A Phase III, Multi-Center, Randomized, Open-Label, Active-Controlled Study to Compare the Efficacy and Safety of F-627 and GRAN® in the Prophylactic Treatment for Chemotherapy-Induced Neutropenia
Phase: PHASE3
Conditions: Breast Cancer, Neutropenia
Sponsor: EVIVE Biotechnology

Protocol Number: SP11631
Version: 4.1; Version Date: Aug. 7, 2018 
Page 1
Clinical Study Protocol 
A Phase III, Multi-Center, Randomized, Open-Label, Active-Controlled Trial to Compare the 
Efficacy and Safety of Recombinant Human Granulocyte Colony Stimulating Factor-Fc Fusion 
Protein (F-627) and Recombinant Human Granulocyte Colony Stimulating Factor (GRAN®) in 
the Prophylactic Treatment for Chemotherapy-Induced Neutropenia 
Protocol Number: 
SP11631 
Investigational Drug: 
Recombinant human granulocyte colony stimulating factor-Fc fusion protein 
(F-627) 
Clinical Phase: 
Phase III 
Current Version No.: 
4.1 
Issue Date of Current Version: 
Aug. 7, 2018 
Original Version No./Issue Date: 
4.0/May 7, 2018 
Sponsor: 
Generon (Shanghai) Corporation Ltd. 
Confidential 
Statement of ownership: This protocol is the property of Generon (Shanghai) Corporation Ltd.  
and may not be distributed, copied, or published by any individual or entity without authorization. 
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Protocol Revision History 
Protocol Title: A Phase III, Multi-Center, Randomized, Open-Label, Active-Controlled Trial to 
Compare the Efficacy and Safety of Recombinant Human Granulocyte Colony Stimulating Factor-Fc 
Fusion Protein (F-627) and Recombinant Human Granulocyte Colony Stimulating Factor (GRAN®) in 
the Prophylactic Treatment for Chemotherapy-Induced Neutropenia 
Protocol Number: SP11631 
Protocol Revision History: 
Version Number 
Issue Date: 
2.0 
Mar. 2, 2017 
3.0 
Jun. 19, 2017 
Amendment I 
Oct. 31, 2017 
Amendment I (Combined Version) 
Oct. 31, 2017 
4.0 
May 7, 2018 
4.1 
Aug. 7, 2018 
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Synopsis 
Protocol Number 
SP11631 
Title 
A Phase III, Multi-Center, Randomized, Open-Label, Active-Controlled, Trial to Compare 
the Efficacy and Safety of Recombinant Human Granulocyte Colony Stimulating Factor-Fc 
Fusion Protein (F-627) and Recombinant Human Granulocyte Colony Stimulating Factor 
(GRAN®) in the Prophylactic Treatment for Chemotherapy-Induced Neutropenia 
Sponsor 
Generon (Shanghai) Corporation, Ltd. 
Clinical Phase 
Phase III 
Study Drug 
Investigational Drug: Recombinant human granulocyte colony stimulating factor-Fc fusion 
protein (F-627) 
Reference Drug: Recombinant Human Granulocyte Colony Stimulating Factor for Injection 
(GRAN®) 
Study Population 
Female patients with breast cancer will be enrolled to receive at least 4 cycles of EC 
chemotherapy, that is: epirubicin 100 mg/m2 and cyclophosphamide 600 mg/m2. 
Study Design 
A multi-center, randomized, open-label, active-controlled phase III clinical trial 
Number of Subjects 
240 
Primary Objective and 
Endpoints 
The primary objective of this study is to compare the efficacy of recombinant human 
granulocyte colony stimulating factor-Fc fusion protein (F-627) versus recombinant human 
granulocyte colony stimulating factor (GRAN®) in the first cycle of prophylactic therapy in 
patients with breast cancer receiving EC chemotherapy. The primary endpoint is defined as 
the duration (days) of grade 3 or 4 (moderate and severe) neutropenia, that is, the number of 
days in which ANC < 1.0 × 109/L in cycle 1. 
Secondary Objectives 
and Endpoints 
•
The incidence of grade 3 or 4 neutropenia (ANC < 1.0 × 109/L and ANC < 0.5 × 109/L,
respectively) in each cycle
•
The durations (days) of grade 3 or 4 neutropenia (ANC < 1.0 × 109/L and ANC < 0.5 ×
109/L, respectively) in cycles 2-4
•
The incidence and duration (days) of grade 4 neutropenia (ANC < 0.5 × 109/L) in each
cycle
•
The overall duration (days) of grade 3 or 4 neutropenia (ANC < 1.0 × 109/L and
ANC < 0.5 × 109/L, respectively) in overall 4 cycles
•
The incidence and duration (days) of grade 2 or above neutropenia (ANC < 1.5 × 109/L)
in each cycle
•
Incidence of febrile neutropenia (FN) (defined as ANC < 1.0×109/L; a single measurement
of body temperature > 38.3°C or a temperature ≥ 38.0 °C sustained over 1 h)
•
Profile of neutrophil count over time
•
The neutrophil count nadir from day 3 to day 13 of cycle 1
•
The time (days) of ANC nadir returns to 2.0 × 109/L in each cycle
Safety Objectives and 
Endpoints 
To compare the safety of F-627 and GRAN® by monitoring adverse events/serious adverse 
events, laboratory measurements, 12-lead ECG, abdominal ultrasound, physical examination, 
vital signs and symptoms. 
Exploratory Objectives 
and Endpoints 
To evaluate the potential immunogenicity of F-627 by testing anti-F-627 antibodies in serum. 
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Study Design 
This is a multi-center, randomized, open-label, and active-controlled phase III clinical trial 
with 240 enrollment of subjects with breast cancer to receive 4 cycles of EC chemotherapy, 
that is: epirubicin 100 mg/m2, i.v. + cyclophosphamide 600 mg/m2, i.v. on day 1, repeat cycle 
every 21 days for 4 cycles. After completing the evaluation for overall 4 cycles, subjects will 
receive subsequent treatments according to routine practice. The investigator must ensure that 
a recommended dose is given in cycle 1, delayed or reduced doses due to toxicities other 
than myelotoxicity (such as cardiotoxicity) in cycles 2-4 are permitted. 
Eligible subjects are randomized to F-627 or GRAN® in a 1:1 ratio before day 1 of cycle 1. 
Treatment allocations remained unchanged during the entire treatment period. Subjects will 
receive F-627 (20 mg/dose, s.c.) or GRAN® [5 μg/kg/day, s.c., once daily (± 4 h) up to 
2 weeks or until neutrophil count returns to 5.0 × 109/L] on day 3 of each cycle, i.e., 48 ± 4 h 
after the start of chemotherapy. During the trial, except for the blood routine test (neutrophil 
count) in the first cycle of treatment performed by the central laboratory, the other laboratory 
measurements are performed locally; adverse events/serious adverse events are collected, 
along with examinations such as laboratory measurements, 12-lead ECG and abdominal 
ultrasound. 
The last visit should be completed 3 weeks after the last chemotherapy dose. A follow-up 
visit by telephone should be completed 30 days after the last dose. 
Inclusion Criteria 
Patients satisfying all the following criteria can be included: 
1.
Willing to sign the informed consent form and able to comply with protocol requirements;
2.
18-75 years old;
3.
Female postoperative patients with breast cancer who require adjuvant chemotherapy, and
are planned to receive 4 cycles of EC chemotherapy, (epirubicin 100 mg/m2 +
cyclophosphamide 600 mg/m2);
4.
ECOG performance status ≤ 2;
5.
Absolute neutrophil count (ANC) ≥ 2.0 × 109/L, hemoglobin (Hb) ≥ 11.0 g/dL, and
platelet (PLT) ≥ 100 × 109/L prior to enrollment; 
6.
Hepatic and renal function: Total bilirubin ≤ 1.5 × ULN, ALT and AST ≤ 2.5 × ULN,
serum creatinine ≤ 1.5 × ULN;
7.
Left ventricular ejection fraction greater than 50%;
8.
Women without child-bearing potential, i.e., women who have had menopause for at least
1 year or who have undergone sterilization (bilateral tubal ligation, double oophorectomy
or hysterectomy); patients with child-bearing potential should agree to take appropriate
contraceptive measures, including condoms, spermicidal condoms, foams, gels,
contraceptive barrier, intrauterine devices (IUD), and contraceptives (oral or injection),
starting from 1 month before the start of the study until 30 days after the end of the study.
Exclusion Criteria 
Patients who meet any of the following criteria must be excluded from this study: 
1.
Radiation therapy within 4 weeks prior to enrollment;
2.
Breast cancer patients who have received neoadjuvant chemotherapy before surgery;
3.
Prior bone marrow or stem cell transplant;
4.
With other malignant tumors other than breast cancer;
5.
Patients who have received a treatment with recombinant human granulocyte stimulating
factor within 6 weeks prior to randomization; 
6.
Diagnosed with acute congestive heart failure, cardiomyopathy, or myocardial infarction
by clinical diagnosis, ECG or other approaches;
7.
With any disease that may cause splenomegaly;
8.
With acute infection, chronic active Hepatitis B within 1 year (unless patients tested
negative for HBsAg prior to enrollment), or Hepatitis C;
9.
Women in pregnancy or breastfeeding;
10. Known HIV positive or AIDS;
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11. With active tuberculosis (TB); history of TB exposure, unless negative for tuberculin test;
TB patients undergoing treatment; or suspected TB evaluated by chest x-ray;
12. With sickle cell anemia;
13. With alcohol or drug abuse that may affect the compliance with the study;
14. With known hypersensitivity to granulocyte colony stimulating factor or excipients;
15. Patients treated with other investigational products within 1 month or 5 half-lives of the
other investigational products prior to enrollment (whichever is longer);
16. Patients with diseases or symptoms unsuitable for participating in the trial. For example,
the study drugs may compromise the health of the patient or the assessment of adverse
events may be affected.
Criteria for 
Withdrawal 
Subjects have the right to withdraw from the study at any time without any reason. Subjects 
who withdraw from the study at any time will be required to complete the last evaluation and 
relevant examinations. 
1.
Subject withdraws voluntarily;
2.
Occurrence of uncontrolled grade 3 or 4 adverse events related to the study drug as judged
by the investigator; 
3.
Subjects fail to comply with the study protocol;
4.
Discontinuation by the investigator under safety considerations or in the best interest of
the subject when the subject's condition changes;
5.
Pregnancy;
6.
Death.
Dosing Regimen 
Chemotherapy Regimen 
All enrolled breast cancer patients are treated with at least 4 cycles of EC chemotherapy, 
namely: epirubicin 100 mg/m2, i.v. + cyclophosphamide 600 mg/m2, i.v. on day 1, repeat 
cycle every 21 days for 4 cycles. The investigator must ensure that a recommended dose is 
given in cycle 1, delayed or reduced doses due to toxicities other than myelotoxicity (such as 
cardiotoxicity) in cycles 2-4 are permitted. After 4 cycles of treatment and evaluation, 
subjects will receive subsequent treatment according to routine practice. 
Study Drug 
F-627 treatment arm: 20 mg/dose, one subcutaneous injection on day 3 of each cycle (48 ± 4 h
after the initiation of chemotherapy) for 4 cycles.
GRAN® treatment arm: 5μg/kg/day, one subcutaneous injection daily (± 4 h) starting from 
day 3 of each cycle (48 ± 4 h after the initiation of chemotherapy) for ≤ 2 weeks or until 
neutrophil count recovers from nadir to 5.0 × 109/L, for a total of 4 cycles. GRAN® can 
be discontinued by the investigators according to the ANC test results obtained from local 
laboratories. 
Treatment allocation will remain unchanged during the entire treatment period (4 cycles). 
Concomitant Therapy 
The following medications are prohibited during the study: recombinant human granulocyte 
colony stimulating factor (rhG-CSF) and recombinant human granulocyte-macrophage 
colony stimulating factor (rhGM-CSF); traditional Chinese medicines known clearly with 
neutropoiesis-inducing potential; lithium, which may contribute to the release of neutrophils; 
and prophylactic antibiotics. The investigator may choose appropriate treatment at their 
discretion. 
Randomization, 
Statistical Hypothesis, 
and Stratification 
Central randomization is performed using the Interactive Web-Response System (IWRS). 
Breast cancer patients who meet the inclusion criteria are randomized to 2 treatment arms 
(i.e., F-627 and GRAN® treatment arms) in a 1:1 ratio. 
Efficacy analyses will be based on the Intent-to-Treat (ITT) and Per-Protocol (PP) analysis 
sets. Safety analyses will be based on the Safety set. Non-inferiority analysis will be used for 
the primary efficacy analysis, with an equivalence margin of 1 day. 
There is no plan for interim analysis. 
