Clinical trial NCT03084237
Conditions: Breast Cancer
Sponsor: Shanghai Henlius Biotech
Start date: 2016-11-01; Completion date: 2021-09-28
Enrollment: 652 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase III, double-blind, randomized multicenter study to compare the efficacy and to evaluate the safety and immunogenicity of HLX02 and European Union (EU)-sourced Herceptin® in patients with human epidermal growth factor receptor 2 (HER2)-positive, locally recurrent or previously untreated metastatic breast cancer.

Detailed description:
This is a Phase III, double-blind, randomized multicenter study to compare the efficacy and to evaluate the safety and immunogenicity of HLX02 and European Union (EU)-sourced Herceptin® in patients with human epidermal growth factor receptor 2 (HER2)-positive, recurrent or previously untreated metastatic breast cancer. Eligible patients will be assessed centrally for HER2 status and the presence of at least one measurable target lesion before randomization. Patients will undergo a tumor assessment for evaluation of response according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) every 6 weeks up to 24 weeks (regardless of the number of cycles actually given); thereafter, assessments will be done every 9 weeks (after Cycles 11, 14, and 17) or earlier in the case of clinical signs of progression.

Arms: arm 1: HLX02+Docetaxel arm 2: Herceptin®+Docetaxel
Interventions: intervention 1: HLX02 intervention 2: Herceptin® intervention 3: docetaxel
Intervention descriptions: intervention 1: 8 mg/kg administered intravenously over 90 minutes as a loading dose on Day 1, Cycle 1 then 6 mg/kg every 3 weeks for subsequent cycles. intervention 2: 8 mg/kg administered intravenously over 90 minutes as a loading dose on Day 1, Cycle 1 then 6 mg/kg every 3 weeks for subsequent cycles intervention 3: 75 mg/m2 will be administered on Day 2, Cycle 1.then be given every 3 weeks on Day 1 of each subsequent cycle

Protocol documents:
Prot_SAP_000.pdf: 
Sponsor: Shanghai Henlius Biotech, Inc. 
 
1 
Protocol: HLX02-BC01 v5.0 
Drug Name: HLX02 
17 JULY 2017 
Confidential 
Clinical Study Protocol 
Protocol Title:  
Double-blind, Randomized, Multicenter, Phase III Clinical 
Study to Compare the Efficacy and to Evaluate the Safety 
and Immunogenicity of Trastuzumab Biosimilar HLX02 and 
EU-sourced Herceptin® in Previously Untreated 
HER2-Overexpressing Metastatic Breast Cancer 
Protocol Number: 
HLX02-BC01 
Date of Protocol: 
 
 
17 JULY 2017 v5.0 (Final version) 
Product: 
HLX02 (trastuzumab) 
EUDRACT No.: 
2016-000206-10 
Study Phase: 
III  
Sponsor: 
Shanghai Henlius Biotech, Inc. 
1F, Building A, 150 Copernicus Road 
China (Shanghai) Pilot Free Trade Zone 
Project Managers: 
Black Li 
Shanghai Henlius Biotech, Inc. 
as above 
 
Fanny Chong 
Quintiles Hong Kong Ltd 
Unit 2212-19, Level 22, Metroplaza Tower 1 
22 Hing Fong Road, Kwai Fong 
New Territories, Hong Kong 
Medical Monitors:  
Zhidan Chen, MD, PhD 
Shanghai Henlius Biotech, Inc. 
as above 
 
Liang Wan, MD 
Quintiles 
5F Building A, 388 Feng Lin Road 
Shanghai 200032 China 
 
Maria Zolotareva, MD 
Quintiles 
Sredniy Prospect, 36/40 Letter “K” 
199004, St Petersburg, Russia 
International Study Coordinator: 
Binghe Xu, MD, PhD 
Cancer Hospital, Chinese Academy of Medical Sciences 
Panjiayuan, Chaoyang District 
Beijing 100021, P.R. China 
Telephone number: +86 1087788826 
Confidentiality Statement 
This confidential information in this document is provided to you as an Investigator or consultant for review by you, your 
staff, and the applicable Institutional Review Board/Independent Ethics Committee.  Your acceptance of this document 
constitutes agreement that you will not disclose the information contained herein to others without written authorization 
from the Sponsor. 






Sponsor: Shanghai Henlius Biotech, Inc. 
 
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Protocol: HLX02-BC01 v5.0 
Drug Name: HLX02 
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Synopsis 
Name of Sponsor/Company: 
Shanghai Henlius Biotech, Inc 
Name of Finished Product: 
Experimental Drug: 
Not applicable 
HLX02 
Name of Comparator: 
Herceptin® 
Name of Active Ingredient: 
Trastuzumab 
Title of Study: 
Double-blind, Randomized, Multicenter, Phase III Clinical Study to Compare the 
Efficacy and to Evaluate the Safety and Immunogenicity of Trastuzumab Biosimilar 
HLX02 and EU-sourced Herceptin® in Previously Untreated HER2-Overexpressing 
Metastatic Breast Cancer 
Protocol No: 
HLX02-BC01 
Investigators: 
International study coordinator Binghe Xu at the Cancer Hospital, Chinese Academy 
of Medical Sciences, Beijing, China 
Study center(s): 
Approximately 83 study centers worldwide 
Study period: Screening (up to 28 days), Treatment Period (maximum 
12 months), Safety Follow-up (30 days after last dose of study drug), Survival 
Follow-up (up to 36 months). 
End of study: Will be 36 months after the last patient has been randomized. 
Phase:   
III 
Study design: This is a Phase III, double-blind, randomized multicenter study to compare the efficacy and to 
evaluate the safety and immunogenicity of HLX02 and European Union (EU)-sourced Herceptin® in patients 
with human epidermal growth factor receptor 2 (HER2)-positive, recurrent or previously untreated metastatic 
breast cancer.  Eligible patients will be assessed centrally for HER2 status and the presence of at least one 
measurable target lesion before randomization.  Patients will undergo a tumor assessment for evaluation of 
response according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) every 
6 weeks up to 24 weeks (regardless of the number of cycles actually given); thereafter, assessments will be 
done every 9 weeks (after Cycles 11, 14, and 17) or earlier in the case of clinical signs of progression.  All 
patients will remain in the study until Investigator-assessed disease progression, excessive toxicity, 
Investigator’s judgment, withdrawal of consent, lost to follow-up, death, start of a new anticancer therapy, 
study termination by the Sponsor, or for a maximum of 12 months of treatment, whichever occurs first.  After 
the Treatment Period (up to 12 months), patients will be referred to the local institution and will continue 
therapy in accordance with local practice.  All patients will undergo a Safety Follow-up Visit 30 (±2) days 
after the last dose of study drug.  Cardiac safety monitoring and immunogenicity testing will continue up to 
12 months after randomization in all patients.  Survival Follow-up will occur every 3 months until 12 months 
after randomization; thereafter, overall survival (OS) data will be collected by telephone call every 3 months 
for up to 36 months after randomization.   
Objectives: 
Primary: 
To compare the efficacy of HLX02 versus EU-sourced Herceptin® in combination with docetaxel using 
overall response rate (ORR) up to Week 24 (ORR24) after up to 8 cycles of treatment to demonstrate clinical 
bioequivalence. 
Secondary: 
• To evaluate the safety, tolerability, and immunogenicity of HLX02 and EU-sourced Herceptin® given in 
combination with docetaxel. 


Sponsor: Shanghai Henlius Biotech, Inc. 
 
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Protocol: HLX02-BC01 v5.0 
Drug Name: HLX02 
17 JULY 2017 
Confidential 
• To compare the efficacy of HLX02 versus EU-sourced Herceptin® in combination with docetaxel, in 
terms of duration of response (DoR), clinical benefit rate (CBR), disease control rate (DCR), 
progression-free survival (PFS) up to 12 months, and OS at 12, 24, and 36 months. 
• To measure the exposure to trastuzumab following HLX02 or EU-sourced Herceptin®. 
Exploratory: 
• Exploratory population pharmacokinetic (PopPK) analysis. 
Rationale and methodology: 
HLX02 is developed as a proposed biosimilar to Herceptin® to meet the need for alternatives to high-priced 
biologic agents in oncology treatments.  This study will be conducted in patients with HER2-positive, 
recurrent or previously untreated metastatic breast cancer.  The patients will be stratified for estrogen 
receptor/progesterone receptor (ER/PgR) status, prior neo-/adjuvant therapy with Herceptin®, and ethnicity 
(Asian and non-Asian), then randomized into 2 treatment arms in a 1:1 ratio to receive HLX02 or 
EU-sourced Herceptin® in combination with docetaxel according to the current standard of care.  HLX02 or 
Herceptin® and docetaxel will be given once every 3 weeks for a maximum of 12 months.  Tumor response 
for the primary efficacy analysis will be evaluated by central imaging review (CIR) for an independent, 
blinded determination of tumor response up to Week 24, after completion of up to 8 cycles of treatment.  A 
CIR will occur at Screening to confirm eligibility and at Week 6, 12, 18, and 24 to compare the pattern of 
response.  No CIR is required after Week 24.  As of Cycle 9, patients will remain in the study and be 
followed every 9 weeks for other efficacy parameters such as DoR and PFS up to 12 months.  Overall 
survival will be estimated at 12, 24, and 36 months.   
Planned number of patients: 
A maximum of 304 patients will be enrolled in each arm to yield 
289 evaluable patients per arm for the primary efficacy analysis in the 
intent-to-treat (ITT) population, accounting for a dropout rate of 5%. 
Diagnosis: 
Patients with HER2-positive, recurrent or metastatic breast cancer as 
centrally assessed by fluorescence in situ hybridization (FISH) or 
immunohistochemistry (IHC) who have not received prior systemic 
chemotherapy, biological or targeted agents for their recurrent or metastatic 
disease.  Patients can have metastatic disease either at time of diagnosis, or 
after prior diagnosis of early breast cancer, provided neo-/adjuvant 
treatment containing trastuzumab and/or lapatinib was completed at least 
12 months before the diagnosis of recurrent disease (local or metastatic) or 
neo-/adjuvant therapy containing a taxane (and no trastuzumab/lapatinib) 
was stopped at least 6 months before the diagnosis of recurrent (local or 
metastatic) disease.  Neo-/adjuvant therapy with other cytotoxics only must 
have been stopped at least 4 weeks before randomization. 
Investigational and 
comparator product, dose 
and route of administration: 
Investigational product HLX02 (proposed biosimilar to trastuzumab) or 
comparator product EU-sourced Herceptin® (trastuzumab) will be 
administered intravenously as a loading dose of 8 mg/kg over 90 minutes 
on Day 1, Cycle 1, and then every 3 weeks for subsequent cycles at 
6 mg/kg over 30-90 minutes (i.e. any duration between 30 and 90 minutes 
from Cycle 2 onwards) if the previous dose was well tolerated.  If an 
infusion-related reaction (IRR) occurs, the infusion should be immediately 
interrupted (in patients with non-serious IRRs, at the Investigator’s 
discretion, the infusion may be slowed) and the patient should be monitored 
until resolution of all symptoms.  These symptoms can be treated with an 
analgesic/antipyretic such as meperidine or paracetamol.  Serious reactions 
must be treated with supportive therapy such as oxygen, beta-agonists, and 
corticosteroids.  If a second episode of serious IRR occurs despite 
prophylactic use of steroids (see section on prophylactic drugs below) 
treatment will be permanently discontinued.  Treatment with HLX02 or 


Sponsor: Shanghai Henlius Biotech, Inc. 
 
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Protocol: HLX02-BC01 v5.0 
Drug Name: HLX02 
17 JULY 2017 
Confidential 
Herceptin® will continue for a maximum of 12 months, or until 
Investigator-assessed disease progression, excessive toxicity, Investigator’s 
judgment, withdrawal of consent, lost to follow-up, death, start of a new 
anticancer therapy, or study termination by the Sponsor, whichever occurs 
first.  HLX02 or Herceptin® administration may be delayed but no dose 
reduction is allowed.  If a patient misses a dose of HLX02 or Herceptin® by 
less than 1 week after the planned date, the usual maintenance dose 
(6 mg/kg) should be given as soon as possible.  Do not wait until the next 
planned cycle.  If a patient misses a dose of HLX02 or Herceptin® for 
≥1 week (i.e. the 2 sequential administrations are given ≥4 weeks apart), a 
re-loading dose of HLX02 or Herceptin® (8 mg/kg) should be given.  
Subsequent maintenance HLX02 or Herceptin® doses of 6 mg/kg will then 
be given every 3 weeks, starting 3 weeks later.  If re-loading is required, 
docetaxel administration (at the dose that was last tolerated) will be 
restarted on the same day as the re-loading dose, to coincide with the start 
of a new cycle.  If a patient has a study drug interruption ≥9 weeks for a 
trastuzumab-related toxicity, they will be discontinued from the study. 
Associated product: 
Docetaxel will be administered as an intravenous dose of 75 mg/m² over 
60 minutes according to prescribing information.  Patient weight must be 
monitored before any subsequent administration and furosemide (or 
equivalent diuretic) will be given orally in the case of fluid retention.  
Premedication with steroids (see section on prophylactic drugs below) will 
be given.  If a severe IRR occurs, docetaxel will be permanently 
discontinued.  The first dose of docetaxel will be given on Day 2 (HLX02 
or Herceptin® given on Day 1).  If well tolerated, as determined by the 
Investigator, then the same dose will be given every 3 weeks on Day 1 of 
each subsequent cycle always starting 60 minutes after the end of the 
HLX02 or Herceptin® infusion.  Note: At the Investigator’s discretion, the 
dose of docetaxel can be increased to 100 mg/m² in patients who have 
tolerated at least 1 administration of 75 mg/m² without febrile neutropenia, 
Grade 4 neutropenia >5 days, ANC <100/μL more than 1 day, or any 
non-hematological toxicities of > Grade 2.  If treatment is withheld for 
more than 1 week for granulocyte recovery, or if a febrile neutropenic 
episode occurs at any time during therapy, prophylactic G-CSF will be 
administered with all subsequent cycles.  Prophylactic use of G-CSF before 
the first cycle is not allowed unless the patient had prior severe neutropenia 
during neo-/adjuvant therapy. 
At any time during the Treatment Period, docetaxel should be discontinued 
for progressive disease or unacceptable toxicity.  After Cycle 8, 
continuation of docetaxel treatment is at the discretion of the Investigator.  
At the time docetaxel is permanently discontinued for any reason other than 
disease progression, the patient can continue on Herceptin® or HLX02 
alone if still benefiting from the treatment. 
Prophylactic drugs: 
All patients treated with docetaxel will be given either oral or intravenous 
dexamethasone as follows:  
Oral: on Day 2 of Cycle 1, patients will be given 7.5-8 mg (depending on 
the available tablet dosage form) dexamethasone orally at 24 hours (about 
the same time as the HLX02 or Herceptin® infusion on Day 1) and 12 hours 
before the start of the docetaxel infusion.  In subsequent cycles (Cycle 2 
onwards), administration of 7.5-8 mg dexamethasone orally will occur at 
24 hours and 12 hours before the HLX02 or Herceptin® infusion, followed 


Sponsor: Shanghai Henlius Biotech, Inc. 
 
7 
Protocol: HLX02-BC01 v5.0 
Drug Name: HLX02 
17 JULY 2017 
Confidential 
1 hour later by the docetaxel infusion.  After the docetaxel infusion, 
7.5-8 mg dexamethasone should be given twice daily for a further 48 hours.  
Intravenous: on Day 2 of Cycle 1, patients will be given 20 mg 
dexamethasone intravenously approximately 30 minutes before the start of 
the docetaxel infusion.  In subsequent cycles (Cycle 2 onwards), patients 
will be given 20 mg dexamethasone intravenously after the HLX02 or 
Herceptin® infusion and before the docetaxel infusion.  After the docetaxel 
infusion, 7.5-8 mg dexamethasone should be given twice daily for 48 hours. 
Key inclusion criteria: 
• Male or female ≥18 years of age on day of signing the informed consent form (ICF) 
• Histologically or cytologically confirmed adenocarcinoma of the breast 
• Recurrent disease not amenable to curative surgery or radiation therapy, or metastatic disease with an 
indication for a taxane-containing therapy 
• Availability of formalin-fixed paraffin-embedded tissue block from the primary tumor, or a metastatic 
lesion, to confirm HER2-positivity by the central laboratory, based on FISH amplification ratio ≥2.0 or 
IHC score 3+, and for hormone status (ER/PgR) determination (local or central laboratory).  If not 
possible, a fresh biopsy is required 
• No prior systemic anticancer agent such as chemotherapy, biological or targeted agent for metastatic 
disease with the exception of hormonal therapy, which must be stopped at least 2 weeks before 
randomization.  Use of herbal remedies or traditional Chinese medicines for anticancer, hematologic or 
liver function, or anti-infective treatment must be stopped at the time of the ICF signature (at least 
2 weeks before randomization) 
• For patients with recurrent disease, prior neo-/adjuvant therapy containing trastuzumab and/or lapatinib 
must have been stopped at least 12 months before the diagnosis of recurrent (local or metastatic) disease 
(i.e. a disease-free interval of ≥12 months).  If trastuzumab/lapatinib was not used, prior neo-/adjuvant 
therapy with a taxane must have been stopped at least 6 months before the diagnosis of recurrent (local or 
metastatic) disease (i.e. a disease-free interval of ≥6 months).  If only other cytotoxics were given, they 
must be stopped at least 4 weeks before randomization.  Any hormonal therapy must be stopped at the 
time of the ICF signature (at least 2 weeks before randomization) 
• Measurable disease (at least one measurable target lesion assessed by CIR; bone-only or central nervous 
system [CNS]-only metastases are not allowed) 
• Eastern Cooperative Oncology Group performance status of 0-1 
• Left ventricular ejection fraction (LVEF) within institutional range of normal at baseline (within 42 days 
before randomization) as determined by either echocardiography (ECHO) or multigated acquisition 
(MUGA) scan 
• Adequate hematologic, hepatic and renal function 
• Estimated life expectancy ≥3 months 
• Female patients are eligible to enter and participate in the study if they are of:  
- 
Non-childbearing potential  
- 
Childbearing potential, have a negative serum pregnancy test at Screening (within 7 days of the first 
investigational/comparator product administration), are not breast feeding, and use highly-effective 
or acceptable contraceptive measures before study entry and throughout the study until 7 months 
after the last investigational/comparator product administration 
• Male patients with partners of childbearing potential are eligible to enter and participate in the study if 
they are willing to use highly-effective or acceptable contraceptive measures before study entry and 
throughout the study until 7 months after the last investigational/comparator product administration 


Sponsor: Shanghai Henlius Biotech, Inc. 
 
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Protocol: HLX02-BC01 v5.0 
Drug Name: HLX02 
17 JULY 2017 
Confidential 
Key exclusion criteria: 
• Previously- or currently-treated (systemic chemotherapy, biological, or targeted agent, or any other 
anticancer agent) metastatic breast cancer with the exception of hormonal therapy 
• Known brain metastasis or other CNS metastasis that is either symptomatic or untreated.  Central nervous 
system metastases that have been treated by complete resection and/or radiotherapy demonstrating 
stability or improvement are not an exclusion criterion provided they are stable as shown by computed 
tomography (CT) scan for at least 4 weeks before Screening without evidence of cerebral edema and no 
requirements for corticosteroids or anticonvulsants 
• Underlying medical conditions or current severe, uncontrolled systemic disease that, in the Investigator’s 
opinion, will make the administration of study drug hazardous.  A major surgical procedure (defined as a 
procedure that would require more than 3 weeks without study treatment) within 4 weeks prior to 
enrolment or anticipation of the need for major surgery during the course of study 
• Current uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg) or unstable angina  
• History of chronic heart failure of any New York Heart Association criteria, or left ventricular 
hypertrophy.  Current serious cardiac arrhythmia requiring treatment (except atrial fibrillation, 
paroxysmal supraventricular tachycardia) or clinically significant conduction defects as seen on 
electrocardiogram.  History of myocardial infarction within 6 months of randomization.  History of LVEF 
decline to below 50% during or after prior trastuzumab neo-adjuvant or adjuvant therapy.  Significant 
cardiac murmurs either on examination or ECHO 
• History of prior exposure to doxorubicin >360 mg/m² (or equivalent) 
• Use of oral, injected or implanted hormonal methods of contraception 
• Known hypersensitivity to any of the study drugs 
• Residual non-hematologic toxicity ≥ Grade 2 from prior therapy. 
Criteria for evaluation: 
Primary Efficacy Endpoint: 
• 
ORR24, calculated as the proportion of patients with a best response of complete response (CR) or partial 
response (PR) from first assessment up to Week 24 according to RECIST 1.1.  The response does not 
need to be confirmed.  Overall tumor response will be assessed by blinded, independent CIR according 
to RECIST 1.1 
Secondary Efficacy Endpoints: 
• ORR at Week 6, 12, 18, and 24 by CIR 
• DoR, defined as the time from first documentation of CR or PR to the first documentation of progression.  
After Week 24, assessments are made by the Investigator 
• DCR, defined as the proportion of patients who achieve CR, PR, or stable disease (SD) of at least 
12 weeks 
• CBR, defined as the proportion of patients who achieve CR, PR, or durable SD (SD ≥24 weeks) 
• PFS up to 12 months, defined as the probability of being alive without documented progression up to 
12 months after randomization, calculated using the Kaplan-Meier method 
• Overall survival at 12, 24, and 36 months, defined as the probability of being alive 12, 24, and 36 months 
after randomization, calculated using the Kaplan-Meier method 
Pharmacokinetic (PK) and Immunogenicity Data: 
In all patients, PK blood samples to determine serum trastuzumab concentrations will be collected prior to 
infusion at Cycle 1 (at the time of blood sampling for assessment of hematology and level of HER2 shed 
antigen), and starting at Cycle 3, prior to infusion every 3 cycles (approximately every 9 weeks), at the same 
time as sample collections to assess for the presence of anti-drug antibodies (ADA)/neutralizing ADA 
(NADA) while on treatment with HLX02 or Herceptin®. 


