An Open-label, Dose Escalation Phase 1 Study to Investigate HLX06, a Humanized Monoclonal Antibody Targeting Human Vascular Endothelial Growth Factor Receptor-2, in Patients With Advanced Solid Tumors Refractory to Standard Therapy
Phase: PHASE1
Conditions: Solid Tumor, Adult
Sponsor: Henlix, Inc

                                                                              HLX06-001 
A Phase 1 Study of HLX06, a Humanized Monoclonal Antibody 
Targeting Human Vascular Endothelial Growth Factor Receptor-2 
in Patients with Advanced Solid Tumors Refractory to Standard 
Therapy 
 
 
Sponsor 
Henlix Biotech Co. Ltd.  
5F, No 36, Ln 15, Sec 6, 
Minquan East Road, 
Taipei, Taiwan 114. 
Protocol No. 
HLX06-001 
Version 
1.0 
Document Date 
 
Approval Date 
2017-July-26 
2017-Nov-07 by TMU-Joint 
Institutional Review Board 
Medical Monitor 
H. Eugene Liu, MD, PhD 
Email: medical@henlix.com 
Office fax: 886-227927901 
Office phone: 886-2-
27927927 ext. 106 
 
 
 
 
Confidentiality Statement 
This document contains confidential information that is the property of Henlix 
Biotech Co. Ltd, and must not be disclosed to anyone other than the recipient clinical 
investigator(s) and members of the institutional review board and independent ethic 
committee. This information cannot be used for any purpose other than evaluation or 
conduct of the clinical investigation without prior written consent of the Sponsor. 

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Table of contents 
Synopsis of the Study ...............................................................................................................12 
1. 
Background information and scientific rationale .............................................................21 
1.1. 
Background Information ..........................................................................................21 
1.2. 
Rationale to develop new anti-VEGFR2 monoclonal antibody ...............................21 
1.3. 
Potential Risk and Benefits ......................................................................................22 
1.3.1. 
Known potential risks .......................................................................................22 
1.3.2. 
Known potential benefits ..................................................................................23 
2. 
Objectives .........................................................................................................................24 
2.1. 
Primary Objective .....................................................................................................24 
2.2. 
Secondary Objectives ...............................................................................................24 
3. 
Overview of Study design and endpoints .........................................................................25 
3.1. 
Description of the Study Design ...............................................................................25 
3.1.1. 
Accelerated titration design and cohort size .....................................................25 
3.1.2. 
Bayesian optimal interval design and rules of dose escalation and de-escalation 
 
                                                                                                                          25 
3.2. 
Justification of dose levels and starting dose ............................................................26 
3.3. 
Treatment duration ...................................................................................................27 
3.4. 
Follow-up period ......................................................................................................28 
3.5. 
Primary endpoints of the study .................................................................................28 
3.6. 
Secondary endpoints of the study .............................................................................28 
4. 
Study enrollment and withdrawal .....................................................................................29 
4.1. 
Study population .......................................................................................................29 
4.2. 
Inclusion criteria .......................................................................................................29 
4.3. 
Exclusion criteria ......................................................................................................30 
4.4. 
Randomization and blinding .....................................................................................31 

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5. 
Study drug and its preparation ..........................................................................................32 
5.1. 
Investigational product (IP) and non-investigational product ..................................32 
5.2. 
Description of IP .......................................................................................................32 
5.3. 
Product appearance, storage, stability and formulation ............................................32 
5.4. 
Packaging and labeling .............................................................................................33 
5.5. 
Ordering investigational products ............................................................................33 
5.6. 
Preparation of investigational product and administration .......................................33 
5.6.1. 
Three DON’Ts in preparation of HLX06 for infusion .....................................34 
5.7. 
Drug accountability ..................................................................................................34 
5.8. 
Disposal of investigational product ..........................................................................34 
6. 
Assessment of safety and management of toxicities ........................................................35 
6.1. 
Dose limiting toxicities (DLTs) ................................................................................35 
6.2. 
Stopping rules for clinical deterioration ...................................................................35 
6.3. 
Strategies to mitigate the risk of severe adverse events and toxicities .....................36 
6.4. 
Management of possible toxicities ...........................................................................36 
7. 
Study Schedules and procedrues ......................................................................................41 
7.1. 
Screening period .......................................................................................................41 
7.1.1. 
Assessments in the Screening Period ...............................................................41 
7.2. 
Treatment period ......................................................................................................43 
7.2.1. 
Interval of the first infusion between new patients in a cohort .........................44 
7.2.2. 
The requirement of hospitalization for the infusion of IP ................................44 
7.2.3. 
Procedure for subsequent infusions in a cycle. .................................................46 
7.2.4. 
Infusion delays, missed doses and dose adjustment .........................................47 
7.2.5. 
Discontinuation of patients from treatment ......................................................48 
7.2.6. 
Replacement of participants .............................................................................49 
7.3. 
Follow-up period ......................................................................................................49 
7.3.1. 
Survival follow up ............................................................................................50 

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7.4. 
Post study access to investigational product .............................................................50 
7.5. 
Records of concomitant medications and procedures ..............................................50 
7.5.1. 
Prohibited concomitant medications and procedures .......................................50 
7.5.2. 
Permitted concomitant medications and procedures ........................................51 
7.5.3. 
Effective contraceptive measures .....................................................................52 
7.5.4. 
Treatment of isolated lesions. ...........................................................................52 
7.6. 
Study participation ....................................................................................................52 
8. 
Evaluation of Safety, immunogenicity and efficacy .........................................................54 
8.1. 
Evaluation of safety and tolerability .........................................................................54 
8.2. 
Immunogenicity ........................................................................................................54 
8.3. 
Efficacy evaluation ...................................................................................................54 
9. 
Pharmacokinetic and pharmacodynamic evaluations .......................................................56 
9.1. 
Pharmacokinetic studies ...........................................................................................56 
9.2. 
Pharmacodynamic study ...........................................................................................56 
10. Adverse event reporting ...................................................................................................57 
10.1. 
Definitions of an adverse event and causality analysis ........................................57 
10.2. 
Adverse event collection period ...........................................................................58 
10.3. 
Relationship to study drug ....................................................................................58 
10.4. 
Serious adverse events ..........................................................................................59 
10.5. 
Notification of serious adverse events ..................................................................60 
10.5.1. 
Reporting responsibility ...................................................................................60 
10.5.2. 
Reporting procedures ........................................................................................61 
10.5.3. 
Contact persons and numbers ...........................................................................61 
10.6. 
Overdose ...............................................................................................................61 
10.7. 
Pregnancy .............................................................................................................62 
10.7.1. 
Reporting of pregnancy ....................................................................................62 
10.8. 
Rapid notification of adverse events of significance ............................................62 

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10.9. 
Other safety considerations ..................................................................................63 
11. Description of statistical methods .....................................................................................64 
11.1. 
Bayesian optimal interval design and sample size determination ........................64 
11.1.1. 
Determination of MTD .....................................................................................64 
11.1.2. 
Operating characteristics ..................................................................................64 
11.1.3. 
Sensitivity analysis ...........................................................................................65 
11.2. 
Study population ...................................................................................................66 
11.2.1. 
All enrolled population .....................................................................................66 
11.2.2. 
All treated population .......................................................................................66 
11.2.3. 
Pharmacokinetic data set ..................................................................................66 
11.2.4. 
Response evaluable data set .............................................................................66 
11.2.5. 
Exploratory pharmacodynamic study ...............................................................66 
11.3. 
Statistical considerations ......................................................................................67 
11.3.1. 
Demographics and baseline characteristics ......................................................67 
11.3.2. 
Extent of exposure ............................................................................................67 
11.3.3. 
Concomitant medications .................................................................................67 
11.3.4. 
Efficacy .............................................................................................................67 
11.3.5. 
Safety evaluation ..............................................................................................67 
11.3.6. 
Immunogenicity ................................................................................................69 
11.3.7. 
Pharmacokinetic analysis .................................................................................69 
11.3.8. 
Pharmacodynamic analysis ...............................................................................70 
12. Ethical aspects ..................................................................................................................71 
12.1. 
Ethics and good clinical practice ..........................................................................71 
12.2. 
Confidentiality of study patients ...........................................................................71 
12.3. 
Institutional review board (IRB)/independent ethics committee (IEC) ................71 
12.4. 
Informed consent ..................................................................................................72 
13. Administrative requirements ............................................................................................74 

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13.1. 
Protocol amendments ...........................................................................................74 
13.2. 
Monitoring procedures .........................................................................................75 
13.3. 
Investigator site training .......................................................................................75 
13.4. 
Recording of data and retention of documents .....................................................76 
13.5. 
Study drug record .................................................................................................77 
13.6. 
Case report forms .................................................................................................77 
13.7. 
Auditing procedures .............................................................................................78 
13.8. 
Publication policy .................................................................................................78 
13.9. 
Disclosure and confidentiality ..............................................................................80 
13.10. 
Discontinuation of study .......................................................................................80 
13.11. 
Data management .................................................................................................80 
13.11.1. 
Data collection ..............................................................................................80 
13.11.2. 
Database management and quality control ...................................................80 
13.12. 
Compensation policy ............................................................................................81 
14. Schedule of assessments ...................................................................................................82 
15. Appendices .......................................................................................................................86 
15.1. 
ECOG performance status ......................................................... 86_Toc489009302 
15.2. 
Child-Pugh scoring table for estimation of liver reserve ......................................87 
15.3. 
Adverse event severity scoring system .................................................................88 
15.4. 
RECIST criteria 1.1 ..............................................................................................89 
15.5. 
R codes used to derive the dose escalation and de-escalation ..............................97 
15.6. 
Pregnancy notification worksheet ........................................................................98 
16. References ........................................................................................................................99 
 

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List of Tables 
Table 1. Dose escalation rule .................................................... Error! Bookmark not defined. 
Table 2 Operating Characteristics of the BOIN design ............................................................65 
Table 3. Sensitivity analysis of BOIN design using scenario 1 in Table 2 ..............................65 
Table 4. Grading and description of ECOG PS ........................................................................86 
Table 5. Grading and Description of AE ..................................................................................88 
Table 6. Classification of responses .........................................................................................90 
Table 7. Definition of lesions and imaging modality and their requirement ............................92 

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List of figures 
Figure 1. A hypothetical chart of dose escalation and de-escalation. .......................................20 
 

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Statement of Compliance 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidentiality. This documentation includes the study 
protocol, Investigator’s Brochure, electronic data capture (EDC) system, and other scientific 
data. 
This study will not be conducted without the prior written approval of a properly constituted 
Investigational Review Board (IRB) or Independent Ethics Committee (IEC). 
No changes will be made to the study protocol without prior written approval of the Sponsor 
and the IRB or IEC, except where necessary to eliminate an immediate hazard to the patients. 
I have read and understood and agree to abide by all the conditions and instructions contained 
in this protocol. 
 
 
 
 
 
 
 
Investigator:  
 
 
Name of Site: 
 
(Printed name)  
 
 
 
Signature: 
 
 
Date: 
 
 
 
 
  
(YYYY-MMM-DD) 
 

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List of Abbreviations and Definition of Terms 
ADA 
Anti-drug antibody 
ADCC 
Antibody-dependent cellular cytotoxicity 
AE 
Adverse event 
AFP 
Alpha-fetoprotein 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil counts 
aPTT 
Activated Partial prothrombin time 
AST 
Aspartate aminotransferase 
ATD 
Accelerated titration design 
AUC 
Area under curve 
BOIN 
Bayesian optimal interval design 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count  
CEA 
Carcinoma embryonic antigen 
CI 
Confidence interval 
CR 
Complete response 
CRF 
Case report form 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose limiting toxicity 
ECG 
Electrocardiography 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal growth factor receptor 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GCP 
Good clinical practice 
Hb 
Hemoglobin 
HBcAb 
Hepatitis B core antibody 
HBeAg 
Hepatitis B “e” antigen 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 

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HCG 
Human chorionic gonadotropin 
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IC50 
50% inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
IND 
Investigational new drug application 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional review board 
IV 
Intravenous 
KDR 
Kinase domain receptor  
LDH 
Lactate dehydrogenase 
LLN 
Lower limit of normal 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
MUGA 
Multigated acquisition  
NCI 
National Cancer Institute 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Pharmacodynamics 
PD 
Progressive disease 
PFS 
Progression free survival 
PK 
Pharmacokinetics 
PO 
Per OS 
PR  
Partial response 
PS 
Performance status 
Q3W 
Every three weeks 
QD 
Once every day 
QOL 
Quality of Life 

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QW 
Once every week 
RBC 
Red blood cells 
RECIST 
Response evaluation criteria in solid tumors 
RP2D 
Recommended phase 2 dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SRC 
Safety review committee 
SUSAR 
Suspected unexpected serious adverse reaction 
TSH 
Thyroid-stimulating hormone 
ULN 
upper limit of normal values 
VEGF 
Vascular endothelial growth factor 
VEGFR2 
Vascular endothelial growth factor receptor 2 
WBC 
White blood cell (counts) 
WHODD 
World Health Organization Drug Dictionary  
WWCBP 
Women with child bearing potential 

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SYNOPSIS OF THE STUDY 
Title 
A Phase 1 Study of HLX06, a Humanized Monoclonal Antibody Targeting Human Vascular 
Endothelial Growth Factor Receptor-2 in Patients with Advanced Solid Tumors Refractory to 
Standard Therapy.  
Sponsor 
Henlix Biotech Co. LTD 
Investigational product 
HLX06 recombinant anti-vascular endothelial growth factor receptor 2 (VEGFR2) human IgG1 
monoclonal antibody. 
Study type 
Interventional 
Study phase 
Phase 1 first-in-human study. 
Primary objective  
To identify safety and the maximum tolerated dose (MTD) of HLX06 in patients with 
advanced or metastatic tumors refractory to standard therapy. 
Secondary objectives 
 
The pharmacokinetics of HLX06 at different doses in patients. 
 
The pharmacodynamics of HLX06 at different doses in patients. 
 
The immunogenicity of HLX06 in human beings. 
 
The anti-tumor effects of HLX06 in patients. 
 
The potential prognostic and predictive biomarkers of HLX06 for advanced solid 
tumors. 
Primary outcome measures 
 
Numbers and percentage of patients with adverse events (AEs). 
 
Maximum tolerated dose of HLX06. 
Secondary outcome measures 

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 
Maximum concentration (Cmax) in different cohorts. 
 
Minimum concentration (Cmin) in different cohorts. 
 
Area under concentration (AUC0-tau) in different cohorts. 
 
Half-life (T1/2) of HLX06 in different cohorts. 
 
Clearance (CL) rate of HLX06 in different cohorts. 
 
Volume of distribution (Vss) at steady state in different cohorts. 
 
The presence and percentage of anti-HLX06 antibody (immunogenicity). 
 
Disease control rate.  
 
Overall response rate. 
 
Duration of response 
 
Eligibility criteria 
Inclusion criteria 
 
Eligible patients must be 18-years of age or older or per local regulations. 
 
Patients with histologically-proven measurable or evaluable advanced or metastatic solid 
tumors who have failed standard therapy or for whom no standard therapy is available. 
(For patients with hepatocellular carcinoma, the diagnosis needs to be supported by 
dynamic CT/MRI, if pathological confirmation is not attainable) 
 
Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 at the time of 
study entry. 
 
Able to provide informed consent. 
 
A life expectancy longer than three months. 
 
Adequate hematologic functions, as defined by: absolute neutrophil counts ≥ 1500/mm3; 
a hemoglobin level ≥ 10 gm/dL; a platelet count ≥ 100,000/mm3. 
 
Adequate hepatic function defined by: a total bilirubin level ≤ 1.5x of upper limit of 
normal (ULN); aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤ 
2.5 x of ULN or ≤ 5x of ULN in known hepatic metastases or with primary hepatocellular 
carcinoma. 
 
Adequate renal function, as defined by the creatinine clearance rate ≥ 50 mL/minute by 
Cockcroft-Gault formula. 
 
Adequate cardiac function defined as left ventricular ejection fraction (LVEF)≥ 50%. 
 
Use of effective contraceptive measures if procreative potential exists. 

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 
At least 28 days from prior major surgery, prior cytotoxic chemotherapy, or prior therapy 
with investigational agents (or medical device) or local radiotherapy before 1st infusion 
of HLX06. 
 
For patients with hepatocellular carcinoma, their Child-Pugh score has to be A. 
 
Able to be followed up as required by the study protocol. 
Exclusion criteria 
 
Patients with large centrally located pulmonary lesions adjacent to or invading large blood 
vessels. 
 
Hemoptysis more than ½ teaspoon (approximately 2-3 mL) of red blood per day. 
 
Patients who still have ≥ grade 2 toxicities from prior therapies. 
 
Concurrent unstable or uncontrolled medical conditions with either of the followings: 
o Active systemic infections; 
o Poorly controlled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic 
blood pressure ≥100 mmHg), or poor compliance with anti-hypertensive agents; 
o Clinically significant arrhythmia, unstable angina pectoris, congestive heart failure 
(class III or IV of New York Heart Association [NYHA]) or acute myocardial 
infarction within 6 months; 
o Uncontrolled diabetes or poor compliance with hypoglycemics; 
o The presence of chronically unhealed wound or ulcers 
o Other chronic diseases, which, in the opinion of the investigator, could compromise 
safety of the patient or the integrity of study. 
 
Newly-diagnosed or symptomatic brain metastases (patients with a history of brain 
metastases must have received definitive surgery or radiotherapy, be clinically stable, and 
not taking steroids for brain edema). Anticonvulsants are allowed. 
 
Any concurrent malignancy other than basal cell carcinoma or carcinoma in situ of the 
cervix. (Patients with a previous malignancy but without evidence of disease for ≥ 3 years 
are allowed to participate). 
 
Pregnancy (confirmed by serum beta human chorionic gonadotropin [ßHCG]) or breast-
feeding (for female patients only). 
 
A known history or clinical evidence of a deep vein or arterial thrombosis, or pulmonary 
embolism within 6 months of first infusion of HLX06. 
 
Less than six weeks from last infusion of ramucirumab, or any other anti-VEGF 
monoclonal antibody therapy (Last treatment with other monoclonal antibodies targeting 

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proteins other than anti-angiogenic factors is permitted if ≥ 4 weeks prior to the first 
infusion of HLX06). 
 
Proteinuria ≥ 2+ in routine urinalysis (patients with a protein value of ≤500 mg confirmed 
by a 24-hour urine collection are eligible). 
 
Known history of human immunodeficiency virus infection (HIV). 
 