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Abbreviations 
Abbreviations and Terms 
Definitions 
AE 
Adverse Event 
AKP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Transaminase 
AUC 
Area Under Concentration-Time Curve 
BSA 
Body Surface Area 
CFDA 
China Food and Drug Administration 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiography 
EC 
Name of Chemotherapy Regimen (Epirubicin + Cyclophosphamide) 
ECOG 
Eastern Cooperative Oncology Group (to determine Performance Status) 
FDA 
U.S. Food and Drug Administration 
IEC 
Independent Ethics Committee 
IRB 
Independent Review Board 
GCP 
Good Clinical Practice 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICF 
Informed Consent Form 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean Residence Time 
NCI 
National Cancer Institute 
NOEAL 
No-Observed-Adverse-Effect-Level 
RECIST 
Response Evaluation Criteria in Solid Tumors 
PD 
Progression of Disease 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
rhG-CSF 
Recombinant Human Granulocyte Colony Stimulating Factor 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis Plan 
TAC 
Name of Chemotherapy Regimen (Taxotere + Adriamycin + Cyclophosphamide) 
Tmax 
Time to Peak 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell Count 
WHO 
World Health Organization 
WHODD 
WHO Drug Dictionary 
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Table of Contents 
Synopsis .................................................................................................................................................. 15 
Abbreviations ........................................................................................................................................ 18 
Table of Contents .................................................................................................................................. 19 
List of Figures and Tables .................................................................................................................... 22 
1.0 
BACKGROUND AND PRINCIPLES ............................................................................... 23 
1.1 
Introduction to F-627 ......................................................................................................... 23 
1.1.1 Name, structure, and physicochemical properties ...................................................... 23 
1.1.2 Mechanism of action ................................................................................................... 23 
1.1.3 Preclinical pharmacokinetics study ............................................................................ 23 
1.1.4 Preclinical pharmacology study ................................................................................. 24 
1.1.5 Preclinical toxicology study ........................................................................................ 24 
1.1.6 Previous clinical studies ............................................................................................. 25 
1.2 
Principles ............................................................................................................................ 28 
2.0 
OBJECTIVES ...................................................................................................................... 30 
2.1 
Primary Objective .............................................................................................................. 30 
2.2 
Secondary Objectives ......................................................................................................... 30 
2.3 
Safety Objectives ............................................................................................................... 30 
2.4 
Exploratory Objectives ...................................................................................................... 30 
3.0 
STUDY DESIGN ................................................................................................................. 31 
3.1 
Overall Study Design and Treatment Plan ......................................................................... 31 
3.1.1 Principles of study design ........................................................................................... 32 
3.1.2 Principles of dose selection......................................................................................... 32 
3.1.3 Selection of comparator .............................................................................................. 33 
3.2 
Randomization ................................................................................................................... 34 
3.3 
Blinding .............................................................................................................................. 34 
3.4 
Study Sites and Number of Subjects .................................................................................. 34 
4.0 
STUDY POPULATION ...................................................................................................... 35 
4.1 
Study Population ................................................................................................................ 35 
4.2 
Inclusion Criteria................................................................................................................ 35 
4.3 
Exclusion Criteria .............................................................................................................. 35 
4.4 
Withdrawal ......................................................................................................................... 36 
4.4.1 Criteria for withdrawal ............................................................................................... 36 
4.4.2 Procedure for withdrawal ........................................................................................... 36 
4.4.3 Visits for withdrawals ................................................................................................. 36 
4.5 
Replacement Principle ....................................................................................................... 36 
4.5.1 Subject replacement .................................................................................................... 36 
5.0 
TRIAL PROCEDURE ........................................................................................................ 37 
5.1 
Schedule of Study Procedures and Evaluations ................................................................. 39 
5.1.1 Evaluations during screening ..................................................................................... 39 
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5.1.2 Enrollment of eligible patients .................................................................................... 39 
5.1.3 Evaluations during treatment ...................................................................................... 40 
5.1.4 Evaluations at end of study ......................................................................................... 41 
5.1.5 Unscheduled evaluations ............................................................................................ 41 
5.2 
Definitions and Evaluation Criteria of Study Endpoints ................................................... 42 
5.2.1 Efficacy evaluation ...................................................................................................... 42 
5.2.2 Safety evaluation ......................................................................................................... 42 
5.3 
Immunogenicity Evaluation ............................................................................................... 44 
6.0 
TREATMENT PLAN .......................................................................................................... 45 
6.1 
Study Drugs........................................................................................................................ 45 
6.1.1 Dose and mode of administration ............................................................................... 45 
6.1.2 Dosage form, packaging, labeling, and storage of study drugs ................................. 45 
6.1.3 Drug accountability .................................................................................................... 46 
6.2 
Chemotherapy .................................................................................................................... 46 
6.2.1 Dose and mode of administration of chemotherapy drugs ......................................... 46 
6.2.2 Principles of dose adjustment and management ......................................................... 46 
6.3 
Combined and Prohibited Medications .............................................................................. 47 
7.0 
SAFETY ................................................................................................................................ 48 
7.1 
Adverse Events (AEs) and Abnormal Values of Laboratory Measurements .................... 48 
7.1.1 Clinical AEs ................................................................................................................ 48 
7.1.2 Treatment and follow-up of AEs ................................................................................. 50 
7.1.3 Abnormal values of laboratory measurements ........................................................... 50 
7.2 
AE Management ................................................................................................................ 51 
7.2.1 AE reporting ................................................................................................................ 51 
7.2.2 SAE reporting (immediate) ......................................................................................... 51 
7.2.3 Special non-SAE reporting.......................................................................................... 51 
7.2.4 Pregnancy ................................................................................................................... 52 
8.0 
STATISTICAL ANALYSIS PLAN ................................................................................... 53 
8.1 
Statistical Analysis Plan ..................................................................................................... 53 
8.1.1 Sample size estimation ................................................................................................ 53 
8.1.2 Analysis sets ................................................................................................................ 53 
8.1.3 Statistical analysis methods ........................................................................................ 53 
8.1.4 Demographics and baseline characteristics ............................................................... 54 
8.1.5 Efficacy analysis ......................................................................................................... 54 
8.1.6 Safety analysis ............................................................................................................. 55 
8.1.7 Exploratory analysis of F-627 immunogenicity .......................................................... 55 
8.1.8 Interim analysis ........................................................................................................... 55 
8.1.9 Data quality assurance ............................................................................................... 56 
8.2 
Terminology ....................................................................................................................... 56 
9.0 
ETHICS ................................................................................................................................ 57 
9.1 
Local Regulations and Declaration of Helsinki ................................................................. 57 
9.2 
Informed Consent ............................................................................................................... 57 
9.3 
Privacy Protection .............................................................................................................. 57 
9.4 
Independent Ethics Committee/Review Board .................................................................. 57 
9.5 
Protocol Amendment ......................................................................................................... 58 
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10.0 
STUDY TERMINATION ................................................................................................... 59 
11.0 
RETENTION OF TRIAL DOCUMENTS, ELECTRONIC CASE REPORT FORMS 
(eCRFs), AND RECORDS ................................................................................................................... 60 
11.1 
Trial Documents and Document Retention ........................................................................ 60 
11.2 
Source Documents and Data .............................................................................................. 60 
11.3 
Electronic Case Report Forms (eCRFs) ............................................................................. 60 
12.0 
MONITORING AND AUDITING ..................................................................................... 62 
12.1 
Trial Monitoring and Verification of Source Data ............................................................. 62 
12.2 
On-Site Audits/Inspections ................................................................................................ 62 
13.0 
CONFIDENTIALITY AND USE OF TRIAL RESULTS ............................................... 63 
14.0 
REFERENCES .................................................................................................................... 64
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List of Figures and Tables 
Table 1. 
Comparison of PK parameters between F-627 and pegfilgrastim. ..................................... 24 
Table 2. 
Summary of F-627 preclinical safety evaluation tests. ...................................................... 25 
Table 3. 
Summary of F-627 clinical studies. .................................................................................... 26 
Table 4. 
Study flow diagram. ........................................................................................................... 32 
Table 5. 
Rationale for F-627 doses in clinical trials. ........................................................................ 33 
Table 6. 
Schedule of study procedures. ............................................................................................ 37 
Table 7. 
Laboratory measurements. ................................................................................................. 43 
Table 8. 
Criteria for immunogenicity of F-627. ............................................................................... 44 
Table 9. 
Dose and mode of administration. ...................................................................................... 45 
Table 10. 
F-627 product information. ................................................................................................ 45
Table 11. 
Dose and administration of chemotherapy drugs. .............................................................. 46 
Table 12. 
Grading of adverse events. ................................................................................................. 48 
Table 13. 
Criteria for causality evaluation. ........................................................................................ 49 
Table 14. 
Criteria for serious adverse events. .................................................................................... 49 
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1.0 
BACKGROUND AND PRINCIPLES 
1.1 
Introduction to F-627 
1.1.1 
Name, structure, and physicochemical properties 
F-627, a recombinant human granulocyte colony stimulating factor-Fc fusion protein (rhG-CSF-Fc),
is a biological product (category 1) with intellectual property rights developed by Generon (Shanghai)
Corporation Ltd. This rhG‐CSF‐Fc fusion protein is a rhG‐CSF dimer expressed in CHO cells and
based on the technology of Fc fusion protein, and has long-acting properties. The Fc fragment is derived
from human immunoglobulin. The half-life of IgG immunoglobulins can be up to 3 weeks in human blood.
In the construction of the G-CSF-Fc fusion protein, a peptide linker comprising 16 amino acids was 
added between G-CSF and IgG2-Fc, so as to keep the Fc domain of the fusion protein away from the G‐
CSFR binding site and improve its bioactivity. In addition, the peptide linker may keep one G-CSF away 
from another G-CSF domain, and produce an rhG-CSF-Fc in a dimeric form with 2 G-CSF molecules on 
a single Fc fusion protein. The rhG-CSF-Fc dimer may have a stronger receptor activation compared 
with an rhG-CSF monomer, and thereby the bioactivity of the fusion protein can be further improved. 
1.1.2 
Mechanism of action 
The human granulocyte colony stimulating factor receptor (G-CSF receptor, G-CSFR) is a specific, 
single-chain receptor with high affinity to G-CSF. The density of G-CSF receptors on the cell surface 
becomes higher as the neutrophils grow more mature. G-CSF: G-CSFR compound exists in a 2:2 ratio, 
i.e., 2 ligands bind to 2 receptors. Each G-CSF molecule binds to one receptor. Only when two receptors
binding to G-CSF ligands interact with each other to form a 2:2 dimer, the C-terminal of the G-CSF
receptor may activate the downstream signaling molecule, JAK2 (Janus tyrosine kinase 2). JAK2 then
initiates gene transcription by activating STAT3, resulting in cell proliferation. Theoretically, dimeric
ligands may activate downstream signaling pathways faster and stronger than monomeric ligands.
G-CSF receptors on neutrophils can not only transmit G-CSF signal, but also regulate the G-CSF
concentration in the blood. During an infection or a neutropenic period, G-CSF concentrations in the
blood will increase to stimulate the production of neutrophils. When absolute neutrophil count increases,
the binding of G-CSF in the blood also increases, thereby maintaining a relatively stable G-CSF
concentration in vivo.
In addition, a clinical study of rhG-CSF showed that hematopoietic precursor cells and hematopoietic 
stem cells in peripheral blood increased significantly after the injection of rhG-CSF. This process is 
known as peripheral blood precursor cell (PBPC) and/or peripheral blood stem cell (PBSC) mobilization. 
Many hematopoietic growth factors such as SCF, FL, GM-CSF, and IL-3, as well as reagents affecting 
bone marrow matrix proteins and adhesion molecules have the similar function of PBPC and/or PBSC 
mobilization. 
1.1.3 
Preclinical pharmacokinetics study 
Pharmacokinetic studies of F-627 in rats and cynomolgus monkeys showed that F-627 is a long-acting 
drug in vivo. F-627 demonstrated nonlinear pharmacokinetics. Increases in blood drug concentration and 
ANC (PD response) are dose-dependent. F-627 (100 μg/kg) adminstered to rats via subcutaneous injection 
showed T1/2 of 7.6 ± 1.3 hrs, Cmax of 162 ng/mL and AUC of 4217 ± 641 ng/mL·hr; pegfilgrastim 
(Neulasta, 100 μg/kg) administered to rats showed T1/2 of 7.1 hrs and AUC of 1600 ng/mL·hr (FDA IND). 
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In the cynomolgus monkey model with cyclophosphamide-induced neutropenia, we compared the PK 
parameters of F-627 and Pegfilgrastim at the equivalent dose after the first dose (as shown in Table 1). 
Results showed that the PK parameters of F-627 and pegfilgrastim at the equivalent dose were comparable. 
However, F-627 resulted in a faster neutrophil recovery compared with pegfilgrastim. 
Table 1. Comparison of PK parameters between F-627 and pegfilgrastim. 
Dose (60 µg/kg) 
Tmax (h) 
Cmax (ng/mL) 
AUC (ng/mL*hr) 
T½ (h) 
F-627 (Female)
8.0 
776±155 
21289±5744 
8.9 
F-627 (Male)
8.0 
566±162 
14515±7324 
11 
Pegfilgrastim (Female)
12.0 
482±88 
25571±474 
8.2 
Pegfilgrastim (Male)
8.0 
574±87 
21894±2616 
8.7 
Note: The table shows the PK data after the first dose in the cynomolgus monkey model with cyclophosphamide-induced 
neutropenia. 
1.1.4 
Preclinical pharmacology study 
In vitro bioactivity study of F-627 
The in vitro bioactivity study of F-627 showed that the ED50 of F-627 was 0.68 ng/mL (7.58 pM) in the 
proliferative response of M-NFS-60 cell line. The effect of F-627 on M-NFS-60 proliferation can be 
neutralized by anti-human G-CSF monoclonal antibodies. The activation of intracellular signaling 
pathways following G-CSF ligand-receptor binding was studied by detecting G-CSF-activated 
phosphorylated STAT3. Similar to filgrastim (Neupogen) and pegfilgrastim (Neulasta), F-627 can 
effectively activate phosphorylated STAT3 signaling and stimulate cell proliferation in M-NFS-60 cell 
line. 
In vivo pharmacodynamics study of F-627 
In vivo bioactivity study of F-627 showed that: a single subcutaneous injection of F-627 in normal mice, 
rats, and cynomolgus monkeys resulted in increases of peripheral blood white blood cell count (WBC) 
and absolute neutrophil count (ANC) in a dose-dependent manner. The minimum effective dose of F-627 
in rats was 3.0 μg/kg. A single subcutaneous injection of F-627 100μg/kg in mice showed that 
phosphorylated STAT3 levels in bone marrow cells increased 17-fold compared to baselines. Peak ANC 
in peripheral blood appeared at 48 hrs after the dose, and recovered to normal levels at 72 hrs. F-627 was 
significantly superior to Neulasta and rhG-CSF at the same molar dose of G-CSF in terms of ANC 
increase and duration. 