Sponsor: Shanghai Henlius Biotech, Inc. 
 
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Protocol: HLX02-BC01 v5.0 
Drug Name: HLX02 
17 JULY 2017 
Confidential 
Additional blood samples for the determination of trastuzumab in serum will be collected in all enrolled 
patients at the following time points: 
• Cycle 1, Day 1, at the end of infusion  
• Cycles 4 and 8, prior to infusion (at the time of blood sampling for assessment of hematology) 
• Cycle 8, Day 1, at the end of infusion 
Blood samples to test for the baseline level of HER2 shed antigen and for antibodies against trastuzumab 
(ADA/NADA) must be collected in all patients within 7 days prior to the first administration of study drug 
(Screening).  In addition to the on-treatment ADA/NADA samples described above, a blood sample will also 
be taken at the Safety Follow-up Visit to assess for the presence of ADA/NADA (along with blood sampling 
for routine laboratory tests). 
Safety: 
Safety and tolerability of HLX02 or Herceptin® and docetaxel assessed throughout the study by the 
incidence, severity and causality of serious adverse events (SAEs), adverse events (AEs) and adverse events 
of special interest (AESI), coded to preferred term and system organ class using the Medical Dictionary for 
Regulatory Activities and graded according to the National Cancer Institute’s Common Terminology Criteria 
for Adverse Events version 4.03 (NCI CTCAE v4.03).  Patients will be monitored by physical examination, 
vital signs, electrocardiograms, and laboratory tests classified for severity using NCI CTCAE v4.03.  Cardiac 
function will be evaluated by ECHO or MUGA scan using the same method throughout the entire study 
period (ECHO is preferred).  Cardiac assessments will be performed after every 3 cycles (within 3 days of 
the start of Cycles 4, 7, 10, etc.) or more frequently if clinically indicated; at the Safety Follow-up Visit; and 
during Survival Follow-up (every 3 months until 12 months after randomization if study treatment has been 
discontinued). 
Statistical methods: 
Sample Size determination using the difference in proportion of patients with ORR24 in the ITT and 
per-protocol (PP) populations: 
The difference in rate of ORR (Herceptin®- control) and its two-sided 95% confidence interval (CI) was 
calculated by pooling the results of the subgroup of patients with HER2-positive tumors defined as FISH 
positive or IHC 2+ and 3+, from 2 published randomized studies comparing ORR following treatment with 
Herceptin® + paclitaxel or equivalent versus paclitaxel or equivalent alone (Genentech, 2010, Table 9; Marty 
et al, 2005, Table 2).  Using the Der Simonian-Laird estimate random effect model (Der Simonian and Laird, 
1986), the difference in ORR and its 95% CI was estimated to be 0.2493 [0.1579; 0.3407].  The metabin 
function of the meta library of the R language (R Core Team, 2012) was used to implement this estimate.  An 
equivalence limit marginally tighter than the lower bound of this CI is used as the criterion of equivalence: 
[-0.1350; 0.1350].  Given the published ORRs for ITT populations in Marty et al (2005: 61%), 
CLEOPATRA (Baselga et al, 2012: 69%), and HERITAGE (Hope et al, 2016: 64%) trials, a conservative 
rate of 60% ORR24 was assumed for the ITT population.  A sample size of 289 evaluable patients per arm 
was calculated to yield 84% power to show equivalence using the above equivalence limits [-0.1350; 0.1350] 
with the two-sided 95% CI for the difference in ORR24 HLX02-Herceptin® in the ITT population.  Assuming 
a 5% dropout rate, the number of patients required to be randomized is approximately 304 per arm.  Swain et 
al (2015) has approximately 8% of patients discontinuing who would be excluded from a PP population.  
Based on this, a 10% drop in patients is assumed in the PP population, compared to the ITT population, 
making a total of approximately 15% dropout in the PP population.  It is assumed that 3% of ITT patients 
with ORR fail to be included in the PP population (e.g. due to protocol deviations other than early 
discontinuation).  Under these assumptions the denominator for ORR will decrease by 10%, compared to that 
of the ITT population, but the number of ORRs will decrease by only 3%.  It is thus assumed there will be a 
higher rate of 65% ORR24 in the PP population.  With these assumptions, 304 patients per arm will yield a 
sample size for the PP population of approximately 258 and the study will have 80% power to show 
equivalence in the PP population. 
A blinded sample size re-estimation procedure is planned after the primary efficacy data at Week 24 are 
available in the first 300 patients.  A Data Monitoring Committee will oversee the re-estimation procedure as 
well as review safety data and monitor the overall conduct of the study. 


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Protocol: HLX02-BC01 v5.0 
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Efficacy: The primary endpoint will be the ORR24.  Equivalence will be concluded if the two-sided 95% CI 
of the difference of the 2 proportions is completely contained within the interval [-0.1350; 0.1350].  Two-
sided 95% CIs for the difference between the 2 treatment arms in ORR24 will be presented, controlling for 
randomizing stratification factors using Mantel-Haenszel weights for the strata.  The ITT population will be 
considered the primary population for the efficacy analyses.  Repeat analyses using the PP population will 
explore robustness of results; the robustness to missing data of conclusions from the ITT analysis will be 
assessed via sensitivity analyses.  Overall objective response at Week 6, 12, 18, and 24 by CIR will be 
analyzed in a similar way to that of the primary endpoint to show the pattern of response.  For time-to-event 
secondary endpoints (DoR, PFS up to 12 months and OS at 12, 24, and 36 months), Kaplan-Meier estimates 
(product-limit estimates) will be presented by treatment arm together with a summary of associated statistics 
(i.e. probability of being event-free) and corresponding two-sided 95% CIs.  The CIs for the survival function 
estimates at the time points defined above will be derived using the log-log transformation according to 
Kalbfleisch and Prentice (1980).  The estimate of the standard error will be computed using Greenwood’s 
formula.  A Cox model will be used to compare the hazard ratio (HR).  The point estimates and two-sided 
95% CIs of the HR will be reported.  Binary secondary endpoints (ORR at other time points, DCR and CBR) 
will be analyzed in a similar way to that of the primary endpoint but ratios will be estimated, controlling for 
randomizing stratification factors through a log binomial model. 
Safety: Descriptive statistics will be used to present SAEs, AEs and AESI and other safety variables. 
Pharmacokinetics: Trastuzumab concentrations in serum will be summarized descriptively by study 
population, treatment and scheduled collection time.  Exposure to trastuzumab will be further evaluated with 
respect to specific disease characteristics such as baseline levels of shed antigen.  Additional PopPK 
modeling and/or correlation between trastuzumab exposure and response (safety, immunogenicity and/or 
efficacy) data may be evaluated separately, as appropriate.  If performed, a separate analysis plan will be 
prepared and results will be reported separately from the Clinical Study Report. 
Database Locks: The first database lock will occur once response assessment data up to Week 24 are 
available for all patients, at which time the designated unblinded study team will conduct analyses on the 
primary efficacy data, as well as PK, safety/immunogenicity and survival data, up to Week 24.  All 
Investigators, site teams, and patients will remain blinded until the end of the Treatment Period (up to 
12 months after the last patient randomized), which is when the second database lock will occur.  At that 
time, analyses will be conducted on all efficacy, PK, safety and survival data over 12 months for all patients.  
The final database lock will occur 36 months after last patient randomized in order to report OS.  


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Protocol: HLX02-BC01 v5.0 
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TABLE OF CONTENTS 
SIGNATURE OF SPONSOR .................................................................................................2 
SIGNATURE OF INTERNATIONAL STUDY COORDINATOR....................................3 
SYNOPSIS ................................................................................................................................4 
TABLE OF CONTENTS ......................................................................................................11 
1.0 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................16 
2.0 
INTRODUCTION......................................................................................................19 
2.1 
Background Information...............................................................................19 
2.2 
Rationale .........................................................................................................20 
2.3 
Hypothesis .......................................................................................................20 
2.4 
Risk Assessment .............................................................................................21 
3.0 
STUDY OBJECTIVE(S) ...........................................................................................22 
3.1 
Primary Objective ..........................................................................................22 
3.2 
Secondary Objectives.....................................................................................22 
3.3 
Exploratory Objective ...................................................................................22 
4.0 
INVESTIGATIONAL PLAN ...................................................................................23 
4.1 
Summary of Study Design .............................................................................23 
4.2 
Discussion of Study Design ............................................................................29 
4.3 
Selection of Study Population .......................................................................30 
4.3.1 
Inclusion Criteria ...............................................................................30 
4.3.2 
Exclusion Criteria ..............................................................................33 
4.3.3 
Patient Withdrawal ............................................................................34 
5.0 
STUDY TREATMENTS ...........................................................................................35 
5.1 
Treatments Administered .............................................................................35 
5.2 
Identity of Investigational, Comparator, and Associated 
Products ..........................................................................................................35 
5.3 
Packaging and Labelling ...............................................................................36 
5.4 
Method of Assigning Patients to Treatment Arm .......................................36 
5.5 
Selection of Doses in the Study .....................................................................37 
5.6 
Selection and Timing of Dose for Each Patient ...........................................37 
5.6.1 
Administration ...................................................................................37 
5.6.2 
HLX02 and Herceptin® Main Toxicities and 
Administration Modifications ...........................................................39 


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5.6.3 
Docetaxel Dose Modifications ..........................................................42 
5.7 
Blinding ...........................................................................................................43 
5.8 
Prior and Concomitant Treatments .............................................................44 
5.8.1 
Excluded Medications .......................................................................45 
5.8.2 
Allowed Medications .........................................................................45 
5.9 
Medical Care of Patients after the End of the Treatment 
Period ..............................................................................................................47 
5.10 
Treatment Compliance ..................................................................................47 
5.11 
Study Medication Accountability .................................................................47 
6.0 
EFFICACY, SAFETY, AND PHARMACOKINETIC 
ASSESSMENTS .........................................................................................................48 
6.1 
Efficacy............................................................................................................48 
6.1.1 
Primary Efficacy ................................................................................48 
6.1.1.1 
Tumor Assessments .........................................................48 
6.1.1.2 
Central Independent Review of MRI/CT 
Scans and Local Imaging Assessment .............................49 
6.1.2 
Efficacy Endpoints ............................................................................50 
6.2 
Safety ...............................................................................................................51 
6.2.1 
Adverse Events ..................................................................................51 
6.2.1.1 
Reporting of Serious and Non-serious 
Adverse Events ................................................................54 
6.2.1.2 
Reporting of Serious Adverse Events to 
Regulatory Agencies and Investigators ...........................54 
6.2.1.3 
Reporting Adverse Events of Special Interest: 
Cardiac AEs .....................................................................55 
6.2.1.4 
Reporting Adverse Events of Special Interest: 
Infusion-related Reactions ...............................................55 
6.2.1.5 
Reporting Adverse Events of Special Interest: 
Hematotoxicity ................................................................56 
6.2.1.6 
Follow-Up of Adverse Events .........................................56 
6.2.1.7 
Progression of Underlying Malignancy ...........................56 
6.2.1.8 
Pregnancy ........................................................................57 
6.2.2 
Clinical Laboratory Evaluations ........................................................57 
6.2.3 
Vital Signs, Physical Findings and Other Safety 
Assessments .......................................................................................59 
6.2.3.1 
Vital Signs .......................................................................59 
6.2.3.2 
Physical Examination ......................................................59 
6.2.3.3 
Electrocardiogram ...........................................................59 
6.2.3.4 
Cardiac function ..............................................................59 
6.3 
Pharmacokinetics ...........................................................................................59 
6.4 
Other Assessments .........................................................................................61 
6.4.1 
Immunogenicity (Anti-drug Antibodies) ...........................................61 
6.4.2 
Tumor Samples (ER/PgR and HER2) at Screening ..........................62 


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6.5 
Appropriateness of Measurements ...............................................................62 
7.0 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................63 
7.1 
Monitoring ......................................................................................................63 
7.2 
Data Management/Coding ............................................................................64 
7.3 
Quality Assurance Audit ...............................................................................66 
8.0 
STATISTICS ..............................................................................................................67 
8.1 
Determination of Sample Size .......................................................................67 
8.2 
Statistical Methods .........................................................................................67 
8.2.1 
Data for Analysis ...............................................................................68 
8.2.2 
Analysis Populations .........................................................................68 
8.2.3 
Missing Data ......................................................................................68 
8.3 
Patient Disposition .........................................................................................69 
8.4 
Patient Characteristics ..................................................................................69 
8.5 
Efficacy Analyses ...........................................................................................69 
8.5.1 
Primary Analyses ...............................................................................69 
8.5.2 
Secondary Analyses ...........................................................................69 
8.5.3 
Subgroup Analyses ............................................................................70 
8.6 
Safety ...............................................................................................................70 
8.6.1 
Adverse Events ..................................................................................70 
8.6.2 
Clinical Laboratory Evaluations ........................................................70 
8.6.3 
Vital Signs Measurements, Physical Findings and Other 
Safety Evaluations .............................................................................70 
8.7 
Immunogenicity..............................................................................................70 
8.8 
Pharmacokinetic Analyses ............................................................................70 
8.9 
Interim Analyses ............................................................................................71 
8.9.1 
Blinded Sample Size Re-estimation ..................................................71 
8.9.2 
Data Monitoring Committee ..............................................................71 
8.9.3 
Database Locks and Clinical Study Reports .....................................71 
9.0 
ETHICS ......................................................................................................................72 
9.1 
Institutional Review Board or Independent Ethics Committee ................72 
9.2 
Ethical Conduct of the Study ........................................................................72 
9.3 
Patient Information and Informed Consent ................................................72 
10.0 
STUDY ADMINISTRATION...................................................................................73 
10.1 
ADMINISTRATIVE STRUCTURE ............................................................73 
10.2 
Data Handling and Record Keeping ............................................................73 
10.3 
Direct Access to Source Data/Documents ....................................................74 
10.4 
Investigator Information ...............................................................................74 
10.4.1 
Investigator Obligations ....................................................................74 
10.4.2 
Protocol Signatures ............................................................................74 


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10.4.3 
Publication Policy ..............................................................................74 
10.5 
Financing and Insurance ...............................................................................74 
11.0 
REFERENCES ...........................................................................................................75 
12.0 
APPENDICES ............................................................................................................77 
APPENDIX 1:  SIGNATURE OF INVESTIGATOR ........................................................78 
APPENDIX 2:  NYHA ...........................................................................................................79 
APPENDIX 3:  ECOG PERFORMANCE STATUS ..........................................................80 
APPENDIX 4:  RECIST 1.1 ..................................................................................................81 
 


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LIST OF TABLES 
Table 4-1 
Schedule of Events ...........................................................................................25 
Table 5-1 
Docetaxel Dose Adjustments ...........................................................................43 
Table 6-1 
Schedule of Blood Sampling for Pharmacokinetic and 
Immunogenicity Assessments ..........................................................................61 
 
LIST OF FIGURES 
Figure 4-1 
Schematic of Study Design for Protocol HLX02-BC01 ..................................24 
 


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1.0 LIST OF ABBREVIATIONS AND DEFINITIONS OF 
TERMS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody(ies) 
AE 
Adverse event 
AESI 
Adverse event(s) of special interest 
ALK 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
ANC 
Absolute neutrophil count 
aPPT 
Activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase  
CAP 
College of American Pathologists 
CBR 
Clinical benefit rate 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CIR 
Central imaging review 
CNS 
Central nervous system 
CR 
Complete response 
CSR 
Clinical Study Report 
CT 
Computed tomography (scan) 
DCR 
Disease control rate 
DMC 
Data Monitoring Committee 
DoR 
Duration of response 
ECG 
Electrocardiogram 
ECHO 
Echocardiography 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
ER 
Estrogen receptor 
EU 
European Union 


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Abbreviation 
Definition 
FFPE 
Formalin-fixed paraffin-embedded 
FISH 
Fluorescence in situ hybridization 
GCP 
Good Clinical Practice 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
HBV-DNA 
Hepatitis B virus-deoxyribonucleic acid 
HER2 
Human epidermal growth factor receptor 2 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
ITT 
Intent-to-treat 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MUGA 
Multigated acquisition (scan) 
NADA 
Neutralizing anti-drug antibody(ies) 
NCI-CTCAE v4.03 
National Cancer Institute’s Common Terminology Criteria for 
Adverse Events version 4.03 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
ORR24 
Overall response rate at 24 weeks 
OS 
Overall survival 
PET 
Positron emission tomography (scan) 


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Abbreviation 
Definition 
PFS 
Progression-free survival 
PgR 
Progesterone receptor 
PK 
Pharmacokinetic 
PopPK 
Population pharmacokinetic 
PP 
Per-protocol 
PPT 
Partial thromboplastin time 
PR 
Partial response 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors version 1.1  
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SD 
Stable disease 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamate-pyruvate transaminase 
SOP 
Standard operating procedures 
ULN 
Upper limit of normal 


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2.0 INTRODUCTION 
2.1 
Background Information 
Breast cancer is the most common cancer in women, with a global incidence of more than 
1.5 million patients and a mortality rate of approximately 500,000 deaths per year.1  In 
western countries, metastatic breast cancer makes up less than 1% of all cancers in men and 
its incidence seems to vary according to different geographical areas and ethnic groups.2  
Although rare, metastatic breast cancer in men appears to be increasing as reported by the 
Surveillance, Epidemiology and End Results Program of the National Cancer Institute, and 
reviewed by the United Kingdom Association of Cancer Registries.3 
Of the total number of patients diagnosed with breast cancer, 20% to 25% have tumors that 
exhibit human epidermal growth factor receptor 2 (HER2) protein overexpression or gene 
amplification.  HER2 belongs to a family of 4 transmembrane receptor tyrosine kinases that 
mediate the growth, differentiation and survival of cells.4,5  HER2 overexpression is 
associated with aggressive tumor biology and with poor clinical outcomes compared with 
tumors that do not have HER2 overexpression.6 
Trastuzumab is a humanized monoclonal antibody that specifically binds to the extracellular 
parts of HER2 to competitively inhibit the receptor function, resulting in the inhibition of 
tumor cell growth (see the latest Investigator’s Brochure for HLX02).  Trastuzumab was 
initially developed by Genentech and Roche and approved by the United States’ Food and 
Drug Administration in 1998 with the brand name of Herceptin®.  Herceptin® demonstrated 
clinical activity in patients with HER2-overexpressing metastatic breast cancer, both as 
single-agent therapy and in combination with chemotherapy.  A pivotal Phase III study 
demonstrated that the combination of trastuzumab and different chemotherapies (including 
paclitaxel) significantly prolonged time to progression and overall survival (OS) compared 
with chemotherapy alone in patients with HER2-overexpressing metastatic breast cancer.7  In 
another randomized Phase II study, the addition of trastuzumab to docetaxel showed 
improved response rate, time to progression, and OS compared with docetaxel alone.8  
Herceptin® was also approved by the European Medicines Agency (EMA) in 2006 and the 
Chinese Food and Drug Administration in 2002 for use as monotherapy in patients with 
HER2-positive metastatic breast cancer who have received one or more chemotherapy 
regimens and in combination with a taxane for metastatic disease.  More recently, Herceptin® 
was approved in the adjuvant setting by all Agencies (for more details see the latest 
Investigator’s Brochure for HLX02). 
Shanghai Henlius Biotech, Inc. (the Sponsor) is currently developing a recombinant 
anti-HER2 humanized monoclonal antibody for injection (HLX02) as a proposed biosimilar 


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drug to trastuzumab (Roche Herceptin®), formulated as 150 mg/vial.  Since demonstration of 
similarity in quality and non-clinical study is a prerequisite for clinical development, the 
Sponsor has conducted a number of studies on the substance, formulation, and technology of 
HLX02, as well as structure confirmation, batch development and quality comparisons with 
the original drug, Herceptin®.  Drug stability and packaging have also been tested.  
Comparison of the structural characteristics, physiochemical properties and biological 
activities between HLX02 and Herceptin® was performed in accordance with EMA 
guidelines (EMEA/CHMP/BWP/247713/2012).  A series of in vitro and in vivo studies was 
performed in order to demonstrate similarity between HLX02 and Herceptin®.  A risk-based 
approach was taken to the non-clinical evaluation of HLX02 based on the EMA guideline 
(EMA/CHMP/BMWP/403543/2010).  Comparison-based pre-clinical studies on the 
pharmacology, pharmacodynamics, pharmacokinetic (PK) profile and toxicology of HLX02 
have shown that the drug shares a high similarity with Herceptin® (see the latest 
Investigator’s Brochure for HLX02). 
As a second step in the development of HLX02 as a proposed biosimilar of trastuzumab, a 
Phase I clinical study comparing HLX02 with European Union (EU)-sourced and China-
sourced Herceptin® is currently being conducted in healthy volunteers in China.  The study is 
conducted in accordance with the EMA guidelines for monoclonal antibodies 
(EMA/CHMP/BMWP/403543/2010). 
2.2 
Rationale 
HLX02 is being developed as a proposed biosimilar to the approved drug, Herceptin® to 
meet the need for an alternative to this high-priced biologic agent.  The efficacy and safety of 
trastuzumab have already been demonstrated during the development of Herceptin®.  The 
objective of this Phase III study is to compare the efficacy and to evaluate safety and 
immunogenicity of HLX02 + docetaxel and EU-sourced Herceptin® + docetaxel in patients 
with HER2-positive, recurrent or previously untreated metastatic breast cancer.  Blood 
samples will be collected to measure trastuzumab concentrations. 
This Phase III study will be performed in compliance with the protocol, International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
Good Clinical Practice (GCP), in accordance with the EMA guidelines for monoclonal 
antibodies and with applicable local regulatory requirements in other participating countries. 
2.3 
Hypothesis 
The primary hypothesis for the primary efficacy analysis is that HLX02 is neither inferior nor 
superior to Herceptin® based on a pre-specified equivalence margin. 