The patient is the investigator, sub-investigator or any one directly involved in the conduct 
of the study. 
Study design 
This study employs the modified accelerated titration design (ATD) 2A[1] and Bayesian 
optimal interval design (BOIN) to assign patients in the study cohort and identify MTD. 
ATD 2A design assumes that the toxicities and effects increase monotonically with doses. 
It starts with a rapid initial escalation phase by using cohorts of a single new patient to lower 
the probability of exposing patients to sub-therapeutic doses.[1] When moderate-to-severe 
toxicities emerge at higher doses, the acceleration phase ends and the study returns to cohorts 
with 3 new patients.  
The BOIN design is a novel adaptive dose-finding method that allows dose escalation and 
de-escalation and estimates the posterior probability of toxicity rate using updated 
information [2]. This design is considered to have higher probability of identifying the MTD. 
Dose levels and sample size: 250, 500, 750, 900, 1200, 1500 mg (flat dose, with no adjustment 
of body weight or body surface area)[3]. A maximum of 30 patients will be enrolled in the 
phase 1 study. Patients who withdraw from the study during the first cycle due to reasons not 
related to treatment-emergent toxicities will be replaced. 
Dose escalation sequence is modified from the Fibonacci sequence. 
Determination of starting dose and its dose levels: the starting dose is 500  mg (flat dose), 
which is at dose level 2 and approximately equal to 1/6 of human equivalent dose of highest 
non-severely toxic dose (HNSTD) in the cynomolgus study[4]. 
Target toxicity rate: 30% 
Study cycle: Every four weeks. 
ATD phase and cohort size 

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The accelerated phase starts with one new patient per cohort. When the patient does not 
experience dose-limiting toxicities (defined later) during the first cycle of treatment at the 
assigned dose level, the next new patient will be assigned to the next higher dose level of 
HLX06 (ie. intrapatient dose escalation is NOT allowed).  
When the first instance of first-cycle dose-limiting toxicities (DLTs), or the second instance 
of first-cycle grade≥2 toxicities of any types occurs, the acceleration phase stops and the 
cohort expands to three new patients at the current and subsequent dose levels and switch 
to BOIN design.  
Dose escalation/de-escalation rule and Bayesian optimal interval design (BOIN) 
After the end of acceleration phase, the decision to escalate or de-escalate in subsequent 
cohorts is based on the numbers of patients experiencing DLTs and the total number of 
patients treated at the current dose level (Table 1). The decision to escalate or de-escalate is 
based by pre-defined safety and toxicity boundary. If the probability of the DLT rate falls 
below the safety boundary, the dose for the next cohort escalates. By contrast, if the 
probability of DLTs arises above the toxicity boundary, the dose de-escalates in the next 
cohort. Otherwise, the dose level stays the same in the next cohort. The enrollment continues 
until the maximum of 30 patients is reached. The safety boundary in this study is set at 21% 
(70% of target rate); and the toxicity boundary, at 39%, (130% of target rate), respectively. 
The detailed rules are described on page 19 . A hypothetical scheme of ATD and BOIN 
design in the 30 patients  is shown in Figure 1.[2] 
Rules of early stop 
This study also employs two rules for early stopping of the study.  
1. Stop the trial if the lowest dose (250 mg) is eliminated due to overt toxicities. 
2. Stop the trial and estimate the MTD if the number of new patients treated at the current 
dose level reaches 15. 
Determination of MTD 
After the trial is completed, we determine the MTD based on the isotonic regression as 
specified in Yuan et al[5]. The determined MTD is the dose for which the isotonic estimate 
of the toxicity rate is closest to the target toxicity rate of 30%. If there are ties, we select the 
higher dose level when the isotonic estimate is lower than the target toxicity rate; and we 
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The parameters of BOIN design, operating characteristics and sensitivity analysis are 
described in the protocol. 
Definition of DLTs 
DLTs are side effects of a drug or other treatment that are serious enough to prevent an 
increase in dose or level of that treatment during the first cycle (first 4 weeks) of treatment. 
Common Toxicity Criteria for Adverse Events (CTCAE) 4.0 are used for grading of 
toxicities in this study.  
The definitions of DLT include: 
 
Grade-4 nonhematologic toxicities; 
 
Grade≥3 febrile neutropenia;  
 
Any grade-3 non-hematologic toxicities lasting more than 3 days despite of optimal 
supportive care;  
 
Grade-3 nonhematologic laboratory abnormalities that persist more than one week and 
require medical intervention or hospitalization; 
 
Grade-4 thrombocytopenia requiring platelet transfusion or leading to life-threatening 
bleeding event. 
 
Grade-4 neutropenia > 7 days. 
Treatment cycle and route of administration:  
Each cycle consists of 4 weekly intravenous infusions at the assigned dose level. 
Patients with good tolerability and disease control will continue treatment until disease 
progression or up to the maximum of one year, withdrawal from study or death, whichever 
comes first. If the individual patient still benefits from the Investigational Product after one year 
of treatment, extending the treatment beyond one year may be arranged with the Sponsor. 
Pre-medications 
Primary prophylaxis for first infusion reaction of HLX06 is NOT mandatory. If the patients 
experience infusion reactions, allergic reactions, nausea, vomiting or other symptoms/signs 
related to infusion of experimental drugs, pre-medications to mitigate these reactions with 
antihistamine, acetaminophen, corticosteroid or 5-HT3 antagonist or by institutional guidelines 
are permitted in subsequent infusions. Infusion time is two hours. 

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Treatment evaluation 
RECIST criteria 1.1 will be used for treatment evaluation1. 
1. For the first 24 weeks, treatment evaluation is conducted every 8 weeks (i.e. every 2 
cycles) despite treatment delay.  
2. After 24 weeks, treatment evaluation is conducted every 12 weeks (3 cycles).  
Dose modification scheme 
Dose modification is based on the toxicities from previous infusions. Patients who experience 
reversible DLTs are allowed to receive additional infusions at the next lower dose level, 
provided that the toxicities have reverted to grade≤1 in 28 days after last infusion, and that the 
patients still meet the inclusion criteria for adequate organ functions. 
 For patients who experience DLTs, re-escalation to the dose level that causes DLT is not 
permitted. Up to two dose-level reductions per patient are allowed in this study. 
Pharmacokinetic studies 
To measure the serum concentration of HLX06, blood samples will be collected pre-dose 
(within one hour), immediately after infusion (within 30 minutes), and at 2, 4, 8, 24, 48, 96, and 
168 hours from the 1st and 4th infusion in cycle 1.  
Additional time points include pre-dose and after 2nd and 3rd infusions (30 minutes allowable) 
in cycle 1. Thereafter, the blood levels of HLX06 will be measured before the first infusion of 
cycle 2 to cycle 6 or up to 24 weeks, whichever comes first; on the 28-day follow-up visit, 
whenever possible. 
Non-compartmental pharmacokinetic analysis will be used to estimate the PK parameters. 
Pharmacodynamic studies 
Serum concentrations of VEGF-A, soluble VEGFR-1, soluble VEGFR-2 will be measured 
before and after each infusion in cycle 1 in conjunction with pharmacokinetic studies. 
Immunogenicity studies 
                                                     
1 For patients with hepatocellular carcinoma, mRECIST is used to evaluate treatment effect[6] 

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Serum samples used to evaluate the presence of antibody against HLX06 will be obtained prior 
to every infusion of HLX06 in cycle 1 and before the first infusion in subsequent 5 cycles or up 
to 24 weeks, whichever comes first; at the end of therapy, and at the 28-day follow-up visit, 
whenever possible. 
Table 1. Dose escalation table 
No. of patients treated at current dose level  
3 
6 
9 
12 
15 
Escalate if # of DLT 
0 
1 
2 
3 
3 
Remain at the same dose if # of DLT 
1 
2 
3 
4 
4,5 
De-escalate if # of DLT 
2 
3 
4 
5 
6 
Eliminate if # of DLT 
3 
4 
6 
7 
8 
 
The rules to escalate or de-escalate are as follows: 
(a) “Eliminate” means that we eliminate the current and higher doses from the trial to prevent 
treating any future patients at these doses because they are overly toxic. 
(b) When we eliminate a dose, we automatically de-escalate the dose to the next lower level. 
When the lowest dose is eliminated, we stop the trial 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, we treat the 
new patients at the current dose. 
(d) If the current dose is the lowest dose and the rule indicates dose de-escalation, we will treat 
the new patients at the lowest dose unless the number of DLTs reaches the elimination boundary, 
at which point we will terminate the trial for safety. 
(e)  If the current dose is the highest dose and the rule indicates dose escalation, we will treat 
the new patients at the highest dose up to maximum 30 patients. 
(f). If the number of new patients treated at the current dose reaches 15, stop the trial and 
determine the MTD based on data from enrolled patients.  
 

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Figure 1. A hypothetical chart of dose escalation and de-escalation.  
The number indicates the enrolled patient number. Each circle represents one patient. A square 
box indicates a cohort. Dotted arrow indicates the lowering to next lower dose if a patient 
experiences DLT in previous infusions. Open cycle indicates no DLT during the 1st cycle of 
therapy. Gray cycle indicates grade 2 toxicities during the first cycle. Filled cycle indicates DLT 
during the first cycle of treatment.  
 

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1. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
1.1. Background Information 
Angiogenesis plays an important role in cancer development. More than a dozen different 
proteins have been identified as angiogenic activators, including vascular endothelial growth 
factor (VEGF), basic fibroblast growth factor, angigenin. The VEGF family and their receptors 
(VEGFR) are well characterized for their role in neoplastic angiogenesis. The best known 
monoclonal antibody targeting angiogenesis is bevacizumab (Avastin®). Bevacizumab has 
been approved for multiple cancers, including lung, ovarian, colorectal and brain cancer 
(https://www.avastin.com). Among them, VEGFR2 belongs to type V receptor tyrosine kinase 
encoded by KDR gene, and is expressed in vascular endothelial cells. It is a primary responder 
to vascular endothelial growth factor signal that regulates endothelial migration and 
proliferation. The expression of VEGFR2 can be found in multiple tumor types, including 
angiosarcoma, Kaposi sarcoma. In epithelial carcinoma, VEGFR2 expression can be found in 
mesothelioma, non-small cell lung cancer, and embryonal carcinoma[7]. The tissue levels of 
VEGF-C and VEGFR2 significantly correlate with the progression and prognosis of cancer.[8] 
Targeting angiogenesis using either small molecule inhibitors or biological agents have been 
widely used in current cancer management. Current approved anti-angiogenesis biological 
agents include bevacizumab, ramucirumab, aflibercept. Among them, ramucirumab (IMC-
1121B) targets vascular endothelial growth factor receptor 2 (VEGFR2). Ramucirumab has 
been approved for use in combination with paclitaxel for second-line treatment of patients with 
advanced gastric or gastroesophageal junction adenocarcinoma[9]. 
Ramucirumab is a fully human IgG1 monoclonal antibody that binds with high affinity to the 
extracellular domain of VEGFR2. It was discovered from an antibody phase display library 
from pooled B lymphocytes of healthy human donors. The EC50 of ramucirumab is 
approximately 0.15 nM. A crystal structure analysis demonstrates the binding of its Fab to 
domain 3 of VEGFR2 near N-terminus. It blocks the VEGF signaling by both steric blocking 
of its ligand and changing the receptor conformation[9]. 
1.2. Rationale to develop new anti-VEGFR2 monoclonal antibody 
Although ramucirumab has been approved for gastric cancer, its improvement in overall 
survival is still not satisfactory. It prolongs the overall survival by 6 weeks when combined with 
paclitaxel. So far, there is not biomarker available to predict the efficacy of ramucirumab. 

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Therefore, a new monoclonal antibody also targeting VEGFR2 might provide better efficacy 
for cancer patients.  
HLX06 is a new monoclonal antibody targeting VEGFR2. It has better binding affinity to 
VEGFR2, and also binds to different region in VEGFR2. In vitro studies have demonstrated 
the growth inhibition of human endothelial cells, and HLX06 has shown growth inhibition of 
tumors in xenogeneic studies. 
Nonclinical studies up to weekly 150 mg/kg in cynomolgus monkeys for 13 weeks have shown 
good tolerability without evident toxicities (please refer to Investigator’s brochure). HLX06 
shows cross-reactivity to both monkey and human VEGFR2, but does not bind rodent VEGFR2. 
This study is the first-in-human study to address the safety and tolerability of HLX06 in patients 
with metastatic or recurrent cancer. 
1.3. Potential Risk and Benefits 
1.3.1. Known potential risks 
HLX06 has not been tested in human before and its potential toxicities are unknown. Based on 
the nonclinical studies, HLX06 reacts with human and monkey VEGFR2, but not murine 
VEGFR2, so its prediction of toxicities in human is based on the monkey study with limited 
numbers. However, HLX06 is not the first monoclonal antibody targeting VEGFR2 to go into 
humans. Ramucirumab, a VEGFR-2 monoclonal antibody, has been widely used in different 
cancers with more than 1000 patients. When ramucirumab is used alone in a patient population 
similar to this study, the most common toxicity is grade-3 hypertension.[10] No increased risk 
of bleeding, venous thrombosis, proteinuria, or gastrointestinal perforation occurred[9]. 
However, when ramucirumab is used in combination with cytotoxic agents, it has a different 
toxicity profile. In the study with paclitaxel, the most common grade-3 or higher toxicities are 
neutropenia, leucopenia, hypertension, fatigue and abdominal pain.[11] When ramucirumab is 
used with FOLFOX chemotherapy as first-line therapy for colorectal cancer patients, the most 
common grade-3 or higher toxicities are neutropenia, fatigue, and neuropathy[12]. Based on 
the same target and similar mode of action by HLX06 in cancer cells, we expect the toxicity 
profile is likely to be similar to those observed in ramucirumab monotherapy. Although 
ramucirumab appears to be more tolerable than bevacizumab, Investigators have to remain 
vigilant given that no prior safety data are available for HLX06.  

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1.3.2. Known potential benefits 
This study enrolls metastatic or recurrent patients who have failed standard therapy. Its benefit 
for patients who participate in this study remains unclear. However, based on prior study of 
ramucirumab in gastric cancer patients who have failed first-line chemotherapy, ramucirumab 
monotherapy improves overall survival up to two months[13]. When ramucirumab was tested 
at different doses in metastatic patients with different cancer types, 60% had stable disease with 
median duration of 12.7 months[10, 14]. Stable disease ≥4 months occurred in 20% of patients 
without warning toxicities. Based on similar mode of action, we expect the activity of HLX06 
likely to be similar to that of ramucirumab. 
 

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2. OBJECTIVES 
2.1. Primary Objective 
To identify safety and the maximum tolerated dose (MTD) of HLX06 in patients with advanced 
or metastatic tumors refractory to standard therapy. 
2.2. Secondary Objectives 
 
The pharmacokinetics of HLX06 at different doses in patients. 
 
The pharmacodynamics of HLX06 at different doses in patients. 
 
The immunogenicity of HLX06 in human beings. 
 
The anti-tumor effects of HLX06 in patients. 
 
The potential prognostic and predictive biomarkers of HLX06 for advanced solid 
tumors. 

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3. OVERVIEW OF STUDY DESIGN AND ENDPOINTS 
3.1. Description of the Study Design 
This study is a prospective, open-label, dose-escalation study of HLX06 in patients with 
metastatic or recurrent solid tumors who have failed standard therapy.  
This study integrates the modified accelerated titration design 2A (ATD) and Bayesian optimal 
interval design (BOIN) to determine the MTD of HLX06[1, 2]. The safety and PK profiles, and 
immunogenicity as well as the preliminary efficacy will also be examined.  
Eligible patients who fulfill the eligibility criteria will receive weekly infusion of HLX06 at the 
assigned dose level until disease progression or to the maximum of one year, withdrawal from 
study or death, whichever comes first.  
Each cycle of treatment is comprised of 4 doses of investigational product administered weekly.  
This study plans to enroll a maximum of 30 patients. Patients who withdraw from the study for 
reasons not related to treatment-emergent toxicities during the first cycle will be replaced. 
3.1.1. Accelerated titration design and cohort size 
In the ATD 2A design, the study starts with acceleration phase. In this phase, each cohort 
consists of one NEW patient for each dose level. After first cycle of treatment, the patient will 
be evaluated for the toxicities in last cycle. If this patient does not have DLTs, the next patient 
is allowed to receive the treatment at the next higher dose level. 
In the acceleration phase, the newly enrolled patients start at the highest dose level, in which 
no moderate toxicities are observed in prior patients. 
When the first instance of first-cycle DLT or the second instance of first-cycle grade≥2 
toxicities of any types occurs, acceleration phase ends and the cohorts for the current dose level 
expand to three NEW patients and the study switches the BOIN design phase.  
In the acceleration phase, intra-patient dose escalation is NOT allowed.  
3.1.2. Bayesian optimal interval design and rules of dose escalation and de-
escalation 
After the acceleration phase, the study uses BOIN design to determine rule of dose escalation 
and de-escalation. First, the target toxicity rate in this study is set at 30%, which is the most 

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common toxicity rate for conventional 3+3 design, indicating that for an oncologic agent, the 
toxicity rate higher than 30% is NOT desirable[15].  
Different from the rule-based 3+3 design, the decision to escalate or de-escalate in BOIN design 
is based on the posterior probability of DLTs from updated information. The probability of 
DLTs is determined by the number of DLTs and the cumulative number of patients treated at 
the current dose. The safety boundary to escalate the dose is set at 70% of target toxicity rate 
(i.e. 21%); and the toxicity boundary is, at 130% of target toxicity rate (i.e. 39%), respectively. 
If the probability of DLTs at the current dose level falls below 21%, the dose in the next cohort 
escalates to the next higher level. By contrast, when the probability of DLT at the current dose 
level arises above 39% (130% of target rate), the dose in the next cohort de-escalate to the next 
lower level. The dose level for the next cohort remains the same if the probability of toxicity is 
within the safety and toxicity boundary. The enrollment continues until the maximum of 30 
patients are reached.  
The detailed rule of dose escalation and de-escalation is tabulated in Table 1. 
There are also two pre-set EARLY STOPPING RULES in this study. 
 Stop the trial if the lowest dose (dose level 1) is eliminated due to overt toxicities. 
 Stop the trial and estimate the MTD if the number of new patients treated at the current 
dose level reaches 15 
The detailed statistical methods for dose escalation and de-escalation and estimation of MTD 
are described in Section 11. This study uses R software and BOIN package for setting up the 
specifications. The detailed R codes for this study are described in the Appendix (Section 15.5). 
Patients who experience DLTs may be allowed to continue the treatment at the next lower dose 
level after the toxicities revert to grade≤1 in 28 days after last infusion, if the Investigator judges 
that the patient still meet the inclusion criteria and might benefit from continuous treatment. 
For patients who experience DLTs, re-escalation to the dose level causing DLT is not permitted. 
Up to two dose-level reductions per patient are allowed in this study. 
3.2. Justification of dose levels and starting dose 
Six dose levels are planned: 250, 500, 750, 900, 1200, 1500 mg flat dose. The reason for using 
flat dosing instead of body weight-adjusted dosing is based on previous population 
pharmacokinetic studies for multiple monoclonal antibody drugs[3, 16, 17]. Patients will be 
assigned to a dose level in the order of study entry. The starting dose of 500 mg (dose level 2) 

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is based on ICH guidance and determined to be equal to 1/6 of the human equivalent dose of 
the highest non-severely toxic dose (HNSTD)[4, 18]. 
In BOIN design, the decision to escalate or de-escalate is based on the probability of toxicities 
from updated information on pre-defined toxicity rate, which is set at 30% in this study. When 
the probability of DLT is lower than 21% (70% of target rate), the dose in the next cohort 
escalates to the next level. By contrast, when the probability of DLT is higher than 39% (130% 
of target rate), the dose in the next cohort de-escalate to the next lower level. The enrollment 
continues until the maximum of 30 patients is reached. 
The rule of dose escalation and de-escalation is tabulated in Table 1. 
There are two early stopping rules set in this study. 
 