In the cyclophosphamide-induced neutropenic model of cynomolgus monkeys, F-627 not only shortened 
the recovery time of ANC, but also reduced the ANC decrease compared with filgrastim (rhG-CSF) and 
pegfilgrastim (Neulasta), thereby preventing severe neutropenia. F-627 demonstrated superior 
pharmacological effects over the same dose (60 µg/kg) of pegfilgrastim. 
1.1.5 
Preclinical toxicology study 
A systematic preclinical safety evaluation of F-627 has been conducted. Refer to Table 2 for the details of 
safety evaluation. 
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Table 2. Summary of F-627 preclinical safety evaluation tests. 
Animal 
Study Title 
Dose (µg/kg) 
Administration 
Observation 
Time 
NOAEL 
(µg/kg) 
Rat 
Acute toxicity study 
100,500,2500,7500 
Single 
2 weeks 
Rat 
Dose range finding toxicity 
study 
30,100,300,1500 
Repeat 
4 weeks 
Rat 
Repeat dosing toxicity study 
100,300,1000 
Repeat 
Administration: 
3 months 
Recovery 
period: 1 month 
1000 
Cynomolgus 
Monkey 
Acute toxicity study 
300,3000 
Single 
2 weeks 
Cynomolgus 
Monkey 
Repeat dosing toxicity study 
75,225,675 
Repeat 
Administration: 
3 months 
Recovery 
period: 1 month 
675 
Mouse 
Safety pharmacology study - 
spontaneous activity 
30,120,480 
Single 
10 minutes 
Mouse 
Safety pharmacology study - 
synergy of sodium 
pentobarbital hypnotic effect 
in mice 
30,120,480 
Single 
30 minutes 
Mouse 
Safety pharmacology study - 
hypnotic effect of sodium 
pentobarbital of subthreshold 
dose 
30,120,480 
Single 
30 minutes 
Rabbit 
Muscular irritation study 
400,1600 
Single 
48 hours, 
16 days 
Rabbit 
Vascular irritation study 
400,1600 
Single 
48 hours, 
16 days 
Guinea Pig 
Active anaphylaxis test 
Sensitization phase: 
100, 500; 
Challenge phase: 
sensitization dose × 2 
Sensitization: 
5 times, once 
every other 
day 
30 minutes, 
3 hours 
Rabbit 
RBC in vitro hemolysis test 
1000µg/mL 
In vitro 
incubation 
3 hours 
In the 3-month repeat dosing toxicity studies, the no-observed-adverse-event-level (NOAEL) of F-627 
was 1000 µg/kg in rats and 675 µg/kg in cynomolgus monkeys, which were the high dose selected in the 
dose design. 
1.1.6 
Previous clinical studies 
At present, a total of 7 clinical studies involving F-627 either have been completed or are ongoing, which 
include 2 phase I clinical trials in healthy subjects, 3 phase I clinical trials in patients with breast cancer, 
and 2 phase II clinical trials in patients with breast cancer. Refer to Table 3 for the summary of F-627 
clinical studies. Six of these clinical trials have been completed. One clinical trial has completed subject 
recruitment and follow-up, and is now in the process of data analysis. 
A total of 54 healthy subjects and 410 breast cancer patients have participated in the F-627 clinical trials 
sponsored by Generon (Shanghai) Corporation Ltd. The doses used in these trials ranged from 30 to 
360 µg/kg/dose, or were fixed doses of 10 and 20 mg/dose. The longest duration of treatment was 
6 cycles, with one subcutaneous injection per cycle. The chemotherapy regimens used for treating breast 
cancer patients include TAC (docetaxel + doxorubicin + cyclophosphamide), EC (epirubicin + 
cyclophosphamide), and TC (docetaxel + cyclophosphamide). 
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Table 3 Summary of F-627 clinical studies. 
Study No. 
(Status) 
Study 
Population/No. 
of Subjects 
Study Design 
Treatment Arm 
Study Period 
SP-CDR-1-1302 
(Completed) 
Randomized 
138 female 
patients with breast 
cancer 
Location: China 
A multi-center, 
randomized, 
open-label, 
active-controlled, 
dose-finding 
phase II clinical 
trial 
Chemotherapy regimen: EC 
F-627 10 mg/dose and 20 mg/dose,
administered subcutaneously on
day 3 after chemotherapy for 4
continuous cycles. Comparator
arm: GRAN® 5 µg/kg/day,
administered subcutaneously from 
day 3 after chemotherapy for
no longer than 2 weeks, for
4 continuous cycles
Jul. 3, 2014–Nov. 
22, 2015 
GC-627-02 
(Completed) 
Randomized 232 
patients with stage 
I-IV invasive
breast cancer
Location: U.S.,
Ukraine, and
Russia
A multi-center, 
randomized, 
open-label, 
active-controlled, 
dose-finding 
phase II clinical 
trial 
Chemotherapy regimen: TC or 
TAC F-627 80, 240, and 320 
µg/kg/dose, administered 
subcutaneously on day 2 after 
chemotherapy for 4 continuous 
cycles. Comparator arm: Neulasta 
(pegfilgrastim) 6 mg/day, 
administered subcutaneously on 
day 2 after chemotherapy for 
4 continuous cycles 
Aug. 10, 2012–
Oct. 24, 2014 
GC-F-627-01 
(Completed) 
30 healthy male 
subjects 
Location: Australia 
A single-center, 
open-label, 
single-dose, 
dose-escalation 
phase I clinical 
trial 
F-627 30, 60, 120, 240, and
320 µg/kg, administered
subcutaneously on day 1 of the
treatment period
May 25, 2010–
Nov. 18, 2010 
2012-F-627-CH1 
(Completed) 
Randomized 
18 female patients 
with breast cancer 
Location: China 
A single-center, 
open-label, single- 
and repeated-dose, 
dose-escalation 
phase I clinical 
trial 
Chemotherapy regimen: EC F-627 
80, 240, 320 µg/kg/dose, 
administered subcutaneously on 
day 3 after chemotherapy for 
4 continuous cycles 
Dec. 27, 2012–
Dec. 3, 2013 
SP-CDR-1-1301 
(Completed) 
Randomized 
15 female patients 
with breast cancer 
Location: China 
A multi-center, 
open-label phase 
Ib clinical trial 
Chemotherapy regimen: TAC 
F-627 240 and 320 µg/kg/dose,
administered subcutaneously on
day 3 after chemotherapy for
6 continuous cycles
Feb. 25, 2014–
Aug. 19, 2015 
SP11502 
(Study 
completed, 
currently 
undergoing data 
analysis) 
Randomized 
7 female patients 
with breast cancer 
Location: China 
A phase Ib 
clinical trial 
Chemotherapy regimen: TAC 
F-627 320 µg/kg/dose,
administered subcutaneously on
the same day following
chemotherapy (4 hrs within the
completion of chemotherapy) for
6 continuous cycles
Aug. 25, 2015–
Mar. 30, 2016 
GC-F-627-03 
(Completed) 
15 healthy male 
subjects 
Location: Australia 
A multi-center, 
randomized, 
open-label phase 
Ib clinical trial 
F-627 lyophilized powder or
pre-filled syringe, 20 mg/dose,
administered subcutaneously
on day 1 of the treatment period
Feb. 3, 2016–
Feb. 22, 2016 
EC = epirubicin + cyclophosphamide; TAC = Taxotere® [docetaxel] + doxorubicin + cyclophosphamide; TC = Taxotere® 
[docetaxel] + cyclophosphamide 
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Safety of F-627 
Generally, F-627 is safe and well tolerated. The incidence rate of serious adverse events (SAEs) is low 
with no report of death and significantly abnormal laboratory measurements. The most common SAE is 
febrile neutropenia. All SAEs are unrelated to the study drug except for 2 cases in the SP-CRD-1-1302 
trial. In this study, one case in the F-627 10 mg/dose arm and one case in the GRAN® arm were 
determined to be related to the study drug (causality with study drug was "cannot be determined" in both 
cases, which was classified as "related"). 
Two subjects withdrew from the study due to treatment-emergent adverse events (TEAEs). In the 
GC-627-02 study, one subject in the F-627 80 µg/kg/dose arm withdrew due to moderate uveitis, which 
was probably related to the study drug. In addition, in the SP-CDR-1-1302 study, one subject in the 
GRAN® arm withdrew due to fever. Causality with study drug could not be determined by the 
investigator. 
The most common drug-related TEAEs were back distress, osteodynia, pain in extremity, pain joint, and 
general malaise. These TEAEs are also commonly seen with other recombinant human granulocyte 
colony stimulating factors (rhG-CSFs). F-627 has a low incidence rate of injection site reactions 
compared with GRAN® and Neulasta® (PEGylated rhG-CSF), and a dose-response relationship was not 
observed. 
The incidence rate and severity of TEAEs of F-627 are similar with those of Neulasta® and GRAN®. 
In the SP-CDR-1-1302 study, F-627 had a lower incidence rate of TEAEs compared with GRAN®. 
The incidence rate and severity of TEAEs are similar across different doses of F-627. 
In the analysis of serum anti-F-627 antibodies, the incidence rate of positive result in binding assay was 
very low and the results of the following confirmatory assay were negative. Neutralizing antibodies were 
not detected. 
Abnormalities with clinical significance in ECGs were not observed. During the study, the incidence rate 
of cardiovascular events was low. 
In summary, the incidence rate of SAEs was low and unrelated to the study drug. There were only 
2 subjects who withdrew due to TEAEs. Abnormalities with clinical significance were not found in vital 
signs, laboratory measurements, and ECGs. F-627 has good safety and is similar with other marketed 
rhG-CSFs such as GRAN® and Neulasta. Significant immunogenicity was not observed for F-627. 
Efficacy of F-627 
SP-CDR-1-1302 is a randomized, open-label, active-controlled, dose-finding phase II clinical study 
which randomized 138 breast cancer patients to receive EC chemotherapy and F-627 10 mg/dose, F-627 
20 mg/dose, or GRAN® 5 µg/kg/dose (up to 2 weeks or when ANC recovers to 5.0 × 109/L from nadir) 
24 hours (day 3) after chemotherapy for 4 continuous cycles. 
The primary endpoint is the duration (days) of grade 3 or 4 neutropenia in cycle 1, that is, the number of 
days in which ANC < 1.0 × 109/L. Non-inferiority was established when comparing F-627 10 mg/dose 
and F-627 20 mg/dose with GRAN®. No significant differences were observed between F-627 20 
mg/dose arm, F-627 10 mg/dose arm, and GRAN® arm in the incidence rate and duration of neutropenia, 
ANC nadir, as well as the time of ANC recovered to 2.0 × 109/L from nadir. F-627 20 mg/dose was 
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slightly superior to F-627 10 mg/dose, supporting the use of F-627 20 mg/dose as the recommended 
dose for phase III clinical trials. The ANC-time profile was similar between F-627 10 mg/dose and 
20 mg/dose, and GRAN®. Febrile neutropenia was not observed in overall 4 cycles. 
In addition, a randomized, open-label, active-controlled, dose-finding phase II clinical study (GC-627-02) 
recruited 232 patients with stage I-IV breast cancer in Europe and in the United States. These patients 
were treated with either TC or TAC chemotherapy. The primary endpoint was duration of grade 3 or 
4 neutropenia. Non-inferiority was established when comparing 3 dose levels of F-627 (80, 240, and 
320 µg/kg) with Neulasta. There were no significant differences between F-627 240 and 320 µg/kg 
and Neulasta in the incidence rate and duration of neutropenia, ANC nadir, as well as the time of ANC 
recovered to 2.0 × 109/L from nadir. 
Pharmacokinetics/pharmacodynamics (PK/PD) of F-627 
Five studies evaluated the PK/PD of F-627, of which 2 involved healthy subjects and 3 involved female 
subjects with breast cancers. 
GC-F-627-01: This study evaluated the safety and PK/PD of 5 dose levels of F-627 in healthy males 
(30, 60, 120, 240, and 360 µg/kg). Results suggested that F-627 demonstrated nonlinear PK. Cmax and 
T1/2 increased with the increasing dose. Tmax and AUC(0-inf) increased with the increasing dose from 
30 to 240 µg/kg, but leveled off at the dose of above 240 µg/kg. Mean T1/2 was between 43.9–71.4 hrs. 
Clearance (CL) decreased with the increasing dose but leveled off at 240 and 360 µg/kg, suggesting that 
clearance peaked at high concentrations of F-627. 
The study also found dose-dependent increases in leukocytes, neutrophils and CD34+, which peaked at 
36–96 hrs after dose administration. Tmax was delayed to 96–120 hrs for high-dose F-627. 
2012-F-627-CH1: This study evaluated the PK of F-627 80, 240, and 320 µg/kg given on day 3 
(48 hrs) after chemotherapy for 4 continuous cycles in breast cancer patients receiving epirubicin/ 
cyclophosphamide (EC) chemotherapy. In cycles 1 and 3, Cmax and AUC increased with the increasing 
dose, with the increases higher in cycle 1 than in cycle 3. In cycle 1, Cmax in cycle 1 leveled off between 
240–320 µg/kg; clearance decreased with the increasing dose and leveled off between 240–320 µg/kg. 
In cycle 3, AUC showed a dose-dependent increase between 240–320 µg/kg. Mean T1/2 was 34–56 hrs. 
SP-CDR-1-1301: This study evaluated the PK of F-627 (7 subjects in the 240 µg/kg arm and 8 subjects in 
the 320 µg/kg arm) in breast cancer patients receiving docetaxel/doxorubicin/cyclophosphamide (TAC) 
chemotherapy in cycles 1 and 3. F-627 was administered subcutaneously on day 2 (24 hrs) after 
chemotherapy for 6 continuous cycles. In cycles 1 and 3, Cmax and AUC increased in a dose-dependent 
manner, with the increases higher in cycle 1 than in cycle 3. Mean T1/2 was 26–33 hrs. 
