecular protein preparations or HBM4003 
or toripalimab or its excipients. 
3. Previous and concomitant drugs or treatments to be excluded like: 
• Anti-CTLA4 drug; 
• For part 1, anti-PD1 anti-PDL1 or anti-PDL2 treatment was received within 8 
weeks prior to the start of the study; 
• For part 2, patients received anti-PD1, anti-PDL1 or anti-PDL2 treatment 
during the relapse or metastasis stage, and the time from the last treatment is 
short than 12 months before the first dose; 
• Received other antitumor treatment (including chemotherapy, radiation, 
targeted therapy, or biotherapy), antitumor vaccine, chinese herbal medicine or 
proprietary medicine with anti-tumor effect, Immunosuppressant or 
glucocorticoid, Transfusion of PLT or RBC prior to initiation of study 
treatment; 
• live attenuated vaccine was received before study administration or planned 
during the study period. 
4. Insufficient recovery from previous treatments. 
5. Diseases that may affect the efficacy and safety of the investigational product, 
including but not limited to active infection, active autoimmune disease or 
autoimmune disease, primary immunodeficiency disease, any clinically significant 
cardiovascular disease, severe pulmonary insufficiency, organ transplantation, etc. 
6. A history of other malignant diseases within 5 years before the first dose. 
7. Symptomatic, active, or urgent treatment-requiring central nervous system (CNS) 
metastasis with imaging evidence (based on CT or MRI assessment). 
8. Subjects with pleural effusion, pericardial effusion, or ascites that could not be 
stabilized by repeated drainage or other methods were determined by investigator. 
9. Patients who the investigator believes may have other factors that will affect the 
efficacy or safety evaluation of this study (e.g., mental disorders, alcoholism, drug use, 
etc.). 
10. Women who are pregnant or breastfeeding, or who plan to become pregnant during the 
study period and within 3 months after the last administration of the investigational 
product.  
Investigational Product (IP):  
HBM4003 is supplied as a liquid intravenous dosage form in 20 mg/mL, 4 mL/vial.  

Harbour BioMed                                                                                                                                        Study Number: 4003.6  
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─ Dose: Dose levels for the dose escalation phase are presented in the dose escalation 
schedule. In the dose expansion phase, the RP2D determined in the escalation phase 
serves as the expansion dose.  
─ Usage: Intravenous infusion, every 21 days as a treatment cycle. See the dose escalation 
schedule for details.  
Terapril Injection, strength 40 mg/ml, 6 ml/vial.  
─ Dose: fixed dose once every 21 days in both dose escalation and dose expansion phases.  
─ Usage: Intravenous infusion, every 21 days as a treatment cycle. For the method of 
product dilution and intravenous drip administration, please refer to the package insert.  
Control Product:  
Not applicable for this study.  
Duration of treatment:  
Individual Subject Treatment Duration  
Study drug will be administered on Day 1 of each 21-day treatment cycle. For subjects in 
whom disease progression was observed, treatment could continue if the patient had stable or 
decreasing clinical symptoms and clinical benefit was determined by the investigator and 
confirmed by the sponsor. Each subject will receive study drug for a maximum of 2 years or 
until confirmed disease progression, confirmed inability to benefit from therapy, intolerance, or 
withdrawal of consent, whichever occurs first.  
The expected duration of treatment for each subject will vary based on the number of 
cycles completed; the number of cycles will depend on whether the subject is benefiting from 
the treatment. The study consists of a 4-week screening period, a 21-day treatment cycle (which 
can be repeated depending on the potential for clinical benefit), an EOT visit after treatment 
discontinuation, and 2 subsequent visits 28 days (± 7 days) and 84 days (± 7 days) after the 
last dose of study medication.  
Study End Time  
The end of the entire study is defined as 12 months after the last dose of study drug for the 
last subject.  
Assessment:  
Safety Assessments  
Safety assessments included monitoring and recording of all AEs and serious adverse 
events (SAEs), physical examinations, ECOG performance status, vital signs including pulse 
rate and blood pressure, 12 electrocardiograms, echocardiograms (to examine LVEF), 
hematology tests, clinical chemistry tests, urine tests, and concomitant medications.  
In Part 1, the number of patients with DLTs during Cycle 1 (21 days) after the first dose 