Stop the trial if the lowest dose (dose level 1, i.e. 250 mg) is eliminated due to overt 
toxicities. 
 
Stop the trial and estimate the MTD if the number of new patients treated at the current 
dose level reaches 15 
The detailed statistical methods for dose escalation and de-escalation and determination of 
MTD are described in Section 11. Description of Statistical Methods. The detailed R script for 
this study is described in. Section 15.5. 
3.3. Treatment duration 
If the patients experience no adverse reactions that lead to treatment delay or discontinuation, 
treatment continues weekly until disease progression, to the maximum of one year, withdrawal 
from study or death, whichever comes first.  
Detailed procedures for the evaluation and treatment are described in Section. 7.2.  
Toxicities will be evaluated and graded by the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) 4.0 or until the toxicities revert to grade ≤1.  
Serial serum samples will be collected during the 1st and 4th week of 1st cycle of treatment at 
scheduled time points for determination of the PK of HLX06. Additional time points include 
before and after 2nd and 3rd infusions in cycle 1. Thereafter, the blood levels of HLX06 will be 
measured before and after the first infusion in each cycle up to 24 weeks, , and on the 28-day 
follow-up visit (Follow-up Visit 1) whenever possible. 

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This study also incorporates optional pharmacodynamic study by examining the serum levels 
of VEGF-A, soluble VEGFR-1, soluble VEGFR-2 before and after first and 4th infusion in 
cycle 1 in conjunction with pharmacokinetic studies.  
3.4. Follow-up period 
The details of follow-up are described in Section 7.3. 
3.5. Primary endpoints of the study 
 Primary outcome measures 
 Numbers and percentage of patients with adverse events (AEs). 
 Maximum tolerated dose of HLX06. 
3.6. Secondary endpoints of the study 
 Maximum concentration (Cmax) in different cohorts. 
 Minimum concentration (Cmin) in different cohorts. 
 Area under concentration (AUC0-tau) in different cohorts. 
 Half-life (T1/2) of HLX06 in different cohorts. 
 Clearance (CL) rate of HLX06 in different cohorts. 
 Volume of distribution (Vss) at steady state in different cohorts. 
 The presence and percentage of anti-HLX06 antibody (immunogenicity). 
 Disease control rate  
 Overall response rate. 
 Duration of response 
 

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4. STUDY ENROLLMENT AND WITHDRAWAL 
4.1. Study population 
A maximum of 30 patients will be enrolled (if no patients require replacement). Patients with 
metastatic or recurrent solid tumors who have failed standard therapy can be considered eligible 
for enrollment.  
4.2. Inclusion criteria 
 
Eligible patients must be 18-years of age or older or per local regulations. 
 
Patients with histologically-proven measurable or evaluable advanced or metastatic solid 
tumors who have failed standard therapy or for whom no standard therapy is available. 
(For patients with hepatocellular carcinoma, the diagnosis needs to be supported by 
dynamic CT/MRI, if pathological confirmation is not attainable) 
 
Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 at the time of 
study entry. 
 
Able to provide informed consent. 
 
A life expectancy longer than three months. 
 
Adequate hematologic functions, as defined by: absolute neutrophil counts ≥ 1500/mm3; 
a hemoglobin level ≥ 10 gm/dL; a platelet count ≥ 100,000/mm3. 
 
Adequate hepatic function defined by: a total bilirubin level ≤ 1.5x of upper limit of 
normal (ULN); aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤ 
2.5 x of ULN or ≤ 5x of ULN in known hepatic metastases or with primary hepatocellular 
carcinoma. 
 
Adequate renal function, as defined by the creatinine clearance rate ≥ 50 mL/minute by 
Cockcroft-Gault formula. 
 
Adequate cardiac function defined as left ventricular ejection fraction (LVEF)≥ 50%. 
 
Use of effective contraceptive measures if procreative potential exists. 
 
At least 28 days from prior major surgery, prior cytotoxic chemotherapy, or prior therapy 
with investigational agents (or medical device) or local radiotherapy before 1st infusion 
of HLX06. 
 
For patients with hepatocellular carcinoma, their Child-Pugh score has to be A. 
 
Able to be followed up as required by the study protocol. 
 
 

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The ECOG performance table is listed in Appendix 15. Detailed the Child-Pugh score is listed 
in Appendix 15.2. 
4.3. Exclusion criteria 
 
Patients with large centrally located pulmonary lesions adjacent to or invading large blood 
vessels. 
 
Hemoptysis more than ½ teaspoon (approximately 2-3 mL) of red blood per day. 
 
Patients who still have ≥ grade 2 toxicities from prior therapies. 
 
Concurrent unstable or uncontrolled medical conditions with either of the followings: 
o Active systemic infections; 
o Poorly controlled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic 
blood pressure ≥100 mmHg), or poor compliance with anti-hypertensive agents; 
o Clinically significant arrhythmia, unstable angina pectoris, congestive heart failure 
(class III or IV of New York Heart Association [NYHA]) or acute myocardial 
infarction within 6 months; 
o Uncontrolled diabetes or poor compliance with hypoglycemics; 
o The presence of chronically unhealed wound or ulcers 
o Other chronic diseases, which, in the opinion of the investigator, could compromise 
safety of the patient or the integrity of study. 
 
Newly-diagnosed or symptomatic brain metastases (patients with a history of brain 
metastases must have received definitive surgery or radiotherapy, be clinically stable, and 
not taking steroids for brain edema). Anticonvulsants are allowed. 
 
Any concurrent malignancy other than basal cell carcinoma or carcinoma in situ of the 
cervix. (Patients with a previous malignancy but without evidence of disease for ≥ 3 years 
are allowed to participate). 
 
Pregnancy (confirmed by serum beta human chorionic gonadotropin [ßHCG]) or breast-
feeding (for female patients only). 
 
A known history or clinical evidence of a deep vein or arterial thrombosis, or pulmonary 
embolism within 6 months of first infusion of HLX06. 
 
Less than six weeks from last infusion of ramucirumab, or any other anti-VEGF 
monoclonal antibody therapy (Last treatment with other monoclonal antibodies targeting 
proteins other than anti-angiogenic factors is permitted if ≥ 4 weeks prior to the first 
infusion of HLX06). 

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 
Proteinuria ≥ 2+ in routine urinalysis (patients with a protein value of ≤500 mg confirmed 
by a 24-hour urine collection are eligible). 
 
Known history of human immunodeficiency virus infection (HIV). 
 
The patient is the investigator, sub-investigator or any one directly involved in the conduct 
of the study. 
 
4.4. Randomization and blinding 
o 
Blinding is not applicable as this is an open-label study. 
o 
The patients of the study are not randomized. 
The study site will contact the Sponsor or its designee for treatment assignment once a patient 
is determined to be eligible for enrollment. Patients who meet all the eligibility criteria will be 
assigned a number and the dose level for the first infusion as determined by the Sponsor or its 
designee. Once assigned, numbers for any screening failures, non-treated, non-evaluable, or 
discontinued subjects will not be re-used. 
 

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5. STUDY DRUG AND ITS PREPARATION 
All protocol-specified investigational and non-investigational products are considered study 
drugs. 
5.1. Investigational product (IP) and non-investigational product 
An investigational product, also known as investigational medicinal product in some regions, 
is defined as follows: A test article or pharmaceutical form of an active ingredient or placebo 
that is tested or used as a reference in a clinical trial, including a product with a marketing 
authorization when used or assembled (formulated or packaged) in a way different from the 
approved form, used for an unapproved indication, or used to gain further information about an 
approved use. 
The IP is HLX06 in this study. 
Other medications used in the study as support or escape medication for preventative, 
diagnostic, or therapeutic reasons, as components of the standard of care for a given diagnosis, 
are considered non-investigational products.  
In this protocol, non-investigational product(s) is/are: Not applicable for this study. 
5.2. Description of IP 
HLX06 is recombinant human IgG1 monoclonal antibody directed against human VEGFR2. 
The study agent will be provided by the Sponsor. The rest of medications are provided by study 
sites. 
5.3. Product appearance, storage, stability and formulation 
HLX06 is supplied in a single-use 10 mL vial. Each vial contains 100 mg active drug in 10 mL 
clear, colorless solution and should be stored at 2-8 ºC. The drug is expected to be stable up to 
two years when stored at 2-8 ºC. In addition to the active ingredient, the main ingredients in the 
solution are sucrose, sodium chloride, sodium citrate, and polysorbate 80. Detailed information 
on formulation is described in the Investigator’s brochure. The product storage manager should 
ensure that the investigational product is stored in accordance with the environmental 
conditions (temperature, light, and humidity) as determined by the Sponsor. If concerns 

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regarding the quality or appearance of the investigational product arise, do not dispense the 
investigational product and contact the Sponsor immediately. 
Investigational product should be stored in a secure area per local regulations. It is the 
responsibility of the Investigator to ensure that investigational product is only dispensed to 
study patients. Investigational product must be dispensed only from official study site by 
authorized personnel according to local regulations. 
5.4. Packaging and labeling 
The investigational product will be packaged and labeled per current good manufacturing 
practices (GMP).  
5.5. Ordering investigational products 
Clinical supplies may be requested by completing a Request Form and faxing it or e-mail it to 
the Drug Supply Coordinator of the Sponsor or its designee.  
5.6. Preparation of investigational product and administration 
HLX06 is intended for intravenous injection only with final concentration no more than 10 
mg/mL 
To minimize the error in the adjustment of infusion rate, HLX06 is constituted to the final 
volume of 200 mL with normal saline and infused intravenously in two hours, regardless of 
the assigned dose level. Diluted HLX06, if not used in 4 hours, should be stored at 2-8 ºC and 
be used in 24 hours. 
 The following procedure is required to prepare the HLX06 solution. 
Confirm the dose needed to be infused and calculate the volume needed. Draw up the volume 
of a vial of HLX06 using a sterile syringe. 
Fill HLX06 in a sterile evacuated container or bag such as glass containers, polyolefin bags 
(ethylene vinyl acetate bags, DEHP plasticized PVC bags, or PVC bags).  
Repeat the procedure until the calculated volume has been put in to the container. Use a new 
needle for each vial.  
Dilute the drawn HLX06 with sterile 0.9% saline solution to make the final volume of 200 mL. 

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Administer through a low protein binding 0.22-micrometer in-line filter (placed as proximal to 
the patient as practical). Affix the infusion line and prime it with diluted HLX06 before starting 
the infusion. Set the infusion rate to 100 mL per hour.  
At the end of infusion period, flush the line with sufficient amount of normal saline. 
5.6.1. Three DON’Ts in preparation of HLX06 for infusion 
 
DON’T enter the vial more than once. 
 
DON’T piggyback to the patient’s other infusion line. HLX06 should be infused using a 
separate infusion line. 
 
DON’T administer HLX06 as an intravenous push or bolus injection. 
5.7. Drug accountability 
HLX06 must be kept in an appropriate, secure locked area and stored in accordance with the 
conditions specified on the labels. 
The Investigator or designated study person must maintain an accurate record of dispensing the 
investigational product in a Drug Accountability Log, a copy of which must be given to the 
Sponsor at the end of the study. The Drug Accountability Log will record the investigational 
products received, dosages prepared, time prepared, doses dispensed, and doses and/or vials 
destroyed. The Drug Accountability Log will be reviewed by the field monitor during site visits 
and at the completion of the study. 
5.8. Disposal of investigational product 
If investigational products are to be destroyed on site, it is the investigator’s responsibility to 
ensure that arrangements have been made for the disposal, procedures for proper disposal have 
been established according to applicable regulations, guidelines and institutional procedures, 
and appropriate records of the disposal have been documented. Unused HLX06 should be 
returned to the Sponsor after the study. Used vials can be disposed at the study site following 
institutional guidelines for investigational product. Vials without proper labeling or suspected 
of contamination should not be used and returned to the Sponsor. 
 

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6. ASSESSMENT OF SAFETY AND MANAGEMENT OF TOXICITIES 
6.1. Dose limiting toxicities (DLTs) 
DLTs are side effects of a drug or other treatment that are serious enough to prevent an increase 
in dose or level of that treatment in a clinical study. We use Common Toxicity Criteria for 
Adverse Events (CTCAE) 4.0 for grading of toxicities in this study.  
The definition of DLTs in this study is the toxicities during the first cycle of treatment: 
A DLT will be considered to be IP-related unless there is a clear, well-documented, alternative 
explanation for the toxicity. Delayed DLTs are adverse events that meet the criteria of DLTs 
that occur after the first cycle of treatment. Delayed DLTs need to be evaluated on a case-by-
case basis to make sure that there is no cumulative damage to vital organ function. 
Delayed DLTs will also be considered to estimate the MTD for HLX06 in this study. 
All adverse events that meet DLT or delayed DLT criteria, as well as any Grade 3 or 4 infusion 
reactions no matter whether the event is a DLT must be reported to the Sponsor or its designee, 
within 24 hours. 
6.2. Stopping rules for clinical deterioration 
Clinical deterioration is defined by the clinical condition of the patient has worsened and, in the 
Investigator’s opinion, is attributable to disease progression. Such deterioration is not likely to 
be reversed with additional administration of Investigational Product and supportive care. The 
decision to continue or stop treatment should be discussed with the Medical Monitor and 
documented in the study records. 
Events that suggest clinical deterioration include, but not limited to the following: 
 
Performance status decrease of at least 2 points from baseline  
 
Skeletal related events defined by the following 
 
Pathologic bone fracture in the region of cancer involvement   
 
Cancer related surgery to bone   
 
Spinal cord or nerve root compression  
 
Bladder outlet or urethral obstruction 
 
Development of new central nervous system metastases 

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 
Patients that develop new CNS metastases in the setting of improving baseline disease 
may have focal radiation, resection, or other local curative procedures performed after 
consultation with the Medical Monitor. 
 
If continued study therapy is deemed to offer the patient potential benefit, patients may 
be allowed to restart study therapy after recovery from symptoms related to the 
procedure performed (i.e., local edema) and steroid dosing at < 10 mg prednisone/day 
or equivalent.  
 
Patients that have locally curative procedures while on study drug and subsequently 
develop new CNS metastases at a subsequent imaging assessment should discontinue 
study therapy and enter the follow-up period. 
 
Or any setting where the initiation of new anti-neoplastic therapy has been deemed 
beneficial to the patient even in the absence of any such documented clinical events. 
6.3. Strategies to mitigate the risk of severe adverse events and toxicities 
To mitigate the risk of HLX06 first-in-human use, the interval of first infusion of investigational 
product between NEW patients in a cohort is 24 hours or longer.  
6.4. Management of possible toxicities 
HLX06 has not been used in human beings before. There is no clinical experience to define 
expected toxicities to humans. Based on its mode of action, the spectrum of toxicities is 
expected to be similar to what have been described for anti-angiogenesis agents, such as 
bevacizumab, ramucirumab or other small molecule inhibitors for anti-angiogenesis (e.g. 
sunitinib, sorafenib). The following are the common or severe toxicities by bevacizumab and 
ramucirumab and their respective management. 
Allergic reaction/hypersensitivity and infusion-related reactions: Fever, chills, shakes, 
itching, rash, hyper- or hypotension, difficulty breathing. It is likely that most infusion-related 
adverse events will occur within the first 24 hours after beginning the infusion, and may be 
treated by slowing or interruption of the infusion, or with supportive treatment as indicated. 
The common agents used to treat hypersensitivity agents are anti-histamine, H2-blockers, 
corticosteroid. Severe anaphylactic reactions might require epinephrine treatment. Infusion 
reaction should be graded according to NCI CTCAE criteria. Treatment recommendations are 
as follows: 

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o Grade 1 symptoms: If the Investigator assesses that it is a mild reaction and infusion 
interruption is not indicated, the prophylactic pre-medications are recommended: 
diphendydramine 30-50 mg (depending on institutional availability or equivalent 
medications), acetaminophen 325-500 mg PO at least 30 minutes before additional IP 
infusion. 
o Grade 2 symptoms: If the Investigator assesses that it is a moderate reaction, 
requiring therapy or infusion interruption, stop the IP infusion and begin with 
intravenous infusion of normal saline, and treat the patients with diphenhydramine 
30-50 mg (or equivalent medications) intravenously, and dexamethasone 10 mg (or 
corticosteroids with equivalent potency) intravenously. After the symptoms have 
subsided, restart the infusion at 50% of original infusion rate. Monitor the patient 
closely. If the symptoms recur, no further IP infusion at that visit. Prophylactic pre-
medications with diphenhydramine, acetaminophen and corticosteroid are indicated 
for future infusion of IP.  
o Grade ≥3 symptoms: It is severe reaction, and recurs, or does not rapidly respond to 
symptomatic treatment and interruption of infusion, stop the infusion of IP 
immediately. Consider 0.2 to 1 mg of 1:10,000 solution of epinephrine for 
subcutaneous administration. Diphenhydramine 30-50 mg intravenous with 
methylpredisolone 100 mg (or equivalent) intravenously, as needed. Hospitalization 
might be needed for possible clinical sequelae.  
 
Hypertension: Hypertension is among the most common toxicities of anti-angiogenic therapy. 
The incidence of hypertension could reach 20% by a single anti-angiogenic agent. Initiation of 
antihypertensive medications should be considered when BP is >140/90mmHg or if there is an 
increase in DBP ≥20mmHg. If SBP >160mmHg, DBP >100mmHg, hypertensive crisis or if 
antihypertensive interventions do not provide appropriate BP control, the dose level of HLX06 
should be decreased or held until antihypertensive therapy is effectively titrated. Although 
appropriate BP control is essential, excessive lowering of BP may also have detrimental 
cardiovascular consequences; careful selection of doses and close BP monitoring are crucial to 
avoid episodes of hypotension. Multiple antihypertensive drugs are being used to treat anti-
angiogenic therapy-induced hypertension including calcium channel blockers, inhibitors of the 
renin-angiotensin system, beta-blockers and diuretics. At this time, however, no clinical 
evidence favoring one antihypertensive agent over another is available [19]. 
 