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2.4 
Risk Assessment 
Clinical testing has shown that the benefit of Herceptin® is greatest in patients with tumors 
strongly overexpressing HER2, i.e. in tumors graded 3+ by immunohistochemistry (IHC), 
and/or with HER2 gene amplification, as determined by fluorescence in situ hybridization 
(FISH).9 
In the reference study, using the same regimen as the one proposed for this biosimilar study, 
a total of 186 patients were randomized to receive either trastuzumab + docetaxel or 
docetaxel alone.8  The addition of trastuzumab to 100 mg/m2 docetaxel for at least 6 cycles 
resulted in superior clinical efficacy with improved overall response rate (ORR; 61% versus 
34%; P = 0.0002), OS (median, 31.2 versus 22.7 months; P = 0.0325), time to progressive 
disease (median, 11.7 versus 6.1 months; P = 0.0001), time to treatment failure (median,  
9.8 versus 5.3 months; P = 0.0001), and duration of response (median, 11.7 versus 
5.7 months; P = 0.009).  There was little difference in the number and severity of adverse 
events (AEs) between the groups.  Grade 3 to 4 neutropenia was seen more commonly with 
the combination (32%) than with docetaxel alone (22%), and there was a slightly higher 
incidence of febrile neutropenia in the combination group (23% versus 17%).  More patients 
in the combination group had left ventricular ejection fraction (LVEF) decreases ≥15% 
compared with the docetaxel alone group (17% versus 8%), and 1 patient (1%) in the 
combination group experienced symptomatic congestive heart failure (CHF).8  
Based on these results, trastuzumab is considered to be well tolerated in combination with 
standard chemotherapy for metastatic breast cancer, provided that adequate patient selection 
is made particularly in terms of cardiac baseline conditions.  Indeed the most significant AE 
observed in patients who receive trastuzumab is cardiac dysfunction, reflected by 
asymptomatic decreases in LVEF and, less frequently, by clinically symptomatic CHF.  Risk 
factors for cardiac failure include co-administration with anthracycline-based chemotherapy, 
increasing age, a declining LVEF during treatment to below the lower limit of normal, and 
the use of anti-hypertensive medications.9  In our well selected patient population undergoing 
proper surveillance, the benefit of adding trastuzumab largely exceeds the risk of cardiac 
AEs.  Other potential risks, given the safety profile of Herceptin®, are pulmonary events, 
hypersensitivity reactions or infusion-related reactions (IRR), and immunogenicity. 


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3.0 STUDY OBJECTIVE(S) 
3.1 
Primary Objective 
The primary objective of the study is to compare the efficacy of HLX02 versus EU-sourced 
Herceptin® in combination with docetaxel using ORR up to Week 24 (ORR24) after up to 
8 cycles of treatment to demonstrate clinical bioequivalence. 
3.2 
Secondary Objectives 
The secondary objectives of the study are as follows: 
• 
To evaluate the safety, tolerability, and immunogenicity of HLX02 and EU-sourced 
Herceptin® given in combination with docetaxel. 
• 
To compare the efficacy of HLX02 versus EU-sourced Herceptin® in combination with 
docetaxel, in terms of duration of response (DoR), clinical benefit rate (CBR), disease 
control rate (DCR), progression-free survival (PFS) up to 12 months, and OS at 12, 24, 
and 36 months. 
• 
To measure the exposure to trastuzumab following HLX02 or EU-sourced Herceptin®. 
3.3 
Exploratory Objective 
• 
Exploratory population pharmacokinetic (PopPK) analysis. 
 


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4.0 INVESTIGATIONAL PLAN 
4.1 
Summary of Study Design 
This is a Phase III, double-blind, randomized, multicenter study to compare the efficacy and 
to evaluate the safety and immunogenicity of HLX02 and EU-sourced Herceptin® in patients 
with HER2-positive, recurrent or previously untreated metastatic breast cancer.  A maximum 
of 608 patients with a confirmed measurable target lesion by CIR will be enrolled.  Patients 
will be stratified for estrogen receptor/progesterone receptor (ER/PgR) status, prior 
neo-/adjuvant therapy with Herceptin®, and ethnicity (Asian and non-Asian), then 
randomized into 2 treatment arms in a 1:1 ratio to receive HLX02 or EU-sourced Herceptin® 
in combination with docetaxel according to the current standard of care.  HLX02 or EU-
sourced Herceptin® will be administered intravenously, initially at a loading dose of 8 mg/kg 
on Day 1, Cycle 1 then at a dose of 6 mg/kg once every 3 weeks in 3-weekly cycles for up to 
a maximum of 12 months.  Docetaxel 75 mg/m2 will be administered intravenously (after 
HLX02 or EU-sourced Herceptin®) once every 3 weeks for at least 8 cycles and thereafter at 
the Investigator’s discretion for up to a maximum of 12 months. 
The evaluation of tumor response will be measured according to Response Evaluation 
Criteria in Solid Tumors version 1.1 (RECIST 1.1).  The Investigator will assess the response 
every 6 weeks up to 24 weeks (regardless of the number of cycles actually given); thereafter 
assessments will be done every 9 weeks (after Cycles 11, 14, and 17) or earlier in the case of 
clinical signs of progression.  Tumor response for the primary efficacy analysis will be 
evaluated by central imaging review (CIR) for an independent, blinded determination of 
tumor response up to Week 24, after completion of up to 8 cycles of treatment.  A CIR will 
occur at Screening to confirm eligibility and at Week 6, 12, 18, and 24 to assess the pattern 
of response; no CIR is required after Week 24 (see Section 6.1.1.2).  As of Cycle 9, patients 
will remain in the study and be followed every 9 weeks for other efficacy parameters such as 
DoR and PFS up to 12 months, and OS at 12, 24, and 36 months.  All patients will remain in 
the study until Investigator-assessed disease progression, excessive toxicity, Investigator’s 
judgment, withdrawal of consent, lost to follow-up, death, start of a new anticancer therapy, 
study termination by the Sponsor, or for a maximum of 12 months of treatment, whichever 
occurs first.  At the end of the Treatment Period (up to 12 month), patients will be referred to 
the local institution and will continue therapy in accordance with local practice.  All patients 
will undergo a Safety Follow-up Visit 30 (±2) days after the last dose of study drug 
(maximum of 17 cycles).  Cardiac safety monitoring and immunogenicity testing will 
continue up to 12 months after randomization in all patients.  Survival Follow-up will occur 
every 3 months until 12 months after randomization; thereafter, survival data will be 
collected by telephone call every 3 months for up to 36 months after randomization. 


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Extended PK samples will be collected in all patients to further support the Phase I data 
obtained from healthy volunteers.  Compliance with PK sample collections as well as 
recording of PK sampling information on the patients’ electronic case report form (eCRF) 
will be closely monitored.  As part of the extended sample collections, trough trastuzumab 
levels (defined as PK samples collected at the time of the laboratory tests within a maximum 
of 3 days prior to Day 1 of the cycle) will be correlated with baseline levels of the circulating 
extracellular domain of the HER2 receptor (shed antigen). 
Collection of PK samples at the same time as the scheduled anti-drug antibody 
(ADA)/neutralizing ADA (NADA) assessment will occur in all patients to fully measure the 
effect of potential ADA formation on trastuzumab exposure for both HLX02 and EU-sourced 
Herceptin®.  As of Cycle 3, blood sampling for ADA/NADA assessment will continue every 
3 cycles (approximately every 9 weeks) up to 12 months.   
A maximum of 304 patients will be enrolled in each arm to yield 289 evaluable patients for 
the primary efficacy analysis in the intent-to-treat (ITT) population accounting for a dropout 
rate of 5%.  Patients will be enrolled from approximately 83 centers worldwide. 
End of study will occur 36 months after the last patient is randomized.   
The study design is presented in Figure 4-1 and the schedule of events is presented in  
Table 4-1. 
Figure 4-1 
Schematic of Study Design for Protocol HLX02-BC01 
 
 


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Table 4-1 
Schedule of Events 
Assessments 
Screening 
Period 
(baseline)1 
Randomization 
Treatment Period 
(each cycle is 3 weeks) 
Safety  
Follow-up3 
Survival  
Follow-up4 
---------------- 12 months (52 weeks) ---------------- 
---- 24 months ----
HLX02 or Herceptin + Docetaxel2 
 
 
Days 
-28 to -1 
Every Cycle 
Day 1 
Every Cycle 
Day 8 
30 days  
post-treatment 
Every 3 months 
Visit Window (days) 
- 
±3 
±1 
±2 
±7 
Informed Consent5 
X 
 
- 
- 
- 
- 
Inclusion/Exclusion criteria 
X 
 
- 
- 
- 
- 
Hormone and HER2 status6 
X 
 
- 
- 
- 
- 
Demographics/Medical history7 
X 
 
- 
- 
- 
- 
Physical examination/Vital signs8 
X 
 
X 
- 
X 
- 
Weight8 
X 
 
X 
 
 
 
ECOG performance status (see Appendix 3) 
X 
 
- 
- 
X 
- 
12-lead ECG9 
X 
 
X 
- 
X 
- 
Pregnancy serum test10 
X 
 
X 
(every 3 cycles) 
- 
X 
- 
HIV, hepatitis B and C11 
X 
 
- 
- 
- 
- 
LVEF (ECHO or MUGA scan)12 
X 
 
X 
(every 3 cycles) 
- 
X12 
- 
HLX02 or Herceptin® 
- 
 
X 
- 
- 
- 
Docetaxel 
- 
 
X13 
- 
- 
- 
Adverse events14 
X 
 
X 
X 
- 
Tumor assessment (imaging)15  
X15 
 
Week 6, 12, 18, 24 then every 9 weeks (after 
Cycles 11, 14, 17) 
X 
- 
Concomitant medications 
X 
 
X 
X 
X 
- 
Hematology16 
X 
 
X 
X16 
X 
- 
Serum chemistry panel and coagulation16 
X 
 
X 
- 
X 
- 
Urinalysis (including pregnancy test)17 
X 
 
X 
- 
X 
- 


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Assessments 
Screening 
Period 
(baseline)1 
Randomization 
Treatment Period 
(each cycle is 3 weeks) 
Safety  
Follow-up3 
Survival  
Follow-up4 
---------------- 12 months (52 weeks) ---------------- 
---- 24 months ----
HLX02 or Herceptin + Docetaxel2 
 
 
Days 
-28 to -1 
Every Cycle 
Day 1 
Every Cycle 
Day 8 
30 days  
post-treatment 
Every 3 months 
Visit Window (days) 
- 
±3 
±1 
±2 
±7 
Pharmacokinetic blood sampling18 
 
 
X18 
 
- 
- 
Serum test for ADA/NADA19 
X 
 
At Cycle 3, then every 3 cycles  
(approx. every 9 weeks) 
X 
- 
Overall survival 
 
 
Every 3 months 
 
X 
ADA = anti-drug antibodies; AE = adverse event; CT = computed tomography; ECG = electrocardiogram; ECHO = echocardiography; ECOG = Eastern Corporative Oncology 
Group; eCRF = electronic case report form; ER = estrogen receptor; FISH = fluorescence in situ hybridization; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface 
antigen; HBV-DNA = hepatitis B virus deoxyribonucleic acid; HER2 = human epidermal growth factor receptor 2; HIV = human immunodeficiency virus; 
IHC = immunohistochemistry; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; MUGA = multigated acquisition; NADA = neutralizing anti-drug 
antibodies; NCI-CTCAE = National Cancer Institute’s Common Terminology Criteria for Adverse Events; OS = overall survival; PgR = progesterone receptor; 
PK = Pharmacokinetic; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors version 1.1; RNA = ribonucleic acid.
 
 
 
1. During the Screening period, routine laboratory tests (serum chemistry, hematology, immunogenicity test, and urinalysis) will be performed within 7 days prior to enrollment.
2. If docetaxel is permanently discontinued for any reason other than disease progression, the patient can continue on HLX02 or Herceptin® alone if the patient is still benefiting 
from the treatment. 
3. The Safety Follow-up Visit will take place 30 (±2) days after the last administration of docetaxel and/or HLX02 or Herceptin®, whichever occurs last at the end of the 
12-month Treatment Period, or earlier for any reason except withdrawal of consent. 
4. Survival Follow-up will occur every 3 months, at the time of tumor assessment during the Treatment Period, up to 12 months after randomization; thereafter survival data 
will be collected by telephone call up to 36 months after randomization. 
5. Signed informed consent form must be obtained prior to performing any protocol-specific procedure. 
6. Hormone status (ER and PgR) determined by IHC at a local or central laboratory.  For HER2 status, a previous local IHC test with a score of IHC 2+ or 3+ can be used as a 
Prescreening evaluation but will not be sufficient for enrollment.  To be eligible, a patient must be confirmed as HER2-positive by a central laboratory using FISH 
(amplification ratio ≥2.0) or IHC (score of 3+) test.  Patients with a previous local IHC score of 2+ must be tested centrally by FISH and those patients with a previous local 
IHC score of 3+ must be confirmed centrally by IHC. 
7. Complete medical history including breast cancer and significant diseases, demographics (i.e. age, sex, race and ethnicity), and all medications taken during the 90 days 
before randomization including anticancer therapies.  Prior anticancer treatments, including neo-/adjuvant therapy and hormone therapy, should also be recorded on the 
eCRF. 
8. Vital signs include temperature, pulse, respiratory rate and blood pressure.  Height and body weight will be measured at baseline.  Weight will also be measured on Day 1 
(maximum 3 days before Day 1) of every treatment cycle for confirmation of body surface area calculation (to be calculated each cycle by the Interactive Web/Voice 
Response System).  The dose will be adjusted only if the patient’s weight changes by more than ±10% from baseline.  Symptom-directed physical examination will be 
performed every cycle with particular attention to cardiovascular signs and symptoms. 


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9. 12-lead ECG assessments will be performed while the patient is in supine or semi-recumbent position after resting for 5 minutes.  Screening ECG should be performed within 
5 days before Day 1.  An ECG will be repeated at every cycle (within 3 days prior to Cycles 2, 3, etc.) at the time of the LVEF assessment (where applicable), and at the 
Safety Follow-up Visit. 
10. Women of childbearing potential must have a negative serum pregnancy test at Screening (within 7 days of the first administration of HLX02 or Herceptin®); then a serum 
pregnancy test should be done during the Treatment Period within 3 days prior to Cycles 3, 6, 9, etc. (every third cycle), and at the Safety Follow-up Visit  At any time 
point, if a urine test (see Footnote 17) is found to be positive, the pregnancy must be confirmed with a serum test via the local laboratory. 
11. Blood samples will be analyzed at the local laboratory for HBcAb and HBsAg (if HBcAb or HBsAg positive, HBV-DNA should be tested), hepatitis C (hepatitis C antibody 
and/or hepatitis C virus RNA should be tested), and HIV. 
12. LVEF will be calculated to monitor cardiac safety at Screening within 42 days before randomization, after every 3 cycles (within 3 days prior to Cycles 4, 7, 10, etc.), or 
more frequently if clinically indicated, at the Safety Follow-up Visit, and during Survival Follow-up (every 3 months until 12 months after randomization if study 
treatment has been discontinued).  The same method of assessment, either ECHO (preferred) or MUGA scan must be used throughout the entire study period.  Patients for 
whom study drug was permanently discontinued due to a drop in LVEF should continue to have LVEF assessments repeated as clinically indicated, with a maximum interval 
between LVEF assessments of 3 months until the LVEF values return to ≥50%. 
13. The first dose of docetaxel will be administered on Day 2, Cycle 1.  Subsequent doses will be administered on Day 1 of each cycle always 60 minutes after the 
administration of HLX02 or Herceptin®.  Continuation of docetaxel after Cycle 8 is at the Investigator’s discretion. Treatment will continue up to a maximum of 12 months 
(17 cycles). 
14. All AEs (including abnormal laboratory values that translate into clinical symptoms), graded as per NCI-CTCAE v4.03, are to be collected from the time of signed informed 
consent on a continuous reporting basis.  All AEs, whether gradable by NCI-CTCAE or not, will be evaluated for seriousness.  Cardiac AEs will be collected up to 12 months 
after randomization in line with LVEF calculations. 
15. Tumor assessments (based on RECIST 1.1) must be performed at Screening (baseline), at Week 6, 12, 18, and 24 (regardless of the number of cycles actually given), and 
then every 9 weeks (between Days 15-21 after Cycles 11, 14, and 17) by CT or MRI, using the same method throughout the whole study.  At the Safety Follow-up Visit, a 
tumor measurement must be repeated unless the patient has undergone a CT scan within the last 4 weeks.  Bone scans or X-rays and brain CT scan/MRI should be performed 
at Screening if clinically indicated and during the Treatment Period as clinically indicated.  Positron emission tomography scans are not accepted for assessment of efficacy.  
At baseline CT/MRI of the chest and abdomen (including liver, spleen, and adrenals) must be performed, and pelvis if clinically indicated; then the assessment will be done 
according to initial findings and emerging clinical symptoms.  For patients who discontinue study drug for reasons other than death, Investigator-assessed disease 
progression, excessive toxicity, or withdrawal of consent, efforts should be made to continue to perform scheduled tumor assessments for up to a maximum of 12 months 
after randomization or until patient death, Investigator-assessed disease progression, withdrawal of consent, or start of a new anticancer therapy.  Note: The tumor 
measurement at Screening will undergo central imaging review to confirm eligibility before the patient can be randomized. 
16. Routine laboratory tests (hematology [complete blood count with differential], serum chemistry, coagulation, and urinalysis) will be performed by the local laboratory.  At 
Screening, eligibility must be confirmed by a test collected no more than 7 days prior to Day 1 and for subsequent cycles, laboratory tests must be performed within a 
maximum of 3 days prior to Day 1 of each cycle (i.e. before HLX02 or Herceptin® administration).  The results must be available before each study drug infusion.  An 
additional hematology blood test will be performed on Day 8 of each cycle, either at the study center or another hospital, during the period docetaxel is administered but not 
during the period study drug is administered alone.  In case therapeutic doses of anticoagulants are started during the Treatment Period, international normalized ratio and 
activated partial thromboplastin time (or partial thromboplastin time) will be repeated 3 days prior to each cycle. 
17. Urinalysis tests, including red blood cells, glucose, ketones, leukocytes, nitrites, pH, and proteins, will be performed at baseline, before each cycle and at the Safety 
Follow-up Visit.  For all women of childbearing potential, a urine pregnancy test must be done before each cycle (when a serum test is not performed; see Footnote 10), then 
monthly until 6 months after the Safety Follow-up Visit.  If a urine test is found to be positive, the pregnancy must be confirmed with a serum test (beta human chorionic 
gonadotropin) via the local laboratory. 
18. PK blood samples will be collected from all patients at Cycle 1 within 7 days prior to infusion at the time of blood sampling for assessment of hematology, baseline level of 
shed antigen, and the test for antibodies against trastuzumab (ADA/NADA). Then, starting at Cycle 3, within 3 days prior to infusion every 3 cycles (approximately every 
9 weeks; Cycles 6, 9, 12, and 15), PK samples will be collected at the same time as sample collections to assess for the presence of ADA/NADA while on treatment with 


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HLX02 or Herceptin®.  Extended PK collections will be collected from all patients in Cycle 1 on Day 1 at the end of infusion, then at Cycles 4 and 8 prior to infusion (at the 
same time as blood sampling for assessment of hematology) and Cycle 8 Day 1 at the end of infusion. 
19. Blood samples to test for antibodies against trastuzumab (ADA/NADA) must be collected in all patients within 7 days prior to the first administration of study drug and, 
starting at Cycle 3, within 3 days prior to study drug infusion every 3 cycles (approximately every 9 weeks; Cycles 6, 9, 12, and 15) subsequently, and also at the Safety 
Follow-up Visit.  While on treatment, the samples should be collected at the same time as the PK sample (and blood sampling for hematology). 
 