In these two studies, pharmacodynamics endpoints such as the shortening of the duration of neutropenia, 
the increase of ANC nadir, and the shortening of the time ANC recovered to normal from nadir, were 
dose-dependent. 
1.2 
Principles 
Cancer is a threat to human health with an increasing incidence rate. Cytotoxic chemotherapeutic agents 
are still the major therapy for cancer. Myelosuppression is one of the most common toxicities in 
chemotherapy. The inhibition of granulocytes, such as neutropenia, is a primary concern by clinical 
physician. Neutropenia not only increases the risk of infections and death in cancer patients, but also has 
detrimental effects on quality life of patients. Neutropenia is also the main factor leading to 
chemotherapy delay or dose reduction. The treatment of neutropenia is still an unmet clinical need. 
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Recombinant human granulocyte colony stimulating factor (rhG-CSF) has been in use for approximately 
25 years. Filgrastim (Neupogen) and Lenograstim have a half-life of only 3 hours and thus require daily 
administration. The average cycle is 11 days before ANC returns to normal levels. PEGylated rhG-CSF 
(Pegfilgrastim, Neulasta) has a half-life of 30–80 hours and requires just one administration for each 
chemotherapy cycle. Clinically, G-CSF can be used as primary prophylaxis (starting from cycle 1 until 
the chemotherapy treatment is completed) or secondary prophylaxis (in the following cycles if severe 
neutropenia or FN occurs after chemotherapy). The European Organization for Research and Treatment 
of Cancer (EORTC), American Society of Clinical Oncology (ASCO), and National Comprehensive 
Cancer Network (NCCN) all recommend to use G-CSF as prophylaxis in chemotherapy regimens if the 
incidence rate of FN ≥ 20%, or if the incidence rate of FN is 10–20% and chemotherapy is considered to 
be a risk factor. 
Among the adjuvant chemotherapy regimens recommended by the NCCN 2014 guideline for breast 
cancer, preferred regimens include docetaxel + doxorubicin + cyclophosphamide (TAC), dose-dense 
doxorubicin + cyclophosphamide (AC) → dose-dense paclitaxel (P), doxorubicin + cyclophosphamide 
(AC) → paclitaxel/docetaxel (P/T), epirubicin + cyclophosphamide (EC) → paclitaxel/docetaxel (P/T), 
docetaxel + cyclophosphamide (TC), epirubicin + cyclophosphamide (EC), and doxorubicin + 
cyclophosphamide (AC)2. Common regimens used in China are AC/EC→P or AC/EC→T for they have 
milder myelotoxicity compared with TAC/TEC or TA/TE regimens; TC is also one of the common 
chemotherapy regimens. A large phase III clinical trial showed that 61% of patients developed grade 3-4 
neutropenia and 5% developed febrile neutropenia when receiving the TC regimen, while 55% of 
patients developed grade 3-4 neutropenia and 2.5% developed febrile neutropenia (FN) when receiving 
the AC regimen3, 4. In another phase III clinical trial, the incidence rates of grade 3-4 neutropenia were 54% 
with EC regimen (E:120 mg/m2+C:600 mg/m2) and 64% with sequential D (docetaxel) followed by EC; 
the incidence rates of FN were 2.8% and 6.6% for EC regimen and sequential D (docetaxel) followed by 
EC respectively. 8Also, a phase III clinical trial comparing EC regimen (E:90 mg/m2 + C:600 mg/m2) and 
ED regimen (E:120 mg/m2 + D:75 mg/m2) found that the incidence rates of leukopenia were 74% and 
81%, respectively and the incidence rates of infections (including FN) were 6.3% and 7.2%, respectively. 
Chemotherapy regimens with high-dose epirubicin require supportive care with G-CSF.9. 
The study population for this trial is breast cancer patients receiving EC chemotherapy. Data show that 
the incidence rate of FN in EC chemotherapy regimen is between 10–20%. 
F-627 (recombinant human granulocyte colony stimulating factor-Fc fusion protein, rhG-CSF-Fc),
a rhG-CSF dimer, is a biological product developed by Generon (Shanghai) Corporation Ltd. PK/PD
studies in breast cancer patients showed that median T1/2 of F-627 was 34.7–56.4 hours after a single
dose for each cycle. A phase II clinical trial confirmed that F-627 is non-inferior to standard doses of
pegfilgrastim (Neulasta) or filgrastim (GRAN®) when used as prophylactic treatment for
chemotherapy-induced neutropenia. The main adverse reactions were osteodynia, pain joint, pain in
extremity, and injection site rash, similar to the side effects of rhG-CSF. F-627 had lower incidence rates
of osteodynia, pain joint, and pain in extremity compared with GRAN®. This confirmatory phase III
clinical trial will be carried out with a larger sample size, with breast cancer patients receiving EC
chemotherapy as the study population. This study will compare the efficacy and safety of F-627
pre-filled syringes (20 mg) with GRAN® to support the grant of marketing approval of F-627 in China.
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2.0 
OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to compare the efficacy of recombinant human granulocyte colony 
stimulating factor-Fc fusion protein (F-627) versus recombinant human granulocyte colony stimulating 
factor (GRAN®) in the first cycle of prophylactic treatment in subjects with breast cancer receiving 
chemotherapy. The primary endpoint is the duration (days) of grade 3 or 4 (moderate and severe) 
neutropenia in cycle 1, that is, the number of days in which ANC < 1.0 × 109/L in cycle 1. 
2.2 
Secondary Objectives 
•
The incidence rate of grade 3 or 4 neutropenia (ANC < 1.0 × 109/L and < 0.5 × 109/L, respectively)
in each cycle
•
The duration (days) of grade 3 or 4 neutropenia (ANC < 1.0 × 109/L and < 0.5 × 109/L, respectively)
in cycles 2–4
•
The incidence rate and duration (days) of grade 4 neutropenia (ANC < 0.5 × 109/L) in each cycle
•
The overall duration (days) of grade 3 or 4 neutropenia (ANC < 1.0 × 109/L and < 0.5 × 109/L,
respectively) in overall 4 cycles
•
The incidence rate and duration (days) of grade 2 or greater neutropenia (ANC < 1.5 × 109/L) in
each cycle
•
Incidence rate of febrile neutropenia (FN) (defined as ANC < 1.0×109/L; a single measurement of
body temperature > 38.3 °C or a temperature ≥ 38.0 °C sustained over 1 hr)
•
ANC-time profile
•
The ANC nadir from day 3 to day 13 of cycle 1
•
The time (days) of ANC nadir recovers to 2.0 × 109/L in each cycle
2.3 
Safety Objectives 
To evaluate the safety of F-627 and GRAN®. Safety endpoints include adverse events and serious 
adverse events, laboratory measurements, physical examinations, vital signs, and symptoms. 
2.4 
Exploratory Objectives 
To evaluate the immunogenic potential of F-627 by testing serum anti-F-627 antibodies. 
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3.0 
STUDY DESIGN 
3.1 
Overall Study Design and Treatment Plan 
This is a multi-center, randomized, open-label, active-controlled phase Ⅲ clinical trial. A total of 
240 postoperative subjects with breast cancer will be enrolled to receive at least 4 cycles of EC 
chemotherapy, namely: epirubicin 100 mg/m2 + cyclophosphamide 600 mg/m2, i.v. on day 1, repeat 
cycle every 21 days for 4 cycles. After completing the evaluation for the first 4 cycles, subjects will 
receive subsequent treatments according to routine clinical practice. The investigator must ensure that 
the first cycle of treatment follows the recommended dosages for chemotherapy. In cycles 2–4, dose 
delays and reductions due to toxicities other than myelotoxicity (such as cardiotoxicity) are permitted. 
Dosages are permitted to be individualized based on subject conditions. 
As shown in the flow diagram in Table 4, patients are randomized before day 1 of the cycle 1 to F-627 
arm or GRAN® arm in a 1:1 ratio. Treatment allocation will remain unchanged during the entire 
treatment period (4 cycles). On day 3 of each cycle, that is, 48±4 hours after the start of chemotherapy, 
subjects will receive F-627 (20 mg/dose, s.c.) or GRAN® (5 µg/kg/day, s.c., once daily [±4 hrs] for 
≤ 2 weeks or until ANC recovers to 5.0 × 109/L from nadir [investigators may refer to ANC results 
from respective study sites to decide when to discontinue GRAN®]). All laboratory measurements are 
performed at individual study sites except for the routine blood test (neutrophil count) in cycle 1, which is 
performed at the central laboratory. Adverse events/serious adverse events are recorded, along with 
laboratory measurements, 12-lead ECGs and abdominal ultrasounds. 
The last visit will be completed 3 weeks after the last chemotherapy dose. A follow-up visit by telephone 
will be completed 30 days after the last dose. 
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Table 4. Study flow diagram. 
3.1.1 
Principles of study design 
This is a multi-center, randomized, open-label, active-controlled phase III clinical trial. Randomization 
and the utilization of comparator conform to the standard methods. 
3.1.2 
Principles of dose selection 
Selection of Chemotherapy Dose 
Standard doses of EC chemotherapy will be used: epirubicin [Pharmorubicin®] 100 mg/m2, i.v. + 
cyclophosphamide 600 mg/m2, i.v. on day 1, repeat cycle every 21 days for 4 cycles. 
Dose Selection of Investigational Drug 
Results from 3-month repeat dosing toxicity studies showed that the no-observed-adverse-effect-level 
(NOAEL) of F-627 was 1000 µg/kg in rats and 675 µg/kg in cynomolgus monkeys. 
Patients with breast cancer 
[epirubicin + cyclophosphamide]
Day 1 of cycle 1 
Randomized to F-627 or GRAN®  
arm [1:1 ratio]
Day 1 of cycles 1–4 
Chemotherapy
Day 1 of cycles 1–4 
Chemotherapy
Day 3 of cycles 1–4 F-627 
20 mg s.c.
Day 3 of cycles 1–4 GRAN® 
5 µg/kg/day qd s.c. 
(≤2 weeks, or discontinue 
when ANC recovers to  
5.0 × 109/L from nadir)
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Table 5. Rationale for F-627 doses in clinical trials. 
Pegfilgrastim 
F-627
Repeat Dosing Toxicity Study in Rats 
100, 300, and 1000 µg/kg, once a week 
for 3/6 months 
100, 300, and 1000 µg/kg, once a 
week for 3 months, followed by a 
recovery period of 1 month 
NOAEL in Rats 
1000 µg/kg 
1000 µg/kg 
Repeat Dosing Toxicity Study in 
Monkeys 
75, 250, and 750 µg/kg, once a week for 
1 month, followed by a recovery period 
of 1 month 
75, 225, and 675 µg/kg, once a week 
for 3 months, followed by a recovery 
period of 1 month 
NOAEL in Monkeys 
750 µg/kg 
675 µg/kg 
Phase I Clinical Trial in Healthy 
Volunteers 
30, 60, 100, 300 µg/kg 
30, 60, 120, 240, 360 µg/kg 
Phase I Clinical Trial in Subjects with 
Breast Cancer 
60,100,300 µg/kg 
80,240,320 µg/kg 
Recommended Dose for Clinical 
Trials 
6 mg/dose 
20 mg/dose 
A total of 54 healthy subjects and 410 breast cancer patients have participated in F-627 clinical trials. 
The doses used in these trials ranged from 30-360 µg/kg/dose, or were fixed doses of 10 and 20 mg/dose 
(Refer to Table 5 for rationale for F-627 doses in clinical trials). Overall, the incidence rates of serious 
adverse events (SAEs) were low and unrelated to the study drug. Only 2 subjects withdrew due to TEAEs. 
F-627 has good safety. The most common drug-related TEAEs were back distress, osteodynia, pain in
extremity, pain joint, and general malaise. These TEAEs are also commonly seen with other marketed
recombinant human granulocyte colony stimulating factors (rhG-CSFs) such as GRAN® and Neulasta. In
the SP-CDR-1-1302 study, F-627 had a lower incidence rate of TEAEs compared with GRAN®.
Data from 138 patients with breast cancer were analyzed in a phase II clinical trial (SP-CDR-1-1302). 
Results indicated that non-inferiority was established when comparing F-627 10 mg/dose and 20 mg/dose 
with GRAN® in terms of the primary endpoint, or, the duration of grade 3–4 neutropenia in cycle 1. 
No significant differences were observed between F-627 10 mg/dose, 20 mg/dose and GRAN® in the 
incidence rate and duration of neutropenia, ANC nadir, as well as the time of ANC recovered to 2.0 × 
109/L from nadir. In addition, a phase II clinical study (GC-627-02) recruited 232 patients with stage I-IV 
breast cancer in Europe and in the United States. These patients were treated with either TC or TAC 
chemotherapy. Non-inferiority was established when comparing 3 dose levels of F-627 (80, 240, and 
320 µg/kg) with Neulasta in terms of the primary endpoint. There were no significant differences 
between F-627 240 and 320 µg/kg and Neulasta in the incidence rate and duration of neutropenia, 
ANC nadir, as well as the time of ANC recovered to 2.0 × 109/L from nadir. 
Moreover, PK/PD showed good correlation. Cmax and AUC0-inf increased in a dose-dependent manner 
and pharmacodynamics indicators also improved. Thus, F-627 20 mg is used for this phase III clinical 
trial. 
3.1.3 
Selection of comparator 
rhG-CSF has been used clinically for almost 20 years. There are multiple rhG-CSF products of different 
manufacturers approved in China, including originator products and biosimilars, of which 2 are PEGylated 
rhG-CSF biosimilars. GRAN® (manufactured by Kyowa Hakko Kirin China Pharmaceutical Co., Ltd.) has 
been selected as the comparator for this phase III clinical trial due to the reliability and stable quality of this 
originator product.  