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of study drug at each dose level.  
Tumor response assessment  
Tumor response is assessed according to RECIST 1.1 (and mRECIST for patients with 
hepatocellular carcinoma) during study treatment. Tumor assessments will be performed at 
baseline, every 6 weeks (± 1 week) for 12 months prior to first study drug administration, and 
every 12 weeks (± 2 weeks) thereafter for a maximum of 12 months from study drug 
administration, or until new therapy is initiated, radiographic disease progression per RECIST 
1.1 is documented (Eisenhauer et al, 2009), or the subject continues treatment with study drug 
after disease progression per RECIST 1.1 but is no longer of clinical benefit in the judgment of 
the investigator, whichever occurs first.  
Magnetic resonance imaging (MRI) may be used in exceptional cases. For each subject, it 
should be ensured that the same imaging method is used for efficacy evaluation throughout this 
study.  
Evaluation of Pharmacokinetics (PK)  
The plasma concentrations of HBM4003 and Tiprilizumab will be collected and analyzed 
at specific blood sampling time points as shown in the study flow chart.  
The kinetic parameters of HBM4003, including Cmax, Tmax, AUC0-tau, AUC0-inf, t1/2, 
Vd, CL, etc. will be evaluated in subjects in dose escalation group and during multiple dose 
administration.  
In addition, all HBM4003 plasma concentration data obtained in this study will be used 
for population PK analysis to develop a PK model to characterize the PK profile of HBM4003. 
Population pharmacokinetic (popPK) results will be reported separately.  
Dose-Response Assessment  
Individual subject exposure parameters were estimated based on the parameter estimates 
from the final PK model developed for further dose-response (exposure-response) analyses, 
including PK/efficacy and PK/safety correlation analyses. The relationship between exposure 
to Toripalimab and efficacy and adverse events will also be assessed. Results of these analyses 
will be reported separately.  
Immunogenicity Assessment  
ADAs for HBM4003 and teripilimumab will be collected and analyzed at specific blood 
collection time points as described in the Study Flow Chart. For ADA positive individuals, 
neutralizing antibodies will be analyzed.  
Pharmacodynamic (PD) and Biomarker Assessments  
Pharmacodynamic and blood biomarker assessments will be collected and analyzed at 
specific blood collection time points as specified in the Study Flow Chart.  
The subject must provide fresh tumor tissue specimens before the first dose of study drug 
or archived tumor tissue specimens (formalin-fixed paraffin-embedded [FFPE] tissue blocks or 
at least 8 unstained FFPE slides) after the most recent treatment for the detection of exploratory 
indicators such as PD-L1 expression and tumor microenvironment markers. If a subject is 

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unable to provide a fresh tumor sample or archived tumor tissue sample after the most recent 
treatment, and only an archival tumor sample before the most recent treatment, the PI will 
discuss with the sponsor to determine whether the subject can be enrolled in the study. If there 
are lesions that can be biopsied and the risk of the biopsy procedure is acceptable, it is 
encouraged to provide a fresh tissue specimen for comparative analysis at the Week 6 CT/MRI 
tumor response assessment. If tumor biopsy is not performed at Week 6, tumor biopsy is 
encouraged at 28 days (± 7 days) after last dose of study drug.  
See Section 8.13 and Laboratory Manual for details of the biomarker test items to be 
analyzed.  
Safety Review Committee (SRC):  
In Part 1, the SRC will review all subjects for clinical relevance of safety data at the end 
of the first treatment cycle at each dose level and its relationship to HBM4003 treatment.  
Based on the safety information, the SRC will make recommendations regarding the 
continuation, modification, or termination of the study. The right to discontinue, modify, or 
terminate the study remains with the sponsor. Details on the SRC will be described in a separate 
document.  
Statistical Analysis Methods:  
The design consists of two parts, with Part 1 being dose escalation to determine the dose 
to be administered in the Part 2 dose expansion design.  
The dose escalation phase will use the i3 + 3 algorithm to guide dose decisions. The MTD 
will be determined by isotonic regression estimation.  
Descriptive and exploratory statistical analyses will be used in both the dose escalation and 
dose expansion phases.