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4.2 
Discussion of Study Design 
This study is designed to compare the efficacy, and to evaluate safety and immunogenicity of 
HLX02 and EU-sourced Herceptin® when administered in combination with docetaxel in 
patients with HER2-positive, recurrent or previously untreated metastatic breast cancer.  The 
design is considered appropriate for the evaluation of biosimilarity of HLX02 to Herceptin® 
as it complies with EMA biosimilar guidelines. 
A double-blind, randomized design is used to avoid bias in the assessment of the primary 
endpoint of tumor measurement and ensure that the outcome is not affected by known and 
unknown differences in prognostic factors between treatment arms.  The standard 
chemotherapy chosen is docetaxel, based on the reference study conducted with the 
comparator.6  Such a regimen is a widely-used standard combination, the efficacy of which 
was recently further documented in a large pivotal study where the combination was used as 
the control regimen.10  Moreover, docetaxel allows a 3-weekly schedule that is less 
demanding than the weekly schedule recommended for paclitaxel. 
The dose of HLX02 was selected as per the Herceptin® label for a 3-weekly regimen, i.e. 
Herceptin® as a loading dose of 8 mg/kg and maintenance dose of 6 mg/kg every 3 weeks.  
This regimen was shown to be well tolerated and beneficial in patients with 
HER2-overexpressing metastatic breast cancer.  A treatment period of at least 8 cycles is 
considered adequate for the comparison of ORR since most patients will have achieved 
tumor shrinkage by that time.  Patients showing benefit from treatment will continue for a 
maximum of 12 months of treatment, or until Investigator-assessed disease progression, 
excessive toxicity, Investigator’s judgment, withdrawal of consent, lost to follow-up, death, 
start of a new anticancer therapy, or study termination by the Sponsor, whichever occurs 
first. 
Endpoints of ORR and PFS based on tumor assessments using RECIST 1.1 are widely used 
and accepted measurements of efficacy in oncology studies; however, in accordance with 
EMA guidelines, for the purpose of demonstrating biosimilarity, the most sensitive endpoint 
must be chosen to allow the detection of differences between the 2 treatment arms.  In 
metastatic breast cancer, the most sensitive endpoint is ORR, and since the study aims to 
compare ORR up to Week 24, ORR24 was chosen to establish biosimilarity.  The calculation 
of equivalence margins is discussed in Section 8.1. 
Blood samples to determine trastuzumab concentrations will be collected each time a blood 
sample is collected for ADA/NADA assessment while on treatment.  This will allow 
determination as to whether potential ADA/NADA formation may affect trastuzumab 
exposure and the interpretation of efficacy and/or safety findings.  A limited number of 
additional PK blood samples will be collected during the first 8 cycles of treatment to 


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measure the exposure to trastuzumab following HLX02 or Herceptin® and, if appropriate, to 
initiate additional PopPK analyses and/or correlate trastuzumab exposure and response 
(safety, immunogenicity and/or efficacy).  Baseline level of shed antigen level will be 
collected. 
4.3 
Selection of Study Population 
4.3.1 
Inclusion Criteria 
Patients may be entered in the study only if they meet all of the following criteria: 
1. Patients have voluntarily agreed to participate and given written informed consent.  
2. Male or female ≥18 years of age on day of signing the informed consent form (ICF).  
3. Histologically or cytologically confirmed adenocarcinoma of the breast. 
4. Recurrent disease not amenable to curative surgery or radiation therapy, or metastatic 
disease with an indication for a taxane-containing therapy. 
5. Availability of formalin-fixed paraffin-embedded (FFPE) tissue block from the primary 
tumor, or a metastatic lesion, to confirm HER2-positivity by the central laboratory, based 
on FISH amplification ratio ≥2.0 or IHC score 3+, and for hormone status (ER/PgR) 
determination (local or central laboratory).11  If not possible, a fresh biopsy is required 
(see Section 6.4.2). 
6. No prior systemic anticancer agent such as chemotherapy, biological or targeted agent for 
metastatic disease with the exception of hormonal therapy, which must be stopped at least 
2 weeks before randomization.  Use of herbal remedies or traditional Chinese medicines 
for anticancer, hematologic or liver function, or anti-infective treatment must be stopped 
at the time of the ICF signature (at least 2 weeks before randomization). 
7. For patients with recurrent disease, prior neo-/adjuvant therapy containing trastuzumab 
and/or lapatinib must have been stopped at least 12 months before the diagnosis of 
recurrent (local or metastatic) disease (i.e. a disease-free interval of ≥12 months).  If 
trastuzumab/lapatinib was not used, prior neo-/adjuvant therapy with a taxane must have 
been stopped at least 6 months before the diagnosis of recurrent (local or metastatic) 
disease (i.e. a disease-free interval of ≥6 months).  If only other cytotoxics were given, 
they must be stopped at least 4 weeks before randomization.  Any hormonal therapy must 
be stopped at the time of the ICF signature (at least 2 weeks before randomization). 
8. Measurable disease (at least one measurable target lesion assessed by CIR; bone-only or 
central nervous system [CNS]-only metastases are not allowed).  


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9. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 
10. LVEF within institutional range of normal at baseline (within 42 days before 
randomization) as determined by either echocardiography (ECHO) or multigated 
acquisition (MUGA) scan. 
11. Adequate hematologic, hepatic and renal function as indicated by the following 
laboratory values: 
• 
Absolute neutrophil count (ANC) ≥1,500/mL without granulocyte-colony stimulating 
factor (G-CSF) or other medical support 
• 
Platelets ≥100,000/mL 
• 
Hemoglobin ≥9 g/dL without transfusion or other medical support within 14 days 
• 
Serum creatinine ≤1.5 x upper limit of normal (ULN) and creatinine clearance rate 
≥50 mL/min, calculated according to Cockroft-Gault formula (Note: if the calculated 
creatinine clearance is <50 mL/min, a 24-hour creatinine clearance test may be 
requested by the Investigator for confirmation.  Patients with a 24-hour creatinine 
clearance <50 mL/min should be excluded) 
• 
Serum total bilirubin ≤1.5 x ULN (unless the patient has documented Gilbert’s 
syndrome) without any medical support within 14 days 
• 
Serum aspartate aminotransferase/glutamic-oxaloacetic transaminase (AST/SGOT) or 
serum alanine aminotransferase/glutamate-pyruvate transaminase (ALT/SGPT) 
≤2.5 x ULN (≤5 x ULN in the case of liver metastases) provided alkaline phosphatase 
(ALK) is ≤2.5 x ULN.  In the case of bone metastasis, serum ALK can be 
>2.5 x ULN if AST and ALT are ≤1.5 x ULN without any medical support within 
14 days 
• 
International normalized ratio (INR), and activated partial prothrombin time (aPTT) 
or partial prothrombin time (PTT) ≤1.5 x ULN. 
12. Estimated life expectancy ≥3 months. 
13. Female patients are eligible to enter and participate in the study if they are of:  
• 
Non-childbearing potential (i.e. physiologically incapable of becoming pregnant), 
including any female who: 
− Has had a hysterectomy 
− Has had a bilateral oophorectomy (ovariectomy) 
− Has had a bilateral tubal ligation 
− Is postmenopausal (total cessation of menses for ≥1 year) 


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• 
Childbearing potential, have a negative serum pregnancy test at Screening (within 
7 days of the first investigational/comparator product administration), are not breast 
feeding, and use highly-effective or acceptable contraceptive measures (no oral, 
injected or implanted hormonal methods are allowed) before study entry and 
throughout the study until 7 months after the last investigational/comparator product 
administration.  Highly-effective or acceptable contraceptive measures, when used 
consistently and in accordance with both the product label and the instructions of the 
physician, are defined as follows: 
− Vasectomized partner who is sterile prior to the female patient’s entry and is the 
sole sexual partner for that female 
− Any intrauterine device with a documented failure rate of less than 1% per year 
− Double-barrier contraception (considered acceptable but not highly effective), 
defined as condom with spermicidal jelly, foam, suppository, or film; OR 
diaphragm with spermicide; OR male condom and diaphragm 
− Male partners must agree to use a highly-effective non-hormonal form of 
contraception or 2 effective forms of non-hormonal contraception.  Contraception 
use must continue for the duration of study treatment and for at least 7 months 
after the last dose of study treatment. 
14. Male patients with partners of childbearing potential are eligible to enter and participate 
in the study if they, and their female partners, are willing to use highly-effective or 
acceptable contraceptive measures before study entry and throughout the study until 
7 months after the last investigational/comparator product administration.  
Highly-effective or acceptable contraceptive measures, when used consistently and in 
accordance with both the product label and the instructions of the physician, are defined 
as follows: 
• 
No oral, injected or implanted hormonal contraceptive methods are allowed for male 
patients but can be used by their female partners   
• 
Vasectomized male patient who is sterile prior to the patient’s entry and has one 
sexual partner 
• 
Any intrauterine device with a documented failure rate of less than 1% per year 
• 
Double-barrier contraception (considered acceptable but not highly effective), defined 
as condom with spermicidal jelly, foam, suppository, or film; OR diaphragm with 
spermicide; OR male condom and diaphragm.  


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4.3.2 
Exclusion Criteria 
Patients will not be entered in the study for any of the following reasons: 
1. Previously- or currently-treated (systemic chemotherapy, biological, or targeted agent, or 
any other anticancer agent) metastatic breast cancer with the exception of hormonal 
therapy. 
2. Known brain metastasis or other CNS metastasis that is either symptomatic or untreated.  
Central nervous system metastases that have been treated by complete resection and/or 
radiotherapy demonstrating stability or improvement are not an exclusion criterion 
provided they are stable as shown by computed tomography (CT) scan for at least 
4 weeks before Screening without evidence of cerebral edema and no requirements for 
corticosteroids or anticonvulsants. 
3. Participation in another clinical study within 4 weeks before enrollment (3 months for 
studies involving monoclonal therapy) or the intention of participating in another clinical 
study during any part of the study period. 
4. History of other malignancy within the last 5 years, except for carcinoma in-situ of the 
cervix, basal cell carcinoma or squamous cell carcinoma of the skin that has been 
previously treated with curative intent. 
5. Known history of human immunodeficiency virus (HIV). 
6. Clinically significant active infection requiring therapy; positive tests for hepatitis B 
(defined as the presence of hepatitis core antibody [HBcAb] or hepatitis B surface 
antigen [HBsAg], and hepatitis B virus-deoxyribonucleic acid 
[HBV-DNA] >1000 cps/mL or > lower limit of quantification according to the local 
laboratory method); or hepatitis C (hepatitis C antibody and/or hepatitis C virus 
ribonucleic acid [RNA]). 
7. Underlying medical conditions or current severe, uncontrolled systemic disease that, in 
the Investigator’s opinion, will make the administration of study drug hazardous.  A 
major surgical procedure (defined as a procedure that would require more than 3 weeks 
without study treatment) within 4 weeks prior to enrollment or anticipation of the need 
for major surgery during the course of study. 
8. Current uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg) or 
unstable angina.   
9. History of chronic heart failure based on any New York Heart Association (NYHA) 
criteria, or left ventricular hypertrophy.  Current serious cardiac arrhythmia requiring 


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treatment (except atrial fibrillation, paroxysmal supraventricular tachycardia) or clinically 
significant conduction defects as seen on electrocardiogram (ECG).  History of 
myocardial infarction within 6 months of randomization.  History of LVEF decline to 
below 50% during or after previous trastuzumab neo-adjuvant or adjuvant therapy.  
Significant cardiac murmurs either on examination or ECHO. 
10. History of prior exposure to doxorubicin >360 mg/m² (or equivalent). 
 
Note: Equivalents include epirubicin >720 mg/m2; mitoxantrone >120 mg/m2; 
idarubicin >90 mg/m2; liposomal doxorubicin or other anthracycline greater than the 
equivalent of 360 mg/m2 of doxorubicin.  If more than one anthracycline has been used, 
then the cumulative dose must not exceed the equivalent of 360 mg/m2 of doxorubicin. 
11. Use of oral, injected or implanted hormonal methods of contraception. 
12. Chronic daily use of corticoids (equivalent to >10 mg/day methylprednisolone) by oral 
intake (inhalation is permitted). 
13. Known hypersensitivity to any of the study drugs. 
14. Residual non-hematologic toxicity ≥ Grade 2 from prior therapy. 
4.3.3 
Patient Withdrawal 
All patients are free to withdraw from participation in the study at any time, for any reason, 
specified or unspecified, and without prejudice to further treatment.  The criteria for 
enrollment are to be followed explicitly.  If a patient who does not meet enrollment criteria is 
inadvertently enrolled, that patient should be withdrawn from the study and the Sponsor or 
the contract research organization, Quintiles, must be contacted.   
Investigators may withdraw patients from the study and/or from study treatment in the event 
of intercurrent illness, AEs, protocol violation, administrative reasons, or for other reasons.  
Patients who prematurely withdraw from study treatment will continue being followed for 
post-treatment assessments at the Safety Follow-up Visit, unless patients withdraw consent.  
Excessive patient withdrawals can render the study uninterpretable; therefore, unnecessary 
withdrawal of patients should be avoided. 
If a patient decides to withdraw, all efforts should be made to complete and report study 
assessments as thoroughly as possible.  The Investigator should contact the patient or a 
responsible relative by telephone or through a personal visit to establish as completely as 
possible the reason for the withdrawal.  A complete final evaluation at the time of the 
patient’s withdrawal should be made with an explanation of why the patient is withdrawing 


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from the study.  If the reason for removal of a patient from the study is an AE, the principal 
specific event will be recorded on the eCRF. 
5.0 STUDY TREATMENTS 
5.1 
Treatments Administered 
Patients will be randomized to 1 of 2 treatment arms: 
Arm A, HLX02 (investigational product) + docetaxel 
• 
HLX02 8 mg/kg administered intravenously over 90 minutes as a loading dose on 
Day 1, Cycle 1 then 6 mg/kg every 3 weeks for subsequent cycles. 
Or 
Arm B, EU-sourced Herceptin® (comparator) + docetaxel 
• 
EU-sourced Herceptin® 8 mg/kg administered intravenously over 90 minutes as a loading 
dose on Day 1, Cycle 1 then 6 mg/kg every 3 weeks for subsequent cycles. 
In both treatment arms, treatment with HLX02 or Herceptin® will continue for a maximum of 
12 months (17 cycles), or until Investigator-assessed disease progression, excessive toxicity, 
Investigator’s judgment, withdrawal of consent, lost to follow-up, death, start of a new 
anticancer therapy, or study termination by the Sponsor, whichever occurs first. 
In both treatment arms docetaxel 75 mg/m2 will be administered on Day 2, Cycle 1.  All 
patients will be given prophylactic dexamethasone (see Section 5.8.2).  If well tolerated, as 
determined by the Investigator, then the same dose will be given every 3 weeks on Day 1 of 
each subsequent cycle always after HLX02 or Herceptin®.  Each dose will be 
administered intravenously over 60 minutes according to the currently approved prescribing 
information.  Treatment with docetaxel will continue for at least 8 cycles unless there is 
disease progression or excessive toxicity.  After Cycle 8, continuation of docetaxel treatment 
is at the discretion of the Investigator.  Once Herceptin®/HLX02 is no longer being given in 
combination with docetaxel and the patient has tolerated a number of Herceptin®/HLX02 
infusions, dexamethasone need not be given; however, this will depend on each individual 
case, local standard practice, and the Investigator’s judgment. 
5.2 
Identity of Investigational, Comparator, and Associated Products 
HLX02 (trastuzumab), the investigational product, is a recombinant anti-HER2 humanized 
monoclonal antibody for injection and is manufactured by Shanghai Henlius 
Biopharmaceuticals Co., Ltd (a wholly-owned subsidiary of Shanghai Henlius Biotech, Inc.).  


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The clinical preparation of HLX02 is a sterile, white to pale yellow, preservative-free, 
lyophilized powder.  Each vial contains 150 mg of concentrated powder for solution for 
infusion.  After reconstitution with sterile water for injection, the solution is a colorless or 
pale yellow, transparent liquid.  
Herceptin® (trastuzumab), the comparator product, is a humanized immunoglobulin G1 
monoclonal antibody produced by mammalian (Chinese hamster ovary) cell suspension 
culture.  The drug is manufactured by Roche Pharmaceuticals.  The clinical preparation of 
Herceptin® is a white to pale yellow lyophilized powder.  Each vial contains 150 mg of 
concentrated powder for solution for infusion.  After reconstitution with sterile water for 
injection, the solution is a colorless or pale yellow, transparent liquid.9  
Vials of HLX02 and Herceptin® should be stored in the refrigerator at 2 to 8ºC (36-46ºF).  
The reconstituted solution is physically and chemically stable for 48 hours at 2 to 8°C.  
Solutions for intravenous infusion are physically and chemically stable in polyvinylchloride, 
polyethylene or polypropylene bags containing sodium chloride 9 mg/mL (0.9%) solution for 
injection for 24 hours at temperatures not exceeding 30°C (86°F).   
Study drug will be supplied to the centers by a third party vendor.   
Docetaxel, the associated product, will be supplied centrally.  Refer to the docetaxel currently 
approved prescribing information on formulation, preparation, storage, and administration. 
5.3 
Packaging and Labelling 
Vials of HLX02 and EU-Herceptin® will be labelled by a third party.  The labels will contain 
the following information: the pharmaceutical dosage form, route of administration, 
identification number, the protocol number, use-by date, storage details, and all other details 
required by local regulations and Good Manufacturing Practice. 
5.4 
Method of Assigning Patients to Treatment Arm 
Once the patient meets all eligibility criteria, the study center will request the study 
medication assignment using the Interactive Web Response System/Interactive Voice 
Response System (IWRS/IVRS).   
All randomized patients will be managed by IWRS/IVRS.  Designated study personnel at the 
investigational centers will be assigned password-protected, coded identification numbers, 
which give them authorization to access the IWRS/IVRS to randomize patients.  The system 
will present a menu of questions by which the study personnel will identify the patient and 
confirm eligibility.  When all questions have been answered, the IWRS/IVRS will assign a 


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randomization identification number.  Confirmation of the randomization will be sent via fax 
to the investigational center, the Sponsor and Quintiles representatives. 
A complete block randomization scheme will be applied to achieve balance in treatment 
assignment within each of the strata, as defined by the following stratification factors: 
ER/PgR status, prior neo-/adjuvant therapy with Herceptin®, and ethnicity (Asian and 
non-Asian). 
5.5 
Selection of Doses in the Study 
The dose of HLX02 was selected as per Herceptin® label for a 3-weekly regimen.  In these 
studies, Herceptin® as a loading dose of 8 mg/kg and maintenance dose of 6 mg/kg every 
3 weeks was well tolerated and beneficial in patients with HER2-overexpressing metastatic 
breast cancer.9  
A starting dose of docetaxel 75 mg/m2 is in accordance with the currently approved 
prescribing information.  
5.6 
Selection and Timing of Dose for Each Patient 
5.6.1 
Administration 
On Day 1 of every treatment cycle, body weight will be used to calculate the required dose of 
HLX02 or Herceptin® and docetaxel (study drug).  All patients will be given prophylactic 
dexamethasone (see Section 5.8.2).  The Investigator must make sure that any weight change 
is not due to fluid retention.  If it is due to fluid retention, the patient must be given oral 
furosemide (or equivalent diuretic).  The dose will be adjusted only if the patient’s weight 
changes by more than ±10% from baseline.  Any change in dose must be documented in the 
eCRF.   
If either HLX02/Herceptin® or docetaxel must be delayed for a day or more (maximum 
14 days), both agents should be delayed for the same timeframe.  If delayed by more than 
14 days, the agent that led to the delay will be omitted and given at the next scheduled cycle. 
Administered dose of all study drugs, date/time of start of infusion, date/time of end of 
infusion and any interruptions must be documented in the eCRF.  Interruptions should be 
documented as time the infusion stopped and time that the infusion is restarted. 
HLX02 or Herceptin® 
On Day 1, Cycle 1, either HLX02 or Herceptin® will be administered as an intravenous 
loading dose of 8 mg/kg over 90 minutes, then 6 mg/kg on Day 1 of every subsequent cycle 
(i.e. every 3 weeks) over 30-90 minutes (i.e. any duration between 30 and 90 minutes from 
Cycle 2 onwards) if the previous dose was well tolerated.  