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Dose Selection of Comparator 
According to the product labeling, GRAN® is recommended to be given at a dose of 5 µg/kg, once a day 
from day 3 of each cycle, for ≤ 2 weeks or until ANC recovers to 5.0 × 109/L. 
3.2 
Randomization 
After signing the informed consent form, subjects will be assigned a unique subject number in sequential 
order. The investigator should document the subject number in the electronic case report form (eCRF), 
original medical records, and study documents. Central randomization is performed in this study using 
the Interactive Web-Response System (IWRS). After eligible patients provide a signed informed consent 
form, authorized investigators will log in to the IWRS system and key in relevant information. The 
system will then randomize subjects to 2 different arms, F-627 or GRAN®. 
3.3 
Blinding 
No blinding is applied in this study. 
3.4 
Study Sites and Number of Subjects 
This is a multi-center clinical trial. Approximately 20 sites will participate in this study. 
This study plans to recruit 240 patients with breast cancer and randomize them to F-627 or GRAN® arm 
at a 1:1 ratio. 
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4.0 
STUDY POPULATION 
4.1 
Study Population 
The study population is patients with breast cancer who plan on receiving at least 4 cycles of EC 
chemotherapy. 
4.2 
Inclusion Criteria 
All of the following criteria must be met for a subject to be enrolled: 
1.
Willing to sign the informed consent form and able to comply with protocol requirements;
2.
18–75 years old;
3.
Female postoperative patients with breast cancer who require adjuvant chemotherapy, and are
planned to receive at least 4 cycles of EC chemotherapy, namely epirubicin 100 mg/m2 +
cyclophosphamide 600 mg/m2;
4.
ECOG performance status ≤ 2;
5.
Absolute neutrophil count (ANC) ≥ 2.0 × 109/L, hemoglobin (Hb) ≥ 11.0 g/dL, and platelet (PLT)
≥ 100 × 109/L prior to enrollment;
6.
Hepatic and renal functions: Total bilirubin ≤ 1.5 × ULN, ALT and AST ≤ 2.5 × ULN, serum
creatinine ≤ 1.5 × ULN;
7.
Left ventricular ejection fraction > 50%;
8.
Women without child-bearing potential, i.e., women who have had menopause for at least 1 year or
who have undergone sterilization (bilateral tubal ligation, double oophorectomy or hysterectomy);
patients with child-bearing potential should agree to take appropriate contraceptive measures,
including condoms, spermicidal condoms, foams, gels, contraceptive barrier, intrauterine devices
(IUD), and contraceptives (oral or injection), starting from 1 month before the start of the study until
30 days after the end of the study.
4.3 
Exclusion Criteria 
Patients who meet any of the following must be excluded from this study. 
1.
Radiation therapy within 4 weeks prior to enrollment;
2.
Patients with breast cancer who have received neoadjuvant chemotherapy before surgery;
3.
Prior bone marrow or stem cell transplant;
4.
With other malignant tumors other than breast cancer;
5.
Patients who have received a treatment with recombinant human granulocyte colony stimulating
factor within 6 weeks prior to randomization;
6.
Diagnosed with acute congestive heart failure, cardiomyopathy, or myocardial infarction by clinical
diagnosis, ECG or other approaches;
7.
With any disease that may cause splenomegaly;
8.
With acute infection, chronic active Hepatitis B within 1 year (unless patients tested negative for
HBsAg prior to enrollment), or Hepatitis C;
9.
Women in pregnancy or breastfeeding;
10. Known HIV positive or AIDS;
11. With active tuberculosis (TB); history of TB exposure, unless negative for tuberculin test;
TB patients undergoing treatment; or suspected TB evaluated by chest x-ray;
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12. With sickle cell anemia;
13. With alcohol or drug abuse that may affect the compliance with the study;
14. With known hypersensitivity to granulocyte colony stimulating factor or excipients;
15. Have received any other investigational drug within 1 month or 5 half-lives of the investigational
drugs prior to enrollment (whichever is longer);
16. Patients with diseases or symptoms unsuitable for participating in the trial. For example, the study
drugs may compromise the health of the patient or the assessment of adverse events may be
affected.
4.4 
Withdrawal 
Subjects have the right to withdraw from the study at any time without any reason. The medical rights of 
the subjects will not be affected by the withdrawal of the study. 
4.4.1 
Criteria for withdrawal 
1.
Subject withdraws voluntarily;
2.
Occurrence of uncontrolled grade 3 or 4 adverse events related to the study drug as judged by the
investigator;
3.
Subjects fail to comply with the study protocol;
4.
Termination by the investigator under safety considerations or in the best interest of the subject
when the subject's condition changes;
5.
Pregnancy;
6.
Death.
4.4.2 
Procedure for withdrawal 
Subjects who withdraw from the study at any time will be required to complete the last evaluation and 
relevant examinations. 
4.4.3 
Visits for withdrawals 
If a subject withdraws from the study, the investigator should ask if the subject is willing to continue 
follow-up visits, and document the discussion in the medical history and case report form. If a subject is 
lost to follow-up, the investigator should make every effort to contact the subject or her family members 
to understand and document the reason for the withdrawal, and complete the final evaluation. 
If a subject voluntarily withdraws from the study, request for a telephone visit 30 days after the subject's 
last dose. If the subject refuses, no further data needs to be collected. 
If the study for a subject is terminated due to an adverse event, the event should be followed until it 
recovers to normal or baseline levels and be documented in the electronic case report form (eCRF). 
4.5 
Replacement Principle 
4.5.1 
Subject replacement 
This trial will not plan on replacing the subjects who terminate the trial early. 
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5.0 
TRIAL PROCEDURE 
The schedule of study procedures is detailed in Table 6. 
Table 6. Schedule of study procedures. 
Treatment 
Period 
Items 
Screening 
Day -21 to 
Day -1 
Cycles 1–4 
End of Study 
Day 21 of 
Cycle 4j 
Day 1 
Day 3 
Days 
3–21 
Informed Consent 
Form 
× 
Inclusion/Exclusion 
Criteria 
× 
Tumor History 
× 
Concomitant 
Diseases 
× 
× 
× 
× 
× 
Combined 
Medications 
× 
× 
× 
× 
× 
Physical 
Examinationa 
× 
× 
× 
Weight/Heightb 
× 
× 
× 
Blood Pressure, Heart 
Rate 
× 
× 
× 
Body Temperaturec 
× 
× 
× 
× 
× 
Abdominal 
Ultrasoundd 
× 
× 
× 
12-lead ECGd
× 
× 
× 
Echocardiography 
× 
Chest X-Ray or CT 
× 
Laboratory 
Measurements 
Routine Blood Teste 
× 
× 
× 
× 
× 
Blood Biochemistry 
× 
× 
× 
Urinalysis 
× 
× 
× 
Pregnancy Test 
× 
× 
Serum Anti-F-627 
Antibodiesf 
× 
× 
Chemotherapyg 
× 
Study Drugh 
× 
× 
Adverse Eventsi 
× 
× 
× 
× 
× 
Note: 
a.
A complete physical examination is required during screening. Corresponding physical examination is
completed based on subject condition on day 1 of cycles 1–4 (vital organs);
b.
Height is only measured during screening. Weight is measured on day 1 of each cycle (measurements within
3 days prior to treatment are acceptable) and at the end of the study;
c.
Temperature is measured during screening, on day 1 of each cycle, and at the end of the study. On days 3–
21 of each cycle, temperature is measured when ANC < 1.0 × 109/L;
d.
Abdominal ultrasound should be performed during screening or before the start of cycle 1 and at the end of
the study. The time window for abdominal ultrasound is +/– 3 days. The 12-Lead ECG should be performed
during screening (ECGs performed within 7 days prior to randomization can be used as the result for cycle 1),
before the start of each cycle, and at the end of the study. The time window for 12-Lead ECG is +/–3 days;
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e.
Routine blood test is performed on days 3, 5, 7, 8, 9, 10, 11, 13, 15, and 21 of cycle 1, and on days 3, 5, 7, 9,
11, 13, 15, and 21 of cycles 2–4. Laboratory measurements (routine blood test, blood biochemistry,
urinalysis, and pregnancy test) within 7 days before cycle 1 (day 1) were acceptable and did not need to be
repeated. The time window for laboratory measurements (routine blood test, blood biochemistry, urinalysis,
and pregnancy test) before cycles 2–4 was –within –3 days;
f.
Blood samples are collected on day 1 (±1 day) of each cycle and day 21 (±1 day) of cycle 4, as well as
90 days (±7 days) after the last visit (day 21 of cycle 4), to test for serum anti-F-627 antibodies. Results from
the test on day 1 of cycle 1 are used as baseline.
g.
The investigator will decide on the dose and time of the next chemotherapy based on the patient's actual
conditions. Results of routine blood test must meet the following criteria prior to the start of the next cycle of
chemotherapy: ANC ≥ 2.0 × 109/L, PLT ≥ 80 × 109/L, and liver and renal functions should meet the standard
as described in "Inclusion Criteria". A 14 day recovery period is permitted if these criteria are not met prior to
the scheduled cycle 2, cycle 3, and cycle 4. If the criteria described above are still not met after 14 days,
the patient is not eligible to enter the cycle 2, cycle 3, or cycle 4 of this study.
h.
On day 3 of each cycle (48±4 hours after the start of chemotherapy), subjects will receive F-627 20 mg
subcutaneously or GRAN® (5 µg/kg/day, s.c., once daily [±4 hrs] for ≤ 2 weeks or until ANC recovers to
5.0 × 109/L from nadir [investigators may refer to ANC results from respective study sites to decide when
to discontinue GRAN®]);
i.
Adverse events are evaluated according to NCI CTCAE 4.03. Adverse events that occur within 30 days after
the last dose are included in the safety evaluation. Serious adverse events should be reported;
j.
The last visit should be completed on day 21 of cycle 4. A follow-up visit by telephone should be completed
30 days (±3 days) after the last dose;
Note: Routine blood test during cycle 1, as well as all serum anti-F-627 antibody assays are performed at the central laboratory. 
Routine blood test, blood biochemistry, pregnancy test, and urinalysis during screening and cycles 2–4, and at the end of the 
study are performed at study sites. In cycle 1, when necessary, investigators can conduct routine blood test at their respective 
study sites based on subject conditions, in order to provide necessary treatment to prevent the risks from neutropenia. 
Appropriate measures are taken for chemotherapy-related toxicities based on the investigator's clinical judgment and routine 
clinical practice. 
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5.1 
Schedule of Study Procedures and Evaluations 
5.1.1 
Evaluations during screening 
In principle, all subjects must sign the informed consent form approved by the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) prior to any study-related examinations. Since the 
examinations and evaluations during screening are often part of the routine clinical practice, results of 
echocardiography and chest x-ray or CT prior to signing the informed consent form can be used to avoid 
repeated examinations. 
The screening period is 21 days before the start of study. The following examinations and evaluations are 
required to be completed prior to dosing: 
1)
Signing the informed consent form
2)
Medical history inquiry
3)
Record treatment measurements for concurrent diseases within the past 2 weeks and anti-neoplastic
treatments received within the past year
4)
Physical examination
5)
Measurement of height (cm)
6)
ECOG performance status scoring
7)
Measurement of body temperature
8)
Measurement of blood pressure and heart rate
9)
Laboratory measurements:
•
Routine blood test
•
Blood biochemistry
•
Urinalysis
•
Pregnancy test
10) Abdominal ultrasound (include at least the liver and spleen)
11) 12-lead ECG
12) Left ventricular ejection fraction (LVEF) measured by echocardiography to assess cardiac function
13) Chest x-ray (frontal and lateral) or chest CT
Patients must satisfy all the eligibility criteria, i.e. meet all the inclusion criteria and not meet any of the 
exclusion criteria, to participate in this trial. 
5.1.2 
Enrollment of eligible patients 
An eligible patient will be assigned a subject code which is unique to identify the patient. This code will 
remain constant throughout the study. 
The investigator should reconfirm the eligibility of the subject prior to the chemotherapy. The investigator 
will log in to the IWRS system for central randomization. Subjects will be randomized to 2 different arms, 
F-627 or GRAN®. Treatment allocation will remain unchanged during the entire treatment period.
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5.1.3 
Evaluations during treatment 
The following examinations and evaluations are required on day 1 of cycle 1: 
1)
Randomization (before cycle 1)
2)
Measurement of height and weight for body surface area
3)
Blood pressure and heart rate
4)
Body temperature
5)
Physical examination
6)
Laboratory measurements:
•
Routine blood test
•
Blood biochemistry
•
Urinalysis
7)
Serum anti-F-627 antibody assay
8)
12-Lead ECG (not required if performed during screening)
9)
Abdominal ultrasound (not required if performed during screening)
10) Record and evaluate AEs and SAEs (defined in Section 7.0);
11) Record combined medications
The following examinations and evaluations are required on days 3–21 of cycle 1: 
1)
Laboratory measurements:
•
Routine blood test: on days 3, 5, 7, 8, 9, 10, 11, 13, 15, and 21
2)
Body temperature (when ANC < 1.0 × 109/L)
3)
Record and evaluate AEs and SAEs
4)
Record combined medications
The following examinations and evaluations are required on day 1 of cycles 2–4: 
1)
Measurement of weight
2)
Blood pressure and heart rate
3)
Body temperature
4)
Physical examination
5)
Laboratory measurements:
•
Routine blood test
•
Blood biochemistry
•
Urinalysis
6)
Blood sampling for serum anti-F-627 antibody assay
7)
12-lead ECG
8)
Record and evaluate AEs and SAEs (defined in Section 7.0);
9)
Record combined medications
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The following examinations and evaluations are required on days 3–21 of cycles 2–4: 
1)
Temperature (when ANC < 1.0 × 109/L)
2)
Laboratory measurements:
•
Routine blood test: on days 3, 5, 7, 9, 11, 13, 15, and 21
3)
Record and evaluate AEs and SAEs
4)
Record combined medications
5.1.4 
Evaluations at end of study 
The following examinations and evaluations are required to be performed at the completion of 
4 chemotherapy cycles (on day 21±1 of cycle 4): 
1)
Physical examination
2)
Measurement of weight
3)
Body temperature
4)
Blood pressure and heart rate
5)
Laboratory measurements:
•
Routine blood test
•
Blood biochemistry
•
Urinalysis
•
Pregnancy test
6)
Serum anti-F-627 antibody assay
7)
Abdominal ultrasound
8)
12-lead ECG
9)
Record and evaluate AEs and SAEs
10)
Record combined medications
The following evaluations should be completed in the follow-up visit by telephone (30 days after the last 
dose): Subjects who withdraw from the study or complete the study are required to have a follow-up visit 
by telephone 30±3 days after the last dose to follow their general conditions, disease recurrence, 
combined medications, doctor's visits, hospitalizations and other information, and evaluate the 
AEs/SAEs. 