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Bowel perforation: Clinical trials have revealed that 1-4% of colorectal cancer patients 
receiving bevacizumab could develop spontaneous bowel perforation. It could also occur in 
patients who have no involvement of cancer in the gastrointestinal tract. Several risk factors for 
bevacizumab-associated bowel perforation have been identified, including a history of peptic 
ulcer disease, diverticulitis, colitis, intestinal obstruction, tumor necrosis, recent sigmoidoscopy 
or cumulative dose of bevacizumab, radiotherapy, or emergent surgery while receiving 
bevacizumab, it is still unclear which patients are specifically at risk for this complication. 
Gastrointestinal perforation could lead to peritonitis, requiring emergent operative intervention, 
fistula formation or intra-abdominal abscess[20].  Bowel perforation could be hard to diagnose 
in patients without symptoms. If the symptoms are present, it usually presents as acute abdomen 
due to peritoneal contamination, hemoperitoneum, or free intra-abdominal air, or intra-
abdominal abscess. The management of bowel perforation depends on the timing of the 
presentation, the overall condition of the patients and the goals of treatment. Medical treatment 
is usually ineffective. More likely, patients need to receive surgical intervention. The long half-
life of monoclonal antibody increases the risk of unplanned, urgent surgical procedures. For 
patients who have received HLX06 therapy, surgery within 28 days following their last 
treatment should be avoided. If surgery is necessary, risk-and-benefit assessment should be 
conducted by experienced surgeons. 
 
Severe proteinuria: This is another common side effects observed in anti-angiogenic therapy. 
Severe proteinuria including nephritic syndrome may cause significant morbidity with a 
possible consequence of renal failure and fatality. It is recommended to suspend anti-angiogenic 
therapy at least temporarily for proteinuria ≥2 g/24 hours and to discontinue the therapy for 
nephrotic syndrome. The risks of severe proteinuria include higher dose of therapy, concurrent 
use of chemotherapy and renal cell carcinoma.[21] There are no evidence-based guidances for 
the management of anti-antigenic therapy-induced proteinuria. If proteinuria is ≥ 2 g/24 hours 
during HLX06 therapy, stop the therapy, and the patients might resume the therapy after 
proteinuria decreases to <2 g/ 24 hours at the next lower dose level, if the benefit of HLX06 is 
deemed to outweigh the risks, as judged by the Investigator. 
 
Bleeding: This is a frequent complication of anti-angiogenic therapy. Two meta-analyses have 
found that the use of bevacizumab in combination with chemotherapy for the treatment of 
various tumor types conferred an increased risk of severe and fatal bleeding events and 
treatment-related mortality versus chemotherapy alone. Most cases involve low-grade 
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treatment. Epistaxis is another common bleeding. Studies have shown that the rates of grade 1-
2 epistaxis range from 5-26%. Mild-to-moderate Epistaxis is usually managed conservatively. 
However, in severe cases, operative hemostatic intervention might be indicated. In such cases, 
otolaryngologists with experience in managing drug-induced bleeding should be consulted. 
Intracranial hemorrhages are associated with bevacizumab use especially in patients with 
glioblastoma multiforme[22]. The highest incidence of high-grade bleeding is associated with 
non-small cell lung cancer, especially with squamous cell histology. This risk is particularly 
high in patients with persistent hemoptysis before study. This led the exclusion of patients with 
this histology and patients with hemoptysis in most of subsequent clinical studies for lung 
cancer. Well patient selection might be the best strategy to prevent this complication. Once 
bleeding is identified, appropriate management is based on the site and the degree of bleeding. 
In sites where bleeding cannot be controlled by compression, or when the degree of bleeding is 
severe, surgical intervention might be needed for better control.  
 
Poor wound healing and fistula formation: Anti-angiogenic therapy compromises 
neovasculization, and affects wound healing. Pooled analysis from bevacizumab studies found 
13% wound-healing complication. When surgery was done within 2 weeks after last 
bevacizumab dose, the risk of poor healing is higher. So far, specific recommendation for the 
management of poor wound healing has not been established. General recommendation is that 
surgery should be avoided within 60 days of bevacizumab when chemotherapy is used together 
or within 28 days when monotherapy is used.[23] 
 
Thromboembolism: Anti-angiogenic therapy not only increases the risk of bleeding, it also 
increases the risk of thromboembolism[22]. The risk factors associated with thromboembolism 
is age older than 65, advanced cancer, and the location of tumors. The incidence of 
thromboembolism was highest in patients with colorectal cancer.  However, there is not 
standard recommendation for prevention of thromboembolism by prophylactic use of anti-
coagulants. The Investigator should remain high alert on the emergence of thromboembolism 
and manage the complication accordingly. 
 
Tumor lysis syndrome: Tumor lysis syndrome has been described in patients receiving 
chemotherapy/ bevacizumab or sunitinib[24]. This may result in asymptomatic laboratory 
abnormalities to clinical changes secondary to electrolyte disturbances, including cardiac 
arrhythmias, neuromuscular irritability, tetany, seizures, and mental status changes 
(hypocalcemia), acute renal failure (hyperuricemia and hyperphosphatemia), and metabolic 

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acidosis (acute renal failure and lactic acidosis). The management of tumor lysis syndrome 
induced by anti-angiogenic therapy is similar to that by other anti-cancer agents. In general, 
resumption of anti-cancer therapy is judged by the patient’s condition and the decision of 
Investigator. 
 

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7. STUDY SCHEDULES AND PROCEDRUES 
The study of each patient is divided into three periods: screening, treatment and follow-up.  
7.1. Screening period 
As soon as a patient is considered for this study, and before performing any study procedures, 
the patient needs to have the nature of the study explained and will be asked to provide a written 
informed consent. A written, signed and dated, informed consent form (ICF) must be obtained 
before any study-specific assessments are initiated. A copy of the signed ICF will be given to 
the patient and a copy will be filed in the medical record.  The original version needs to be kept 
on file with the study records.  
Screening assessments must be completed within 28 days prior to the first infusion of the IP 
(HLX06). Any results falling outside of the reference ranges may be repeated at the discretion 
of the investigators.   
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
patients, and to ensure that the study results can be used. It is imperative that patients fully meet 
all the eligibility criteria. The study population and detailed Inclusion and Exclusion criteria are 
listed in Section 4 . 
Baseline imaging performed as part of the patient’s previous routine care before signing the 
ICF and completed within 42 days before the first infusion of IP can be used as pre-treatment 
imaging, without the need to repeat the imaging studies. 
If there is a question about eligibility and enrollment, the Investigator should consult with the 
Sponsor’s Medical Monitor, or designee, before enrolling into the study. 
The screening procedures can be done at inpatient or outpatient setting based on the situation 
in different site. 
7.1.1. Assessments in the Screening Period 
Patients will be evaluated for entry criteria during the Screening Period within 28 days before 
the first infusion of study drug. The following procedures and evaluations need to be completed 
for each patient before Day 1: 
1. A written, signed-and-dated informed consent should be obtained before any screening 
procedures and receiving study drugs. 

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2. Inclusion and exclusion criteria are cross-checked. 
3. Demographics and medical history (to include collection of prior medications 
administered to the patient during the Screening Period, prior and concurrent medical 
conditions, and baseline signs and symptoms)2 
4. Diagnosis confirmation and stage3 
5. History of tumor-specific therapy including chemotherapy and radiotherapy or any 
other forms of therapy. 
6. ECOG performance status  
7. Vital signs (temperature, pulse, respiratory rate and blood pressure), weight and height. 
8. Physical examination including an elective neurological examination. 
9. Documentation of disease assessment 
10. Baseline condition assessment (record the amount of hemoptysis, if present). 
11. Documentation of measurable diseases. 
12. Review of pathology reports including mutation status 
13. Complete blood count (CBC) with differentials and D-dimer. 
14. Coagulation profile: prothrombin time, partial thromboplastin time, international 
normalized ratio (PT/INR/PTT).  
15. Blood chemistry profile: Fasting glucose, blood urea nitrogen (BUN), creatinine, ALT, 
AST, total protein, albumin, globulin, alkaline phosphatase, total bilirubin, sodium, 
potassium, 
chloride, 
calcium, 
magnesium, 
phosphorus, 
uric 
acid, 
lactate 
dehydrogenase (LDH), IgG and IgM.  
16. Lipid profile: total cholesterol, triglyceride. 
17. Thyroid function tests: thyroid-stimulating hormone (TSH), T3, free thyroxine (FT4)  
18. Serum lipase and amylase. 
19. Hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), Hepatitis C 
antibody (anti-HCV). 
20. Tumor markers (CEA, CA199, CA125, CA153, alpha-fetoprotein and PSA5) 
21. Serum βHCG test for female patients with child-bearing potential6. 
                                                     
2 Baseline signs and symptoms: Clinical adverse events occurring after signing informed consent, but 
before study drug administration are to be recorded on the Medical History/Current Medical Conditions 
CRF 
3 If all patients should have confirmed pathologic diagnosis, if not, a pathology review might be necessary. 
4 If no prior record of pathologic diagnosis is available, a tumor biopsy is required. 
5 PSA is needed for patients with prostate cancer. 
6 Postmenopausal women must be amenorrheic for at least 12 months in order not to be considered of 
child-bearing potential. 

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22. Urinalysis7. 
23. Chest radiograph (X-ray) 
24. 12-lead electrocardiogram (ECG). 
25. Tumor imaging with contrasted computerized tomography or MRI (chest, abdomen 
and pelvis) for tumor assessment (if the imaging studies are less than 6 weeks before 
1st infusion of IP, no need to repeat the studies). 
26. Contrasted brain CT/MRI (if the imaging studies are less than 8 weeks before 1st 
infusion of HLX06, no need to repeat the test). 
27. Cardiac ultrasound or a MUGA scan 
28. Bone scan (if signs or symptoms suggestive of bone metastases are present). 
Confirmative X-ray, CT or MRI for bone metastases for patients with positive bone 
scan. The selection of imaging modality is based on the discretion of investigators for 
the benefit of patients. 
29. Concomitant medications including alternative medicines. 
30. Assessment of adverse events from prior therapies. 
 
7.2. Treatment period 
The treatment of the study is divided in cycles with associated evaluation and procedures that 
must be performed at specific time points. Subjects who meet inclusion/exclusion criteria may 
start the Investigation Product (IP) treatment within 28 days of Screening period. Each cycle of 
treatment is FOUR weeks. Enrolled patients will receive FOUR weekly infusions of IP in a 
cycle.  
Following cycle 1, the decision whether to treat the patients with additional cycles of IP and 
which dose level to use in the next cycle will be determined by the toxicities of the prior cycle 
(refer to Section 7.2.2.1).  
A patient who is withdrawn from the study before the completion of the first cycle for a reason 
other than treatment-emergent toxicities will be replaced. 
                                                     
7 Urinalysis includes: color, turbidity, specific gravity, pH, leukocyte, nitrite, protein, glucose, ketones, 
urobilinogen, bilirubin, blood cells. If the urinalysis indicates significant proteinuria (> 30 mg or >=2+ 
by urine dipstick), urinalysis must be repeated. If the repeat dipstick protein value is >30 mg or >= 2+ by 
urine dipstick, 24-hour urine collection is required to calculate total protein. 

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7.2.1. Interval of the first infusion between new patients in a cohort 
The interval of the first infusion between NEW patients in a cohort is 24 hours or longer, 
regardless of the dose level. This is to ensure the safety of patients in a cohort, in case there 
were excessive toxicities. 
7.2.2. The requirement of hospitalization for the infusion of IP 
The Investigator may hospitalize the patients for the first infusion of IP and the PK/PD studies 
in cycle 1. Based on the reactions during and after the first infusion in cycle 1, it is up to the 
Investigator to determine whether extended hospitalization for observation and PK/PD studies 
are necessary. It is also the Investigator’s discretion to determine whether hospitalization is 
needed for subsequent infusions. 
7.2.2.1. 
Determination of the dose level for the first infusion in a cycle 
This study adopts an adaptive trial design, which is different from conventional 3+3 design. 
Please refer to Section 3 for the detail of study design. 
In the accelerated phase, Investigators and the study staff need to assess the toxicities in 
the first cycle and communicate with the Study Monitor or its designee the dose level 
before the first infusion in the next NEW patient.  
7.2.2.2. 
Pre-medications for the first and subsequent infusions in a cycle 
Primary prophylaxis for first infusion reaction of HLX06 is NOT mandatory. If the patients 
experience infusion reactions, allergic reactions, nausea, vomiting or other symptoms/signs 
related to infusion of experimental drugs, pre-medications to mitigate these reactions with 
antihistamine, acetaminophen, corticosteroid or 5-HT3 antagonist are permitted in subsequent 
infusions. Investigators could also follow institutional guidelines for pre-medications for 
infusion-related conditions.  
7.2.2.3. 
Procedures for the first infusion in a cycle. 
For preparation of IP and the requirement for infusion set, please refer to Section 5.6.  
Treatment will begin with the first intravenous infusion of IP (Day 1) and will continue every 
7 days for a total of 4 doses (Days 1, 8, 15 and 22) in a cycle with the response assessment 
described in Section 8. 

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The followings are the procedure required before the first infusion in each cycle: (the laboratory 
tests before the first infusion may be waived, if the interval between screening tests and first 
infusion is less than 7 days, and the Investigator judges that the patient’s condition remains 
stationary). 
1. Vital sign measurements to include temperature, pulse, and blood pressure will be 
obtained as defined in the Section 14. 
2. Weight 
3. Physical examination (including measurement of vital signs as well as pulmonary, heart, 
abdomen, and skin assessments with selective neurological examination) 
4. ECOG performance status 
5. 12-lead ECG8 
6. Complete blood count (CBC) with differentials, and D-dimer 
7. Tumor markers9 (CEA, CA199, CA125, CA153, alpha-fetoprotein and PSA10) 
8. Coagulation profile: prothrombin time, partial thromboplastin time, international 
normalized ratio (PT/PTT/INR). 
9. Blood chemistry profile: Fasting glucose, blood urea nitrogen (BUN), creatinine, ALT, 
AST, total protein, albumin, globulin, alkaline phosphatase, total bilirubin, sodium, 
potassium, 
chloride, 
calcium, 
magnesium, 
phosphorus, 
uric 
acid, 
lactate 
dehydrogenase (LDH), IgG, and IgM 11 
10. Thyroid function tests: thyroid-stimulating hormone (TSH), T3, free thyroxine (FT4)12 
11. Urinalysis.  
12. Urine pregnancy test for female patients with child-bearing potential.13. 
13. Infusions of IP (after all other evaluations for the visit according to the Time and Events 
Table have been completed except for the post-infusion pharmacokinetic samples) 
                                                     
8 ECG must be done predose and within 30 minutes after the end of 1st infusion. 
9 If the tests have been done during the Screening period, no need to repeat the tests before 1st infusion 
in cycle 1. These should be done every 8 weeks in the first 24 weeks and every 12 weeks thereafter. 
10For prostate cancer only.  
11 Lab data must be performed and reviewed before dosing. Any new Grade ≥ 3 laboratory abnormality, 
such as liver function test elevations, electrolyte fluctuation, or hematologic deterioration should be 
assessed for potential risk before dosing. In the event of uncertainty, the Medical Monitor should be 
contacted. 
12 If thyroid function tests have been performed in the Screening period, no need to repeat before the first 
infusion in cycle 1, but repeat the thyroid function tests every 8 weeks before the first 24 weeks and every 
12 weeks after 24 weeks. 
13 In the screening period, serum pregnancy test is used. Before the first infusion, urine pregnancy is used. 
A positive urine pregnancy test must be verified by a serum βHCG test. Postmenopausal women must 
be amenorrheic for at least 12 months in order not to be considered of child-bearing potential. 

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14. Assessment of adverse events 
15. Obtaining serum samples for pharmacokinetics as outlined in Section 9 (post-infusion 
samples should be drawn from a site other than the infusion site [i.e., contralateral arm] 
on infusion days.)14 
16. Obtaining serum samples for pharmacodynamics 15 
17. Obtaining serum samples for immunogenicity (collected before infusions) 
Following Cycle 1, patients may receive additional cycles of therapy until disease progression, 
up to a maximum of one year, withdrawal from study or death, whichever occurs first. If the 
patient’s disease remains stable and the patient is deemed to benefit from continuous treatment 
of IP, additional treatment beyond one year will be evaluated on a case-by-case basis and 
arranged between the Investigator and the Sponsor. 
The evaluations performed for the first infusion in subsequent cycles are the same (except for 
the PK/PD studies) and the results will be recorded on the CRF. Details are tabulated in Section 
14. 
7.2.2.4. 
Management for the infusion-related reactions 
For patients who experience first infusion reactions, please refer to Section 6.4 for the procedure 
and management. 
7.2.3. Procedures for subsequent infusions in a cycle 
Following the first infusion in a cycle, patients may receive additional infusions on day 8, 15 
and 22 to complete the cycle of treatment. The maximum duration of IP to be administered to 
an individual patient in this study is one year.  
The evaluations performed for the second to fourth infusion in a cycle are as follows:  
1. Vital sign measurements to include temperature, pulse, and blood pressure will be 
obtained as defined in the Section 14. 
2. Weight 
3. Elective physical examination (including measurement of vital signs as well as 
pulmonary, heart, abdomen, and skin assessments) 
                                                     
14 Detailed pharmacokinetic studies are conducted in the first week in Cycle 1 only. 
15 The samples are collected before and after one hour of first infusion in Cycle 1. Please refer to Section 
9  for detailed time points. 

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4. ECOG performance status 
5. Clinical laboratory tests (local and central laboratories) (Note: Lab data must be 
performed and reviewed before dosing) 
6. Complete blood count (CBC) with differentials and D-dimer 
7. Blood chemistry profile: fasting glucose, BUN, creatinine, alkaline phosphatase, ALT, 
AST, total bilirubin, total protein, albumin, globulin, sodium, potassium, chloride, 
calcium, magnesium, phosphorus, uric acid, lactate dehydrogenase16.  
8. Urinalysis. 
9. Serum sampling for pharmacokinetic studies (for first cycle only) 
10. Infusion of IP 
11. AE assessment 
7.2.4. Infusion delays, missed doses and dose adjustment 
7.2.4.1. 
Infusion delays and missed doses 
Every effort should be made to schedule visits within the protocol-specified windows.  
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 3 days (including), the procedures at the 
original scheduled time point should be performed. 
If the delay is more than 3 days, the procedures at the next infusion should be performed (the 
infusion at the original scheduled visit will be considered a missed dose). 
Patients with infusion delays > 28 days should normally discontinue treatment and enter the 
Follow-up Period. If the Investigator intend to continue the treatment for patients who have 
infusion delay >28 days, specific consultation and agreement between the Investigator and the 
Medical Monitor are required in setting where benefit/risk may justify continued use of 
Investigational Product. 
7.2.4.2. 
Dose modification for subsequent infusions 
This study allows dose adjustment for toxicities. Dose modification is based on the toxicities 
from previous infusions. Patients who experience reversible DLTs are allowed to receive 
                                                     
16 Any new Grade≥3 laboratory abnormality, 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. 

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additional infusions at the next lower dose level, provided that the toxicities have reverted to 
grade≤1 in 28 days after last infusion, and that the patients still meet the inclusion criteria for 
adequate organ functions. Dose modification for reasons other than toxicities is not allowed, 
unless it is scientifically justifiable and must be agreed by the Sponsor.  
For patients who experience DLTs, re-escalation to the dose level causing DLT is not permitted. 
Up to two dose-level reductions per patient are allowed in this study.  
7.2.5. Discontinuation of patients from treatment 
Each patient has the right to withdraw from the study any time. Patients MUST discontinue 
Investigational Product (and non-investigational product at the discretion of the Investigator) 
for any of the following reasons: 
 
Withdrawal of informed consent (patient’s decision to withdraw for any reason)  
 
Any clinical adverse event (AE), laboratory abnormality or inter-current illness, which, in 
the opinion of the investigator, indicates that continued participation in the study is not in 
the best interest of the patient. 
 