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Appropriate aseptic technique should be used.  Each vial of the study drug is reconstituted 
with 7.2 mL of water for injection.  Use of other reconstitution solvents should be avoided.  
This yields a 7.4 mL solution for single-dose use, containing approximately 21 mg/mL 
trastuzumab.  A volume overage of 4% ensures that the labelled dose of 150 mg can be 
withdrawn from each vial.   
The drug should be carefully handled during reconstitution.  Causing excessive foaming 
during reconstitution or shaking the reconstituted drug may result in problems with the 
amount of solution that can be withdrawn from the vial:  
• 
Using a sterile syringe, slowly inject 7.2 mL of water for injection in the vial containing 
the study drug, directing the stream into the lyophilized cake. 
• 
Swirl vial gently to aid reconstitution.  DO NOT SHAKE. 
Slight foaming of the product upon reconstitution is not unusual.  Allow the vial to stand 
undisturbed for approximately 5 minutes.  The reconstituted drug should be essentially free 
of visible particulates. 
Volume of the solution required: 
Volume (in mL) = Body Weight (in kg) × Dose (8 mg/kg for loading or 6 mg/kg for maintenance) 
21 mg/mL (concentration of reconstituted solution) 
The appropriate amount of solution should be withdrawn from the vial and added to a 
polyvinylchloride, polyethylene or polypropylene infusion bag containing 250 mL of 0.9% 
sodium chloride solution.  Do not use with glucose-containing solutions.  The bag should be 
gently inverted to mix the solution in order to avoid foaming.  Parenteral solutions should be 
inspected visually for particulates and discoloration prior to administration.  Once the 
infusion is prepared it should be administered immediately over 90 minutes for the loading 
dose or 30-90 minutes for the maintenance dose.  The study drug should always be 
administered before docetaxel.  
Docetaxel 
On Day 2, Cycle 1, docetaxel 75 mg/m2 will be administered over 60 minutes according to 
currently approved prescribing information.  If well tolerated, as determined by the 
Investigator, then the same dose will be given every 3 weeks on Day 1 of each subsequent 
cycle always starting 60 minutes after the end of the HLX02 or Herceptin® infusion.  As 
of Cycle 2, according to tolerance and local practice, the Investigator can increase the dose of 
docetaxel to 100 mg/m² (see Section 5.6.3). 


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5.6.2 
HLX02 and Herceptin® Main Toxicities and Administration Modifications 
In case the whole loading dose of HLX02 or Herceptin® could not be administered due to an 
infusion reaction or other reason, the following guidelines apply: 
• 
The patient should receive at least 50% of the loading dose in the first week.  Therefore, 
if the patient receives less than 50% of the Cycle 1 dose, the patient should receive the 
remainder before Day 22, preferably within the first week.  Thereafter, the patient should 
receive the usual maintenance dose 3 weeks after the first interrupted dose, as routinely 
scheduled.  For example, if a patient received only approximately 50% of the scheduled 
loading dose (i.e. only 4 mg/kg instead of 8 mg/kg), the patient should receive the 
remaining dose (4 mg/kg), preferably in the first week, and then regular maintenance 
doses (6 mg/kg) on Day 22, as routinely scheduled. 
• 
If the patient receives between 50–75% of the dose, the patient should receive the 
remainder before Day 22, preferably within the first 2 weeks of Cycle 1.  For example, if 
a patient received only approximately 60% of the scheduled loading dose, the patient 
should receive the remaining 40%, within 2 weeks after the interrupted loading dose.  
Thereafter, the patient should receive the regular maintenance doses on Day 22, as 
routinely scheduled. 
• 
If the patient receives ≥75% of the loading dose, additional loading is probably not 
necessary.  However, the remainder of the loading dose may be given at the Investigator's 
discretion.  In such a case, the remainder may be given at any time before the next 
scheduled dose or the patient may be given an additional loading dose on Day 22.  If, 
after receiving an incomplete loading dose on Day 1, the patient cannot attend the site 
until Day 22, the patient should receive a second loading dose on Day 22.  However, 
every effort should be made to give the remainder of the dose prior to Day 22. 
In the case of toxicity, HLX02 and Herceptin® administration may be delayed but no dose 
reduction is allowed.  If a patient misses a dose of HLX02 or Herceptin® by less than 1 week 
after the planned date, the usual maintenance dose (6 mg/kg) should be given as soon as 
possible.  Do not wait until the next planned cycle.  If a patient misses a dose of HLX02 or 
Herceptin® for ≥1 week (i.e. the 2 sequential administrations are given ≥4 weeks apart), a 
re-loading dose of HLX02 or Herceptin® (8 mg/kg) should be given.  Subsequent 
maintenance HLX02 or Herceptin® doses of 6 mg/kg will then be given every 3 weeks, 
starting 3 weeks later.  If re-loading is required, docetaxel administration (at the dose that 
was last tolerated) will be restarted on the same day as the re-loading dose, to coincide with 
the start of a new cycle.  If a patient has a study drug interruption ≥9 weeks for a 
trastuzumab-related toxicity, they will be discontinued from the study (see the Herceptin® 
package insert for further details). 


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In general, AEs that occur in patients enrolled in this study can be managed referring to the 
Herceptin® package insert or following standard practice at the study site.  Guidance for 
managing specific reactions (cardiac dysfunction; IRRs and hypersensitivity; hematologic 
toxicity; pulmonary events) is provided below. 
Cardiac Dysfunction 
At baseline all patients must have LVEF within institutional range of normal and LVEF will 
be monitored in accordance with the Schedule of Events (see Table 4-1).  If an Investigator is 
concerned that an AE may be related to cardiac dysfunction, an additional LVEF 
measurement should be performed (see Section 6.2.1.3 for details on reporting cardiac AEs). 
The safety of continuation or resumption of trastuzumab in patients who experience cardiac 
dysfunction has not been prospectively studied.  Either reference trastuzumab or HLX02 
must be withheld for at least 4 weeks if ≥16% absolute decrease in LVEF from pre-treatment 
levels or LVEF is below institutional normal range and ≥10% absolute decrease in LVEF.  A 
repeat LVEF assessment must be performed within approximately 3 weeks.  Treatment 
resumption is allowed if within 4-8 weeks the LVEF returns to within normal limits and the 
absolute decrease from baseline is ≤15%.  Treatment should be discontinued for a persistent 
(>8 weeks) decline in LVEF or on suspension of treatment on more than three occasions for 
cardiac toxicity.12   All such patients should be referred for assessment by a cardiologist and 
followed up.  If symptomatic cardiac failure develops during study treatment, it should be 
treated with standard medicinal products for CHF.9  Most patients who developed CHF or 
asymptomatic cardiac dysfunction in pivotal studies improved with standard CHF treatment 
consisting of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and 
a beta-blocker.  The majority of patients with cardiac symptoms and evidence of a clinical 
benefit of Herceptin® treatment continued on therapy without additional clinical cardiac 
events.  
Trastuzumab may persist in the circulation for up to 7 months after stopping the treatment 
based on population PK analysis of all available data.9  Patients who receive anthracyclines 
after stopping trastuzumab may possibly be at increased risk of cardiac dysfunction.  If 
possible, physicians should avoid anthracycline-based therapy for up to 7 months after 
stopping trastuzumab.  If anthracyclines are used, the patient's cardiac function should be 
monitored carefully. 
Infusion-related Reactions and Hypersensitivity 
Serious IRRs to the study drug infusion including dyspnea, hypotension, wheezing, 
hypertension, bronchospasm, supraventricular tachyarrhythmia, reduced oxygen saturation, 
anaphylaxis, respiratory distress, urticaria and angioedema have been reported.9  The 
majority of these events occur during or within 2.5 hours of the start of the first infusion.  If 


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an IRR occurs, the infusion should be immediately interrupted (in patients with non-serious 
IRRs, at the Investigator’s discretion, the infusion may be slowed) and the patient should be 
monitored until resolution of all observed symptoms. 
These symptoms can be treated with an analgesic/antipyretic such as meperidine or 
paracetamol.  Serious reactions have been treated successfully with supportive therapy such 
as oxygen, beta-agonists, and corticosteroids.  If a second episode of serious IRR occurs 
despite prophylactic use of steroids (see Section 5.8.2) treatment will be permanently 
discontinued. 
In rare cases, these serious reactions are associated with a clinical course culminating in a 
fatal outcome.  Patients experiencing dyspnea at rest due to complications of advanced 
malignancy and comorbidities may be at increased risk of a fatal infusion reaction; therefore, 
these patients should not be treated with trastuzumab. 
Initial improvement followed by clinical deterioration and delayed reactions with rapid 
clinical deterioration have also been reported.  Fatalities have occurred within hours and up 
to 1 week following infusion.  On very rare occasions, patients have experienced the onset of 
infusion symptoms and pulmonary symptoms more than 6 hours after the start of the 
trastuzumab infusion. 
Hematologic Toxicity 
Febrile neutropenia and leukopenia have occurred very commonly after infusion with 
trastuzumab.9  Commonly occurring adverse reactions include anemia, thrombocytopenia 
and neutropenia.  The frequency of occurrence of hypoprothrombinemia is not known.  The 
risk of neutropenia may be slightly increased when trastuzumab is administered with 
docetaxel following anthracycline therapy. 
Pulmonary Events 
Severe pulmonary events have been reported with the use of trastuzumab in the 
post-marketing setting.9  These events have occasionally been fatal.  In addition, cases of 
interstitial lung disease including lung infiltrates, acute respiratory distress syndrome, 
pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary edema and 
respiratory insufficiency have been reported.  Risk factors associated with interstitial lung 
disease include prior or concomitant therapy with other anti-neoplastic therapies known to be 
associated with it such as taxanes, gemcitabine, vinorelbine and radiation therapy.  These 
events may occur as part of an IRR or with a delayed onset.  Patients experiencing dyspnea at 
rest due to complications of advanced malignancy and comorbidities may be at increased risk 
of pulmonary events.  Therefore, these patients should not be treated with trastuzumab.  


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Caution should be exercised for pneumonitis, especially in patients being treated 
concomitantly with taxanes. 
5.6.3 
Docetaxel Dose Modifications 
Any docetaxel dose increase or decrease should be documented in the eCRF (see 
Section 5.6.1).  All patients will be given prophylactic dexamethasone (see Section 5.8.2 for 
regimen).  If an IRR occurs, the infusion should be immediately interrupted (in patients with 
non-serious IRRs, at the Investigator’s discretion, the infusion may be slowed) and the 
patient should be monitored until resolution of all observed symptoms. 
Dose Increase 
After an initial dose of docetaxel, patients who do not experience febrile neutropenia, severe 
or cumulative cutaneous reactions, or severe peripheral neuropathy may tolerate higher 
doses.  Consequently, at the Investigator’s discretion, the dose of docetaxel can be increased 
to 100 mg/m2 in patients who have tolerated at least 1 administration of 75 mg/m2 without 
any of the following: 
• 
Febrile neutropenia (≥38.5ºC  and neutrophils <500 cells/mm3 
for more than 1 week) 
• 
Grade 4 neutropenia for more than 5 days 
• 
ANC <100/μL for more than 1 day; or  
• 
Any non-hematological toxicities of > Grade 2 (National Cancer Institute’s Common 
Terminology Criteria for Adverse Events version 4.03 [NCI-CTCAE v4.03]).   
If treatment is withheld for more than 1 week for granulocyte recovery, or if a febrile 
neutropenic episode (≥38.5ºC and neutrophils <500 cells/mm3 
for more than 1 week) occurs 
at any time during therapy, prophylactic G-CSF will be administered (according to the 
package insert) with all subsequent cycles.  Prophylactic use of G-CSF before the first cycle 
is not allowed unless the patient had prior severe neutropenia during neo-/adjuvant therapy. 
The recommendations given in the prescribing information for docetaxel should be strictly 
followed. 
Dose Delay 
Docetaxel may be delayed due to toxicities.  If docetaxel is delayed for more than 3 weeks 
with no recovery, the patient should be withdrawn from docetaxel treatment.   
Dose Decrease 
Docetaxel dose modifications will be allowed for myelosuppression, hepatic dysfunction, and 
other toxicities according to the parameters in Table 5-1. 


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Table 5-1 
Docetaxel Dose Adjustments 
Docetaxel Dose 
When 
75 mg/m2 
Starting dose: 
• 
Administer only if neutrophil count is ≥1500 cell/mm3 
55 mg/m2 (or 75 mg/m2 
if dose previously 
increased to 100 mg/m2) 
25% reduced dose in case of any of the following toxicities: 
• 
Febrile neutropenia or neutrophils <500 cells/mm3 for more 
than 1 week (after fully recovering to a neutrophil count 
≥1,500 cells/mm3) 
• 
Platelet count <100,000 cells/mm3 (after recovering to a 
platelet count ≥100,000 cells/mm3) 
• 
Severe or cumulative cutaneous reactions 
Permanently  
discontinue  
docetaxel 
After any of the following toxicities: 
• 
Severe hypersensitivity reactions 
• 
Peripheral neuropathy ≥ Grade 3 (without recovery after delay 
of 3 weeks) 
• 
Severe or cumulative cutaneous reactions that continue at a 
dose of 55 mg/m2 without recovery 
• 
Febrile neutropenia or neutrophils <500 cells/mm3 without 
recovery 
• 
Platelet count <100,000 cells/mm3 without recovery 
• 
Serum total bilirubin >1.5 x ULN without recovery 
• 
Serum transaminase (AST/ALT) levels >1.5 x ULN concurrent 
with serum ALK levels >2.5 x ULN (unless there is bone 
metastasis) 
ALK = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
ULN = upper limit of normal. 
 
At any time during the Treatment Period, docetaxel should be discontinued for progressive 
disease or unacceptable toxicity.  If, despite adequate prophylaxis with dexamethasone (or 
equivalent), a severe IRR occurs, docetaxel will be permanently discontinued.  After Cycle 8, 
continuation of docetaxel treatment is at the discretion of the Investigator.   
If docetaxel is permanently discontinued for any reason other than disease progression, 
the patient can continue on HLX02 or Herceptin® alone if they are still benefiting from 
the treatment.  
5.7 
Blinding 
This is a randomized, double-blind, bioequivalence study with limited access to the 
randomization code.  The treatment each patient receives will not be disclosed to the 
Investigator, study center staff, patient, Sponsor, or Quintiles with the exception of the 


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designated unblinded study team at the time of the first database lock for the primary 
analysis. 
The vials of HLX02 and Herceptin® are not identical in appearance.  To ensure the 
Investigator and patient stay blinded, an unblinded pharmacist team at each center will 
reconstitute the study drug for each patient.  After the drug has been reconstituted, the 
unblinded pharmacist or designee will label the intravenous bag with the correct patient 
number so the study team will not know what treatment is contained therein. 
The blind must not be broken during the course of the study unless, in the opinion of the 
Investigator, it is absolutely necessary to safely treat the patient.  If it is medically imperative 
to know what study drug the patient is receiving, the study drug should be temporarily 
discontinued if, in the opinion of the Investigator, continuing the drug could negatively affect 
the outcome of the patient’s treatment. 
The decision to break the blind in emergency situations remains the responsibility of the 
Investigator and will not be delayed or refused by the Sponsor; however, the Investigator 
may contact the Quintiles Medical Monitor prior to breaking the blind to discuss the 
unblinding and what would be in the best interests of the patient.  The Investigator should 
ensure that the code is broken only in accordance with the protocol.  The Investigator should 
promptly notify the Quintiles Medical Monitor of the emergency unblinding and the reason 
for breaking the blind and this should be clearly documented by the Investigator in the 
patient’s source documentation.  The process for breaking the blind will be handled through 
the IWRS/IVRS using an emergency unblinding personal identification number.  If the blind 
is broken, it may be broken for only the patient in question. 
5.8 
Prior and Concomitant Treatments 
At Screening, all medications taken in the 90 days before randomization, including 
anticancer therapies, will be recorded on the eCRF.  Prior anticancer treatments, including 
but not limited to neo-/adjuvant therapy and hormone therapy, should also be recorded on the 
eCRF at Screening. 
All concomitant medications including herbal remedies and traditional Chinese 
medicines must be recorded on the eCRF. 


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5.8.1 
Excluded Medications 
The use of excluded medication is a protocol violation and should be recorded in the eCRF.  
The following is not permitted during the study:  
• 
Treatment with other systemic anticancer agents (e.g. chemotherapy, hormonal therapy, 
immunotherapy).  To lessen the risk of resistance, prior neo-/adjuvant therapy containing 
trastuzumab and/or lapatinib must have been stopped at least 12 months before the 
diagnosis of recurrent (local or metastatic) disease (a disease-free interval of 
≥12 months).  If trastuzumab/lapatinib was not used, prior neo-/adjuvant therapy with a 
taxane must have been stopped at least 6 months before the diagnosis of recurrent (local 
or metastatic) disease (a disease-free interval of ≥6 months).  Use with other cytotoxics 
must have been stopped at least 4 weeks before randomization.  Any hormonal therapy 
must be stopped at the time of the ICF signature (at least 2 weeks before randomization). 
• 
Use of oral, injected or implanted hormonal methods of contraception. 
• 
Concurrent investigational agents of any type.   
• 
Chronic daily use of corticoids (equivalent to >10 mg/day methylprednisolone) by oral 
intake (inhalation is permitted).  Such use must be stopped at least 28 days before first 
infusion with no planned requirement for the corticoid over the next 12 months.   
• 
Herbal remedies and traditional Chinese medicines for anticancer, hematologic or liver 
function, or anti-infective treatment are prohibited during the study.  Herbal remedies and 
traditional Chinese medicines must be stopped at the time of the ICF signature (at least 
2 weeks before randomization). 
• 
No other therapeutic modality is permitted such as intrathecal therapy or radiotherapy. 
5.8.2 
Allowed Medications 
Prophylactic steroids 
To decrease the risk of IRRs and nausea/vomiting, all patients treated with docetaxel will be 
given either oral or intravenous dexamethasone as follows:  
Oral: on Day 2 of Cycle 1, patients will be given 7.5-8 mg (depending on the available tablet 
dosage form) dexamethasone orally at 24 hours (about the same time as the HLX02 or 
Herceptin® infusion on Day 1) and 12 hours before the start of the docetaxel infusion.  In 
subsequent cycles (Cycle 2 onwards), administration of 7.5-8 mg dexamethasone orally will 
occur at 24 hours and 12 hours before the HLX02 or Herceptin® infusion, followed 1 hour 


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later by the docetaxel infusion.  After the docetaxel infusion, 7.5-8 mg dexamethasone should 
be given twice daily for a further 48 hours.   
Intravenous: on Day 2 of Cycle 1, patients will be given 20 mg dexamethasone intravenously 
approximately 30 minutes before the start of the docetaxel infusion.  In subsequent cycles 
(Cycle 2 onwards), patients will be given 20 mg dexamethasone intravenously after the 
HLX02 or Herceptin® infusion and before the docetaxel infusion.  After the docetaxel 
infusion, 7.5-8 mg dexamethasone should be given twice daily for 48 hours as described 
above. 
Once Herceptin®/HLX02 is no longer being given in combination with docetaxel, and the 
patient has tolerated a number of Herceptin®/HLX02 infusions, dexamethasone need not be 
given; however, this will depend on each individual case, local standard practice, and the 
Investigator’s judgment. 
Other allowed medications 
Patients should receive full supportive care including transfusion of blood and blood 
products, antibiotics, etc., according to standard of care when necessary. 
All protocol-allowed medications taken by the patient for concomitant disease should 
continue as necessary during the study.  Treatments prescribed to patients should be adapted 
according to the local standard of care practice.  The following list of allowed medications is 
provided as guidance: 
• 
Anti-emetics: 
If required 
• 
Anti-coagulation therapy: 
Permitted for maintenance of patency of 
permanent indwelling intravenous catheters 
• 
Paracetamol (acetaminophen) or 
other analgesics: 
If required 
• 
Anti-diarrhea medication: 
If required, e.g. loperamide 
• 
Granulocyte-colony stimulating 
factor: 
May be used according to the product license 
and according to the currently approved 
prescribing information for docetaxel and 
American Society of Clinical Oncology clinical 
guidelines.13  Granulocyte-colony stimulating 
factor may not be given as prophylaxis before 
the first cycle (see Section 5.6.3). 