5.1.5 
Unscheduled evaluations 
Additional visits may be arranged accordingly during treatment for potential safety concerns or 
necessary tumor assessments. 
After the visit on day 21 of cycle 4, the investigator may arrange an unscheduled visit 2 weeks later based 
on the subject conditions in order to evaluate the AEs. 
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5.2 
Definitions and Evaluation Criteria of Study Endpoints 
5.2.1 
Efficacy evaluation 
5.2.1.1 
Efficacy endpoints 
Primary endpoint: 
The primary endpoint is the duration (days) of grade 3 or 4 (moderate or severe) neutropenia in cycle 1, 
that is, the number of days in which ANC < 1.0 × 109/L. 
Secondary endpoints include: 
•
The incidence rate of grade 3 or 4 neutropenia (ANC < 1.0 × 109/L) in each cycle
•
The duration (days) of grade 3 or 4 neutropenia (ANC < 1.0 × 109/L) in cycles 2–4
•
The incidence rate and duration (days) of grade 4 neutropenia (ANC < 0.5 × 109/L) in each cycle
•
The duration (days) of grade 3 or 4 neutropenia (ANC < 1.0 × 109/L and < 0.5 × 109/L, respectively)
in the 4 cycles
•
The incidence rate of febrile neutropenia (FN) [FN is defined as ANC < 1.0 × 109/L with the body
temperature in a single measurement > 38.3 °C or a fever ≥ 38.0 °C lasting for greater than 1 hour]
•
ANC-time profile
•
ANC nadir between days 3–13 in cycle 1
•
The incidence rate and duration (days) of grade 2 or greater neutropenia (ANC < 1.5 × 109/L) in
each cycle
•
The time (days) of ANC nadir recovers to 2.0 × 109/L in each cycle
5.2.1.2 
Methods for evaluating efficacy endpoints 
Efficacy endpoint should be determined by routine blood test (including ANC). The sampling time points 
for routine blood test specified in the protocol meet the evaluation of efficacy endpoint. 
Routine blood test is completed at the central laboratory during cycle 1 and at the study sites for cycles 2–
4. Results of ANC in cycle 1 are the primary efficacy endpoint. The central laboratory will provide each
study site with materials and Central Laboratory Service Manual, as well as appropriate guidance and
training.
5.2.2 
Safety evaluation 
5.2.2.1 
Safety endpoints 
Safety evaluations include all observed and recorded AEs, physical examinations, vital signs, ECOG 
performance status score, laboratory measurements, ECG, and abdominal ultrasound change. 
5.2.2.2 
Methods for evaluating safety endpoints 
Adverse events (AEs) 
Refer to Section 7.0 for the definitions of adverse events, which are graded based on NCI CTCAE v4.03. 
Corresponding interventions should be given timely by the investigators. 
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Physical status based on ECOG PS scoring 
Performance status score (ECOG score): 5 grades, 0 = Fully active, able to carry on all performance 
without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light nature or office work; 2 = Ambulatory and capable of all self care but unable to carry out 
any work activities; up and about more than 50% of waking hours; 3 = Capable of only limited self care; 
confined to bed or chair more than 50% of waking hours; 4 = Completely disabled; cannot carry on any 
self care; totally confined to bed or chair; 5 = Death. 
Laboratory Measurements 
Routine blood test measurements and F-627 antibodies are tested at the central laboratory in cycle 1. 
Routine blood test, blood biochemistry, serum pregnancy test, and urinalysis are completed at each study 
site during cycles 2–4 and at the end of study. In cycle 1, when necessary, investigators can conduct routine 
blood test at the clinical laboratory of their respective study sites based on subject conditions, in order to 
provide necessary treatment to prevent the risks from neutropenia. 
The central laboratory will provide the materials and brochures, and also appropriate training and 
guidance. Refer to Table 7 for all laboratory measurements. 
Table 7. Laboratory measurements. 
Routine blood 
test 
Red blood cell, hemoglobin, white blood cell, platelet count, differential blood count (neutrophils, 
lymphocytes, monocytes, basophils and eosinophils), hematocrit, mean corpuscular hemoglobin 
(MCH), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), 
etc. 
Blood 
biochemistry 
Total protein (TP), albumin (ALB), blood glucose, blood urea nitrogen, creatinine, 
alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total bilirubin, aspartate 
transaminase (AST), γ-glutamyl transpeptidase, alanine transaminase (ALT), Ca, P, 
K, and Na, etc. 
Urinalysis 
pH, specific gravity, protein, urinary casts, RBC, and urine glucose and ketones; Microscopic 
urinalysis is required if the urinary dipstick is positive for WBC and/or hemoglobin 
The investigator must document the sampling time points and test results in the electronic case report 
form (eCRF). 
Refer to Section 7.0 to determine whether a laboratory abnormality with clinical significance meets the 
criteria for an adverse event and needs to be documented in the eCRFs. 
12-lead ECG:
Including heart rate, PR interval, QRS interval, QT interval, and QTc; 
Abdominal ultrasound: 
Including at least the liver and spleen; special attention to splenomegaly if any. 
Physical examinations: 
Including general conditions, skin, lymph nodes, eyes, ears, nose, mouth, throat, neck, thyroid, chest, 
lungs, cardiovascular system, abdomen, limbs, nervous system, musculoskeletal system, etc. 
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Body temperature: 
Oral temperature is the standard, but tympanic, axillary, or rectal temperatures are also acceptable. 
Clinically significant abnormalities in physical examinations, vital signs, ECOG score, 12-lead ECG, 
and abdominal ultrasound during the study have to be reported as AEs. 
5.3 
Immunogenicity Evaluation 
5.3.1.1 
Immunogenicity endpoints 
To evaluate the immunogenic potential of F-627 by testing serum anti-F-627 antibodies. 
5.3.1.2 
Methods for evaluating immunogenicity 
Serum anti-F-627 antibody assay primarily consists of three sequential assays, that is, binding assay - 
electrochemiluminescence by MSD (ECL), confirmatory assay - binding inhibition assay, and 
neutralization assay - cell-based neutralization assay. Firstly, all collected serum samples are subjected to 
a binding assay for antibody detection by ECL. Secondly, serum samples with positive binding assays 
are further subjected to a confirmatory assay, in which the antibody should be blocked and inhibited 
before ECL detection. After titering assay, serum samples with positive confirmatory assays are further 
subjected to the neutralizing assay to determine whether the biological function of G-CSF is neutralized 
by the antibodies in the serum sample using a cell-based platform. Criteria for immunogenicity analysis 
results are shown in Table 8. 
Serum anti-F-627 antibody assays are performed at the central laboratory according to the laboratory 
SOP. 
The central laboratory will provide each study site with materials and Central Laboratory Service Manual, 
as well as appropriate guidance and training. 
Table 8. Criteria for immunogenicity of F-627. 
Binding Assay 
Confirmatory Assay 
Neutralizing Assay 
Judgment of Results 
Step One 
- 
Negative 
Step Two 
+ 
- 
Negative 
Step Three 
+ 
+ 
- 
Negative 
+ 
+ 
+ 
Positive 
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6.0 
TREATMENT PLAN 
6.1 
Study Drugs 
6.1.1 
Dose and mode of administration 
Refer to Table 9 below for a summary of dose and mode of administration of study drug. 
Table 9. Dose and mode of administration. 
Study 
Drug 
Dose 
Route of 
administration 
Dosing Interval 
F-627
20 mg/dose 
Subcutaneous 
Day 3 of each cycle, i.e., 48±4 hrs after the start of chemotherapy 
GRAN® 
5 µg/kg/day* 
Subcutaneous 
Since day 3 of each cycle, i.e., 48±4 hours after starting chemotherapy, 
continuous treatment for ≤ 2weeks or until ANC recovers to 5.0×109/L 
from nadir (investigators may refer to ANC test results from the clinical 
laboratory of respective study sites to decide when to discontinue 
GRAN®) 
Note: *: The actual dose is rounded to the nearest whole number, but the difference between the actual and theoretical doses 
should be within ± 5%. 
6.1.2 
Dosage form, packaging, labeling, and storage of study drugs 
Investigational Drug: Recombinant human granulocyte colony stimulating factor-Fc fusion 
protein (F-627) 
The investigational drug used in this study is recombinant human granulocyte colony stimulating 
factor-Fc fusion protein (F-627), 20 mg/mL prefilled syringes. The product information of F-627 is 
presented in Table 10. 
Prior to use, the safety cap should be removed before subcutaneous injection. The medication should not 
be placed at room temperature for more than 1 hour. 
Table 10. F-627 product information. 
Product 
Dosage Form 
Strength 
Ingredients and Excipients 
F-627
Prefilled syringe 
20 mg/mL 
20 mg/mL of F-627, sodium acetate, sorbitol, polysorbate 
20, and Ethylenediaminetetraacetic acid (EDTA), pH 5.2 
The label of the investigational drug should contain the following information: name of the 
investigational drug, medication number, protocol number, storage conditions, mode of administration, 
batch number, expiration date, and standard text "for clinical trial use only". The investigational drug is 
provided by the sponsor. 
The drug should be stored as specified in a sealed container at 2–8 °C away from light, and under the 
management of designated personnel. If the temperature exceeds the storage condition during transport 
and storage, record and report the incident to the sponsor. 
Reference Drug: Recombinant human granulocyte colony stimulating factor (GRAN®) 
The specification of the reference drug GRAN®: 300 µg/0.7 mL/vial, liquid preparation (ampoules), 
stored at 2–8 °C and managed by designated staff. The drug must not be frozen. 
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The reference drug is provided by the sponsor. If the temperature exceeds the storage condition during 
transport and storage, record and report the incident to the sponsor. 
6.1.3 
Drug accountability 
The receipt, dispense (use), return, and disposal of the study drug should be accurately documented in the 
drug accountability record and drug inventory sheet. The investigator must ensure that the study drug is 
restricted to study subjects. 
The study drug may be disposed at the study sites or by a third-party designated by Generon (Shanghai) 
Corporation Ltd. If the study drug is to be disposed at study site, the study site's SOP for study drug 
disposal must be strictly followed. The method and location of disposal, as well as the quantity of 
disposed drugs must be documented. 
6.2 
Chemotherapy 
6.2.1 
Dose and mode of administration of chemotherapy drugs 
Each subject is treated with 4 cycles of EC chemotherapy. The dose and mode of administration of the 
chemotherapy drugs are shown in Table 11: 
Table 11. Dose and administration of chemotherapy drugs. 
Study Drug 
Dose 
Route of 
administration 
Dosing Interval
Cycle 
Epirubicin 
[Pharmorubicin®] 
100 mg/m2 
i.v.
Day 1 of each 3-week cycle 
4 
Cyclophosphamide 
600 mg/m2 
i.v.
Day 1 of each 3-week cycle 
4 
After 4 cycles of EC treatment, each subject will receive subsequent treatment according to routine 
clinical practice. 
Note: 1. The actual total dose of chemotherapy drugs should be maintained at 95–105% of the theoretical 
total dose; 
2. The recommended time for the start of cycle 1 is within 1 month of the surgery. Subsequent cycles
should not be delayed for more than 2 weeks. The following criteria must be met prior to starting the next
cycle of chemotherapy: ANC ≥ 2.0 × 109/L, PLT ≥ 80 × 109/L, and liver and renal functions meeting
"Inclusion Criteria". A 14 day recovery period is permitted if these criteria are not met prior to the
scheduled cycle 2, cycle 3, and cycle 4. If the criteria described above are still not met after 14 days, the
patient is not eligible to enter the cycle 2, cycle 3, or cycle 4 of this study.
6.2.2 
Principles of dose adjustment and management 
The treatment-emergent toxicities are evaluated using NCI CTCAE v4.03. 
The investigator must ensure that the first cycle of treatment follows the recommended chemotherapy 
regimen; in cycles 2–4, dose delay and reduction due to toxicities (such as cardiotoxicity) other than 
myelotoxicity are permitted, or the investigator may individualize the dosage based on subject 
conditions. 
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Investigators should assess the subject conditions before starting each treatment cycle, including the 
severity, duration, and recovery of toxicities. Investigators will then take appropriate actions, such as 
adjusting, delaying, or suspending the dose. 
6.3 
Combined and Prohibited Medications 
The investigators may decide on the appropriate treatment for infusion reactions caused by the study drug, 
such as paracetamol, meperidine (dolantin), or chlorpheniramine or other antihistamines. 
The following medications are prohibited in the study: recombinant human granulocyte colony 
stimulating factor (rhG-CSF) and recombinant human granulocyte-macrophage colony stimulating 
factor (rhGM-CSF); traditional Chinese medicines with indications for promoting neutrophil production; 
lithium, which may contribute to the release of neutrophils; and prophylactic antibiotics. 