Pregnancy or beginning breastfeeding  
 
Termination of the study by the Sponsor 
 
Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
illness  
 
Poor compliance with protocol.  
 
Discretion of the investigator. 
 
Disease progression or clinical deterioration that no further benefit from treatment is likely 
(clinical deterioration should be guided by clinical observation described in Section 6.2 
and Investigator’s judgment). 
 
Dosing delays longer than 28 days 
All patients who discontinue should comply with protocol specified follow-up procedures 
as outlined in Section 7.2.5 . The only exception to this requirement is when a patient 
withdraws consent for all study procedures or loses the ability to consent freely (i.e., is 
imprisoned or involuntarily incarcerated for the treatment of either a psychiatric or physical 
illness). 

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7.2.6. Replacement of participants 
A patient who is withdrawn from the study before the first 4 weeks after first infusion of IP 
may be replaced with a new one to receive the same dose level if the withdrawal from the 
study is not related to treatment-emergent toxicities. 
7.3. Follow-up period 
After completion of the Treatment period, the patients will have 6 monthly follow-up visits. All 
patients should complete Follow-up Visit 1 (28 ± 3 days after the last dose of IP).  
The procedures for the follow-up visits are as follows: 
1. Physical examination 
2. Vital signs 
3. ECOG performance status 
4. AE assessment 
5. 12-lead ECG 
6. CBC with differentials and D-dimer 
7. Coagulation profile: PT, INR, aPTT 
8. Blood chemistry profile: fasting glucose, BUN, creatinine, alkaline phosphatase, ALT, 
AST, total bilirubin, total protein, albumin, globulin, sodium, potassium, chloride, 
calcium, magnesium, phosphorus, uric acid, lactate dehydrogenase, IgG and IgM.  
9. Thyroid function tests: TSH, T3 and free T417. 
10. Urinalysis. 
11. Urine pregnancy test for female patients with child-bearing potential18 
12. Concomitant medications 
13. Tumor assessment: if the prior imaging studies are done more than 8 weeks ago) 
14. Pharmacokinetic and pharmacodynamic studies19. 
If the patient refuses or is unable to attend the follow-up visit 1, the reason(s) should be noted 
in the patient’s source documentation. 
                                                     
17 Every 8 weeks. 
18 A positive urine pregnancy test needs to be verified by a serum beta-HCG test. Postmenopausal women 
must be amenorrheic for at least 12 months in order not to be considered of child-bearing potential. 
 
19 Only for follow-up visit 1. 

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Completion of subsequent follow-up visits (Follow-up Visits 2 and beyond) will depend on the 
status of the patients at the end of treatment. Except for patients who discontinue due to 
worsening PD, all patients will be followed from the last dose of IP for approximately 6 months 
until relapse, initiation of a new therapy or the toxicities stabilized or ≤ grade 1. The evaluations 
performed during the Follow-up Visits will be recorded on the CRF. 
Whether or not each patient completes the study drug treatment through the first cycle will be 
documented on the CRF, including how many doses in Cycle 1 were received. Patients will be 
considered to have completed Cycle 1 treatment if they completed 4 infusions of IP in Cycle 1 
and completed all evaluations at the end of Cycle 1. 
7.3.1. Survival follow up 
Following completion of the treatment and follow-up periods, all patients will be followed for 
survival after completion of treatment phases and through the follow-up period of the protocol.  
Patients will have their survival status assessed approximately every 3 months by either a 
telephone or in-person contact until study completion or termination by the Sponsor.  
7.4. Post study access to Investigational Product 
At the end of the protocol-specific periods of active study therapy, the Sponsor will not continue 
to supply study drugs to the patients/investigators unless the Sponsor decide to extend the study. 
The Investigator should ensure that the patients receives appropriate standard care to the 
condition under the study. 
7.5. Records of concomitant medications and procedures 
All medications, including pharmacologic doses of vitamins, herbal medicines, or other 
alternative medicine all transfusions, including blood component therapies, IV immunoglobulin, 
and hematopoietic growth factors administered within 28 days before first infusion are to be 
documented in the appropriate source documents and the CRF, along with the reason for and 
details of therapy use. Results of assessments must be reviewed by the safety review committee 
(SRC) before administering the first dose of the next cycle.  
7.5.1. Prohibited concomitant medications and procedures 
The following medications, therapies, and procedures are prohibited during the study: 
 
Any investigational agent other than HLX06. 

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 
Any anti-neoplastic treatment with activity against epithelial cancer other than 
investigational product. 
 
Radiation therapy unless for pain relief at local lesion. 
 
Any surgery for the management of the patient’s disease, unless for life-threatening 
situations during treatment period. 
 
Thrombopoietin-mimetics.  
 
Myeloid growth factors to stimulate faster granulocytic recovery, unless for neutropenic 
fever. 
 
Erythropoietic agent is not permitted, except for the management of patients with 
treatment-emergent renal failure or those with documented low erythropoietin. 
 
Non-steroidal anti-inflammatory drugs (NSAIDs), unless for pain relief. 
 
Live vaccines are NOT allowed during the study. 
7.5.2. Permitted concomitant medications and procedures 
Prophylactic pre-medications: Medications intended to prevent infusion reactions or other 
toxicities are permitted by previous experience with HLX06 in a patient as described in Section 
6.4. 
Corticosteroid use: Inhaled or intranasal corticosteroids (with minimal systemic absorption) 
may be continued if the patient is on a stable dose. Non-absorbed intra-articular corticosteroid 
injections are permitted. Stable corticosteroid use with less than 10 mg prednisone is permitted. 
Prophylactic antimicrobial agents: If the patient is considered to have high-risk for infection 
during the study period, prophylactic antimicrobial agents are allowed until the risk is lowered. 
Prophylactic antibiotics are to be provided according to institutional guidelines at the study 
center. If no institutional guidelines exist, prophylactic antimicrobial therapy (e.g., oral 
fluoroquinolone [levofloxacin or ciprofloxacin] for bacterial infections, oral fluconazole for 
fungal infections, and oral famciclovir 250 mg twice daily or equivalent for viral infections) are 
allowed for high-risk patients from the start of investigational product administration until the 
infection risk is lowered or recovery of white blood cells (WBCs). 
Transfusion support: The use of blood components is recommended during the study period. 
Packed red blood cell (RBC) transfusion is recommended for hemoglobin ≤8.0 g/dL or per 
institutional guidelines. Platelet transfusion is recommended for platelet counts ≤20×109/L or 
with signs of bleeding or per institutional guidelines. 
Palliative therapies: Palliative therapies (e.g. focal radiotherapy for pain, thoracentesis, or 
paracentesis for comfort may be administered after consultation with the Medical Monitor. 

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Vaccines: the use of killed or attenuated vaccines for the prevention of influenza is permitted 
at any time without a study drug washout interval. The use of other killed or attenuated vaccines 
for the prevention of infectious diseases may be permitted on a case-by-case basis and must be 
discussed with the Medical Monitor prior to its use. A washout interval prior to and post 
vaccination while on study may be required in these instances. Any vaccinations given while 
on study must be documented in the patient’s medical records and in the CRF. 
All patients should be maintained on the same concomitant medications throughout the study 
period, as medically feasible. Any new concomitant medications prescribed for the patient or 
changes to dosing/schedule of concomitant medications should be recorded on the appropriate 
CRF page. The addition of a new concomitant medication for which there is a concern that it 
may not be permitted should be first reviewed with the Medical Monitor. 
No concomitant medication information will be collected following patient discontinuation 
from the study except for concomitant medication use associated with study drug-related 
adverse events or adverse events that lead to discontinuation from study. 
7.5.3. Effective contraceptive measures 
For female patients of child-bearing potential and male patients whose sexual partners are of 
child-bearing potential, patients should agree to use an effective method of contraception during 
the treatment period and for at least 180 days following the last dose of study drugs.  
Effective contraceptive measures include: (a) intrauterine device plus one barrier method; (b) 
oral, implantable or injectable contraceptive plus one barrier method; or (c) tow barrier methods. 
Effective barrier methods are male or female condoms, diaphragms, and spermicides (cream or 
gel that contain a chemical to kill sperms). 
7.5.4. Treatment of isolated lesions.  
Treatment of isolated/symptomatic lesions by local surgery or radiation therapy is permitted for 
palliative or potentially curative management at any time beyond Cycle 2.  
All interventions should be discussed in advance with the Medical Monitor. 
7.6. Study participation 
Each subject will have their study participation documented, including the number of cycles 
completed, the duration of the Follow-up Period, and if discontinuing from the study, the reason 

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for discontinuation. At the end of each cycle, the subject continuation status for each subject 
will be documented on the CRF. 
If for any reason, either study treatment or observations were discontinued, the reason will be 
recorded. The primary reasons for discontinuation will be documented: 
 Adverse event(s) 
 Protocol violation or deviation 
 Disease progression 
 Subject withdrew consent 
 Subject is lost to follow-up 
 Death 
 Other unspecific reasons 
 
 

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8. EVALUATION OF SAFETY, IMMUNOGENICITY AND EFFICACY 
8.1. Evaluation of safety and tolerability 
The primary objective of this study intends to evaluate the safety and tolerability of IP. The 
following evaluations will be performed to measure the safety and tolerability: 
Clinical laboratory tests (blood, urine sampling for clinical laboratory parameters), ECOG 
performance status, physical examinations including vital sign measurements, ECG, and the 
incidence and severity of treatment-emergent adverse events.  
8.2. Immunogenicity 
Immunogenicity refers to the development of an immune response to the HLX06 itself, and is 
characterized by the antibodies (ADA) that the patients may develop to react with HLX06. 
These may result in more rapid clearance of the IP from the bloodstream or predispose the 
patient to infusion reactions upon retreatment with IP at a later date. The ADA may also likely 
potentiate the drug effect by prolonging its half-life. Blood samples for immunogenicity 
analysis are mandatory and will be collected from all patients prior to every infusion of IP in 
Cycle 1 and before first infusion in subsequent 5 cycles or up to 18 weeks, whichever comes 
first and on the day of follow-up visit 1.  
8.3. Efficacy evaluation 
The efficacy parameters are the disease control rate (number of patients with CR/PR/SD divided 
by the total number of patients treated), and objective response rate (ORR) (number of patients 
with confirmed responses of CR or PR, divided by the total number of treated patients with 
measurable disease at baseline). Tumor response status will be assessed using RECIST 1 
The response to treatment will be assessed in the following schedule:  
1. For the first 24 weeks, treatment evaluation is conducted every 8 weeks (regardless of 
treatment delay).  
2. After 24 weeks, treatment evaluation is conducted every 12 weeks  
Tumor specific antigen levels (i.e. CEA, CA125, CA19-9, AFP, PSA for prostate cancer) are 
not used to confirm response, but they will be measured to provide ancillary support for disease 
response when appropriate in some tumor types. 
 

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Efficacy evaluation should use the same modalities. Repeat bone scan for metastatic bone 
disease is indicated based on clinical judgement by the Investigator. 

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9. PHARMACOKINETIC AND PHARMACODYNAMIC EVALUATIONS 
9.1. Pharmacokinetic studies 
Pharmacokinetic study is mandatory for all patients in this study. Blood samples should be 
drawn from a site other than the infusion site (i.e., contralateral arm) on days of infusion. If the 
infusion was interrupted, the reason for interruption will also be documented on the CRF.  
For pharmacokinetic analysis of HLX06, blood samples of 5 mL were drawn pre-dose (within 
one hour before first infusion), after the end of infusion (within 30 minutes) and at 2, 4, 8 (±15 
minutes allowable) hours as well as at 24, 48, 96, and 168 hours after the end of 1st and 4th 
infusion in Cycle 1. Additional time points include pre-dose and after the end of 2nd and 3rd 
infusions (within 30 minutes) in Cycle 1. Thereafter, the serum levels of HLX06 will be 
measured before the first infusion of Cycle 2 to Cycle 6 or up to 24 weeks, whichever comes 
first; and on the day of follow-up visit 1, whenever possible. 
Blood samples will be processed to collect serum and stored at -70 degrees Celsius. Serum 
samples will be analyzed for HLX06 by a validated ELISA method.  
Non-compartmental pharmacokinetic analysis will be used to estimate the PK parameters. The 
following parameters are determined from the serum concentration data of HLX06: maximum 
serum concentration (Cmax), time to reach Cmax (Tmax), elimination rate constant (λz) , elimination 
half-life (t1/2), area under the serum concentration-versus-time curve within one dosing interval 
(AUC0-tau), area under the serum concentration-versus-time curve until infinity (AUC0-inf), 
volume of distribution during terminal phase (Vz), and at steady state (Vss), total body clearance 
from serum CL, and mean residence time (MRT). Cmax, and Tmax are taken directly from the 
plasma concentration curve, terminal half-life is determined from the terminal slope of the log-
transformed plasma concentration curve using linear regression on terminal data points of the 
curve. 
Concentrations below the lower limit of quantification, which are before the last quantifiable 
data point, are taken as zero for calculating the AUC. Pharmacokinetic results are presented 
only descriptively. No statistical tests are performed with pharmacokinetic parameters. 
9.2. Pharmacodynamic study 
This study also incorporates mandatory pharmacodynamic study by examining serum 
concentrations of VEGF-A, soluble VEGFR-1, soluble VEGFR-2. The sampling time points 
are pre-dose and after each infusion in cycle 1 in conjunction with pharmacokinetic studies. 

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10. ADVERSE EVENT REPORTING 
10.1. Definitions of an adverse event and causality analysis 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation patient administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment.  An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not the event is considered causally related to the use of the product. 
Each adverse event is to be reported on an Adverse Event CRF page. Adverse events are graded 
using the Cancer Therapy Evaluation Program (CTEP) CTCAE, Version 4.0 in this study. 
If CTCAE grading does not exist for an adverse event, the severity of mild (1), moderate (2), 
severe (3), life-threatening (4), and death related to an adverse event (5) will be used. 
Information about all adverse events, whether volunteered by the patient, discovered by 
Investigator questioning, or detected through physical examination, laboratory testing, or other 
means, will be collected and recorded on the Adverse Event CRF page and followed as 
appropriate.  
Adverse event monitoring should be continued until adverse event resolution/stabilization 
(whichever is later).  
Medical conditions/diseases present before the infusion of study drug are only considered 
adverse events if they worsen after receiving any study drug. Clinical events occurring before 
the administration of study drug but after signing the ICF are to be recorded on the Medical 
History/Current Medical Conditions CRF page. All laboratory values are to be reviewed by the 
Investigator and abnormal values will be graded according to CTCAE Version 4 and reported 
in the study report.  
A laboratory abnormality is considered an adverse event if it results in any one of the following: 
 
discontinuation from study drug,  
 
necessitates therapeutic medical intervention, 
 
if the Investigator assesses the abnormality as an adverse event, or 
 
any laboratory test that is clinically significant or meets the definition of an SAE 
It is expected that wherever possible, the clinical, rather than the laboratory term would be used 
by the reporting investigator (e.g. anemia versus low hemoglobin value). These adverse events 

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will be recorded on the Adverse Events CRF page and will include all signs, symptoms, or 
diagnosis associated with them. 
The following is required for the description of each adverse event: 
Description  
Duration (start and end dates)  
CTCAE Grade 1 through 5 or severity if CTCAE is not available  
Relationship to the study drug - related or not related  
Action(s) taken with study drug  
Whether event was serious   
Whether event is ongoing 
10.2. Adverse event collection period 
All protocol-related serious adverse events must be collected from the signing of the study 
specific informed consent until study drug administration. 
All serious and non-serious adverse events reported from the time of study drug administration 
until 28 days following last infusion of study drug administration will be collected, whether 
elicited or spontaneously reported by the patient. 
Serious adverse events occurring after the study-specific informed consent is signed but prior 
to the first dose of the investigational product will be collected only if they are considered by 
the investigator to be causally related to the study required procedures. 
10.3. Relationship to study drug  
The following is used to assess the relationship of the AE to the use of study results. 
Assessments are to be recorded on the appropriate CRF page. 
Causality 
Description 
Probably Related 
An adverse event has a strong temporal relationship 
to study drug or recurs on re-challenge and another 
cause of event is unlikely or significantly less likely. 
Possibly Related 
An adverse event has a strong temporal relationship 
to the study drug and another cause of event is 

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Causality 
Description 
equally or less likely compared to the potential 
relationship to study drug. 
Probably Not Related 
An adverse event has little or no temporal 
relationship to the study drug and/or a more likely 
Other cause of event exists. 
Not Related 
An adverse event is due to an underlying or 
concurrent illness or effect of another drug and is not 
related to the study drug (e.g., has no temporal 
relationship to study drug or has a much more likely 
Other cause of event). 
For causality assessments, events meeting the categories of probably or possibly will be 
considered "associated." Events that are probably not or not related will be considered "not 
associated."  In addition, when the investigator has not reported causality or deemed it not 
assessable, it will consider the event associated. 
Remedial Action(s) Taken 
The remedial actions taken in response to an adverse event are to be recorded in the medical 
record. The options included but not limited to the following: 
No action taken 
Study drug permanently discontinued due to this adverse event 
Study drug temporarily interrupted 
10.4. Serious adverse events 
A serious adverse event is defined in general as an untoward (unfavorable) adverse event which: 
is fatal or life-threatening; 
requires or prolongs hospitalization;   
is significantly or permanently disabling or incapacitating;   
constitutes a congenital anomaly or a birth defect; or 
may jeopardize the patient and may require medical or surgical intervention to prevent one of 
the outcomes listed above. 

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Hospitalizations occurring under the following circumstances are not considered serious 
adverse events:  
Admission to a hospice for respite care;  
Hospitalizations planned before entry into the clinical study;  
Hospitalization for elective treatment of a condition unrelated to the studied indication or its 
treatment;  
Hospitalization on an emergency, outpatient basis that does not result in admission (unless 
fulfilling the criteria above);  
Hospitalization as part of the normal treatment or monitoring of the studied indication;  
Hospitalization to facilitate the work up of a ≤ Grade 2 adverse event, including overnight 
hospitalization following study drug administration for non-medical reasons.  
10.5. Notification of serious adverse events 
10.5.1. Reporting responsibility 
Any serious adverse event occurring in a patient after he/she has provided informed consent, 
and while receiving study treatment must be reported. All patients who withdraw from the study 
should be monitored for at least 28 days following the last dose of IP for the occurrence of 
serious adverse events considered by the Investigator to be related to IP treatment. Patients 
should be contacted at least once within 28 days following the last dose of IP. Telephone contact 
is acceptable and should be within ±10 days of the 28-day time point. After 28 days following 
the last dose of IP, any serious adverse events considered by the Investigator to be related to IP 
treatment must also be reported. The timeframe for reporting after discontinuation of study drug 
may be extended if there is a strong suspicion that the IP has not yet been eliminated or the 
pharmacodynamic effects of the IP persist beyond 28 days. All serious adverse events must also 
be reported for the timeframe in which the study drug interferes with the standard medical 
treatment given to a patient. 
Each serious adverse event must be reported by the Investigator to the Medical Monitor or its, 
or designee, within 24 hours of learning of its occurrence, even if it is not felt be related to IP. 
Serious adverse events occurring after 28 days from the last dose of IP must be reported if 
deemed related to IP. The report must include the adverse event term, patient identifier, 
attribution, description, concomitant medications used to treat the adverse event, and any other 
relevant information. Follow-up information about a previously reported serious adverse event 
must also be reported to the Sponsor or its designee within 24 hours of receiving the information. 