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• 
Bisphosphonates: 
Administered according to their label 
instructions at the discretion of the Investigator 
according to local practice. 
5.9 
Medical Care of Patients after the End of the Treatment Period 
At the defined end of the Treatment Period (up to 12 months), patients will be referred to the 
local institution and will continue therapy in accordance with local practice.  The Sponsor 
will not provide any additional care to patients after they leave the study because such care 
should not differ from what is normally expected for patients with breast cancer. 
5.10 Treatment Compliance 
The prescribed dosage of HLX02 or Herceptin® and the route of administration may not be 
changed and administration may only be delayed in the case of toxicity (see Section 5.6).  
Any deviations from the intended regimen must be recorded in the source documents and 
eCRFs.  
5.11 Study Medication Accountability 
The Investigator, a member of the investigational staff, or a hospital pharmacist must 
maintain an adequate record of the receipt and distribution of all study drugs using the Drug 
Accountability Form.  These forms must be available for inspection at any time. 
All study medication supplies should be accounted for at the termination of the study and a 
written explanation provided for discrepancies.  All unused study drug supplies and 
packaging materials are to be inventoried and returned to the Sponsor or designee by the 
Investigator.  The Investigator is not permitted to return or destroy unused clinical drug 
supplies or packaging materials unless authorized by the Sponsor or designee. 


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6.0 EFFICACY, SAFETY, AND PHARMACOKINETIC 
ASSESSMENTS 
6.1 
Efficacy 
6.1.1 
Primary Efficacy 
Primary efficacy assessment (ORR24) will be conducted by CIR for an independent, blinded 
determination of tumor response up to Week 24 after completion of up to 8 cycles of 
treatment. 
6.1.1.1 
Tumor Assessments 
The tumor measurement at Screening will be reviewed by CIR to confirm eligibility before 
the patient can be randomized.  For further details on who will conduct the tumor 
assessments during the study, see Section 6.1.1.2.  Assessments to evaluate tumor response 
during the study will be performed according to the Schedule of Events (Table 4-1).  
Assessments will be based on enhanced CT or magnetic resonance imaging (MRI) scan 
results; the tumor size will be measured and the overall response will be assessed according 
to RECIST 1.1.  A summary of RECIST 1.1 is provided in Appendix 4.  Tumor assessments 
will be recorded on the eCRF.  
The same tumor assessment technique must be used throughout the study for response 
evaluation.  Positron emission tomography (known as PET scan) is not accepted as a sole 
method to assess efficacy.  Enhanced CT/MRI is preferred and if used, must be used 
throughout the study period.  The minimum CT or MRI scans at Screening (baseline) 
examination should include:  
• 
CT or MRI scan of the chest and abdomen (including liver, spleen, and adrenals), and 
pelvis if clinically indicated 
• 
CT or MRI scan of the brain and/or spine where there is clinical suspicion of CNS 
metastases 
• 
An isotope bone scan (with bone X-ray[s] as necessary) at baseline if clinically indicated.  
It should be repeated during the study in the event of clinical suspicion of progression of 
existing bone lesions and/or the appearance of new bone lesions 
• 
Medical photography to monitor (sub) cutaneous skin lesions. 
For patients with multiple measurable lesions, a maximum of 2 lesions per organ and 
5 lesions in total that are representative of all involved organs should be designated as target 
lesions and recorded and measured at Screening. 


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All other lesions should be identified as non-target lesions and should be recorded at 
baseline.  Measurements of these lesions are not required but the presence or absence of each 
should be noted throughout the Treatment Period. 
In cases where there is suspicion of progression before the next scheduled assessment, an 
unscheduled assessment is to be performed.  The reason for the unscheduled assessment will 
be reported on the eCRF. 
Tumor assessments will be performed at Week 6, 12, 18, and 24, regardless of the number of 
cycles actually given, and then every 9 weeks (between Days 15-21 after Cycles 11, 14, and 
17); see the Schedule of Events (Table 4-1).  If a tumor assessment must be performed early 
or late, subsequent assessments will be performed at the planned date if at least 4 weeks 
apart.  Every effort should be made to maintain the planned schedule for tumor assessments 
every 6 weeks up to Week 24 and every 9 weeks up to 12 months.  
For patients who discontinue study drug for reasons other than death, Investigator-assessed 
disease progression, excessive toxicity, or withdrawal of consent, efforts should be made to 
continue to perform scheduled tumor assessments for up to a maximum of 12 months, or 
until patient death, Investigator-assessed disease progression, withdrawal of consent, or start 
of a new anticancer therapy.   
6.1.1.2 
Central Independent Review of MRI/CT Scans and Local Imaging Assessment 
All imaging and overall response assessments will be made according to RECIST 1.1 (see 
Appendix 4).  Tumor measurements will be assessed by CIR at Screening (baseline) to 
determine eligibility before randomization can occur.  During the Treatment Period, all 
treatment decisions will be made by the Investigator using tumor assessments by the local 
radiologist.  Imaging performed at Week 6, 12, 18, and 24 will be sent for CIR to compare 
the pattern of response.  Best ORR up to Week 24 by CIR will be used for the primary 
efficacy analysis.  After Week 24, the response evaluation will be made by the local 
Investigator/radiologist and no CIR will be performed.  Response duration will be evaluated 
by the local Investigator/radiologist if progression is documented after Week 24 imaging.   
Images for the CIR must be acquired according to Imaging Guidelines provided by the 
vendor and then transmitted to the CIR facility.  In addition, bone scans, x-rays, cytologic 
data (e.g. relevant cytology reports documenting malignant pleural effusions, bone marrow 
aspirations, cerebral spinal fluid, etc.), baseline scans, and relevant clinical information 
including medical photography will be forwarded to the CIR facility to aid in the overall 
response assessment.   
Full details are listed in the CIR Charter and in the Imaging Guidelines. 


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6.1.2 
Efficacy Endpoints 
The primary endpoint is the ORR24, calculated as the proportion of patients with a best 
response of CR or PR from first assessment up to Week 24 according to RECIST 1.1.  The 
response does not need to be confirmed.  Overall tumor response will be assessed by blinded, 
independent CIR according to RECIST 1.1.   
The secondary endpoints are the following: 
• 
ORR at Week 6, 12, 18, and 24 by CIR 
• 
DoR, defined as the time form first documentation of CR or PR to the first documentation 
of progression up to 12 months after randomization.  After Week 24, assessments are 
made by the Investigator 
• 
DCR, defined as the proportion of patients who achieve CR, PR, or SD of at least 
12 weeks 
• 
CBR, defined as the proportion of patients who achieve CR, PR, or durable SD 
(SD ≥24 weeks) 
• 
PFS up to 12 months, defined as the probability of being alive without documented 
progression 12 months after randomization, calculated using the Kaplan-Meier method 
• 
OS at 12, 24, and 36 months, defined as the probability of being alive 12, 24, and 
36 months after randomization, calculated using the Kaplan-Meier method. 
Progressive disease is defined as at least a 20% increase in the sum of the diameters of target 
lesion(s), taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new 
lesions is also considered progression.) 
Patients will undergo Survival Follow-up every 3 months during the 12-month Treatment 
Period; thereafter, survival data will be collected every 3 months by telephone call up to 
36 months after randomization. 
Stable disease is defined as neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease, taking as reference the smallest sum diameters 
while on study.   


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6.2 
Safety 
6.2.1 
Adverse Events 
Definition of AE:  An AE is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
Definition of serious adverse event (SAE):  An SAE, experience or reaction, is any untoward 
medical occurrence (whether considered to be related to study drug or not) that at any dose: 
• 
Results in death 
• 
Is life-threatening (the patient is at a risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it were more severe) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization: Hospital 
admissions and/or surgical operations planned before or during a study are not considered 
AEs if the illness or disease existed before the patient was enrolled in the study, provided 
that it did not deteriorate in an unexpected way during the study 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital abnormality/birth defect 
• 
Other:  Medically significant events, which do not meet any of the criteria above, but 
may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the other serious outcomes listed in the definition above.  Examples of such events 
are blood dyscrasias (e.g. neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization. 
Events that do not meet the definition of a SAE 
Elective hospitalizations to administer, or to simplify study treatment or study procedures 
(e.g. an overnight stay to facilitate chemotherapy and related hydration therapy application) 
are not considered SAEs.  However, all events leading to unplanned hospitalizations or 
unplanned prolongation of an elective hospitalization (e.g. undesirable effects of any 
administered treatment) must be documented and reported as SAEs. 


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Events not to be considered as AEs/SAEs  
Medical conditions present at the initial study visit that do not worsen in severity or 
frequency during the study are defined as baseline medical conditions, and are NOT to be 
considered as AEs/SAEs.  Progression of disease is not to be reported as an AE/SAE (see 
Section 6.2.1.7).  With regard to laboratory values, see under ‘Abnormal laboratory findings 
and other abnormal investigational findings’ below.  
Adverse events of special interest (AESI) 
Certain AEs will be considered of special interest.  These include, but may not be limited to, 
cardiac events (in particular CHF), infusion reactions, allergic-like reactions and 
hypersensitivity, and hematotoxicity events.  See Section 6.2.1.3 for details on reporting 
AESI.  Cardiac safety data will be collected up to 12 months after randomization in all 
patients. 
Severity 
Intensity of all AEs will be graded according to NCI-CTCAE v4.03 using Grades 1 to 5.  
Adverse events not listed on the NCI-CTCAE should be graded as mild to life-threatening as 
follows: 
• 
Grade 1 
Mild 
Discomfort noticed but no disruption of normal 
daily activity 
• 
Grade 2 
Moderate 
Discomfort sufficient to reduce or affect daily 
activity 
• 
Grade 3 
Severe 
Inability to work or perform normal daily activity 
• 
Grade 4 
Life-threatening 
An immediate threat to life or leading to a 
permanent mental or physical conditions that 
prevents work or performing normal daily 
activities 
• 
Grade 5 
Death 
AE resulting in death 
Relationship 
The causal relationship between the study drug and the AE will be assessed by the 
Investigator as unrelated, unlikely to be related, possibly related, probably related, or 
unknown (unable to judge).  
Adverse events can be classified as “unrelated” if there is not a reasonable possibility that the 
study drug caused the AE. 


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An “unlikely” relationship suggests that only a remote connection exists between the study 
drug and the reported AE.  Other conditions, including chronic illness, progression or 
expression of the disease state or reaction to concomitant medication, appear to explain the 
reported AE. 
A “possible” relationship suggests that the association of the AE with the study drug is 
unknown; however, the AE is not reasonably supported by other conditions. 
A “probable” relationship suggests that a reasonable temporal sequence of the AE with drug 
administration exists and, in the Investigator’s clinical judgment, it is likely that a causal 
relationship exists between the drug administration and the AE, and other conditions 
(concurrent illness, progression or expression of disease state or concomitant medication 
reactions) do not appear to explain the AE. 
All efforts should be made to classify the AE according to the above categories.  The 
category “unknown” (unable to judge) may be used only if the causality is not assessable, 
e.g. because of insufficient evidence, conflicting evidence, conflicting data, or poor 
documentation. 
An Adverse Drug Reaction is defined as all noxious and unintended responses to a medicinal 
product related to any dose.   
An Unexpected Adverse Drug Reaction is defined as any adverse reaction, the nature of 
which is not consistent with the applicable product information. 
The Investigator is responsible for recording all AEs observed during the study period.  Each 
AE is to be evaluated for duration, severity, seriousness and causal relationship to the study 
drug.  The action taken and the outcome must also be recorded.   
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as a SAE.  “Fatal” will be recorded as the outcome of this specific event and death 
will not be recorded as separate event.  Only, if no cause of death can be reported (for 
example, sudden death, unexplained death), the death per se might be reported as an SAE. 
Abnormal laboratory findings and other abnormal investigational findings 
Abnormal laboratory findings and other abnormal investigational findings (e.g. on an ECG 
trace) should not be reported as AEs unless they are associated with clinical signs and 
symptoms, lead to treatment discontinuation or are considered otherwise medically important 
by the Investigator.  If a laboratory abnormality fulfills these criteria, the identified medical 
condition (e.g. anemia, increased ALT) – if it can be – must be reported as the AE rather than 
the abnormal value itself. 


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6.2.1.1 
Reporting of Serious and Non-serious Adverse Events 
Adverse events, serious and non-serious, will be collected from the time of informed consent 
and up to 30 days after the last dose of study drug at the Safety Follow-up Visit. 
For all patients that have received at least 1 dose of study drug, all new non-cardiac, 
non-serious AEs (regardless of relatedness assessment) must be collected during the study 
through to the Safety Follow-up Visit.   
For all patients who have received at least 1 dose of study drug, any clinical AE or abnormal 
laboratory test value that is serious (as defined in Section 6.2.1 above) and which occurs 
during the course of the study, regardless of the treatment arm, must be reported to the 
Sponsors within 1 working day of the Investigator becoming aware of the event (expedited 
reporting). 
Related SAEs (cardiac and non-cardiac) MUST be collected and reported regardless of the 
time elapsed from the last study drug administration, even if the study has been closed. 
Any SAE, whether or not related to the study drug, must be reported immediately (within 
24 hours of the study center’s knowledge of the event) via Electronic Data Capture (EDC) at 
the center (details on reporting of SAEs are included in separate guidelines issued to each 
center). 
The report will contain as much available information concerning the SAE to enable 
Quintiles to file a report, which satisfies regulatory reporting requirements.  In addition to the 
initial 24-hour report, a completed, separate SAE Report form is to be sent to Quintiles 
Lifecycle Services within 48 hours of the event.  If the SAE occurs in China, a Chinese 
version of the SAE Report form must be completed and signed by the Principal Investigator 
and sent to the Sponsor.  All details on reporting of SAEs are included in separate guidelines 
issued to each center.  These timelines apply to initial reports of SAEs and to all follow-up 
reports.   
All SAEs will be recorded on the SAE Report form, the Adverse Events form in the eCRF, 
and source documents.  Criteria for documenting the relationship to study drug as well as 
severity and outcome will be the same as those previously described.   
All SAEs that are spontaneously reported within 30 days of a patient's last visit are to be 
collected and reported as previously described. 
6.2.1.2 
Reporting of Serious Adverse Events to Regulatory Agencies and Investigators 
Investigators will be notified by the Sponsor or Quintiles of all SAEs that require prompt 
submission to their Institutional Review Board (IRB) or Independent Ethics Committee 


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(IEC).  Investigators should provide written documentation of IRB/IEC notification for each 
report to the Sponsor or Quintiles.  The Sponsor or Quintiles will ensure that all SAEs are 
reported to the appropriate Regulatory Agencies.   
6.2.1.3 
Reporting Adverse Events of Special Interest: Cardiac AEs 
All cardiac AEs occurring during the study and up to 12 months after randomization in line 
with LVEF calculations, irrespective of causal relationship (unrelated, unlikely to be related, 
possibly related, probably related, or unknown) or severity (serious or non-serious), will be 
reported. 
Symptomatic Left Ventricular Systolic Dysfunction 
Symptomatic left ventricular systolic dysfunction should be reported as an SAE as CHF and 
not as individual signs and symptoms thereof.  Congestive heart failure should be graded 
according to NCI-CTCAE Version 4.03 for "left ventricular systolic dysfunction" and the 
NYHA classification (see Appendix 2). 
Asymptomatic Left Ventricular Systolic Dysfunction 
In general, asymptomatic declines in LVEF should not be reported as AEs since LVEF data 
are collected separately in the eCRF.  Exceptions to this rule are as follows: 
• 
An asymptomatic decline in LVEF to a value 10 percentage points below baseline or 
lower, and <50% must be reported as an AE  
• 
An asymptomatic decline in LVEF requiring treatment or leading to discontinuation of 
study treatment must be reported in an expedited manner by using the SAE.  
In both cases, it should be reported as left ventricular systolic dysfunction and graded 
according to NCI-CTCAE, v4.03. 
6.2.1.4 
Reporting Adverse Events of Special Interest: Infusion-related Reactions 
Serious IRRs to the study drug infusion include dyspnea, hypotension, wheezing, 
hypertension, bronchospasm, supraventricular tachyarrhythmia, reduced oxygen saturation, 
anaphylaxis, respiratory distress, urticaria and angioedema (see Section 5.6.2).  
Patients should be informed about the potential occurrence of IRRs and be educated on how 
to contact the center staff if needed.  All patients will be closely monitored during the first 
cycle of administration.  
If an AE is considered to be an IRR by the Investigator, the AE should be reported with the 
event term “infusion-related reactions” and not as individual signs and symptoms.  Signs and 


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symptoms should be entered in the appropriate part of the eCRF.  Infusion-related reactions 
should be graded according to NCI-CTCAE v4.03.  
6.2.1.5 
Reporting Adverse Events of Special Interest: Hematotoxicity 
Febrile neutropenia, leukopenia, anemia, thrombocytopenia and neutropenia have all been 
reported with infusions of the study drug. 
Abnormal laboratory findings should not be reported as AEs unless they are associated with 
clinical signs and symptoms, lead to treatment discontinuation or are considered otherwise 
medically important by the Investigator.  If a laboratory abnormality fulfills these criteria, the 
identified medical condition (e.g. anemia, neutropenia) – if it can be – must be reported as 
the AE rather than the abnormal value itself. 
6.2.1.6 
Follow-Up of Adverse Events 
Any AEs observed from the signing of informed consent up to 30 days after the last dose of 
study treatment (Safety Follow-up Visit) will be followed up to resolution.  Resolution means 
that the patient has returned to a baseline state of health or the Investigator does not expect 
any further improvement or worsening of the AE.   
6.2.1.7 
Progression of Underlying Malignancy 
Progression of underlying malignancy is not reported as an AE if it is clearly consistent with 
the suspected progression of the underlying cancer as defined by RECIST 1.1.  
Hospitalization due solely to the progression of underlying malignancy should NOT be 
reported as an SAE.  Clinical symptoms of progression may be reported as AEs if the 
symptom cannot be determined as exclusively due to the progression of the underlying 
malignancy or does not fit the expected pattern of progression for the disease under study. 
Symptomatic clinical deterioration may occur in some patients.  In this situation, progressive 
disease is evident in the patient’s clinical symptoms but is not supported by the tumor 
measurements; or, the progressive disease is so evident that the Investigator may elect not to 
perform further disease assessments.  In such cases, the determination of clinical progression 
is based on symptomatic deterioration.  These determinations should be a rare exception as 
every effort should be made to document the objective progression of underlying 
malignancy. 
If there is any uncertainty about an AE being due only to the disease under study, it should be 
reported as an AE or SAE. 