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7.0 
SAFETY 
7.1 
Adverse Events (AEs) and Abnormal Values of Laboratory Measurements 
7.1.1 
Clinical AEs 
An adverse event is defined as any untoward medical condition in a patient or clinical study 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), symptoms, or disease temporally associated with the use of a medicinal product 
(study drug), whether or not considered related to the medicinal product. 
If an elective surgery/treatment has been scheduled prior to the study, then it is not considered as an AE. 
However, if the disease worsens during the trial (e.g. surgery/treatment is required earlier than 
scheduled), then the elective surgery/treatment due to disease worsening is considered as an AE. 
AEs and corresponding severity during the trial should be recorded in the eCRFs. Refer to Section 7.1.1.1 
for detailed severity. A causality evaluation between AEs and treatment should also be performed. 
7.1.1.1 
Severity 
AEs are graded according to NCI CTCAE v4.03. 
Investigators should use the following guideline to assess the severity of adverse events that are not 
graded by NCI CTCAE (Table 12) : 
Table 12. Grading of adverse events. 
Grade 
Definition 
Mild 
The AE causes discomfort but does not affect activities of daily living 
Moderate 
The AE causes discomfort and affects activities of daily living 
Severe 
The subject cannot work or perform activities of daily living 
Life-Threatening/Disabling 
The AE is life-threatening, or results in disability or incapacity, severely affecting 
activities of daily life 
Fatal 
Death 
7.1.1.2 
Causality with study drug 
The investigator will use "definitely related", "probably related", "possibly related", "unlikely related", 
and "unrelated" to determine the degree of causality between treatment and an AE. Refer to the Table 13 
for the criteria. 
1)
Definitely/probably related:
This category applies to AEs that are considered highly likely to be caused by the study drug. The event 
is considered probably related if three of the followings are met: 
a)
Plausible time relationship to administration.
b)
Cannot be reasonably explained by known signs and symptoms, environmental or toxic factors,
or other treatments received.
c)
The AE resolved or improved after treatment suspension or dose reduction (with one exception
where the AE does not resolve after suspending treatment, such as (1) myelosuppression,
(2) delayed dyskinesia).
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d)
Consistent with the recognized toxicity of the suspected drug.
e)
Positive rechallenge.
2)
Possibly related
This category applies to AEs that are not likely to be caused by the study drug, but cannot be ruled out 
with certainty. The AE is considered possibly related if two of the followings are met: 
a)
Plausible time relationship to administration.
b)
Can be explained by disease, environmental or toxic factors, or other treatments received.
c)
Consistent with the recognized toxicity of the suspected drug.
3)
Unlikely related (meet 2 criteria)
This category of adverse events generally meets the following criteria: 
a)
Implausible time relationship to administration.
b)
Plausibly explained by disease, environmental or toxic factors, or other treatments received.
c)
Not consistent with the recognized toxicity of the suspected drug.
d)
Negative rechallenge.
4)
Unrelated
This category applies to AEs that are clearly caused by other factors (disease, environment, etc.) and does 
not meet the criteria for "unlikely related", "possibly related", "probably related", and "certainly related". 
Table 13. Criteria for causality evaluation. 
Criteria 
Definitely/Probably Related 
Possibly 
Related 
Unlikely 
Related 
Unrelated 
Clearly Caused by Other Factors 
- 
- 
- 
+ 
Plausible Time Relationship to 
Administration 
+ 
+ 
- 
- 
May be Explained by Disease 
- 
+ 
+ 
+ 
Recognized Toxicity of the Suspected 
Drug 
+ 
+ 
- 
- 
Positive Dechallenge 
+ 
- 
- 
- 
Positive Rechallenge 
+ 
- 
- 
- 
7.1.1.3 
Serious adverse events (SAEs) 
An AE meets any one of the followings is considered as an SAE. The investigator should report the SAE 
to the sponsor and regulatory authorities according to relevant regulations within 24 hours of learning of 
the event. 
Table 14. Criteria for serious adverse events. 
Serious Adverse Event 
Definition 
Death 
An adverse event that causes the death. 
Life-threatening 
An AE in which the subject is at immediate risk of death at the time of event if no 
medical interventions are taken as judged by the investigator, not an event that 
hypothetically might cause death or worsening. 
Hospitalization 
An AE that leads to hospitalization, excluding emergency or outpatient visits. 
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Prolonged hospitalization 
An AE occurs during the hospitalization and results in prolonged hospitalization. 
Congenital anomaly 
An abnormality present at birth or after birth, or any malformations leading to 
abortion. 
Permanent or significant 
disability/incapacity 
An AE that has important effect on the subject's daily life. Incapacity does not 
include medical events of relative minor importance, such as headache, nausea, 
vomited, diarrhoea, influenza, or accidental injury (e.g. ankle sprains). 
Important Medical Events 
Requiring Pharmaceutical 
or Surgical Interventions 
to Prevent Serious Outcomes 
Important medical events may not be immediately life-threatening, or result in death 
or hospitalization, but may jeopardize the subject and require pharmaceutical or 
surgical interventions to prevent any of the above outcomes (i.e. death, life threat, 
hospitalization or prolonged hospitalization, and congenital anomaly). These events 
may include allergic bronchospasm requiring treatment in an emergency room or at 
home, convulsions that do not result in hospitalization, or drug dependence or abuse. 
A severe AE refers to the severity of the event, and is not necessarily an SAE, e.g. persistent vomiting for 
several hours is considered as a severe AE, but not an SAE clinically. 
After the initial report of an SAE, medical history, autopsy report, and other necessary documents should 
be provided as required. 
The severity, causality with the study drug, interventions taken and outcome of an SAE should be 
included in the report. 
7.1.2 
Treatment and follow-up of AEs 
An AE should be followed until it returns to the baseline level or until it is stabilized. If an AE does not 
return to the baseline level or cannot be stabilized, a reasonable explanation should be recorded in the 
eCRFs. 
7.1.3 
Abnormal values of laboratory measurements 
Results of laboratory measurements should be recorded in the eCRFs. Abnormal values of laboratory 
measurements that meet the criteria for SAEs should be recorded in the SAE reports and the CRFs as AEs 
simultaneously. 
Clinically significant abnormal values of laboratory measurements should be recorded in eCRFs as 
independent AEs if at least one of the followings is met: 
•
Accompanied by clinical symptoms
•
Resulting in changes in administration (such as dose adjustment, treatment suspension, or
permanent discontinuation)
•
Requiring changes in combined treatment (such as the addition, suspension, discontinuation of,
or changes to combined medication or treatment)
7.1.3.1 
Follow-up of abnormal values of laboratory measurements 
Any clinically significant abnormal values of laboratory measurements that cannot be explained should 
be retested and followed until returning to the baseline levels, or provided with a reasonable explanation 
and recorded in the CRFs. 
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7.2 
AE Management 
7.2.1 
AE reporting 
The investigator should closely monitor the clinical and laboratory evidence of each AE in the study. All 
AEs should be evaluated and recorded in detail, including the date of onset, symptoms, severity, outcome, 
duration, result of the event, relationship to the study drug, the diagnosis of the AE, and measures taken. 
The investigator should provide other potential information on causes of SAEs that are considered 
possibly unrelated to the study drug. 
For an AE considered intermittent, the nature and severity should be similar between each occurrence. 
All AEs should be recorded, regardless of whether they are collected from the subject's medical history, 
investigator's observation, or self-reporting by the subject. 
All AEs should be followed until satisfactory resolution. 
All SAEs that occur from signing the informed consent form and randomization until 30 days after the 
last dose of the study drug should be recorded, including AEs that occurred prior to the randomization 
and worsened during the treatment period, regardless of whether they are collected from the 
investigator's observation or self-reporting by the subject. 
7.2.2 
SAE reporting (immediate) 
If any AEs or abnormal values of laboratory measurements that occur from signing the informed consent 
form until 30 days after the last dose is considered as an SAE, the investigator must report the SAE to the 
sponsor and regulatory authorities according to relevant regulations within 24 hours of learning of the 
event, regardless of whether interventions are given. 
For SAEs occurring within the above-mentioned period, those considered related to the study drug 
should also be reported. 
7.2.3 
Special non-SAE reporting 
Progression of disease: 
Tumor progression should not be reported as an AE or SAE. A second cancer can be instead. 
Infusion reaction: 
Other than reporting an "infusion reaction", symptoms and AEs associated with the study drug or 
chemotherapy should also be reported. An AE may be related to the infusion if the event occurs during or 
within 24 hours from the chemotherapy infusion. 
The following data should be collected: 
•
Special symptoms to be recorded in the eCRFs;
•
Severity of each AE;
•
Symptoms that occur within 24 hours from the infusion, e.g. fever, rigours, and hypotension.
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7.2.4 
Pregnancy 
Subjects who become pregnant during the trial must notify the investigator immediately and discontinue 
the study drug and chemotherapy. Subjects who become pregnant within 90 days after the completion of 
treatment should also notify the investigator. The investigator must report the pregnancy to the sponsor 
within 24 hours. The investigator should discuss with the subject about the risks of continuing pregnancy 
and potential effects on the fetus. The pregnancy should be followed until satisfactory resolution. 
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8.0 
STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan 
8.1.1 
Sample size estimation 
The primary endpoint is the duration of grade 3 or 4 neutropenia in cycle 1. The non-inferiority/ 
equivalence margin for F-627 and GRAN® is defined to be 1 day5-7. Although the maximum standard 
deviations for the two F-627 phase II clinical trials SP-CDR-1-1302 and GC-627-02 were 1.33 and 
1.58 days, respectively, it is conservatively assumed that the standard deviation for this study is 1.75 days. 
In the case of a one-sided α = 0.025 and a power of 95%, 94 subjects are required for each arm, and in 
consideration of a 15-20% drop-out rate, 120 subjects are needed for each arm (a total of 240 subjects). 
8.1.2 
Analysis sets 
Efficacy analyses will be based on the ITT and PP analysis sets. The safety analysis will be performed 
using the safety set. Definitions of each analysis set are as follows: 
Intent-to-treat (ITT) set: all randomized subjects who have received the study drug and underwent at least 
one post-baseline efficacy evaluation. The ITT set is primarily used for efficacy evaluation. 
Per-protocol (PP) set A: subjects in the ITT analysis exclusive of subjects with "major protocol violations, 
serious medication noncompliance, lost to follow-up, or withdrawal" during cycle 1. The PP set A is only 
used for analyses of endpoints related to cycle 1. 
Per-protocol (PP) set B: subjects in the ITT set exclusive of subjects with "major protocol violations, 
serious medication noncompliance, lost to follow-up, or withdrawal" in any cycle. The PP set B is used 
for PP set analyses of endpoints only related to overall cycles. The PP sets are primarily used to evaluate 
treatment efficacy. 
Safety set: all randomized subjects who received at least one dose of the study drug. The safety set is 
primarily used for safety evaluation. 
Major protocol violations are confirmed before the database locking. The definitions of major protocol 
violations are as follows: 
•
Serious violations of inclusion/exclusion criteria;
•
Administration of a wrong study drug (not the originally randomized treatment);
•
Administration of a wrong dose
•
Other major protocol violations considered by the sponsor.
8.1.3 
Statistical analysis methods 
8.1.3.1 
Significance level and statistical software 
Unless otherwise specified, a one-sided test with a significance level of 0.025 for the non-inferiority test 
will be used. Other tests will use a two-sided test with a significance level of 0.05. Statistical analyses are 
performed using SAS 9.1.3 or above. 
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8.1.3.2 
Statistical analysis 
Efficacy analyses will be performed using both the intent-to-treat (ITT) and per-protocol (PP) sets. 
Safety analyses will be performed using the safety set. Appropriate statistical methods will be selected 
according to the nature of data distribution. Refer to the statistical analysis plan for detailed explanations 
regarding the statistical analysis methods. 
8.1.4 
Demographics and baseline characteristics 
Demographics and baseline characteristics of each dose arm will be summarized using descriptive 
statistics; continuous variables will be summarized using numbers of cases, means, standard deviations, 
medians, minimums, and maximums; categorical variables will be summarized using frequencies and 
percentages. 
8.1.5 
Efficacy analysis 
8.1.5.1 
Primary efficacy analysis 
The primary efficacy endpoint will test the non-inferiority of F-627 to GRAN® in terms of the duration of 
grade 3 neutropenia (including grade 4 or severe neutropenia) in cycle 1. The hypotheses for 
noninferiority between F-627 and GRAN® are as follows: 
H0: µF-627 (20 mg/dose) - µGRAN® > 1 day; H1: µF -627 (20mg/dose) - µGRAN® ≤ 1 day 
This is a non-inferiority test. A two-sided 95% confidence interval will be established using the 
Hodges-Lehmann estimator (F-627 - GRAN®). Non-inferiority is established if the upper limit of the 
two-sided 95% confidence interval for the difference in the duration of grade 3 or 4 neutropenia is 
≤ 1 day. 
Refer to the statistical analysis plan for detailed explanations regarding the statistical analysis methods. 
8.1.5.2 
Secondary efficacy analysis 
The duration of grade 3 neutropenia in cycles 2–4 
The duration of neutropenia in cycles 2-4 will be compared between F-627 and GRAN® using the same 
method as that for the primary endpoint analysis. The 95% confidence interval will be calculated. 
The incidence rate of grade 3 neutropenia in cycles 2–4 
The frequency and incidence rate of grade 3 neutropenia in cycles 2–4 will be compared between F-627 
and GRAN®. The differences between F-627 and GRAN® are compared using Fisher's exact test. 
The overall duration of grade 3 neutropenia in overall 4 cycles 
The method is the same as the secondary endpoint analysis of overall duration of grade 3 neutropenia in 
overall 4 cycles. 
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The duration of grade 4 neutropenia in cycles 1–4 
The method is the same as the secondary endpoint analysis of the duration of grade 3 neutropenia in 
cycles 2–4. 
The incidence rate of grade 4 neutropenia in cycles 1–4 
The frequency and incidence rate of grade 3 neutropenia in each cycle will be compared between F-627 
and GRAN®. The differences between F-627 and GRAN® are compared using Fisher's exact test. 
ANC - time profile 
The efficacies of F-627 and GRAN® are compared by plotting ANC - time logarithmic curves. 
The time of ANC recovered to 2.0 × 109/L from nadir 
The time of ANC recovered to 2.0 × 109/L from nadir is compared by the same analysis method, 
calculating 95% confidence intervals. 
Febrile neutropenia 
The frequency and incidence rate of febrile neutropenia are summarized by different dose arms and 
cycles. The differences between F-627 and GRAN® are compared using Fisher's exact test. 
ANC nadir 
The ANC nadir in cycle 1 was compared between different dose arms using the same method as that for 
the primary endpoint with 95% confidence intervals calculated. 
8.1.6 
Safety analysis 
Safety analysis is performed using the safety set. AEs and laboratory measurements are evaluated based 
on NCI CTC AE 4.03. All AEs that occur during the treatment period 30 days after the last dose will be 
tabulated in nature of the event, frequency, severity, and causality with the study drug. All clinically 
significant laboratory measurements, physical examinations, vital signs, and treatment suspensions, and 
permanent discontinuations due to AEs will be reported and tabulated. All safety data and comparisons 
with the baseline values will be tabulated and summarized in detail. AEs and laboratory data will be 
summarized using descriptive statistics. 
In addition, any abnormal values in physical examinations, vital signs, abdominal ultrasound, and ECG 
should be presented. 
8.1.7 
Exploratory analysis of F-627 immunogenicity 
Analysis of F-627 immunogenicity should be performed in a population with at least one result of serum 
F-627 antibody assay after F-627 treatment. All results of serum anti-F-627 antibody assays will be
tabulated and summarized for descriptive statistics only.
8.1.8 
Interim analysis 
This study has no scheduled interim analysis. 
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8.1.9 
Data quality assurance 
The standard operating procedure (SOP) of contract research organization (CRO) describes the quality 
assurance procedure of the clinical trial data. 
The clinical research associate will check the eCRFs and drug dispensing log to ensure the data accuracy 
and reliability. 
Data from the eCRFs is entered into the database and checked and verified by the computer system. Any 
inconsistent data should be resolved by the investigator. 
8.2 
Terminology 
AEs, medical history, and surgical history are coded by system organ class (SOC) and preferred term (PT) 
in ICH Medical Dictionary for Regulatory Activities (MedDRA). 
Combined medications are coded using the Anatomical Therapeutic Chemical (ATC) Classification 
System of the WHO Drug Dictionary (WHODD). 
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9.0 
ETHICS 
9.1 
Local Regulations and Declaration of Helsinki 
The study should be conducted in accordance with the Good Clinical Practice (ICH GCP) based on the 
Declaration of Helsinki and national laws and regulations applicable to clinical trials in order to 
maximize the protection of subjects. 
9.2 
Informed Consent 
The investigator or its authorized representative must obtain the informed consent forms signed by the 
subjects participating in this study. The investigator should explain to the subjects the nature, objectives, 
potential risks and benefits of this trial, and should inform the subjects that they may withdraw from the 
study at any time for any reason. 
The subject's legal representative must sign the informed consent form if the subject is unable to do so. If 
both the subject and legal representative are unable to read the informed consent form, a neutral witness 
must be present during the entire informed consent discussion. After the subject and legal representative 
verbally agree to participate in the study, the witness must sign the informed consent form and ensure that 
the subject and legal representative have fully understood the content. 
The informed consent will be documented in the eCRFs. If the safety results lead to major changes in the 
risk/benefit assessment, the informed consent form must be reviewed and revised whenever necessary. 
All subjects (including those who are receiving treatment) must be informed of the latest information and 
sign the revised informed consent form prior to trial continuation. 
Subjects should be aware that they may withdraw from the study at any time for any reason. 
9.3 
Privacy Protection 
The investigator must ensure that subjects' privacy is not disclosed to any unauthorized third parties. The 
eCRFs and other documents submitted to the sponsor should not contain the names of the subjects and the 
subjects are distinguished only by their identification codes. The investigator can retain the enrollment list 
containing the identification code, name, and address of each subject. Documents such as the informed 
consent forms should be kept strictly confidential and should not be submitted to the sponsor. 
9.4 
Independent Ethics Committee/Review Board 
The clinical study protocol and amendments, Investigator’s Brochure, informed consent form, clinical 
trial information for subjects (such as subject recruitment advertisements), and other necessary 
documents must be reviewed by the Independent Ethics Committee/Review Board (IEC/IRB). 
IEC/IRB approval must be obtained prior to the trial commencement. The date of the committee meeting 
and approval should be indicated in the approval letter to the investigator. 
Any protocol amendments must be officially approved or filed by the IEC/IRB. 
All SAEs must be reported to the ethics committee and regulatory authorities according to relevant 
regulations. 
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The investigator must also report to the IEC/IRB immediately if a protocol violation that may increase 
subject risks occurs during the trial. 
9.5 
Protocol Amendment 
The protocol amendment must be submitted and approved by the IEC/IRB. Before the amendment is 
approved by the IEC/IRB, the investigators should still follow the original study protocol, unless the 
content of the protocol amendment can immediately eliminate potential harms to the subjects, or the 
content of the protocol amendment only involves changes in study management (such as changes in 
phone numbers, etc.) or typos. 
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10.0 
STUDY TERMINATION 
The sponsor has the right to terminate the study. Both the sponsor and investigator must arrange the 
related procedures after review and negotiation. After deciding to terminate the study, the sponsor and 
investigators must give full consideration to protecting the interests of the subjects. 
After the study is terminated, the sponsor must notify the regulatory authorities in writing, and the 
investigator or sponsor must notify the IEC/IRB in writing. 
Additionally, the investigator must return, destroy, or retain the trial information as requested by the 
sponsor. 
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11.0 
RETENTION OF TRIAL DOCUMENTS, ELECTRONIC CASE 
REPORT FORMS (eCRFs), AND RECORDS 
In accordance with ICH GCP requirements, the sponsor or its authorized representative should conduct 
monitoring and audits to ensure that the trial materials and records are available on site. 
11.1 
Trial Documents and Document Retention 
The investigators must document the trial process adequately and accurately for data verification. These 
documents can be divided into two categories, investigators' documents and subjects' source data. 
Investigators' documents include the study protocols and amendments, case report forms and data 
clarification forms, approval certificates and correspondences with the IEC/IRB and regulatory 
authorities, template of the informed consent form, drug records, resumes and authorization forms of the 
study personnel, and other necessary documents and correspondences. 
Subjects' source documents (pre-defined key efficacy/safety data to be recorded) include 
inpatient/outpatient medical records, doctor's and nurse's orders, appointment dates of visits, original 
laboratory measurement results, ECG, EEG, X-ray, pathology reports and special assessment reports, 
signed informed consent forms, consultation records, and subject screening and enrollment lists. 
The investigator must keep these documents for 5 years after the completion or termination of the trial. 
After 5 years, please consult with the sponsor regarding the retention of these documents. 
If the investigators are willing to transfer the trial documents to other parties or places, the sponsor should 
be informed in advance. 
If the investigator cannot ensure that these documents are kept safely at the study site, the investigators 
and sponsor can cooperatively transfer the documents to other places for storage. These documents must 
be sealed in order for retrieve at the time of regulatory audits. If these documents are still in use, 
photocopies may be kept at other places. 
11.2 
Source Documents and Data 
When CRFs are illegible or an error occurs during data transfer, the investigator is required to provide the 
source data of trial documents or medical records upon the request from the sponsor. If there are special 
concerns or queries and/or requests from regulatory authorities, complete study records should be 
available in the case that subject privacy is protected. 
Each study site is responsible for collecting and keeping the source documents for each subject. 
11.3 
Electronic Case Report Forms (eCRFs) 
In this study, data will be documented on electronic case report forms (eCRFs). All study sites will 
receive training and guidance on how to fill out eCRFs correctly. 
The investigator/study coordinator should be authorized and trained to fill in the eCRFs. The eCRFs 
should be completed timely and owned by the sponsor. Except for the sponsor's authorized 
representatives or drug administration personnel, the contents of eCRFs cannot be disclosed to any third 
parties in any way without the written consent of the sponsor. 
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The principal investigator is responsible to ensure the completion, review, and approval of eCRFs. 
The eCRFs must be signed by the principal investigator or authorized investigator to signify that the 
information in the eCRFs is completed and accurate. The principal investigator is ultimately responsible 
for the accuracy and authenticity of the clinical and laboratory data in the eCRFs at any time. Subjects' 
source data are kept at the study sites. The information documented in the eCRFs must be consistent with 
subjects' source data. 
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12.0 
MONITORING AND AUDITING 
12.1 
Trial Monitoring and Verification of Source Data 
The clinical research associate (CRA) appointed by the sponsor will conduct regular on-site monitoring 
to ensure that the study protocol is strictly implemented and the study data is accurate and complete. 
Besides, regular communication (through email, telephone, or fax) is required to ensure that all activities 
of the study meet the requirements of the study protocol and regulations. 
During the daily visits, the clinical research associate should verify that the CRFs are filled in according 
to the protocol requirements and that data are complete, consistent, and accurate. The clinical research 
associate should also obtain laboratory measurements and other subject records to verify the accuracy of 
data filled in the CRFs. All clinical trial conclusions should be ensured to be based on the source data. 
The investigators (or their assistants) should assist the clinical research associate in resolving any queries 
raised during monitoring. 
12.2 
On-Site Audits/Inspections 
The investigator should ensure that when the sponsor, IEC/IRB, or the drug administration department is 
performing on-site audits/inspections, they can directly obtain the source documents related to the trial, 
eCRFs, and other study documents, and be fully supported and cooperated with. The data in the eCRFs 
should be directly derived from the source data. The purpose of audits/inspections is to systematically 
and independently examine all the activities and documents related to the study, ensuring that the 
activities have been carried out and the data have been documented and analyzed in accordance with 
the study protocol, ICH GCP guidelines and regulatory requirements. 
The investigator must immediately notify the sponsor when regulatory authorities request to inspect the 
study site. 
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13.0 
CONFIDENTIALITY AND USE OF TRIAL RESULTS 
All unpublished information of the investigational drug provided by the sponsor, such as indications, 
dosage forms, production processes, and other study data, are the proprietary intellectual property and 
confidential materials belonging to the sponsor. The investigators should agree that all the disclosed 
information are used for this study only and should not be used for other purposes without the written 
consent of the sponsor. The study results are owned by the sponsor. 
The investigator should agree that study results will be used for drug registration and publication in 
China and other countries. The names, addresses, qualifications, and responsibilities of investigators 
must be reported to the drug administration department. 
The sponsor is responsible for writing the final clinical study report. The principal investigator is 
required to state that the study report accurately describes the trial process and results. Trial results 
should be submitted to the drug administration department or IEC/IRB. 
All documents and information provided by the sponsor and from this trial are intellectual properties 
belonging to the sponsor. The investigator has the right to publish the results. However, a complete copy 
of the paper or abstract should be sent to the sponsor at least 45 days before the submission. The sponsor 
reserves the right to review and approve the paper to be published, including the presentation or abstract 
that uses data from this trial. The investigator must comply with the confidentiality requirements of the 
sponsor for such information, and agree to retain it for an additional 90 days if necessary, in order that the 
sponsor has enough time to apply for patent or other intellectual property protection. 
The sponsor and the investigator should reach an agreement regarding the way and time to publish the 
paper prior to the trial commencement. 
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14.0 
REFERENCES 
1.
L Roskos, B B Yang et al. Pharmacokinetic/Pharmacodynamic Modeling of Pegfilgrastim in
Healthy Subjects. J. Clin Pharmacol 2006; 46: 747-757.
2.
Nature Review Cancer, 2006, vol 6: 63-74 National Comprehensive Cancer Network (NCCN),
Version 2010.
3.
Stephen E. Jones, Michael A. Savin et al. Phase III Trial Comparing Doxorubicin Plus
Cyclophosphamide with Docetaxel Plus Cyclophosphamide as Adjuvant Therapy for Operable
Breast Cancer. J Clin Oncol. 2006; 24: 5381-5387.
4.
Martin M, Pienkowski P, Mackey J, et al. Adjuvant docetaxel for node-positive breast cancer.
N Engl J Med 2005; 352: 2302-2313.
5.
F. A. Holmes, S. E. Jones, J. O’Shaughnessy et al. Comparable efficacy and safety profiles of
once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia:
a multicenter dose-finding study in women with breast cancer. Ann Oncol. 2002; 13: 903-9.
6.
F.A. Homes, J.A. O5Shaughnessy, S. Vukelija, et al. Blinded, Randomized, Multicenter Study to
Evaluate Single Administration Pefilgrastim Once per Cycle Versus Daily Filgrastim as an Adjunct
to Chemotherapy in Patients with High-Risk Stage II or Stage III/IV Breast Cancer. J Clin Oncol
2002; 20: 727-731.
7.
M. D. Green, H. Koelbl, J. Baselga et al. A randomized double-blind multicenter phase III study
of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving
myelosuppressive chemotherapy. Annals of Oncology 2003; 14: 29-35.
8.
Katy L Cooper, Jason Madan, Sophie Whyte et al. Granulocyte colony stimulating factors for
febrile neutropenia prophylaxis following chemotherapy: systematic review and metaanalysis.
BMC Cancer 2011; 11:404.
9.
A multicenter phase III prospective randomized trial of high-dose epirubicin in combination with
cyclophosphamide (EC) versus docetaxel followed by EC in node-positive breast cancer. GOIM
(Gruppo Oncologico Italia Meridionale) 9902 study. Annals of Oncology 2012; 23: 1121-112.
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