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The Sponsor, or its designee, may contact the Investigator to obtain further information about 
a reported serious adverse event. If warranted, an Investigator Alert may be issued to inform all 
Investigators involved in any study with the same IP that a serious adverse event has been 
reported. 
10.5.2. Reporting procedures 
The Investigator must complete the Serious Adverse Event Report Form in English, assess the 
causal relationship to study drug, and send the completed form to the SAE Reporting FAX 
Number within 24 hours, to the Sponsor or its designee. The Medical Monitor will review the 
Serious Adverse Event Report Form and the supporting source documents during monitoring 
visits. Follow-up information should also be sent to the Medical Monitor that receives the 
original Serious Adverse Event Form, within 24 hours of the time the information is known. 
Either a new Serious Adverse Event Report Form is faxed (indicating that the information is a 
follow-up), or the original form may be re-faxed (with the new information highlighted and a 
new date provided). The follow-up report should describe whether the serious adverse event 
has resolved or is continuing, if and how it was treated, and whether the patient continued or 
permanently discontinued study participation. The form(s) and FAX confirmation sheet(s) must 
be retained in the investigational site study file.  
The Investigator is responsible for informing the Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) of the serious adverse event and providing them with all relevant 
initial and follow-up information about the event. The Sponsor or its designee will 
communicate serious adverse events to the study sites as required by local regulatory authorities. 
10.5.3. Contact persons and numbers 
The contact person and the phone/fax number are listed on the cover page of this protocol. 
10.6. Overdose 
An overdose is defined as the accidental or intentional ingestion/infusion of any excessive dose 
of a product. For reporting purposes, the Sponsor considers an overdose, regardless of adverse 
outcome, as a serious adverse event in Section 10.4   

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10.7. Pregnancy 
Pregnancy testing must be performed in all women with childbearing potential (WWCBP) 
throughout the study as specified in the Time and Event Schedule table, and the results of all 
pregnancy tests (positive or negative) are to be recorded on the CRF. All WWCBP must have 
a negative serum pregnancy test in the screening period and negative urine pregnancy tests 
during the study. If the pregnancy test is positive, the patient must not receive IP and must not 
continue in the study. The patient will be followed to determine the outcome of the pregnancy.  
In addition, all WWCBP should be instructed to contact the Investigator immediately if they 
suspect that they might be pregnant (e.g., missed or late menstrual period) at any time in the 
study period or during the 28-day period following their last dose of study drug.  
Male patients should contact the Investigator immediately if they suspect they may have 
fathered a child during the study or during the 28-day period following their last dose of study 
drug. When possible, such pregnancies should be followed (to term) to determine the outcome. 
10.7.1. Reporting of pregnancy 
Initial information on a pregnancy (during or after the study as defined above) must be reported 
immediately to Sponsor and the outcome information provided once the outcome is known. 
The Serious Adverse Event Form must be faxed to the Sponsor or its designee according to 
Serious Adverse Event reporting procedures described in Section 10.4. A separated Pregnancy 
notification worksheet in Appendix 15.7 should also be filed to the Sponsor or its designee. 
For female patients, protocol-required procedures for study discontinuation and follow-up must 
be performed unless contraindicated by pregnancy (e.g., x-ray studies, CT scan). Other 
appropriate pregnancy follow-up procedures should be considered if indicated. Follow-up 
information regarding the course of the pregnancy, including perinatal and neonatal outcome 
must be reported. Infants should be followed for a minimum of 8 weeks.  
For male patients, follow-up information regarding the course of the partner’s pregnancy, 
including perinatal and neonatal outcome should be reported when possible. 
10.8. Rapid notification of adverse events of significance 
In addition to serious adverse events, the following adverse events will be reported within 24 
hours using the same rapid notification procedures that are used for serious adverse events  
(described in Section 10.5), even if the nature of the adverse event is not deemed serious: 

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Adverse events that potentially meet DLT criteria. 
Adverse events that potentially meet the delayed DLT criteria. 
Grade 3 or 4 infusion reactions whether or not the event is a DLT. 
10.9. Other safety considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a non-serious or serious AE, 
as appropriate, and reported accordingly. 
 

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11. DESCRIPTION OF STATISTICAL METHODS 
11.1. Bayesian optimal interval design and sample size determination 
We will employ the Bayesian optimal interval (BOIN) design (Liu and Yuan, 2015) to find the 
MTD. The BOIN design is a novel Bayesian dose-finding method that optimizes patient ethics 
by minimizing the chance of exposing patients to sub-therapeutic and overly toxic doses. The 
BOIN design yields an average performance comparable to that of the continual reassessment 
method (CRM) in terms of selecting the MTD, but has a lower risk of assigning patients to sub-
therapeutic or overly toxic doses (i.e., better patient ethics). 
The target toxicity rate for the MTD is 0.3 and the maximum sample size is 30. We will enroll 
and treat patients in cohorts of size 3. But in this study, there are two early stopping rules: (1) 
when the lowest dose level is eliminated due to toxicity and (2) when the new patient number 
at certain dose level reaches 15.  
The dose escalation/de-escalation rules have been described in the Synopsis and tabulated in 
Table 1. The R codes used in the BOIN 2.4 package to derive the rules are listed in Section 
15.5. 
11.1.1. Determination of MTD 
After the trial is completed, we determine the MTD based on the isotonic regression as specified 
in Yuan et al[5].The MTD will be determined by the number of patients with DLT in the first 
cycle and the total number of patients treated at certain dose level. The BOIN package in R will 
be used to estimate MTD. The determined MTD is the dose for which the isotonic estimate of 
the toxicity rate is closest to the target toxicity rate of 30%. If there are ties, we select the higher 
dose level when the isotonic estimate is lower than the target toxicity rate; and we select the 
lower dose level when the isotonic estimate is greater than the target toxicity rate.  
11.1.2. Operating characteristics 
The following table (Table 2) shows the operating characteristics of the proposed design for 
this trial with 6 scenarios defined by different DLT rates for 6 dose levels. These operating 
characteristics are based on 1000 simulations of the trial using the acceptable toxicity range 
[0.21, 0.39]. The operating characteristics show that the design selects the true MTD with high 
probabilities and allocate more patients to the dose levels with the DLT rate close to 0.3. 
 

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Table 2 Operating Characteristics of the BOIN design  
Toxicity 
range 
 
 
Dose level 
Number of 
pts 
% early 
stopping  
 
1 
2 
3 
4 
5 
6 
 
 
 
True DLT rate 
0.05 
0.10 
0.30 
0.45 
0.60 
0.8 
 
 
[0.21, 0.39] 
Selection % 
0.3 
18.9 
58.5 
20.0 
2.3 
0 
27.7 
0.0 
 
# pts treated 
3.6 
7.2 
10.9 
5.2 
0.8 
0 
 
 
 
True DLT rate 
0.12 
0.30 
0.46 
0.60 
0.70 
0.9 
 
 
[0.21, 0.39] 
Selection % 
21.2 
57.7 
19.0 
1.7 
0.2 
0 
25.1 
0.2 
 
# pts treated 
7.4 
11.2 
5.6 
0.9 
0.1 
0 
 
 
 
True DLT rate 
0.26 
0.50 
0.65 
0.75 
0.80 
0.9 
 
 
[0.21, 0.39] 
Selection % 
73.1 
18.2 
0.3 
0 
0 
 
20.1 
8.4 
 
# pts treated 
12.4 
6.7 
0.9 
0 
0 
 
 
 
 
True DLT rate 
0.05 
0.10 
0.16 
0.30 
0.50 
0.7 
 
 
[0.21, 0.39] 
Selection % 
0.2 
2.7 
23.7 
55.7 
17.1 
0.6 
29.2 
0.0 
 
# pts treated 
3.7 
4.7 
7.3 
9.1 
3.9 
0.4 
 
 
 
True DLT rate 
0.02 
0.03 
0.05 
0.12 
0.30 
0.45 
 
 
[0.21, 0.39] 
Selection % 
0 
0.1 
0.6 
19.9 
55.7 
23.7 
29.8 
0.0 
 
# pts treated 
3.2 
3.4 
3.8 
6.7 
8.5 
4.3 
 
 
 
True DLT rate 
0.5 
0.65 
0.75 
0.80 
0.90 
0.95 
 
 
[0.21, 0.39] 
Selection % 
35.8 
0.5 
0 
0 
0 
0 
11.3 
63.7 
 
# pts treated 
10 
1.3 
0 
0 
0 
 
 
 
 
11.1.3. Sensitivity analysis 
To examine the robustness of the proposed BOIN design, we use the BOIN package in R to 
examine the sensitivity of BOIN design with respect to acceptable toxicity region. The 
following table shows the simulation results under narrower [0.24, 0.36] or wider toxicity 
region, while keeping the other simulation parameters unchanged.  
We can see that the results are generally similar to those reported in Table 2. 
Table 3. Sensitivity analysis of BOIN design using scenario 1 in Table 2 
Toxicity 
range 
 
Dose level 
Number of 
pts 
% early 
stopping  
 
1 
2 
3 
4 
5 
6 
 
 
 
True DLT rate 
0.05 
0.10 
0.30 
0.45 
0.60 
0.8 
 
 
[0.18, 0.36] 
Selection % 
0.6 
18.1 
56.4 
23.2 
1.7 
0 
29.2 
0.0 
 
# pts treated 
5 
10.0 
9.8 
4.0 
0.5 
0 
 
 
 
True DLT rate 
0.05 
0.10 
0.30 
0.45 
0.6 
0.8 
 
 

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Toxicity 
range 
 
Dose level 
Number of 
pts 
% early 
stopping  
 
1 
2 
3 
4 
5 
6 
 
 
[0.18,0.42] 
Selection % 
0.9 
20.5 
57.5 
19.6 
1.5 
0 
25.1 
0.2 
 
# pts treated 
3.7 
7.2 
10.8 
4.8 
0.7 
0 
 
 
 
11.2. Study population 
11.2.1. All enrolled population 
All patients who sign informed consent form will be included. Patient disposition will be 
tabulated using this data set. 
11.2.2. All treated population 
All patients who receive at least one infusion or any partial dose of Investigation Product. This 
population will be used for safety analyses and efficacy analyses. 
11.2.3. Pharmacokinetic data set 
All available concentration-time data from patients who receive Investigational Product will be 
reported. All available PK parameter values will be included in the PK data set and reported, 
but only patients with adequate PK profiles will be included in the summary statistics and 
statistical analysis. 
11.2.4. Response evaluable data set 
Response-evaluable patients will be defined as all subjects who receive at least one infusion of 
Investigational Product, have a baseline tumor assessment with measurable disease, and one of 
the following: (1) at least one on-treatment tumor evaluation, (2) clinical progression, or (3) 
death prior to the first one-treatment tumor evaluation. 
11.2.5. Exploratory pharmacodynamic study 
All patients who receive at least one infusion of Investigational Product and have at least one 
measure of specific marker will be included in the data set for that marker. All treated patients 
with at least one baseline measurement and at least one on-treatment measurement will be 
included for the PD assessments. 

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11.3. Statistical considerations 
11.3.1. Demographics and baseline characteristics 
The demographics and baseline characteristics of the patients including age, sex, race, ethnicity, 
weight, baseline disease diagnosis, and medical conditions will be summarized by dose levels 
using descriptive statistics. 
11.3.2. Extent of exposure 
The dose of Investigational product received by patients will be summarized by dose level. A 
by-patient listing of treatment exposure will be generated. 
11.3.3. Concomitant medications 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHODD). Concomitant medications will be summarized. Tabulation will be made with 
respect to the proportion of subjects taking at least 1 concomitant medication for each preferred 
term during the study. A listing of concomitant medications by subject will be provided. 
11.3.4. Efficacy 
The primary efficacy parameter is the objective response rate: (ORR, umber of subjects with 
confirmed responses of CR or PR), divided by the total number of treated subjects with 
measurable disease at baseline). Tumor response status will be defined according to RECIST 
1.1 (Appendix 15.4). To perform an evaluation of anti-tumor activity, BOR outcomes, ORR, 
and disease control rate (DCR: number of patients with CR, PR, or SD divided by the total 
number of treated patients with measurable disease at baseline) will be tabulated by overall 
frequency distribution. Median time to response and duration of response will be summarized 
for those subjects with confirmed responses, using Kaplan-Meier methods; PFS will be 
similarly summarized. Listings of individual tumor measurements, tumor burden and % 
changes in tumor burden will be provided. Changes in tumor burden will be presented 
graphically for each disease type, e.g. by waterfall or other plots. 
11.3.5. Safety evaluation 
The following safety parameters will be evaluated:  

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11.3.5.1. 
Adverse events 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a patient or clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of investigational product, whether or not considered related to the investigational product. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a patient (To prevent reporting bias, patients should not be 
questioned regarding the specific occurrence of one or more AEs.)  
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur within 70 days of 
discontinuation of dosing or within 30 days of the last visit for screen failures. The investigator 
should collect any SAE occurring after these time periods that is believed to be related to study 
drug or protocol-specified procedure. An SAE report should be completed for any event where 
doubt exists regarding its status of seriousness. If the investigator believes that an SAE is not 
related to study drug, but is potentially related to the conditions of the study (such as withdrawal 
of previous therapy, or a complication of a study procedure), the relationship should be 
specified in the narrative section of the SAE Report Form. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
to categorize a system organ class and a preferred term for each adverse event. The number of 
subjects who experienced at least 1 adverse event, study drug related adverse event, severe 
(Grade≥ 3) adverse event, serious adverse event, and the number of subjects withdrawn due to 
adverse events will be summarized. For each system organ class and preferred term, summaries 
will be made with respect to the number and proportion of subjects having at least 1 occurrence 
of an adverse event during the study, using the worst grade reported within a subject. The 
incidence of adverse events will be presented overall, by system organ class and preferred term, 
intensity (based on NCI CTCAE Version 4.0), and additional grouping by severity and 
relationship to study drug. Individual listings of adverse events will be provided. DLTs and 
study drug-related Grade ≥ 2 adverse events will be listed individually. 

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11.3.5.2. 
Physical examination 
Abnormal findings in physical examinations will be recorded as adverse events or baseline 
medical history and will be included in the respective summaries. 
11.3.5.3. 
Vital signs 
Vital signs measurements will be summarized by dose level using descriptive statistics. 
11.3.5.4. 
ECG 
12-lead ECG results will be summarized by dose level. 
11.3.5.5. 
Clinical laboratory tests 
Clinical laboratory test values outside the normal range will be flagged in the data listing. 
Laboratory data will be summarized by dose level using descriptive statistics. The results of the 
immune safety tests will be summarized appropriately. NCI CTCAE Version 4.0 Grade will be 
assigned to some of the laboratory parameters, which are included in CTCAE Version 4.0. 
Laboratory values will be listed. The laboratory values which are outside normal range will be 
flagged as H (above high normal limit), L (below lower normal limit), or A (abnormal) in the 
data listings. The NCI CTCAE Version 4.0 Grade will also be flagged in the data listings. 
11.3.5.6. 
ECOG performance status 
ECOG performance status will be summarized by dose level using descriptive statistics. 
11.3.6. Immunogenicity 
A listing will be provided of all available immunogenicity data. A listing of immunogenicity 
data from those subjects with at least one positive Human Anti-Human Antibody (HAHA) at 
any time point will be provided by dose regimen. The frequency of subjects with at least one 
positive HAHA assessment, frequency of subjects who develop HAHA after a negative baseline 
assessment will be provided by dose. To examine the potential relationship between 
immunogenicity and safety, the frequency and type of AEs of special interest may be examined 
by overall immunogenicity status. 
11.3.7. Pharmacokinetic analysis 
The pharmacokinetic parameters will be calculated and listed for each patient and treatment 
cycle, alone with summary statistics including arithmetic and geometric means; standard 

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deviation; minimum, maximum, and median values; and coefficients of variations. The PK data 
will also be displayed graphically, as appropriate. Exploratory analyses on the PK data and their 
relationship to PD, safety, and immunogenicity evaluation may be investigated. 
Pharmacokinetic concentrations from limited samples will be listed, and may be used in 
combination with other studies for exposure-response or population pharmacokinetic modeling. 
11.3.8. Pharmacodynamic analysis 
The PD data will be assessed descriptively whenever possible and by exploratory statistical the 
relationship between PK and PD will be explored and the strength of the relationship will be 
assessed, whenever possible, comparisons of both raw and relative-to-baseline data.  
 

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12. ETHICAL ASPECTS 
12.1. Ethics and good clinical practice 
This study must be carried out in compliance with the protocol and the requirement of Clinical 
Practice (GCP), as described in International Conference on Harmonization (ICH) Harmonized 
Tripartite Guidelines (ICH E6R1 and its addendum) or similar regulations published by local 
regulatory agencies (e.g. the GCP guidance published by Taiwan Food and Drug 
Administration or Chinese Food and Drug Administration, US Code of Federal Regulations, 
Title 21, Part 50[21CFR50], and Title 21, Part 312[21CFR312]).  
The protocol and any amendments and the patient informed consent will receive Institutional 
Review Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion before 
initiation of the study. Study personnel involved in conducting this study will be qualified by 
education, training, and experience to perform their respective tasks.  
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (e.g., loss of medical license, debarment). 
All potential serious breaches must be reported to the Sponsor immediately. A serious breach 
is a breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
patients of the study or the scientific value of the study. 
12.2. Confidentiality of study patients 
Investigators must assure that the privacy of patients, including their personal identity and all 
personal medical information, will be protected at all times, as required by law. In CRFs and 
other study documents submitted to the Sponsor or its designee, patients will be identified by 
their initials, patient number, date of birth, and gender. 
Personal medical information may be reviewed and/or copied for research, quality assurance, 
and/or data analysis. This review may be conducted by the study monitor, properly authorized 
persons on behalf of the Sponsor, an independent auditor, IRBs/IECs or regulatory authorities. 
Personal medical information will always be treated as confidential. 
12.3. Institutional review board (IRB)/independent ethics committee (IEC) 
Before implementing this study, the protocol, the proposed ICF, and other information provided 
to patients must be reviewed by an IRB/IEC. A signed and dated statement that the protocol, 

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and ICF, patient recruitment materials/process (eg, recruitment advertisements), and any other 
written information to be provided to patients have been approved by the IRB/IEC must be 
given to the Sponsor or its designee before study initiation. The name of the chairperson of the 
IRB/IEC (preferred) or the IRB’s Health and Human Safety Assurance number must be 
supplied to or its designee along with the IRB approval. Any amendments to the protocol which 
need formal approval, as required by local law or procedure, will be approved by this committee. 
The IRB/IEC will also be notified of all other administrative amendments (i.e., administrative 
changes). 
The Investigator or Sponsor or its designee should also provide the IRB/IEC with a copy of the 
Investigator Brochure or product labeling, information to be provided to patients and any 
updates.  
The investigator or sponsor should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments and administrative letters) according to 
regulatory requirements or institution procedures. 
12.4. Informed consent 
Investigators must ensure that patients, or, in those situations where consent cannot be given by 
patients, their legally acceptable representatives, are clearly and fully informed about the 
purpose, potential risks/benefits, and other critical issues regarding clinical studies in which 
they volunteer to participate.  
The Investigators, or their designees, will explain to each patient (or legally authorized 
representative) the nature of the research study, its purpose, the procedures involved, the 
expected duration of patient participation, alternative treatment options, potential risks and 
benefits involved, and any discomfort which may occur during the patient’s participation in the 
study. Each patient will be informed that participation in the study is voluntary and that he/she 
may withdraw from the study at any time and that withdrawal of consent will not affect his/her 
subsequent medical care or relationship with the treating physician and caring medical team. 
The ICF must be submitted by the Investigator with the protocol for IRB/IEC approval. The 
Sponsor or its designee supplies a proposed ICF template that complies with regulatory 
requirements, includes all elements required by ICH, GCP and applicable local regulatory 
requirements, and is considered appropriate for the study. The sample informed consent form 
will adhere to the ethical principles that have their origin in the Declaration of Helsinki. Any 
changes to the proposed ICF suggested by the Investigator must be agreed to by the Sponsor or 

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its designee before submission to the IRB/IEC, and a copy of the approved version must be 
provided to the Study Monitor or its designee after IRB/IEC approval. 
Investigator must: 
Provide a copy of the consent form and written information about the study in the language in 
which the patient is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 
Allow time necessary for patient or patient's legally acceptable representative to inquire about 
the details of the study. 
Obtain an informed consent signed and personally dated by the patient or the patient's legally 
acceptable representative and by the person who conducted the informed consent discussion.  
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the patients, prior to the beginning of the study, 
and after any revisions are completed for new information. 
If informed consent is initially given by a patient’s legally acceptable representative or legal 
guardian, and the patient subsequently becomes capable of making and communicating their 
informed consent during the study, then consent must additionally be obtained from the patient. 
Revise the informed consent whenever important new information becomes available that is 
relevant to the patient's consent. The investigator, or a person designated by the Investigator, 
should fully inform the patient or the patient's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
patient's willingness to continue participation in the study. This communication should be 
documented.  
The consent form must also include a statement that the regulatory authorities have direct access 
to patient records.  
Patients who meet the eligibility criteria but are unable to give their written consent (e.g., stroke 
patients) may only be enrolled in the study with the consent of a legally acceptable 
representative. The patient must also be informed about the nature of the study to the extent 
compatible with the patients’ understanding, and should they become capable, personally sign 
and date the consent form as soon as possible.  
The rights, safety, and well-being of the study patients are the most important considerations 
and should prevail over interests of science and society. 

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13. ADMINISTRATIVE REQUIREMENTS 
13.1. Protocol amendments 
Any change or modification to this protocol requires a written protocol amendment that must 
be approved by the Sponsor before implementation. Amendments significantly affecting the 
safety of patients, the scope of the investigation, or the scientific quality of the study require 
additional approval by the IRB/IEC of all centers and, by the local regulatory authority. A copy 
of the written approval of the IRB/IEC must be given to the study monitor, or their designee. 
Examples of amendments requiring such approval are: 
Increase in drug dosage or duration of exposure of patients, or any significant increase in the 
number of patients under study;  
Significant change in the study design (e.g., addition or deletion of a control group, or rule of 
dose escalation or de-escalation); 
Increase in the number of procedures to which patients are exposed; or 
Addition or deletion of a test procedure intended to improve safety monitoring. 
These requirements for approval should in no way prevent any immediate action from being 
taken by the Investigator or by the Sponsor in the interests of preserving the safety of all patients 
in the study. If an immediate change to the protocol is deemed by the Investigator to be 
necessary and is implemented by him/her for safety reasons, the Sponsor should be notified and 
the IRB/IEC for the study site should be informed within 1 working day. Any significant 
deviation must be documented in the CRF. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to: (1) IRB/IEC for review and approval/favorable opinion; (2) the Sponsor 
and (3) regulatory Authority(ies), if required by local regulations. 
If an amendment substantially alters the study design or increases the potential risk to the patient: 
(1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from patients 
currently enrolled in the study if they are affected by the amendment; and (3) the new form 
must be used to obtain consent from new patients prior to enrollment. 
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB/IEC approval; however, the IRB/IEC for each center must be kept 
informed of such administrative changes. Examples of administrative changes not requiring 

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formal protocol amendments and IRB/IEC approval that can be treated as administrative 
amendments include, but are not limited to: (1) changes in the staff used to monitor studies; (2) 
minor changes in the packaging or labeling of study drug. 
13.2. Monitoring procedures 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a representative 
from the Sponsor will review the protocol, CRFs, and other study documents with the 
Investigators and their staff. During the study, the study monitor, or its designee, will visit the 
site regularly to check the completeness and timely updates of patient records, accuracy of 
entries on the CRFs, adherence to the protocol and to GCP, progress of enrollment, and also to 
ensure that study drug is being stored, dispensed, and accounted for according to specifications. 
The Investigator must give the study monitor access to relevant hospital or clinical records to 
confirm their consistency with the CRF entries. No information in these records about the 
identity of the patients will leave the study center. Monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of serious adverse events, compliance of local regulations and recording of 
efficacy and safety variables. Additional checks of the consistency of source data with the CRFs 
are performed according to the study-specific monitoring plan. 
Representatives of the Sponsor or its designee must be allowed to visit all study site locations 
periodically to assess the data quality and study integrity. On site they will review study records 
and directly compare them with source documents, discuss the conduct of the study with the 
Investigator, and verify that the facilities remain acceptable. 
In addition, the study may be evaluated by assigned auditors from the Sponsor and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. The audit reports will be kept confidential. 
The Investigator must notify the Sponsor or its designee promptly of any inspections scheduled 
by regulatory authorities, and promptly forward copies of inspection reports to the Sponsor or 
its designee. 
13.3. Investigator site training 
The Sponsor or its designee will provide quality investigational staff training prior to study 
initiation. Training topics will include but are not limited to: GCP, AE reporting, study details 

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and procedures electronic CRFs, study documentation, informed consent, and enrollment of 
women with child bearing potential and patients in vulnerable population. 
13.4. Recording of data and retention of documents 
All information required by the protocol should be provided; any omissions or corrections 
should be explained. All CRFs should be completed and available for collection within a timely 
manner, preferably no more than 10 days after the patient’s visit (except for the last visit of the 
last patient, which should be completed in a timely manner, preferably within 5 working days), 
so that the study monitor may check the entries for completeness, accuracy and legibility, ensure 
the CRF is signed by the Investigator and transmit the data to the Sponsor or its designee. 
All entries to the CRF must be made clearly in black ball-point or ink pen to ensure the legibility 
of self-copying or photocopied pages. Corrections will be made by placing a single horizontal 
line through the incorrect entry, so that the original entry can still be seen, and placing the 
revised entry beside it. The revised entry must be initialed and dated by a member of the 
Investigator’s research team authorized to make CRF entries. Correction fluid must not be 
used. 
If Electronic Data Capture (EDC) system is deployed, the eCRF will be completed by the 
authorized study site personnel. Electronic queries will be used to communicate eligible 
discrepant data with the study sites. 
The Investigator must maintain source documents for each patient in the study. All information 
on CRFs will be traceable to these source documents, which are generally maintained in the 
patient’s file. The source documents will contain all demographic and medical information, 
including laboratory data, ECGs, etc., and also a copy of the signed informed consent, which 
should indicate the study number and title of the study. 
Essential documents, as listed below, will be retained by the Investigator for the maximum 
period required to comply with national and international regulations, or institutional 
procedures, or for the period specified by the sponsor, whichever is longer.  
The Sponsor will notify the Investigator(s)/institution(s) when study-related records are no 
longer required to be retained. The Investigator agrees to adhere to the document retention 
procedures by signing the protocol. The investigator must contact the Sponsor or its designee 
prior to destroying any records associated with the study. 

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If the Investigator withdraws from the study (eg, relocation, retirement, conflict of interest), the 
records shall be transferred to a mutually agreed upon designee (eg, another Investigator, IRB). 
Notice of such transfer will be documented and given in writing to the Sponsor. 
Essential documents include: (1) signed protocol and all amendments; (2) IRB/IEC approvals 
for the study protocol and all amendments; (3) all source documents and laboratory records; (4) 
CRF copies; (5) patients’ ICF; (6) any other pertinent study documents. 
13.5. Study drug record 
It is the responsibility of the Investigator to ensure that a current disposition record of 
investigational product (those supplied by the Sponsor or its designee) is maintained at each 
study site where study drug is inventoried and dispensed. Records or logs must comply with 
applicable local regulations and guidelines and should include: 
 
amount received and placed in storage area 
 
amount currently in storage area 
 
label ID number or batch number  
 
amount dispensed to and returned by each patient, including unique patient identifiers 
 
amount transferred to another area/site for dispensing or storage 
 
non-study disposition (eg, lost, wasted) 
 
amount destroyed at study site, if applicable 
 
amount returned to the sponsor or its designee 
 
dates 
and 
initials 
of 
person 
responsible for 
Investigational 
Product 
(IP) 
dispensing/accountability, as per the Delegation of Authority Form. 
The sponsor will provide forms to facilitate inventory control if the investigational site does not 
have an established system that meets these requirements. 
13.6. Case report forms 
An Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation on each 
individual treated or entered in the investigation. Data reported on the CRF that are derived 
from source documents must be consistent with the source documents or the discrepancies must 
be documented. 
For sites using the electronic data capture tool, electronic CRFs will be prepared for all data 
collection fields except for fields specific to SAEs and pregnancy, which will be reported on 

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the SAE form and Pregnancy Notification worksheet, respectively. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided 
by the sponsor.  
The confidentiality of records that could identify patients must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).  
The investigator will maintain a signature sheet to document signatures and initials of all 
persons authorized to make entries and/or corrections on CRFs. The completed CRF, including 
any paper SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by a qualified 
physician who is an Investigator or sub-Investigator. For electronic CRFs, review and 
approval/signature is completed electronically through the BMS electronic data capture tool. 
The investigator must retain a copy of the CRFs including records of the changes and 
corrections.  
Each individual electronically signing electronic CRFs must meet the training requirements and 
must only access the electronic data capture tool using the assigned user account provided by 
the Sponsor. User accounts are not to be shared or reassigned to other individuals, not 
authorized for the study. 
13.7. Auditing procedures 
In addition to the routine monitoring procedures, the Sponsor or its designee, may conduct 
audits of clinical research activities in accordance with internal SOPs to evaluate compliance 
with the principles of GCP. The Sponsor, its designee, or a regulatory authority may wish to 
conduct an inspection (during the study or after its completion). If an inspection is requested by 
a regulatory authority, the Investigator will inform the Sponsor immediately that this request 
has been made. 
13.8. Publication policy 
Any formal presentation or publication of data collected from this study will be considered as 
a joint publication by the Investigator(s) and the appropriate personnel of the Sponsor. 
Authorship will be determined by mutual agreement. The arrangement of authorship is based 
on the contribution of the study by the Investigators. The principle of authorship of any 
publication resulting from this study is as follows: (International Committee of Medical Journal 
Editor, 2006) 
 Authorship credit must be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 

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or revising it critically for important intellectual content; (3) final approval of the 
version to be published. Authors must meet conditions 1, 2, and 3. 
 When a large, multicenter group has conducted the work, the group must identify the 
individuals who accept direct responsibility for the manuscript. These individuals must 
fully meet the criteria for authorship defined above.  
 Acquisition of funding, collection of data, or general supervision of the research group, 
alone, does not justify authorship.  
 All persons designated as authors must qualify for authorship, and all those who qualify 
must be listed.  
 Each author must have participated sufficiently in the work to take public responsibility 
for appropriate portions of the content. 
For multicenter studies, it is mandatory that the first publication be based on data from all 
centers, analyzed as stipulated in the protocol by statisticians assigned by the Sponsor, and not 
by the Investigators themselves.  
Investigators participating in multicenter studies agree not to present data gathered from one 
center or a small group of centers before the full, initial publication, unless formally agreed to 
by all other Investigators and the Sponsor. 
The data collected during this study are confidential and proprietary to the Sponsor. Any 
publications or abstracts arising from this study require approval by the Sponsor prior to 
publication or presentation and must adhere to the publication requirements as set forth in the 
approved clinical trial agreement (CTA) and the protocol. All draft publications, including 
abstracts or detailed summaries of any proposed presentations, must be submitted to the 
Sponsor at the earliest practicable time for review. Publication of any confidential or proprietary 
information of the IP should be approved for the proposed presentation or abstract and may 
delay publication for purposes of filing a patent application or other business arrangement. 
The Sponsor must receive copies of any intended communication in advance of submission (at 
least 28 days for a journal submission and 14days for an abstract or oral presentation). The 
Sponsor will review the communications for accuracy (thus avoiding potential discrepancies 
with submissions to health authorities), verify that confidential information is not being 
inadvertently disclosed, and provide any relevant supplementary information. Authorship of 
communications arising from pooled data may include members from each of the contributing 
centers, as well as representative personnel from the Sponsor. 

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13.9. Disclosure and confidentiality 
By signing the protocol, the Investigator agrees to keep all information generated in connection 
with the study or provided by the Sponsor or its designee in strict confidence and to request 
similar confidentiality from his/her staff and the IRB/IEC. Study documents provided by the 
Sponsor (protocols, Investigators’ Brochures, CRFs, and other materials) will be stored 
appropriately to ensure their confidentiality. Such confidential information may not be 
disclosed to others without direct written authorization from the Sponsor, except to the extent 
necessary to obtain informed consent from patients who wish to participate in the study.  
13.10. Discontinuation of study 
The Sponsor reserves the right to discontinue any study for any reason at any time.   
13.11. Data management 
13.11.1. 
Data collection 
Investigators must enter the information required by the protocol onto the CRFs that are printed 
on “no carbon required” paper. The study monitors or designees will review the CRFs for 
completeness and accuracy, and instruct site personnel to make any required corrections or 
additions. The CRFs will be forwarded to the Sponsor, or its designee, with one copy retained 
at the study site. 
If Electronic Data Capture (EDC) system is deployed, eCRF will be completed by the 
authorized study site personnel. An electronic version of the final eCRF book for each patient 
will be forwarded to the study sites for record keeping at the study site closure. 
13.11.2. 
Database management and quality control 
The information entered into the database will be systematically checked by data management 
staff from the Sponsor, or its designee.  
Obvious errors will be corrected by the personnel from the Sponsor, or its designee after 
verification with the Investigator. Other errors, omissions, or requests for clarification will be 
queried; queries will be returned to the study site  for resolution using  a Data Clarification 
Form  (DCF). A copy of the signed DCF will be kept with the CRFs. After receipt in Data 
Management, the resolutions will be entered into the database. Quality control audits of all key 
safety and efficacy data in the database will be conducted as agreed upon by relevant team 
members.  

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If EDC is deployed, data will be entered into the EDC system by the authorized study site 
personnel. Electronic queries will be used to communicate eligible discrepant data with the 
study sites. When the database has been declared to be complete and accurate, the database will 
be locked. Any changes to the database after that time can only be made by joint written 
agreement of the Sponsor study team. 
13.12. Compensation policy 
The sponsor will take out insurance and will take other necessary measures to compensate 
patients in this study for adverse health outcomes which occur during the trial.  
The informed consent information sheet will describe compensation which can be received 
during the clinical trial. However, this will not apply to anything resulting from an intentional 
act or the negligence of the medical institution or an intentional act or the gross negligence of 
the subject. 
 

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14. SCHEDULE OF ASSESSMENTS 
Procedure 
Screening 
Cycle1 
Cycle 2~6 
Cycle 7 and after 
Follow-up period 
Days 
 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
 
Weeks 
-4 to 0 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline conditions2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pathology review3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE assessment4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x 
DLT evaluation5 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Efficacy assessment6 
 
Assess every 8 weeks in the first 24 weeks and every 12 weeks thereafter 
 
                                                     
1 Medical history includes collection of prior medications administered to the patient during the Screening Period, prior and concurrent medical conditions, baseline signs and 
symptoms. 
2 Baseline condition includes vital signs, performance status, adverse events left from prior therapies, amount of hemoptysis. 
3 Pathology review includes confirmation of pathology, its mutation status4 AE assessment includes the adverse events left from prior therapies, the AE occurs after signing 
informed consent, but before the 1st infusion of IP. 
4 AE assessment includes the adverse events left from prior therapies, the AE occurs after signing informed consent, but before the 1st infusion of IP. 
5 DLT defining period is the first 4 weeks after the start of treatment. 
6 Efficacy assessment is done every 8 weeks in the first 24 weeks, every 12 weeks thereafter. 

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Procedure 
Screening 
Cycle1 
Cycle 2~6 
Cycle 7 and after 
Follow-up period 
Days 
 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
 
Weeks 
-4 to 0 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
 
Survival status7 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Treatment/Drug Administration 
Hospitalization for infusion and PK 
study 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
HLX06 infusion 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical procedures 
Vital signs/weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory procedures 
CBC w/ DC and D-dimer 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lipid profile9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT/PTT/INR  
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Tumor markers11 
X 
Every 8 weeks in the first 24 weeks and every 12 weeks thereafter 
 
Thyroid function tests12 
X 
Every 8 weeks in the first 24 weeks and every 12 weeks thereafter 
x 
Pregnancy test (serum HCG) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine HCG) 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 

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7 Every three months by either phone or in direct contact after the completion of follow-up visits. 
8 The screening procedures include performance status, hematology panel, chemistry panel, coagulation, urinalysis, lipid profile, serum lipase and amylase, thyroid function tests 
(TSH, T3, free T4) need to be completed with 28 days prior to first infusion of HLX06. If the hematology panel, chemistry panel, coagulation, urinalysis, serum lipase and amylase 
thyroid function tests are completed within 7 days of first infusion, they do not need to be repeated. Hematology panel: CBC with differentials, D-dimers level. Blood chemistry 
panel: fasting glucose, blood urea nitrogen (BUN), creatinine, ALT, AST, total protein, albumin, globulin, alkaline phosphatase, total bilirubin, sodium, potassium, chloride, 
calcium, magnesium, phosphorus, uric acid, lactate dehydrogenase (LDH), IgG and IgM.  All the blood tests need to be performed in fasting state. 
9 Total cholesterol and triglyceride. 
10Urinalysis panel: color, turbidity, specific gravity, pH, leukocyte, nitrite, protein, glucose, ketones, urobilinogen, bilirubin, blood cells. If the urinalysis indicates significant 
proteinuria (> 30 mg or >=2+ by urine dipstick), urinalysis must be repeated. If the repeat dipstick protein value is >30 mg or >= 2+ by urine dipstick, 24-hour urine collection is 
required to calculate total protein. 
11 Tumor markers include CEA, CA199, CA125, CA153, AFP and PSA. PSA is only indicated for patients with prostate cancer. These should be done every 8 weeks in the first 
24 weeks, and every 12 weeks thereafter. 
12 Thyroid function tests include TSH, T3, free T4. They are done at Screening, every 8 weeks in the first 24 weeks, and every 12 weeks thereafter. 

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Procedure 
Screening 
Cycle1 
Cycle 2~6 
Cycle 7 and after 
Follow-up period 
Days 
 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
 
Weeks 
-4 to 0 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
 
HBsAg, HBcAb, and anti-HCV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum lipase and amylase 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK study13 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
Immunogenicity study14 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
Optional PD study15 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Imaging procedures 
12-lead ECG16 
X 
X 
 
 
 
X 
 
 
 
x 
 
 
 
X 
Cardiac ultrasound 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-Ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor assessment CT/MRI imaging 
X 
Every 8 weeks in the first 24 weeks and every 12 weeks thereafter 
X 
Brain CT/MRI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone scan 
X 
Repeat bone scan for metastatic bone disease is indicated based on clinical 
judgement by the Investigator 
 
                                                     
13 Pharmacokinetic analysis of HLX06: blood samples of 5 mL were drawn within one hour before and at the end of infusion, 2, 4, 8 (±15 minutes allowable) hours as well as at 
24, 48, 96, and 168 hours after the start of 1st and 4th infusion in Cycle 1. Additional time points include before and after 2nd and 3rd infusions in Cycle 1. Thereafter, the serum 
levels of HLX06 will be measured before the first infusion of Cycle 2 to Cycle 6 or up to 24 weeks, whichever comes first; and on the day follow-up visit 1, whenever possible. 
14 Blood samples for immunogenicity will be collected from all patients prior to every infusion of IP in Cycle 1 and before first infusion in subsequent 5 cycles or up to 18 weeks, 
whichever comes first; and on the day of follow-up visit 1. 
15 The sampling time points are predose and after each infusion (within 30 minutes) in cycle 1 in conjunction with pharmacokinetic studies. 
16 At screening, predose and after the end of 1st infusion (within 30 minutes) of each cycle and on the day of follow-up visit 1. 

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15. APPENDICES 
15.1. ECOG performance status 
Table 4. Grading and description of ECOG PS 
Grade  
 Description 
0   
Fully active, able to carry on all pre-disease performance 
without restriction.  
1   
Restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature, e.g., 
light house work, office work.  
2   
Ambulatory and capable of all self-care but unable to carry 
out any work activities. Up and about more than 50% of 
waking hours.  
3   
Capable of only limited selfcare, confined to bed or chair 
more than 50% of waking hours.  
4   
Completely disabled. Cannot carry on any selfcare. Totally 
confined to bed or chair.  
5   
Dead 

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15.2. Child-Pugh scoring table for estimation of liver reserve 
Score 
1 
2 
3 
Encephalopathy 
None 
Mild 
Marked 
Ascites 
None 
Mild to moderate 
Severe 
Bilirubin (mg/dL) 
< 2 
2-3 
>3 
Albumin (g/mL) 
>3.5 
2.8-3.5 
<2.8 
Prothrombin time 
Seconds prolonged or 
INR 
 
<4 
<1.7 
 
4-6 
1.7-2.3 
 
>6 
>2.3 
 
Score 
Description 
Points 
A 
Mild; well-compensated 
5-6 
B 
Moderate; significant 
functional compromise 
7-9 
C 
Severe; decompensated 
10-15 
 
 

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15.3. Adverse event severity scoring system 
Table 5. Grading and Description of AE 
Grade  
Standard Adverse Event Severity Scoring System 
1 
MILD  
Aware of sign or symptom, but easily tolerated 
2 
MODERATE:  
Discomfort enough to cause interference with 
usual activity  
3 
SEVERE:  
Incapacitating, with inability to work or do usual 
activity 
4 
LIFE-THREATENING: 
Refers to an event in which the patient was, in the 
view of the investigator, at risk of death at the time 
of the event. 
5 
FATAL 
 

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15.4. RECIST criteria 1.1 
Solid tumor response 
Measurable disease/target lesions and non-measurable disease/non-target lesions are to be 
evaluated according to the new standardized  RECIST criteria[25]. Each category (measurable 
and non-measurable lesions) will be assessed and reported independently. 
Method 
CT scans (or MRI) will be performed to evaluate tumor response. All measurements should be 
taken and recorded in metric notation (mm) using a ruler or calipers.  
CT and MRI are the best currently available and reproducible methods to measure target lesions 
and qualitatively assess non-target lesions selected for response assessment. Conventional CT 
(non-spiral or non-helical) and conventional MRI (MRI performed without fast scanning 
techniques) should produce images contiguously reconstructed at 10 mm or less. Spiral (helical 
or multidetector) CT should produce images contiguously reconstructed between 5 and 8 mm. 
Lesions identified on a chest x-ray should be imaged by a CT or MRI scan. 
The same method of assessment and the same technique should be used to characterize each 
site of disease at baseline and during follow-up evaluations. 
Documentation of Target and Non-Target Lesions 
All measurable or target lesions, up to a maximum of 5 lesions per organ and 10 lesions total, 
representative of all sites of disease, will be identified and measured at baseline and followed 
as target lesions throughout the study. Target lesions should be selected on the basis of their 
size (longest diameter) and suitability for accurate reproducibility and measurement on follow-
up imaging. The SLD for all target lesions will be calculated and reported as the baseline SLD. 
The baseline SLD will be used as a reference by which to characterize the objective tumor 
response at each subsequent tumor assessment timepoint. The smallest sum of the longest 
diameters recorded since baseline will be used as reference when evaluating for progression. 
All other lesions (or sites of disease) should be identified as non-target lesions and should be 
recorded at baseline.  
Measurement of these lesions is not required, but the presence, absence, or worsening of each 
should be documented throughout follow-up. 
Response Confirmation 

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To be assigned a status of CR or PR, changes in tumor measurements must be confirmed by 
consecutive repeat assessments that should be performed no less than 28 days after the criteria 
for response are first met.  
Overall time point responses for all possible combinations of responses in target and non-target 
lesions with or without the appearance of new lesion. 
Table 6. Classification of responses 
Target lesions  Nontarget lesions  
New lesions  
Overall response  
CR   
CR  
CR   
CR/NA  
SD  
UE/ND  
No  
No  
No  
CR  
PR  
UE  
PR  
PR  
Non-PD/NA  
UE/ND  
No  
No  
PR  
UE  
SD  
SD  
Non-PD/NA  
UE/ND  
No  
No  
SD  
UE  
PD   
Any  
Any  
Any  
PD  
Any  
Yes or no*  
Yes or no*  
Yes*   
PD  
PD  
PD  
UE  
Non-PD/NA  
No  
UE  
ND  
Non-PD/NA  
No   
UE  
NA  
SD  
No  
SD  
NA  
CR  
No  
CR 
CR: complete response; PR: partial response SD: stable disease; PD: progressive response; UE: 
unable to evaluate (any target or non-target lesion present at baseline which was not assessed 
or unable to be evaluated leading to an inability to = determine the status of that particular tumor 
for that time point); NA: not applicable;(no target or nontarget lesions identified at baseline); 
ND: not done (scans not performed at this timepoint) 

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Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time are to be classified as having 
“symptomatic deterioration.” 
 

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Table 7. Definition of lesions and imaging modality and their requirement 
Definitions 
Description 
Measurable lesions 
Target lesions that can be measured accurately in at 
least one dimension (longest diameter to be 
recorded) as ≥20 mm with conventional techniques, 
or as ≥10 mm with spiral (helical) computed 
tomography (CT) scan or two (2) times the 
reconstruction interval (RI) when using spiral 
(helical) or multidetector CT, but not less than 10 
mm.   
Non-measurable lesions 
Non-target lesions not classified as measurable 
lesions (longest diameter <20 mm with conventional 
techniques or <10 mm with spiral CT scan) and truly 
non-measurable lesions. These include bone lesions 
on BS, effusions, and leptomeningeal disease. Any 
measurable lesions that were not classified as target 
lesions will be classified as non-target lesions. 
Target lesions 
All measurable lesions up to a maximum of 5 lesions 
and 2 lesions per organ, representative of all 
involved organs, are to be identified as target lesions 
and recorded and measured. Target lesions are to be 
selected on the basis of their size (those with the 
longest diameter) and their suitability for accurate 
repeated 
measurements 
(either 
by 
imaging 
techniques or clinically). 
All lesions other than target lesions (or sites of 
disease) are to be identified as nontarget lesions and 
are to be recorded. Measurements of these lesions are 
not required, but the presence or absence of each is 
to be noted. 

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Definitions 
Description 
Longest diameter for target lesions - The sum of the 
longest diameter for all target lesions (SLD). 
Complete response - Disappearance of all target 
lesions.   
Partial response: At least a 30% decrease in the sum 
of the longest diameter of target lesions, taking as 
reference the Screening sum longest diameter.  
Stable disease: Neither sufficient shrinkage to 
qualify for partial response nor sufficient increase to 
qualify for progressive disease.  
Progressive disease: At least a 20% increase in the 
sum of the longest diameters of target lesions (with 
addition of diameters of any newly emergent 
measurable lesions), taking as reference the smallest 
sum of the longest diameters (nadir) recorded since 
screening.  
UE/ND/NA 
Non-target lesions 
All lesions other than target lesions (or sites of 
disease) are to be identified as nontarget lesions and 
are to be recorded. Measurements of these lesions are 
not required, but the presence or absence of each is 
to be noted.  
Complete response: Disappearance of all non-
target lesions.   
Incomplete response/stable disease: Persistence of 
one or more non-target lesion(s).   
Progressive disease: Unequivocal progression of a 
non-target lesion or appearance of 1 or more new 
lesions.   

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Definitions 
Description 
UE/ND/NA 
Best overall response 
The best overall response is the confirmed overall 
response. To be assigned a best overall response of 
partial response or complete response, change in 
tumor measurements must be confirmed by repeat 
assessment no less than 4 weeks after the criteria for 
response of CR or PR are first met. 
Methods of 
measurements 
The same imaging modality, method of assessment, 
and technique must be used throughout the study to 
characterize each identified and reported lesion.  
All measurements are to be made with a ruler or 
calipers; measurements are to be recorded in metric 
notation. 
Clinical examination 
Clinically detected lesions are only to be considered 
measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes). For skin 
lesions, documentation by color photography—
including a ruler to estimate the size of the lesion—
is recommended. 
Chest X-ray 
Lesions on the chest X-ray are to be acceptable as 
measurable lesions when they are clearly defined 
and surrounded by aerated lung. Chest X ray is to 
be performed in full inspiration in the poster-
anterior projection. The film to tube distance is to 
remain constant between examinations. If patients 
with advanced disease are not well enough to fulfill 
these criteria, such situations are to be reported 
together with the measurements. Lesions bordering 
the thoracic wall, and lesions bordering or 

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Definitions 
Description 
involving the mediastinum, are not suitable for 
measurements by chest x-ray. 
Computed 
Tomography 
and Magnetic Resonance 
Imaging 
CT is the primary imaging modality of choice. 
Conventional CT and magnetic resonance imaging 
(MRI) are to be performed with contiguous cuts of 
10 mm or less in slice thickness. Spiral CT is to be 
performed 
by 
use 
of 
a 
5mm 
contiguous 
reconstruction algorithm. CT scans of the thorax, 
abdomen, and pelvis are to be contiguous throughout 
the anatomic region of interest. The minimum size of 
the lesion is to be no less than double the slice 
thickness.  
The longest diameter of each target lesion is to be 
selected in the axial plane only.  For spiral CT  
scanners,  the  minimum  size  of  any  given  lesion  
at Screening  may  be  10  mm,  provided  the  images  
are  reconstructed contiguously  at  5  mm  intervals.  
For conventional CT scanners, the minimum-sized 
lesion is to be 20 mm by use of a contiguous slice 
thickness of 10 mm.  
In patients in whom the abdomen and pelvis have 
been imaged, oral contrast agents are to be given to 
accentuate the bowel against other soft-tissue 
masses. Intravenous contrast agents are also to be 
given, unless contraindicated for medical reasons 
such as allergy. An adequate volume of a suitable 
contrast agent is to be given so that the metastases 
are demonstrated the best effect. All images from 
each examination are to be included and not 
selected” images of the apparent lesion.  

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Definitions 
Description 
All window settings are to be included, particularly 
in the thorax, where the lung and soft-tissue windows 
are to be considered. Lesions are to be measured on 
the same window setting on each examination.  
When MRI is used, lesions are to be measured in the 
same anatomic plane by use of the same imaging 
sequences on subsequent examinations. Wherever 
possible, the same scanner is to be used. 
Bone scan 
Bone scans are to be used for the assessment of non-
target lesions only. 
Ultrasound 
Ultrasound is not to be used to measure tumor lesions 
that are clinically not easily accessible. 
 
 

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15.6. R codes used to derive the dose escalation and de-escalation  
Table 1 is generated with software R 3.4 with BOIN package 2.4. Various scenarios of toxicity 
distribution with target toxicity rate at different dose levels are generated with dfcrm package. 
Operative characteristics of the study design are also generated with BOIN package. 
The R script for this study is as follows: 
if(!require(“pacman”)){ 
install.packages(“pacman”)} 
pacman::p_load(BOIN, dfcrm) 
target<-0.3 # target toxicity rate# 
nc<-10 #number of cohorts 
cs<-3 # cohort size 
nes<- 15 # number of pts in a cohort for early stop# 
sb<-target*0.7 #set up the safe boundary, narrower than default# 
tb<-target*1.3 #set up the toxic boundary,narrower than default# 
get.boundary(target=target,ncohort=nc, cohortsize = cs, n.earlystop = nes, p.saf =sb, p.tox = tb, 
extrasafe = FALSE, offset = 0.05) 
# get operating characteristics 
# use dfcrm to get priors 
delta<-0.09 # the acceptable range of DLT 
mtd0<-3 # prior MTD, usu. the starting dose# 
k<-6 # number of dose levels 
p0<-getprior(halfwidth=delta, target=target, nu=mtd0, nlevel=k, model = "empiric") 
p1<-round(p0, digits = 2) 
p1 # the toxicity probability distribution 
get.oc(target = target, p.true = p1, ncohort = nc, cohortsize = cs, n.earlystop = nes, p.saf = sb, 
p.tox = tb, extrasafe = FALSE, ntrial = 1000) # get operative characteristic 
 
 

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15.8. Pregnancy notification worksheet 
Study No. 
HLX06FIH 
Site No.: 
Patient ID No. 
Patient Initial 
Did the patient withdraw from the Study?   Yes____.       No._________ 
Sex 
SEX Code: 
(  ) Female patient 
(  ) Male patient partner 
 
 
Estimated Date of Conception 
Day 
Month 
Year 
 
 
 
 
 
 
 
 
 
 
Investigational Product Administration Starting Date 
Day 
Month 
Year 
 
 
 
 
 
 
 
 
 
 
Investigational Product Administration Stop Date 
Day 
Month 
Year 
 
 
 
 
 
 
 
 
 
 
Investigator Name: 
Tel: 
Institution: 
Site No.: 
Address: 
 
 
FAX to: Henlix Biotech Co. Ltd, Attn: Shufan Lin 
FAX NO. +886-2-27927901                            TEL: +886-2-27927901 
Day 
Month 
Year 
 
 
 
 
 
 
 
 
 

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17. REFERENCES 
1. 
Dancey, J., B. Freidlin, and L. Rubinstein, Accelerated titration designs. Statistical 
methods for dose finding experiments, 2006: p. 91. 
2. 
Yuan, Y., et al., Bayesian optimal interval design: a simple and well-performing design 
for phase 1 oncology trials. Clin Cancer Res, 2016. 22: p. 4291-301. 
3. 
Wang, D., et al., Fixed dosing versus body size-based dosing of monoclonal antibodies 
in adult clinical trials. Pharmacokinet Pharmacodyn, 2009. 49: p. 1012-24. 
4. 
Hansen, A., et al., Choice of starting dose for biopharmaceuticals in first-in-human 
phase 1 cancer clinical trials. The Oncologist, 2015. 20: p. 653-59. 
5. 
Liu, S. and Y. Yuan, Bayesian optimal interval design for phase 1 clinical trials. J Royal 
Stat  Soc, 2015. 64: p. 507-23. 
6. 
Lencioni, R. and J.M. Llovet, Modified RECIST (mRECIST) asessment for hepatocellular 
carcinoma. Semin Liver Dis, 2010. 30: p. 52-60. 
7. 
Miettinen, M., et al., Vascular endothelial growth factor receptor 2 (VEGFR2) as a 
marker for malignant vascular tumors and mesothelioma - immunohistochemical 
study of 262 vascular endothelial and 1640 nonvascular tumors. Am J Surg Pathol, 
2012. 36(4): p. 629-39. 
8. 
Nishida, N., et al., Angiogenesis in cancer. Vasc Health Risk Manag, 2006. 2(3): p. 213-
19. 
9. 
Shimodaira, Y., et al., Ramucirumab for the treatment of gastroesophageal cancers. 
Expert Opin Orphan Drugs, 2015. 3(6): p. 737-46. 
10. 
Spratlin, J.L., et al., Phase I pharmacologic and biologic study of ramucirumab (IMC-
1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular 
endothelial growth factor receptor-2. J Clin Oncol, 2010. 28(5): p. 780-7. 
11. 
Muro, K., et al., Subgroup analysis of East Asians in RAINBOW: A phase 3 trial of 
ramucirumab plus paclitaxel for advanced gastric cancer. J Gastroenterol Hepatol, 
2016. 31(3): p. 581-9. 
12. 
Garcia-Carbonero, R., et al., An open-label phase II study evaluating the safety and 
efficacy of ramucirumab combined with mFOLFOX-6 as first-line therapy for 
metastatic colorectal cancer. Oncologist, 2014. 19(4): p. 350-1. 
13. 
Oholendt, A.L. and J.L. Zadlo, Ramucirumab: A New Therapy for Advanced Gastric 
Cancer. J Adv Pract Oncol, 2015. 6(1): p. 71-5. 
14. 
Chiorean, E.G., et al., Phase I study of every 2- or 3-week dosing of ramucirumab, a 
human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial 
growth factor receptor-2 in patients with advanced solid tumors. Ann Oncol, 2015. 
26(6): p. 1230-7. 
15. 
Le Tourneau, C., J. Lee, and L. Siu, Dose escalation methods in phase 1 cancer clinical 
trials. J Natl Cancer Inst, 2009. 101: p. 708-20. 
16. 
Dirk, N. and B. Meibohm, Population pharmacokinetics of therapeutic monoclonal 
antibodies. Clin Pharmacokinet, 2010. 49(10): p. 633-59. 

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17. 
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