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6.2.1.8 
Pregnancy 
There are no clinical studies of trastuzumab or docetaxel in pregnant women; therefore, 
neither drug should be used during pregnancy.  In female patients of childbearing potential, 
or male patients with partners of childbearing potential, appropriate contraceptive measures 
are mandatory during study treatment (e.g. barrier method [condoms, diaphragm]; 
intrauterine devices; surgical methods, or abstinence).  Contraceptive measures are 
recommended for at least 7 months following the last dose of either trastuzumab or 
docetaxel. 
A female patient who becomes pregnant during the study must be withdrawn from study 
treatment.  The Investigator should report all pregnancies within 24 hours to the Sponsor or 
Quintiles.  The Investigator should counsel the patient and discuss the risks of continuing 
with the pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Pregnancies occurring up to 7 months after the 
completion of study medication must also be reported to the Investigator. 
It is not known whether trastuzumab or docetaxel is excreted in human milk.  Women should 
be advised to discontinue nursing during study treatment and not to breastfeed for at least 
7 months following the last dose. 
6.2.2 
Clinical Laboratory Evaluations 
All local laboratory sample collection and testing will be scheduled as indicated in Table 4-1.  
Additional assessments may be performed as clinically indicated.  Reference ranges for the 
local laboratory parameters must be supplied to the Sponsor or Quintiles before the study 
starts.   
Clinical laboratory tests will be reviewed for results of potential clinical significance at all 
time points throughout the study.  The Investigator will evaluate any change in laboratory 
values and assess severity using NCI-CTCAE v4.03.  Abnormal laboratory findings should 
not be reported as AEs unless they are associated with clinical signs and symptoms, lead to 
treatment discontinuation or are considered otherwise medically important by the 
Investigator.  If a laboratory abnormality fulfills these criteria, the identified medical 
condition (e.g. anemia, increased ALT) must be reported as the AE rather than the abnormal 
value itself. 
The following routine safety tests will be performed at a local laboratory: 
• 
Hematology (approximately 2 mL): hemoglobin, hematocrit, platelet count, red blood 
cell count, and white blood cell count with differential (neutrophils, lymphocytes, 


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monocytes, eosinophils, basophils and other cells).  Additional tests may be performed 
per the institution’s standard practice.  
• 
Blood chemistry (approximately 3 mL): sodium, potassium, bicarbonate/carbon dioxide 
combining power, chloride, blood urea nitrogen/urea, calcium, uric acid, total protein, 
albumin, ALK, ALT (SGPT), AST (SGOT), gamma-glutamyl transpeptidase, lactate 
dehydrogenase, total bilirubin, creatinine, and non-fasting or fasting blood glucose (if 
possible a fasting glucose should be done at baseline).  Additional tests may be 
performed per the institution’s standard practice.  
• 
Coagulation (approximately 2 mL): all patients will have INR and aPTT or PTT testing at 
baseline.  Patients on therapeutic doses of anti-coagulants should have INR and aPTT or 
PTT measurements repeated during the study, at least before the start of every treatment 
cycle, and when clinically indicated. 
• 
Pregnancy test: performed on women of childbearing potential via serum beta human 
chorionic gonadotropin at the beginning of the study (approximately 3 mL), before every 
third cycle, and at the Safety Follow-up Visit.  Pregnancy tests will also be done via a 
urine test during the Treatment Period and up to 6 months after the Safety Follow-up 
Visit (see Table 4-1).  If a urine test is positive, the pregnancy must be confirmed with a 
serum beta human chorionic gonadotropin test via the local laboratory. 
• 
Urinalysis: all patients will have a urinalysis panel for standard tests before each cycle 
(including red blood cells, glucose, ketones, leukocytes, nitrites, pH, and proteins).  For 
women of childbearing potential, a urine pregnancy test will be done before each cycle 
(when the serum test is not performed; see Table 4-1), then monthly for 6 months after 
the Safety Follow-up Visit.  If a urine test is positive, the pregnancy must be confirmed 
with a serum beta human chorionic gonadotropin test via the local laboratory. 
Laboratory assessments should be available prior to each administration of study drug for 
dose modification or delay requirements.  During the Treatment Period, these assessments 
must be performed within 3 days prior to the administration of study drug at each cycle. 
Screening blood samples: hepatitis B (HBcAb and HBsAg; if either is positive, HBV-DNA 
should be tested), hepatitis C (hepatitis C antibody and/or hepatitis C virus RNA should be 
tested), and HIV (approximately 6 mL), tested at a local laboratory. 
The procedures for collecting and, if required, the storage and shipping of sample material 
are provided in the Laboratory Manual.  


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6.2.3 
Vital Signs, Physical Findings and Other Safety Assessments 
All assessments will be recorded in the eCRF. 
6.2.3.1 
Vital Signs 
Vital signs will be measured in accordance with the schedule in Table 4-1 and will include 
sitting temperature, pulse, respiratory rate, and blood pressure. 
6.2.3.2 
Physical Examination 
A symptom-directed physical examination will be performed with particular attention to 
cardio-vascular signs and symptoms in accordance with the schedule in Table 4-1. 
Height and body weight will be measured at baseline.  Weight will also be measured on 
Day 1 of every treatment cycle for confirmation of body surface area calculation (calculated 
by IWRS/IVRS at each cycle). 
6.2.3.3 
Electrocardiogram 
A 12-lead ECG will be performed in accordance with the schedule in Table 4-1.  Tracings 
will be collected while the patient is in supine or semi-recumbent position after having rested 
for 5 minutes. 
6.2.3.4 
Cardiac function 
All patients must have their LVEF assessed by ECHO or MUGA in accordance with the 
Schedule of Events in Table 4-1.  The same method must be used throughout the study 
period (ECHO is preferred because it can detect wall-motion abnormalities). 
Calculations of LVEF are to be performed using the modified Simpson method or per local 
standard, and LVEF must be within normal range at baseline (within 42 days before 
randomization) as determined by the local facility before a patient can be enrolled in the 
study.  The lower limit of normal for the LVEF facility will be reported along with the LVEF 
result. 
6.3 
Pharmacokinetics 
In all patients, PK blood samples to determine serum trastuzumab concentrations (5 mL per 
sample) will be collected prior to infusion at Cycle 1 (at the time of blood sampling for 
assessment of hematology and baseline level of shed antigen), and starting at Cycle 3, prior 
to infusion, every 3 cycles (approximately every 9 weeks), at the same time as sample 
collections to assess for the presence of ADA/NADA while on treatment with HLX02 or 
Herceptin® (see also Section 6.4.1).  The schedule of blood sampling for PK assessments is 
summarized in Table 6-1. 


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Additional blood samples for the determination of trastuzumab in serum will be collected in 
all enrolled patients.  Compliance with PK sample collections, appropriate sample 
handling/processing/shipment as well recording of PK sampling information in the patients’ 
eCRF (see below) will be closely monitored.  The PK samples will be collected at the 
following time points: 
• 
Cycle 1, Day 1, at the end of infusion  
• 
Cycles 4 and 8, prior to infusion (at the time of blood sampling for assessment of 
hematology) 
• 
Cycle 8, Day 1, at the end of infusion 
In general, at the visits scheduled for assessment of clinical laboratories and PK, it is 
suggested that the samples be collected in the following order if possible: PK sample (then 
ADA/NADA sample if scheduled) then clinical laboratory samples.  
Note: For all cycles with predose PK collections, trough trastuzumab levels will be defined 
as the PK samples collected at the time of the laboratory tests within a maximum of 3 days 
prior to Day 1 of the next cycle.   
Note: The end-of-infusion samples on Day 1 of Cycles 1 and 8 must not be collected at the 
infusion site or from the same arm of the infusion site (e.g. if study drug is infused into the 
right arm, the PK sample must be collected from the left arm). 
The following information will be documented in the eCRF: administered dose of HLX02 or 
Herceptin®, start/stop date and time of HLX02 or Herceptin® infusion of last cycle (i.e. prior 
to the sample collected for trastuzumab level analysis); date and time of each blood sample 
collected for trastuzumab analysis; and start/stop date and time of HLX02 or Herceptin® 
infusion on visit day. 
Determination of concentrations of trastuzumab in serum will be performed by a 
Sponsor-contracted bioanalytical laboratory using validated analytical methods.  The 
procedures for collecting, handling, storing and, if required, shipping of samples are 
described in a separate Laboratory Manual. 


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Table 6-1 
Schedule of Blood Sampling for Pharmacokinetic and Immunogenicity 
Assessments 
Cycle/Day 
Visit Window 
(days) 
Sampling for 
PK assessments
Sampling for  
ADA/NADA 
assessments 
Shed Antigen 
Cycle 12  
-71 
Pre-infusion 
(5 mL) 
Pre-infusion 
(1.5 mL) 
Cycle 1, Day 13 
 
End of infusion 
(5 mL) 
- 
- 
Prior to Cycles 3, 6, 9, 12, and 
152 
-31 
Pre-infusion 
(5 mL) 
- 
Prior to Cycles 4 and 83 
(at the time of hematology 
sample collection) 
-31 
Pre-infusion 
(5 mL) 
- 
- 
Cycle 8, Day 13 
 
End of infusion 
(5 mL) 
- 
- 
Safety Follow-up 
(30 ±2 days) 
±24 
- 
X 
(5 mL) 
- 
ADA = anti-drug antibodies; NADA = neutralizing anti-drug antibodies; PK=pharmacokinetic. 
1. 
Prior to Cycle 1, samples for ADA/NADA, PK, clinical laboratory including hematology and shed antigen must be 
collected within 7 days before infusion.  For subsequent cycles, PK and ADA/NADA samples, as appropriate, 
must be collected within 3 days before infusion. 
2. 
PK and ADA/NADA time-matched samples while patients remain on treatment with HLX02 or Herceptin®: prior 
to infusion at Cycle 1, then starting at Cycle 3, prior to infusion every 3 cycles (approximately every 9 weeks). 
3. 
Extended PK samples: end of infusion at Cycle 1, prior to infusion at Cycles 4 and 8, and end of infusion at 
Cycle 8. 
4. 
The Safety Follow-up Visit will take place 30 (±2) days after last administration of docetaxel and/or after last 
administration of HLX02 or Herceptin®, whichever occurs last.  A blood sample to test for antibodies against 
trastuzumab (ADA/NADA) will also be collected at the Safety Follow-up Visit. 
Note: In general, at the visits scheduled for assessment of clinical laboratories and PK, it is suggested that the samples 
be collected in the following order if possible: PK sample (then ADA/NADA sample if scheduled) then clinical 
laboratory samples including hematology.  
6.4 
Other Assessments 
6.4.1 
Immunogenicity (Anti-drug Antibodies) 
Blood samples (5 mL per sample) for testing of the incidence and titer of ADA against 
trastuzumab and the incidence of any NADA will be collected in all patients during the study 
in accordance with Table 6-1.  A blood sample will be taken at the Safety Follow-up Visit to 
assess for the presence of ADA/NADA (along with blood sampling for routine laboratory 
tests). 
Samples will initially be screened for antibodies.  A confirmation assay will be used to 
confirm the positive status for samples which scored potentially positivity by the Screening 
assay.  In confirmed positive samples, the relative titer of the antibody will be determined as 
well as whether the confirmed positive sample represent a neutralizing antibody. 


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The samples will be submitted to a Sponsor-contracted bioanalytical laboratory and 
measured using validated assays. 
The procedures for collecting, handling, storing and, if required, shipping of ADA samples 
are described in a separate Laboratory Manual.  
6.4.2 
Tumor Samples (ER/PgR and HER2) at Screening 
To be included in the study, patients must have a FFPE tissue block from the primary tumor 
or a metastatic lesion to confirm HER2-positivity;11 if not available, a fresh biopsy sample 
will be collected.  While a previous local IHC test with a score of IHC 2+ or 3+ can be used 
as a Prescreening evaluation to determine if a patient might be suitable, this will not be 
sufficient for enrollment.  For a patient to be eligible, they must be HER2-positive as 
confirmed by the central laboratory using a FISH or IHC test, i.e. patients with a previous 
local IHC score of 2+ must be tested centrally by FISH and those patients with a previous 
local IHC score of 3+ must be confirmed centrally by IHC.  HER2-positive is defined as an 
amplification ratio ≥2.0 if using FISH or a score of 3+ if using IHC.  All results obtained 
from the central laboratory will be recorded in the eCRF. 
Tumor tissue samples will be submitted in the form of either paraffin blocks or unstained, 
freshly cut slides containing formalin-fixed tumor tissue.  Because uncontrolled oxidation 
processes on the slides may affect slides, tumor tissue blocks are preferred.  However, if a 
tumor block is not available, 7-13 (depending on the tests required; please refer to the 
laboratory manual for more information) unstained freshly cut slides of 4 μm will be 
submitted (the number of slides submitted may be reduced pending on the regulatory and or 
IEC requirements of some countries).  The slides must be sent to the central laboratory within 
2 weeks of being cut.  Slides sent to the central laboratory will not be returned to the 
institution from which they were sent. 
Patients will be stratified before randomization by their tumor’s hormonal status (ER and 
PgR), as determined by IHC either at a local or central laboratory.  Other stratification factors 
include prior neo-/adjuvant therapy with Herceptin® and ethnicity (Asian and non-Asian). 
The procedures for collecting, storage and shipping of sample material are provided in the 
Laboratory Manual.  
6.5 
Appropriateness of Measurements 
Efficacy assessments are standard and reliable for an oncology study.  The safety 
assessments are standard and relevant to the particular study drug and comparator being 
investigated.  


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7.0 QUALITY CONTROL AND QUALITY ASSURANCE 
According to the Guidelines of Good Clinical Practice (CPMP/ICH/135/95), the Sponsor is 
responsible for implementing and maintaining quality assurance and quality control systems 
with written Standard Operating Procedures (SOPs).   
Quality control will be applied to each stage of data handling.   
The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data: 
• 
Investigator meeting(s) 
• 
Central review of primary efficacy variable 
• 
Center Initiation Visit 
• 
Early center visits post-enrollment 
• 
Routine center monitoring 
• 
Ongoing center communication and training 
• 
Data management quality control checks 
• 
Continuous data acquisition and cleaning 
• 
Internal review of data 
• 
Quality control check of the final Clinical Study Report (CSR). 
In addition, Sponsor and/or Quintiles Clinical Quality Assurance Department may conduct 
periodic audits of the study processes, including, but not limited to study center, center visits, 
central laboratories, vendors, clinical database, and final CSR.  When audits are conducted, 
access must be authorized for all study related documents including medical history and 
concomitant medication documentation to authorized Sponsor’s representatives and 
Regulatory Agencies. 
7.1 
Monitoring 
The Sponsor has engaged the services of a contract research organization, Quintiles, to 
perform all monitoring functions within this clinical study.  Quintiles’ monitors will work in 
accordance with Quintiles’ SOPs and have the same rights and responsibilities as monitors 
from the Sponsor organization.  Monitors will establish and maintain regular contact between 
the Investigator and the Sponsor. 


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Monitors will evaluate the competence of each study center, informing the Sponsor about any 
problems relating to facilities, technical equipment or medical staff.  During the study, 
monitors will check that written informed consent has been obtained from all patients 
correctly and that data are recorded correctly and completely.  Monitors are also entitled to 
compare entries in eCRFs with corresponding source data and to inform the Investigator of 
any errors or omissions.  Monitors will also control adherence to the protocol at the study 
center.  They will arrange for the supply of investigational product and ensure appropriate 
storage conditions are maintained. 
Monitoring visits will be conducted according to all applicable regulatory requirements and 
standards.  Regular monitoring visits will be made to each center while patients are enrolled 
in the study.  The monitor will make written reports to the Sponsor on each occasion contact 
with the Investigator is made, regardless of whether it is by phone or in person. 
During monitoring visits, entries in the eCRFs will be compared with the original source 
documents (source data verification).  For the following items, this check will be 100%:  
• 
Patient identification number 
• 
Patient consent obtained 
• 
Patient eligibility criteria (inclusion and exclusion criteria) 
• 
Efficacy variables 
• 
Medical record of AE. 
For all other items, at least 70% of the data will be checked. 
7.2 
Data Management/Coding 
Data generated within this clinical study will be handled according to the relevant SOPs of 
the Data Management and Biostatistics departments of Quintiles.   
Electronic Data Capture will be used for this study, meaning that all eCRF data will be 
entered in electronic forms at the study center.  Data collection will be completed by 
authorized study center staff designated by the Investigator.  Appropriate training and 
security measures will be completed with the Investigator and all authorized study center 
staff prior to the study being initiated and any data being entered into the system for any 
study patients. 
All data must be entered in English.  The eCRFs should always reflect the latest observations 
on the patients participating in the study.  Therefore, the eCRFs are to be completed as soon 
as possible during or after the patient’s visit.  To avoid inter-observer variability, every effort 


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should be made to ensure that the same individual who made the initial baseline 
determinations completes all efficacy and safety evaluations.  The Investigator must verify 
that all data entries in the eCRFs are accurate and correct.  If some assessments are not done, 
or if certain information is not available or not applicable or unknown, the Investigator 
should indicate this in the eCRF.  The Investigator will be required to electronically sign off 
on the clinical data.   
The monitor will review the eCRFs and evaluate them for completeness and consistency.  
The eCRF will be compared with the source documents to ensure that there are no 
discrepancies between critical data.  All entries, corrections and alterations are to be made by 
the Principal Investigator or his/her designee.  The monitor cannot enter data in the eCRFs.  
Once clinical data of the eCRF have been submitted to the central server, corrections to the 
data fields will be audit trailed, meaning that the reason for change, the name of the person 
who performed the change, together with time and date will be logged.  Roles and rights of 
the site staff responsible for entering the clinical data into the eCRF will be determined in 
advance.  If additional corrections are needed, the responsible monitor or Data Manager will 
raise a query in the EDC application.  The appropriate study center staff will answer queries 
sent to the Investigator.  This will be audit trailed by the EDC application meaning that the 
name of investigational staff, time and date stamp are captured. 
The eCRF is essentially considered a data entry form and should not constitute the original 
(or source) medical records unless otherwise specified.  Source documents are all documents 
used by the Investigator or hospital that relate to the patient’s medical history, that verify the 
existence of the patient, the inclusion and exclusion criteria and all records covering the 
patient’s participation in the study.  They include laboratory notes, ECG results, memoranda, 
pharmacy dispensing records, patient files, etc. 
The Investigator is responsible for maintaining source documents.  These will be made 
available for inspection by the study monitor at each monitoring visit.  The Investigator must 
submit a completed eCRF for each patient who receives study medication, regardless of 
duration.  All supportive documentation submitted with the eCRF, such as laboratory or 
hospital records, should be clearly identified with the study and patient number.  Any 
personal information, including patient name, should be removed or rendered illegible to 
preserve individual confidentiality. 
Electronic case report form records will be automatically appended with the identification of 
the creator, by means of their unique UserID.  Specified records will be electronically signed 
by the Investigator to document his/her review of the data and acknowledgement that the data 
are accurate.  This will be facilitated by means of the Investigator’s unique UserID and 
password; date and time stamps will be added automatically at time of electronic signature.  


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If an entry on an eCRF requires change, the correction should be made in accordance with 
the relevant software procedures.  All changes will be fully recorded in a protected audit trail, 
and a reason for the change will be required. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA).  Concomitant medications will be coded using WHODRUG.  
7.3 
Quality Assurance Audit 
Study centers, the study database and study documentation may be subject to a Quality 
Assurance audit during the course of the study by the Sponsor or Quintiles on behalf of the 
Sponsor.  In addition, inspections may be conducted by regulatory bodies at their discretion.   


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8.0 STATISTICS 
8.1 
Determination of Sample Size 
The difference in rate of ORR (Herceptin® - control) and its two-sided 95% confidence 
interval (CI) was calculated by pooling the results of the subgroup of patients with 
HER2-positive tumors defined as FISH positive or IHC 2+ and 3+, from 2 published 
randomized studies comparing ORR following treatment with Herceptin® + paclitaxel or 
equivalent, versus paclitaxel or equivalent alone (Genentech, 2010, Table 9;12 Marty et al, 
2005,8 Table 2).  Using the Der Simonian-Laird14 estimate random effect model, the 
difference in ORR and its 95% CI was estimated to be 0.2493 [0.1579; 0.3407].  The metabin 
function of the meta library of the R language15 was used to implement this estimate.  An 
equivalence limit marginally tighter than the lower bound of this confidence interval is used 
as the criterion of equivalence: [-0.1350, 0.1350].  Given the published ORRs for ITT 
populations in Marty et al6 (61%), CLEOPATRA10 (69%), and HERITAGE16 (64%) trials, a 
conservative rate of 60% ORR24 was assumed for the ITT population.  A sample size of 
289 evaluable patients per arm was calculated to yield 84% power to show equivalence using 
the above equivalence limits [-0.1350, 0.1350] with the two-sided 95% CI for the difference 
in ORR24 HLX02-Herceptin® in the ITT population.  Assuming a 5% dropout rate, the 
number of patients required to be randomized is approximately 304 per arm.  Swain et al17 
have approximately 8% patients discontinuing who would be excluded from a PP population. 
Based on this, a 10% drop in patients is assumed in the PP population, compared to the ITT 
population, making a total of approximately 15% dropout in the PP population.  It is assumed 
that 3% of ITT patients with ORR fail to be included in the PP population (e.g. due to 
protocol deviations other than early discontinuation).  Under these assumptions the 
denominator for ORR will decrease by 10%, compared to that of the ITT population, but the 
number of ORRs will decrease by only 3%.  It is thus assumed there will be a higher rate of 
65% ORR24 in the PP population.  With these assumptions, 304 patients per arm will yield a 
sample size for the PP population of approximately 258 and the study will have 80% power 
to show equivalence in the PP population. 
A blinded sample size re-estimation procedure is planned after the primary efficacy data at 
Week 24 are available in the first 300 patients (see Section 8.9.1). 
8.2 
Statistical Methods 
Baseline characteristics of the patient sample will be described using summary statistics.  All 
estimates will be reported with standard deviation or 95% CI.  All analyses, summaries, and 
listings will be performed using SAS® software (9.4 or higher).  Full details of the statistical 
analysis methods will be provided in the Statistical Analysis Plan. 


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8.2.1 
Data for Analysis 
All details regarding the statistical analysis and the preparation of tables, listings and figures 
will be described in the Statistical Analysis Plan prepared by Quintiles and approved by the 
Sponsor before database lock.  The statistical analysis will be performed by Quintiles.   
8.2.2 
Analysis Populations 
Definitions for each analysis population include: 
• 
Safety population will comprise all patients who have received study drug once and have 
at least 1 safety assessment post-treatment. 
• 
Intent-to-treat (ITT) population will comprise all patients who were randomized. 
• 
Per-protocol (PP) population will comprise all patients who have at least 8 cycles of 
treatment and have at least 1 tumor measurement after treatment, or discontinued 
treatment early due to Investigator-assessed disease progression or excessive toxicity, and 
do not have major protocol deviations/violations. 
• 
Pharmacokinetic population will comprise all patients who received study drug and who 
have at least 1 measured concentration at a scheduled PK time point after the start of 
study drug without any protocol deviations or events which may affect the PK results.  
8.2.3 
Missing Data 
The Investigator will make all possible effort to ensure that most patients will undergo at 
least 1 tumor assessment during the first 8 cycles of treatment and patients are followed for 
survival until 12 months after randomization. 
For the primary efficacy analysis of the ITT population, patients who discontinued for any 
reason before a response was documented at least once will be counted as non-responders. 
For the PP efficacy analysis, patients for whom the efficacy endpoint is missing, i.e. patients 
without at least 1 valid post-treatment evaluation, are excluded from the PP Population, 
except those who are withdrawn due to toxicity, early progression or death, in which case the 
patients will be classified as non-responders.   
Sensitivity analyses to assess the robustness of conclusions to missing data will be carried out 
if there are more than 5% of patients missing evaluations in either treatment arm.  Sensitivity 
analyses will include an analysis that assumes that outcomes are missing at random.  Such an 
analysis is likely to be conservative in the context of assessing equivalence because under the 
missing-at-random assumption missing outcomes tend to reflect any differences between 
treatment groups found in the observed outcomes.  In addition, results of a pattern-mixture 


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model will be presented where, for patients discontinuing due to an AE, the probability of 
ORR is assumed to be reduced by some clinically-plausible constant (a “delta-adjustment”18).  
Further details of the method for dealing with missing data and of the implementation of the 
sensitivity analyses will be described in the Statistical Analysis Plan.  
8.3 
Patient Disposition 
The disposition summary will include all enrolled patients. 
8.4 
Patient Characteristics 
Patient characteristics will be summarized as described in the Statistical Analysis Plan. 
8.5 
Efficacy Analyses 
8.5.1 
Primary Analyses 
The primary endpoint is ORR24, calculated as the proportion of patients with a best response 
of CR or PR from first assessment up to Week 24 according to RECIST 1.1.  Equivalence 
will be concluded if the two-sided 95% CI of the difference in the 2 proportions is 
completely contained within the interval [-0.1350; 0.1350].  Two-sided 95% CIs for the 
difference between the 2 treatment arms in ORR24 will be presented, controlling for 
randomizing stratification factors using Mantel-Haenszel weights for the strata.   
The ITT population will be considered the primary population for the efficacy analyses.  
Repeat analyses using the PP population will explore robustness of results; the robustness to 
missing data of conclusions from the ITT analysis will be assessed via sensitivity analyses.  
8.5.2 
Secondary Analyses 
Overall objective response at Week 6, 12, 18, and 24 by CIR will be analyzed in a similar 
way to that of the primary endpoint to show the pattern of response.  
For time-to-event secondary endpoints (DoR, PFS up to 12 months and OS at 12, 24, and 
36 months), Kaplan-Meier estimates (product-limit estimates) will be presented by treatment 
arm together with a summary of associated statistics (i.e. the probability of being event-free) 
and corresponding two-sided 95% CIs.  The CIs for the survival function estimates at the 
time points defined above will be derived using the log-log transformation according to 
Kalbfleisch and Prentice.19  The estimate of the standard error will be computed using 
Greenwood’s formula.  A Cox model will be used to compare the hazard ratio (HR).  The 
point estimates and 95% CIs of the HR will be reported.  Binary secondary endpoints (DCR 
and CBR) will be analyzed in a similar way to that of the primary endpoint except that ratios 


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will be estimated, controlling for randomizing stratification factors through a log binomial 
model. 
8.5.3 
Subgroup Analyses 
Any subgroup analyses will be exploratory (post hoc) in nature.  The details of these 
analyses, if any, will be described in the Statistical Analysis Plan. 
8.6 
Safety 
All safety variables will be summarized using the safety population at the post-baseline 
evaluation during the Treatment Period.   
8.6.1 
Adverse Events 
Treatment-emergent adverse events are defined as AEs that first occurred or worsened in 
severity after the first administration of the study drug.  Adverse event summaries will 
include incidence of treatment-emergent AEs by MedDRA preferred term and system organ 
class, SAEs including deaths, AEs that led to study drug discontinuation, AESI, and AEs by 
maximum severity (graded according to NCI-CTCAE v4.03) and relationship to study drug.   
8.6.2 
Clinical Laboratory Evaluations 
Laboratory assessments will be presented as mean changes from baseline and incidence of 
abnormal values.  Shift tables will be presented for selected parameters. 
8.6.3 
Vital Signs Measurements, Physical Findings and Other Safety Evaluations 
Vital signs, LVEF and other safety evaluations will be summarized.  Shift tables will be 
presented for selected parameters.  
8.7 
Immunogenicity 
Immunogenicity results, including overall ADA results (Screening, confirmatory, and titers, 
as appropriate), NADA results, and the time course of antibodies (defined as the time to first 
post-dose observation of a positive ADA response) will be listed.  The number and percent of 
patients testing positive for ADA or NADA will be summarized by treatment over time.  If 
applicable, the time to interconversion of antibodies may be summarized by treatment using 
appropriate descriptive statistics. 
8.8 
Pharmacokinetic Analyses 
Trastuzumab concentrations in serum will be summarized descriptively by study population, 
treatment and scheduled collection time.  Exposure to trastuzumab will be further evaluated 


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with respect to specific disease characteristics such as baseline levels of shed antigen and 
correlated with tumor response and major safety findings. 
Additional PopPK modeling and/or correlation between trastuzumab exposure and response 
(safety, immunogenicity and/or efficacy) data may be evaluated separately, as appropriate.  If 
performed, a separate analysis plan will be prepared and results will be reported separately 
from the clinical study report. 
8.9 
Interim Analyses 
8.9.1 
Blinded Sample Size Re-estimation 
After 300 patients have been evaluated for response at Week 24, the pooled ORR24 will be 
calculated, and a blinded sample size re-estimation procedure will take place to ensure at 
least 80% power using the conditional power from the observed ORR difference and 
adjusting considering the actual dropout rate observed during this period.  The procedure will 
be overseen by a Data Monitoring Committee (DMC). 
Details on the procedure and the formulae to be used will be documented in the Statistical 
Analysis Plan. 
8.9.2 
Data Monitoring Committee 
A DMC will be established to oversee the blinded sample size re-estimation procedure; to 
review safety data at regular intervals in order to safeguard the interests of study participants; 
and to monitor the overall conduct of the study.  Responsibilities of the DMC will be fully 
documented in the DMC Charter. 
8.9.3 
Database Locks and Clinical Study Reports 
Once response assessment data at Week 24 are available for all patients, there will be a first 
database lock and the designated unblinded study team will conduct analyses on the primary 
efficacy data, as well as PK, safety/immunogenicity and survival data, up to Week 24, for 
submission of a CSR to the relevant Regulatory Agencies.  The results will only be shared 
with a small number of study members who are not involved in the direct running of the 
study itself.  All Investigators, site teams, and patients will remain blinded for the rest of the 
Treatment Period (up to 12 months after the last patient randomized), which is when the 
second database lock will occur.   
At the time of the second database lock, a separate CSR with all efficacy, PK, safety and 
survival data up to 12 months for all patients will be submitted to the relevant Regulatory 
Agencies.   


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The final database lock will occur 36 months after the last patient randomized in order to 
report final OS data to the relevant Regulatory Agencies. 
9.0 ETHICS 
9.1 
Institutional Review Board or Independent Ethics Committee 
An Ethics Committee should approve the final protocol, including the final version of the 
ICF and any other written information and/or materials to be provided to the patients.  The 
Investigator will provide the contract research organization, Quintiles (on behalf of the 
Sponsor), with documentation of IRB/IEC approval of the protocol and informed consent 
before the study may begin at the study center(s).  The Investigator should submit the written 
approval to Quintiles before enrollment of any patient into the study. 
The Sponsor should approve any modifications to the ICF that are needed to meet local 
requirements. 
The Investigator will supply documentation to Quintiles of required IRB/IEC’s annual 
renewal of the protocol, and any approvals of revisions to the informed consent document or 
amendments to the protocol. 
The Investigator will report promptly to the IRB/IEC, any new information that may 
adversely affect the safety of patients or the conduct of the study.  Similarly, the Investigator 
will submit written summaries of the study status to the IRB/IEC annually, or more 
frequently if requested by the IRB/IEC.  Upon completion of the study, the Investigator will 
provide the ethics committee with a brief report of the outcome of the study, if required. 
9.2 
Ethical Conduct of the Study 
This study will be conducted in compliance with the protocol, and the informed consent will 
be obtained according to the ethical principles stated in the Declaration of Helsinki, the 
applicable guidelines of ICH for GCP and the applicable drug and data protection laws and 
regulations of the countries where the study will be conducted. 
9.3 
Patient Information and Informed Consent 
The ICF will be used to explain the risks and benefits of study participation to the patient in 
simple terms before the patient will be entered into the study.  The ICF contains a statement 
that the consent is freely given, that the patient is aware of the risks and benefits of entering 
the study, and that the patient is free to withdraw from the study at any time.  Written consent 
must be given by the patient and/or legal representative, after the receipt of detailed 


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information on the study.  A signed copy of the informed consent and any additional patient 
information must be given to each patient or the patient’s legally accepted representative. 
The Investigator is responsible for ensuring that informed consent is obtained from each 
patient or legal representative and for obtaining the appropriate signatures and dates on the 
informed consent document prior to the performance of any protocol procedures and prior to 
the administration of study medication.  The Investigator will provide each patient with a 
copy of the signed and dated consent form.   
10.0 STUDY ADMINISTRATION 
10.1 ADMINISTRATIVE STRUCTURE 
Study monitoring, pharmacovigilance, data management, biostatistics and medical writing, 
and vendor management will be performed by the contract research organization, Quintiles.  
Cenduit will be responsible for randomization via IWRS/IVRS.  Medical monitoring will be 
shared by the Sponsor and Quintiles.  Drug supplies will be the responsibility of a third party 
vendor.  Both central and local laboratories will be used.  
10.2 Data Handling and Record Keeping 
It is the Investigator’s responsibility to maintain essential study documents (protocol and 
protocol amendments, completed eCRFs, signed ICFs, relevant correspondence, and all other 
supporting documentation).  The study site should plan on retaining such documents for 
approximately 15 years after study completion.  The study site should retain such documents 
until at least 2 years after the last approval of a marketing application in an ICH region and 
until there are no pending or contemplated marketing applications in an ICH region or at 
least 2 years after the formal discontinuation of clinical development of the investigational 
product.  These documents should be retained for a longer period if required by the 
applicable regulatory requirements or the hospital, institution, or private practice in which the 
study is being conducted.  Patient identification codes (patient names and corresponding 
study numbers) will be retained for this same period of time.  These documents may be 
transferred to another responsible party, acceptable to Sponsor, who agrees to abide by the 
retention policies.  Written notification of transfer must be submitted to Sponsor.  The 
Investigator must contact Sponsor prior to disposing of any study records.   
Any documents that would lead to a breaking of the blind must only be accessible to the 
designated unblinded team until the official unblinding occurs.  


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10.3 Direct Access to Source Data/Documents 
The Investigator will prepare and maintain adequate and accurate source documents to record 
all observations and other pertinent data for each patient randomized into the study.   
The Investigator will allow the Sponsor, Quintiles, and authorized Regulatory Agencies to 
have direct access to all documents pertaining to the study, including individual patient 
medical records, as appropriate. 
10.4 Investigator Information 
10.4.1 
Investigator Obligations 
This study will be conducted in accordance with the ICH-GCP; and European Legislation; 
and the ethical principles that have their origin in the Declaration of Helsinki.   
The Investigator agrees to conduct the clinical study in compliance with this protocol after 
the approval of the protocol by the IEC/IRB in compliance with local regulatory 
requirements.  The Investigator and the Sponsor will sign the protocol to confirm this 
agreement.  
10.4.2 
Protocol Signatures 
After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or representative (Appendix 1).  By signing the 
protocol, the Investigator confirms in writing that he/she has read, understands and will 
strictly adhere to the study protocol and will conduct the study in accordance with ICH-GCP 
and applicable regulatory requirements.  The study will not be able to start at any center 
where the Investigator has not signed the protocol.  
10.4.3 
Publication Policy 
The data generated by this study are confidential information of the Sponsor.  The Sponsor 
will make the results of the study publicly available.  The publication policy with respect to 
the Investigator and study center will be set forth in the Clinical Trial Agreement.  
10.5 Financing and Insurance 
Sponsor will provide insurance in accordance with local guidelines and requirements as a 
minimum for the patients participating in this study.  The terms of the insurance will be kept 
in the study files. 
 
 


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11.0 REFERENCES  
1  International Agency for Research on Cancer. Available from: URL 
http://globocan.iarc.fr/Pages/fact_sheets_population.aspx; Globocan 2012. Accessed 
2015 Nov. 
2  Contractor KB, Kaur K, Rodrigues GS, Kulkarni DM, Singhal H. Male breast cancer: is 
the scenario changing. World J Surg Oncol. 2008 Jun; 6:58. 
3  Speirs V, Shaaban AM. The rising incidence of male breast cancer. Breast Cancer Res 
Treat. 2009 May; 115(2):429-30. 
4  Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL et al. Human 
breast cancer: correlation of relapse and survival with amplification of the HER-2/neu 
oncogene. Science. 1987 Jan; 235(4785):177-82. 
5  Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE et al. Studies of the 
HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989 May; 
244(4905):707-12. 
6  Cooke T, Reeves J, Lanigan A, Stanton P. HER2 as a prognostic and predictive marker 
for breast cancer. Ann Oncol. 2001; 12(1):S23-8. 
7  Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A et al. Use of 
chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that 
overexpresses HER2. N Engl J Med. 2001 Mar; 344(11):783-92. 
8  Marty M, Cognetti F, Maraninchi D, Synder R, Mauriac L, Tubiana-Hulin M et al. 
Randomized Phase II trial of the efficacy and safety of trastuzumab combined with 
docetaxel in patients with human epidermal growth factor receptor 2–positive metastatic 
breast cancer administered as first-line treatment: the M77001 Study Group. J Clin 
Oncol. 2005 Jul; 23(19):4265-74. 
9  Herceptin Product Information. Available from: URL:  
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000278/WC500074922.pdf. Accessed 2016 May. 
10  Baselga J, Cortés J, Kim S-B, Im SA, Hegg R, Im YH et al. Pertuzumab plus trastuzumab 
plus docetaxel for metastatic breast cancer. N Engl J Med. 2012; 366:109-19. 
11  Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH et al. 
Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: 
American Society of Clinical Oncology/College of American Pathologists clinical 
practice guideline update. J Clin Oncol. 2013 Nov; 31(31):3997-4013. 
12 Genentech. Final labeling text, Herceptin; 2010.  Available from: URL 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/103792s5250lbl.pdf  
Accessed 2017 Mar. 
13  Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L et al. 2006 
update of recommendations for the use of white blood cell growth factors: an evidence-
 
 


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based clinical practice guideline. American Society of Clinical Oncology. J Clin Oncol. 
2006 Jul; 24(19):3187-205. 
14  Der Simonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 7 (3). 
1986:177–188. 
15  R Core Team. R: A language and environment for statistical computing. R Foundation for 
Statistical Computing. Vienna, Austria; 2012. 
16  Hope SR, Barve A, Waller CF, Hernandez-Bronchud M, Herson J, Yuan J et al. Heritage: 
A phase III safety and efficacy trial of the proposed trastuzumab biosimilar Myl-1401O 
versus Herceptin. J Clin Oncol. 2016; 34(suppl; abstr LBA503). 
17  Swain SM, Baselga J, Kim S-B, Ro J, Semiglazov V, Compone M et al. Pertuzumab, 
trastuzumab, and docetaxel in HER2-Positive Metastatic Breast Cancer. N Engl J Med. 
2015; 372:724-34. 
18  O’Kelly M and Ratitch B. Clinical trials with missing data: a guide for practitioners. John 
Wiley & Sons, Ltd. Chichester, United Kingdom; 2014. 
19  Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. John Wiley & 
Sons, Inc. New York, United States of America; 1980. 


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12.0 APPENDICES 
 


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APPENDIX 1:  SIGNATURE OF INVESTIGATOR 
PROTOCOL TITLE: 
Double-blind, Randomized, Multicenter, Phase III Clinical 
Study to Compare the Efficacy and to Evaluate the Safety and Immunogenicity of 
Trastuzumab Biosimilar HLX02 and EU-sourced Herceptin® in Previously Untreated 
HER2-Overexpressing Metastatic Breast Cancer 
PROTOCOL NO: 
HLX02-BC01 
This protocol is a confidential communication of Shanghai Henlius Biotech, Inc.   
I confirm that I have read this protocol, I understand it, and I will work according to this 
protocol.  I will also work consistently with the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with good clinical practices and the applicable 
laws and regulations.  Acceptance of this document constitutes my agreement that no 
unpublished information contained herein will be published or disclosed without prior written 
approval from Shanghai Henlius Biotech, Inc. 
Instructions to the Investigator:  Please SIGN and DATE this signature page.  PRINT your name, title, and the 
name of the center in which the study will be conducted.  Return the signed copy to Quintiles. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:      
__________________________         Date:  ____________ 
Printed Name:                                ___________________________ 
Investigator Title:                           ___________________________ 
 
Name/Address of Center:               ___________________________ 
 
___________________________ 
 
___________________________ 
 


Shanghai Henlius Biotech, Inc. 
 
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Protocol: HLX02-BC01 v5.0 
Drug Name: HLX02 
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Confidential 
APPENDIX 2:  NYHA 
When there is a reasonable uncertainty that the symptoms or signs are not of cardiac origin, the diagnosis should 
be No heart disease. 
Functional Capacity 
Objective Assessment 
Class I. Patients with cardiac disease but without resulting limitation of 
physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
A. No objective evidence of 
cardiovascular disease. 
Class II. Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain. 
B. Objective evidence of 
minimal cardiovascular 
disease. 
Class III. Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary activity 
causes fatigue, palpitation, dyspnea, or anginal pain. 
C. Objective evidence of 
moderately severe 
cardiovascular disease. 
Class IV. Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or the anginal 
syndrome may be present even at rest. If any physical activity is undertaken, 
discomfort is increased. 
D. Objective evidence of 
severe cardiovascular 
disease. 
 *The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the 
Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256. 
 
 


Shanghai Henlius Biotech, Inc. 
 
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Protocol: HLX02-BC01 v5.0 
Drug Name: HLX02 
17 JULY 2017 
Confidential 
APPENDIX 3:  ECOG PERFORMANCE STATUS 
Developed by the Eastern Cooperative Oncology Group, Robert L. Comis, MD, Group Chair* 
GRADE 
ECOG PERFORMANCE STATUS 
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 selfcare 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 
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982;5:649-655. 
 
 


Shanghai Henlius Biotech, Inc. 
 
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Protocol: HLX02-BC01 v5.0 
Drug Name: HLX02 
17 JULY 2017 
Confidential 
APPENDIX 4:  RECIST 1.1  
See attached guidelines. 
 
Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R et al. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 
2009; 45:228-247   
[internet:  http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf ]